FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Chen, J Shukla, V Farci, P Andricovich, J Jogunoori, W Kwong, LN Katz, LH Shetty, K Rashid, A Su, X White, J Li, L Wang, AY Blechacz, B Raju, GS Davila, M Nguyen, BN Stroehlein, JR Chen, J Kim, SS Levin, H Machida, K Tsukamoto, H Michaely, P Tzatsos, A Mishra, B Amdur, R Mishra, L AF Chen, Jian Shukla, Vivek Farci, Patrizia Andricovich, Jaclyn Jogunoori, Wilma Kwong, Lawrence N. Katz, Lior H. Shetty, Kirti Rashid, Asif Su, Xiaoping White, Jon Li, Lei Wang, Alan Yaoqi Blechacz, Boris Raju, Gottumukkala S. Davila, Marta Nguyen, Bao-Ngoc Stroehlein, John R. Chen, Junjie Kim, Sang Soo Levin, Heather Machida, Keigo Tsukamoto, Hidekazu Michaely, Peter Tzatsos, Alexandros Mishra, Bibhuti Amdur, Richard Mishra, Lopa TI Loss of the Transforming Growth Factor-beta Effector beta 2-Spectrin Promotes Genomic Instability SO HEPATOLOGY LA English DT Article ID FANCONI-ANEMIA; TGF-BETA; DNA-DAMAGE; MAMMALIAN-CELLS; REPAIR PATHWAY; STEM-CELLS; SPECTRIN; CANCER; MICE; CARCINOGENESIS AB Exposure to genotoxins such as ethanol- derived acetaldehyde leads to DNA damage and liver injury and promotes the development of cancer. We report here a major role for the transforming growth factor b/ mothers against decapentaplegic homolog 3 adaptor beta 2-Spectrin (beta 2SP, gene Sptbn1) in maintaining genomic stability following alcohol- induced DNA damage. b2SP supports DNA repair through beta 2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of beta 2SP leads to decreased Fancd2 levels and sensitizes beta 2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor beta stimulation is regulated by the beta 2SP/ mothers against decapentaplegic homolog 3 complex. Conclusion: Dysfunctional transforming growth factor beta/beta 2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. C1 [Chen, Jian; Shukla, Vivek; Katz, Lior H.; Blechacz, Boris; Raju, Gottumukkala S.; Davila, Marta; Stroehlein, John R.] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA. [Shukla, Vivek] Natl Canc Inst, Thorac & Gastrointestinal Oncol Branch, Thorac Oncol Sect, Bethesda, MD USA. [Farci, Patrizia] Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Infect Dis Lab, Hepat Pathogenesis Sect, Bethesda, MD USA. [Andricovich, Jaclyn; Tzatsos, Alexandros] George Washington Univ, Dept Anat & Regenerat Biol, Washington, DC USA. [Jogunoori, Wilma; White, Jon; Mishra, Bibhuti; Mishra, Lopa] Vet Affairs Med Ctr, Inst Clin Res, Washington, DC USA. [Kwong, Lawrence N.] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX USA. [Katz, Lior H.] Sheba Med Ctr, Dept Gastroenterol, Tel Hashomer, Israel. [Shetty, Kirti] Johns Hopkins Univ, Sch Med, Div Gastroenterol & Hepatol, Baltimore, MD USA. [Rashid, Asif] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Su, Xiaoping] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Li, Lei; Chen, Junjie] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA. [Wang, Alan Yaoqi] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Levin, Heather; Mishra, Bibhuti; Amdur, Richard; Mishra, Lopa] George Washington Univ, Dept Surg, Washington, DC USA. [Kim, Sang Soo] Natl Canc Ctr, Radiat Med Branch, Goyang, South Korea. [Machida, Keigo; Tsukamoto, Hidekazu] Southern Calif Res Ctr ALPD & Cirrhosis, Los Angeles, CA USA. [Machida, Keigo] Univ Southern Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA USA. [Tsukamoto, Hidekazu] Univ Southern Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA USA. [Tsukamoto, Hidekazu] Greater Angeles Healthcare Syst, Dept Vet Affairs, Los Angeles, CA USA. [Michaely, Peter] Univ Texas Southwestern Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA. [Mishra, Bibhuti; Amdur, Richard; Mishra, Lopa] George Washington Univ, Ctr Translat Med, Dept Surg, Washington, DC USA. RP Mishra, L (reprint author), George Washington Univ, Ctr Translat Med, Med Fac Associates, Dept Surg, 2300 Eye St NW,Ross Hall 554, Washington, DC 20037 USA. EM lopamishra2@gmail.com FU National Institute of Health [R01AA023146, R01CA042857, P01CA130821]; Multidisciplinary Research Program Proposal and Science & Technology Acquisition FX Supported by the National Institute of Health (grants R01AA023146, R01CA042857, and P01CA130821, to L.M.; R01AA019392, to H.T. and L.M.), the Multidisciplinary Research Program Proposal (L. M.), and Science & Technology Acquisition and Retention Funding (L. M.). NR 33 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD FEB PY 2017 VL 65 IS 2 BP 678 EP 693 DI 10.1002/hep.28927/suppinfo PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP3RZ UT WOS:000397300700026 PM 28114741 ER PT J AU Goldring, C Antoine, DJ Bonner, F Crozier, J Denning, C Fontana, RJ Hanley, NA Hay, DC Ingelman-Sundberg, M Juhila, S Kitteringham, N Silva-Lima, B Norris, A Pridgeon, C Ross, JA Young, RS Tagle, D Tornesi, B De Water, BV Weaver, RJ Zhang, F Park, BK AF Goldring, Christopher Antoine, Daniel J. Bonner, Frank Crozier, Jonathan Denning, Chris Fontana, Robert J. Hanley, Neil A. Hay, David C. Ingelman-Sundberg, Magnus Juhila, Satu Kitteringham, Neil Silva-Lima, Beatriz Norris, Alan Pridgeon, Chris Ross, James A. Young, Rowena Sison Tagle, Danilo Tornesi, Belen de Water, Bob van Weaver, Richard J. Zhang, Fang Park, B. Kevin TI Stem Cell-Derived Models to Improve Mechanistic Understanding and Prediction of Human Drug-Induced Liver Injury SO HEPATOLOGY LA English DT Review ID HEPATOCYTE-LIKE CELLS; HIGHLY EFFICIENT DIFFERENTIATION; FUNCTIONAL HEPATOCYTES; IN-VITRO; DEFINITIVE ENDODERM; MICROPATTERNED COCULTURES; METABOLIZING-ENZYMES; HEPATIC ENDODERM; GENE CORRECTION; HEPARG CELLS AB Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug- induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury means that no current single-cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug-induced liver injury. Nevertheless, a single-cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell- derived hepatocyte-like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. C1 [Goldring, Christopher; Antoine, Daniel J.; Kitteringham, Neil; Norris, Alan; Pridgeon, Chris; Young, Rowena Sison; Zhang, Fang; Park, B. Kevin] Univ Liverpool, IMRC Ctr Drug Safety Sci, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England. [Bonner, Frank] Stem Cells Safer Med, London, England. [Crozier, Jonathan] European Partnership Alternat Approaches Anim, Brussels, Belgium. [Denning, Chris] Univ Nottingham, Ctr Biomol Sci, Dept Stem Cell Biol, Nottingham, England. [Fontana, Robert J.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI USA. [Hanley, Neil A.] Univ Manchester, Ctr Endocrinol & Diabet, Manchester M13 9PL, Lancs, England. [Hanley, Neil A.] Cent Manchester Univ Hosp, NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Hay, David C.] Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh, Midlothian, Scotland. [Ingelman-Sundberg, Magnus] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. [Juhila, Satu] R&D Vitro Biol, Espoo, Finland. [Silva-Lima, Beatriz] Univ Lisbon, Fac Pharm, Lisbon, Portugal. [Tagle, Danilo] Natl Inst Hlth, Natl Ctr Adv Translat Sci, Bethesda, MD USA. [Tornesi, Belen] Abbvie Global Pharmaceut Res & Dev, N Chicago, IL USA. [de Water, Bob van] Leiden Univ, Leiden Acad Ctr Drug Res, Fac Sci, Gorlaeus Labs, Leiden, Netherlands. [Weaver, Richard J.] Inst Rech Int Servier, Suresnes, France. RP Goldring, C (reprint author), Univ Liverpool, MRC Ctr Drug Safety Sci, Dept Mol & Clin Pharmacol, Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England. EM C.E.P.Goldring@liverpool.ac.uk FU Medical Research Council [MR/L006758/1]; European Community under the Innovative Medicine Initiative project MIP-DILI [115336]; Stem Cells for Safer Medicines; Engineering and Physical Sciences Research Council; British Heart Foundation; Heart Research UK; Medical Research Council; Refinement and Reduction of Animals in Research; Wellcome Trust and Stem Cells for Safer Medicines; Innovative Medicines Initiative Joint Undertaking [115439]; European Union's Seventh Framework Programme (FP7); European Federation of Pharmaceutical Industries and Associations companies in-kind contributions; Swedish Research Council; EC FP7 project DETECTIVE [266838]; Innovative Medicine Initiative MIP-DILI project [115336]; Horizon2020 EU-ToxRisk project [681002]; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK065184] FX Supported by the Medical Research Council (MR/L006758/1) and the European Community under the Innovative Medicine Initiative project MIP-DILI (115336, to C.G., D.J.A., N.K., A.N.,C.P., R.S.Y., F.Z., B.K.P.); Stem Cells for Safer Medicines (to F.B.); the Engineering and Physical Sciences Research Council, British Heart Foundation, Heart Research UK, the Medical Research Council, and the National Centre for the Replacement, Refinement and Reduction of Animals in Research (to C.D.); the Wellcome Trust and Stem Cells for Safer Medicines (to N.A.H.); the Innovative Medicines Initiative Joint Undertaking (115439, to J.R.), resources of which are composed of the financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations companies in-kind contributions; The Swedish Research Council and the European Community under the Innovative Medicine Initiative project MIP-DILI (115336, to M.I.-S.); and the EC FP7 project DETECTIVE (266838), the Innovative Medicine Initiative MIP-DILI project (115336), and the Horizon2020 EU-ToxRisk project (681002, to B.v.d.W.). R.J.F. is a member of the Drug-Induced Liver Injury Network, a U01 cooperative agreement supported by the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK065184). NR 78 TC 0 Z9 0 U1 2 U2 2 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD FEB PY 2017 VL 65 IS 2 BP 710 EP 721 DI 10.1002/hep.28886 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP3RZ UT WOS:000397300700028 PM 27775817 ER PT J AU Spengler, EK Kleiner, DE Fontana, RJ AF Spengler, Erin K. Kleiner, David E. Fontana, Robert J. TI Vemurafenib-Induced Granulomatous Hepatitis SO HEPATOLOGY LA English DT Article ID HEPATOTOXICITY AB Vemurafenib (Zelboraf; Genentech, CA) is a highly effective oral chemotherapy agent for patients with metastatic melanoma who carry the BRAF V600E mutation. Side effects of this protein kinase inhibitor (PKI) include arthralgia, rash, and fatigue, which are reported in up to one third of treated patients. Mild abnormalities in liver biochemistries were reported with vemurafenib use in 30% of subjects, 11% developed severe laboratory abnormalities, and acute liver failure has been reported (Table 1). Herein, a case of severe vemurafenib-induced granulomatous hepatitis leading to chronic cholestasis is reported along with a review of the hepatotoxicity of other PKIs. C1 [Spengler, Erin K.; Fontana, Robert J.] Univ Michigan, Div Gastroenterol & Hepatol, Ann Arbor, MI USA. [Kleiner, David E.] NIH, NCI, Pathol Lab, Bethesda, MD USA. RP Fontana, RJ (reprint author), 3912 Taubman Ctr, Ann Arbor, MI 48109 USA. EM rfontana@med.umich.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health (University of Michigan, Ann Arbor) [U01DK065184]; Intramural Division; National Cancer Institute; National Institutes of Health FX Dr. Fontana is a site investigator in the Drug-Induced Liver Injury Network, which is structured as a U01 cooperative agreement supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (U01DK065184, University of Michigan, Ann Arbor); additional support by the Intramural Division, National Cancer Institute, National Institutes of Health. NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD FEB PY 2017 VL 65 IS 2 BP 745 EP 748 DI 10.1002/hep.28692 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP3RZ UT WOS:000397300700032 PM 27335285 ER PT J AU Healy, MW Yamasaki, M Patounakis, G Richter, KS Devine, K DeCherney, AH Hill, MJ AF Healy, Mae Wu Yamasaki, Meghan Patounakis, George Richter, Kevin S. Devine, Kate DeCherney, Alan H. Hill, Micah J. TI The slow growing embryo and premature progesterone elevation: compounding factors for embryo-endometrial asynchrony SO HUMAN REPRODUCTION LA English DT Article DE elevated progesterone; fresh transfer versus frozen embryo transfer cycles; live birth; day 5 versus day 6 embryo transfer cycles ID IN-VITRO FERTILIZATION; COMPROMISE PREGNANCY RATES; BLASTOCYST TRANSFERS; HIGH RESPONDERS; LIVE BIRTH; CYCLES; LEVEL; RECEPTIVITY; PROGRESSION; ANEUPLOIDY AB STUDY QUESTION: Is there an association of progesterone (P-4) on the day of trigger with live birth in autologous ART transfer cycles on day 5 versus day 6? SUMMARY ANSWER: P4 had a greater negative effect on live birth in day 6 fresh transfers compared to day 5 fresh transfers. WHAT IS KNOWN ALREADY: Premature P4 elevation is associated with lower live birth rates in fresh autologous ART cycles, likely due to worsened endometrial-embryo asynchrony. Few studies have evaluated whether the effect of an elevated P4 on the day of trigger is different on live birth rates with a day 5 compared to a day 6 embryo transfer. STUDY DESIGN SIZE, DURATION: This was a retrospective cohort study with autologous IVF cycles with fresh embryo transfers on day 5 and day 6 from 2011 to 2014. A total of 4120 day 5 and 230 day 6 fresh autologous embryo transfers were included. The primary outcome was live birth, defined as a live born baby at 24 weeks gestation or later. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients from a large private ART practice were included. Analysis was performed with generalized estimating equations (GEE) modeling and receiver operating characteristic (ROC) curves. MAIN RESULTS AND THE ROLE OF CHANCE: Day 6 transfers were less likely to have good quality embryos (73% versus 83%, P < 0.001) but the cohorts had similar rates of blastocyst stage transfer (92% versus 91%, P = 0.92). Live birth was less likely in fresh day 6 versus day 5 embryo transfers (34% versus 46%, P = 0.01) even when controlling for embryo confounders. In adjusted GEE models, the effect of P4 as a continuous variable on live birth was more pronounced on day 6 (P < 0.001). Similarly, the effect of P-4 > 1.5 ng/ml on day of trigger was more pronounced on day 6 than day 5 (P < 0.001). Day 6 live birth rates were 8% lower than day 5 when P4 was in the normal range (P = 0.04), but became 17% lower when P4 was > 1.5 ng/ml (P < 0.01). ROC curves for P4 predicting live birth demonstrated a greater AUC in day 6 transfers (AUC 0.59, 95% CI 0.51-0.66) than day 5 (AUC 0.54, 95% CI 0.52-0.55). Interaction testing of P-4 x day of embryo transfer was highly significant (P < 0.001), further suggesting that the effect of P4 was more pronounced on day 6 embryo transfer. In fresh oocyte retrieval cycles with elevated P4, a subsequent 760 frozen-thaw transfers did not demonstrate a difference between embryos that were frozen after blastulation on day 5 versus 6. LIMITATIONS REASONS FOR CAUTION: Limitations include the retrospective design and the inability to control for certain confounding variables, such as thaw survival rates between day 5 and day 6 blastocysts. Also, the data set lacks the known ploidy status of the embryos and the progesterone assay is not currently optimized to discriminate between patients with a P-4 of 1.5 versus 1.8 ng/ml. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests further endometrial-embryo asynchrony when a slow growing embryo is combined with an advanced endometrium, ultimately leading to decreased live births. This suggests that premature elevated P4 may be a factor in the lower live birth rates in day 6 fresh embryo transfers. Further studies are needed to evaluate if a frozen embryo transfer cycle can ameliorate the effect of elevated P-4 on the day of trigger among these slower growing embryos that reach blastocyst staging on day 6. C1 [Healy, Mae Wu; Patounakis, George; DeCherney, Alan H.; Hill, Micah J.] Natl Inst Hlth, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Healy, Mae Wu; Yamasaki, Meghan; Hill, Micah J.] Walter Reed Natl Mil Med Ctr, Dept Obstet & Gynaecol, Bethesda, MD USA. [Richter, Kevin S.; Devine, Kate] Shady Grove Fertil Sci Ctr, Rockville, MD USA. RP No Org, 10 Ctr Dr, Bethesda, MD USA. EM mae.healy@mail.nih.gov NR 24 TC 0 Z9 0 U1 0 U2 0 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 FEB 1 PY 2017 VL 32 IS 2 BP 362 EP 367 DI 10.1093/humrep/dew296 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EO8MO UT WOS:000396943600015 PM 27986817 ER PT J AU Maggio, DM Singh, A Iorgulescu, JB Bleicher, DH Ghosh, M Lopez, MM Tuesta, LM Flora, G Dietrich, WD Pearse, DD AF Maggio, Dominic M. Singh, Amanpreet Iorgulescu, J. Bryan Bleicher, Drew H. Ghosh, Mousumi Lopez, Michael M. Tuesta, Luis M. Flora, Govinder Dietrich, W. Dalton Pearse, Damien D. TI Identifying the Long-Term Role of Inducible Nitric Oxide Synthase after Contusive Spinal Cord Injury Using a Transgenic Mouse Model SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Article DE oxidative stress; neuroprotection; angiogenesis; inducible nitric oxide synthase; knockout; axon; function ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; TRAUMATIC BRAIN-INJURY; CELLULAR INFLAMMATORY RESPONSE; ROOT GANGLION NEURONS; MICE LACKING; FUNCTIONAL RECOVERY; OXIDATIVE DAMAGE; NEUROLOGICAL DEFICITS; CORTICOSPINAL TRACT; LIPID-PEROXIDATION AB Inducible nitric oxide synthase (iNOS) is a potent mediator of oxidative stress during neuroinflammation triggered by neurotrauma or neurodegeneration. We previously demonstrated that acute iNOS inhibition attenuated iNOS levels and promoted neuroprotection and functional recovery after spinal cord injury (SCI). The present study investigated the effects of chronic iNOS ablation after SCI using inos-null mice. iNOS(-/-) knockout and wild-type (WT) control mice underwent a moderate thoracic (T8) contusive SCI. Locomotor function was assessed weekly, using the Basso Mouse Scale (BMS), and at the endpoint (six weeks), by footprint analysis. At the endpoint, the volume of preserved white and gray matter, as well as the number of dorsal column axons and perilesional blood vessels rostral to the injury, were quantified. At weeks two and three after SCI, iNOS(-/-) mice exhibited a significant locomotor improvement compared to WT controls, although a sustained improvement was not observed during later weeks. At the endpoint, iNOS(-/-) mice showed significantly less preserved white and gray matter, as well as fewer dorsal column axons and perilesional blood vessels, compared to WT controls. While short-term antagonism of iNOS provides histological and functional benefits, its long-term ablation after SCI may be deleterious, blocking protective or reparative processes important for angiogenesis and tissue preservation. C1 [Maggio, Dominic M.; Singh, Amanpreet; Iorgulescu, J. Bryan; Bleicher, Drew H.; Ghosh, Mousumi; Lopez, Michael M.; Tuesta, Luis M.; Flora, Govinder; Dietrich, W. Dalton; Pearse, Damien D.] Univ Miami, Miller Sch Med, Miami Project Cure Paralysis, Miami, FL 33136 USA. [Maggio, Dominic M.] Univ Virginia, Dept Neurol Surg, Sch Med, Charlottesville, VA 22908 USA. [Maggio, Dominic M.] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Iorgulescu, J. Bryan] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ghosh, Mousumi; Dietrich, W. Dalton; Pearse, Damien D.] Univ Miami, Dept Neurol Surg, Miller Sch Med, Miami, FL 33136 USA. [Tuesta, Luis M.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Dietrich, W. Dalton; Pearse, Damien D.] Univ Miami, Neurosci Program, Miller Sch Med, Miami, FL 33136 USA. [Dietrich, W. Dalton; Pearse, Damien D.] Univ Miami, Miller Sch Med, Interdisciplinary Stem Cell Inst, Miami, FL 33136 USA. [Dietrich, W. Dalton] Univ Miami, Dept Neurol, Miller Sch Med, Miami, FL 33136 USA. [Dietrich, W. Dalton] Univ Miami, Miller Sch Med, Dept Cell Biol & Anat, Miami, FL 33136 USA. [Pearse, Damien D.] Bruce W Carter Dept Vet Affairs Med Ctr, Miami, FL 33136 USA. RP Pearse, DD (reprint author), Univ Miami, Miller Sch Med, Miami Project Cure Paralysis, Miami, FL 33136 USA.; Pearse, DD (reprint author), Univ Miami, Dept Neurol Surg, Miller Sch Med, Miami, FL 33136 USA.; Pearse, DD (reprint author), Univ Miami, Neurosci Program, Miller Sch Med, Miami, FL 33136 USA.; Pearse, DD (reprint author), Univ Miami, Miller Sch Med, Interdisciplinary Stem Cell Inst, Miami, FL 33136 USA.; Pearse, DD (reprint author), Bruce W Carter Dept Vet Affairs Med Ctr, Miami, FL 33136 USA. EM dominic.maggio@nih.gov; amanpu@gmail.com; jbi2001@med.cornell.edu; drew.bleicher@jhsmiami.org; mghosh@med.miami.edu; Michael.Lopez@mch.com; luis_tuesta@hms.harvard.edu; gjsflora@gmail.com; ddietrich@miami.edu; DPearse@med.miami.edu FU United States Army Medical Research and Material Command (U.S. Army Battlefield Exercise and Combat Related Spinal Cord Injury Research award) [W81XWH05-01-0061]; Buoniconti Fund; Miami Project to Cure Paralysis; Lois Pope Neuroscience Summer Research Fellowship; John M. and Jocelyn H.K. Watkins Distinguished Chair in Cell Therapies FX We gratefully acknowledge the Miami Project Animal Core Facility for performing experimental SCI and post-operative animal care. The Miami Project Histology and Imaging Cores are thanked for their invaluable assistance. This work was supported by United States Army Medical Research and Material Command (U.S. Army Battlefield Exercise and Combat Related Spinal Cord Injury Research award W81XWH05-01-0061), The Buoniconti Fund, The Miami Project to Cure Paralysis, and The Lois Pope Neuroscience Summer Research Fellowship, Damien D. Pearse acknowledges support from The John M. and Jocelyn H.K. Watkins Distinguished Chair in Cell Therapies. NR 91 TC 0 Z9 0 U1 0 U2 0 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD FEB PY 2017 VL 18 IS 2 AR 245 DI 10.3390/ijms18020245 PG 15 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA EM6YD UT WOS:000395457700015 ER PT J AU Traynor, BJ Rademakers, R AF Traynor, Bryan J. Rademakers, Rosa TI Dementia Research-A Roadmap for the Next Decade SO JAMA NEUROLOGY LA English DT Editorial Material ID DISEASE; TAU C1 [Traynor, Bryan J.] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Traynor, Bryan J.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Rademakers, Rosa] Mayo Clin Florida, Dept Neurosci, Jacksonville, FL USA. RP Traynor, BJ (reprint author), NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM traynorb@mail.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 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 FEB 1 PY 2017 VL 74 IS 2 BP 141 EP 142 DI 10.1001/jamaneurol.2016.5004 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA EM9XA UT WOS:000395663600002 PM 27942708 ER PT J AU Brown, P AF Brown, Paul TI A New Standard for the Laboratory Diagnosis of Sporadic Creutzfeldt-Jakob Disease SO JAMA NEUROLOGY LA English DT Editorial Material ID QUAKING-INDUCED CONVERSION; CYCLIC AMPLIFICATION; NASAL BRUSHINGS; PRION PROTEIN C1 [Brown, Paul] NIH, Lab Cent Nervous Syst Studies, Bldg 10, Bethesda, MD 20892 USA. RP Brown, P (reprint author), 7815 Exeter Rd, Bethesda, MD 20814 USA. EM paulwbrown@comcast.net NR 14 TC 0 Z9 0 U1 0 U2 0 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 FEB 1 PY 2017 VL 74 IS 2 BP 144 EP 145 DI 10.1001/jamaneurol.2016.4877 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA EM9XA UT WOS:000395663600004 PM 27942712 ER PT J AU Bongianni, M Orru, C Groveman, BR Sacchetto, L Fiorini, M Tonoli, G Triva, G Capaldi, S Testi, S Ferrari, S Cagnin, A Ladogana, A Poleggi, A Colaizzo, E Tiple, D Vaianella, L Castriciano, S Marchioni, D Hughson, AG Imperiale, D Cattaruzza, T Fabrizi, GM Pocchiari, M Monaco, S Caughey, B Zanusso, G AF Bongianni, Matilde Orru, Christina Groveman, Bradley R. Sacchetto, Luca Fiorini, Michele Tonoli, Giovanni Triva, Giorgio Capaldi, Stefano Testi, Silvia Ferrari, Sergio Cagnin, Annachiara Ladogana, Anna Poleggi, Anna Colaizzo, Elisa Tiple, Dorina Vaianella, Luana Castriciano, Santina Marchioni, Daniele Hughson, Andrew G. Imperiale, Daniele Cattaruzza, Tatiana Fabrizi, Gian Maria Pocchiari, Maurizio Monaco, Salvatore Caughey, Byron Zanusso, Gianluigi TI Diagnosis of Human Prion Disease Using Real-Time Quaking-Induced Conversion Testing of Olfactory Mucosa and Cerebrospinal Fluid Samples SO JAMA NEUROLOGY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; NASAL BRUSHINGS; CRITERIA; PROTEIN; CJD; EUROPE AB IMPORTANCE Early and accurate in vivo diagnosis of Creutzfeldt-Jakob disease (CJD) is necessary for quickly distinguishing treatable from untreatable rapidly progressive dementias and for future therapeutic trials. This early diagnosis is becoming possible using the real-time quaking-induced conversion (RT-QulC) seeding assay, which detects minute amounts of the disease-specific pathologic prion protein in cerebrospinal fluid (CSF) or olfactory mucosa ( OM) samples. OBJECTIVE To develop an algorithm for accurate and early diagnosis of CJD by using the RT-QulC assay on CSF samples, OM samples, or both. DESIGN, SETTING, AND PARTICIPANTS In this case-control study, samples of CSF and OM were collected from 86 patients with a clinical diagnosis of probable (n=51), possible (n=24), or suspected (n=11) CJD and 104 negative control samples (54 CSF and 50 OM). The CSF and OM samples were analyzed using conventional RT-QulC. The CSF samples underwent further testing using improved RT-QuIC conditions. In addition, the diagnostic performance of a novel, easy-to-use, gentle flocked swab for sampling of OM was evaluated. Data were collected from January 1 to June 30, 2015. MAIN OUTCOME AND MEASURES Correlations between RT-QuIC results and the final diagnosis of recruited patients. RESULTS Among the 86 patients (37 men [43%] and 49 women [57%];mean [SD] age, 65.7 [11.5] years) included for analysis, all 61 patients with sporadic CJD had positive RT-QuIC findings using OM or CSF samples or both for an overall RT-QuIC diagnostic sensitivity of 100% (95% Cl, 93%-100%). All patients with a final diagnosis of non-prion disease (71 CSF and 67 OM samples) had negative RT-QuIC findings for 100% specificity ( 95% CI, 94%-100%). Of 8 symptomatic patients with various mutations causing CJD or Gerstmann-Strussler-Scheinker syndrome, 6 had positive and 2 had negative RT-QuIC findings for a sensitivity of 75%( 95% CI, 36%-96%). CONCLUSIONS AND RELEVANCE A proposed diagnostic algorithm for sporadic CJD combines CSF and OM RT-QuIC testing to provide virtually 100% diagnostic sensitivity and specificity in the clinical phase of the disease. C1 [Bongianni, Matilde; Fiorini, Michele; Testi, Silvia; Ferrari, Sergio; Fabrizi, Gian Maria; Monaco, Salvatore; Zanusso, Gianluigi] Univ Verona, Dept Neurosci Biomed & Movement Sci, Policlin GB Rossi, Piazzale LA Scuro 10, I-37134 Verona, Italy. [Orru, Christina; Groveman, Bradley R.; Hughson, Andrew G.; Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Sacchetto, Luca; Marchioni, Daniele] Univ Verona, Dept Surg Sci Dent Gynecol & Pediat, Verona, Italy. [Tonoli, Giovanni] Osped Santa Maria Misericordia, Struttura Complessa Otorinolaringoiatria, Rovigo, Italy. [Triva, Giorgio; Castriciano, Santina] Copan Italia SpA, Brescia, Italy. [Capaldi, Stefano] Univ Verona, Biocrystallog Lab, Dept Biotechnol, Verona, Italy. [Cagnin, Annachiara] Univ Padua, Dept Neurosci, Padua, Italy. [Cagnin, Annachiara] San Camillo Hosp, Ist Ricovero & Cura Carattere Sci, Venice, Italy. [Ladogana, Anna; Poleggi, Anna; Colaizzo, Elisa; Tiple, Dorina; Vaianella, Luana; Pocchiari, Maurizio] Ist Super Sanita, Dept Cell Biol & Neurosci, Rome, Italy. [Imperiale, Daniele] Osped Maria Vittoria, Neurol Unit, Turin, Italy. [Cattaruzza, Tatiana] Osped Cattinara, Neurol Unit, Trieste, Italy. RP Zanusso, G (reprint author), Univ Verona, Dept Neurosci Biomed & Movement Sci, Policlin GB Rossi, Piazzale LA Scuro 10, I-37134 Verona, Italy. EM gianluigi.zanusso@univr.it FU Alliance Biosecure Foundation FX This study was supported in part by grant FABS2013 "In vivo diagnosis of definite CJD" from Alliance Biosecure Foundation, joint projects OLFASSAY and Joint Programming Neurodegenerative Disease from the University of Verona (Dr Zanusso), and the Intramural Research Program of the National Institute of Allergy and Infectious Disease (Drs Orru, Groveman, and Caughey and Mr Hughson). NR 30 TC 1 Z9 1 U1 0 U2 0 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 FEB 1 PY 2017 VL 74 IS 2 BP 155 EP 162 DI 10.1001/jamaneurol.2016.4614 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EM9XA UT WOS:000395663600010 PM 27942718 ER PT J AU Eydelman, MB Tarver, ME Ferris, F AF Eydelman, Malvina B. Tarver, Michelle E. Ferris, Frederick, III TI Listening to the Patients-The Laser-Assisted In Situ Keratomileusis Quality of Life Collaboration Project SO JAMA OPHTHALMOLOGY LA English DT Editorial Material C1 [Eydelman, Malvina B.; Tarver, Michelle E.] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Ferris, Frederick, III] NEI, Bethesda, MD 20892 USA. RP Eydelman, MB (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD FEB 1 PY 2017 VL 135 IS 2 BP 83 EP 84 DI 10.1001/jamaophthalmol.2016.4585 PG 2 WC Ophthalmology SC Ophthalmology GA EM9PE UT WOS:000395642800006 ER PT J AU Ferris, FL Maguire, MG Glassman, AR Ying, GS Martin, DF AF Ferris, Frederick L., III Maguire, Maureen G. Glassman, Adam R. Ying, Gui-shuang Martin, Daniel F. TI Evaluating Effects of Switching Anti-Vascular Endothelial Growth Factor Drugs for Age-Related Macular Degeneration and Diabetic Macular Edema SO JAMA OPHTHALMOLOGY LA English DT Article ID RANIBIZUMAB; BEVACIZUMAB; AFLIBERCEPT AB IMPORTANCE When a patient with neovascular age-related macular degeneration or diabetic macular edema does not respond to an initial anti-vascular endothelial growth factor agent, usually after several injections, ophthalmologists may switch to another anti-vascular endothelial growth factor agent. Authors of case series have suggested beneficial effects from switching. However, to our knowledge, there are no studies with an appropriate control group to evaluate how such patients would do without switching agents. OBJECTIVE To assess outcomes in patients who have a poor initial response but continue treatment without switching agents. DESIGN, SETTING, AND PARTICIPANTS We obtained data from 2 multicenter clinical trials, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and the Diabetic Retinopathy Clinical Research Network (DRCR. net). Based on typical clinical reasons for switching agents, we developed "switching rules" at both 3 and 6 months after initiation of treatment. Using these switching rules, we identified a 3-month and a 6-month cohort of "treatment failures" from both CATT and DRCR. net studies. INTERVENTIONS Although the cohorts from each study met criteria for switching, they were treated with the initial agent throughout the study (bevacizumab or ranibizumab in CATT and ranibizumab in DRCR. net). MAIN OUTCOMES AND MEASURES Primary outcomeswere change in visual acuity and change in central retinal thickness on optical coherence tomography from the 3-or 6-month visit at which switching rules were met. RESULTS The 126 patients from CATT and the 59 patients from DRCR. net who were selected for the switching analysis were similar in age, sex and race/ethnicity to the overall study populations. Among the participants who met the criteria for switching, the CATT participants were a mean (SD) of 79.7 (7.8) years of age, 65.9% women, and 97.6% white, while the DRCR. net participants were a mean (SD) of 65.5 (9.3) years of age, 44.1% women, and 76.3% white In all 4 cohorts, there was a 3-to 5-letter improvement in mean visual acuity over the 3 months after the switching rules were met, although all patients continued on their originally assigned treatment. Mean central retinal thickness also improved by 40 to 70 mu M. CONCLUSIONS AND RELEVANCE These results demonstrate the importance of having a comparison group to evaluate the effect of switching anti-vascular endothelial growth factor agents for treatment of neovascular age-related macular degeneration or diabetic macular edema. Without a comparison group, it is impossible to know whether any improvement observed after switching was related to the new treatment or was related to regression to the mean and time effects as observed in the 4 cohorts presented here. Randomization to switching or not switching drugs would provide a basis for valid conclusions about the effects of switching. C1 [Ferris, Frederick L., III] NEI, NIH, Bethesda, MD 20892 USA. [Maguire, Maureen G.; Ying, Gui-shuang] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Glassman, Adam R.] Jaeb Ctr Hlth Res, 15310 Amberly Dr,Ste 350, Tampa, FL 33647 USA. [Martin, Daniel F.] Cleveland Clin, Cole Eye Inst, Cleveland, OH 44106 USA. RP Glassman, AR (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Ste 350, Tampa, FL 33647 USA. EM drcrstat2@jaeb.org FU National Eye Institute, National Institutes of Health, and the US Department of Health and Human Services [EY017823, EY017825, EY017826, EY017828, EY023689]; National Eye Institute and the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health [EY14231, EY23207, EY18817] FX Comparison of Age-Related Macular Degeneration Treatments Trials was supported by cooperative agreements EY017823, EY017825, EY017826, EY017828, EY023689, and R21EY023689 from the National Eye Institute, National Institutes of Health, and the US Department of Health and Human Services. Diabetic Retinopathy Clinical Research Network was supported by cooperative agreements EY14231, EY23207, and EY18817 from the National Eye Institute and the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, and the US Department of Health and Human Services. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD FEB 1 PY 2017 VL 135 IS 2 BP 145 EP 149 DI 10.1001/jamaophthalmol.2016.4820 PG 5 WC Ophthalmology SC Ophthalmology GA EM9PE UT WOS:000395642800017 ER PT J AU Davis, RJ Boyce, AM Mydlarz, WK AF Davis, Ruth J. Boyce, Alison M. Mydlarz, Wojciech K. TI A Toddler With Nasal Congestion and a Limp SO JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Editorial Material ID MCCUNE-ALBRIGHT SYNDROME C1 [Davis, Ruth J.; Mydlarz, Wojciech K.] NIDCD, Head & Neck Surg Branch, NIH, Bethesda, MD USA. [Boyce, Alison M.] Natl Inst Dent & Craniofacial Res, Sect Skeletal Disorders & Mineral Homeostasis, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Boyce, Alison M.] Childrens Natl Hlth Syst, Div Endocrinol & Diabet, Washington, DC USA. [Boyce, Alison M.] Childrens Natl Hlth Syst, Bone Hlth Program, Div Orthoped & Sports Med, Washington, DC USA. [Mydlarz, Wojciech K.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 6420 Rockledge Dr,Ste 4920, Baltimore, MD 20817 USA. RP Mydlarz, WK (reprint author), Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 6420 Rockledge Dr,Ste 4920, Baltimore, MD 20817 USA. EM mydlarz@jhmi.edu OI Davis, Ruth/0000-0001-9592-932X FU National Institutes of Health (NIH); National Institute on Deafness; National Institute of Dental and Craniofacial Research FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), the National Institute on Deafness and Other Communication Disorders, and the National Institute of Dental and Craniofacial Research. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6181 EI 2168-619X J9 JAMA OTOLARYNGOL JI JAMA Otolaryngol-Head Neck Surg. PD FEB PY 2017 VL 143 IS 2 BP 191 EP 192 DI 10.1001/jamaoto.2016.2392 PG 2 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA EN0KM UT WOS:000395698800018 PM 27737440 ER PT J AU Gupta, N Asi, N Farah, W Almasri, J Barrionuevo, P Alsawas, M Wang, Z Haymond, MW Brown, RJ Murad, MH AF Gupta, Nidhi Asi, Noor Farah, Wigdan Almasri, Jehad Barrionuevo, Patricia Alsawas, Mouaz Wang, Zhen Haymond, Morey W. Brown, Rebecca J. Murad, M. Hassan TI Clinical Features and Management of Non-HIV-Related Lipodystrophy in Children: A Systematic Review SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Review ID FAMILIAL PARTIAL LIPODYSTROPHY; CONGENITAL GENERALIZED LIPODYSTROPHY; LEPTIN-REPLACEMENT THERAPY; A/C R482W MUTATION; OF-THE-LITERATURE; MANDIBULOACRAL DYSPLASIA; PHENOTYPIC HETEROGENEITY; INSULIN-RESISTANCE; DUNNIGAN VARIETY; LMNA MUTATIONS AB Context: Lipodystrophy syndromes are characterized by generalized or partial absence of adipose tissue. Objective: We conducted a systematic review to synthesize data on clinical and metabolic features of lipodystrophy (age at onset,, 18 years). Data Source: Sources included Medline, Embase, Cochrane Library, Scopus and Non- Indexed Citations from inception through January 2016. Study Selection: Search terms included lipodystrophy, and age 0 to 18 years. Patients with unambiguous diagnosis of lipodystrophy were included. Lipodystrophy secondary to HIV treatment was excluded. Data Synthesis: We identified 1141 patients from 351 studies. Generalized fat loss involving face, neck, abdomen, thorax, and upper and lower limbs was explicitly reported in 65% to 93% of patients with congenital generalized lipodystrophy (CGL) and acquired generalized lipodystrophy (AGL). In familial partial lipodystrophy (FPL), fat loss occurred from upper and lower limbs, with sparing of face and neck. In acquired partial lipodystrophy (APL), upper limbs were involved while lower limbs were spared. Other features were prominent musculature, acromegaloid, acanthosis nigricans and hepatosplenomegaly. Diabetes mellitus was diagnosed in 48% (n = 222) of patients with CGL (mean age at onset, 5.3 years). Hypertriglyceridemia was observed in CGL, AGL and FPL. Multiple interventions were used, with most patients receiving >= 3 interventions and being >= 18 years of age at the initiation of interventions. Conclusions: To our knowledge, this is the largest reported pooled database describing lipodystrophy patients with age at onset, 18 years. We have suggested core and supportive clinical features and summarized data on available interventions, outcomes and mortality. C1 [Gupta, Nidhi; Asi, Noor; Farah, Wigdan; Almasri, Jehad; Barrionuevo, Patricia; Alsawas, Mouaz; Wang, Zhen; Murad, M. Hassan] Mayo Clin, Coll Med, Evidence Based Practice Ctr, 200 First St Southwest, Rochester, MN 55905 USA. [Gupta, Nidhi] Mayo Clin, Coll Med, Div Pediat Endocrinol, Rochester, MN 55905 USA. [Haymond, Morey W.] Baylor Coll Med, Childrens Nutr Res Ctr, Dept Pediat, Houston, TX 77030 USA. [Brown, Rebecca J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Murad, MH (reprint author), Mayo Clin, Coll Med, Evidence Based Practice Ctr, 200 First St Southwest, Rochester, MN 55905 USA. EM murad.mohammad@mayo.edu FU Pediatric Endocrine Society through educational grant from Astra Zeneca; CTSA from the National Center for Advancing Translational Sciences [UL1 TR000135] FX This study was funded by the Pediatric Endocrine Society through an educational grant from Astra Zeneca; the investigators had no contact with Astra Zeneca. This publication was also supported by CTSA Grant UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 68 TC 0 Z9 0 U1 0 U2 0 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 FEB 1 PY 2017 VL 102 IS 2 BP 363 EP 374 DI 10.1210/jc.2016-2271 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP2VE UT WOS:000397240900007 PM 27967300 ER PT J AU Gkourogianni, A Andrew, M Tyzinski, L Crocker, M Douglas, J Dunbar, N Fairchild, J Funari, MFA Heath, KE Jorge, AAL Kurtzman, T LaFranchi, S Lalani, S Lebl, J Lin, YZ Los, E Newbern, D Nowak, C Olson, M Popovic, J Pruhova, S Elblova, L Quintos, JB Segerlund, E Sentchordi, L Shinawi, M Stattin, EL Swartz, J del Angel, AG Cuellar, SD Hosono, H Sanchez-Lara, PA Hwa, V Baron, J Nilsson, O Dauber, A AF Gkourogianni, Alexandra Andrew, Melissa Tyzinski, Leah Crocker, Melissa Douglas, Jessica Dunbar, Nancy Fairchild, Jan Funari, Mariana F. A. Heath, Karen E. Jorge, Alexander A. L. Kurtzman, Tracey LaFranchi, Stephen Lalani, Seema Lebl, Jan Lin, Yuezhen Los, Evan Newbern, Dorothee Nowak, Catherine Olson, Micah Popovic, Jadranka pruhova, Stepanka Elblova, Lenka Quintos, Jose Bernardo Segerlund, Emma Sentchordi, Lucia Shinawi, Marwan Stattin, Eva-Lena Swartz, Jonathan Gonzalez del Angel, Ariadna Cuellar, Sinhue Diaz Hosono, Hidekazu Sanchez-Lara, Pedro A. Hwa, Vivian Baron, Jeffrey Nilsson, Ola Dauber, Andrew TI Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID IDIOPATHIC SHORT STATURE; GROWTH-HORMONE; PUBERTAL CHANGES; BONE MATURATION; UNITED-STATES; GENE; CHILDREN; HEIGHT; OSTEOARTHRITIS; PREVALENCE AB Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, + 1.3 years; range, + 0.0 to + 3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients. C1 [Gkourogianni, Alexandra; Segerlund, Emma; Nilsson, Ola] Karolinska Inst & Karolinska Univ Hosp, Div Pediat Endocrinol, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden. [Andrew, Melissa; Tyzinski, Leah; Dauber, Andrew] Cincinnati Childrens Hosp Med Ctr, Div Endocrinol, Cincinnati Ctr Growth Disorders, Cincinnati, OH 70941 USA. [Crocker, Melissa; Swartz, Jonathan] Boston Childrens Hosp, Endocrinol, Boston, MA USA. [Douglas, Jessica; Nowak, Catherine] Boston Childrens Hosp, Boston, MA 02115 USA. [Dunbar, Nancy] Div Pediat Endocrinol, Connecticut Childrens Med Ctr, Hartford, CT 06106 USA. [Fairchild, Jan] Womens & Childrens Hosp, Dept Endocrinol & Diabet, South Australia 5006, Australia. [Funari, Mariana F. A.; Jorge, Alexander A. L.] Univ S ao Paulo, Unidade Endocrinologia Desenvolvimento LIM 42, Disciplina Endocrinologia, Faculdade Medicina, BR-05508020 Sao Paulo, Brazil. [Heath, Karen E.; Sentchordi, Lucia] Univ Auto noma Madrid, Hosp Univ Paz, Inst Med & Mol Genet INGEMM & Skeletal Dysplasia, IdiPAZ, Madrid 20849, Spain. [Kurtzman, Tracey] El Rio Community Hlth Ctr, Tucson, AZ 85745 USA. [Los, Evan] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97239 USA. [Lalani, Seema] Molecular & Human Genet, Dublin, Ireland. [Lin, Yuezhen] Baylor Coll Med, Pediatr Endocrinol & Metab, Houston, TX 77030 USA. [Fairchild, Jan; LaFranchi, Stephen; Elblova, Lenka] Charles Univ Prague & Univ Hosp Motol, Second Fac Med, Dept Pediat, Prague 11636, Czech Republic. Phoenix Childrens Hosp, Divis Endocrinol, Phoenix, AZ 85016 USA. [Popovic, Jadranka] Univ Pittsburgh Med Ctr, Childrens Hosp Pittsburgh, Pittsburgh, PA 15237 USA. [Quintos, Jose Bernardo] Childrens Hosp, Providence, RI 02903 USA. [Segerlund, Emma] Sunderby Hosp, S-95442 Sunderby, Sweden. [Sentchordi, Lucia] Hosp Univ Infanta Sofia, Dept Pediat, Madrid 28703, Spain. [Shinawi, Marwan] Washington Univ, Divis Genet, St Louis, MO 63130 USA. [Stattin, Eva-Lena] Uppsala Univ, Sci Life Lab, Dept Immunol, Genet & Pathol, S-75236 Uppsala, Sweden. [Gonzalez del Angel, Ariadna; Cuellar, Sinhue Diaz] Inst Nacl Pediat, Dept Gene tica Humana, Lab Biolog Mol Insurgentes Cuicuilco, Insurgentes Cuicuilco, Mexico City 04530, DF, Mexico. [Hosono, Hidekazu] Childrens Med Ctr, Santa Barbara, CA 93111 USA. [Sanchez-Lara, Pedro A.] Childrens Hosp Angeles, Ctr Personalized Med, Los Angeles, CA 90027 USA. [Baron, Jeffrey; Nilsson, Ola] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Inst Hlth, Sect Growth & Dev, Bethesda, MD 20892 USA. [Dauber, Andrew] Orebro Univ & Univ Hosp, Department ofMed Sci, S-70185 Orebro, Sweden. RP Gkourogianni, A (reprint author), Karolinska Inst & Karolinska Univ Hosp, Div Pediat Endocrinol, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden. FU Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health [1K23HD073351]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Swedish Research Council [521-2014-3063, 2015-02227]; Swedish Governmental Agency for Innovation Systems (Vinnova) [2014-01438]; Marianne and Marcus Wallenberg Foundation [2014-0096]; Stockholm County Council; Swedish Society of Medicine; Byggmastare Olle Engkvist's Foundation; HKH Kronprinsessan Lovisas forening for barnasjukvard; Sallskapet Barnavard; Stiftelsen Frimurare Barnhuset i Stockholm; Karolinska Institutet; Sao Paulo Research Foundation (FAPESP), Brazil [2013/03236-5]; Spanish Ministry of Education and Science [SAF2012-30871, SAF2015-66831-R]; Czech Health Research Council [AZV 16-31211A]; Project for Conceptual Development of Research Organization, Ministry of Health, Czech Republic [00064203/6001] FX The work of A.D. was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health (Grant 1K23HD073351). The work of J.B. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The work of O.N. and A.G. was supported by the Swedish Research Council (Grants 521-2014-3063 and 2015-02227), the Swedish Governmental Agency for Innovation Systems (Vinnova) (Grant 2014-01438), the Marianne and Marcus Wallenberg Foundation (Grant 2014-0096), the Stockholm County Council, the Swedish Society of Medicine, Byggmastare Olle Engkvist's Foundation, HKH Kronprinsessan Lovisas forening for barnasjukvard, Sallskapet Barnavard, Stiftelsen Frimurare Barnhuset i Stockholm, and Karolinska Institutet. A.A.L.J. was supported by Grant 2013/03236-5 from the Sao Paulo Research Foundation (FAPESP), Brazil. The work of K.E.H. and L.S. was supported by grants from the Spanish Ministry of Education and Science (Grants SAF2012-30871 and SAF2015-66831-R). The work of J.L., S.P., and L.E. was supported by the Czech Health Research Council (Grant AZV 16-31211A) and the Project for Conceptual Development of Research Organization (Grant 00064203/6001), Ministry of Health, Czech Republic. NR 33 TC 0 Z9 0 U1 0 U2 0 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 FEB 1 PY 2017 VL 102 IS 2 BP 460 EP 469 DI 10.1210/jc.2016-3313 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP2VE UT WOS:000397240900018 PM 27870580 ER PT J AU Galiatsatos, P AF Galiatsatos, Panagis TI Critical care medicine and community involvement in addressing health disparities SO JOURNAL OF CRITICAL CARE LA English DT Editorial Material ID UNITED-STATES; CRITICAL ILLNESS; ADMISSIONS C1 [Galiatsatos, Panagis] Natl Inst Hlth, Crit Care Med, Bethesda, MD 20892 USA. RP Galiatsatos, P (reprint author), Natl Inst Hlth, Crit Care Med, Bethesda, MD 20892 USA. NR 13 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 0883-9441 EI 1557-8615 J9 J CRIT CARE JI J. Crit. Care PD FEB PY 2017 VL 37 BP 246 EP 247 DI 10.1016/j.jcrc.2016.08.026 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA EO9UW UT WOS:000397034600044 PM 27745790 ER PT J AU McLoughlin, KC Ripley, RT AF McLoughlin, Kaitlin C. Ripley, R. Taylor TI Clinical nomograms: Is a picture worth a thousand words? SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material ID LUNG-CANCER; ADENOCARCINOMA C1 [McLoughlin, Kaitlin C.; Ripley, R. Taylor] NCI, Thorac & Gastrointestinal Oncol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ripley, RT (reprint author), NCI, CCR, Thorac & Gastrointestinal Oncol Branch, Bldg 10,4-3952,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM Taylor.Ripley@nih.gov NR 12 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD FEB PY 2017 VL 153 IS 2 BP 470 EP 471 DI 10.1016/j.jtcvs.2016.11.002 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA EO7TY UT WOS:000396894200077 PM 27939030 ER PT J AU Huang, YT Ma, YC Gao, P Yao, Z AF Huang, Yuting Ma, Yuchi Gao, Peng Yao, Zhi TI Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy SO JOURNAL OF THORACIC DISEASE LA English DT Article DE CD47; xenograft; syngeneic; antibody-dependent cell-mediated cytotoxicity (ADCC); calreticulin ID REGULATORY PROTEIN-ALPHA; IMMUNE CHECKPOINT INHIBITOR; NON-HODGKIN-LYMPHOMA; SIRP-ALPHA; MEDIATED DESTRUCTION; HUMAN-CELLS; STEM-CELLS; PHAGOCYTOSIS; BINDING; MACROPHAGES AB Targeting CD47 is in the spotlight of cancer immunotherapy. Blocking CD47 triggers the recognition and elimination of cancer cells by the innate immunity. There are three CD47 antagonists in phase I clinical trials, but their potential efficacies are highly controversial. We raise our concern that NOD-based xenograft hosts tend to overestimate, while syngeneic mouse models could substantially underestimate the efficacy of anti-CD47 therapy. Such discrepancy may be resulted from specific reagent that alters CD47 clustering, and the highly variable avidities of interspecies and intraspecies CD47-SIRP alpha interaction. This problem can be addressed by alternative animal models for better recapitulation of human CD47-SIRP alpha interaction. Both fragment crystallizable (Fc) fragment-dependent effects, like antibody-dependent cellmediated cytotoxicity (ADCC), and Fc-independent CD47 intrinsic functions are involved in anti-CD47 therapy. The latter may be SIRP alpha-dependent or SIRP alpha-independent, such as the case of calreticulin. It has not reached a consensus which of the factors predominate the process, but the answer to this question will determine the optimal pharmaceutical and clinical design of CD47 targeting strategies. C1 [Huang, Yuting; Yao, Zhi] Tianjin Med Univ, Sch Basic Med Sci, Key Lab,Educ Minist China,Dept Immunol, Tianjin Key Lab Cellular & Mol Immunol, Tianjin 300071, Peoples R China. [Ma, Yuchi] NHLBI, Ctr Mol Med, NIH, Bethesda, MD USA. [Gao, Peng] Univ Dist Columbia, Washington, DC 20008 USA. RP Yao, Z (reprint author), Tianjin Med Univ, Sch Basic Med Sci, Key Lab,Educ Minist China,Dept Immunol, Tianjin Key Lab Cellular & Mol Immunol, Tianjin 300071, Peoples R China.; Gao, P (reprint author), Univ Dist Columbia, Washington, DC 20008 USA. EM gopher1_6@163.com; yaozhi@tmu.edu.cn FU National Natural Science Foundation of China [81502247]; Major Project for Essential Drug Research and Development by the Ministry of Science and Technology [2014ZX09101005-004] FX The present study was supported by the National Natural Science Foundation of China (81502247) and Major Project for Essential Drug Research and Development by the Ministry of Science and Technology (2014ZX09101005-004). NR 34 TC 0 Z9 0 U1 0 U2 0 PU PIONEER BIOSCIENCE PUBL CO PI HONG KONG PA 9A GOLD SHINE TOWER, 346-348 QUEEN'S RD CENTRAL, SHEUNG WAN, HONG KONG, 00000, PEOPLES R CHINA SN 2072-1439 EI 2077-6624 J9 J THORAC DIS JI J. Thorac. Dis. PD FEB PY 2017 VL 9 IS 2 BP E168 EP E174 DI 10.21037/jtd.2017.02.30 PG 7 WC Respiratory System SC Respiratory System GA EP0EV UT WOS:000397060500019 PM 28275508 ER PT J AU Ratnasingam, S Anderson, BL AF Ratnasingam, Sivalogeswaran Anderson, Barton L. TI What predicts the strength of simultaneous color contrast? SO JOURNAL OF VISION LA English DT Article DE color induction; simultaneous color contrast; color perception ID APPEARANCE; LIGHTNESS; INDUCTION; VARIANCE; TRANSPARENCY; BRIGHTNESS; PERCEPTION; LUMINANCE; STIMULI AB The perceived color of a uniform image patch depends not only on the spectral content of the light that reaches the eye but also on its context. One of the most extensively studied forms of context dependence is a simultaneous contrast display: a center-surround display containing a homogeneous target embedded in a homogenous surround. A number of models have been proposed to account for the chromatic transformations of targets induced by such surrounds, but they were typically derived in the restricted context of experiments using achromatic targets with surrounds that varied along the cardinal axes of color space. There is currently no theoretical consensus that predicts the target color that produces the largest perceived color difference for two arbitrarily chosen surround colors, or what surround would give the largest color induction for an arbitrarily chosen target. Here, we present a method for assessing simultaneous contrast that avoids some of the methodological issues that arise with nulling and matching experiments and diminishes the contribution of temporal adaption. Observers were presented with pairs of center-surround patterns and ordered them from largest to smallest in perceived dissimilarity. We find that the perceived difference for two arbitrarily chosen surrounds is largest when the target falls on the line connecting the two surrounds in color space. We also find that the magnitude of induction is larger for larger differences between chromatic targets and surrounds of the same hue. Our results are consistent with the direction law (Ekroll & Faul, 2012b), and with a generalization of Kirschmann's fourth law, even for viewing conditions that do not favor temporal adaptation. C1 [Ratnasingam, Sivalogeswaran; Anderson, Barton L.] Univ Sydney, Sch Psychol, Sydney, NSW 2006, Australia. [Ratnasingam, Sivalogeswaran] Natl Inst Hlth, Natl Eye Inst, Sensorimotor Res Lab, Bethesda, MD USA. RP Ratnasingam, S; Anderson, BL (reprint author), Univ Sydney, Sch Psychol, Sydney, NSW 2006, Australia.; Ratnasingam, S (reprint author), Natl Inst Hlth, Natl Eye Inst, Bethesda, MD USA. EM sivalogeswaran.ratnasingam@nih.gov; barton.anderson@sydney.edu.au FU Australian Research Council FX The research reported here was supported by a grant from the Australian Research Council to B.L. Anderson. This research work was carried out while Dr. Ratnasingam was at University of Sydney, revised while he was at the Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology (MIT), and at Laboratory of Sensorimotor Research, National Eye Institute, NIH. NR 30 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 1534-7362 J9 J VISION JI J. Vision PD FEB PY 2017 VL 17 IS 2 AR 13 DI 10.1167/17.2.13 PG 17 WC Ophthalmology SC Ophthalmology GA EP2NL UT WOS:000397220000013 PM 28245494 ER PT J AU Roshanravan, B Patel, KV Fried, LF Robinson-Cohen, C de Boer, IH Harris, T Murphy, RA Satterfield, S Goodpaster, BH Shlipak, M Newman, AB Kestenbaum, B AF Roshanravan, Baback Patel, Kushang V. Fried, Linda F. Robinson-Cohen, Cassianne de Boer, Ian H. Harris, Tamara Murphy, Rachel A. Satterfield, Suzanne Goodpaster, Bret H. Shlipak, Michael Newman, Anne B. Kestenbaum, Bryan CA Hlth ABC Study TI Association of Muscle Endurance, Fatigability, and Strength With Functional Limitation and Mortality in the Health Aging and Body Composition Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Mobility; Muscle; Fatigue; Strength; Sarcopenia ID CHRONIC KIDNEY-DISEASE; OLDER-ADULTS; WALKING SPEED; MOBILITY DISABILITY; CYSTATIN C; GAIT SPEED; FRAILTY; PREVALENCE; CREATININE; INCHIANTI AB Background: Mobility limitation is highly prevalent among older adults and is central to the loss of functional independence. Dynamic isokinetic muscle fatigue testing may reveal increased vulnerability to disability and mortality beyond strength testing. Methods: We studied community-dwelling older adults enrolled in the Health Aging and Body Composition study (age range: 71-82) free of mobility disability and who underwent isokinetic muscle fatigue testing in 1999-2000 (n = 1,963). Isokinetic quadriceps work and fatigue index was determined over 30 repetitions and compared with isometric quadriceps maximum torque. Work was normalized to leg lean mass accounting for gender-specific differences (specific work). The primary outcome was incident persistent severe lower extremity limitation (PSLL), defined as two consecutive reports of either having a lot of difficulty or being unable to walk 1/4 mile or climb 10 steps without resting. The secondary outcome was all-cause mortality. Results: There were 608 (31%) occurrences of incident PSLL and 488 (25%) deaths during median follow-up of 9.3 years. After adjustment, lower isokinetic work was associated with significantly greater risks of PSLL and mortality across the full measured range. Hazard ratios per standard deviation lower specific isokinetic work were 1.22 (95% CI 1.12, 1.33) for PSLL and 1.21 (95% CI 1.13, 1.30) for mortality, respectively. Lower isometric strength was associated with PSLL, but not mortality. Fatigue index was not associated with PSLL or mortality. Conclusions: Muscle endurance, estimated by isokinetic work, is an indicator of muscle health associated with mobility limitation and mortality providing important insight beyond strength testing. C1 [Roshanravan, Baback; Robinson-Cohen, Cassianne; de Boer, Ian H.; Kestenbaum, Bryan] Univ Washington, Dept Med, Div Nephrol, Kidney Res Inst, 325 9th Ave,Room 3NJ350,Box 359606, Seattle, WA 98104 USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Fried, Linda F.] Univ Pittsburgh, Sch Med, Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15260 USA. [Harris, Tamara] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Murphy, Rachel A.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Goodpaster, Bret H.] Florida Hosp, Orlando, FL USA. [Goodpaster, Bret H.] Sanford Burnham Presbys Translat Res Inst Metab &, Orlando, FL USA. [Shlipak, Michael] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. [Newman, Anne B.] Univ Pittsburgh, Sch Med, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Roshanravan, B (reprint author), Univ Washington, Dept Med, Div Nephrol, Kidney Res Inst, 325 9th Ave,Room 3NJ350,Box 359606, Seattle, WA 98104 USA. EM broshanr@uw.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [K23-DK099442]; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050]; NINR [R01-NR012459]; NIH, National Institute on Aging; Northwest Kidney Centers FX This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K23-DK099442 to B.R.); National Institute on Aging (NIA) Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; NIA grant R01-AG028050; and NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. This work was also supported by an unrestricted fund from the Northwest Kidney Centers (B.R.). NR 30 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2017 VL 72 IS 2 BP 284 EP 291 DI 10.1093/gerona/glw210 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EP2EC UT WOS:000397194800019 PM 27907890 ER PT J AU Bryant, LH Kim, SJ Hobson, M Milo, B Kovacs, ZI Jikaria, N Lewis, BK Aronova, MA Sousa, AA Zhang, GF Leapman, RD Frank, JA AF Bryant, L. Henry, Jr. Kim, Saejeong J. Hobson, Matthew Milo, Blerta Kovacs, Zsofia I. Jikaria, Neekita Lewis, Bobbi K. Aronova, Maria A. Sousa, Alioscka A. Zhang, Guofeng Leapman, Richard D. Frank, Joseph A. TI Physicochemical characterization of ferumoxytol, heparin and protamine nanocomplexes for improved magnetic labeling of stem cells SO NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE LA English DT Article DE Ferumoxytol; Heparin; Protamine; Cell labeling; Stem cells ID IRON-OXIDE NANOPARTICLES; IMAGING TRACKING; CONTRAST AGENT; IN-VITRO; MRI; TRANSPLANTATION; POLY(L-LYSINE); TRANSLATION; TRANSPORT; FERAHEME AB Stem cell-based therapies have become a major focus in regenerative medicine and to treat diseases. A straightforward approach combining three drugs, heparin (H), protamine (P) with ferumoxytol (F) in the form of nanocomplexes (NCs) effectively labeled stem cells for cellular MRI. We report on the physicochemical characteristics for optimizing the H, P, and F components in different ratios, and mixing sequences, producing NCs that varied in hydrodynamic size. NC size depended on the order in which drugs were mixed in media. Electron microscopy of HPF or FHP showed that F was located on the surface of spheroidal shaped HP complexes. Human stem cells incubated with FHP NCs resulted in a significantly greater iron concentration per cell compared to that found in HPF NCs with the same concentration of F. These results indicate that FHP could be useful for labeling stem cells in translational studies in the clinic. Published by Elsevier Inc. C1 [Bryant, L. Henry, Jr.; Frank, Joseph A.] Ctr Clin, Lab Diagnost Radiol Res Radiol & Imaging Sci, Bethesda, MD USA. [Kim, Saejeong J.; Hobson, Matthew; Milo, Blerta; Kovacs, Zsofia I.; Jikaria, Neekita; Lewis, Bobbi K.; Frank, Joseph A.] NIH, Frank Lab Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Aronova, Maria A.; Sousa, Alioscka A.; Zhang, Guofeng; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Sousa, Alioscka A.] Univ Fed Sao Paulo, Dept Biochem, Sao Paulo, Brazil. RP Bryant, LH (reprint author), Bldg 10 Room 1N306A,10 Ctr Dr MSC, Bethesda, MD 20892 USA.; Frank, JA (reprint author), Bldg 10 Room B1N256,10 Ctr Dr MSC, Bethesda, MD 20892 USA. EM HBryant@cc.nih.gov; jfrank@helix.nih.gov FU Intramural Research Program of the Clinical Center at the National Institutes of Health; Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health FX This work was supported by the Intramural Research Programs of the Clinical Center and of the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health. NR 41 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1549-9634 EI 1549-9642 J9 NANOMED-NANOTECHNOL JI Nanomed.-Nanotechnol. Biol. Med. PD FEB PY 2017 VL 13 IS 2 BP 503 EP 513 DI 10.1016/j.nano.2016.07.011 PG 11 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA EO8LI UT WOS:000396940200016 PM 27520728 ER PT J AU Inagaki, S Ghirlando, R AF Inagaki, Sayaka Ghirlando, Rodolfo TI Nanodisc characterization by analytical ultracentrifugation SO NANOTECHNOLOGY REVIEWS LA English DT Review DE analytical ultracentrifugation; lipid; membrane protein; nanodisc. ID HIGH-DENSITY-LIPOPROTEIN; PHOSPHOLIPID-BILAYER NANODISCS; SEDIMENTATION COEFFICIENT DISTRIBUTIONS; RESOLUTION STRUCTURE DETERMINATION; INTEGRAL MEMBRANE-PROTEINS; SMALL-ANGLE SCATTERING; NEUTRON REFLECTIVITY; BIOLOGICAL-MEMBRANES; MONOMERIC RHODOPSIN; DETERGENT SOLUTIONS AB Due to their unique properties, tunable size, and ability to provide a near native lipid environment, nanodiscs have found widespread use for the structural and functional studies of reconstituted membrane proteins. They have also been developed, albeit in a few applications, for therapeutic and biomedical use. For these studies and applications, it is essential to characterize the nanodisc preparations in terms of their monodispersity, size, and composition, as these can influence the properties of the membrane protein of interest. Of the many biophysical methods utilized for the study and characterization of nanodiscs, we show that analytical ultracentrifugation is able to report on sample homogeneity, shape, size, composition, and membrane protein stoichiometry or oligomerization state in a direct and simple fashion. The method is truly versatile and does not require nanodisc modification or disassembly. C1 [Ghirlando, Rodolfo] Natl Inst Diabet & Digest & Kidney Dis, Natl Inst Hlth, Mol Biol Lab, Bethesda, MD USA. RP Inagaki, S (reprint author), Natl Inst Neurol Disorders & Stroke, Natl Inst Hlth, Basic Neurosci Program, Bldg 35A,Room 3D963,35A Convent Dr, Bethesda, MD 20892 USA. EM inagakisn@ninds.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Neurological Disorders and Stroke; National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Neurological Disorders and Stroke (S.I.), and the National Institute of Diabetes and Digestive and Kidney Diseases (R.G.). The authors thank Dr. Marie-Paule Strub and Dr. Joseph A. Mindell for helpful comments and suggestions and apologize to colleagues whose work was not cited due to space limitations. NR 105 TC 0 Z9 0 U1 3 U2 3 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 2191-9089 EI 2191-9097 J9 NANOTECHNOL REV JI Nanotechnol. Rev. PD FEB PY 2017 VL 6 IS 1 SI SI BP 3 EP 14 DI 10.1515/ntrev-2016-0082 PG 12 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EP2ZE UT WOS:000397251400002 ER PT J AU Choi, YJ Tyagi, R McNulty, SN Rosa, BA Ozersky, P Martin, J Hallsworth-Pepin, K Unnasch, TR Norice, CT Nutman, TB Weil, GJ Fischer, PU Mitreva, M AF Choi, Young-Jun Tyagi, Rahul McNulty, Samantha N. Rosa, Bruce A. Ozersky, Philip Martin, John Hallsworth-Pepin, Kymberlie Unnasch, Thomas R. Norice, Carmelle T. Nutman, Thomas B. Weil, Gary J. Fischer, Peter U. Mitreva, Makedonka TI Genomic diversity in Onchocerca volvulus and its Wolbachia endosymbiont SO NATURE MICROBIOLOGY LA English DT Article ID SIMULIUM-DAMNOSUM COMPLEX; SEQUENCING DATA; CONTROL-PROGRAM; RAIN-FOREST; OCULAR ONCHOCERCIASIS; POPULATION-GENETICS; WEST-AFRICA; SAVANNA; MITOCHONDRIAL; INFECTION AB Ongoing elimination efforts have altered the global distribution of Onchocerca volvulus, the agent of river blindness, and further population restructuring is expected as efforts continue. Therefore, a better understanding of population genetic processes and their effect on biogeography is needed to support elimination goals. We describe O. volvulus genome variation in 27 isolates from the early 1990s (before widespread mass treatment) from four distinct locales: Ecuador, Uganda, the West African forest and the West African savanna. We observed genetic substructuring between Ecuador and West Africa and between the West African forest and savanna bioclimes, with evidence of unidirectional gene flow from savanna to forest strains. We identified forest: savanna-discriminatory genomic regions and report a set of ancestry informative loci that can be used to differentiate between forest, savanna and admixed isolates, which has not previously been possible. We observed mito-nuclear discordance possibly stemming from incomplete lineage sorting. The catalogue of the nuclear, mitochondrial and endosymbiont DNA variants generated in this study will support future basic and translational onchocerciasis research, with particular relevance for ongoing control programmes, and boost efforts to characterize drug, vaccine and diagnostic targets. C1 [Choi, Young-Jun; Tyagi, Rahul; McNulty, Samantha N.; Rosa, Bruce A.; Ozersky, Philip; Martin, John; Hallsworth-Pepin, Kymberlie; Mitreva, Makedonka] Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA. [Unnasch, Thomas R.] Univ S Florida, Dept Global Hlth, Global Hlth Infect Dis Res Program, Tampa, FL 33612 USA. [Norice, Carmelle T.; Nutman, Thomas B.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Weil, Gary J.; Fischer, Peter U.; Mitreva, Makedonka] Washington Univ, Div Infect Dis, Dept Med, Sch Med, St Louis, MO 63110 USA. RP Mitreva, M (reprint author), Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA.; Mitreva, M (reprint author), Washington Univ, Div Infect Dis, Dept Med, Sch Med, St Louis, MO 63110 USA. EM mmitreva@wustl.edu FU NIH-NHGRI [U54HG003079]; NIH-NIAID [R01AI081803]; Bill & Melinda Gates Foundation [OPP GH 1083853]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX The sequencing work was funded by NIH-NHGRI (U54HG003079) and the genetic variation analysis was funded by NIH-NIAID (R01AI081803) and the Bill & Melinda Gates Foundation (OPP GH 1083853). The study was also funded, in part, by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation. The authors thank the faculty and staff of the McDonnell Genome Institute who contributed to this study, and thank the physicians and fieldworkers in the endemic countries for their extensive help in collecting the parasite material. The unpublished RNAseq data used in this study were produced by the parasite genomics group at the Wellcome Trust Sanger Institute in collaboration with the laboratories of T. B. Nutman and S. Lustigman. NR 75 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2058-5276 J9 NAT MICROBIOL JI NAT. MICROBIOL PD FEB PY 2017 VL 2 IS 2 AR 16207 DI 10.1038/nmicrobiol.2016.207 PG 10 WC Microbiology SC Microbiology GA EP0VN UT WOS:000397104900010 PM 27869792 ER PT J AU Cotton, JA Bennuru, S Grote, A Harsha, B Tracey, A Beech, R Doyle, SR Dunn, M Hotopp, JCD Holroyd, N Kikuchi, T Lambert, O Mhashilkar, A Mutowo, P Nursimulu, N Ribeiro, JMC Rogers, MB Stanley, E Swapna, LS Tsai, IJ Unnasch, TR Voronin, D Parkinson, J Nutman, TB Ghedin, E Berriman, M Lustigman, S AF Cotton, James A. Bennuru, Sasisekhar Grote, Alexandra Harsha, Bhavana Tracey, Alan Beech, Robin Doyle, Stephen R. Dunn, Matthew Hotopp, Julie C. Dunning Holroyd, Nancy Kikuchi, Taisei Lambert, Olivia Mhashilkar, Amruta Mutowo, Prudence Nursimulu, Nirvana Ribeiro, Jose M. C. Rogers, Matthew B. Stanley, Eleanor Swapna, Lakshmipuram S. Tsai, Isheng J. Unnasch, Thomas R. Voronin, Denis Parkinson, John Nutman, Thomas B. Ghedin, Elodie Berriman, Matthew Lustigman, Sara TI The genome of Onchocerca volvulus, agent of river blindness SO NATURE MICROBIOLOGY LA English DT Article ID PURINE NUCLEOSIDE PHOSPHORYLASE; NEGLECTED TROPICAL DISEASES; PARASITE BRUGIA-MALAYI; RECEPTOR GENE FAMILY; CAENORHABDITIS-ELEGANS; IVERMECTIN TREATMENT; LOA-LOA; ACETYLCHOLINE-RECEPTOR; PHYLOGENETIC ANALYSIS; FILARIAL PARASITE AB Human onchocerciasis is a serious neglected tropical disease caused by the filarial nematode Onchocerca volvulus that can lead to blindness and chronic disability. Control of the disease relies largely on mass administration of a single drug, and the development of new drugs and vaccines depends on a better knowledge of parasite biology. Here, we describe the chromosomes of O. volvulus and its Wolbachia endosymbiont. We provide the highest-quality sequence assembly for any parasitic nematode to date, giving a glimpse into the evolution of filarial parasite chromosomes and proteomes. This resource was used to investigate gene families with key functions that could be potentially exploited as targets for future drugs. Using metabolic reconstruction of the nematode and its endosymbiont, we identified enzymes that are likely to be essential for O. volvulus viability. In addition, we have generated a list of proteins that could be targeted by Federal-Drug-Agency-approved but repurposed drugs, providing starting points for anti-onchocerciasis drug development. C1 [Cotton, James A.; Harsha, Bhavana; Tracey, Alan; Doyle, Stephen R.; Dunn, Matthew; Holroyd, Nancy; Kikuchi, Taisei; Lambert, Olivia; Tsai, Isheng J.; Berriman, Matthew] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England. [Bennuru, Sasisekhar; Nutman, Thomas B.] NIH, Natl Inst Allergy & Infect Dis, Lab Parasit Dis, Bethesda, MD 20892 USA. [Grote, Alexandra; Ghedin, Elodie] New York Univ, Ctr Genom & Syst Biol, Dept Biol, New York, NY 10003 USA. [Beech, Robin] McGill Univ, Inst Parasitol, Montreal, PQ H9X 3V9, Canada. [Hotopp, Julie C. Dunning] Univ Maryland, Inst Genome Sci, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 USA. [Unnasch, Thomas R.] Univ S Florida, Coll Publ Hlth, Global Hlth Infect Dis Res Program, Dept Global Hlth, Tampa, FL 33612 USA. [Mutowo, Prudence] European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England. [Nursimulu, Nirvana] Univ Toronto, Dept Comp Sci, Toronto, ON M5S 3G4, Canada. [Nursimulu, Nirvana] Hosp Sick Children, Div Mol Struct & Funct, Res Inst, Toronto, ON M5G IX8, Canada. [Ribeiro, Jose M. C.] NIH, Natl Inst Allergy & Infect Dis, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Rogers, Matthew B.] Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Pittsburgh, PA 15224 USA. [Lustigman, Sara] New York Blood Ctr, New York, NY 10065 USA. [Parkinson, John] Univ Toronto, Dept Biochem & Mol Genet, Toronto, ON M5S IA8, Canada. [Ghedin, Elodie] New York Univ, Coll Global Publ Hlth, New York, NY 10003 USA. [Kikuchi, Taisei] Miyazaki Univ, Div Parasitol, Fac Med, Miyazaki, Japan. [Stanley, Eleanor] Eagle Genom Ltd, Babraham Hall,Babraham Res Campus, Cambridge CB22 3AT, England. [Tsai, Isheng J.] Acad Sinica, Biodivers Res Ctr, Taipei 11529, Taiwan. RP Berriman, M (reprint author), Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England.; Ghedin, E (reprint author), New York Univ, Ctr Genom & Syst Biol, Dept Biol, New York, NY 10003 USA.; Lustigman, S (reprint author), New York Blood Ctr, New York, NY 10065 USA.; Ghedin, E (reprint author), New York Univ, Coll Global Publ Hlth, New York, NY 10003 USA. EM elodie.ghedin@nyu.edu; mb4@sanger.ac.uk; slustigman@nybloodcenter.org FU Wellcome Trust through Wellcome Trust Sanger Institute, WTSI [098051]; BioProject [PBJEB2965]; NIAID [U19 AI110820]; NIH [DP2-OD007372]; Canadian Institutes of Health Research [84556]; Natural Sciences and Engineering Research Council of Canada [RGPIN-2014-06664]; NYBC; Edna McConnell Clark Foundation; NIH/NIAID [R01 AI42328] FX The O. volvulus and O. ochengi genome sequencing was funded by the Wellcome Trust through the core funding of the Wellcome Trust Sanger Institute, WTSI (grant no. 098051). The unpublished RNAseq data used in this study were produced by the parasite genomics group at the Wellcome Trust Sanger Institute in collaboration with the laboratory of T.B. Nutman and S. Lustigman and are available from the sequence data archives under BioProject PBJEB2965. The authors thank C. Griffiths, N. Park, L. Shirley and DNA Pipelines at WTSI for generating the libraries, J. Keane, M. Aslett and A. Page of WTSI pathogen informatics for informatics support and for providing the pipeline to annotate the Wolbachia genome, N. Tricoche of the New York Blood Center (NYBC) for the generation of O. volvulus D40 juvenile female and male worms, and J. Liu and A. Contreras from the NYBC for preparing all the DNA and RNA samples used in these studies. J.C.D.H. was supported by NIAID (U19 AI110820) as well as an NIH Director's New Innovator Award (DP2-OD007372). J.P., N. N. and L.S.S. were supported by the Canadian Institutes of Health Research (MOP# 84556) and the Natural Sciences and Engineering Research Council of Canada (RGPIN-2014-06664). Additional computing resources were provided through Compute Canada by the University of Toronto SciNet HPC Consortium. S.L. was supported in part by intramural funding from the NYBC, The Edna McConnell Clark Foundation and NIH/NIAID (R01 AI42328). The authors thank the people of the villages around Kumba, Marumba I, Marumba II, Boa Bakundu, Bombanda and Bombele, Cameroon, who were part of the field studies that enabled the collection of O. volvulus parasite material. The authors also thank P. Enyong and other personnel at the Tropical Medicine Research Station, Kumba, for their assistance in collecting the O. volvulus and O. ochengi parasite material. NR 114 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2058-5276 J9 NAT MICROBIOL JI NAT. MICROBIOL PD FEB PY 2017 VL 2 IS 2 AR 16216 DI 10.1038/nmicrobiol.2016.216 PG 12 WC Microbiology SC Microbiology GA EP0VN UT WOS:000397104900014 PM 27869790 ER PT J AU Giri, A Mok, KY Jansen, I Sharma, M Tesson, C Mangone, G Lesage, S Bras, JM Shulman, JM Sheerin, UM Diez-Fairen, M Pastor, P Marti, MJ Ezquerra, M Tolosa, E Correia-Guedes, L Ferreira, J Amin, N van Duijn, CM van Rooij, J Uitterlinden, AG Kraaij, R Nalls, M Simon-Sanchez, J AF Giri, Anamika Mok, Kin Y. Jansen, Iris Sharma, Manu Tesson, Christelle Mangone, Graziella Lesage, Suzanne Bras, Jose M. Shulman, Joshua M. Sheerin, Una-Marie Diez-Fairen, Monica Pastor, Pau Jose Marti, Maria Ezquerra, Mario Tolosa, Eduardo Correia-Guedes, Leonor Ferreira, Joaquim Amin, Najaf van Duijn, Cornelia M. van Rooij, Jeroen Uitterlinden, Andre G. Kraaij, Robert Nalls, Michael Simon-Sanchez, Javier CA Int Parkinsons Dis Consortium IPDG TI Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population SO NEUROBIOLOGY OF AGING LA English DT Article DE TMEM230; Parkinson's disease; IPDGC; Rotterdam Study Exome Sequencing; Database; SKAT-O; Mutation screening AB Mutations in TMEM230 have recently been associated to Parkinson's disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous missense variants in 2 unrelated PD cases and not in our control database (p.Y106H and p.I162V), and a heterozygous missense variant in 2 PD cases from the same family (p.A163T). However, data presented herein is not sufficient to support the role of any of these variants in PD pathology. A series of unified sequence kernel association tests also failed to show a cumulative effect of rare variation in this gene on the risk of PD in the general Caucasian population. Further evaluation of genetic data from different populations is needed to understand the genetic role of TMEM230 in PD etiology. (C) 2016 Elsevier Inc. All rights reserved. C1 [Giri, Anamika; Sharma, Manu; Simon-Sanchez, Javier] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Giri, Anamika; Jansen, Iris; Simon-Sanchez, Javier] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany. [Mok, Kin Y.; Bras, Jose M.; Sheerin, Una-Marie] UCL Inst Neurol, Dept Mol Neuroscience, London, England. [Jansen, Iris] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Sharma, Manu] Univ Tubingen, Ctr Genet Epidemiol, Inst Clin Epidemiol & Appl Biometry, Tubingen, Germany. [Mangone, Graziella; Lesage, Suzanne] Univ Paris 06, Sorbonne Univ,UMR S 1127, UPMC,ICM,INSERM U 1127,CNRS,UMR 7225,AP HP, Pitie Salpetriere Hosp,Inst Cerveau Moelle epinie, Paris, France. [Shulman, Joshua M.] Baylor Coll Med, Dept Neurol & Mol & Human Genet, Houston, TX USA. [Diez-Fairen, Monica; Pastor, Pau] Hosp Univ Mutua Terrassa, Dept Neurol, Movement Disorders Unit, Barcelona, Spain. [Jose Marti, Maria; Ezquerra, Mario; Tolosa, Eduardo] Hosp Clin Barcelona, Neurol Serv, Movement Disorders Unit, Barcelona, Spain. [Jose Marti, Maria; Ezquerra, Mario; Tolosa, Eduardo] Inst Biomed Res August Pi Sunyer IDIBAPS, Barcelona, Spain. [Jose Marti, Maria; Ezquerra, Mario] CIBERNED, Barcelona, Spain. [Correia-Guedes, Leonor; Uitterlinden, Andre G.] Hosp Santa Maria, Centro Hospitalar Lisboa Norte, Dept Neurosci, Lisbon, Portugal. [Ferreira, Joaquim] Univ Lisbon, Fac Med, Inst Mol Med, Lisbon, Portugal. [van Duijn, Cornelia M.; Uitterlinden, Andre G.; Kraaij, Robert] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [van Rooij, Jeroen; Uitterlinden, Andre G.; Kraaij, Robert] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [van Rooij, Jeroen; Uitterlinden, Andre G.; Kraaij, Robert] NCHA, Rotterdam, Netherlands. [Nalls, Michael] Natl Inst Aging, Neurogenet Lab, Bethesda, MD USA. RP Simon-Sanchez, J (reprint author), Otfried Muller Strasse 23, D-72076 Tubingen, Germany. EM javier.simon-sanchez@dzne.de NR 8 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD FEB PY 2017 VL 50 AR 167.e11 DI 10.1016/j.neurobiolaging.2016.10.004 PG 3 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA EO7SY UT WOS:000396891600021 ER PT J AU Weihl, CC Mammen, AL AF Weihl, C. C. Mammen, A. L. TI Sporadic inclusion body myositis - a myodegenerative disease or an inflammatory myopathy SO NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY LA English DT Review DE myositis ID MONOCLONAL-ANTIBODY ANALYSIS; VALOSIN-CONTAINING PROTEIN; AMYOTROPHIC-LATERAL-SCLEROSIS; CYTOSOLIC 5'-NUCLEOTIDASE 1A; MONONUCLEAR-CELLS; FRONTOTEMPORAL DEMENTIA; SQSTM1 MUTATIONS; MUSCLE BIOPSIES; DISTAL MYOPATHY; PAGET-DISEASE AB Sporadic inclusion body myositis (sIBM) is an insidious late-onset progressive myopathy that typically affects patients over the age of 50. Clinically, patients develop a characteristic pattern of weakness that affects the forearm flexors and knee extensors. Muscle biopsy, often utilized in the diagnosis, demonstrates a chronic myopathy with mixed pathologies harbouring intramyofiber protein inclusions and endomysial inflammation. The co-existence of these pathologic features (that is, inflammation and protein aggregation) has divided the field of sIBM research into two opposing (albeit slowly unifying) camps regarding disease pathogenesis. The present review explores the recent evidence supporting these distinct pathogenic mechanisms. Future therapies that are designed to target both aspects of sIBM pathologies will likely be necessary to treat sIBM. C1 [Weihl, C. C.] Washington Univ, Sch Med, Dept Neurol, 660 S Euclid Ave, St Louis, MO 63110 USA. [Weihl, C. C.] Washington Univ, Sch Med, Hope Ctr Neurol Dis, 660 S Euclid Ave, St Louis, MO 63110 USA. [Mammen, A. L.] NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Express, NIH, Bethesda, MD 20892 USA. RP Weihl, CC (reprint author), Washington Univ, Sch Med, Dept Neurol, 660 S Euclid Ave, St Louis, MO 63110 USA.; Weihl, CC (reprint author), Washington Univ, Sch Med, Hope Ctr Neurol Dis, 660 S Euclid Ave, St Louis, MO 63110 USA. EM weihlc@wustl.edu NR 61 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0305-1846 EI 1365-2990 J9 NEUROPATH APPL NEURO JI Neuropathol. Appl. Neurobiol. PD FEB PY 2017 VL 43 IS 1 BP 82 EP 91 DI 10.1111/nan.12384 PG 10 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA EO8GL UT WOS:000396927100006 PM 28111778 ER PT J AU Wipfli, HL Berman, M Hanson, K Kelder, S Solis, A Villanti, AC Ribeiro, CMP Meissner, HI Anderson, R AF Wipfli, Heather L. Berman, Micah Hanson, Kacey Kelder, Steven Solis, Amy Villanti, Andrea C. Ribeiro, Carla M. P. Meissner, Helen I. Anderson, Roger TI Defining Tobacco Regulatory Science Competencies SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID FOOD AB Introduction: In 2013, the National Institutes of Health and the Food and Drug Administration funded a network of 14 Tobacco Centers of Regulatory Science (TCORS) with a mission that included research and training. A cross-TCORS Panel was established to define tobacco regulatory science (TRS) competencies to help harmonize and guide their emerging educational programs. The purpose of this paper is to describe the Panel's work to develop core TRS domains and competencies. Methods: The Panel developed the list of domains and competencies using a semistructured Delphi method divided into four phases occurring between November 2013 and August 2015. Results: The final proposed list included a total of 51 competencies across six core domains and 28 competencies across five specialized domains. Conclusions: There is a need for continued discussion to establish the utility of the proposed set of competencies for emerging TRS curricula and to identify the best strategies for incorporating these competencies into TRS training programs. Given the field's broad multidisciplinary nature, further experience is needed to refine the core domains that should be covered in TRS training programs versus knowledge obtained in more specialized programs. Implications: Regulatory science to inform the regulation of tobacco products is an emerging field. The paper provides an initial list of core and specialized domains and competencies to be used in developing curricula for new and emerging training programs aimed at preparing a new cohort of scientists to conduct critical TRS research. C1 [Wipfli, Heather L.] Univ Southern Calif, Dept Prevent Med, 2001 N Soto St, Los Angeles, CA 90089 USA. [Berman, Micah] Ohio State Univ, Coll Publ Hlth, Columbus, OH 43210 USA. [Berman, Micah] Ohio State Univ, Moritz Coll Law, Columbus, OH 43210 USA. [Hanson, Kacey; Kelder, Steven] Univ Texas Hlth Sci Ctr Houston, Austin, TX USA. [Solis, Amy] Westat Corp, Rockville, MD USA. [Villanti, Andrea C.] Truth Initiat, Schroeder Inst Tobacco Res & Policy Studies, Washington, DC USA. [Ribeiro, Carla M. P.] Univ North Carolina Chapel Hill, Dept Med, Div Pulm, Marsico Lung Inst, Chapel Hill, NC USA. [Ribeiro, Carla M. P.] Univ North Carolina Chapel Hill, Cyst Fibrosis Ctr, Chapel Hill, NC USA. [Ribeiro, Carla M. P.] Univ North Carolina Chapel Hill, Dept Cell Biol & Physiol, Chapel Hill, NC USA. [Meissner, Helen I.] NIH, Off Dis Prevent, Bldg 10, Bethesda, MD 20892 USA. [Anderson, Roger] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. RP Wipfli, HL (reprint author), Univ Southern Calif, Dept Prevent Med, 2001 N Soto St, Los Angeles, CA 90089 USA. EM hwipfli@med.usc.edu FU NIH [P50-HL-120163-01, P50-CA-180523-01, P50-DA-036105-01, P50-DA-036128-01, P50-CA-180890-01, P50-DA-036114-01, P50-CA-179546-01, P50-DA-036151-01, P50-DA-036107-01, P50-CA-180905-01, P50-CA-180906-01, P50-CA-180907-01, P50-CA-180908-01, P50-HL-120100-01, U54-CA-189222-01]; FDA Center for Tobacco Products (CTP) FX Research reported in this publication was supported by grant numbers P50-HL-120163-01, P50-CA-180523-01, P50-DA-036105-01, P50-DA-036128-01, P50-CA-180890-01, P50-DA-036114-01, P50-CA-179546-01, P50-DA-036151-01, P50-DA-036107-01, P50-CA-180905-01, P50-CA-180906-01, P50-CA-180907-01, P50-CA-180908-01, P50-HL-120100-01, and U54-CA-189222-01 from the NIH and FDA Center for Tobacco Products (CTP). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration. NR 8 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 19 IS 2 BP 222 EP 230 DI 10.1093/ntr/ntw178 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA EP0DL UT WOS:000397056900013 PM 27613917 ER PT J AU Zhang, Y Matsuzaka, T Yano, H Furuta, Y Nakano, T Ishikawa, K Fukuyo, M Takahashi, N Suzuki, Y Sugano, S Ide, H Kobayashi, I AF Zhang, Yingbiao Matsuzaka, Tomoyuki Yano, Hirokazu Furuta, Yoshikazu Nakano, Toshiaki Ishikawa, Ken Fukuyo, Masaki Takahashi, Noriko Suzuki, Yutaka Sugano, Sumio Ide, Hiroshi Kobayashi, Ichizo TI Restriction glycosylases: involvement of endonuclease activities in the restriction process SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ARCHAEON PYROCOCCUS-ABYSSI; BASE EXCISION-REPAIR; MODIFICATION SYSTEMS; DNA METHYLTRANSFERASE; ESCHERICHIA-COLI; MODIFICATION GENES; EXONUCLEASE-III; PABI FAMILY; ENZYMES; RECOMBINATION AB All restriction enzymes examined are phosphodiesterases generating 3'-OH and 5'-P ends, but one restriction enzyme (restriction glycosylase) excises unmethylated bases from its recognition sequence. Whether its restriction activity involves endonucleolytic cleavage remains unclear. One report on this enzyme, R. PabI from a hyperthermophile, ascribed the breakage to high temperature while another showed its weak AP lyase activity generates atypical ends. Here, we addressed this issue in mesophiles. We purified R. PabI homologs from Campylobacter coli (R. CcoLI) and Helicobacter py-lori (R. HpyAXII) and demonstrated their DNA cleavage, DNA glycosylase and AP lyase activities in vitro at 37. C. The AP lyase activity is more coupled with glycosylase activity in R. CcoLI than in R. PabI. R. CcoLI/R. PabI expression caused restriction of incoming bacteriophage/plasmid DNA and endogenous chromosomal DNA within Escherichia coli at 37 degrees C. The R. PabI-mediated restriction was promoted by AP endonuclease action in vivo or in vitro. These results reveal the role of endonucleolytic DNA cleavage in restriction and yet point to diversity among the endonucleases. The cleaved ends are difficult to repair in vivo, which may indicate their biologi-cal significance. These results support generalization of the concept of restriction-modification system to the concept of self-recognizing epigenetic system, which combines any epigenetic labeling and any DNA damaging. C1 [Zhang, Yingbiao; Yano, Hirokazu; Furuta, Yoshikazu; Takahashi, Noriko; Suzuki, Yutaka; Sugano, Sumio; Kobayashi, Ichizo] Univ Tokyo, Grad Sch Frontier Sci, Formerly Dept Med Genome Sci, Dept Computat Biol & Med Sci, Tokyo 1088639, Japan. [Matsuzaka, Tomoyuki; Nakano, Toshiaki; Ide, Hiroshi] Hiroshima Univ, Grad Sch Sci, Dept Math & Life Sci, Hiroshima 7398526, Japan. [Yano, Hirokazu; Furuta, Yoshikazu; Takahashi, Noriko; Kobayashi, Ichizo] Univ Tokyo, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan. [Yano, Hirokazu] Univ Tsukuba, Fac Life & Environm Sci, Tsukuba, Ibaraki 3058572, Japan. [Ishikawa, Ken] Natl Canc Inst, Natl Inst Hlth, Frederick, MD 21702 USA. [Fukuyo, Masaki] Chiba Univ, Grad Sch Med, Dept Mol Oncol, Chiba 2608670, Japan. [Kobayashi, Ichizo] Tohoku Univ, Grad Sch Life Sci, Sendai, Miyagi 9808577, Japan. [Kobayashi, Ichizo] Kyorin Univ, Fac Med, Mitaka, Tokyo 1818611, Japan. [Kobayashi, Ichizo] Univ Paris Sud, Univ Paris Saclay, CNRS, CEA,Inst Integrat Biol Cell I2BC, F-91198 Gif Sur Yvette, France. [Kobayashi, Ichizo] Jawaharlal Nehru Ctr Adv Sci Res, Bengaluru 560064, India. RP Kobayashi, I (reprint author), Univ Tokyo, Grad Sch Frontier Sci, Formerly Dept Med Genome Sci, Dept Computat Biol & Med Sci, Tokyo 1088639, Japan.; Kobayashi, I (reprint author), Univ Tokyo, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan.; Kobayashi, I (reprint author), Tohoku Univ, Grad Sch Life Sci, Sendai, Miyagi 9808577, Japan.; Kobayashi, I (reprint author), Kyorin Univ, Fac Med, Mitaka, Tokyo 1818611, Japan.; Kobayashi, I (reprint author), Univ Paris Sud, Univ Paris Saclay, CNRS, CEA,Inst Integrat Biol Cell I2BC, F-91198 Gif Sur Yvette, France.; Kobayashi, I (reprint author), Jawaharlal Nehru Ctr Adv Sci Res, Bengaluru 560064, India. EM ikobaya@ims.u-tokyo.ac.jp OI Yano, Hirokazu/0000-0001-5144-3459 FU MEXT KAKENHI [221S0002]; JSPS KAKENHI [26650123, 15K14572, 15K18665]; Ichiro Kanehara foundation of promotion of medical sciences and medical care; Jean d'Alembert scholarship from Universite Paris-Saclay FX MEXT KAKENHI [221S0002 to I.K.]; JSPS KAKENHI [26650123 and 15K14572 to I.K., 15K18665 to H.Y.]; Ichiro Kanehara foundation of promotion of medical sciences and medical care. Funding for open access charge: Jean d'Alembert scholarship from Universite Paris-Saclay. NR 38 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2017 VL 45 IS 3 BP 1392 EP 1403 DI 10.1093/nar/gkw1250 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO9KQ UT WOS:000397008000033 PM 28180312 ER PT J AU Popuri, V Huang, J Ramamoorthy, M Tadokoro, T Croteau, DL Bohr, VA AF Popuri, Venkateswarlu Huang, Jing Ramamoorthy, Mahesh Tadokoro, Takashi Croteau, Deborah L. Bohr, Vilhelm A. TI RECQL5 plays co-operative and complementary roles with WRN syndrome helicase (vol 41, 881, 2013) SO NUCLEIC ACIDS RESEARCH LA English DT Correction C1 [Popuri, Venkateswarlu; Huang, Jing; Ramamoorthy, Mahesh; Tadokoro, Takashi; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM vbohr@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2017 VL 45 IS 3 BP 1566 EP 1566 DI 10.1093/narlgkw1216 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO9KQ UT WOS:000397008000047 PM 28180303 ER PT J AU Kranz, S Dodd, KW Juan, WY Johnson, LK Jahns, L AF Kranz, Sibylle Dodd, Kevin W. Juan, Wen Yen Johnson, Luann K. Jahns, Lisa TI Whole Grains Contribute Only a Small Proportion of Dietary Fiber to the US Diet SO NUTRIENTS LA English DT Article DE whole grain intake; dietary fiber; nutrition monitoring; Dietary Guidelines for Americans; healthy diet; sources of dietary fiber ID NUTRITION EXAMINATION SURVEY; NATIONAL-HEALTH; CARDIOVASCULAR-DISEASE; FOOD SOURCES; BODY-WEIGHT; ENERGY; CONSUMPTION; BENEFITS; OBESITY; ADULTS AB Dietary fiber (DF), found in whole fruits, vegetables, and whole grains (WG), is considered a nutrient of concern in the US diet and increased consumption is recommended. The present study was designed to highlight this critical importance of the difference between WG, high-fiber WG, and sources of fiber that are not from WG. The study is based on the two-day diets reported consumed by the nationally representative sample of Americans participating in What We Eat In America, the dietary component of the National Health and Nutrition Examination Survey from 2003-2010. Foods consumed were classified into tertiles of DF and WG and the contribution of fiber by differing levels of WG content were examined. Foods containing high amounts of WG and DF only contributed about 7% of total fiber intake. Overall, grain-based foods contributed 54.5% of all DF consumed. Approximately 39% of DF came from grain foods that contained no WG, rather these foods contained refined grains, which contain only small amounts of DF but are consumed in large quantities. All WG-containing foods combined contributed a total of 15.3% of DF in the American diet. Thus, public health messaging needs to be changed to specifically encourage consumption of WG foods with high levels of DF to address both recommendations. C1 [Kranz, Sibylle] Univ Virginia, Dept Kinesiol, Charlottesville, VA 22904 USA. [Dodd, Kevin W.] Natl Canc Inst, Bethesda, MD 20892 USA. [Juan, Wen Yen] US FDA, Nutr Assessment & Evaluat, Off Nutr & Food Labeling, Ctr Food & Appl Nutr, College Pk, MD 20740 USA. [Johnson, Luann K.; Jahns, Lisa] USDA, Agr Res Serv, Grand Forks Human Nutr Res Ctr, Grand Forks, ND 58203 USA. RP Kranz, S (reprint author), Univ Virginia, Dept Kinesiol, Charlottesville, VA 22904 USA. EM sibylle.kranz@virginia.edu; doddk@mail.nih.gov; wenyen.juan@fda.hhs.gov; luann.johnson@ars.usda.gov; lisa.jahns@ars.usda.gov FU USDA/Agricultural Research Service [USDA 3062-51000-051-00D]; Kellogg Citizenship Fund FX Financial support was provided by the USDA/Agricultural Research Service, (USDA 3062-51000-051-00D) and The Kellogg Citizenship Fund. NR 36 TC 0 Z9 0 U1 1 U2 1 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD FEB PY 2017 VL 9 IS 2 AR 153 DI 10.3390/nu9020153 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EO9QL UT WOS:000397023100066 ER PT J AU Colloca, L Enck, P DeGrazia, D AF Colloca, Luana Enck, Paul DeGrazia, David TI Using placebos as an opioid-sparing method of pain management Reply SO PAIN LA English DT Letter ID TRENDS C1 [Colloca, Luana] Univ Maryland, Sch Nursing, Dept Pain Translat Symptom Sci, Baltimore, MD 21201 USA. [Colloca, Luana] Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. [Colloca, Luana] Univ Maryland, Ctr Adv Chron Pain Res, Baltimore, MD 21201 USA. [Enck, Paul] Univ Hosp Tuebingen, Dept Internal Med 6, Psychosomat Med & Psychotherapy, Tubingen, Germany. [DeGrazia, David] Natl Inst Hlth, Dept Bioeth, Bethesda, MD USA. [DeGrazia, David] George Washington Univ, Dept Philosophy, Washington, DC USA. RP Colloca, L (reprint author), Univ Maryland, Sch Nursing, Dept Pain Translat Symptom Sci, Baltimore, MD 21201 USA.; Colloca, L (reprint author), Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA.; Colloca, L (reprint author), Univ Maryland, Ctr Adv Chron Pain Res, Baltimore, MD 21201 USA. EM colloca@son.umaryland.edu FU National Institute of Dental and Craniofacial Research (NIDCR) [R01DE025946]; National Institutes of Health Clinical Center FX This research was supported by the National Institute of Dental and Craniofacial Research (NIDCR, R01DE025946, LC) and, in part, by intramural funds from the National Institutes of Health Clinical Center (DDG). The funding agencies have no roles in the study. NR 6 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD FEB PY 2017 VL 158 IS 2 BP 361 EP 362 DI 10.1097/j.pain.0000000000000757 PG 3 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA EO9NN UT WOS:000397015500021 PM 28092327 ER PT J AU Aviles-Santa, ML Perez, CM Schneiderman, N Savage, PJ Kaplan, RC Teng, YP Suarez, EL Cai, JW Giachello, AL Talavera, GA Cowie, CC AF Aviles-Santa, M. Larissa Perez, Cynthia M. Schneiderman, Neil Savage, Peter J. Kaplan, Robert C. Teng, Yanping Suarez, Erick L. Cai, Jianwen Giachello, Aida L. Talavera, Gregory A. Cowie, Catherine C. TI Detecting prediabetes among Hispanics/Latinos from diverse heritage groups: Does the test matter? Findings from the Hispanic Community Health Study/Study of Latinos SO PREVENTIVE MEDICINE LA English DT Article DE Prediabetic state; Hispanics; Latinos; Hypertension; Obesity; LDL cholesterol; Triglycerides ID FASTING PLASMA-GLUCOSE; CORONARY-HEART-DISEASE; NUTRITION EXAMINATION SURVEY; CARDIOVASCULAR RISK-FACTORS; MEXICAN-AMERICANS; DIABETES-MELLITUS; HEMOGLOBIN A1C; TOLERANCE TEST; US POPULATION; NATIONAL-HEALTH AB The objectives of this analysis were to compare the ability of fasting plasma glucose (FPG), post oral load plasma glucose (2hPG), and hemoglobin A(1c) (HbA(1c)) to identify U.S. Hispanic/Latino individuals with prediabetes, and to assess its cardiovascular risk factor correlates. This is a cross-sectional analysis of baseline data from 15,507 adults without self-reported diabetes mellitus from six Hispanic/Latino heritage groups, enrolled in the Hispanic Community Health Study/Study of Latinos, which takes place in four U.S. communities. The prevalence of prediabetes was determined according to individual or combinations of ADA-defined cut points: FPG = 5.6-7.0 mmol/L, 2hPG = 7.8-11.1 mmol/L, and HbA1c = 5.7%-6.4% (39-46 mmol/mol). The sensitivity of these criteria to detect prediabetes was estimated. The prevalence ratios (PRs) for selected cardiovascular risk factors were compared among alternative categories of prediabetes versus normoglycemia [ FPG < 5.6 mmol/L and 2hPG < 7.8 mmol/L and HbA(1c) < 5.7% (39 mmol/mol)]. Approximately 36% of individuals met any of the ADA prediabetes criteria. Using 2hPG as the gold standard, the sensitivity of FPG was 40.1%, HbA(1c) was 45.6%, and that of HbA(1c) + FPG was 62.2%. The number of significant PRs for cardiovascular risk factors was higher among individuals with isolated 2hPG = 7.8-11.1mmol/L, FPG = 5.6-7.0 mmol/L + HbA(1c) = 5.7%-6.4%, or those who met the three prediabetes criteria. Assessing FPG, HbA(1c), and cardiovascular risk factors in Hispanics/Latinos at risk might enhance the early prevention of diabetes mellitus and cardiovascular complications in this young and growing population, independent of their heritage group. Published by Elsevier Inc. C1 [Aviles-Santa, M. Larissa] NHLBI, 6701 Rockledge Dr,Room 10188, Bethesda, MD 20892 USA. [Perez, Cynthia M.; Suarez, Erick L.] Univ Puerto Rico, Grad Sch Publ Hlth, Dept Biostat & Epidemiol, Med Sci Campus,POB 365067, San Juan, PR 00936 USA. [Schneiderman, Neil] Univ Miami, 5665 Ponce de Leon Blvd,Room 408,POB 248185, Coral Gables, FL 33124 USA. [Savage, Peter J.; Cowie, Catherine C.] NIDDK, 6707 Democracy Blvd, Bethesda, MD 20982 USA. [Kaplan, Robert C.] Albert Einstein Coll Med, Belfer Bldg,Room 1306C,1300 Morris Pk Ave, Bronx, NY 10461 USA. [Teng, Yanping; Cai, Jianwen] Univ North Carolina Chapel Hill, 137 East Franklin St,Suite 203, Chapel Hill, NC 27514 USA. [Giachello, Aida L.] Northwestern Univ, Feinberg Sch Med, 680 N Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. [Talavera, Gregory A.] San Diego State Univ, Inst Behav & Community Hlth, Grad Sch Publ Hlth, 450 Fourth Ave,Suite 400, Chula Vista, CA 91910 USA. RP Aviles-Santa, ML (reprint author), NHLBI, 6701 Rockledge Dr,Room 10188, Bethesda, MD 20892 USA. EM avilessantal@nhlbi.nih.gov; cynthia.perez1@upr.edu; nschneid@miami.edu; savagep@niddk.nih.gov; robert.kaplan@einstein.yu.edu; tengunc@email.unc.edu; erick.suarez@upr.edu; cai@bios.unc.edu; a-giachello@northwestern.edu; gtalavera@mail.sdsu.edu; CowieC@Extra.niddk.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC65233, N01-HC65234, N01-HC65235, N01-HC65236, N01-HC65237]; National Institute on Minority Health and Health Disparities; National Institute on Deafness and Other Communication Disorders; National Institute of Dental and Craniofacial Research; National Institute of Diabetes, Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; NIH Office of Dietary Supplements FX The first phase of the Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following NIH Institutes/Offices collaborated and co-funded the first phase of the study: the National Institute on Minority Health and Health Disparities; the National Institute on Deafness and Other Communication Disorders; the National Institute of Dental and Craniofacial Research; the National Institute of Diabetes, Digestive and Kidney Diseases; the National Institute of Neurological Disorders and Stroke; and the NIH Office of Dietary Supplements. NR 52 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD FEB PY 2017 VL 95 IS 1 BP 110 EP 118 DI 10.1016/j.ypmed.2016.12.009 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EP3SY UT WOS:000397303200015 PM 27956225 ER PT J AU Fortney, JC Unutzer, J Wrenn, G Pyne, JM Smith, GR Schoenbaum, M Harbin, HT AF Fortney, John C. Unutzer, Jurgen Wrenn, Glenda Pyne, Jeffrey M. Smith, G. Richard Schoenbaum, Michael Harbin, Henry T. TI A Tipping Point for Measurement-Based Care SO PSYCHIATRIC SERVICES LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; MENTAL-HEALTH-SERVICES; CLINICAL SUPPORT TOOLS; TREATMENT ENHANCEMENT PROGRAM; MAJOR DEPRESSIVE DISORDER; TREATMENT FAILURE; PSYCHOTHERAPY OUTCOMES; COLLABORATIVE CARE; BIPOLAR DISORDER; CLIENT FEEDBACK AB Objective: Measurement- based care involves the systematic administration of symptom rating scales and use of the results to drive clinical decision making at the level of the individual patient. This literature review examined the theoretical and empirical support for measurement- based care. Methods: Articles were identified through search strategies in PubMed and Google Scholar. Additional citations in the references of retrieved articles were identified, and experts assembled for a focus group conducted by the Kennedy Forum were consulted. Results: Fifty-one relevant articles were reviewed. There are numerous brief structured symptom rating scales that have strong psychometric properties. Virtually all randomized controlled trials with frequent and timely feedback of patientreported symptoms to the provider during the medication management and psychotherapy encounters significantly improved outcomes. Ineffective approaches included one-time screening, assessing symptoms infrequently, and feeding back outcomes to providers outside the context of the clinical encounter. In addition to the empirical evidence about efficacy, there is mounting evidence from large-scale pragmatic trials and clinical demonstration projects that measurement-based care is feasible to implement on a large scale and is highly acceptable to patients and providers. Conclusions: In addition to the primary gains ofmeasurementbased care for individual patients, there are also potential secondary and tertiary gains to be made when individual patient data are aggregated. Specifically, aggregated symptom rating scale data can be used for professional development at the provider level and for quality improvement at the clinic level and to inform payers about the value of mental health services delivered at the health care system level. C1 [Fortney, John C.; Unutzer, Jurgen] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Fortney, John C.] Puget Sound Vet Healthcare Syst, HSR&D Ctr Innovat Vet Ctr & Value Driven Care, Seattle, WA USA. [Wrenn, Glenda] Morehouse Sch Med, Dept Psychiat, Atlanta, GA 30310 USA. [Pyne, Jeffrey M.; Smith, G. Richard] Univ Arkansas Med Sci, Dept Psychiat, Little Rock, AR 72205 USA. [Pyne, Jeffrey M.] Cent Arkansas Vet Healthcare Syst, HSR&D Ctr Mental Healthcare & Outcomes Res, Little Rock, AR USA. [Schoenbaum, Michael] NIMH, Dept Epidemiol & Econ, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Fortney, JC (reprint author), Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. EM fortneyj@uw.edu FU Kennedy Forum FX This literature review was supported by funding from the Kennedy Forum. The authors are grateful for the helpful contributions of experts assembled by the Kennedy Forum at a focus group held March 2-3, 2015, in Washington, D.C. The opinions expressed in this article are those of the individual authors and do not necessarily represent the views of the Kennedy Forum or the focus group participants. The contents of this article do not represent the views of the U.S. Department of Veterans Affairs, the National Institute of Mental Health, or the United States government. NR 67 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD FEB 1 PY 2017 VL 68 IS 2 BP 179 EP 188 DI 10.1176/appi.ps.201500439 PG 10 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA EP0PZ UT WOS:000397090500014 PM 27582237 ER PT J AU Ward, MM Guthrie, LC AF Ward, Michael M. Guthrie, Lori C. TI Applicability of patient utilities as measures of overall quality of life in rheumatoid arthritis clinical trials SO RHEUMATOLOGY LA English DT Article DE rheumatoid arthritis; time trade-off; standard gamble; utilities ID TIME-TRADE-OFF; DISEASE-ACTIVITY MEASURES; HEALTH STATES; VALUING HEALTH; CORE SET; RESPONSIVENESS; VALIDITY; OUTCOMES; VALUES; INSTRUMENTS AB Objective. The aim was to determine whether the time trade-off (TTO) and standard gamble utilities can detect treatment-related improvement in overall quality of life in patients with active RA. Methods. We measured TTO and standard gamble utilities in 192 patients before and after escalation of anti-rheumatic treatment in a prospective longitudinal study. We also examined associations between changes in utilities and patient-reported improvement during the study, and with EULAR responses. Results. Mean TTO at baseline was 0.68 (median 0.82) and mean standard gamble 0.80 (median 0.93). Both utilities improved significantly with treatment. Standardized response means, a measure of responsiveness, were 0.37 for the TTO and 0.20 for the standard gamble, and comparable to those of two mental health measures and the CRP, but lower than other RA activity measures. Changes in utilities were not significantly associated with patient-reported improvement. The standard gamble, but not the TTO, had a graded association with EULAR responses. Conclusion. Utilities by the TTO and standard gamble were able to detect improvement in overall quality of life with anti-rheumatic treatment in patients with active RA, suggesting applicability in clinical trials. The standard gamble was associated with reference measures of improvement, although not as strongly as measures of RA activity, as expected with its generic orientation. C1 [Ward, Michael M.; Guthrie, Lori C.] Natl Inst Arthrits & Musculoskeletal & Skin Dis, Natl Inst Hlth, Intramural Res Program, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), Natl Inst Arthrits & Musculoskeletal & Skin Dis, Natl Inst Hlth, 10 CRC,4-1339,10 Ctr Dr,MSC 1468, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural Research Program; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institutes of Health [ZIA-AR041153]; United States Public Health Service [RO1-AR45177] FX This study was supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (ZIA-AR041153) and United States Public Health Service grant RO1-AR45177. NR 47 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 56 IS 2 BP 239 EP 246 DI 10.1093/rheumatology/kew294 PG 8 WC Rheumatology SC Rheumatology GA EP0BA UT WOS:000397050600012 PM 27789761 ER PT J AU Burwen, DR Wu, CY Cirillo, D Rossouw, JE Margolis, KL Limacher, M Wallace, R Allison, M Eaton, CB Safford, M Freiberg, M AF Burwen, Dale R. Wu, Chunyuan Cirillo, Dominic Rossouw, Jacques E. Margolis, Karen L. Limacher, Marian Wallace, Robert Allison, Matthew Eaton, Charles B. Safford, Monika Freiberg, Matthew TI Venous thromboembolism incidence, recurrence, and mortality based on Women's Health Initiative data and Medicare claims SO THROMBOSIS RESEARCH LA English DT Article DE Venous thromboembolism; Medicare claims; Deep venous thrombosis; Pulmonary embolism ID QUALITY-OF-LIFE; DEEP-VEIN THROMBOSIS; PULMONARY-EMBOLISM; UNITED-STATES; RISK-FACTORS; LINE CHARACTERISTICS; ADMINISTRATIVE DATA; TRAUMA PATIENTS; CARE-UNIT; CANCER AB Introduction: Our objective was to compare Medicare claims to physician review and adjudication of medical records for identifying venous thromboembolism (VTE), and to assess VTE incidence, recurrence, and mortality in a large national cohort of post-menopausal women followed up to 19 years. Materials and methods: We used detailed clinical data from the Women's Health Initiative (WHI) linked to Medicare claims. Agreement between data sources was evaluated among 16,003 women during 1993-2010. A claims based definition was selected to analyze VTE occurrence and impact among 71,267 women during 1993-2012. Results: Our VTE definition had 83% sensitivity. Positive predictive value was 69% when all records were included, and 94% after limiting Medicare records to those with a WHI hospitalization adjudicated. Annualized VTE incidence was 4.06/1000 person-years (PY), recurrence was 5.30/100 PY, and both rates varied by race/ethnicity. Post-VTE mortality within 1 year was 22.49% from all causes, including 1.01% from pulmonary embolism, 10.40% from cancer, and 11.08% from other causes. Cancer-related VTE compared to non-cancer VTE had significantly (p < 0.001) higher recurrence (9.86/100 PY vs. 4.43/100 PY) and mortality from all causes (45.89% vs. 12.28%), but not from pulmonary embolism (0.40% vs. 1.27%). Conclusions: Medicare claims compared reasonably well to physician adjudication. The combined data sources provided new insights about VTE burden and prognosis in older women. C1 [Burwen, Dale R.; Rossouw, Jacques E.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Wu, Chunyuan] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Cirillo, Dominic] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Margolis, Karen L.] HealthPartners Inst Educ & Res, Minneapolis, MN USA. [Limacher, Marian] Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL USA. [Wallace, Robert] Univ Iowa, Iowa City, IA USA. [Allison, Matthew] Univ Calif San Diego, San Diego, CA 92103 USA. [Eaton, Charles B.] Brown Univ, Dept Family Med & Epidemiol, Pawtucket, RI USA. [Eaton, Charles B.] Mem Hosp Rhode Isl, Pawtucket, RI USA. [Safford, Monika] Univ Alabama Birmingham, Birmingham, AL USA. [Freiberg, Matthew] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. RP Burwen, DR (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM dale.burwen@ahrq.hhs.gov OI Cirillo, Dominic/0000-0001-7017-221X FU National Heart, Lung, and Blood Institute, National Institutes of Health; U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C] FX The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, and HHSN268201100004C. The opinions expressed are those of the authors and do not necessarily reflect the views of the U.S. Department of Health and Human Services or the National Institutes of Health. NR 57 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 150 BP 78 EP 85 DI 10.1016/j.thromres.2016.11.015 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EO9YY UT WOS:000397045200015 PM 28063368 ER PT J AU Eder, AF Yau, YY West, K AF Eder, Anne F. Yau, Yu Ying West, Kamille TI The effect of iron balance on platelet counts in blood donors SO TRANSFUSION LA English DT Article ID DEFICIENCY ANEMIA; SERUM FERRITIN; THROMBOCYTOSIS; PARAMETERS; THERAPY; WOMEN AB BACKGROUND: Thrombocytosis (or, less commonly, thrombocytopenia) is associated with iron-deficiency anemia and resolves with iron therapy. Many volunteer blood donors have low iron stores, with or without anemia. Iron balance could affect platelet counts in blood donors. STUDY DESIGN AND METHODS: Whole blood donors deferred for finger-stick hemoglobin levels less than 12.5 g/dL were evaluated by complete blood count and serum iron panel before and after oral iron treatment. Group assignment for iron depletion was based on serum ferritin cutoffs of less than 20 mu g/L for women and less than 30 mg/L for men or was based on changes in serum ferritin levels after iron replacement. RESULTS: Among 1273 Hb-deferred whole blood donors, 55% (619 of 1128) of the women and 70% (102 of 145) of the men were iron depleted. Iron-depleted donors had higher platelet counts compared with donors who had normal ferritin levels (women: 286 vs. 268 x 10(3)/mu L; p < 0.0001; men: 246 vs. 222 x 10(3)/mu L; p - 0.0454). Only 4.4% of iron-depleted donors had thrombocytosis (> 400 x 10(3)/mu L) compared with 2.0% of donors who had normal ferritin levels (p = 0.017). Iron replacement decreased platelet counts in iron-depleted female donors (mean, -19,800/mu L; interquartile range, 8000 to -45,000/mu L), but not in donors who had normal or stable ferritin levels. The same trends were observed in male donors. CONCLUSION: Iron-depleted donors had higher platelet counts than donors who had adequate iron stores. Oral iron replacement decreased platelet counts on average by about 20,000/mu L in iron-depleted donors but had no effect on platelet counts in donors who had normal or stable ferritin levels. C1 [Eder, Anne F.; Yau, Yu Ying; West, Kamille] NIH, Dept Transfus Med, Blood Serv Sect, Ctr Clin, Bethesda, MD 20892 USA. RP West, K (reprint author), NIH, Dept Transfus Med, Ctr Clin, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. EM Kamille.West@nih.gov NR 22 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD FEB PY 2017 VL 57 IS 2 BP 304 EP 312 DI 10.1111/rf.13881 PG 9 WC Hematology SC Hematology GA EO9ZW UT WOS:000397047600013 PM 27900761 ER PT J AU Hao, SY Feng, J Park, DM Gao, ZX AF Hao, Shuyu Feng, Jie Park, Deric M. Gao, Zhixian TI Glioma in Patients with Autosomal-Dominant Polycystic Kidney Disease SO WORLD NEUROSURGERY LA English DT Article DE Autosomal-dominant polycystic kidney disease; Glioma; Treatment ID INTRACRANIAL ANEURYSMS AB BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is an inherited systemic condition with a predominant feature of cyst formation in both kidneys. An association with intracranial glioma has not been described previously in ADPKD. CASE DESCRIPTION: We report 2 cases of glioma in patients with ADPKD. One patient had a cystic lesion with contrast enhancement in the right temporal lobe as revealed by magnetic resonance imaging and an aneurysm in left sylvian fissure confirmed by computed tomography angiography. Subsequent histopathologic analysis of the resected enhancing lesion confirmed the diagnosis of glioblastoma (World Health Organization grade IV). The second patient was found to harbor a solid lesion in the right parietal lobe. This lesion also proved to be an astrocytoma (World Health Organization grade II). CONCLUSIONS: These 2 independent cases of glioma suggest an unusual clinical manifestation of ADPKD. The potential association between ADPKD and glioma pathogenesis should be further explored. C1 [Hao, Shuyu; Gao, Zhixian] Beijing Tiantan Hosp, Dept Neurosurg, Beijing, Peoples R China. [Feng, Jie] Capital Med Univ, Beijing Neurosurg Inst, Beijing, Peoples R China. [Hao, Shuyu; Gao, Zhixian] China Natl Clin Res Ctr Neurol Dis, Beijing, Peoples R China. [Hao, Shuyu; Park, Deric M.] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. RP Gao, ZX (reprint author), Beijing Tiantan Hosp, Dept Neurosurg, Beijing, Peoples R China.; Gao, ZX (reprint author), China Natl Clin Res Ctr Neurol Dis, Beijing, Peoples R China. EM zhixian_g@163.com FU Beijing Nova program [2012033] FX This work was supported by the Beijing Nova program (No. 2012033). NR 11 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 1878-8750 EI 1878-8769 J9 WORLD NEUROSURG JI World Neurosurg. PD FEB PY 2017 VL 98 AR UNSP 885.e1 DI 10.1016/j.wneu.2016.08.045 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EO9SL UT WOS:000397028300183 PM 27565461 ER PT J AU Takyar, V Kleiner, DE Koh, C AF Takyar, Varun Kleiner, David E. Koh, Christopher TI A Wolf in Sheep's Clothing in the Era of Non-Invasive Staging: Non-Hodgkin's Lymphoma Masquerading as Serologic HCV Cirrhosis SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Letter ID HEPATITIS-C VIRUS C1 [Takyar, Varun; Koh, Christopher] NIDDK, Liver Dis Branch, NIH, 10 Ctr Dr,CRC Bldg 10,RM 4-5722, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Takyar, V (reprint author), NIDDK, Liver Dis Branch, NIH, 10 Ctr Dr,CRC Bldg 10,RM 4-5722, Bethesda, MD 20892 USA. EM varun.takyar@nih.gov FU intramural Liver Diseases Branch of NIDDK [NCT00001971] FX The intramural Liver Diseases Branch of NIDDK (NCT00001971). NR 4 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD FEB PY 2017 VL 112 IS 2 BP 398 EP 399 DI 10.1038/ajg.2016.550 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK7VP UT WOS:000394133600044 PM 28154396 ER PT J AU Deng, SW Ansari, S Ilkit, M Rafati, H Hedayati, MT Taghizadeh-Armaki, M Nasrollahi-Omran, A Tolooe, A Zhan, P Liao, WQ van der Lee, HA Verweij, PE Seyedmousavi, S AF Deng, Shuwen Ansari, Saham Ilkit, Macit Rafati, Haleh Hedayati, Mohammad T. Taghizadeh-Armaki, Mojtaba Nasrollahi-Omran, Ayatollah Tolooe, Ali Zhan, Ping Liao, Wanqing van der Lee, Henrich A. Verweij, Paul E. Seyedmousavi, Seyedmojtaba TI In Vitro Antifungal Susceptibility Profiles of 12 Antifungal Drugs against 55 Trichophyton schoenleinii Isolates from Tinea Capitis Favosa Patients in Iran, Turkey, and China SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article DE Trichophyton schoenleinii; tinea capitis favosa; antifungal susceptibility testing ID DERMATOPHYTE STRAINS; AGENTS; GRISEOFULVIN; FLUCONAZOLE; CHILDREN; TEHRAN; UPDATE AB Trichophyton schoenleinii is an anthropophilic dermatophyte mainly causing tinea favosa of the scalp in certain regions of the world, especially Africa and Asia. We investigated the in vitro susceptibilities of 55 T. schoenleinii isolates collected over the last 30 years from Iran, Turkey, and China to 12 antifungals using the CLSI broth microdilution method. Our results revealed that terbinafine and ketoconazole were the most potent antifungal agents among those tested, independently of the geographic regions where strains were isolated. C1 [Deng, Shuwen; Liao, Wanqing] Second Mil Med Univ, Changzheng Hosp, Shanghai Key Lab Mol Med Mycol, Shanghai, Peoples R China. [Deng, Shuwen; Liao, Wanqing] Xinjiang Med Univ, Hosp 1, Xinjiang, Peoples R China. [Ansari, Saham] Shahid Beheshti Univ Med Sci, Sch Med, Dept Med Mycol & Parasitol, Tehran, Iran. [Ilkit, Macit] Cukurova Univ, Fac Med, Dept Microbiol, Div Mycol, Adana, Turkey. [Rafati, Haleh] Erasmus Univ, Med Ctr, Dept Biochem, Rotterdam, Netherlands. [Hedayati, Mohammad T.; Taghizadeh-Armaki, Mojtaba; Seyedmousavi, Seyedmojtaba] Mazandaran Univ Med Sci, Invas Fungi Res Ctr, Sari, Iran. [Hedayati, Mohammad T.; Taghizadeh-Armaki, Mojtaba] Mazandaran Univ Med Sci, Sch Med, Dept Med Mycol & Parasitol, Sari, Iran. [Nasrollahi-Omran, Ayatollah] Islamic Azad Univ, Fac Med, Dept Med Mycol, Tonekabon Branch, Tonekabon, Iran. [Tolooe, Ali] Univ Tehran, Fac Vet Med, Tehran, Iran. [Zhan, Ping] Dermatol Hosp Jiangxi Prov, Jiangxi Prov Inst Dermatol, Nanchang, Jiangxi, Peoples R China. [van der Lee, Henrich A.; Verweij, Paul E.; Seyedmousavi, Seyedmojtaba] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands. [Seyedmousavi, Seyedmojtaba] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Seyedmousavi, S (reprint author), Mazandaran Univ Med Sci, Invas Fungi Res Ctr, Sari, Iran.; Seyedmousavi, S (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands.; Seyedmousavi, S (reprint author), NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Seyedmousavi@nih.gov OI Hedayati, Mohammad T./0000-0001-6415-4648 FU Astellas Pharma B.V.; Gilead Sciences; Astellas; Merck Sharp Dohme (MSD); F2G; Bio-Rad FX S.S. has received a research grant from Astellas Pharma B.V. P.E.V. has received research grants from Gilead Sciences, Astellas, Merck Sharp & Dohme (MSD), F2G, and Bio-Rad, is a speaker for Gilead Sciences and MSD, and is on the advisory boards for Pfizer, MSD, and F2G. NR 32 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2017 VL 61 IS 2 AR e01753-16 DI 10.1128/AAC.01753-16 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA EK7JQ UT WOS:000394102500031 ER PT J AU Seibel, NL Shad, AT Bekersky, I Groll, AH Gonzalez, C Wood, LV Jarosinski, P Buell, D Hope, WW Walsh, TJ AF Seibel, Nita L. Shad, Aziza T. Bekersky, Ihor Groll, Andreas H. Gonzalez, Corina Wood, Lauren V. Jarosinski, Paul Buell, Donald Hope, William W. Walsh, Thomas J. TI Safety, Tolerability, and Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Pediatric Patients SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article DE antimicrobial safety and tolerability; hematological malignancies; liposomal amphotericin B; pediatrics; pharmacokinetics ID STEM-CELL TRANSPLANTATION; INVASIVE FUNGAL-INFECTIONS; POPULATION PHARMACOKINETICS; ANTIFUNGAL PROPHYLAXIS; NEUTROPENIC PATIENTS; PERSISTENT FEVER; LIPID COMPLEX; CHILDREN; AMBISOME; ASPERGILLOSIS AB The safety, tolerability, and pharmacokinetics of the liposomal formulation of amphotericin B (L-AMB) were evaluated in 40 immunocompromised children and adolescents. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study with 10 to 13 patients in each of the four dosage cohorts. Each cohort received daily dosages of 2.5, 5.0, 7.5, or 10 mg of amphotericin B in the form of L-AMB per kg of body weight. Neutropenic patients between the ages of 1 and 17 years were enrolled to receive empirical antifungal therapy or treatment of documented invasive fungal infections. The pharmacokinetic parameters of L-AMB were measured as those of amphotericin B by high-performance liquid chromatography and calculated by noncompartmental methods. There were nine adverse-event-related discontinuations, four of which were related to infusions. Infusion-related side effects occurred for 63 (11%) of 565 infusions, with 5 patients experiencing acute infusion-related reactions (7.5- and 10-mg/kg dosage levels). Serum creatinine levels increased from 0.45 +/- 0.04 mg/dl to 0.63 +/- 0.06 mg/dl in the overall population (P +/- 0.003), with significant increases in dosage cohorts receiving 5.0 and 10 mg/kg/day. At the higher dosage level of 10 mg/kg, there was a trend toward greater hypokalemia and vomiting. The area under the concentration-time curve from 0 to 24 h (AUC(0-24)) values for L-AMB on day 1 increased from 54.7 +/- 32.9 to 430 +/- 566 mu g . h/ml in patients receiving 2.5 and 10.0 mg/kg/day, respectively. These findings demonstrate that L-AMB can be administered to pediatric patients at dosages similar to those for adults and that azotemia may develop, especially in those receiving >= 5.0 mg/kg/day. C1 [Seibel, Nita L.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Seibel, Nita L.] George Washington Univ, Sch Med & Publ Hlth, Washington, DC USA. [Seibel, Nita L.] NCI, Clin Invest Branch, Canc Treatment Evaluat Program, Bethesda, MD 20892 USA. [Shad, Aziza T.; Gonzalez, Corina] MedStar Georgetown Univ Hosp, Dept Pediat, Div Pediat Hematol Oncol, Washington, DC USA. [Bekersky, Ihor; Buell, Donald] Astellas Pharma USA Inc, Deerfield, IL USA. [Groll, Andreas H.; Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Groll, Andreas H.] Univ Childrens Hosp, Dept Pediat Hematol & Oncol, Munster, Germany. [Wood, Lauren V.] NCI, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Jarosinski, Paul] NIH, Dept Pharm, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Hope, William W.] Univ Liverpool, Dept Mol & Clin Pharmacol, Antimicrobial Pharmacodynam & Therapeut, Liverpool, Merseyside, England. [Walsh, Thomas J.] Weill Cornell Med, Transplantat Oncol Infect Dis Program, New York, NY 10065 USA. [Walsh, Thomas J.] Weill Cornell Med, Dept Pediat, New York, NY 10065 USA. [Walsh, Thomas J.] Weill Cornell Med, Dept Microbiol & Immunol, New York, NY 10065 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA.; Walsh, TJ (reprint author), Weill Cornell Med, Transplantat Oncol Infect Dis Program, New York, NY 10065 USA.; Walsh, TJ (reprint author), Weill Cornell Med, Dept Pediat, New York, NY 10065 USA.; Walsh, TJ (reprint author), Weill Cornell Med, Dept Microbiol & Immunol, New York, NY 10065 USA. EM thw2003@med.cornell.edu OI Hope, William/0000-0001-6187-878X FU Astellas Pharma USA; National Institutes of Health; Astellas; Novartis; Merck/Cubist; Pfizer; Theravance; Merck; Pfizer, Inc.; Gilead Sciences; F2G FX This work was supported in part by grants from Astellas Pharma USA. This work also was supported in part by the intramural research program of the National Institutes of Health. The opinions expressed in this paper are the authors' and do not reflect those of the National Institutes of Health (NIH) Clinical Center, the NIH, the Department of Health and Human Services, or the Federal Government. T.J.W. is a scholar of the Henry Schueler Foundation, an Investigator of the Save Our Sick Kids Foundation, and a scholar of pediatric infectious diseases of the Sharp Family Foundation.; T.J.W. has received research grants for experimental and clinical antimicrobial pharmacotherapeutics from Astellas, Novartis, Merck/Cubist, Pfizer, and Theravance, and he has served as a consultant to Astellas, Merck/Cubist, Contrafect, Novartis, Pfizer, and Methylgene. W.W.H. has acted as a consultant and received research support from Merck, Pfizer, Inc., Astellas, Gilead Sciences, and F2G. NR 46 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2017 VL 61 IS 2 AR e01477-16 DI 10.1128/AAC.01477-16 PG 11 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA EK7JQ UT WOS:000394102500014 ER PT J AU Demirci, S Dogan, A Turkmen, NB Telci, D Rizvanov, AA Sahin, F AF Demirci, Selami Dogan, Aysegul Turkmen, Nese Basak Telci, Dilek Rizvanov, Albert A. Sahin, Fikrettin TI Schiff base-Poloxamer P85 combination demonstrates chemotherapeutic effect on prostate cancer cells in vitro SO BIOMEDICINE & PHARMACOTHERAPY LA English DT Article DE Schiff base; P85; Poloxamer; Prostate cancer; Chemotherapy ID PLURONIC BLOCK-COPOLYMERS; STATISTICS; DOCETAXEL; ANGIOGENESIS; DOXORUBICIN; INHIBITION; COMPLEXES; VIVO AB Prostate cancer is a multistep and complicated cancer type that is regulated by androgens at the cellular level and remains the second commonest cause of death among men. Discovery and development of novel chemotherapeutic agents enabling rapid tumor cell death with minimal toxic effects to healthy tissues might greatly improve the safety of chemotherapy. The present study evaluates the anti-cancer activity of a novel heterodinuclear copper(II) Mn(II) complex (Schiff base) in combination with poly(ethylene oxide) and poly(propylene oxide) block copolymer (Pluronic) P85. We used assays for cell proliferation, apoptosis, cell migration and invasion, DNA binding and cleavage to elucidate the molecular mechanisms of action, in addition to the antiinflammatory potency of the new combination. The combined treatment of Schiff base and P85 lead to a remarkable anti-cancer effect on prostate cancer cell lines. Cell proliferation was inhibited in Schiff base-P85 treatment. The activity of this formulation is on DNA binding and cleavage and prevents inflammation in in vitro conditions. This is the first study presenting the anti-cancer activity of the present Schiff base derivative and its combination with P85 to treat prostate cancer in vitro. (C) 2016 Elsevier Masson SAS. All rights reserved. C1 [Demirci, Selami; Dogan, Aysegul; Telci, Dilek; Sahin, Fikrettin] Yeditepe Univ, Fac Engn & Architecture, Dept Genet & Bioengn, Istanbul, Turkey. [Demirci, Selami] NHLBI, NIH, Bethesda, MD 20892 USA. [Dogan, Aysegul] NCI, CDBL, NIH, Frederick, MD 21701 USA. [Turkmen, Nese Basak] Univ Inonu, Dept Pharmaceut Toxicol, Malatya, Turkey. [Rizvanov, Albert A.] Kazan Fed Univ, Kazan, Russia. RP Dogan, A (reprint author), Yeditepe Univ, Fac Engn & Architecture, Dept Genet & Bioengn, Istanbul, Turkey. EM aguldgn@gmail.com RI Rizvanov, Albert/H-4486-2013 OI Rizvanov, Albert/0000-0002-9427-5739 FU Department of Genetics and Bioengineering, Yeditepe University, Turkey FX The work was supported by the Department of Genetics and Bioengineering, Yeditepe University, Turkey. NR 37 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0753-3322 EI 1950-6007 J9 BIOMED PHARMACOTHER JI Biomed. Pharmacother. PD FEB PY 2017 VL 86 BP 492 EP 501 DI 10.1016/j.biopha.2016.11.101 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA EM7WU UT WOS:000395523800061 PM 28012929 ER PT J AU McCaskill-Stevens, W Pearson, DC Kramer, BS Ford, LG Lippman, SM AF McCaskill-Stevens, Worta Pearson, Deborah C. Kramer, Barnett S. Ford, Leslie G. Lippman, Scott M. TI Identifying and Creating the Next Generation of Community-Based Cancer Prevention Studies: Summary of a National Cancer Institute Think Tank SO CANCER PREVENTION RESEARCH LA English DT Review ID EPITHELIAL GENE-EXPRESSION; COLORECTAL-CANCER; LUNG-CANCER; IMMUNOSURVEILLANCE; DEHYDROGENASE; NICOTINAMIDE; IMMUNITY; DISEASE; MOUSE; TRIAL AB In late 2015, the NCI Division of Cancer Prevention convened cancer prevention research experts and stakeholders to discuss the current state of cancer prevention research, identify key prevention research priorities for the NCI, and identify studies that could be conducted within the NCI Community Oncology Research Program. Goals included identifying cancer prevention research opportunities offering the highest return on investment, exploring the concept of precision prevention and what is needed to advance this area of research, and identifying possible targets for prevention. Four study populations were considered for cancer prevention research: healthy people, those at increased risk for a specific cancer, people with preneoplastic lesions, and children, adolescents, and young adults. Priorities that emerged include screening (e. g., surveillance intervals, tomosynthesis vs. digitalmammography), a pre-cancer genome atlas (PreTCGA), HPV vaccines, immunoprevention of noninfectious origins, and overdiagnosis. Challenges exist, as the priority list is ambitious and potentially expensive. Clinical trials need to be carefully designed to include and maximize prospective tissue collection. Exploring existing cofunding mechanisms will likely be necessary. Finally, relationships with a new generation of physician specialists will need to be cultivated to reach the target populations. C1 [McCaskill-Stevens, Worta; Pearson, Deborah C.; Kramer, Barnett S.; Ford, Leslie G.] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. [Lippman, Scott M.] UC San Diego Hlth, Moores Canc Ctr, La Jolla, CA USA. RP McCaskill-Stevens, W (reprint author), NCI, 9609 Med Ctr Dr,Room 5E446, Bethesda, MD 20892 USA. EM wm57h@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 31 TC 1 Z9 1 U1 0 U2 0 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 FEB PY 2017 VL 10 IS 2 BP 99 EP 107 PG 9 WC Oncology SC Oncology GA EM8KR UT WOS:000395560600001 PM 27965286 ER PT J AU Seabloom, DE Galbraith, AR Haynes, AM Antonides, JD Wuertz, BR Miller, WA Miller, KA Steele, VE Miller, MS Clapper, ML O'Sullivan, MG Ondrey, FG AF Seabloom, Donna E. Galbraith, Arthur R. Haynes, Anna M. Antonides, Jennifer D. Wuertz, Beverly R. Miller, Wendy A. Miller, Kimberly A. Steele, Vernon E. Miller, Mark Steven Clapper, Margie L. O'Sullivan, M. Gerard Ondrey, Frank G. TI Fixed-Dose Combinations of Pioglitazone and Metformin for Lung Cancer Prevention SO CANCER PREVENTION RESEARCH LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; FACTOR-KAPPA-B; MALE F344 RATS; DIABETIC-PATIENTS; BRONCHIAL EPITHELIUM; CALORIE RESTRICTION; ENDOTHELIAL-CELLS; GROWTH-INHIBITION; CARCINOMA CELLS; TUMOR-INCIDENCE AB Combination treatment with pioglitazone and metformin is utilized clinically in the treatment of type II diabetes. Treatment with this drug combination reduced the development of aerodigestive cancers in this patient population. Our goal is to expand this treatment into clinical lung cancer chemoprevention. We hypothesized that dietary delivery of metformin/pioglitazone would prevent lung adenoma formation in A/J mice in a benzo[a] pyrene (B[a] P)-induced carcinogenesis model while modulating chemoprevention and anti-inflammatory biomarkers in residual adenomas. We found that metformin (500 and 850 mg/kg/d) and pioglitazone (15 mg/kg/d) produced statistically significant decreases in lung adenoma formation both as singleagent treatments and in combination, compared with untreated controls, after 15 weeks. Treatment with metformin alone and in combination with pioglitazone resulted in statistically significant decreases in lung adenoma formation at both early-and late-stage interventions. Pioglitazone alone resulted in significant decreases in adenoma formation only at early treatment intervention. We conclude that oral metformin is a viable chemopreventive treatment at doses ranging from 500 to 1,000 mg/kg/d. Pioglitazone at 15 mg/kg/d is a viable chemopreventive agent at earlystage interventions. Combination metformin and pioglitazone performed equal to metformin alone and better than pioglitazone at 15 mg/kg/d. Because the drugs are already FDAapproved, rapid movement to human clinical studies is possible. C1 [Seabloom, Donna E.; Galbraith, Arthur R.; Haynes, Anna M.; Antonides, Jennifer D.; Wuertz, Beverly R.; Ondrey, Frank G.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Seabloom, Donna E.; Haynes, Anna M.; Wuertz, Beverly R.; Ondrey, Frank G.] Univ Minnesota, Coll Pharm, AeroCore Inhalat Testing, Minneapolis, MN 55455 USA. [Wuertz, Beverly R.; Miller, Wendy A.; Miller, Kimberly A.; Ondrey, Frank G.] Univ Minnesota, Dept Otolaryngol, Minneapolis, MN USA. [Steele, Vernon E.; Miller, Mark Steven] NCI, Div Canc Prevent, Rockville, MD USA. [Clapper, Margie L.] Fox Chase Canc Ctr, Philadelphia, PA USA. [O'Sullivan, M. Gerard] Univ Minnesota, Masonic Canc Ctr, Comparat Pathol, Minneapolis, MN USA. RP Ondrey, FG (reprint author), Univ Minneapolis, MMC396,420 Delaware St SE, Minneapolis, MN 55455 USA. EM ondre002@umn.edu FU NCI [N01CN25002-78, HHSN-261201200015I]; Lions Multiple District 5M Hearing Foundation of Minnesota (Translational Biomarker Initiatives for Medical Students) FX This work was supported by the NCI (Subcontract for Preclinical ContractN01CN25002-78, Primary Contract Number: Contract #HHSN-261201200015I, F.G. Ondrey) and the Lions Multiple District 5M Hearing Foundation of Minnesota, (Translational Biomarker Initiatives for Medical Students, F.G. Ondrey). NR 50 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 10 IS 2 BP 116 EP 123 PG 8 WC Oncology SC Oncology GA EM8KR UT WOS:000395560600003 PM 28052934 ER PT J AU Seabloom, DE Galbraith, AR Haynes, AM Antonides, JD Wuertz, BR Miller, WA Miller, KA Steele, VE Suen, CS O'Sullivan, MG Ondrey, FG AF Seabloom, Donna E. Galbraith, Arthur R. Haynes, Anna M. Antonides, Jennifer D. Wuertz, Beverly R. Miller, Wendy A. Miller, Kimberly A. Steele, Vernon E. Suen, Chen S. O'Sullivan, M. Gerard Ondrey, Frank G. TI Safety and Preclinical Efficacy of Aerosol Pioglitazone on Lung Adenoma Prevention in A/J Mice SO CANCER PREVENTION RESEARCH LA English DT Article ID ACID RECEPTOR-BETA; PROLIFERATOR-ACTIVATED RECEPTORS; SQUAMOUS-CELL CARCINOMA; RETINOIC ACID; VITAMIN-A; PULMONARY CARCINOGENESIS; CHEMOPREVENTIVE AGENT; BRONCHIAL EPITHELIUM; 13-CIS-RETINOIC ACID; INHALATION DELIVERY AB Pioglitazone is a PPARg agonist commonly prescribed for the clinical treatment of diabetes. We sought to expand its use to lung cancer prevention in a benzo[a] pyrene (B[a] P) mouse model with direct lung delivery via inhalation. Initially, we conducted inhalational toxicity experiments with 0, 15, 50, 150, and 450 mg/kg body weight/day pioglitazone in 40 A/J mice. We examined the animals for any physical toxicity and bronchoalveolar lavage fluids for inflammatory and cytotoxicitymarkers. Doses up to and including 450 mg/kg bw/d failed to demonstrate toxicity with aerosol pioglitazone. For chemoprevention experiments, A/J mice were randomized to treatment groups of inhaled doses of 0, 50, 150, or 450 mg/kg bw/d pioglitazone 1 or 8 weeks after the last dose of B[a] P. For the early treatment group, we found up to 32% decrease in lung adenoma formation with 450 mg/kg bw/d pioglitazone. We repeated the treatments in a second late-stage experiment and found up to 44% decreases in lung adenoma formation in doses of pioglitazone of 150 and 450 mg/kg bw/day. Both the early-and the late-stage experiments demonstrated biologically relevant and statistically significant decreases in adenoma formation. We conclude that aerosol pioglitazone is well-tolerated in the A/J mouse model and a promising chemoprevention agent for the lower respiratory tract. C1 [Seabloom, Donna E.; Haynes, Anna M.; Wuertz, Beverly R.; Ondrey, Frank G.] Univ Minnesota, Coll Pharm, AeroCore Inhalat Testing, Minneapolis, MN 55455 USA. [Galbraith, Arthur R.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Wuertz, Beverly R.; Miller, Wendy A.; Miller, Kimberly A.; Ondrey, Frank G.] Univ Minnesota, Dept Otolaryngol, MMC396,420 Delaware St SE, Minneapolis, MN 55455 USA. [Steele, Vernon E.; Suen, Chen S.] NCI, Div Canc Prevent, Rockville, MD USA. [O'Sullivan, M. Gerard] Univ Minnesota, Masonic Canc Ctr, Comparat Pathol, Minneapolis, MN USA. RP Ondrey, FG (reprint author), Univ Minnesota, Dept Otolaryngol, MMC396,420 Delaware St SE, Minneapolis, MN 55455 USA. EM ondre002@umn.edu FU NCI [N01CN43309, HHSN261200433009C]; Lions Multiple District 5M Hearing Foundation of Minnesota (Translational Biomarker Initiatives for Medical Students) FX This work was supported by the NCI (Subcontract for Preclinical Contract N01CN43309, Primary Contract Number: HHSN261200433009C, F.G. Ondrey) and the Lions Multiple District 5M Hearing Foundation of Minnesota (Translational Biomarker Initiatives for Medical Students, F.G. Ondrey). NR 50 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 10 IS 2 BP 124 EP 132 PG 9 WC Oncology SC Oncology GA EM8KR UT WOS:000395560600004 PM 27993834 ER PT J AU Gilbert, K Luking, K Pagliaccio, D Luby, J Barch, D AF Gilbert, Kirsten Luking, Katherine Pagliaccio, David Luby, Joan Barch, Deanna TI Dampening, Positive Rumination, and Positive Life Events: Associations with Depressive Symptoms in Children at Risk for Depression SO COGNITIVE THERAPY AND RESEARCH LA English DT Article DE Positive affect regulation; Dampening; Positive rumination; Risk for depression; Children ID MAJOR DEPRESSION; EMOTION REGULATION; RESPONSE STYLES; DISORDERS; MOOD; PSYCHOPATHOLOGY; STRESS; AGE AB Blunted positive affect is characteristic of depression. Altered positive affect regulation may contribute to this blunting, and two regulation strategies, dampening positive affect and positive rumination, have been implicated in depression. However, the conditions under which these strategies impart risk/protective effects prior to onset of depression are unknown. The current study examined 81 healthy children (age 7-10) at low and high risk for depression on the basis of maternal history of depression and tested how dampening and positive rumination interacted with the experience of recent positive life events to predict depressive symptoms. Children at high and low risk did not differ in their use of dampening or positive rumination. However, elevated use of dampening in the context of many positive life events predicted current depressive symptoms, and specifically anhedonic symptoms, in children at low-risk for depression. These findings held when controlling for negative rumination and negative life events. Positive rumination did not interact with positive life events but was associated with higher depressive symptoms in high-risk children. Results indicate that prior to the onset of depression, positive life events may impart risk when dampening positive affect is utilized in this context, while positive rumination may increase risk for depressive symptoms. C1 [Gilbert, Kirsten; Luby, Joan; Barch, Deanna] Washington Univ, Dept Psychiat, 4444 Forest Pk Ave, St Louis, MO 63110 USA. [Luking, Katherine] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Pagliaccio, David] NIMH, Emot & Dev Branch, Bethesda, MD 20892 USA. [Barch, Deanna] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Barch, Deanna] Washington Univ, Dept Radiol, St Louis, MO USA. RP Gilbert, K (reprint author), Washington Univ, Dept Psychiat, 4444 Forest Pk Ave, St Louis, MO 63110 USA. EM gilbertk@wustl.psychiatry.edu FU Sidney R. Baer Jr. Foundation; Brain and Behavior Research Foundation; National Institute of Mental Health [MH097335, MH100019-03] FX This study was funded by the Sidney R. Baer Jr. Foundation; Brain and Behavior Research Foundation and the National Institute of Mental Health (MH097335, MH100019-03). NR 45 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-5916 EI 1573-2819 J9 COGNITIVE THER RES JI Cogn. Ther. Res. PD FEB PY 2017 VL 41 IS 1 BP 31 EP 42 DI 10.1007/s10608-016-9798-5 PG 12 WC Psychology, Clinical SC Psychology GA EK9UG UT WOS:000394268800003 ER PT J AU Cefalu, WT Buse, JB Tuomilehto, J Fleming, GA Ferrannini, E Gerstein, HC Bennett, PH Ramachandran, A Raz, I Rosenstock, J Kahn, SE AF Cefalu, William T. Buse, John B. Tuomilehto, Jaakko Fleming, G. Alexander Ferrannini, Ele Gerstein, Hertzel C. Bennett, Peter H. Ramachandran, Ambady Raz, Itamar Rosenstock, Julio Kahn, Steven E. TI Update and Next Steps for Real-World Translation of Interventions for Type 2 Diabetes Prevention: Reflections From a Diabetes Care Editors' Expert Forum. Diabetes Care 2016; 39: 1186-1201 SO DIABETES CARE LA English DT Editorial Material C1 [Cefalu, William T.] Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Buse, John B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland. [Tuomilehto, Jaakko] Dasman Diabet Inst, Dasman, Kuwait. [Tuomilehto, Jaakko] King Abdulaziz Univ, Saudi Diabet Res Grp, Jeddah, Saudi Arabia. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Fleming, G. Alexander] Kinexum, Harpers Ferry, WV USA. [Ferrannini, Ele] CNR, Inst Clin Physiol, Pisa, Italy. [Gerstein, Hertzel C.] McMaster Univ, Hamilton, ON, Canada. [Gerstein, Hertzel C.] Hamilton Hlth Sci, Hamilton, ON, Canada. [Bennett, Peter H.] NIH, Phoenix, AZ USA. [Ramachandran, Ambady] India Diabet Res Fdn, Madras, Tamil Nadu, India. [Ramachandran, Ambady] Dr A Ramachandrans Diabet Hosp, Madras, Tamil Nadu, India. [Raz, Itamar] Hadassah Hebrew Univ Hosp, Dept Internal Med, Diabet Unit, Jerusalem, Israel. [Rosenstock, Julio] Med City, Dallas Diabet Res Ctr, Dallas, TX 75390 USA. [Rosenstock, Julio] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. RP Cefalu, WT (reprint author), Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. EM william.cefalu@pbrc.edu FU National Institutes of Health (NIH) [1U54-GM-104940, P50-AT-002776] FX W.T.C. is supported in part by National Institutes of Health (NIH) grant 1U54-GM-104940, which funds the Louisiana Clinical and Translational Science Center, and NIH grant P50-AT-002776. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2017 VL 40 IS 2 BP E23 EP E24 DI 10.2337/dci16-0036 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EL2ZL UT WOS:000394489300009 PM 28108540 ER PT J AU Lewis, MR Macauley, RC Sheehan, PR Staten, MA Phillips, LS Rasouli, N Pittas, AG AF Lewis, Michael R. Macauley, Robert C. Sheehan, Patricia R. Staten, Myrlene A. Phillips, Lawrence S. Rasouli, Neda Pittas, Anastassios G. CA D2d Res Grp TI Management of Hemoglobin Variants Detected Incidentally in HbA(1c) Testing: A Common Problem Currently Lacking a Standard Approach SO DIABETES CARE LA English DT Editorial Material ID SICKLE-CELL TRAIT C1 [Lewis, Michael R.] Univ Vermont, Dept Pathol & Lab Med, Burlington, VT 05405 USA. [Macauley, Robert C.] Univ Vermont, Dept Pediat, Burlington, VT USA. [Sheehan, Patricia R.; Pittas, Anastassios G.] Tufts Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA USA. [Staten, Myrlene A.] NIDDK, Kelly Govt Solut, Bethesda, MD 20892 USA. [Phillips, Lawrence S.] Atlanta VA Med Ctr, Decatur, GA USA. [Phillips, Lawrence S.] Emory Univ, Sch Med, Dept Med, Div Endocrinol Metab & Lipids, Atlanta, GA USA. [Rasouli, Neda] Univ Colorado, Sch Med, Dept Med, Div Endocrinol Metab & Diabet, Aurora, CO USA. RP Lewis, MR (reprint author), Univ Vermont, Dept Pathol & Lab Med, Burlington, VT 05405 USA. EM michael.lewis@uvmhealth.org FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Office of the Director; National Institutes of Health Office of Dietary Supplements [U01-DK-098245]; American Diabetes Association [1-14-D2d-01] FX The D2d Study is supported by a U01 multicenter clinical study cooperative agreement research grant from National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Office of the Director, and the National Institutes of Health Office of Dietary Supplements (U01-DK-098245). Funding is also provided by the American Diabetes Association (1-14-D2d-01). NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2017 VL 40 IS 2 BP E8 EP E9 DI 10.2337/dc16-1667 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EL2ZL UT WOS:000394489300002 PM 27899488 ER PT J AU Lochmuller, H Le Cam, Y Jonker, AH Lau, LPL Baynam, G Kaufmann, P Lasko, P Dawkins, HJS Austin, CP Boycott, KM AF Lochmuller, Hanns Le Cam, Yann Jonker, Anneliene H. Lau, Lilian P. L. Baynam, Gareth Kaufmann, Petra Lasko, Paul Dawkins, Hugh J. S. Austin, Christopher P. Boycott, Kym M. CA IRDiRC Sci Comm TI 'IRDiRC Recognized Resources': a new mechanism to support scientists to conduct efficient, high-quality research for rare diseases SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MATCHMAKING AB The International Rare Diseases Research Consortium (IRDiRC) has created a quality label, 'IRDiRC Recognized Resources', formerly known as 'IRDiRC Recommended'. It is a peer-reviewed quality indicator process established based on the IRDiRC Policies and Guidelines to designate resources (ie, standards, guidelines, tools, and platforms) designed to accelerate the pace of discoveries and translation into clinical applications for the rare disease (RD) research community. In its first year of implementation, 13 resources successfully applied for this designation, each focused on key areas essential to IRDiRC objectives and to the field of RD research more broadly. These included data sharing for discovery, knowledge organisation and ontologies, networking patient registries, and therapeutic development. 'IRDiRC Recognized Resources' is a mechanism aimed to provide community-approved contributions to RD research higher visibility, and encourage researchers to adopt recognised standards, guidelines, tools, and platforms that facilitate research advances guided by the principles of interoperability and sharing. C1 [Lochmuller, Hanns] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne, Tyne & Wear, England. [Le Cam, Yann] European Org Rare Dis EURORDIS, Paris, France. [Jonker, Anneliene H.; Lau, Lilian P. L.] IRDiRC Sci Secretariat, Inserm US 14, Paris, France. [Baynam, Gareth] King Edward Mem Hosp, Genet Serv Western Australia, Perth, WA, Australia. [Baynam, Gareth] Western Australian Register Dev Anomalies, Perth, WA, Australia. [Kaufmann, Petra; Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Lasko, Paul] McGill Univ, Dept Biol, Montreal, PQ, Canada. [Dawkins, Hugh J. S.] Govt Western Australia, Publ Hlth Div, Off Populat Hlth Genom, Dept Hlth, Perth, WA, Australia. [Boycott, Kym M.] Univ Ottawa, Childrens Hosp Eastern Ontario, Res Inst, Dept Genet, Ottawa, ON, Canada. RP Boycott, KM (reprint author), Childrens Hosp Eastern Ontario, Res Inst, Dept Genet, 401 Smyth Rd, Ottawa, ON K1H 8L1, Canada. EM kboycott@cheo.on.ca FU European FP7 contract, 'SUPPORT-IRDiRC' [305207] FX The 'IRDiRC Recognized Resources' initiative has been supported by members of the IRDiRC Scientific Committees. Members include Fowzan Sami Alkuraya, Diego Ardigo, Michael Bamshad, Gert-Jan Boudewijn van Ommen, Anthony Brookes, Han Brunner, Angel Carracedo, Seng Cheng, Gema Chicano, Robin Conwit, Johan den Dunnen, Xavier Estivill, Jack Goldblatt, Stephen Groft, Shuling Guo, Adam Heathfield, Bartha Maria Knoppers, Jeffrey Krischer, Milan Macek, Sandrine Marreaud, Gert Matthijs, Woong-Yang Park, Samantha Parker, Asla Pitkanen, Catherine Rademaker, Pak-Chung Sham, Rumen Stefanov, Hendrik Stunnenberg, Domenica Taruscio, Josep Torrent i Farnell, Anne Zajicek, and Feng Zhang. We also acknowledge Segolene, Ayme, former Coordinator of the IRDiRC Scientific Secretariat, for her assistance in launching this initiative. The work was supported by the European FP7 contract, 'SUPPORT-IRDiRC' (No. 305207). CPA has contributed to this work in his capacity as Chair of the IRDiRC Consortium Assembly, not in his role as Director of the National Center for Advancing Translational Sciences. NR 17 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD FEB PY 2017 VL 25 IS 2 BP 162 EP 165 DI 10.1038/ejhg.2016.137 PG 4 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EK7RM UT WOS:000394122900004 PM 27782107 ER PT J AU Watkins-Chow, DE Varshney, GK Garrett, LJ Chen, ZL Jimenez, EA Rivas, C Bishop, KS Sood, R Harper, UL Pavan, WJ Burgess, SM AF Watkins-Chow, Dawn E. Varshney, Gaurav K. Garrett, Lisa J. Chen, Zelin Jimenez, Erin A. Rivas, Cecilia Bishop, Kevin S. Sood, Raman Harper, Ursula L. Pavan, William J. Burgess, Shawn M. TI Highly Efficient Cpf1-Mediated Gene Targeting in Mice Following High Concentration Pronuclear Injection SO G3-GENES GENOMES GENETICS LA English DT Article DE Cpf1 nuclease; genome editing; CRISPR; mouse ID KNOCKOUT MICE; GENERATION; CPF1; RNA AB Cpf1 has emerged as an alternative to the Cas9 RNA-guided nuclease. Here we show that gene targeting rates in mice using Cpf1 can meet, or even surpass, Cas9 targeting rates (approaching 100% targeting), but require higher concentrations of mRNA and guide. We also demonstrate that coinjecting two guides with close targeting sites can result in synergistic genomic cutting, even if one of the guides has minimal cutting activity. C1 [Watkins-Chow, Dawn E.; Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Garrett, Lisa J.; Rivas, Cecilia] NHGRI, Embryon Stem Cell & Transgen Mouse Core, NIH, Bethesda, MD 20892 USA. [Chen, Zelin; Jimenez, Erin A.; Burgess, Shawn M.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Bishop, Kevin S.; Sood, Raman] NHGRI, Zebrafish Core, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Harper, Ursula L.] NHGRI, Genom Core, NIH, Bethesda, MD 20892 USA. [Varshney, Gaurav K.] Oklahoma Med Res Fdn, Funct & Chem Genom Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. RP Pavan, WJ (reprint author), NHGRI, NIH, Bldg 49,Room 4A82,49 Convent Dr, Bethesda, MD 20892 USA.; Burgess, SM (reprint author), NHGRI, NIH, Bldg 50,Room 5537,50 South Dr, Bethesda, MD 20892 USA. EM bpavan@mail.nih.gov; burgess@mail.nih.gov OI Watkins-Chow, Dawn/0000-0002-4355-0868; Varshney, Gaurav K./0000-0002-0429-1904 FU Intramural Research Program of the National Human Genome Research Institute at the National Institutes of Health [ZIA HG000183-15, HG000136-11] FX We thank Feng Zhang and Bernd Zetsche for providing the AsCpf1 plasmid and valuable advice, Arturo Incao for genomic DNA preparation and PCR amplification, Gene Elliott for assistance with microinjections, Laura Baxter for careful reading of the manuscript, and Abdel Elkahloun and Weiwei Wu of the NHGRI Microarray Core for assistance assessing RNA quality. This research was supported by the Intramural Research Program of the National Human Genome Research Institute at the National Institutes of Health (S.M.B.: ZIA HG000183-15 and W.J.P.: HG000136-11) NR 13 TC 0 Z9 0 U1 2 U2 2 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 FEB PY 2017 VL 7 IS 2 BP 719 EP 722 DI 10.1534/g3.116.038091 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA EL1CC UT WOS:000394357100033 PM 28040780 ER PT J AU de Souza, DAS Faucz, FR de Alexandre, RB Santana, MA de Souza, ELS Reis, FJC Pereira-Ferrari, L Sotomaior, VS Culpi, L Phillips, JA Raskin, S AF de Souza, D. A. S. Faucz, F. R. de Alexandre, R. B. Santana, M. A. de Souza, E. L. S. Reis, F. J. C. Pereira-Ferrari, L. Sotomaior, V. S. Culpi, L. Phillips, J. A., III Raskin, S. TI Cystic fibrosis in Afro-Brazilians: XK haplotypes analysis supports the European origin of p.F508del mutation SO GENETICA LA English DT Article DE Cystic fibrosis; CFTR; XK haplotypes; p.F508del; Afro-Brazilians ID LINKED DNA POLYMORPHISMS; LINKAGE DISEQUILIBRIUM; DELTA-F508 MUTATION; AFRICAN FAMILIES; CFTR GENE; LOCUS; IDENTIFICATION; POPULATION; MARKERS; FREQUENCY AB Cystic fibrosis (CF) is a common autosomal recessive disorder, being the p.F508del the most frequent mutation. Also, a nearby restriction fragment length polymorphism (RFLP) named XK (KM19 and XV2C) is non-randomly associated with specific CF alleles. Our aim was to analyze the occurrence of the p.F508del mutation and XK haplotypes in Afro-Brazilians CF patients and controls, since these data is available for the other two main ethnic groups found in Brazil (Euro-Brazilians and Brazilian Amerindians), contributing for the whole comprehension of these haplotypes in the Brazilian population. A total of 103 patients and 54 controls were studied. PCR and PCR-RFLP methodologies were used to identify the presence of the p.F508del and the XK haplotype in the subjects. The combined data show that 84.2% of p.F508del mutation is associated with haplotype B and only 15.8% with haplotype A; no other haplotypes were found to be associated with this mutation. Our data suggest that the occurrence of p.F508del mutation and haplotype B in Afro-Brazilian patients occurs probably due to admixture with Euro-descendants. Therefore this mutation and haplotype could be used as a admixture marker. C1 [de Souza, D. A. S.; Faucz, F. R.; de Alexandre, R. B.; Sotomaior, V. S.; Raskin, S.] Pontificia Univ Catolica Parana PUCPR, Sch Hlth & Biosci, Grp Adv Mol Invest NIMA, Curitiba, Parana, Brazil. [de Souza, D. A. S.] Fundacao Oswaldo Cruz, Funct Genom Lab, Carlos Chagas Inst, Curitiba, Parana, Brazil. [Faucz, F. R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Santana, M. A.] Octavio Mangabeira Hosp, Reference Ctr Cyst Fibrosis, Salvador, BA, Brazil. [de Souza, E. L. S.] Univ Fed Bahia, Div Pediat, Salvador, BA, Brazil. [Reis, F. J. C.] Univ Fed Minas Gerais, Div Pneumol, Dept Pediat, Belo Horizonte, MG, Brazil. [Pereira-Ferrari, L.; Culpi, L.] UniBrasil, Dept Biomed, Curitiba, Parana, Brazil. [Phillips, J. A., III] Vanderbilt Univ, Sch Med, Dept Pediat, Div Med Genet & Genom Med, Nashville, TN 37212 USA. [de Souza, D. A. S.] 61H Travessa Chile, BR-83035200 Sao Jose Dos Pinhais, Parana, Brazil. RP de Souza, DAS (reprint author), Pontificia Univ Catolica Parana PUCPR, Sch Hlth & Biosci, Grp Adv Mol Invest NIMA, Curitiba, Parana, Brazil.; de Souza, DAS (reprint author), Fundacao Oswaldo Cruz, Funct Genom Lab, Carlos Chagas Inst, Curitiba, Parana, Brazil.; de Souza, DAS (reprint author), 61H Travessa Chile, BR-83035200 Sao Jose Dos Pinhais, Parana, Brazil. EM denise_andreass@yahoo.com.br FU National Institutes of Health [DK35592, HD28819]; DECIT/CNPq (Science and Technology Department of Ministry of Health) FX We thank Diane Cooper, MSLS, NIH Library, for providing assistance in writing this manuscript. This research was supported in part by National Institutes of Health through Grants DK35592 and HD28819 (awarded to John A. Phillips III) and by DECIT/CNPq (Science and Technology Department of Ministry of Health) through a grant to Salmo Raskin. NR 29 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0016-6707 EI 1573-6857 J9 GENETICA JI Genetica PD FEB PY 2017 VL 145 IS 1 BP 19 EP 25 DI 10.1007/s10709-016-9942-x PG 7 WC Genetics & Heredity SC Genetics & Heredity GA EL1GU UT WOS:000394369300003 PM 28160168 ER PT J AU Meyer, R Freitag-Wolf, S Blindow, S Buning, J Habermann, JK AF Meyer, Ruediger Freitag-Wolf, Sandra Blindow, Silke Buening, Juergen Habermann, Jens K. TI Combining aneuploidy and dysplasia for colitis' cancer risk assessment outperforms current surveillance efficiency: a meta-analysis SO INTERNATIONAL JOURNAL OF COLORECTAL DISEASE LA English DT Article DE Ulcerative colitis-associated colorectal carcinoma; NuclearDNA ploidy; Cancer risk assessment; Meta-analysis ID INFLAMMATORY-BOWEL-DISEASE; LONGSTANDING ULCERATIVE-COLITIS; FLOW CYTOMETRIC ANALYSIS; POPULATION-BASED COHORT; BRONCHIAL CELL ATYPIA; COLORECTAL-CANCER; DNA-ANEUPLOIDY; COLON-CANCER; OBSERVER VARIATION; IMAGE CYTOMETRY AB Cancer risk assessment for ulcerative colitis patients by evaluating histological changes through colonoscopy surveillance is still challenging. Thus, additional parameters of high prognostic impact for the development of colitis-associated carcinoma are necessary. This meta-analysis was conducted to clarify the value of aneuploidy as predictor for individual cancer risk compared with current surveillance parameters. A systematic web-based search identified studies published in English that addressed the relevance of the ploidy status for individual cancer risk during surveillance in comparison to neoplastic mucosal changes. The resulting data were included into a meta-analysis, and odds ratios (OR) were calculated for aneuploidy or dysplasia or aneuploidy plus dysplasia. Twelve studies addressing the relevance of aneuploidy compared to dyplasia were comprehensively evaluated and further used for meta-analysis. The meta-analysis revealed that aneuploidy (OR 5.31 [95 % CI 2.03, 13.93]) is an equally effective parameter for cancer risk assessment in ulcerative colitis patients as dysplasia (OR 4.93 [1.61, 15.11]). Strikingly, the combined assessment of dysplasia and aneuploidy is superior compared to applying each parameter alone (OR 8.99 [3.08, 26.26]). This meta-analysis reveals that aneuploidy is an equally effective parameter for individual cancer risk assessment in ulcerative colitis as the detection of dysplasia. More important, the combined assessment of dysplasia and aneuploidy outperforms the use of each parameter alone. We suggest image cytometry for ploidy assessment to become an additional feature of consensus criteria to individually assess cancer risk in UC. C1 [Meyer, Ruediger; Blindow, Silke; Habermann, Jens K.] Univ Lubeck, Sect Translat Surg Oncol & Biobanking, Dept Surg, Campus Lubeck,Ratzeburger Allee 160, D-23538 Lubeck, Germany. [Meyer, Ruediger; Blindow, Silke; Habermann, Jens K.] Univ Med Ctr Schleswig Holstein, Campus Lubeck,Ratzeburger Allee 160, D-23538 Lubeck, Germany. [Meyer, Ruediger] NCI, Sect Canc Genom, NIH, 50 South Dr, Bethesda, MD 20892 USA. [Freitag-Wolf, Sandra] Univ Med Ctr Schleswig Holstein, Inst Med Informat & Stat, Campus Kiel,Brunswiker Str 10, D-24105 Kiel, Germany. [Buening, Juergen] Univ Med Ctr Schleswig Holstein, Gastroenterol Unit, Dept Internal Med 1, Campus Lubeck,Ratzeburger Allee 160, D-23538 Lubeck, Germany. RP Habermann, JK (reprint author), Univ Lubeck, Sect Translat Surg Oncol & Biobanking, Dept Surg, Campus Lubeck,Ratzeburger Allee 160, D-23538 Lubeck, Germany.; Habermann, JK (reprint author), Univ Med Ctr Schleswig Holstein, Campus Lubeck,Ratzeburger Allee 160, D-23538 Lubeck, Germany. EM Jens.Habermann@uksh.de FU German Cancer Aid Foundation (DKH e.V.) [108446]; Mildred Scheel postdoctoral scholarship of the German Cancer Aid FX This study was conducted in connection to the North German Tumor Bank of Colorectal Cancer (ColoNet), generously supported by the German Cancer Aid Foundation (DKH e.V. #108446). Rudiger Meyer is supported by a Mildred Scheel postdoctoral scholarship of the German Cancer Aid. NR 58 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-1958 EI 1432-1262 J9 INT J COLORECTAL DIS JI Int. J. Colorectal Dis. PD FEB PY 2017 VL 32 IS 2 BP 171 EP 182 DI 10.1007/s00384-016-2684-5 PG 12 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA EK8FO UT WOS:000394159500002 PM 27766414 ER PT J AU Jerschow, E Edin, M Pelletier, T Abuzeid, W Akbar, N Gibber, M Fried, M Lih, FB Gruzdev, A Bradbury, JA Han, W Hudes, G Keskin, T Schuster, V Spivack, S Zeldin, D Rosenstreich, D AF Jerschow, Elina Edin, Matthew Pelletier, Teresa Abuzeid, Waleed Akbar, Nadeem Gibber, Marc Fried, Marvin Lih, Fred B. Gruzdev, Artiom Bradbury, J. Alyce Han, Weigup Hudes, Golda Keskin, Taha Schuster, Victor Spivack, Simon Zeldin, Darryl Rosenstreich, David TI Plasma 15-Hydroxyeicosatetraenoic Acid Predicts Treatment Outcomes in Aspirin-Exacerbated Respiratory Disease SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 03-16, 2017 CL Atlanta, GA SP Amer Acad Allergy, Asthma & Immunol C1 [Jerschow, Elina] Montefiore Med Ctr, Albert Einstein Coll Med, New York, NY USA. [Edin, Matthew; Lih, Fred B.; Gruzdev, Artiom; Bradbury, J. Alyce; Zeldin, Darryl] NIEHS, NIH, Res Triangle Pk, NC USA. [Pelletier, Teresa; Han, Weigup] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Abuzeid, Waleed; Akbar, Nadeem; Gibber, Marc; Fried, Marvin; Hudes, Golda; Keskin, Taha; Schuster, Victor; Spivack, Simon; Rosenstreich, David] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2017 VL 139 IS 2 SU S MA 23 BP AB7 EP AB7 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA EO8NM UT WOS:000396946000024 ER PT J AU Lin, AA Nutman, TB AF Lin, Adora A. Nutman, Thomas B. TI IL-10 Differentially Affects IgE and IgG4 Production Through Distinct Mechanisms SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 03-16, 2017 CL Atlanta, GA SP Amer Acad Allergy, Asthma & Immunol C1 [Lin, Adora A.; Nutman, Thomas B.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2017 VL 139 IS 2 SU S MA 39 BP AB12 EP AB12 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA EO8NM UT WOS:000396946000040 ER PT J AU Wallace, GL Dudley, K Anthony, L Pugliese, CE Orionzi, B Clasen, L Lee, NR Giedd, JN Martin, A Raznahan, A Kenworthy, L AF Wallace, Gregory L. Dudley, Katerina Anthony, Laura Pugliese, Cara E. Orionzi, Bako Clasen, Liv Lee, Nancy Raitano Giedd, Jay N. Martin, Alex Raznahan, Armin Kenworthy, Lauren TI Divergence of Age-Related Differences in Social-Communication: Improvements for Typically Developing Youth but Declines for Youth with Autism Spectrum Disorder SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism; Social; Communication; Repetitive behavior; Age; Social Responsiveness Scale ID DIAGNOSTIC INTERVIEW; CHILDHOOD; TRAITS; ADOLESCENCE; IMPAIRMENT; BEHAVIORS; DEFICITS; ADULTS AB Although social-communication difficulties and repetitive behaviors are hallmark features of autism spectrum disorder (ASD) and persist across the lifespan, very few studies have compared age-related differences in these behaviors between youth with ASD and same-age typically developing (TD) peers. We examined this issue using SRS-2 (Social Responsiveness Scale-Second Edition) measures of social-communicative functioning and repetitive behaviors in a stratified cross-sectional sample of 324 youth with ASD in the absence of intellectual disability, and 438 TD youth (aged 4-29 years). An age-by-group interaction emerged indicating that TD youth exhibited age-related improvements in social-communication scores while the ASD group demonstrated age-related declines in these scores. This suggests that adolescents/adults with ASD may fall increasingly behind their same-age peers in social-communicative skills. C1 [Wallace, Gregory L.] George Washington Univ, Dept Speech & Hearing Sci, 2115 G St NW,Room 201, Washington, DC 20052 USA. [Wallace, Gregory L.; Orionzi, Bako; Martin, Alex] NIMH, Lab Brain & Cognit, Intramural Res Program, Bethesda, MD 20892 USA. [Dudley, Katerina; Anthony, Laura; Pugliese, Cara E.; Kenworthy, Lauren] Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Childrens Res Inst, Washington, DC 20010 USA. [Clasen, Liv; Lee, Nancy Raitano; Giedd, Jay N.; Raznahan, Armin] NIMH, Child Psychiat Branch, Intramural Res Program, Bldg 10, Bethesda, MD 20892 USA. RP Wallace, GL (reprint author), George Washington Univ, Dept Speech & Hearing Sci, 2115 G St NW,Room 201, Washington, DC 20052 USA.; Wallace, GL (reprint author), NIMH, Lab Brain & Cognit, Intramural Res Program, Bethesda, MD 20892 USA. EM gwallac1@gwu.edu FU Intramural Research Program at NIMH, NIH [1-ZIA-MH002794, 1-ZIA-MH002920]; Gudelsky Family Foundation; IDDRC Grant [HD046388-01A2]; T32 Grant [5P30HD040677-15] FX This work was supported by the Intramural Research Program at NIMH, NIH under Grants 1-ZIA-MH002794, 1-ZIA-MH002920. LA, CEP, and LK were supported by The Gudelsky Family Foundation and an IDDRC Grant HD046388-01A2. CEP was supported by a T32 Grant 5P30HD040677-15. We would like to express our gratitude to the individuals and families who volunteered their time to contribute to this research. NR 26 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD FEB PY 2017 VL 47 IS 2 BP 472 EP 479 DI 10.1007/s10803-016-2972-5 PG 8 WC Psychology, Developmental SC Psychology GA EL1DL UT WOS:000394360600022 PM 27878739 ER PT J AU Larsen, KR Michie, S Hekler, EB Gibson, B Spruijt-Metz, D Ahern, D Cole-Lewis, H Ellis, RJB Hesse, B Moser, RP Yi, J AF Larsen, Kai R. Michie, Susan Hekler, Eric B. Gibson, Bryan Spruijt-Metz, Donna Ahern, David Cole-Lewis, Heather Ellis, Rebecca J. Bartlett Hesse, Bradford Moser, Richard P. Yi, Jean TI Behavior change interventions: the potential of ontologies for advancing science and practice SO JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Behavior change interventions; Ontologies; Controlled vocabularies; Taxonomies; Mechanisms of action; Behaviors ID THEORETICAL DOMAINS FRAMEWORK; SOCIAL-SCIENCES; BIG DATA; SYSTEMS; VALIDATION; KNOWLEDGE; CONSENSUS AB A central goal of behavioral medicine is the creation of evidence-based interventions for promoting behavior change. Scientific knowledge about behavior change could be more effectively accumulated using "ontologies." In information science, an ontology is a systematic method for articulating a "controlled vocabulary" of agreed-upon terms and their inter-relationships. It involves three core elements: (1) a controlled vocabulary specifying and defining existing classes; (2) specification of the inter-relationships between classes; and (3) codification in a computer-readable format to enable knowledge generation, organization, reuse, integration, and analysis. This paper introduces ontologies, provides a review of current efforts to create ontologies related to behavior change interventions and suggests future work. This paper was written by behavioral medicine and information science experts and was developed in partnership between the Society of Behavioral Medicine's Technology Special Interest Group (SIG) and the Theories and Techniques of Behavior Change Interventions SIG. In recent years significant progress has been made in the foundational work needed to develop ontologies of behavior change. Ontologies of behavior change could facilitate a transformation of behavioral science from a field in which data from different experiments are siloed into one in which data across experiments could be compared and/or integrated. This could facilitate new approaches to hypothesis generation and knowledge discovery in behavioral science. C1 [Larsen, Kai R.] Univ Colorado, Leeds Sch Business, Boulder, CO 80309 USA. [Michie, Susan] UCL, Ctr Behav Change, London, England. [Hekler, Eric B.] Arizona State Univ, Sch Nutr & Hlth Promot, Phoenix, AZ USA. [Gibson, Bryan] Univ Utah, Dept Biomed Informat, Salt Lake City, UT USA. [Spruijt-Metz, Donna] Univ Southern Calif, Dept Psychol, Ctr Econ & Social Res, Los Angeles, CA USA. [Ahern, David] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Cole-Lewis, Heather] Johnson & Johnson Hlth & Wellness Solut, New Brunswick, NJ USA. [Ellis, Rebecca J. Bartlett] Indiana Univ, Sch Nursing, Indianapolis, IN 46204 USA. [Hesse, Bradford] NCI, NIH, Bethesda, MD 20892 USA. [Moser, Richard P.] NCI, Behav Res Program, Rockville, MD USA. [Yi, Jean] Fred Hutch, Div Clin Res, Seattle, WA USA. RP Larsen, KR (reprint author), Univ Colorado, Leeds Sch Business, Boulder, CO 80309 USA. EM kai.larsen@colorado.edu; s.michie@ucl.ac.uk; ehekler@asu.edu; bryan.gibson@utah.edu; dmetz@usc.edu; dahern@partners.org; hcolelew@its.jnj.com; rjbartle@iu.edu; hesseb@mail.nih.gov; moserr@mail.nih.gov; jyi@fredhutch.org OI Bartlett Ellis, Rebecca/0000-0001-5990-3595 NR 67 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0160-7715 EI 1573-3521 J9 J BEHAV MED JI J. Behav. Med. PD FEB PY 2017 VL 40 IS 1 BP 6 EP 22 DI 10.1007/s10865-016-9768-0 PG 17 WC Psychology, Clinical SC Psychology GA EL0WK UT WOS:000394342300002 PM 27481101 ER PT J AU Small, H Tseng, H Patek, M AF Small, Henry Tseng, Hung Patek, Mike TI Discovering discoveries: Identifying biomedical discoveries using citation contexts SO JOURNAL OF INFORMETRICS LA English DT Article DE Discovery; Biomedicine; Citation contexts; Citances; Machine learning; Pubmed central ID SCIENTIFIC DISCOVERY AB A procedure for identifying discoveries in the biomedical sciences is described that makes use of citation context information, or more precisely citing sentences, drawn from the PubMed Central database. The procedure focuses on use of specific terms in the citing sentences and the joint appearance of cited references. After a manual screening process to remove non -discoveries, a list of over 100 discoveries and their associated articles is compiled and characterized by subject matter and by type of discovery. The phenomenon of multiple discovery is shown to play an important role. The onset and timing of recognition of the articles are studied by comparing the number of citing sentences with and without discovery terms, and show both early onset and delays in recognition. A comparative analysis of the vocabularies of the discovery and non -discovery sentences reveals the types of words and concepts that scientists associate with discoveries. A machine learning application is used to efficiently extend the list. Implications of the findings for understanding the nature and justification of scientific discoveries are discussed. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Small, Henry] SciTech Strategies Inc, 105 Rolling Rd, Bala Cynwyd, PA 19004 USA. [Tseng, Hung] NIAMSD, NIH, 6701 Democracy Blvd, Bethesda, MD 20892 USA. [Patek, Mike] SciTech Strategies Inc, 58 Russell St, Keene, NH 03431 USA. RP Small, H (reprint author), SciTech Strategies Inc, 105 Rolling Rd, Bala Cynwyd, PA 19004 USA. EM hsmall@mapofscience.com; tsengh@mail.nih.gov; mpatek@gmail.com NR 42 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1751-1577 EI 1875-5879 J9 J INFORMETR JI J. Informetr. PD FEB PY 2017 VL 11 IS 1 BP 46 EP 62 DI 10.1016/j.joi.2016.11.001 PG 17 WC Computer Science, Interdisciplinary Applications; Information Science & Library Science SC Computer Science; Information Science & Library Science GA EO3SM UT WOS:000396614600004 ER PT J AU Zoon, KC AF Zoon, Kathryn C. TI Sidney Pestka (1936-2016) SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Biographical-Item C1 [Zoon, Kathryn C.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Zoon, KC (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 EI 1557-7465 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD FEB PY 2017 VL 37 IS 2 BP 51 EP 51 DI 10.1089/jir.2017.29004.spe PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA EL3BZ UT WOS:000394495900001 PM 28103128 ER PT J AU Smith, RL Gallicchio, L Flaws, JA AF Smith, Rebecca L. Gallicchio, Lisa Flaws, Jodi A. TI Factors Affecting Sexual Activity in Midlife Women: Results from the Midlife Health Study SO JOURNAL OF WOMENS HEALTH LA English DT Article DE sexual activity; menopause; cohort study ID MENOPAUSAL TRANSITION; CLIMACTERIC YEARS; HOT FLASHES; DYSFUNCTION; BEHAVIOR; ANDROGEN; HORMONES AB Background: The objective of this study was to identify (1) the importance of a number of potential factors affecting the likelihood of sexual activity in perimenopausal women and (2) the likelihood of a number of barriers to sexual activity. Methods: A cohort of 780 women undergoing menopausal transition was surveyed annually for up to 7 years. Data were collected on sexual activity and, if not sexually active, reasons for no sexual activity, as well as a number of potential risk factors. Height and weight were measured at an annual clinic visit; serum hormone concentrations were assayed using blood samples donated annually. Data were examined with logistic regression models using the individual as a random effect, with subset analysis of nonsexually active women to determine the likelihood of each barrier. All factors with univariate associations of p < 0.1 were considered in multivariate model building with stepwise addition. Results: A total of 2440 woman-years were included in the analysis of sexual activity. The likelihood of sexual activity increased for women living with a partner, with perceived quality of life, and with less frequent hot flashes. Among 513 woman-years reporting no sexual activity, women living with a partner and women reporting frequent fatigue were less likely to lack a sexual partner, but were more likely to have sexual difficulties. Women with more physical work than average and women with higher serum estradiol levels were less likely to have sexual difficulties. Conclusions: The factors associated with sexual activity in menopausal women are complex, indicating that an individualized approach to improving sexual activity is required. C1 [Smith, Rebecca L.] Univ Illinois, Coll Vet Med, Dept Pathobiol, 2001 S Lincoln Ave,VM BSB 2627, Urbana, IL 61803 USA. [Gallicchio, Lisa] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Flaws, Jodi A.] Univ Illinois, Coll Vet Med, Dept Comparat Biomed, Urbana, IL 61801 USA. RP Smith, RL (reprint author), Univ Illinois, Coll Vet Med, Dept Pathobiol, 2001 S Lincoln Ave,VM BSB 2627, Urbana, IL 61803 USA. EM rlsdvm@illinois.edu FU National Institute on Aging [R01 AG18400] FX This study was funded by a grant from the National Institute on Aging (R01 AG18400). NR 24 TC 1 Z9 1 U1 1 U2 1 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 FEB PY 2017 VL 26 IS 2 BP 103 EP 108 DI 10.1089/jwh.2016.5881 PG 6 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 EL0RQ UT WOS:000394329900004 PM 27653205 ER PT J AU Beydoun, HA Williams, M Beydoun, MA Eid, SM Zonderman, AB AF Beydoun, Hind A. Williams, Megan Beydoun, May A. Eid, Shaker M. Zonderman, Alan B. TI Relationship of Physical Intimate Partner Violence with Mental Health Diagnoses in the Nationwide Emergency Department Sample SO JOURNAL OF WOMENS HEALTH LA English DT Article DE intimate partner violence; mental health; emergency department; surveillance ID RANDOMIZED-CONTROLLED-TRIAL; POSTTRAUMATIC-STRESS-DISORDER; SEXUALLY-TRANSMITTED INFECTION; HIV PREVENTION TRIAL; PRIMARY-CARE; ADULT WOMEN; DEPRESSIVE SYMPTOMS; AMERICAN WOMEN; UNITED-STATES; CHINESE WOMEN AB Objectives: We examined associations of physical intimate partner violence (PIPV) with selected mental health disorders using a nationally representative sample of emergency department (ED) discharges corresponding to men and women (18-64 years) from the 2010 Nationwide Emergency Department Sample. Methods: PIPV was determined using International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) external cause of injury code E967.3 (battering by spouse or partner). ICD-9-CM clinical classification of discharge diagnoses was used to identify mental health disorders. Multivariable logistic regression models were constructed to estimate adjusted odds ratios (ORadj) and their 95% confidence intervals (CIs). Results: PIPV prevalence was estimated at 0.36 per 1000 ED discharges. The strongest correlates of PIPV were alcohol-related (ORadj = 3.02, 95% CI: 2.62-3.50), adjustment (ORadj = 2.37, 95% CI: 1.56-3.58), intentional self-harm (ORadj = 1.41, 95% CI: 1.05-1.89), anxiety (ORadj = 1.23, 95% CI: 1.07-1.40), drug-related (ORadj = 1.22, 95% CI: 1.01-1.47), and mood (ORadj = 1.16, 95% CI: 1.04-1.31) disorders. PIPV's association with alcohol-related disorders was stronger among women (ORadj = 3.22, 95% CI: 2.79-3.72) versus men (ORadj = 1.98, 95% CI: 1.42-2.77). Similarly, drug-related disorders were stronger correlates of PIPV among women (ORadj = 1.32, 95% CI: 1.09-1.60) versus men (ORadj = 0.59, 95% CI: 0.31-1.16). Conclusions: In EDs, PIPV was linked to several mental health disorders, with women experiencing comorbid PIPV and substance use more frequently than men. C1 [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, 651 Colley Ave,401, Norfolk, VA 23507 USA. [Williams, Megan; Beydoun, May A.; Zonderman, Alan B.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Williams, Megan] Univ Maryland Baltimore Cty, Catonsville, MD USA. [Eid, Shaker M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Beydoun, HA (reprint author), Eastern Virginia Med Sch, Grad Program Publ Hlth, 651 Colley Ave,401, Norfolk, VA 23507 USA. EM hindb1972@gmail.com FU NIA/NIH/IRP; Johns Hopkins University School of Medicine FX This study was supported, in part, by the NIA/NIH/IRP in collaboration with Johns Hopkins University School of Medicine. The authors thank Ms. Nicolle Mode for her critical review of the article. NR 109 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2017 VL 26 IS 2 BP 141 EP 151 DI 10.1089/jwh.2016.5840 PG 11 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 EL0RQ UT WOS:000394329900009 PM 27509203 ER PT J AU Felisiak-Golabek, A Inaguma, S Kowalik, A Wasag, B Wang, ZF Lasota, J Miettinen, MM AF Felisiak-Golabek, Anna Inaguma, Shingo Kowalik, Artur Wasag, Bartosz Wang, Zeng-Feng Lasota, Jerzy Miettinen, Markku M. TI SP174 Antibody Lacks Specificity for NRAS Q61R and Cross-Reacts with HRAS-and KRAS-Q61R Mutant Proteins in Malignant Melanoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Aichi Med Univ, Sch Med, Nagakute, Aichi 48011, Japan. Holycross Canc Ctr, Kielce, Swietokrzyskie, Poland. Med Univ Gdansk, Gdansk, Pomorskie, Poland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 501 BP 128A EP 129A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724400500 ER PT J AU Allgaeuer, M Ferre, EMN Heller, T Lionakis, M Quezado, MM AF Allgaeuer, Michael Ferre, Elise M. N. Heller, Theo Lionakis, Michail Quezado, Martha M. TI Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) Associated Gastritis - A Variable Phenotype SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 NCI, NIH, Bethesda, MD 20892 USA. NIDDK, NIH, Bethesda, MD 20892 USA. NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 626 BP 158A EP 158A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724400624 ER PT J AU Inaguma, S Felisiak-Golabek, A Wang, ZF Lasota, J Miettinen, MM AF Inaguma, Shingo Felisiak-Golabek, Anna Wang, Zengfeng Lasota, Jerzy Miettinen, Markku M. TI Mismatch Repair System Molecule Immunophenotype and BRAF V600E Genotype of PD-L1-Positive Primary and Metastatic Colorectal Carcinomas SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Aichi Med Univ, Nagakute, Aichi, Japan. NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 702 BP 176A EP 176A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724400700 ER PT J AU Noe, M Wood, LD Hackeng, W Brosens, LAA Bhaijee, F Debeljak, M Yu, J Boyce, A Robinson, C Eshleman, JR Hruban, RH Goggins, MG Collins, MT Lennon, AM Montgomery, EA AF Noe, Michael Wood, Laura D. Hackeng, Wenzel Brosens, Lodewijk A. A. Bhaijee, Feriyl Debeljak, Marija Yu, Jun Boyce, Alison Robinson, Cemre Eshleman, James R. Hruban, Ralph H. Goggins, Michael G. Collins, Michael T. Lennon, Anne Marie Montgomery, Elizabeth A. TI Gastrointestinal and Pancreatic Findings in Patients with McCune-Albright Syndrome SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Johns Hopkins Univ, Baltimore, MD USA. Univ Med Ctr Utrecht, Utrecht, Netherlands. NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 761 BP 190A EP 190A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724401034 ER PT J AU Del Valle, JAB Zheng, QZ Esopi, D Rubenstein, M Hubbard, GK Moncaliano, MC Hruszkewycz, A Vaghasia, A Yegnasubramanian, S Wheelan, SJ Meeker, A Heaphy, CM De Marzo, AM AF Del Valle, Javier A. Baena Zheng, Qizhi Esopi, David Rubenstein, Michael Hubbard, Gretchen K. Moncaliano, Maria C. Hruszkewycz, Andrew Vaghasia, Ajay Yegnasubramanian, Srinivasan Wheelan, Sarah J. Meeker, Alan Heaphy, Christopher M. De Marzo, Angelo M. TI MYC Drives Overexpression of Telomerase RNA (hTR/TERC) in Prostate Cancer SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Fdn Santa Fe Bogota, Bogota, DC, Colombia. Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 853 BP 212A EP 212A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724401126 ER PT J AU Merino, MJ Ricketts, C Xu, NZ Linehan, W Moreno, V AF Merino, Maria J. Ricketts, Christopher Xu Naizhen Linehan, WMarston Moreno, Vanessa TI What the Pathologist Needs to Know About the Role of Fumarate Hydratase in the Diagnosis of HLRCC Renal Cancer SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 [Merino, Maria J.; Ricketts, Christopher; Xu Naizhen; Linehan, WMarston; Moreno, Vanessa] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 982 BP 243A EP 243A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724401256 ER PT J AU Moreno, V Xu, NZ Srinivasan, R Linehan, MW Merino, MJ AF Moreno, Vanessa Xu Naizhen Srinivasan, Ramaprasad Linehan, Marston W. Merino, Maria J. TI The Unrecognized Morphologies of HLRCC Renal Cancer That Pathologists Need to Know. Molecular and IHC Findings SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 [Moreno, Vanessa; Xu Naizhen; Srinivasan, Ramaprasad; Linehan, Marston W.; Merino, Maria J.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 989 BP 245A EP 245A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724401263 ER PT J AU Lee, S Sahasrabuddhe, V Mendoza-Cervantes, D Rose, S Zhao, R Duggan, M AF Lee, Sandra Sahasrabuddhe, Vikrant Mendoza-Cervantes, Diana Rose, Sarah Zhao, Rachel Duggan, Maire TI Tissue-Based Immunohistochemical Biomarker Expression in Glandular Malignancies of the Cervix: A Systematic Review and Meta-Analysis SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 South Hlth Campus, Calgary, AB, Canada. NCI, Bethesda, MD 20892 USA. Univ Calgary, Calgary, AB, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1191 BP 296A EP 296A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724401467 ER PT J AU Thompson, LDR Jo, VY Agaimy, A Llombart-Bosch, A Morales, GN Machado, I Miettinen, MM Bishop, JA AF Thompson, Lester D. R. Jo, Vickie Y. Agaimy, Abbas Llombart-Bosch, Antonio Morales, Gema N. Machado, Isidro Miettinen, Markku M. Bishop, Justin A. TI Thirty-Nine Cases of Sinonasal Tract Alveolar Rhabdomyosarcoma in Adults SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 SCPMG, Woodland Hills, CA USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Univ Klinikum Erlangen, Erlangen, Germany. Univ Valencia, Valencia, Spain. Inst Oncol, Valencia, Spain. NIH, Bldg 10, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1338 BP 333A EP 333A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724401614 ER PT J AU Balakrishna, JP Hsu, A Ombrello, A Wang, WX Holland, SM Hickstein, DD Kastner, DL Aksentijevich, I Calvo, KR AF Balakrishna, Jayalakshmi P. Hsu, Amy Ombrello, Amanda Wang, Weixin Holland, Steven M. Hickstein, Dennis D. Kastner, Daniel L. Aksentijevich, Ivona Calvo, Katherine R. TI Spectrum of Bone Marrow Pathology in Patients with Germline Mutations in CECR1 SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 NIH, CC, DLM, Bldg 10, Bethesda, MD 20892 USA. NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1358 BP 338A EP 338A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724401634 ER PT J AU Boyer, D McKelvie, P de Leval, L Edlefsen, KL Ko, YH Aberman, Z Kovach, A Masih, A Nishino, H Weiss, L Meeker, A Nardi, V Palisoc, M Shao, LN Pittaluga, S Ferry, JA Harris, N Sohani, A AF Boyer, Daniel McKelvie, Penelope de Leval, Laurence Edlefsen, Kerstin L. Ko, Young-Hyeh Aberman, Zachary Kovach, Alexandra Masih, Aneal Nishino, Ha Weiss, Lawrence Meeker, Alan Nardi, Valentina Palisoc, Maryknoll Shao, Lina Pittaluga, Stefania Ferry, Judith A. Harris, Nancy Sohani, Aliyah TI Fibrin-Associated EBV plus Large B-Cell Lymphoma: An Indolent Neoplasm Distinct from DLBCL-CI SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Univ Michigan, Ann Arbor, MI 48109 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. St Vincents Hosp, Melbourne, Vic, Australia. CHU Vaudois, Lausanne, Switzerland. Univ Washington, Seattle, WA 98195 USA. Sungkyunkwan Univ, Seoul, South Korea. Florida Int Univ, Miami, FL 33199 USA. Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. Holmes Reg Med Ctr, Melbourne, FL USA. North Shore Med Ctr, Salem, MA USA. NeoGen Labs, Aliso Viejo, CA USA. Johns Hopkins Univ, Baltimore, MD USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1363 BP 339A EP 340A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724401639 ER PT J AU Egan, C Laurent, C Kallen, ME Pileri, S Campo, E Swerdlow, SH Piris, M Chan, WC Warnke, R Gascoyne, R Raffeld, M Pittaluga, S Jaffe, ES AF Egan, Caoimhe Laurent, Camille Kallen, Michael E. Pileri, Stefano Campo, Elias Swerdlow, Steven H. Piris, Miguel Chan, Wing C. Warnke, Roger Gascoyne, Randy Raffeld, Mark Pittaluga, Stefania Jaffe, Elaine S. TI Expansion of PD-1-Positive T-cells in Nodal Marginal Zone Lymphoma (MZL) - A Diagnostic Pitfall SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 NIH, Bldg 10, Bethesda, MD 20892 USA. Inst Univ Canc Oncopole, Toulouse, France. European Inst Oncol, Milan, Italy. Univ Barcelona, Barcelona, Spain. Univ Pittsburgh, Pittsburgh, PA USA. Hosp Univ Marques de Valdecilla, Santander, Spain. City Hope Med Ctr, Duarte, CA USA. Stanford Univ, Stanford, CA 94305 USA. British Columbia Canc Agcy, Vancouver, BC, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1390 BP 346A EP 346A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724401666 ER PT J AU Florea, AD Young, NS Maric, I Jordan, EK Jiang, CJ Ahmad, F Braylan, R AF Florea, Alina Dulau Young, Neal S. Maric, Irina Jordan, Elaine K. Jiang, Chunjie Ahmad, Farhan Braylan, Raul TI Immunophenotypic Abnormalities Highly Suggestive of Paroxysmal Nocturnal Hemoglobinuria (PNH) Can Be Detected with Routine Flow Cytometric Analysis of Bone Marrow (BM) SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 [Florea, Alina Dulau; Young, Neal S.; Maric, Irina; Jordan, Elaine K.; Jiang, Chunjie; Ahmad, Farhan; Braylan, Raul] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1389 BP 346A EP 346A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724401665 ER PT J AU Trindade, CJ Hahn, J Sharma, S Maric, D Maric, I AF Trindade, Christopher J. Hahn, Jamie Sharma, Sachein Maric, Dragan Maric, Irina TI Immunophenotypic Differentiation Pattern of Eosinopoiesis in Human Bone Marrow: A New Flow Cytometric Tool for Studying Eosinophil Maturation SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 [Trindade, Christopher J.; Hahn, Jamie; Sharma, Sachein; Maric, Dragan; Maric, Irina] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1530 BP 381A EP 382A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402014 ER PT J AU Trindade, CJ Mao, ZWJ Wood, BL AF Trindade, Christopher J. Mao, Zhengwei J. Wood, Brent L. TI Evaluation of Novel Markers for Minimal Residual Disease Testing in B-ALL for Children's Oncology Group Studies SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. Seattle Canc Care Alliance, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1529 BP 381A EP 381A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402013 ER PT J AU Wake, L Wang, WX Rao, K Uzel, G Calvo, KR AF Wake, Laura Wang, Weixin Rao, Koneti Uzel, Gulbu Calvo, Katherine R. TI Bone Marrow Features in Patients with Germline Mutations in CTLA4 Overlap with Aplastic Anemia and LGL Leukemia SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 NIH, Bldg 10, Bethesda, MD 20892 USA. NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1535 BP 383A EP 383A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402019 ER PT J AU Wang, HW Sharma, S Hahn, J Komarow, H Eisch, R Metcalfe, DD Maric, I AF Wang, Hao-Wei Sharma, Sachein Hahn, Jamie Komarow, Hirsh Eisch, Robin Metcalfe, Dean D. Maric, Irina TI PD-L1 and PD-1 Expression Patterns in Systemic Mastocytosis SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 [Wang, Hao-Wei; Sharma, Sachein; Hahn, Jamie; Komarow, Hirsh; Eisch, Robin; Metcalfe, Dean D.; Maric, Irina] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1536 BP 383A EP 383A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402020 ER PT J AU Joneja, U Miettinen, MM Kshettry, V Evans, JJ Curtis, MT AF Joneja, Upasana Miettinen, Markku M. Kshettry, Varun Evans, James J. Curtis, Mark T. TI Loss of Expression of SWI/SNF Chromatin Remodeling Complex Proteins in Sporadic Pituitary Adenomas SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1741 BP 434A EP 434A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402222 ER PT J AU Bellolio, E Roa, JC Villaseca, M Ferreccio, C Adsay, V Losada, H Van Dyke, A Vivallo, C Becker, R Medina, K Fuentealba, P Araya, JC Koshiol, J AF Bellolio, Enrique Carlos Roa, Juan Villaseca, Miguel Ferreccio, Catterina Adsay, Volkan Losada, Hector Van Dyke, Alison Vivallo, Carolina Becker, Renato Medina, Karie Fuentealba, Patricia Carlos Araya, Juan Koshiol, Jill TI Pathologic Findings from Totally Sampled and Mapped Gallbladders in a High-Risk Population SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Univ La Frontera, Temuco, Chile. Pontificia Univ Catolica Chile, Santiago, Chile. Emory Univ, Atlanta, GA 30322 USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1774 BP 442A EP 442A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402255 ER PT J AU Chu, J Jang, KT Roa, JC Hong, SM Lee, KB Koshiol, J Memis, B Muraki, T Reid, MD Goodman, MM Nash, R Jang, J Adsay, V Kim, H Choi, H AF Chu, Jinah Jang, Kee-Taek Roa, Juan Carlos Hong, Seung-Mo Lee, Kyoung Bun Koshiol, Jill Memis, Bahar Muraki, Takahashi Reid, Michelle D. Goodman, Michael M. Nash, Rebecca Jang, Jinyoung Adsay, Volkan Kim, Haeryoung Choi, Hyejeong TI Prognostic Validation of T2-Substaging of Gallbladder Carcinomas: Survival Analysis of 127 Korean Cases with T2 Substaging and Survival Correlation SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Samsung Med Ctr, Seoul, South Korea. Pontificia Univ Catolica Chile, Santiago, Metropolitana, Chile. Asan Med Ctr, Seoul, South Korea. Seoul Natl Univ Hosp, Seoul, South Korea. Seoul Natl Bundang Hosp, Seongnam, Gyeonggi Do, South Korea. Ulsan Univ Hosp, Ulsan, South Korea. NCI, Rockville, MD USA. Emory Univ Hosp, 1364 Clifton Rd NE, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1778 BP 443A EP 443A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402259 ER PT J AU Memis, B Reid, MD Bedolla, G Roa, JC Araya, JC Bellolio, E Villaseca, M Van Dyke, A Xue, Y Quigley, B Krasinskas, A Polito, H Ghosh, A Koshiol, J Adsay, V AF Memis, Bahar Reid, Michelle D. Bedolla, Gabriella Roa, Juan Carlos Araya, Juan Carlos Bellolio, Enrique Villaseca, Miguel Van Dyke, Alison Xue, Yue Quigley, Brian Krasinskas, Alyssa Polito, Humbert Ghosh, Abheek Koshiol, Jill Adsay, Volkan TI Pathologic Findings in Gallbladders: An Analysis of the True Frequency and Distribution in 203 Totally Sampled and Mapped Gallbladders from a North American Population SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Emory Univ, Atlanta, GA 30322 USA. Pontificia Univ Catolica Chile, Santiago, Chile. Univ La Frontera, Temuco, Chile. NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1795 BP 447A EP 447A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402276 ER PT J AU Reid, MD Graham, R Memis, B Kipp, B Fritcher, EB Roa, JC Araya, JC Villaseca, MA Bellolio, E Losada, H Sarmiento, JM Koshiol, J Adsay, V AF Reid, Michelle D. Graham, Rondell Memis, Bahar Kipp, Benjamin Fritcher, Emily Barr Roa, Juan Carlos Araya, Juan Carlos Villaseca, Miguel Angel Bellolio, Enrique Losada, Hector Sarmiento, Juan M. Koshiol, Jill Adsay, Volkan TI FISH'ing to Verify the Nature of Different Epithelial Alterations in the Gallbladder: Molecular Abnormalities Are Common in Neoplastic but Not in Reactive Lesions, Thus Validating the Santiago Criteria and Potential Usefulness of FISH as an Adjunct in Diagnosis SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 04-10, 2017 CL San Antonio, TX SP US & Canadian Acad Pathol C1 Emory, Atlanta, GA USA. Mayo Clin, Rochester, MN USA. Pontificia Univ Catolica Chile, Santiago, Chile. Univ La Frontera, Temuco, Chile. NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2017 VL 97 SU 1 MA 1808 BP 450A EP 450A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA EK1YT UT WOS:000393724402289 ER PT J AU Cronise, RJ Sinclair, DA Bremer, AA AF Cronise, Raymond J. Sinclair, David A. Bremer, Andrew A. TI Response to Wood re: "Oxidative Priority, Meal Frequency, and the Energy Economy of Food and Activity: Implications for Longevity, Obesity, and Cardiometabolic Disease'' SO METABOLIC SYNDROME AND RELATED DISORDERS LA English DT Article ID CALORIC RESTRICTION; RHESUS-MONKEYS; HEALTH; HUMANS C1 [Cronise, Raymond J.] Thermogenex, Huntsville, AL USA. [Sinclair, David A.] Harvard Med Sch, Dept Genet, Boston, MA USA. [Sinclair, David A.] Univ New South Wales, Sch Med Sci, Dept Pharmacol, Sydney, NSW, Australia. [Bremer, Andrew A.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, 6707 Democracy Blvd,Bldg 2DEM,Room 6067, Bethesda, MD 20892 USA. RP Bremer, AA (reprint author), NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, 6707 Democracy Blvd,Bldg 2DEM,Room 6067, Bethesda, MD 20892 USA. EM andrew.bremer@nih.gov FU NIDDK NIH HHS [T32 DK007161] NR 13 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-4196 EI 1557-8518 J9 METAB SYNDR RELAT D JI Metab. Syndr. Relat. Disord. PD FEB PY 2017 VL 15 IS 1 BP 4 EP 5 DI 10.1089/met.2017.0004 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EL1GI UT WOS:000394368100003 PM 28165301 ER PT J AU Cronise, RJ Sinclair, DA Bremer, AA AF Cronise, Raymond J. Sinclair, David A. Bremer, Andrew A. TI Oxidative Priority, Meal Frequency, and the Energy Economy of Food and Activity: Implications for Longevity, Obesity, and Cardiometabolic Disease SO METABOLIC SYNDROME AND RELATED DISORDERS LA English DT Review DE oxidative priority; metabolism; obesity; longevity; cardiometabolic disease ID BROWN ADIPOSE-TISSUE; DE-NOVO LIPOGENESIS; BODY-WEIGHT REGULATION; CARDIOVASCULAR-DISEASE; METHIONINE RESTRICTION; CALORIE RESTRICTION; METABOLIC SYNDROME; LIFE-SPAN; INSULIN SENSITIVITY; AMBIENT-TEMPERATURE AB In most modern societies, the relationship that many individuals have with food has fundamentally changed from previous generations. People have shifted away from viewing food as primarily sustenance, and rather now seek out foods based on pure palatability or specific nutrition. However, it is far from clear what optimal nutrition is for the general population or specific individuals. We previously described the Food Triangle as a way to organize food based on an increasing energy density paradigm, and now expand on this model to predict the impact of oxidative priority and both nutrient and fiber density in relation to caloric load. When combined with meal frequency, integrated energy expenditure, macronutrient oxidative priority, and fuel partitioning expressed by the respiratory quotient, our model also offers a novel explanation for chronic overnutrition and the cause of excess body fat accumulation. Herein, we not only review how metabolism is a dynamic process subject to many regulators that mediate the fate of ingested calories but also discuss how the Food Triangle predicts the oxidative priority of ingested foods and provides a conceptual paradigm for healthy eating supported by health and longevity research. C1 [Cronise, Raymond J.] Thermogenex, Huntsville, AL USA. [Sinclair, David A.] Harvard Med Sch, Dept Genet, Boston, MA USA. [Sinclair, David A.] Univ New South Wales, Sch Med Sci, Dept Pharmacol, Sydney, NSW, Australia. [Bremer, Andrew A.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, 6707 Democracy Blvd,Bldg 2DEM,Room 6067, Bethesda, MD 20892 USA. RP Bremer, AA (reprint author), NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, 6707 Democracy Blvd,Bldg 2DEM,Room 6067, Bethesda, MD 20892 USA. EM andrew.bremer@nih.gov FU NIH [R01 AG028730] FX This work received funding support from NIH grant R01 AG028730 to D.A.S. NR 104 TC 2 Z9 2 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-4196 EI 1557-8518 J9 METAB SYNDR RELAT D JI Metab. Syndr. Relat. Disord. PD FEB PY 2017 VL 15 IS 1 BP 6 EP U65 DI 10.1089/met.2016.0108 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EL1GI UT WOS:000394368100004 PM 27869525 ER PT J AU Olfson, M Mojtabai, R Merikangas, KR Compton, WM Wang, S Grant, BF Blanco, C AF Olfson, M. Mojtabai, R. Merikangas, K. R. Compton, W. M. Wang, S. Grant, B. F. Blanco, C. TI Reexamining associations between mania, depression, anxiety and substance use disorders: results from a prospective national cohort SO MOLECULAR PSYCHIATRY LA English DT Article ID GENERAL-POPULATION SAMPLE; ALCOHOL-USE-DISORDER; PSYCHIATRIC DIAGNOSTIC MODULES; TREATMENT ENHANCEMENT PROGRAM; BIPOLAR I DISORDER; EPIDEMIOLOGIC-SURVEY; MAJOR DEPRESSION; RISK-FACTORS; GENDER-DIFFERENCES; STEP-BD AB Separate inheritance of mania and depression together with high rates of clinical overlap of mania with anxiety and substance use disorders provide a basis for re-examining the specificity of the prospective association of manic and depression episodes that is a hallmark of bipolar disorder. We analyzed information from 34 653 adults in Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions, a longitudinal nationally representative survey of US adults interviewed 3 years apart. Psychiatric disorders were assessed by a structured interview. We used logistic regression analyses to estimate the strength of associations between Wave 1 manic episodes and Wave 2 depression, anxiety and substance use disorders controlling for background characteristics and lifetime Wave 1 disorders. Corresponding analyses examined associations between Wave 1 major depressive episode with manic episodes and other psychiatric disorders. In multivariable models, Wave 1 manic episodes significantly increased the odds of Wave 2 major depressive episodes (adjusted odds ratio (AOR): 1.7; 95% confidence interval: 1.3-2.2) and any anxiety disorder (AOR: 1.8; 1.4-2.2), although not of substance use disorders (AOR: 1.2; 0.9-1.5). Conversely, Wave 1 major depressive episodes significantly increased risk of Wave 2 manic episodes (AOR: 2.2; 1.7-2.9) and anxiety disorders (AOR: 1.7; 1.5-2.0), although not substance use disorders (AOR: 1.0; 0.9-1.2). Adults with manic episodes have an approximately equivalent relative risk of developing depression episodes and anxiety disorders. Greater research and clinical focus is warranted on connections between manic episodes and anxiety disorders. C1 [Olfson, M.; Wang, S.] Columbia Univ, Dept Psychiat, Coll Phys & Surg, Med Ctr,New York State Psychiat Inst, 1051 Riverside Dr, New York, NY 10027 USA. [Mojtabai, R.] Johns Hopkins Univ, Dept Mental Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Mojtabai, R.] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. [Merikangas, K. R.] NIMH, Bethesda, MD 20892 USA. [Compton, W. M.; Blanco, C.] NIDA, Bethesda, MD 20892 USA. [Grant, B. F.] NIAAA, Bethesda, MD USA. RP Olfson, M (reprint author), Columbia Univ, Dept Psychiat, Coll Phys & Surg, Med Ctr,New York State Psychiat Inst, 1051 Riverside Dr, New York, NY 10027 USA. EM mo49@cumc.columbia.edu FU National Institute on Alcohol Abuse and Alcoholism; Intramural Program, NIAAA, National Institutes of Health; Agency for Healthcare Research and Quality [U18 HS021112]; New York State Psychiatric Institute; National Institute on Drug Abuse; National Institute of Mental Health; AHRQ FX The National Epidemiologic Survey on Alcohol and Related Conditions was sponsored by the National Institute on Alcohol Abuse and Alcoholism and funded, in part, by the Intramural Program, NIAAA, National Institutes of Health. The findings and conclusions of this study are those of the authors and do not necessarily reflect the views of the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, the National Institute of Mental Health or the US Department of Health and Human Services. Work on this manuscript was supported by Grant U18 HS021112 from the Agency for Healthcare Research and Quality grant (Dr Olfson) and the New York State Psychiatric Institute (Drs Olfson and Wang). Work by Drs Blanco and Compton was supported by the National Institute on Drug Abuse, work by Dr Merikangas was supported by the National Institute of Mental Health and work by Dr Grant was supported by the National Institute on Alcohol abuse and Alcoholism. Drs Blanco, Compton, Merikangas and Grant had no role in the grant from AHRQ. The sponsors had no additional role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. Dr Wang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 50 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2017 VL 22 IS 2 BP 235 EP 241 DI 10.1038/mp.2016.64 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA EK7JR UT WOS:000394102600012 PM 27137742 ER PT J AU Qin, XY Cao, C Cawley, NX Liu, TT Yuan, J Loh, YP Cheng, Y AF Qin, X-Y Cao, C. Cawley, N. X. Liu, T-T Yuan, J. Loh, Y. P. Cheng, Y. TI Decreased peripheral brain-derived neurotrophic factor levels in Alzheimer's disease: a meta-analysis study (N=7277) SO MOLECULAR PSYCHIATRY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; NEUROPROTECTIVE PROTEIN ADNP; BDNF SERUM CONCENTRATIONS; VAL66MET POLYMORPHISM; AMYLOID-BETA; AEROBIC EXERCISE; INDUCED NEUROTOXICITY; MAJOR DEPRESSION; CONTROLLED-TRIAL; PARIETAL CORTEX AB Studies suggest that dysfunction of brain-derived neurotrophic factor (BDNF) is a possible contributor to the pathology and symptoms of Alzheimer's disease (AD). Several studies report reduced peripheral blood levels of BDNF in AD, but findings are inconsistent. This study sought to quantitatively summarize the clinical BDNF data in patients with AD and mild cognitive impairment (MCI, a prodromal stage of AD) with a meta-analytical technique. A systematic search of Pubmed, PsycINFO and the Cochrane Library identified 29 articles for inclusion in the meta-analysis. Random-effects meta-analysis showed that patients with AD had significantly decreased baseline peripheral blood levels of BDNF compared with healthy control (HC) subjects (24 studies, Hedges' g = - 0.339, 95% confidence interval (CI) = - 0.572 to - 0.106, P = 0.004). MCI subjects showed a trend for decreased BDNF levels compared with HC subjects (14 studies, Hedges' g = - 0.201, 95% CI = - 0.413 to 0.010, P = 0.062). No differences were found between AD and MCI subjects in BDNF levels (11 studies, Hedges' g = 0.058, 95% CI = - 0.120 to 0.236, P = 0.522). Interestingly, the effective sizes and statistical significance improved after excluding studies with reported medication in patients (between AD and HC: 18 studies, Hedges' g = - 0.492, P < 0.001; between MCI and HC: 11 studies, Hedges' g = - 0.339, P = 0.003). These results strengthen the clinical evidence that AD or MCI is accompanied by reduced peripheral blood BDNF levels, supporting an association between the decreasing levels of BDNF and the progression of AD. C1 [Qin, X-Y; Cao, C.; Liu, T-T; Yuan, J.] Minzu Univ China, Sect Translat Neurosci, Coll Life & Environm Sci, Beijing, Peoples R China. [Cawley, N. X.; Loh, Y. P.; Cheng, Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, NIH, Bldg 49,Room 6C80,49 Convent Dr, Bethesda, MD 20892 USA. RP Cheng, Y (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, NIH, Bldg 49,Room 6C80,49 Convent Dr, Bethesda, MD 20892 USA. EM chengy4@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA; Minzu University 985 Academic Team-building Fund [YLDX01013, 2015MDTD13C, 25C, 08C]; 111 Project of China [B08044] FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA, the Minzu University 985 Academic Team-building Fund (YLDX01013, 2015MDTD13C, 25C and 08C) and the 111 Project of China (B08044). NR 118 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2017 VL 22 IS 2 BP 312 EP 320 DI 10.1038/mp.2016.62 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA EK7JR UT WOS:000394102600022 PM 27113997 ER PT J AU Linehan, WM Ricketts, CJ AF Linehan, W. Marston Ricketts, Christopher J. TI RCC - advances in targeted therapeutics and genomics SO NATURE REVIEWS UROLOGY LA English DT Review ID RENAL-CELL CARCINOMA; KIDNEY CANCER; ANTAGONIST; EVEROLIMUS AB Recent advances have been exciting in the genomics of and targeted therapeutics for renal cell carcinoma (RCC). New agents have been approved for advanced RCC, a novel agent targeting hypoxia-inducible factor 2a has shown considerable promise and molecular characterization of papillary RCC provides the foundation for development of targeted therapeutic approaches for this disease. C1 [Linehan, W. Marston; Ricketts, Christopher J.] NCI, Ctr Canc Res, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Ctr Canc Res, Urol Oncol Branch, Bethesda, MD 20892 USA. EM WML@nih.gov NR 10 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 1759-4812 EI 1759-4820 J9 NAT REV UROL JI Nat. Rev. Urol. PD FEB PY 2017 VL 14 IS 2 DI 10.1038/nrurol.2016.260 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EK9EP UT WOS:000394227100013 ER PT J AU Siddiqui, NY Cameron, AP Cella, D Bradley, CS Lai, HH Helmuth, ME Wiseman, J Griffith, JW Amundsen, CL Kenton, KS Clemens, JQ Kreder, KJ Merion, RM Kirkali, Z Kusek, JW AF Siddiqui, Nazema Y. Cameron, Anne P. Cella, David Bradley, Catherine S. Lai, H. Henry Helmuth, Margaret E. Wiseman, Jonathan Griffith, James W. Amundsen, Cindy L. Kenton, Kimberly S. Clemens, J. Quentin Kreder, Karl J. Merion, Robert M. Kirkali, Ziya Kusek, John W. TI INTRA-DETRUSOR AND INTRA-AUGMENT INJECTION OF ONABOTULINUM TOXIN A IMPROVES REFRACTORY STORAGE SYMPTOMS AFTER AUGMENTATION CYSTOPLASTY SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Winter Meeting of the Society-of-Urodynamics-Female-Pelvic-Medicine-and-Urogenital-Reconstruct ion CY FEB 28-MAR 04, 2017 CL Scottsdale, AZ SP Soc Urodynam Female Pelv Med & Urogenital Reconstruct C1 [Siddiqui, Nazema Y.] Duke Univ, Med Ctr, Durham, NC USA. [Cameron, Anne P.; Clemens, J. Quentin] Univ Michigan, Ann Arbor, MI 48109 USA. [Cella, David] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Bradley, Catherine S.] Univ Iowa, Carver Coll Med, Dept Ob Gyn, Iowa City, IA USA. [Lai, H. Henry] Washington Univ, Sch Med, St Louis, MO USA. [Helmuth, Margaret E.; Wiseman, Jonathan; Merion, Robert M.] Arbor Res Collaborat Hlth, Ann Arbor, MI USA. [Griffith, James W.] Northwestern Univ, Chicago, IL 60611 USA. [Amundsen, Cindy L.] Duke Univ, Dept Obstet & Gynecol, Durham, NC USA. [Kreder, Karl J.] Univ Iowa, Iowa City, IA USA. [Kirkali, Ziya; Kusek, John W.] NIDDK, 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 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD FEB PY 2017 VL 36 SU S1 MA M6 BP S34 EP S35 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EL5MJ UT WOS:000394664900055 ER PT J AU Bui, JK Halvas, EK Fyne, E Sobolewski, MD Koontz, D Shao, W Luke, B Hong, FF Kearney, MF Mellors, JW AF Bui, John K. Halvas, Elias K. Fyne, Elizabeth Sobolewski, Michele D. Koontz, Dianna Shao, Wei Luke, Brian Hong, Feiyu F. Kearney, Mary F. Mellors, John W. TI Ex vivo activation of CD4(+) T-cells from donors on suppressive ART can lead to sustained production of infectious HIV-1 from a subset of infected cells SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIRETROVIRAL THERAPY; LATENT RESERVOIR; GENE-EXPRESSION; IN-VIVO; PERSISTENCE; QUANTIFICATION; PATHOGENESIS; EXHAUSTION; PROLIFERATION AB The fate of HIV-infected cells after reversal of proviral latency is not well characterized. Simonetti, et al. recently showed that CD4(+) T-cells containing intact proviruses can clonally expand in vivo and produce low-level infectious viremia. We hypothesized that reversal of HIV latency by activation of CD4(+) T-cells can lead to the expansion of a subset of virus-producing cells rather than their elimination. We established an ex vivo cell culture system involving stimulation of CD4(+) T-cells from donors on suppressive antiretroviral therapy (ART) with PMA/ionomycin (day 1-7), followed by rest (day 7-21), and then repeat stimulation (day 21-28), always in the presence of high concentrations of raltegravir and efavirenz to effectively block new cycles of viral replication. HIV DNA and virion RNA in the supernatant were quantified by qPCR. Single genome sequencing (SGS) of p6-PR-RT was performed to genetically characterize proviruses and virion-associated genomic RNA. The replication-competence of the virions produced was determined by the viral outgrowth assay (VOA) and SGS of co-culture supernatants from multiple time points. Experiments were performed with purified CD4(+) T-cells from five consecutively recruited donors who had been on suppressive ART for > 2 years. In all experiments, HIV RNA levels in supernatant increased following initial stimulation, decreased or remained stable during the rest period, and increased again with repeat stimulation. HIV DNA levels did not show a consistent pattern of change. SGS of proviruses revealed diverse outcomes of infected cell populations, ranging from their apparent elimination to persistence and expansion. Importantly, a subset of infected cells expanded and produced infectious virus continuously after stimulation. These findings underscore the complexity of eliminating reservoirs of HIV-infected cells and highlight the need for new strategies to kill HIV-infected cells before they can proliferate. C1 [Bui, John K.; Halvas, Elias K.; Fyne, Elizabeth; Sobolewski, Michele D.; Koontz, Dianna; Hong, Feiyu F.; Mellors, John W.] Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15213 USA. [Bui, John K.] Howard Hughes Med Inst, Howard Hughes Med Res Fellows Program, Bethesda, MD 20817 USA. [Shao, Wei; Luke, Brian] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD USA. [Kearney, Mary F.] NCI, HIV Dynam & Replicat Program, Frederick, MD 21701 USA. RP Mellors, JW (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15213 USA. EM jwm1@pitt.edu FU Leidos Biomedical Research (National Cancer Institute ) [12XS547, HHSN26120080001E]; Bill & Melinda Gates Foundation [OPP1115715]; Howard Hughes Medical Institute (HHMI) Medical Research Fellows Program FX This work was supported by Leidos Biomedical Research (Grant Number: 12XS547 / National Cancer Institute HHSN26120080001E https://www.leidos.com/about/companies/leidosbiomedical-research , http://www.cancer.gov/) and the Bill & Melinda Gates Foundation (Grant Number: OPP1115715, http://www.gatesfoundation.org/). JKB is a recipient of funding through the Howard Hughes Medical Institute (HHMI) Medical Research Fellows Program (http://www.hhmi.org/programs/medical-researchfellows-program). The funders had no role in study design, data collection and analysis, decision to publish, orpreparation of the manuscript. NR 42 TC 1 Z9 1 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 FEB PY 2017 VL 13 IS 2 AR e1006230 DI 10.1371/journal.ppat.1006230 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EN1BH UT WOS:000395744700039 ER PT J AU Goo, L VanBlargan, LA Dowd, KA Diamond, MS Pierson, TC AF Goo, Leslie VanBlargan, Laura A. Dowd, Kimberly A. Diamond, Michael S. Pierson, Theodore C. TI A single mutation in the envelope protein modulates flavivirus antigenicity, stability, and pathogenesis SO PLOS PATHOGENS LA English DT Article ID WEST-NILE-VIRUS; ANTIBODY-MEDIATED NEUTRALIZATION; CROSS-REACTIVE ANTIBODIES; TICK-BORNE ENCEPHALITIS; PR-M JUNCTION; DENGUE VIRUS; IN-VIVO; MONOCLONAL-ANTIBODY; AEDES-AEGYPTI; ZIKA VIRUS AB The structural flexibility or 'breathing' of the envelope (E) protein of flaviviruses allows virions to sample an ensemble of conformations at equilibrium. The molecular basis and functional consequences of virus conformational dynamics are poorly understood. Here, we identified a single mutation at residue 198 (T198F) of the West Nile virus (WNV) E protein domain I-II hinge that regulates virus breathing. The T198F mutation resulted in a similar to 70-fold increase in sensitivity to neutralization by a monoclonal antibody targeting a cryptic epitope in the fusion loop. Increased exposure of this otherwise poorly accessible fusion loop epitope was accompanied by reduced virus stability in solution at physiological temperatures. Introduction of a mutation at the analogous residue of dengue virus (DENV), but not Zika virus (ZIKV), E protein also increased accessibility of the cryptic fusion loop epitope and decreased virus stability in solution, suggesting that this residue modulates the structural ensembles sampled by distinct flaviviruses at equilibrium in a context dependent manner. Although the T198F mutation did not substantially impair WNV growth kinetics in vitro, studies in mice revealed attenuation of WNV T198F infection. Overall, our study provides insight into the molecular basis and the in vitro and in vivo consequences of flavivirus breathing. C1 [Goo, Leslie; Dowd, Kimberly A.; Pierson, Theodore C.] Natl Inst Hlth, Viral Pathogenesis Sect, Bethesda, MD USA. [VanBlargan, Laura A.; Diamond, Michael S.] Washington Univ Sch Med, Ctr Human Immunol & Immunotherapy Programs, Dept Med, St Louis, MO USA. [VanBlargan, Laura A.; Diamond, Michael S.] Washington Univ Sch Med, Ctr Human Immunol & Immunotherapy Programs, Dept Mol Microbiol, St Louis, MO USA. [VanBlargan, Laura A.; Diamond, Michael S.] Washington Univ Sch Med, Ctr Human Immunol & Immunotherapy Programs, Dept Pathol & Immunol, St Louis, MO USA. RP Pierson, TC (reprint author), Natl Inst Hlth, Viral Pathogenesis Sect, Bethesda, MD USA. EM piersontc@mail.nih.gov FU Burroughs Wellcome Fund; National Institutes of Health [R01 A1073755]; National Institute of Allergy and Infectious Diseases Division of Intramural Research FX This work was supported by grants from the Burroughs Wellcome Fund (MSD) and the National Institutes of Health (R01 A1073755) (MSD), and by the National Institute of Allergy and Infectious Diseases Division of Intramural Research (TCP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 126 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2017 VL 13 IS 2 AR e1006178 DI 10.1371/journal.ppat.1006178 PG 32 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EN1BH UT WOS:000395744700015 PM 28207910 ER PT J AU Qin, L Da, F Fisher, EL Tan, DCS Nguyen, TH Fu, CL Tan, VY McCausland, JW Sturdevant, DE Joo, HS Queck, SY Cheung, GYC Otto, M AF Qin, Li Da, Fei Fisher, Emilie L. Tan, Daniel C. S. Nguyen, Thuan H. Fu, Chih-Lung Tan, Vee Y. McCausland, Joshua W. Sturdevant, Daniel E. Joo, Hwang-Soo Queck, Shu Y. Cheung, Gordon Y. C. Otto, Michael TI Toxin Mediates Sepsis Caused by Methicillin-Resistant Staphylococcus epidermidis SO PLOS PATHOGENS LA English DT Article ID COAGULASE-NEGATIVE STAPHYLOCOCCI; PHENOL-SOLUBLE MODULINS; VIRULENCE FACTORS; SENSING SYSTEM; AUREUS; INFECTIONS; EVOLUTION; RNA AB Bacterial sepsis is a major killer in hospitalized patients. Coagulase-negative staphylococci (CNS) with the leading species Staphylococcus epidermidis are the most frequent causes of nosocomial sepsis, with most infectious isolates being methicillin-resistant. However, which bacterial factors underlie the pathogenesis of CNS sepsis is unknown. While it has been commonly believed that invariant structures on the surface of CNS trigger sepsis by causing an over-reaction of the immune system, we show here that sepsis caused by methicillinresistant S. epidermidis is to a large extent mediated by the methicillin resistance islandencoded peptide toxin, PSM-mec. PSM-mec contributed to bacterial survival in whole human blood and resistance to neutrophil-mediated killing, and caused significantly increased mortality and cytokine expression in a mouse sepsis model. Furthermore, we show that the PSM-mec peptide itself, rather than the regulatory RNA in which its gene is embedded, is responsible for the observed virulence phenotype. This finding is of particular importance given the contrasting roles of the psm-mec locus that have been reported in S. aureus strains, inasmuch as our findings suggest that the psm-mec locus may exert effects in the background of S. aureus strains that differ from its original role in the CNS environment due to originally "unintended" interferences. Notably, while toxins have never been clearly implied in CNS infections, our tissue culture and mouse infection model data indicate that an important type of infection caused by the predominant CNS species is mediated to a large extent by a toxin. These findings suggest that CNS infections may be amenable to virulence- targeted drug development approaches. C1 [Qin, Li; Da, Fei; Fisher, Emilie L.; Tan, Daniel C. S.; Nguyen, Thuan H.; Fu, Chih-Lung; Tan, Vee Y.; McCausland, Joshua W.; Joo, Hwang-Soo; Queck, Shu Y.; Cheung, Gordon Y. C.; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Bacteriol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Qin, Li] Huazhong Univ Sci & Technol, Tongji Med Coll, Wuhan Hosp 1, Dept Dermatol, Wuhan, Peoples R China. [Da, Fei] Fourth Mil Med Univ, Dept Pharmacol, Sch Pharm, Xian, Peoples R China. [Sturdevant, Daniel E.] NIAID, Res Technol Branch, Rocky Mt Labs, Hamilton, MT USA. [Tan, Daniel C. S.] Univ New South Wales, Sch Med Sci, Dept Anat, Sydney, NSW, Australia. [Queck, Shu Y.] Biomerieux Singapore Pte Ltd, Singapore, Singapore. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Bacteriol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) [AI001080-15] FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) (https://www.niaid.nih.gov/about/dir), grant AI001080-15 (to MO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 1 Z9 1 U1 1 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 FEB PY 2017 VL 13 IS 2 AR e1006153 DI 10.1371/journal.ppat.1006153 PG 16 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EN1BH UT WOS:000395744700007 ER PT J AU Chaudhry, AA Gul, M Chaudhry, AA Moore, W AF Chaudhry, Ammar A. Gul, Maryam Chaudhry, Abbas A. Moore, William TI Case 238: Spontaneous Pneumothorax Secondary to Intrapulmonary Necrobiotic Rheumatoid Nodule SO RADIOLOGY LA English DT Editorial Material ID HIGH-RESOLUTION CT; LUNG-DISEASE; ARTHRITIS; CHEST AB A 54-year-old white woman with a history of rheumatoid arthritis who was taking glucocorticoids and methotrexate presented to the emergency department in December with worsening shortness of breath and chest heaviness for 1 week. She reported additional symptoms of weakness, headache, and arthralgia primarily involving her bilateral hands, wrist, ankles, and feet. She denied experiencing fevers, syncope or presyncope, focal neurologic deficits, chest pain, nausea, vomiting, unintentional weight loss, or recent trauma. Additional medical history included hypertension, asthma, degenerative disk disease, and migraine, all of which were reportedly controlled with medications. This patient had a smoking history of 80 pack-years, but she had quit smoking 2 months prior to presentation. She denied abuse of alcohol or recreational drugs and reported she was up-to-date on her immunizations, including those for pneumonia and flu. Family history was pertinent for breast cancer in her mother, sister, and maternal aunt. The patient reported normal findings at screening mammography and colonoscopy. A physical examination was remarkable for slightly asymmetric breath sounds, which appeared to be diminished on the right side. This patient had multiple joint deformities, most notably in the bilateral metacarpophalangeal joints. Initial electrocardiography findings and cardiac biomarkers were negative. Her complete blood count and basic metabolic profile were unremarkable. Posteroanterior and lateral chest radiographs were obtained in the emergency department. Subsequently, computed tomography (CT) of the chest was performed. C1 [Chaudhry, Ammar A.; Chaudhry, Abbas A.; Moore, William] SUNY Stony Brook, Med Ctr, Dept Radiol, HSC Level 4,Room 120,East Loop Rd, Stony Brook, NY 11794 USA. [Gul, Maryam] Winthrop Univ Hosp, Dept Internal Med, Mineola, NY 11501 USA. [Chaudhry, Ammar A.] Johns Hopkins Med Inst, 600 N Wolfe St,PhippsB100, Baltimore, MD 21287 USA. [Gul, Maryam] NIAMSD, NIH, Bethesda, MD 20892 USA. [Chaudhry, Abbas A.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Moore, William] NYU, Langone Hosp, New York, NY USA. RP Chaudhry, AA (reprint author), SUNY Stony Brook, Med Ctr, Dept Radiol, HSC Level 4,Room 120,East Loop Rd, Stony Brook, NY 11794 USA.; Chaudhry, AA (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM achaud23@jhmi.edu NR 16 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 282 IS 2 BP 602 EP 608 DI 10.1148/radiol.2016150224 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EM7VY UT WOS:000395521600035 PM 28099107 ER PT J AU Arancio, O Bezprozvanny, I Berger, T Bouteiller, JM Carrillo, M Disterhoft, J Foskett, K Khachaturian, AS LaFerla, F Landfield, PW Masliah, E Mattson, M Michaelis, ML Nixon, R Snyder, H Stutzmann, G Thibault, O Yang, A Khachaturian, ZS Scholz, K AF Arancio, Ottavio Bezprozvanny, Ilya Berger, Theodore Bouteiller, Jean-Marie Carrillo, Maria Disterhoft, John Foskett, Kevin Khachaturian, Ara S. LaFerla, Frank Landfield, Philip W. Masliah, Eliezer Mattson, Mark Michaelis, Mary L. Nixon, Ralph Snyder, Heather Stutzmann, Grace Thibault, Olivier Yang, Austin Khachaturian, Zaven S. Scholz, Ken CA Alzheimer's Assoc Calcium Hyp TI Calcium Hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis SO ALZHEIMERS & DEMENTIA LA English DT Review DE Calcium; Hypothesis; Aging; Alzheimer's disease; Dementia; Neuron; Neurodegeneration; Model; Aging mechanism; Brain; Performance; Development; Amyloid; Tau ID PLASMA-MEMBRANE CA2+-ATPASE; DISORDERS; CALPAINS; BETA; RATS AB This article updates the Calcium Hypothesis of Alzheimer's disease and brain aging on the basis of emerging evidence since 1994 (The present article, with the subtitle "New evidence for a central role of Ca2+ in neurodegeneration," includes three appendices that provide context and further explanations for the rationale for the revisions in the updated hypothesis-the three appendices are as follows: Appendix I "Emerging concepts on potential pathogenic roles of [Ca2+]," Appendix II Future studies to validate the central role of dysregulated [Ca2+] in neurodegeneration, and Appendix III Epilogue: towards a comprehensive hypothesis.) (Marx J. Fresh evidence points to an old suspect: calcium. Science 2007; 318:384385). The aim is not only to re-evaluate the original key claims of the hypothesis with a critical eye but also to identify gaps in knowledge required to validate relevant claims and delineate additional studies and/or data that are needed. Some of the key challenges for this effort included examination of questions regarding (1) the temporal and spatial relationships of molecular mechanisms that regulate neuronal calcium ion (Ca2+), (2) the role of changes in concentration of calcium ion [Ca2+] in various subcellular compartments of neurons, (3) how alterations in Ca2+ signaling affect the performance of neurons under various conditions, ranging from optimal functioning in a healthy state to conditions of decline and deterioration in performance during aging and in disease, and (4) new ideas about the contributions of aging, genetic, and environmental factors to the causal relationships between dysregulation of [Ca2+] and the functioning of neurons (see Appendices I and II). The updated Calcium Hypothesis also includes revised postulates that are intended to promote further crucial experiments to confirm or reject the various predictions of the hypothesis (see Appendix III). (C) 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved. C1 [Arancio, Ottavio] Columbia Univ, New York, NY 10027 USA. [Bezprozvanny, Ilya] UTSMC, Dallas, TX USA. [Berger, Theodore; Bouteiller, Jean-Marie] USC, Los Angeles, CA USA. [Carrillo, Maria; Snyder, Heather] Alzheimers Assoc, Chicago, IL USA. [Disterhoft, John] Northwestern Univ, Evanston, IL 60208 USA. [Foskett, Kevin] Univ Penn, Philadelphia, PA 19104 USA. [Khachaturian, Ara S.; Khachaturian, Zaven S.] Alzheimers & Dementia, Rockville, MD 20850 USA. [LaFerla, Frank] UCI, Irvine, CA USA. [Masliah, Eliezer] UCSD, La Jolla, CA USA. [Mattson, Mark; Yang, Austin] NIA, NIH, Bethesda, MD 20892 USA. [Michaelis, Mary L.] Univ Kansas, Lawrence, KS 66045 USA. [Nixon, Ralph] NYU, New York, NY 10003 USA. [Stutzmann, Grace] Rosalind Franklin Chicago Med Sch, N Chicago, IL USA. [Thibault, Olivier] Univ Kentucky, Lexington, KY 40506 USA. RP Khachaturian, ZS (reprint author), Alzheimers & Dementia, Rockville, MD 20850 USA. EM adj@kra.net NR 32 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD FEB PY 2017 VL 13 IS 2 BP 178 EP 182 DI 10.1016/j.jalz.2016.12.006 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA EL6II UT WOS:000394724900008 ER PT J AU Nakamura, Y Ohler, ZW Householder, D Nagaya, T Sato, K Okuyama, S Ogata, F Daar, D Hoa, T Choyke, PL Kobayashi, H AF Nakamura, Yuko Ohler, Zoe Weaver Householder, Deborah Nagaya, Tadanobu Sato, Kazuhide Okuyama, Shuhei Ogata, Fusa Daar, Dagane Hoa, Tieu Choyke, Peter L. Kobayashi, Hisataka TI Near Infrared Photoimmunotherapy in a Transgenic Mouse Model of Spontaneous Epidermal Growth Factor Receptor (EGFR)-expressing Lung Cancer SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID IN-VIVO; MONOCLONAL-ANTIBODIES; METASTATIC MODEL; EXPRESSION; TUMORS; MICE AB Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of antibodies for targeting tumors with the toxicity induced by a sensitive photoabsorber following exposure to NIR light. Most studies of NIR-PIT have been performed in xenograft models of cancer. The purpose of this study was to evaluate the therapeutic effects of NIR-PIT in a transgenic model of spontaneous lung cancer expressing human EGFR (hEGFR-TL). Mice were separated into 3 groups for the following treatments: (1) no treatment (control); (2) 150 mg of photoabsorber, IR700, conjugated to panitumumab, an antibody targeting EGFR [antibody-photoabsorber conjugate (APC)] intravenously (i. v.) only; (3) 150 mg of APC i. v. with NIR light administration. Each treatment was performed every week up to three weeks. MRI was performed 1 day before and 3, 6, 13, 20, 27, and 34 days after first NIR-PIT. The relative volume of lung tumors was calculated from the tumor volume at each MRI time point divided by the initial volume. Steel test for multiple comparisons was used to compare the tumor volume ratio with that of control. Tumor volume ratio was inhibited significantly in the NIR-PIT group compared with control group (P < 0.01 at all time points). In conclusion, NIR-PIT effectively treated a spontaneous lung cancer in a hEGFR-TL transgenic mouse model. MRI successfully monitored the therapeutic effects of NIR-PIT. C1 [Nakamura, Yuko; Nagaya, Tadanobu; Sato, Kazuhide; Okuyama, Shuhei; Ogata, Fusa; Daar, Dagane; Hoa, Tieu; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Ohler, Zoe Weaver; Householder, Deborah] Leidos Biomed Res Inc, Ctr Adv Preclin Res, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU Intramural Research Program of the NIH; NCI; Center for Cancer Research FX All authors were supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. NR 28 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD FEB PY 2017 VL 16 IS 2 BP 408 EP 414 DI 10.1158/1535-7163.MCT-16-0663 PG 7 WC Oncology SC Oncology GA EM8LV UT WOS:000395563700015 PM 28151706 ER PT J AU White, SF Geraci, M Lewis, E Leshin, J Teng, C Averbeck, B Meffert, H Ernst, M Blair, JR Grillon, C Blair, KS AF White, Stuart F. Geraci, Marilla Lewis, Elizabeth Leshin, Joseph Teng, Cindy Averbeck, Bruno Meffert, Harma Ernst, Monique Blair, James R. Grillon, Christian Blair, Karina S. TI Prediction Error Representation in Individuals With Generalized Anxiety Disorder During Passive Avoidance SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID VENTROMEDIAL PREFRONTAL CORTEX; DECISION-MAKING; SOCIAL PHOBIA; RISK; UNCERTAINTY; IMPAIRMENT AB Objective: Deficits in reinforcement-based decision making have been reported in generalized anxiety disorder. However, the pathophysiology of these deficits is largely unknown; published studies have mainly examined adolescents, and the integrity of core functional processes underpinning decision making remains undetermined. In particular, it is unclear whether the representation of reinforcement prediction error (PE) (the difference between received and expected reinforcement) is disrupted in generalized anxiety disorder. This study addresses these issues in adults with the disorder. Method: Forty-six unmedicated individuals with generalized anxiety disorder and 32 healthy comparison subjects group-matched on IQ, gender, and age performed a passive avoidance task while undergoing functional MRI. Data analyses were performed using a computational modeling approach. Results: Behaviorally, individuals with generalized anxiety disorder showed impaired reinforcement-based decision making. Imaging results revealed that during feedback, individuals with generalized anxiety disorder relative to healthy subjects showed a reduced correlation between PE and activity within the ventromedial prefrontal cortex, ventral striatum, and other structures implicated in decision making. In addition, individuals with generalized anxiety disorder relative to healthy participants showed a reduced correlation between punishment PEs, but not reward PEs, and activity within the left and right lentiform nucleus/putamen. Conclusions: This is the first study to identify computational impairments during decision making in generalized anxiety disorder. PE signaling is significantly disrupted in individuals with the disorder and may lead to their decision-making deficits and excessive worry about everyday problems by disrupting the online updating ("reality check") of the current relationship between the expected values of current response options and the actual received rewards and punishments. C1 [White, Stuart F.] NIMH, Sect Affect Cognit Neurosci, Bethesda, MD 20892 USA. NIMH, Sect Fear & Anxiety, Bethesda, MD 20892 USA. NIMH, Unit Learning & Decis Making, Bethesda, MD 20892 USA. Boys Town Natl Res Hosp, Ctr Neurobehav Res, Boys Town, NE USA. RP White, SF (reprint author), NIMH, Sect Affect Cognit Neurosci, Bethesda, MD 20892 USA. EM stuart.white@boystown.org FU Intramural Research Program of NIMH [1-ZIA-MH002860, 1-ZIA-MH002928, 1-ZIA-MH002798] FX Supported by the Intramural Research Program of NIMH (1-ZIA-MH002860; principal investigator, Dr. Blair; 1-ZIA-MH002928; principal investigator, Dr. Averbeck; 1-ZIA-MH002798; principal investigator, Dr. Grillon). NR 28 TC 1 Z9 1 U1 2 U2 2 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 FEB 1 PY 2017 VL 174 IS 2 BP 110 EP 117 DI 10.1176/appi.ajp.2016.15111410 PG 8 WC Psychiatry SC Psychiatry GA EO4JW UT WOS:000396662200008 PM 27631963 ER PT J AU Altice, CK Banegas, MP Tucker-Seeley, RD Yabroff, KR AF Altice, Cheryl K. Banegas, Matthew P. Tucker-Seeley, Reginald D. Yabroff, K. Robin TI Financial Hardships Experienced by Cancer Survivors: A Systematic Review SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID OUT-OF-POCKET; CARE EXPENDITURE BURDEN; UNITED-STATES; BREAST-CANCER; HEALTH-CARE; ECONOMIC BURDEN; COLORECTAL-CANCER; PROSTATE-CANCER; MULTIPLE-MYELOMA; INDIRECT COSTS AB Background: With rising cancer care costs, including high-priced cancer drugs, financial hardship is increasingly documented among cancer survivors in the United States; research findings have not been synthesized. Methods: We conducted a systematic review of articles published between 1990 and 2015 describing the financial hardship experienced by cancer survivors using PubMed, Embase, Scopus, and CINAHL databases. We categorized measures of financial hardship into: material conditions (eg, out-of-pocket costs, productivity loss, medical debt, or bankruptcy), psychological responses (eg, distress or worry), and coping behaviors (eg, skipped medications). We abstracted findings and conducted a qualitative synthesis. Results: Among 676 studies identified, 45 met the inclusion criteria and were incorporated in the review. The majority of the studies (82%, n = 37) reported financial hardship as a material condition measure; others reported psychological (7%, n = 3) and behavioral measures (16%, n = 7). Financial hardship measures were heterogeneous within each broad category, and the prevalence of financial hardship varied by the measure used and population studied. Mean annual productivity loss ranged from $ 380 to $ 8236, 12% to 62% of survivors reported being in debt because of their treatment, 47% to 49% of survivors reported experiencing some form of financial distress, and 4% to 45% of survivors did not adhere to recommended prescription medication because of cost. Conclusions: Financial hardship is common among cancer survivors, although we found substantial heterogeneity in its prevalence. Our findings highlight the need for consistent use of definitions, terms, and measures to determine the best intervention targets and inform intervention development in order to prevent and minimize the impact of financial hardship experienced by cancer survivors. C1 [Altice, Cheryl K.; Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Banegas, Matthew P.] Kaiser Permanente, Ctr Hlth Res, Portland, OR USA. [Tucker-Seeley, Reginald D.] Harvard Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Tucker-Seeley, Reginald D.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Yabroff, KR (reprint author), US Dept HHS, Div Hlth Care Financing Policy, Off Hlth Policy, Planning & Evaluat, 200 Independence Ave SW, Washington, DC 20201 USA. EM robin.yabroff@hhs.gov FU National Cancer Institute K01 Career Development Grant [K01 CA169041] FX Dr. Tucker-Seeley was supported by a National Cancer Institute K01 Career Development Grant (K01 CA169041). NR 82 TC 1 Z9 1 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD FEB PY 2017 VL 109 IS 2 AR djw205 DI 10.1093/jnci/djw205 PG 17 WC Oncology SC Oncology GA EO6AM UT WOS:000396774100004 ER PT J AU Casulo, C O'Connor, O Shustov, A Fanale, M Friedberg, JW Leonard, JP Kahl, BS Little, RF Pinter-Brown, L Advani, R Horwitz, S AF Casulo, Carla O'Connor, Owen Shustov, Andrei Fanale, Michelle Friedberg, Jonathan W. Leonard, John P. Kahl, Brad S. Little, Richard F. Pinter-Brown, Lauren Advani, Ranjani Horwitz, Steven TI T-Cell Lymphoma: Recent Advances in Characterization and New Opportunities for Treatment SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID NON-HODGKIN-LYMPHOMA; PHASE-II; BRENTUXIMAB VEDOTIN; PROGNOSTIC-FACTORS; MYCOSIS-FUNGOIDES; OPEN-LABEL; MUTATIONS; EXPRESSION; TRIAL; KINASE AB Peripheral T-cell lymphomas (PTCLs) are uncommon, heterogeneous, and aggressive non-Hodgkin's lymphomas. Despite progress in the last several years resulting in a deeper understanding of PTCL biology and pathogenesis, there is currently no accepted single standard of care for newly diagnosed patients, and for those with relapsed or refractory disease, prognosis is dismal. The National Cancer Institute convened a Clinical Trials Planning Meeting to advance the national clinical trial agenda in lymphoma. The objective was to identify unmet needs specific to five major lymphoma subtypes and develop strategies to address them. This consensus statement reviews recent advances in the molecular and genetic characterization of PTCL that may inform novel treatments, proposes strategies to test novel therapies in the relapsed setting with the hopes of rapid advancement into frontline trials, and underscores the need for the identification and development of active and biologically rational therapies to cure PTCL at higher rates, with iterative biomarker evaluation. C1 [Casulo, Carla; Friedberg, Jonathan W.] Univ Rochester, Wilmot Canc Ctr, Rochester, NY USA. [O'Connor, Owen] Columbia Univ, Med Ctr, New York, NY USA. [Shustov, Andrei] Seattle Canc Care Alliance, Seattle, WA USA. [Fanale, Michelle] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Leonard, John P.] Weil Cornell Univ, Dept Med, New York, NY USA. [Kahl, Brad S.] Washington Univ, Div Oncol, St Louis, MO USA. [Little, Richard F.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Pinter-Brown, Lauren] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Orange, CA 92668 USA. [Advani, Ranjani] Stanford Univ, Stanford Canc Inst, Stanford, CA 94305 USA. [Horwitz, Steven] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RP Casulo, C (reprint author), Univ Rochester, Wilmot Canc Inst, Lymphoma Program, 601 Elmwood Ave,Box 704, Rochester, NY 14642 USA. EM carla_casulo@urmc.rochester.edu FU Office of the Director, Coordinating Center for Clinical Trials, National Cancer Institute/National Institutes of Health FX Partial support was from the Office of the Director, Coordinating Center for Clinical Trials, National Cancer Institute/National Institutes of Health. NR 57 TC 0 Z9 0 U1 2 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 FEB PY 2017 VL 109 IS 2 AR djw248 DI 10.1093/jnci/djw248 PG 9 WC Oncology SC Oncology GA EO6AM UT WOS:000396774100011 ER PT J AU Guise, JM Geller, S Regensteiner, JG Raymond, N Nagel, J AF Guise, Jeanne-Marie Geller, Stacie Regensteiner, Judith G. Raymond, Nancy Nagel, Joan CA Building Interdisciplinary Res Car TI Team Mentoring for Interdisciplinary Team Science: Lessons From K12 Scholars and Directors SO ACADEMIC MEDICINE LA English DT Article ID TRANSLATIONAL SCIENCE; ACADEMIC MEDICINE; FAMILY MEDICINE; PRIMARY-CARE; ROLE MODELS; FACULTY; FELLOWS; PRODUCTIVITY; PSYCHIATRY; SATISFACTION AB Purpose Mentoring is critical for academic success. As science transitions to a team science model, team mentoring may have advantages. The goal of this study was to understand the process, benefits, and challenges of team mentoring relating to career development and research. Method A national survey was conducted of Building Interdisciplinary Research Careers in Women's Health (BIRCWH) program directors-current and former scholars from 27 active National Institutes of Health (NIH)-funded BIRCWH NIH K12 programs-to characterize and understand the value and challenges of the team approach to mentoring. Quantitative data were analyzed descriptively, and qualitative data were analyzed thematically. Results Responses were received from 25/27 (93%) program directors, 78/108 (72%) current scholars, and 91/162 (56%) former scholars. Scholars reported that team mentoring was beneficial to their career development (152/169; 90%) and research (148/169; 88%). Reported advantages included a diversity of opinions, expanded networking, development of stronger study designs, and modeling of different career paths. Challenges included scheduling and managing conflicting opinions. Advice by directors offered to junior faculty entering team mentoring included the following: not to be intimidated by senior mentors, be willing to navigate conflicting advice, be proactive about scheduling and guiding discussions, have an open mind to different approaches, be explicit about expectations and mentors' roles (including importance of having a primary mentor to help navigate discussions), and meet in person as a team. Conclusions These findings suggest that interdisciplinary/interprofessional team mentoring has many important advantages, but that skills are required to optimally utilize multiple perspectives. C1 [Guise, Jeanne-Marie] Oregon Hlth & Sci Univ, Div Maternal Fetal Med, Dept Obstet & Gynecol,Dept Emergency Med, Dept Publ Hlth & Prevent Med,Dept Med Informat &, Portland, OR 97201 USA. [Geller, Stacie] Univ Illinois, Coll Med, Dept Obstet & Gynecol, Chicago, IL 60612 USA. [Geller, Stacie] Univ Illinois, Coll Med, Ctr Res Women & Gender, Chicago, IL 60612 USA. [Regensteiner, Judith G.] Univ Colorado, Div Gen Internal Med, Denver, CO USA. [Regensteiner, Judith G.] Univ Colorado, Div Cardiol, Denver, CO USA. [Regensteiner, Judith G.] Univ Colorado, Ctr Womens Hlth Res, Denver, CO USA. [Raymond, Nancy] Univ Minnesota, Dept Psychiat, Powell Ctr Womens Hlth, Minneapolis, MN 55455 USA. [Nagel, Joan] NIH, Div Clin Innovat, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. RP Guise, JM (reprint author), Oregon Hlth & Sci Univ, Mail Code L466,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM guisej@ohsu.edu FU Building Interdisciplinary Research Careers in Women's Health (BIRCWH); NIH [OHSU K12 HD043488, U Colorado K12HD057022, UIC K12HD055892, U Minn K12HD055887] FX Building Interdisciplinary Research Careers in Women's Health (BIRCWH) programs are funded through the National Institutes of Health (NIH) Office of Research on Women's Health and the NIH through the following grants: OHSU K12 HD043488, U Colorado K12HD057022, UIC K12HD055892, U Minn K12HD055887. NR 34 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD FEB PY 2017 VL 92 IS 2 BP 214 EP 221 DI 10.1097/ACM.0000000000001330 PG 8 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA EK1IA UT WOS:000393677800026 PM 27556675 ER PT J AU Levell, JR Caferro, T Chenail, G Dix, I Dooley, J Firestone, B Fortin, PD Giraldes, J Gould, T Growney, JD Jones, MD Kulathila, R Lin, F Liu, G Mueller, A van der Plas, S Slocum, K Smith, T Terranova, R Toure, BB Tyagi, V Wagner, T Xie, XL Xu, M Yang, FS Zhou, LPX Pagliarini, R Cho, YS AF Levell, Julian R. Caferro, Thomas Chenail, Gregg Dix, Ina Dooley, Julia Firestone, Brant Fortin, Pascal D. Giraldes, John Gould, Ty Growney, Joseph D. Jones, Michael D. Kulathila, Raviraj Lin, Fallon Liu, Gang Mueller, Arne van der Plas, Simon Slocum, Kelly Smith, Troy Terranova, Remi Toure, B. Barry Tyagi, Viraj Wagner, Trixie Xie, Xiaoling Xu, Ming Yang, Fan S. Zhou, Liping X. Pagliarini, Raymond Cho, Young Shin TI Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1 SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Mutant IDH1 inhibitor; allosteric inhibition; 2-HG; preclinical in vivo activity; 3-pyrimidin-4-yloxazolidin-2-one; chirality-defined potency ID ISOCITRATE DEHYDROGENASE; SELECTIVE-INHIBITION; SMALL-MOLECULE; MUTATION; CANCER AB High throughput screening and subsequent hit validation identified 4-isopropyl-3-2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDHI2S, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1(wt). Initial structure-activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood-brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model. C1 [Levell, Julian R.; Caferro, Thomas; Chenail, Gregg; Dix, Ina; Dooley, Julia; Firestone, Brant; Fortin, Pascal D.; Giraldes, John; Gould, Ty; Growney, Joseph D.; Jones, Michael D.; Kulathila, Raviraj; Lin, Fallon; Liu, Gang; Mueller, Arne; van der Plas, Simon; Slocum, Kelly; Smith, Troy; Terranova, Remi; Toure, B. Barry; Tyagi, Viraj; Wagner, Trixie; Xie, Xiaoling; Xu, Ming; Yang, Fan S.; Zhou, Liping X.; Pagliarini, Raymond; Cho, Young Shin] Novartis Inst Biomed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA. [Levell, Julian R.] Constellat Pharmaceut, 215 First St,Suite 200, Cambridge, MA 02142 USA. [Fortin, Pascal D.; Toure, B. Barry] Relay Therapeut, 215 First St,Suite 300, Cambridge, MA 02142 USA. [Xu, Ming] DuPont Co Inc, 1007 Market St, Wilmington, DE 19898 USA. [Giraldes, John] NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Zhou, Liping X.] Ipsen Biosci Inc, 650 East Kendall St, Cambridge, MA 02142 USA. [Firestone, Brant] Surface Oncol, 215 First St,Suite 400-S, Cambridge, MA 02142 USA. RP Pagliarini, R; Cho, YS (reprint author), Novartis Inst Biomed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA. EM raymond.pagliarini@novartis.com; youngshin.cho@novartis.com NR 17 TC 0 Z9 0 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD FEB PY 2017 VL 8 IS 2 BP 151 EP 156 DI 10.1021/acsmedchemlett.6b00334 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EK5AI UT WOS:000393938900004 PM 28197303 ER PT J AU Echeverria, C Diaz, A Suarez, B Bevilacqua, JA Bonnemann, C Bertini, E Castiglioni, C AF Echeverria, Constanza Diaz, Alejandra Suarez, Bernardita Bevilacqua, Jorge A. Bonnemann, Carsten Bertini, Enrico Castiglioni, Claudia TI Keloids, Spontaneous or After Minor Skin Injury: Importance of Not Missing Bethlem Myopathy SO ACTA DERMATO-VENEREOLOGICA LA English DT Editorial Material ID COLLAGEN VI MYOPATHIES; INHERITANCE; SEVERITY; MATRIX; MUSCLE C1 [Echeverria, Constanza] Pontificia Univ Catolica Chile, Sch Med, Santiago, Chile. [Diaz, Alejandra; Suarez, Bernardita] Nat Inst Rehabil, Pedro Aguirre Cerda, Chile. Univ Chile, Hosp Clin, Dept Neurol & Neurocirugia, Santiago, Chile. [Bevilacqua, Jorge A.] Univ Chile, Fac Med, Programa Anat & Biol Desarrollo, Santiago, Chile. [Suarez, Bernardita; Castiglioni, Claudia] Clin Las Condes, Dept Pediat, Neurol Unit, Lo Fontecilla 441, Santiago, Chile. [Bonnemann, Carsten] NINDS, Neuromuscular & Neurogenet Disorders Childhood S, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Bertini, Enrico] Bambino Gesu Pediat Hosp, IRCCS, Dept Neurosci, Unit Neuromuscular & Neurodegenerat Disorders, Rome, Italy. RP Castiglioni, C (reprint author), Clin Las Condes, Dept Pediat, Neurol Unit, Lo Fontecilla 441, Santiago, Chile. EM ccastiglioni@clc.cl FU Intramural NIH HHS [ZIA NS003129-06, Z99 NS999999] NR 15 TC 0 Z9 0 U1 1 U2 1 PU ACTA DERMATO-VENEREOLOGICA PI UPPSALA PA TRADGARDSGATAN 14, UPPSALA, SE-753 09, SWEDEN SN 0001-5555 EI 1651-2057 J9 ACTA DERM-VENEREOL JI Acta Derm.-Venereol. PD FEB PY 2017 VL 97 IS 2 BP 297 EP 298 DI 10.2340/00015555-2523 PG 2 WC Dermatology SC Dermatology GA EK4KM UT WOS:000393895500035 PM 27563703 ER PT J AU White, AM AF White, Aaron M. TI Commentary on Patrick and Colleagues: High-Intensity Drinking Among Young Adults in the United States: Prevalence, Frequency, and Developmental Change SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Editorial Material ID COLLEGE-FRESHMEN DRINK; SELF-REPORTED DRINKING; ALCOHOL-CONSUMPTION; BINGE DRINKING; STUDENTS; PERSPECTIVE; PREVENTION; THRESHOLD; IMPACT; INJURY C1 [White, Aaron M.] NIAAA, Off Director, Rockville, MD 20852 USA. RP White, AM (reprint author), NIAAA, Off Director, NIH, 5635 Fishers Lane,Room 2091, Bethesda, MD 20892 USA. EM whitea4@mail.nih.gov NR 38 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2017 VL 41 IS 2 BP 270 EP 274 DI 10.1111/acer.13306 PG 5 WC Substance Abuse SC Substance Abuse GA EK4IV UT WOS:000393891200006 PM 28102543 ER PT J AU Rohn, MCH Lee, MR Kleuter, SB Schwandt, ML Falk, DE Leggio, L AF Rohn, Matthew C. H. Lee, Mary R. Kleuter, Samuel B. Schwandt, Melanie L. Falk, Daniel E. Leggio, Lorenzo TI Differences Between Treatment-Seeking and Nontreatment-Seeking Alcohol-Dependent Research Participants: An Exploratory Analysis SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol Use Disorder; Alcohol Dependence; Treatment; Treatment Seeking; Nontreatment Seeking ID NATIONAL EPIDEMIOLOGIC SURVEY; USE DISORDER; FAMILY-HISTORY; QUESTIONNAIRE; PREDICTORS; ABUSE; MODEL; ENTRY; MEDICATIONS; BARRIERS AB Background: Alcoholism is a chronic relapsing disorder with complex behavioral and functional heterogeneity. To date, attempts to characterize subgroups of alcohol-dependent (AD) individuals have largely been focused on categorical distinctions based on behaviors such as ability to abstain, age of onset, and drinking motives, but these have failed to yield predictors of treatment response and disease course. The distinction between AD individuals who are or are not interested in treatment holds significant implications for interpreting results of human laboratory studies with nontreatment seekers and clinical trials with treatment-seeking AD patients. However, despite their crucial role in alcohol-related research, these 2 groups are poorly defined. In this exploratory analysis, we attempt to better define the phenotypic differences between these 2 experimentally relevant populations. Methods: We analyzed data from AD individuals who participated in screening protocols to evaluate their suitability for participation in either treatment or nontreatment research studies at NIAAA. Scores on individual measures from a battery of behavioral, neuropsychological, and blood laboratory measures were compared between those who presented seeking treatment for AD and those who were not seeking treatment. Differences in each measure were assessed between the 2 groups. In addition, we explored whether significant differences were apparent when drinking behavior was used as a covariate. Results: Treatment seekers manifested more impairment compared to nontreatment seekers on a wide variety of measures in the following categories: alcohol drinking, personality, impulsivity, trauma/stress, cognition, aggression, mood, and liver enzyme tests. Treatment seekers endorsed a greater number of AD criteria. Several measures including elevations in liver enzyme tests remained significantly different between the 2 groups when average daily alcohol consumption per drinking day was used as a covariate. Conclusions: Treatment-seeking, compared to nontreatment-seeking AD subjects who present for alcohol-related research studies, differ in characteristics beyond the quantity of alcohol consumption. Implications of these differences with respect to clinical research for treatments of AD are discussed. C1 [Rohn, Matthew C. H.; Lee, Mary R.; Kleuter, Samuel B.; Leggio, Lorenzo] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Bethesda, MD 20892 USA. [Rohn, Matthew C. H.; Lee, Mary R.; Kleuter, Samuel B.; Leggio, Lorenzo] NIDA, NIH, Bethesda, MD 20892 USA. [Schwandt, Melanie L.] NIAAA, Off Clin Director, NIH, Bethesda, MD USA. [Falk, Daniel E.] NIAAA, Div Medicat Dev, Bethesda, MD USA. [Leggio, Lorenzo] Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Providence, RI 02912 USA. RP Lee, MR; Leggio, L (reprint author), NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Bethesda, MD 20892 USA.; Lee, MR; Leggio, L (reprint author), NIDA, Bethesda, MD 20892 USA. EM leemary@mail.nih.gov; lorenzo.leggio@nih.gov FU NIH [ZIA-AA000218]; Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Research Program of the National Institute on Drug Abuse (NIDA) FX This work was supported by NIH intramural funding ZIA-AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology; PI: Leggio), jointly supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Intramural Research Program of the National Institute on Drug Abuse (NIDA). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 38 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2017 VL 41 IS 2 BP 414 EP 420 DI 10.1111/acer.13304 PG 7 WC Substance Abuse SC Substance Abuse GA EK4IV UT WOS:000393891200021 PM 28129451 ER PT J AU Takyar, V Koh, C AF Takyar, V. Koh, C. TI Letter: need to re-evaluate non-invasive markers for staging fibrosis in chronic delta hepatitis - authors' reply SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Letter ID METAANALYSIS; PREVALENCE C1 [Takyar, V.; Koh, C.] Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Koh, C (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM christopher.koh@nih.gov FU Intramural NIH HHS [Z99 DK999999] NR 8 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD FEB PY 2017 VL 45 IS 4 BP 575 EP 576 DI 10.1111/apt.13898 PG 2 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA EK2XL UT WOS:000393790200020 PM 28074516 ER PT J AU Norton, JM Newman, EP Romancito, G Mahooty, S Kuracina, T Narva, AS AF Norton, Jenna M. Newman, Eileen P. Romancito, Gayle Mahooty, Stephanie Kuracina, Theresa Narva, Andrew S. TI Improving Outcomes for Patients with Chronic Kidney Disease: Part 1 SO AMERICAN JOURNAL OF NURSING LA English DT Article DE chronic kidney disease; collaborative care; end-stage renal disease; interdisciplinary care; kidney disease ID DIETARY-SODIUM RESTRICTION; GLOMERULAR-FILTRATION-RATE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; CREATININE RATIO; PREDICTIVE MODEL; SERUM CREATININE; RENAL-DISEASE; PROGRESSION AB The burden of chronic kidney disease (CKD) is rising both in this country and worldwide. An estimated 10% to 15% of U.S. adults are currently living with CKD. Reducing the CKD burden requires a systematic, interdisciplinary approach to care. The greatest opportunities to reduce the impact of CKD arise early, when most patients are being followed in primary care; yet many clinicians are inadequately educated on this disease. Nurses are well positioned to facilitate the implementation of collaborative care. This two-part article aims to provide nurses with the basic information necessary to assess and manage patients with CKD. Part 1 offers an overview of the disease, describes identification and etiology, and discusses ways to slow disease progression. Part 2, which will appear next month, addresses disease complications and treatment of kidney failure. C1 [Norton, Jenna M.] NIDDK, Natl Kidney & Urol Sci Translat Program, NIH, Bethesda, MD 20892 USA. [Narva, Andrew S.] NIDDK, Natl Kidney Dis Educ Program, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. [Romancito, Gayle] Indian Hlth Serv, Zuni Comprehens Community Hlth Ctr, Zuni, NM USA. [Mahooty, Stephanie] Renal Med Associates, Albuquerque, NM USA. [Mahooty, Stephanie] Desert Kidney Associates, Albuquerque, NM USA. [Kuracina, Theresa] Indian Hlth Serv, Albuquerque Indian Hlth Ctr, Albuquerque, NM USA. [Norton, Jenna M.; Newman, Eileen P.; Narva, Andrew S.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Romancito, Gayle; Kuracina, Theresa] Indian Hlth Serv, Rockville, MD USA. RP Norton, JM (reprint author), NIDDK, Natl Kidney & Urol Sci Translat Program, NIH, Bethesda, MD 20892 USA. NR 71 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0002-936X EI 1538-7488 J9 AM J NURS JI Am. J. Nurs. PD FEB PY 2017 VL 117 IS 2 BP 22 EP 32 PG 11 WC Nursing SC Nursing GA EK2UP UT WOS:000393782500015 PM 28085685 ER PT J AU Fong, S Chiorini, JA Sneyd, J Suresh, V AF Fong, Shelley Chiorini, John A. Sneyd, James Suresh, Vinod TI Computational modeling of epithelial fluid and ion transport in the parotid duct after transfection of human aquaporin-1 SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE parotid duct; aquaporin transfection; membrane transport ID SALIVARY-GLAND; HCO3-SECRETION; MINIATURE PIG; SUBMANDIBULAR-GLAND; CHANNELS; MOUSE; CELLS; RAT; CFTR; PH AB Previous studies have shown that localized delivery of the aquaporin-1 (AQP1) gene to the parotid duct can restore saliva flow in minipigs following irradiation-induced salivary hypofunction. The resulting flow rate and electrochemistry of secreted saliva contradicts current understanding of ductal fluid transport. We hypothesized that changes in expression of ion transport proteins have occurred following AQP1 transfection. We use a mathematical model of ion and fluid transport across the parotid duct epithelial cells to predict the expression profile of ion transporters that are consistent with the experimental measurements of saliva composition and secretion rates. Using a baseline set of parameters, the model reproduces the data for the irradiated, non-AQP1-transfected case. We propose three scenarios which may have occurred after transfection, which differ in the location of the AQP1 gene. The first scenario places AQP1 within nonsecretory cells, and requires that epithelial sodium channel (ENaC) expression is greatly reduced (1.3% of baseline), and ductal bicarbonate concentration is increased from 40.6 to 137.0 mM, to drive water secretion into the duct. The second scenario introduces the AQP1 gene into all ductal cells. The final scenario has AQP1 primarily in the proximal duct cells which secrete water under baseline conditions. We find the change in the remaining cells includes a 95.8% reduction in ENaC expression, enabling us to reproduce all experimental ionic concentrations within 9 mM. These findings provide a mechanistic basis for the observations and will guide the further development of gene transfer therapy for salivary hypofunction. NEW & NOTEWORTHY Following transfection of aquaporin into the parotid ducts of minipigs with salivary hypofunction, the resulting increase in salivary flow rates contradicts current understanding of ductal fluid transport. We show that the change in saliva electrochemistry and flow rate can be explained by changes in expression of ion transporters in the ductal cell membranes, using a mathematical model replicating a single parotid duct. C1 [Fong, Shelley; Suresh, Vinod] Univ Auckland, Auckland Bioengn Inst, Auckland, New Zealand. [Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Sneyd, James] Univ Auckland, Dept Math, Auckland, New Zealand. [Suresh, Vinod] Univ Auckland, Dept Engn Sci, Auckland, New Zealand. RP Fong, S (reprint author), Auckland Bioengn Inst, 70 Symonds St, Auckland, New Zealand. EM sfon036@aucklanduni.ac.nz FU Marsden Fund by the Royal Society of New Zealand [UOA1411]; National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH); University of Auckland Doctoral Scholarship FX This research was supported by the Marsden Fund (grant UOA1411) by the Royal Society of New Zealand (Recipient: V. Suresh), http://www.royalsociety.org.nz/programmes/funds/marsden/; a National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH) intramural research grant to J. A. Chiorini; and University of Auckland Doctoral Scholarship (Recipient: S. Fong), http://www.auckland.ac.nz. NR 44 TC 0 Z9 0 U1 2 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 EI 1522-1547 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD FEB PY 2017 VL 312 IS 2 BP G153 EP G163 DI 10.1152/ajpgi.00374.2016 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA EK4HF UT WOS:000393887000006 PM 27932503 ER PT J AU Kaufmann, H Norcliffe-Kaufmann, L Palma, JA Biaggioni, I Low, PA Singer, W Goldstein, DS Peltier, AC Shibao, CA Gibbons, CH Freeman, R Robertson, D AF Kaufmann, Horacio Norcliffe-Kaufmann, Lucy Palma, Jose-Alberto Biaggioni, Italo Low, Phillip A. Singer, Wolfgang Goldstein, David S. Peltier, Amanda C. Shibao, Cyndia A. Gibbons, Christopher H. Freeman, Roy Robertson, David CA Autonomic Disorders Consortium TI Natural history of pure autonomic failure: A United States prospective cohort SO ANNALS OF NEUROLOGY LA English DT Article ID SLEEP BEHAVIOR DISORDER; MULTIPLE SYSTEM ATROPHY; LEWY BODY DISEASE; PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; VALSALVA MANEUVER; HYPOTENSION; DIAGNOSIS; BODIES; MULTICENTER AB ObjectiveTo define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy. MethodsOne hundred patients who presented with pure autonomic failure were recruited at 5 medical centers in the United States. Seventy-four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular autonomic function tests. ResultsAt enrollment, patients were 6812 years old (median +/- interquartile range) and had had autonomic failure for 5 +/- 7 years. Within 4 years of follow-up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (n=13), Parkinson disease (n=6), or multiple system atrophy (n=6). The presence of probable rapid eye movement (REM) sleep behavior disorder was strongly associated with the development of a manifest central nervous system (CNS) synucleinopathy (odds ratio=7.1). Patients who phenoconverted to multiple system atrophy had younger age at onset of autonomic failure, severe bladder/bowel dysfunction, preserved olfaction, and a cardiac chronotropic response upon tilt>10 beats per minute. Those who phenoconverted to Parkinson disease or dementia with Lewy bodies had decreased olfaction, a lesser chronotropic response to tilt, and a longer duration of illness. The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell. InterpretationPatients presenting with pure autonomic failure are at high risk of phenoconverting to a manifest CNS synucleinopathy. Specific clinical features predict future diagnosis. Ann Neurol 2017;81:287-297 C1 [Kaufmann, Horacio; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto] NYU, Sch Med, Dept Neurol, New York, NY 10016 USA. [Biaggioni, Italo; Peltier, Amanda C.; Shibao, Cyndia A.; Robertson, David] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Biaggioni, Italo; Peltier, Amanda C.; Shibao, Cyndia A.; Robertson, David] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. [Low, Phillip A.; Singer, Wolfgang] Mayo Clin, Dept Neurol, Rochester, MN USA. [Goldstein, David S.] NINDS, Clin Neurocardiol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Gibbons, Christopher H.; Freeman, Roy] Harvard Med Sch, Dept Neurol, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Kaufmann, H (reprint author), NYU, Sch Med, 530 First Ave Suite 9Q, New York, NY 10016 USA. EM Horacio.Kaufmann@nyumc.org OI Kaufmann, Horacio/0000-0002-1851-9981; Peltier, Amanda/0000-0003-1097-7715 FU NIH Rare Disease Clinical Research Network [U54-NS065736] FX Supported by the NIH Rare Disease Clinical Research Network (U54-NS065736, all authors). NR 53 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2017 VL 81 IS 2 BP 287 EP 297 DI 10.1002/ana.24877 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EM0GM UT WOS:000394996800013 PM 28093795 ER PT J AU Pinal-Fernandez, I Parks, C Werner, JL Albayda, J Paik, JJ Danoff, SK Casciola-Rosen, L Christopher-Stine, L Mammen, AL AF Pinal-Fernandez, Iago Parks, Cassie Werner, Jessie L. Albayda, Jemima Paik, Julie J. Danoff, Sonye K. Casciola-Rosen, Livia Christopher-Stine, Lisa Mammen, Andrew L. TI Longitudinal Course of Disease in a Large Cohort of Myositis Patients With Autoantibodies Recognizing the Signal Recognition Particle SO ARTHRITIS CARE & RESEARCH LA English DT Article ID JUVENILE DERMATOMYOSITIS; INFLAMMATORY MYOPATHY; NECROTIZING MYOPATHY; CASE SERIES; POLYMYOSITIS; FEATURES; ANTIBODIES; ADULT; RITUXIMAB; AGE AB ObjectivePatients with immune-mediated necrotizing myopathy (IMNM) often have autoantibodies recognizing the signal recognition particle (SRP) or HMG-CoA reductase (HMGCR). Here, we studied a cohort of anti-SRP patients to identify factors associated with disease severity and clinical improvement; we also compared the severity of weakness in those with anti-SRP versus anti-HMGCR autoantibodies. MethodsAll anti-SRP patients in the Johns Hopkins Myositis Cohort from 2002 to 2015 were included. Longitudinal information regarding proximal muscle strength, creatine kinase (CK) levels, and immunosuppressive therapy was recorded at each visit. Univariate and multivariate multilevel regression models were used to assess prognostic factors influencing recovery. Strength in the anti-SRP patients was compared to strength in 49 previously described anti-HMGCR subjects. ResultsData from 37 anti-SRP patients and 380 total clinic visits were analyzed. Younger age at onset was associated with more severe weakness at the first visit (P=0.02) and all subsequent visits (P=0.002). Only 50% of patients reached near-full or full strength after 4 years of treatment, and most of these continued to have elevated CK levels. Rituximab appeared to be effective in 13 of 17 anti-SRP patients. Anti-SRP patients were significantly weaker than those with anti-HMGCR autoantibodies (-1.3 strength points; P=0.001). ConclusionYounger age at onset is associated with more severe weakness in anti-SRP myositis. Furthermore, even among anti-SRP patients whose strength improved with immunosuppression, most had ongoing disease activity as demonstrated by elevated CK levels. Finally, anti-SRP patients were significantly weaker than anti-HMGCR patients, providing evidence that these autoantibodies are associated with distinct forms of IMNM. C1 [Pinal-Fernandez, Iago; Parks, Cassie; Mammen, Andrew L.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Werner, Jessie L.; Albayda, Jemima; Paik, Julie J.; Danoff, Sonye K.; Casciola-Rosen, Livia; Christopher-Stine, Lisa; Mammen, Andrew L.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Pinal-Fernandez, I; Mammen, AL (reprint author), NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Express, NIH, 50 South Dr,Room 1141,Bldg 50,MSC 8024, Bethesda, MD 20892 USA. EM iagopf@yahoo.es; andrew.mammen@nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH; Johns Hopkins Rheumatic Disease Research Core Center (NIH) [P30-AR-053503]; Huayi and Siuling Zhang Discovery Fund FX Supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH and the Johns Hopkins Rheumatic Disease Research Core Center (NIH grant P30-AR-053503). Drs. Christopher-Stine and Danoff's work was supported by the Huayi and Siuling Zhang Discovery Fund. NR 27 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD FEB PY 2017 VL 69 IS 2 BP 263 EP 270 DI 10.1002/acr.22920 PG 8 WC Rheumatology SC Rheumatology GA EK4CU UT WOS:000393875500014 PM 27111848 ER PT J AU Place, RF Krieger, CC Neumann, S Gershengorn, MC AF Place, Robert F. Krieger, Christine C. Neumann, Susanne Gershengorn, Marvin C. TI Inhibiting thyrotropin/insulin-like growth factor 1 receptor crosstalk to treat Graves' ophthalmopathy: studies in orbital fibroblasts in vitro SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article ID THYROID-STIMULATING HORMONE; CONCISE GUIDE; HYALURONIC-ACID; PHARMACOLOGY; DISEASE; ANTIBODY; TSH; PATHOGENESIS; COMBINATION; ACTIVATION AB BACKGROUND AND PURPOSE Crosstalk between thyrotropin (TSH) receptors and insulin-like growth factor 1 (IGF-1) receptors initiated by activation of TSH receptors could be important in the development of Graves' ophthalmopathy (GO). Specifically, TSH receptor activation alone is sufficient to stimulate hyaluronic acid (HA) secretion, a major component of GO, through both IGF-1 receptor-dependent and independent pathways. Although an anti-IGF-1 receptor antibody is in clinical trials, its effectiveness depends on the relative importance of IGF-1 versus TSH receptor signalling in GO pathogenesis. EXPERIMENTAL APPROACH TSH and IGF-1 receptor antagonists were used to probe TSH/IGF-1 receptor crosstalk in primary cultures of Graves' orbital fibroblasts (GOFs) following activation with monoclonal TSH receptor antibody, M22. Inhibition of HA secretion following TSH receptor stimulation was measured by modified HA ELISA. KEY RESULTS TSH receptor antagonist, ANTAG3 (NCGC00242364), inhibited both IGF-1 receptor -dependent and -independent pathways at all doses of M22; whereas IGF-1 receptor antagonists linsitinib and 1H7 (inhibitory antibody) lost efficacy at high M22 doses. Combining TSH and IGF-1 receptor antagonists exhibited Loewe additivity within the IGF-1 receptor-dependent component of the M22 concentration-response. Similar effects were observed in GOFs activated by autoantibodies from GO patients' sera. CONCLUSIONS AND IMPLICATIONS Our data support TSH and IGF-1 receptors as therapeutic targets for GO, but reveal putative conditions for anti-IGF-1 receptor resistance. Combination treatments antagonizing both receptors yield additive effects by inhibiting crosstalk triggered by TSH receptor stimulatory antibodies. Combination therapy may be an effective strategy for dose reduction and/or compensate for any loss of anti-IGF-1 receptor efficacy. C1 [Place, Robert F.; Krieger, Christine C.; Neumann, Susanne; Gershengorn, Marvin C.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. RP Krieger, CC (reprint author), NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. EM christine.krieger@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, USA [DK011006] FX We would wish to thank Ms. Bernice Marcus-Samuels for her assistance with experiments. We would like to acknowledge the support Drs. Neil Miller, Prem Subramanian, Nicholas Mahoney and Shannath Merbs (Johns Hopkins School of Medicine, Baltimore, MD, USA) who have kindly provided materials for our experiments, as well as Dr. Monica Skarulin, Mr. Brent Abel, Ms. Anula Bhusry, Dr. Mary Walter and the members of the NIDDK Clinical Core for providing and processing the blood samples from GO patients. This work was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, USA (DK011006 to MCK). NR 32 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD FEB PY 2017 VL 174 IS 4 BP 328 EP 340 DI 10.1111/bph.13693 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4NJ UT WOS:000393903500004 PM 27987211 ER PT J AU O'Brien, KM Whelan, DR Sandler, DP Weinberg, CR AF O'Brien, Katie M. Whelan, Denis R. Sandler, Dale P. Weinberg, Clarice R. TI Eating Disorders and Breast Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID COMORBIDITY-SURVEY-REPLICATION; ANOREXIA-NERVOSA; RISK; WOMEN; PREGNANCY; OUTCOMES; FERTILITY; PATTERNS; COHORT; PREVALENCE AB Background: Eating disorders such as anorexia nervosa and bulimia nervosa affect overall and reproductive health and may also affect breast cancer risk. We studied the association between self-reported eating disorders and breast cancer risk in a prospective cohort study. Methods: In 2003-2009, the Sister Study enrolled women ages 35-74 years who had a sister with breast cancer but had never had it themselves. Using data from 47,813 women, we estimated adjusted HRs and 95% confidence intervals (CI) for the association between eating disorders and invasive breast cancer over a median of 5.4 years of follow-up. Results: Three percent (n = 1,569) of participants reported a history of an eating disorder. Compared with women who never had an eating disorder, women who reported eating disorders in the past had reduced breast cancer risk (HR = 0.62; 95% CI, 0.42-0.92). Conclusions: In this large prospective, observational cohort study, we observed an inverse association between having a history of an eating disorder and invasive breast cancer. Impact: Historical eating disorders may be associated with a long-term reduction in breast cancer risk. (C)2016 AACR. C1 [O'Brien, Katie M.; Whelan, Denis R.; Weinberg, Clarice R.] NIEHS, Biostat & Computat Biol Branch, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. [Whelan, Denis R.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Sandler, Dale P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), NIEHS, Biostat & Computat Biol Branch, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM weinber2@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences [Z01-ES044005, Z01-ES102245] FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences (project Z01-ES044005 to D.P. Sandler and Z01-ES102245 to C.R. Weinberg). NR 37 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2017 VL 26 IS 2 BP 206 EP 211 DI 10.1158/1055-9965.EPI-16-0587 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EK4PL UT WOS:000393909000007 PM 27756775 ER PT J AU Reyes-Guzman, CM Pfeiffer, RM Lubin, J Freedman, ND Cleary, SD Levine, PH Caporaso, NE AF Reyes-Guzman, Carolyn M. Pfeiffer, Ruth M. Lubin, Jay Freedman, Neal D. Cleary, Sean D. Levine, Paul H. Caporaso, Neil E. TI Determinants of Light and Intermittent Smoking in the United States: Results from Three Pooled National Health Surveys SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CURRENT CIGARETTE-SMOKING; NON-HISPANIC WHITES; NONDAILY SMOKERS; PSYCHIATRIC-DISORDERS; DESCRIPTIVE ANALYSIS; NICOTINE DEPENDENCE; MENTAL-ILLNESS; HEAVY SMOKERS; TOBACCO USE; LONG-TERM AB Background: Light and/or intermittent smokers have been the fastest growing segment of cigarette smokers in the United States over the past two decades. Defining their behavioral characteristics is a critical public health priority. Methods: Our sample included 78,229 U.S. adults from three pooled contemporary population-based surveys: the 2012 NHIS, 2012 NSDUH, and 2011-2012 NHANES. We classified current smokers into four categories (light and intermittent [LITS], light-daily, heavier-intermittent, and heavier-daily) and assessed smoking behaviors, illicit drug use, and mental health indicators using weighted analyses. Results: Analyses associated smoking categories with nicotine dependence, age of smoking initiation, race/ethnicity, and other demographic and behavioral factors. Compared with heavier-daily smokers, smokers who were LITS were most likely to have mild or no nicotine dependence (weighted odds ratio [OR], 16.92; 95% confidence interval [CI], 13.10-21.85), to start smoking cigarettes regularly after age 21 (OR, 3.42; 95% CI, 2.84-4.12), and to be Hispanic (OR, 5.38; 95% CI, 4.38-6.61). Additional significant results were found for other categories of smokers. Conclusions: Based on pooled data from three large national surveys, light and/or intermittent smokers differed in smoking, drug use, and mental health behaviors from heavier-daily, former, and never smokers. Notable differences by level of smoking frequency and intensity were observed for nicotine dependence, age of smoking initiation, and race/ethnicity. Impact: Our results may help focus preventive measures and policies for the growing number of light and/or intermittent smokers in the United States because smoking patterns vary by behavioral and socioeconomic factors. (C)2016 AACR. C1 [Reyes-Guzman, Carolyn M.; Pfeiffer, Ruth M.; Lubin, Jay; Freedman, Neal D.; Caporaso, Neil E.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Reyes-Guzman, Carolyn M.; Cleary, Sean D.] George Washington Univ, Sch Publ Hlth, Milken Inst, Dept Biostat & Epidemiol, Washington, DC USA. [Levine, Paul H.] Univ Nebraska Med Ctr, Coll Publ Hlth, Dept Epidemiol, Nebraska Med Ctr, Omaha, NE USA. RP Reyes-Guzman, CM (reprint author), NCI, 9609 Med Ctr Dr,Room 7E212,MSC 9769, Bethesda, MD 20892 USA. EM reyesguzmancm@mail.nih.gov FU Intramural Research Program in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute FX This study was supported by the Intramural Research Program in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. NR 78 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 26 IS 2 BP 228 EP 239 DI 10.1158/1055-9965.EPI-16-0028 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EK4PL UT WOS:000393909000010 PM 27760782 ER PT J AU Yu, GQ Phillips, S Gail, MH Goedert, JJ Humphrys, M Ravel, J Ren, YF Caporaso, NE AF Yu, Guoqin Phillips, Steve Gail, Mitchell H. Goedert, James J. Humphrys, Michael Ravel, Jacques Ren, Yanfang Caporaso, Neil E. TI Evaluation of Buccal Cell Samples for Studies of Oral Microbiota SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GUT MICROBIOME; DISEASE; CANCER; ADULTS; HEALTH; RISK AB Background: The human microbiota is postulated to affect cancer risk, but collecting microbiota specimens with prospective follow-up for diseases will take time. Buccal cell samples have been obtained from mouthwash for the study of human genomic DNA in many cohort studies. Here, we evaluate the feasibility of using buccal cell samples to examine associations of human microbiota and disease risk. Methods: We obtained buccal cells from mouthwash in 41 healthy participants using a protocol that is widely employed to obtain buccal cells for the study of human DNA. We compared oral microbiota from buccal cells with that from eight other oral sample types collected by following the protocols of the Human Microbiome Project. Microbiota profiles were determined by sequencing 16S rRNA gene V3-V4 region. Results: Compared with each of the eight other oral samples, the buccal cell samples had significantly more observed species (P < 0.002) and higher alpha diversity (Shannon index, P < 0.02). The microbial communities were more similar (smaller beta diversity) among buccal cells samples than in the other samples (P < 0.001 for 12 of 16 weighted and unweighted UniFrac distance comparisons). Buccal cell microbial profiles closely resembled saliva but were distinct from dental plaque and tongue dorsum. Conclusions: Stored buccal cell samples in prospective cohort studies are a promising resource to study associations of oral microbiota with disease. Impact: The feasibility of using existing buccal cell collections in large prospective cohorts allows investigations of the role of oral microbiota in chronic disease etiology in large population studies possible today. (C)2016 AACR. C1 [Yu, Guoqin; Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Phillips, Steve; Ren, Yanfang] Univ Rochester, Eastman Inst Oral Hlth, Rochester, NY USA. [Gail, Mitchell H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Humphrys, Michael; Ravel, Jacques] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. RP Yu, GQ; Caporaso, NE (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. EM guoqin.yu@nih.gov; caporasn@mail.nih.gov FU Division of Cancer Epidemiology and Genetics, NCI at the NIH FX This work was supported by intramural research funding at Division of Cancer Epidemiology and Genetics, NCI at the NIH. NR 24 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2017 VL 26 IS 2 BP 249 EP 253 DI 10.1158/1055-9965.EPI-16-0538 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EK4PL UT WOS:000393909000012 PM 27770008 ER PT J AU Koppen, H Boele, HJ Palm-Meinders, IH Koutstaal, BJ Horlings, CGC Koekkoek, BK van der Geest, J Smit, AE van Buchem, MA Launer, LJ Terwindt, GM Bloem, BR Kruit, MC Ferrari, MD De Zeeuw, CI AF Koppen, Hille Boele, Henk-Jan Palm-Meinders, Inge H. Koutstaal, Bastiaan J. Horlings, Corinne G. C. Koekkoek, Bas K. van der Geest, Jos Smit, Albertine E. van Buchem, Mark A. Launer, Lenore J. Terwindt, Gisela M. Bloem, Bas R. Kruit, Mark C. Ferrari, Michel D. De Zeeuw, Chris I. TI Cerebellar function and ischemic brain lesions in migraine patients from the general population SO CEPHALALGIA LA English DT Article DE Migraine; hemiplegic migraine; cerebellum; infarcts; magnetic resonance imaging ID FAMILIAL HEMIPLEGIC MIGRAINE; HEADACHE; BALANCE; LOCALIZATION; METAANALYSIS; DYSFUNCTION; MOVEMENTS; VELOCITY; VERTIGO; ATAXIA AB Objective: The objective of this article is to obtain detailed quantitative assessment of cerebellar function and structure in unselected migraine patients and controls from the general population. Methods: A total of 282 clinically well-defined participants (migraine with aura n = 111; migraine without aura n = 89; non-migraine controls n = 82; age range 43-72; 72% female) from a population-based study were subjected to a range of sensitive and validated cerebellar tests that cover functions of all main parts of the cerebellar cortex, including cere-brocerebellum, spinocerebellum, and vestibulocerebellum. In addition, all participants underwent magnetic resonance imaging (MRI) of the brain to screen for cerebellar lesions. As a positive control, the same cerebellar tests were conducted in 13 patients with familial hemiplegic migraine type 1 (FHM1; age range 19-64; 69% female) all carrying a CACNA1A mutation known to affect cerebellar function. Results: MRI revealed cerebellar ischemic lesions in 17/196 (8.5%) migraine patients and 3/79 (4%) controls, which were always located in the posterior lobe except for one control. With regard to the cerebellar tests, there were no differences between migraine patients with aura, migraine patients without aura, and controls for the: (i) Purdue-peg-board test for fine motor skills (assembly scores p = 0.1); (ii) block-design test for visuospatial ability (mean scaled scores p = 0.2); (iii) prism-adaptation task for limb learning (shift scores p = 0.8); (iv) eyeblink-conditioning task for learning-dependent timing (peak-time p = 0.1); and (v) body-sway test for balance capabilities (pitch velocity score under two-legs stance condition p = 0.5). Among migraine patients, those with cerebellar ischaemic lesions performed worse than those without lesions on the assembly scores of the pegboard task (p<0.005), but not on the primary outcome measures of the other tasks. Compared with controls and non-hemiplegic migraine patients, FHM1 patients showed substantially more deficits on all primary outcomes, including Purdue-peg assembly (p<0.05), block-design scaled score (p<0.001), shift in prism-adaptation (p<0.001), peak-time of conditioned eyeblink responses (p<0.05) and pitch-velocity score during stance-sway test (p<0.001). Conclusions: Unselected migraine patients from the general population show normal cerebellar functions despite having increased prevalence of ischaemic lesions in the cerebellar posterior lobe. Except for an impaired pegboard test revealing deficits in fine motor skills, these lesions appear to have little functional impact. In contrast, all cerebellar functions were significantly impaired in participants with FHM1. C1 [Koppen, Hille] Haga Hosp, Dept Neurol, The Hague, Netherlands. [Koppen, Hille; Terwindt, Gisela M.; Ferrari, Michel D.] Leiden Univ, Med Ctr, Dept Neurol, NL-2300 RA Leiden, Netherlands. [Boele, Henk-Jan; Koutstaal, Bastiaan J.; Koekkoek, Bas K.; van der Geest, Jos; Smit, Albertine E.; De Zeeuw, Chris I.] Erasmus MC, Dept Neurosci, Rotterdam, Netherlands. [Palm-Meinders, Inge H.; van Buchem, Mark A.; Kruit, Mark C.] Leiden Univ, Med Ctr, Dept Radiol, NL-2300 RA Leiden, Netherlands. [Horlings, Corinne G. C.; Bloem, Bas R.] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands. [Launer, Lenore J.] NIH, Lab Epidemiol Demog & Biometry, Bldg 10, Bethesda, MD 20892 USA. [De Zeeuw, Chris I.] Royal Acad Arts & Sci KNAW, Netherlands Inst Neurosci, Amsterdam, Netherlands. RP Koppen, H (reprint author), HagaZiekenhuis, Dept Neurol, Leyweg 275, NL-2545 CH The Hague, Netherlands. EM h.koppen@hagaziekenhuis.nl FU NWO-ALW; NWO-ZON-MW; Neuro-Basic; EU-ERC; Prinses Beatrix Fonds; NWO [903-52-291, 907-00-217]; VICI [VICI 918-56-602]; Spinoza; Dutch Heart Foundation [2007B016]; National Institutes of Health (NIH) [1R01NS061382-01]; VIDI [917-11-319]; Intramural Research Program, National Institute on Aging, NIH FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from NWO-ALW, NWO-ZON-MW, Neuro-Basic, EU-ERC, and Prinses Beatrix Fonds (all CIDZ), NWO (903-52-291, MDF), VICI (VICI 918-56-602, MDF), Spinoza (2009, MDF), Dutch Heart Foundation (2007B016, MDF and MCK), National Institutes of Health (NIH) (1R01NS061382-01, MDF and MCK), NWO (907-00-217, GMT) and VIDI (917-11-319, GT), Intramural Research Program, National Institute on Aging, NIH (LJL). NR 48 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0333-1024 EI 1468-2982 J9 CEPHALALGIA JI Cephalalgia PD FEB PY 2017 VL 37 IS 2 BP 177 EP 190 DI 10.1177/0333102416643527 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EK4KO UT WOS:000393895700009 PM 27059879 ER PT J AU Goldstein, DS Holmes, C Sullivan, P Donadio, V Isonaka, R Zhong, E Pourier, B Vernino, S Kopin, IJ Sharabi, Y AF Goldstein, David S. Holmes, Courtney Sullivan, Patti Donadio, Vincenzo Isonaka, Risa Zhong, Elizabeth Pourier, Bobby Vernino, Steven Kopin, Irwin J. Sharabi, Yehonatan TI Autoimmunity-associated autonomic failure with sympathetic denervation SO CLINICAL AUTONOMIC RESEARCH LA English DT Article DE Autonomic failure; Sympathetic; Catecholamine; Norepinephrine; Autoimmunity ID PANDYSAUTONOMIA AB We report a case of autoimmunity-associated autonomic failure in a young adult woman who developed arthritis followed 3 years later by pandysautonomia. There was early recovery of parasympathetic functions but persistent neurogenic orthostatic hypotension from post-ganglionic sympathetic denervation. Clinical laboratory testing indicated variable amounts of sympathetic neuronal re-sprouting in the heart, kidneys, eyes, and body as a whole upon follow-up evaluation after 1.5 years. C1 [Goldstein, David S.; Holmes, Courtney; Sullivan, Patti; Isonaka, Risa; Zhong, Elizabeth; Pourier, Bobby; Kopin, Irwin J.] NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, 9000 Rockville Pike MSC 1620,Bldg 10 Room 5N220, Bethesda, MD 20892 USA. [Donadio, Vincenzo] IRCCS Ist Sci Neurol, Bologna, Italy. [Vernino, Steven] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Sharabi, Yehonatan] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel. [Sharabi, Yehonatan] Chaim Sheba Med Ctr, Tel Hashomer, Israel. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, 9000 Rockville Pike MSC 1620,Bldg 10 Room 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke (NINDS) [1ZIANS003034] FX Funding was provided by the National Institute of Neurological Disorders and Stroke (NINDS), project number 1ZIANS003034. NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0959-9851 EI 1619-1560 J9 CLIN AUTON RES JI Clin. Auton. Res. PD FEB PY 2017 VL 27 IS 1 BP 57 EP 62 DI 10.1007/s10286-016-0388-0 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EK8OK UT WOS:000394183100010 PM 27838780 ER PT J AU Gao, JJ Tan, M Pohlmann, PR Swain, SM AF Gao, Jennifer J. Tan, Ming Pohlmann, Paula R. Swain, Sandra M. TI HALT-D: A Phase II Evaluation of Crofelemer for the Prevention and Prophylaxis of Diarrhea in Patients With Breast Cancer on Pertuzumab-Based Regimens SO CLINICAL BREAST CANCER LA English DT Article DE Breast cancer; Chemotherapy induced diarrhea; Crofelemer; HER2; Pertuzumab ID PLUS TRASTUZUMAB; SAFETY; EFFICACY; CHEMOTHERAPY; COMBINATION; PACLITAXEL; MANAGEMENT; TRIAL; WOMEN AB Approximately 40% to 80% of patients receiving pertuzumab-directed therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer will develop chemotherapy-induced diarrhea (CID). Loperamide and octreotide are frequently used to treat CID after diarrhea occurs, but neither is used prophylactically or targets the underlying mechanism. Previous studies suggest blocking epidermal growth factor receptor may cause excess chloride secretion, resulting in diarrhea. Crofelemer is derived from the red latex of the Croton lechleri tree, blocks gastrointestinal cystic fibrosis transmembrane regulator and calcium-activated chloride channels, and is U.S. Food and Drug Administration approved for relief of diarrhea in HIV/AIDS patients on anti-retroviral therapy. Crofelemer is not systemically absorbed, has relatively few side effects, and presents a targeted approach at preventing CID in patients receiving pertuzumab-based therapy. HALT-D (DiarrHeA Prevention and ProphyLaxis with Crofelemer in HER2-Positive Breast Cancer Patients Receiving Trastuzumab, Pertuzumab, and Docetaxel or Paclitaxel with or without Carboplatin, NCT02910219) is a phase II, randomized, open-label trial that aims to recruit 46 patients from 3 MedStar sites. Adults with HER2-positive breast cancer being treated with trastuzumab, pertuzumab, and docetaxel or paclitaxel (THP) or trastuzumab, pertuzumab, docetaxel, and carboplatin (TCHP) will be randomized to receive crofelemer or no medication for diarrhea prophylaxis. The primary endpoint is incidence of all grade diarrhea for >= 2 consecutive days during cycles 1 to 2 of THP or TCHP. Secondary endpoints include overall incidence, duration, and severity of diarrhea; time to onset of diarrhea; use of other anti-diarrheal medications; stool frequency and consistency; and quality of life. HALT-D will provide important information about the feasibility and tolerability of crofelemer in preventing diarrhea for patients receiving THP or TCHP. C1 [Gao, Jennifer J.] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Tan, Ming] Georgetown Univ, Med Ctr, Dept Biostat Bioinformat & Biomath, Washington, DC 20007 USA. [Pohlmann, Paula R.; Swain, Sandra M.] Medstar Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Swain, SM (reprint author), MedStar Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Res Dev, 4000 Reservoir Rd NW,120 Bldg D, Washington, DC 20057 USA.; Swain, SM (reprint author), MedStar Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Med, 4000 Reservoir Rd NW,120 Bldg D, Washington, DC 20057 USA. EM Sandra.Swain@georgetown.edu OI Swain, Sandra/0000-0002-1320-3830 FU Genentech, Inc. FX This study is funded by Genentech, Inc. Crofelemer is provided by Napo Pharmaceuticals. The authors have stated that they have no conflicts of interest. NR 14 TC 0 Z9 0 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1526-8209 EI 1938-0666 J9 CLIN BREAST CANCER JI Clin. Breast Cancer PD FEB PY 2017 VL 17 IS 1 BP 76 EP 78 DI 10.1016/j.clbc.2016.08.005 PG 3 WC Oncology SC Oncology GA EK5IW UT WOS:000393961100017 PM 27692565 ER PT J AU Faridi, R Rehman, AU Morell, RJ Friedman, PL Demain, L Zahra, S Khan, AA Tohlob, D Assir, MZ Beaman, G Khan, SN Newman, WG Riazuddin, S Friedman, TB AF Faridi, R. Rehman, A. U. Morell, R. J. Friedman, P. L. Demain, L. Zahra, S. Khan, A. A. Tohlob, D. Assir, M. Z. Beaman, G. Khan, S. N. Newman, W. G. Riazuddin, S. Friedman, T. B. TI Mutations of SGO2 and CLDN14 collectively cause coincidental Perrault syndrome SO CLINICAL GENETICS LA English DT Article DE CLDN14; cohesin; coincidental syndrome; infertility; ovarian insufficiency; Perrault syndrome; Sgol2a; SGO2; Shugoshin-2 ID RECESSIVE DEAFNESS DFNB29; HEARING-LOSS; DEFICIENCY; MEIOSIS; MICE AB Perrault syndrome (PS) is a genetically heterogeneous disorder characterized by primary ovarian insufficiency (POI) in females and sensorineural hearing loss in males and females. In many PS subjects, causative variants have not been found in the five reported PS genes. The objective of this study was to identify the genetic cause of PS in an extended consanguineous family with six deaf individuals. Whole exome sequencing (WES) was completed on four affected members of a large family, and variants and co-segregation was confirmed by Sanger sequencing. All hearing impaired individuals, including the proband, are homozygous for a pathogenic variant of CLDN14, but this only explains the deafness. The PS proband is also homozygous for a frameshift variant (c. 1453_1454delGA, p.(Glu485Lysfs* 5)) in exon 7 of SGO2 encoding shugoshin 2, which is the likely cause of her concurrent ovarian insufficiency. In mouse, Sgol2a encoding shugoshin-like 2a is necessary during meiosis in both sexes to maintain the integrity of the cohesin complex that tethers sister chromatids. Human SGO2 has not previously been implicated in any disorder, but in this case of POI and perhaps others, it is a candidate for unexplained infertility. C1 [Faridi, R.; Rehman, A. U.; Friedman, T. B.] Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Bethesda, MD USA. [Faridi, R.; Zahra, S.; Khan, A. A.; Khan, S. N.] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Morell, R. J.] NIDCD, Genom & Computat Biol Core, NIH, Bethesda, MD USA. [Friedman, P. L.] NIH, Internal Med Consult Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Demain, L.; Tohlob, D.; Beaman, G.; Newman, W. G.] Univ Manchester, Manchester Ctr Genom Med, Manchester, Lancs, England. [Demain, L.; Tohlob, D.; Beaman, G.; Newman, W. G.] NHS Fdn Trust, Cent Manchester Univ Hosp, Manchester, Lancs, England. [Tohlob, D.] Mansoura Univ, Fac Med, Dept Clin Pathol, Mansoura, Egypt. [Assir, M. Z.] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. [Assir, M. Z.; Riazuddin, S.] Shaheed Zulfiqar Ali Bhutto Med Univ, Inst Med Sci, Islamabad, Pakistan. [Riazuddin, S.] Allama Iqbal Med Res Ctr, Jinnah Hosp Complex, Lahore, Pakistan. [Rehman, A. U.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Friedman, TB (reprint author), Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, John Edward Porter Neurosci Res Ctr, NIH, Room 1F-141,35A Convent Dr, Bethesda, MD 20892 USA. EM friedman@nidcd.nih.gov OI Newman, William/0000-0002-6382-4678 FU NIDCD/NIH [DC000048-19, DC000086-01]; Higher Education Commission of Pakistan; Action on Hearing Loss, UK FX The authors thank the subjects in this study for their participation, Andrew J. Griffith and Leslie G. Biesecker for their critiques of our manuscript and Dr. Mehwish Pervaiz and Dr. Shazia Khalid Khan, Department of Gynecology, Jinnah Hospital Lahore, Pakistan for clinical evaluation of patients. This research was supported (in part) by the Intramural Research Program of the NIDCD/NIH to T. B. F. (DC000048-19) and R. J. M. (DC000086-01), the Higher Education Commission of Pakistan to S. R., and an Action on Hearing Loss, UK grant to W. G. N. Written informed consents were obtained from all participants in this study. Institutional Review Board approval was obtained from the Combined Neurosciences Blue Panel at the National Institutes of Health (OH-93-N-016), from National Centre of Excellence in Molecular Biology at the University of the Punjab and from the National Health Service Research Ethics Committee (05/Q1404/49) and the University of Manchester. T. B. F. takes responsibility for the integrity and accuracy of the data analyses. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 23 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 EI 1399-0004 J9 CLIN GENET JI Clin. Genet. PD FEB PY 2017 VL 91 IS 2 SI SI BP 328 EP 332 DI 10.1111/cge.12867 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA EK9EN UT WOS:000394226900018 PM 27629923 ER PT J AU Chaturvedi, A Dey, AK Joshi, AA Mehta, NN AF Chaturvedi, Abhishek Dey, Amit K. Joshi, Aditya A. Mehta, Nehal N. TI Vascular Inflammation Imaging in Psoriasis SO CURRENT CARDIOVASCULAR IMAGING REPORTS LA English DT Article DE Psoriasis; Vascular inflammation; Arterial inflammation; Atherosclerosis; FDG PET CT ID POSITRON-EMISSION-TOMOGRAPHY; ATHEROSCLEROTIC PLAQUE INFLAMMATION; TYPE-2 DIABETES-MELLITUS; F-18-FDG PET; FDG-PET/CT; CARDIOVASCULAR RISK; LARGE ARTERIES; PARTICLE-SIZE; SKIN DEEP; DISEASE AB Purpose of Review Psoriasis is a common, chronic inflammatory skin disease driven by immune dysregulation involving helper T cell 17 pathways. Psoriasis is associated with systemic inflammation, which increases the risk of joint disease ( psoriatic arthritis), subclinical cardiovascular disease, and major adverse cardiovascular events, especially in young patients with severe skin disease. Furthermore, vascular inflammation by 18-fluorodeoxyglucose positron emission tomography/computed tomography ( FDG PET/CT) provides a valuable tool with utility in predicting future cardiovascular events. As such, psoriasis provides a clinical human model to characterize the vascular disease by non-invasive imaging techniques such as vascular inflammation by FDG PET/CT. Recent Findings FDG PET/CT has garnered considerable interest in multiple completed and ongoing cardiovascular and psoriasis trials. Indeed, recent studies have shown that psoriasis is associated with increased vascular inflammation. Furthermore, a dose-response was demonstrated between severity of skin disease and severity of vascular inflammation in psoriasis. Additionally, observational studies have reported that treatment of psoriasis decreases vascular inflammation with several randomized trials still ongoing. Emerging data from a single report demonstrated that use of FDG PET/MRI may provide soft tissue localization of the FDG tracer in the aorta and the carotids but larger studies are underway. Summary This review outlines the initial use, development, and current utility of FDG PET/CT in psoriasis covering cross-sectional and longitudinal studies that examined the relationship between psoriasis, severity of skin disease, presence of joint disease, treatment of skin disease, and emerging techniques to identify vascular inflammation as a marker of cardiovascular risk in psoriasis. C1 [Chaturvedi, Abhishek; Dey, Amit K.; Joshi, Aditya A.; Mehta, Nehal N.] NHLBI, NIH, Clin Res Ctr, 10 Ctr Dr,Room 5-5140, Bethesda, MD 20892 USA. RP Mehta, NN (reprint author), NHLBI, NIH, Clin Res Ctr, 10 Ctr Dr,Room 5-5140, Bethesda, MD 20892 USA. EM abhishek.chaturvedi@nih.gov; amit.dey@nih.gov; adi0601@gmail.com; nehal.mehta@nih.gov NR 77 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1941-9066 EI 1941-9074 J9 CURR CARDIOVASC IMAG JI CURR. CARDIOVASC. IMAGING REP. PD FEB PY 2017 VL 10 IS 2 AR 4 DI 10.1007/s12410-017-9401-9 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EL0TY UT WOS:000394335900001 ER PT J AU Gladwin, TE Wiers, CE Wiers, RW AF Gladwin, Thomas E. Wiers, Corinde E. Wiers, Reinout W. TI Interventions aimed at automatic processes in addiction: considering necessary conditions for efficacy SO CURRENT OPINION IN BEHAVIORAL SCIENCES LA English DT Review ID COGNITIVE BIAS MODIFICATION; DIRECT-CURRENT STIMULATION; ABSTINENT ALCOHOLIC PATIENTS; RANDOMIZED CONTROLLED-TRIAL; ATTENTIONAL BIAS; WORKING-MEMORY; PREFRONTAL CORTEX; DRINKING BEHAVIOR; ACTION-TENDENCIES; IMPLICIT COGNITION AB Automatic processes related to addiction can be directly targeted in novel training paradigms. First studies have demonstrated that Cognitive Bias Modification (CBM) targeting approach biases can enhance treatment outcomes when added to regular treatment. However, the overall efficacy of CBM is debated. We argue that considering the modulating role of motivation and the mediating role of actual bias change are essential to drawing valid conclusions. Findings on mediating cognitive and neural mechanisms underlying clinical effects provide further sources of evidence on CBM. Taken together the literature supports the claim that cognitive bias change can improve clinical outcome, but that there are necessary conditions that must be met. Improved theoretical understanding of changing biases and new techniques such as neuromodulation may be needed to optimally apply CBM to help patients overcome addictive behavior. C1 [Gladwin, Thomas E.; Wiers, Reinout W.] Univ Amsterdam, Dept Psychol, Addict Dev & Psychopathol ADAPT Lab, ABC,Res Prior Area Yield, NL-1012 WX Amsterdam, Netherlands. [Gladwin, Thomas E.] Minist Def, Res Ctr Mil Mental Hlth, Utrecht, Netherlands. [Wiers, Corinde E.] NIAAA, NIH, Bethesda, MD USA. RP Wiers, RW (reprint author), Univ Amsterdam, Dept Psychol, Addict Dev & Psychopathol ADAPT Lab, ABC,Res Prior Area Yield, NL-1012 WX Amsterdam, Netherlands. EM r.wiers@uva.nl OI Wiers, Reinout/0000-0002-4312-9766 NR 78 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-1546 EI 2352-1554 J9 CURR OPIN BEHAV SCI JI Curr. Opin. Behav. Sci. PD FEB PY 2017 VL 13 BP 19 EP 24 DI 10.1016/j.cobeha.2016.08.001 PG 6 WC Behavioral Sciences SC Behavioral Sciences GA EM5AL UT WOS:000395324200005 ER PT J AU Bachi, K Sierra, S Volkow, ND Goldstein, RZ Alia-Klein, N AF Bachi, Keren Sierra, Salvador Volkow, Nora D. Goldstein, Rita Z. Alia-Klein, Nelly TI Is biological aging accelerated in drug addiction? SO CURRENT OPINION IN BEHAVIORAL SCIENCES LA English DT Review ID LEUKOCYTE TELOMERE LENGTH; OXIDATIVE STRESS; MICROGLIAL ACTIVATION; COCAINE DEPENDENCE; PERIPHERAL ORGANS; RAT-BRAIN; DISEASE; ABUSE; DISORDERS; TOXICITY AB Drug-addiction may trigger early onset of age-related disease, due to drug-induced multi-system toxicity and perilous lifestyle, which remains mostly undetected and untreated. We present the literature on pathophysiological processes that may hasten aging and its relevance to addiction, including: oxidative stress and cellular aging, inflammation in periphery and brain, decline in brain volume and function, and early onset of cardiac, cerebrovascular, kidney, and liver disease. Timely detection of accelerated aging in addiction is crucial for the prevention of premature morbidity and mortality. C1 [Bachi, Keren; Goldstein, Rita Z.; Alia-Klein, Nelly] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Bachi, Keren; Goldstein, Rita Z.; Alia-Klein, Nelly] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Sierra, Salvador] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD USA. RP Alia-Klein, N (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.; Alia-Klein, N (reprint author), Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. EM nelly.alia-klein@mssm.edu FU National Institute on Drug Abuse [T32-DA007135-31, 1U01DA041174, R01DA041528]; National Institutes of Health [R01MH090134]; Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai; Social Work Services support, Icahn School of Medicine at Mount Sinai; Alfonso Martin Escudero Foundation FX This work was supported by: the National Institute on Drug Abuse: [KB: T32-DA007135-31; NDV: Intramural funding; RZG: 1U01DA041174, R01DA041528]; the National Institutes of Health [NAK: R01MH090134]; Department of Preventive Medicine, and Social Work Services support, Icahn School of Medicine at Mount Sinai [KB]; Grant from Alfonso Martin Escudero Foundation [SS]. NR 67 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-1546 EI 2352-1554 J9 CURR OPIN BEHAV SCI JI Curr. Opin. Behav. Sci. PD FEB PY 2017 VL 13 BP 34 EP 39 DI 10.1016/j.cobeha.2016.09.007 PG 6 WC Behavioral Sciences SC Behavioral Sciences GA EM5AL UT WOS:000395324200007 PM 27774503 ER PT J AU Tunstall, BJ Carmack, SA Koob, GF Vendruscolo, LF AF Tunstall, Brendan J. Carmack, Stephanie A. Koob, George F. Vendruscolo, Leandro F. TI Dysregulation of brain stress systems mediates compulsive alcohol drinking SO CURRENT OPINION IN BEHAVIORAL SCIENCES LA English DT Review ID ETHANOL-DEPENDENT RATS; CORTICOTROPIN-RELEASING-FACTOR; RECEPTOR ANTAGONISM; EXCESSIVE DRINKING; NUCLEUS-ACCUMBENS; ACAMPROSATE; EXPOSURE; RELAPSE; CONSUMPTION; GABAPENTIN AB The transition from moderate to compulsive alcohol drinking is driven by increasingly dysfunctional reward and stress systems. We review behavioral and pharmacological studies of alcohol self-administration in rats that were mainly conducted within the framework of the alcohol vapor model of dependence. We discuss neurotransmitter systems that are implicated in alcohol drinking, with a focus on contrasting those neurotransmitter systems that drive behavior in the dependent versus nondependent states. We hypothesize that the identification of systems that become increasingly dysfunctional in alcohol dependence will reveal possible targets for successful interventions to reduce the motivation that drives compulsive alcohol drinking. In our opinion, drugs that normalize, rather than block, a hypofunctional reward system by restoring the function of hypothalamic stress systems and desensitize extrahypothalamic stress systems have the potential to selectively and effectively curb compulsive alcohol drinking. C1 [Tunstall, Brendan J.; Carmack, Stephanie A.; Koob, George F.; Vendruscolo, Leandro F.] NIDA, NIH, Baltimore, MD 21224 USA. RP Vendruscolo, LF (reprint author), NIDA, NIH, Baltimore, MD 21224 USA. EM leandro.vendruscolo@nih.gov FU National Institute on Drug Abuse (NIDA) Intramural Research Program FX The National Institute on Drug Abuse (NIDA) Intramural Research Program supported this work. The authors thank Michael Arends for editorial assistance and NIDA media services for assistance in figure preparation. NR 49 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-1546 EI 2352-1554 J9 CURR OPIN BEHAV SCI JI Curr. Opin. Behav. Sci. PD FEB PY 2017 VL 13 BP 85 EP 90 DI 10.1016/j.cobeha.2016.10.006 PG 6 WC Behavioral Sciences SC Behavioral Sciences GA EM5AL UT WOS:000395324200014 ER PT J AU Planutis, A Xue, L Trainor, CD Dangeti, M Gillinder, K Siatecka, M Nebor, D Peters, LL Perkins, AC Bieker, JJ AF Planutis, Antanas Xue, Li Trainor, Cecelia D. Dangeti, Mohan Gillinder, Kevin Siatecka, Miroslawa Nebor, Danitza Peters, Luanne L. Perkins, Andrew C. Bieker, James J. TI Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development SO DEVELOPMENT LA English DT Article DE Erythropoiesis; Transcription factor; Anemia; Monoallelic mutation; Cytokine effects; Mouse ID KRUPPEL-LIKE FACTOR; TERMINAL ERYTHROID-DIFFERENTIATION; CONGENITAL DYSERYTHROPOIETIC ANEMIA; TRANSCRIPTION FACTOR KLF1; GLOBIN GENE-EXPRESSION; INEFFECTIVE ERYTHROPOIESIS; CELL-DIFFERENTIATION; IRON HOMEOSTASIS; BETA-THALASSEMIA; 3 FINGERS AB Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states. C1 [Planutis, Antanas; Xue, Li; Dangeti, Mohan; Siatecka, Miroslawa; Bieker, James J.] Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY 10029 USA. [Trainor, Cecelia D.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Gillinder, Kevin; Perkins, Andrew C.] Univ Queensland, Mater Res Inst, Woolloongabba, Qld 4102, Australia. [Siatecka, Miroslawa] Adam Mickiewicz Univ, Dept Genet, PL-61614 Poznan, Poland. [Nebor, Danitza; Peters, Luanne L.] Jackson Lab, Bar Harbor, ME 04609 USA. [Perkins, Andrew C.] Princess Alexandra Hosp, Brisbane, Qld 4102, Australia. [Bieker, James J.] Mt Sinai Sch Med, Black Family Stem Cell Inst, New York, NY 10029 USA. [Bieker, James J.] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Bieker, James J.] Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. RP Bieker, JJ (reprint author), Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY 10029 USA.; Bieker, JJ (reprint author), Mt Sinai Sch Med, Black Family Stem Cell Inst, New York, NY 10029 USA.; Bieker, JJ (reprint author), Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA.; Bieker, JJ (reprint author), Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. EM james.bieker@mssm.edu FU National Institutes of Health Public Health Service [R01 DK46865, R01 DK100692]; National Science Centre [2013/09/B/NZ1/01879]; National Health and Medical Research Council [APP1082429]; National Cancer Institute [P30 CA034196]; National Institutes of Health Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by two National Institutes of Health Public Health Service grants (R01 DK46865 to J.J.B. and R01 DK100692 to L.L.P.), by a National Science Centre grant (2013/09/B/NZ1/01879 to M.S.), by a National Health and Medical Research Council grant (APP1082429 to A.C.P.) and by a grant from the National Cancer Institute to the Jackson Laboratory (P30 CA034196). C.D.T. was supported by the National Institutes of Health Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. D.N. is an American Society for Hematology Scholar. Deposited in PMC for release after 12 months. NR 77 TC 0 Z9 0 U1 1 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD FEB 1 PY 2017 VL 144 IS 3 BP 430 EP 440 DI 10.1242/dev.145656 PG 11 WC Developmental Biology SC Developmental Biology GA EK2OR UT WOS:000393767100008 PM 28143845 ER PT J AU Kannan, R Song, JK Karpova, T Clarke, A Shivalkar, M Wang, B Kotlyanskaya, L Kuzina, I Gu, Q Giniger, E AF Kannan, Ramakrishnan Song, Jeong-Kuen Karpova, Tatiana Clarke, Akanni Shivalkar, Madhuri Wang, Benjamin Kotlyanskaya, Lyudmila Kuzina, Irina Gu, Qun Giniger, Edward TI The Abl pathway bifurcates to balance Enabled and Rac signaling in axon patterning in Drosophila SO DEVELOPMENT LA English DT Article DE Abl; Disabled; Rac; Trio; FRET; Axon guidance ID ABELSON TYROSINE KINASE; RESONANCE ENERGY-TRANSFER; ACTIN CYTOSKELETON; ENA/VASP PROTEINS; ARP2/3 COMPLEX; WAVE COMPLEX; GENETIC INTERACTIONS; WASP/SCAR PROTEINS; FAMILY KINASES; CELL-MIGRATION AB The Abl tyrosine kinase signaling network controls cell migration, epithelial organization, axon patterning and other aspects of development. Although individual components are known, the relationships among them remain unresolved. We now use FRET measurements of pathway activity, analysis of protein localization and genetic epistasis to dissect the structure of this network in Drosophila. We find that the adaptor protein Disabled stimulates Abl kinase activity. Abl suppresses the actin-regulatory factor Enabled, and we find that Abl also acts through the GEF Trio to stimulate the signaling activity of Rac GTPase: Abl gates the activity of the spectrin repeats of Trio, allowing them to relieve intramolecular repression of Trio GEF activity by the Trio N-terminal domain. Finally, we show that a key target of Abl signaling in axons is the WAVE complex that promotes the formation of branched actin networks. Thus, we show that Abl constitutes a bifurcating network, suppressing Ena activity in parallel with stimulation of WAVE. We suggest that the balancing of linear and branched actin networks by Abl is likely to be central to its regulation of axon patterning. C1 [Kannan, Ramakrishnan; Song, Jeong-Kuen; Clarke, Akanni; Shivalkar, Madhuri; Wang, Benjamin; Kotlyanskaya, Lyudmila; Kuzina, Irina; Gu, Qun; Giniger, Edward] NINDS, NIH, Bethesda, MD 20892 USA. [Karpova, Tatiana] NCI, NIH, Bethesda, MD 20892 USA. [Kannan, Ramakrishnan] Natl Inst Mental Hlth & Neurosci, NRC, Dept Psychiat, Bangalore 40, Karnataka, India. [Song, Jeong-Kuen] L&J Biosci, 19 Fristfield Rd, Gaithersburg, MD 20878 USA. RP Giniger, E (reprint author), NINDS, NIH, Bethesda, MD 20892 USA. EM ginigere@ninds.nih.gov OI Giniger, Edward/0000-0002-8340-6158 FU Basic Neuroscience Program of the National Institute of Neurological Disorders and Stroke (NINDS) Intramural Research Program [Z01-NS003013]; Department of Biotechnology Ramalingaswami re-entry fellowship from the Government of India FX These experiments were supported by the Basic Neuroscience Program of the National Institute of Neurological Disorders and Stroke (NINDS) Intramural Research Program (grant Z01-NS003013) to E.G. R.K. was supported in part by a Department of Biotechnology Ramalingaswami re-entry fellowship from the Government of India. Deposited in PMC for release after 12 months. NR 77 TC 0 Z9 0 U1 0 U2 0 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 FEB 1 PY 2017 VL 144 IS 3 BP 487 EP 498 DI 10.1242/dev.143776 PG 12 WC Developmental Biology SC Developmental Biology GA EK2OR UT WOS:000393767100013 PM 28087633 ER PT J AU Zhou, LQ Baibakov, B Canagarajah, B Xiong, B Dean, J AF Zhou, Liquan Baibakov, Boris Canagarajah, Bertram Xiong, Bo Dean, Jurrien TI Genetic mosaics and time-lapse imaging identify functions of histone H3.3 residues in mouse oocytes and embryos SO DEVELOPMENT LA English DT Article DE Histone H3.3; Genetic mosaics; Cell fate decision; Protamine-to-histone exchange ID NOVO DNA METHYLATION; PREIMPLANTATION EMBRYOS; VARIANT H3.3; MAMMALIAN EMBRYO; PEDIATRIC GLIOBLASTOMA; ZONA-PELLUCIDA; ZINC SPARKS; CELL FATE; CHROMATIN; GENOME AB During development from oocyte to embryo, genetic programs in mouse germ cells are reshaped by chromatin remodeling to orchestrate the onset of development. Epigenetic modifications of specific amino acid residues of core histones and their isoforms can dramatically alter activation and suppression of gene expression. H3.3 is a histone H3 variant that plays essential roles in mouse oocytes and early embryos, but the functional role of individual amino acid residues has been unclear because of technical hurdles. Here, we describe two strategies that successfully investigated the functions of three individual H3.3 residues in oogenesis, cleavage-stage embryogenesis and early development. We first generated genetic mosaic ovaries and blastocysts with stochastic expression of wild-type or mutant H3.3 alleles and showed dominant negative effects of H3.3R26 and H3.3K27 in modulating oogenesis and partitioning cells to the inner cell mass of the early embryo. Time-lapse imaging assays also revealed the essential roles of H3.3K56 in efficient H2B incorporation and paternal pronuclei formation. Application of these strategies can be extended to investigate roles of additional H3.3 residues and has implications for use in other developmental systems. C1 [Zhou, Liquan; Baibakov, Boris; Canagarajah, Bertram; Xiong, Bo; Dean, Jurrien] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Xiong, Bo] Nanjing Agr Univ, Coll Anim Sci & Technol, Nanjing 210095, Jiangsu, Peoples R China. RP Zhou, LQ; Dean, J (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM li-quan.zhou@nih.gov; jurrien.dean@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [DK015603-09] FX This research was support by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (DK015603-09). Deposited in PMC for release after 12 months. NR 58 TC 0 Z9 0 U1 2 U2 2 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 FEB 1 PY 2017 VL 144 IS 3 BP 519 EP 528 DI 10.1242/dev.141390 PG 10 WC Developmental Biology SC Developmental Biology GA EK2OR UT WOS:000393767100016 PM 27993980 ER PT J AU Walker-Sperling, VE Pohlmeyer, CW Veenhuis, RT May, M Luna, KA Kirkpatrick, AR Laeyendecker, O Cox, AL Carrington, M Bailey, JR Arduino, RC Blankson, JN AF Walker-Sperling, Victoria E. Pohlmeyer, Christopher W. Veenhuis, Rebecca T. May, Megan Luna, Krystle A. Kirkpatrick, Allison R. Laeyendecker, Oliver Cox, Andrea L. Carrington, Mary Bailey, Justin R. Arduino, Roberto C. Blankson, Joel N. TI Factors Associated With the Control of Viral Replication and Virologic Breakthrough in a Recently Infected HIV-1 Controller SO EBIOMEDICINE LA English DT Article DE HIV-1; HIV controllers; NK cells; CD8+ T cells; Transmission pair ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD8(+) T-CELLS; NATURAL-KILLER-CELLS; ELITE SUPPRESSORS; ANTIRETROVIRAL THERAPY; IMMUNE CONTROL; LOW-FREQUENCY; HLA-B; CAPACITY; VIREMIA AB HIV-1 controllers are patients who control HIV-1 viral replication without antiretroviral therapy. Control is achieved very early in the course of infection, but the mechanisms through which viral replication is restricted are not fully understood. We describe a patient who presented with acute HIV-1 infection and was found to have an HIV-1 RNA level of <100 copies/mL. She did not have any known protective HLA alleles, but significant immune activation of CD8 + T cells and natural killer (NK) cells was present, and both cell types inhibited viral replication. Virus cultured from this patient replicated as well in vitro as virus isolated from her partner, a patient with AIDS who was the source of transmission. Virologic breakthrough occurred 9 months after her initial presentation and was associated with an increase in CD4 + T cell activation levels and a significant decrease in NK cell inhibitory capacity. Remarkably, CD8 + T cell inhibitory capacity was preserved and there were no new escape mutations in targeted Gag epitopes. These findings suggest that fully replication-competent virus can be controlled in acute HIV-1 infection in some patients without protective HLA alleles and that NK cell responses may contribute to this early control of viral replication. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Walker-Sperling, Victoria E.; Pohlmeyer, Christopher W.; Veenhuis, Rebecca T.; May, Megan; Laeyendecker, Oliver; Cox, Andrea L.; Bailey, Justin R.; Blankson, Joel N.] Johns Hopkins Univ, Sch Med, Ctr AIDS Res, Dept Med, Baltimore, MD 21218 USA. [Luna, Krystle A.] Univ Texas MD Anderson Canc Ctr, Dept Med, Austin, TX USA. [Kirkpatrick, Allison R.; Laeyendecker, Oliver] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. [Carrington, Mary] Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Arduino, Roberto C.] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Div Infect Dis, Houston, TX 77030 USA. [Carrington, Mary] MIT, Ragon Inst, Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Carrington, Mary] Harvard Univ, Cambridge, MA 02138 USA. RP Blankson, JN (reprint author), Johns Hopkins Univ, Sch Med, Ctr AIDS Res, Dept Med, Baltimore, MD 21218 USA.; Arduino, RC (reprint author), Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Div Infect Dis, Houston, TX 77030 USA. EM jblanks@jhmi.edu FU Johns Hopkins University Center for AIDS Research [P30AI094189, 2R56AI080328-05A1, 1R01AI120024-01]; Frederick National Laboratory for Cancer Research [HHSN261200800001E]; NIH, Frederick National Lab, Center for Cancer Research FX Funded by the Johns Hopkins University Center for AIDS Research (P30AI094189) and 2R56AI080328-05A1 and 1R01AI120024-01 (JNB) and with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E and in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. 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 50 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD FEB PY 2017 VL 16 BP 141 EP 149 DI 10.1016/j.ebiom.2017.01.034 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EM4DB UT WOS:000395262400027 PM 28159573 ER PT J AU Noguchi, S Ogawa, M Malicdan, MC Nonaka, I Nishino, I AF Noguchi, Satoru Ogawa, Megumu Malicdan, May Christine Nonaka, Ikuya Nishino, Ichizo TI Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy SO EBIOMEDICINE LA English DT Article DE Collagen; Fibrosis; IGF-1; Mesenchymal; Mouse; Muscular dystrophy; Skeletal muscles; Weakness ID CONNECTIVE-TISSUE FIBROBLASTS; SKELETAL-MUSCLE; FIBRO/ADIPOGENIC PROGENITORS; MITOCHONDRIAL DYSFUNCTION; MESENCHYMAL PROGENITORS; ULLRICH-DISEASE; SATELLITE CELLS; REGENERATION; AUTOPHAGY; MOUSE AB Congenital muscular dystrophies with collagen VI deficiency are inherited muscle disorders with a broad spectrum of clinical presentation and are caused by mutations in one of COL6A1-3 genes. Muscle pathology is characterized by fiber size variation and increased interstitial fibrosis and adipogenesis. In this study, we define critical events that contribute to muscle weakness and fibrosis in a mouse model with collagen VI deficiency. The Col6a1(GT/GT) mice develop non-progressive weakness from younger age, accompanied by stunted muscle growth due to reduced IGF-1 signaling activity. In addition, the Col6a1(GT/GT) mice have high numbers of interstitial skeletal muscle mesenchymal progenitor cells, which dramatically increase with repeated myofiber necrosis/regeneration. Our results suggest that impaired neonatal muscle growth and the activation of the mesenchymal cells in skeletal muscles contribute to the pathology of collagen VI deficient muscular dystrophy, and more importantly, provide the insights on the therapeutic strategies for collagen VI deficiency. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Noguchi, Satoru; Ogawa, Megumu; Nonaka, Ikuya; Nishino, Ichizo] Natl Inst Neurosci, Dept Neuromuscular Res, Kodaira, Tokyo, Japan. [Noguchi, Satoru; Nishino, Ichizo] Natl Ctr Neurol & Psychiat, Translat Med Ctr, Dept Clin Dev, Kodaira, Tokyo, Japan. [Malicdan, May Christine] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Malicdan, May Christine] NIH, Undiagnosed Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA. RP Noguchi, S (reprint author), Natl Inst Neurosci, Dept Neuromuscular Res, Kodaira, Tokyo, Japan. EM noguchi@ncnp.go.jp FU Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP [28-6]; Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare from Japan Agency for Medical Research and Development, AMED [H25-Shinkei Kin-Ippan-004]; JSPS KAKENHI [JP26293214, JP15H04846]; NHGRI Intramural Research Program of the National Institutes of Health, USA FX This study is partially supported by Intramural Research Grant (28-6) for Neurological and Psychiatric Disorders of NCNP, by Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare (H25-Shinkei Kin-Ippan-004) from Japan Agency for Medical Research and Development, AMED, and by JSPS KAKENHI (JP26293214, JP15H04846). M.C.V.M. is supported by the NHGRI Intramural Research Program of the National Institutes of Health, USA. NR 30 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD FEB PY 2017 VL 15 BP 193 EP 202 DI 10.1016/j.ebiom.2016.12.011 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EM4BL UT WOS:000395258200023 PM 28043812 ER PT J AU Zhang, J Li, JY Wang, P Chen, G Mendola, P Sherman, S Ying, Q AF Zhang, Jie Li, Jingyi Wang, Peng Chen, Gang Mendola, Pauline Sherman, Seth Ying, Qi TI Estimating population exposure to ambient polycyclic aromatic hydrocarbon in the United States - Part I: Model development and evaluation SO ENVIRONMENT INTERNATIONAL LA English DT Article DE PAH; United States; CMAQ; SMOKE; Speciation profiles; Exposure; Model performance ID GAS-PHASE REACTIONS; SIMULATED ATMOSPHERIC CONDITIONS; AIR PARTITION-COEFFICIENTS; SECONDARY ORGANIC AEROSOL; CHEMICAL-TRANSPORT MODEL; SOURCE APPORTIONMENT; CANCER-RISK; OH RADICALS; PAH CONCENTRATIONS; HYDROXYL RADICALS AB PAHs (polycyclic aromatic hydrocarbons) in the environment are of significant concern due to their negative impact on human health. PAH measurements at the air toxics monitoring network stations alone are not sufficient to provide a complete picture of ambient PAH levels or to allow accurate assessment of public exposure in the United States. In this study, speciation profiles for PAHs were prepared using data assembled from existing emission profile data bases, and the Sparse Matrix Operator Kernel Emissions (SMOKE) model was used to generate the gridded national emissions of 16 priority PAHs in the US. The estimated emissions were applied to simulate ambient concentration of PAHs for January, April, July and October 2011, using a modified Community Multiscale Air Quality (CMAQ) model (v5.0.1) that treats the gas and particle phase partitioning of PAHs and their reactions in the gas phase and on particle surface. Predicted daily PAH concentrations at 61 air toxics monitoring sites generally agreed with observations, and averaging the predictions over a month reduced the overall error. The best model performance was obtained at rural sites, with an average mean fractional bias (MFB) of -0.03 and mean fractional error (MFE) of 0.70. Concentrations at suburban and urban sites were underestimated with overall MFB = -0.57 and MFE = 0.89. Predicted PAH concentrations were highest in January with better model performance (MFB = 0.12, MFE = 0.69; including all sites), and lowest in July with worse model performance (MFB = 0.90, MFE = 1.08). Including heterogeneous reactions of several PAHs with O-3 on particle surface reduced the over-prediction bias in winter, although significant uncertainties were expected due to relative simple treatment of the heterogeneous reactions in the current model. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Zhang, Jie; Li, Jingyi; Wang, Peng; Chen, Gang; Ying, Qi] Texas A&M Univ, Zachary Dept Civil Engn, College Stn, TX 77845 USA. [Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Sherman, Seth] Emmes Corp, Rockville, MD 20850 USA. [Li, Jingyi] Princeton Univ, Program Atmospher & Ocean Sci, Princeton, NJ 08544 USA. RP Ying, Q (reprint author), Texas A&M Univ, Zachary Dept Civil Engn, College Stn, TX 77845 USA. EM qying@civil.tamu.edu OI Mendola, Pauline/0000-0001-5330-2844 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Air Quality and Reproductive Health [HHSN27520080 00021, HHSN27500008] FX This work was partially supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The data included in this paper were obtained from the Air Quality and Reproductive Health study supported through Contract No. HHSN27520080 00021, Task Order No. HHSN27500008 awarded to The EMMES Corporation. The authors have no conflicts of interests to disclose. The authors want to acknowledge the Texas A&M Supercomputing Facility (http://sc.tamu.edu) and the Texas Advanced Computing Center (http://www.tacc.utexas.edu/) for providing computing resources essential for completing the research reported in this paper. NR 67 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD FEB PY 2017 VL 99 BP 263 EP 274 DI 10.1016/j.envint.2016.12.002 PG 12 WC Environmental Sciences SC Environmental Sciences & Ecology GA EK6UZ UT WOS:000394062700026 PM 27988136 ER PT J AU Shaw, P Polanczyk, GV AF Shaw, Philip Polanczyk, Guilherme V. TI Combining epidemiological and neurobiological perspectives to characterize the lifetime trajectories of ADHD SO EUROPEAN CHILD & ADOLESCENT PSYCHIATRY LA English DT Editorial Material ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; YOUNG ADULTHOOD; BIRTH COHORT; CHILDHOOD; SYMPTOMS; PERSISTENCE; CHILDREN C1 [Shaw, Philip] NHGRI, Social & Behav Res Branch, NIH, BB37,Bldg 31, Bethesda, MD 20892 USA. [Shaw, Philip] NIMH, NIH, BB37,Bldg 31, Bethesda, MD 20892 USA. [Polanczyk, Guilherme V.] Univ Sao Paulo, Sch Med, Dept Psychiat, Rua Dr Ovidio Pires de Campos 785, BR-05403010 Sao Paulo, Brazil. RP Polanczyk, GV (reprint author), Univ Sao Paulo, Sch Med, Dept Psychiat, Rua Dr Ovidio Pires de Campos 785, BR-05403010 Sao Paulo, Brazil. EM shawp@mail.nih.gov; gvp@usp.br NR 14 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1018-8827 EI 1435-165X J9 EUR CHILD ADOLES PSY JI Eur. Child Adolesc. Psych. PD FEB PY 2017 VL 26 IS 2 BP 139 EP 141 DI 10.1007/s00787-017-0944-8 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA EL2PV UT WOS:000394462800002 PM 28108778 ER PT J AU Linker, A Yang, A Roper, N Whitaker, E Korenstein, D AF Linker, Anne Yang, Annie Roper, Nitin Whitaker, Evans Korenstein, Deborah TI Impact of industry collaboration on randomised controlled trials in oncology SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Conflict of interest; Disclosure; Drug industry; Collaboration; Randomised controlled trials ID CONFLICTS-OF-INTEREST; PHARMACEUTICAL-INDUSTRY; MODIFIED INTENTION; AMERICAN SOCIETY; CLINICAL-TRIALS; TREAT ANALYSIS; CANCER TRIALS; REGISTRATION; PUBLICATION; ASSOCIATION AB Background: Industry funders can simply provide money or collaborate in trial design, analysis or reporting of clinical trials. Our aim was to assess the impact of industry collaboration on trial methodology and results of randomised controlled trials (RCT). Methods: We searched PubMed for oncology RCTs published May 2013 to December 2015 in peer-reviewed journals with impact factor > 5 requiring reporting of funder role. Two authors extracted methodologic (primary end-point; blinding of the patient, clinician and outcomes assessor; and analysis) and outcome data. We used descriptive statistics and two-sided Fisher exact tests to compare characteristics of trials with collaboration, with industry funding only, and without industry funding. Results: We included 224 trials. Compared to those without industry funding, trials with collaboration used more placebo control (RR 3.59, 95% CI [1.88-6.83], p < 0001), intention-to-treat analysis (RR 1.32, 95% CI [1.04-1.67], p = 02), and blinding of patients (RR 3.05, 95% CI [1.71-5-44], p < 0001), clinicians (RR 3.36, 95% CI [1.83-6.16], p <=.001) and outcomes assessors (RR 3.03, 95% CI [1.57-5-83], p = 0002). They did not differ in use of overall survival as a primary end-point (RR 1.27 95% CI [0.72-2.24]) and were similarly likely to report positive results (RR 1.11 95% CI [0.85-1.46], p = 0.45). Studies with funding only did not differ from those without funding. Conclusions: Oncology RCTs with industry collaboration were more likely to use some high quality methods than those without industry funding, with similar rates of positive results. Our findings suggest that collaboration is not associated with trial outcomes and that mandatory disclosure of funder roles may mitigate bias. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Linker, Anne] Univ Calif San Francisco, 631 Diamond St, San Francisco, CA 94114 USA. [Yang, Annie] Mem Sloan Kettering Canc Ctr, Ctr Hlth Policy & Outcomes, 485 Lexington Ave,2nd Floor, New York, NY 10017 USA. [Roper, Nitin] NCI, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Whitaker, Evans] Univ Calif San Francisco, Lib & Ctr Knowledge Management, 530 Parnassus Ave, San Francisco, CA 94143 USA. [Korenstein, Deborah] Mem Sloan Kettering Canc Ctr, Dept Med, 485 Lexington Ave,2nd Floor, New York, NY 10017 USA. RP Korenstein, D (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 485 Lexington Ave,2nd Floor, New York, NY 10017 USA. EM Anne.linker@ucsf.edu; yanga1@mskcc.org; Nitin.roper@nih.gov; Evans.whitaker@ucsf.edu; korenstd@mskcc.org FU Cancer Center Support Grant from the National Cancer Institute to Memorial Sloan Kettering Cancer Center [P30 CA008748] FX Dr. Korenstein's work on this paper was supported by a Cancer Center Support Grant from the National Cancer Institute to Memorial Sloan Kettering Cancer Center (award number P30 CA008748). NR 39 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD FEB PY 2017 VL 72 BP 71 EP 77 DI 10.1016/j.ejca.2016.11.005 PG 7 WC Oncology SC Oncology GA EK6YK UT WOS:000394072000009 PM 28027518 ER PT J AU Yazinski, SA Comaills, V Buisson, R Genois, MM Nguyen, HD Ho, CK Kwan, TT Morris, R Lauffer, S Nussenzweig, A Ramaswamy, S Benes, CH Haber, DA Maheswaran, S Birrer, MJ Zou, L AF Yazinski, Stephanie A. Comaills, Valentine Buisson, Remi Genois, Marie-Michelle Nguyen, Hai Dang Ho, Chu Kwen Kwan, Tanya Todorova Morris, Robert Lauffer, Sam Nussenzweig, Andre Ramaswamy, Sridhar Benes, Cyril H. Haber, Daniel A. Maheswaran, Shyamala Birrer, Michael J. Zou, Lee TI ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells SO GENES & DEVELOPMENT LA English DT Article DE ATR; BRCA-deficient cancer; PARP inhibitor ID DNA-DAMAGE RESPONSE; 5' END RESECTION; POLY(ADP-RIBOSE) POLYMERASE; REPLICATION FORKS; MEDIATED PHOSPHORYLATION; PLATINUM RESISTANCE; PANCREATIC-CANCER; MAMMARY-TUMORS; PROTEIN-KINASE; MUTANT-CELLS AB Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRis) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRis also overcome the bypass of BRCA1/ 2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers. C1 [Yazinski, Stephanie A.; Comaills, Valentine; Buisson, Remi; Genois, Marie-Michelle; Nguyen, Hai Dang; Ho, Chu Kwen; Kwan, Tanya Todorova; Morris, Robert; Lauffer, Sam; Ramaswamy, Sridhar; Benes, Cyril H.; Haber, Daniel A.; Maheswaran, Shyamala; Birrer, Michael J.; Zou, Lee] Harvard Med Sch, Ctr Canc, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Kwan, Tanya Todorova] Massachusetts Gen Hosp, Howard Hughes Med Inst, Charlestown, MA 02129 USA. [Lauffer, Sam; Birrer, Michael J.] Massachusetts Gen Hosp, Gillette Ctr, Boston, MA 02115 USA. [Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. RP Zou, L (reprint author), Harvard Med Sch, Ctr Canc, Massachusetts Gen Hosp, Charlestown, MA 02129 USA.; Zou, L (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. EM zou.lee@mgh.harvard.edu FU National Institutes of Health [GM076388, CA197779, CA129933]; National Cancer Institute Federal Share of Program Income; Jim and Ann Orr MGH Research Scholar Award; Susan Komen for the Cure [KG09042]; Wellcome Trust [102696]; National Institutes of Health instrumentation [1S10RR023440-01A1]; Department of Defense [W81XWH-13-1-0027]; Philippe Foundation FX We thank S. Cantor, J. Chen, D. Durocher, N. Dyson, L. Ellisen, S. Orsulic, and B. Xia for reagents and discussions. This work was supported by grants from the National Institutes of Health (GM076388 and CA197779 to L.Z., and CA129933 to D.A.H.), National Cancer Institute Federal Share of Program Income (to L.Z.), Jim and Ann Orr MGH Research Scholar Award (to L.Z.), Susan Komen for the Cure (KG09042 to S.M.), and the Wellcome Trust (102696 to C.H.B.). The Flow Cytometry Core is supported by National Institutes of Health instrumentation grant 1S10RR023440-01A1. S.A.Y. was supported by a fellowship from the Department of Defense (W81XWH-13-1-0027). V.C. and R.B. have received support from the Philippe Foundation. M.-M.G. is a fellow of Fonds de recherche du Quebec-Sante. H.D.N. was a Medical Discovery Post-doctoral Fellow. R.B. was a Marsha Rivkin Scholar. L.Z. is the James and Patricia Poitras Endowed Chair in Cancer Research. NR 79 TC 0 Z9 0 U1 2 U2 2 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 FEB 1 PY 2017 VL 31 IS 3 BP 318 EP 332 DI 10.1101/gad.290957.116 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA EN1UQ UT WOS:000395796100010 PM 28242626 ER PT J AU Howard, DB Harvey, BK AF Howard, Douglas B. Harvey, Brandon K. TI Assaying the Stability and Inactivation of AAV Serotype 1 Vectors SO HUMAN GENE THERAPY METHODS LA English DT Article DE adeno-associated virus; AAV; stability; decontamination; inactivation ID RECOMBINANT ADENOASSOCIATED VIRUS; HUMAN GENE-THERAPY; RESPONSES; NEURONS; TRIAL; RATS AB Adeno-associated virus (AAV) vectors are a commonplace tool for gene delivery ranging from cell culture to human gene therapy. One feature that makes AAV a desirable vector is its stability, in regard to both the duration of transgene expression and retention of infectivity as a viral particle. This study examined the stability of AAV serotype 1 (AAV1) vectors under different conditions. First, transducibility after storage at 4 degrees C decreased 20% over 7 weeks. Over 10 freeze-thaw cycles, the resulting transduction efficiency became variable at 60-120% of a single thaw. Using small stainless steel slugs to mimic a biosafety cabinet or metal lab bench surface, it was found that an AAV1 vector can be reconstituted after 6 days of storage at room temperature. The stability of AAV is a desired feature, but effective decontamination procedures must be available for safety and experimental integrity. Multiple disinfectants commonly used in the laboratory for ability to inactivate an AAV1 vector were tested, and it was found that autoclaving, 0.25% peracetic acid, iodine, or 10% Clorox bleach completely prevented AAV-mediated transgene expression. These data suggest that peracetic acid should be used for inactivating AAV1 vectors on metal-based surfaces or instruments in order to avoid inadvertent transgene expression in human cells or cross-contamination of instruments. C1 [Howard, Douglas B.; Harvey, Brandon K.] NIDA, Intramural Res Program, Baltimore, MD USA. RP Harvey, BK (reprint author), NIDA, NIH, Suite 200,Room 06A729,251 Bayview Blvd, Baltimore, MD 21224 USA. EM bharvey@mail.nih.gov FU National Institute on Drug Abuse FX This work was supported by the Intramural Research Program at the National Institute on Drug Abuse. We acknowledge Dr. Ira Baum, Dr. Christopher Richie, Ms. Lowella Fortuno, Ms. Carrie Wertheim, and Dr. Rajtarun Madangopal for technical contributions and experimental suggestions. We thank Ms. Janette Lebron and Dr. Deon Harvey for assistance with editing the manuscript. We thank Arrow Metal Fabricators of Baltimore, MD, for contributing the metal slugs used for testing. A portion of this work was presented at the American Society for Gene and Cell Therapy Meeting 2014 and was published as an abstract. NR 22 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1946-6536 EI 1946-6544 J9 HUM GENE THER METHOD JI Hum. Gene Ther. Methods PD FEB PY 2017 VL 28 IS 1 SI SI BP 39 EP 48 DI 10.1089/hgtb.2016.180 PN 1 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA EK2SE UT WOS:000393776200004 PM 28192678 ER PT J AU Chen, Y Squires, A Seifabadi, R Xu, S Agarwal, HK Bernardo, M Pinto, PA Choyke, P Wood, B Tse, ZTH AF Chen, Yue Squires, Alexander Seifabadi, Reza Xu, Sheng Agarwal, Harsh Kumar Bernardo, Marcelino Pinto, Peter A. Choyke, Peter Wood, Bradford Tse, Zion Tsz Ho TI Robotic System for MRI-Guided Focal Laser Ablation in the Prostate SO IEEE-ASME TRANSACTIONS ON MECHATRONICS LA English DT Article DE Focal laser ablation (FLA); image guided therapy; MRI; prostate cancer; robot ID PNEUMATIC STEPPER MOTOR; CANCER; THERAPY; GUIDANCE; BIOPSY AB MRI-conditional robotic platforms have proved to be an effective approach for image-guided interventions. In this study, a computer-assisted, pneumatically actuated robot is designed, built, and tested for MRI-guided prostate cancer focal laser ablation (FLA). The robotic manipulator provides two active planar degrees of freedom (DoFs) by using a customized CoreXY frame and one passive rotational DoF. A remote insertion mechanism improves the surgical workflow by keeping the patients inside the scanner during needle insertion. The robotic manipulator is tested in a 3T MR scanner to evaluate its MR compliance, and the results demonstrated that the signal-to-noise ratio (SNR) variation is less than 8%. The in-scanner template positioning accuracy test demonstrates that the manipulator achieves high targeting accuracy with a mean error of 0.46 mm and a standard deviation of 0.25 mm. Phantom studies have shown that the needle insertion accuracy of the manipulator is within 2 mm (mean = 1.7 mm, standard deviation = 0.2 mm). C1 [Chen, Yue; Squires, Alexander; Tse, Zion Tsz Ho] Univ Georgia, Coll Engn, Athens, GA 30605 USA. [Seifabadi, Reza; Xu, Sheng; Bernardo, Marcelino; Pinto, Peter A.; Choyke, Peter; Wood, Bradford] NIH, Dept Radiol & Imaging Sci, Ctr Intervent Oncol, Bldg 10, Bethesda, MD 20892 USA. [Agarwal, Harsh Kumar] Philips Res North Amer, Briarcliff Manor, NY 10510 USA. [Agarwal, Harsh Kumar] Samsung Res & Dev Inst, Bangalore 560037, Karnataka, India. [Choyke, Peter] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Chen, Y (reprint author), Univ Georgia, Coll Engn, Athens, GA 30605 USA. EM ychen@uga.edu; asquires@uga.edu; reza.seifabadi@nih.gov; xus2@cc.nih.gov; harsh.agarwal@philips.com; bernardme@mail.nih.gov; pintop@mail.nih.gov; pchoyke@nih.gov; bwood@nih.gov; ziontse@uga.edu FU National Institutes of Health (NIH) Bench-to-Bedside Award; NIH Center for Interventional Oncology Grant; National Science Foundation (NSF) I-Corps Team Grant [1617340]; UGA-AU Inter-Institutional Seed Funding; American Society for Quality Dr. Richard J. Schlesinger Grant; PHS from the Clinical and Translational Science Award Program [UL1TR000454]; NIH National Center for Advancing Translational Sciences FX This study was supported in part by the National Institutes of Health (NIH) Bench-to-Bedside Award, the NIH Center for Interventional Oncology Grant, the National Science Foundation (NSF) I-Corps Team Grant (1617340), the UGA-AU Inter-Institutional Seed Funding, the American Society for Quality Dr. Richard J. Schlesinger Grant, the PHS Grant UL1TR000454 from the Clinical and Translational Science Award Program, and the NIH National Center for Advancing Translational Sciences. (Yue Chen and Alexander Squires contributed equally to this work.) NR 37 TC 0 Z9 0 U1 4 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1083-4435 EI 1941-014X J9 IEEE-ASME T MECH JI IEEE-ASME Trans. Mechatron. PD FEB PY 2017 VL 22 IS 1 BP 107 EP 114 DI 10.1109/TMECH.2016.2611570 PG 8 WC Automation & Control Systems; Engineering, Manufacturing; Engineering, Electrical & Electronic; Engineering, Mechanical SC Automation & Control Systems; Engineering GA EN1DG UT WOS:000395750100013 ER PT J AU Pettigrew, RI Heetderks, WJ Kelley, CA Peng, GCY Krosnick, SH Jakeman, LB Egan, KD Marge, M AF Pettigrew, Roderic I. Heetderks, William J. Kelley, Christine A. Peng, Grace C. Y. Krosnick, Steven H. Jakeman, Lyn B. Egan, Katharine D. Marge, Michael TI Epidural Spinal Stimulation to Improve Bladder, Bowel, and Sexual Function in Individuals With Spinal Cord Injuries: A Framework for Clinical Research SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Autonomic nervous system dysfunctions; epidural spinal cord stimulation (SCS); interventions for spinal cord injuries; paralysis; spinal cord injury (SCI); spinal mapping for bladder; bowel; sexual functions ID PRESERVED CORTICOSPINAL CONDUCTION; DEEP BRAIN-STIMULATION; QUALITY-OF-LIFE; BASIC DATA SET; ELECTRICAL-STIMULATION; VOLUNTARY MOVEMENT; CONTRACTIONS; RECOVERY; RATS; DYSFUNCTION AB While some recent studies that apply epidural spinal cord stimulation (SCS) have demonstrated a breakthrough in improvement of the health and quality of the life of persons with spinal cord injury (SCI), the numbers of people who have received SCS are small. This is in sharp contrast to the thousands of persons worldwide living with SCI who have no practical recourse or hope of recovery of lost functions. Thus, the vision is to understand the full potential of this new intervention and to determine if it is safe and effective in a larger cohort, and if it is scalable so that it can be made available to all those who might benefit. To achieve this vision, the National Institute of Biomedical Imaging and Bioengineering called for and organized a consortium of multiple stakeholder groups: foundations addressing paralysis, federal and public agencies, industrial partners, academicians, and researchers, all interested in the same goal. Based on input from consortium participants, we have reasoned that a first step is to define a scalable SCS approach that is effective in restoring lost autonomic physiology, specifically bladder, bowel, and sexual function. These functions are most critical for improving the quality of life of persons living with SCI. This report outlines a framework for conducting the research needed to define such an effective SCS procedure that might seek Food and Drug Administration approval and be implemented at the population level. C1 [Pettigrew, Roderic I.; Heetderks, William J.; Kelley, Christine A.; Peng, Grace C. Y.; Krosnick, Steven H.; Egan, Katharine D.; Marge, Michael] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. [Heetderks, William J.] US FDA, Rockville, MD 20857 USA. [Jakeman, Lyn B.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Kelley, CA (reprint author), Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. EM kelleyc@mail.nih.gov FU National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health FX This work was supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health. NR 49 TC 0 Z9 0 U1 1 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 EI 1558-2531 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD FEB PY 2017 VL 64 IS 2 BP 253 EP 262 DI 10.1109/TBME.2016.2637301 PG 10 WC Engineering, Biomedical SC Engineering GA EL5UO UT WOS:000394686900001 PM 28113186 ER PT J AU Groves, DW Olivieri, LJ Shanbhag, SM Bronson, KC Yu, JH Nelson, EA Rollison, SF Stagliano, MS John, AS Kuehl, K Chen, MY AF Groves, Daniel W. Olivieri, Laura J. Shanbhag, Sujata M. Bronson, Kathie C. Yu, Jeannie H. Nelson, Evan A. Rollison, Shirley F. Stagliano, Michael S. John, Anitha S. Kuehl, Karen Chen, Marcus Y. TI Feasibility of low radiation dose retrospectively-gated cardiac CT for functional analysis in adult congenital heart disease SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Adult congenital heart disease; Cardiac computed tomography; Systolic function; Radiation dose ID DUAL-SOURCE CT; CARDIOVASCULAR MAGNETIC-RESONANCE; RIGHT-VENTRICULAR FUNCTION; COMPUTED-TOMOGRAPHY; QUANTITATIVE ASSESSMENT; CORONARY-ANGIOGRAPHY; EXPOSURE; GUIDELINES; CANCER; RISK AB Background: The use of cardiac computed tomography (CT) in the evaluation of adult congenital heart disease patients is limited due to concerns of high radiation doses. The purpose of this study was to prospectively assess whether low radiation dose cardiac CT is feasible to evaluate ventricular systolic function in adults with congenital heart disease. Methods: The study group included 30 consecutive patients with significant congenital heart disease who underwent a total of 35 ECG-gated cardiac CT scans utilizing a 320-detector row CT scanner. Each study included a non-contrast scan and subsequent contrast-enhanced retrospectively-gated acquisition. Effective radiation dose was estimated by multiplying the dose length product by a k-factor of 0.014 mSv/mGy cm. Results: The mean age of the patients was 34.4 +/- 8.9 years, 60% were men, and mean body mass index was 24.2 +/- 4.3 kg/m(2). A majority of patients (n= 28, 93.3%) had contraindications to cardiac MRI. A tube potential of 80 kV was used in 27 (77.1%) of the contrast-enhanced scans. The mean signal-to-noise and contrast-to-noise ratios were 11.5 +/- 3.9 and 10.3 +/- 3.7, respectively. The median radiation dose for non-contrast and contrast-enhanced images were 0.1 mSv (0.07-0.2 mSv) and 0.94 mSv (0.5-2.1 mSv), respectively. All 35 CT scans were successfully analyzed for ventricular systolic function. Conclusions: A low radiation contrast-enhanced, retrospectively-gated cardiac CT with a median radiation dose of less than 1 mSv was successful in evaluating ventricular systolic function in 30 consecutive adult congenital heart disease patients who underwent a total of 35 scans. Published by Elsevier Ireland Ltd. C1 [Groves, Daniel W.; Shanbhag, Sujata M.; Bronson, Kathie C.; Yu, Jeannie H.; Nelson, Evan A.; Rollison, Shirley F.; Stagliano, Michael S.; Chen, Marcus Y.] NHLBI, Dept Hlth & Human Serv, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch,NIH, Bldg 10, Bethesda, MD 20892 USA. [Olivieri, Laura J.; John, Anitha S.; Kuehl, Karen] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. RP Chen, MY (reprint author), NHLBI, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch, NIH, 10 Ctr Dr,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM chenmy@nhlbi.nih.gov FU National Institutes of Health [1ZIAHL006138-05] FX This work was supported by the National Institutes of Health (grant number 1ZIAHL006138-05). NR 34 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD FEB 1 PY 2017 VL 228 BP 180 EP 183 DI 10.1016/j.ijcard.2016.11.108 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ7NJ UT WOS:000393408600029 PM 27865183 ER PT J AU Watson, MJ Sidana, A Singer, EA Gupta, GN Rastinehad, AR Vourganti, S Bratslavsky, G Metwalli, AR AF Watson, Matthew J. Sidana, Abhinav Singer, Eric A. Gupta, Gopal N. Rastinehad, Ardeshir R. Vourganti, Srinivas Bratslavsky, Gennady Metwalli, Adam R. TI Re: Csaba Berczi, Ben Thomas, Zsolt Bacso, Tibor Flasko. Bilateral renal cancers: oncological and functional outcomes. Int Urol Nephrol 2016 (Epub ahead of print) SO INTERNATIONAL UROLOGY AND NEPHROLOGY LA English DT Letter ID PARTIAL NEPHRECTOMY; KIDNEY C1 [Watson, Matthew J.; Sidana, Abhinav; Metwalli, Adam R.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Singer, Eric A.] Rutgers Canc Inst New Jersey, Sect Urol Oncol, New Brunswick, NJ USA. [Gupta, Gopal N.] Loyola Univ, Med Ctr, Dept Urol, Chicago, IL 60611 USA. [Rastinehad, Ardeshir R.] Icahn Sch Med Mt Sinai, Dept Urol & Radiol, New York, NY 10029 USA. [Vourganti, Srinivas] Rush Univ, Dept Urol, Med Ctr, Chicago, IL 60612 USA. [Bratslavsky, Gennady] SUNY Upstate Med Ctr, Dept Urol, Syracuse, NY USA. RP Metwalli, AR (reprint author), NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. EM adam.metwalli@nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-1623 EI 1573-2584 J9 INT UROL NEPHROL JI Int. Urol. Nephrol. PD FEB PY 2017 VL 49 IS 2 BP 267 EP 268 DI 10.1007/s11255-016-1433-6 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EK8CJ UT WOS:000394151200013 PM 27812784 ER PT J AU First, MB Kendler, KS Leibenluft, E AF First, Michael B. Kendler, Kenneth S. Leibenluft, Ellen TI The Future of the DSM Implementing a Continuous Improvement Model SO JAMA PSYCHIATRY LA English DT Editorial Material C1 [First, Michael B.] New York State Psychiat Inst & Hosp, Div Clin Phenomenol, 1051 Riverside Dr,Unit 60, New York, NY 10032 USA. [First, Michael B.] Columbia Univ, Dept Psychiat, Med Ctr, New York, NY USA. [Kendler, Kenneth S.] Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA. [Kendler, Kenneth S.] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA 23284 USA. [Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, Bethesda, MD 20892 USA. RP First, MB (reprint author), New York State Psychiat Inst & Hosp, Div Clin Phenomenol, 1051 Riverside Dr,Unit 60, New York, NY 10032 USA. EM mbf2@columbia.edu NR 4 TC 0 Z9 0 U1 0 U2 0 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 FEB 1 PY 2017 VL 74 IS 2 BP 115 EP 116 DI 10.1001/jamapsychiatry.2016.3004 PG 2 WC Psychiatry SC Psychiatry GA EM6NT UT WOS:000395430100001 PM 27851854 ER PT J AU Scott, J Murray, G Henry, C Morken, G Scott, E Angst, J Merikangas, KR Hickie, IB AF Scott, Jan Murray, Greg Henry, Chantal Morken, Gunnar Scott, Elizabeth Angst, Jules Merikangas, Kathleen R. Hickie, Ian B. TI Activation in Bipolar Disorders A Systematic Review SO JAMA PSYCHIATRY LA English DT Review ID CLINICAL-TRIAL PARTICIPANTS; BEHAVIORAL-PATTERN MONITOR; CIRCADIAN ACTIVITY RHYTHM; PSYCHOMOTOR ACTIVITY; SPECTRUM DISORDERS; MANIC SYMPTOMS; RATING-SCALE; MIXED EPISODES; SLEEP; INDIVIDUALS AB IMPORTANCE Increased activity and energy alongside mood change are identified in the DSM-5 as cardinal symptoms of mania and hypomania. A wide range of existing research suggests that this revision may be valid, but systematic integration of the evidence has not been reported. The term activation is understood as emerging from underlying physiological change and having objective (observable motor activity) and related subjective (energy) levels. OBJECTIVES To systematically review studies of the clinical phenomenon of activation in bipolar disorder, to determine whether activation is statistically abnormal in bipolar disorder and demonstrably distinct from mood, and to identify any significant between-and within-individual differences in the dynamics of activation. EVIDENCE REVIEW This systematic review of MEDLINE, PsycINFO, EMBASE, CINAHL, and PubMed databases from January 1, 1970, until September 30, 2016, identified 56 of a possible 3284 citations for (1) data-driven analyses of the dimensions and factor structure of mania and bipolar depression and (2) longitudinal studies reporting real-time objective monitoring or momentary assessment of daytime activity in individuals with bipolar disorder compared with other clinical or healthy control samples. Hand search of reference lists, specialty journals, websites, published conference proceedings, and dissertation abstracts and contact with other researchers ensured inclusion of gray literature and additional analyses as well as raw data if appropriate. Quality assessment was perfomed using the National Institutes of Health quality assessment tool. FINDINGS A total of 56 studies met eligibility criteria for inclusion in the review including 29 analyses of the factor structure of bipolar disorder, 3 of activity data from experimental sampling or ecological momentary assessment, and 20 actigraphy and 4 laboratory-based studies. Synthesizing findings across the studies revealed that the most robust finding was that mean levels of activity are lower during euthymia and depression in patients with bipolar disorder compared with healthy controls and other comparison groups (11 studies). The 7 ecological and laboratory studies show less organized or predictable patterns of behavior and a relative lack of habituation among patients with bipolar disorders compared with others. Factor analytic studies provide fairly consistent evidence that mood and activation represent distinct dimensions of bipolar disorder. Ten studies that examined interindividual and intraindividual patterns of activity suggest that mania may be better characterized by differences in robustness, variability, predictability, or complexity of activation rather than mean levels of activity. CONCLUSIONS AND RELEVANCE Within the limitations of the data, this synthesis of available evidence broadly supports the elevation of activation as a criterion A symptom for bipolar disorder in DSM-5. Although the importance of activation in bipolar disorders has been acknowledged for more than a century, this review suggests that this critical construct is understudied and should be the topic of more systematic high-quality research. C1 [Scott, Jan] Newcastle Univ, Inst Neurosci, Dept Acad Psychiat, Newcastle, NSW, Australia. [Murray, Greg] Swinburne Univ Technol, Dept Psychol, Melbourne, Vic, Australia. [Henry, Chantal] Pole Psychiat Univ, Hop A Chenevier, Paris, France. [Morken, Gunnar] Norwegian Univ Sci & Technol, Dept Neurosci, Trondheim, Norway. [Scott, Elizabeth] Univ Notre Dame, Dept Med, Sydney, NSW, Australia. [Angst, Jules] Univ Zurich, Hosp Psychiat, Dept Psychiat Psychotherapy & Psychosomat, Zurich, Switzerland. [Merikangas, Kathleen R.] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [Hickie, Ian B.] Univ Sydney, Brain & Mind Ctr, Sydney, NSW, Australia. RP Scott, J (reprint author), Newcastle Univ, Inst Neurosci, Acad Psychiat, Newcastle, NSW NE6 4BE, Australia. EM jan.scott@newcastle.ac.uk FU UK Medical Research Council; UK Research for Patient Benefit program [PB-PG-0609-16166]; Janssen-Cilag; Institut National de la Sante et de la Recherche Medicale; Assistance Publique-Hopitaux de Paris; Labex Biopsy; AstraZeneca; Lundbeck; Otsuka FX Dr J. Scott reports being a visiting professor at Diderot University, the Norwegian University of Science and Technology, and The University of Sydney; receiving grant funding from the UK Medical Research Council (including for projects on a cohort of bipolar II disorders, randomized trials of cognitive behavioral therapy, and actigraphic monitoring in bipolar disorders) and from the UK Research for Patient Benefit program (PB-PG-0609-16166: Early identification and intervention in young people at risk of mood disorders); and receiving a personal fee from Janssen-Cilag for a nonpromotional talk on sleep problems. Dr Henry reports receiving grants from Institut National de la Sante et de la Recherche Medicale, Assistance Publique-Hopitaux de Paris, and Labex Biopsy, during the conduct of the review; and receiving personal fees from AstraZeneca, Lundbeck, and Otsuka. Dr E. Scott reports receiving honoraria for educational seminars related to the clinical management of depressive disorders supported by Servier and Eli Lilly; participating in a national advisory board for the antidepressant compound desvenlafaxine succinate (Pristiq), manufactured by Pfizer; and serving as the National Coordinator of an antidepressant trial sponsored by Servier. Dr Merikangas reports serving as the leader of the recently established collaborative network called mMARCH, which is coordinated by a workgroup of the National Institute of Mental Health that several other authors have been invited to join. Dr Hickie reports serving as a Commissioner in Australia's new National Mental Health Commission from 2012; leading a range of community-based and pharmaceutical industry-supported depression awareness and education and training programs; leading projects for health professionals and the community supported by governmental, community agency, and pharmaceutical industry partners (Wyeth, Eli Lily, Servier, Pfizer, and AstraZeneca); receiving honoraria for presentations of his own work at educational seminars supported by several nongovernment organizations and by Servier, Pfizer, AstraZeneca, and Eli Lilly; being a member of the Medical Advisory Panel for Medibank Private and a Board Member of Psychosis Australia Trust; leading an investigator-initiated study of the effects of agomelatine on circadian parameters (supported in part by Servier); and participating in a multicenter clinical trial of the effects of agomelatine on sleep architecture in depression and a Servier-supported study of major depression and sleep disturbance in primary care settings. No other disclosures were reported. NR 75 TC 1 Z9 1 U1 2 U2 2 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 FEB 1 PY 2017 VL 74 IS 2 BP 189 EP 196 DI 10.1001/jamapsychiatry.2016.3459 PG 8 WC Psychiatry SC Psychiatry GA EM6NT UT WOS:000395430100014 PM 28002572 ER PT J AU Banegas, MP John, EM Slattery, ML Gomez, SL Yu, M LaCroix, AZ Pee, D Chlebowski, RT Hines, LM Thompson, CA Gail, MH AF Banegas, Matthew P. John, Esther M. Slattery, Martha L. Gomez, Scarlett Lin Yu, Mandi LaCroix, Andrea Z. Pee, David Chlebowski, Rowan T. Hines, Lisa M. Thompson, Cynthia A. Gail, Mitchell H. TI Projecting Individualized Absolute Invasive Breast Cancer Risk in US Hispanic Women SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID WHITE WOMEN; MAMMOGRAPHIC DENSITY; AMERICAN WOMEN; GAIL MODEL; POPULATION; HISTORY; ASSOCIATION; VALIDATION; PREDICTION; FAMILY AB Background: There is no model to estimate absolute invasive breast cancer risk for Hispanic women. Methods: The San Francisco Bay Area Breast Cancer Study (SFBCS) provided data on Hispanic breast cancer case patients (533 US-born, 553 foreign-born) and control participants (464 US-born, 947 foreign-born). These data yielded estimates of relative risk (RR) and attributable risk (AR) separately for US-born and foreign-born women. Nativity-specific absolute risks were estimated by combining RR and AR information with nativity-specific invasive breast cancer incidence and competing mortality rates from the California Cancer Registry and Surveillance, Epidemiology, and End Results program to develop the Hispanic risk model (HRM). In independent data, we assessed model calibration through observed/expected (O/E) ratios, and we estimated discriminatory accuracy with the area under the receiver operating characteristic curve (AUC) statistic. Results: The US-born HRM included age at first full-term pregnancy, biopsy for benign breast disease, and family history of breast cancer; the foreign-born HRM also included age at menarche. The HRM estimated lower risks than the National Cancer Institute's Breast Cancer Risk Assessment Tool (BCRAT) for US-born Hispanic women, but higher risks in foreign-born women. In independent data from the Women's Health Initiative, the HRM was well calibrated for US-born women (observed/expected [O/E] ratio - 1.07, 95% confidence interval [CI] - 0.81 to 1.40), but seemed to overestimate risk in foreign-born women (O/E ratio - 0.66, 95% CI - 0.41 to 1.07). The AUC was 0.564 (95% CI = 0.485 to 0.644) for US-born and 0.625 (95% CI = 0.487 to 0.764) for foreign-born women. Conclusions: The HRM is the first absolute risk model that is based entirely on data specific to Hispanic women by nativity. Further studies in Hispanic women are warranted to evaluate its validity. C1 [Banegas, Matthew P.] Ctr Hlth Res, Kaiser Permanente Northwest, 3800 N Interstate Ave, Portland, OR 97227 USA. [John, Esther M.; Gomez, Scarlett Lin] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.; Gomez, Scarlett Lin] Stanford Univ Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA USA. [John, Esther M.; Gomez, Scarlett Lin] Stanford Univ Sch Med, Stanford Canc Inst, Stanford, CA USA. [Slattery, Martha L.] Univ Utah, Dept Med, Salt Lake City, UT USA. [Yu, Mandi] Div Canc Control & Populat Sci, Surveillance Res Program, Rockville, MD USA. [Gail, Mitchell H.] Div Canc Epidemiol & Genet, Bethesda, MD USA. [Yu, Mandi] Natl Canc Inst, Bethesda, MD USA. [LaCroix, Andrea Z.] Univ Calif San Diego, Div Epidemiol Family & Prevent Med, San Diego, CA USA. [Pee, David] Informat Management Serv Inc, Rockville, MD USA. [Chlebowski, Rowan T.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA USA. [Hines, Lisa M.] Univ Colorado Colorado Springs, Dept Biol, Colorado Springs, CO USA. [Thompson, Cynthia A.] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. RP Banegas, MP (reprint author), Ctr Hlth Res, Kaiser Permanente Northwest, 3800 N Interstate Ave, Portland, OR 97227 USA. EM matthew.p.banegas@kpchr.org FU Cancer Prevention Fellowship Program of the Division of Cancer Prevention; National Cancer Institute [CA63446, CA77305, CA078682, CA078762, CA078552, CA078802, CA14002]; US Department of Defense [DAMD17-96-1-6071]; California Breast Cancer Research Program [7PB-0068]; National Cancer Institute's Surveillance, Epidemiology, and End Results Program [NNSH261201000140C, HHSN261201000140C, HHSN261201000035C, HHSN261201000034C]; Stanford Cancer Institute; California Department of Public Health [103885]; Centers for Disease Control and Prevention's National Program of Cancer Registries [U58DP003862-01]; National Heart, Lung, and Blood Institute, National Institutes of Health; US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX This work was supported by the Cancer Prevention Fellowship Program of the Division of Cancer Prevention and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. The San Francisco Bay Area Breast Cancer Study (SFBCS) was supported by grants CA63446 and CA77305 (to E. M. John) from the National Cancer Institute, grant DAMD17-96-1-6071 (to E. M. John) from the US Department of Defense, and grant 7PB-0068 (to E. M. John) from the California Breast Cancer Research Program. The 4-Corners Breast Cancer Study was funded by grants CA078682, CA078762, CA078552, and CA078802 from the National Cancer Institute. The Breast Cancer Health Disparities Study was funded by grant CA14002 (to M. L. Slattery) from the National Cancer Institute. Dr. Gomez was supported by the National Cancer Institute's Surveillance,; Epidemiology, and End Results Program under contract NNSH261201000140C awarded to the Cancer Prevention Institute of California and by the Stanford Cancer Institute. The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology, and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement U58DP003862-01 awarded to the California Department of Public Health. The Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 32 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD FEB PY 2017 VL 109 IS 2 AR djw215 DI 10.1093/jnci/djw215 PG 8 WC Oncology SC Oncology GA EO2DU UT WOS:000396507600006 ER PT J AU Sayre, NL Sifuentes, M Holstein, D Cheng, SY Zhu, XG Lechleiter, JD AF Sayre, Naomi L. Sifuentes, Mikaela Holstein, Deborah Cheng, Sheue-yann Zhu, Xuguang Lechleiter, James D. TI Stimulation of astrocyte fatty acid oxidation by thyroid hormone is protective against ischemic stroke-induced damage SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE Astrocyte; fatty acid oxidation; neuroprotection; stroke; thyroid hormone ID MUSCLE IN-VIVO; TRIFUNCTIONAL PROTEIN; ENERGY-METABOLISM; BRAIN METABOLISM; RECEPTOR; MITOCHONDRIA; NEURONS; INVOLVEMENT; ACTIVATION; MODEL AB We previously demonstrated that stimulation of astrocyte mitochondrial ATP production via P2Y(1) receptor agonists was neuroprotective after cerebral ischemic stroke. Another mechanism that increases ATP production is fatty acid oxidation (FAO). We show that in primary human astrocytes, FAO and ATP production are stimulated by 3,3,5 triiodo-L-thyronine (T3). We tested whether T3-stimulated FAO enhances neuroprotection, and show that T3 increased astrocyte survival after either hydrogen peroxide exposure or oxygen glucose deprivation. T3-mediated ATP production and protection were both eliminated with etomoxir, an inhibitor of FAO. T3-mediated protection in vitro was also dependent on astrocytes expressing HADHA (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase), which we previously showed was critical for T3-mediated FAO in fibroblasts. Consistent with previous reports, T3-treatment decreased stroke volumes in mice. While T3 decreased stroke volume in etomoxir-treated mice, T3 had no protective effect on stroke volume in HADHA +/- mice or in mice unable to upregulate astrocyte-specific energy production. In vivo, 95% of HADHA co-localize with glial-fibrillary acidic protein, suggesting the effect of HADHA is astrocyte mediated. These results suggest that astrocyte-FAO modulates lesion size and is required for T3-mediated neuroprotection post-stroke. To our knowledge, this is the first report of a neuroprotective role for FAO in the brain. C1 [Sayre, Naomi L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Neurosurg, San Antonio, TX 78229 USA. [Sifuentes, Mikaela; Holstein, Deborah; Lechleiter, James D.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Cheng, Sheue-yann; Zhu, Xuguang] NIH, Mol Biol Lab, Gene Regulat Sect, Bethesda, MD 20892 USA. [Lechleiter, James D.] Univ Texas Hlth Sci Ctr San Antonio, South Texas Res Facil Neurosci Ctr, Dept Cellular & Struct Biol, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. RP Lechleiter, JD (reprint author), Univ Texas Hlth Sci Ctr San Antonio, South Texas Res Facil Neurosci Ctr, Dept Cellular & Struct Biol, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM Lechleiter@uthscsa.edu OI Sifuentes, Mikaela/0000-0002-7914-4183 FU NIH [AG007218]; AHA [13Post16820029] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The research in this paper was supported by NIH AG007218 (JDL) and AHA 13Post16820029 (NLS). NR 36 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD FEB PY 2017 VL 37 IS 2 BP 514 EP 527 DI 10.1177/0271678X16629153 PG 14 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EK4NN UT WOS:000393903900011 PM 26873887 ER PT J AU Benveniste, H Lazebnik, Y Volkow, ND AF Benveniste, Helene Lazebnik, Yuri Volkow, Nora D. TI Seeing how we smell SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID DOPAMINE TRANSPORTERS; ALZHEIMERS-DISEASE; CLASSIFICATION; NEUROGENESIS; BINDING AB PET allows noninvasive imaging of a variety of events in the body, including the activity of neuronal circuits in the brain that are involved in cognition and behaviors, by using radiotracers that detect relevant biological reactions. A major impediment to expanding PET applications to study the brain has been the lack of radiotracers that can identify and measure specific types of neurons or glial cells. In this issue of the JCI, Van de Bittner and colleagues describe a promising step toward solving this problem by identifying and describing a radiotracer, [C-11]GV1-57, that appears to specifically label olfactory sensory neurons (OSNs), which are essential for olfaction (Figure 1). This tracer, if its specificity is confirmed, has the potential to become a prototype for future radiotracers that can identify other neuronal cell types and would allow visualization and in-depth characterization of these neurons and their genesis. C1 [Benveniste, Helene] Yale Sch Med, Dept Anesthesiol, New Haven, CT USA. [Lazebnik, Yuri] Lerna Consulting LLC, New Haven, CT USA. [Volkow, Nora D.] NIAAA, Lab Neuroimaging, NIH, Bethesda, MD USA. RP Benveniste, H (reprint author), Yale Sch Med, Dept Anesthesiol, New Haven, CT USA. EM helene.benveniste@yale.edu NR 20 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB 1 PY 2017 VL 127 IS 2 BP 447 EP 449 DI 10.1172/JCI91305 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK8HI UT WOS:000394164100006 PM 28112677 ER PT J AU Bradley, SJ Bourgognon, JM Sanger, HE Verity, N Mogg, AJ White, DJ Butcher, AJ Moreno, JA Molloy, C Macedo-Hatch, T Edwards, JM Wess, J Pawlak, R Read, DJ Sexton, PM Broad, LM Steinert, JR Mallucci, GR Christopoulos, A Felder, CC Tobin, AB AF Bradley, Sophie J. Bourgognon, Julie-Myrtille Sanger, Helen E. Verity, Nicholas Mogg, Adrian J. White, David J. Butcher, Adrian J. Moreno, Julie A. Molloy, Colin Macedo-Hatch, Timothy Edwards, Jennifer M. Wess, Jurgen Pawlak, Robert Read, David J. Sexton, Patrick M. Broad, Lisa M. Steinert, Joern R. Mallucci, Giovanna R. Christopoulos, Arthur Felder, Christian C. Tobin, Andrew B. TI M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID RECEPTOR AGONIST XANOMELINE; ANTIPSYCHOTIC-LIKE ACTIVITY; PROTEIN-COUPLED RECEPTORS; LONG-TERM DEPRESSION; ACETYLCHOLINE-RECEPTOR; ALZHEIMERS-DISEASE; AMPA RECEPTORS; CHOLINERGIC INNERVATION; SYNAPTIC PLASTICITY; MOUSE MODEL AB The current frontline symptomatic treatment for Alzheimer's disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR-selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD. C1 [Bradley, Sophie J.; Molloy, Colin; Tobin, Andrew B.] Univ Glasgow, Coll Med Vet & Life Sci, Ctr Translat Pharmacol, Inst Mol Cell & Syst Biol, Glasgow G12 8QQ, Lanark, Scotland. [Bourgognon, Julie-Myrtille; Verity, Nicholas; Butcher, Adrian J.; Moreno, Julie A.; Macedo-Hatch, Timothy; Edwards, Jennifer M.; Read, David J.; Steinert, Joern R.; Mallucci, Giovanna R.] Univ Leicester, MRC Toxicol Unit, Leicester, Leics, England. [Sanger, Helen E.; Mogg, Adrian J.; Broad, Lisa M.] Eli Lilly & Co, Neurosci, Windlesham, Surrey, England. [White, David J.] Univ Leicester, Cent Res Facil, Leicester, Leics, England. [Wess, Jurgen] NIDDK, Bioorgan Chem Lab, Mol Signaling Sect, Bethesda, MD 20892 USA. [Pawlak, Robert] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England. [Sexton, Patrick M.; Christopoulos, Arthur] Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic, Australia. [Sexton, Patrick M.; Christopoulos, Arthur] Monash Univ, Dept Pharmacol, Parkville, Vic, Australia. [Mallucci, Giovanna R.] Univ Cambridge, Dept Clin Neurosci, Cambridge, England. [Felder, Christian C.] Eli Lilly & Co, Lilly Corp Ctr, Neurosci, Indianapolis, IN USA. RP Tobin, AB (reprint author), Univ Glasgow, Coll Med Vet & Life Sci, Ctr Translat Pharmacol, Inst Mol Cell & Syst Biol, Glasgow G12 8QQ, Lanark, Scotland. EM andrew.tobin@glasgow.ac.uk FU Wellcome Trust Collaborative Award [201529/Z/16/Z]; Medical Research Council; Eli Lilly Company; Lilly Research Award Program (LRAP) grant (Eli Lilly); NIH [P30AG008017]; Marie Curie grant "Extrabrain" (European Commission) FX ABT, AC, and PMS received funding from a Wellcome Trust Collaborative Award (201529/Z/16/Z). ABT, SJB, AJB, and TMH were funded through a Medical Research Council programme leader grant provided by the MRC Toxicology Unit. CCF, LMB, AJM, and HES were funded by the Eli Lilly Company. JMB received funding through a Lilly Research Award Program (LRAP) grant (Eli Lilly). RP received funding from the Marie Curie grant "Extrabrain" (European Commission). AC is a senior principal research fellow and PMS a principal research fellow of the National Health and Medical Research Council of Australia. Tissue samples were from Randy Woltjer at the Oregon Alzheimer's Disease Center. The Oregon Alzheimer's Disease Center is supported by NIH grant P30AG008017. The authors would also like to thank Peter Scammells and Shailesh Mistry for synthesis of BQZ-12; Graham Wishart for providing the exposure data; Richard Vivier, Donna Farley, Mark Ward, and Siobhan Dennis for technical assistance; and Kok Choi Kong for initial fear-conditioning experiments. NR 57 TC 0 Z9 0 U1 5 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB 1 PY 2017 VL 127 IS 2 BP 487 EP 499 DI 10.1172/JCI87526 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK8HI UT WOS:000394164100011 PM 27991860 ER PT J AU Chen, M Shrestha, YB Podyma, B Cui, ZZ Naglieri, B Sun, H Ho, T Wilson, EA Li, YQ Gavrilova, O Weinstein, LS AF Chen, Min Shrestha, Yogendra B. Podyma, Brandon Cui, Zhenzhong Naglieri, Benedetta Sun, Hui Ho, Thuy Wilson, Eric A. Li, Yong-Qi Gavrilova, Oksana Weinstein, Lee S. TI G(s)alpha deficiency in the dorsomedial hypothalamus underlies obesity associated with G(s)alpha mutations SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID BROWN ADIPOSE-TISSUE; PSEUDOHYPOPARATHYROIDISM TYPE 1A; SYMPATHETIC-NERVE ACTIVITY; RAPHE PALLIDUS; ENERGY-EXPENDITURE; MEDULLARY RAPHE; PARAVENTRICULAR NUCLEUS; MELANOCORTIN RECEPTORS; TARGETED DISRUPTION; LIPID-METABOLISM AB G(s)alpha, encoded by Gnas, mediates hormone and neurotransmitter receptor-stimulated cAMP generation. Heterozygous G(s)alpha-inactivating mutations lead to obesity in Albright hereditary osteodystrophy (AHO) patients, but only when the mutations occur on the maternal allele. This parent-of-origin effect is due to G(s)alpha imprinting in the CNS, although the relevant CNS regions are unknown. We have now shown that mice with a Gnas gene deletion disrupting G(s)alpha expression on the maternal allele, but not the paternal allele, in the dorsomedial nucleus of the hypothalamus (DMH) developed obesity and reduced energy expenditure without hyperphagia. Although maternal Gnas deletion impaired activation of brown adipose tissue (BAT) in mice, their responses to cold environment remained intact. Similar findings were observed in mice with DMH-specific deficiency of melanocortin MC4R receptors, which are known to activate G(s)alpha. Our results show that G(s)alpha imprinting in the DMH underlies the parent-of-origin metabolic phenotype that results from G(s)alpha mutations and that DMH MC4R/G(s)alpha signaling is important for regulation of energy expenditure and BAT activation, but not the metabolic response to cold. C1 [Chen, Min; Shrestha, Yogendra B.; Podyma, Brandon; Naglieri, Benedetta; Sun, Hui; Ho, Thuy; Wilson, Eric A.; Li, Yong-Qi; Weinstein, Lee S.] NIDDK, NIH, Metab Dis Branch, Bldg 10,Room 8C101, Bethesda, MD 20892 USA. [Cui, Zhenzhong; Gavrilova, Oksana] NIDDK, NIH, Mouse Metab Core Lab, Bethesda, MD USA. RP Weinstein, LS (reprint author), NIDDK, NIH, Metab Dis Branch, Bldg 10,Room 8C101, Bethesda, MD 20892 USA. EM leew@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX We would like to thank the National Institute of Diabetes and Digestive and Kidney Diseases Mouse Metabolism Core Laboratory for technical assistance and B. Lowell and D. Bartsch for providing mouse lines. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 44 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB 1 PY 2017 VL 127 IS 2 BP 500 EP 510 DI 10.1172/JCI88622 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK8HI UT WOS:000394164100012 PM 27991864 ER PT J AU Calcutt, NA Smith, DR Frizzi, K Sabbir, MG Chowdhury, SKR Mixcoatl-Zecuatl, T Saleh, A Muttalib, N Van der Ploeg, R Ochoa, J Gopaul, A Tessler, L Wess, J Jolivalt, CG Fernyhough, P AF Calcutt, Nigel A. Smith, Darrell R. Frizzi, Katie Sabbir, Mohammad Golam Chowdhury, Subir K. Roy Mixcoatl-Zecuatl, Teresa Saleh, Ali Muttalib, Nabeel Van der Ploeg, Randy Ochoa, Joseline Gopaul, Allison Tessler, Lori Wess, Juergen Jolivalt, Corinne G. Fernyhough, Paul TI Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ACTIVATED PROTEIN-KINASE; ADULT SENSORY NEURONS; DORSAL-ROOT GANGLIA; DIABETIC-NEUROPATHY; MITOCHONDRIAL DYSFUNCTION; CHOLINE-ACETYLTRANSFERASE; NEURITE OUTGROWTH; ACETYLCHOLINE-RECEPTOR; AXONAL DEGENERATION; OXIDATIVE STRESS AB Sensory neurons have the capacity to produce, release, and respond to acetylcholine (ACh), but the functional role of cholinergic systems in adult mammalian peripheral sensory nerves has not been established. Here, we have reported that neurite outgrowth from adult sensory neurons that were maintained under subsaturating neurotrophic factor conditions operates under cholinergic constraint that is mediated by muscarinic receptor-dependent regulation of mitochondrial function via AMPK. Sensory neurons from mice lacking the muscarinic ACh type 1 receptor (M1R) exhibited enhanced neurite outgrowth, confirming the role of M1R in tonic suppression of axonal plasticity. M1R-deficient mice made diabetic with streptozotocin were protected from physiological and structural indices of sensory neuropathy. Pharmacological blockade of M1R using specific or selective antagonists, pirenzepine, VU0255035, or muscarinic toxin 7 (MT7) activated AMPK and overcame diabetesinduced mitochondrial dysfunction in vitro and in vivo. These antimuscarinic drugs prevented or reversed indices of peripheral neuropathy, such as depletion of sensory nerve terminals, thermal hypoalgesia, and nerve conduction slowing in diverse rodent models of diabetes. Pirenzepine and MT7 also prevented peripheral neuropathy induced by the chemotherapeutic agents dichloroacetate and paclitaxel or HIV envelope protein gp120. As a variety of antimuscarinic drugs are approved for clinical use against other conditions, prompt translation of this therapeutic approach to clinical trials is feasible. C1 [Calcutt, Nigel A.; Frizzi, Katie; Mixcoatl-Zecuatl, Teresa; Muttalib, Nabeel; Ochoa, Joseline; Gopaul, Allison; Jolivalt, Corinne G.] UCSD, Dept Pathol, La Jolla, CA USA. [Smith, Darrell R.; Sabbir, Mohammad Golam; Chowdhury, Subir K. Roy; Van der Ploeg, Randy; Tessler, Lori; Fernyhough, Paul] St Boniface Hosp Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada. [Wess, Juergen] NIDDK, Mol Signalling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. [Fernyhough, Paul] Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada. RP Fernyhough, P (reprint author), St Boniface Gen Hosp, Res Ctr, R4046-351 Tache Ave, Winnipeg, MB R2H 2A6, Canada. EM pfernyhough@sbrc.ca FU JDRF [14-2006-341, 17-2008-1047, 17-2011-252]; Canadian Institutes of Health Research [RPA-124953, MOP-130282]; NIH [DK057629, NS081082, DP3DK094346-01, DK076169, 23789-5, AG039736]; St. Boniface Hospital Research Foundation FX This work was funded by grants 14-2006-341, 17-2008-1047, and 17-2011-252 from the JDRF and grants RPA-124953 and MOP-130282 from the Canadian Institutes of Health Research (to PF), grants DK057629, NS081082, DP3DK094346-01 (sub-award), and DK076169 (sub-award 23789-5) from the NIH (to NAC) and NIH grant AG039736 (to CGJ). We are grateful to St. Boniface Hospital Research Foundation for support. We thank Michael Czubryt (University of Manitoba) for reporter plasmids, Jason Dyck (University of Alberta) for adenoviral constructs, Jeffrey Conn (Vanderbilt Center for Neuroscience Drug Discovery) for gifts of VU0255035, and Nick Anderson, Alex Marquez, Dwane Morrow, Allison Quach, Mahalakshmi Razdan, Graziella Te, and Vanessa Thompson for expert technical assistance. NR 87 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB 1 PY 2017 VL 127 IS 2 BP 608 EP 622 DI 10.1172/JCI88321 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK8HI UT WOS:000394164100022 PM 28094765 ER PT J AU Wu, CJ Feng, X Lu, M Morimura, S Udey, MC AF Wu, Chuan-Jin Feng, Xu Lu, Michael Morimura, Sohshi Udey, Mark C. TI Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CONGENITAL TUFTING ENTEROPATHY; CELL ADHESION MOLECULE; TIGHT JUNCTION; PROTEASE MATRIPTASE; SERINE-PROTEASE; STEM-CELLS; IN-VITRO; ACTIVATION; BARRIER; ANTIGEN AB Congenital tufting enteropathy (CTE) is a severe autosomal recessive human diarrheal disorder with characteristic intestinal epithelial dysplasia. CTE can be caused by mutations in genes encoding EpCAM, a putative adhesion molecule, and HAI-2, a cell surface protease inhibitor. A similar phenotype occurs in mice whose intestinal epithelial cells (IECs) fail to express the tight junction-associated protein claudin-7. EpCAM stabilizes claudin-7 in IECs, and HAI-2 regulates the cell surface serine protease matriptase, a known modifier of intestinal epithelial physiology. Therefore, we hypothesized that HAI-2, matriptase, EpCAM, and claudin-7 were functionally linked. Herein we have demonstrated that active matriptase cleaves EpCAM after Arg80 and that loss of HAI-2 in IECs led to unrestrained matriptase activity and efficient cleavage of EpCAM. Cleavage of EpCAM decreased its ability to associate with claudin-7 and targeted it for internalization and lysosomal degradation in conjunction with claudin-7. CTE-associated HAI-2 mutant proteins exhibited reduced ability to inhibit matriptase and also failed to efficiently stabilize claudin-7 in IECs. These results identify EpCAM as a substrate of matriptase and link HAI-2, matriptase, EpCAM, and claudin-7 in a functionally important pathway that causes disease when it is dysregulated. C1 [Wu, Chuan-Jin; Feng, Xu; Lu, Michael; Morimura, Sohshi; Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N240E, Bethesda, MD 20892 USA. RP Udey, MC (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N240E, Bethesda, MD 20892 USA. EM udeym@mail.nih.gov FU Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute FX This research was supported by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute. NR 44 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB 1 PY 2017 VL 127 IS 2 BP 623 EP 634 DI 10.1172/JCI88428 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK8HI UT WOS:000394164100023 PM 28094766 ER PT J AU Wollenberg, KR Desjardins, CA Zalutskaya, A Slodovnikova, V Oler, AJ Quinones, M Abeel, T Chapman, SB Tartakovsky, M Gabrielian, A Hoffner, S Skrahin, A Birren, BW Rosenthal, A Skrahina, A Earl, AM AF Wollenberg, Kurt R. Desjardins, Christopher A. Zalutskaya, Aksana Slodovnikova, Vervara Oler, Andrew J. Quinones, Mariam Abeel, Thomas Chapman, Sinead B. Tartakovsky, Michael Gabrielian, Andrei Hoffner, Sven Skrahin, Aliaksandr Birren, Bruce W. Rosenthal, Alexander Skrahina, Alena Earl, Ashlee M. TI Whole-Genome Sequencing of Mycobacterium tuberculosis Provides Insight into the Evolution and Genetic Composition of Drug-Resistant Tuberculosis in Belarus SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article DE Mycobacterium tuberculosis; multidrug resistant; extensively drug resistant; Belarus AB The emergence and spread of drug-resistant Mycobacterium tuberculosis (DR-TB) are critical global health issues. Eastern Europe has some of the highest incidences of DR-TB, particularly multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. To better understand the genetic composition and evolution of MDR- and XDR-TB in the region, we sequenced and analyzed the genomes of 138 M. tuberculosis isolates from 97 patients sampled between 2010 and 2013 in Minsk, Belarus. MDR and XDR-TB isolates were significantly more likely to belong to the Beijing lineage than to the Euro-American lineage, and known resistance-conferring loci accounted for the majority of phenotypic resistance to first-and second-line drugs in MDR and XDR-TB. Using a phylogenomic approach, we estimated that the majority of MDR-TB was due to the recent transmission of already-resistant M. tuberculosis strains rather than repeated de novo evolution of resistance within patients, while XDR-TB was acquired through both routes. Longitudinal sampling of M. tuberculosis from 34 patients with treatment failure showed that most strains persisted genetically unchanged during treatment or acquired resistance to fluoroquinolones. HIV+ patients were significantly more likely to have multiple infections over time than HIV+ patients, highlighting a specific need for careful infection control in these patients. These data provide a better understanding of the genomic composition, transmission, and evolution of MDR-and XDR-TB in Belarus and will enable improved diagnostics, treatment protocols, and prognostic decision-making. C1 [Wollenberg, Kurt R.; Oler, Andrew J.; Quinones, Mariam; Tartakovsky, Michael; Gabrielian, Andrei; Rosenthal, Alexander] NIAID, Off Cyber Infrastruct & Computat Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Desjardins, Christopher A.; Abeel, Thomas; Chapman, Sinead B.; Birren, Bruce W.; Earl, Ashlee M.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Zalutskaya, Aksana; Slodovnikova, Vervara; Skrahina, Alena] Republ Sci & Pract Ctr Pulmonol & TB, Minsk, Byelarus. [Hoffner, Sven] Publ Hlth Agcy Sweden, Dept Microbiol, Solna, Sweden. [Skrahin, Aliaksandr] Belarusian State Med Univ, Minsk, Byelarus. RP Earl, AM (reprint author), Broad Inst MIT & Harvard, Cambridge, MA USA.; Skrahina, A (reprint author), Republ Sci & Pract Ctr Pulmonol & TB, Minsk, Byelarus. EM alena.skrahina@gmail.com; aearl@broadinstitute.org FU federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services [HHSN272200900018C, U19AI110818]; federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services under BCBB Support Services [GS35F0373X]; federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services under U.S. Civilian Research and Development Foundation (CRDF) [BOB1-31120-MK-13] FX This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services, under contract HHSN272200900018C and grant U19AI110818 to the Broad Institute and under BCBB Support Services contract GS35F0373X to MSC, Inc., and under the U.S. Civilian Research and Development Foundation (CRDF) agreement BOB1-31120-MK-13. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 23 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD FEB PY 2017 VL 55 IS 2 BP 457 EP 469 DI 10.1128/JCM.02116-16 PG 13 WC Microbiology SC Microbiology GA EK0LF UT WOS:000393617300015 PM 27903602 ER PT J AU Miller, JS Mulray, K Fichter, D Cunningham, K Anderson, R Bruchey, A Davis, RJ Thurm, A AF Miller, J. S. Mulray, K. Fichter, D. Cunningham, K. Anderson, R. Bruchey, A. Davis, R. J. Thurm, A. TI Red Flags for Creatine Transporter Deficiency, and Potential Outcome Variables for the Severely Impaired SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Meeting Abstract C1 [Miller, J. S.] Univ Penn, Psychiat, Philadelphia, PA 19104 USA. [Mulray, K.; Anderson, R.] Childrens Hosp Philadelphia, Speech & Language Pathol, Philadelphia, PA 19104 USA. [Fichter, D.; Cunningham, K.] Childrens Hosp Philadelphia, Occupat Therapy, Philadelphia, PA 19104 USA. [Bruchey, A.; Davis, R. J.] Lumos Pharma Inc, Austin, TX USA. [Thurm, A.] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0196-206X EI 1536-7312 J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD FEB-MAR PY 2017 VL 38 IS 2 MA 23 BP S6 EP S6 PG 1 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA EK5EZ UT WOS:000393951000022 ER PT J AU Mispireta, ML Caulfield, LE Zavaleta, N Merialdi, M Putnick, DL Bornstein, MH DiPietro, JA AF Mispireta, M. L. Caulfield, L. E. Zavaleta, N. Merialdi, M. Putnick, D. L. Bornstein, M. H. DiPietro, J. A. TI Effect of maternal zinc supplementation on the cardiometabolic profile of Peruvian children: results from a randomized clinical trial SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Article DE cardiovascular; metabolic; zinc ID FASTING PLASMA-GLUCOSE; INSULIN-RESISTANCE; METABOLIC SYNDROME; BODY-COMPOSITION; MICRONUTRIENT SUPPLEMENTATION; POSTNATAL-GROWTH; BLOOD-PRESSURE; RURAL NEPAL; RISK; FETAL AB Zinc is an essential micronutrient for the development of the fetal renal, cardiovascular and metabolic systems; however, there is limited evidence of its effects on the postnatal cardiometabolic function. In this study, we evaluated the effect of maternal zinc supplementation during pregnancy on the cardiometabolic profile of the offspring in childhood. A total of 242 pregnant women were randomly assigned to receive a daily supplement containing iron + folic acid with or without zinc. A follow-up study was conducted when children of participating mothers were 4.5 years of age to evaluate their cardiometabolic profile, including anthropometric measures of body size and composition, blood pressure, lipid profile and insulin resistance. No difference in measures of child cardiometabolic risk depending on whether mothers received supplemental zinc during pregnancy. Our results do not support the hypothesis that maternal zinc supplementation reduces the risk of offspring cardiometabolic disease. C1 [Mispireta, M. L.] Idaho State Univ, Kasiska Sch Hlth Profess, Pocatello, ID 83209 USA. [Mispireta, M. L.; Caulfield, L. E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Human Nutr, 615 North Wolfe St,Room W2041, Baltimore, MD 21205 USA. [DiPietro, J. A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD USA. [Zavaleta, N.] Inst Invest Nutr, Lima, Peru. [Merialdi, M.] Becton Dickinson, Global Hlth Div, Franklin Lakes, NJ USA. [Putnick, D. L.; Bornstein, M. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Caulfield, LE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Human Nutr, 615 North Wolfe St,Room W2041, Baltimore, MD 21205 USA. EM lcaulfi1@jhu.edu FU Nestle Research Foundation, Lausanne, Switzerland; Consiglio Nazionale delle Ricerche, Italy; Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD) [HD042675]; Division of Health Sciences at Idaho State University; American Heart Association [09PRE2390038]; NICHD, NIH FX The prenatal study was supported by the Nestle Research Foundation, Lausanne, Switzerland, and M.M. was supported in part by the Consiglio Nazionale delle Ricerche, Italy. The follow-up study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD: HD042675). The conduct of biochemical analyses was supported by the Division of Health Sciences at Idaho State University through their Enhancement Fund Competition. M.L.M. was supported in part by a predoctoral fellowship from the American Heart Association (09PRE2390038). As intramural scientists, the participation of M.H.B. and D.L.P. in the study was supported by NICHD, NIH. NR 56 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 EI 2040-1752 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD FEB PY 2017 VL 8 IS 1 BP 56 EP 64 DI 10.1017/S2040174416000568 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EK1HK UT WOS:000393676200005 PM 27748235 ER PT J AU Diamanti, MA Gupta, J Bennecke, M De Oliveira, T Ramakrishnan, M Braczynski, AK Richter, B Beli, P Hu, YL Saleh, M Mittelbronn, M Dikic, I Greten, FR AF Diamanti, Michaela A. Gupta, Jalaj Bennecke, Moritz De Oliveira, Tiago Ramakrishnan, Mallika Braczynski, Anne K. Richter, Benjamin Beli, Petra Hu, Yinling Saleh, Maya Mittelbronn, Michel Dikic, Ivan Greten, Florian R. TI IKK alpha controls ATG16L1 degradation to prevent ER stress during inflammation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NF-KAPPA-B; CHRONIC INTESTINAL INFLAMMATION; ENDOPLASMIC-RETICULUM STRESS; GENOME-WIDE ASSOCIATION; CROHNS-DISEASE; BOWEL-DISEASE; PANETH CELLS; AUTOPHAGY; EXPRESSION; MICE AB Inhibition of the I kappa B kinase complex (IKK) has been implicated in the therapy of several chronic inflammatory diseases including inflammatory bowel diseases. In this study, using mice with an inactivatable IKK alpha kinase (Ikk alpha(AA/AA)), we show that loss of IKK alpha function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKK alpha-mutant intestinal epithelial cells because of elevated caspase 12 activation during an enhanced unfolded protein response (UPR). Induction of the UPR is linked to decreased ATG16L1 stabilization in Ikk alpha(AA/AA) mice. We demonstrate that both TNF-R and nucleotide-binding oligomerization domain stimulation promote ATG16L1 stabilization via IKK alpha-dependent phosphorylation of ATG16L1 at Ser278. Thus, we propose IKK alpha as a central mediator sensing both cytokine and microbial stimulation to suppress endoplasmic reticulum stress, thereby assuring antiinflammatory function during acute intestinal inflammation. C1 [Diamanti, Michaela A.; Gupta, Jalaj; De Oliveira, Tiago; Ramakrishnan, Mallika; Greten, Florian R.] Inst Tumor Biol & Expt Therapy, Georg Speyer Haus, D-60596 Frankfurt, Germany. [Bennecke, Moritz] Tech Univ Munich, Klinikum Rechts Isar, Inst Mol Immunol, D-81675 Munich, Germany. [Braczynski, Anne K.; Mittelbronn, Michel] Goethe Univ, Goethe Univ Hosp, Inst Neurol, Edinger Inst, D-60323 Frankfurt, Germany. [Richter, Benjamin; Dikic, Ivan] Goethe Univ, Sch Med, Buchmann Inst Mol Life Sci, Inst Biochem 2, D-60323 Frankfurt, Germany. [Beli, Petra] Inst Mol Biol, D-55128 Mainz, Germany. [Hu, Yinling] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Saleh, Maya] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada. RP Greten, FR (reprint author), Inst Tumor Biol & Expt Therapy, Georg Speyer Haus, D-60596 Frankfurt, Germany. EM greten@gsh.uni-frankfurt.de FU LOE WE Center for Cell and Gene Therapy Frankfurt [III L 4-518/17.004]; Georg-Speyer-Haus; Deutsche Forschungsgemeinschaft [SFB 1177, Gr1916/11-1]; European Research Council [ROS CAN-281967] FX This work was supported in part by the LOE WE Center for Cell and Gene Therapy Frankfurt (III L 4-518/17.004) and institutional funds from the Georg-Speyer-Haus, as well as grants from the Deutsche Forschungsgemeinschaft (SFB 1177 and Gr1916/11-1) and the European Research Council (ROS CAN-281967) to F.R. Greten. NR 55 TC 0 Z9 0 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD FEB PY 2017 VL 214 IS 2 BP 423 EP 437 DI 10.1084/jem.20161867 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EK9NO UT WOS:000394251400011 PM 28082356 ER PT J AU Cutrufello, PT Gadomski, SJ Ratamess, NA AF Cutrufello, Paul T. Gadomski, Stephen J. Ratamess, Nicholas A. TI AN EVALUATION OF AGONIST: ANTAGONIST STRENGTH RATIOS AND POSTURE AMONG POWERLIFTERS SO JOURNAL OF STRENGTH AND CONDITIONING RESEARCH LA English DT Article DE weight training; pelvic tilt; muscle imbalance ID PECTORALIS MINOR MUSCLE; LUMBAR LORDOSIS; POWER LIFTERS; BACK SQUAT; SHOULDER; WEIGHT; RELIABILITY; DEADLIFT; LENGTH; JOINT AB Powerlifters routinely focus on 3 exercises: bench press, squat, and deadlift. This focus may predispose them to the development of muscle imbalances in either the upper or lower extremity which might also influence posture. Therefore, the purpose of the present study was to examine the agonist: antagonist strength ratios and their relationship to postural measures among powerlifters. An ex post facto study design compared 15 male powerlifters (35.3 +/- 13.7 years old) and 15 age-matched controls (34.9 +/- 14.6 years old). Maximal isometric strength tests were conducted using handheld dynamometry. Posture was evaluated using pectoralis minor length, pelvic tilt, thoracic kyphosis, and lumbar lordosis. Strength imbalances were observed for shoulder horizontal adduction: abduction (2.57 +/- 0.58 vs. 1.78 +/- 0.28; p < 0.001) and knee flexion: extension (0.61 +/- 0.15 vs. 0.50 +/- 0.10; p = 0.033). Pectoralis minor length was significantly shorter among the powerlifters (6.1 +/- 1.9 vs. 4.2 +/- 1.4; p = 0.005); however, there was no statistical difference in thoracic kyphosis (37.7 +/- 9.4 vs. 39.1 +/- 10.9; p = 0.722), pelvic tilt (10.6 +/- 3.6 vs. 11.3 +/- 3.7; p = 0.622), or lumbar lordosis (25.0 +/- 7.6 vs. 23.0 +/- 8.4; p = 0.500) angles. Strength imbalances, including shoulder horizontal adduction: abduction and knee flexion: extension, and a shortened pectoralisminor may evolve as training adaptations among powerlifters, whereas thoracic kyphosis, pelvic tilt, and lumbar lordosis remain unchanged. C1 [Cutrufello, Paul T.] Univ Scranton, Dept Exercise Sci & Sport, Scranton, PA 18510 USA. [Gadomski, Stephen J.] NIH, Frederick Natl Lab Canc Res, Frederick, MD USA. [Ratamess, Nicholas A.] Coll New Jersey, Dept Hlth & Exercise Sci, Ewing, NJ USA. RP Cutrufello, PT (reprint author), Univ Scranton, Dept Exercise Sci & Sport, Scranton, PA 18510 USA. EM paul.cutrufello@scranton.edu NR 30 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1064-8011 EI 1533-4287 J9 J STRENGTH COND RES JI J. Strength Cond. Res. PD FEB PY 2017 VL 31 IS 2 BP 298 EP 304 PG 7 WC Sport Sciences SC Sport Sciences GA EK2OH UT WOS:000393766100007 PM 27893477 ER PT J AU Emmanuel, B Sidique, N Zhang, X Poonia, B Sneller, MC Kottilil, S AF Emmanuel, B. Sidique, N. Zhang, X. Poonia, B. Sneller, M. C. Kottilil, S. TI Decline of cellular activation in non-B cells after rituximab treatment in hepatitis C-associated mixed cryoglobulinemia vasculitis SO JOURNAL OF VIRAL HEPATITIS LA English DT Article DE chronic hepatitis C; hepatitis C virus; mixed cryoglobulinemia; rituximab; vasculitis ID VIRUS-INFECTION; UNITED-STATES; THERAPY; EFFICACY; MODEL AB Mixed cryoglobulinemic vasculitis is associated with the monoclonal expansion of pathognomonic B cells in chronic hepatitis C. Recently, treatment with B-cell depletion, including rituximab, a CD20 monoclonal antibody, has been successful in achieving remission from the active disease. We investigated whether B-cell depletion therapy has an impact on activation of non-B cells in the periphery. Results demonstrated that B-cell depletion therapy is associated with a statistically significant decline in activated T cells, from pretherapy to follow-up while on rituximab therapy: CD4+ CD38+ HLA-DR+ (DR+), CD8+ CD38, CD8+ CD38+ DR+, and CD8+ DR+. Birmingham Vasculitis Activity Score and cryoglobulin had a strong correlation coefficient (R) of 0.72 (P=.0005), while cryoglobulin showed moderate correlation with CD8+ DR+ (R=.61), CD3+ CD38+ DR+ (R=.57), CD3+ DR+ (R=.50), CD4+ CD38+ DR+ (R=. 53), CD4+ DR+ (R=. 52), and CD8+ CD38+ DR+ (R=. 67). These results suggest B-cell expansion has a direct and indirect effect on the pathogenesis of Hepatitis C-associated mixed cryoglobulinemic vasculitis. C1 [Emmanuel, B.; Poonia, B.; Kottilil, S.] Univ Maryland, Sch Med, Inst Human Virol, Div Clin Care & Res, Baltimore, MD 21201 USA. [Sidique, N.; Zhang, X.; Sneller, M. C.; Kottilil, S.] NIAID, Lab Immunoregulat, Dept Hlth & Human Serv, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), Univ Maryland, Sch Med, Inst Human Virol, Div Clin Care & Res, Baltimore, MD 21201 USA. EM Skottilil@ihv.umaryland.edu FU Gilead Sciences FX S.K. reports research grants from Gilead Sciences. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. NR 21 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1352-0504 EI 1365-2893 J9 J VIRAL HEPATITIS JI J. Viral Hepatitis PD FEB PY 2017 VL 24 IS 2 BP 128 EP 131 DI 10.1111/jvh.12618 PG 4 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA EK3ZS UT WOS:000393867500005 PM 27666584 ER PT J AU Moncla, LH Weiler, AM Barry, G Weinfurter, JT Dinis, JM Charlier, O Lauck, M Bailey, AL Wahl-Jensen, V Nelson, CW Johnson, JC Cai, YY Goldberg, TL O'Connor, DH Jahrling, PB Kuhn, JH Friedrich, TC AF Moncla, Louise H. Weiler, Andrea M. Barry, Gabrielle Weinfurter, Jason T. Dinis, Jorge M. Charlier, Olivia Lauck, Michael Bailey, Adam L. Wahl-Jensen, Victoria Nelson, Chase W. Johnson, Joshua C. Cai, Yingyun Goldberg, Tony L. O'Connor, David H. Jahrling, Peter B. Kuhn, Jens H. Friedrich, Thomas C. TI Within-Host Evolution of Simian Arteriviruses in Crab-Eating Macaques SO JOURNAL OF VIROLOGY LA English DT Article DE evolution; simian arterivirus; simian hemorrhagic fever virus; virology; within-host diversity ID RESPIRATORY SYNDROME VIRUS; HEMORRHAGIC-FEVER; NEUTRALIZATION EPITOPE; GP5 ECTODOMAIN; MONKEYS; INFECTION; DISEASE; IDENTIFICATION; TRANSMISSION; PATHOLOGY AB Simian arteriviruses are a diverse clade of viruses infecting captive and wild nonhuman primates. We recently reported that Kibale red colobus virus 1 (KRCV-1) causes a mild and self-limiting disease in experimentally infected crab-eating macaques, while simian hemorrhagic fever virus (SHFV) causes lethal viral hemorrhagic fever. Here we characterize how these viruses evolved during replication in cell culture and in experimentally infected macaques. During passage in cell culture, 68 substitutions that were localized in open reading frames (ORFs) likely associated with host cell entry and exit became fixed in the KRCV-1 genome. However, we did not detect any strong signatures of selection during replication in macaques. We uncovered patterns of evolution that were distinct from those observed in surveys of wild red colobus monkeys, suggesting that these species may exert different adaptive challenges for KRCV-1. During SHFV infection, we detected signatures of selection on ORF 5a and on a small subset of sites in the genome. Overall, our data suggest that patterns of evolution differ markedly among simian arteriviruses and among host species. IMPORTANCE Certain RNA viruses can cross species barriers and cause disease in new hosts. Simian arteriviruses are a diverse group of related viruses that infect captive and wild nonhuman primates, with associated disease severity ranging from apparently asymptomatic infections to severe, viral hemorrhagic fevers. We infected nonhuman primate cell cultures and then crab-eating macaques with either simian hemorrhagic fever virus (SHFV) or Kibale red colobus virus 1 (KRCV-1) and assessed within-host viral evolution. We found that KRCV-1 quickly acquired a large number of substitutions in its genome during replication in cell culture but that evolution in macaques was limited. In contrast, we detected selection focused on SHFV ORFs 5a and 5, which encode putative membrane proteins. These patterns suggest that in addition to diverse pathogenic phenotypes, these viruses may also exhibit distinct patterns of within-host evolution both in vitro and in vivo. C1 [Moncla, Louise H.; Dinis, Jorge M.; Charlier, Olivia; Lauck, Michael; Goldberg, Tony L.; O'Connor, David H.; Friedrich, Thomas C.] Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA. [Moncla, Louise H.; Dinis, Jorge M.; Lauck, Michael] Univ Wisconsin, Microbiol Doctoral Training Program, Madison, WI USA. [Moncla, Louise H.; Weiler, Andrea M.; Barry, Gabrielle; Weinfurter, Jason T.; Dinis, Jorge M.; Lauck, Michael; Bailey, Adam L.; Goldberg, Tony L.; O'Connor, David H.; Friedrich, Thomas C.] Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. [Bailey, Adam L.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. [Wahl-Jensen, Victoria; Johnson, Joshua C.; Cai, Yingyun; Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [Nelson, Chase W.] Amer Museum Nat Hist, Sackler Inst Comparat Genom, New York, NY 10024 USA. RP Friedrich, TC (reprint author), Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA.; Friedrich, TC (reprint author), Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. EM thomasf@primate.wisc.edu FU NIH National Research Service Award [T32 GM07215]; U.S. National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I]; National Institutes of Health (NIH) as part of the joint NIH-NSF Ecology of Infectious Disease program [TW009237, R01 AI077376]; Office of Research Infrastructure Programs (ORIP) [P51OD011106]; Gerstner Scholars Fellowship from the Gerstner Family Foundation at the American Museum of Natural History; Wisconsin Distinguished Graduate Fellowship FX L.H.M. was supported in part by NIH National Research Service Award T32 GM07215 and through a Wisconsin Distinguished Graduate Fellowship provided by John and Tashia Morgridge. This work was funded in part through Battelle Memorial Institute's prime contract with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) under contract no. HHSN272200700016I. J.C.J. performed this work as an employee of Battelle Memorial Institute. Subcontractors to Battelle Memorial Institute who performed this work are V.W.-J., Y.C., and J.H.K., employees of Tunnell Government Services, Inc. This work was also funded by National Institutes of Health (NIH) grant TW009237 as part of the joint NIH-NSF Ecology of Infectious Disease program, grant R01 AI077376, and Office of Research Infrastructure Programs (ORIP) grant P51OD011106. C.W.N. was funded by the Gerstner Scholars Fellowship from the Gerstner Family Foundation at the American Museum of Natural History. NR 46 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2017 VL 91 IS 4 AR UNSP e02231 DI 10.1128/JVI.02231-16 PG 19 WC Virology SC Virology GA EK4FU UT WOS:000393883300032 ER PT J AU Shaw, JM Miller-Novak, LK Mohanram, V McKinnon, K Demberg, T Vargas-Inchaustegui, DA Venzon, D Robert-Guroff, M AF Shaw, Julia M. Miller-Novak, Leia K. Mohanram, Venkatramanan McKinnon, Katherine Demberg, Thorsten Vargas-Inchaustegui, Diego A. Venzon, David Robert-Guroff, Marjorie TI Influence of Plasma Cell Niche Factors on the Recruitment and Maintenance of IRF4(hi) Plasma Cells and Plasmablasts in Vaccinated, Simian Immunodeficiency Virus-Infected Rhesus Macaques with Low and High Viremia SO JOURNAL OF VIROLOGY LA English DT Article DE SIV rhesus macaque model; plasma cell; plasma cell niche factors; plasmablast ID HUMAN BONE-MARROW; MEMORY B-CELLS; HIV-INFECTION; MONOCLONAL-ANTIBODIES; SIV INFECTION; LYMPH-NODES; ANTIRETROVIRAL THERAPY; SURVIVAL NICHES; GENE-EXPRESSION; IN-VITRO AB In a recent study, we found that protection following simian immunodeficiency virus (SIV) exposure correlated with rectal plasma cell frequency in vaccinated female rhesus macaques. We sought to determine if the same macaques maintained high mucosal plasma cell frequencies postinfection and if this translated to reduced viremia. Although delayed SIV acquisition did not predict subsequent viral control, alterations existed in the distribution of plasma cells and plasmablasts between macaques that exhibited high or low viremia. Flow cytometric analysis of cells from rectal biopsy specimens, bone marrow, and mesenteric lymph nodes of vaccinated infected, unvaccinated infected, and uninfected macaques identified two main IRF4(hi) subsets of interest: CD138(+) plasma cells, and CD138(-) lasmablasts. In rectal tissue, plasma cell frequency positively correlated with plasma viremia and unvaccinated macaques had increased plasma cells and plasmablasts compared to vaccinated animals. Likewise, plasmablast frequency in the mesenteric lymph node correlated with viremia. However, in bone marrow, plasmablast frequency negatively correlated with viremia. Accordingly, low-viremic macaques had a higher frequency of both bone marrow IRF4hi subsets than did animals with high viremia. Significant reciprocal relationships between rectal and bone marrow plasmablasts suggested that efficient trafficking to the bone marrow as opposed to the rectal mucosa was linked to viral control. mRNA expression analysis of proteins involved in establishment of plasma cell niches in sorted bone marrow and rectal cell populations further supported this model and revealed differential mRNA expression patterns in these tissues. IMPORTANCE As key antibody producers, plasma cells and plasmablasts are critical components of vaccine-induced immunity to human immunodeficiency virus type 1 (HIV-1) in humans and SIV in the macaque model; however, few have attempted to examine the role of these cells in viral suppression postinfection. Our results suggest that plasmablast trafficking to and retention in the bone marrow play a previously unappreciated role in viral control and contrast the potential contribution of mucosal plasma cells to mediate protection at sites of infection with that of bone marrow plasmablasts and plasma cells to control viremia during chronic infection. Manipulation of niche factors influencing the distribution and maintenance of these critical antibody-secreting cells may serve as potential therapeutic targets to enhance antiviral responses postvaccination and postinfection. C1 [Shaw, Julia M.; Miller-Novak, Leia K.; Mohanram, Venkatramanan; McKinnon, Katherine; Demberg, Thorsten; Vargas-Inchaustegui, Diego A.; Robert-Guroff, Marjorie] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Data Management & Biostat Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shaw, Julia M.] NIAID, Div Allergy Immunol & Transplantat, NIH, Rockville, MD USA. [Miller-Novak, Leia K.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Silver Spring, MD USA. [Mohanram, Venkatramanan] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Demberg, Thorsten] Immat US Inc, Houston, TX USA. [Vargas-Inchaustegui, Diego A.] NIAID, Viral Dis Lab, Mol Struct Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 85 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2017 VL 91 IS 4 AR UNSP e01727 DI 10.1128/JVI.01727-16 PG 19 WC Virology SC Virology GA EK4FU UT WOS:000393883300012 ER PT J AU Ye, LL Lee, JH Xu, LF Mohammed, AUR Li, WY Hale, JS Tan, WG Wu, TQ Davis, CW Ahmed, R Araki, K AF Ye, Lilin Lee, Junghwa Xu, Lifan Mohammed, Ata-Ur-Rasheed Li, Weiyan Hale, J. Scott Tan, Wendy G. Wu, Tuoqi Davis, Carl W. Ahmed, Rafi Araki, Koichi TI mTOR Promotes Antiviral Humoral Immunity by Differentially Regulating CD4 Helper T Cell and B Cell Responses SO JOURNAL OF VIROLOGY LA English DT Article DE B cell responses; CD4 T cells; Th1/Tfh response; humoral immunity; immunization; mTOR; rapamycin; viral immunity; viral infection ID ACUTE VIRAL-INFECTION; FOLLICULAR HELPER; TRANSCRIPTION FACTOR; MAMMALIAN TARGET; MEMORY; RAPAMYCIN; METABOLISM; EFFECTOR; DISEASE; TRANSPLANTATION AB mTOR has important roles in regulation of both innate and adaptive immunity, but whether and how mTOR modulates humoral immune responses have yet to be fully understood. To address this issue, we examined the effects of rapamycin, a specific inhibitor of mTOR, on B cell and CD4 T cell responses during acute infection with lymphocytic choriomeningitis virus. Rapamycin treatment resulted in suppression of virus-specific B cell responses by inhibiting proliferation of germinal center (GC) B cells. In contrast, the number of memory CD4 T cells was increased in rapamycin-treated mice. However, the drug treatment caused a striking bias of CD4 T cell differentiation into Th1 cells and substantially impaired formation of follicular helper T (Tfh) cells, which are essential for humoral immunity. Further experiments in which mTOR signaling was modulated by RNA interference (RNAi) revealed that B cells were the primary target cells of rapamycin for the impaired humoral immunity and that reduced Tfh formation in rapamycin-treated mice was due to lower GC B cell responses that are essential for Tfh generation. Additionally, we found that rapamycin had minimal effects on B cell responses activated by lipopolysaccharide (LPS), which stimulates B cells in an antigen-independent manner, suggesting that rapamycin specifically inhibits B cell responses induced by B cell receptor stimulation with antigen. Together, these findings demonstrate that mTOR signals play an essential role in antigen-specific humoral immune responses by differentially regulating B cell and CD4 T cell responses during acute viral infection and that rapamycin treatment alters the interplay of immune cell subsets involved in antiviral humoral immunity. IMPORTANCE mTOR is a serine/threonine kinase involved in a variety of cellular activities. Although its specific inhibitor, rapamycin, is currently used as an immunosuppressive drug in transplant patients, it has been reported that rapamycin can also stimulate pathogen-specific cellular immunity in certain circumstances. However, whether and how mTOR regulates humoral immunity are not well understood. Here we found that rapamycin treatment predominantly inhibited GC B cell responses during viral infection and that this led to biased helper CD4 T cell differentiation as well as impaired antibody responses. These findings suggest that inhibition of B cell responses by rapamycin may play an important role in regulation of allograft-specific antibody responses to prevent organ rejection in transplant recipients. Our results also show that consideration of antibody responses is required in cases where rapamycin is used to stimulate vaccine-induced immunity. C1 [Ye, Lilin; Xu, Lifan] Third Mil Med Univ, Inst Immunol, Chongqing, Peoples R China. [Ye, Lilin; Lee, Junghwa; Mohammed, Ata-Ur-Rasheed; Li, Weiyan; Hale, J. Scott; Tan, Wendy G.; Wu, Tuoqi; Davis, Carl W.; Ahmed, Rafi; Araki, Koichi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Ye, Lilin; Lee, Junghwa; Mohammed, Ata-Ur-Rasheed; Li, Weiyan; Hale, J. Scott; Tan, Wendy G.; Wu, Tuoqi; Davis, Carl W.; Ahmed, Rafi; Araki, Koichi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Wu, Tuoqi] NIH, Natl Human Genome Res Inst, Bethesda, MD USA. RP Araki, K (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA.; Araki, K (reprint author), Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. EM karaki@emory.edu FU National Institutes of Health (NIH) [AI030048]; National Basic Research Program of China (973 Program) [2013CB531500] FX This work was supported by the National Institutes of Health (NIH) (grant AI030048 to R.A.) and by the National Basic Research Program of China (973 Program; grant 2013CB531500 to L.Y.). NR 40 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2017 VL 91 IS 4 AR UNSP e01653 DI 10.1128/JVI.01653-16 PG 17 WC Virology SC Virology GA EK4FU UT WOS:000393883300008 ER PT J AU Sudarmono, P Aman, A Arif, M Syarif, AK Kosasih, H Karyana, M Chotpitayasunondh, T Vandepitte, WP Boonyasiri, A Lapphra, K Chokephaibulkit, K Rattanaumpawan, P Thamlikitkul, V Laongnualpanich, A Teparrakkul, P Srisamang, P Phuc, PH Hai, LT Kinh, NV Phu, BD Hung, NT Thuong, TC Tuan, HM Yen, LM Chau, NVV Limmathurotsakul, D Thaipadungpanit, J Blacksell, S Day, N Thwaites, G Wertheim, H Tan, LV Rahman, M van Doorn, HR Lau, CY AF Sudarmono, Pratiwi Aman, Abu Tholib Arif, Mansyur Syarif, Armaji Kamaludi Kosasih, Herman Karyana, Muhammad Chotpitayasunondh, Tawee Vandepitte, Warunee Punpanich Boonyasiri, Adiratha Lapphra, Keswadee Chokephaibulkit, Kulkanya Rattanaumpawan, Pinyo Thamlikitkul, Visanu Laongnualpanich, Achara Teparrakkul, Prapit Srisamang, Pramot Phan Huu Phuc Le Thanh Hai Nguyen Van Kinh Bui Duc Phu Nguyen Thanh Hung Tang Chi Thuong Ha Manh Tuan Lam Minh Yen Nguyen Van Vinh Chau Limmathurotsakul, Direk Thaipadungpanit, Janjira Blacksell, Stuart Day, Nicholas Thwaites, Guy Wertheim, Heiman Le Van Tan Rahman, Motiur van Doorn, H. Rogier Lau, Chuen-Yen CA Southeast Asia Infect Dis Clinical TI Causes and outcomes of sepsis in southeast Asia: a multinational multicentre cross-sectional study SO LANCET GLOBAL HEALTH LA English DT Article ID SEPTIC SHOCK; INTERNATIONAL GUIDELINES; FEVER; CHILDREN; DEFINITIONS; MANAGEMENT; CAMPAIGN; THAILAND; DISEASE; VIETNAM AB Background Improved understanding of pathogens that cause sepsis would aid management and antimicrobial selection. In this study, we aimed to identify the causative pathogens of sepsis in southeast Asia. Methods In this multinational multicentre cross-sectional study of community-acquired sepsis and severe sepsis, we prospectively recruited children (age =30 days and < 18 years) and adults (age =18 years) at 13 public hospitals in Indonesia (n=3), Thailand (n=4), and Vietnam (n=6). Hospitalised patients with suspected or documented communityacquired infection, with at least three diagnostic criteria for sepsis according to the Surviving Sepsis Campaign 2012, and within 24 h of admission were enrolled. Blood from every patient, and nasopharyngeal swab, urine, stool, and cerebrospinal fl uid, if indicated, were collected for reference diagnostic tests to identify causative pathogens. We report causative pathogens of sepsis and 28-day mortality. We also estimate mortality associated with enrolment with severe sepsis. This study was registered with ClinicalTrials. gov, number NCT02157259. Findings From Dec 16, 2013, to Dec 14, 2015, 4736 patients were screened and 1578 patients (763 children and 815 adults) were enrolled. Dengue viruses (n=122 [8%]), Leptospira spp (n=95 [6%]), rickettsial pathogens (n=96 [6%]), Escherichia coli (n=76 [5%]), and infl uenza viruses (n=65 [4%]) were commonly identifi ed in both age groups; whereas Plasmodium spp (n=12 [1%]) and Salmonella enterica serovar Typhi (n=3 [0.2%]) were rarely observed. Emerging pathogens identifi ed included hantaviruses (n=28 [2%]), non-typhoidal Salmonella spp (n=21 [1%]), Streptococcus suis (n=18 [1%]), Acinetobacter spp (n=12 [1%]), and Burkholderia pseudomallei (n=5 [<1%]). 28-day mortality occurred in 14 (2%) of 731 children with known statuses and 108 (13%) of 804 adults. Severe sepsis was identifi ed on enrolment in 194 (28%) of 731 children and 546 (68%) of 804 adults, and was associated with increased mortality (adjusted odds ratio 5.3, 95% CI 2.7-10.4; p< 0.001). Interpretation Sepsis in southeast Asia is caused by a wide range of known and emerging pathogens, and is associated with substantial mortality. C1 [Sudarmono, Pratiwi] Dr Cipto Mangunkusumo Hosp, Jakarta, Indonesia. [Aman, Abu Tholib] Dr Sardjito Hosp, Yogyakarta, Indonesia. [Arif, Mansyur] Dr Wahidin Sudirohusodo Hosp, Makassar, Indonesia. [Syarif, Armaji Kamaludi; Kosasih, Herman; Karyana, Muhammad] Natl Inst Hlth Res & Dev, Jakarta, Indonesia. [Chotpitayasunondh, Tawee; Vandepitte, Warunee Punpanich] Queen Sirikit Natl Inst Child Hlth, Bangkok, Thailand. [Boonyasiri, Adiratha; Lapphra, Keswadee; Chokephaibulkit, Kulkanya; Rattanaumpawan, Pinyo; Thamlikitkul, Visanu] Siriraj Hosp, Bangkok, Thailand. [Laongnualpanich, Achara] Chiang Rai Prachanukroh Hosp, Chiang Rai, Thailand. [Teparrakkul, Prapit; Srisamang, Pramot] Sappasithiprasong Hosp, Ubon Ratchathani, Thailand. [Phan Huu Phuc; Le Thanh Hai] Natl Hosp Peadiatr, Hanoi, Vietnam. [Nguyen Van Kinh] Natl Hosp Trop Dis, Hanoi, Vietnam. [Bui Duc Phu] Hue Cent Hosp, Hue, Vietnam. [Nguyen Thanh Hung; Tang Chi Thuong] Childrens Hosp 1, Ho Chi Minh City, Vietnam. [Ha Manh Tuan] Childrens Hosp 2, Ho Chi Minh City, Vietnam. [Lam Minh Yen; Nguyen Van Vinh Chau] Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Limmathurotsakul, Direk; Thaipadungpanit, Janjira; Blacksell, Stuart; Day, Nicholas] Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand. [Thwaites, Guy; Wertheim, Heiman; Le Van Tan; Rahman, Motiur; van Doorn, H. Rogier] Univ Oxford, Clin Res Unit, Hanoi, Vietnam. [Lau, Chuen-Yen] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Limmathurotsakul, D (reprint author), Mahidol Univ, Fac Trop Med, 420-6 Rajvithi Rd, Bangkok 10400, Thailand. EM direk@tropmedres.ac FU National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Institutes of Health, USA; Wellcome Trust, UK FX National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA, and Wellcome Trust, UK. NR 32 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD FEB PY 2017 VL 5 IS 2 BP E157 EP E167 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EN9SW UT WOS:000396340900021 ER PT J AU Kim, C Szabo, E Guha, U Rajan, A AF Kim, Chul Szabo, Eva Guha, Udayan Rajan, Arun TI Consolidative local therapy in oligometastatic patients SO LANCET ONCOLOGY LA English DT Letter ID CELL LUNG-CANCER C1 [Kim, Chul; Guha, Udayan; Rajan, Arun] NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. [Szabo, Eva] NCI, Lung & Upper Aerodigest Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Rajan, A (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. EM rajana@mail.nih.gov NR 5 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD FEB PY 2017 VL 18 IS 2 BP E61 EP E61 PG 1 WC Oncology SC Oncology GA EN9TR UT WOS:000396343000002 ER PT J AU Collins, PY Delgado, RA Pringle, BA Roca, C Phillips, A AF Collins, Pamela Y. Delgado, Roberto A. Pringle, Beverly A. Roca, Catherine Phillips, Anthony TI Suicide prevention in Arctic Indigenous communities SO LANCET PSYCHIATRY LA English DT Editorial Material C1 [Collins, Pamela Y.; Delgado, Roberto A.; Pringle, Beverly A.; Roca, Catherine] NIMH, Off Res Dispar & Global Mental Hlth, Bethesda, MD 20892 USA. [Phillips, Anthony] Djavad Mowafaghian Ctr Brain Hlth, Canadian Inst Hlth Res, Inst Neurosci Mental Hlth & Addict, Vancouver, BC, Canada. RP Collins, PY (reprint author), NIMH, Off Res Dispar & Global Mental Hlth, Bethesda, MD 20892 USA. EM pamela.collins@nih.gov NR 11 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD FEB PY 2017 VL 4 IS 2 BP 92 EP 94 PG 4 WC Psychiatry SC Psychiatry GA EN9VB UT WOS:000396346600008 PM 28137384 ER PT J AU Saleh, LM Wang, W Herman, SEM Saba, NS Anastas, V Barber, E Corrigan-Cummins, M Farooqui, M Sun, C Sarasua, SM Zhao, Z Abousamra, NK Elbaz, O Abdelghaffar, HA Wiestner, A Calvo, KR AF Saleh, L. M. Wang, W. Herman, S. E. M. Saba, N. S. Anastas, V. Barber, E. Corrigan-Cummins, M. Farooqui, M. Sun, C. Sarasua, S. M. Zhao, Z. Abousamra, N. K. Elbaz, O. Abdelghaffar, H. A. Wiestner, A. Calvo, K. R. TI Ibrutinib downregulates a subset of miRNA leading to upregulation of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia SO LEUKEMIA LA English DT Article ID BRUTONS TYROSINE KINASE; DISEASE PROGRESSION; MICRORNA SIGNATURE; TARGETING SMAD4; CLL PATIENTS; TGF-BETA; MIR-34A; EXPRESSION; MICROENVIRONMENT; PATHOGENESIS AB The lymph node (LN) is the site of chronic lymphocytic leukemia (CLL) cell activation and proliferation. Aberrant microRNA (miRNA) expression has been shown to have a role in CLL pathogenesis; however, a comparison of miRNA expression between CLL cells in the LN and the peripheral blood (PB) has previously not been reported. On the basis of the analysis of 17 paired LN and PB samples from CLL patients, we identify a panel of miRNAs that are increased in LN CLL cells correlating with an activation phenotype. When evaluated in CLL cells from 38 patients pre and post treatment with ibrutinib, a subset of these miRNAs (miR-22, miR-34a, miR-146b and miR-181b) was significantly decreased in response to ibrutinib. A concomitant increase in putative miRNA target transcripts (ARID1B, ARID2, ATM, CYLD, FOXP1, HDAC1, IBTK, PTEN and SMAD4) was also observed. Functional studies confirmed targets of ibrutinib-responsive miRNAs to include messenger RNA transcripts of multiple tumor suppressors. Knockdown of endogenous miR-34a and miR146b resulted in increased transcription of tumor suppressors and inhibition of cell proliferation. These findings demonstrate that ibrutinib downregulates the expression of a subset of miRNAs related to B-cell activation leading to increased expression of miRNA targets including tumor suppressors and a reduction in cell proliferation. C1 [Saleh, L. M.; Wang, W.; Anastas, V.; Barber, E.; Corrigan-Cummins, M.; Zhao, Z.; Calvo, K. R.] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Herman, S. E. M.; Saba, N. S.; Farooqui, M.; Sun, C.; Wiestner, A.] NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Sarasua, S. M.] Greenwood Genet Ctr, Greenwood, SC 29646 USA. [Sarasua, S. M.] Clemson Univ, Sch Nursing, Clemson, SC USA. [Saleh, L. M.; Abousamra, N. K.; Elbaz, O.; Abdelghaffar, H. A.] Mansoura Univ, Fac Med, Clin Pathol Dept, Mansoura, Egypt. RP Calvo, KR (reprint author), NIH, Dept Lab Med, 10 Ctr Dr,Bldg 10,Room 2C06, Bethesda, MD 20892 USA. EM calvok@cc.nih.gov FU National Institutes of Health Division of Intramural Research; NIH Clinical Center; National Heart, Lung and Blood Institute FX This work was supported by the National Institutes of Health Division of Intramural Research, NIH Clinical Center, and National Heart, Lung and Blood Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services. We thank Dr Masanori Daibata (Kochi University Medical School, Kochi, Japan) for use of the SP53 cell line. NR 63 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD FEB PY 2017 VL 31 IS 2 BP 340 EP 349 DI 10.1038/leu.2016.181 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA EK6UE UT WOS:000394058800010 PM 27431016 ER PT J AU Metherel, AH Domenichiello, AF Kitson, AP Lin, YH Bazinet, RP AF Metherel, Adam H. Domenichiello, Anthony F. Kitson, Alex P. Lin, Yu-Hong Bazinet, Richard P. TI Serum n-3 Tetracosapentaenoic Acid and Tetracosahexaenoic Acid Increase Following Higher Dietary alpha-Linolenic Acid but not Docosahexaenoic Acid SO LIPIDS LA English DT Article DE n-3 Tetracosapentaenoic acid; Tetracosahexaenoic acid; alpha-Linolenic acid; Docosahexaenoic acid; Serum ID POLYUNSATURATED FATTY-ACIDS; EICOSAPENTAENOIC ACID; RAT-LIVER; BRAIN; METABOLISM; PLASMA; DHA; RETROCONVERSION; BIOSYNTHESIS; DEPRIVATION AB n-3 Tetracosapentaenoic acid (24:5n-3, TPAn-3) and tetracosahexaenoic acid (24:6n-3, THA) are believed to be important intermediates to docosahexaenoic acid (DHA, 22:6n-3) synthesis. The purpose of this study is to report for the first time serum concentrations of TPAn-3 and THA and their response to changing dietary alpha-linolenic acid (18:3n-3, ALA) and DHA. The responses will then be used in an attempt to predict the location of these fatty acids in relation to DHA in the biosynthetic pathway. Male Long Evans rats (n = 6 per group) were fed either a low (0.1% of total fatty acids), medium (3%) or high (10%) ALA diet with no added DHA, or a low (0%), medium (0.2%) or high (2%) DHA diet with a background of 2% ALA for 8 weeks post-weaning. Serum n-3 and n-6 polyunsaturated fatty acid (PUFA) concentrations (nmol/mL +/- SEM) were determined by gas chromatography-mass spectrometry. Serum THA increases from low (0.3 +/- 0.1) to medium (5.8 +/- 0.7) but not from medium to high (4.6 +/- 0.9) dietary ALA, while serum TPAn-3 increases with increasing dietary ALA from 0.09 +/- 0.04 to 0.70 +/- 0.09 to 1.23 +/- 0.14 nmol/mL. Following DHA feeding, neither TPAn-3 or THA change across all dietary DHA intake levels. Serum TPAn-3 demonstrates a similar response to dietary DHA. In conclusion, this is the first study to demonstrate that increases in dietary ALA but not DHA increase serum TPAn-3 and THA in rats, suggesting that both fatty acids are precursors to DHA in the biosynthetic pathway. C1 [Metherel, Adam H.; Domenichiello, Anthony F.; Kitson, Alex P.; Bazinet, Richard P.] Univ Toronto, Dept Nutr Sci, Fac Med, 150 Coll St,Room 307,Fitzgerald Bldg, Toronto, ON M5S 3E2, Canada. [Lin, Yu-Hong] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. RP Metherel, AH (reprint author), Univ Toronto, Dept Nutr Sci, Fac Med, 150 Coll St,Room 307,Fitzgerald Bldg, Toronto, ON M5S 3E2, Canada. EM adam.metherel@utoronto.ca FU Natural Sciences and Engineering Research Council of Canada [482597] FX This study was funded by a grant to Richard P. Bazinet through the Natural Sciences and Engineering Research Council of Canada (482597). Richard P. Bazinet holds a Canada Research Chair in Brain Lipid Metabolism. NR 33 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0024-4201 EI 1558-9307 J9 LIPIDS JI Lipids PD FEB PY 2017 VL 52 IS 2 BP 167 EP 172 DI 10.1007/s11745-016-4223-0 PG 6 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA EK9JH UT WOS:000394240000007 PM 28005226 ER PT J AU Pool, JE Braun, DT Lack, JB AF Pool, John E. Braun, Dylan T. Lack, Justin B. TI Parallel Evolution of Cold Tolerance within Drosophila melanogaster SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE Drosophila melanogaster; cold tolerance; parallel evolution; local adaptation ID GENETIC REFERENCE PANEL; INBREEDING DEPRESSION; EUROPEAN ADMIXTURE; LOCAL ADAPTATION; GENOMIC ANALYSIS; POPULATION; REVEALS; AFRICAN; TRAITS; RESISTANCE AB Drosophila melanogaster originated in tropical Africa before expanding into strikingly different temperate climates in Eurasia and beyond. Here, we find elevated cold tolerance in three distinct geographic regions: beyond the well-studied non-African case, we show that populations from the highlands of Ethiopia and South Africa have significantly increased cold tolerance as well. We observe greater cold tolerance in outbred versus inbred flies, but only in populations with higher inversion frequencies. Each cold-adapted population shows lower inversion frequencies than a closely-related warm-adapted population, suggesting that inversion frequencies may decrease with altitude in addition to latitude. Using the F-ST-based "Population Branch Excess" statistic (PBE), we found only limited evidence for parallel genetic differentiation at the scale of similar to 4 kb windows, specifically between Ethiopian and South African cold-adapted populations. And yet, when we looked for single nucleotide polymorphisms (SNPs) with codirectional frequency change in two or three cold-adapted populations, strong genomic enrichments were observed from all comparisons. These findings could reflect an important role for selection on standing genetic variation leading to "soft sweeps". One SNP showed sufficient codirectional frequency change in all cold-adapted populations to achieve experiment-wide significance: an intronic variant in the synaptic gene Prosap. Another codirectional outlier SNP, at senseless-2, had a strong association with our cold trait measurements, but in the opposite direction as predicted. More generally, proteins involved in neurotransmission were enriched as potential targets of parallel adaptation. The ability to study cold tolerance evolution in a parallel framework will enhance this classic study system for climate adaptation. C1 [Pool, John E.; Braun, Dylan T.] Univ Wisconsin, Genet Lab, Madison, WI USA. [Lack, Justin B.] Ctr Canc Res, Natl Canc Inst, NIH, Bethesda, MD 20892 USA. RP Pool, JE (reprint author), Univ Wisconsin, Genet Lab, Madison, WI USA. EM jpool@wisc.edu FU National Institutes of Health [R01 GM111797, F32 GM106594] FX This work was funded by the National Institutes of Health through a grant to JEP [R01 GM111797] and a fellowship to JBL [F32 GM106594]. We thank Tom Turner and two anonymous reviewers for helpful comments on this manuscript. NR 47 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2017 VL 34 IS 2 BP 349 EP 360 DI 10.1093/molbev/msw232 PG 12 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA EO2FF UT WOS:000396511300006 PM 27777283 ER PT J AU Yao, PJ Manor, U Petralia, RS Brose, RD Wu, RTY Ott, C Wang, YX Charnoff, A Lippincott-Schwartz, J Mattson, MP AF Yao, Pamela J. Manor, Uri Petralia, Ronald S. Brose, Rebecca D. Wu, Ryan T. Y. Ott, Carolyn Wang, Ya-Xian Charnoff, Ari Lippincott-Schwartz, Jennifer Mattson, Mark P. TI Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID GROWTH-FACTOR; FISSION; SYNAPSES; RECEPTOR; ACTIN; DRP1; NEUROPLASTICITY; MEDULLOBLASTOMA; TRANSMISSION; DEGENERATION AB Mitochondria are essential organelles whose biogenesis, structure, and function are regulated by many signaling pathways. We present evidence that, in hippocampal neurons, activation of the Sonic hedgehog (Shh) signaling pathway affects multiple aspects of mitochondria. Mitochondrial mass was increased significantly in neurons treated with Shh. Using biochemical and fluorescence imaging analyses, we show that Shh signaling activity reduces mitochondrial fission and promotes mitochondrial elongation, at least in part, via suppression of the mitochondrial fission protein dynamin-like GTPase Drp1. Mitochondria from Shh-treated neurons were more electron-dense, as revealed by electron microscopy, and had higher membrane potential and respiratory activity. We further show that Shh protects neurons against a variety of stresses, including the mitochondrial poison rotenone, amyloid beta-peptide, hydrogen peroxide, and high levels of glutamate. Collectively our data suggest a link between Shh pathway activity and the physiological properties of mitochondria in hippocampal neurons. C1 [Yao, Pamela J.; Brose, Rebecca D.; Wu, Ryan T. Y.; Mattson, Mark P.] NIA, Lab Neurosci, NIH, Baltimore, MD 21224 USA. [Manor, Uri; Ott, Carolyn; Charnoff, Ari; Lippincott-Schwartz, Jennifer] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Petralia, Ronald S.; Wang, Ya-Xian] Natl Inst Deafness & Other Commun Disorders, Adv Imaging Core, NIH, Bethesda, MD 20892 USA. [Manor, Uri] Salk Inst Biol Studies, Waitt Adv Biophoton Ctr, La Jolla, CA 92037 USA. [Ott, Carolyn] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. RP Yao, PJ (reprint author), NIA, Lab Neurosci, NIH, Baltimore, MD 21224 USA. EM yaopa@grc.nia.nih.gov FU National Institutes of Health/National Institute on Aging; National Institute on Deafness and Other Communication Disorders; National Institute of Child Health and Human Development FX This study was supported by the Intramural Research Programs of the National Institutes of Health/National Institute on Aging, National Institute on Deafness and Other Communication Disorders, and National Institute of Child Health and Human Development. The Advanced Imaging Core code is ZIC DC000081. NR 58 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2017 VL 28 IS 3 BP 387 EP 395 DI 10.1091/mbc.E16-07-0553 PG 9 WC Cell Biology SC Cell Biology GA EK9UF UT WOS:000394268700006 PM 27932496 ER PT J AU Cherok, E Xu, S Li, SA Das, S Meltzer, WA Zalzman, M Wang, CX Karbowski, M AF Cherok, Edward Xu, Shan Li, Sunan Das, Shweta Meltzer, W. Alex Zalzman, Michal Wang, Chunxin Karbowski, Mariusz TI Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5-dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MAMMALIAN-CELLS; QUALITY-CONTROL; OUTER-MEMBRANE; METABOLIC-REGULATION; PEROXISOMAL FISSION; MITOFUSIN 1; FUSION; PROTEIN; APOPTOSIS; MARCH5 AB MARCH5, an OMM-associated E3 ubiquitin ligase, controls mitochondrial function. Despite its importance, the mechanism and factors controlling MARCH5 activity are largely unknown. Here we report that the MARCH5 C-terminal domain plays a critical role in degradation of MARCH5 substrates, likely by facilitating release of ubiquitinated proteins from the OMM. We also found that the mitochondrial fission proteins Drp1 and Mff negatively regulate MARCH5' s activity toward MiD49 and Mcl1. Knockouts of either Drp1 or Mff led to reduced expression, shorter half-lives, and increased ubiquitination of MiD49 and Mcl1. Effects of Mff and Drp1 depletion on degradation rates and ubiquitination of Mcl1 and MiD49 were eliminated in Drp1(-/-)/MARCH5(-/-) and Mff(-/-)/MARCH5(-/-) cells. Our data show that it is not mitochondrial morphology per se but rather Mff and Drp1 that directly control MARCH5. Consistently, we find that Mff is an integral component of the MARCH5/p97/Npl4 complex, which is also controlled by MARCH5' s C-terminal domain. Furthermore, not only mitochondrial fission but also fusion is regulated through Mff and Drp1 protein activities. Thus, in addition to their canonical roles in mitochondrial fission, Mff and Drp1 also act as regulatory factors that control mitochondrial fission and fusion. C1 [Cherok, Edward; Xu, Shan; Li, Sunan; Das, Shweta; Karbowski, Mariusz] Univ Maryland, Sch Med, Ctr Biomed Engn & Technol, Baltimore, MD 21201 USA. [Cherok, Edward; Xu, Shan; Li, Sunan; Das, Shweta; Meltzer, W. Alex; Zalzman, Michal; Karbowski, Mariusz] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Wang, Chunxin] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Li, Sunan] NINDS, Synapt Funct Sect, NIH, Bethesda, MD 20892 USA. RP Karbowski, M (reprint author), Univ Maryland, Sch Med, Ctr Biomed Engn & Technol, Baltimore, MD 21201 USA.; Karbowski, M (reprint author), Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. EM mkarbowski@umaryland.edu FU National Institute of General Medical Science [RO1 GM083131]; Intramural Research Program of the National Institutes of Neurological Disorders and Stroke, National Institutes of Health FX We thank Pamela Wright for insightful comments on the manuscript, Alma Arnold for help with Airyscan imaging, Carl Zeiss Microscopy for access to an LSM 880/Airyscan imaging system, David Goodlett and staff of University of Maryland School of Pharmacy Mass Spectrometry Center for help with mass spectrometry protein analysis, and Liron Boyman and W. Jonathan Lederer for access to the LSM510 imaging system and help with mitochondrial fusion assays. We also gratefully acknowledge financial support from the National Institute of General Medical Science (Grant RO1 GM083131 to M.K.). C.W. is supported in part by the Intramural Research Program of the National Institutes of Neurological Disorders and Stroke, National Institutes of Health. NR 76 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2017 VL 28 IS 3 BP 396 EP 410 DI 10.1091/mbc.E16-04-0208 PG 15 WC Cell Biology SC Cell Biology GA EK9UF UT WOS:000394268700007 PM 27932492 ER PT J AU Bird, JE Barzik, M Drummond, MC Sutton, DC Goodman, SM Morozko, EL Cole, SM Boukhvalova, AK Skidmore, J Syam, D Wilson, EA Fitzgerald, T Rehman, AU Martin, DM Boger, ET Belyantseva, IA Friedman, TB AF Bird, Jonathan E. Barzik, Melanie Drummond, Meghan C. Sutton, Daniel C. Goodman, Spencer M. Morozko, Eva L. Cole, Stacey M. Boukhvalova, Alexandra K. Skidmore, Jennifer Syam, Diana Wilson, Elizabeth A. Fitzgerald, Tracy Rehman, Atteeq U. Martin, Donna M. Boger, Erich T. Belyantseva, Inna A. Friedman, Thomas B. TI Harnessing molecular motors for nanoscale pulldown in live cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; MAMMALIAN 2-HYBRID SYSTEM; GREEN FLUORESCENT PROTEIN; REMODELING FACTOR CHD4; MYOSIN-X; LIVING CELLS; DNA-DAMAGE; INNER-EAR; MICROSCOPY; FILOPODIA AB Protein-protein interactions (PPIs) regulate assembly of macromolecular complexes, yet remain challenging to study within the native cytoplasm where they normally exert their biological effect. Here we miniaturize the concept of affinity pulldown, a gold-standard in vitro PPI interrogation technique, to perform nanoscale pulldowns (NanoSPDs) within living cells. NanoSPD hijacks the normal process of intracellular trafficking by myosin motors to forcibly pull fluorescently tagged protein complexes along filopodial actin filaments. Using dual-color total internal reflection fluorescence microscopy, we demonstrate complex formation by showing that bait and prey molecules are simultaneously trafficked and actively concentrated into a nanoscopic volume at the tips of filopodia. The resulting molecular traffic jams at filopodial tips amplify fluorescence intensities and allow PPIs to be interrogated using standard epifluorescence microscopy. A rigorous quantification framework and software tool are provided to statistically evaluate NanoSPD data sets. We demonstrate the capabilities of NanoSPD for a range of nuclear and cytoplasmic PPIs implicated in human deafness, in addition to dissecting these interactions using domain mapping and mutagenesis experiments. The NanoSPD methodology is extensible for use with other fluorescent molecules, in addition to proteins, and the platform can be easily scaled for high-throughput applications. C1 [Bird, Jonathan E.; Barzik, Melanie; Drummond, Meghan C.; Sutton, Daniel C.; Goodman, Spencer M.; Morozko, Eva L.; Cole, Stacey M.; Boukhvalova, Alexandra K.; Wilson, Elizabeth A.; Rehman, Atteeq U.; Boger, Erich T.; Belyantseva, Inna A.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Lab Mol Genet, NIH, Bethesda, MD 20814 USA. [Fitzgerald, Tracy] Natl Inst Deafness & Other Commun Disorders, Mouse Auditory Testing Core Facil, NIH, Bethesda, MD 20814 USA. [Skidmore, Jennifer; Syam, Diana; Martin, Donna M.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Martin, Donna M.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Rehman, Atteeq U.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Bird, JE (reprint author), Natl Inst Deafness & Other Commun Disorders, Lab Mol Genet, NIH, Bethesda, MD 20814 USA. EM jonathan.bird@nih.gov FU Intramural Research Program of the NIH, NIDCD [DC000039]; NIDCD [DC000080]; extramural funds NIDCD [R01 DC009410] FX We thank Giovanni Mann and Yasuharu Takagi for insightful discussions; Dennis Drayna, James Sellers, and Matthias Machner for critical reading; and Joseph Duda for technical assistance. We are grateful to John Hammer, III (National Heart, Lung, and Blood Institute), for the gift of Myo5a and Mlph cDNA and to the animal care staff at both the NIDCD and the University of Michigan. This work is supported (in part) by the Intramural Research Program of the NIH, NIDCD DC000039 (to T.B.F.), NIDCD DC000080 (to T.F.), and extramural funds NIDCD R01 DC009410 (to D.M.M.). NR 70 TC 0 Z9 0 U1 3 U2 3 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 FEB PY 2017 VL 28 IS 3 BP 463 EP 475 DI 10.1091/mbc.E16-08-0583 PG 13 WC Cell Biology SC Cell Biology GA EK9UF UT WOS:000394268700012 PM 27932498 ER PT J AU Lee, J Sengupta, P Brzostowski, J Lippincott-Schwartz, J Pierce, SK AF Lee, Jinmin Sengupta, Prabuddha Brzostowski, Joseph Lippincott-Schwartz, Jennifer Pierce, Susan K. TI The nanoscale spatial organization of B-cell receptors on immunoglobulin M- and G-expressing human B-cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ANTIGEN RECEPTOR; LOCALIZATION MICROSCOPY; IGG; INITIATION; SYNAPSE; ACTIVATION; TAIL AB B-cell activation is initiated by the binding of antigen to the B-cell receptor (BCR). Here we used dSTORM superresolution imaging to characterize the nanoscale spatial organization of immunoglobulin M (IgM) and IgG BCRs on the surfaces of resting and antigen-activated human peripheral blood B-cells. We provide insights into both the fundamental process of antigen-driven BCR clustering and differences in the spatial organization of IgM and IgG BCRs that may contribute to the characteristic differences in the responses of naive and memory B-cells to antigen. We provide evidence that although both IgM and IgG BCRs reside in highly heterogeneous protein islands that vary in size and number of BCR single-molecule localizations, both resting and activated B-cells intrinsically maintain a high - frequency of single isolated BCR localizations, which likely represent BCR monomers. IgG BCRs are more clustered than IgM BCRs on resting cells and form larger protein islands after antigen activation. Small, dense BCR clusters likely formed via protein-protein interactions are present on the surface of resting cells, and antigen activation induces these to come together to form less dense, larger islands, a process likely governed, at least in part, by protein-lipid interactions. C1 [Lee, Jinmin; Brzostowski, Joseph; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Sengupta, Prabuddha; Lippincott-Schwartz, Jennifer] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. [Sengupta, Prabuddha; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM spierce@nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Howard Hughes Medical Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Howard Hughes Medical Institute. NR 38 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2017 VL 28 IS 4 BP 511 EP 523 DI 10.1091/mbc.E16-06-0452 PG 13 WC Cell Biology SC Cell Biology GA EK9VA UT WOS:000394270800002 PM 27974642 ER PT J AU Van Itallie, CM Tietgens, AJ Anderson, JM AF Van Itallie, Christina M. Tietgens, Amber Jean Anderson, James M. TI Visualizing the dynamic coupling of claudin strands to the actin cytoskeleton through ZO-1 SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID TIGHT JUNCTION STRANDS; STRUCTURED ILLUMINATION MICROSCOPY; CHARGE SELECTIVITY; OCCLUDING JUNCTIONS; BARRIER FUNCTION; ZONULA ADHERENS; PROTEIN ZO-1; CELL; BINDING; PHOSPHORYLATION AB The organization and integrity of epithelial tight junctions depend on interactions between claudins, ZO scaffolding proteins, and the cytoskeleton. However, although binding between claudins and ZO-1/2/3 and between ZO-1/2/3 and numerous cytoskeletal proteins has been demonstrated in vitro, fluorescence recovery after photobleaching analysis suggests interactions in vivo are likely highly dynamic. Here we use superresolution live-cell imaging in a model fibroblast system to examine relationships between claudins, ZO-1, occludin, and actin. We find that GFP claudins make easily visualized dynamic strand patches between two fibroblasts; strand dynamics is constrained by ZO-1 binding. Claudin association with actin is also dependent on ZO-1, but colocalization demonstrates intermittent rather than continuous association between claudin, ZO-1, and actin. Independent of interaction with ZO-1 or actin, claudin strands break and reanneal; pulse-chase-pulse analysis using SNAP-tagged claudins showed preferential incorporation of newly synthesized claudins into break sites. Although claudin strand behavior in fibroblasts may not fully recapitulate that of epithelial tight junction strands, this is the first direct demonstration of the ability of ZO-1 to stabilize claudin strands. We speculate that intermittent tethering of claudins to actin may allow for accommodation of the paracellular seal to physiological or pathological alterations in cell shape or movement. C1 [Van Itallie, Christina M.; Tietgens, Amber Jean; Anderson, James M.] NHLBI, Lab Tight Junct Struct & Funct, 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 appreciate invaluable help from Xufeng Wu, Light Microscopy Core Facility, National Heart, Lung, and Blood Institute. We thank Luke Lavis (Janelia Research Campus, Howard Hughes Medical Institute) via Jordan Beach (National Heart, Lung, and Blood Institute) for the gift of Janelia Fluor 646, John Hammer (National Heart, Lung, and Blood Institute) for the gift of the pHalo C1 cDNA, and Robert Fischer (National Heart, Lung, and Blood Institute) for tdTomato F-tractin. We also thank Bechara Kachar (National Institute for Deafness and other Communication Disorders) for thoughtful comments on the data and Karin Fredriksson and members of the Clare Waterman and John Hammer laboratories for helpful discussions and technical advice. This research was supported by the Division of Intramural Research, National Institutes of Health. NR 42 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2017 VL 28 IS 4 BP 524 EP 534 DI 10.1091/mbc.E16-10-0698 PG 11 WC Cell Biology SC Cell Biology GA EK9VA UT WOS:000394270800003 PM 27974639 ER PT J AU Airan, RD Meyer, RA Ellens, NPK Rhodes, KR Farahani, K Pomper, MG Kadam, SD Green, JJ AF Airan, Raag D. Meyer, Randall A. Ellens, Nicholas P. K. Rhodes, Kelly R. Farahani, Keyvan Pomper, Martin G. Kadam, Shilpa D. Green, Jordan J. TI Noninvasive Targeted Transcranial Neuromodulation via Focused Ultrasound Gated Drug Release from Nanoemulsions SO NANO LETTERS LA English DT Article DE Neuromodulation; focused ultrasound; nanoparticles; gated drug release ID BLOOD-BRAIN-BARRIER; IN-VIVO NEUROSTIMULATION; PERFLUOROCARBON NANODROPLETS; ENHANCED DELIVERY; MOUSE MODEL; SUPPRESSION; ANESTHESIA; PROPOFOL; THERAPY; RATS AB Targeted, noninvasive neuromodulation of the brain of an otherwise awake subject could revolutionize both basic and clinical neuroscience. Toward this goal, we have developed nanoparticles that allow noninvasive uncaging of a neuromodulatory drug, in this case the small molecule anesthetic propofol, upon the application of focused ultrasound. These nanoparticles are composed of biodegradable and biocompatible constituents and are activated using sonication parameters that are readily achievable by current clinical transcranial focused ultrasound systems. These particles are potent enough that their activation can silence seizures in an acute rat seizure model. Notably, there is no evidence of brain parenchymal damage or blood brain barrier opening with their use. Further development of these particles promises noninvasive, focal, and image-guided clinical neuromodulation along a variety of pharmacological axes. C1 [Airan, Raag D.; Ellens, Nicholas P. K.; Farahani, Keyvan; Pomper, Martin G.] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD 21231 USA. [Airan, Raag D.; Meyer, Randall A.; Rhodes, Kelly R.; Green, Jordan J.] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21231 USA. [Airan, Raag D.; Meyer, Randall A.; Rhodes, Kelly R.; Green, Jordan J.] Johns Hopkins Univ, Sch Med, Translat Tissue Engn Ctr, Baltimore, MD 21231 USA. [Airan, Raag D.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Meyer, Randall A.; Pomper, Martin G.; Green, Jordan J.] Johns Hopkins Univ, Inst NanoBioTechnol, Baltimore, MD 21231 USA. [Farahani, Keyvan] NCI, NIH, Bethesda, MD 20892 USA. [Pomper, Martin G.; Green, Jordan J.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA. [Kadam, Shilpa D.] Kennedy Krieger Inst, Hugo Moser Res Inst, Neurosci Lab, Baltimore, MD 21287 USA. [Kadam, Shilpa D.] Johns Hopkins Med Inst, Dept Neurol, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Dept Mat Sci & Engn, Baltimore, MD 21231 USA. RP Airan, RD (reprint author), Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD 21231 USA.; Airan, RD; Green, JJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21231 USA.; Airan, RD; Green, JJ (reprint author), Johns Hopkins Univ, Sch Med, Translat Tissue Engn Ctr, Baltimore, MD 21231 USA.; Airan, RD (reprint author), Stanford Univ, Dept Radiol, Stanford, CA 94305 USA.; Green, JJ (reprint author), Johns Hopkins Univ, Inst NanoBioTechnol, Baltimore, MD 21231 USA.; Green, JJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA. EM rairan@stanford.edu; green@jhu.edu OI Green, Jordan/0000-0003-4176-3808; Kadam, Shilpa/0000-0001-5136-9594 FU NIH [NIBIB R01EB016721, R01EB022148, NICHD R21HD073105, NCI P50CA058236, NCI F31CA214147]; Philips Inc.; Foundation of the American Society for Neuroradiology; Walter and Mary Ciceric Foundation; Achievement Rewards for College Scientists Metro-DC Chapter; National Science Foundation [DGE-1232825] FX This work was funded via grant support from the NIH (NIBIB R01EB016721 and R01EB022148, J.J.G.; NICHD R21HD073105, S.D.K; NCI P50CA058236, M.G.P.; NCI F31CA214147, R.A.M.), Philips Inc., the Foundation of the American Society for Neuroradiology, and the Walter and Mary Ciceric Foundation. R.A.M. thanks that Achievement Rewards for College Scientists Metro-DC Chapter for fellowship support. K.RR. thanks the National Science Foundation Graduate Research Fellowship Program (DGE-1232825) for fellowship support. NR 28 TC 0 Z9 0 U1 3 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 EI 1530-6992 J9 NANO LETT JI Nano Lett. PD FEB PY 2017 VL 17 IS 2 BP 652 EP 659 DI 10.1021/acs.nanolett.6b03517 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EK3SW UT WOS:000393848800008 PM 28094959 ER PT J AU Andreoni, A Lin, S Liu, HJ Blankenship, RE Yan, H Woodbury, NW AF Andreoni, Alessio Lin, Su Liu, Haijun Blankenship, Robert E. Yan, Hao Woodbury, Neal W. TI Orange Carotenoid Protein as a Control Element in an Antenna System Based on a DNA Nanostructure SO NANO LETTERS LA English DT Article DE Orange carotenoid protein; DNA nanotechnology; artificial light-harvesting; photoprotection; fluorescence spectroscopy; energy transfer ID CYANOBACTERIAL PHOTOPROTECTION; CRYSTAL-STRUCTURE; ENERGY-DISSIPATION; PCC 6803; LIGHT; MECHANISM; PHOTOACTIVATION; IDENTIFICATION; PHOTOSYNTHESIS; REARRANGEMENTS AB Taking inspiration from photosynthetic mechanisms in natural systems, we introduced a light-sensitive photo protective quenching element to an artificial light harvesting antenna model to control the flow of energy as a function of light intensity excitation. The orange carotenoid protein (OCP) is a nonphotochemical quencher in cyanobacteria: under high-light conditions, the protein undergoes a spectral shift, and by binding to the phycobilisome, it absorbs excess light and dissipates it as heat. By the use of DNA as a scaffold, an antenna system made of organic dyes (Cy3 and Cy5) was constructed, and OCP was assembled on it as a modulated quenching element. By controlling the illumination intensity, it is possible to switch the direction of excitation energy transfer from the donor Cy3 to either of two acceptors. Under low-light conditions, energy is transferred from Cy3 to Cy5, and under intense illumination, energy is partially transferred to OCP as well. These results demonstrate the feasibility of controlling the pathway of energy transfer using light intensity in an engineered light-harvesting system. C1 [Andreoni, Alessio; Lin, Su; Woodbury, Neal W.] Arizona State Univ, Biodesign Ctr Innovat Med, Tempe, AZ 85287 USA. [Andreoni, Alessio; Yan, Hao] Arizona State Univ, Biodesign Ctr Mol Design & Biomimet, Biodesign Inst, Tempe, AZ 85287 USA. [Liu, Haijun; Blankenship, Robert E.] Washington Univ, Dept Biol, St Louis, MO 63130 USA. [Liu, Haijun; Blankenship, Robert E.] Washington Univ, Dept Chem, St Louis, MO 63130 USA. [Lin, Su; Yan, Hao; Woodbury, Neal W.] Arizona State Univ, Sch Mol Sci, Tempe, AZ 85287 USA. [Andreoni, Alessio] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Liu, Haijun] Benson Hill Biosyst, St Louis, MO USA. RP Andreoni, A; Woodbury, NW (reprint author), Arizona State Univ, Biodesign Ctr Innovat Med, Tempe, AZ 85287 USA.; Andreoni, A (reprint author), Arizona State Univ, Biodesign Ctr Mol Design & Biomimet, Biodesign Inst, Tempe, AZ 85287 USA.; Woodbury, NW (reprint author), Arizona State Univ, Sch Mol Sci, Tempe, AZ 85287 USA.; Andreoni, A (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM aandreon@asu.edu; nwoodbury@asu.edu RI Andreoni, Alessio/G-3100-2012 OI Andreoni, Alessio/0000-0003-4415-2770 FU DOD MURI [W911NF-12-1-0420]; NSF [MCB-1157788]; Department of Energy Office of Basic Energy Sciences [DE-FG02-07ER15902] FX This work was funded by the DOD MURI award W911NF-12-1-0420 (A.A., S.L., H.Y., and N.W.W.) and NSF grants MCB-1157788 (A.A and S.L.), and the Department of Energy Office of Basic Energy Sciences (grant no. DE-FG02-07ER15902; H.L. and R.E.B.). NR 39 TC 0 Z9 0 U1 8 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 EI 1530-6992 J9 NANO LETT JI Nano Lett. PD FEB PY 2017 VL 17 IS 2 BP 1174 EP 1180 DI 10.1021/acs.nanolett.6b04846 PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EK3SW UT WOS:000393848800081 PM 28081606 ER PT J AU Morales, M Margolis, EB AF Morales, Marisela Margolis, Elyssa B. TI Ventral tegmental area: cellular heterogeneity, connectivity and behaviour SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID MIDBRAIN DOPAMINE NEURONS; RAT PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; LATERAL HABENULA; MESOLIMBIC DOPAMINE; GLUTAMATE NEURONS; GABA NEURONS; ULTRASTRUCTURAL-LOCALIZATION; NONDOPAMINERGIC NEURONS; TYROSINE-HYDROXYLASE AB Dopamine-releasing neurons of the ventral tegmental area (VTA) have central roles in reward-related and goal-directed behaviours. VTA dopamine-releasing neurons are heterogeneous in their afferent and efferent connectivity and, in some cases, release GABA or glutamate in addition to dopamine. Recent findings show that motivational signals arising from the VTA can also be carried by non-dopamine-releasing projection neurons, which have their own specific connectivity. Both dopamine-releasing and non-dopamine-releasing VTA neurons integrate afferent signals with local inhibitory or excitatory inputs to generate particular output firing patterns. Various individual inputs, outputs and local connections have been shown to be sufficient to generate reward-or aversion-related behaviour, indicative of the impressive contribution of this small population of neurons to behaviour. C1 [Morales, Marisela] NIDA, Neuronal Networks Sect, Integrat Neurosci Res Branch, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. [Margolis, Elyssa B.] Univ Calif San Francisco, Wheeler Ctr, Dept Neurol, Neurobiol Addict Alcoholism & Addict Res Grp, 675 Nelson Rising Lane, San Francisco, CA 94158 USA. RP Morales, M (reprint author), NIDA, Neuronal Networks Sect, Integrat Neurosci Res Branch, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM mmorales@intra.nida.nih.gov FU Intramural Research Program (IRP) of the National Institute on Drug Abuse (IRP/NIDA/NIH); National Institute on Drug Abuse Award [R01 DA030529] FX The authors thank D. Root, D. Barker, C. Mejias-Aponte, H.-L. Wang and Z. Shiliang for constructive criticism of the initial manuscript. Work on this article was supported by the Intramural Research Program (IRP) of the National Institute on Drug Abuse (IRP/NIDA/NIH) to M.M. and by the National Institute on Drug Abuse Award R01 DA030529 to E.B.M. NR 145 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD FEB PY 2017 VL 18 IS 2 BP 73 EP 85 DI 10.1038/nrn.2016.165 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EK4ZW UT WOS:000393937700006 PM 28053327 ER PT J AU Sitaram, R Ros, T Stoeckel, L Haller, S Scharnowski, F Lewis-Peacock, J Weiskopf, N Blefari, ML Rana, M Oblak, E Birbaumer, N Sulzer, J AF Sitaram, Ranganatha Ros, Tomas Stoeckel, Luke Haller, Sven Scharnowski, Frank Lewis-Peacock, Jarrod Weiskopf, Nikolaus Blefari, Maria Laura Rana, Mohit Oblak, Ethan Birbaumer, Niels Sulzer, James TI Closed-loop brain training: the science of neurofeedback SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID REAL-TIME FMRI; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; RANDOMIZED CONTROLLED-TRIAL; STATE FUNCTIONAL CONNECTIVITY; DIRECT-CURRENT STIMULATION; ANTERIOR CINGULATE CORTEX; CONTROLLED CLINICAL-TRIAL; SLOW CORTICAL POTENTIALS; DEFAULT MODE NETWORK AB Neurofeedback is a psychophysiological procedure in which online feedback of neural activation is provided to the participant for the purpose of self-regulation. Learning control over specific neural substrates has been shown to change specific behaviours. As a progenitor of brain machine interfaces, neurofeedback has provided a novel way to investigate brain function and neuroplasticity. In this Review, we examine the mechanisms underlying neurofeedback, which have started to be uncovered. We also discuss how neurofeedback is being used in novel experimental and clinical paradigms from a multidisciplinary perspective, encompassing neuroscientific, neuroengineering and learning-science viewpoints. C1 [Sitaram, Ranganatha; Rana, Mohit] Pontificia Univ Catolica Chile, Inst Biol & Med Engn, Dept Psychiat, Vicu Mackenna 4860 Hernan Briones,Piso 2, Santiago 7820436, Chile. [Sitaram, Ranganatha; Rana, Mohit] Pontificia Univ Catolica Chile, Sect Neurosci, Vicu Mackenna 4860 Hernan Briones,Piso 2, Santiago 7820436, Chile. [Ros, Tomas] Univ Geneva, Neurol & Imaging Cognit Lab, 1 Rue Michel Servet, CH-1211 Geneva, Switzerland. [Stoeckel, Luke] NIDDK, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. [Haller, Sven] Affidea Ctr Diagnost Radiol Carouge CDRC, Cios Fonderie 1, CH-1277 Carouge, Switzerland. [Scharnowski, Frank] Univ Zurich, Psychiat Univ Hosp, Lenggstr 31, CH-8032 Zurich, Switzerland. [Lewis-Peacock, Jarrod] Univ Texas Austin, Imaging Res Ctr, Dept Psychol, 108 Dean Keeton St, Austin, TX 78712 USA. [Weiskopf, Nikolaus] Max Planck Inst Human Cognit & Brain Sci, Dept Neurophys, Stephanstr1, D-04103 Leipzig, Germany. [Weiskopf, Nikolaus] UCL, Wellcome Trust Ctr Neuroimaging, Inst Neurol, 12 Queen Sq, London WC1N 3BG, England. [Blefari, Maria Laura] Ecole Polytech Fed Lausanne, Ctr Neuroprosthet, Defitech Chair Brain Machine Interface, Chemin Mines 9, CH-1202 Geneva, Switzerland. [Oblak, Ethan; Sulzer, James] Univ Texas Austin, Dept Mech Engn, 204 E Dean Keeton St, Austin, TX 78712 USA. [Birbaumer, Niels] Wyss Ctr Bio & Neuroengn, Chenin Mines 9, CH-1202 Geneva, Switzerland. RP Sitaram, R (reprint author), Pontificia Univ Catolica Chile, Inst Biol & Med Engn, Dept Psychiat, Vicu Mackenna 4860 Hernan Briones,Piso 2, Santiago 7820436, Chile.; Sitaram, R (reprint author), Pontificia Univ Catolica Chile, Sect Neurosci, Vicu Mackenna 4860 Hernan Briones,Piso 2, Santiago 7820436, Chile.; Sulzer, J (reprint author), Univ Texas Austin, Dept Mech Engn, 204 E Dean Keeton St, Austin, TX 78712 USA. EM rasitaram@uc.cl; james.sulzer@austin.utexas.edu OI Haller, Sven/0000-0001-7433-0203 FU Comision Nacional de Investigacien Cientffica neurofeedback TecnolOgica de Chile (Conicyt) through Fondo Nacional de Desarrollo Cientffico neurofeedback Tecnolegico, Fondecyt [11121153]; Vicerrectorla de Investigacien de la Pontificia Universidad Catelica de Chile [15/2013]; Institute for Medical and Biological Engineering and Department of Psychiatry, Pontificia Universidad Catelica de Chile; Medical Faculty of the University of Tubingen [2114-1-0]; Singapore Baden Wurttemberg Life Sciences; ERA-Net (European Research Area) New INDIGO project - Bundesministerium fur Bildung und Forschung (BMBF) [01 DQ13004]; BRAINTRAIN European research network [602186]; European Research Council (ERC) [616905]; Wellcome Trust [0915/Z/10/Z]; Swiss National Science Foundation [BSSG10_155915]; US National Institutes of Health (NIH) [K23DA032612]; Norman E. Zinberg Fellowship in Addiction Psychiatry at Harvard Medical School; Charles A. King Trust; McGovern Institute Neurotechnology Program; Deutsche Forschungsgemeinschaft (DFG); EU Project LUMINOUS; BMBF, MOTOR-BIC und EMOIO; Eva und Horst Kehler Stiftung; Baden Wilrftemberg-Stiftung; EU Project BRAINTRAIN; NIH [5K12HD073945-02] FX The authors thank S. Ruiz and D. Schnyer for their valuable help in reviewing the manuscript before submission. R.S. is supported by the Comision Nacional de Investigacien Cientffica neurofeedback TecnolOgica de Chile (Conicyt) through Fondo Nacional de Desarrollo Cientffico neurofeedback Tecnolegico, Fondecyt (project number 11121153); Vicerrectorla de Investigacien de la Pontificia Universidad Catelica de Chile (Proyecto de Investigacion Interdisciplina number15/2013); Institute for Medical and Biological Engineering and Department of Psychiatry, Pontificia Universidad Catelica de Chile; the Medical Faculty of the University of Tubingen through the Fortune funding (project number 2114-1-0); the Singapore Baden Wurttemberg Life Sciences grant; the ERA-Net (European Research Area) New INDIGO project funded by the Bundesministerium fur Bildung und Forschung (BMBF) (project number 01 DQ13004). N.W. is supported by the BRAINTRAIN European research network (Collaborative Project, grant agreement number 602186); the European Research Council (ERC) (grant agreement number 616905); and a Centre Grant by the Wellcome Trust (0915/Z/10/Z). F.S. is supported by the Swiss National Science Foundation (BSSG10_155915). L.S. is supported by the US National Institutes of Health (NIH) (K23DA032612); the Norman E. Zinberg Fellowship in Addiction Psychiatry at Harvard Medical School; the Charles A. King Trust; the McGovern Institute Neurotechnology Program; and private funds to the Massachusetts General Hospital Department of Psychiatry. N.B. is supported by Deutsche Forschungsgemeinschaft (DFG); EU Project LUMINOUS; BMBF, MOTOR-BIC und EMOIO; Eva und Horst Kehler Stiftung; Baden Wilrftemberg-Stiftung; and EU Project BRAINTRAIN. J.S. is supported by NIH 5K12HD073945-02. NR 215 TC 2 Z9 2 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD FEB PY 2017 VL 18 IS 2 BP 86 EP 100 DI 10.1038/nrn.2016.164 PG 15 WC Neurosciences SC Neurosciences & Neurology GA EK4ZW UT WOS:000393937700007 PM 28003656 ER PT J AU Poldrack, RA Baker, CI Durnez, J Gorgolewski, KJ Matthews, PM Munafo, MR Nichols, TE Poline, JB Vul, E Yarkoni, T AF Poldrack, Russell A. Baker, Chris I. Durnez, Joke Gorgolewski, Krzysztof J. Matthews, Paul M. Munafo, Marcus R. Nichols, Thomas E. Poline, Jean-Baptiste Vul, Edward Yarkoni, Tal TI Scanning the horizon: towards transparent and reproducible neuroimaging research SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID HUMAN BRAIN-FUNCTION; WIDE ASSOCIATION; FMRI; BEHAVIOR; CORTEX; REPRESENTATIONS; IDENTIFICATION; NEUROSCIENCE; FLEXIBILITY; RELIABILITY AB Functional neuroimaging techniques have transformed our ability to probe the neurobiological basis of behaviour and are increasingly being applied by the wider neuroscience community. However, concerns have recently been raised that the conclusions that are drawn from some human neuroimaging studies are either spurious or not generalizable. Problems such as low statistical power, flexibility in data analysis, software errors and a lack of direct replication apply to many fields, but perhaps particularly to functional MRI. Here, we discuss these problems, outline current and suggested best practices, and describe how we think the field should evolve to produce the most meaningful and reliable answers to neuroscientific questions. C1 [Poldrack, Russell A.; Durnez, Joke; Gorgolewski, Krzysztof J.] Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. [Poldrack, Russell A.; Durnez, Joke; Gorgolewski, Krzysztof J.] Stanford Univ, Stanford Ctr Reproducible Neurosci, Stanford, CA 94305 USA. [Baker, Chris I.] NIMH, Lab Brain & Cognit, US NIH, Bethesda, MD 20892 USA. [Durnez, Joke] CEA Saclay, Inst Natl Rech Informat & Automat INRIA Parieta, Neurospin, Bldg 145, F-91191 Gif Sur Yvette, France. [Matthews, Paul M.] Hammersmith Hosp, Imperial Coll, Dept Med, Div Brain Sci, London W12 0NN, England. [Munafo, Marcus R.] Univ Bristol, MRC, Integrat Epidemiol Unit, Bristol BS8 1BN, Avon, England. [Munafo, Marcus R.] Univ Bristol, UK Ctr Tobacco & Alcohol Studies, Sch Expt Psychol, Bristol BS8 1TU, Avon, England. [Nichols, Thomas E.] Univ Warwick, Dept Stat & WMG, Coventry CV4 7AL, W Midlands, England. [Poline, Jean-Baptiste] Univ Calif Berkeley, Henry H Wheeler Jr Brain Imaging Ctr, Helen Wills Neurosci Inst, 132 Barker Hall 210S, Berkeley, CA 94720 USA. [Vul, Edward] Univ Calif San Diego, Dept Psychol, San Diego, CA 92093 USA. [Yarkoni, Tal] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA. RP Poldrack, RA (reprint author), Stanford Univ, Dept Psychol, Stanford, CA 94305 USA.; Poldrack, RA (reprint author), Stanford Univ, Stanford Ctr Reproducible Neurosci, Stanford, CA 94305 USA. EM russpold@stanford.edu FU Laura and John Arnold Foundation; European Union's Horizon research and innovation programme under the Marie Sklodowska-Curie [706561]; Medical Research Council (MRC) [MC UU 12013/6]; UK Centre for Tobacco and Alcohol Studies, a UK Clinical Research Council Public Health Research Centre of Excellence; British Heart Foundation; Cancer Research UK; Economic and Social Research Council; MRC; National Institute for Health Research, under UK Clinical Research Collaboration; Intramural Research Program of the US National Institutes of Health (NIH)National Institute of Mental Health (NIMH) [ZIA-MH002909]; NIMH [R01MH096906]; Imperial College Healthcare Trust Biomedical Research Centre; Imperial Engineering and Physical Sciences Research Council Mathematics in Healthcare Centre; Wellcome Trust [100309/Z/12/Z]; NIH-National Institute of Neurological Disorders and Stroke [R01NS075066]; NIH-National Institute of Biomedical Imaging and Bioengineering (NIBIB) [R01EB015611]; NIBIB [P41 EBO1 9936]; NIH-National Institute on Drug Abuse [U24DA038653]; Human Connectome Project, WU-Minn Consortium [1U54MH091657]; McDonnell Center for Systems Neuroscience at Washington University FX R.A.P., J.D., J.-B.P. and K.J.G. are supported by the Laura and John Arnold Foundation. J.D. has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 706561. M.R.M. is supported by the Medical Research Council (MRC) (MC UU 12013/6) and is a member of the UK Centre for Tobacco and Alcohol Studies, a UK Clinical Research Council Public Health Research Centre of Excellence. Funding from the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, the MRC and the National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. C.I.B. is supported by the Intramural Research Program of the US National Institutes of Health (NIH)National Institute of Mental Health (NIMH) (ZIA-MH002909). T.Y. is supported by the NIMH (R01MH096906). P.M.M. acknowledges personal support from the Edmond J. Safra Foundation and Lily Safra and research support from the MRC, the Imperial College Healthcare Trust Biomedical Research Centre and the Imperial Engineering and Physical Sciences Research Council Mathematics in Healthcare Centre. T.E.N. is supported by the Wellcome Trust (100309/Z/12/Z), NIH-National Institute of Neurological Disorders and Stroke (R01NS075066) and NIH-National Institute of Biomedical Imaging and Bioengineering (NIBIB) (R01EB015611). J.B.P. is supported by the NIBIB (P41 EBO1 9936) and by NIH-National Institute on Drug Abuse (U24DA038653). Data were provided (in part) by the Human Connectome Project, WU-Minn Consortium (principal investigators: D. Van Essen and K. Ugurbil; 1U54MH091657), which is funded by the 16 Institutes and Centers of the NIH that support the NIH Blueprint for Neuroscience Research, and by the McDonnell Center for Systems Neuroscience at Washington University. The authors thank J. Wexler for performing annotation of Neurosynth data, S. David for providing sample -size data, and R. Cox and P. Taylor for helpful comments on a draft of the manuscript. NR 77 TC 2 Z9 2 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD FEB PY 2017 VL 18 IS 2 BP 115 EP 126 DI 10.1038/nrn.2016.167 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EK4ZW UT WOS:000393937700009 PM 28053326 ER PT J AU Beydoun, HA Beydoun, MA Mishra, NK Rostant, OS Zonderman, AB Eid, SM AF Beydoun, Hind A. Beydoun, May A. Mishra, Nishant K. Rostant, Ola S. Zonderman, Alan B. Eid, Shaker M. TI Comorbid Parkinson's disease, falls and fractures in the 2010 National Emergency Department Sample SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinson's disease; Injury; Emergency Department; Healthcare utilization ID BONE-MINERAL DENSITY; HIP-FRACTURE; RISK-FACTORS; OSTEOPOROSIS; ASSOCIATION; MORTALITY AB Introduction: Parkinson's disease (PD) is a progressive, neurodegenerative disorder of multifactorial etiology affecting similar to 1% of older adults. Research focused on linking PD to falls and bone fractures has been limited in Emergency Department (ED) settings, where most injuries are identified. We assessed whether injured U.S. ED admissions with PD diagnoses were more likely to exhibit comorbid fall- or non-fall related bone fractures and whether a PD diagnosis with a concomitant fall or bone fracture' is linked to worse prognosis. Methods: We performed secondary analyses of 2010 Healthcare Utilization Project National ED Sample from 4,253,987 admissions to U.S. EDs linked to injured elderly patients. ED discharges with ICD-9-CM code (332.0) were identified as PD and those with ICD-9-CM code (800.0-829.0) were used to define bone fracture location. Linear and logistic regression models were constructed to estimate slopes (B) and odds ratios (OR) with 95% confidence intervals (CI). Results: PD admissions had 28% increased adjusted prevalence of bone fracture. Non-fall injuries showed stronger relationship between PD and bone fracture (ORadj = 1.33, 95% CI: 1.22-1.45) than fall injuries (ORadj = 1.06, 95% Cl:CI: 1.01-1.10). PD had the strongest impact on hospitalization length when bone fracture and fall co-occurred, and total charges were directly associated with PD only for fall injuries. Finally, PD status was not related to in-hospital death in this population. Conclusion: Among injured U.S. ED elderly patient visits, those with PD had higher bone fracture prevalence and more resource utilization especially among fall-related injuries. No association of PD with in hospital death was noted. Published by Elsevier Ltd. C1 [Beydoun, Hind A.; Eid, Shaker M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Beydoun, May A.; Rostant, Ola S.; Zonderman, Alan B.] Natl Inst Aging Intramural Res Program, Baltimore, MD USA. [Mishra, Nishant K.] Tulane Univ, Sch Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. RP Beydoun, MA (reprint author), NIA, NIH, Biomed Res Ctr, IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM hindb1972@gmail.com; baydounm@mail.nih.gov; nishmishra@gmail.com; ola.rostant@nih.gov; zondermana@mail.nih.gov; seid1@jhmi.edu OI Mishra, Nishant/0000-0002-9327-3707; Zonderman, Alan B/0000-0002-6523-4778 FU NIA/NIH/IRP; Johns Hopkins University School of Medicine FX This study was supported in part by the NIA/NIH/IRP in collaboration with Johns Hopkins University School of Medicine. NR 23 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD FEB PY 2017 VL 35 BP 30 EP 35 DI 10.1016/j.parkreldis.2016.11.005 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA EK6ZF UT WOS:000394074100005 PM 27887896 ER PT J AU Goldstein, DS Sullivan, P Holmes, C Mash, DC Kopin, IJ Sharabi, Y AF Goldstein, David S. Sullivan, Patti Holmes, Courtney Mash, Deborah C. Kopin, Irwin J. Sharabi, Yehonatan TI Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Cysteinyl-dopamine; Cysteinyl-DOPA; Parkinson's disease; Multiple system atrophy ID STRIATUM AB Background: Severe putamen dopamine depletion characterizes Parkinson's disease (PD) and multiple system atrophy (MSA). The extent of the depletion is greater than can be accounted for by loss of nigrostriatal dopaminergic terminals alone. We used putamen tissue levels and ratios of cysteinyl and parent catechols to explore possible denervation-independent abnormalities of dopamine synthesis and fate in PD and MSA. 5-S-Cysteinyldopa (Cys-DOPA) is produced from spontaneous oxidation of DOPA and 5-S-cysteinyldopamine (Cys-DA) from spontaneous oxidation of DA. Methods: Post-mortem putamen tissue samples from 17 PD and 25 MSA patients and 30 controls were assayed for endogenous catechols including DA, its cytoplasmic metabolites (Cys-DA, 3,4dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethanol, and 3,4-dihydroxyphenylacetaldehyde), and tyrosine hydroxylation products proximal to DA (DOPA and Cys-DOPA). Results: The PD and MSA groups did not differ in mean values of parent or cysteinyl catechols, and the data for the two groups were lumped. In the patients an index of vesicular storage of DA (the ratio of DA to the sum of its cytoplasmic metabolites) averaged 54% of control (p = 0.001), and an index of L-aromatic-amino-acid decarboxylase (LAAAD) activity (the ratio of DA and the sum of its cytoplasmic metabolites to the sum of DOPA + Cys-DOPA) averaged 21% of control (p < 0.0001). An index of innervation (the sum of DOPA + Cys-DOPA) averaged 63% of control (p = 0.01). Interpretation: Based on patterns of parent and cysteinyl catechols in putamen, PD and MSA involve decreased vesicular uptake and decreased LAAAD activity in the residual dopaminergic terminals. The combination seems to contribute importantly to dopamine depletion in these diseases. (C) 2016 Published by Elsevier Ltd. C1 [Goldstein, David S.; Sullivan, Patti; Holmes, Courtney; Kopin, Irwin J.] NINDS, Clin Neurocardiol Sect, CNP, DIR,NIH, Bethesda, MD 20892 USA. [Mash, Deborah C.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Sharabi, Yehonatan] Chaim Sheba Med Ctr, Tel Hashomer, Israel. [Sharabi, Yehonatan] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel. RP Goldstein, DS (reprint author), 9000 Rockville Pike,Bldg 10 Rm 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke [ZIA NS003033] FX The research reported here was supported by the intramural research program of the National Institute of Neurological Disorders and Stroke, project No. ZIA NS003033. NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD FEB PY 2017 VL 35 BP 88 EP 91 DI 10.1016/j.parkreldis.2016.12.011 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA EK6ZF UT WOS:000394074100014 PM 28034624 ER PT J AU Lipton, JM Alter, BP AF Lipton, Jeffrey M. Alter, Blanche P. TI Heritable cancer: Rounding up the not so usual suspects SO PEDIATRIC BLOOD & CANCER LA English DT Editorial Material ID FANCONI-ANEMIA C1 [Lipton, Jeffrey M.] Steven & Alexandra Cohen Childrens Med Ctr New Yo, Div Hematol Oncol & Stem Cell Transplantat, New Hyde Pk, NY 11040 USA. [Lipton, Jeffrey M.] Feinstein Inst Med Res, Manhasset, NY USA. [Lipton, Jeffrey M.] Hofstra Northwell Sch Med, Hempstead, NY USA. [Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. RP Lipton, JM (reprint author), Steven & Alexandra Cohen Childrens Med Ctr New Yo, Div Hematol Oncol & Stem Cell Transplantat, New Hyde Pk, NY 11040 USA. EM jlipton@northwell.edu NR 7 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2017 VL 64 IS 2 BP 219 EP 220 DI 10.1002/pbc.26190 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA EK4NM UT WOS:000393903800001 PM 27718323 ER PT J AU Charu, V Zeger, S Gog, J Bjornstad, ON Kissler, S Simonsen, L Grenfell, BT Viboud, C AF Charu, Vivek Zeger, Scott Gog, Julia Bjornstad, Ottar N. Kissler, Stephen Simonsen, Lone Grenfell, Bryan T. Viboud, Cecile TI Human mobility and the spatial transmission of influenza in the United States SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID INFECTIOUS-DISEASES; PANDEMIC INFLUENZA; GLOBAL CIRCULATION; PARTIAL-LIKELIHOOD; MOVEMENT NETWORK; SPREAD; DYNAMICS; VIRUS; EPIDEMIC; PATTERNS AB Seasonal influenza epidemics offer unique opportunities to study the invasion and re-invasion waves of a pathogen in a partially immune population. Detailed patterns of spread remain elusive, however, due to lack of granular disease data. Here we model high-volume city-level medical claims data and human mobility proxies to explore the drivers of influenza spread in the US during 2002-2010. Although the speed and pathways of spread varied across seasons, seven of eight epidemics likely originated in the Southern US. Each epidemic was associated with 1-5 early long-range transmission events, half of which sparked onward transmission. Gravity model estimates indicate a sharp decay in influenza transmission with the distance between infectious and susceptible cities, consistent with spread dominated by work commutes rather than air traffic. Two early-onset seasons associated with antigenic novelty had particularly localized modes of spread, suggesting that novel strains may spread in a more localized fashion than previously anticipated. C1 [Charu, Vivek; Gog, Julia; Bjornstad, Ottar N.; Simonsen, Lone; Grenfell, Bryan T.; Viboud, Cecile] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Charu, Vivek; Zeger, Scott] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Gog, Julia; Kissler, Stephen] Univ Cambridge, Dept Appl Math & Theoret Phys, Cambridge, England. [Bjornstad, Ottar N.] Penn State Univ, Dept Entomol, State Coll, PA USA. [Simonsen, Lone] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. RP Charu, V (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA.; Charu, V (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. EM vcharu@gmail.com FU Division of International Epidemiology and Population Studies; Fogarty International Center, US National Institutes of Health; Office of Pandemics and Emerging Threats at the United States Department of Health and Human Services; Research And Policy in Infectious Diseases Dynamics (RAPIDD) program; Department of Homeland Security; European Union; Gates doctoral fellowship FX We acknowledge financial support from the in-house research program of the Division of International Epidemiology and Population Studies, The Fogarty International Center, US National Institutes of Health, funded in part by the Office of Pandemics and Emerging Threats at the United States Department of Health and Human Services (CV, VC, LS, BTG). LS, JG, and BTG acknowledge support from the Research And Policy in Infectious Diseases Dynamics (RAPIDD) program led by the Fogarty International Center and funded by the Department of Homeland Security. LS acknowledges support from a European Union Horizon 2020 "Marie Curie" senior fellowship. SK acknowledges support from a Gates doctoral fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 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 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2017 VL 13 IS 2 AR e1005382 DI 10.1371/journal.pcbi.1005382 PG 23 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA EO0OW UT WOS:000396398700008 PM 28187123 ER PT J AU Little, MP Hendry, JH AF Little, Mark P. Hendry, Jolyon H. TI Mathematical models of tissue stem and transit target cell divisions and the risk of radiation- or smoking-associated cancer SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; INDUCED GENOMIC INSTABILITY; COLON-CANCER; IONIZING-RADIATION; COLORECTAL-CANCER; 2-MUTATION MODEL; CARCINOGENESIS; ORIGIN; TUMORS; DIFFERENTIATION AB There is compelling biological data to suggest that cancer arises from a series of mutations in single target cells, resulting in defects in cell renewal and differentiation processes which lead to malignancy. Because much mutagenic damage is expressed following cell division, more-rapidly renewing tissues could be at higher risk because of the larger number of cell replications. Cairns suggested that renewing tissues may reduce cancer risk by partitioning the dividing cell populations into lineages comprising infrequently-dividing long-lived stem cells and frequently-dividing short-lived daughter transit cells. We develop generalizations of three recent cancer-induction models that account for the joint maintenance and renewal of stem and transit cells, also competing processes of partially transformed cell proliferation and differentiation/apoptosis. We are particularly interested in using these models to separately assess the probabilities of mutation and development of cancer associated with "spontaneous" processes and with those linked to a specific environmental mutagen, specifically ionizing radiation or cigarette smoking. All three models demonstrate substantial variation in cancer risks, by at least 20 orders of magnitude, depending on the assumed number of critical mutations required for cancer, and the stem-cell and transition-cell mutation rates. However, in most cases the conditional probabilities of cancer being mutagen-induced range between 7-96%. The relative risks associated with mutagen exposure compared to background rates are also stable, ranging from 1.0-16.0. Very few cancers, generally <0.5%, arise from mutations occurring solely in stem cells rather than in a combination of stem and transit cells. However, for cancers with 2 or 3 critical mutations, a substantial proportion of cancers, in some cases 100%, have at least one mutation derived from a mutated stem cell. Little difference is made to relative risks if competing processes of proliferation and differentiation in the partially transformed stem and transit cell population are allowed for, nor is any difference made if one assumes that transit cells require an extra mutation to confer malignancy from the number required by stem cells. The probability of a cancer being mutagen-induced correlates across cancer sites with the estimated cumulative number of stem cell divisions in the associated tissue (p<0.05), although in some cases there is sensitivity of findings to removal of high-leverage outliers and in some cases only modest variation in probability, but these issues do not affect the validity of the findings. There are no significant correlations (p>0.3) between lifetime cancer-site specific radiation risk and the probability of that cancer being mutagen-induced. These results do not depend on the assumed critical number of mutations leading to cancer, or on the assumed mutagen-associated mutation rate, within the generally-accepted ranges tested. However, there are borderline significant negative correlations (p = 0.08) between the smoking-associated mortality rate difference (current vs former smokers) and the probability of cancer being mutagen-induced. This is only the case where values of the critical number of mutations leading to cancer, k, is 3 or 4 and not for smaller values (1 or 2), but does not strongly depend on the assumed mutagen-associated mutation rate. C1 [Little, Mark P.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20850 USA. [Hendry, Jolyon H.] Christie Hosp, Christie Med Phys & Engn, Wilmslow Rd, Manchester M20 4BX, Lancs, England. [Hendry, Jolyon H.] Univ Manchester, Wilmslow Rd, Manchester M20 4BX, Lancs, England. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20850 USA. EM mark.little@nih.gov FU National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2017 VL 13 IS 2 AR e1005391 DI 10.1371/journal.pcbi.1005391 PG 29 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA EO0OW UT WOS:000396398700016 PM 28196079 ER PT J AU Hall, MD Murray, CA Valdez, MJ Perantoni, AO AF Hall, Michael D. Murray, Caroline A. Valdez, Michael J. Perantoni, Alan O. TI Mesoderm-specific Stat3 deletion affects expression of Sox9 yielding Sox9-dependent phenotypes SO PLOS GENETICS LA English DT Article ID AUTOSOMAL SEX REVERSAL; LEUKEMIA INHIBITORY FACTOR; SRY-RELATED GENE; CAMPOMELIC DYSPLASIA; TARGETED DISRUPTION; BONE-FORMATION; TRANSLOCATION BREAKPOINTS; STAT3-DEFICIENT MICE; INTERLEUKIN-6 FAMILY; KIDNEY DEVELOPMENT AB To date, mutations within the coding region and translocations around the SOX9 gene both constitute the majority of genetic lesions underpinning human campomelic dysplasia (CD). While pathological coding-region mutations typically result in a non-functional SOX9 protein, little is known about what mechanism(s) controls normal SOX9 expression, and subsequently, which signaling pathways may be interrupted by alterations occurring around the SOX9 gene. Here, we report the identification of Stat3 as a key modulator of Sox9 expression in nascent cartilage and developing chondrocytes. Stat3 expression is predominant in tissues of mesodermal origin, and its conditional ablation using mesoderm-specific TCre, in vivo, causes dwarfism and skeletal defects characteristic of CD. Specifically, Stat3 loss results in the expansion of growth plate hypertrophic chondrocytes and deregulation of normal endochondral ossification in all bones examined. Conditional deletion of Stat3 with a Sox9Cre driver produces palate and tracheal irregularities similar to those described in Sox9(+/-) mice. Furthermore, mesodermal deletion of Stat3 causes global embryonic down regulation of Sox9 expression and function in vivo. Mechanistic experiments ex vivo suggest Stat3 can directly activate the expression of Sox9 by binding to its proximal promoter following activation. These findings illuminate a novel role for Stat3 in chondrocytes during skeletal development through modulation of a critical factor, Sox9. Importantly, they further provide the first evidence for the modulation of a gene product other than Sox9 itself which is capable of modeling pathological aspects of CD and underscore a potentially valuable therapeutic target for patients with the disorder. C1 [Hall, Michael D.; Murray, Caroline A.; Valdez, Michael J.; Perantoni, Alan O.] NCI, Canc & Dev Biol Lab, Frederick, MD 21701 USA. RP Perantoni, AO (reprint author), NCI, Canc & Dev Biol Lab, Frederick, MD 21701 USA. EM perantoa@mail.nih.gov FU National Cancer Institute, Center for Cancer Research [ZIA BC 005093] FX This work was supported by National Cancer Institute, Center for Cancer Research intramural funding under project #ZIA BC 005093. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2017 VL 13 IS 2 AR e1006610 DI 10.1371/journal.pgen.1006610 PG 30 WC Genetics & Heredity SC Genetics & Heredity GA EN0SG UT WOS:000395719300026 PM 28166224 ER PT J AU Bibby, K Fischer, RJ Casson, LW de Carvalho, NA Haas, CN Munster, VJ AF Bibby, Kyle Fischer, Robert J. Casson, Leonard W. de Carvalho, Nathalia Aquino Haas, Charles N. Munster, Vincent J. TI Disinfection of Ebola Virus in Sterilized Municipal Wastewater SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID HEMORRHAGIC-FEVER; TRANSMISSION; INACTIVATION; PERSISTENCE; STABILITY; FLUIDS; RISK AB Concerns have been raised regarding handling of Ebola virus contaminated wastewater, as well as the adequacy of proposed disinfection approaches. In the current study, we investigate the inactivation of Ebola virus in sterilized domestic wastewater utilizing sodium hypochlorite addition and pH adjustment. No viral inactivation was observed in the one-hour tests without sodium hypochlorite addition or pH adjustment. No virus was recovered after 20 seconds (i.e. 4.2 log(10) unit inactivation to detection limit) following the addition of 5 and 10 mg L-1 sodium hypochlorite, which resulted in immediate free chlorine residuals of 0.52 and 1.11 mg L-1, respectively. The addition of 1 mg L-1 sodium hypochlorite resulted in an immediate free chlorine residual of 0.16 mg L-1, which inactivated 3.5 log10 units of Ebola virus in 20 seconds. Further inactivation was not evident due to the rapid consumption of the chlorine residual. Elevating the pH to 11.2 was found to significantly increase viral decay over ambient conditions. These results indicate the high susceptibility of the enveloped Ebola virus to disinfection in the presence of free chlorine in municipal wastewater; however, we caution that extension to more complex matrices (e.g. bodily fluids) will require additional verification. C1 [Bibby, Kyle; Casson, Leonard W.; de Carvalho, Nathalia Aquino] Univ Pittsburgh, Dept Civil & Environm Engn, Pittsburgh, PA 15260 USA. [Bibby, Kyle] Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA. [Fischer, Robert J.; Munster, Vincent J.] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. [Haas, Charles N.] Drexel Univ, Dept Civil Architectural & Environm Engn, Philadelphia, PA 19104 USA. RP Bibby, K (reprint author), Univ Pittsburgh, Dept Civil & Environm Engn, Pittsburgh, PA 15260 USA.; Bibby, K (reprint author), Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA.; Munster, VJ (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. EM BibbyKJ@Pitt.edu; munstervj@niaid.nih.gov OI Bibby, Kyle/0000-0003-3142-6090 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Science Foundation [1508415, 1507285] FX This study was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health and National Science Foundation awards 1508415 (KB and LWC) and 1507285 (CNH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2017 VL 11 IS 2 AR e0005299 DI 10.1371/journal.pntd.0005299 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA EN1AD UT WOS:000395741700016 ER PT J AU Grillon, C Robinson, OJ O'Connell, K Davis, A Alvarez, G Pine, DS Ernst, M AF Grillon, C. Robinson, O. J. O'Connell, K. Davis, A. Alvarez, G. Pine, D. S. Ernst, M. TI Clinical anxiety promotes excessive response inhibition SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Anxiety; anxiety disorders; behavioral inhibition; go/nogo; threat of shock ID STOP-SIGNAL TASK; BEHAVIORAL-INHIBITION; SUSTAINED ATTENTION; EXECUTIVE-CONTROL; ANTISACCADE TASK; TRAIT ANXIETY; NEURAL BASIS; DISORDERS; MIND; PSYCHOPATHOLOGY AB Background. Laboratory tasks to delineate anxiety disorder features are used to refine classification and inform our understanding of etiological mechanisms. The present study examines laboratory measures of response inhibition, specifically the inhibition of a pre-potent motor response, in clinical anxiety. Data on associations between anxiety and response inhibition remain inconsistent, perhaps because of dissociable effects of clinical anxiety and experimentally manipulated state anxiety. Few studies directly assess the independent and interacting effects of these two anxiety types (state v. disorder) on response inhibition. The current study accomplished this goal, by manipulating state anxiety in healthy and clinically anxious individuals while they complete a response inhibition task. Method. The study employs the threat-of-shock paradigm, one of the best-established manipulations for robustly increasing state anxiety. Participants included 82 adults (41 healthy; 41 patients with an anxiety disorder). A go/nogo task with highly frequent go trials was administered during alternating periods of safety and shock threat. Signal detection theory was used to quantify response bias and signal-detection sensitivity. Results. There were independent effects of anxiety and clinical anxiety on response inhibition. In both groups, heightened anxiety facilitated response inhibition, leading to reduced nogo commission errors. Compared with the healthy group, clinical anxiety was associated with excessive response inhibition and increased go omission errors in both the safe and threat conditions. Conclusions. Response inhibition and its impact on go omission errors appear to be a promising behavioral marker of clinical anxiety. These results have implications for a dimensional view of clinical anxiety. C1 [Grillon, C.; O'Connell, K.; Davis, A.; Alvarez, G.; Ernst, M.] NIMH, Sect Neurobiol Fear & Anxiety, NIH, North Dr,Bldg 15K,Room 203,MSC 2670, Bethesda, MD 20892 USA. [Robinson, O. J.] UCL, Inst Cognit Neurosci, London, England. [Pine, D. S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. RP Grillon, C (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, NIH, North Dr,Bldg 15K,Room 203,MSC 2670, Bethesda, MD 20892 USA. EM Christian.grillon@nih.gov FU Intramural Research Program of the National Institute of Mental Health [ZIAMH002798, NCT00055224] FX This research was supported by the Intramural Research Program of the National Institute of Mental Health (ZIAMH002798) (protocol 03-M-0093; NCT00055224). NR 61 TC 1 Z9 1 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD FEB PY 2017 VL 47 IS 3 BP 484 EP 494 DI 10.1017/S0033291716002555 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA EN9EN UT WOS:000396303600009 PM 27776562 ER PT J AU Zimowski, M Moye, J Dugoni, B Viox, MH Cohen, H Winfrey, K AF Zimowski, Michele Moye, Jack Dugoni, Bernard Viox, Melissa Heim Cohen, Hildie Winfrey, Krishna TI Home-based anthropometric, blood pressure and pulse measurements in young children by trained data collectors in the National Children's Study SO PUBLIC HEALTH NUTRITION LA English DT Article DE Technical error of measurement; Anthropometry; Intra-rater reliability; Replicate measurements; National Children's Study ID PRESCHOOL-CHILDREN; RELIABILITY AB Objective: The current study assessed whether home-based data collection by trained data collectors can produce high-quality physical measurement data in young children. Design: The study assessed the quality of intra-examiner measurements of blood pressure, pulse rate and anthropometric dimensions using intra-examiner reliability and intra-examiner technical error of measurement (TEM). Setting: Non-clinical, primarily private homes of National Children's Study participants in twenty-two study locations across the USA. Subjects: Children in four age groups: 5-7 months (n 91), 11-16 months (n 393), 23-28 months (n 1410) and 35-40 months (n 800). Results: Absolute TEM ranged in value from 0.09 to 16.21, varying widely by age group and measure, as expected. Relative TEM spanned from 0.27 to 13.71 across age groups and physical measures. Reliabilities for anthropometric measurements by age group and measure ranged from 0.46 to >0.99 with most exceeding 0.90, suggesting that the large majority of anthropometric measures can be collected in a home-based setting on young children by trained data collectors. Reliabilities for blood pressure and pulse rate measurements by age group ranged from 0.21 to 0.74, implying these are less reliably measured with young children when taken in the data collection context described here. Conclusions: Reliability estimates >0.95 for weight, length, height, and thigh, waist and head circumference, and >0.90 for triceps and subscapular skinfolds, indicate that these measures can be collected in the field by trained data collectors without compromising data quality. These estimates can be used for interim evaluations of data collector training and measurement protocols. C1 [Zimowski, Michele; Dugoni, Bernard; Viox, Melissa Heim; Cohen, Hildie; Winfrey, Krishna] Univ Chicago, NORC, 55 East Monroe St, Chicago, IL 60603 USA. [Moye, Jack] NICHHD, Bethesda, MD 20892 USA. RP Viox, MH (reprint author), Univ Chicago, NORC, 55 East Monroe St, Chicago, IL 60603 USA. EM HeimViox-Melissa@norc.org FU NICHD, Office of the Director of the National Institutes of Health (through NICHD) [HHSN275201000015C] FX Financial support: This analysis was conducted as part of the National Children's Study, supported by the NICHD, and funded, through its appropriation, by the Office of the Director of the National Institutes of Health (through NICHD contract number HHSN275201000015C). The funder was involved in design and writing of this article. NR 21 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 EI 1475-2727 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD FEB PY 2017 VL 20 IS 2 BP 200 EP 209 DI 10.1017/S1368980016002378 PG 10 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA EK4HB UT WOS:000393886600002 PM 27629790 ER PT J AU Moinpour, CM Donaldson, GW Davis, KM Potosky, AL Jensen, RE Gralow, JR Back, AL Hwang, JJ Yoon, J Bernard, DL Loeffler, DR Rothrock, NE Hays, RD Reeve, BB Smith, AW Hahn, EA Cella, D AF Moinpour, Carol M. Donaldson, Gary W. Davis, Kimberly M. Potosky, Arnold L. Jensen, Roxanne E. Gralow, Julie R. Back, Anthony L. Hwang, Jimmy J. Yoon, Jihye Bernard, Debra L. Loeffler, Deena R. Rothrock, Nan E. Hays, Ron D. Reeve, Bryce B. Smith, Ashley Wilder Hahn, Elizabeth A. Cella, David TI The challenge of measuring intra-individual change in fatigue during cancer treatment SO QUALITY OF LIFE RESEARCH LA English DT Article DE Measured change; Intra-individual change; Fatigue; Patient-reported outcomes; Cancer ID PATIENT-REPORTED OUTCOMES; QUALITY-OF-LIFE; INFORMATION-SYSTEM PROMIS; MINIMALLY IMPORTANT DIFFERENCES; CLINICAL-PRACTICE; FUNCTIONAL ASSESSMENT; ADAPTIVE TESTS; HEALTH-STATUS; ITEM BANKS; SURVIVORS AB To evaluate how well three different patient-reported outcomes (PROs) measure individual change. Two hundred and fourteen patients (from two sites) initiating first or new chemotherapy for any stage of breast or gastrointestinal cancer participated. The 13-item FACIT Fatigue scale, a 7-item PROMISA (R) Fatigue Short Form (PROMIS 7a), and the PROMISA (R) Fatigue computer adaptive test (CAT) were administered monthly online for 6 months. Reliability of measured change was defined, under a population mixed effects model, as the ratio of estimated systematic variance in rate of change to the estimated total variance of measured individual differences in rate of change. Precision of individual measured change, the standard error of measurement of change, was given by the square root of the rate-of-change sampling variance. Linear and quadratic models were examined up to 3 and up to 6 months. A linear model for measured change showed the following by 6 and 3 months, respectively: PROMIS CAT (0.363 and 0.342); PROMIS SF (0.408 and 0.533); FACIT (0.459 and 0.473). Quadratic models offered no noteworthy improvement over linear models. Both reliability and precision results demonstrate the need to improve the measurement of intra-individual change. These results illustrate the challenge of reliably measuring individual change in fatigue with a level of confidence required for intervention. Optimizing clinically useful measurement of intra-individual differences over time continues to pose a challenge for PROs. C1 [Moinpour, Carol M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Donaldson, Gary W.] Univ Utah, Dept Anesthesiol, Pain Res Ctr, Salt Lake City, UT USA. [Davis, Kimberly M.; Potosky, Arnold L.; Jensen, Roxanne E.] Georgetown Univ, Med Ctr, Hlth Serv Res, Washington, DC 20007 USA. [Davis, Kimberly M.; Potosky, Arnold L.; Jensen, Roxanne E.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Gralow, Julie R.; Back, Anthony L.; Bernard, Debra L.] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, 1124 Columbia St, Seattle, WA 98104 USA. [Hwang, Jimmy J.] Carolinas HealthCare Syst, Levine Canc Inst, Hematol Oncol, Charlotte, NC USA. [Yoon, Jihye] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Loeffler, Deena R.] Cyst Fibrosis Fdn, Bethesda, MD USA. [Hays, Ron D.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Hays, Ron D.] Univ Calif Los Angeles, Dept Hlth Serv Res, Los Angeles, CA USA. [Reeve, Bryce B.] Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, Chapel Hill, NC USA. [Smith, Ashley Wilder] NCI, Outcomes Res Branch, Bethesda, MD 20892 USA. [Rothrock, Nan E.; Hahn, Elizabeth A.; Cella, David] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Rothrock, Nan E.; Hahn, Elizabeth A.; Cella, David] Northwestern Univ, Feinberg Sch Med, Ctr Patient Ctr Outcomes, Chicago, IL 60611 USA. RP Moinpour, CM (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM cmoinpou@fredhutch.org FU National Institutes of Health (Georgetown University) [U01AR057971] FX This work was supported by National Institutes of Health (Georgetown University, PIs: Arnold L. Potosky, PhD and Carol M. Moinpour, PhD (Fred Hutchinson Cancer Research Center, Seattle), U01AR057971. NR 47 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD FEB PY 2017 VL 26 IS 2 BP 259 EP 271 DI 10.1007/s11136-016-1372-9 PG 13 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EK8AF UT WOS:000394145600002 PM 27469506 ER PT J AU Hays, RD Chawla, N Kent, EE Arora, NK AF Hays, Ron D. Chawla, Neetu Kent, Erin E. Arora, Neeraj K. TI Measurement equivalence of the Consumer Assessment of Healthcare Providers and Systems (CAHPS((R))) Medicare survey items between Whites and Asians SO QUALITY OF LIFE RESEARCH LA English DT Article DE Patient evaluations of health care; Measurement equivalence; CAHPS; Asians ID MANAGED CARE; RATINGS; LANGUAGE; SATISFACTION; EXPERIENCES; DISPARITIES; HISPANICS; ENROLLEES; AMERICANS; QUALITY AB Asians report worse experiences with care than Whites. This could be due to true differences in care received, expectations about care, or survey response styles. We examined responses to the Consumer Assessment of Healthcare Providers and Systems (CAHPS(A (R))) Medicare survey items by Whites and Asians, controlling for underlying level on the CAHPS constructs. We conducted multiple group analyses to evaluate measurement equivalence of CAHPS Medicare survey data between White and Asian Medicare beneficiaries for CAHPS reporting composites (communication with personal doctor, access to care, plan customer service) and global ratings of care using pooled data from 2007 to 2011. Responses were obtained from 1,326,410 non-Hispanic Whites and 40,672 non-Hispanic Asians (hereafter referred to as Whites and Asians). The median age for Whites was 70, with 24 % 80 or older, and 70 for Asians, with 23 % 80 or older. Fifty-eight percent of Whites and 56 % of Asians were female. A model without group-specific estimates fit the data as well as a model that included 12 group-specific estimates (7 factor loadings, 3 measured variable errors, and 2 item intercepts): Comparative Fit Index = 0.947 and 0.948; root-mean-square error of approximation = 0.052 and 0.052, respectively). Differences in latent CAHPS score means between Whites and Hispanics estimated from the two models were similar, differing by 0.053 SD or less. This study provides support for measurement equivalence of the CAHPS Medicare survey composites (communication, access, customer service) and global ratings between White and Asian respondents, supporting comparisons of care experiences between the two groups. C1 [Hays, Ron D.] Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Ctr Maximizing Outcomes & Res Effectiveness C MOR, 911 Broxton Ave, Los Angeles, CA 90024 USA. [Chawla, Neetu] Kaiser Permanente, Div Res, Oakland, CA USA. [Kent, Erin E.] NCI, Rockville, MD USA. [Arora, Neeraj K.] Patient Ctr Outcomes Res Inst, Washington, DC USA. RP Hays, RD (reprint author), Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Ctr Maximizing Outcomes & Res Effectiveness C MOR, 911 Broxton Ave, Los Angeles, CA 90024 USA. EM drhays@g.ucla.edu FU National Cancer Institute [HHSN261201000166U]; NIA [P30-AG021684]; NIMHD [P20-MD000182] FX The authors would like to thank Karen L. Spritzer for her input, and we acknowledge use of data from the SEER-CAHPS data linkage resource, funded by a National Cancer Institute contract (HHSN261201000166U). Dr. Hays was supported by grants from the NIA (P30-AG021684) and the NIMHD (P20-MD000182). The opinions expressed in the manuscript are those of the authors and do not necessarily reflect the study sponsors or their institutional affiliations. NR 29 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD FEB PY 2017 VL 26 IS 2 BP 311 EP 318 DI 10.1007/s11136-016-1383-6 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EK8AF UT WOS:000394145600007 PM 27495274 ER PT J AU Vahidnia, F Stramer, SL Kessler, D Shaz, B Leparc, G Krysztof, DE Glynn, SA Custer, B AF Vahidnia, Farnaz Stramer, Susan L. Kessler, Debra Shaz, Beth Leparc, German Krysztof, David E. Glynn, Simone A. Custer, Brian TI Recent viral infection in US blood donors and health-related quality of life (HRQOL) SO QUALITY OF LIFE RESEARCH LA English DT Article DE Health-related quality of life; EQ-5D; Acute viral hepatitis; HIV infection; HTLV infection; Blood donors ID HEPATITIS-C VIRUS; IMPACT; HIV; EUROQOL; EQ-5D; INDIVIDUALS; DIAGNOSIS; SYMPTOMS; STATE AB Blood donors are considered to be one of the healthiest populations, but relatively little is known about their perceived quality of life. The objective was to examine HRQOL in donors infected with HIV, HBV, HCV or HTLV and a comparison group. Donors with confirmed viral infection (cases) and donors who tested false-positive (controls) participated in a multicenter study of US blood donors (2010-2013), funded by the National Heart, Lung and Blood Institute (NHLBI). HRQOL was measured by the EuroQol Five Dimension (EQ-5D) instrument and EQ-5D visual analogue scale (VAS). The lower 25th aEuro degrees of EQ-5D index or VAS score of controls was defined as a "lower HRQOL." A total of 1574 controls completed the HRQOL assessment with a mean EQ-5D index of 0.94 (SD = 0.10) and EQ-VAS of 87.6 (SD = 10.6). Mean EQ-5D index for 192 HIV-, 315 HCV- and 195 HTLV-positive donors were significantly lower than the controls (0.86, 0.83 and 0.87; SD = 0.18, 0.20 and 0.16, respectively, p < 0.001). HBV-positive donors (n = 290) had a similar mean EQ-5D index (0.93, SD = 0.14, p = 0.05) to controls. Anxiety/depression was reported by 34 % of cases, compared with 13 % of controls. In multivariable modeling, the odds of lower HRQOL in HIV, HBV, HCV and HTLV cases were 2.1, 1.6, 2.6 and 2.3 times that of controls, respectively (p < 0.05). HRQOL reported by blood donors with recent viral infections was relatively high but lower than controls. On average, HRQOL among HCV-positive donors was the lowest and HBV-positive donors reported scores similar to donors without infection. C1 [Vahidnia, Farnaz; Custer, Brian] Blood Syst Res Inst, 270 Masonic Ave, San Francisco, CA 94118 USA. [Stramer, Susan L.; Krysztof, David E.] Amer Red Cross, Gaithersburg, MD USA. [Kessler, Debra; Shaz, Beth] New York Blood Ctr, New York, NY 10021 USA. [Leparc, German] OneBlood, Tampa, FL USA. [Glynn, Simone A.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Custer, Brian] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Vahidnia, F (reprint author), Blood Syst Res Inst, 270 Masonic Ave, San Francisco, CA 94118 USA. EM Fvahidnia@bloodsystems.org FU Retrovirus Epidemiology Donor Study-II (REDS-II) by National Heart, Lung and Blood Institute, National Institutes of Health [HHSN26820041717] FX This study was funded by research contract HHSN26820041717 from the Retrovirus Epidemiology Donor Study-II (REDS-II) sponsored by the National Heart, Lung and Blood Institute, National Institutes of Health. NR 41 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD FEB PY 2017 VL 26 IS 2 BP 349 EP 357 DI 10.1007/s11136-016-1392-5 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EK8AF UT WOS:000394145600011 PM 27534773 ER PT J AU Vodovotz, Y Xia, A Read, EL Bassaganya-Riera, J Hafler, DA Sontag, E Wang, J Tsang, JS Day, JD Kleinstein, SH Butte, AJ Altman, MC Hammond, R Sealfon, SC AF Vodovotz, Yoram Xia, Ashley Read, Elizabeth L. Bassaganya-Riera, Josep Hafler, David A. Sontag, Eduardo Wang, Jin Tsang, John S. Day, Judy D. Kleinstein, Steven H. Butte, Atul J. Altman, Matthew C. Hammond, Ross Sealfon, Stuart C. TI Solving Immunology? SO TRENDS IN IMMUNOLOGY LA English DT Review ID MYCOBACTERIUM-TUBERCULOSIS INFECTION; AGENT-BASED MODEL; AFFINITY MATURATION; CLINICAL-TRIALS; IMMUNE-SYSTEM; GERMINAL CENTER; RAS ACTIVATION; T-CELLS; B-CELLS; EXPRESSION AB Emergent responses of the immune system result from the integration of molecular and cellular networks over time and across multiple organs. High content and high-throughput analysis technologies, concomitantly with data driven and mechanistic modeling, hold promise for the systematic interrogation of these complex pathways. However, connecting genetic variation and molecular mechanisms to individual phenotypes and health outcomes has proven elusive. Gaps remain in data, and disagreements persist about the value of mechanistic modeling for immunology. Here, we present the perspectives that emerged from the National Institute of Allergy and Infectious Disease (NIAID) workshop 'Complex Systems Science, Modeling and Immunity' and subsequent discussions regarding the potential synergy of high-throughput data acquisition, data-driven modeling, and mechanistic modeling to define new mechanisms of immunological disease and to accelerate the translation of these insights into therapies. C1 [Vodovotz, Yoram] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Vodovotz, Yoram] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA. [Vodovotz, Yoram] Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA USA. [Vodovotz, Yoram] Univ Pittsburgh, Dept Clin & Translat Sci, Pittsburgh, PA USA. [Vodovotz, Yoram] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA USA. [Vodovotz, Yoram] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA USA. [Xia, Ashley] NIAID, Div Allergy Immunol & Transplantat, NIH, 5601 Fishers Lane,Room 7A78,MSC 9828, Rockville, MD 20852 USA. [Read, Elizabeth L.] Univ Calif Irvine, Dept Mol Biol & Biochem, Dept Chem Engn & Mat Sci, Irvine, CA 92697 USA. [Bassaganya-Riera, Josep] Virginia Tech, Biocomplex Inst, 1015 Life Sci Circle, Blacksburg, VA 24060 USA. [Hafler, David A.] Yale Sch Med, Dept Neurol, New Haven, CT 06520 USA. [Hafler, David A.] Yale Sch Med, Dept Immunobiol, New Haven, CT 06520 USA. [Sontag, Eduardo] Rutgers State Univ, Inst Quantitat Biol, Dept Math, New Brunswick, NJ 08903 USA. [Sontag, Eduardo] Rutgers State Univ, Canc Inst NJ, New Brunswick, NJ 08903 USA. [Wang, Jin] Chinese Acad Sci, State Key Lab Electroanalyt Chem, Changchun Inst Appl Chem, Changchun 130022, Peoples R China. [Wang, Jin] SUNY Stony Brook, Dept Chem & Phys, Stony Brook, NY 11794 USA. [Tsang, John S.] NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, NIH,Ctr Human Immunol, Bethesda, MD 20892 USA. [Day, Judy D.] Univ Tennessee, Dept Math, Natl Inst Math & Biol Synth, Knoxville, TN 37996 USA. [Day, Judy D.] Univ Tennessee, Dept Elect Engn & Comp Sci, Natl Inst Math & Biol Synth, Knoxville, TN 37996 USA. [Kleinstein, Steven H.] Yale Sch Med, Dept Pathol, New Haven, CT 06511 USA. [Kleinstein, Steven H.] Yale Sch Med, Dept Immunobiol, New Haven, CT 06511 USA. [Kleinstein, Steven H.] Yale Univ, Interdept Pgram Computat Biol & Bioinformat, New Haven, CT 06511 USA. [Butte, Atul J.] Univ Calif San Francisco, Inst Computat Hlth Sci, Mission Hall 550 16th St,4th Floor,Box 0110, San Francisco, CA 94158 USA. [Altman, Matthew C.] Univ Washington, Dept Allergy & Infect Dis, Seattle, WA 98109 USA. [Hammond, Ross] Brookings Inst, Econ Studies Program, Ctr Social Dynam & Policy, Washington, DC 20036 USA. [Sealfon, Stuart C.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, Ctr Adv Res Diagnost Assays, Inst Immunol, New York, NY 10029 USA. [Sealfon, Stuart C.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Sealfon, Stuart C.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Sealfon, Stuart C.] Icahn Sch Med Mt Sinai, Dept Pharmacol, New York, NY 10029 USA. [Sealfon, Stuart C.] Icahn Sch Med Mt Sinai, Dept Syst Therapeut, New York, NY 10029 USA. [Xia, Ashley] NIDDK, Mol Transducers Phys Act MoTrPAC, Div Diabet Endocrinol & Metab Dis DEM, NIH, 6707 Democracy Blvd,RM 6074, Bethesda, MD 20817 USA. RP Sealfon, SC (reprint author), Icahn Sch Med Mt Sinai, Friedman Brain Inst, Ctr Adv Res Diagnost Assays, Inst Immunol, New York, NY 10029 USA.; Sealfon, SC (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA.; Sealfon, SC (reprint author), Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA.; Sealfon, SC (reprint author), Icahn Sch Med Mt Sinai, Dept Pharmacol, New York, NY 10029 USA.; Sealfon, SC (reprint author), Icahn Sch Med Mt Sinai, Dept Syst Therapeut, New York, NY 10029 USA. EM stuart.sealfon@mssm.edu FU NIAID FX We gratefully acknowledge the NIAID for sponsoring this workshop and the efforts of the organizing committee, including: Timothy Gondre-Lewis, Katarzyna Bourcier, Joseph Breen, Wendy Davidson, Alison Augustine-Deckhut, Mark Robien, and Charles Hackett, as well as Isaac Rodriguez-Chavez from NIDCR for his valuable suggestions during the meeting. We thank the many attendees and participants in the workshop for their input and Jill Gregory for creating the illustration. We also thank Waj Mehal, Raquel Hontecillas, Vida Abedi, and Christophe Benoist for critical comments and/or textual suggestions. We apologize for the absence of the discussion of many approaches and of many important references due to space and citation constraints. NR 80 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 38 IS 2 BP 116 EP 127 DI 10.1016/j.it.2016.11.006 PG 12 WC Immunology SC Immunology GA EK8TH UT WOS:000394197000005 PM 27986392 ER PT J AU Eldridge, MAG Richmond, BJ AF Eldridge, Mark A. G. Richmond, Barry J. TI Resisting the Urge to Act: DREADDs Modifying Habits SO TRENDS IN NEUROSCIENCES LA English DT Editorial Material AB Recently, Meyer and Bucci used chemogenetic technology - artificial excitatory and inhibitory receptors - to modulate neuronal activity in two connected brain regions in opposite directions simultaneously. This innovative manipulation revealed that the two regions studied, orbitofrontal cortex and nucleus accumbens, are not sequentially dependent during contextual decision-making. C1 [Eldridge, Mark A. G.; Richmond, Barry J.] NIMH, Sect Neural Coding & Computat, Neuropsychol Lab, NIH,DHHS, Bldg 49,Rm 1B80, Bethesda, MD 20892 USA. RP Eldridge, MAG; Richmond, BJ (reprint author), NIMH, Sect Neural Coding & Computat, Neuropsychol Lab, NIH,DHHS, Bldg 49,Rm 1B80, Bethesda, MD 20892 USA. EM Mark.Eldridge@nih.gov; Barry.Richmond@nih.gov FU Intramural Research Program of NIMH FX MAGE and BJR are supported by the Intramural Research Program of NIMH. The material reflects the views of the authors and does not represent views of the US Government. NR 11 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD FEB PY 2017 VL 40 IS 2 BP 61 EP 62 DI 10.1016/j.tins.2016.12.002 PG 2 WC Neurosciences SC Neurosciences & Neurology GA EK6XE UT WOS:000394068600001 PM 28104285 ER PT J AU Calkins, ME Moore, TM Satterthwaite, TD Wolf, DH Turetsky, BI Roalf, DR Merikangas, KR Ruparel, K Kohler, CG Gur, RC Gur, RE AF Calkins, Monica E. Moore, Tyler M. Satterthwaite, Theodore D. Wolf, Daniel H. Turetsky, Bruce I. Roalf, David R. Merikangas, Kathleen R. Ruparel, Kosha Kohler, Christian G. Gur, Ruben C. Gur, Raquel E. TI Persistence of psychosis spectrum symptoms in the Philadelphia Neurodevelopmental Cohort: a prospective two-year follow-up SO WORLD PSYCHIATRY LA English DT Article DE Psychosis spectrum symptoms; psychotic-like experiences; schizotypy; persistence; youth; follow-up; predictors ID LONGITUDINAL GENERAL-POPULATION; CLINICAL HIGH-RISK; MENTAL-DISORDERS; COMMUNITY SAMPLE; EXPERIENCES; SCHIZOPHRENIA; YOUTH; METAANALYSIS; CONTINUUM; ADOLESCENCE AB Prospective evaluation of youths with early psychotic-like experiences can enrich our knowledge of clinical, biobehavioral and environmental risk and protective factors associated with the development of psychotic disorders. We aimed to investigate the predictors of persistence or worsening of psychosis spectrum features among US youth through the first large systematic study to evaluate subclinical symptoms in the community. Based on Time 1 screen of 9,498 youth (age 8-21) from the Philadelphia Neurodevelopmental Cohort, a subsample of participants was enrolled based on the presence (N=249) or absence (N=254) of baseline psychosis spectrum symptoms, prior participation in neuroimaging, and current neuroimaging eligibility. They were invited to participate in a Time 2 assessment two years on average following Time 1. Participants were administered the Structured Interview for Prodromal Syndromes, conducted blind to initial screen status, along with the Schizotypal Personality Questionnaire and other clinical measures, computerized neurocognitive testing, and neuroimaging. Clinical and demographic predictors of symptom persistence were examined using logistic regression. At Time 2, psychosis spectrum features persisted or worsened in 51.4% of youths. Symptom persistence was predicted by higher severity of subclinical psychosis, lower global functioning, and prior psychiatric medication at baseline. Youths classified as having psychosis spectrum symptoms at baseline but not at follow-up nonetheless exhibited comparatively higher symptom levels and lower functioning at both baseline and follow-up than typically developing youths. In addition, psychosis spectrum features emerged in a small number of young people who previously had not reported significant symptoms but who had exhibited early clinical warning signs. Together, our findings indicate that varying courses of psychosis spectrum symptoms are evident early in US youth, supporting the importance of investigating psychosis risk as a dynamic developmental process. Neurocognition, brain structure and function, and genomics may be integrated with clinical data to provide early indices of symptom persistence and worsening in youths at risk for psychosis. C1 [Calkins, Monica E.; Moore, Tyler M.; Satterthwaite, Theodore D.; Wolf, Daniel H.; Turetsky, Bruce I.; Roalf, David R.; Ruparel, Kosha; Kohler, Christian G.; Gur, Ruben C.; Gur, Raquel E.] Univ Penn, Dept Psychiat, Neuropsychiat Sect, Perelman Sch Med, Philadelphia, PA 19104 USA. [Merikangas, Kathleen R.] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Calkins, ME (reprint author), Univ Penn, Dept Psychiat, Neuropsychiat Sect, Perelman Sch Med, Philadelphia, PA 19104 USA. FU National Institute of Mental Health [MH089983, MH089924, K08MH079364, R01MH101111]; Dowshen Program for Neuroscience FX The authors thank the participants in this study, and all the members of the recruitment, assessment and data teams whose efforts made this work possible. This study was supported by the National Institute of Mental Health (grants nos. MH089983 and MH089924, K08MH079364, R01MH101111) and the Dowshen Program for Neuroscience. NR 67 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1723-8617 EI 2051-5545 J9 WORLD PSYCHIATRY JI World Psychiatry PD FEB PY 2017 VL 16 IS 1 BP 62 EP 76 DI 10.1002/wps.20386 PG 15 WC Psychiatry SC Psychiatry GA EK3XZ UT WOS:000393863000018 PM 28127907 ER PT J AU Leibenluft, E AF Leibenluft, Ellen TI Irritability in children: what we know and what we need to learn SO WORLD PSYCHIATRY LA English DT Editorial Material ID DISRUPTIVE MOOD DYSREGULATION; DISORDERS; BIAS C1 [Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Leibenluft, E (reprint author), NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, Intramural Res Program, Bethesda, MD 20892 USA. FU Intramural Research Program of the NIMH [ZIA MH002786, ZIA MH002778] FX The author acknowledges support from the Intramural Research Program of the NIMH (grants nos. ZIA MH002786 and ZIA MH002778), and is grateful to D. Pine and M. Brotman for helpful comments. NR 11 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1723-8617 EI 2051-5545 J9 WORLD PSYCHIATRY JI World Psychiatry PD FEB PY 2017 VL 16 IS 1 BP 100 EP 101 DI 10.1002/wps.20397 PG 2 WC Psychiatry SC Psychiatry GA EK3XZ UT WOS:000393863000021 PM 28127909 ER PT J AU Locke, SJ Deziel, NC Koh, DH Graubard, BI Purdue, MP Friesen, MC AF Locke, Sarah J. Deziel, Nicole C. Koh, Dong-Hee Graubard, Barry I. Purdue, Mark P. Friesen, Melissa C. TI Evaluating predictors of lead exposure for activities disturbing materials painted with or containing lead using historic published data from US workplaces SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE lead; occupational exposure; exposure determinants; meta-regression; population-based studies ID CRYSTALLINE SILICA EXPOSURE; OCCUPATIONAL-EXPOSURE; CONSTRUCTION-INDUSTRY; METALWORKING FLUIDS; BLADDER-CANCER; QUANTITATIVE EXPOSURE; TRENDS; DETERMINANTS; BENZENE; HEALTH AB ObjectivesWe evaluated predictors of differences in published occupational lead concentrations for activities disturbing material painted with or containing lead in U.S. workplaces to aid historical exposure reconstruction. MethodsFor the aforementioned tasks, 221 air and 113 blood lead summary results (1960-2010) were extracted from a previously developed database. Differences in the natural log-transformed geometric mean (GM) for year, industry, job, and other ancillary variables were evaluated in meta-regression models that weighted each summary result by its inverse variance and sample size. ResultsAir and blood lead GMs declined 5%/year and 6%/year, respectively, in most industries. Exposure contrast in the GMs across the nine jobs and five industries was higher based on air versus blood concentrations. For welding activities, blood lead GMs were 1.7 times higher in worst-case versus non-worst case scenarios. ConclusionsJob, industry, and time-specific exposure differences were identified; other determinants were too sparse or collinear to characterize. Am. J. Ind. Med. 60:189-197, 2017. (c) 2017 Wiley Periodicals, Inc. C1 [Locke, Sarah J.; Purdue, Mark P.; Friesen, Melissa C.] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. [Deziel, Nicole C.] Yale Univ, Yale Sch Publ Hlth, New Haven, CT USA. [Koh, Dong-Hee] Catholic Kwandong Univ, Int St Marys Hosp, Dept Occupat & Environm Med, Incheon, South Korea. [Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. RP Locke, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH, 9609 Med Ctr Dr,Rm 6E608, Rockville, MD 20850 USA. EM lockesj@mail.nih.gov RI Friesen, Melissa/A-5362-2009 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health [Z01 CP10122-19] FX This study was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (Z01 CP10122-19). NR 33 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 EI 1097-0274 J9 AM J IND MED JI Am. J. Ind. Med. PD FEB PY 2017 VL 60 IS 2 BP 189 EP 197 DI 10.1002/ajim.22679 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EK3ZL UT WOS:000393866800005 PM 28079279 ER PT J AU Denson, LA McDonald, SA Das, A Schendel, DE Skogstrand, K Hougaard, DM Shankaran, S Higgins, RD Carlo, WA Ehrenkranz, RA AF Denson, Lee A. McDonald, Scott A. Das, Abhik Schendel, Diana E. Skogstrand, Kristin Hougaard, David M. Shankaran, Seetha Higgins, Rosemary D. Carlo, Waldemar A. Ehrenkranz, Richard A. CA Cytokines Study Subcomm NICHD Neon TI Early Elevation in Interleukin-6 is Associated with Reduced Growth in Extremely Low Birth Weight Infants SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE cytokines; growth retardation; growth velocity; preterm infant; sepsis ID PRETERM INFANTS; BINDING-PROTEINS; CROHNS-DISEASE; IGF-I; PREMATURE-INFANTS; CRITICALLY-ILL; CHILDREN; INFLAMMATION; INFECTION; POLYMORPHISM AB Objective To determine whether reduced growth velocity (GV) in extremely low birth weight infants is preceded by elevated inflammatory cytokines. Study Design GV was determined at 36 weeks' postrnenstrual age (PMA) in 768 infants 401 to 1,000 g birth weight (BW). Association between blood cytokines measured through day of life 21 and GV was explored using linear regression models that adjusted for late-onset sepsis (LOS), BW, small for gestational age (SGA), gender, race, energy intake, and center. Results Serum interleukin-6 (IL-6) was increased at days 14 and 21 in LOS infants. LOS was associated with reduced energy intake and GV for weight (weight-GV) at 36 weeks' PMA. Linear regression analysis controlling for LOS and energy intake showed significant relationships between increased IL-6 at days 14 and 21 with reduced weight-GV at 36 weeks' PMA (p < 0.0001). The relationship between day 21 IL-6 and weight-GV was not associated with LOS (p = 0.12) when controlling for BW and energy intake. Both BW (p = 0.02) and energy intake (p = 0.003) influenced the relationship between day 14 IL-6 and weight-GV. Conclusion IL-6 elevation during the first month of life is associated with lower weight-GV at 36 weeks' PMA and may have a direct effect upon energy balance and postnatal growth. C1 [Denson, Lee A.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA. [Denson, Lee A.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [McDonald, Scott A.; Das, Abhik] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Schendel, Diana E.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. [Skogstrand, Kristin; Hougaard, David M.] Statens Serum Inst, Sect Neonatal Screening & Hormones, Dept Clin Biochem & Immunol, Copenhagen, Denmark. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Neonatal Perinatal Med, Detroit, MI USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Div Neonatol, Birmingham, AL USA. [Ehrenkranz, Richard A.] Yale New Haven Childrens Hosp, Dept Pediat, Div Perinatal Med, New Haven, CT USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, New Haven, CT USA. RP Denson, LA (reprint author), MLC 2010,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM lee.denson@cchmc.org FU United States Public Health Service; Human Development (NICHD) Neonatal Research Network; NIH [R01 DK058259]; National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Centers for Disease Control and Prevention FX The study was supported by United States Public Health Service grants to the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network and NIH grant R01 DK058259 to Dr. Denson.; The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Centers for Disease Control and Prevention provided grant support for recruitment for 1999-2001 and data analysis for the Neonatal Research Network's Cytokines Study. In addition, Dr. Denson received support from National Institutes of Health through grant R01 DK058259. The funding agencies provided overall oversight for study conduct, but all data analyses and interpretation were independent of the funding agencies. We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. NR 28 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2017 VL 34 IS 3 BP 240 EP 247 DI 10.1055/s-0036-1585419 PG 8 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA EK1YP UT WOS:000393724000006 PM 27455401 ER PT J AU Violi, F Carnevale, R Loffredo, L Pignatelli, P Gallin, JI AF Violi, Francesco Carnevale, Roberto Loffredo, Lorenzo Pignatelli, Pasquale Gallin, John I. TI NADPH Oxidase-2 and Atherothrombosis Insight From Chronic Granulomatous Disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Review DE atherosclerosis; eicosanoids; foam cells; monocytes; oxidative stress ID CORONARY-ARTERY-DISEASE; OXIDATIVE STRESS; SUPEROXIDE-PRODUCTION; PLATELET ACTIVATION; CARDIOVASCULAR-DISEASE; VASCULAR SUPEROXIDE; C242T POLYMORPHISM; ENDOTHELIAL-CELLS; HYDROGEN-PEROXIDE; APOE(-/-) MICE AB The phagocytic cell enzyme NADPH oxidase-2 (Nox2) is critical for killing micro-organisms via production of reactive oxygen species and thus is a key element of the innate immune system. Nox2 is also detectable in endothelial cells and platelets where it has vasoconstrictive and aggregating properties, respectively. Patients with X-linked chronic granulomatous disease with hereditary Nox2 deficiency not only have impaired bacterial killing but, in association with loss of Nox2 function, also have enhanced carotid artery dilation, impaired platelet-related thrombosis, and reduced carotid atherosclerotic burden. Experimental studies corroborated these reports in chronic granulomatous disease by demonstrating (1) Nox2 is upregulated in atherosclerotic plaque, and this upregulation significantly correlates with oxidative stress and (2) pharmacological inhibition of Nox2 is associated with a delayed atherosclerotic progression in animal models. Furthermore, the role of Nox2 in platelet-associated thrombosis was substantiated by experiments showing impaired platelet activation in animals treated with a Nox2 inhibitor or impaired platelet aggregation along with reduced platelet-related thrombosis in the mouse knockout model of Nox2. Interestingly, in chronic granulomatous disease patients and in the mouse knockout model of Nox2, no defects of primary hemostasis were detected. This review analyses experimental and clinical data suggesting Nox2 is a potential target for counteracting the atherothrombotic process. C1 [Violi, Francesco; Loffredo, Lorenzo; Pignatelli, Pasquale] Sapienza Univ, Policlin Umberto 1, Div Clin Med 1, Rome, Italy. [Carnevale, Roberto] Sapienza Univ Rome, Dept Med Surg Sci & Biotechnol, Latina, Italy. [Gallin, John I.] NIAID, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Violi, F (reprint author), Dept Internal Med & Med Specialties, Viale Policlin 155, I-00161 Rome, Italy. EM francesco.violi@uniroma1.it NR 55 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD FEB PY 2017 VL 37 IS 2 BP 218 EP 225 DI 10.1161/ATVBAHA.116.308351 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EJ9ZI UT WOS:000393585700009 PM 27932349 ER PT J AU Zhu, QM Ko, KA Ture, S Mastrangelo, MA Chen, MH Johnson, AD O'Donnell, CJ Morrell, CN Miano, JM Lowenstein, CJ AF Zhu, Qiuyu Martin Ko, Kyung Ae Ture, Sara Mastrangelo, Michael A. Chen, Ming-Huei Johnson, Andrew D. O'Donnell, Christopher J. Morrell, Craig N. Miano, Joseph M. Lowenstein, Charles J. TI Novel Thrombotic Function of a Human SNP in STXBP5 Revealed by CRISPR/Cas9 Gene Editing in Mice SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE gene editing; genome-wide association study; phenotype; thrombosis; von Willebrand factor ID VON-WILLEBRAND-FACTOR; GENOME-WIDE ASSOCIATION; BINDING PROTEIN STXBP5; NEUROTRANSMITTER RELEASE; ARTERIAL THROMBOSIS; PLATELET SECRETION; PLASMA-LEVELS; TOMOSYN; EXOCYTOSIS; SYNTAXIN AB Objective-To identify and characterize the effect of a SNP (single-nucleotide polymorphism) in the STXBP5 locus that is associated with altered thrombosis in humans. GWAS (genome-wide association studies) have identified numerous SNPs associated with human thrombotic phenotypes, but determining the functional significance of an individual candidate SNP can be challenging, particularly when in vivo modeling is required. Recent GWAS led to the discovery of STXBP5 as a regulator of platelet secretion in humans. Further clinical studies have identified genetic variants of STXBP5 that are linked to altered plasma von Willebrand factor levels and thrombosis in humans, but the functional significance of these variants in STXBP5 is not understood. Approach and Results-We used CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated 9) techniques to produce a precise mouse model carrying a human coding SNP rs1039084 (encoding human p. N436S) in the STXBP5 locus associated with decreased thrombosis. Mice carrying the orthologous human mutation (encoding p. N437S in mouse STXBP5) have lower plasma von Willebrand factor levels, decreased thrombosis, and decreased platelet secretion compared with wild-type mice. This thrombosis phenotype recapitulates the phenotype of humans carrying the minor allele of rs1039084. Decreased plasma von Willebrand factor and platelet activation may partially explain the decreased thrombotic phenotype in mutant mice. Conclusions-Using precise mammalian genome editing, we have identified a human nonsynonymous SNP rs1039084 in the STXBP5 locus as a causal variant for a decreased thrombotic phenotype. CRISPR/Cas9 genetic editing facilitates the rapid and efficient generation of animals to study the function of human genetic variation in vascular diseases. C1 [Zhu, Qiuyu Martin; Ko, Kyung Ae; Ture, Sara; Mastrangelo, Michael A.; Morrell, Craig N.; Miano, Joseph M.; Lowenstein, Charles J.] Univ Rochester, Med Ctr, Dept Med, Aab Cardiovasc Res Inst, Rochester, NY 14627 USA. [Chen, Ming-Huei; Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, NIH, Framingham, MA USA. [Chen, Ming-Huei; Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Div, Boston, MA USA. RP Lowenstein, CJ (reprint author), Box CVRI,601 Elmwood Ave, Rochester, NY 14642 USA. EM charles_lowenstein@urmc.rochester.edu FU National Institutes of Health (NIH)/NHLBI grant [HL108372, HL124042, HL117907, HL124018]; Howard Hughes Medical Institute Med-into-Grad Fellowship in Cardiovascular Sciences; American Heart Association [14GRNT19020033, 13PRE17050105] FX This work was supported by National Institutes of Health (NIH)/NHLBI grant HL108372 (C.J. Lowenstein), HL124042 (C.J. Lowenstein), HL117907 (J.M. Miano), and HL124018 (C.N. Morrell); the Howard Hughes Medical Institute Med-into-Grad Fellowship in Cardiovascular Sciences (C.J. Lowenstein, Q.M. Zhu); the American Heart Association 14GRNT19020033 (C.J. Lowenstein) and 13PRE17050105 (Q.M. Zhu). NR 44 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD FEB PY 2017 VL 37 IS 2 BP 264 EP + DI 10.1161/ATVBAHA.116.308614 PG 24 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EJ9ZI UT WOS:000393585700014 PM 28062498 ER PT J AU Brinton, L Figueroa, J Adjei, E Ansong, D Biritwum, R Edusei, L Nyarko, KM Wiafe, S Yarney, J Addai, BW Awuah, B Clegg-Lamptey, JN AF Brinton, Louise Figueroa, Jonine Adjei, Ernest Ansong, Daniel Biritwum, Richard Edusei, Lawrence Nyarko, Kofi M. Wiafe, Seth Yarney, Joel Addai, Beatrice Wiafe Awuah, Baffour Clegg-Lamptey, Joe Nat CA Ghana Breast Hlth Study Team TI Factors contributing to delays in diagnosis of breast cancers in Ghana, West Africa SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Epidemiology; Diagnosis delays; Africa ID WOMEN; AWARENESS; NIGERIA; BARRIERS; KUMASI; RWANDA AB Late diagnoses and poor prognoses of breast cancer are common throughout Africa. To identify responsible factors, we utilized data from a population-based case-control study involving 1184 women with breast malignancies conducted in three hospitals in Accra and Kumasi, Ghana. Interviews focused on potential breast cancer risk factors as well as factors that might contribute to presentation delays. We calculated odds ratios (OR) and 95% confidence intervals (CI) comparing malignances with biopsy masses larger than 5 cm. (62.4% of the 1027 cases with measurable lesions) to smaller lesions. In multivariate analyses, strong predictors of larger masses were limited education (OR 1.96, 95% CI 1.32-2.90 < primary vs. >= senior secondary school), being separated/divorced or widowed (1.75, 1.18-2.60 and 2.25, 1.43-3.55, respectively, vs. currently married), delay in care seeking after onset of symptoms (2.64, 1.77-3.95 for >= 12 vs. <= 2 months), care having initially been sought from someone other than a doctor/nurse (1.86, 0.85-4.09), and frequent use of herbal medications/treatment (1.51, 0.95-2.43 for >= 3x/day usage vs. none). Particularly high risks associated with these factors were found among less educated women; for example, women with less than junior secondary schooling who delayed seeking care for breast symptoms for 6 months or longer were at nearly 4-times the risk of more educated women who promptly sought assistance. Our findings suggest that additional communication, particularly among less educated women, could promote earlier breast cancer diagnoses. Involvement of individuals other than medical practitioners, including traditional healers, may be helpful in this process. C1 [Brinton, Louise; Figueroa, Jonine] NCI, 9609 Med Ctr Dr,Room 7E-442,MSC 9776, Bethesda, MD 20892 USA. [Figueroa, Jonine] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Adjei, Ernest; Ansong, Daniel; Awuah, Baffour] Komfo Anoyke Teaching Hosp, Kumasi, Ghana. [Biritwum, Richard; Nyarko, Kofi M.; Clegg-Lamptey, Joe Nat] Univ Ghana, Accra, Ghana. [Edusei, Lawrence; Yarney, Joel; Clegg-Lamptey, Joe Nat] Korle Bu Teaching Hosp, Accra, Ghana. [Wiafe, Seth; Addai, Beatrice Wiafe] Peace & Love Hosp, Kumasi, Ghana. RP Brinton, L (reprint author), NCI, 9609 Med Ctr Dr,Room 7E-442,MSC 9776, Bethesda, MD 20892 USA. EM brintonl@mail.nih.gov FU National Cancer Institute (NCI) FX This study was supported by the intramural research program of the National Cancer Institute (NCI). NR 27 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2017 VL 162 IS 1 BP 105 EP 114 DI 10.1007/s10549-016-4088-1 PG 10 WC Oncology SC Oncology GA EK7XE UT WOS:000394137700012 PM 28025716 ER PT J AU Chen, ZL Wang, X Jin, TT Wang, Y Hong, CS Tan, L Dai, TY Wu, L Zhuang, ZP Shi, CM AF Chen, Zelin Wang, Xin Jin, Taotao Wang, Yu Hong, Christopher S. Tan, Li Dai, Tingyu Wu, Liao Zhuang, Zhengping Shi, Chunmeng TI Increase in the radioresistance of normal skin fibroblasts but not tumor cells by mechanical injury SO CELL DEATH & DISEASE LA English DT Article ID MESENCHYMAL STEM-CELLS; STRAND BREAK REPAIR; DNA-DAMAGE; IONIZING-RADIATION; ACTIVATION; PATHWAY; ASTROCYTES; PROTECTS; SURVIVAL; KINASE AB The timing of radiation after mechanical injury such as in the case of surgery is considered a clinical challenge because radiation is assumed to impair wound healing. However, the physiological responses and underlying mechanisms of this healing impairment are still unclear. Here, we show that mechanical injury occurring before ionizing radiation decreases radiation-induced cell damage and increases cell repair in normal fibroblasts but not tumor cells in vitro and in vivo. At the molecular level, mechanical injury interrupts focal adhesion complexes and cell-cell cadherin interactions, transducing mechanical signals into intracellular chemical signals via activation of the phosphatidylinositol 3-kinase (PI3K), Akt, and glycogen synthase kinase 3 beta (GSK-3 beta) pathways. We show that subsequent nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and beta-catenin strengthen the stemness, antioxidant capabilities, and DNA double-strand break repair abilities of fibroblasts, ultimately contributing to increased radioresistance. Our findings demonstrate that mechanical injury to normal fibroblasts enhances radioresistance and may therefore question conventional wisdom surrounding the timing of radiation after surgery. C1 [Chen, Zelin; Wang, Xin; Jin, Taotao; Wang, Yu; Tan, Li; Dai, Tingyu; Wu, Liao; Shi, Chunmeng] Third Mil Med Univ, Inst Combined Injury, State Key Lab Trauma Burns & Combined Injury, Chongqing Engn Res Ctr Nanomed,Coll Prevent Med, Chongqing 400038, Peoples R China. [Hong, Christopher S.; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Shi, CM (reprint author), Third Mil Med Univ, Inst Combined Injury, State Key Lab Trauma Burns & Combined Injury, Chongqing Engn Res Ctr Nanomed,Coll Prevent Med, Chongqing 400038, Peoples R China. EM shicm@sina.com FU State Key Basic Research Development Program [2012CB518103]; Natural Science Foundation Programs [81372727]; Program of New Century Excellent Talents in University from Ministry of Education [NCET-11-0869]; [BWS13C016]; [CSTC2013jcyjys10002]; [AWS14007-01] FX This work was supported by the State Key Basic Research Development Program (2012CB518103), Natural Science Foundation Programs (81372727), Program of New Century Excellent Talents in University (NCET-11-0869) from Ministry of Education and intramural research project grants (BWS13C016, CSTC2013jcyjys10002 and AWS14007-01). NR 49 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD FEB PY 2017 VL 8 AR e2573 DI 10.1038/cddis.2016.416 PG 12 WC Cell Biology SC Cell Biology GA EK1JD UT WOS:000393680700029 PM 28151479 ER PT J AU Sakamachi, Y Morioka, S Mihaly, SR Takaesu, G Foley, JF Fessler, MB Ninomiya-Tsuji, J AF Sakamachi, Yosuke Morioka, Sho Mihaly, September R. Takaesu, Giichi Foley, Julie F. Fessler, Michael B. Ninomiya-Tsuji, Jun TI TAK1 regulates resident macrophages by protecting lysosomal integrity SO CELL DEATH & DISEASE LA English DT Article ID HEMATOPOIETIC STEM-CELLS; REACTIVE OXYGEN; KINASE TAK1; TNF-ALPHA; KAPPA-B; APOPTOSIS; DEATH; INFLAMMATION; MICE; NECROPTOSIS AB Hematopoietic cell survival and death is critical for development of a functional immune system. Here, we report that a protein kinase, TAK1, is selectively required for resident macrophage integrity during embryogenesis. Hematopoietic lineage-specific deletion of Tak1 gene (Tak1(HKO)) caused accumulation of cellular debris in the thymus in perinatal mice. Although no overt alteration in thymocytes and blood myeloid populations was observed in Tak1(HKO) mice, we found that thymic and lung macrophages were diminished. In the in vitro setting, Tak1 deficiency caused profound disruption of lysosomes and killed bone marrow-derived macrophages (BMDMs) without any exogenous stressors. Inhibition of the lysosomal protease, cathepsin B, partially blocked Tak1-deficient BMDM death, suggesting that leakage of the lysosomal contents is in part the cause of cell death. To identify the trigger of this cell death, we examined involvement of TNF and Toll-like receptor pathways. Among them, we found that deletion of Tnfr1 partially rescued cell death. Finally, we show that Tnfr1 deletion partially restored thymic and lung macrophages in vivo. These results suggest that autocrine and potentially paracrine TNF kills Tak1-deficient macrophages during development. Our results reveal that TAK1 signaling maintains proper macrophage populations through protecting lysosomal integrity. C1 [Sakamachi, Yosuke; Morioka, Sho; Mihaly, September R.; Takaesu, Giichi; Ninomiya-Tsuji, Jun] North Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Foley, Julie F.] NIEHS, Cellular & Mol Pathol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Fessler, Michael B.] NIEHS, Immun Inflammat & Dis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Morioka, Sho] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Box 800734,Jordan Hall 7315, Charlottesville, VA 22908 USA. [Takaesu, Giichi] Univ Ryukyus, Trop Biosphere Res Ctr, Okinawa 9030213, Japan. RP Ninomiya-Tsuji, J (reprint author), North Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. EM Jun_Tsuji@ncsu.edu FU National Institutes of Health [GM068812, GM112986]; National Institute of Environmental Health Sciences Intramural Grant [Z01 ES102005]; National Institutes of Health Training Grant [T32 ES007046] FX We thank S Akira for Tak1-floxed mice, and V Dixit and K Newton for Ripk3-/- mice. This work was supported by the National Institutes of Health Grants GM068812 and GM112986 (to JN-T), and by the National Institute of Environmental Health Sciences Intramural Grant Z01 ES102005 (to MBF). YS was partly supported by National Institutes of Health Training Grant T32 ES007046. NR 57 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD FEB PY 2017 VL 8 AR e2598 DI 10.1038/cddis.2017.23 PG 11 WC Cell Biology SC Cell Biology GA EK1JD UT WOS:000393680700015 PM 28182011 ER PT J AU Shaikh, AG Wong, AL Optican, LM Zee, DS AF Shaikh, Aasef G. Wong, Aaron L. Optican, Lance M. Zee, David S. TI Impaired Motor Learning in a Disorder of the Inferior Olive: Is the Cerebellum Confused? SO CEREBELLUM LA English DT Article DE Saccade; Dysmetria; Oscillations; Nystagmus; Cerebellum; Inferior olive ID SACCADIC EYE-MOVEMENTS; COMPLEX SPIKE ACTIVITY; OCULOMOTOR VERMIS; ADAPTIVE-CONTROL; GAIN ADAPTATION; PURKINJE-CELLS; LESIONS; MEMORY; PLASTICITY; NUCLEI AB An attractive hypothesis about how the brain learns to keep its motor commands accurate is centered on the idea that the cerebellar cortex associates error signals carried by climbing fibers with simultaneous activity in parallel fibers. Motor learning can be impaired if the error signals are not transmitted, are incorrect, or are misinterpreted by the cerebellar cortex. Learning might also be impaired if the brain is overwhelmed with a sustained barrage of meaningless information unrelated to simultaneously appearing error signals about incorrect performance. We test this concept in subjects with syndrome of oculopalatal tremor (OPT), a rare disease with spontaneous, irregular, roughly pendular oscillations of the eyes thought to reflect an abnormal, synchronous, spontaneous discharge to the cerebellum from the degenerating neurons in the inferior olive. We examined motor learning during a short-term, saccade adaptation paradigm in patients with OPT and found a unique pattern of disturbed adaptation, quite different from the abnormal adaption when the cerebellum is involved directly. Both fast (seconds) and slow (minutes) timescales of learning were impaired. We suggest that the spontaneous, continuous, synchronous output from the inferior olive prevents the cerebellum from receiving the error signals it needs for appropriate motor learning. The important message from this study is that impaired motor adaptation and resultant dysmetria is not the exclusive feature of cerebellar disorders, but it also highlights disorders of the inferior olive and its connections to the cerebellum. C1 [Shaikh, Aasef G.] Case Western Reserve Univ, Dept Neurol, 11100 Euclid Ave, Cleveland, OH 44110 USA. [Shaikh, Aasef G.] Louis Stoke Cleveland VA Med Ctr, Neurol Serv, Daroff DelOsso Ocular Motil Lab, Cleveland, OH 44106 USA. [Wong, Aaron L.; Zee, David S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Optican, Lance M.] NEI, Sensorimotor Res Lab, NIH, DHHS, Bldg 10, Bethesda, MD 20892 USA. RP Shaikh, AG (reprint author), Case Western Reserve Univ, Dept Neurol, 11100 Euclid Ave, Cleveland, OH 44110 USA.; Shaikh, AG (reprint author), Louis Stoke Cleveland VA Med Ctr, Neurol Serv, Daroff DelOsso Ocular Motil Lab, Cleveland, OH 44106 USA. EM aasefshaikh@gmail.com FU Gustavus Louis Pfeiffer Foundation; Dystonia Medical Research Foundation; NIH [EY001849]; NIH/NEI FX Authors are thankful to Dr. John Leigh for critical comments and suggestions. This research was selected for the American Academy of Neurology, 2015 Alliance Founders Award. Grants from Gustavus Louis Pfeiffer Foundation (DSZ and AGS), Dystonia Medical Research Foundation (AGS), and NIH EY001849 (DSZ) supported this work. Dr. Optican received NIH/NEI intramural support. The authors have no conflict of interest. NR 47 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1473-4222 EI 1473-4230 J9 CEREBELLUM JI Cerebellum PD FEB PY 2017 VL 16 IS 1 BP 158 EP 167 DI 10.1007/s12311-016-0785-x PG 10 WC Neurosciences SC Neurosciences & Neurology GA EJ9ZM UT WOS:000393586100018 PM 27165043 ER PT J AU Caligiore, D Pezzulo, G Baldassarre, G Bostan, AC Strick, PL Doya, K Helmich, RC Dirkx, M Houk, J Jorntell, H Lago-Rodriguez, A Galea, JM Miall, RC Popa, T Kishore, A Verschure, PFMJ Zucca, R Herreros, I AF Caligiore, Daniele Pezzulo, Giovanni Baldassarre, Gianluca Bostan, Andreea C. Strick, Peter L. Doya, Kenji Helmich, Rick C. Dirkx, Michiel Houk, James Jorntell, Henrik Lago-Rodriguez, Angel Galea, Joseph M. Miall, R. Chris Popa, Traian Kishore, Asha Verschure, Paul F. M. J. Zucca, Riccardo Herreros, Ivan TI Consensus Paper: Towards a Systems-Level View of Cerebellar Function: the Interplay Between Cerebellum, Basal Ganglia, and Cortex SO CEREBELLUM LA English DT Article DE Basal ganglia cerebellum anatomical link; Nucleo-olivary inhibition; Movement disorders; Parkinson's disease tremor; Cerebellar motor and cognitive function; Non-invasive brain stimulation ID LEVODOPA-INDUCED DYSKINESIAS; PRIMARY MOTOR CORTEX; SPINOCEREBELLAR TRACT NEURONS; PARKINSONIAN RESTING TREMOR; DIRECT-CURRENT STIMULATION; CEREBRAL-CORTEX; CORTICAL PLASTICITY; BIDIRECTIONAL PLASTICITY; BILATERAL STIMULATION; VOLUNTARY MOVEMENTS AB Despite increasing evidence suggesting the cerebellum works in concert with the cortex and basal ganglia, the nature of the reciprocal interactions between these three brain regions remains unclear. This consensus paper gathers diverse recent views on a variety of important roles played by the cerebellum within the cerebello-basal ganglia-thalamo-cortical system across a range of motor and cognitive functions. The paper includes theoretical and empirical contributions, which cover the following topics: recent evidence supporting the dynamical interplay between cerebellum, basal ganglia, and cortical areas in humans and other animals; theoretical neuroscience perspectives and empirical evidence on the reciprocal influences between cerebellum, basal ganglia, and cortex in learning and control processes; and data suggesting possible roles of the cerebellum in basal ganglia movement disorders. Although starting from different backgrounds and dealing with different topics, all the contributors agree that viewing the cerebellum, basal ganglia, and cortex as an integrated system enables us to understand the function of these areas in radically different ways. In addition, there is unanimous consensus between the authors that future experimental and computational work is needed to understand the function of cerebellar-basal ganglia circuitry in both motor and non-motor functions. The paper reports the most advanced perspectives on the role of the cerebellum within the cerebello-basal ganglia-thalamo-cortical system and illustrates other elements of consensus as well as disagreements and open questions in the field. C1 [Caligiore, Daniele; Pezzulo, Giovanni; Baldassarre, Gianluca] CNR, ISTC, Via San Martino della Battaglia 44, I-00185 Rome, Italy. [Bostan, Andreea C.; Strick, Peter L.] Univ Pittsburgh, Syst Neurosci Inst, Dept Neurobiol, 3501 Fifth Ave,4079 BST 3, Pittsburgh, PA 15261 USA. [Bostan, Andreea C.; Strick, Peter L.] Univ Pittsburgh, Ctr Neural Basis Cognit, 3501 Fifth Ave,4079 BST 3, Pittsburgh, PA 15261 USA. [Doya, Kenji] Okinawa Inst Sci & Technol, Neural Computat Unit, 1919-1 Tancha, Onna Son, Okinawa 9040495, Japan. [Helmich, Rick C.; Dirkx, Michiel] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, HP 935,POB 9101, NL-6500 HB Nijmegen, Netherlands. [Houk, James] Northwestern Univ, Dept Physiol, Feinberg Sch Med, 303 East Chicago Ave M211, Chicago, IL 60611 USA. [Jorntell, Henrik] Lund Univ, Neural Basis Sensorimotor Control, Dept Expt Med Sci, BMC F10 Tornavagen 10, S-22184 Lund, Sweden. [Lago-Rodriguez, Angel; Galea, Joseph M.; Miall, R. Chris] Univ Birmingham, Sch Psychol, Birmingham B15 2TT, W Midlands, England. [Popa, Traian] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20982 USA. [Kishore, Asha] Sree Chitra Tirunal Inst Med Sci & Technol, Comprehens Care Ctr Movement Disorders, Trivandrum 695011, Kerala, India. [Verschure, Paul F. M. J.; Zucca, Riccardo; Herreros, Ivan] Univ Pompeu Fabra, Dept Informat & Commun Technol, Barcelona, Spain. [Verschure, Paul F. M. J.] Catalan Inst Res & Adv Studies ICREA, Barcelona, Spain. RP Caligiore, D (reprint author), CNR, ISTC, Via San Martino della Battaglia 44, I-00185 Rome, Italy. EM daniele.caligiore@istc.cnr.it; giovanni.pezzulo@istc.cnr.it; gianluca.baldassarre@istc.cnr.it; acb42@pitt.edu; strickp@pitt.edu; doya@oist.jp; rick.helmich@radboudumc.nl; Michiel.Dirkx@radboudumc.nl; j-houk@northwestern.edu; henrik.jorntell@med.lu.se; A.Lago-Rodriguez@bham.ac.uk; J.Galea@bham.ac.uk; R.C.Miall@bham.ac.uk; traian.popa@nih.gov; asha@sctimst.ac.in; paul.verschure@upf.edu; riccardo.zucca@upf.edu; ivan.herreros@upf.edu OI Pezzulo, Giovanni/0000-0001-6813-8282; Popa, Traian/0000-0003-1160-4830 FU European Commission [ICT IP-231722, socSMC-641321H2020-FETPROACT-2014]; Human Frontier Science Program (HFSP) [RGY0088/2014]; Office of Research and Development, Medical Research Service, Department of Veterans Affairs; National Institutes of Health [R01 NS24328, R01 MH56661, P40 OD010996, P30 NS076405]; European Research Council [637488]; MRC [R/J012610/1]; Wellcome Trust [WT087554]; European Research Council under the European Union/ERC [341196] FX The present research was supported by the European Commission 7th Framework Programme (FP7/2007-2013), "Challenge 2-Cognitive Systems, Interaction, Robotics," grant agreement No. ICT IP-231722, project "IM-CLeVeR-Intrinsically Motivated Cumulative Learning Versatile Robots" to D. Caligiore; by the Human Frontier Science Program (HFSP), award number RGY0088/2014 to G. Pezzulo; in parts by funds from the Office of Research and Development, Medical Research Service, Department of Veterans Affairs and National Institutes of Health Grants R01 NS24328, R01 MH56661, P40 OD010996, and P30 NS076405 to P. L. Strick; by the European Research Council project MotMotLearn (637488) to J. Galea; by the MRC (grant R/J012610/1) to R.C. Miall and Wellcome Trust, grant WT087554 to R.C. Miall and A. Lago-Rodriguez; by the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. 341196 to P. F. M. J. Verschure; and by the European Commission's Horizon 2020 socSMC (under agreement number socSMC-641321H2020-FETPROACT-2014) to I. Herreros. We thank the two anonymous reviewers and Professor Michael A. Arbib who have contributed to enhance the quality of this consensus paper with precious comments. NR 205 TC 4 Z9 4 U1 6 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1473-4222 EI 1473-4230 J9 CEREBELLUM JI Cerebellum PD FEB PY 2017 VL 16 IS 1 BP 203 EP 229 DI 10.1007/s12311-016-0763-3 PG 27 WC Neurosciences SC Neurosciences & Neurology GA EJ9ZM UT WOS:000393586100022 PM 26873754 ER PT J AU Gojo, I Beumer, JH Pratz, KW McDevitt, MA Baer, MR Blackford, AL Smith, BD Gore, SD Carraway, HE Showel, MM Levis, MJ Dezern, AE Gladstone, DE Ji, JJ Wang, LH Kinders, RJ Pouquet, M Ali-Walbi, I Rudek, MA Poh, W Herman, JG Karnitz, LM Kaufmann, SH Chen, A Karp, JE AF Gojo, Ivana Beumer, Jan H. Pratz, Keith W. McDevitt, Michael A. Baer, Maria R. Blackford, Amanda L. Smith, B. Douglas Gore, Steven D. Carraway, Hetty E. Showel, Margaret M. Levis, Mark J. Dezern, Amy E. Gladstone, Douglas E. Ji, Jiuping Jay Wang, Lihua Kinders, Robert J. Pouquet, Marie Ali-Walbi, Ismail Rudek, Michelle A. Poh, Weijie Herman, James G. Karnitz, Larry M. Kaufmann, Scott H. Chen, Alice Karp, Judith E. TI A Phase 1 Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute Myeloid Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE; HUMAN PLASMA; DNA-DAMAGE; THERAPY; REPAIR; ABT-888; ADULTS; TUMORS; CELLS; CYCLOPHOSPHAMIDE AB Purpose: In preclinical studies, the PARP inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies. Experimental Design: Patients received veliparib [20-200 mg once a day on day 1 and twice daily on days 4-12 in cycle 1 (days 1-8 in cycle >= 2)] and temozolomide [150-200 mg/m(2) daily on days 3-9 in cycle 1 (days 1-5 in cycle >= 2)] every 28 to 56 days. Veliparib pharmacokinetics and pharmacodynamics [ability to inhibit poly(ADP-ribose) polymer (PAR) formation and induce H2AX phosphorylation] were assessed. Pretreatment levels of MGMT and PARP1 protein, methylation of the MGMT promoter, and integrity of the Fanconi anemia pathway were also examined. Results: Forty-eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting > 7 days. The MTD was veliparib 150 mg twice daily with temozolomide 200 mg/m(2) daily. The complete response (CR) rate was 17% (8/48 patients). Veliparib exposure as well as inhibition of PAR polymer formation increased dose proportionately. A veliparib-induced increase in H2AX phosphorylation in CD34(+) cells was observed in responders. Three of 4 patients with MGMT promoter methylation achieved CR. Conclusions: Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and MGMT methylation as potential response predictors appears warranted. (C) 2016 AACR. C1 [Gojo, Ivana; Pratz, Keith W.; McDevitt, Michael A.; Smith, B. Douglas; Gore, Steven D.; Carraway, Hetty E.; Showel, Margaret M.; Levis, Mark J.; Dezern, Amy E.; Gladstone, Douglas E.; Rudek, Michelle A.; Poh, Weijie; Herman, James G.; Karp, Judith E.] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21287 USA. [Beumer, Jan H.] Univ Pittsburgh, Inst Canc, Canc Therapeut Program, Pittsburgh, PA USA. [Beumer, Jan H.; Pouquet, Marie; Ali-Walbi, Ismail] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA USA. [Baer, Maria R.] Univ Maryland, Dept Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Blackford, Amanda L.] Johns Hopkins Univ Hosp, Dept Stat, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Ji, Jiuping Jay; Wang, Lihua; Kinders, Robert J.] SAIC Frederick Inc, Lab Human Toxicol & Pharmacol, Appl Dev Res Support Directorate, NCI Frederick, Frederick, MD USA. [Karnitz, Larry M.; Kaufmann, Scott H.] Mayo Clin, Div Oncol Res, Rochester, MN USA. [Karnitz, Larry M.; Kaufmann, Scott H.] Mayo Clin, Dept Mol Pharmacol, Rochester, MN USA. [Chen, Alice] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Gojo, I (reprint author), Sidney Kimmel Comprehens Canc Ctr, Johns Hopkins Div Hematol Malignancies, 1650 Orleans St,Room 346,Bldg CRB1, Baltimore, MD 21287 USA. EM igojo1@jhmi.edu FU NIH [U01CA070095, U01CA099168, UM1CA186690, UM1CA186691, N01CM5701716]; Cancer Pharmacokinetics and Pharmacodynamics Facility at University of Pittsburgh Cancer Institute [P30CA047904]; Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH) [P30 CA006973, UL1 TR 001079]; NCI, NIH [HHSN261200800001E] FX This work is supported by NIH grants U01CA070095, U01CA099168, UM1CA186690, UM1CA186691, and N01CM5701716. The project described was also supported by the Cancer Pharmacokinetics and Pharmacodynamics Facility at University of Pittsburgh Cancer Institute (P30CA047904) and the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 TR 001079). Frederick National Laboratory support was provided by NCI, NIH, under contract no. HHSN261200800001E. Merck & Co., Inc. provided temozolomide for this study. NR 41 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2017 VL 23 IS 3 BP 697 EP 706 DI 10.1158/1078-0432.CCR-16-0984 PG 10 WC Oncology SC Oncology GA EK4GB UT WOS:000393884000011 PM 27503200 ER PT J AU Pratz, KW Rudek, MA Gojo, I Litzow, MR McDevitt, MA Ji, JP Karnitz, LM Herman, JG Kinders, RJ Smith, BD Gore, SD Carraway, HE Showel, MM Gladstone, DE Levis, MJ Tsai, HL Rosner, G Chen, A Kaufmann, SH Karp, JE AF Pratz, Keith W. Rudek, Michelle A. Gojo, Ivana Litzow, Mark R. McDevitt, Michael A. Ji, Jiuping Karnitz, Larry M. Herman, James G. Kinders, Robert J. Smith, B. Douglas Gore, Steven D. Carraway, Hetty E. Showel, Margaret M. Gladstone, Douglas E. Levis, Mark J. Tsai, Hua-Ling Rosner, Gary Chen, Alice Kaufmann, Scott H. Karp, Judith E. TI A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE MYELOID-LEUKEMIA; POLY(ADP-RIBOSE) POLYMERASE INHIBITOR; BONE-MARROW; REPAIR; CANCER; ABT-888; CELLS; TRANSFORMATION; MUTATION; RECOMMENDATIONS AB Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone. Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML). Results: A total of 99 patients received veliparib 10-100 mg orally twice daily on days 1-8, 1-14, or 1-21 along with continuous infusion topotecan 1.0-1.2 mg/m(2)/d+carboplatin 120-150 mg/m(2)/d on days 3-7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m(2)/d+carboplatin 150 mg/m(2)/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage-induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27-0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34(+) leukemia cells, with greater phosphorylation in cells from responders. Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN-or CMML-related acute leukemias. (C)2016 AACR. C1 [Pratz, Keith W.; Rudek, Michelle A.; Gojo, Ivana; McDevitt, Michael A.; Herman, James G.; Smith, B. Douglas; Gore, Steven D.; Carraway, Hetty E.; Showel, Margaret M.; Gladstone, Douglas E.; Levis, Mark J.; Tsai, Hua-Ling; Rosner, Gary; Karp, Judith E.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Litzow, Mark R.; Karnitz, Larry M.; Kaufmann, Scott H.] Mayo Clin, Rochester, MN USA. [Ji, Jiuping] Frederick Natl Lab Canc Res, Natl Clin Target Validat Lab, Bethesda, MD USA. [Kinders, Robert J.] Frederick Natl Lab Canc Res, Frederick, MD USA. [Chen, Alice] NCI, IDB, CTEP, Rockville, MD USA. [Herman, James G.] Univ Pittsburgh, Pittsburgh, PA USA. [Gore, Steven D.] Yale Canc Ctr, New Haven, CT USA. [Carraway, Hetty E.] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. RP Pratz, KW (reprint author), Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Div Hematol Malignancies, Bunting Blaustein Canc Res Bldg,1650 Orleans St, Baltimore, MD 21231 USA. EM Kpratz1@jhmi.edu FU NIH [U01 CA070095, UM1CA186691, U01 CA69912, UM1 CA186686, P30 CA006973, UL1 TR 001079]; NCI [HHSN261200800001E] FX This work is supported by NIH grants U01 CA070095, UM1CA186691, U01 CA69912, and UM1 CA186686. The Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins was funded by NIH grants P30 CA006973 and UL1 TR 001079. The National Clinical Target validation lab was funded by NCI Contract no HHSN261200800001E. NR 46 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2017 VL 23 IS 4 BP 899 EP 907 DI 10.1158/1078-0432.CCR-16-1274 PG 9 WC Oncology SC Oncology GA EK4GS UT WOS:000393885700005 PM 27551000 ER PT J AU Jdey, W Thierry, S Russo, C Devun, F Al Abo, M Noguiez-Hellin, P Sun, JS Barillot, E Zinovyev, A Kuperstein, I Pommier, Y Dutreix, M AF Jdey, Wael Thierry, Sylvain Russo, Christophe Devun, Flavien Al Abo, Muthana Noguiez-Hellin, Patricia Sun, Jian-Sheng Barillot, Emmanuel Zinovyev, Andrei Kuperstein, Inna Pommier, Yves Dutreix, Marie TI Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors SO CLINICAL CANCER RESEARCH LA English DT Article ID BRCA MUTATION CARRIERS; DNA-REPAIR; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; THERAPEUTIC STRATEGY; OVARIAN-CANCER; MUTANT-CELLS; NETWORK; DAMAGE; SUSCEPTIBILITY AB Purpose: Cancer treatments using tumor defects in DNA repair pathways have shown promising results but are restricted to small subpopulations of patients. The most advanced drugs in this field are PARP inhibitors (PARPi), which trigger synthetic lethality in tumors with homologous recombination (HR) deficiency. Using AsiDNA, an inhibitor of HR and nonhomologous end joining, together with PARPi should allow bypassing the genetic restriction for PARPi efficacy. Experimental Design: We characterized the DNA repair inhibition activity of PARPi (olaparib) and AsiDNA by monitoring repair foci formation and DNA damage. We analyzed the cell survival to standalone and combined treatments of 21 tumor cells and three nontumor cells. In 12 breast cancer (BC) cell lines, correlation with sensitivity to each drug and transcriptome were statistically analyzed to identify resistance pathways. Results: Molecular analyses demonstrate that olaparib and AsiDNA respectively prevent recruitment of XRCC1 and RAD51/53BP1 repair enzymes to damage sites. Combination of both drugs increases the accumulation of unrepaired damage resulting in an increase of cell death in all tumor cells. In contrast, nontumor cells do not show an increase of DNA damage nor lethality. Analysis of multilevel omics data from BC cells highlighted different DNA repair and cell-cycle molecular profiles associated with resistance to AsiDNA or olaparib, rationalizing combined treatment. Treatment synergy was also confirmed with six other PARPi in development. Conclusions: Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status. (C)2016 AACR. C1 [Jdey, Wael; Thierry, Sylvain; Dutreix, Marie] PSL Res Univ, CNRS, Inst Curie, INSERM, Orsay, France. [Jdey, Wael; Thierry, Sylvain; Dutreix, Marie] Univ Paris Saclay, Univ Paris Sud, CNRS, INSERM, Orsay, France. [Jdey, Wael; Devun, Flavien; Noguiez-Hellin, Patricia; Sun, Jian-Sheng] Genopole, DNA Therapeut, Evry, France. [Russo, Christophe; Barillot, Emmanuel; Zinovyev, Andrei; Kuperstein, Inna] PSL Res Univ, Inst Curie, INSERM, Paris, France. [Al Abo, Muthana; Pommier, Yves] NCI, NIH, Bethesda, MD 20892 USA. RP Dutreix, M (reprint author), Univ Paris 11, Inst Curie, Bldg 112,15 Rue Georges Clemenceau, F-91405 Orsay, France. EM marie.dutreix@curie.fr FU SIRIC-Curie; program PIC SysBio of the Institut Curie; Centre National de la Recherche Scientifique; Institut National de la Sante Et de la Recherche Medicale; fellowship CIFFRE-ANRT [2013/0907]; Institut National du Cancer [TRANSLA13-081] FX This work was supported by the SIRIC-Curie, the program PIC SysBio of the Institut Curie, the Centre National de la Recherche Scientifique, and the Institut National de la Sante Et de la Recherche Medicale. W. Jdey was supported by a fellowship CIFFRE-ANRT (2013/0907). S. Thierry was supported by the Institut National du Cancer (TRANSLA13-081). NR 38 TC 0 Z9 0 U1 5 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2017 VL 23 IS 4 BP 1001 EP 1011 DI 10.1158/1078-0432.CCR-16-1193 PG 11 WC Oncology SC Oncology GA EK4GS UT WOS:000393885700015 PM 27559053 ER PT J AU Apte, MS Cooper, JP AF Apte, Manasi S. Cooper, Julia Promisel TI Life and cancer without telomerase: ALT and other strategies for making sure ends (don't) meet SO CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE Telomere; telomerase; genome stability; chromatin; heterochromatin; ALT; HAATI; recombination; DNA damage response ID SACCHAROMYCES-CEREVISIAE TELOMERES; REPEAT-CONTAINING RNA; FISSION YEAST; MAMMALIAN TELOMERES; DNA-REPLICATION; HUMAN-CELLS; DROSOPHILA TELOMERES; CHROMOSOME ENDS; GENE-EXPRESSION; PROTEIN COMPLEX AB While most cancer cells rely on telomerase expression/re-activation for linear chromosome maintenance and sustained proliferation, a significant population of cancers (10-15%) employs telomerase-independent strategies, collectively dubbed Alternative Lengthening of Telomeres (ALT). Most ALT cells relax the usual role of telomeres as inhibitors of local homologous recombination while maintaining the ability of telomeres to prohibit local non-homologous end joining reactions. Here we review current concepts surrounding how ALT telomeres achieve this new balance via alterations in chromatin landscape, DNA damage repair processes and handling of telomeric transcription. We also discuss telomerase independent end maintenance strategies utilized by other organisms, including fruitflies and yeasts, to draw parallels and contrasts and highlight additional modes, beyond ALT, that may be available to telomerase-minus cancers. We conclude by commenting on promises and challenges in the development of effective anti-ALT cancer therapies. C1 [Apte, Manasi S.; Cooper, Julia Promisel] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cooper, JP (reprint author), NCI, Lab Biochem & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM julie.cooper@nih.gov FU National Cancer Institute, National Institutes of Health, USA FX Work in the Cooper lab is supported by the National Cancer Institute, National Institutes of Health, USA. NR 168 TC 0 Z9 0 U1 8 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1040-9238 EI 1549-7798 J9 CRIT REV BIOCHEM MOL JI Crit. Rev. Biochem. Mol. Biol. PD FEB PY 2017 VL 52 IS 1 BP 57 EP 73 DI 10.1080/10409238.2016.1260090 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK2PV UT WOS:000393770100004 PM 27892716 ER PT J AU Jin, DJ Martin, CM Sun, Z Cagliero, C Zhou, YN AF Jin, Ding Jun Martin, Carmen Mata Sun, Zhe Cagliero, Cedric Zhou, Yan Ning TI Nucleolus-like compartmentalization of the transcription machinery in fast-growing bacterial cells SO CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE RNA polymerase; bacterial nucleolus; 3D organization of transcription machinery; chromosome territories; transcription factories ID ESCHERICHIA-COLI CHROMOSOME; RIBOSOMAL-RNA OPERONS; UNITS IN-VIVO; SPATIAL-ORGANIZATION; SUPERRESOLUTION MICROSCOPY; STRUCTURED ILLUMINATION; SALMONELLA-TYPHIMURIUM; ACTIVE TRANSCRIPTION; STRINGENT RESPONSE; DNA-REPLICATION AB We have learned a great deal about RNA polymerase (RNA Pol), transcription factors, and the transcriptional regulation mechanisms in prokaryotes for specific genes, operons, or transcriptomes. However, we have only begun to understand how the transcription machinery is three-dimensionally (3D) organized into bacterial chromosome territories to orchestrate the transcription process and to maintain harmony with the replication machinery in the cell. Much progress has been made recently in our understanding of the spatial organization of the transcription machinery in fast-growing Escherichia coli cells using state-of-the-art superresolution imaging techniques. Co-imaging of RNA polymerase (RNA Pol) with DNA and transcription elongation factors involved in ribosomal RNA (rRNA) synthesis, and ribosome biogenesis has revealed similarities between bacteria and eukaryotes in the spatial organization of the transcription machinery for growth genes, most of which are rRNA genes. Evidence supports the notion that RNA Pol molecules are concentrated, forming foci at the clustering of rRNA operons resembling the eukaryotic nucleolus. RNA Pol foci are proposed to be active transcription factories for both rRNA genes expression and ribosome biogenesis to support maximal growth in optimal growing conditions. Thus, in fast-growing bacterial cells, RNA Pol foci mimic eukaryotic Pol I activity, and transcription factories resemble nucleolus-like compartmentation. In addition, the transcription and replication machineries are mostly segregated in space to avoid the conflict between the two major cellular functions in fast-growing cells. C1 [Jin, Ding Jun; Martin, Carmen Mata; Sun, Zhe; Cagliero, Cedric; Zhou, Yan Ning] NCI, Transcript Control Sect, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA. [Cagliero, Cedric] Labs Inc, Frederick, MD 21704 USA. RP Jin, DJ (reprint author), NCI, Transcript Control Sect, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA. EM jind@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 59 TC 0 Z9 0 U1 3 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1040-9238 EI 1549-7798 J9 CRIT REV BIOCHEM MOL JI Crit. Rev. Biochem. Mol. Biol. PD FEB PY 2017 VL 52 IS 1 BP 96 EP 106 DI 10.1080/10409238.2016.1269717 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK2PV UT WOS:000393770100006 PM 28006965 ER PT J AU Dogan, A Demirci, S Kiratli, B Sahin, F AF Dogan, Aysegul Demirci, Selami Kiratli, Binnur Sahin, Fikrettin TI Cytoglobin: a potential marker for adipogenic differentiation in preadipocytes in vitro SO CYTOTECHNOLOGY LA English DT Article DE Cytoglobin; Obesity; 3T3-F442A; Preadipocyte; Adipogenic differentiation ID ADIPOCYTE DIFFERENTIATION; KEY REGULATOR; NEUROGLOBIN; EXPRESSION; OBESITY; CELLS; LOCALIZATION; FIBROGENESIS; TISSUES; GLOBIN AB Obesity, mainly characterized by the excess fat storage, is a global health problem resulting in serious morbidity and mortality. Identification of molecular mechanisms in adipogenic differentiation pathway might lead to development of new strategies for diagnosis, prevention and therapy of obesity and associated diseases. Discovery of new genes and proteins in the differentiation pathway could help to understand the key specific regulators of the adipogenesis. Cytoglobin (Cygb), identified as a new globin family member protein, is expressed in various tissues. Although its interaction with oxygen and nitric oxide indicates the potential role in antioxidant pathways, the exact role remains unclear. In the current study, expression level of Cygb was determined in proliferating and differentiating 3T3-F442A cells by gene expression and protein expression analysis. Results revealed that Cygb expression up-regulated in differentiated cells in parallel with adipogenic differentiation markers; PPAR gamma, CEBP alpha and FABP4 expressions. Besides, Cygb overexpression in preadipocytes contributed to the adipogenic differentiation as verified by detection of higher lipid droplets and increased PPAR gamma, CEBP alpha and FABP4 expressions with respect to control cells. These findings will shed light on the unknown roles of Cygb in adipogenesis and obesity. C1 [Dogan, Aysegul; Demirci, Selami; Kiratli, Binnur; Sahin, Fikrettin] Yeditepe Univ, Dept Genet & Bioengn, Fac Engn & Architecture, Kayisdagi Cad 26 Agustos Yerlesimi, TR-34755 Istanbul, Turkey. [Dogan, Aysegul] NCI, CDBL, NIH, Frederick, MD 21701 USA. [Demirci, Selami] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Demirci, S (reprint author), Yeditepe Univ, Dept Genet & Bioengn, Fac Engn & Architecture, Kayisdagi Cad 26 Agustos Yerlesimi, TR-34755 Istanbul, Turkey. EM selamidemirci@hotmail.com NR 21 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-9069 EI 1573-0778 J9 CYTOTECHNOLOGY JI Cytotechnology PD FEB PY 2017 VL 69 IS 1 BP 157 EP 165 DI 10.1007/s10616-016-0047-2 PG 9 WC Biotechnology & Applied Microbiology; Cell Biology SC Biotechnology & Applied Microbiology; Cell Biology GA EK2GG UT WOS:000393745200013 PM 27928650 ER PT J AU Frank, EG McDonald, JP Yang, W Woodgate, R AF Frank, Ekaterina G. McDonald, John P. Yang, Wei Woodgate, Roger TI Mouse DNA polymerase iota lacking the forty-two amino acids encoded by exon-2 is catalytically inactive in vitro SO DNA REPAIR LA English DT Article DE DNA polymerase iota; 129-derived strains of mice; Y-family DNA polymerase; Mutagenesis; Translesion DNA synthesis ID ERROR-PRONE; POL-IOTA; STRUCTURAL BASIS; ACTIVE-SITE; REPLICATION; BYPASS; MICE; ETA; CELLS; FIDELITY AB In 2003, we reported that 129-derived strains of mice carry a naturally occurring nonsense mutation at codon 27 of the Poll gene that would produce a pol iota, peptide of just 26 amino acids, rather then the full-length 717 amino acid wild-type polymerase. In support of the genomic analysis, no pol iota protein was detected in testes extracts from 129X1/SvJmice, where wild-type pol iota is normally highly expressed. The early truncation in pol iota. occurs before any structural domains of the polymerase are synthesized and as a consequence, we reasoned that 129-derived strains of mice should be considered as functionally defective in pol iota activity. However, it has recently been reported that during the maturation of the Poli mRNA in 129-derived strains, exon- 2 is sometimes skipped and that an exon-2-less pol iota protein of 675 amino acids is synthesized that retains catalytic activity in vitro and in vivo. From a structural perspective, we found this idea untenable, given that the amino acids encoded by exon-2 include residues critical for the coordination of the metal ions required for catalysis, as well as the structural integrity of the DNA polymerase. To determine if the exon-2-less pol iota isoform possesses catalytic activity in vitro, we have purified a glutathione-tagged full-length exon-2-less (675 amino acid) pol iota protein from baculovirus infected insect cells and compared the activity of the isoform to full-length (717 amino acid) GST-tagged wild-type mouse pol iota in vitro. Reaction conditions were performed under a range of magnesium or manganese concentrations, as well as different template sequence contexts. Wild-type mouse pol iota exhibited robust characteristic properties previously associated with human pol iota's biochemical properties. However, we did not detect any polymerase activity associated with the exon-2-less pol iota enzyme under the same reaction conditions and conclude that exon-2-less pol iota is indeed rendered catalytically inactive in vitro. Published by Elsevier B.V. C1 [Frank, Ekaterina G.; McDonald, John P.; Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. [Yang, Wei] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. EM woodgate@nih.gov FU National Institutes of Health/National Institute of Child Health and Human Development Intramural Research Program; National Institutes of Health/National Institute Diabetes and Digestive and Kidney Diseases Intramural Research Program FX We thank Alena Makarova for kindly sharing unpublished data on her own group's studies on the exon-2-less poli mutant and for helpful and stimulating discussions. This work was supported by funds from the National Institutes of Health/National Institute of Child Health and Human Development Intramural Research Program to RW and National Institutes of Health/National Institute Diabetes and Digestive and Kidney Diseases Intramural Research Program to WY. NR 33 TC 0 Z9 0 U1 4 U2 4 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 FEB PY 2017 VL 50 BP 71 EP 76 DI 10.1016/j.dnarep.2016.12.004 PG 6 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA EK1XK UT WOS:000393720900008 PM 28077247 ER PT J AU Coyne, GO Chen, AP Meehan, R Doroshow, JH AF Coyne, Geraldine O'Sullivan Chen, Alice P. Meehan, Robert Doroshow, James H. TI PARP Inhibitors in Reproductive System Cancers: Current Use and Developments SO DRUGS LA English DT Article ID NEGATIVE BREAST-CANCER; BRCA MUTATION CARRIERS; OLAPARIB MAINTENANCE THERAPY; RIBOSE POLYMERASE INHIBITOR; RECURRENT OVARIAN-CANCER; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; ANTICANCER THERAPY; PHASE-II; SYNTHETIC LETHALITY AB The repair of DNA damage is a critical cellular process governed by multiple biochemical pathways that are often found to be defective in cancer cells. The poly(ADP-ribose) polymerase (PARP) family of proteins controls response to single-strand DNA breaks by detecting these damaged sites and recruiting the proper factors for repair. Blocking this pathway forces cells to utilize complementary mechanisms to repair DNA damage. While PARP inhibition may not, in itself, be sufficient to cause tumor cell death, inhibition of DNA repair with PARP inhibitors is an effective cytotoxic strategy when it is used in patients who carry other defective DNA-repair mechanisms, such as mutations in the genes BRCA 1 and 2. This discovery has supported the development of PARP inhibitors (PARPi), agents that have proven effective against various types of tumors that carry BRCA mutations. With the application of next-generation sequencing of tumors, there is increased interest in looking beyond BRCA mutations to identify genetic and epigenetic aberrations that might lead to similar defects in DNA repair, conferring susceptibility to PARP inhibition. Identification of these genetic lesions and the development of screening assays for their detection may allow for the selection of patients most likely to respond to this class of anticancer agents. This article provides an overview of clinical trial results obtained with PARPi and describes the companion diagnostic assays being established for patient selection. In addition, we review known mechanisms for resistance to PARPi and potential strategies for combining these agents with other types of therapy. C1 [Coyne, Geraldine O'Sullivan; Chen, Alice P.; Meehan, Robert; Doroshow, James H.] NCI, Early Clin Trials Dev Program, Div Canc Treatment & Diag, NIH, 31 Ctr Dr,Room 3A44, Bethesda, MD 20892 USA. [Coyne, Geraldine O'Sullivan; Chen, Alice P.; Meehan, Robert; Doroshow, James H.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Doroshow, JH (reprint author), NCI, Early Clin Trials Dev Program, Div Canc Treatment & Diag, NIH, 31 Ctr Dr,Room 3A44, Bethesda, MD 20892 USA.; Doroshow, JH (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov FU federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract Number HHSN261200800001E. NR 100 TC 0 Z9 0 U1 2 U2 2 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0012-6667 EI 1179-1950 J9 DRUGS JI Drugs PD FEB PY 2017 VL 77 IS 2 BP 113 EP 130 DI 10.1007/s40265-016-0688-7 PG 18 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EK1JY UT WOS:000393682800001 ER PT J AU Pacurari, M May, I Tchounwou, PB AF Pacurari, M. May, I. Tchounwou, P. B. TI Effects of lipopolysaccharide, multiwalled carbon nantoubes, and the combination on lung alveolar epithelial cells SO ENVIRONMENTAL TOXICOLOGY LA English DT Article DE alveolar epithelial cells; cell migration; collagen; ECM; LPS; MWCNT; MMP-9; MMP-12; NF-kappa B; TGF beta ID NF-KAPPA-B; OBSTRUCTIVE PULMONARY-DISEASE; BETA/SMAD SIGNALING PATHWAY; MATRIX METALLOPROTEINASES; FIBROTIC RESPONSE; NANOTUBES INDUCE; MMP-9 PRODUCTION; TGF-BETA; FIBROSIS; INFLAMMATION AB Multiwalled carbon nanotubes (MWCNT) have been shown to induce lung fibrosis in animal models, however the underlying molecular factors/mechanisms are still unclear. In this study, we investigated the effects of lipopolysaccharide (LPS), MWCNT, and the combination of LPS and MWCNT on the expression of matrix metalloproteinase-9 and metalloproteinase-12 (MMP-9, MMP-12), collagen 3A1 (Col3A1), and transforming growth factor beta (TGF) in alveolar epithelial A549 cells. MMPs are proteinases that degrade extracellular matrix and play a role in lung fibrosis. A549 cells were exposed to LPS (1ng/mL), MWCNT (20g/mL), and the combination and analyzed for paracellular permeability, TGF, Col3A1, MMP-9, MMP-12, NF-B activation, and cell migration by real-time PCR and immunofluorescence. LPS, the combination of LPS and MWCNT, and MWCNT only at the highest tested dose induced blue dextran extravasation. LPS and MWCNT increased the expression of TGF and its downstream target gene Col3A, and MMP-9 and MMP-12 mRNA. MWCNT potently induced cell migration toward wound healing, whereas LPS slightly induced cell migration. Both, LPS and MWCNT, induced NF-B nuclear translocation. Our results indicate that MWCNT activated alveolar epithelial cells to promote fibrogenesis, and that LPS differentially primes molecular factors involved in lung remodeling. These findings suggest a role of alveolar epithelial cells in fibrogenesis and also may aid in the design and development of tests for screening of fibrogenic agents. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 445-455, 2017. C1 [Pacurari, M.; Tchounwou, P. B.] Jackson State Univ, Coll Sci Engn & Technol, Dept Biol, Jackson, MS 39217 USA. [Pacurari, M.; Tchounwou, P. B.] Jackson State Univ, Coll Sci Engn & Technol, NIH RCMI Ctr Environm Hlth, Jackson, MS 39217 USA. [May, I.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. RP Pacurari, M (reprint author), Jackson State Univ, Coll Sci Engn & Technol, Dept Biol, Jackson, MS 39217 USA.; Pacurari, M (reprint author), Jackson State Univ, Coll Sci Engn & Technol, NIH RCMI Ctr Environm Hlth, Jackson, MS 39217 USA. EM maricica.pacurari@jsums.edu FU NIH/ RCMI/JSU [G12MD007581]; NIH/RISE [R25GM067122] FX Contract grant sponsor: Career Development Grant through NIH/ RCMI/JSU Grant G12MD007581 and NIH/RISE Grant R25GM067122. NR 64 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1520-4081 EI 1522-7278 J9 ENVIRON TOXICOL JI Environ. Toxicol. PD FEB PY 2017 VL 32 IS 2 BP 445 EP 455 DI 10.1002/tox.22248 PG 11 WC Environmental Sciences; Toxicology; Water Resources SC Environmental Sciences & Ecology; Toxicology; Water Resources GA EK3AX UT WOS:000393799500009 PM 26880698 ER PT J AU Shevach, EM AF Shevach, Ethan M. TI Garp as a therapeutic target for modulation of T regulatory cell function SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE GARP; latent TGF-beta; T regulatory cells; foxp3; suppression; integrins ID GROWTH-FACTOR-BETA; LATENT TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; REPETITIONS PREDOMINANT; INTESTINAL INFLAMMATION; TGF-BETA-1 PRODUCTION; FOXP3 EXPRESSION; ORAL TOLERANCE; DIFFERENTIATION; ACTIVATION AB Introduction: Foxp3(+) T regulatory cells (Tregs) play critical roles in immune homeostasis primarily by suppressing many aspects of the immune response. Tregs uniquely express GARP on their cell surface and GARP functions as a delivery system for latent TGF-. As Treg-derived TGF- may mediate the suppressive functions of Tregs, GARP may represent a target to inhibit Treg suppression in cancer or augment suppression in autoimmunity.Areas covered: This article will focus on 1) the role of Treg-derived TGF- in the suppressive activity of Treg, 2) the cellular and molecular regulation of expression of GARP on mouse and human Tregs, 3) the role of integrins in the activation of latent-TGF-/GARP complex, 4) an overview of our present understanding of the function of the latent-TGF-/GARP complex.Expert opinion: Two approaches are outlined for targeting the L-TGF-1/GARP complex for therapeutic purposes. Tregs play a major role in suppressive effector T cell responses to tumors and TGF-1 may be a major contributor to this process. One approach is to specifically block the production of active TGF-1 from Tregs as an adjunct to tumor immunotherapy. The second approach in autoimmunity is to selectively enhance the production of TGF- by Tregs at sites of chronic inflammation. C1 [Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Cellular Immunol Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX This work was supported by funds from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. NR 68 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1472-8222 EI 1744-7631 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD FEB PY 2017 VL 21 IS 2 BP 191 EP 200 DI 10.1080/14728222.2017.1275568 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK2LK UT WOS:000393758600008 PM 28001437 ER PT J AU Machado-Vieira, R Salem, H Frey, BN Barbosa, IG Teixeira, AL AF Machado-Vieira, Rodrigo Salem, Haitham Frey, Benicio N. Barbosa, Izabela G. Teixeira, Antonio L. TI Convergent lines of evidence support the role of uric acid levels as a potential biomarker in bipolar disorder SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Letter ID PURINERGIC SYSTEM; CONTROLLED-TRIAL; DOUBLE-BLIND; MANIA; ALLOPURINOL; DYSFUNCTION; MODEL C1 NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Salem, Haitham; Teixeira, Antonio L.] Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Frey, Benicio N.] McMaster Univ, Dept Psychiat & Behav Neurosci, Hamilton, ON, Canada. [Frey, Benicio N.] St Josephs Healthcare, Mood Disorders Program, Hamilton, ON, Canada. [Frey, Benicio N.] St Josephs Healthcare, Womens Hlth Concerns Clin, Hamilton, ON, Canada. [Barbosa, Izabela G.; Teixeira, Antonio L.] Univ Fed Minas Gerais, Sch Med, Interdisciplinary Lab Med Invest, Belo Horizonte, MG, Brazil. RP Teixeira, AL (reprint author), Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Dept Psychiat & Behav Sci, Houston, TX 77030 USA.; Teixeira, AL (reprint author), Univ Fed Minas Gerais, Sch Med, Interdisciplinary Lab Med Invest, Belo Horizonte, MG, Brazil. EM altexr@gmail.com NR 14 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1473-7159 EI 1744-8352 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD FEB PY 2017 VL 17 IS 2 BP 107 EP 108 DI 10.1080/14737159.2017.1270758 PG 2 WC Pathology SC Pathology GA EK4IM UT WOS:000393890300002 PM 27935358 ER PT J AU Arnold, MA Barr, FG AF Arnold, Michael A. Barr, Fredric G. TI Molecular diagnostics in the management of rhabdomyosarcoma SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE Rhabdomyosarcoma; molecular testing; risk stratification; fusion oncogene; gene amplification; MYOD1; RAS; FGFR4; NCOA2; VGLL2 ID CHILDRENS ONCOLOGY GROUP; SOFT-TISSUE SARCOMA; GENE-EXPRESSION SIGNATURE; ALVEOLAR RHABDOMYOSARCOMA; EMBRYONAL RHABDOMYOSARCOMA; FUSION STATUS; PEDIATRIC RHABDOMYOSARCOMA; IN-VIVO; IDENTIFICATION; MYOD1 AB Introduction: A classification of rhabdomyosarcoma (RMS) with prognostic relevance has primarily relied on clinical features and histologic classification as either embryonal or alveolar RMS. The PAX3-FOXO1 and PAX7-FOXO1 gene fusions occur in 80% of cases with the alveolar subtype and are more predictive of outcome than histologic classification. Identifying additional molecular hallmarks that further subclassify RMS is an active area of research.Areas Covered: The authors review the current state of the PAX3-FOXO1 and PAX7-FOXO1 fusions as prognostic biomarkers. Emerging biomarkers, including mRNA expression profiling, MYOD1 mutations, RAS pathway mutations and gene fusions involving NCOA2 or VGLL2 are also reviewed.Expert commentary: Strategies for modifying RMS risk stratification based on molecular biomarkers are emerging with the potential to transform the clinical management of RMS, ultimately improving patient outcomes by tailoring therapy to predicted patient risk and identifying targets for novel therapies. C1 [Arnold, Michael A.] Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH USA. [Arnold, Michael A.] Ohio State Univ, Dept Pathol, Wexner Med Ctr, Columbus, OH 43210 USA. [Barr, Fredric G.] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. RP Barr, FG (reprint author), NCI, Pathol Lab, Ctr Canc Res, 10 Ctr Dr,Room 2S235D,MSC1500, Bethesda, MD 20892 USA. EM barrfg@mail.nih.gov OI Arnold, Michael/0000-0002-6921-3720 NR 51 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1473-7159 EI 1744-8352 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD FEB PY 2017 VL 17 IS 2 BP 189 EP 194 DI 10.1080/14737159.2017.1275965 PG 6 WC Pathology SC Pathology GA EK4IM UT WOS:000393890300010 PM 28058850 ER PT J AU Michaud, M Prinz, WA Jouhet, J AF Michaud, Morgane Prinz, William A. Jouhet, Juliette TI Glycerolipid synthesis and lipid trafficking in plant mitochondria SO FEBS JOURNAL LA English DT Review DE lipid trafficking; membrane biogenesis; membrane contact sites; mitochondria; phosphate starvation; plants ID MEMBRANE CONTACT SITES; CASTOR BEAN ENDOSPERM; ARABIDOPSIS-THALIANA; ENDOPLASMIC-RETICULUM; PLASMA-MEMBRANE; PHOSPHATIDYLCHOLINE SYNTHESIS; CARDIOLIPIN SYNTHASE; PHOSPHATIDYLSERINE DECARBOXYLASE; PHOSPHATE DEPRIVATION; N-METHYLTRANSFERASE AB Lipid trafficking between mitochondria and other organelles is required for mitochondrial membrane biogenesis and signaling. This lipid exchange occurs by poorly understood nonvesicular mechanisms. In yeast and mammalian cells, this lipid exchange is thought to take place at contact sites between mitochondria and the ER or vacuolar membranes. Some proteins involved in the tethering between membranes or in the transfer of lipids in mitochondria have been identified. However, in plants, little is known about the synthesis of mitochondrial membranes. Mitochondrial membrane biogenesis is particularly important and noteworthy in plants as the lipid composition of mitochondrial membranes is dramatically changed during phosphate starvation and other stresses. This review focuses on the principal pathways involved in the synthesis of the most abundant mitochondrial glycerolipids in plants and the lipid trafficking that is required for plant mitochondria membrane biogenesis. C1 [Michaud, Morgane; Prinz, William A.] NIDDK, Lab Cell & Mol Biol, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. [Michaud, Morgane; Jouhet, Juliette] Univ Grenoble Alpes, Lab Physiol Cellulaire & Vegetale, UMR CNRS 5168, CEA,INRA, Grenoble, France. RP Michaud, M (reprint author), NIDDK, Lab Cell & Mol Biol, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. EM morgane.michaud@nih.gov FU Institute of Diabetes and Digestive and Kidney Diseases; ANR Chloromitolipid [ANR-12-JS2-001] FX This work was supported by the intramural research program of the Institute of Diabetes and Digestive and Kidney Diseases and the ANR Chloromitolipid (ANR-12-JS2-001). NR 84 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD FEB PY 2017 VL 284 IS 3 BP 376 EP 390 DI 10.1111/febs.13812 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK0FJ UT WOS:000393601800003 PM 27406373 ER PT J AU Lubkowski, J Durbin, SV Silva, MCC Farnsworth, D Gildersleeve, JC Oliva, MLV Wlodawer, A AF Lubkowski, Jacek Durbin, Sarah V. Silva, Mariana C. C. Farnsworth, David Gildersleeve, Jeffrey C. Oliva, Maria Luiza V. Wlodawer, Alexander TI Structural analysis and unique molecular recognition properties of a Bauhinia forficata lectin that inhibits cancer cell growth SO FEBS JOURNAL LA English DT Article DE cancer cell growth inhibition; carbohydrate binding; crystal structure; lectin; Tn antigen ID PHASE PEPTIDE-SYNTHESIS; TN-ANTIGEN; GRIFFONIA-SIMPLICIFOLIA; VATAIREA MACROCARPA; CRYSTAL-STRUCTURE; LEGUME LECTINS; PLANT-LECTINS; PROTEINS; COMPLEX; BINDING AB Lectins have been used at length for basic research and clinical applications. New insights into the molecular recognition properties enhance our basic understanding of carbohydrate-protein interactions and aid in the design/development of new lectins. In this study, we used a combination of cell-based assays, glycan microarrays, and X-ray crystallography to evaluate the structure and function of the recombinant Bauhinia forficata lectin (BfL). The lectin was shown to be cytostatic for several cancer cell lines included in the NCI-60 panel; in particular, it inhibited growth of melanoma cancer cells (LOX IMVI) by over 95%. BfL is dimeric in solution and highly specific for binding of oligosaccharides and glycopeptides with terminal N-acetylgalactosamine (GalNAc). BfL was found to have especially strong binding (apparent K-d = 0.5-1.0 nM) to the tumor-associated Tn antigen. High-resolution crystal structures were determined for the ligand-free lectin, as well as for its complexes with three Tn glycopeptides, globotetraose, and the blood group A antigen. Extensive analysis of the eight crystal structures and comparison to structures of related lectins revealed several unique features of GalNAc recognition. Of special note, the carboxylate group of Glu126, lining the glycan-binding pocket, forms H-bonds with both the N-acetyl of GalNAc and the peptide amido group of Tn antigens. Stabilization provided by Glu126 is described here for the first time for any GalNAc-specific lectin. Taken together, the results provide new insights into the molecular recognition of carbohydrates and provide a structural understanding that will enable rational engineering of BfL for a variety of applications. Database Structural data are available in the PDB under the accession numbers 5T50, 5T52, 5T55, 5T54, 5T5L, 5T5J, 5T5P, and 5T5O. C1 [Lubkowski, Jacek; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Durbin, Sarah V.; Farnsworth, David; Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Silva, Mariana C. C.; Oliva, Maria Luiza V.] Univ Fed Sao Paulo, Escola Paulista Med, Sao Paulo, SP, Brazil. RP Lubkowski, J (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM lubkowsj@mail.nih.gov FU National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2009/53766-5, 2012/06366-4, 2014/22649-1]; FAPESP (PD-BEPE) [2014/22649-1]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX We thank Dr Jerry Alexandratos for performing the analytical ultracentrifugation experiments and the staff of the NCI DTP for the NCI-60 assays. We thank the Consortium for Functional Glycomics (GM62116; The Scripps Research Institute), Professors Tom Tolbert (University of Kansas), Lai-Xi Wang (University of Maryland), Xuefei Huang (Michigan State University), Todd Lowary (University of Alberta), and Dr Joseph Barchi (National Cancer Institute) for contributing glycans for the array. This project was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP processes 2009/53766-5, 2012/06366-4 and 2014/22649-1). MCCS was supported by a postdoctoral fellowship from FAPESP (PD-BEPE proc. 2014/22649-1). Diffraction data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at www.ser-cat.org/members.html. Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. NR 50 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD FEB PY 2017 VL 284 IS 3 BP 429 EP 450 DI 10.1111/febs.13989 PG 22 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK0FJ UT WOS:000393601800008 PM 27973758 ER PT J AU Doyle, JM Streeter, RA AF Doyle, Jamie Mihoko Streeter, Robin A. TI Veterans' Location in Health Professional Shortage Areas: Implications for Access to Care and Workforce Supply SO HEALTH SERVICES RESEARCH LA English DT Article DE Veterans; access; rural health care; community-based care; geographic analysis ID NURSE-PRACTITIONER AB Objective. To describe the distribution of Veterans in areas of the United States where there are potentially inadequate supplies of health professionals, and to explore opportunities suggested by this distribution for fostering health workforce flexibility. Data Sources. County-level data from the 2015-2016 Health Resources and Services Administration's (HRSA's) Area Health Resources Files (AHRF) were used to estimate Veteran populations in HRSA-designated health professional shortage areas (HPSAs). This information was then linked to 2015 VA health facility information from the Department of Veterans Affairs. Study Design. Potential Veteran populations living in Shortage Area Counties with no VHA facilities were estimated, and the composition of these populations was explored by Census division and state. Principal Findings. Nationwide, approximately 24 percent of all Veterans and 23 percent of Veterans enrolled in VHA health care live in Shortage Area Counties. These estimates mask considerable variation across states. Conclusions. An examination of Veterans residing in Shortage Area Counties suggests extensive maldistribution of health services across the United States and the continued need to find ways to improve health care access for all Veterans. Effective avenues for doing so may include increasing health workforce flexibility through expansion of nurse practitioner scopes of practice. C1 [Doyle, Jamie Mihoko] NIH, Off Extramural Res, Off Director, 6705 Rockledge Dr,Room 4164, Bethesda, MD 20817 USA. [Doyle, Jamie Mihoko; Streeter, Robin A.] Natl Ctr Hlth Workforce Anal, Hlth Resources & Serv Adm, Rockville, MD USA. RP Doyle, JM (reprint author), NIH, Off Extramural Res, Off Director, 6705 Rockledge Dr,Room 4164, Bethesda, MD 20817 USA. EM jamie.doyle@nih.gov NR 30 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD FEB PY 2017 VL 52 SU S1 BP 459 EP 480 DI 10.1111/1475-6773.12633 PG 22 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EJ9XE UT WOS:000393579700007 PM 27957733 ER PT J AU Nugent, AC Luber, B Carver, FW Robinson, SE Coppola, R Zarate, CA AF Nugent, Allison C. Luber, Bruce Carver, Frederick W. Robinson, Stephen E. Coppola, Richard Zarate, Carlos A., Jr. TI Deriving frequency-dependent spatial patterns in MEG-derived resting state sensorimotor network: A novel multiband ICA technique SO HUMAN BRAIN MAPPING LA English DT Article DE magnetoencephalography; resting-state; oscillations; independent components analysis; synthetic aperture magnetometry; connectivity; network ID INDEPENDENT COMPONENT ANALYSIS; FUNCTIONAL CONNECTIVITY; BRAIN NETWORKS; DEFAULT MODE; FMRI DATA; SYNCHRONIZATION; OSCILLATIONS; MAGNETOENCEPHALOGRAPHY; SCHIZOPHRENIA; DYNAMICS AB Recently, independent components analysis (ICA) of resting state magnetoencephalography (MEG) recordings has revealed resting state networks (RSNs) that exhibit fluctuations of band-limited power envelopes. Most of the work in this area has concentrated on networks derived from the power envelope of beta bandpass-filtered data. Although research has demonstrated that most networks show maximal correlation in the beta band, little is known about how spatial patterns of correlations may differ across frequencies. This study analyzed MEG data from 18 healthy subjects to determine if the spatial patterns of RSNs differed between delta, theta, alpha, beta, gamma, and high gamma frequency bands. To validate our method, we focused on the sensorimotor network, which is well-characterized and robust in both MEG and functional magnetic resonance imaging (fMRI) resting state data. Synthetic aperture magnetometry (SAM) was used to project signals into anatomical source space separately in each band before a group temporal ICA was performed over all subjects and bands. This method preserved the inherent correlation structure of the data and reflected connectivity derived from single-band ICA, but also allowed identification of spatial spectral modes that are consistent across subjects. The implications of these results on our understanding of sensorimotor function are discussed, as are the potential applications of this technique. Hum Brain Mapp 38:779-791, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Nugent, Allison C.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 9000 Rockville Pike,MSC 1030, Bethesda, MD 20892 USA. [Luber, Bruce] NIMH, Noninvas Neurostimulat Unit, NIH, 9000 Rockville Pike,MSC 1030, Bethesda, MD 20892 USA. [Carver, Frederick W.; Robinson, Stephen E.; Coppola, Richard] NIMH, Magnetoencephalog Core Facil, NIH, 9000 Rockville Pike,MSC 1030, Bethesda, MD 20892 USA. RP Nugent, AC (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 9000 Rockville Pike,MSC 1030, Bethesda, MD 20892 USA. EM nugenta@mail.nih.gov FU NARSAD; Brain & Behavior Mood Disorders Research Award FX Contract grant sponsor: NARSAD Independent Investigator (to C. A. Z.); Contract grant sponsor: Brain & Behavior Mood Disorders Research Award (to C. A. Z.). NR 39 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD FEB PY 2017 VL 38 IS 2 BP 779 EP 791 DI 10.1002/hbm.23417 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EK2WC UT WOS:000393786500015 PM 27770478 ER PT J AU Cunningham, SI Tomasi, D Volkow, ND AF Cunningham, Samantha I. Tomasi, Dardo Volkow, Nora D. TI Structural and functional connectivity of the precuneus and thalamus to the default mode network SO HUMAN BRAIN MAPPING LA English DT Article DE default mode network; precuneus; thalamus; diffusion tensor imaging; resting-state fMRI; Human Connectome Project ID RESTING-STATE FMRI; PREFRONTAL CORTEX; RHESUS-MONKEY; WHITE-MATTER; IMPAIRED CONSCIOUSNESS; ANGULAR GYRUS; BRAIN-INJURY; SYSTEM; HUBS; DISORDERS AB Neuroimaging studies have identified functional interactions between the thalamus, precuneus, and default mode network (DMN) in studies of consciousness. However, less is known about the structural connectivity of the precuneus and thalamus to regions within the DMN. We used diffusion tensor imaging (DTI) to parcellate the precuneus and thalamus based on their probabilistic white matter connectivity to each other and DMN regions of interest (ROIs) in 37 healthy subjects from the Human Connectome Database. We further assessed resting-state functional connectivity (RSFC) among the precuneus, thalamus, and DMN ROIs. The precuneus was found to have the greatest structural connectivity with the thalamus, where connection fractional anisotropy (FA) increased with age. The precuneus also showed significant structural connectivity to the hippocampus and middle pre-frontal cortex, but minimal connectivity to the angular gyrus and midcingulate cortex. In contrast, the precuneus exhibited significant RSFC with the thalamus and the strongest RSFC with the AG. Significant symmetrical structural connectivity was found between the thalamus and hippocampus, mPFC, sFG, and precuneus that followed known thalamocortical pathways, while thalamic RSFC was strongest with the precuneus and hippocampus. Overall, these findings reveal high levels of structural and functional connectivity linking the thalamus, precuneus, and DMN. Differences between structural and functional connectivity (such as between the precuneus and AG) may be interpreted to reflect dynamic shifts in RSFC for cortical hub-regions involved with consciousness, but could also reflect the limitations of DTI to detect superficial white matter tracts that connect cortico-cortical regions. Hum Brain Mapp 38:938-956, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Cunningham, Samantha I.; Tomasi, Dardo; Volkow, Nora D.] NIAAA, NIH, Bethesda, MD USA. [Volkow, Nora D.] NIDA, NIH, Bethesda, MD 20892 USA. RP Cunningham, SI (reprint author), NIAAA, Lab Neuroimaging, NIH, MSC 1013,10 Ctr Dr,Room B2L124, Bethesda, MD 20892 USA. EM samicunn@gmail.com FU National Institutes of Health Intramural Research Program FX Contract grant sponsor: National Institutes of Health Intramural Research Program. NR 66 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD FEB PY 2017 VL 38 IS 2 BP 938 EP 956 DI 10.1002/hbm.23429 PG 19 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EK2WC UT WOS:000393786500027 PM 27739612 ER PT J AU Sadeghi, N Gilmore, JH Gerig, G AF Sadeghi, Neda Gilmore, John H. Gerig, Guido TI Twin-singleton developmental study of brain white matter anatomy SO HUMAN BRAIN MAPPING LA English DT Article DE twins; longitudinal brain imaging; early brain development; DTI; nonlinear mixed effects modeling; diffusion; white matter; Gompertz function ID MIXED EFFECTS MODELS; DIFFUSION-TENSOR; STATISTICAL-ANALYSIS; MATURATION; IMAGES; MRI; HERITABILITY; GROWTH; BIRTH; DTI AB Twin studies provide valuable insights into the analysis of genetic and environmental factors influencing human brain development. However, these findings may not generalize to singletons due to differences in pre- and postnatal environments. One would expect the effect of these differences to be greater during the early years of life. To address this concern, we compare longitudinal diffusion data of white matter regions for 26 singletons and 76 twins (monozygotic and dizygotic) from birth to 2 years of age. We use nonlinear mixed effect modeling where the temporal changes in the diffusion parameters are described by the Gompertz function. The Gompertz function describes growth trajectory in terms of intuitive parameters: asymptote, delay, and speed. We analyzed fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) for 21 regions of interest (ROIs). These ROIs included areas in the association, projection, and commissural fiber tracts. We did not find any differences in the diffusion parameters between monozygotic and dizygotic twins. In addition, FA and RD showed no developmental differences between singletons and twins for the regions analyzed. However, the delay parameter of the Gompertz function of AD for the anterior limb of the internal capsule and anterior corona radiata was significantly different between singletons and twins. Further analysis indicated that the differences are small, and twins catch up by the first few months of life. These results suggest that the effects of differences of pre- and postnatal environments between twins and singletons are minimal on white matter development and disappear early in life. Hum Brain Mapp 38:1009-1024, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Sadeghi, Neda] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Quantitat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Gilmore, John H.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Gerig, Guido] NYU, Tandon Sch Engn, Dept Comp Sci & Engn, Brooklyn, NY USA. RP Sadeghi, N (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Quantitat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. EM neda.sadeghi@nih.gov OI Gerig, Guido/0000-0002-9547-6233 FU NIH [R01 MH070890, R01 HD05300, NA-MIC U54 EB005149, U01 NS082086]; NIH Conte Center [MH064065] FX Contract grant sponsor: NIH; Contract grant number: R01 MH070890, R01 HD05300 and Conte Center MH064065; Contract grant sponsor: NIH; Contract grant number: NA-MIC U54 EB005149 and U01 NS082086 NR 42 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD FEB PY 2017 VL 38 IS 2 BP 1009 EP 1024 DI 10.1002/hbm.23435 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EK2WC UT WOS:000393786500032 PM 27739634 ER PT J AU Hamdeh, S Altayar, O Alreddawi, S Murad, M Baidoo, L Hanauer, S AF Hamdeh, Shadi Altayar, Osama Alreddawi, Sama Murad, Mohammad Baidoo, Leonard Hanauer, Stephen TI Does Inflammatory Bowel Disease Carry an Increased Risk of Genitourinary Cancers: A Meta-Analysis SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract CT Advances-in-Inflammatory-Bowel-Diseases-Crohn's-and-Colitis Foundation's National Clinical and Research Conference CY DEC 08-10, 2016 CL Orlando, FL SP Advances Inflammatory Bowel Dis Crohns & Colitis Fdn C1 [Hamdeh, Shadi; Baidoo, Leonard; Hanauer, Stephen] Northwestern Univ, Chicago, IL 60611 USA. [Altayar, Osama] Washington Univ, Sch Med, St Louis, MO USA. [Alreddawi, Sama] NIH, Bldg 10, Bethesda, MD 20892 USA. [Murad, Mohammad] Mayo Clin, Rochester, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD FEB PY 2017 VL 23 SU 1 MA P-071 BP S28 EP S29 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4MX UT WOS:000393902100085 ER PT J AU de Moor, JS Dowling, EC Ekwueme, DU Guy, GP Rodriguez, J Virgo, KS Han, XS Kent, EE Li, CY Litzelman, K McNeel, TS Liu, BM Yabroff, KR AF de Moor, Janet S. Dowling, Emily C. Ekwueme, Donatus U. Guy, Gery P., Jr. Rodriguez, Juan Virgo, Katherine S. Han, Xuesong Kent, Erin E. Li, Chunyu Litzelman, Kristen McNeel, Timothy S. Liu, Benmei Yabroff, K. Robin TI Employment implications of informal cancer caregiving SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Neoplasms; Caregivers; Employment; Cost-of-illness; Quality of life ID DISTRESSED FAMILY CAREGIVERS; BREAST-CANCER; HEALTH-CARE; SURVIVORS; BURDEN; WORK; LUNG; ACCESS; IMPACT; TIME AB Purpose Previous research describing how informal cancer caregiving impacts employment has been conducted in small samples or a single disease site. This paper provides population-based estimates of the effect of informal cancer caregiving on employment and characterizes employment changes made by caregivers. Methods The samples included cancer survivors with a friend or family caregiver, participating in either the Medical Expenditure Panel Survey Experiences with Cancer Survivorship Survey (ECSS) (n = 458) or the LIVESTRONG 2012 Survey for People Affected by Cancer (SPAC) (n = 4706). Descriptive statistics characterized the sample of survivors and their caregivers' employment changes. Multivariable logistic regression identified predictors of caregivers' extended employment changes, comprising time off and changes to hours, duties, or employment status. Results Among survivors with an informal caregiver, 25 % from the ECSS and 29 % from the SPAC reported that their caregivers made extended employment changes. Approximately 8 % of survivors had caregivers who took time off from work lasting >= 2 months. Caregivers who made extended employment changes were more likely to care for survivors: treated with chemotherapy or transplant; closer to diagnosis or end of treatment; who experienced functional limitations; and made work changes due to cancer themselves compared to caregivers who did not make extended employment changes. Conclusions Many informal cancer caregivers make employment changes to provide care during survivors' treatment and recovery. Implications for cancer survivors This study describes cancer caregiving in a prevalent sample of cancer survivors, thereby reflecting the experiences of individuals with many different cancer types and places in the cancer treatment trajectory. C1 [de Moor, Janet S.; Kent, Erin E.; Litzelman, Kristen; Liu, Benmei; Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Dowling, Emily C.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Ekwueme, Donatus U.; Guy, Gery P., Jr.; Rodriguez, Juan; Li, Chunyu] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Han, Xuesong] Amer Canc Soc, Surveillance & Hlth Serv Res Program, Atlanta, GA 30329 USA. [Virgo, Katherine S.] Emory Univ, Rollins Sch Publ Hlth, Dept Hlth Policy & Management, Atlanta, GA 30322 USA. [McNeel, Timothy S.] Informat Management Serv Inc, Calverton, MD USA. [de Moor, Janet S.] NCI, Healthcare Assessment Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,3E438,MSC 9764, Bethesda, MD 20892 USA. RP de Moor, JS (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA.; de Moor, JS (reprint author), NCI, Healthcare Assessment Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,3E438,MSC 9764, Bethesda, MD 20892 USA. EM demoorjs@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 32 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD FEB PY 2017 VL 11 IS 1 BP 48 EP 57 DI 10.1007/s11764-016-0560-5 PG 10 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA EK1GZ UT WOS:000393675100006 PM 27423439 ER PT J AU Kunitake, H Russell, MM Zheng, P Yothers, G Land, SR Petersen, L Fehrenbacher, L Giguere, JK Wickerham, DL Ko, CY Ganz, PA AF Kunitake, Hiroko Russell, Marcia M. Zheng, Ping Yothers, Greg Land, Stephanie R. Petersen, Laura Fehrenbacher, Louis Giguere, Jeffery K. Wickerham, D. Lawrence Ko, Clifford Y. Ganz, Patricia A. TI Quality of life and symptoms in long-term survivors of colorectal cancer: results from NSABP protocol LTS-01 SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Quality of life; Colorectal cancer; Survivors ID SURGICAL ADJUVANT BREAST; COLON-CANCER; HEALTH SURVEY; STAGE-II; PROJECT; VALIDATION; LEUCOVORIN; FATIGUE; FLUOROURACIL; CHEMOTHERAPY AB Purpose Little is known about health-related quality of life (HRQL) in long-term survivors (LTS) of colorectal cancer (CRC). Methods Long-term CRC survivors (>= 5 years) treated in previous National Surgical Adjuvant Breast and Bowel Project trials were recruited from 60 sites. After obtaining consent, a telephone survey was administered, which included HRQL instruments to measure physical health (Instrumental Activities of Daily Living [IADL], SF-12 Physical Component Scale [PCS], SF-36 Vitality Scale), mental health (SF-12 Mental Component Scale [MCS], Life Orientation Test, and Impact of Cancer), and clinical symptoms (Fatigue Symptom Inventory [FSI], European Organization for Research and Treatment of Cancer Colorectal Module [EORTC-CR38], and Brief Pain Inventory). A multivariable model identified predictors of overall quality of life (global health rating). Results Participants (N = 708) had significantly higher HRQL compared with age group-matched non-cancer controls with higher mean scores on SF-12 PCS (49.5 vs. 43.7, p = < 0.05), MCS (55.6 vs. 52.1, p = < 0.05), and SF-36 Vitality Scale (67.1 vs. 59.9, p = < 0.05). Multivariable modeling has demonstrated that better overall physical and mental health (PCS and MCS), positive body image (EORTC-CR38 scale), and less fatigue (FSI), were strongly associated with overall quality of life as measured by the global health rating. Interestingly, ability to perform IADLs, experience of cancer, gastrointestinal complaints, and pain, were not important predictors. Conclusions In long-term CRC survivors, overall physical and mental health was excellent compared with general population. Other disease-related symptoms did not detract from good overall health. Implications for cancer survivors LTS of CRC within the setting of a clinical trial have higher HRQL than the general population, and treatment regimens do not appear to be associated with any significant late effects on quality of life. Trial Registration: NSABP LTS-01: NCT00410579. C1 [Kunitake, Hiroko; Russell, Marcia M.; Wickerham, D. Lawrence; Ko, Clifford Y.; Ganz, Patricia A.] NRG Oncol, Natl Surg Adjuvant Breast & Bowel Project NSABP, Pittsburgh, PA 15213 USA. [Kunitake, Hiroko] Boston Univ, Sch Med, Boston, MA 02118 USA. [Russell, Marcia M.; Ko, Clifford Y.] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, David Geffen Sch Med, 11301 Wilshire Blvd,Mail Code 10H2, Los Angeles, CA 90073 USA. [Zheng, Ping; Yothers, Greg] Univ Pittsburgh, Dept Hlth Policy & Management, Pittsburgh, PA USA. [Yothers, Greg] Univ Pittsburgh, Pittsburgh, PA USA. [Land, Stephanie R.] NCI, Bethesda, MD 20892 USA. [Petersen, Laura] UCLA Jonsson Comprehens Canc Ctr, Los Angeles, CA USA. [Fehrenbacher, Louis] Kaiser Permanente Oncol Clin Trials Northern Cali, Vallejo, CA USA. [Giguere, Jeffery K.] Greenville Hlth Syst Canc Inst, Greenville, SC USA. [Wickerham, D. Lawrence] Allegheny Hlth Network Canc Inst, Pittsburgh, PA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, UCLA Sch Med, Los Angeles, CA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, UCLA Sch Publ Hlth, Los Angeles, CA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Yothers, Greg] NRG Oncol, Pittsburgh, PA USA. RP Russell, MM (reprint author), NRG Oncol, Natl Surg Adjuvant Breast & Bowel Project NSABP, Pittsburgh, PA 15213 USA.; Russell, MM (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, David Geffen Sch Med, 11301 Wilshire Blvd,Mail Code 10H2, Los Angeles, CA 90073 USA. EM Marcia.Russell2@va.gov FU National Institutes of Health, US Department of Health and Human Services, Public Health Service [U10-CA180868, U10-CA180822, UG1CA189867]; American Cancer Society [RSGPB-05-236-01-CPPB] FX The National Cancer Institute at the National Institutes of Health, US Department of Health and Human Services, Public Health Service grants U10-CA180868 (NCTN), U10-CA180822 (NRG SDMC), and UG1CA189867 (NCORP), and grant RSGPB-05-236-01-CPPB from the American Cancer Society (UCLA) are acknowledged. NR 34 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD FEB PY 2017 VL 11 IS 1 BP 111 EP 118 DI 10.1007/s11764-016-0567-y PG 8 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA EK1GZ UT WOS:000393675100013 PM 27562475 ER PT J AU Gornick, MC Scherer, AM Sutton, EJ Ryan, KA Exe, NL Li, M Uhlmann, WR Kim, SYH Roberts, JS De Vries, RG AF Gornick, Michele C. Scherer, Aaron M. Sutton, Erica J. Ryan, Kerry A. Exe, Nicole L. Li, Ming Uhlmann, Wendy R. Kim, Scott Y. H. Roberts, J. Scott De Vries, Raymond G. TI Effect of Public Deliberation on Attitudes toward Return of Secondary Results in Genomic Sequencing SO JOURNAL OF GENETIC COUNSELING LA English DT Article DE Ethics; Deliberative democracy; Surveys; Participant preferences; Return of secondary genomic results ID INCIDENTAL FINDINGS; CANCER; VARIANTS; VIEWS; RISK; COMMUNICATION; PARTICIPANTS; DEMOCRACY; CONSENT; ETHICS AB The increased use of genomic sequencing in clinical diagnostics and therapeutics makes imperative the development of guidelines and policies about how to handle secondary findings. For reasons both practical and ethical, the creation of these guidelines must take into consideration the informed opinions of the lay public. As part of a larger Clinical Sequencing Exploratory Research (CSER) consortium project, we organized a deliberative democracy (DD) session that engaged 66 participants in dialogue about the benefits and risks associated with the return of secondary findings from clinical genomic sequencing. Participants were educated about the scientific and ethical aspects of the disclosure of secondary findings by experts in medical genetics and bioethics, and then engaged in facilitated discussion of policy options for the disclosure of three types of secondary findings: 1) medically actionable results; 2) adult onset disorders found in children; and 3) carrier status. Participants' opinions were collected via surveys administered one month before, immediately following, and one month after the DD session. Post DD session, participants were significantly more willing to support policies that do not allow access to secondary findings related to adult onset conditions in children (I (2) (2, N = 62) = 13.300, p = 0.001) or carrier status (I (2) (2, N = 60) = 11.375, p = 0.003). After one month, the level of support for the policy denying access to secondary findings regarding adult-onset conditions remained significantly higher than the pre-DD level, although less than immediately post-DD (I (2) (1, N = 60) = 2.465, p = 0.041). Our findings suggest that education and deliberation enhance public appreciation of the scientific and ethical complexities of genome sequencing. C1 [Gornick, Michele C.; Scherer, Aaron M.; Ryan, Kerry A.; Exe, Nicole L.; Uhlmann, Wendy R.; Roberts, J. Scott; De Vries, Raymond G.] Univ Michigan, Dept Internal Med, Ctr Bioeth & Social Sci Med, 2800 Plymouth Rd,NCRC Bldg 16,457S, Ann Arbor, MI 48109 USA. [Gornick, Michele C.] Ann Arbor Vet Affairs Hlth Serv Res & Dev, Ann Arbor, MI 48109 USA. [Sutton, Erica J.] Mayo Clin, Biomed Eth Program, Rochester, MN USA. [Li, Ming; Roberts, J. Scott] Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. [Uhlmann, Wendy R.] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA. [Uhlmann, Wendy R.] Univ Michigan, Dept Internal Med, Mol Med & Genet, Ann Arbor, MI 48109 USA. [Kim, Scott Y. H.] NIH, Dept Bioeth, Bethesda, MA USA. [De Vries, Raymond G.] Univ Michigan, Dept Learning Hlth Sci, Sch Med, Ann Arbor, MI 48109 USA. RP Gornick, MC (reprint author), Univ Michigan, Dept Internal Med, Ctr Bioeth & Social Sci Med, 2800 Plymouth Rd,NCRC Bldg 16,457S, Ann Arbor, MI 48109 USA.; Gornick, MC (reprint author), Ann Arbor Vet Affairs Hlth Serv Res & Dev, Ann Arbor, MI 48109 USA. EM gornickm@med.umich.edu FU National Human Genome Research Institute Clinical Sequencing Exploratory Research Consortium grant [1UM1HG006508] FX The authors would like to thank all of the individuals who participated in this study, including the external advisors, DD session facilitators, and presenters Drs. Robert Green and Wylie Burke. The work was supported by the National Human Genome Research Institute Clinical Sequencing Exploratory Research Consortium grant 1UM1HG006508. The sponsor had no role in the study design, collection, analysis, or interpretation of data; writing of the report; or the decision to submit paper for publication. The ideas and opinions expressed in this paper do not represent any position or policy of the National Institutes of Health, the Department of Health and Human Services, or the U.S. government. NR 37 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 EI 1573-3599 J9 J GENET COUNS JI J. Genet. Couns. PD FEB PY 2017 VL 26 IS 1 BP 122 EP 132 DI 10.1007/s10897-016-9987-0 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA EK3KY UT WOS:000393826500013 PM 27307100 ER PT J AU Elrick, A Ashida, S Ivanovich, J Lyons, S Biesecker, BB Goodman, MS Kaphingst, KA AF Elrick, Ashley Ashida, Sato Ivanovich, Jennifer Lyons, Sarah Biesecker, Barbara B. Goodman, Melody S. Kaphingst, Kimberly A. TI Psychosocial and Clinical Factors Associated with Family Communication of Cancer Genetic Test Results among Women Diagnosed with Breast Cancer at a Young Age SO JOURNAL OF GENETIC COUNSELING LA English DT Article DE Genetics; BRCA 1/2; Family communication; Breast cancer ID RISK PERCEPTIONS; INFORMATION; WORRY; MUTATIONS; BRCA1; PREVALENCE; ILLNESS AB Genetic test results have medical implications beyond the patient that extend to biological family members. We examined psychosocial and clinical factors associated with communication of genetic test results within families. Women (N = 1080) diagnosed with breast cancer at age 40 or younger completed an online survey; 920 women that reported prior cancer genetic testing were included in analysis. We examined the proportion of immediate family members to whom they communicated genetic test results, and built multivariable regression models to examine clinical and psychosocial variables associated with the proportion score. Participants were most likely to communicate test results to their mother (83 %) and least likely to their son (45 %). Participants who carried a BRCA mutation (OR = 1.34; 95 % CI = 1.06, 1.70), had higher interest in genomic information (OR = 1.55; 95 % CI = 1.26, 1.91) and lower genetic worry (OR = 0.91; 95 % CI = 0.86, 0.96) communicated genetic test results to a greater proportion of their immediate family members. Participants with a BRCA1/2 mutation shared their genetic test results with more male family members (OR = 1.72; 95 % CI = 1.02, 2.89). Our findings suggest that patients with high worry about genetic risks, low interest in genomic information, or receive a negative genetic test result will likely need additional support to encourage family communication. C1 [Elrick, Ashley; Kaphingst, Kimberly A.] Univ Utah, Dept Commun, LNCO, 255 Cent Campus Dr, Salt Lake City, UT 84112 USA. [Ashida, Sato] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. [Ivanovich, Jennifer; Lyons, Sarah; Goodman, Melody S.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Biesecker, Barbara B.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Kaphingst, Kimberly A.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. RP Elrick, A (reprint author), Univ Utah, Dept Commun, LNCO, 255 Cent Campus Dr, Salt Lake City, UT 84112 USA. EM Ashley.Elrick@hci.utah.edu FU National Human Genome Research Institute's Intramural Research Program; [R01 CA168608] FX This study was funded by R01 CA168608. Effort for BBB was supported by the National Human Genome Research Institute's Intramural Research Program. NR 32 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 EI 1573-3599 J9 J GENET COUNS JI J. Genet. Couns. PD FEB PY 2017 VL 26 IS 1 BP 173 EP 181 DI 10.1007/s10897-016-9995-0 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EK3KY UT WOS:000393826500018 PM 27422778 ER PT J AU Shah, SK AF Shah, Seema K. TI When to start paediatric testing of the adult HIV cure research agenda? SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID ANTIRETROVIRAL THERAPY; CHILDREN; TRIALS; STANDARDS; REMISSION; ETHICS; DEBATE; DRUGS; RISK AB Ethical guidelines recommend that experimental interventions should be tested in adults first before they are tested and approved in children. Some challenge this paradigm, however, and recommend initiating paediatric testing after preliminary safety testing in adults in certain cases. For instance, commentators have argued for accelerated testing of HIV vaccines in children. Additionally, HIV cure research on the use of very early therapy (VET) in infants, prompted in part by the Mississippi baby case, is one example of a strategy that is currently being tested in infants before it has been well tested in adults. Because infants' immune systems are still developing, the timing of HIV transmission is easier to identify in infants than in adults, and infants who receive VET might never develop the viral reservoirs that make HIV so difficult to eradicate, infants may be uniquely situated to achieve HIV cure or sustained viral remission. Several commentators have now argued for earlier initiation of HIV cure interventions other than (or in addition to) VET in children. HIV cure research is therefore a good case for re-examining the important question of when to initiate paediatric research. I will argue that, despite the potential for HIV cure research to benefit children and the scientific value of involving children in this research, the HIV cure agenda should not accelerate the involvement of children for the following reasons: HIV cure research is highly speculative, risky, aimed at combination approaches and does not compare favourably with the available alternatives. I conclude by drawing general implications for the initiation of paediatric testing, including that interventions that have to be used in combination with others and cures for chronic diseases may not be valuable enough to justify early paediatric testing. C1 [Shah, Seema K.] NIH, Dept Bioeth, 10 Ctr Dr Bldg 10Rm 1C118, Bethesda, MD 20892 USA. RP Shah, SK (reprint author), NIH, Dept Bioeth, 10 Ctr Dr Bldg 10Rm 1C118, Bethesda, MD 20892 USA. EM shahse@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH) Clinical Center; National Institute of Allergy and Infectious Diseases (NIAID) FX The Intramural Research Program of the National Institutes of Health (NIH) Clinical Center and the National Institute of Allergy and Infectious Diseases (NIAID) supported this research. NR 31 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD FEB PY 2017 VL 43 IS 2 BP 82 EP 86 DI 10.1136/medethics-2015-103116 PG 5 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EK0NU UT WOS:000393624200006 PM 27259546 ER PT J AU Bromwich, D Millum, JR AF Bromwich, Danielle Millum, Joseph R. TI Informed consent to HIV cure research SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID ETHICAL CONSIDERATIONS; TRIALS; INTERVENTIONS; PARTICIPANTS; QUALITY; FORMS AB Trials with highly unfavourable risk-benefit ratios for participants, like HIV cure trials, raise questions about the quality of the consent of research participants. Why, it may be asked, would a person with HIV who is doing well on antiretroviral therapy be willing to jeopardise his health by enrolling in such a trial? We distinguish three concerns: first, how information is communicated to potential participants; second, participants' motivations for enrolling in potentially high risk research with no prospect of direct benefit; and third, participants' understanding of the details of the trials in which they enrol. We argue that the communication concern is relevant to the validity of informed consent and the quality of decision making, that the motivation concern does not identify a genuine problem with either the validity of consent or the quality of decision making and that the understanding concern may not be relevant to the validity of consent but is relevant to the quality of decision making. In doing so, we derive guidance points for researchers recruiting and enrolling participants into their HIV cure trials, as well as the research ethics committees reviewing proposed studies. C1 [Bromwich, Danielle] Univ Massachusetts, Dept Philosophy, 100 Morrissey BLVD, Boston, MA 02125 USA. [Millum, Joseph R.] NIH, Clin Ctr Dept Bioeth, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Bromwich, D (reprint author), Univ Massachusetts, Dept Philosophy, 100 Morrissey BLVD, Boston, MA 02125 USA. EM danielle.bromwich@umb.edu FU National Institute of Allergy and Infectious Diseases [1 R56 AI114617-01] FX National Institute of Allergy and Infectious Diseases (1 R56 AI114617-01). Clinical Center intramural funding. NR 33 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD FEB PY 2017 VL 43 IS 2 BP 108 EP 113 DI 10.1136/medethics-2015-103122 PG 6 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EK0NU UT WOS:000393624200012 PM 27288096 ER PT J AU Harris, RA Bajo, M Bell, RL Blednov, YA Varodayan, FP Truitt, JM de Guglielmo, G Lasek, AW Logrip, ML Vendruscolo, LF Roberts, AJ Roberts, E George, O Mayfield, J Billiar, TR Hackam, DJ Mayfield, RD Koob, GF Roberto, M Homanics, GE AF Harris, R. Adron Bajo, Michal Bell, Richard L. Blednov, Yuri A. Varodayan, Florence P. Truitt, Jay M. de Guglielmo, Giordano Lasek, Amy W. Logrip, Marian L. Vendruscolo, Leandro F. Roberts, Amanda J. Roberts, Edward George, Olivier Mayfield, Jody Billiar, Timothy R. Hackam, David J. Mayfield, R. Dayne Koob, George F. Roberto, Marisa Homanics, Gregg E. TI Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents SO JOURNAL OF NEUROSCIENCE LA English DT Article DE (+)-naloxone; chronic intermittent ethanol vapor; drinking-in-the-dark; lipopolysaccharide; operant self-administration; Toll-like receptor 4 knock-out ID RECEPTOR 4 TLR4; INCREASES GABAERGIC TRANSMISSION; CORTICOTROPIN-RELEASING FACTOR; AMINOBUTYRIC-ACID RELEASE; ALCOHOL-INDUCED SEDATION; ANXIETY-LIKE BEHAVIOR; RAT CENTRAL NUCLEUS; CENTRAL AMYGDALA; DEPENDENT RATS; INDUCED NEUROINFLAMMATION AB Toll-like receptor 4 (TLR4) is a critical component of innate immune signaling and has been implicated in alcohol responses in preclinical and clinical models. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium tested the hypothesis that TLR4 mediates excessive ethanol drinking using the following models: (1) Tlr4 knock-out (KO) rats, (2) selective knockdown of Tlr4 mRNA in mouse nucleus accumbens (NAc), and (3) injection of the TLR4 antagonist (+)-naloxone in mice. Lipopolysaccharide (LPS) decreased food/water intake and body weight in ethanol-naive and ethanol-trained wild-type (WT), but not Tlr4 KO rats. There were no consistent genotypic differences in two-bottle choice chronic ethanol intake or operant self-administration in rats before or after dependence. In mice, (+)-naloxone did not decrease drinking-in-the-dark and only modestly inhibited dependence-driven consumption at the highest dose. Tlr4 knockdown in mouse NAc did not decrease drinking in the two-bottle choice continuous or intermittent access tests. However, the latency to ethanol-induced loss of righting reflex increased and the duration decreased in KO versus WT rats. In rat central amygdala neurons, deletion of Tlr4 altered GABA(A) receptor function, but not GABA release. Although there were no genotype differences in acute ethanol effects before or after chronic intermittent ethanol exposure, genotype differences were observed after LPS exposure. Using different species and sexes, different methods to inhibit TLR4 signaling, and different ethanol consumption tests, our comprehensive studies indicate that TLR4 may play a role in ethanol-induced sedation and GABA(A) receptor function, but does not regulate excessive drinking directly and would not be an effective therapeutic target. C1 [Harris, R. Adron; Blednov, Yuri A.; Truitt, Jay M.; Mayfield, Jody; Mayfield, R. Dayne] Univ Texas Austin, Waggoner Ctr Alcohol & Addict Res, 2500 Speedway, Austin, TX 78712 USA. [Bajo, Michal; Varodayan, Florence P.; de Guglielmo, Giordano; Logrip, Marian L.; Vendruscolo, Leandro F.; George, Olivier; Koob, George F.; Roberto, Marisa] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Bell, Richard L.] Indiana Univ Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. [Lasek, Amy W.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Roberts, Amanda J.] Scripps Res Inst, Mol & Cellular Neurosci Dept, La Jolla, CA 92037 USA. [Roberts, Amanda J.] Scripps Res Inst, Mouse Behav Assessment Core, La Jolla, CA 92037 USA. [Roberts, Edward] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Billiar, Timothy R.; Hackam, David J.] Univ Pittsburgh, Dept Surg, 497 Scaife Hall, Pittsburgh, PA 15213 USA. [Homanics, Gregg E.] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA 15261 USA. [Homanics, Gregg E.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15261 USA. [Logrip, Marian L.] Indiana Univ Purdue Univ Indianapolis, Dept Psychol, Indianapolis, IN USA. [Vendruscolo, Leandro F.] NIDA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Koob, George F.] NIAAA, NIH, Bethesda, MD USA. RP Harris, RA (reprint author), Univ Texas Austin, Waggoner Ctr Alcohol & Addict Res, 2500 Speedway, Austin, TX 78712 USA. EM harris@austin.utexas.edu OI harris, robert/0000-0001-8870-5950; Bell, Richard/0000-0002-0525-0485 FU National Institutes of Health (National Institute on Alcohol Abuse and Alcoholism) [U01 AA013517, AA013498, U24 AA015512, U01 AA013522, U01 AA013520, U01 AA020926, P0 AA020683, U01 AA013523, AA020893, AA016654, U01 AA020889]; National Institutes of Health (Integrative Neuroscience Initiative on Alcoholism) FX This work was supported by the National Institutes of Health (Integrative Neuroscience Initiative on Alcoholism and the National Institute on Alcohol Abuse and Alcoholism Grants U01 AA013517 and AA013498 to M.R., Grants U24 AA015512 and U01 AA013522 to R.L.B., Grant U01 AA013520 to Y.A.B. and R.A.H., Grants U01 AA020926 and P0 AA020683 to R.D.M., Grants U01 AA013523 and AA020893 to A.J.R., Grant AA016654 to A.W.L., and Grant U01 AA020889 to G.E.H.). (GFK). We thank Jillian Benavidez, Mendy Black, Molly Brennan, Carolyn Ferguson, Tali Nadav, Lindsay Cates, and Donghong He for expert technical assistance and Brigitte Kieffer and Jahan Dadgar for providing the EGFP-Cre construct. NR 76 TC 1 Z9 1 U1 5 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 1 PY 2017 VL 37 IS 5 BP 1139 EP 1155 DI 10.1523/JNEUROSCI.2002-16.2016 PG 17 WC Neurosciences SC Neurosciences & Neurology GA EJ9TT UT WOS:000393570700008 PM 27986929 ER PT J AU Pitcher, D Japee, S Rauth, L Ungerleider, XG AF Pitcher, David Japee, Shruti Rauth, Lionel Ungerleider, XLeslie G. TI The Superior Temporal Sulcus Is Causally Connected to the Amygdala: A Combined TBS-fMRI Study SO JOURNAL OF NEUROSCIENCE LA English DT Article DE amygdala; face perception; face processing; STS; TMS ID FUSIFORM FACE AREA; MACAQUE MONKEY AMYGDALA; HUMAN NEURAL SYSTEM; FACIAL-EXPRESSION; ACQUIRED PROSOPAGNOSIA; IMPAIRED RECOGNITION; CORTICAL INPUTS; HUMAN BRAIN; PERCEPTION; CORTEX AB Nonhuman primate neuroanatomical studies have identified a cortical pathway from the superior temporal sulcus (STS) projecting into dorsal subregions of the amygdala, but whether this same pathway exists in humans is unknown. Here, we addressed this question by combining theta burst transcranial magnetic stimulation (TBS) with fMRI to test the prediction that the STS and amygdala are functionally connected during face perception. Human participants (N = 17) were scanned, over two sessions, while viewing 3 s video clips of moving faces, bodies, and objects. During these sessions, TBS was delivered over the face-selective right posterior STS (rpSTS) or over the vertex control site. A region-of-interest analysis revealed results consistent with our hypothesis. Namely, TBS delivered over the rpSTS reduced the neural response to faces (but not to bodies or objects) in the rpSTS, right anterior STS (raSTS), and right amygdala, compared with TBS delivered over the vertex. By contrast, TBS delivered over the rpSTS did not significantly reduce the neural response to faces in the right fusiform face area or right occipital face area. This pattern of results is consistent with the existence of a cortico-amygdala pathway in humans for processing face information projecting from the rpSTS, via the raSTS, into the amygdala. This conclusion is consistent with nonhuman primate neuroanatomy and with existing face perception models. C1 [Pitcher, David] Univ York, Dept Psychol, York YO10 5DD, N Yorkshire, England. [Japee, Shruti; Rauth, Lionel; Ungerleider, XLeslie G.] NIMH, Sect Neurocircuitry, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Pitcher, D (reprint author), Univ York, Dept Psychol, York YO10 5DD, N Yorkshire, England. EM david.pitcher@york.ac.uk FU National Institute of Mental Health Intramural Research Program FX This work was supported by the National Institute of Mental Health Intramural Research Program. We thank Geena Ianni and Kelsey Holiday for help with data collection; and Nancy Kanwisher for providing experimental stimuli. NR 40 TC 0 Z9 0 U1 3 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 1 PY 2017 VL 37 IS 5 BP 1156 EP 1161 DI 10.1523/JNEUROSCI.0114-16.2016 PG 6 WC Neurosciences SC Neurosciences & Neurology GA EJ9TT UT WOS:000393570700009 PM 28011742 ER PT J AU Moreno, E Quiroz, C Rea, W Cai, NS Mallol, J Cortes, A Lluis, C Canela, EI Casado, V Ferre, S AF Moreno, Estefania Quiroz, Cesar Rea, William Cai, Ning-Sheng Mallol, Josefa Cortes, Antoni Lluis, Carme Canela, Enric I. Casado, Vicent Ferre, Sergi TI Functional mu-Opioid-Galanin Receptor Heteromers in the Ventral Tegmental Area SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dopamine; galanin receptor; MAPK; opioid receptor; receptor heteromer; ventral tegmental area ID NUCLEUS-ACCUMBENS; ALLOSTERIC INTERACTIONS; DOPAMINE OVERFLOW; FEEDING-BEHAVIOR; PLACE PREFERENCE; OPIATE REWARD; MECHANISMS; WITHDRAWAL; ADDICTION; AGONIST AB The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of mu-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKTandCREBphosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders. C1 [Moreno, Estefania; Mallol, Josefa; Cortes, Antoni; Lluis, Carme; Canela, Enric I.; Casado, Vicent] Univ Barcelona, Fac Biol, Ctr Biomed Res Neurodegenerat Dis Network, Inst Biomed, E-08028 Barcelona, Spain. [Moreno, Estefania; Mallol, Josefa; Cortes, Antoni; Lluis, Carme; Canela, Enric I.; Casado, Vicent] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biomed, Inst Biomed, E-08028 Barcelona, Spain. [Quiroz, Cesar; Rea, William; Cai, Ning-Sheng; Ferre, Sergi] NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Ferre, S (reprint author), NIDA, Integrat Neurobiol Sect, Intramural Res Program, Triad Technol Bldg,333 Cassell Dr, Baltimore, MD 21224 USA.; Casado, V (reprint author), Univ Barcelona, Fac Biol, Dept Biochem & Mol Biomed, Diagonal 643, E-08028 Barcelona, Spain. EM vcasado@ub.edu; sferre@intra.nida.nih.gov RI Ferre, Sergi/K-6115-2014; Canela, Enric I./M-8726-2013 OI Ferre, Sergi/0000-0002-1747-1779; Canela, Enric I./0000-0003-4992-7440 FU Government of Catalonia [2014-SGR-1236]; Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas [CB06/05/0064]; Ministerio de Economia y Competitividad; European Regional Development Funds of the European Union [SAF2014-54840-R]; Fundacio La Marato de TV3 [20140610]; intramural funds of the National Institute on Drug Abuse FX This work was supported by Government of Catalonia Grant 2014-SGR-1236, "Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas" Grant CB06/05/0064, "Ministerio de Economia y Competitividad" and European Regional Development Funds of the European Union Grant SAF2014-54840-R, "Fundacio La Marato de TV3" Grant 20140610, and intramural funds of the National Institute on Drug Abuse. NR 43 TC 0 Z9 0 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 1 PY 2017 VL 37 IS 5 BP 1176 EP 1186 DI 10.1523/JNEUROSCI.2442-16.2016 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EJ9TT UT WOS:000393570700011 PM 28007761 ER PT J AU Foster, MW Gwinn, WM Kelly, FL Brass, DM Valente, AM Moseley, MA Thompson, JW Morgan, DL Palmer, SM AF Foster, Matthew W. Gwinn, William M. Kelly, Francine L. Brass, David M. Valente, Ashlee M. Moseley, M. Arthur Thompson, J. Will Morgan, Daniel L. Palmer, Scott M. TI Proteomic Analysis of Primary Human Airway Epithelial Cells Exposed to the Respiratory Toxicant Diacetyl SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE BO; butter flavoring; butanedione; cornified envelope; pentanedione; repetin; RSPH4A; PRM; TGM1; squamous metaplasia ID BRONCHIOLITIS OBLITERANS; SQUAMOUS METAPLASIA; EPIDERMAL DIFFERENTIATION; INTERMEDIATE-FILAMENTS; TARGETED PROTEOMICS; FLAVORING AGENTS; II KERATINS; STEM-CELLS; PROTEIN; LUNG AB Occupational exposures to the diketone flavoring agent, diacetyl, have been associated with bronchiolitis obliterans, a rare condition of airway fibrosis. Model studies in rodents have suggested that the airway epithelium is a major site of diacetyl toxicity, but the effects of diacetyl exposure upon the human airway epithelium are poorly characterized. Here we performed quantitative LC-MS/MS-based proteomics to study the effects of repeated diacetyl vapor exposures on 3D organotypic cultures of human primary tracheobronchial epithelial cells. Using a label-free approach, we quantified approximately 3400 proteins and 5700 phosphopeptides in cell lysates across four independent donors. Altered expression of proteins and phosphopeptides were suggestive of loss of cilia and increased squamous differentiation in diacetyl-exposed cells. These phenomena were confirmed by immunofluorescence staining of culture cross sections. Hyperphosphorylation and cross-linking of basal cell keratin were also observed in diacetyltreated cells, and we used parallel reaction monitoring to confidently localize and quantify previously uncharacterized sites of phosphorylation in keratin 6. Collectively, these data identify numerous molecular changes in the epithelium that may be important to the pathogenesis of flavoring-induced bronchiolitis obliterans. More generally, this study highlights the utility of quantitative proteomics for the study of in vitro models of airway injury and disease. C1 [Foster, Matthew W.; Kelly, Francine L.; Brass, David M.; Valente, Ashlee M.; Palmer, Scott M.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Foster, Matthew W.; Moseley, M. Arthur; Thompson, J. Will] Duke Univ, Med Ctr, Duke Prote & Metabol Shared Resource, Durham, NC 27710 USA. [Gwinn, William M.; Morgan, Daniel L.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Foster, MW (reprint author), Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA.; Foster, MW (reprint author), Duke Univ, Med Ctr, Duke Prote & Metabol Shared Resource, Durham, NC 27710 USA. EM mwfoster@duke.edu FU [R21 OH010490] FX This work was supported in part by R21 OH010490 (M.W.F. and S.M.P.) NR 51 TC 0 Z9 0 U1 7 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD FEB PY 2017 VL 16 IS 2 BP 538 EP 549 DI 10.1021/acs.jproteome.6b00672 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA EJ9IK UT WOS:000393539600017 PM 27966365 ER PT J AU Banerjee, S Grayson, PC AF Banerjee, Shubhasree Grayson, Peter C. TI Vasculitis Around the World: Epidemiologic Insights into Causality and a Need for Global Partnerships SO JOURNAL OF RHEUMATOLOGY LA English DT Editorial Material ID ANTIBODY-ASSOCIATED VASCULITIS; ANCA-ASSOCIATED VASCULITIS; GIANT-CELL ARTERITIS; TAKAYASU-ARTERITIS; MICROSCOPIC POLYANGIITIS; JAPAN; FEATURES C1 [Banerjee, Shubhasree; Grayson, Peter C.] NIAMSD, US NIH, Vasculitis Translat Res Program, Bethesda, MD 20892 USA. RP Grayson, PC (reprint author), NIH, 10 Ctr Dr,Bldg 10,6N Rm 216G, Bethesda, MD 20892 USA. EM peter.grayson@nih.gov FU NIAMS FX Supported through the Intramural Research Program at NIAMS. NR 17 TC 0 Z9 0 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD FEB PY 2017 VL 44 IS 2 BP 136 EP 139 DI 10.3899/jrheum.161468 PG 4 WC Rheumatology SC Rheumatology GA EK4PN UT WOS:000393909300002 PM 28148752 ER PT J AU Gebreab, SY Manna, ZG Khan, RJ Riestra, P Xu, RH Davis, SK AF Gebreab, Samson Y. Manna, Zerai G. Khan, Rumana J. Riestra, Pia Xu, Ruihua Davis, Sharon K. TI Less Than Ideal Cardiovascular Health Is Associated With Shorter Leukocyte Telomere Length: The National Health and Nutrition Examination Surveys, 1999-2002 SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE aging; AHA Scientific Statement; cardiovascular disease risk factors; cardiovascular health; diverse populations; epidemiology; inflammation; leukocyte telomere length; telomere genetics ID CORONARY-ARTERY CALCIUM; AGE-RELATED DISEASE; AFRICAN-AMERICANS; POSTMENOPAUSAL WOMEN; OXIDATIVE STRESS; GENETIC ANCESTRY; ATHEROSCLEROSIS; RISK; MORTALITY; ADULTS AB Background-The associations between individual cardiovascular disease risk factors and leukocyte telomere length (LTL) have been inconclusive. We investigated the association between LTL and overall cardiovascular health (CVH) as defined by the American Heart Association and whether the association is modified by sex and race/ethnicity. Methods and Results-We included 5194 adults (aged >= 20) from the National Health and Nutrition Examination Survey 1999-2002. CVH was defined as a composite score of the 7 metrics (smoking, physical activity, diet, body mass index, blood pressure, total cholesterol, and fasting blood glucose) and categorized as "poor," "intermediate," and "ideal." LTL was assayed from whole blood using the quantitative polymerase chain reaction method relative to standard reference DNA. Multivariable linear regression models were used to estimate the association between CVH and log-transformed LTL. We found strong graded association between CVH and LTL in the overall sample, with evidence of dose-response relationship (P for trend= 0.013). Individuals with poor and intermediate CVH had significantly shorter LTL than individuals with ideal CVH (-3.4% [95% CI=-6.0%, -0.8%] and -2.4% [-4.4%, -0.3%], respectively), after adjustment for demographic variables, socioeconomic status, and C-reactive protein. The association was stronger in women (-6.6% [-10.2%, -2.9%] for poor vs ideal CVH) and non-Hispanic whites (-4.3% [-7.1%, -1.4%] for poor vs ideal CVH). Conclusions-The findings suggest that less-than-ideal CVH is associated with shorter LTL, but this association varies by sex and race/ethnicity. Future longitudinal research is needed to elucidate the mechanisms that underlie the association between CVH and LTL. C1 [Gebreab, Samson Y.; Khan, Rumana J.; Riestra, Pia; Xu, Ruihua; Davis, Sharon K.] NHGRI, Cardiovasc Dis Sect,Social Epidemiol Res Unit, Metab Cardiovasc & Inflammatory Dis Genom Branch, NIH, 10 Ctr Dr,Room 7N316,MSC 1644, Bethesda, MD 20892 USA. [Manna, Zerai G.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Gebreab, SY (reprint author), NHGRI, Cardiovasc Dis Sect,Social Epidemiol Res Unit, Metab Cardiovasc & Inflammatory Dis Genom Branch, NIH, 10 Ctr Dr,Room 7N316,MSC 1644, Bethesda, MD 20892 USA. EM samson.gebreab@nih.gov FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This research is supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 60 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2017 VL 6 IS 2 AR e004105 DI 10.1161/JAHA.116.004105 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EK0CS UT WOS:000393594700011 ER PT J AU Nagy, Z Szabo, PM Grolmusz, VK Perge, P Igaz, I Patocs, A Igaz, P AF Nagy, Z. Szabo, P. M. Grolmusz, V. K. Perge, P. Igaz, I. Patocs, A. Igaz, P. TI MEN1 and microRNAs: The link between sporadic pituitary, parathyroid and adrenocortical tumors? SO MEDICAL HYPOTHESES LA English DT Article DE Pituitary; Parathyroid; Adrenal cortex; Tumor; MEN1; MicroRNA ID ENDOCRINE NEOPLASIA TYPE-1; SUPPRESSOR MENIN; DOWN-REGULATION; TRANSCRIPTION FACTORS; CELL-PROLIFERATION; EXPRESSION; ADENOMAS; CARCINOMA; PATHWAY; PATHOGENESIS AB Sporadic tumors of the pituitary, parathyroids and adrenal cortex are unique, as their benign forms are very common, but malignant forms are exceptionally rare. Hereditary forms of these tumors occur in multiple endocrine neoplasia syndrome type 1 (MEN1). We hypothesize that the pathogenic link among the sporadic tumors of these organs of different germ layers might be represented by common molecular pathways involving the MEN1 gene and microRNAs (miR). miR-24 might be a microRNA linking the three tumor entities, but other candidates such as miR-142-3p and microRNAs forming the DLK1-MEG3 miRNA cluster might also be of importance. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Nagy, Z.; Grolmusz, V. K.; Perge, P.; Igaz, P.] Semmelweis Univ, Fac Med, Dept Med 2, Szentkiralyi Str 46, H-1088 Budapest, Hungary. [Szabo, P. M.] NCI, NIH, DCID, BRP, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Grolmusz, V. K.; Patocs, A.] Hungarian Acad Sci, Lendulet Res Grp 2013, Szentkiralyi Str 46, H-1088 Budapest, Hungary. [Grolmusz, V. K.; Patocs, A.] Semmelweis Univ, Szentkiralyi Str 46, H-1088 Budapest, Hungary. [Igaz, I.] Szt Imre Teaching Hosp Budapest, Dept Gastroenterol, Budapest, Hungary. [Patocs, A.] Semmelweis Univ, Dept Lab Med, Fac Med, Szentkiralyi Str 46, H-1088 Budapest, Hungary. RP Igaz, P (reprint author), Semmelweis Univ, Fac Med, Dept Med 2, Szentkiralyi Str 46, H-1088 Budapest, Hungary. EM igaz.peter@med.semmelweis-univ.hu RI Igaz, Peter/D-3081-2014 OI Igaz, Peter/0000-0003-2192-554X FU National Research, Development and Innovation Office - NKFIH [K115398] FX This study has been supported by a grant from the National Research, Development and Innovation Office - NKFIH (grant K115398) to Dr. Peter Igaz. NR 61 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0306-9877 EI 1532-2777 J9 MED HYPOTHESES JI Med. Hypotheses PD FEB PY 2017 VL 99 BP 40 EP 44 DI 10.1016/j.mehy.2016.12.007 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK1XT UT WOS:000393721800008 PM 28110695 ER PT J AU Thurston, RC Johnson, BD Shufelt, CL Braunstein, GD Berga, SL Stanczyk, FZ Pepine, CJ Bittner, V Reis, SE Thompson, DV Kelsey, SF Sopko, G Merz, CNB AF Thurston, Rebecca C. Johnson, B. Delia Shufelt, Chrisandra L. Braunstein, Glenn D. Berga, Sarah L. Stanczyk, Frank Z. Pepine, Carl J. Bittner, Vera Reis, Steven E. Thompson, Diane V. Kelsey, Sheryl F. Sopko, George Merz, C. Noel Bairey TI Menopausal symptoms and cardiovascular disease mortality in the Women's Ischemia Syndrome Evaluation (WISE) SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Endothelial dysfunction; Hot flashes cardiovascular disease; Menopausal symptoms; Mortality; Vasomotor symptoms ID POSTMENOPAUSAL HORMONE-THERAPY; CORONARY-ARTERY-DISEASE; VASOMOTOR SYMPTOMS; HOT FLASHES; MIDLIFE WOMEN; RISK-FACTORS; NATION; HEALTH; TRANSITION; FLUSHES AB Objective: Studies have linked vasomotor symptoms (VMS) to markers of cardiovascular disease (CVD) risk, yet few have considered clinical cardiovascular events. Data suggest that associations may depend upon the age that symptoms occur. We examined associations between VMS and cardiovascular events and endothelial function, considering age of symptom onset. Methods: The Women's Ischemia Syndrome Evaluation enrolled women referred for coronary angiography for suspected myocardial ischemia. A total of 254 women aged more than 50 years, postmenopausal, with both ovaries, not taking hormone therapy underwent a baseline evaluation, were followed annually (median = 6.0 y), and the National Death Index was searched to ascertain CVD mortality (median = 9.3 y). A subset of participants underwent brachial artery ultrasound for flow-mediated dilation (FMD). Receiver-operating curve analysis was used to determine vasomotor symptom groups (symptoms beginning < age 42 [early onset], beginning >= 42 [later onset], never) which were examined in relation to cardiovascular events and FMD in Cox proportional hazard and linear regression models. Results: Women reporting early onset VMS (HR = 3.35, 95% CI = 1.23-7.86, P = 0.005) and women who never had VMS (HR = 2.17, 95% CI = 1.02-4.62, P = 0.05) had higher CVD mortality than women with later onset symptoms (multivariable models). Women with early onset VMS had lower FMD than women with later onset symptoms (b = -4.31, SE = 2.10, P = 0.04, multivariable). Conclusions: Women with signs and symptoms of ischemia who had VMS beginning early in midlife had higher CVD mortality and reduced endothelial function relative to women with later onset symptoms. Future research should evaluate the vascular phenotype of women with early midlife VMS. C1 [Thurston, Rebecca C.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Thurston, Rebecca C.; Johnson, B. Delia; Kelsey, Sheryl F.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Shufelt, Chrisandra L.; Braunstein, Glenn D.; Merz, C. Noel Bairey] Cedars Sinai Heart Inst, Barbra Streisand Womens Heart Ctr, Los Angeles, CA USA. [Berga, Sarah L.] Wake Forest Sch Med, Sect Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, Winston Salem, NC USA. [Stanczyk, Frank Z.] Univ Southern Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA USA. [Pepine, Carl J.] Univ Florida, Dept Med, Div Cardiol, Gainesville, FL USA. [Bittner, Vera] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Reis, Steven E.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Thompson, Diane V.] Allegheny Gen Hosp, Dept Med, Div Cardiol, Pittsburgh, PA 15212 USA. [Sopko, George] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Thurston, RC (reprint author), Univ Pittsburgh, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15213 USA. EM thurstonrc@upmc.edu FU National Heart, Lung and Blood Institutes (NHLBI) [N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, RO1-HL-073412-01]; Gustavus and Louis Pfeiffer Research Foundation, Danville, New Jersey; Women's Guild of Cedars-Sinai Medical Center, Los Angeles, California; Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, Pennsylvania; QMED, Inc, Laurence Harbor, New Jersey; Edythe L. Broad Endowment; Barbra Streisand Women's Cardiovascular Research and Education Program; Linda Joy Pollin Women's Heart Health Program; Constance Austin Fellowship Endowment; Cedars-Sinai Medical Center, Los Angeles; Erika Glazer Women's Heart Health Project; Cedars-Sinai Medical Center, Los Angeles, California; NHLBI grant [K24HL123565] FX This work was supported by contracts from the National Heart, Lung and Blood Institutes (NHLBI), nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, RO1-HL-073412-01; grants U0164829, U01 HL649141, U01 HL649241; and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, New Jersey, The Women's Guild of Cedars-Sinai Medical Center, Los Angeles, California, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, Pennsylvania, and QMED, Inc, Laurence Harbor, New Jersey, and the Edythe L. Broad Endowment, the Barbra Streisand Women's Cardiovascular Research and Education Program, the Linda Joy Pollin Women's Heart Health Program, and the Constance Austin Fellowship Endowment, Cedars-Sinai Medical Center, Los Angeles and the Erika Glazer Women's Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, California, and by an NHLBI grant K24HL123565 to Thurston. NR 35 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD FEB PY 2017 VL 24 IS 2 BP 126 EP 132 DI 10.1097/GME.0000000000000731 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EK2LM UT WOS:000393758800003 PM 27676638 ER PT J AU Beach, JR Bruun, KS Shao, L Li, D Swider, Z Remmert, K Zhang, YF Conti, MA Adelstein, RS Rusan, NM Betzig, E Hammer, JA AF Beach, Jordan R. Bruun, Kyle S. Shao, Lin Li, Dong Swider, Zac Remmert, Kirsten Zhang, Yingfan Conti, Mary A. Adelstein, Robert S. Rusan, Nasser M. Betzig, Eric Hammer, John A. TI Actin dynamics and competition for myosin monomer govern the sequential amplification of myosin filaments SO NATURE CELL BIOLOGY LA English DT Article ID LIGHT-CHAIN KINASE; SMOOTH-MUSCLE; PLATELET MYOSIN; VERTEBRATE NONMUSCLE; II MINIFILAMENTS; RHO-KINASE; PHOSPHORYLATION; ORGANIZATION; POLYMERIZATION; CONFORMATION AB The cellular mechanisms governing non-muscle myosin II (NM2) filament assembly are largely unknown. Using EGFP-NM2A knock-in fibroblasts and multiple super-resolution imaging modalities, we characterized and quantified the sequential amplification of NM2 filaments within lamellae, wherein filaments emanating from single nucleation events continuously partition, forming filament clusters that populate large-scale actomyosin structures deeper in the cell. Individual partitioning events coincide spatially and temporally with the movements of diverging actin fibres, suppression of which inhibits partitioning. These and other data indicate that NM2A filaments are partitioned by the dynamic movements of actin fibres to which they are bound. Finally, we showed that partition frequency and filament growth rate in the lamella depend on MLCK, and that MLCK is competing with centrally active ROCK for a limiting pool of monomer with which to drive lamellar filament assembly. Together, our results provide new insights into the mechanism and spatio-temporal regulation of NM2 filament assembly in cells. C1 [Beach, Jordan R.; Bruun, Kyle S.; Swider, Zac; Remmert, Kirsten; Rusan, Nasser M.; Hammer, John A.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Shao, Lin; Li, Dong; Betzig, Eric] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. [Zhang, Yingfan; Conti, Mary A.; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Beach, JR; Hammer, JA (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. EM jordan.beach@nih.gov; hammerj@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999, Z01 HL000514-25] NR 37 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD FEB PY 2017 VL 19 IS 2 BP 85 EP 93 DI 10.1038/ncb3463 PG 9 WC Cell Biology SC Cell Biology GA EJ8BL UT WOS:000393447200004 PM 28114272 ER PT J AU Fu, MG Blackshear, PJ AF Fu, Mingui Blackshear, Perry J. TI RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; AU-RICH ELEMENTS; HELPER T-CELLS; COSTIMULATOR MESSENGER-RNA; CONSTITUTIVE-DECAY ELEMENT; GENOME-WIDE ANALYSIS; STRUCTURAL BASIS; TRISTETRAPROLIN-DEFICIENCY; INFLAMMATORY DISEASE AB Nearly 60 CCCH zinc finger proteins have been identified in humans and mice. These proteins are involved in the regulation of multiple steps of RNA metabolism, including mRNA splicing, polyadenylation, transportation, translation and decay. Several CCCH zinc finger proteins, such as tristetraprolin (TTP), roquin 1 and MCPIP1 (also known as regnase 1), are crucial for many aspects of immune regulation by targeting mRNAs for degradation and modulation of signalling pathways. In this Review, we focus on the emerging roles of CCCH zinc finger proteins in the regulation of immune responses through their effects on cytokine production, immune cell activation and immune homeostasis. C1 [Fu, Mingui] Univ Missouri, Dept Basic Med Sci, Sch Med, 2411 Holmes St, Kansas City, MO 64108 USA. [Fu, Mingui] Univ Missouri, Shock Trauma Res Ctr, Sch Med, 2411 Holmes St, Kansas City, MO 64108 USA. [Blackshear, Perry J.] NIEHS, Signal Transduct Lab, Res Triangle Pk, NC 27709 USA. RP Fu, MG (reprint author), Univ Missouri, Dept Basic Med Sci, Sch Med, 2411 Holmes St, Kansas City, MO 64108 USA.; Fu, MG (reprint author), Univ Missouri, Shock Trauma Res Ctr, Sch Med, 2411 Holmes St, Kansas City, MO 64108 USA. EM fum@umkc.edu FU US National Institutes of Health Grant [AI103618]; University of Missouri Research Board Award; Intramural Research Program of the National Institute of Environmental Health Sciences, US National Institutes of Health FX The authors thank C. J. Papasian and V. Heissmeyer for critical reading and comments on the manuscript. This work was supported by a US National Institutes of Health Grant (AI103618) and a University of Missouri Research Board Award (to M.F.) and by the Intramural Research Program of the National Institute of Environmental Health Sciences, US National Institutes of Health (to P.J.B.). NR 105 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD FEB PY 2017 VL 17 IS 2 BP 130 EP 143 DI 10.1038/nri.2016.129 PG 14 WC Immunology SC Immunology GA EK2CD UT WOS:000393734100011 PM 27990022 ER PT J AU Varner, MW Rice, MM Landon, MB Casey, BM Reddy, UM Wapner, RJ Rouse, DJ Tita, ATN Thorp, JM Chien, EK Saade, GR Peaceman, AM Blackwell, SC Vandorsten, JP AF Varner, Michael W. Rice, Madeline Murguia Landon, Mark B. Casey, Brian M. Reddy, Uma M. Wapner, Ronald J. Rouse, Dwight J. Tita, Alan T. N. Thorp, John M. Chien, Edward K. Saade, George R. Peaceman, Alan M. Blackwell, Sean C. Vandorsten, J. Peter CA Eunice Kennedy Shriver Natl Inst C Maternal-Fetal Med Units MFMU Netw TI Pregnancies After the Diagnosis of Mild Gestational Diabetes Mellitus and Risk of Cardiometabolic Disorders SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; WOMEN; PREECLAMPSIA; WEIGHT AB OBJECTIVE: To assess the association of subsequent pregnancy with subsequent metabolic syndrome and type II diabetes mellitus after a pregnancy complicated by mild gestational diabetes mellitus (GDM). METHODS: We conducted a prospective observational follow-up study of women with mild GDM randomized from 2002 to 2007 to usual care or dietary intervention and glucose self-monitoring. Women were evaluated 5-10 years after the parent study. Participants were grouped according to the number of subsequent pregnancies (group A, none [reference]; group B, one; group C, two or greater). Serum triglycerides, glucose tolerance, high-density lipoprotein cholesterol, blood pressure, and waist circumference were assessed. Metabolic syndrome was diagnosed by American Heart Association and National Heart Lung and Blood Institute criteria. Multivariable regression was used to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: Of 905 eligible women from the original trial, 483 agreed to participate, 426 of whom were included in this analysis. Groups A, B, and C consisted of 212, 143, and 71 women, respectively. Of women with subsequent pregnancies, 32% (69/214) had another pregnancy complicated with GDM. No difference between groups was observed for metabolic syndrome (group A, 34%; group B, 33%; group C, 30%). Subsequent pregnancies were associated with diabetes mellitus outside of pregnancy (group A, 5.2%; group B, 10.5%, RR 2.62, 95% CI 1.16-5.91; group C, 11.3%, RR 2.83, 95% CI 1.06-7.59), and if complicated with GDM (no subsequent GDM pregnancy, RR 1.99, 95% CI 0.82-4.84; subsequent GDM pregnancy, RR 3.75, 95% CI 1.60-8.82). CONCLUSION: In women with prior mild GDM, subsequent pregnancies did not increase the frequency of metabolic syndrome, but subsequent pregnancies with GDM increased the risk of diabetes mellitus outside of pregnancy. C1 Univ Utah, Hlth Sci Ctr, Dept Obstet, Salt Lake City, UT USA. Univ Utah, Hlth Sci Ctr, Dept Gynecol, Salt Lake City, UT USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. Columbia Univ, New York, NY USA. Brown Univ, Providence, RI 02912 USA. Univ Alabama Birmingham, Birmingham, AL USA. Univ N Carolina, Chapel Hill, NC USA. Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. Univ Texas Med Branch, Galveston, TX 77555 USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. Med Univ South Carolina, Charleston, SC USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Varner, MW (reprint author), Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, 30 North 1900 East,Room 2A226, Salt Lake City, UT 84132 USA. EM michael.varner@hsc.utah.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD27915, HD36801, HD34208, HD34116, HD40485, HD40500, HD27869, HD40560, HD40544, HD53097, HD40512, HD40545]; National Institutes of Health's National Center for Advancing Translational Sciences [UL1TR001070, UL1TR000439] FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD27915, HD36801, HD34208, HD34116, HD40485, HD40500, HD27869, HD40560, HD40544, HD53097, HD40512, HD40545) and the National Institutes of Health's National Center for Advancing Translational Sciences (UL1TR001070, UL1TR000439). NR 17 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2017 VL 129 IS 2 BP 273 EP 280 DI 10.1097/AOG.0000000000001863 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EK1CE UT WOS:000393662600005 PM 28079773 ER PT J AU David, JM Dominguez, C Palena, C AF David, Justin M. Dominguez, Charli Palena, Claudia TI Pharmacological and immunological targeting of tumor mesenchymalization SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Epithelial-mesenchymal transition; Brachyury; Cancer vaccine; Stemness ID CANCER STEM-CELLS; TRANSCRIPTION FACTOR BRACHYURY; EGFR INHIBITOR RESISTANCE; METASTATIC BREAST-CANCER; HUMAN CARCINOMA-CELLS; E-CADHERIN EXPRESSION; PHASE-I TRIAL; TGF-BETA; LUNG-CANCER; GROWTH-FACTOR AB Controlling the spread of carcinoma cells to distant organs is the foremost challenge in cancer treatment, as metastatic disease is generally resistant to therapy and is ultimately incurable for the majority of patients. The plasticity of tumor cell phenotype, in which the behaviors and functions of individual tumor cells differ markedly depending upon intrinsic and extrinsic factors, is now known to be a central mechanism in cancer progression. Our expanding knowledge of epithelial and mesenchymal phenotypic states in tumor cells, and the dynamic nature of the transitions between these phenotypes has created new opportunities to intervene to better control the behavior of tumor cells. There are now a variety of innovative pharmacological approaches to preferentially target tumor cells that have acquired mesenchymal features, including cytotoxic agents that directly kill these cells, and inhibitors that block or revert the process of mesenchymalization. Furthermore, novel immunological strategies have been developed to engage the immune system in seeking out and destroying mesenchymalized tumor cells. This review highlights the relevance of phenotypic plasticity in tumor biology, and discusses recently developed pharmacological and immunological means of targeting this phenomenon. Published by Elsevier Inc. C1 [David, Justin M.; Dominguez, Charli; Palena, Claudia] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Palena, C (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM palenac@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 187 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD FEB PY 2017 VL 170 BP 212 EP 225 DI 10.1016/j.pharmthera.2016.11.011 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK0QF UT WOS:000393631200015 PM 27916651 ER PT J AU Cornu, JN Audet-Walsh, E Drouin, S Bigot, P Valeri, A Fournier, G Azzouzi, AR Roupret, M Cormier, L Chanock, S Guillemette, C Cussenot, O Levesque, E Cancel-Tassin, G AF Cornu, Jean-Nicolas Audet-Walsh, Etienne Drouin, Sarah Bigot, Pierre Valeri, Antoine Fournier, Georges Azzouzi, Abdel-Rahmene Roupret, Morgan Cormier, Luc Chanock, Stephen Guillemette, Chantal Cussenot, Olivier Levesque, Eric Cancel-Tassin, Geraldine TI Correlation between prostate volume and single nucleotide polymorphisms implicated in the steroid pathway SO WORLD JOURNAL OF UROLOGY LA English DT Article DE Prostatectomy; Prostate weight; Single nucleotide polymorphisms; Steroid pathway ID URINARY-TRACT SYMPTOMS; ESTROGEN-RECEPTOR-BETA; METABOLIC SYNDROME; HYPERPLASIA; ASSOCIATION; ALPHA; MICE; BPH; EXPRESSION; PHENOTYPES AB A few preliminary studies have suggested a link between some genetics variants and benign prostatic hyperplasia (BPH). Our goal was to study the link between a set of single nucleotide polymorphisms (SNPs) implicated in the steroid pathway and accurate measurement of prostate volume in a cohort of men who underwent radical prostatectomy. Clinical and pathological data including prostate weight were obtained from 611 Caucasian patients with small volume, localized prostate cancer treated by radical prostatectomy. Patients were genotyped for 90 SNPs located inside or nearby genes implicated in the steroid pathway (Sequenom iPLEX). Correlation between prostate weight and genotypes from each SNP was studied by analysis of covariance, adjusted on age and tumor stage. A Bonferroni correction was applied, and the SNPs implicated were then incorporated in a multivariable model. Seven SNPs located in or nearby genes implicated in steroid hormone metabolism were significantly associated with prostate volume: HSD17B2 (rs1119933), ESR2 (rs8006145), SULT2B1 (rs279451), NQO1 (rs2917670), ESR1 (rs1569788), GSTP1 (rs1138272), and CYP19A1 (rs17523880). Significant association was maintained after multivariate analysis for four SNPs, indicating their independent association with prostate volume. The power of the association of each SNP with prostate volume was comparable to the effect of age. The strongest associations were found with variants in ESR1, ESR2, HSD17B2, and CYP19A1 genes, indicating a potential role of the estrogen signaling pathway in genesis of BPH. Our results are in favor of an implication of estrogen biotransformation and signaling pathways in the pathophysiology of BPH. C1 [Cornu, Jean-Nicolas; Cussenot, Olivier] UPMC Univ Paris 06, Hop Tenon, AP HP, Acad Dept Urol, F-75020 Paris, France. [Cornu, Jean-Nicolas; Drouin, Sarah; Roupret, Morgan; Cussenot, Olivier; Cancel-Tassin, Geraldine] UPMC Univ Paris 06, GRC 5, ONCOTYPE URO, Inst Univ Cancerol, F-75020 Paris, France. [Audet-Walsh, Etienne; Guillemette, Chantal; Levesque, Eric] Univ Laval, CHU Quebec, Pharmacogen Lab, Res Ctr, Quebec City, PQ, Canada. [Audet-Walsh, Etienne; Guillemette, Chantal; Levesque, Eric] Univ Laval, Fac Pharm, Quebec City, PQ, Canada. [Drouin, Sarah; Roupret, Morgan] UPMC Univ Paris 06, Hop Pitie Salpetriere, AP HP, Acad Dept Urol, F-75013 Paris, France. [Bigot, Pierre; Azzouzi, Abdel-Rahmene] CHU Angers, Acad Dept Urol, F-49000 Angers, France. [Valeri, Antoine; Fournier, Georges] CHU Brest, Acad Dept Urol, F-29000 Brest, France. [Valeri, Antoine; Fournier, Georges; Azzouzi, Abdel-Rahmene; Roupret, Morgan; Cormier, Luc; Cussenot, Olivier; Cancel-Tassin, Geraldine] CeRePP, F-75020 Paris, France. [Cormier, Luc] CHU Dijon, Acad Dept Urol, F-21000 Dijon, France. [Chanock, Stephen] NCI, Lab Translat Genom, Dept Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Cornu, JN (reprint author), UPMC Univ Paris 06, Hop Tenon, AP HP, Acad Dept Urol, F-75020 Paris, France.; Cornu, JN (reprint author), UPMC Univ Paris 06, GRC 5, ONCOTYPE URO, Inst Univ Cancerol, F-75020 Paris, France. EM jeannicolas.cornu@gmail.com OI Cancel-Tassin, Geraldine/0000-0002-9583-6382 FU Institut National de Cancer [PHRC AOM06209]; Cancer Research Society; Prostate Cancer Canada [DS2013-22, RS2013-55]; CIHR; Canadian Institutes of Health Research FX We would like to thank Cecile Gaffory and Valerie Ondet for technical assistance. This work was supported by grant from the Institut National de Cancer (PHRC AOM06209), Cancer Research Society to C.G., and Prostate Cancer Canada to E.L. (DS2013-22). E.L. is a recipient of a Prostate Cancer Canada rising star award (RS2013-55) and a CIHR clinician-scientist phase 2 award. E.A.W. was a recipient of a postdoctoral fellowship award from the Canadian Institutes of Health Research. C.G. holds the Canada Research Chair in Pharmacogenomics. NR 35 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-4983 EI 1433-8726 J9 WORLD J UROL JI World J. Urol. PD FEB PY 2017 VL 35 IS 2 BP 293 EP 298 DI 10.1007/s00345-016-1869-4 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EK2SZ UT WOS:000393778300015 PM 27277477 ER PT J AU Rosen, M Kinahan, PE Gimpel, JF Opanowski, A Siegel, BA Hill, GC Weiss, L Shankar, L AF Rosen, Mark Kinahan, Paul E. Gimpel, James F. Opanowski, Adam Siegel, Barry A. Hill, G. Craig Weiss, Linda Shankar, Lalitha TI Performance Observations of Scanner Qualification of NCI-Designated Cancer Centers: Results From the Centers of Quantitative Imaging Excellence (CQIE) Program SO ACADEMIC RADIOLOGY LA English DT Article DE Scanner qualification; cancer imaging; phantom imaging; imaging accreditation; imaging credentialing; clinical trials ID CLINICAL-TRIALS; MULTICENTER TRIALS; AMERICAN-COLLEGE; PET; STANDARDIZATION; CT AB We present an overview of the Centers for Quantitative Imaging Excellence (CQIE) program, which was initiated in 2010 to establish a resource of clinical trial-ready sites within the National Cancer Institute (NCI)-designated Cancer Centers (NCI-CCs) network. The intent was to enable imaging centers in the NCI-CCs network capable of conducting treatment trials with advanced quantitative imaging end points. We describe the motivations for establishing the CQIE, the process used to initiate the network, the methods of site qualification for positron emission tomography, computed tomography, and magnetic resonance imaging, and the results of the evaluations over the subsequent 3 years. C1 [Rosen, Mark] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Kinahan, Paul E.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Gimpel, James F.; Opanowski, Adam] Amer Coll Radiol, Ctr Res & Innovat, Philadelphia, PA 19103 USA. [Siegel, Barry A.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Siegel, Barry A.] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO USA. [Hill, G. Craig] Frederick Natl Lab Canc Res, Canc Imaging Program, Leidos Biomed, Frederick, MD USA. [Weiss, Linda] NCI, Off Canc Ctr, Bethesda, MD 20892 USA. [Shankar, Lalitha] NCI, Canc Imaging Program, Bethesda, MD 20892 USA. RP Gimpel, JF (reprint author), Amer Coll Radiol, Ctr Res & Innovat, Philadelphia, PA 19103 USA. EM jgimpel@acr.org FU Leidos Biomedical Research Inc. [10XS070]; Federal funds from the National Cancer Institute, National Institutes of Health, under NIH [U01CA148131, U01CA190254, U10CA180820, HHSN261200800001E] FX The authors gratefully acknowledge the contributions of the following individuals for their time and effort in support of this publication: Joshua Scheuermann, Walter Witschey, Deborah Harbison, Mehdi Adineh, Janet Reddin, Sereivutha Chao, Howard Higley, Ying Tang, Linda Doody, and Lauren Uzdienski. (Funded through Leidos Biomedical Research Inc., subcontract number 10XS070 to ACRIN for the Cancer Imaging Program, DCTD, NCI. This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under NIH grants U01CA148131, U01CA190254, U10CA180820, and Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.) NR 21 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 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD FEB PY 2017 VL 24 IS 2 BP 232 EP 245 DI 10.1016/j.acra.2016.09.025 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ0NM UT WOS:000392906300018 ER PT J AU Williams, RW Holmes, A AF Williams, Robert W. Holmes, Andrew TI Preface to a special issue on genetic models of alcoholism and alcohol-stress interactions SO ALCOHOL LA English DT Editorial Material ID INBRED STRAINS; MICE; WITHDRAWAL; PREFERENCE; ETHANOL; ABUSE C1 [Williams, Robert W.] Univ Tennessee, Hlth Sci Ctr, Dept Genet Genom & Informat, Memphis, TN 38163 USA. [Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, Rockville, MD 20852 USA. RP Williams, RW (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Genet Genom & Informat, Memphis, TN 38163 USA. EM rwilliams@uthsc.edu; holmesan@mail.nih.gov OI Williams, Robert/0000-0001-8924-4447 NR 13 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD FEB PY 2017 VL 58 SI SI BP 23 EP 24 DI 10.1016/j.alcohol.2016.11.010 PG 2 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA EJ5KG UT WOS:000393256300004 PM 27912921 ER PT J AU Radke, AK Jury, NJ Delpire, E Nakazawa, K Holmes, A AF Radke, Anna K. Jury, Nicholas J. Delpire, Eric Nakazawa, Kazu Holmes, Andrew TI Reduced ethanol drinking following selective cortical interneuron deletion of the GluN2B NMDA receptors subunit SO ALCOHOL LA English DT Article DE Alcohol; Glutamate; Addiction; Cortex; Interneuron ID MESSENGER-RNA EXPRESSION; SEEKING BEHAVIOR; FACILITATES EXTINCTION; SYNAPTIC PLASTICITY; REWARD-SEEKING; ALCOHOL INTAKE; RAT-BRAIN; EXPOSURE; MICE; STRIATUM AB N-Methyl-D-aspartate receptors (NMDAR) are involved in the regulation of alcohol drinking, but the contribution of NMDAR subunits located on specific neuronal populations remains incompletely understood. The current study examined the role of GIuN2B-containing NMDARs expressed on cortical principal neurons and cortical interneurons in mouse ethanol drinking. Consumption of escalating concentrations of ethanol was measured in mice with GIuN2B gene deletion in either cortical principal neurons (GluN2B(CXNULL)) or interneurons (GluN2B(InterNULL)), using a two-bottle choice paradigm. Results showed that GluN2B(InterNULL) but not GluN2B(CxNULL), mice consumed significantly less ethanol, at relatively high concentrations, than non-mutant controls. In a second paradigm in which mice were offered a 15% ethanol concentration, without escalation, GluN2B(CxNULL) mice were again no different from controls. These findings provide novel evidence for a contribution of interneuronal GIuN2B-containing NMDARs in the regulation of ethanol drinking. (C) 2016 Elsevier Inc. All rights reserved. C1 [Radke, Anna K.; Jury, Nicholas J.; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. [Delpire, Eric] Vanderbilt Univ, Sch Med, Dept Anesthesiol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Delpire, Eric] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, 221 Kirkland Hall, Nashville, TN 37235 USA. [Nakazawa, Kazu] Univ Alabama Birmingham, Sch Med, Dept Psychiat & Behav Neurobiol, Birmingham, AL USA. RP Radke, AK (reprint author), 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM aradke@miamioh.edu OI Jury, Nicholas/0000-0002-4233-117X FU NIAAA Intramural Research Program FX We are grateful to Adrina Kocharian and Aaron Limoges for technical assistance. Research was supported by the NIAAA Intramural Research Program. NR 48 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD FEB PY 2017 VL 58 SI SI BP 47 EP 51 DI 10.1016/j.alcohol.2016.07.005 PG 5 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA EJ5KG UT WOS:000393256300007 PM 28109345 ER PT J AU Jury, NJ DiBerto, JF Kash, TL Holmes, A AF Jury, Nicholas J. DiBerto, Jeffrey F. Kash, Thomas L. Holmes, Andrew TI Sex differences in the behavioral sequelae of chronic ethanol exposure SO ALCOHOL LA English DT Article DE Alcohol; Gender; Sex; Addiction; Mouse; Drinking ID SUBSEQUENT WITHDRAWAL SEIZURES; SPRAGUE-DAWLEY RATS; ANXIETY-LIKE BEHAVIOR; LONG-EVANS RATS; FEMALE RATS; ADULT RATS; ALCOHOL PREFERENCE; C57BL/6J MICE; GENDER-DIFFERENCES; ESTROUS CYCLICITY AB Rates of alcohol use disorders (AUDs) differ between men and women, and there is also marked variation between sexes in the effects of acute and chronic alcohol. In parallel to observations in humans, prior studies in rodents have described male/female differences across a range of ethanol-related behaviors, including ethanol drinking. Nonetheless, there remain gaps in our knowledge of the role of sex in moderating the effects of ethanol, particularly in models of chronic ethanol exposure. The goal of the current study was to assess various behavioral sequelae of exposing female C57BL/6J mice to chronic intermittent ethanol (CIE) via ethanol vapors. Following four weeks of CIE exposure, adult male and female mice were compared for ethanol drinking in a two-bottle paradigm, for sensitivity to acute ethanol intoxication (via loss of righting reflex [LORRI) and for anxiety-like behaviors in the novelty-suppressed feeding and marble burying assays. Next, adult and adolescent females were tested on two different two-bottle drinking preparations (fixed or escalating ethanol concentration) after CIE. Results showed that males and females exhibited significantly blunted ethanol-induced LORR following CIE, whereas only males showed increased anxiety-like behavior after CIE. Increased ethanol drinking after CIE was also specific to males, but high baseline drinking in females may have occluded detection of a CIE-induced effect. The failure to observe elevated drinking in females in response to CIE was also seen in females exposed to CIE during adolescence, regardless of whether a fixed or escalating ethanol-concentration two-bottle procedure was employed. Collectively, these data add to the literature on sex differences in ethanol-related behaviors and provide a foundation for future studies examining how the neural consequences of CIE might differ between males and females. Published by Elsevier Inc. C1 [Jury, Nicholas J.; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. [DiBerto, Jeffrey F.; Kash, Thomas L.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USA. [DiBerto, Jeffrey F.; Kash, Thomas L.] Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC USA. RP Jury, NJ (reprint author), 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM nickjury@hotmail.com OI Jury, Nicholas/0000-0002-4233-117X FU National Institute on Alcohol Abuse and Alcoholism Intramural Research Program FX Research was supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program. We would like to thank Erica Bush and Erica Sagalyn for providing excellent technical assistance during the CIE vapor exposure procedure. NR 78 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD FEB PY 2017 VL 58 SI SI BP 53 EP 60 DI 10.1016/j.alcohol.2016.07.007 PG 8 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA EJ5KG UT WOS:000393256300008 PM 27624846 ER PT J AU Halladay, LR Kocharian, A Holmes, A AF Halladay, Lindsay R. Kocharian, Adrina Holmes, Andrew TI Mouse strain differences in punished ethanol self-administration SO ALCOHOL LA English DT Article DE Alcohol; Mouse; Punishment; Addiction; Hippocampus; Amygdala ID CONDITIONED PLACE PREFERENCE; QUANTITATIVE TRAIT LOCI; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CONTEXT-INDUCED RELAPSE; REACTION-TIME-TASK; MORRIS WATER TASK; DBA/2J MICE; INBRED MICE; ALCOHOL INTAKE; BEHAVIORAL SENSITIZATION AB Determining the neural factors contributing to compulsive behaviors such as alcohol-use disorders (AUDs) has become a significant focus of current preclinical research. Comparison of phenotypic differences across genetically distinct mouse strains provides one approach to identify molecular and genetic factors contributing to compulsive-like behaviors. Here we examine a rodent assay for punished ethanol self-administration in four widely used inbred strains known to differ on ethanol-related behaviors: C57BL/6J (B6), DBA/2J (D2), 129S1/Sylmi (S1), and BALB/cJ (BALB). Mice were trained in an operant task (FR1) to reliably lever-press for 10% ethanol using a sucrose-fading procedure. Once trained, mice received a punishment session in which lever pressing resulted in alternating ethanol reward and footshock, followed by tests to probe the effects of punishment on ethanol self-administration. Results indicated significant strain differences in training performance and punished attenuation of ethanol self administration. S1 and BALB showed robust attenuation of ethanol self-administration after punishment, whereas behavior in B6 was attenuated only when the punishment and probe tests were conducted in the same contexts. By contrast, D2 were insensitive to punishment regardless of context, despite receiving more shocks during punishment and exhibiting normal footshock reactivity. Additionally, B6, but not D2, reduced operant self-administration when ethanol was devalued with a bitter tastant. B6 and D2 showed devaluation of sucrose self-administration, and punished suppression of sucrose seeking was context dependent in both the strains. While previous studies have demonstrated avoidance of ethanol in D2, particularly when ethanol is orally available from a bottle, current findings suggest this strain may exhibit heightened compulsive-like self-administration of ethanol, although there are credible alternative explanations for the phenotype of this strain. In sum, these findings offer a foundation for future studies examining the neural and genetic factors underlying AUDs. (C) 2016 Elsevier Inc. All rights reserved. C1 [Halladay, Lindsay R.; Kocharian, Adrina; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. RP Halladay, LR (reprint author), 5625 Fishers Lane Room 2N09, Rockville, MD 20852 USA. EM Lindsay.Halladay@nih.gov FU National Institute on Alcohol Abuse and Alcoholism Intramural Research Program FX Research supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program. NR 95 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD FEB PY 2017 VL 58 SI SI BP 83 EP 92 DI 10.1016/j.alcohol.2016.05.008 PG 10 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA EJ5KG UT WOS:000393256300011 PM 27814928 ER PT J AU Chatterjee, R Davenport, CA Svetkey, LP Batch, BC Lin, PH Ramachandran, VS Fox, ER Harman, J Yeh, HC Selvin, E Correa, A Butler, K Edelman, D AF Chatterjee, Ranee Davenport, Clemontina A. Svetkey, Laura P. Batch, Bryan C. Lin, Pao-Hwa Ramachandran, Vasan S. Fox, Ervin R. Harman, Jane Yeh, Hsin-Chieh Selvin, Elizabeth Correa, Adolfo Butler, Kenneth Edelman, David TI Serum potassium is a predictor of incident diabetes in African Americans with normal aldosterone: the Jackson Heart Study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE potassium; diabetes risk; racial disparity in diabetes risk; diabetes risk factor; African Americans ID ATHEROSCLEROSIS-RISK; LONGITUDINAL CHANGES; INSULIN-RESISTANCE; THIAZIDE DIURETICS; METABOLIC SYNDROME; MEASUREMENT ERROR; NATIONAL-HEALTH; DIETARY-INTAKE; COMMUNITIES; MELLITUS AB Background: Low-normal potassium is a risk factor for diabetes and may account for some of the racial disparity in diabetes risk. Aldosterone affects serum potassium and is associated with insulin resistance. Objectives: We sought to confirm the association between potassium and incident diabetes in an African-American cohort, and to determine the effect of aldosterone on this association. Design: We studied participants from the Jackson Heart Study, an African-American adult cohort, who were without diabetes at baseline. With the use of logistic regression, we characterized the associations of serum, dietary, and urinary potassium with incident diabetes. In addition, we evaluated aldosterone as a potential effect modifier of these associations. Results: Of 2157 participants, 398 developed diabetes over 8 y. In a minimally adjusted model, serum potassium was a significant predictor of incident diabetes (OR: 0.83; 95% CI: 0.74, 0.92 per SD increment in serum potassium). In multivariable models, we found a significant interaction between serum potassium and aldosterone (P = 0.046). In stratified multivariable models, in those with normal aldosterone (<9 ng/dL, 17 = 1163), participants in the highest 2 potassium quartiles had significantly lower odds of incident diabetes than did those in the lowest potassium quartile [OR (95% CI): 0.61 (0.39, 0.97) and 0.54 (0.33, 0.90), respectively]. Among those with high-normal aldosterone (>= 9 ng/dL, n = 202), we found no significant association between serum potassium and incident diabetes. In these stratified models, serum aldosterone was not a significant predictor of incident diabetes. We found no statistically significant associations between dietary or urinary potassium and incident diabetes. Conclusions: In this African-American cohort, we found that aldosterone may modify the association between serum potassium and incident diabetes. In participants with normal aldosterone, high normal serum potassium was associated with a lower risk of diabetes than was low-normal serum potassium. Additional studies are warranted to determine whether serum potassium is a modifiable risk factor that could be a target for diabetes prevention. C1 [Chatterjee, Ranee; Davenport, Clemontina A.; Svetkey, Laura P.; Batch, Bryan C.; Lin, Pao-Hwa; Edelman, David] Duke Univ, Dept Med, Durham, NC 27708 USA. [Ramachandran, Vasan S.] Boston Univ, Dept Med, Boston, MA USA. [Fox, Ervin R.; Correa, Adolfo; Butler, Kenneth] Univ Mississippi, Med Ctr, Dept Med, Jackson, MI USA. [Harman, Jane] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Yeh, Hsin-Chieh; Selvin, Elizabeth] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. RP Chatterjee, R (reprint author), Duke Univ, Dept Med, Durham, NC 27708 USA. EM ranee.chatterjee@duke.edu FU National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; NIH/Duke Clinical and Translational Science Award [KL2TR001115-02]; NIH/National Center for Advancing Translational Sciences [UL1TR001117, KL2TR001115]; NIH/National Institutes of Diabetes and Digestive and Kidney Diseases [K24DK106414]; National Institute on Minority Health and Health Disparities FX The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. RC was supported by NIH/Duke Clinical and Translational Science Award KL2TR001115-02. CAD was partially supported by NIH/National Center for Advancing Translational Sciences grant UL1TR001117. BCB was supported by NIH/National Center for Advancing Translational Sciences grant KL2TR001115. ES was supported by NIH/National Institutes of Diabetes and Digestive and Kidney Diseases grant K24DK106414. NR 38 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 105 IS 2 BP 442 EP 449 DI 10.3945/ajcn.116.143255 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EJ6SK UT WOS:000393348900020 PM 27974310 ER PT J AU Playdon, MC Moore, SC Derkach, A Reedy, J Subar, AF Sampson, JN Albanes, D Gu, FY Kontto, J Lassale, C Liao, LM Mainnisto, S Mondul, AM Weinstein, SJ Irwin, ML Mayne, ST Stolzenberg-Solomon, R AF Playdon, Mary C. Moore, Steven C. Derkach, Andriy Reedy, Jill Subar, Amy F. Sampson, Joshua N. Albanes, Demetrius Gu, Fangyi Kontto, Jukka Lassale, Camille Liao, Linda M. Mainnisto, Satu Mondul, Alison M. Weinstein, Stephanie J. Irwin, Melinda L. Mayne, Susan T. Stolzenberg-Solomon, Rachael TI Identifying biomarkers of dietary patterns by using metabolomics SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE dietary pattern; diet quality; Healthy Eating Index; biomarker; metabolomics; metabolite ID HEALTHY EATING INDEX; RANDOMIZED CONTROLLED-TRIAL; CAROTENE CANCER PREVENTION; BALTIC SEA DIET; MEDITERRANEAN DIET; CARDIOVASCULAR-DISEASE; QUALITY INDEXES; BETA-CAROTENE; ALL-CAUSE; RISK AB Background: Healthy dietary patterns that conform to national dietary guidelines are related to lower chronic disease incidence and longer life span. However, the precise mechanisms involved are unclear. Identifying biomarkers of dietary patterns may provide tools to validate diet quality measurement and determine underlying metabolic pathways influenced by diet quality. Objective: The objective of this study was to examine the correlation of 4 diet quality indexes [the Healthy Eating Index (HEI) 2010, the Alternate Mediterranean Diet Score (aMED), the WHO Healthy Diet Indicator (HDI), and the Baltic Sea Diet (BSD)] with serum metabolites. Design: We evaluated dietary patterns and metabolites in male Finnish smokers (n = 1336) from 5 nested case-control studies within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Participants completed a validated food-frequency questionnaire and provided a fasting serum sample before study randomization (1985-1988). Metabolites were measured with the use of mass spectrometry. We analyzed cross-sectional partial correlations of 1316 metabolites with 4 diet quality indexes, adjusting for age, body mass index, smoking, energy intake, education, and physical activity. We pooled estimates across studies with the use of fixed-effects meta-analysis with Bonferroni correction for multiple comparisons, and conducted metabolic pathway analyses. Results: The HEI-2010, aMED, HDI, and BSD were associated with 23, 46, 23, and 33 metabolites, respectively (17, 21, 11, and 10 metabolites, respectively, were chemically identified; r-range: -0.30 to 0.20; P = 6 X 10(-15) to 8 X 10(-6)). Food-based diet indexes (HEI-2010, aMED, and BSD) were associated with metabolites correlated with most components used to score adherence (e.g., fruit, vegetables, whole grains, fish, and unsaturated fat). HDI correlated with metabolites related to polyunsaturated fat and fiber components, but not other macro- or micronutrients (e.g., percentages of protein and cholesterol). The lysolipid and food and plant xenobiotic pathways were most strongly associated with diet quality. Conclusions: Diet quality, measured by healthy diet indexes, is associated with serum metabolites, with the specific metabolite profile of each diet index related to the diet components used to score adherence. C1 [Playdon, Mary C.; Irwin, Melinda L.; Mayne, Susan T.] Yale Univ, Yale Sch Publ Hlth, New Haven, CT 06520 USA. [Playdon, Mary C.; Moore, Steven C.; Derkach, Andriy; Sampson, Joshua N.; Albanes, Demetrius; Gu, Fangyi; Liao, Linda M.; Weinstein, Stephanie J.; Stolzenberg-Solomon, Rachael] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Reedy, Jill; Subar, Amy F.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Kontto, Jukka; Mainnisto, Satu] Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland. [Lassale, Camille] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Mondul, Alison M.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Irwin, Melinda L.] Yale Canc Ctr, New Haven, CT USA. [Mayne, Susan T.] US FDA, College Pk, MD USA. RP Playdon, MC (reprint author), Yale Univ, Yale Sch Publ Hlth, New Haven, CT 06520 USA.; Playdon, MC (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. EM mary.playdon@nih.gov OI Kontto, Jukka/0000-0003-3899-9852; Irwin, Michael/0000-0001-5801-274X FU Yale-National Cancer Institute predoctoral training grant [T32 CA105666]; NIH Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services FX Supported in part by Yale-National Cancer Institute predoctoral training grant T32 CA105666 to STM. This research was also supported by the NIH Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services. NR 80 TC 1 Z9 1 U1 7 U2 7 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 FEB PY 2017 VL 105 IS 2 BP 450 EP 465 DI 10.3945/ajcn.116.144501 PG 16 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EJ6SK UT WOS:000393348900021 PM 28031192 ER PT J AU Andrews, KW Roseland, JM Gusev, PA Palachuvattil, J Dang, PT Savarala, S Han, F Pehrsson, PR Douglass, LW Dwyer, JT Betz, JM Saldanha, LG Bailey, RL AF Andrews, Karen W. Roseland, Janet M. Gusev, Pavel A. Palachuvattil, Joel Dang, Phuong T. Savarala, Sushma Han, Fei Pehrsson, Pamela R. Douglass, Larry W. Dwyer, Johanna T. Betz, Joseph M. Saldanha, Leila G. Bailey, Regan L. TI Analytical ingredient content and variability of adult multivitamin/mineral products: national estimates for the Dietary Supplement Ingredient Database SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE dietary supplement; reference material; multivitamins; sampling plan; NHANES; quality control; overage; Recommended Dietary Allowance (RDA); upper limit; US Pharmacopeia ID RANDOMIZED CONTROLLED-TRIALS; CARDIOVASCULAR-DISEASE; AMERICA-NHANES; US ADULTS; NUTRITION; VITAMIN; POPULATION; MORTALITY; ACCURACY; RISK AB Background: Multivitamin/mineral products (MVMs) are the dietary supplements most commonly used by US adults. During manufacturing, some ingredients are added in amounts exceeding the label claims to compensate for expected losses during the shelf life. Establishing the health benefits and harms of MVMs requires accurate estimates of nutrient intake from MVMs based on measures of actual rather than labeled ingredient amounts. Objectives: Our goals were to determine relations between analytically measured and labeled ingredient content and to compare adult MVM composition with Recommended Dietary Allowances (RDAs) and Tolerable Upper Intake Levels. Design: Adult MVMs were purchased while following a national sampling plan and chemically analyzed for vitamin and mineral content with certified reference materials in qualified laboratories. For each ingredient, predicted mean percentage differences between analytically obtained and labeled amounts were calculated with the use of regression equations. Results: For 12 of 18 nutrients, most products had labeled amounts at or above RDAs. The mean measured content of all ingredients (except thiamin) exceeded labeled amounts (overages). Predicted mean percentage differences exceeded labeled amounts by 1.5-13% for copper, manganese, magnesium, niacin, phosphorus, potassium, folic acid, riboflavin, and vitamins B-12, C, and E, and by similar to 25% for selenium and iodine, regardless of labeled amount. In contrast, thiamin, vitamin B-6, calcium, iron, and zinc had linear or quadratic relations between the labeled and percentage differences, with ranges from -6.5% to 8.6%, -3.5% to 21%, 7.1% to 29.3%, -0.5% to 16.4%, and -1.9% to 8.1%, respectively. Analytically adjusted ingredient amounts are linked to adult MVMs reported in the NHANES 2003-2008 via the Dietary Supplement Ingredient Database (http://dsid.usda.nih.gov) to facilitate more accurate intake quantification. Conclusions: Vitamin and mineral overages were measured in adult MVMs, most of which already meet RDAs. Therefore, nutrient overexposures from supplements combined with typical food intake may have unintended health consequences, although this would require further examination. C1 [Andrews, Karen W.; Roseland, Janet M.; Gusev, Pavel A.; Palachuvattil, Joel; Dang, Phuong T.; Savarala, Sushma; Han, Fei; Pehrsson, Pamela R.] ARS, Nutrient Data Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. [Dwyer, Johanna T.; Betz, Joseph M.; Saldanha, Leila G.; Bailey, Regan L.] NIH, Off Dietary Supplements, US Dept HHS, Bldg 10, Bethesda, MD 20892 USA. [Bailey, Regan L.] Purdue Univ, Dept Nutr Sci, W Lafayette, IN 47907 USA. RP Andrews, KW (reprint author), ARS, Nutrient Data Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. EM karen.andrews@ars.usda.gov FU NIH Office of Dietary Supplements; USDA Agricultural Research Service FX Supported by the NIH Office of Dietary Supplements and the USDA Agricultural Research Service. NR 40 TC 0 Z9 0 U1 4 U2 4 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 FEB PY 2017 VL 105 IS 2 BP 526 EP 539 DI 10.3945/ajcn.116.134544 PG 14 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EJ6SK UT WOS:000393348900028 PM 27974309 ER PT J AU Zebardast, N Friedman, DS Vitale, S AF Zebardast, Nazlee Friedman, David S. Vitale, Susan TI The Prevalence and Demographic Associations of Presenting Near-Vision Impairment Among Adults Living in the United States SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID VISUAL-ACUITY; PRESBYOPIA; POPULATION; EYE; AUSTRALIA; INDIA AB PURPOSE: To estimate prevalence of presenting near vision impairment (PNVI) among people aged >= 50 years in the United States (US) and examine associations with sociodemographic characteristics. DESIGN: Cross-sectional study. METHODS: A total of 11 016 of 12 781 (88.5%) US adults aged >= 50 years participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2008 with recorded near visual acuity. PNVI was defined as presenting near vision worse than 20/40; functional near-vision impairment (FNVI) was defined as at least "moderate difficulty" with either reading newsprint or near work. Prevalence of PNVI and FNVI were estimated accounting for National Health and Nutrition Examination Survey multistage probability sampling design. Multivariable regression models were used to determine sociodemographic characteristics associated with PNVI. RESULTS: A total of 13.6% of participants had PNVI, with 25.9% reporting concurrent FNVI. Higher odds of PNVI was associated with nonwhite race, older age, male sex, less than high school education, lack of private health insurance, income less than poverty level, lacking/not using near-vision correction at time of examination, and impaired distance vision. Although the majority of participants with PNVI (82.9%) had normal distance vision or uncorrected refractive error, less than half (46.1%) used near-vision correction. Not using near correction was associated with nonwhite race, younger age, male sex, and lack of access to health care. CONCLUSIONS: Approximately 1 in 8 Americans aged >= 50 years have PNVI, with 1 in 4 reporting concurrent FNVI. Demographic factors shown to be important in access to eye care likely influence PNVI and utilization of near-vision correction in the US. As the majority of PNVI is likely correctable with spectacles, allocation of resources to provide corrective lenses to those in need likely has great public. health implications. (C) 2016 Elsevier Inc. All rights reserved. C1 [Zebardast, Nazlee; Friedman, David S.] Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. [Zebardast, Nazlee; Friedman, David S.] Johns Hopkins Univ, Dana Ctr Prevent Ophthalmol, Baltimore, MD USA. [Vitale, Susan] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Zebardast, N (reprint author), Johns Hopkins Univ Hosp, Wilmer Eye Inst, 600 North Wolfe St, Baltimore, MD 21287 USA. EM nzebard1@jhmi.edu FU NATIONAL CENTER FOR HEALTH STATISTICS (NCHS); CENTERS FOR Disease Control and Prevention; National Eye Institute, National Institutes of Health [Z01EY000402] FX THE NHANES IS SPONSORED BY THE NATIONAL CENTER FOR HEALTH STATISTICS (NCHS), CENTERS FOR Disease Control and Prevention. Additional funding for the NHANES Vision Component was provided by the National Eye Institute, National Institutes of Health (Intramural Research Program Z01EY000402). NR 16 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD FEB PY 2017 VL 174 BP 134 EP 144 DI 10.1016/j.ajo.2016.11.004 PG 11 WC Ophthalmology SC Ophthalmology GA EJ3YN UT WOS:000393148800016 PM 27865728 ER PT J AU Zhao, XW Schwartz, CL Pierson, J Giovannoni, SJ McIntosh, JR Nicastroa, D AF Zhao, Xiaowei Schwartz, Cindi L. Pierson, Jason Giovannoni, Stephen J. McIntosh, J. Richard Nicastroa, Daniela TI Three-Dimensional Structure of the Ultraoligotrophic Marine Bacterium "Candidatus Pelagibacter ubique" SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article DE ultramicrobacteria; cryo-electron tomography; type IV pili; PilQ; SAR11 ID TRANSMISSION ELECTRON-MICROSCOPY; TRYPSIN-RESISTANT CORE; N-TERMINAL DOMAIN; CRYOELECTRON TOMOGRAPHY; NEISSERIA-MENINGITIDIS; CAULOBACTER-CRESCENTUS; THERMUS-THERMOPHILUS; SECRETIN PULD; PILQ SECRETIN; CELLS AB SAR11 bacteria are small, heterotrophic, marine alphaproteobacteria found throughout the oceans. They thrive at the low nutrient concentrations typical of open ocean conditions, although the adaptations required for life under those conditions are not well understood. To illuminate this issue, we used cryo-electron tomography to study "Candidatus Pelagibacter ubique" strain HTCC1062, a member of the SAR11 clade. Our results revealed its cellular dimensions and details of its intracellular organization. Frozen-hydrated cells, which were preserved in a life-like state, had an average cell volume (enclosed by the outer membrane) of 0.037 +/- 0.011 mu m(3). Strikingly, the periplasmic space occupied similar to 20% to 50% of the total cell volume in log-phase cells and similar to 50% to 70% in stationary-phase cells. The nucleoid occupied the convex side of the crescent-shaped cells and the ribosomes predominantly occupied the concave side, at a relatively high concentration of 10,000 to 12,000 ribosomes/similar to m(3). Outer membrane pore complexes, likely composed of PilQ, were frequently observed in both log-phase and stationary-phase cells. Long filaments, most likely type IV pili, were found on dividing cells. The physical dimensions, intracellular organization, and morphological changes throughout the life cycle of "Ca. Pelagibacter ubique" provide structural insights into the functional adaptions of these oligotrophic ultramicrobacteria to their habitat. IMPORTANCE Bacterioplankton of the SAR11 clade (Pelagibacterales) are of interest because of their global biogeochemical significance and because they appear to have been molded by unusual evolutionary circumstances that favor simplicity and efficiency. They have adapted to an ecosystem in which nutrient concentrations are near the extreme limits at which transport systems can function adequately, and they have evolved streamlined genomes to execute only functions essential for life. However, little is known about the actual size limitations and cellular features of living oligotrophic ultramicrobacteria. In this study, we have used cryo-electron tomography to obtain accurate physical information about the cellular architecture of "Candidatus Pelagibacter ubique," the first cultivated member of the SAR11 clade. These results provide foundational information for answering questions about the cell architecture and functions of these ultrasmall oligotrophic bacteria. C1 [Zhao, Xiaowei; Nicastroa, Daniela] Univ Texas Southwestern Med Ctr Dallas, Dept Cell Biol & Biophys, Dallas, TX 75390 USA. [Schwartz, Cindi L.; Pierson, Jason; McIntosh, J. Richard; Nicastroa, Daniela] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. [Giovannoni, Stephen J.] Oregon State Univ, Dept Microbiol, Corvallis, OR 97331 USA. [Schwartz, Cindi L.] NIAID, NIH, Rocky Mt Labs, Hamilton, MT USA. [Pierson, Jason] FEI Co, Hillsboro, OR USA. RP Nicastroa, D (reprint author), Univ Texas Southwestern Med Ctr Dallas, Dept Cell Biol & Biophys, Dallas, TX 75390 USA.; Nicastroa, D (reprint author), Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. EM daniela.nicastro@utsouthwestern.edu FU NIH [RR00592]; Marine Microbiology Initiative Investigator Grant from the Gordon and Betty Moore Foundation [GBMF607.01] FX This work was supported by an NIH grant to J.R.M. (grant RR00592) and a Marine Microbiology Initiative Investigator Grant from the Gordon and Betty Moore Foundation (grant GBMF607.01). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 85 TC 0 Z9 0 U1 5 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD FEB PY 2017 VL 83 IS 3 AR UNSP e02807-16 DI 10.1128/AEM.02807-16 PG 14 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA EJ8MW UT WOS:000393480900022 ER PT J AU Winn, BA Shi, Z Carlson, GJ Wang, YF Nguyen, BL Kelly, EM Ross, RD Hamel, E Chaplin, DJ Trawick, ML Pinney, KG AF Winn, Blake A. Shi, Zhe Carlson, Graham J. Wang, Yifan Nguyen, Benson L. Kelly, Evan M. Ross, R. David Hamel, Ernest Chaplin, David J. Trawick, Mary L. Pinney, Kevin G. TI Bioreductively activatable prodrug conjugates of phenstatin designed to target tumor hypoxia SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Bioreductively activatable prodrug; conjugates (BAPCs); Phenstatin; Prodrug synthesis; Tumor-associated hypoxia; Inhibitors of tubulin polymerization ID ANTINEOPLASTIC AGENTS; 2-NITROIMIDAZOLE DERIVATIVES; CELL RADIOSENSITIZERS; BIOLOGICAL-ACTIVITY; COMBRETASTATIN A-4; COMBRETUM-CAFFRUM; CANCER-THERAPY; MECHANISM; TUBULIN; TH-302 AB A variety of solid tumor cancers contain significant regions of hypoxia, which provide unique challenges for targeting by potent anticancer agents. Bioreductively activatable prodrug conjugates (BAPCs) represent a promising strategy for therapeutic intervention. BAPCs are designed to be biologically inert until they come into contact with low oxygen tension, at which point reductase enzyme mediated cleavage releases the parent anticancer agent in a tumor-specific manner. Phenstatin is a potent inhibitor of tubulin polymerization, mimicking the chemical structure and biological activity of the natural product combretastatin A-4. Synthetic approaches have been established for nitrobenzyl, nitroimidazole, nitrofuranyl, and nitrothienyl prodrugs of phenstatin incorporating nor-methyl, mono-methyl, and gem-dimethyl variants of the attached nitro compounds. A series of BAPCs based on phenstatin have been prepared by chemical synthesis and evaluated against the tubulin-microtubule protein system. In a preliminary study using anaerobic conditions, the gem-dimethyl nitrothiophene and gem-dimethyl nitrofuran analogues were shown to undergo efficient enzymatic cleavage in the presence of NADPH cytochrome P450 oxidoreductase. Each of the eleven BAPCs evaluated in this study demonstrated significantly reduced inhibitory activity against tubulin in comparison to the parent anti-cancer agent phenstatin (IC50 = 1.0 mu M). In fact, the majority of the BAPCs (seven of the eleven analogues) were not inhibitors of tubulin polymerization (IC50 > 20 mu M), which represents an anticipated (and desirable) attribute for these prodrugs, since they are intended to be biologically inactive prior to enzyme-mediated cleavage to release phenstatin. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Winn, Blake A.; Shi, Zhe; Carlson, Graham J.; Wang, Yifan; Nguyen, Benson L.; Kelly, Evan M.; Ross, R. David; Chaplin, David J.; Trawick, Mary L.; Pinney, Kevin G.] Baylor Univ, Dept Chem & Biochem, One Bear Pl 97348, Waco, TX 76798 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Chaplin, David J.] Mateon Therapeut Inc, 701 Gateway Blvd,Suite 210, San Francisco, CA 94080 USA. RP Trawick, ML; Pinney, KG (reprint author), Baylor Univ, Dept Chem & Biochem, One Bear Pl 97348, Waco, TX 76798 USA. EM Mary_Lynn_Trawick@baylor.edu; Kevin_Pinney@baylor.edu FU Cancer Prevention and Research Institute of Texas (CPRIT) [RP140399]; National Cancer Institute of the National Institutes of Health [5R01CA140674]; Mateon Therapeutics, Inc. FX The authors are grateful to the Cancer Prevention and Research Institute of Texas (CPRIT, Grant No. RP140399 to K.G.P. and M.L.T.), the National Cancer Institute of the National Institutes of Health (Grant No. 5R01CA140674 to K.G.P. and M.L.T.), and Mateon Therapeutics, Inc. (grant to K.G.P. and M.L.T.) for their financial support of this project. The content of this paper is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. The authors also thank Dr. Michelle Nemec (Director) for the use of the shared Molecular Biosciences Center at Baylor University and Dr. Alejandro Ramirez (Mass Spectrometry Core Facility, Baylor University). The authors are grateful to Ms. Taylor Deushane, Mr. Bunnarack Kuch, Mr. Raj Patel, Mr. Matthew Parsons, and Ms. Evelyn Le for their contributions to the synthesis of advanced intermediates. NR 59 TC 0 Z9 0 U1 7 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 1 PY 2017 VL 27 IS 3 BP 636 EP 641 DI 10.1016/j.bmcl.2016.11.093 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA EJ0LQ UT WOS:000392900600051 PM 28007448 ER PT J AU Reinhold, WC Varma, S Sunshine, M Rajapakse, V Luna, A Kohn, KW Stevenson, H Wang, YH Heyn, H Nogales, V Moran, S Goldstein, DJ Doroshow, JH Meltzer, PS Esteller, M Pommier, Y AF Reinhold, William C. Varma, Sudhir Sunshine, Margot Rajapakse, Vinodh Luna, Augustin Kohn, Kurt W. Stevenson, Holly Wang, Yonghong Heyn, Holger Nogales, Vanesa Moran, Sebastian Goldstein, David J. Doroshow, James H. Meltzer, Paul S. Esteller, Manel Pommier, Yves TI The NCI-60 Methylome and Its Integration into CellMiner SO CANCER RESEARCH LA English DT Article ID DNA METHYLATION; SYSTEMS PHARMACOLOGY; MESSENGER-RNA; CANCER-CELLS; SLFN11; MAINTENANCE; SENSITIVITY; EPIGENETICS; CHALLENGES; PROFILES AB A unique resource for systems pharmacology and genomic studies is the NCI-60 cancer cell line panel, which provides data for the largest publicly available library of compounds with cytotoxic activity (similar to 21,000 compounds), including 108 FDA-approved and 70 clinical trial drugs as well as genomic data, including whole-exome sequencing, gene and miRNA transcripts, DNA copy number, and protein levels. Here, we provide the first readily usable genome-wide DNA methylation database for the NCI-60, including 485,577 probes from the Infinium HumanMethylation450k BeadChip array, which yielded DNA methylation signatures for 17,559 genes integrated into our open access CellMiner version 2.0 (https://discover.nci.nih.gov/cellminer). Among new insights, transcript versus DNA methylation correlations revealed the epithelial/mesenchymal gene functional category as being influenced most heavily by methylation. DNA methylation and copy number integration with transcript levels yielded an assessment of their relative influence for 15,798 genes, including tumor suppressor, mitochondrial, and mismatch repair genes. Four forms of molecular data were combined, providing rationale for microsatellite instability for 8 of the 9 cell lines in which it occurred. Individual cell line analyses showed globalmethylome patterns with overall methylation levels ranging from 17% to 84%. A six-gene model, including PARP1, EP300, KDM5C, SMARCB1, and UHRF1 matched this pattern. In addition, promoter methylation of two translationally relevant genes, Schlafen 11 (SLFN11) and methylguanine methyltransferase (MGMT), served as indicators of therapeutic resistance or susceptibility, respectively. Overall, our database provides a resource of pharmacologic data that can reinforce known therapeutic strategies and identify novel drugs and drug targets across multiple cancer types. (C) 2016 AACR. C1 [Reinhold, William C.; Varma, Sudhir; Sunshine, Margot; Rajapakse, Vinodh; Luna, Augustin; Kohn, Kurt W.; Doroshow, James H.; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Varma, Sudhir; Sunshine, Margot] Syst Res & Applicat Corp, Fairfax, VA USA. [Varma, Sudhir] HiThru Analyt LLC, Laurel, MD USA. [Luna, Augustin] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Luna, Augustin] Harvard Med Sch, Dept Cell Biol, Boston, MA USA. [Stevenson, Holly; Wang, Yonghong; Meltzer, Paul S.] NCI, Genet Branch, Dev Therapeut Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Heyn, Holger; Nogales, Vanesa; Moran, Sebastian; Esteller, Manel] Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program, Barcelona, Catalonia, Spain. [Goldstein, David J.] NCI, Off Director, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Esteller, Manel] Univ Barcelona, Sch Med, Dept Physiol Sci 2, Barcelona, Catalonia, Spain. [Esteller, Manel] ICREA, Barcelona, Catalonia, Spain. RP Reinhold, WC (reprint author), NCI, 9000 Rockville Pike,Bldg 37,Room 5041, Bethesda, MD 20892 USA. EM wcr@mail.nih.gov; pommier@nih.gov RI Moran, Sebastian /G-5293-2013; OI Moran, Sebastian /0000-0003-4192-8983; Heyn, Holger/0000-0002-3276-1889 FU Intramural NIH HHS [ZIC BC011475-01] NR 36 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2017 VL 77 IS 3 BP 601 EP 612 DI 10.1158/0008-5472.CAN-16-0655 PG 12 WC Oncology SC Oncology GA EJ4NP UT WOS:000393194400003 PM 27923837 ER PT J AU Chen, G Nakamura, I Dhanasekaran, R Iguchi, E Tolosa, EJ Romecin, PA Vera, RE Almada, LL Miamen, AG Chaiteerakij, R Zhou, MT Asiedu, MK Moser, CD Han, SS Hu, CL Banini, BA Oseini, AM Chen, YC Fang, Y Yang, DY Shaleh, HM Wang, SQ Wu, DH Song, T Lee, JS Thorgeirsson, SS Chevet, E Shah, VH Fernandez-Zapico, ME Roberts, LR AF Chen, Gang Nakamura, Ikuo Dhanasekaran, Renumathy Iguchi, Eriko Tolosa, Ezequiel J. Romecin, Paola A. Vera, Renzo E. Almada, Luciana L. Miamen, Alexander G. Chaiteerakij, Roongruedee Zhou, Mengtao Asiedu, Michael K. Moser, Catherine D. Han, Shaoshan Hu, Chunling Banini, Bubu A. Oseini, Abdul M. Chen, Yichun Fang, Yong Yang, Dongye Shaleh, Hassan M. Wang, Shaoqing Wu, Dehai Song, Tao Lee, Ju-Seog Thorgeirsson, Snorri S. Chevet, Eric Shah, Vijay H. Fernandez-Zapico, Martin E. Roberts, Lewis R. TI Transcriptional Induction of Periostin by a Sulfatase 2-TGF beta 1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma SO CANCER RESEARCH LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; HEPARAN-SULFATE; CANCER-CELLS; FACTOR-BETA; EXPRESSION; PATHWAY; MICROENVIRONMENT; ACTIVATION; SURVIVAL; PROTEIN AB Existing antiangiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here, we report a novel role for sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of alpha v beta 3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo. The TGF beta 1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, elevated levels of SULF2 with increased microvascular density, POSTN levels, and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development. (C) 2016 AACR. C1 [Chen, Gang; Zhou, Mengtao] Wenzhou Med Univ, Affiliated Hosp 1, Div Hepatobiliary Surg, Wenzhou, Zhejiang, Peoples R China. [Chen, Gang; Nakamura, Ikuo; Dhanasekaran, Renumathy; Miamen, Alexander G.; Chaiteerakij, Roongruedee; Asiedu, Michael K.; Moser, Catherine D.; Han, Shaoshan; Hu, Chunling; Banini, Bubu A.; Oseini, Abdul M.; Chen, Yichun; Fang, Yong; Yang, Dongye; Shaleh, Hassan M.; Wang, Shaoqing; Wu, Dehai; Song, Tao; Shah, Vijay H.; Fernandez-Zapico, Martin E.; Roberts, Lewis R.] Mayo Clin, Coll Med & Sci, Div Gastroenterol & Hepatol, 200 First St SW, Rochester, MN 55905 USA. [Dhanasekaran, Renumathy; Wang, Shaoqing] Stanford Univ, Div Gastroenterol & Hepatol, Palo Alto, CA 94304 USA. [Iguchi, Eriko; Tolosa, Ezequiel J.; Romecin, Paola A.; Vera, Renzo E.; Almada, Luciana L.; Fernandez-Zapico, Martin E.] Mayo Clin, Schulze Ctr Novel Therapeut, Rochester, MN USA. [Chaiteerakij, Roongruedee] Chulalongkorn Univ, Fac Med, Dept Med, Bangkok, Thailand. [Chaiteerakij, Roongruedee] Thai Red Cross Soc, King Chulalongkorn Mem Hosp, Bangkok, Thailand. [Lee, Ju-Seog] MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX USA. [Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. [Chevet, Eric] Univ Rennes 1, INSERM U1242, Oncogenesis Stress Signaling, Chem, Rennes, France. [Chevet, Eric] Ctr Lutte Canc Eugene Marquis, Rennes, France. RP Roberts, LR (reprint author), Mayo Clin, Coll Med & Sci, Div Gastroenterol & Hepatol, 200 First St SW, Rochester, MN 55905 USA. EM roberts.lewis@mayo.edu FU NIH [CA128633, CA165076]; Mayo Clinic Center for Cell Signaling in Gastroenterology [NIDDK P30DK084567]; Mayo Clinic Cancer Center [CA15083]; Mayo Clinic Center for Translational Science Activities (NIH/NCRR CTSA Grant) [UL1 TR000135]; National Natural Science Foundation of China [81201953] FX This work was supported by NIH grants CA128633 to L.R. Roberts and CA165076 to L.R. Roberts and M.E. Fernandez-Zapico; the Mayo Clinic Center for Cell Signaling in Gastroenterology (NIDDK P30DK084567) to L.R. Roberts and M.E. Fernandez-Zapico; the Mayo Clinic Cancer Center (CA15083) to L.R. Roberts; the Mayo Clinic Center for Translational Science Activities (NIH/NCRR CTSA Grant Number UL1 TR000135) to L.R. Roberts; and the National Natural Science Foundation of China81201953 to G. Chen. NR 34 TC 0 Z9 0 U1 4 U2 4 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 FEB 1 PY 2017 VL 77 IS 3 BP 632 EP 645 DI 10.1158/0008-5472.CAN-15-2556 PG 14 WC Oncology SC Oncology GA EJ4NP UT WOS:000393194400006 PM 27872089 ER PT J AU Pellegrini, L Wetzel, A Granno, S Heaton, G Harvey, K AF Pellegrini, Laura Wetzel, Andrea Granno, Simone Heaton, George Harvey, Kirsten TI Back to the tubule: microtubule dynamics in Parkinson's disease SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Parkinson's disease; Cytoskeleton; Microtubule dynamics; Axonal transport; Tau; PARK genes; LRRK2; Wnt signalling; Microtubule targeting agents ID MAJOR ALPHA-TUBULIN; REPEAT KINASE 2; TRANSCRIPTION FACTOR TRAFFICKING; GLYCOGEN-SYNTHASE KINASE-3-BETA; AMYOTROPHIC-LATERAL-SCLEROSIS; AXONAL-TRANSPORT DEFICITS; STRESSED NEURONAL CELLS; BLOOD-BRAIN-BARRIER; TAU GENE-MUTATIONS; ALZHEIMERS-DISEASE AB Cytoskeletal homeostasis is essential for the development, survival and maintenance of an efficient nervous system. Microtubules are highly dynamic polymers important for neuronal growth, morphology, migration and polarity. In cooperation with several classes of binding proteins, microtubules regulate long-distance intracellular cargo trafficking along axons and dendrites. The importance of a delicate interplay between cytoskeletal components is reflected in several human neurodegenerative disorders linked to abnormal microtubule dynamics, including Parkinson's disease (PD). Mounting evidence now suggests PD pathogenesis might be underlined by early cytoskeletal dysfunction. Advances in genetics have identified PD-associated mutations and variants in genes encoding various proteins affecting microtubule function including the microtubule-associated protein tau. In this review, we highlight the role of microtubules, their major posttranslational modifications and microtubule associated proteins in neuronal function. We then present key evidence on the contribution of microtubule dysfunction to PD. Finally, we discuss how regulation of microtubule dynamics with microtubule-targeting agents and deacetylase inhibitors represents a promising strategy for innovative therapeutic development. C1 [Pellegrini, Laura; Wetzel, Andrea; Granno, Simone; Heaton, George; Harvey, Kirsten] UCL, Dept Pharmacol, UCL Sch Pharm, 29-39 Brunswick Sq, London WC1N 1AX, England. [Pellegrini, Laura] NIA, Neurogenet Lab, NIH, 35 Convent Dr, Bethesda, MD 20982 USA. [Granno, Simone] UCL, Dept Neurodegenerat Dis, UCL Inst Neurol, Queen Sq, London, England. RP Harvey, K (reprint author), UCL, Dept Pharmacol, UCL Sch Pharm, 29-39 Brunswick Sq, London WC1N 1AX, England. EM kirsten.harvey@ucl.ac.uk OI Harvey, Kirsten/0000-0002-1291-0728 NR 286 TC 0 Z9 0 U1 13 U2 13 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD FEB PY 2017 VL 74 IS 3 BP 409 EP 434 DI 10.1007/s00018-016-2351-6 PG 26 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EJ2FF UT WOS:000393024800003 PM 27600680 ER PT J AU Kaljas, Y Liu, CQ Skaldin, M Wu, CX Zhou, Q Lu, YN Aksentijevich, I Zavialov, AV AF Kaljas, Yuliia Liu, Chengqian Skaldin, Maksym Wu, Chengxiang Zhou, Qing Lu, Yuanan Aksentijevich, Ivona Zavialov, Andrey V. TI Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE Adenosine; Adenosine deaminases; Immune cells; Adenosine deaminase 2 deficiency ID REGULATORY T-CELLS; SEVERE COMBINED IMMUNODEFICIENCY; ELECTRON-MICROSCOPY; RECEPTORS; PLASMA; MONOCYTES; SYSTEM; BLOOD; CD26; VASCULOPATHY AB At sites of inflammation and tumor growth, the local concentration of extracellular adenosine rapidly increases and plays a role in controlling the immune responses of nearby cells. Adenosine deaminases ADA1 and ADA2 (ADAs) decrease the level of adenosine by converting it to inosine, which serves as a negative feedback mechanism. Mutations in the genes encoding ADAs lead to impaired immune function, which suggests a crucial role for ADAs in immune system regulation. It is not clear why humans and other mammals possess two enzymes with adenosine deaminase activity. Here, we found that ADA2 binds to neutrophils, monocytes, NK cells and B cells that do not express CD26, a receptor for ADA1. Moreover, the analysis of CD4+ T-cell subset revealed that ADA2 specifically binds to regulatory T cells expressing CD39 and lacking the receptor for ADA1. Also, it was found that ADA1 binds to CD16- monocytes, while CD16+ monocytes preferably bind ADA2. A study of the blood samples from ADA2-deficient patients showed a dramatic reduction in the number of lymphocyte subsets and an increased concentration of TNF-alpha in plasma. Our results suggest the existence of a new mechanism, where the activation and survival of immune cells is regulated through the activities of ADA2 or ADA1 anchored to the cell surface. C1 [Kaljas, Yuliia; Liu, Chengqian; Skaldin, Maksym; Zavialov, Andrey V.] Guangzhou Inst Pediat, Guangzhou Women & Childrens Med Ctr, 9 Jinsui Rd, Guangzhou 510623, Guangdong, Peoples R China. [Kaljas, Yuliia; Liu, Chengqian; Skaldin, Maksym; Zavialov, Andrey V.] Univ Turku, Turku Ctr Biotechnol, Tykistokatu 6, FIN-20520 Turku, Finland. [Zhou, Qing] NHGRI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wu, Chengxiang; Lu, Yuanan; Aksentijevich, Ivona] Univ Hawaii Manoa, John A Burns Sch Med, Dept Publ Hlth, Biomed, 1960 East West Rd, Honolulu, HI 96822 USA. [Wu, Chengxiang] Tulane Natl Primate Res Ctr, Div Regenerat Med, 18703 Three River Rd, Covington, LA 70433 USA. RP Zavialov, AV (reprint author), Guangzhou Inst Pediat, Guangzhou Women & Childrens Med Ctr, 9 Jinsui Rd, Guangzhou 510623, Guangdong, Peoples R China.; Zavialov, AV (reprint author), Univ Turku, Turku Ctr Biotechnol, Tykistokatu 6, FIN-20520 Turku, Finland. EM andrey.zavialov@gmail.com FU Finnish Academy [256053] FX This study was supported by a Grant 256053 from the Finnish Academy to A.Z. NR 50 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD FEB PY 2017 VL 74 IS 3 BP 555 EP 570 DI 10.1007/s00018-016-2357-0 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EJ2FF UT WOS:000393024800012 PM 27663683 ER PT J AU Selvin, E Sacks, DB AF Selvin, Elizabeth Sacks, David B. TI Monitoring Glycemic Control in End-Stage Renal Disease: What Should Be Measured? SO CLINICAL CHEMISTRY LA English DT Editorial Material ID GLYCATED ALBUMIN; CARDIOVASCULAR OUTCOMES; RISK; FRUCTOSAMINE; GLUCOSE; HEMODIALYSIS; MANAGEMENT; DIAGNOSIS; HBA(1C); DEATH C1 [Selvin, Elizabeth] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Sacks, David B.] NIH, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. RP Sacks, DB (reprint author), Dept Lab Med, Bldg 10,Rm 2C306,10 Ctr Dr, Bethesda, MD 20892 USA. FU NIH/NIDDK [K24DK106414, 2R01DK089174, R01DK108784]; NIH Intramural Research Program FX E. Selvin, NIH/NIDDK grants K24DK106414, 2R01DK089174, and R01DK108784; D.B. Sacks, NIH Intramural Research Program. NR 15 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 63 IS 2 BP 447 EP 449 DI 10.1373/clinchem.2016.265744 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EJ6WG UT WOS:000393360000002 PM 27974388 ER PT J AU Papadakis, GZ Millo, C Sadowski, SM Karantanas, AH Bagci, U Patronas, NJ AF Papadakis, Georgios Z. Millo, Corina Sadowski, Samira M. Karantanas, Apostolos H. Bagci, Ulas Patronas, Nicholas J. TI Breast Fibroadenoma With Increased Activity on Ga-68 DOTATATE PET/CT SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE breast fibroadenoma; Ga-68 DOTATATE PET/CT; benign tumor; somatostatin receptors ID LESIONS C1 [Papadakis, Georgios Z.; Patronas, Nicholas J.] NCI, Dept Radiol & Imaging Sci, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. [Millo, Corina] NCI, PET Dept, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Sadowski, Samira M.] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Sadowski, Samira M.] Univ Hosp Geneva, Endocrine & Thorac Surg, Geneva, Switzerland. [Karantanas, Apostolos H.] Univ Crete, Dept Radiol, Sch Med, Iraklion, Greece. [Bagci, Ulas] Univ Cent Florida, Dept Elect & Comp Sci, Ctr Res Comp Vis, Orlando, FL 32816 USA. RP Papadakis, GZ (reprint author), NIH, Dept Radiol & Imaging Sci, Warren Grant Magnuson Clin Ctr, Bldg 10,Room 1C370,10 Ctr Dr, Bethesda, MD 20814 USA. EM papadakisg@cc.nih.gov FU Intramural NIH HHS [Z99 DE999999] NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD FEB PY 2017 VL 42 IS 2 BP 145 EP 146 DI 10.1097/RLU.0000000000001463 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ0UB UT WOS:000392924900036 PM 27879489 ER PT J AU Chen, D Bienvenu, OJ Krasnow, J Wang, Y Grados, MA Cullen, B Goes, FS Maher, B Greenberg, BD McLaughlin, NC Rasmussen, SA Fyer, AJ Knowles, JA McCracken, JT Piacentini, J Geller, D Pauls, DL Stewart, SE Murphy, DL Shugart, YY Riddle, MA Nestadt, G Samuels, J AF Chen, David Bienvenu, O. Joseph Krasnow, Janice Wang, Ying Grados, Marco A. Cullen, Bernadette Goes, Fernando S. Maher, Brion Greenberg, Benjamin D. McLaughlin, Nicole C. Rasmussen, Steven A. Fyer, Abby J. Knowles, James A. McCracken, James T. Piacentini, John Geller, Dan Pauls, David L. Stewart, S. Evelyn Murphy, Dennis L. Shugart, Yin-Yao Riddle, Mark A. Nestadt, Gerald Samuels, Jack TI Parental bonding and hoarding in obsessive compulsive disorder SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID OCD COLLABORATIVE GENETICS; SYMPTOM DIMENSIONS; AFFECTIONLESS CONTROL; PERSONALITY-TRAITS; ANXIETY DISORDERS; CLINICAL-SAMPLE; MULTI-INFORMANT; RISK-FACTOR; ATTACHMENT; FAMILY AB Background: Hoarding behavior may indicate a clinically and possibly etiologically distinct subtype of obsessive compulsive disorder (OCD). Empirical evidence supports a relationship between hoarding and emotional over-attachment to objects. However, little is known about the relationship between hoarding and parental attachment in OCD. Method: The study sample included 894 adults diagnosed with DSM-IV OCD who had participated in family and genetic studies of OCD. Participants were assessed for Axis I disorders, personality disorders, and general personality dimensions. The Parental Bonding Instrument (PB1) was used to assess dimensions of perceived parental rearing (care, overprotection, and control). We compared parental PHI scores in the 334 hoarding and 560 non-hoarding participants, separately in men and women. We used logistic regression to evaluate the relationship between parenting scores and hoarding in women, adjusting for other clinical features associated with hoarding. Results: In men, there were no significant differences between hoarding and non-hoarding groups in maternal or paternal parenting scores. In women, the hoarding group had a lower mean score on maternal care (23.4 vs. 25.7, p < 0.01); a higher mean score on maternal protection (9.4 vs. 7.7, p < 0.001); and a higher mean score on maternal control (7.0 vs. 6.2, p < 0.05), compared to the non-hoarding group. The magnitude of the relationships between maternal bonding dimensions and hoarding in women did not change after adjustment for other clinical features. Women who reported low maternal care/high maternal protection had significantly greater odds of hoarding compared to women with high maternal care/low maternal protection (OR = 2.54, 95% CI = 1.60-4.02, p < 0.001). Conclusions: Perceived poor maternal care, maternal overprotection, and maternal overcontrol are associated with hoarding in women with OCD. Parenting dimensions are not related to hoarding in men. These findings provide further support for a hoarding subtype of OCD and for sex-specific differences in etiologic pathways for hoarding in OCD. (C) 2016 Elsevier Inc. All rights reserved. C1 [Chen, David] Loyola Univ, Dept Psychol, Baltimore, MD USA. [Bienvenu, O. Joseph; Krasnow, Janice; Wang, Ying; Grados, Marco A.; Cullen, Bernadette; Goes, Fernando S.; Riddle, Mark A.; Nestadt, Gerald; Samuels, Jack] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 550 N Broadway 902, Baltimore, MD 21205 USA. [Maher, Brion] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Greenberg, Benjamin D.; McLaughlin, Nicole C.; Rasmussen, Steven A.] Butler Hosp, Dept Psychiat & Human Behav, Brown Med Sch, Providence, RI 02906 USA. [Fyer, Abby J.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Fyer, Abby J.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Knowles, James A.] Univ Southern Calif, Dept Psychiat, Sch Med, Los Angeles, CA USA. [McCracken, James T.; Piacentini, John] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Geller, Dan] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Pauls, David L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Pauls, David L.] Harvard Med Sch, Boston, MA USA. [Stewart, S. Evelyn] Univ British Columbia, Dept Psychiat, Fac Med, Vancouver, BC, Canada. [Murphy, Dennis L.] NIMH, Clin Sci Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Shugart, Yin-Yao] NIMH, Unit Stat Genom, Div Intramural Res, Bethesda, MD 20892 USA. RP Samuels, J (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 550 N Broadway 902, Baltimore, MD 21205 USA. EM jacks@jhmi.edu FU National Institutes of Health [MH50214, MH071507, MH79487, MH079488, MH079489, MH079494, K23-MH-64543, NIH/NCRR/OPD-GCRC RR00052]; James E. Marshall OCD Foundation FX This research was supported by National Institutes of Health grants MH50214, MH071507, MH79487, MH079488, MH079489, MH079494, K23-MH-64543, NIH/NCRR/OPD-GCRC RR00052, and by the James E. Marshall OCD Foundation. The funding agencies had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. NR 78 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD FEB PY 2017 VL 73 BP 43 EP 52 DI 10.1016/j.comppsych.2016.11.004 PG 10 WC Psychiatry SC Psychiatry GA EJ3YS UT WOS:000393149300007 PM 27915218 ER PT J AU Odio, CD Marciano, BE Galgiani, JN Holland, SM AF Odio, Camila D. Marciano, Beatriz E. Galgiani, John N. Holland, Steven M. TI Risk Factors for Disseminated Coccidioidomycosis, United States SO EMERGING INFECTIOUS DISEASES LA English DT Article ID SIGNAL TRANSDUCER; TRANSCRIPTION; ACTIVATOR; PULMONARY; IMMITIS; PATIENT AB Of 150,000 new coccidioidomycosis infections that occur annually in the United States, approximate to 1% disseminate; one third of those cases are fatal. Immunocompromised hosts have higher rates of dissemination. We identified 8 patients with disseminated coccidioidomycosis who had defects in the interleukin-12/interferon-gamma and STAT3 axes, indicating that these are critical host defense pathways. C1 [Odio, Camila D.; Marciano, Beatriz E.; Holland, Steven M.] NIH, Bldg 10,Rm 11N248,MSC 1960, Bethesda, MD 20892 USA. [Galgiani, John N.] Univ Arizona, Coll Med, Tucson, AZ USA. [Odio, Camila D.] Yale New Haven Med Ctr, 20 York St, New Haven, CT 06504 USA. RP Holland, SM (reprint author), NIH, Bldg 10,Rm 11N248,MSC 1960, Bethesda, MD 20892 USA. EM smh@nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), USA; NIH Medical Research Scholars Program; NIH FX This study was funded in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), USA.; C.D.O. was funded through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by NIH and generous contributions to the Foundation for the NTH from Pfizer Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, visit the Foundation website (http://fnih.org/work/education-training-0/medical-research-scholars-pro gram). NR 15 TC 0 Z9 0 U1 0 U2 0 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2017 VL 23 IS 2 BP 308 EP 311 DI 10.3201/eid2302.160505 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EJ3CI UT WOS:000393088600021 ER PT J AU Taubenberger, JK Morens, DM AF Taubenberger, Jeffery K. Morens, David M. TI H5Nx Panzootic Bird Flu-Influenza's Newest Worldwide Evolutionary Tour SO EMERGING INFECTIOUS DISEASES LA English DT Editorial Material ID HEMAGGLUTININ; VIRUSES C1 [Taubenberger, Jeffery K.; Morens, David M.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, Bldg 31,Room 7A-03,31 Ctr Dr, Bethesda, MD 20892 USA. EM dm270q@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 8 TC 0 Z9 0 U1 1 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2017 VL 23 IS 2 BP 340 EP 342 DI 10.3201/eid2302.161963 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EJ3CI UT WOS:000393088600029 ER PT J AU Lam, C Ferreira, C Krasnewich, D Toro, C Latham, L Zein, WM Lehky, T Brewer, C Baker, EH Thurm, A Farmer, CA Rosenzweig, SD Lyons, JJ Schreiber, JM Gropman, A Lingala, S Ghany, MG Solomon, B Macnamara, E Davids, M Stratakis, CA Kimonis, V Gahl, WA Wolfe, L AF Lam, Christina Ferreira, Carlos Krasnewich, Donna Toro, Camilo Latham, Lea Zein, Wadih M. Lehky, Tanya Brewer, Carmen Baker, Eva H. Thurm, Audrey Farmer, Cristan A. Rosenzweig, Sergio D. Lyons, Jonathan J. Schreiber, John M. Gropman, Andrea Lingala, Shilpa Ghany, Marc G. Solomon, Beth Macnamara, Ellen Davids, Mariska Stratakis, Constantine A. Kimonis, Virginia Gahl, William A. Wolfe, Lynne TI Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation SO GENETICS IN MEDICINE LA English DT Article DE deglycosylation; glycosylation; natural history; NGLY1; NGLY1-CDDG ID INTELLECTUAL DISABILITY; GLYCOSYLATION; SPECTROSCOPY; MUTATIONS; CELLS; SERUM; NEUROTRANSMITTERS; DEGRADATION; DEFICIENCY; ASPARTATE AB Purpose: The cytosolic enzyme N-glycanase 1,'encoded by NGLY1, catalyzes cleavage of the P-aspartyl glycosylamine bond of N-linked glycoproteins, releasing intact N-glycans from proteins bound for degradation. In this study, we describe the clinical spectrum of NGLY1 deficiency (NGLY1-CDDG). Methods: Prospective natural history protocol. Results: In 12 individuals ages 2 to 21 years with confirmed, biallelic, pathogenic NGLY1 mutations, we identified previously unreported clinical features, including optic atrophy and retinal pigmentary changes/cone dystrophy, delayed bone age, joint hypermobility, and lower than predicted resting energy expenditure. Novel laboratory findings include low cerebral spinal fluid (CSP) total protein and albumin and unusually high antibody titers toward rubella and/or rubeola following vaccination. We also confirmed and further quantified previously reported findings noting that decreased tear production, transient transaminitis, small feet, a complex hyperkinetic movement disorder, and varying degrees of global developmental delay with relatively preserved socialization are the most consistent features. Conclusion: Our prospective phenotyping expands the clinical spectrum of NGLY1-CDDG, offers prognostic information, and provides baseline data for evaluating therapeutic C1 [Lam, Christina; Ferreira, Carlos; Gropman, Andrea; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Ferreira, Carlos] Childrens Natl Med Ctr, Div Genet & Metab, Washington, DC 20010 USA. [Krasnewich, Donna] NIGMS, Div Genet & Dev Biol, NIH, Bethesda, MD USA. [Toro, Camilo; Latham, Lea; Macnamara, Ellen; Davids, Mariska; Gahl, William A.; Wolfe, Lynne] NIH, Undiagnosed Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Zein, Wadih M.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Lehky, Tanya] NINDS, Electromyog Sect, NIH, Bethesda, MD USA. [Brewer, Carmen] NIDCD, Otolaryngol Branch, NIH, Bethesda, MD USA. [Baker, Eva H.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Thurm, Audrey; Farmer, Cristan A.] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. [Rosenzweig, Sergio D.] NIH, Serv Immunol, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Lyons, Jonathan J.] NIAID, Genet & Pathogenesis Allergy Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Schreiber, John M.] NINDS, Clin Epilepsy Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Lingala, Shilpa; Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Solomon, Beth] NIH, Speech & Language Pathol Sect, Dept Rehabil Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. [Kimonis, Virginia] Univ Calif Irvine, Dept Pediat, Div Genet & Genom Med, Irvine, CA 92717 USA. [Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Lam, C (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM lamct@mail.nih.gov OI Thurm, Audrey/0000-0002-0489-9485 FU Common Fund, Office of the Director; NHGRI; NIDCD, NIH, Bethesda, Maryland, USA FX This study was supported by the Common Fund, Office of the Director, and the Intramural Research Program of the NHGRI and NIDCD, NIH, Bethesda, Maryland, USA. We sincerely thank all the individuals and their families for participating in this study, and the advocacy groups NGLY1.org and the Grace Science Foundation, which provided encouragement and emotional support. We thank Hudson Freeze, Kathy Grange, Mena Scavina, Michael J. Gambello, J. Lawrence Merritt II, Marni Falk, and Marwan Shinawi for referring and caring for the affected individuals. We thank Jaak Jaeken for his input regarding the "official naming" of this disorder. Additionally, we are immensely grateful to our collaborators, colleagues, and technical/laboratory assistants for providing continuous discussion, support, and direction for this project. NR 31 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 FEB PY 2017 VL 19 IS 2 BP 160 EP 168 DI 10.1038/gim.2016.75 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EJ9GI UT WOS:000393534200004 PM 27388694 ER PT J AU Khan, NE Bauer, AJ Doros, L Schultz, KAP Decastro, RM Harney, LA Kase, RG Carr, AG Harris, AK Williams, GM Dehner, LR Messinger, YH Stewart, DR AF Khan, Nicholas E. Bauer, Andrew J. Doros, Leslie Schultz, Kris Ann P. Decastro, Rosamma M. Harney, Laura A. Kase, Ron G. Carr, Ann G. Harris, Anne K. Williams, Gretchen M. Dehner, Louis R. Messinger, Yoav H. Stewart, Douglas R. TI Macrocephaly associated with the DICER1 syndrome SO GENETICS IN MEDICINE LA English DT Article DE DICER1; macrocephaly ID PLEUROPULMONARY BLASTOMA; MUTATIONS; GERMLINE AB Purpose: Germ-line mutations in DICER1 increase the risk cif various tumors, including pleuropulmonary blastoma. Macrocephaly and symmetric overgrowth have been reported in some, but not all, patients with mosaic DICER1 RNase Mb mutations. The prevalence of these features in individuals with constitutional germ-line DICERI mutations is unknown. Methods: We analyzed prospectively collected auxology data from 67 DICER1 mutation carriers and 43 family controls. We assessed differences between groups using an exact test for proportions and generalized estimating equations for continuous dependent variables. Results: Twenty-eight DICER1 mutation carriers (42%) were macrocephalic, and none had an occipitofrontal circumference (OFC) below the third centile, which significantly differed from family controls, of whom five were rhacrocephalic (12%) and two had OFC below the third centile (5%) (P < 0.001). DICER1 mutation carriers were taller than familial controls after controlling for gender (P = 0.048), but similar proportions of both groups were above the 97th centile of population norms. Head circumference remained increased after adjusting for differences in height. Conclusion: For the first time, we establish macrocephaly as a common finding in the DICER1 syndrome. Like some other tumor predisposition disorders, macrocephaly may be a useful, albeit a ' subtle, clinical clue to the DICER1 syndrome diagnosis. C1 [Khan, Nicholas E.; Decastro, Rosamma M.; Stewart, Douglas R.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Bauer, Andrew J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Doros, Leslie] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Schultz, Kris Ann P.; Harris, Anne K.; Williams, Gretchen M.; Messinger, Yoav H.] Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. [Schultz, Kris Ann P.; Harris, Anne K.; Williams, Gretchen M.; Messinger, Yoav H.] Int Pleuropulm Blastoma Registry, Minneapolis, MN USA. [Schultz, Kris Ann P.; Harris, Anne K.] Int Ovarian & Testicular Stromal Tumor Registry, Minneapolis, MN USA. [Harney, Laura A.; Kase, Ron G.; Carr, Ann G.] Westat Corp, Rockville, MD USA. [Dehner, Louis R.] Washington Univ, St Louis, MO USA. RP Stewart, DR (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. EM drstewart@mail.nih.gov FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Rockville, MD FX This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Rockville, MD. The authors thank D. Ashley Hill (Children's National Medical Center, Washington, DC) for DICER1 sequencing. NR 19 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 FEB PY 2017 VL 19 IS 2 BP 244 EP 248 DI 10.1038/gim.2016.83 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA EJ9GI UT WOS:000393534200015 PM 27441995 ER PT J AU Chen, YB Liao, XY Zhang, JB Wang, F Qin, HD Zhang, LJ Shugart, YY Zeng, YX Jia, WH AF Chen, Yuan-Bin Liao, Xiao-Yu Zhang, Jiang-Bo Wang, Fang Qin, Hai-De Zhang, Lanjun Shugart, Yin Yao Zeng, Yi-Xin Jia, Wei-Hua TI ADAR2 functions as a tumor suppressor via editing IGFBP7 in esophageal squamous cell carcinoma SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE ADAR2; esophageal neoplasms; IGFBP7; RNA editing; RNA sequencing ID HEPATOCELLULAR-CARCINOMA; HUMAN GLIOBLASTOMA; POOR-PROGNOSIS; RNA; GROWTH; CANCER; GENE; ADENOSINE; RECEPTOR; CARCINOGENESIS AB Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is characterized by heterogeneous genetic and epigenetic changes. Recently, A-to-I RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), was found to be aberrantly regulated during tumorigenesis. We previously reported that ADAR2 was downregulated in ESCC but its role was unclear. Thus, we report here that overexpression of ADAR2 can induce apoptosis in ESCC cell lines and inhibit tumor growth in vitro and in vivo. ADAR2 knockdown inhibited apoptosis in ADAR2 highly expressing tumor cells. RNA-seq assay showed that ADAR2, not ADAR1 or active-site-mutated ADAR2, could edit insulin-like growth factor binding protein 7 (IGFBP7) mRNA in ESCC. IGFBP7 knockdown or ADAR2 catalytic activity destruction abolished the pro-apoptotic function of ADAR2. Mechanistically, RNA editing may stabilize IGFBP7 protein by changing the protease recognition site of matriptase and this is essential for IGFBP7 to induce apoptosis. Western blotting revealed that ADAR2 overexpression could induce IGFBP7-dependent inhibition of Akt signaling. Thus, our data indicate that ADAR2 suppresses tumor growth and induces apoptosis by editing and stabilizing IGFBP7 in ESCC, and this may represent a novel therapeutic target for treating ESCC. C1 [Chen, Yuan-Bin; Liao, Xiao-Yu; Zhang, Jiang-Bo; Wang, Fang; Zhang, Lanjun; Zeng, Yi-Xin; Jia, Wei-Hua] Sun Yat Sen Univ, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med, Ctr Canc, Guangzhou 510060, Guangdong, Peoples R China. [Chen, Yuan-Bin] Qingdao Univ, Affiliated Hosp, Cent Lab, Qingdao 266000, Shandong, Peoples R China. [Liao, Xiao-Yu] Third Mil Med Univ, Xinqiao Hosp, Dept Endocrinol, Chongqing 400037, Peoples R China. [Qin, Hai-De; Shugart, Yin Yao] NIMH, Unit Stat Genom, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. RP Jia, WH (reprint author), Sun Yat Sen Univ, State Key Lab Oncol South China, Ctr Canc, Bldg 2,Room 903,651 Dongfeng Rd East, Guangzhou 510060, Guangdong, Peoples R China. EM jiawh@sysucc.org.cn FU National Natural Science Foundation of China [81502056]; National Science Fund for Distinguished Young Scholars of China [81325018]; Key Project for International Cooperation and Exchange of the National Natural Science Foundation of China [81220108022] FX We thank Professor Xin-Yuan Gun of Sun Yat-sen University Cancer Center for the ESCC cell line. We also thank the Bank of Tumor Resources, Sun Yat-sen University Cancer Center for providing ESCC samples for this study. This study was supported by the grants from the National Natural Science Foundation of China (grant no. 81502056), the National Science Fund for Distinguished Young Scholars of China (grant no. 81325018) and the Key Project for International Cooperation and Exchange of the National Natural Science Foundation of China (grant no. 81220108022). NR 39 TC 0 Z9 0 U1 3 U2 3 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 EI 1791-2423 J9 INT J ONCOL JI Int. J. Oncol. PD FEB PY 2017 VL 50 IS 2 BP 622 EP 630 DI 10.3892/ijo.2016.3823 PG 9 WC Oncology SC Oncology GA EJ3BT UT WOS:000393086800031 PM 28035363 ER PT J AU McCall, WV Lisanby, SH Rosenquist, PB Dooley, M Husain, MM Knapp, RG Petrides, G Rudorfer, MV Young, RC McClintock, SM Mueller, M Prudic, J Greenberg, RM Weiner, RD Bailine, SH Riley, MA McCloud, L Kellner, CH AF McCall, W. Vaughn Lisanby, Sarah H. Rosenquist, Peter B. Dooley, Mary Husain, Mustafa M. Knapp, Rebecca G. Petrides, Georgios Rudorfer, Matthew V. Young, Robert C. McClintock, Shawn M. Mueller, Martina Prudic, Joan Greenberg, Robert M. Weiner, Richard D. Bailine, Samuel H. Riley, Mary Anne McCloud, Laryssa Kellner, Charles H. CA CORE PRIDE Work Grp TI Effects of a right unilateral ultrabrief pulse electroconvulsive therapy course on health related quality of life in elderly depressed patients SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE ECT; Quality of life; Major depressive disorder; Elderly ID NEUROPSYCHIATRIC INTERVIEW MINI; ECT; REMISSION; AGE; RELIABILITY; VALIDATION; INPATIENTS; EFFICACY; OUTCOMES AB Introduction: Patients with Major Depressive Disorder (MDD) referred for electroconvulsive therapy (ECT) have poorer Health Related Quality of Life (HRQOL), compared with other patients with MDD, but ECT is associated with significant and durable improvement in HRQOL. However, no prior research has focused exclusively on elderly patients with MDD receiving ECT. Methods: HRQOL data from 240 depressed patients over the age of 60 was measured with the Medical Outcomes Study Short Form 36 (SF-36). The SF-36 was measured before and after a course of acute ECT. Predictors of change in HRQOL scores were identified by generalized linear modeling. Results: At baseline, participants showed very poor HRQOL. After treatment with ECT, the full sample showed marked and significant improvement across all SF-36 measures, with the largest gains seen in dimensions of mental health. Across all participants, the Physical Component Summary (PCS) score improved by 2.1 standardized points (95% CI, 0.61,3.56), while the Mental Component Summary (MCS) score improved by 12.5 points (95% CI, 7.2,10.8) Compared with non-remitters, remitters showed a trend toward greater improvement in the PCS summary score of 2.7 points (95%CI, -0.45, 5.9), while the improvement in the MCS summary score was significantly greater (8.5 points, 95% CI, 4.6,12.3) in the remitters than non-remitters. Post-ECT SF-36 measurements were consistently and positively related to baseline scores and remitter/non-remitter status or change in depression severity from baseline. Objective measures of cognitive function had no significant relationships to changes in SF-36 scores. Limitations: This study's limitations include that it was an open label study with no comparison group, and generalizability is limited to elderly patients. Discussion: ECT providers and elderly patients with MDD treated with ECT can be confident that ECT will result in improved HRQOL in the short-term. Attaining remission is a key factor in the improvement of HRQOL. Acute changes in select cognitive functions were outweighed by improvement in depressive symptoms in determining the short term HRQOL of the participants treated with ECT. C1 [McCall, W. Vaughn; Rosenquist, Peter B.; Riley, Mary Anne; McCloud, Laryssa] Augusta Univ, Med Coll Georgia, Augusta, GA USA. [Lisanby, Sarah H.; Rudorfer, Matthew V.] NIMH, Bethesda, MD 20892 USA. [Dooley, Mary; Knapp, Rebecca G.; Mueller, Martina] Med Univ South Carolina, Charleston, SC USA. [Husain, Mustafa M.; McClintock, Shawn M.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Petrides, Georgios; Bailine, Samuel H.] Zucker Hillside Hosp, North Shore LIJ Hlth Syst, New York, NY USA. [Young, Robert C.; Prudic, Joan] New York Presbyterian, Weill Cornell Med Ctr, New York, NY USA. [Prudic, Joan] Columbia Univ, New York, NY USA. [Prudic, Joan] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Greenberg, Robert M.] NYU, Sch Med, New York, NY USA. [Weiner, Richard D.] Duke Univ, Sch Med, Durham, NC 27706 USA. [Kellner, Charles H.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. RP McCall, WV (reprint author), Augusta Univ, Dept Psychiat & Hlth Behav, Med Coll Georgia, 997 St Sebastian Way, Augusta, GA 30912 USA. EM wmccall@augusta.edu OI Greenberg, Robert/0000-0001-7078-8970 FU NIMH [U01MH055495-09, 1U01MH086127-01, 7U01MH086127, 3U01MH086127-06S1, U01MH081362, 5U01-MH086122, 5U01MH84241-5, 5U01MH086130, 5U0IMH08612005, U01 MH084241, U01-MH086123]; NIDA; NINDS; NIA; NARSD; Stanley Foundation; Cyberonics; Neuronetics; St. Jude medical (ANS); MagStim; Brainsway; NeoSync; Alkermes; Corcept; HINDS; NIBIB; Brain and Behavior Research Foundation; Stanley Medical Research Foundation; Nexstim; Amgen; Astra Zeneca; Eli Lilly; Proteus; St. Jude Medical; Sunovion; NIH/NIMH FX This work was supported by NIMH grant U01MH055495-09 (Mt Sinai); U01MH055495-09, 1U01MH086127-01 (Wake Forest); 7U01MH086127 and 3U01MH086127-06S1 (Medical College of Georgia); U01MH081362 (Medical University of South Carolina); 5U01-MH086122 (Weill Cornell Medicine); 5U01MH84241-5 (Duke); 5U01MH086130 (Mayo); 5U0IMH08612005 (UTSW); U01 MH084241 (Duke); U01-MH086123 (LIJ).; Dr. McCall has been a scientific advisor for Merck, and Israeli Growth Partners, and a consultant to Luitpold Pharmaceuticals, Inc and Multiple Energy Technologies, LLC. Dr. Kellner receives honoraria from UpToDate, Psychiatric Times, and Northshore-LIJ Health System, and is a consultant to Luitpold Pharmaceuticals, Inc. Dr. Husain has received grant support from NIDA, NINDS, NIA, NARSD, Stanley Foundation, Cyberonics, Neuronetics, St. Jude medical (ANS), MagStim, Brainsway, NeoSync, Alkermes, and Corcept, and has been a consultant to Cerebain Inc. Dr. Young is a consultant to the NIH. Dr. Lisanby has received grant support from HINDS, NIBIB, Brain and Behavior Research Foundation, Stanley Medical Research Foundation, Neosync, Nexstim, and Brainsway. Dr. Petrides has received research support from Amgen, Astra Zeneca, Corcept, Eli Lilly, Proteus, St. Jude Medical, and Sunovion, and he has served on an advisory panel for Corcept. Dr. McClintock has received grant support from the NIH/NIMH and honoraria from TMS Health Solutions. The other authors report no financial relationships with commercial interests. NR 32 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD FEB PY 2017 VL 209 BP 39 EP 45 DI 10.1016/j.jad.2016.11.003 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EJ5EW UT WOS:000393241400008 ER PT J AU Ma, JT Hwang, SJ Pedley, A Massaro, JM Hoffmann, U Chung, RT Benjamin, EJ Levy, D Fox, CS Long, MT AF Ma, Jiantao Hwang, Shih-Jen Pedley, Alison Massaro, Joseph M. Hoffmann, Udo Chung, Raymond T. Benjamin, Emelia J. Levy, Daniel Fox, Caroline S. Long, Michelle T. TI Bi-directional analysis between fatty liver and cardiovascular disease risk factors SO JOURNAL OF HEPATOLOGY LA English DT Article DE Non-alcoholic fatty liver; Type 2 diabetes; Hypertension; Hypertriglyceridemia; Impaired fasting glucose; Metabolic syndrome; Cardiovascular disease risk factors ID METABOLIC SYNDROME; INSULIN-RESISTANCE; NONALCOHOLIC STEATOHEPATITIS; CARDIOMETABOLIC RISK; DIABETES-MELLITUS; ADIPOSE-TISSUE; VISCERAL FAT; HEART; ASSOCIATION; AMINOTRANSFERASE AB Background & Aims: The relations of non-alcoholic fatty liver disease to cardiovascular disease (CVD) risk factors are not fully understood. The objective of our study is to explore the bidirectional relationships of fatty liver to CVD risk factors. Methods: We prospectively evaluated whether liver fat predicted the development of CVD risk factors and whether CVD risk factors predicted new onset fatty liver during 6 years of follow-up in middle- to older-aged Framingham Heart Study participants. We estimated liver fat using multi-detector computed tomography. Results: We included 1051 participants (mean age 45 +/- 6 years, 46% women). The prevalence of fatty liver was 18% at baseline. In participants without fatty liver at baseline, 101 participants developed incident fatty liver over approximately 6 years. Baseline liver fat (per standard deviation increase) was associated with increased odds of incident hypertension (OR 1.42; 95% CI 1.15-1.76; p = 0.001) and incident type 2 diabetes (OR 1.43; 95% CI 1.09-1.88, p <0.001). In a parallel analysis, individuals with hypertension (OR 3.34; 95% CI 2.04-5.49), hypertriglyceridemia (OR 3.04; 95% CI: 1.84-5.02), impaired fasting glucose (OR 2.92; 95% CI 1.76-4.82), or type 2 diabetes (OR 4.15; 95% CI 1.19-14.46) at baseline had higher odds of incident fatty liver compared to individuals without those conditions (all p <0.03). In both analyses, the observed associations remained similar after additional adjustments for measures of adiposity. Conclusions: The present study demonstrated bi-directional relationships between fatty liver and CVD risk factors among middle- to older-aged Framingham Heart Study participants. Lay summary: It is not fully understood whether non-alcoholic fatty liver (NAFLD) disease precedes or develops after increased cardiovascular disease (CVD) risk factors. The findings of our study suggest a bi-directional relationship between NAFLD and CVD risk factors. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Ma, Jiantao; Hwang, Shih-Jen; Pedley, Alison; Massaro, Joseph M.; Benjamin, Emelia J.; Levy, Daniel; Fox, Caroline S.] NHLBI, Framingham Heart Study, Div Intramural Res, Framingham, MA USA. [Ma, Jiantao; Hwang, Shih-Jen; Pedley, Alison; Massaro, Joseph M.; Levy, Daniel; Fox, Caroline S.] NHLBI, Populat Sci Branch, Div Intramural Res, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Hoffmann, Udo] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Chung, Raymond T.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Liver, Gastrointestinal Div, Boston, MA USA. [Benjamin, Emelia J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Dept Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Med Sch, Boston, MA USA. [Long, Michelle T.] Boston Univ, Sch Med, Evans Dept Med, Div Gastroenterol, Boston, MA 02118 USA. RP Long, MT (reprint author), Boston Univ, Sch Med, Sect Gastroenterol, 85 East Concord St 7th Floor, Boston, MA 02118 USA. EM mtlong@bu.edu FU NHLBI FHS [N01-HC-25195, HHSN268201500001I]; [2R01 HL092577]; [R01 HL128914]; [K24 DK078772] FX This work was conducted in part using resources and data from the Framingham Heart Study (FHS) of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institute of Health and Boston University School of Medicine. This work was supported by the NHLBI FHS (N01-HC-25195; HHSN268201500001I). Dr. Benjamin is supported in part by 2R01 HL092577 and R01 HL128914. Dr. Chung is supported in part by K24 DK078772. NR 42 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD FEB PY 2017 VL 66 IS 2 BP 390 EP 397 DI 10.1016/j.jhep.2016.09.022 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EJ5MC UT WOS:000393261200018 PM 27729222 ER PT J AU Akkaya, B Holstein, AH Isaac, C Maz, MP Glass, DD Shevach, EM Akkaya, M AF Akkaya, Billur Holstein, Amanda H. Isaac, Christopher Maz, Mitra P. Glass, Deborah D. Shevach, Ethan M. Akkaya, Munir TI Ex-vivo iTreg differentiation revisited: Convenient alternatives to existing strategies SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE FACS sorting; Magnetic separation; Regulatory T cells; Foxp3; Suppression assay ID REGULATORY T-CELLS; GENERATION AB Ex-vivo differentiation of regulatory T cells (Tregs) from naive CD4(+) T-cells has been widely used in immunological research. Isolation of a highly pure naive T cell population is the key factOr that determines the efficiency of subsequent Treg differentiation. Currently, this step relies mostly on FACS sorting, which is often costly, time consuming, and inconvenient. Alternatively, magnetic separation of T-cells can be performed; yet, available protocols fail to reach sort level purity and consequently result in low Treg differentiation efficiency. Here, we present the results of a comprehensive side-by-side comparison of various magnetic separation strategies and FACS sorting in multiple levels. Additionally, we propose a novel optimized custom made magnetic separation protocol, which not only yields sort level purity and Treg differentiation but also lowers the reagent costs up to 75% compared to the commercially available purification kits. The highly pure naive CD4(+) T-cell population obtained by this versatile method can also be used for differentiation of other T-cell subsets; therefore this protocol may have broad applications in T-cell research. Published by Elsevier B.V. C1 [Akkaya, Billur; Holstein, Amanda H.; Isaac, Christopher; Maz, Mitra P.; Glass, Deborah D.; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Akkaya, Munir] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Akkaya, M (reprint author), NIAID, Twinbrook 2, NIH, 12441 Parklawn Dr,Room 213, Rockville, MD 20852 USA. EM munir.akkaya@nih.gov OI AKKAYA, Munir/0000-0002-9949-9424 FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 10 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 441 BP 67 EP 71 DI 10.1016/j.jim.2016.11.013 PG 5 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA EJ5IG UT WOS:000393250400009 PM 27919837 ER PT J AU Komlosh, ME Benjamini, D Barnett, AS Schram, V Horkay, F Avram, AV Basser, PJ AF Komlosh, M. E. Benjamini, D. Barnett, A. S. Schram, V. Horkay, F. Avram, A. V. Basser, P. J. TI Anisotropic phantom to calibrate high-q diffusion MRI methods SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Anisotropic diffusion; MRI; Phantom; Microstructure; Diffusion; d-PFG; DDE ID AXON DIAMETER DISTRIBUTION; FIELD-GRADIENT; WHITE-MATTER; IN-VIVO; MICROSCOPIC ANISOTROPY; HYDRATED VERMICULITE; CLINICAL SCANNER; CORPUS-CALLOSUM; FIBER-TRACKING; SELF-DIFFUSION AB A silicon oil-filled glass capillary array is proposed as an anisotropic diffusion MRI phantom. Together with a computational/theoretical pipeline these provide a gold standard for calibrating and validating high-q diffusion MRI experiments. The phantom was used to test high angular resolution diffusion imaging (HARDI) and double pulsed-field gradient (d-PFG) MRI acquisition schemes. MRI-based predictions of microcapillary diameter using both acquisition schemes were compared with results from optical microscopy. This phantom design can be used for quality control and quality assurance purposes and for testing and validating proposed microstructure imaging experiments and the processing pipelines used to analyze them. (C) 2016 Elsevier Inc. All rights reserved. C1 [Komlosh, M. E.; Benjamini, D.; Barnett, A. S.; Horkay, F.; Avram, A. V.; Basser, P. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Quantitat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Komlosh, M. E.] Henry M Jackson Fdn Adv Mil Med, Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Schram, V.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Microscopy & Imaging Core, NIH, Bethesda, MD USA. RP Komlosh, ME (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Quantitat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. EM komloshm@mail.nih.gov FU National Institutes of Health [HD000266]; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, [HJF Award] [308049-8.01-60855] FX This work was supported by the National Institutes of Health [Grant numbers HD000266] and The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, [HJF Award Number: 308049-8.01-60855]. NR 61 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD FEB PY 2017 VL 275 BP 19 EP 28 DI 10.1016/j.jmr.2016.11.017 PG 10 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA EJ9GF UT WOS:000393533900003 PM 27951427 ER PT J AU Lonser, RR Nieman, L Oldfield, EH AF Lonser, Russell R. Nieman, Lynnette Oldfield, Edward H. TI Cushing's disease: pathobiology, diagnosis, and management SO JOURNAL OF NEUROSURGERY LA English DT Review DE Cushing's disease; diagnosis; surgery; treatment; oncology ID CORTICOTROPIN-RELEASING-HORMONE; LONG-TERM REMISSION; SINGLE-CENTER EXPERIENCE; GLUCOCORTICOID-RECEPTOR ANTAGONIST; CLINICAL-PRACTICE GUIDELINE; GENDER-RELATED DIFFERENCES; TRANSSPHENOIDAL SURGERY; DIFFERENTIAL-DIAGNOSIS; PITUITARY-ADENOMAS; NEUROLOGIC COMPLICATIONS AB Cushing's disease (CD) is the result of excess secretion of adrenocorticotropic hormone (ACTH) by a benign monoclonal pituitary adenoma. The excessive secretion of ACTH stimulates secretion of cortisol by the adrenal glands, resulting in supraphysiological levels of circulating cortisol. The pathophysiological levels of cortisol are associated with hypertension, diabetes, obesity, and early death. Successful resection of the CD-associated ACTH-secreting pituitary adenoma is the treatment of choice and results in immediate biochemical remission with preservation of pituitary function. Accurate and early identification of CD is critical for effective surgical management and optimal prognosis. The authors review the current pathophysiological principles, diagnostic methods, and management of CD. C1 [Lonser, Russell R.] Ohio State Univ, Dept Neurol Surg, Wexner Med Ctr, 410 W 10th Ave,Doan Hall N1047, Columbus, OH 43210 USA. [Nieman, Lynnette] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Oldfield, Edward H.] Univ Virginia Hlth Syst, Dept Neurol Surg, Charlottesville, VA USA. RP Lonser, RR (reprint author), Ohio State Univ, Dept Neurol Surg, Wexner Med Ctr, 410 W 10th Ave,Doan Hall N1047, Columbus, OH 43210 USA. EM russell.lonser@osumc.edu NR 113 TC 0 Z9 0 U1 5 U2 5 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD FEB PY 2017 VL 126 IS 2 BP 404 EP 417 DI 10.3171/2016.1.JNS152119 PG 14 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EJ3CN UT WOS:000393089100009 PM 27104844 ER PT J AU Zhang, JJ Niu, G Lang, LX Li, F Fan, XR Yang, XF Yao, SB Yan, WG Huo, L Chen, LB Li, ZY Zhu, ZH Chen, XY AF Zhang, Jingjing Niu, Gang Lang, Lixin Li, Fang Fan, Xinrong Yang, Xuefeng Yao, Shaobo Yan, Weigang Huo, Li Chen, Libo Li, Zhiyuan Zhu, Zhaohui Chen, Xiaoyuan TI Clinical Translation of a Dual Integrin alpha(v)beta(3)- and Gastrin-Releasing Peptide Receptor-Targeting PET Radiotracer, Ga-68-BBN-RGD SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE BBN-RGD; PET; first-in-human; integrin alpha(v)beta(3); GRPR; prostate cancer ID PROSTATE-CANCER; LYMPH-NODE; TUMORS; MODEL; GRPR; (99M)TECHNETIUM-HYNIC(TRICINE/TPPTS)-ACA-BOMBESIN(7-14); HETERODIMER; ANTAGONIST; EXPRESSION; GUIDELINES AB This study aimed to document the first-in-human application of a Ga-68-labeled heterodimeric peptide BBN-RGD (bombesin-RGD) that targets both integrin alpha(v)beta(3) and gastrin-releasing peptide receptor (GRPR). We evaluated the safety and assessed the clinical diagnostic value of Ga-68-BBN-RGD PET/CT in prostate cancer patients in comparison with Ga-68-BBN. Methods: Five healthy volunteers (4 men and 1 woman; age range, 28-53 y) were enrolled to validate the safety of Ga-68-BBN-RGD. Dosimetry was calculated using the OLINDA/EXM software. Thirteen patients with prostate cancer (4 newly diagnosed and 9 post therapy) were enrolled. All the patients underwent PET/CT scans 15-30 min after intravenous injection of 1.85 MBq (0:05 mCi) per kilogram of body weight of Ga-68-BBN-RGD and also accepted Ga-68-BBN PET/CT within 2 wk for comparison. Results: With a mean injected dose of 107.3 +/- 14.8 MBq per patient, no side effect was found during the whole procedure and 2 wk follow-up, demonstrating the safety of Ga-68-BBN-RGD. A patient would be exposed to a radiation dose of 2.90 mSv with an injected dose of 129.5 MBq (3.5 mCi), which is much lower than the dose limit set by the Food and Drug Administration. In 13 patients with prostate cancer diagnosed by biopsy, Ga-68-BBN-RGD PET/CT detected 3 of 4 primary tumors, 14 metastatic lymph nodes, and 20 bone lesions with an SUVmax of 4.46 +/- 0.50, 6.26 +/- 2.95, and 4.84 +/- 1.57, respectively. Only 2 of 4 primary tumors, 5 lymph nodes, and 12 bone lesions were positive on Ga-68-BBN PET/CT, with the SUVmax of 2.98 +/- .24, 4.17 +/- 1.89, and 3.61 +/- 1.85, respectively. Conclusion: This study indicates the safety and efficiency of a new type of dual integrin alpha(v)beta(3)- and GRPR-targeting PET radiotracer in prostate cancer diagnosis and staging. C1 [Zhang, Jingjing; Li, Fang; Yao, Shaobo; Huo, Li; Chen, Libo; Zhu, Zhaohui] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Nucl Med, Beijing 100730, Peoples R China. [Zhang, Jingjing; Li, Fang; Fan, Xinrong; Yao, Shaobo; Yan, Weigang; Huo, Li; Chen, Libo; Li, Zhiyuan; Zhu, Zhaohui] Peking Union Med Coll, Beijing, Peoples R China. [Zhang, Jingjing; Niu, Gang; Lang, Lixin; Yang, Xuefeng; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD USA. [Fan, Xinrong; Yan, Weigang] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Urol, Beijing, Peoples R China. [Li, Zhiyuan] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Pathol, Beijing, Peoples R China. RP Li, F (reprint author), Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Nucl Med, Beijing 100730, Peoples R China.; Chen, XY (reprint author), NIH, 35A Convent Dr,GD937, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Natural Science Foundation of China [81171369, 81171370, 81271614]; Special Scientific Research Fund for Public Welfare of Healthcare in China [201402001] FX This work was supported by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), the National Natural Science Foundation of China projects (81171369, 81171370, and 81271614), and a Special Scientific Research Fund for Public Welfare of Healthcare in China (201402001). No other potential conflict of interest relevant to this article was reported. NR 35 TC 0 Z9 0 U1 3 U2 3 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD FEB PY 2017 VL 58 IS 2 BP 228 EP 234 DI 10.2967/jnumed.116.177048 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ6WH UT WOS:000393360100014 PM 27493267 ER PT J AU Ikawa, M Lohith, TG Shrestha, S Telu, S Zoghbi, SS Castellano, S Taliani, S Da Settimo, F Fujita, M Pike, VW Innis, RB AF Ikawa, Masamichi Lohith, Talakad G. Shrestha, Stal Telu, Sanjay Zoghbi, Sami S. Castellano, Sabrina Taliani, Sabrina Da Settimo, Federico Fujita, Masahiro Pike, Victor W. Innis, Robert B. CA Biomarkers Consortium Radioligand TI C-11-ER176, a Radioligand for 18-kDa Translocator Protein, Has Adequate Sensitivity to Robustly Image All Three Affinity Genotypes in Human Brain SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE 18-kDa translocator protein (TSPO); C-11-ER176; positron emission tomography; rs6971 polymorphism; XBD173 ID IN-VIVO; 18 KDA; BENZODIAZEPINE-RECEPTOR; GENETIC-POLYMORPHISM; BINDING; TSPO; NEUROINFLAMMATION; NOMENCLATURE; INFLAMMATION; BIOMARKER AB For PET imaging of 18-kDa translocator protein (TSPO), a biomarker of neuroinflammation, most second-generation radioligands are sensitive to the single nucleotide polymorphism rs6971; however, this is probably not the case for the prototypical agent C-11-PK11195 N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide), which has a relatively lower signal-to-noise ratio. We recently found that C-11-ER176 (C-11-(R)-N-sec-butyl-4-(2-chlorophenyl)-N-methylquinazoline-2-carboxamide), a new analog of C-11-(R)-PK11195, showed little sensitivity to rs6971 when tested in vitro and had high specific binding in monkey brain. This study sought, first, to determine whether the sensitivity of C-11-ER176 in humans is similar to the low sensitivity measured in vitro and, second, to measure the nondisplaceable binding potential (BPND, or the ratio of specific-to-nondisplaceable uptake) of C-11-ER176 in human brain. Methods: Nine healthy volunteers-3 high-affinity binders (HABs), 3 mixed-affinity binders (MABs), and 3 low-affinity binders (LABs)-were studied with whole body C-11-ER176 PET imaging. SUVs from 60 to 120 min after injection derived from each organ were compared between genotypes. Eight separate healthy volunteers-3 HABs, 3 MABs, and 2 LABs-under-went brain PET imaging. The 3 HABs underwent a repeated brain scan after TSPO blockade with XBD173 (N-benzyl-N-ethyl-2-(7-methyl-8-oxo-2-phenylpurin-9-yl)acetamide) to determine nondisplaceable distribution volume (V-ND) via Lassen occupancy plotting and thereby estimate BPND in brain. Results: Regional SUV averaged from 60 to 120 min after injection in brain and peripheral organs with high TSPO densities such as lung and spleen were greater in HABs than in LABs. On the basis of V-ND determined via the occupancy plot, the whole brain BPND for LABs was estimated to be 1.4 +/- 0.8, which was much lower than that for HABs (4.2 +/- 1.3) but about the same as that for HABs with C-11-PBR28 ([methyl-C-11]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine)) (similar to 1.2). Conclusion: Obvious in vivo sensitivity to rs6971 was observed in C-11-ER176 that had not been expected from in vitro studies, suggesting that the future development of any improved radioligand for TSPO should consider the possibility that in vitro properties will not be reflected in vivo. We also found that C-11-ER176 has adequately high BPND for all rs6971 genotypes. Thus, the new radioligand would likely have greater sensitivity in detecting abnormalities in patients. C1 [Ikawa, Masamichi; Lohith, Talakad G.; Shrestha, Stal; Telu, Sanjay; Zoghbi, Sami S.; Fujita, Masahiro; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Castellano, Sabrina] Univ Salerno, Dept Med & Surg, Fisciano, Italy. [Taliani, Sabrina; Da Settimo, Federico] Univ Pisa, Dept Pharm, Pisa, Italy. RP Innis, RB (reprint author), NIMH, Mol Imaging Branch, 10 Ctr Dr,Bldg 10,Room B1D43, Bethesda, MD 20892 USA. EM robert.innis@nih.gov FU IRP-NIMH-NIH [ZIAMH002852, ZIAMH002793, NCT02147392 [14-M-0117], NCT02181582 [14-M-0141]]; Wagner-Torizuka Fellowship of the Society of Nuclear Medicine and Molecular Imaging; NIMH; Foundation for the NIH Biomarkers Consortium FX This study was funded by the IRP-NIMH-NIH (projects ZIAMH002852 and ZIAMH002793 under clinical protocols NCT02147392 [14-M-0117] and NCT02181582 [14-M-0141]); by the 2013/2015 Wagner-Torizuka Fellowship of the Society of Nuclear Medicine and Molecular Imaging (to Masamichi Ikawa); and as a public-private partnership supported by the NIMH and the Foundation for the NIH Biomarkers Consortium (www.biomarkersconsortium.org). No other potential conflict of interest relevant to this article was reported. NR 27 TC 0 Z9 0 U1 3 U2 3 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD FEB PY 2017 VL 58 IS 2 BP 320 EP 325 DI 10.2967/jnumed.116.178996 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ6WH UT WOS:000393360100028 PM 27856631 ER PT J AU Kim, K Wactawski-Wende, J Michels, KA Plowden, TC Chaljub, EN Sjaarda, LA Mumford, SL AF Kim, Keewan Wactawski-Wende, Jean Michels, Kara A. Plowden, Torie C. Chaljub, Ellen N. Sjaarda, Lindsey A. Mumford, Sunni L. TI Dairy Food Intake Is Associated with Reproductive Hormones and Sporadic Anovulation among Healthy Premenopausal Women SO JOURNAL OF NUTRITION LA English DT Article DE dairy; reproductive hormones; estradiol; menstrual cycle; ovulation ID MARGINAL STRUCTURAL MODELS; EUMENORRHEIC WOMEN; MENSTRUAL-CYCLE; OVULATION; BIOCYCLE; ENERGY; RISK; MILK; QUESTIONNAIRE; TESTOSTERONE AB Background: Dairy food intake has been associated with infertility; however, little is known with regard to associations with reproductive hormones or anovulation. Objective: We investigated whether intakes of dairy foods and specific nutrients were associated with reproductive hormone concentrations across the cycle and the risk of sporadic anovulation among healthy women. Methods: We prospectively measured serum reproductive hormones <= 8 times/menstrual cycle for 2 cycles from 259 regularly menstruating women (mean age: 27.3 y). Dairy food intake was assessed via 24-h dietary recalls 4 times/cycle. Dairy food intakes were assessed by 11 total and low- and high-fat dairy products; 2) dairy nutrients, including fat, lactose, calcium, and phosphorus; and 3) dairy foods, including milk, cheese, butter, cream, yogurt, and ice cream categories. Weighted linear mixed models were used to evaluate associations between dairy nutrients or food intakes and hormone concentrations. Modified Poisson regression models with robust error variance were used to evaluate anovulation. Models were adjusted for age, body mass index, race, physical activity, Mediterranean diet score, total energy, protein, fiber, caffeine, and other hormones. Results: Each serving increase in total and low- and high-fat dairy foods and all increases in amounts of all dairy nutrients tested were associated with an similar to 5% reduction in serum estradiol concentrations but were not associated with anovulation. Total and high-fat dairy food intakes were positively associated with serum luteinizing hormone concentrations. We observed associations between intakes of >0 servings of yogurt (RR: 2.1; 95% Cl: 1.2,3.7) and cream (RR: 1.8; 95% Cl: 1.0,3.2) and a higher risk of sporadic anovulation compared with no intake. Conclusions: Our study showed associations between increasing dairy food and nutrient intakes and decreasing estradiol concentrations as well as between cream and yogurt intakes and the risk of sporadic anovulation. These results highlight the potential role of dairy in reproductive function in healthy women. C1 [Kim, Keewan; Michels, Kara A.; Plowden, Torie C.; Chaljub, Ellen N.; Sjaarda, Lindsey A.; Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Plowden, Torie C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. EM mumfords@mail.nih.gov OI Michels, Kara/0000-0003-2431-2079; Kim, Keewan/0000-0002-1892-6739 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH [HHSN275200403394C, HHSN2752011000021, Task 1 HHSN27500001] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (contracts HHSN275200403394C and HHSN2752011000021 and Task 1 HHSN27500001). NR 36 TC 0 Z9 0 U1 2 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 FEB PY 2017 VL 147 IS 2 BP 218 EP 226 DI 10.3945/jn.116.241521 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EJ6XF UT WOS:000393363500010 PM 27881593 ER PT J AU Mumford, SL Weck, J Kannan, K Louis, GMB AF Mumford, Sunni L. Weck, Jennifer Kannan, Kurunthachalam Louis, Germaine M. Buck TI Urinary Phytoestrogen Concentrations Are Not Associated with Incident Endometriosis in Premenopausal Women SO JOURNAL OF NUTRITION LA English DT Article DE phytoestrogens; endometriosis; genistein; daidzein; lignans ID ESTROGEN-RECEPTOR-BETA; POSTMENOPAUSAL WOMEN; STROMAL CELLS; DOUBLE-BLIND; CANCER-RISK; SOY PROTEIN; DIET; ISOFLAVONES; POPULATION; ESTRADIOL AB Background: Phytoestrogens have been associated with subtle hormonal changes, but their effects on endometriosis are largely unknown. Objective: We assessed the association between urinary concentrations of phytoestrogens and incident endometriosis. Methods: We included an operative sample of 495 premenopausal women aged 18-44 y undergoing laparoscopies and laparotomies at 14 clinical sites between 2007 and 2009 and a general population sample of 131 women from the same geographic area who were matched on age and menstruation status. Endometriosis in the surgical sample was assessed by surgical visualization (clinical gold standard), whereas disease in the general population sample was assessed with the use of a pelvic MRI. Urine concentrations of genistein, daidzen, O-desmethylangolensin, equol, enterodiol, and enterolactone were measured at baseline. Poisson regression with robust error variance was used to estimate the risk of an endometriosis diagnosis for each sample after adjusting for age and body mass index (in kg/m(2)). Separate models were run for each phytoestrogen. Results: Overall geometric mean urine concentrations of phytoestrogens were as follows: genistein [88 nmol/L (95% Cl: 72, 108 nmol/L)1, daidzein [194 nmol/L (95% Cl: 160, 236 nmol/L)], O-desmethylangolensin 14 nmol/L (95% Cl: 3,6 nmo1/01, equol nmol/L (95% Cl: 4,6 nmol/LH, enterodiol [29 nmol/L (95% Cl: 22,38 nmol/L)[, and enterolactone [355 nmol/L (95% Cl: 395, 544 nmol/L)I. Geometric mean concentrations of phytoestrogens did not significantly differ by endometriosis status in either sample. Adjusted RRs for endometriosis ranged from 0.87 to 1.09 for the 6 phytoestrogens measured, with all Cls including a value >= 1. Phytoestrogens were not associated with the severity of endometriosis when restricting the analysis to women with moderate-to-severe disease per the revised American Society for Reproductive Medicine criteria. Furthermore, no associations were observed between self-reported high soy intake and endometriosis. Conclusions: Despite endometriosis being an estrogen-dependent disease, we found no evidence that urinary phytoestrogens were associated with a higher risk of an endometriosis diagnosis in either a sample of premenopausal women or in a surgical sample. C1 [Mumford, Sunni L.; Weck, Jennifer; Louis, Germaine M. Buck] Eunice Kennedy Shrive Natl Inst Child Hlth & Huma, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Kannan, Kurunthachalam] SUNY Albany, New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12222 USA. [Kannan, Kurunthachalam] SUNY Albany, Dept Environm Hlth, Albany, NY 12222 USA. RP Mumford, SL (reprint author), Eunice Kennedy Shrive Natl Inst Child Hlth & Huma, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. EM mumfords@mail.nih.gov OI Weck, Jennifer/0000-0002-3246-7380; Buck Louis, Germaine/0000-0002-1774-4490 FU NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development; University of Utah FX Supported by the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and University of Utah. NR 46 TC 0 Z9 0 U1 2 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 FEB PY 2017 VL 147 IS 2 BP 227 EP 234 DI 10.3945/jn.116.238840 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EJ6XF UT WOS:000393363500011 PM 28031375 ER PT J AU Ng, HLH Premilovac, D Rattigan, S Richards, SM Muniyappa, R Quon, MJ Keske, MA AF Ng, Huei L. H. Premilovac, Dino Rattigan, Stephen Richards, Stephen M. Muniyappa, Ranganath Quon, Michael J. Keske, Michelle A. TI Acute vascular and metabolic actions of the green tea polyphenol epigallocatechin 3-gallate in rat skeletal muscle SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Green tea; Epigallocatechin 3-gallate; Endothelium; Metabolism; Microvascular; Skeletal muscle ID INDUCED INSULIN-RESISTANCE; NITRIC-OXIDE SYNTHASE; HIGH-FAT DIET; AORTIC ENDOTHELIAL-CELLS; RED WINE POLYPHENOLS; SPRAGUE-DAWLEY RATS; FRUCTOSE-FED RAT; GLUCOSE-UPTAKE; IN-VIVO; MICROVASCULAR RECRUITMENT AB Epidemiological studies show a dose-dependent relationship between green tea consumption and reduced risk for type 2 diabetes and cardiovascular disease. Bioactive compounds in green tea including the polyphenol epigallocatechin 3-gallate (EGCG) have insulin-mimetic actions on glucose metabolism and vascular function in isolated cell culture studies. The aim of this study is to explore acute vascular and metabolic actions of EGCG in skeletal muscle of Sprague-Dawley rats. Direct vascular and metabolic actions of EGCG were investigated using surgically isolated constant-flow perfused rat hindlimbs. EGCG infused at 0.1, 1, 10 and 100 mu M in 15 min step-wise increments caused dose-dependent vasodilation in 5-hydroxytryptamine pre-constricted hindlimbs. This response was not impaired by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin or the AMP-kinase inhibitor Compound C. The nitric oxide synthase (NOS) inhibitor N-G-Nitro-L-Arginine Methyl Ester (L-NAME) completely blocked EGCG-mediated vasodilation at 0.1-10 mu M, but not at 100 mu M. EGCG at 10 mu M did not alter muscle glucose uptake nor did it augment insulin-stimulated muscle glucose uptake. The acute metabolic and vascular actions of 10 mu M EGCG in vivo were investigated in anaesthetised rats during a hyperinsulinemic-euglycemic clamp (10 mU min(-1) kg(-1) insulin). EGCG and insulin both stimulated comparable increases in muscle microvascular blood flow without an additive effect. EGCG-mediated microvascular action occurred without altering whole body or muscle glucose uptake. We concluded that EGCG has direct NOS-dependent vasodilator actions in skeletal muscle that do not acutely alter muscle glucose uptake or enhance the vascular and metabolic actions of insulin in healthy rats. (C) 2016 Elsevier Inc. All rights reserved. C1 [Ng, Huei L. H.; Rattigan, Stephen; Keske, Michelle A.] Univ Tasmania, Menzies Inst Med Res, Hobart, Tas 7000, Australia. [Premilovac, Dino; Richards, Stephen M.] Univ Tasmania, Sch Med, Hobart, Tas, Australia. [Muniyappa, Ranganath] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Quon, Michael J.] Univ Maryland, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. RP Keske, MA (reprint author), Univ Tasmania, Menzies Inst Med Res, Hobart, Tas 7000, Australia. EM Michelle.Keske@utas.edu.au OI Quon , Michael /0000-0002-5289-3707 FU National Health & Medical Research Council of Australia [1009962, 490034] FX This work was funded by the National Health & Medical Research Council of Australia (grant number 1009962 to M.A.K. and S.R. and grant number 490034 to S.R). NR 56 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 EI 1873-4847 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD FEB PY 2017 VL 40 BP 23 EP 31 DI 10.1016/j.jnutbio.2016.10.005 PG 9 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA EJ5KQ UT WOS:000393257300003 PM 27837678 ER PT J AU Feingold, PL Kwong, MLM Davis, JL Rudloff, U AF Feingold, Paul L. Kwong, Mei Li M. Davis, Jeremy L. Rudloff, Udo TI Adjuvant Intraperitoneal Chemotherapy for the Treatment of Gastric Cancer at Risk for Peritoneal Carcinomatosis: A Systematic Review SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Review DE heated intraperitoneal chemotherapy (HIPEC); adjuvant regional chemotherapy; gastrointestinal malignancies; peritoneal carcinomatosis; systematic review ID PHASE-II TRIAL; UNRESECTABLE HEPATIC-TUMORS; QUALITY-OF-LIFE; CYTOREDUCTIVE SURGERY; CURATIVE RESECTION; RANDOMIZED-TRIAL; MITOMYCIN-C; GASTROESOPHAGEAL JUNCTION; NEOADJUVANT CHEMOTHERAPY; INTRATUMOR HETEROGENEITY AB The peritoneal surface is a frequent site of recurrence following surgery for gastric cancer. A systematic review and random effect analysis was undertaken to analyze current literature regarding the role of adjuvant intraperitoneal chemotherapy in gastric cancer. While pooled analysis supports the use of adjuvant IP chemotherapy in resectable gastric cancer, maximal benefit occured with intra-operative delivery, and possibly the use of MMC. (C) 2016 Wiley Periodicals, Inc. C1 [Feingold, Paul L.; Kwong, Mei Li M.; Davis, Jeremy L.; Rudloff, Udo] NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Rudloff, U (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, Gastrointestinal Oncol Sect, Ctr Canc Res, Bldg 10 Hatfield CRC,Room 4-5950, Bethesda, MD 20892 USA. EM rudloffu@mail.nih.gov OI Feingold, Paul/0000-0002-3194-4309 NR 60 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4790 EI 1096-9098 J9 J SURG ONCOL JI J. Surg. Oncol. PD FEB 1 PY 2017 VL 115 IS 2 BP 192 EP 201 DI 10.1002/jso.24476 PG 10 WC Oncology; Surgery SC Oncology; Surgery GA EJ1BI UT WOS:000392944800015 PM 27878811 ER PT J AU Kim, C Hoang, CD Kesarwala, AH Schrump, DS Guha, U Rajan, A AF Kim, Chul Hoang, Chuong D. Kesarwala, Aparna H. Schrump, David S. Guha, Udayan Rajan, Arun TI Role of Local Ablative Therapy in Patients with Oligometastatic and Oligoprogressive Non-Small Cell Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Review DE Local ablative therapy; NSCLC; Oligometastatic disease; Oligoprogressive disease; Molecular targeted therapy ID TYROSINE KINASE INHIBITORS; BODY RADIATION-THERAPY; METASTATIC COLORECTAL-CANCER; 1ST-LINE SYSTEMIC THERAPY; EGFR MUTATION; ADRENAL METASTASES; BRAIN METASTASES; INTRATUMOR HETEROGENEITY; RADIOFREQUENCY ABLATION; HEPATIC RESECTION AB Because of an improved understanding of lung cancer biology and improvement in systemic treatment, an oligometastatic state in which metastatic disease is present at a limited number of anatomic sites is being increasingly recognized. An oligoprogressive state, which is a similar but distinct entity, refers to disease progression at a limited number of anatomic sites, with continued response or stable disease at other sites of disease. Such an oligoprogressive state is best described in patients with NSCLC treated with molecular targeted therapy. Possible explanations for development of the oligoprogressive state include the presence of underlying clonal heterogeneity and extrinsic selection pressure due to the use of targeted therapy. Traditionally, local ablative therapy (LAT) has been limited to symptom palliation in patients with advanced NSCLC, but the presence of oligometastatic or oligoprogressive disease provides a unique opportunity to evaluate the role of LAT such as surgery, radiation therapy, radio frequency ablation, or cryoablation. There is increasing evidence to support the clinical benefit of LAT in patients with NSCLC with limited metastatic disease and in selected individuals in whom resistance to targeted therapies develops. In the latter instance, adequate treatment of drug resistant clones by LAT could potentially help in avoiding switching systemic therapy prematurely. This review focuses on the biology of oligometastatic and oligoprogressive NSCLC and describes the role of LAT in the treatment of these conditions. Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer. C1 NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Rajan, A (reprint author), NCI, Thorac & GI Oncol Branch, NIH, Room 4-5330,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM rajana@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 75 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD FEB PY 2017 VL 12 IS 2 BP 179 EP 193 DI 10.1016/j.jtho.2016.10.012 PG 15 WC Oncology; Respiratory System SC Oncology; Respiratory System GA EJ5NW UT WOS:000393266000004 PM 27780780 ER PT J AU Best, SM AF Best, Sonja M. TI The Many Faces of the Flavivirus NS5 Protein in Antagonism of Type I Interferon Signaling SO JOURNAL OF VIROLOGY LA English DT Review DE JAK-STAT; NS5; antagonism; dengue virus; flavivirus; interferons; tick-borne encephalitis virus; West Nile virus; yellow fever virus; Zika virus ID WEST-NILE-VIRUS; PATTERN-RECOGNITION RECEPTORS; INNATE IMMUNE-RESPONSES; TICK-BORNE FLAVIVIRUS; DENGUE VIRUS; ZIKA VIRUS; ANTIVIRAL RESPONSE; ALPHA-INTERFERON; RNA-POLYMERASE; RIG-I AB The vector-borne flaviviruses cause severe disease in humans on every inhabited continent on earth. Their transmission by arthropods, particularly mosquitoes, facilitates large emergence events such as witnessed with Zika virus (ZIKV) or West Nile virus in the Americas. Every vector-borne flavivirus examined thus far that causes disease in humans, from dengue virus to ZIKV, antagonizes the host type I interferon (IFN-I) response by preventing JAK-STAT signaling, suggesting that suppression of this pathway is an important determinant of infection. The most direct and potent viral inhibitor of this pathway is the nonstructural protein NS5. However, the mechanisms utilized by NS5 from different flaviviruses are often quite different, sometimes despite close evolutionary relationships between viruses. The varied mechanisms of NS5 as an IFN-I antagonist are also surprising given that the evolution of NS5 is restrained by the requirement to maintain function of two enzymatic activities critical for virus replication, the methyltransferase and RNA-dependent RNA polymerase. This review discusses the different strategies used by flavivirus NS5 to evade the antiviral effects of IFN-I and how this information can be used to better model disease and develop antiviral countermeasures. C1 [Best, Sonja M.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Best, SM (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM sbest@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 110 TC 0 Z9 0 U1 7 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2017 VL 91 IS 3 AR UNSP e01970 DI 10.1128/JVI.01970-16 PG 14 WC Virology SC Virology GA EJ4NR UT WOS:000393194600022 ER PT J AU Cotton, BT Hyde, JL Sarvestani, ST Sosnovtsev, SV Green, KY White, PA Mackenzie, JM AF Cotton, Ben T. Hyde, Jennifer L. Sarvestani, Soroush T. Sosnovtsev, Stanislav V. Green, Kim Y. White, Peter A. Mackenzie, Jason M. TI The Norovirus NS3 Protein Is a Dynamic Lipid- and Microtubule-Associated Protein Involved in Viral RNA Replication SO JOURNAL OF VIROLOGY LA English DT Article DE norovirus; cytoskeleton; virus replication; cellular lipids ID NORWALK VIRUS; NONSTRUCTURAL POLYPROTEIN; RECOMBINATION; GASTROENTERITIS; CALICIVIRUS; INFECTION; CLEAVAGE; COMPLEX; CELLS; LOCALIZATION AB Norovirus (NoV) infections are a significant health burden to society, yet the lack of reliable tissue culture systems has hampered the development of appropriate antiviral therapies. Here we show that the NoV NS3 protein, derived from murine NoV (MNV), is intimately associated with the MNV replication complex and the viral replication intermediate double-stranded RNA (dsRNA). We observed that when expressed individually, MNV NS3 and NS3 encoded by human Norwalk virus (NV) induced the formation of distinct vesicle-like structures that did not colocalize with any particular protein markers to cellular organelles but localized to cellular membranes, in particular those with a high cholesterol content. Both proteins also showed some degree of colocalization with the cytoskeleton marker beta-tubulin. Although the distribution of MNV and NV NS3s were similar, NV NS3 displayed a higher level of colocalization with the Golgi apparatus and the endoplasmic reticulum (ER). However, we observed that although both proteins colocalized in membranes counterstained with filipin, an indicator of cholesterol content, MNV NS3 displayed a greater association with flotillin and stomatin, proteins known to associate with sphingolipid-and cholesterol-rich microdomains. Utilizing time-lapse epifluorescence microscopy, we observed that the membrane-derived vesicular structures induced by MNV NS3 were highly motile and dynamic in nature, and their movement was dependent on intact microtubules. These results begin to interrogate the functions of NoV proteins during virus replication and highlight the conserved properties of the NoV NS3 proteins among the seven Norovirus genogroups. IMPORTANCE Many mechanisms involved in the replication of norovirus still remain unclear, including the role for the NS3 protein, one of seven nonstructural viral proteins, which remains to be elucidated. This study reveals that murine norovirus (MNV) NS3 is intimately associated with the viral replication complex and dsRNA. We observed that the NS3 proteins of both MNV and Norwalk virus (NV) induce prominent vesicular structures and that this formation is dependent on microtubules and cellular cholesterol. Thus, this study contributes to our understanding of protein function within different Norovirus genogroups and expands a growing knowledge base on the interaction between positive-strand RNA [(+) RNA] viruses and cellular membranes that contribute to the biogenesis of virus-induced membrane organelles. This study contributes to our understanding of viral protein function and the ability of a viral protein to recruit specific cellular organelles and lipids that enable replication. C1 [Cotton, Ben T.; Hyde, Jennifer L.] La Trobe Univ, Dept Physiol Anat & Microbiol, Melbourne, Vic, Australia. [Cotton, Ben T.; Sarvestani, Soroush T.; Mackenzie, Jason M.] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Melbourne, Vic, Australia. [Hyde, Jennifer L.] Univ Queensland, Sch Chem & Biol Sci, Brisbane, Qld, Australia. [Sosnovtsev, Stanislav V.; Green, Kim Y.] NIAID, Norovirus Gastroenteritis Unit, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [White, Peter A.] Univ New South Wales, Fac Sci, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia. [Hyde, Jennifer L.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. RP Mackenzie, JM (reprint author), Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Melbourne, Vic, Australia. EM jason.mackenzie@unimelb.edu FU National Health and Medical Council of Australia [1010327, 1083139] FX We thank Stephen Robbins (University of Calgary, Canada) for providing the stomatin and flotillin expression plasmids. We acknowledge the facilities and the scientific and technical assistance of the Australian Microscopy & Microanalysis Research Facility at the Centre for Microscopy and Microanalysis, University of Queensland, and the University of Melbourne's Biological Optical Microscopy Platform (BOMP). Project grants (no. 1010327 and 1083139) awarded to J.M.M. and P.A.W. from the National Health and Medical Council of Australia supported this research. NR 38 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2017 VL 91 IS 3 AR UNSP e02138 DI 10.1128/JVI.02138-16 PG 19 WC Virology SC Virology GA EJ4NR UT WOS:000393194600031 ER PT J AU Liu, XY Happel, C Ziegelbauer, JM AF Liu, Xiaoyan Happel, Christine Ziegelbauer, Joseph M. TI Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs Target GADD45B To Protect Infected Cells from Cell Cycle Arrest and Apoptosis SO JOURNAL OF VIROLOGY LA English DT Article DE DNA damage; Kaposi's sarcoma-associated herpesvirus; cell cycle microRNA ID PRIMARY EFFUSION LYMPHOMA; DNA-DAMAGE RESPONSE; NUCLEAR ANTIGEN; GENE-EXPRESSION; HEPATOCELLULAR-CARCINOMA; ENDOTHELIAL-CELLS; ENCODED MICRORNAS; TUMOR-SUPPRESSOR; GROWTH ARREST; P53 PATHWAY AB Kaposi's sarcoma is one of the most common malignancies in HIV-infected individuals. The responsible agent, Kaposi's sarcoma-associated herpesvirus (KSHV; HHV8), expresses multiple microRNAs (miRNAs), but the targets and functions of these miRNAs are not completely understood. After infection in primary endothelial cells with KSHV, growth arrest DNA damage-inducible gene 45 beta (GADD45B) is one of the most repressed genes using genomic expression profiling. GADD45B was also repressed in mRNA expression profiling experiments when KSHV miRNAs were introduced to uninfected cells. We hypothesized that KSHV miRNAs target human GADD45B to protect cells from consequences of DNA damage, which can be triggered by viral infection. Expression of GADD45B protein is induced by the p53 activator, Nutlin-3, and KSHV miRNA-K9 inhibits this induction. In addition, Nutlin-3 increased apoptosis and cell cycle arrest based on flow cytometry assays. KSHV miR-K9 protected primary endothelial cells from apoptosis and cell cycle arrest following Nutlin-3 treatment. Similar protective phenotypes were seen for targeting GADD45B with short interfering RNAs (siRNAs), as with miR-K9. KSHV miR-K9 also decreased the protein levels of cleaved caspase-3, cleaved caspase-7, and cleaved poly(ADP-ribose) polymerase (PARP). In B lymphocytes latently infected with KSHV, specific inhibitors of KSHV miR-K9 led to increased GADD45B expression and apoptosis, indicating that miR-K9 is important for reducing apoptosis in infected cells. Furthermore, ectopic expression of GADD45B in KSHV-infected cells promoted apoptosis. Together, these results identify a new miRNA target and demonstrate that KSHV miRNAs are important for protecting infected cells from DNA damage responses. IMPORTANCE Kaposi's sarcoma-associated herpesvirus is a leading cause of cancers in individuals with AIDS. Promoting survival of infected cells is essential for maintaining viral infections. A virus needs to combat various cellular defense mechanisms designed to eradicate the viral infection. One such response can include DNA damage response factors, which can promote an arrest in cell growth and trigger cell death. We used a new approach to search for human genes repressed by small nucleic acids (microRNAs) expressed by a gammaherpesvirus (KSHV), which identified a gene called GADD45B as a target of microRNAs. Repression of GADD45B, which is expressed in response to DNA damage, benefited survival of infected cells in response to a DNA damage response. This information could be used to design new treatments for herpesvirus infections. C1 [Liu, Xiaoyan] Zhejiang Univ, Affiliated Hosp 1, Dept Dermatol, Coll Med, Hangzhou, Zhejiang, Peoples R China. [Liu, Xiaoyan; Happel, Christine; Ziegelbauer, Joseph M.] NCI, AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Ziegelbauer, JM (reprint author), NCI, AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. EM ziegelbauerjm@mail.nih.gov OI Ziegelbauer, Joseph/0000-0001-6464-6941 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; China-Natural Science Foundation of Zhejiang Province [LY13H190002, LY16H190001] FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. X. L. was funded by the China-Natural Science Foundation of Zhejiang Province (grants LY13H190002 and LY16H190001). NR 54 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2017 VL 91 IS 3 AR UNSP e02045 DI 10.1128/JVI.02045-16 PG 13 WC Virology SC Virology GA EJ4NR UT WOS:000393194600027 ER PT J AU Pincus, SH Song, KJ Maresh, GA Hamer, DH Dimitrov, DS Chen, WZ Zhang, MY Ghetie, VF Chan-Hui, PY Robinson, JE Vitetta, ES AF Pincus, Seth H. Song, Kejing Maresh, Grace A. Hamer, Dean H. Dimitrov, Dimiter S. Chen, Weizao Zhang, Mei-Yun Ghetie, Victor F. Chan-Hui, Po-Ying Robinson, James E. Vitetta, Ellen S. TI Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins SO JOURNAL OF VIROLOGY LA English DT Article DE HIV envelope; epitope; gp160; immunotoxin; monoclonal antibody ID HUMAN-IMMUNODEFICIENCY-VIRUS; RICIN-A-CHAIN; BROADLY NEUTRALIZING ANTIBODIES; FUSION INHIBITOR T-20; IN-VIVO ACTIVITY; MURINE B-CELLS; ENVELOPE GLYCOPROTEIN; SOLUBLE CD4; NONNEUTRALIZING ANTIBODIES; CONFORMATIONAL DYNAMICS AB The envelope (Env) glycoprotein of HIV is the only intact viral protein expressed on the surface of both virions and infected cells. Env is the target of neutralizing antibodies (Abs) and has been the subject of intense study in efforts to produce HIV vaccines. Therapeutic anti-Env Abs can also exert antiviral effects via Fc-mediated effector mechanisms or as cytotoxic immunoconjugates, such as immunotoxins (ITs). In the course of screening monoclonal antibodies (MAbs) for their ability to deliver cytotoxic agents to infected or Env-transfected cells, we noted disparities in their functional activities. Different MAbs showed diverse functions that did not correlate with each other. For example, MAbs against the external loop region of gp41 made the most effective ITs against infected cells but did not neutralize virus and bound only moderately to the same cells that they killed so effectively when they were used in ITs. There were also differences in IT-mediated killing among transfected and infected cell lines that were unrelated to the binding of the MAb to the target cells. Our studies of a well-characterized antigen demonstrate that MAbs against different epitopes have different functional activities and that the binding of one MAb can influence the interaction of other MAbs that bind elsewhere on the antigen. These results have implications for the use of MAbs and ITs to kill HIV-infected cells and eradicate persistent reservoirs of HIV infection. IMPORTANCE There is increased interest in using antibodies to treat and cure HIV infection. Antibodies can neutralize free virus and kill cells already carrying the virus. The virus envelope (Env) is the only HIV protein expressed on the surfaces of virions and infected cells. In this study, we examined a panel of human anti-Env antibodies for their ability to deliver cell-killing toxins to HIV-infected cells and to perform other antiviral functions. The ability of an antibody to make an effective immunotoxin could not be predicted from its other functional characteristics, such as its neutralizing activity. Anti-HIV immunotoxins could be used to eliminate virus reservoirs that persist despite effective antiretroviral therapy. C1 [Pincus, Seth H.; Song, Kejing; Maresh, Grace A.] Childrens Hosp, Res Inst Children, New Orleans, LA 70118 USA. [Pincus, Seth H.] Louisiana State Univ, Dept Pediat, Hlth Sci Ctr, New Orleans, LA 70112 USA. [Pincus, Seth H.] Louisiana State Univ, Dept Microbiol Immunol & Parasitol, Hlth Sci Ctr, New Orleans, LA 70112 USA. [Hamer, Dean H.] NCI, Biochem Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Dimitrov, Dimiter S.; Chen, Weizao; Zhang, Mei-Yun] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Ghetie, Victor F.; Vitetta, Ellen S.] UT Southwestern Med Ctr, Dept Immunol, Dallas, TX USA. [Ghetie, Victor F.; Vitetta, Ellen S.] UT Southwestern Med Ctr, Dept Microbiol, Dallas, TX USA. [Chan-Hui, Po-Ying] Theraclone Sci, Seattle, WA USA. [Robinson, James E.] Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. [Song, Kejing] LSU Hlth Sci Ctr, Dept Physiol, New Orleans, LA USA. [Maresh, Grace A.] Ochsner Clin Fdn, Jefferson, LA USA. [Zhang, Mei-Yun] Amgen Asia, Shanghai, Peoples R China. RP Pincus, SH (reprint author), Childrens Hosp, Res Inst Children, New Orleans, LA 70118 USA.; Pincus, SH (reprint author), Louisiana State Univ, Dept Pediat, Hlth Sci Ctr, New Orleans, LA 70112 USA.; Pincus, SH (reprint author), Louisiana State Univ, Dept Microbiol Immunol & Parasitol, Hlth Sci Ctr, New Orleans, LA 70112 USA. EM spincu@lsuhsc.edu FU Children's Hospital of New Orleans, NIH [R01 CA074690, R21 AI058714, U54 GM104940]; Bill and Melinda Gates Foundation Grand Challenges Explorations [OPP1045974]; Louisiana Vaccine Center [LEQSF-ENH-PKSFI-PRS-02]; Louisiana State University [14B-11]; Intramural Research Program of the National Cancer Institute; Intramural AIDS Targeted Antiviral Program (IATAP) of NIH; CHAVI [PO1 AI061734]; Simmons Patigian Chair; Horchow Foundation; Cancer Immunobiology Center FX Research support was provided to S.H.P., K.S., and G.A.M. by Children's Hospital of New Orleans, NIH grants R01 CA074690, R21 AI058714, and U54 GM104940 (Louisiana Clinical and Translational Science Center), the Bill and Melinda Gates Foundation Grand Challenges Explorations (OPP1045974), the Louisiana Vaccine Center (Louisiana Board of Regents, LEQSF-ENH-PKSFI-PRS-02), and a LIFT2 grant (number 14B-11) from Louisiana State University. D.H.H., D.S.D., W.C., and M.-Y.Z. were supported by the Intramural Research Program of the National Cancer Institute and by the Intramural AIDS Targeted Antiviral Program (IATAP) of NIH. J.E.R. received support from CHAVI (PO1 AI061734). E.S.V. was supported by the Simmons Patigian Chair, the Horchow Foundation, and the Cancer Immunobiology Center. NR 78 TC 1 Z9 1 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2017 VL 91 IS 3 AR UNSP e01955 DI 10.1128/JVI.01955-16 PG 17 WC Virology SC Virology GA EJ4NR UT WOS:000393194600020 ER PT J AU Pincus, SH Song, KJ Maresh, GA Frank, A Worthylake, D Chung, HK Polacino, P Hamer, DH Coyne, CP Rosenblum, MG Marks, JW Chen, G Weiss, D Ghetie, V Vitetta, ES Robinson, JE Hu, SL AF Pincus, Seth H. Song, Kejing Maresh, Grace A. Frank, Anderson Worthylake, David Chung, Hye-Kyung Polacino, Patricia Hamer, Dean H. Coyne, Cody P. Rosenblum, Michael G. Marks, John W. Chen, Gang Weiss, Deborah Ghetie, Victor Vitetta, Ellen S. Robinson, James E. Hu, Shiu-Lok TI Design and In Vivo Characterization of Immunoconjugates Targeting HIV gp160 SO JOURNAL OF VIROLOGY LA English DT Article DE antibody drug conjugate; human immunodeficiency virus; immunoglobulins; immunotoxins; monoclonal antibodies ID HUMAN-IMMUNODEFICIENCY-VIRUS; RICIN-A-CHAIN; ANTIRETROVIRAL THERAPY; ENVELOPE GLYCOPROTEIN; MONOCLONAL-ANTIBODIES; PSEUDOMONAS EXOTOXIN; DEGLYCOSYLATED RICIN; MOUSE MODEL; PHASE 1/2; IMMUNOTOXIN AB The envelope (Env) glycoprotein of HIV is expressed on the surface of productively infected cells and can be used as a target for cytotoxic immunoconjugates (ICs), in which cell-killing moieties, including toxins, drugs, or radionuclides, are chemically or genetically linked to monoclonal antibodies (MAbs) or other targeting ligands. Such ICs could be used to eliminate persistent reservoirs of HIV infection. We have found that MAbs which bind to the external loop of gp41, e.g., MAb 7B2, make highly effective ICs, particularly when used in combination with soluble CD4. We evaluated the toxicity, immunogenicity, and efficacy of the ICs targeted with 7B2 in mice and in simian-human immunodeficiency virus-infected macaques. In the macaques, we tested immunotoxins (ITs), consisting of protein toxins bound to the targeting agent. ITs were well tolerated and initially efficacious but were ultimately limited by their immunogenicity. In an effort to decrease immunogenicity, we tested different toxic moieties, including recombinant toxins, cytotoxic drugs, and tubulin inhibitors. ICs containing deglycosylated ricin A chain prepared from ricin toxin extracted from castor beans were the most effective in killing HIV-infected cells. Having identified immunogenicity as a major concern, we show that conjugation of IT to polyethylene glycol limits immunogenicity. These studies demonstrate that cytotoxic ICs can target virus-infected cells in vivo but also highlight potential problems to be addressed. IMPORTANCE It is not yet possible to cure HIV infection. Even after years of fully effective antiviral therapy, a persistent reservoir of virus-infected cells remains. Here we propose that a targeted conjugate consisting of an anti-HIV antibody bound to a toxic moiety could function to kill the HIV-infected cells that constitute this reservoir. We tested this approach in HIV- infected cells grown in the lab and in animal infections. Our studies demonstrated that these immunoconjugates are effective both in vitro and in test animals. In particular, ITs constructed with the deglycosylated A chain prepared from native ricin were the most effective in killing cells, but their utility was blunted because they provoked immune reactions that interfered with the therapeutic effects. We then demonstrated that coating of the ITs with polyethylene glycol minimized the immunogenicity, as has been demonstrated with other protein therapies. C1 [Pincus, Seth H.; Song, Kejing; Maresh, Grace A.; Frank, Anderson] Childrens Hosp, Res Inst Children, New Orleans, LA 70118 USA. [Pincus, Seth H.; Worthylake, David] Louisiana State Univ, Dept Pediat, Hlth Sci Ctr, New Orleans, LA 70112 USA. [Pincus, Seth H.; Worthylake, David] Louisiana State Univ, Dept Microbiol Immunol & Parasitol, Hlth Sci Ctr, New Orleans, LA 70112 USA. [Chung, Hye-Kyung; Weiss, Deborah] Adv Biosci Labs Inc, Rockville, MD USA. [Polacino, Patricia; Hu, Shiu-Lok] Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Hamer, Dean H.] NCI, Biochem Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Coyne, Cody P.] Mississippi State Univ, Coll Vet Med, Dept Basic Sci, Mississippi State, MS 39762 USA. [Rosenblum, Michael G.; Marks, John W.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Chen, Gang] Concortis Biosyst, San Diego, CA USA. [Ghetie, Victor] UT Southwestern Med Ctr Dallas, Dept Immunol, Dallas, TX USA. [Ghetie, Victor] UT Southwestern Med Ctr Dallas, Dept Microbiol, Dallas, TX USA. [Robinson, James E.] Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. [Song, Kejing] LSU Hlth Sci Ctr, Dept Physiol, New Orleans, LA USA. [Maresh, Grace A.] Ochsner Clin & Alton Ochsner Med Fdn, Jefferson, LA USA. [Frank, Anderson] UTSW Grad Sch Biomed Sci, Dallas, TX USA. [Weiss, Deborah] BIOQUAL, Rockville, MD USA. RP Pincus, SH (reprint author), Childrens Hosp, Res Inst Children, New Orleans, LA 70118 USA.; Pincus, SH (reprint author), Louisiana State Univ, Dept Pediat, Hlth Sci Ctr, New Orleans, LA 70112 USA.; Pincus, SH (reprint author), Louisiana State Univ, Dept Microbiol Immunol & Parasitol, Hlth Sci Ctr, New Orleans, LA 70112 USA. EM spincu@lsuhsc.edu FU Children's Hospital of New Orleans; NIH [R01 CA074690, R21 AI058714, U54 GM104940, P51 OD010425]; Bill and Melinda Gates Foundation Grand Challenges Explorations [OPP1045974]; Louisiana Vaccine Center (Louisiana Board of Regents) [LEQSF-ENH-PKSFI-PRS-02]; LIFT2 [14B-11]; Louisiana State University; Intramural Research Program of the National Cancer Institute; Intramural AIDS Targeted Antiviral Program (IATAP) of NIH; CHAVI [PO1 AI061734]; IATAP; Clayton Foundation; Horchow Foundation; Cancer Immunobiology Center FX Research support was provided to S.H.P., K.S., A.F.,and G.A.M. by Children's Hospital of New Orleans, NIH grants R01 CA074690, R21 AI058714, and U54 GM104940 (Louisiana Clinical and Translational Science Center), the Bill and Melinda Gates Foundation Grand Challenges Explorations (OPP1045974), the Louisiana Vaccine Center (Louisiana Board of Regents, LEQSF-ENH-PKSFI-PRS-02), and a LIFT2 grant (number 14B-11) from Louisiana State University. P.P. and S.-L. H. received support from NIH grants P51 OD010425 (WaNPRC) and R01 AI076170. D. H. H. was supported by the Intramural Research Program of the National Cancer Institute and by the Intramural AIDS Targeted Antiviral Program (IATAP) of NIH. J.E.R. received support from CHAVI (PO1 AI061734). H.-K.C. and D.W. were also supported by the IATAP. M.G.R. and J.W.M. received funding from the Clayton Foundation. E.S.V. was supported by the Simmons Patigian Chair, the Horchow Foundation, and the Cancer Immunobiology Center. NR 64 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2017 VL 91 IS 3 AR UNSP e01360 DI 10.1128/JVI.01360-16 PG 16 WC Virology SC Virology GA EJ4NR UT WOS:000393194600003 ER PT J AU Amato, R Lim, P Miotto, O Amaratunga, C Dek, D Pearson, RD Almagro-Garcia, J Neal, AT Sreng, S Suon, S Drury, E Jyothi, D Stalker, J Kwiatkowski, DP Fairhurst, RM AF Amato, Roberto Lim, Pharath Miotto, Olivo Amaratunga, Chanaki Dek, Dalin Pearson, Richard D. Almagro-Garcia, Jacob Neal, Aaron T. Sreng, Sokunthea Suon, Seila Drury, Eleanor Jyothi, Dushyanth Stalker, Jim Kwiatkowski, Dominic P. Fairhurst, Rick M. TI Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study SO LANCET INFECTIOUS DISEASES LA English DT Article ID ARTEMISININ-RESISTANT MALARIA; WESTERN CAMBODIA; COPY NUMBER; PARASITES; SPREAD; COHORT; VIVAX AB Background As the prevalence of artemisinin-resistant Plasmodium falciparum malaria increases in the Greater Mekong subregion, emerging resistance to partner drugs in artemisinin combination therapies seriously threatens global efforts to treat and eliminate this disease. Molecular markers that predict failure of artemisinin combination therapy are urgently needed to monitor the spread of partner drug resistance, and to recommend alternative treatments in southeast Asia and beyond. Methods We did a genome-wide association study of 297 P falciparum isolates from Cambodia to investigate the relationship of 11630 exonic single-nucleotide polymorphisms (SNPs) and 43 copy number variations (CNVs) with in-vitro piperaquine 50% inhibitory concentrations (IC(50)s), and tested whether these genetic variants are markers of treatment failure with dihydroartemisinin piperaquine. We then did a survival analysis of 133 patients to determine whether candidate molecular markers predicted parasite recrudescence following dihydroartemisinin piperaquine treatment. Findings Piperaquine IC(50)s increased significantly from 2011 to 2013 in three Cambodian provinces (2011 vs 2013 median IC(50)s: 20.0 nmol/L [IQR 13.7-29.0] vs 39.2 nmol/L [32.8-48.1] for Ratanakiri, 19.3 nmol/L [15.1-26.2] vs 66.2 nmol/L [49.9-83.0] for Preah Vihear, and 19.6 nmol/L [11.9-33.9] vs 81.1 nmol/L [61.3-113.1] for Pursat; all p <= 10(-3); Kruskal-Wallis test). Genome-wide analysis of SNPs identified a chromosome 13 region that associates with raised piperaquine IC(50)s. A non-synonymous SNP (encoding a Glu415Gly substitution) in this region, within a gene encoding an exonuclease, associates with parasite recrudescence following dihydroartemisinin piperaquine treatment. Genome-wide analysis of CNVs revealed that a single copy of the mdrl gene on chromosome 5 and a novel amplification of the plasmepsin 2 and plasmepsin 3 genes on chromosome 14 also associate with raised piperaquine IC(50)s. After adjusting for covariates, both exo-E415G and plasmepsin 2-3 markers significantly associate (p=3.0 x10(-8) and p=1.7 x10(-7), respectively) with decreased treatment efficacy (survival rates 0.38 [95% CI 0.25-0.51] and 0.41 [0.28-0.53], respectively). Interpretation The exo-E415G SNP and plasmepsin 2-3 amplification are markers of piperaquine resistance and dihydroartemisinin piperaquine failures in Cambodia, and can help monitor the spread of these phenotypes into other countries of the Greater Mekong subregion, and elucidate the mechanism of piperaquine resistance. Since plasmepsins are involved in the parasite's haemoglobin-to-haemozoin conversion pathway, targeted by related antimalarials, plasmepsin 2-3 amplification probably mediates piperaquine resistance. Copyright (C) The Author(s). Published by Elsevier Ltd. C1 [Amato, Roberto; Miotto, Olivo; Pearson, Richard D.; Almagro-Garcia, Jacob; Drury, Eleanor; Jyothi, Dushyanth; Kwiatkowski, Dominic P.] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge, England. [Amato, Roberto; Miotto, Olivo; Pearson, Richard D.; Almagro-Garcia, Jacob; Kwiatkowski, Dominic P.] Wellcome Trust Ctr Human Genet, Ctr Genom & Global Hlth, Oxford, England. [Lim, Pharath; Amaratunga, Chanaki; Neal, Aaron T.; Fairhurst, Rick M.] NIAID, NIH, Rockville, MD USA. [Lim, Pharath; Dek, Dalin; Sreng, Sokunthea; Suon, Seila] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. [Miotto, Olivo] Mahidol Univ, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand. RP Amato, R (reprint author), Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge, England. EM ra4@sanger.ac.uk; rfairhurst@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health; Bill & Melinda Gates Foundation [OPP1040463, OPP11188166]; Medical Research Council [G0600718]; UK Department for International Development [M006212]; Wellcome Trust [098051, 090770] FX This work was funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health; Bill & Melinda Gates Foundation (OPP1040463, OPP11188166); Medical Research Council (G0600718); and UK Department for International Development (M006212). This publication uses data from the MalariaGEN Plasmodium falciparum Community Project. Genome sequencing was done by the Wellcome Trust Sanger Institute and the Community Project was coordinated by the MalariaGEN Resource Centre with funding from the Wellcome Trust (098051, 090770). We thank all patients for participating in this study; the staff of the WTSI Sample Logistics, Sequencing, and Informatics facilities for their contribution; Marcus Lee for helpful discussions; and Robert Gwadz and Thomas Wellems for their efforts in support of this work. NR 27 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD FEB PY 2017 VL 17 IS 2 BP 164 EP 173 DI 10.1016/51473-3099(16)30409-1 PG 10 WC Infectious Diseases SC Infectious Diseases GA EJ0NJ UT WOS:000392906000040 PM 27818095 ER PT J AU Inaguma, S Lasota, J Wang, ZF Felisiak-Golabek, A Ikeda, H Miettinen, M AF Inaguma, Shingo Lasota, Jerzy Wang, Zengfeng Felisiak-Golabek, Anna Ikeda, Hiroshi Miettinen, Markku TI Clinicopathologic profile, immunophenotype, and genotype of CD274 (PD-L1)-positive colorectal carcinomas SO MODERN PATHOLOGY LA English DT Article ID CELL LUNG-CANCER; COLON-CANCER; STEM-CELLS; B7 FAMILY; EXPRESSION; PD-1; NIVOLUMAB; MARKER; LIGAND; B7-H1 AB The CD274 (PD-L1)/PDCD1 (PD-1) pathway is crucial for the modulation of immune responses and self-tolerance. Aberrantly expressed CD274 allows tumor cells to evade host immune system and is considered to be a mechanism of adaptive immune resistance. Inhibition of the CD274/PDCD1 immune checkpoint offers a promising new therapeutic strategy. Although CD274-expressing tumor cells have been identified in different types of tumors including colorectal cancer, clinicopathologic profile of these CD274-positive tumors has not been extensively studied. In this study, 454 primary colorectal carcinomas were analyzed histologically and immunohistochemically for CD274, mismatch repair (MMR) proteins, intestinal differentiation marker (CDX2), and stem cell markers (ALCAM, ALDH1A1, and SALL4). CD274-positive colorectal carcinomas (54/454 (12%)) usually (83%) involved the right or transverse colon with poorly differentiated and solid/medullary histology. On the basis of multivariate logistic regression analysis, CD274 positivity was significantly associated with poorly differentiated histotype (OR: 3.32; 95% CI: 1.46-7.51; P = 0.004), MMR deficiency (OR: 10.0; 95% CI: 4.66-21.5; P < 0.001), and 'stem-like' immunophenotype defined by the loss or weak expression of CDX2 and ALCAM-positivity (OR: 5.51; 95% CI: 1.66-18.3; P = 0.005). Mutation analysis of 66 arbitrary selected colorectal carcinomas revealed that CD274-positive tumors usually (88%) carried the BRAF V600E mutation. Thus, colorectal carcinomas defined by CD274 positivity displayed features associated with tumors arising via the serrated neoplasia pathway. Moreover, colorectal carcinomas characterized by lack of CDX2 and prominent expression of ALCAM frequently (71%) showed CD274 positivity. This might suggest association of CD274 expression with 'stem-like' phenotype. Further evaluation of a larger cohort or experimental analyses would be needed to confirm this notion. C1 [Inaguma, Shingo; Lasota, Jerzy; Wang, Zengfeng; Felisiak-Golabek, Anna; Miettinen, Markku] NCI, Pathol Lab, Bldg 10,Room B1B47,Ctr Dr 10, Bethesda, MD 20892 USA. [Inaguma, Shingo; Ikeda, Hiroshi] Aichi Med Univ, Sch Med, Dept Pathol, Nagakute, Aichi, Japan. RP Inaguma, S (reprint author), NCI, Pathol Lab, Bldg 10,Room B1B47,Ctr Dr 10, Bethesda, MD 20892 USA. EM inaguma@aichi-med-u.ac.jp FU National Cancer Institute's intramural research program FX We thank Dr Yasuyuki Arai (National Institutes of Health) for advice on statistical analyses. This work is supported as a part of National Cancer Institute's intramural research program. NR 34 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2017 VL 30 IS 2 BP 278 EP 285 DI 10.1038/modpathol.2016.185 PG 8 WC Pathology SC Pathology GA EJ5KR UT WOS:000393257400012 PM 27813511 ER PT J AU Dey, RJ Dey, B Zheng, Y Cheung, LS Zhou, J Sayre, D Kumar, P Guo, HD Lamichhane, G Sintim, H Bishai, WR AF Dey, Ruchi Jain Dey, Bappaditya Zheng, Yue Cheung, Laurene S. Zhou, Jie Sayre, David Kumar, Pankaj Guo, Haidan Lamichhane, Gyanu Sintim, Herman Bishai, William R. TI Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase SO NATURE CHEMICAL BIOLOGY LA English DT Article ID CYCLIC-DI-AMP; MYCOBACTERIUM-TUBERCULOSIS; DNA SENSOR; GMP-AMP; IFN-BETA; CGAS; PATHWAY; PROTEIN; 2ND-MESSENGER; INFECTION AB Mycobacterium tuberculosis infection leads to cytosolic release of the bacterial cyclic dinucleotide (CDN) c-di-AMP and a host-generated CDN, cGAMP, both of which trigger type I interferon (IFN) expression in a STING-dependent manner. Here we report that M. tuberculosis has developed a mechanism to inhibit STING activation and the type I IFN response via the bacterial phosphodiesterase (PDE) CdnP, which mediates hydrolysis of both bacterial-derived c-di-AMP and host-derived cGAMP. Mutation of cdnP attenuates M. tuberculosis virulence, as does loss of a host CDN PDE known as ENPP1. CdnP is inhibited by both US Food and Drug Administration (FDA)-approved PDE inhibitors and nonhydrolyzable dinucleotide mimetics specifically designed to target the enzyme. These findings reveal a crucial role of CDN homeostasis in governing the outcome of M. tuberculosis infection as well as a unique mechanism of subversion of the host's cytosolic surveillance pathway (CSP) by a bacterial PDE that may serve as an attractive antimicrobial target. C1 [Dey, Ruchi Jain; Dey, Bappaditya; Cheung, Laurene S.; Kumar, Pankaj; Guo, Haidan; Lamichhane, Gyanu; Bishai, William R.] Johns Hopkins Univ, Ctr TB Res, Baltimore, MD USA. [Dey, Ruchi Jain; Dey, Bappaditya; Bishai, William R.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Zheng, Yue; Zhou, Jie; Sayre, David; Sintim, Herman] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Zheng, Yue; Zhou, Jie; Sintim, Herman] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Zheng, Yue; Zhou, Jie; Sintim, Herman] Purdue Univ, Inst Drug Discovery, W Lafayette, IN 47907 USA. [Sintim, Herman] Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN USA. [Dey, Bappaditya] Boston Univ, Natl Emerging Infect Dis Labs, Boston, MA 02215 USA. [Zheng, Yue] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Bishai, WR (reprint author), Johns Hopkins Univ, Ctr TB Res, Baltimore, MD USA.; Bishai, WR (reprint author), Howard Hughes Med Inst, Chevy Chase, MD USA.; Sintim, H (reprint author), Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA.; Sintim, H (reprint author), Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA.; Sintim, H (reprint author), Purdue Univ, Inst Drug Discovery, W Lafayette, IN 47907 USA.; Sintim, H (reprint author), Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN USA. EM hsintim@purdue.edu; wbishail@jhmi.edu FU NIAID [AI037856, AI097138, AI036973]; Howard Hughes Medical Institute; NSF [CHE 1307218, CHE 1636752]; Camille and Dreyfus Foundation; Mehta Research Award; University of Maryland Graduate Dean's Dissertation Fellowship FX We gratefully acknowledge support from NIAID (grants AI037856, AI097138, and AI036973 to W.R.B.), the Howard Hughes Medical Institute (W.R.B.), and the NSF (grants CHE 1307218 and CHE 1636752 to H.O.S.). Funding from the Camille and Dreyfus Foundation (Teacher-Scholar fellowship to H.O.S.) is also acknowledged. Y.Z. is supported by a Mehta Research Award. J.Z. is supported by a University of Maryland Graduate Dean's Dissertation Fellowship. We thank B. Roembke at UMD for help with dinucleotide synthesis. We thank H.W. Virgin IV and D. MacDuff (Washington University School of Medicine, St. Louis, Missouri, USA) for generously providing bone marrow cells from cGAS-deficient mice. We thank A. Sher and K. Mayer-Barber (NIH, Bethesda, Maryland, USA) for generously providing Ifnar1-/- mice. We thank K.-P. Hopfner (Department of Biochemistry and Gene Center, Ludwig-Maximilians-University, Munich, Germany) for providing the plasmid to make DisA. We thank A. Grundling (Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK) for providing the plasmid to make GdpP. We thank Z.-X. Liang (Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore) for providing the plasmid to make YybT. We thank S. Pelly for editing the manuscript. NR 47 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD FEB PY 2017 VL 13 IS 2 BP 210 EP 217 DI 10.1038/NCHEMBIO.2254 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EJ9FW UT WOS:000393533000017 PM 28106876 ER PT J AU Meyer, E Carss, KJ Rankin, J Nichols, JME Grozeva, D Joseph, AP Mencacci, NE Papandreou, A Ng, J Barra, S Ngoh, A Ben-Pazi, H Willemsen, MA Arkadir, D Barnicoat, A Bergman, H Bhate, S Boys, A Darin, N Foulds, N Gutowski, N Hills, A Houlden, H Hurst, JA Israe, Z Kaminska, M Limousin, P Lumsden, D Mckee, S Misra, S Mohammed, SS Nakou, V Nicolai, J Nilsson, M Pall, H Peall, KJ Peters, GB Prabhakar, P Reuter, MS Rump, P Sege, R Sinnema, M Smith, M Turnpenny, P White, SM Wieczorek, D Wiethoff, S Wilson, BT Winter, G Wragg, C Pope, S Heales, SJH Morrogh, D Pittman, A Carr, LJ Perez-Duenas, B Lin, JP Reis, A Gahl, WA Toro, C Bhatia, KP Wood, NW Kamsteeg, EJ Chong, WK Gissen, P Topf, M Dale, RC Chubby, JR Raymond, FL Kurian, MA AF Meyer, Esther Carss, Keren J. Rankin, Julia Nichols, John M. E. Grozeva, Detelina Joseph, Agnel P. Mencacci, Niccolo E. Papandreou, Apostolos Ng, Joanne Barra, Serena Ngoh, Adeline Ben-Pazi, Hilla Willemsen, Michel A. Arkadir, David Barnicoat, Angela Bergman, Hagai Bhate, Sanjay Boys, Amber Darin, Niklas Foulds, Nicola Gutowski, Nicholas Hills, Alison Houlden, Henry Hurst, Jane A. Israe, Zvi Kaminska, Margaret Limousin, Patricia Lumsden, Daniel Mckee, Shane Misra, Shibalik Mohammed, Shekeeb S. Nakou, Vasiliki Nicolai, Joost Nilsson, Magnus Pall, Hardev Peall, Kathryn J. Peters, Gregory B. Prabhakar, Prab Reuter, Miriam S. Rump, Patrick Sege, Reeval Sinnema, Margje Smith, Martin Turnpenny, Peter White, Susan M. Wieczorek, Dagmar Wiethoff, Sarah Wilson, Brian T. Winter, Gidon Wragg, Christopher Pope, Simon Heales, Simon J. H. Morrogh, Deborah Pittman, Alan Carr, Lucinda J. Perez-Duenas, Belen Lin, Jean-Pierre Reis, Andre Gahl, William A. Toro, Camilo Bhatia, Kailash P. Wood, Nicholas W. Kamsteeg, Erik-Jan Chong, Wui K. Gissen, Paul Topf, Maya Dale, Russell C. Chubby, Jonathan R. Raymond, F. Lucy Kurian, Manju A. CA UK10K Consortium Deciphering Dev Disorders Study NIHR BioResource Rare TI Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia SO NATURE GENETICS LA English DT Article ID BRAIN IRON ACCUMULATION; PROTEIN STABILITY; KABUKI SYNDROME; METHYLATION; DISORDERS; NEURODEGENERATION; MECHANISMS; VARIANTS; LEUKEMIA; UPDATE AB Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement. C1 [Meyer, Esther; Ng, Joanne; Barra, Serena; Ngoh, Adeline; Kurian, Manju A.] UCL Inst Child Hlth, London, England. [Carss, Keren J.] Univ Cambridge, NHS Blood & Transplant Ctr, Dept Hematol, Cambridge, England. [Carss, Keren J.; Raymond, F. Lucy] Cambridge Univ Hosp, NIHR BioResource Rare Dis, Cambridge Biomed Campus, Cambridge, England. [Rankin, Julia; Turnpenny, Peter] Royal Devon & Exeter NHS Fdn Trust, Clin Genet, Exeter, Devon, England. [Nichols, John M. E.; Gissen, Paul; Chubby, Jonathan R.] UCL, MRC Lab Mol Cell Biol, London, England. [Nichols, John M. E.; Gissen, Paul; Chubby, Jonathan R.] UCL, Dept Cell & Dev Biol, London, England. [Grozeva, Detelina; Raymond, F. Lucy] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge, England. [Joseph, Agnel P.; Topf, Maya] Univ London, Birkbeck Coll, Dept Biol Sci, Inst Struct & Mol Biol,Crystallog, London, England. [Mencacci, Niccolo E.; Houlden, Henry; Wiethoff, Sarah; Pittman, Alan; Wood, Nicholas W.] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Papandreou, Apostolos; Ng, Joanne; Ngoh, Adeline; Bhate, Sanjay; Prabhakar, Prab; Carr, Lucinda J.; Kurian, Manju A.] Great Ormond St Hosp Sick Children, Dept Neurol, London, England. [Ben-Pazi, Hilla; Winter, Gidon] Shaare Zedek Mem Hosp, Pediatr Neurol & Dev, Jerusalem, Israel. [Willemsen, Michel A.] Radboud Univ Nijmegen Med Ctr, Donders Ctr Brain Cognit & Behav, Dept Paediat Neurol, Nijmegen, Netherlands. [Arkadir, David] Hadassah Med Ctr, Dept Neurol, Jerusalem, Israel. [Arkadir, David] Hebrew Univ Jerusalem, Jerusalem, Israel. [Barnicoat, Angela; Hurst, Jane A.; Wilson, Brian T.] Great Ormond St Hosp Sick Children, Dept Clin Genet, London, England. [Bergman, Hagai] Hebrew Univ Jerusalem, Hadassah Med Ctr, Dept Neurobiol & Neurosurg, Jerusalem, Israel. [Boys, Amber; White, Susan M.] Murdoch Childrens Res Inst, Victoria Clin Genet Serv, Parkville, Vic, Australia. [Darin, Niklas] Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden. [Foulds, Nicola] Southampton Gen Hosp, Dept Clin Genet, Southampton, Hants, England. [Gutowski, Nicholas] Royal Devon & Exeter NHS Fdn Trust, Dept Neurol, Exeter, Devon, England. [Hills, Alison; Wragg, Christopher] Southmead Hosp, Bristol Genet Lab, Pathol Sci, Bristol, Avon, England. [Israe, Zvi] Hadassah Univ Hosp, Funct & Restorat Neurosurg, Jerusalem, Israel. [Kaminska, Margaret; Lumsden, Daniel; Nakou, Vasiliki; Lin, Jean-Pierre] Guys & St Thomas NHS Fdn Trust, Evelina Childrens Hosp, Complex Motor Disorders Serv, London, England. [Limousin, Patricia; Bhatia, Kailash P.] Natl Hosp Neurol & Neurosurg, Sobell Dept, London, England. [Mckee, Shane] Belfast City Hosp, Northern Ireland Reg Genet Serv, Belfast, Antrim, North Ireland. [Misra, Shibalik; Mohammed, Shekeeb S.; Dale, Russell C.] Univ Sydney, Child & Adolescent Hlth, Sydney, NSW, Australia. [Misra, Shibalik; Mohammed, Shekeeb S.; Dale, Russell C.] Univ Sydney, Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW, Australia. [Nicolai, Joost] Maastricht Univ, Med Ctr, Dept Neurol, Maastricht, Netherlands. [Papandreou, Apostolos; Nilsson, Magnus] Pitea Hosp, Dept Pediat, Umea, Sweden. [Nilsson, Magnus] Umea Univ Hosp, Umea, Sweden. [Pall, Hardev] Univ Birmingham, Coll Med & Dent Studies, Birmingham, W Midlands, England. [Peall, Kathryn J.] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Neurosci & Mental Hlth Res Inst, Cardiff, S Glam, Wales. [Peters, Gregory B.] Childrens Hosp Westmead, Dept Cytogenet, Westmead, NSW, Australia. [Reuter, Miriam S.; Reis, Andre] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Rump, Patrick] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Sege, Reeval] Shaare Zedek Med Ctr, Inst Med Genet, Jerusalem, Israel. [Sege, Reeval] Shaare Zedek Med Ctr, Pediat, Jerusalem, Israel. [Sege, Reeval] Hebrew Univ Jerusalem, Sch Med, Jerusalem, Israel. [Sinnema, Margje] Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Sinnema, Margje] Maastricht Univ, Med Ctr, Sch Oncol & Dev Biol GROW, Maastricht, Netherlands. [Smith, Martin] John Radcliffe Hosp, Dept Pediat Neurol, Oxford, England. [White, Susan M.] Univ Melbourne, Dept Pediat, Melbourne, Vic, Australia. [Wieczorek, Dagmar] Univ Duisburg Essen, Inst Human Genet, Essen, Germany. [Wieczorek, Dagmar] Heinrich Heine Univ, Fac Med, Inst Human Genet, Dusseldorf, Germany. [Heales, Simon J. H.] Natl Hosp Neurol & Neurosurg, Neurometab Unit, London, England. [Heales, Simon J. H.] NHS Fdn Trust, Great Ormond St Hosp, Clin Chem, London, England. [Morrogh, Deborah] Great Ormond St Hosp Sick Children, North East Thames Reg Genet Serv, London, England. [Perez-Duenas, Belen] Univ Barcelona, Hosp St Joan de Deu, Dept Child Neurol, Barcelona, Spain. [Perez-Duenas, Belen] Hosp St Joan de Deu, Ctr Biomed Res Rare Dis CIBERER ISCIII, Barcelona, Spain. [Gahl, William A.; Toro, Camilo] US Natl Inst Hlth, Off Director, Common Fund, NIH Undiagnosed Dis Program, Bethesda, MD USA. [Kamsteeg, Erik-Jan] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands. [Chong, Wui K.] Great Ormond St Hosp Sick Children, Dept Radiol, London, England. RP Kurian, MA (reprint author), UCL Inst Child Hlth, London, England.; Kurian, MA (reprint author), Great Ormond St Hosp Sick Children, Dept Neurol, London, England. EM manju.kurian@ucl.ac.uk RI Wood, Nicholas/C-2505-2009; OI Wood, Nicholas/0000-0002-9500-3348; Papandreou, Apostolos/0000-0001-5093-6075; Mohammad, Shekeeb/0000-0003-1219-4781 FU Rosetrees Trust; Great Ormond Street Hospital Children's Charity; Gracious Heart Foundation; UK Department of Health's NIHR Biomedical Research Centers; Daniel Turnberg Trust Fund; MRC; Wellcome Trust (Synaptopathies award); Prusiner-Abramsky Award; Dystonia Society (UK); La Marato de TV3 [20143130]; Ministerio Espanol de Economia y Competitividad [PI15/00287]; Guy's and St Thomas' Charity New Services and Innovation Grant [G060708]; Dystonia Society (UK) [01/2011, 07/2013]; Action Medical Research [AMR-GN2097]; NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust; University College London; University of Cambridge; NIHR for the BioResource for Rare Diseases [RG65966]; Wellcome Trust [UK10K (WT091310)]; DDD study; Health Innovation Challenge Fund [HICF-1009-003]; Intramural Research Program of the National Human Genome Research Institute; Common Fund, NIH Office of the Director; German Ministry of Research and Education as part of National Genome Research Network [0IGS08160, 01GS08167]; German Ministry of Research and Education (German Mental Retardation Network) as part of National Genome Research Network; Deutsche Forschungsgemeinschaft [AB393/2-2]; UK Human Brain Expression Consortium (UKBEC) FX We thank all our patients and their families for taking part in this study and encouraging international collaboration to seek out similar cases. Thanks are given to M. Ishida (GOS-ICH) for kindly providing the fetal cDNA, K. Tuschl (GOS-ICH) for kindly providing the human cDNA panel, L. Bassioni (Great Ormond Street Hospital, GOSH) for kindly selecting DaTSCAN images for the supplementary manuscript, M. Adams (National Hospital for Neurology and Neurosurgery, NHNN) for reviewing the imaging of the patients at NHNN and R. Meijer for helping with the sequencing analysis at the Department of Human Genetics (Nijmegen). We thank G. Moore (GOS-ICH) and P. Stanier (GOS-ICH) for proofreading the manuscript. Many thanks are given to A. Panahian-Jand (GOSH) for excellent administrative support. M.A.K. has a Wellcome Intermediate Clinical Fellowship (WT098524MA). E.M. and M.A.K. received funding from the Rosetrees Trust, the Great Ormond Street Hospital Children's Charity and the Gracious Heart Foundation. N.E.M. receives support from the UK Department of Health's NIHR Biomedical Research Centers funding streams. A. Papandreou has a joint Action Medical Research/British Paediatric Neurology Association Research Training Fellowship. J. Ng has an MRC Research Training Fellowship. A.N. has an Action Medical Research Training Fellowship. H.B.-P. has a DBS training travel grant from the Daniel Turnberg Trust Fund. H.H. is funded by the MRC and Wellcome Trust (Synaptopathies award). D.A. is supported by the Prusiner-Abramsky Award. H.P. has received grant support from the Dystonia Society (UK). K.J.P. has an Academy of Medical Sciences Clinical Starter Grant. B.P.-D. received funding from grants 20143130-La Marato de TV3 and PI15/00287-Ministerio Espanol de Economia y Competitividad. J.-P.L. has been supported by Guy's and St Thomas' Charity New Services and Innovation Grant G060708, the Dystonia Society (UK), grants 01/2011 and 07/2013 and an Action Medical Research, AMR-GN2097. This research was supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust, University College London and University of Cambridge and by funding from the NIHR for the BioResource for Rare Diseases (grant RG65966). This study makes use of data generated by the DECIPHER community. A full list of centers contributing to the generation of the data is available from http://decipher.sanger.ac.uk/ and via e-mail from decipher@sanger.ac.uk. Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and the DDD study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003); see http://www.ddduk.org/access.html for full acknowledgment. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grants 0IGS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W., and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data were provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with the UCL Institute of Neurology (J.A.H., M.R. and D.T.), King's College London (M.R., M.W. and A.R.) and the University of Edinburgh (C.S. and R.W.). NR 40 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD FEB PY 2017 VL 49 IS 2 BP 223 EP 237 DI 10.1038/ng.3740 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA EJ3YM UT WOS:000393148600011 PM 27992417 ER PT J AU Shaw, ND Brand, H Kupchinsky, ZA Bengani, H Plummer, L Jones, TI Erdin, S Williamson, KA Rainger, J Stortchevoi, A Samocha, K Curra, BB Dunican, DS Collins, RL Willer, JR Lek, A Lek, M Nassan, M Pereira, S Kammin, T Lucente, D Silva, A Seabra, CM Chiang, C Ana, Y Ansari, M Rainger, JK Joss, S Smith, JC Lippincott, MF Singh, SS Patel, N Jing, JW Law, JR Ferraro, N Verloes, M Rauch, A Steindl, K Zweier, M Scheer, I Sato, D Okamoto, N Jacobsen, C Tryggestad, J Chernausek, S Schimmenti, LA Brasseur, B Cesaretti, C Garcia-Ortiz, JE Buitrago, TP Silva, OP Hoffman, JD Muhlbauer, W Ruprecht, KW Loeys, BL Shino, M Kaind, AM Cho, CH Morton, CC Meehan, RR van Heyningen, V Liao, EC Balasubramanian, R Hall, JE Seminara, SB Macarthur, D Moore, SA Yoshiura, K Gusella, JF Marsh, JA Graham, JM Lin, AE Katsanis, N Jones, PL Crowley, WF Davis, EE FitzPatrick, DR Talkowski, ME AF Shaw, Natalie D. Brand, Harrison Kupchinsky, Zachary A. Bengani, Hemant Plummer, Lacey Jones, Takako I. Erdin, Serkan Williamson, Kathleen A. Rainger, Joe Stortchevoi, Alexei Samocha, Kaitlin Curra, Benjamin B. Dunican, Donncha S. Collins, Ryan L. Willer, Jason R. Lek, Angela Lek, Monkol Nassan, Malik Pereira, Shahrin Kammin, Tammy Lucente, Diane Silva, Alexandra Seabra, Catarina M. Chiang, Colby Ana, Yu Ansari, Morad Rainger, Jacqueline K. Joss, Shelagh Smith, Jill Clayton Lippincott, Margaret F. Singh, Sylvia S. Patel, Nirav Jing, Jenny W. Law, Jennifer R. Ferraro, Nalton Verloes, Main Rauch, Anita Steindl, Katharina Zweier, Markus Scheer, Ianina Sato, Daisuke Okamoto, Nobuhiko Jacobsen, Christina Tryggestad, Jeanie Chernausek, Steven Schimmenti, Lisa A. Brasseur, Benjamin Cesaretti, Claudia Garcia-Ortiz, Jose E. Pineda Buitrago, Tatiana Perez Silva, Orlando Hoffman, Jodi D. Muehlbauer, Wolfgang Ruprecht, Klaus W. Loeys, Bart L. Shino, Masato Kaind, Angela M. Cho, Chie-Hee Morton, Cynthia C. Meehan, Richard R. van Heyningen, Veronica Liao, Eric C. Balasubramanian, Ravikumar Hall, Janet E. Seminara, Stephanie B. Macarthur, Daniel Moore, Steven A. Yoshiura, Koh-ichiro Gusella, James F. Marsh, Joseph A. Graham, John M., Jr. Lin, Angela E. Katsanis, Nicholas Jones, Peter L. Crowley, William F., Jr. Davis, Erica E. FitzPatrick, David R. Talkowski, Michael E. TI SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome SO NATURE GENETICS LA English DT Article ID X INACTIVATION; CHROMOSOME; EXPRESSION; DOMAIN; FSHD1; GNRH; METHYLATION; INHERITANCE; HYPOPLASIA; PREDICTION AB Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes. C1 [Shaw, Natalie D.; Brand, Harrison; Plummer, Lacey; Lippincott, Margaret F.; Singh, Sylvia S.; Patel, Nirav; Jing, Jenny W.; Balasubramanian, Ravikumar; Hall, Janet E.; Seminara, Stephanie B.; Crowley, William F., Jr.] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, Harvard Reprod Endocrine Sci Ctr, Boston, MA 02114 USA. [Shaw, Natalie D.; Brand, Harrison; Plummer, Lacey; Lippincott, Margaret F.; Singh, Sylvia S.; Patel, Nirav; Jing, Jenny W.; Balasubramanian, Ravikumar; Hall, Janet E.; Seminara, Stephanie B.; Crowley, William F., Jr.] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, NICHD Ctr Excellence Translat Res Fertil & Infert, Boston, MA 02114 USA. [Shaw, Natalie D.; Hall, Janet E.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Brand, Harrison; Erdin, Serkan; Stortchevoi, Alexei; Curra, Benjamin B.; Collins, Ryan L.; Lucente, Diane; Silva, Alexandra; Seabra, Catarina M.; Chiang, Colby; Ana, Yu; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. [Brand, Harrison; Erdin, Serkan; Stortchevoi, Alexei; Curra, Benjamin B.; Collins, Ryan L.; Lucente, Diane; Silva, Alexandra; Seabra, Catarina M.; Chiang, Colby; Ana, Yu; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Brand, Harrison; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Brand, Harrison; Samocha, Kaitlin; Lek, Monkol; Jacobsen, Christina; Liao, Eric C.; Lin, Angela E.; Talkowski, Michael E.] Harvard Med Sch, Boston, MA 02115 USA. [Brand, Harrison; Erdin, Serkan; Samocha, Kaitlin; Lek, Monkol; Morton, Cynthia C.; Macarthur, Daniel; Gusella, James F.; Talkowski, Michael E.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Kupchinsky, Zachary A.; Willer, Jason R.; Katsanis, Nicholas; Davis, Erica E.] Duke Univ, Med Ctr, Ctr Human Dis Modeling, Durham, NC 27708 USA. [Bengani, Hemant; Williamson, Kathleen A.; Rainger, Joe; Dunican, Donncha S.; Ansari, Morad; Rainger, Jacqueline K.; Meehan, Richard R.; van Heyningen, Veronica; Marsh, Joseph A.; FitzPatrick, David R.] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Jones, Takako I.; Jones, Peter L.] Univ Massachusetts Med Sch, Dept Cell & Dev Biol, Worcester, MA 01655 USA. [Samocha, Kaitlin; Lek, Monkol; Macarthur, Daniel] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Collins, Ryan L.] Harvard Med Sch, Div Med Sci, Program Bioinformat & Integrat Genom, Boston, MA 02115 USA. [Lek, Angela; Gusella, James F.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Nassan, Malik] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 55905 USA. [Pereira, Shahrin; Kammin, Tammy; Morton, Cynthia C.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, 75 Francis St, Boston, MA 02115 USA. [Seabra, Catarina M.] Univ Porto, GABBA Program, Oporto, Portugal. [Joss, Shelagh] South Glasgow Univ Hosp, West Scotland Genet Serv, Glasgow, Lanark, Scotland. [Smith, Jill Clayton] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, Fac Med & Human Sci,Inst Human Dev, Manchester, Lancs, England. [Law, Jennifer R.] Univ N Carolina, Div Pediat Endocrinol, Chapel Hill, NC 27514 USA. [Ferraro, Nalton] Boston Childrens Hosp, Dept Oral & Maxillofacial Surg, Boston, MA USA. [Verloes, Main] Robert Debre Hosp, Dept Genet, Paris, France. [Rauch, Anita; Steindl, Katharina; Zweier, Markus] Univ Zurich, Clin Res Prior Program Rare Dis, Inst Med Genet, Schlieren, Switzerland. [Rauch, Anita; Steindl, Katharina; Zweier, Markus] Univ Zurich, Clin Res Prior Program Rare Dis, Radiz Rare Dis Initiat Zurich, Schlieren, Switzerland. [Scheer, Ianina] Childrens Hosp, Dept Diagnost Imaging, Zurich, Switzerland. [Sato, Daisuke] Hokkaido Univ, Grad Sch Med, Dept Pediat, Sapporo, Hokkaido, Japan. [Okamoto, Nobuhiko] Osaka Med Ctr, Dept Med Genet, Osaka, Japan. [Okamoto, Nobuhiko] Res Inst Maternal & Child Hlth, Osaka, Japan. [Jacobsen, Christina] Boston Childrens Hosp, Div Endocrinol & Genet, Boston, MA 02115 USA. [Tryggestad, Jeanie] Univ Oklahoma, Hlth Sci Ctr, Dept Pediat, Oklahoma City, OK 73190 USA. [Schimmenti, Lisa A.] Mayo Clin, Dept Otorhinolaryngol, Rochester, MN 55905 USA. [Schimmenti, Lisa A.] Mayo Clin, Dep Clin Genom, Rochester, MN 55905 USA. [Brasseur, Benjamin] Univ Miami, Leonard M Miller Sch Med, DeWitt Daughtry Family Dept Surg, Miami, FL 33146 USA. [Cesaretti, Claudia] Osped Maggiore Policlin, Fdn IRCCS Ca Granda, Med Genet Unit, Milan, Italy. [Garcia-Ortiz, Jose E.] Inst Mexicano Seguro Social, Ctr Invest Biomed Occidente, Div Genet, Guadalajara, Mexico. [Pineda Buitrago, Tatiana] San Jose State Univ, Fdn Hosp Infantil, Bogota, Colombia. [Perez Silva, Orlando] Acad Nacl Med Colombia, Bogota, Colombia. [Hoffman, Jodi D.] Tufts Med Ctr, Div Genet, Boston, MA 02111 USA. [Hoffman, Jodi D.] Tufts Med Ctr, Div Maternal Fetal Med, Boston, MA 02111 USA. [Muehlbauer, Wolfgang] ATOS Klin, Dept Plast & Aesthet Surg, Munich, Germany. [Ruprecht, Klaus W.] Univ Hosp Saarland, Dept Ophthalmol, Homburg, Germany. [Loeys, Bart L.] Univ Antwerp, Ctr Med Genet, Antwerp, Belgium. [Loeys, Bart L.] Univ Antwerp Hosp, Antwerp, Belgium. [Shino, Masato] Gunma Univ, Grad Sch Med, Dept Otolaryngol Head & Neck Surg, Gunma, Japan. [Kaind, Angela M.] Charite, Biol & Neurobiol, Berlin, Germany. [Kaind, Angela M.] Berlin Inst Hlth, Berlin, Germany. [Cho, Chie-Hee] Univ Hosp Bern, Inselspital, Dept Diagnost Intervent & Pediat Radiol, Bern, Switzerland. [Liao, Eric C.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Liao, Eric C.] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. [Liao, Eric C.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Macarthur, Daniel; Talkowski, Michael E.] Broad Inst MIT & Harvard, Ctr Mendelian Genom, Cambridge, MA 02142 USA. [Moore, Steven A.] Univ Iowa, Carver Coll Med, Dept Pathol, Iowa City, IA 52242 USA. [Yoshiura, Koh-ichiro] Nagasaki Univ, Grad Sch Biomed Sci, Dept Human Genet, Nagasaki, Japan. [Graham, John M., Jr.] Cedars Sinai Med Ctr, Dept Pediat, Los Angeles, CA 90048 USA. [Lin, Angela E.] MassGeneral Hosp Children, Med Genet, Boston, MA 02114 USA. RP Talkowski, ME (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA.; Talkowski, ME (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.; Talkowski, ME (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Talkowski, ME (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Talkowski, ME (reprint author), Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA.; Davis, EE (reprint author), Duke Univ, Med Ctr, Ctr Human Dis Modeling, Durham, NC 27708 USA.; FitzPatrick, DR (reprint author), Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.; Talkowski, ME (reprint author), Broad Inst MIT & Harvard, Ctr Mendelian Genom, Cambridge, MA 02142 USA. EM erica.davis@duke.edu; david.fitzpatrick@igmm.ed.ac.uk; talkowski@chgr.mgh.harvard.edu OI van Heyningen, Veronica/0000-0003-0359-0141; Erdin, Serkan/0000-0001-6587-2625; Shaw, Natalie/0000-0002-0847-9170; Loeys, Bart/0000-0003-3703-9518; Hall, Janet/0000-0003-4644-3061; FitzPatrick, David R./0000-0003-4861-969X; Marsh, Joseph/0000-0003-4132-0628 FU National Institutes of Health ((NIH)) [R00MH095867, R01HD081256, P01GM061354, T32HD007396, P50HD028138]; MGH Robert and Laura Reynolds Research Scholar Award [R01HD043341]; March of Dimes [FY15-255]; Medical Research Council [MR/M02122X/1]; German Research Foundation [SFB665]; Berlin Institute of Health (BIH) [CRG1]; Medical Research Council (MRC) Human Genetics Unit award [MC_PC_U127574433]; University of Edinburgh Institute of Genomics and Molecular Medicine Translational Initiative Fund; [K23HD073304-02]; [1SI2ES025429-01]; [P50DK096415]; [R01AR062587]; [U54-NS053672] FX We thank all participants, family members and clinical staff for their generous contributions of time and materials to this research. We thank T. Gillis, J. Ruliera, C. Hanscom, C. Antolik and M. Anderson for technical assistance. This project was funded by grants from the National Institutes of Health ((NIH) R00MH095867 and R01HD081256 to M.E.T.; P01GM061354 to M.E.T., J.F.G., C.C.M. and E.C.L.; T32HD007396 to H. Brand; P50HD028138 to W.F.C., S.B.S., M.E.T., N.K. and E.E.D.; R01HD043341 and MGH Robert and Laura Reynolds Research Scholar Award to S.B.S.; K23HD073304-02 and 1SI2ES025429-01 to N.D.S.; P50DK096415 to N.K. and R01AR062587 to P.L.J.); the March of Dimes (FY15-255 to M.E.T.); the Medical Research Council (MR/M02122X/1 to J.A.M.); the German Research Foundation (SFB665 to A.M.K.) and the Berlin Institute of Health (BIH-CRG1 to A.M.K.). D.R.F., R.R.M. (MC_PC_U127574433), D.S.D., H. Bengani, K.A.W., J.R., J.K.R. and J.A.M. are funded by program grants from the Medical Research Council (MRC) Human Genetics Unit award to the University of Edinburgh. M.A. is funded by the University of Edinburgh Institute of Genomics and Molecular Medicine Translational Initiative Fund. S.A.M. is supported by U54-NS053672, which funds the Iowa, Paul D. Wellstone Muscular Dystrophy Cooperative Research Center. N.K. is supported as a Distinguished Jean and George Brumley Professor at Duke University, and M.E.T. is supported as the Desmond and Ann Heathwood MGH Research Scholar. NR 52 TC 1 Z9 1 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD FEB PY 2017 VL 49 IS 2 BP 238 EP 248 DI 10.1038/ng.3743 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA EJ3YM UT WOS:000393148600012 PM 28067909 ER PT J AU Stanton, BZ Hodges, C Calarco, JP Braun, SMG Ku, WL Kadoch, C Zhao, K Crabtree, GR AF Stanton, Benjamin Z. Hodges, Courtney Calarco, Joseph P. Braun, Simon M. G. Ku, Wai Lim Kadoch, Cigall Zhao, Keji Crabtree, Gerald R. TI Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin SO NATURE GENETICS LA English DT Article ID EMBRYONIC STEM-CELLS; REMODELING COMPLEXES; NEURAL DEVELOPMENT; CANCER GENOME; BAF COMPLEXES; POLYCOMB; FAMILY; GENE; DNA; TRANSFORMATION AB Trithorax-group proteins and their mammalian homologs, including those in BAF (mSWI/SNF) complexes, are known to oppose the activity of Polycomb repressive complexes (PRCs)(1-5). This opposition underlies the tumor-suppressive role of BAF subunits(3,5-7) and is expected to contribute to neurodevelopmental disorders(8,9). However, the mechanisms underlying opposition to Polycomb silencing are poorly understood. Here we report that recurrent disease-associated mutations in BAF subunits induce genome-wide increases in PRC deposition and activity. We show that point mutations in SMARCA4 (also known as BRG1) mapping to the ATPase domain cause loss of direct binding between BAF and PRC1 that occurs independently of chromatin. Release of this direct interaction is ATP dependent, consistent with a transient eviction mechanism. Using a new chemical-induced proximity assay, we find that BAF directly evicts Polycomb factors within minutes of its occupancy, thereby establishing a new mechanism for the widespread BAF-PRC opposition underlying development and disease. C1 [Stanton, Benjamin Z.; Hodges, Courtney; Calarco, Joseph P.; Braun, Simon M. G.; Crabtree, Gerald R.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Stanton, Benjamin Z.; Hodges, Courtney; Calarco, Joseph P.; Braun, Simon M. G.; Crabtree, Gerald R.] Stanford Univ, Dept Dev Biol, Sch Med, Stanford, CA 94305 USA. [Stanton, Benjamin Z.; Ku, Wai Lim; Zhao, Keji] NHLBI, Syst Biol Ctr, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA. [Kadoch, Cigall] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Kadoch, Cigall] Harvard Med Sch, Boston, MA USA. [Kadoch, Cigall] Broad Inst MIT & Harvard, Cambridge, MA USA. [Crabtree, Gerald R.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Crabtree, GR (reprint author), Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA.; Crabtree, GR (reprint author), Stanford Univ, Dept Dev Biol, Sch Med, Stanford, CA 94305 USA.; Zhao, K (reprint author), NHLBI, Syst Biol Ctr, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA.; Crabtree, GR (reprint author), Howard Hughes Med Inst, Chevy Chase, MD USA. EM zhaok@hlbi.nih.gov; crabtree@stanford.edu OI Hodges, Courtney/0000-0003-4441-497X FU NIH S10 Shared Instrumentation Grant [1S10RR02664701]; SFARI Foundation; NIH grants [R37NS046789, R01CA163915]; Division of Intramural Research, NHLBI/NIH; Swiss National Science Foundation (SNSF) postdoctoral fellowship; NCI career transition award [K99CA187565] FX This paper is dedicated to the memory of Joseph P. Calarco, a great friend and passionate scientist. We apologize to our colleagues whose work we could not cite owing to space constraints. We thank G. Hu, W Jin, E. Chory, J. Bradner, and D. Hargreaves for helpful discussions and E. Miller for sharing curated GEO data sets. Aridla conditional deletion cells were a gift from D. Hargreaves (Salk Institute). All libraries were sequenced by the DNA Sequencing and Genomics Core facility of NHLBI. Analysis was performed using the Stanford BioX3 cluster, supported by NIH S10 Shared Instrumentation Grant 1S10RR02664701. This work was also supported by the SFARI Foundation (G.R.C.), NIH grants R37NS046789 (G.R.C.) and R01CA163915 (G.R.C.), and the Division of Intramural Research, NHLBI/NIH (K.Z.). G.R.C. is an HHMI Investigator. S.M.G.B. is supported by a Swiss National Science Foundation (SNSF) postdoctoral fellowship. C.H. is supported by NCI career transition award K99CA187565. NR 50 TC 3 Z9 3 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD FEB PY 2017 VL 49 IS 2 BP 282 EP 288 DI 10.1038/ng.3735 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA EJ3YM UT WOS:000393148600018 PM 27941795 ER PT J AU Kim, Y Lee, HM Xiong, Y Sciaky, N Hulbert, SW Cao, XY Everitt, JI Jin, J Roth, BL Jiang, YH AF Kim, Yuna Lee, Hyeong-Min Xiong, Yan Sciaky, Noah Hulbert, Samuel W. Cao, Xinyu Everitt, Jeffrey I. Jin, Jian Roth, Bryan L. Jiang, Yong-hui TI Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome SO NATURE MEDICINE LA English DT Article ID SMALL NUCLEOLAR RNA; NOVO DNA METHYLATION; PATERNAL DELETION; CHEMICAL PROBE; REGION; UBE3A; GLP; MUTATIONS; MAGEL2; TRANSCRIPT AB Prader-Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11-q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642 two selective inhibitors of euchromatic histone lysine N-methyltransferase-2 (EHMT2, also known as G9a)-activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster SNORD116, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (Snrpn (S)) to ubiquitin protein ligase E3A (Ube3a (U)) (mouse model referred to hereafter as m(+)/p(Delta s-U)). Both UNC0642 and UNC0638 caused a selective reduction of the dimethylation of histone H3 lysine 9 (H3K9me2) at PWS-IC, without changing DNA methylation, when analyzed by bisulfite genomic sequencing. This indicates that histone modification is essential for the imprinting of candidate genes underlying PWS. UNC0642 displayed therapeutic effects in the PWS mouse model by improving the survival and the growth of in m(+)/p(Delta s-U) newborn pups. This study provides the first proof of principle for an epigenetics-based therapy for PWS. C1 [Kim, Yuna; Cao, Xinyu; Jiang, Yong-hui] Duke Univ, Sch Med, Dept Pediat, Durham, NC 27708 USA. [Lee, Hyeong-Min] Univ N Carolina, Dept Cell Biol & Physiol, Sch Med, Chapel Hill, NC USA. [Lee, Hyeong-Min; Sciaky, Noah; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC 27514 USA. [Xiong, Yan; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA. [Xiong, Yan; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Hulbert, Samuel W.; Jiang, Yong-hui] Duke Univ, Sch Med, Dept Neurobiol, Durham, NC 27708 USA. [Everitt, Jeffrey I.] Duke Univ, Sch Med, Dept Pathol, Durham, NC 27706 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Div Chem Biol & Med Chem, Program Neurosci, Chapel Hill, NC 27514 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, NIMH Psychoact Drug Screening Program, Chapel Hill, NC 27514 USA. [Jiang, Yong-hui] Duke Univ, Sch Med, Program Genet & Genom, Durham, NC 27708 USA. RP Jiang, YH (reprint author), Duke Univ, Sch Med, Dept Pediat, Durham, NC 27708 USA.; Roth, BL (reprint author), Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC 27514 USA.; Jiang, YH (reprint author), Duke Univ, Sch Med, Dept Neurobiol, Durham, NC 27708 USA.; Roth, BL (reprint author), Univ N Carolina, Sch Med, Div Chem Biol & Med Chem, Program Neurosci, Chapel Hill, NC 27514 USA.; Roth, BL (reprint author), Univ N Carolina, Sch Med, NIMH Psychoact Drug Screening Program, Chapel Hill, NC 27514 USA.; Jiang, YH (reprint author), Duke Univ, Sch Med, Program Genet & Genom, Durham, NC 27708 USA. EM bryan_roth@med.unc.edu; yong-hui.jiang@duke.edu OI Everitt, Jeffrey/0000-0003-0273-6284 FU US National Institutes of Health [HD077197, R01GM103893]; Foundation for Prader Willi Syndrome Research (FPWR) FX We thank A. Beaudet at Baylor College of Medicine for providing the SnrpnEGFP mice and some of the PWS cell lines; B. Philpot and M. Zlyka (University of North Carolina at Chapel Hill) for discussion. K. Konze for his advice on the ChIP experiment; S.-O. Han for his advice on blood-sample collection; C. Means and R. Rodriguiz for their assistance with neurological screening; and A. Bey for proofreading and discussion. This study is supported by grants from the US National Institutes of Health (HD077197 to Y.-H.J. and R01GM103893 to J.J.). Y.-H. Jiang is also supported by a grant from the Foundation for Prader Willi Syndrome Research (FPWR). We thank the International Rett Syndrome Foundation and GlaxoSmithKline for providing the CNS-penetrating drug library (SMART library) and Published Kinase Inhibitor Set (PKIS), the NIMH Psychoactive Drug Screening Program (B.L. Roth) and the Michael Hooker Chair of Translational Proteomics (B.L. Roth). NR 54 TC 0 Z9 0 U1 7 U2 7 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 FEB PY 2017 VL 23 IS 2 BP 213 EP 222 DI 10.1038/nm.4257 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EK2AH UT WOS:000393729000013 PM 28024084 ER PT J AU Berg, JS Agrawal, PB Bailey, DB Beggs, AH Brenner, SE Brower, AM Cakici, JA Ceyhan-Birsoy, O Chan, K Chen, F Currier, RJ Dukhovny, D Green, RC Harris-Wai, J Holm, IA Iglesias, B Joseph, G Kingsmore, SF Koenig, BA Kwok, PY Lantos, J Leeder, SJ Lewis, MA McGuire, AL Milko, LV Mooney, SD Parad, RB Pereira, S Petrikin, J Powell, BC Powell, CM Puck, JM Rehm, HL Risch, N Roche, M Shieh, JT Veeraraghavan, N Watson, MS Willig, L Yu, TW Urv, T Wise, AL AF Berg, Jonathan S. Agrawal, Pankaj B. Bailey, Donald B., Jr. Beggs, Alan H. Brenner, Steven E. Brower, Amy M. Cakici, Julie A. Ceyhan-Birsoy, Ozge Chan, Kee Chen, Flavia Currier, Robert J. Dukhovny, Dmitry Green, Robert C. Harris-Wai, Julie Holm, Ingrid A. Iglesias, Brenda Joseph, Galen Kingsmore, Stephen F. Koenig, Barbara A. Kwok, Pui-Yan Lantos, John Leeder, Steven J. Lewis, Megan A. McGuire, Amy L. Milko, Laura V. Mooney, Sean D. Parad, Richard B. Pereira, Stacey Petrikin, Joshua Powell, Bradford C. Powell, Cynthia M. Puck, Jennifer M. Rehm, Heidi L. Risch, Neil Roche, Myra Shieh, Joseph T. Veeraraghavan, Narayanan Watson, Michael S. Willig, Laurel Yu, Timothy W. Urv, Tiina Wise, Anastasia L. TI Newborn Sequencing in Genomic Medicine and Public Health SO PEDIATRICS LA English DT Article ID TANDEM MASS-SPECTROMETRY; SHARED DECISION-MAKING; INTENSIVE-CARE-UNIT; WHOLE-GENOME; INCIDENTAL FINDINGS; CLINICAL-PRACTICE; INBORN-ERRORS; EXOME; INFANTS; HEMOGLOBINOPATHIES AB The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening. C1 [Berg, Jonathan S.; Milko, Laura V.; Powell, Bradford C.] Univ N Carolina, Chapel Hill Sch Med, Dept Genet, Chapel Hill, NC USA. [Powell, Cynthia M.; Roche, Myra] Univ N Carolina, Chapel Hill Sch Med, Dept Pediat, Chapel Hill, NC USA. [Agrawal, Pankaj B.] Harvard Med Sch, Boston Childrens Hosp, Div Newborn Med, Manton Ctr Orphan Dis Res, Boston, MA USA. [Agrawal, Pankaj B.; Beggs, Alan H.; Holm, Ingrid A.; Yu, Timothy W.] Harvard Med Sch, Boston Childrens Hosp, Div Genet & Genom, Manton Ctr Orphan Dis Res, Boston, MA USA. [Ceyhan-Birsoy, Ozge; Rehm, Heidi L.] Harvard Med Sch, Lab Mol Med, Brigham & Womens Hosp, Boston, MA USA. [Green, Robert C.] Harvard Med Sch, Div Genet, Brigham & Womens Hosp, Boston, MA USA. [Parad, Richard B.] Harvard Med Sch, Dept Pediat Newborn Med, Brigham & Womens Hosp, Boston, MA USA. [Bailey, Donald B., Jr.; Lewis, Megan A.] RTI Int, Res Triangle Pk, NC USA. [Brenner, Steven E.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Brower, Amy M.; Watson, Michael S.] Amer Coll Med Genet & Genom, Bethesda, MD USA. [Cakici, Julie A.; Kingsmore, Stephen F.] Rady Childrens Inst Genom Med, San Diego, CA USA. [Chan, Kee] Univ Illinois, Chicago Sch Publ Hlth, Chicago, IL USA. [Chen, Flavia; Risch, Neil] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Harris-Wai, Julie] Univ Calif San Francisco, Inst Hlth & Aging, San Francisco, CA USA. [Joseph, Galen] Univ Calif San Francisco, Dept Anthropol Hist & Social Med, San Francisco, CA USA. [Kwok, Pui-Yan] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA USA. [Kwok, Pui-Yan] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Shieh, Joseph T.] Univ Calif San Francisco, Dept Pediat, Benioff Childrens Hosp, San Francisco, CA USA. [Puck, Jennifer M.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Currier, Robert J.] Calif Dept Publ Hlth, Genet Dis Screening Program, Sacramento, CA USA. [Dukhovny, Dmitry] Oregon Hlth & Sci Univ, Dept Pediat, 3181 Sw Sam Jackson Pk Rd, Portland, OR 97201 USA. [Dukhovny, Dmitry] Oregon Hlth & Sci Univ, Dept Neonatol, Portland, OR 97201 USA. [Iglesias, Brenda; Wise, Anastasia L.] NIH, Natl Human Genome Res Inst, Bldg 10, Bethesda, MD 20892 USA. [Urv, Tiina] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Lantos, John; Leeder, Steven J.] Childrens Mercy Hosp, Dept Pediat, Kansas City, MO 64108 USA. [McGuire, Amy L.; Pereira, Stacey] Baylor Coll Med, Ctr Med Eth & Hlth Policy, Houston, TX 77030 USA. [Mooney, Sean D.] Univ Washington, Seattle, WA 98195 USA. RP Berg, JS (reprint author), Univ North Carolina Chapel Hill, Dept Genet, 120 Mason Farm Rd, Chapel Hill, NC 27599 USA. EM jonathan_berg@med.unc.edu FU National Institute of Health [1U19HD077693, 1U19HD077632, 1U19HD077627, 1U19HD077671]; Newborn Screening Translational Research Network [HHSN275201300011C]; National Institutes of Health (NIH) FX Supported by National Institute of Health grants 1U19HD077693, 1U19HD077632, 1U19HD077627, and 1U19HD077671. Newborn Screening Translational Research Network is funded through a contract from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HHSN275201300011C). Funded by the National Institutes of Health (NIH). NR 62 TC 0 Z9 0 U1 2 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD FEB PY 2017 VL 139 IS 2 AR e20162252 DI 10.1542/peds.2016-2252 PG 13 WC Pediatrics SC Pediatrics GA EJ2JC UT WOS:000393035100054 ER PT J AU Yeung, EH Sundaram, R Ghassabian, A Xie, YL Louis, GB AF Yeung, Edwina H. Sundaram, Rajeshwari Ghassabian, Akhgar Xie, Yunlong Louis, Germaine Buck TI Parental Obesity and Early Childhood Development SO PEDIATRICS LA English DT Article ID BODY-MASS INDEX; MATERNAL PREPREGNANCY OVERWEIGHT; GESTATIONAL WEIGHT-GAIN; PATERNAL OBESITY; UPSTATE KIDS; BIRTH COHORT; CHILDRENS DEVELOPMENT; COGNITION; RISK; NEURODEVELOPMENT AB BACKGROUND: Previous studies identified associations between maternal obesity and childhood neurodevelopment, but few examined paternal obesity despite potentially distinct genetic/epigenetic effects related to developmental programming. METHODS: Upstate KIDS (2008-2010) recruited mothers from New York State (excluding New York City) at similar to 4 months postpartum. Parents completed the Ages and Stages Questionnaire (ASQ) when their children were 4, 8, 12, 18, 24, 30, and 36 months of age corrected for gestation. The ASQ is validated to screen for delays in 5 developmental domains (ie, fine motor, gross motor, communication, personal-social functioning, and problem-solving ability). Analyses included 3759 singletons and 1062 nonrelated twins with >= 1 ASQs returned. Adjusted odds ratios (aORs) and 95% confidence intervals were estimated by using generalized linear mixed models accounting for maternal covariates (ie, age, race, education, insurance, marital status, parity, and pregnancy smoking). RESULTS: Compared with normal/underweight mothers (BMI < 25), children of obese mothers (26% with BMI >= 30) had increased odds of failing the fine motor domain (aOR 1.67; confidence interval 1.12-2.47). The association remained after additional adjustment for paternal BMI (1.67; 1.11-2.52). Paternal obesity (29%) was associated with increased risk of failing the personal-social domain (1.75; 1.13-2.71), albeit attenuated after adjustment for maternal obesity (aOR 1.71; 1.08-2.70). Children whose parents both had BMI >= 35 were likely to additionally fail the problem-solving domain (2.93; 1.09-7.85). CONCLUSIONS: Findings suggest that maternal and paternal obesity are each associated with specific delays in early childhood development, emphasizing the importance of family information when screening child development. C1 [Yeung, Edwina H.; Ghassabian, Akhgar] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth, 6710B Rockledge Dr,Rm 3122,MSC 7004, Rockville, MD 20817 USA. [Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth, Rockville, MD USA. [Xie, Yunlong] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Glotech Inc, Div Intramural Populat Hlth, Rockville, MD USA. [Louis, Germaine Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Off Director, Rockville, MD USA. RP Yeung, EH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth, 6710B Rockledge Dr,Rm 3122,MSC 7004, Rockville, MD 20817 USA. EM yeungedw@mail.nih.gov OI Buck Louis, Germaine/0000-0002-1774-4490; Yeung, Edwina/0000-0002-3851-2613; Sundaram, Rajeshwari/0000-0002-6918-5002 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275201200005C, HHSN267200700019C]; National Institutes of Health (NIH) FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts HHSN275201200005C, HHSN267200700019C). The sponsor played no role in the study design, data collection, data analysis or interpretation, writing of the manuscript, or the decision to submit the article for publication. Funded by the National Institutes of Health (NIH). NR 46 TC 0 Z9 0 U1 10 U2 10 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD FEB PY 2017 VL 139 IS 2 AR e20161459 DI 10.1542/peds.2016-1459 PG 10 WC Pediatrics SC Pediatrics GA EJ2JC UT WOS:000393035100006 ER PT J AU Ballard, ED Cwik, M Van Eck, K Goldstein, M Alfes, C Wilson, ME Virden, JM Horowitz, LM Wilcox, HC AF Ballard, Elizabeth D. Cwik, Mary Van Eck, Kathryn Goldstein, Mitchell Alfes, Clarissa Wilson, Mary Ellen Virden, Jane M. Horowitz, Lisa M. Wilcox, Holly C. TI Identification of At-Risk Youth by Suicide Screening in a Pediatric Emergency Department SO PREVENTION SCIENCE LA English DT Article DE Suicide; Emergency department; Screening; Pediatrics ID DELIBERATE SELF-HARM; ADOLESCENT SUICIDE; CARE; PREVENTION; VISITS; CHILDREN; BEHAVIOR; TRENDS; NURSES; TRIAL AB The pediatric emergency department (ED) is a critical location for the identification of children and adolescents at risk for suicide. Screening instruments that can be easily incorporated into clinical practice in EDs to identify and intervene with patients at increased suicide risk is a promising suicide prevention strategy and patient safety objective. This study is a retrospective review of the implementation of a brief suicide screen for pediatric psychiatric ED patients as standard of care. The Ask Suicide Screening Questions (ASQ) was implemented in an urban pediatric ED for patients with psychiatric presenting complaints. Nursing compliance rates, identification of at-risk patients, and sensitivity for repeated ED visits were evaluated using medical records from 970 patients. The ASQ was implemented with a compliance rate of 79 %. Fifty-three percent of the patients who screened positive (237/448) did not present to the ED with suicide-related complaints. These identified patients were more likely to be male, African American, and have externalizing behavior diagnoses. The ASQ demonstrated a sensitivity of 93 % and specificity of 43 % to predict return ED visits with suicide-related presenting complaints within 6 months of the index visit. Brief suicide screening instruments can be incorporated into standard of care in pediatric ED settings. Such screens can identify patients who do not directly report suicide-related presenting complaints at triage and who may be at particular risk for future suicidal behavior. Results have the potential to inform suicide prevention strategies in pediatric EDs. C1 [Ballard, Elizabeth D.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bldg 10,CRC Room 7-3345,MSC 1282, Bethesda, MD 20892 USA. [Cwik, Mary; Alfes, Clarissa; Wilcox, Holly C.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Cwik, Mary] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Amer Indian Hlth, Baltimore, MD USA. [Van Eck, Kathryn; Wilcox, Holly C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Van Eck, Kathryn; Goldstein, Mitchell] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Wilson, Mary Ellen; Virden, Jane M.] Johns Hopkins Univ Hosp, Pediat Emergency Dept, Baltimore, MD 21287 USA. [Horowitz, Lisa M.] NIMH, Off Clin Director, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ballard, ED (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bldg 10,CRC Room 7-3345,MSC 1282, Bethesda, MD 20892 USA. EM Elizabeth.Ballard@nih.gov FU Garrett Lee Smith grant from the Substance Abuse and Mental Health Services Administration (SAMHSA) [U79SM061751] FX This study was supported in part by an award from the Garrett Lee Smith grant U79SM061751 from the Substance Abuse and Mental Health Services Administration (SAMHSA). The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. NR 38 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 EI 1573-6695 J9 PREV SCI JI Prev. Sci. PD FEB PY 2017 VL 18 IS 2 BP 174 EP 182 DI 10.1007/s11121-016-0717-5 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ6CI UT WOS:000393305700005 PM 27678381 ER PT J AU Hill, MJ Royster, GD Taneja, M Healy, MW Zarek, SM Christy, AY DeCherney, AH Widra, E Devine, K AF Hill, Micah J. Royster, G. Donald Taneja, Mansi Healy, Mae Wu Zarek, Shvetha M. Christy, Alicia Y. DeCherney, Alan H. Widra, Eric Devine, Kate TI Does elevated progesterone on day of oocyte maturation play a role in the racial disparities in IVF outcomes? SO REPRODUCTIVE BIOMEDICINE ONLINE LA English DT Article DE ART outcomes; ethnicity; racial disparity; serum progesterone level ID IN-VITRO FERTILIZATION; PREGNANCY RATES; WHITE WOMEN; PARENTAL CONSANGUINITY; BLASTOCYST TRANSFERS; ETHNIC-DIFFERENCES; UTERINE LEIOMYOMA; AFRICAN-AMERICAN; EMBRYO-TRANSFER; CYCLES AB The aim of this study was to evaluate if premature progesterone elevation on the last day of assisted reproduction technique stimulation contributes to racial disparities in IVF outcome. A total of 3289 assisted reproduction technique cycles were evaluated in Latino, Asian, African American, and white women. Live birth was more likely in white women (42.6%) compared with Asian (34.8%) and African American women (36.3%), but was similar to Latino women (40.7%). In all racial groups, progesterone was negatively associated with live birth and the negative effect of progesterone persisted when adjusting for confounders. Although the effect of elevated progesterone was similar in all racial groups, the prevalence of elevated progesterone differed. Progesterone > 1.5 ng/ml occurred in only 10.6% of cycles in white women compared with 18.0% in Latino and 20.2% in Asian women. Progesterone > 2 ng/ml occurred in only 2.3% of cycles in white women compared with 6.3% in Latino, 5.9% in Asian and 4.4% in African American women. The increased prevalence of premature elevated progesterone persisted when controlling for IVF stimulation parameters. In conclusion, premature progesterone elevation had a negative effect on live birth in all racial groups studied. The prevalence of elevated progesterone was higher in racial minorities. Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd. C1 [Hill, Micah J.; Royster, G. Donald; Healy, Mae Wu; Zarek, Shvetha M.; Christy, Alicia Y.; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Taneja, Mansi] Inova Fairfax Hosp, Fairfax, VA USA. [Widra, Eric; Devine, Kate] Shady Grove Fertil Sci Ctr, Rockville, MD USA. RP Hill, MJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. EM hillmicah@mail.nih.gov OI Hill, Micah/0000-0002-3104-7763 FU Intramural NIH HHS [Z99 HD999999] NR 35 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1472-6483 EI 1472-6491 J9 REPROD BIOMED ONLINE JI Reprod. Biomed. Online PD FEB PY 2017 VL 34 IS 2 BP 154 EP 161 DI 10.1016/j.rbmo.2016.11.002 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EJ4FB UT WOS:000393171200005 PM 27887992 ER PT J AU Xu, ZZ Zhen, BG Park, Y Zhu, B AF Xu, Zhenzhen Zhen, Boguang Park, Yongsoek Zhu, Bin TI Designing therapeutic cancer vaccine trials with delayed treatment effect SO STATISTICS IN MEDICINE LA English DT Article DE delayed treatment effect; therapeutic cancer vaccine; cancer immunotherapy; sample size and power calculation; non-proportional hazard assumption; cancer clinical trial ID COMPLEX CLINICAL-TRIALS; SAMPLE-SIZE CALCULATION; CENSORED SURVIVAL-DATA; LOG-RANK TEST; END-POINTS; TIME-LAG; IMMUNOTHERAPY; EVENT; TESTS; POWER AB Arming the immune system against cancer has emerged as a powerful tool in oncology during recent years. Instead of poisoning a tumor or destroying it with radiation, therapeutic cancer vaccine, a type of cancer immunotherapy, unleashes the immune system to combat cancer. This indirect mechanism-of-action of vaccines poses the possibility of a delayed onset of clinical effect, which results in a delayed separation of survival curves between the experimental and control groups in therapeutic cancer vaccine trials with time-to-event endpoints. This violates the proportional hazard assumption. As a result, the conventional study design based on the regular log-rank test ignoring the delayed effect would lead to a loss of power. In this paper, we propose two innovative approaches for sample size and power calculation using the piecewise weighted log-rank test to properly and efficiently incorporate the delayed effect into the study design. Both theoretical derivations and empirical studies demonstrate that the proposed methods, accounting for the delayed effect, can reduce sample size dramatically while achieving the target power relative to a standard practice. Copyright (C) 2016 John Wiley & Sons, Ltd. C1 [Xu, Zhenzhen; Zhen, Boguang] US FDA, CBER, Silver Spring, MD 20993 USA. [Park, Yongsoek] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15260 USA. [Zhu, Bin] NCI, DCEG, Bethesda, MD 20892 USA. RP Xu, ZZ (reprint author), US FDA, CBER, Silver Spring, MD 20993 USA. EM Zhenzhen.Xu@fda.hhs.gov NR 22 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD FEB PY 2017 VL 36 IS 4 BP 592 EP 605 DI 10.1002/sim.7157 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA EJ6BV UT WOS:000393304400003 PM 27807870 ER PT J AU Gomperts, ED Schwartz, J Donfield, SM Lail, AE Astermark, J Hoots, WK Winkler, CA Berntorp, E AF Gomperts, Edward D. Schwartz, John Donfield, Sharyne M. Lail, Alice E. Astermark, Jan Hoots, W. Keith Winkler, Cheryl A. Berntorp, Erik TI y The importance of genetic factors for the development of arthropathy: a longitudinal study of children and adolescents with haemophilia A SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Genetics; haemophilia; haemarthrosis; joint range of motion; arthritis ID GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; JOINT DISEASE; PSORIATIC-ARTHRITIS; IN-VITRO; PROPHYLAXIS; SUSCEPTIBILITY; IRON; PATHOGENESIS; METAANALYSIS AB Haemophilia A is a congenital bleeding disorder characterised by recurrent haemorrhages into the major joints. Haemophilic arthropathy is a well-established outcome of recurrent joint bleeding; however, it is clear that multiple factors determine the extent and severity of its occurrence. We sought to identify genetic factors related to abnormalities in range of motion (ROM) in the knees, ankles and elbows in a cohort of children and adolescents with haemophilia A not treated primarily with regular prophylaxis. Using data from the Haemophilia Growth and Development Study, we examined associations between 13,342 genetic markers and ROM scores measured at six-month intervals for up to seven years. As a first step, ordered logistic regression models were fit for each joint separately. A subset of SNP markers showing significant effects (p<0.01) on the right and left sides for at least two joints were included in a full model fit using a multivariate generalised linear mixed model assuming an ordinal response. The models contained all ROM scores obtained at all visits. Twenty-five markers analysed in the full model showed either increased or decreased risk of ROM abnormalities at the p<0.001 level. Several genes identified at either the first or second stage of the analysis have been associated with arthritis in a variety of large studies. Our results support the likelihood that risk for haemophilic arthropathy is associated with genetic factors, the identification of which holds promise for further advancing the individualisation of treatment. C1 [Gomperts, Edward D.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Gomperts, Edward D.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Schwartz, John; Donfield, Sharyne M.; Lail, Alice E.] Rho Inc, Dept Biostat, Chapel Hill, NC USA. [Astermark, Jan; Berntorp, Erik] Lund Univ, Ctr Thrombosis & Haemostasis, Malmo, Sweden. [Hoots, W. Keith] NHLBI, Div Blood Dis & Resources, NIH, Bldg 10, Bethesda, MD 20892 USA. [Winkler, Cheryl A.] NCI, Basic Res Lab, Ctr Canc Res, NIH,Leidos Biomed Res Inc,Frederick Natl Lab Canc, Frederick, MD 21701 USA. RP Gomperts, ED (reprint author), Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90033 USA.; Gomperts, ED (reprint author), Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. EM EGomperts@chla.usc.edu FU National Institutes of Health, National Institute of Child Health and Human Development [R01-HD-41224]; Lund University, Centre for Thrombosis and Haemostasis, Sickle University Hospital Malmo/Lund, Malmo, Sweden; Baxter BioScience; NIH National Cancer Institute (NCI) [HHSN261200800001E]; Intramural Research Program of the NIH-NCI Center for Cancer Research FX This work is supported by the National Institutes of Health, National Institute of Child Health and Human Development, R01-HD-41224; by the Lund University, Centre for Thrombosis and Haemostasis, Sickle University Hospital Malmo/Lund, Malmo, Sweden; by an investigator-initiated grant from Baxter BioScience; and in part with federal funds from the NIH National Cancer Institute (NCI) under Contract No. HHSN261200800001E, and the Intramural Research Program of the NIH-NCI Center for Cancer Research. NR 42 TC 0 Z9 0 U1 2 U2 2 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD FEB PY 2017 VL 117 IS 2 BP 277 EP 285 DI 10.1160/TH16-06-0440 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EJ6VU UT WOS:000393358700010 PM 27929201 ER PT J AU Tharmaphornpilas, P Jiamsiri, S Boonchaiya, S Rochanathimoke, O Thinyounyong, W Tuntiwitayapun, S Guntapong, R Riewpaiboon, A Rasdjarmrearnsook, AO Glass, RI AF Tharmaphornpilas, Piyanit Jiamsiri, Suchada Boonchaiya, Somchit Rochanathimoke, Onwipa Thinyounyong, Wiravan Tuntiwitayapun, Sumana Guntapong, Ratigorn Riewpaiboon, Arthorn Rasdjarmrearnsook, Aim-on Glass, Roger I. TI Evaluating the first introduction of rotavirus vaccine in Thailand: Moving from evidence to policy SO VACCINE LA English DT Article DE Rotavirus vaccine; Vaccine effectiveness; Vaccine impact ID POLYMERASE CHAIN-REACTION; DOUBLE-BLIND; GASTROENTERITIS; EFFICACY; INFANTS; SURVEILLANCE; STRAINS; SAFETY; IMPACT; LIFE AB Background: We assessed the effectiveness and possible impact of introducing rotavirus vaccine into the routine immunization program. Methods: Two provinces were selected for an observational study, one where vaccine was introduced and another where vaccine was not available. In these areas, two sub-studies were linked. The prospective cohort study enrolled children 2 month old and followed them to the age of 18 months to detect all diarrhea episodes. The hospital surveillance study enrolled all children up to age 5 hospitalized with diarrhea whose fecal samples were tested for rotavirus. Rates of rotavirus hospitalizations in older children who had not been vaccinated in both settings provided data to determine whether immunization had an indirect herd effect. The key endpoints for the study were both vaccine effectiveness (VE) based upon hospitalized rotavirus diarrhea and herd protection. Findings: From the cohort study, the overall VE for hospitalized rotavirus diarrhea was 88% (95%Cl 76-94). Data from hospital surveillance indicated that for 2 consecutive years, the seasonal peak of rota virus admissions was no longer present in the vaccinated area. Herd protection was observed among older children born before the rotavirus vaccine program was introduced, who experienced a 40-69% reduction in admission for rotavirus. Conclusions: Rotavirus vaccine was highly effective in preventing diarrheal hospitalizations and in conferring herd protection among older children who had not been vaccinated. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Tharmaphornpilas, Piyanit; Jiamsiri, Suchada; Boonchaiya, Somchit; Rasdjarmrearnsook, Aim-on] Minist Publ Hlth, Dept Dis Control, Nonthaburi, Thailand. [Rochanathimoke, Onwipa; Riewpaiboon, Arthorn] Mahidol Univ, Fac Pharm, Bangkok, Thailand. [Thinyounyong, Wiravan] Phetchabun Prov Hlth Off, Phetchabun, Thailand. [Tuntiwitayapun, Sumana] Sukhothai Prov Hlth Off, Sukhothai, Thailand. [Guntapong, Ratigorn] Minist Publ Hlth, Dept Med Sci, Nonthaburi, Thailand. [Glass, Roger I.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Tharmaphornpilas, P (reprint author), Minist Publ Hlth, Dept Dis Control, Muang 11000, Nonthaburi, Thailand. EM piyanit@health.moph.go.th FU Department of Disease Control FX We thank the public health staff of Sukhothai and Phetchabun provinces for their help in collecting field data and following up subjects, the Department of Disease Control for their administrative support. We are grateful to the Ad Hoc Group of Experts on Rotavirus from the Immunization Practice Subcommittee for their valuable suggestions. This study was fully funded by the Department of Disease Control. NR 24 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD FEB 1 PY 2017 VL 35 IS 5 BP 796 EP 801 DI 10.1016/j.vaccine.2016.12.043 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EJ5KS UT WOS:000393257500012 PM 28057385 ER PT J AU Collar, AL Clarke, EC Anaya, E Merrill, D Yarborough, S Anthony, SM Kuhn, JH Merle, C Theisen, M Bradfute, SB AF Collar, Amanda L. Clarke, Elizabeth C. Anaya, Eduardo Merrill, Denise Yarborough, Sarah Anthony, Scott M. Kuhn, Jens H. Merle, Christine Theisen, Manfred Bradfute, Steven B. TI Comparison of N- and O-linked glycosylation patterns of ebolavirus glycoproteins SO VIROLOGY LA English DT Article DE Bundibugyo virus; Ebola virus; Ebolavirus; Filoviridae; Filovirus; Glycan; Glycoprotein; Glycosylation; Sudan virus; Tai Forest virus ID VIRUS GLYCOPROTEIN; PROTECTIVE EFFICACY; MASS-SPECTROMETRY; NONHUMAN-PRIMATES; INSECT CELLS; GLYCANS; PROTEIN; ANTIGENICITY; REPLICATION; FILOVIRUSES AB Ebolaviruses are emerging pathogens that cause severe and often fatal viral hemorrhagic fevers. Four distinct ebolaviruses are known to cause Ebola virus disease in humans. The ebolavirus envelope glycoprotein (GP(1,2)) is heavily glycosylated, but the precise glycosylation patterns of ebolaviruses are largely unknown. Here we demonstrate that approximately 50 different N-glycan structures are present in GP(1,2) derived from the four pathogenic ebolaviruses, including high mannose, hybrid, and bi-, tri-, and tetra-antennary complex glycans with and without fucose and sialic acid. The overall N-glycan composition is similar between the different ebolavirus GP(1,2)s. In contrast, the amount and type of O-glycan structures varies widely between ebolavirus GP(1,2)s. Notably, this O-glycan dissimilarity is also present between two variants of Ebola virus, the original Yambuku variant and the Makona variant responsible for the most recent Western African epidemic. The data presented here should serve as the foundation for future ebolaviral entry and immunogenicity studies. C1 [Collar, Amanda L.; Clarke, Elizabeth C.; Merrill, Denise; Bradfute, Steven B.] Univ New Mexico, Dept Internal Med, Div Infect Dis, Ctr Global Hlth, Albuquerque, NM 87131 USA. [Anaya, Eduardo] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Yarborough, Sarah] Univ New Mexico, Undergrad Pipeline Network, Albuquerque, NM 87131 USA. [Anthony, Scott M.] Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, Div Clin Res, NIH, Frederick, MD USA. [Merle, Christine; Theisen, Manfred] Proteodynam SARL, Riom, France. RP Bradfute, SB (reprint author), Univ New Mexico, Internal Med MSC10 5550, Albuquerque, NM 87131 USA. EM sbradfute@salud.unm.edu FU Defense Threat Reduction Agency [HDTRA1-15-1-0061]; Battelle Memorial Institute's prime; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I] FX We thank Laura Bollinger (IRF-Frederick) for critically editing this paper. The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the US Department of Health and Human Services, or of the institutions and companies affiliated with the authors. This project was supported by Defense Threat Reduction Agency grant HDTRA1-15-1-0061 (S.B.B.). The content of the information does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred. This work was also supported in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016I. A subcontractor to Battelle Memorial Institute who performed this work is: J.H.K., an employee of Tunnell Government Services, Inc. NR 28 TC 0 Z9 0 U1 4 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB PY 2017 VL 502 BP 39 EP 47 DI 10.1016/j.virol.2016.12.010 PG 9 WC Virology SC Virology GA EJ5OQ UT WOS:000393268000006 PM 27984785 ER PT J AU Gallagher, JR Torian, U McCraw, DM Harris, AK AF Gallagher, John R. Torian, Udana McCraw, Dustin M. Harris, Audray K. TI Characterization of the disassembly and reassembly of the HBV glycoprotein surface antigen, a pliable nanoparticle vaccine platform SO VIROLOGY LA English DT Article DE Glycoprotein nanoparticles; Virus structure; Vaccines; Assembly; Disassembly; Reassembly; Electron microscopy; Tomography; HBV surface antigen ID VIRUS-LIKE PARTICLES; HEPATITIS-B VACCINES; CAPSID PROTEIN; CRYOELECTRON MICROSCOPY; AUSTRALIA-ANTIGEN; IN-VITRO; HEMAGGLUTININ; RECOMBINANT; TOMOGRAPHY; VIRIONS AB While nanoparticle vaccine technology is gaining interest due to the success of vaccines like those for the human papillomavirus that is based on viral capsid nanoparticles, little information is available on the disassembly and reassembly of viral surface glycoprotein-based nanoparticles. One such particle is the hepatitis B virus surface antigen (sAg) that exists as nanoparticles. Here we show, using biochemical analysis coupled with electron microscopy, that sAg nanoparticle disassembly requires both reducing agent to disrupt intermolecular disulfide bonds, and detergent to disrupt hydrophobic interactions that stabilize the nanoparticle. Particles were otherwise resistant to salt and urea, suggesting the driving mechanism of particle formation involves hydrophobic interactions. We reassembled isolated sAg protein into nanoparticles by detergent removal and reassembly resulted in a wider distribution of particle diameters. Knowledge of these driving forces of nanoparticle assembly and stability should facilitate construction of epitope-displaying nanoparticles that can be used as immunogens in vaccines. C1 [Gallagher, John R.; Torian, Udana; McCraw, Dustin M.; Harris, Audray K.] NIAID, Infect Dis Lab, NIH, 50 South Dr,Room 6351, Bethesda, MD 20892 USA. RP Harris, AK (reprint author), NIAID, Infect Dis Lab, NIH, 50 South Dr,Room 6351, Bethesda, MD 20892 USA. EM harrisau@mail.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI001180] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (Grant number: AI001180). We thank Dennis Winkler (NIAMS, NIH) for aid with electron microscopy data collection and Paul Wingfield (NIAMS, NIH) for providing the reagent of the recombinant surface antigen (sAg) from yeast. NR 53 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB PY 2017 VL 502 BP 176 EP 187 DI 10.1016/j.virol.2016.12.025 PG 12 WC Virology SC Virology GA EJ5OQ UT WOS:000393268000021 PM 28061386 ER PT J AU Dimopoulos, A Sicko, RJ Kay, DM Rigler, SL Fan, R Romitti, PA Browne, ML Druschel, CM Caggana, M Brody, LC Mills, JL AF Dimopoulos, Aggeliki Sicko, Robert J. Kay, Denise M. Rigler, Shannon L. Fan, Ruzong Romitti, Paul A. Browne, Marilyn L. Druschel, Charlotte M. Caggana, Michele Brody, Lawrence C. Mills, James L. TI Copy number variants in a population-based investigation of Klippel-Trenaunay syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE angiogenesis; chromatin modification; copy number variant; DNMT3A; HDAC9; ING5; Klippel-Trenaunay syndrome; SALL3 ID BODY-MASS INDEX; WEBER-SYNDROME; MOLECULAR CHARACTERIZATION; CAPILLARY MALFORMATION; DEFECTS; GENE; IDENTIFICATION; ANGIOGENESIS; METHYLATION; OVERGROWTH AB Klippel-Trenaunay syndrome (KTS) is a rare congenital vascular disorder that is thought to occur sporadically; however, reports of familial occurrence suggest a genetic component. We examined KTS cases to identify novel, potentially causal copy number variants (CNVs). We identified 17 KTS cases from all live-births occurring in New York (1998-2010). Extracted DNA was genotyped using Illumina microarrays and CNVs were called using PennCNV software. CNVs selected for follow-up had 10 single nucleotide polymorphisms (SNPs) and minimal overlap with in-house controls or controls from the Database of Genomic Variants. We identified 15 candidate CNVs in seven cases; among them a deletion in two cases within transcripts of HDAC9, a histone deacetylase essential for angiogenic sprouting of endothelial cells. One of them also had a duplication upstream of SALL3, a transcription factor essential for embryonic development that inhibits DNMT3A, a DNA methyltransferase responsible for embryonic de novo DNA methylation. Another case had a duplication spanning ING5, a histone acetylation regulator active during embryogenesis. We identified rare genetic variants related to chromatin modification which may have a key role in regulating vascular development during embryogenesis. Further investigation of their implications in the pathogenesis of KTS is warranted. (c) 2016 Wiley Periodicals, Inc. C1 [Dimopoulos, Aggeliki; Rigler, Shannon L.; Fan, Ruzong; Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Rm 7B03R,MSC 7510, Bethesda, MD 20892 USA. [Sicko, Robert J.; Kay, Denise M.; Caggana, Michele] New York State Dept Hlth, Wadsworth Ctr, Div Genet, Albany, NY USA. [Romitti, Paul A.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Browne, Marilyn L.; Druschel, Charlotte M.] New York State Dept Hlth, Congenital Malformat Registry, Albany, NY USA. [Browne, Marilyn L.; Druschel, Charlotte M.] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Rensselaer, NY USA. [Brody, Lawrence C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Mills, JL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Rm 7B03R,MSC 7510, Bethesda, MD 20892 USA. EM jamesmills@nih.gov FU Intramural Research Program of the National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275201100001I, HHSN27500005]; NICHD [1-DK-73431] FX Grant sponsor: Intramural Research Program of the National Institutes of Health; Grant sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development; Grant numbers: HHSN275201100001I, HHSN27500005; Grant sponsor: NICHD; Grant number: 1-DK-73431. NR 49 TC 1 Z9 1 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 FEB PY 2017 VL 173 IS 2 BP 352 EP 359 DI 10.1002/ajmg.a.37868 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA EJ4OD UT WOS:000393195800011 PM 27901321 ER PT J AU Ferreira, CR Devaney, JM Hofherr, SE Pollard, LM Cusmano-Ozog, K AF Ferreira, Carlos R. Devaney, Joseph M. Hofherr, Sean E. Pollard, Laura M. Cusmano-Ozog, Kristina TI Hereditary fructose intolerance mimicking a biochemical phenotype of mucolipidosis: A review of the literature of secondary causes of lysosomal enzyme activity elevation in serum SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE hereditary fructose intolerance; mucolipidosis; lysosomal enzyme activity; transferrin isoelectric focusing ID BETA-N-ACETYLGLUCOSAMINIDASE; ALPHA-L-FUCOSIDASE; VIRUS-INFECTED PATIENTS; ACID-HYDROLASES; D-MANNOSIDASE; GLUCURONIDASE ACTIVITY; METABOLIC CONTROL; GAUCHERS-DISEASE; CYSTIC-FIBROSIS; GRAVES-DISEASE AB We describe a patient with failure to thrive, hepatomegaly, liver dysfunction, and elevation of multiple plasma lysosomal enzyme activities mimicking mucolipidosis II or III, in whom a diagnosis of hereditary fructose intolerance (HFI) was ultimately obtained. She presented before introduction of solid foods, given her consumption of a fructose-containing infant formula. We present the most extensive panel of lysosomal enzyme activities reported to date in a patient with HFI, and propose that multiple enzyme elevations in plasma, especially when in conjunction with a normal plasma -mannosidase activity, should elicit a differential diagnosis of HFI. We also performed a review of the literature on the different etiologies of elevated lysosomal enzyme activities in serum or plasma. (c) 2016 Wiley Periodicals, Inc. C1 [Ferreira, Carlos R.] NHGRI, NIH, Bethesda, MD 20892 USA. [Ferreira, Carlos R.; Cusmano-Ozog, Kristina] Childrens Natl Hlth Syst, Div Genet & Metab, Washington, DC USA. [Devaney, Joseph M.; Hofherr, Sean E.; Cusmano-Ozog, Kristina] Childrens Natl Hlth Syst, Div Lab Med, Washington, DC USA. [Pollard, Laura M.] Greenwood Genet Ctr, Biochem Genet Lab, Greenwood, SC 29646 USA. RP Ferreira, CR (reprint author), NHGRI, 10 Ctr Dr,Bldg 10,Room 5D38, Bethesda, MD 20892 USA. EM ferreiracr@mail.nih.gov NR 55 TC 1 Z9 1 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 FEB PY 2017 VL 173 IS 2 BP 501 EP 509 DI 10.1002/ajmg.a.38023 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EJ4OD UT WOS:000393195800029 PM 27797444 ER PT J AU Baker, EH Levin, SW Zhang, Z Mukherjee, AB AF Baker, E. H. Levin, S. W. Zhang, Z. Mukherjee, A. B. TI MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID MOUSE MODEL; DISEASE; SPECTROSCOPY; ASPARTATE; GENETICS; INCL; NCL AB BACKGROUND AND PURPOSE: Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase 1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood death. As part of a project studying the treatment benefits of a combination of cysteamine bitartrate and N-acetyl cysteine, we made serial measurements of patients' brain volumes with MR imaging. MATERIALS AND METHODS: Ten patients with infantile neuronal ceroid lipofuscinosis participating in a treatment/follow-up study underwent brain MR imaging that included high-resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brain stem, and thalamus. Patients' brain volumes were compared with those of a healthy population. RESULTS: Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss and may never have been normal postnatally. The thalamus dropped out of the normal range around 6 months of age; the cerebellum, around 2 years of age; and the brain stem, around 3 years of age. CONCLUSIONS: Rapid cerebral volume loss was expected on the basis of previous qualitative reports. Because our study did not include a nontreatment arm and because progression of brain volumes in infantile neuronal ceroid lipofuscinosis has not been previously quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions. C1 [Baker, E. H.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. [Levin, S. W.; Zhang, Z.; Mukherjee, A. B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Endocrinol & Mol Genet, NIH, Bethesda, MD USA. RP Baker, EH (reprint author), NIH, Dept Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. EM bakere@mail.nih.gov OI Mukherjee, Anil B./0000-0003-4445-5464 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [01-CH-0086] FX This research was supported in full by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (protocol 01-CH-0086). Healthy volunteers were studied under protocols 89-M-0006 and 11-M-0144. NR 25 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD FEB PY 2017 VL 38 IS 2 BP 376 EP 382 DI 10.3174/ajnr.A4978 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EJ4EQ UT WOS:000393170100032 PM 27765741 ER PT J AU Jimmerson, LC Clayton, CW MaWhinney, S Meissner, EG Sims, Z Kottilil, S Kiser, JJ AF Jimmerson, Leah C. Clayton, Carolyn W. MaWhinney, Samantha Meissner, Eric G. Sims, Zayani Kottilil, Shyamasundaran Kiser, Jennifer J. TI Effects of ribavirin/sofosbuvir treatment and ITPA phenotype on endogenous purines SO ANTIVIRAL RESEARCH LA English DT Article DE Ribavirin triphosphate; Anemia; ITPA activity; Adenosine triphosphate; Guanosine triphosphate; Inosine triphosphate ID CHRONIC HEPATITIS-C; RIBAVIRIN-INDUCED ANEMIA; INDUCED HEMOLYTIC-ANEMIA; HUMAN-ERYTHROCYTES; PLUS RIBAVIRIN; VIRUS-INFECTION; GENE PROTECT; BONE-MARROW; THERAPY; HCV AB Ribavirin (RBV), a purine analog, causes hemolytic anemia in some patients. In vitro, anemia appears to result from depletion of endogenous purines, but there are limited data in vivo. Single nucleotide polymorphisms in the gene encoding the inosine triphosphatase (ITPA) enzyme have been associated with protection against RBV-induced anemia and may mediate the effect of RBV treatment on endogenous purines. The purpose of this work was to determine the effect of RBV treatment on endogenous purine concentrations in individuals being treated for chronic hepatitis C virus (HCV) infection. Adenosine triphosphate (ATP), guanosine triphosphate (GTP), inosine triphosphate (ITP) and ribavirin triphosphate (RTP) were measured in whole blood obtained from 47 HCV-infected individuals at day zero (baseline), day three, day 28 and day 84 of RBV/sofosbuvir (SOF) treatment. ATP decreased -35.1% and -38.6% (p < 0.0001) at day 28 and day 84 of treatment, respectively compared to baseline. The decrease in ATP was greater in patients with <= 60% ITPA activity compared to those with 100% ITPA activity (-29.4% vs. -9.6%). GTP did not change during treatment but was 16.5% (p = 0.01) higher per 100 pmol/10(6) cells RTP in those with 100% ITPA activity. No significant change or effect of RTP or ITPA phenotype was noted for ITP. In summary, only ATP was reduced by RBV/SOF treatment and ITPA variants had larger reductions in ATP suggesting RBV-induced anemia is due to a different mechanism than predicted from in-vitro studies. These data emphasize the importance of characterizing the effect of nucleos(t)ide analog treatment on endogenous purines in-vivo. (C) 2016 Published by Elsevier B.V. C1 [Jimmerson, Leah C.; Kiser, Jennifer J.] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Anschutz Med Campus,12850 Montview Blvd,V20 C238, Aurora, CO 80045 USA. [Clayton, Carolyn W.; MaWhinney, Samantha] Univ Colorado, Sch Publ Hlth Aurora, Aurora, CO USA. [Meissner, Eric G.; Sims, Zayani; Kottilil, Shyamasundaran] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD USA. [Meissner, Eric G.] Med Univ South Carolina, Div Infect Dis, Dept Microbiol & Immunol, Charleston, SC USA. [Kottilil, Shyamasundaran] Univ Maryland, Inst Human Virol, Div Clin Care & Res, Baltimore, MD 21201 USA. RP Kiser, JJ (reprint author), Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Anschutz Med Campus,12850 Montview Blvd,V20 C238, Aurora, CO 80045 USA. EM Jennifer.kiser@ucdenver.edu FU International Maternal Pediatric Adolescent AIDS Clinical Trials Network [UM1AI068632]; Colorado Clinical Translational Sciences Institute [1UL1 RR025780]; [R03 DK096121] FX This work was supported by R03 DK096121 (JJK), the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (UM1AI068632 to JJK), and the Colorado Clinical Translational Sciences Institute (1UL1 RR025780). NR 42 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD FEB PY 2017 VL 138 BP 79 EP 85 DI 10.1016/j.antiviral.2016.12.005 PG 7 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA EJ1ZE UT WOS:000393008400010 PM 27956135 ER PT J AU Moran, LM Phillips, KA Kowalczyk, WJ Ghitza, UE Agage, DA Epstein, DH Preston, KL AF Moran, Landhing M. Phillips, Karran A. Kowalczyk, William J. Ghitza, Udi E. Agage, Daniel A. Epstein, David H. Preston, Kenzie L. TI Aripiprazole for cocaine abstinence: a randomized-controlled trial with ecological momentary assessment SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE cocaine; D2 partial agonists; ecological momentary assessment; human; relapse prevention ID DISCRIMINATIVE-STIMULUS; D-AMPHETAMINE; HUMANS; RELAPSE; DRUG; METHAMPHETAMINE; REINSTATEMENT; MODEL AB Aripiprazole blocks psychostimulant seeking in a rat model of relapse. However, in humans, it may increase ongoing use. We tested aripiprazole specifically for relapse prevention. Methadone-maintained outpatients who were abstinent from cocaine in weeks 11-12 were randomized to double-blind aripiprazole (15 mg daily) or placebo in weeks 13-27 after 12 weeks of contingency management. Participants reported craving through ecological momentary assessment. We stopped the trial because very few (18/41) participants fulfilled the abstinence criterion. The results suggested that aripiprazole delayed lapse [hazard ratio (HR)= 0.45, 95% confidence interval (CI) = 0.14-1.42, P = 0.17] and relapse (HR = 0.31, 95% CI = 0.07-1.27, P = 0.10), but the effects did not reach statistical significance. Unexpectedly, the proportion of participants reporting cocaine craving was higher in the aripiprazole group (Fisher's exact P = 0.026), although the frequency of craving was similar in the aripiprazole and placebo groups (1.89 vs. 1.16%, r(effect) = 0.43, 95% CI = -0.08-0.76). The results suggest that in recently abstinent cocaine users, aripiprazole might delay relapse, but might also slightly increase craving. Difficulty in trial implementation underscores the fact that initial abstinence from cocaine is not a trivial hurdle. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved. C1 [Moran, Landhing M.; Phillips, Karran A.; Kowalczyk, William J.; Agage, Daniel A.; Epstein, David H.; Preston, Kenzie L.] NIDA, Clin Pharmacol & Therapeut Res Branch, Bethesda, MD 20892 USA. [Ghitza, Udi E.] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. RP Preston, KL (reprint author), NIDA, Intramural Res Program, Treatment Sect, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM kpreston@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse FX Support for this study was provided by the Intramural Research Program of the National Institute on Drug Abuse. NR 23 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0955-8810 EI 1473-5849 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD FEB PY 2017 VL 28 IS 1 BP 63 EP 73 DI 10.1097/FBP.0000000000000268 PG 11 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA EI9IY UT WOS:000392822600007 PM 27755017 ER PT J AU Slezak, JM Desai, RI Katz, JL AF Slezak, Jonathan M. Desai, Rajeev I. Katz, Jonathan L. TI Further delineation between typical and atypical dopamine uptake inhibitors: effects on food-maintained behavior and food consumption SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE AHN 1-055; atypical dopamine transport inhibitors; benztropine analogs; cocaine; 4-Cl-BZT; food intake; GBR 12909; JHW 007; progressive-ratio schedule; rat ID PROGRESSIVE-RATIO PERFORMANCE; NUCLEUS-ACCUMBENS; FEEDING-BEHAVIOR; JHW 007; COCAINE; ANALOGS; AMPHETAMINE; DRUGS; SCHEDULE; FENFLURAMINE AB The present studies compared the acute effects of benztropine analogs (4-Cl-BZT, JHW 007, AHN 1-055), which are atypical dopamine uptake inhibitors, with those of the standard dopamine uptake inhibitors GBR 12909 and cocaine, on the reinforcing efficacy of food and food intake in male Sprague-Dawley rats. Repeated drug effects of JHW 007 on food intake were also determined. The number of ratios completed under a progressive-ratio schedule of food delivery was used as an index of reinforcing efficacy. Food intake was determined by measuring powdered laboratory-chow consumption during daily 40 min food-availability time periods. Under the progressive-ratio schedule, cocaine and GBR 12909 dose-dependently increased the number of ratios completed. JHW 007 decreased ratios completed, whereas neither 4-Cl-BZT nor AHN 1-055 increased ratios completed with a magnitude that approximated any of the increases produced by cocaine or GBR 12909. Acute administration of each drug dose-dependently decreased food intake; however, the benztropine analogs were more potent than cocaine and GBR 12909. A reduction in food intake emerged after repeated administration of a low dose of JHW 007. Future studies that compare JHW 007 with standard anorectic drugs (e.g. phentermine) and continue investigation of the repeated drug effects under similar experimental procedures are clearly warranted. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved. C1 [Slezak, Jonathan M.] Mt St Marys Univ, Dept Psychol, Emmitsburg, MD USA. [Desai, Rajeev I.; Katz, Jonathan L.] NIDA, Psychobiol Sect, Mol Neuropsychiat Res Branch, Intramural Res Program,NIH, Baltimore, MD USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 FU Intramural Research Program of the National Institute on Drug Abuse; NIH/NIDA/IRP FX The authors thank Maryann Carrigan for administrative assistance and Bettye Campbell for expert technical assistance. This study was supported by the Intramural Research Program of the National Institute on Drug Abuse. The compounds reported here were synthesized by Jianjing Cao in the Medicinal Chemistry Section of the NIDA Intramural Research Program.; This study was funded by NIH/NIDA/IRP. NR 35 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0955-8810 EI 1473-5849 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD FEB PY 2017 VL 28 IS 1 BP 74 EP 82 DI 10.1097/FBP.0000000000000278 PG 9 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA EI9IY UT WOS:000392822600008 PM 27926573 ER PT J AU Battiwalla, M Tichelli, A Majhail, NS AF Battiwalla, Minoo Tichelli, Andre Majhail, Navneet S. TI Long-Term Survivorship after Hematopoietic Cell Transplantation: Roadmap for Research and Care SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Review DE National Institutes of Health consensus; Late effects; Hematopoietic cell transplantation; Review Educational; 2017; Survivorship ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; POPULATION-BASED COHORT; CONSENSUS DEVELOPMENT PROJECT; CONGESTIVE-HEART-FAILURE; ACUTE MYELOID-LEUKEMIA; LYMPHOPROLIFERATIVE DISORDERS; INFECTIOUS COMPLICATIONS; MYELODYSPLASTIC SYNDROME; CLINICAL-TRIALS AB The number of survivors after hematopoietic cell transplantation (HCT) is expected to dramatically increase over the next decade. Significant and unique challenges confront survivors for decades after their underlying indication (malignancy or marrow failure) has been cured by HCT. The National Institutes of Health (NIH) Late Effects Consensus Conference in June 2016 brought together international experts in the field to plan the next phase of survivorship efforts. Working groups laid out the roadmap for collaborative research and health care delivery. Potentially lethal late effects (cardiac/vascular, subsequent neoplasms, and infectious), patient centered outcomes, health care delivery, and research methodology are highlighted here. Important recommendations from the NIH Consensus Conference provide fresh perspectives for the future. As HCT evolves into a safer and higher-volume procedure, this marks a time for concerted action to ensure that no survivor is left behind. Published by Elsevier Inc. on behalf of the American Society for Blood and Marrow Transplantation. C1 [Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Tichelli, Andre] Univ Hosp, Hematol, Basel, Switzerland. [Majhail, Navneet S.] Cleveland Clin, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA. RP Battiwalla, M (reprint author), NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bldg 10 CRC,Room 5-3581,10 Ctr Dr MSC 1202, Bethesda, MD 20892 USA. EM minoo.battiwalla@nih.gov FU Division of Intramural Research, NHLBI, NIH FX This research was supported by the Division of Intramural Research, NHLBI, NIH. NR 110 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2017 VL 23 IS 2 BP 184 EP 192 DI 10.1016/j.bbmt.2016.11.004 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EJ0JK UT WOS:000392894300003 PM 27818318 ER PT J AU Armenian, SH Chemaitilly, W Chen, M Chow, EJ Duncan, CN Jones, LW Pulsipher, MA Remaley, AT Rovo, A Salooja, N Battiwalla, M AF Armenian, Saro H. Chemaitilly, Wassim Chen, Marcus Chow, Eric J. Duncan, Christine N. Jones, Lee W. Pulsipher, Michael A. Remaley, Alan T. Rovo, Alicia Salooja, Nina Battiwalla, Minoo TI National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Cardiovascular Disease and Associated Risk Factors Working Group Report SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE National Institutes of Health consensus; Late effects; Hematopoietic cell transplantation; Cardiovascular disease; Cardiovascular risk factors; Chronic disease; Survivorship ID BONE-MARROW-TRANSPLANTATION; LONG-TERM SURVIVORS; IMPAIRED GLUCOSE-TOLERANCE; AMERICAN-HEART-ASSOCIATION; VERSUS-HOST-DISEASE; VENTRICULAR EJECTION FRACTION; ACUTE LYMPHOBLASTIC-LEUKEMIA; CHILDHOOD-CANCER-SURVIVOR; TOTAL-BODY IRRADIATION; HIGH BLOOD-PRESSURE AB A number of studies have shown that autologous and allogeneic hematopoietic cell transplantation (HCT) contribute to an increased incidence of cardiovascular disease (CVD) and worsening of cardiovascular risk factors that could contribute to further CVD over time. These observations, combined with a notable increase in the number of survivors after HCT in recent years, highlight the need for studies aimed at modifying risk or preventing these outcomes by changing specific approaches and/or post-HCT interventions. To address these issues, the National Heart, Lung and Blood Institute and National Cancer Institute co-sponsored an international initiative on late effects after HCT. This report summarizes the major gaps in knowledge along with detailed recommendations regarding study priorities from the Cardiovascular Disease and Associated Risk Factors Committee, a multidisciplinary panel of international experts. The committee calls for specific studies aimed at understanding and preventing arterial disease and cardiac dysfunction (heart failure, valvular disease, and arrhythmias), as well as decreasing cardiovascular risk factors (hypertension, hyperglycemia, dyslipidemia, and sarcopenic obesity) after HCT. (C) 2017 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. C1 [Armenian, Saro H.] City Hope Natl Med Ctr, Dept Populat Sci, Duarte, CA USA. [Chemaitilly, Wassim] St Jude Childrens Res Hosp, Pediat Med Dept, 332 N Lauderdale St, Memphis, TN 38105 USA. [Chen, Marcus; Remaley, Alan T.] NHLBI, Cardiovasc & Pulm Branch, Bldg 10, Bethesda, MD 20892 USA. [Chow, Eric J.] Fred Hutchinson Canc Res Ctr, Clin Res & Publ Hlth Sci Div, 1124 Columbia St, Seattle, WA 98104 USA. [Duncan, Christine N.] Dana Farber Canc Inst, Pediat Stem Cell Transplant Ctr, Boston, MA 02115 USA. [Jones, Lee W.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Pulsipher, Michael A.] Childrens Hosp Los Angeles, Childrens Ctr Canc & Blood Dis, Los Angeles, CA 90027 USA. [Rovo, Alicia] Univ Hosp Bern, Dept Hematol, Bern, Switzerland. [Salooja, Nina] Imperial Coll London, Dept Med, London, England. [Battiwalla, Minoo] NHLBI, Hematopoiet Transplantat Sect, Bldg 10, Bethesda, MD 20892 USA. RP Armenian, SH (reprint author), City Hope Natl Med Ctr, Ctr Comprehens Canc, 1500 East Duarte Rd, Duarte, CA 91010 USA. EM sarmenian@coh.org FU National Heart, Lung and Blood Institute (NHLBI); National Cancer Institute (NCI) FX This initiative was sponsored jointly by the National Heart, Lung and Blood Institute (NHLBI) and National Cancer Institute (NCI). NR 108 TC 2 Z9 2 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2017 VL 23 IS 2 BP 201 EP 210 DI 10.1016/j.bbmt.2016.08.019 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EJ0JK UT WOS:000392894300005 PM 27590105 ER PT J AU Cooke, KR Luznik, L Sarantopoulos, S Hakim, FT Jagasia, M Fowler, DH van den Brink, MRM Hansen, JA Parkman, R Miklos, DB Martin, PJ Paczesny, S Vogelsang, G Pavletic, S Ritz, J Schultz, KR Blazar, BR AF Cooke, Kenneth R. Luznik, Leo Sarantopoulos, Stefanie Hakim, Frances T. Jagasia, Madan Fowler, Daniel H. van den Brink, Marcel R. M. Hansen, John A. Parkman, Robertson Miklos, David B. Martin, Paul J. Paczesny, Sophie Vogelsang, Georgia Pavletic, Steven Ritz, Jerome Schultz, Kirk R. Blazar, Bruce R. TI The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; Blood and marrow transplantation; lmmune mechanisms; Clinical manifestations ID STEM-CELL TRANSPLANTATION; REGULATORY T-CELLS; BONE-MARROW-TRANSPLANTATION; MINOR HISTOCOMPATIBILITY ANTIGENS; BRONCHIOLITIS OBLITERANS SYNDROME; NECROSIS-FACTOR-ALPHA; IDIOPATHIC-PNEUMONIA-SYNDROME; WORKING GROUP-REPORT; NONINFECTIOUS PULMONARY COMPLICATIONS; SYSTEMIC-LUPUS-ERYTHEMATOSUS AB Chronic graft-versus-host disease (GVHD) is the leading cause of late, nonrelapse mortality and disability in allogeneic hematopoietic cell transplantation recipients and a major obstacle to improving outcomes. The biology of chronic GVHD remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: Summarize the current state of the science regarding pathogenic mechanisms of chronic GVHD and critical knowledge gaps. Develop Working hypotheses overriding concepts for chronic GVHD development. Define the usefulness of current preclinical models to test working hypotheses and ultimately discover and develop new therapeutic strategies. Identify shortcomings of preclinical models, and define criteria for the creation of additional models to address these limitations. This document is intended as a review of our understanding of chronic GVHD biology and therapies resulting from preclinical studies, and as a platform for developing innovative clinical strategies to prevent and treat chronic GVHD. Published by Elsevier Inc. on behalf of the American Society for Blood and Marrow Transplantation. C1 [Cooke, Kenneth R.; Luznik, Leo; Vogelsang, Georgia] Johns Hopkins Univ Hosp, Dept Oncol, Sidney Kimmel Canc Ctr, Baltimore, MD 21287 USA. [Sarantopoulos, Stefanie] Duke Univ, Div Hematol Malignancies & Cellular Therapy, Dept Immunol, Durham, NC USA. [Sarantopoulos, Stefanie] Duke Univ, Duke Canc Inst, Durham, NC USA. [Hakim, Frances T.; Fowler, Daniel H.; Pavletic, Steven] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Jagasia, Madan] Vanderbilt Univ, Dept Med, Med Ctr, Div Hematol Oncol, Nashville, TN USA. [van den Brink, Marcel R. M.] Mem Sloan Kettering Canc Ctr, Dept Immunol, New York, NY 10021 USA. [van den Brink, Marcel R. M.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Hansen, John A.; Martin, Paul J.] Univ Washington, Dept Med, Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA USA. [Parkman, Robertson] Stanford Univ, Div Pediat Stem Cell Transplantat & Regenerat Med, Palo Alto, CA 94304 USA. [Miklos, David B.] Stanford Univ, Div Blood & Marrow Transplantat, Palo Alto, CA 94304 USA. [Paczesny, Sophie] Indiana Univ Sch Med, Wells Ctr Pediat Res, Dept Pediat, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46202 USA. [Paczesny, Sophie] Indiana Univ Sch Med, Wells Ctr Pediat Res, Dept Immunol, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46202 USA. [Ritz, Jerome] Harvard Med Sch, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA USA. [Schultz, Kirk R.] Univ British Columbia, Dept Pediat, Michael Cuccione Childhood Canc Res Program, BC Childrens Hosp, Vancouver, BC, Canada. [Blazar, Bruce R.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. RP Cooke, KR (reprint author), Johns Hopkins Univ Hosp, Dept Oncol, Sidney Kimmel Canc Ctr, Baltimore, MD 21287 USA.; Schultz, KR (reprint author), Univ British Columbia, Dept Pediat, Michael Cuccione Childhood Canc Res Program, BC Childrens Hosp, Vancouver, BC, Canada.; Blazar, BR (reprint author), Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA.; Blazar, BR (reprint author), Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. EM kcooke5@jhmi.edu; kschultz@mail.ubc.ca; blaza001@umn.edu FU Office of Rare Disease Research, National Center for Advancing Translational Sciences; National Institute of Allergy and Infectious Diseases, Division of Allergy Immunology and Transplantation; National Heart Lung and Blood Institute, Division of Blood Diseases and Resources; Leukemia and Lymphoma Society of America; Meredith A. Cowden Foundation; National Institutes of Health's National Cancer Institute, Center for Cancer Research; Intramural Research Program and Division of Cancer Treatment and Diagnosis; Cancer Therapy Evaluation Program FX This work was supported by the National Institutes of Health's National Cancer Institute, Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research, National Center for Advancing Translational Sciences; National Institute of Allergy and Infectious Diseases, Division of Allergy Immunology and Transplantation; National Heart Lung and Blood Institute, Division of Blood Diseases and Resources; the Leukemia and Lymphoma Society of America; and the Meredith A. Cowden Foundation. The opinions expressed here are those of the authors and do not represent the official position of the National Institutes of Health, the National Cancer Institute, or the United States Government. NR 336 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2017 VL 23 IS 2 BP 211 EP 234 DI 10.1016/j.bbmt.2016.09.023 PG 24 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EJ0JK UT WOS:000392894300006 PM 27713092 ER PT J AU Karnieli, O Friedner, OM Allickson, JG Zhang, N Jung, S Fiorentini, D Abraham, E Eaker, SS Yong, TK Chan, A Griffiths, S When, AK Oh, S Karnieli, O AF Karnieli, Ohad Friedner, Oryan Makler Allickson, Julie G. Zhang, Nan Jung, Sunghoon Fiorentini, David Abraham, Eytan Eaker, Shannon S. Yong, Tan Kah Chan, Allan Griffiths, Sarah When, Amy K. Oh, Steve Karnieli, Ohad TI A consensus introduction to serum replacements and serum-free media for cellular therapies SO CYTOTHERAPY LA English DT Review DE serum replacement; serum free; defined media; cell therapy; animal component free; platelet lysate; cGMP media; fetal bovine serum; human serum; xeno free ID MESENCHYMAL STEM-CELLS; FETAL BOVINE SERUM; HUMAN PLATELET LYSATE; STROMAL CELLS; ADOPTIVE IMMUNOTHERAPY; CLINICAL-TRIALS; CULTURE-MEDIA; ANIMAL SERUM; IN-VITRO; T-CELLS AB The cell therapy industry is a fast-growing industry targeted toward a myriad of clinical indications. As the cell therapy industry matures and clinical trials hit their pivotal Phase 3 studies, there will be a significant need for scale-up, process validation, and critical raw material quality assurance. Part of the well discussed challenges of upscaling manufacturing processes there is a less discussed issue relating to the availability of raw materials in the needed quality and quantities. The FDA recently noted that over 80% of the 66 investigational new drug (IND) applications for mesenchymal stem cell (MSC) products analyzed described the use of FBS during manufacturing. Accumulated data from the past years show an acceleration in serum consumption by at least 10%-15% annually, which suggests that the global demand for serum may soon exceed the supply. Ongoing concerns of safety issues due to risks of various pathogen contaminations, as well as issues related to the aforementioned serum variability that can affect final product reproducibility, are strong motivators to search for serum substitutes or serum-free media. it is important to note that there are no accepted definitions for most of these terms which leads to misleading's and misunderstandings, where the same term might be defined differently by different vendors, manufacturer, and users. It is the drug developer's responsibility to clarify what the supplied labels mean and to identify the correct questions and audits to ensure quality. The paper reviews the available serum replacements, main components, basic strategies for replacement of serum and suggests definitions. C1 [Karnieli, Ohad; Karnieli, Ohad] Karnieli Ltd & ATVIO Biotech, 57 Tamar St, IL-36015 Ticon, Israel. [Karnieli, Ohad; Karnieli, Ohad] ATVIO Biotech, 57 Tamar St, IL-36015 Ticon, Israel. [Friedner, Oryan Makler] Pluristem Therapeut, Matam Pk, Haifa, Israel. [Allickson, Julie G.] Wake Forest Univ, Bowman Gray Sch Med, Wake Forest Inst Regenerat Med, Regenerat Med Clin Ctr, Winston Salem, NC 27109 USA. [Zhang, Nan] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Jung, Sunghoon; Abraham, Eytan] Cell Therapy Res & Technol Lonza Walkersville, Walkersville, MD USA. [Fiorentini, David] Biol Ind Ltd, Beit Haemek, Israel. [Eaker, Shannon S.] GE Healthcare Cell Therapy Div, Marlborough, MA USA. [Yong, Tan Kah; Chan, Allan; Oh, Steve] Bioproc Technol Inst, Singapore, Singapore. [Griffiths, Sarah] Stimlabs, Roswell, GA USA. [When, Amy K.] Irvine Sci, Santa Ana, CA USA. RP Karnieli, O (reprint author), Karnieli Ltd & ATVIO Biotech, 57 Tamar St, IL-36015 Ticon, Israel.; Karnieli, O (reprint author), ATVIO Biotech, 57 Tamar St, IL-36015 Ticon, Israel. EM Ohad@karnieli.com NR 55 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD FEB PY 2017 VL 19 IS 2 BP 155 EP 169 DI 10.1016/j.icyt.2016.11.011 PG 15 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA EJ0HZ UT WOS:000392890500001 PM 28017599 ER PT J AU Nogare, DD Nikaido, M Somers, K Head, J Piotrowski, T Chitnis, AB AF Nogare, Damian Dalle Nikaido, Masataka Somers, Katherine Head, Jeffery Piotrowski, Tatjana Chitnis, Ajay B. TI In toto imaging of the migrating Zebrafish lateral line primordium at single cell resolution SO DEVELOPMENTAL BIOLOGY LA English DT Article ID WNT/BETA-CATENIN; EXPRESSION; SYSTEM; MORPHOGENESIS; NEUROMASTS; EMBRYOS; ORGAN; MICE; GLIA AB The zebrafish Posterior Lateral Line primordium (PLLp) has emerged as an important model system for studying many aspects of development, including cell migration, cell type specification and tissue morphogenesis. Despite this, basic aspects of PLLp biology remain incompletely understood. The PLLp is a group of approximately 140 cells which pioneers the formation of the Posterior Lateral Line (LL) system by migrating along the length of the embryo, periodically depositing clusters of epithelial cells, which will go on to form the mature sense organs of the lateral line, called neuromasts. The neuromasts are formed within the migrating PLLp as protoneuromasts: the first protoneuromast is formed close to the trailing end and additional protoneuromasts are formed sequentially, progressively closer to the leading edge of the migrating collective. We imaged the migration of PLL primordia and tracked every cell in the lateral line system over the course of migration. From this data set we unambiguously determined the lineage and fate of every cell deposited by the migrating PLLp. We show that, on average, proliferation across the entire PLLp is weakly patterned, with leading cells tending to divide more slowly than trailing cells. Neuromasts are formed sequentially by local expansion of existing cells along the length of the PLLp, not by self-renewing stem cell-like divisions of a restricted leading population that is highly proliferative. The fate of deposited cells, either within neuromasts or as intemeuromast cells (in between deposited neuromasts) is not determined by any obvious stereotyped lineages. Instead, it is determined somewhat stochasitcailly, as a function of a cells distance from the center of a maturing protoneuromast. Together, our data provide a rigorous baseline for the behavior of the PLLp, which can be used to inform further study of this important model system. C1 [Nogare, Damian Dalle; Somers, Katherine; Head, Jeffery; Chitnis, Ajay B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Nikaido, Masataka; Piotrowski, Tatjana] Stowers Inst Med Res, Kansas City, MO 64110 USA. [Nikaido, Masataka] Univ Hyogo, Grad Sch Life Sci, Kobe, Hyogo, Japan. RP Nogare, DD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM dalledam@mail.nih.gov FU Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) [HD001012] FX This work was supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) [HD001012] and by institutional support from the Stowers Institute for Medical Research. This work was performed under animal study protocol numbers 15-039 (DDN, KS, JH, and ABC) and 2014-0129 (MN and TP). NR 26 TC 0 Z9 0 U1 5 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD FEB 1 PY 2017 VL 422 IS 1 BP 14 EP 23 DI 10.1016/j.ydbio.2016.12.015 PG 10 WC Developmental Biology SC Developmental Biology GA EJ0NG UT WOS:000392905700003 PM 27965055 ER PT J AU Downward, GS Hu, W Rothman, N Reiss, B Tromp, P Wu, GP Wei, FS Xu, J Seow, WJ Chapman, RS Lan, Q Vermeulen, R AF Downward, George S. Hu, Wei Rothman, Nat Reiss, Boris Tromp, Peter Wu, Guoping Wei, Fusheng Xu, Jun Seow, Wei Jie Chapman, Robert S. Lan, Qing Vermeulen, Roel TI Quartz in ash, and air in a high lung cancer incidence area in China SO ENVIRONMENTAL POLLUTION LA English DT Article DE Solid fuels; Quartz; Household air pollution; Lung cancer ID POLYCYCLIC AROMATIC-HYDROCARBONS; COAL COMBUSTION EMISSIONS; XUAN-WEI; RETROSPECTIVE COHORT; CURRENT PROGRESS; FUYUAN COUNTIES; RISK; EXPOSURE; POLLUTION; MORTALITY AB Exposure to crystalline silica (quartz) has been implicated as a potential cause of the high lung cancer rates in the neighbouring counties of Xuanwei and Fuyuan, China, where the domestic combustion of locally sourced "smoky" coal (a bituminous coal) is responsible for some of the highest lung cancer rates in the nation, irrespective of gender or smoking status. Previous studies have shown that smoky coal contains approximately twice as much quartz when compared to alternative fuels in the area, although it is unclear how the quartz in coal relates to household air pollution. Samples of ash and fine particulate matter (PM2.5) were collected from 163 households and analysed for quartz content by Fourier transformed infrared spectroscopy (FT-IR). Additionally, air samples from 12 further households, were analysed by scanning electron microscopy (SEM) to evaluate particle structure and silica content. The majority (89%) of household air samples had undetectable quartz levels (<0.2 mu g/m(3)) with no clear differences by fuel-type. SEM analyses indicated that there were higher amounts of silica in the smoke of smoky coal than smokeless coal (0.27 mu g/m(3) vs. 0.03 mu g/m(3)). We also identified fibre-like particles in a higher concentration within the smoke of smoky coal than smokeless coal (5800 fibres/m(3) vs. 550 fibres/m(3)). Ash analysis suggested that the bulk of the quartz in smoky coal went on to form part of the ash. These findings indicate that the quartz within smoky coal does not become adequately airborne during the combustion process to cause significant lung cancer risk, instead going on to form part of the ash. The identification of fibre-like particles in air samples is an interesting finding, although the clinical relevance of this finding remains unclear. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Downward, George S.; Reiss, Boris; Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, Utrecht, Netherlands. [Hu, Wei; Rothman, Nat; Seow, Wei Jie; Lan, Qing] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Tromp, Peter] TNO, Netherlands Org Appl Res, Utrecht, Netherlands. [Wu, Guoping; Wei, Fusheng] China Natl Environm Monitoring Ctr, Beijing, Peoples R China. [Xu, Jun] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Chapman, Robert S.] Chulalongkorn Univ, Coll Publ Hlth Sci, Bangkok, Thailand. RP Downward, GS (reprint author), Univ Utrecht, Inst Risk Assessment Sci, Yalelaan 2, NL-3584 CM Utrecht, Netherlands. EM g.s.downward@uu.nl FU National Institutes of Health [HHSN261201400122P] FX This project was supported by the National Institutes of Health intramural research program (HHSN261201400122P). 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. The authors would like to acknowledge Johan Beekhuizen and Meng Wang from the Institute for Risk Assessment Sciences, Utrecht University for their support in the production of Fig. 1; David Large, of the Department of Chemical and Environmental Engineering, University of Nottingham, for the analysis and interpretation of mineral structures within coal samples; and RPS Analyse by, The Netherlands for their work in analysing ash and air samples. NR 25 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0269-7491 EI 1873-6424 J9 ENVIRON POLLUT JI Environ. Pollut. PD FEB PY 2017 VL 221 BP 318 EP 325 DI 10.1016/j.envpol.2016.11.081 PG 8 WC Environmental Sciences SC Environmental Sciences & Ecology GA EI8OV UT WOS:000392767900032 PM 27939206 ER PT J AU Beachler, DC Tota, JE Silver, MI Kreimer, AR Hildesheim, A Wentzensen, N Schiffman, M Shiels, MS AF Beachler, Daniel C. Tota, Joseph E. Silver, Michelle I. Kreimer, Aimee R. Hildesheim, Allan Wentzensen, Nicolas Schiffman, Mark Shiels, Meredith S. TI Trends in cervical cancer incidence in younger US women from 2000 to 2013 SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Cervical cancer; Screening; Pap test; SEER; Epidemiology ID UNITED-STATES; HUMAN-PAPILLOMAVIRUS; POPULATION; GUIDELINES; NEOPLASIA; SOCIETY AB Objective. This study aimed to assess the temporal trends in invasive cervical cancer (ICC) incidence rates among 21-25 year-olds. US guidelines no longer recommend screening prior to age 21, and concerns have been raised that delayed screening initiation may increase ICC incidence among young women. Methods. This study utilized ICC incidence data from 18 US population-based cancer registries in SEER from 2000 to 2013 and Pap test prevalence data from the Behavioral Risk Factor Surveillance System from 1996 to 2012. Trends were evaluated with annual percent changes (APCs) using Joinpoint regression. Results. The prevalence of never having a Pap test before age 21 increased from 22.0% in 1996-2004 to 38.3% in 2006-2012 (APC = +5.48, 95%CI = +4.20, +7.50). Despite this decline in screening, ICC incidence among 21-23 year olds significantly declined between 2000 and 13 (APC = -5.36, 95%CI = -7.83,-2.82), particularly from 2006 to 2013 (APC = -9.70, 95%CI = -15.79, -3.17). ICC incidence remained constant among 24-25 year olds (APC = +0.45, 95%CI = -2.00, 2.97). Compared to women born in 1978-1985, women born in 1986-1991 had a higher prevalence of never receiving a Pap test prior to 21 (35.4% vs. 22.1%, p < 0.001), but a lower ICC incidence at 21-23 (0.98 vs. 1.55 per 100,000, p < 0.001). Conclusion. While US females born in 1986-1991 were less likely to receive a Pap test before age 21, diagnoses of ICC in the early 20s were rare and lower than for those born in earlier years. This provides reassurance that the updated guidelines to delay screening until 21 has not resulted in a population-level increase in ICC rates among young women. Published by Elsevier Inc. C1 [Beachler, Daniel C.; Tota, Joseph E.; Silver, Michelle I.; Kreimer, Aimee R.; Hildesheim, Allan; Wentzensen, Nicolas; Schiffman, Mark; Shiels, Meredith S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Beachler, DC (reprint author), NCI, 9609 Med Ctr Dr,RM 6-E220, Bethesda, MD 20892 USA. EM daniel.beachler@nih.gov FU Intramural Research Program of the National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. NR 26 TC 1 Z9 1 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2017 VL 144 IS 2 BP 391 EP 395 DI 10.1016/j.ygyno.2016.11.031 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA EJ0FY UT WOS:000392885200030 PM 27894752 ER PT J AU Contrera, KJ Betz, J Deal, J Choi, JS Ayonayon, HN Harris, T Helzner, E Martin, KR Mehta, K Pratt, S Rubin, SM Satterfield, S Yaffe, K Simonsick, EM Lin, FR AF Contrera, Kevin J. Betz, Josh Deal, Jennifer Choi, Janet S. Ayonayon, Hilsa N. Harris, Tamara Helzner, Elizabeth Martin, Kathryn R. Mehta, Kala Pratt, Sheila Rubin, Susan M. Satterfield, Suzanne Yaffe, Kristine Simonsick, Eleanor M. Lin, Frank R. CA Hlth ABC Study TI Association of Hearing Impairment and Anxiety in Older Adults SO JOURNAL OF AGING AND HEALTH LA English DT Article DE hearing; anxiety; mental health; geriatrics ID NUTRITION EXAMINATION SURVEY; OF-THE-LITERATURE; PHYSICAL FUNCTION; BODY-COMPOSITION; NATIONAL-HEALTH; LOSS PREVALENCE; UNITED-STATES; RISK-FACTORS; US ADULTS; DEPRESSION AB Objective: The objective of the study is was investigate the association between hearing impairment and anxiety. Method: We conducted a cross-sectional analysis of 1,732 community-based adults aged 76 to 85 years who participated in the Health Aging and Body Composition (ABC) study. Logistic regression models were adjusted for demographic and cardiovascular risk factors. Hearing impairment was defined by the speech-frequency pure tone average. Anxiety was defined as reporting two symptoms of at least a little or one symptom quite a bit on the three-item Hopkins Symptom Checklist. Results: Compared with individuals with no hearing impairment, the odds of prevalent anxiety were higher among individuals with mild hearing impairment (odds ratio [OR] = 1.32, 95% confidence interval [CI] = [1.01, 1.73]) and moderate or greater hearing impairment (OR = 1.59, 95% CI = [1.14, 2.22]). Hearing aid use was not significantly associated with lower odds of anxiety. Discussion: Hearing impairment is independently associated with greater odds of anxiety symptoms in older adults. C1 [Contrera, Kevin J.; Betz, Josh; Deal, Jennifer; Choi, Janet S.; Pratt, Sheila; Lin, Frank R.] Johns Hopkins Univ, Baltimore, MD USA. [Ayonayon, Hilsa N.; Rubin, Susan M.; Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Harris, Tamara; Simonsick, Eleanor M.] NIA, Baltimore, MD 21224 USA. [Helzner, Elizabeth] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Martin, Kathryn R.] Sch Med & Dent, Inst Appl Hlth Sci, Aberdeen, Scotland. [Mehta, Kala; Pratt, Sheila] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. RP Lin, FR (reprint author), Johns Hopkins Univ, Johns Hopkins Ctr Aging & Hlth, 2024 E Monument St,Suite 2-700, Baltimore, MD 21205 USA. EM flin1@jhmi.edu OI Betz, Joshua/0000-0003-4488-9799 FU Eleanor Schwartz Charitable Foundation; Triological Society/American College of Surgeons Clinician Scientist Award; Johns Hopkins Institute for Clinical and Translational Research; National Institutes of Health (NIH) [K23DC011279, TL1 TR001078]; National Institute on Aging (NIA) [R01-AG028050, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institute of Nursing Research [R01-NR012459]; NIH Intramural Research Program FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This article was supported in part by the Eleanor Schwartz Charitable Foundation; a Triological Society/American College of Surgeons Clinician Scientist Award; the Johns Hopkins Institute for Clinical and Translational Research; the National Institutes of Health (NIH; Grant Numbers K23DC011279, TL1 TR001078); the National Institute on Aging (NIA; Grant Number R01-AG028050, and Contract Numbers N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106); National Institute of Nursing Research (Grant Number R01-NR012459); and the NIH Intramural Research Program. NR 39 TC 0 Z9 0 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0898-2643 EI 1552-6887 J9 J AGING HEALTH JI J. Aging Health PD FEB PY 2017 VL 29 IS 1 BP 172 EP 184 DI 10.1177/0898264316634571 PG 13 WC Gerontology; Health Policy & Services SC Geriatrics & Gerontology; Health Care Sciences & Services GA EI9ZR UT WOS:000392868600008 ER PT J AU Ko, D Rahman, F Martins, MAP Hylek, EM Ellinor, PT Schnabel, RB Benjamin, EJ Christophersen, IE AF Ko, Darae Rahman, Faisal Martins, Maria A. P. Hylek, Elaine M. Ellinor, Patrick T. Schnabel, Renate B. Benjamin, Emelia J. Christophersen, Ingrid E. TI Atrial fibrillation in women: treatment SO NATURE REVIEWS CARDIOLOGY LA English DT Review ID ACUTE MYOCARDIAL-INFARCTION; GENDER-RELATED DIFFERENCES; RANDOMIZED CONTROLLED-TRIALS; SEX-RELATED DIFFERENCES; ORAL ANTICOAGULANT USE; VITAMIN-K ANTAGONISTS; STABLE INR CONTROL; CATHETER ABLATION; STROKE PREVENTION; ISCHEMIC-STROKE AB Sex-specific differences in the epidemiology, pathophysiology, presentation, prognosis, and treatment of atrial fibrillation (AF) are increasingly recognized. Women with AF generally experience worse symptoms, poorer quality of life, and have higher risk of stroke and death than men with AF. Effective treatment of the arrhythmia in women is critical to reduce the rate of adverse events. We review the current evidence on sex-specific differences in the utilization and outcomes of treatments for AF, including rate-control and rhythm-control strategies, and stroke-prevention therapy. In addition, we provide a critical evaluation of potential disparities and biases in health-care use that might be associated with differences in the outcomes between women and men. We underscore current knowledge gaps that need to be addressed in future studies to improve the management of AF in women. In particular, we suggest several strategies to produce high-quality evidence from randomized clinical trials for women with AF. C1 [Ellinor, Patrick T.; Christophersen, Ingrid E.] Harvard Med Sch, Cardiac Arrhythmia Serv, 55 Fruit St, Boston, MA 02114 USA. [Ellinor, Patrick T.; Christophersen, Ingrid E.] Harvard Med Sch, Cardiovasc Res Ctr, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [Ko, Darae; Rahman, Faisal; Hylek, Elaine M.] Boston Univ, Dept Internal Med, Boston Med Ctr, Sch Med, 72 East Concord St, Boston, MA 02118 USA. [Martins, Maria A. P.] Univ Fed Minas Gerais, Dept Prod Farmaceut, Fac Farm, Av Pres Antonio Carlos,6627 Pampulha, BR-31270901 Belo Horizonte, MG, Brazil. [Martins, Maria A. P.; Benjamin, Emelia J.] Boston Univ, 73 Mt Wayte Ave, Framingham, MA 01702 USA. [Martins, Maria A. P.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. [Schnabel, Renate B.] Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Martinistr 52, D-20246 Hamburg, Germany. [Schnabel, Renate B.] DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Kiel Lubeck, D-13347 Berlin, Germany. [Benjamin, Emelia J.] Boston Univ, Boston Med Ctr, Sect Cardiovasc Med, Sch Med, 72 East Concord St, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Boston Med Ctr, Sect Prevent Med, Sch Med, 72 East Concord St, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Dept Epidemiol, Sch Publ Hlth, 715 Albany St, Boston, MA 02118 USA. [Christophersen, Ingrid E.] Baerum Hosp, Vestre Viken Hosp Trust, Dept Med Res, Sogneprest Munthe Kaas Vei 100, N-1346 Gjettum, Norway. RP Christophersen, IE (reprint author), Harvard Med Sch, Cardiac Arrhythmia Serv, 55 Fruit St, Boston, MA 02114 USA.; Christophersen, IE (reprint author), Harvard Med Sch, Cardiovasc Res Ctr, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM ichristophersen@mgh.harvard.edu FU National Heart, Lung, and Blood Institute award [5T32HL007224-38]; NIH Clinical and Translational Science Award programme [UL1-TR000157]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazilian government programme for postdoctorate degree abroad [200639/2015-3]; NCRR/NIH [U54TR001012, KL2RR025770, TL1RR025769, 1R01HL106029-03]; NIH [2RO1HL092577, 1K24HL105780]; AHA [13EIA14220013]; Fondation Leducq [14CVD01]; European Research Council under the European Union's Horizon research and innovation programme [648131]; German Ministry of Research and Education e:Med Systems Medicine programme [BMBF 0IZX1408A]; Deutsche Forschungsgemeinschaft (German Research Foundation) Emmy Noether Program [SCHN 1149/3-1]; NIH/NHLBI [HHSN2682015000011, N01-HC25195, 2R01HL092577, 1R01HL128914]; Research Council of Norway [240149/F20] FX D.K. is supported by the National Heart, Lung, and Blood Institute award 5T32HL007224-38 and the NIH Clinical and Translational Science Award programme UL1-TR000157. M.A.P.M. is supported by the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazilian government programme for postdoctorate degree abroad (grant number 200639/2015-3). E.M.H is supported in part through NCRR/NIH U54TR001012, KL2RR025770, TL1RR025769, and 1R01HL106029-03. P.T. E is supported by grants from the NIH (2RO1HL092577, 1K24HL105780), an Established Investigator Award from the AHA (13EIA14220013), and the Fondation Leducq (14CVD01). R.B.S. is supported by the European Research Council under the European Union's Horizon 2020 research and innovation programme (agreement No 648131), the Junior Research Alliance symAtrial project funded by the German Ministry of Research and Education (BMBF 0IZX1408A) e:Med Systems Medicine programme and by Deutsche Forschungsgemeinschaft (German Research Foundation) Emmy Noether Program SCHN 1149/3-1. E.J.B. is supported in part through NIH/NHLBI HHSN2682015000011, N01-HC25195, 2R01HL092577, and 1R01HL128914. I.E.C. is supported by a mobility grant from the Research Council of Norway (240149/F20). NR 137 TC 0 Z9 0 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 EI 1759-5010 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD FEB PY 2017 VL 14 IS 2 BP 113 EP 124 DI 10.1038/nrcardio.2016.171 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ0KJ UT WOS:000392897000009 PM 27786235 ER PT J AU Aladjem, MI Redon, CE AF Aladjem, Mirit I. Redon, Christophe E. TI Order from clutter: selective interactions at mammalian replication origins SO NATURE REVIEWS GENETICS LA English DT Review ID HBO1 HISTONE ACETYLASE; COMMON FRAGILE SITES; MULTIPLE FUNCTIONAL ELEMENTS; EUKARYOTIC DNA-REPLICATION; MEIER-GORLIN SYNDROME; S-PHASE CHECKPOINT; BETA-GLOBIN LOCUS; BINDING-PROTEIN; HUMAN-CELLS; RECOGNITION COMPLEX AB Mammalian chromosome duplication progresses in a precise order and is subject to constraints that are often relaxed in developmental disorders and malignancies. Molecular information about the regulation of DNA replication at the chromatin level is lacking because protein complexes that initiate replication seem to bind chromatin indiscriminately. High-throughput sequencing and mathematical modelling have yielded detailed genome-wide replication initiation maps. Combining these maps and models with functional genetic analyses suggests that distinct DNA protein interactions at subgroups of replication initiation sites (replication origins) modulate the ubiquitous replication machinery and supports an emerging model that delineates how indiscriminate DNA-binding patterns translate into a consistent, organized replication programme. C1 [Aladjem, Mirit I.; Redon, Christophe E.] NCI, Dev Therapeut Branch, Ctr Canc Res, 37 Convent Dr, Bethesda, MD 20892 USA. RP Aladjem, MI (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, 37 Convent Dr, Bethesda, MD 20892 USA. EM aladjemm@mail.nih.gov FU intramural programme of the Centre for Cancer Research, National Cancer Institute, US National Institutes of Health FX The authors thank H. Fu, K. Utani, S. Jang, J. Murai, F. E. lndig and A. B. Marks for critical reading of the manuscript, and would like to apologize to colleagues whose primary work could not be cited directly owing to space limitations. Work in the authors' laboratory is funded by the intramural programme of the Centre for Cancer Research, National Cancer Institute, US National Institutes of Health. NR 177 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD FEB PY 2017 VL 18 IS 2 BP 101 EP 116 DI 10.1038/nrg.2016.141 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA EJ0NR UT WOS:000392906800008 PM 27867195 ER PT J AU Rivero-Hinojosa, S Kang, S Lobanenkov, VV Zentner, GE AF Rivero-Hinojosa, Samuel Kang, Sungyun Lobanenkov, Victor V. Zentner, Gabriel E. TI Testis-specific transcriptional regulators selectively occupy BORIS-bound CTCF target regions in mouse male germ cells SO SCIENTIFIC REPORTS LA English DT Article ID IMPRINTING CONTROL REGION; RNA-POLYMERASE-II; CPG METHYLATION; X-INACTIVATION; HUMAN SPERM; BINDING; CHROMATIN; GENE; EXPRESSION; INSULATOR AB Despite sharing the same sequence specificity in vitro and in vivo, CCCTC-binding factor (CTCF) and its paralog brother of the regulator of imprinted sites (BORIS) are simultaneously expressed in germ cells. Recently, ChIP-seq analysis revealed two classes of CTCF/BORIS-bound regions: single CTCF target sites (1xCTSes) that are bound by CTCF alone (CTCF-only) or double CTCF target sites (2xCTSes) simultaneously bound by CTCF and BORIS (CTCF&BORIS) or BORIS alone (BORIS-only) in germ cells and in BORIS-positive somatic cancer cells. BORIS-bound regions (CTCF&BORIS and BORIS-only sites) are, on average, enriched for RNA polymerase II (RNAPII) binding and histone retention in mature spermatozoa relative to CTCF-only sites, but little else is known about them. We show that subsets of CTCF&BORIS and BORIS-only sites are occupied by several testis-specific transcriptional regulators (TSTRs) and associated with highly expressed germ cell-specific genes and histone retention in mature spermatozoa. We also demonstrate a physical interaction between BORIS and one of the analyzed TSTRs, TATA-binding protein (TBP)-associated factor 7-like (TAF7L). Our data suggest that CTCF and BORIS cooperate with additional TSTRs to regulate gene expression in developing male gametes and histone retention in mature spermatozoa, potentially priming certain regions of the genome for rapid activation following fertilization. C1 [Rivero-Hinojosa, Samuel; Lobanenkov, Victor V.] NIAID, Mol Pathol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Kang, Sungyun; Zentner, Gabriel E.] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Rivero-Hinojosa, Samuel] Childrens Natl Med Ctr, Ctr Canc & Immunol Res, Washington, DC 20010 USA. RP Zentner, GE (reprint author), Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. EM gzentner@indiana.edu FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Indiana University startup funds FX We thank Drs Dmitry Loukinov, Elena Pugacheva, and Sue Robinson for invaluable practical assistance during the portion of this work carried out in the Lobanenkov lab and members of the Lobanenkov and Zentner labs for helpful comments on the manuscript. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health [to VVL] and Indiana University startup funds [to GEZ]. NR 71 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 1 PY 2017 VL 7 AR 41279 DI 10.1038/srep41279 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ6AB UT WOS:000393299500001 PM 28145452 ER PT J AU Wahl, A Ho, PT Denton, PW Garrett, KL Hudgens, MG Swartz, G O'Neill, C Veronese, F Kashuba, AD Garcia, JV AF Wahl, Angela Ho, Phong T. Denton, Paul W. Garrett, Katy L. Hudgens, Michael G. Swartz, Glenn O'Neill, Cynthia Veronese, Fulvia Kashuba, Angela D. Garcia, J. Victor TI Predicting HIV Pre- exposure Prophylaxis Efficacy for Women using a Preclinical PharmacokineticPharmacodynamic In Vivo Model SO SCIENTIFIC REPORTS LA English DT Article ID HUMANIZED BLT MICE; TENOFOVIR DISOPROXIL FUMARATE; FEMALE REPRODUCTIVE-TRACT; PREEXPOSURE PROPHYLAXIS; POSTEXPOSURE PROPHYLAXIS; MUCOSAL TISSUE; AFRICAN WOMEN; TRANSMISSION; INFECTION; PHARMACOKINETICS AB The efficacy of HIV pre-exposure prophylaxis (PrEP) relies on adherence and may also depend on the route of HIV acquisition. Clinical studies of systemic tenofovir disoproxil fumarate (TDF) PrEP revealed reduced efficacy in women compared to men with similar degrees of adherence. To select the most effective PrEP strategies, preclinical studies are critically needed to establish correlations between drug concentrations (pharmacokinetics [PK]) and protective efficacy (pharmacodynamics [PD]). We utilized an in vivo preclinical model to perform a PK-PD analysis of systemic TDF PrEP for vaginal HIV acquisition. TDF PrEP prevented vaginal HIV acquisition in a dose-dependent manner. PK-PD modeling of tenofovir (TFV) in plasma, female reproductive tract tissue, cervicovaginal lavage fluid and its intracellular metabolite (TFV diphosphate) revealed that TDF PrEP efficacy was best described by plasma TFV levels. When administered at 50 mg/kg, TDF achieved plasma TFV concentrations (370 ng/ml) that closely mimicked those observed in humans and demonstrated the same risk reduction (70%) previously attained in women with high adherence. This PK-PD model mimics the human condition and can be applied to other PrEP approaches and routes of HIV acquisition, accelerating clinical implementation of the most efficacious PrEP strategies. C1 [Wahl, Angela; Ho, Phong T.; Denton, Paul W.; Garcia, J. Victor] Univ North Carolina Chapel Hill, Sch Med, Ctr AIDS Res, Div Infect Dis, Chapel Hill, NC 27599 USA. [Garrett, Katy L.; Kashuba, Angela D.] Univ North Carolina Chapel Hill, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27599 USA. [Hudgens, Michael G.] Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Biostat, Chapel Hill, NC 27599 USA. [Swartz, Glenn; O'Neill, Cynthia] Adv Biosci Labs, Rockville, MD 20850 USA. [Veronese, Fulvia] NIAID, Prevent Sci Program, Div Aids, NIH, Bethesda, MD 20852 USA. [Denton, Paul W.] Aarhus Univ, Dept Clin Med, DK-8200 Aarhus, Denmark. [Denton, Paul W.] Aarhus Univ, Hosp Skejby, Dept Infect Dis Q, DK-8200 Aarhus, Denmark. RP Wahl, A (reprint author), Univ North Carolina Chapel Hill, Sch Med, Ctr AIDS Res, Div Infect Dis, Chapel Hill, NC 27599 USA. EM awahl@med.unc.edu OI Denton, Paul/0000-0003-2458-8147 FU NIH NIAID [P30 AI50410, UNC-14005-002-0145-212, HHSN 272201000001C] FX We thank Drs Leslie Marshall and James Cummins (Prevention Sciences Program, Division of AIDS, NIAID, NIH) for their insight and critical comments throughout this study. We thank Garcia laboratory members and UNC Division of Laboratory Animal Medicine technicians for their assistance. The following materials were obtained through a MTA with the NIH AIDS Research and Reference Reagent Program: pYK-JR-CSF, TZM-bl cells, and TDF. TDF was also provided by Jim Rooney (Gilead Sciences Inc., Foster City, CA). This work was supported by the subcontract UNC-14005-002-0145-212 (AW) under the Prime NIH NIAID Contract HHSN 272201000001C (Advanced Bioscience laboratories) and NIH NIAID grant P30 AI50410 (UNC Center for AIDS Research). NR 39 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 1 PY 2017 VL 7 AR 41098 DI 10.1038/srep41098 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4DH UT WOS:000393165800001 PM 28145472 ER PT J AU Yang, JJ Kitada, R Kochiyama, T Yu, YH Makita, K Araki, Y Wu, JL Sadato, N AF Yang, Jiajia Kitada, Ryo Kochiyama, Takanori Yu, Yinghua Makita, Kai Araki, Yuta Wu, Jinglong Sadato, Norihiro TI Brain networks involved in tactile speed classification of moving dot patterns: the effects of speed and dot periodicity SO SCIENTIFIC REPORTS LA English DT Article ID SOMATOSENSORY CORTEX; PSYCHOPHYSIOLOGICAL INTERACTIONS; VIBRATORY STIMULI; DECISION-MAKING; SPATIAL ACUITY; MOTION; PERCEPTION; FMRI; TEXTURE; SHAPE AB Humans are able to judge the speed of an object's motion by touch. Research has suggested that tactile judgment of speed is influenced by physical properties of the moving object, though the neural mechanisms underlying this process remain poorly understood. In the present study, functional magnetic resonance imaging was used to investigate brain networks that may be involved in tactile speed classification and how such networks may be affected by an object's texture. Participants were asked to classify the speed of 2-D raised dot patterns passing under their right middle finger. Activity in the parietal operculum, insula, and inferior and superior frontal gyri was positively related to the motion speed of dot patterns. Activity in the postcentral gyrus and superior parietal lobule was sensitive to dot periodicity. Psycho-physiological interaction (PPI) analysis revealed that dot periodicity modulated functional connectivity between the parietal operculum (related to speed) and postcentral gyrus (related to dot periodicity). These results suggest that texture-sensitive activity in the primary somatosensory cortex and superior parietal lobule influences brain networks associated with tactually-extracted motion speed. Such effects may be related to the influence of surface texture on tactile speed judgment. C1 [Yang, Jiajia; Yu, Yinghua; Araki, Yuta; Wu, Jinglong] Okayama Univ, Grad Sch Nat Sci & Technol, Div Med Bioengn, Okayama 7008530, Japan. [Yang, Jiajia; Yu, Yinghua] NIMH, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. [Kitada, Ryo] Nanyang Technol Univ, Sch Humanities & Social Sci, 14 Nanyang Dr, Singapore 637332, Singapore. [Kitada, Ryo; Sadato, Norihiro] Natl Inst Physiol Sci, Div Cerebral Integrat, Okazaki, Aichi 4448585, Japan. [Kitada, Ryo; Sadato, Norihiro] Grad Univ Adv Studies, SOKENDAI, Dept Physiol Sci, Hayama 2400193, Japan. [Kochiyama, Takanori] ATR Brain Act Imaging Ctr, Seika Cho, Hiroshima 6190288, Japan. [Makita, Kai] Hiroshima Univ, Inst Biomed & Hlth Sci, Hiroshima 730, Japan. [Wu, Jinglong] Minist Educ, Key Lab Biomimet Robots & Syst, Beijing, Peoples R China. RP Wu, JL (reprint author), Okayama Univ, Grad Sch Nat Sci & Technol, Div Med Bioengn, Okayama 7008530, Japan.; Kitada, R (reprint author), Nanyang Technol Univ, Sch Humanities & Social Sci, 14 Nanyang Dr, Singapore 637332, Singapore.; Kitada, R (reprint author), Natl Inst Physiol Sci, Div Cerebral Integrat, Okazaki, Aichi 4448585, Japan.; Kitada, R (reprint author), Grad Univ Adv Studies, SOKENDAI, Dept Physiol Sci, Hayama 2400193, Japan.; Wu, JL (reprint author), Minist Educ, Key Lab Biomimet Robots & Syst, Beijing, Peoples R China. EM ryo.kitada@gmail.com; wu@mech.okayama-u.ac.jp FU Japan Society for the Promotion of Science [23700326]; Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [25135734, 16H01680]; MEXT of Japan [21220005, 15H01846]; JSPS of Japan [25249026, 25303013, 24686034] FX The authors declare no competing financial interests. This work was supported by a Grant-in-aid for Young Scientists (B) (#23700326) from the Japan Society for the Promotion of Science and by a Grant-in-Aid for Scientific Research on Innovative Areas (#25135734 and #16H01680) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan to RK; by a Grant-in-Aid for Scientific Research (S) (#21220005) and (A) (#15H01846) and "Development of biomarker candidates for social behavior" carried out under the Strategic Research Program for Brain Sciences from the MEXT of Japan to NS; by a Grant-in-aid for Scientific Research (A) (#25249026) and (B) (#25303013) from the JSPS of Japan to JW; and by a Grant-in-aid for Young Scientists (A) (#24686034) from the JSPS of Japan to JY. NR 53 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 1 PY 2017 VL 7 AR 40931 DI 10.1038/srep40931 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4CM UT WOS:000393163600001 PM 28145505 ER PT J AU van Doremalen, N Hijazeen, ZSK Holloway, P Al Omari, B McDowell, C Adney, D Talafha, HA Guitian, J Steel, J Amarin, N Tibbo, M Abu-Basha, E Al-Majali, AM Munster, VJ Richt, JA AF van Doremalen, Neeltje Hijazeen, Zaidoun S. K. Holloway, Peter Al Omari, Bilal McDowell, Chester Adney, Danielle Talafha, Hani A. Guitian, Javier Steel, John Amarin, Nadim Tibbo, Markos Abu-Basha, Ehab Al-Majali, Ahmad M. Munster, Vincent J. Richt, Juergen A. TI High Prevalence of Middle East Respiratory Coronavirus in Young Dromedary Camels in Jordan SO VECTOR-BORNE AND ZOONOTIC DISEASES LA English DT Article DE dromedary camel; Jordan; MERS-CoV; phylogeny; serology ID MERS CORONAVIRUS; INFECTION; VARIANTS AB Prevalence of Middle East respiratory syndrome coronavirus (MERS-CoV) was determined in 45 dromedary camels from two geographically separated herds in Jordan. Virus shedding was only detected in swabs obtained from the respiratory tract and primarily observed in camels younger than 3 years. MERS-CoV seroprevalence increased with age of camels. Bovine and sheep sera were seronegative. Phylogenetic analysis of partial S2 clustered the Jordanian MERS-CoV strains with contemporary MERS-CoV strains associated with nosocomial outbreaks. C1 [van Doremalen, Neeltje; Munster, Vincent J.] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Hijazeen, Zaidoun S. K.] Food & Agr Org United Nations FAO, Amman, Jordan. [Holloway, Peter; Guitian, Javier] Royal Vet Coll, Vet Epidemiol Econ & Publ Hlth Grp, Hatfield, Herts, England. [Al Omari, Bilal; Talafha, Hani A.; Abu-Basha, Ehab; Al-Majali, Ahmad M.] Jordan Univ Sci & Technol, Fac Vet Med, Dept Vet Med Sci, Irbid, Jordan. [McDowell, Chester; Richt, Juergen A.] Kansas State Univ, Coll Vet Med, Dept Diagnost Med & Pathobiol, Manhattan, KS 66506 USA. [Adney, Danielle] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Steel, John] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Amarin, Nadim] MENA, Boehringer Ingelheim, Dubai, U Arab Emirates. [Tibbo, Markos] FAO Reg Off Near East & North Africa, Cairo, Egypt. RP Richt, JA (reprint author), Kansas State Univ, Coll Vet Med, Dept Diagnost Med & Pathobiol, Manhattan, KS 66506 USA.; Munster, VJ (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, 903 South 4th St, Hamilton, MT 59840 USA. EM vincent.munster@nih.gov; jricht@ksu.edu RI Guitian, Javier/C-3022-2009; OI Guitian, Javier/0000-0003-0799-0476; Munster, Vincent/0000-0002-2288-3196 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Jordan University of Science and Technology [272/2015]; Emory University; Food and Agriculture Organization of the United Nations' of the USAID; Kansas Bioscience Authority FX This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, the Jordan University of Science and Technology project 272/2015, internal support from Emory University, the Food and Agriculture Organization of the United Nations' component of the USAID-funded Emerging Pandemic Threats phase 2 (EPT-2) Program and the Kansas Bioscience Authority. We want to sincerely thank Boehringer Ingelheim for logistic assistance provided before and during research, and Austin Athman for assistance with figures. NR 12 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-3667 EI 1557-7759 J9 VECTOR-BORNE ZOONOT JI Vector-Borne Zoonotic Dis. PD FEB PY 2017 VL 17 IS 2 BP 155 EP 159 DI 10.1089/vbz.2016.2062 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA EJ0FD UT WOS:000392883100010 PM 28009529 ER PT J AU Leggio, L Lee, MR AF Leggio, Lorenzo Lee, Mary R. TI Treatment of Alcohol Use Disorder in Patients with Alcoholic Liver Disease SO AMERICAN JOURNAL OF MEDICINE LA English DT Review DE Alcohol use disorder; Alcoholic liver disease; Liver disease; Treatment ID HEPATITIS-C VIRUS; CARBOHYDRATE-DEFICIENT TRANSFERRIN; PRIMARY-CARE; HEAVY DRINKING; CAGE QUESTIONNAIRE; PROSPECTIVE COHORT; BRIEF INTERVENTION; NATURAL-HISTORY; UNITED-STATES; SUBSTANCE USE AB Alcohol is a leading cause of liver disease worldwide. Although alcohol abstinence is the crucial therapeutic goal for patients with alcoholic liver disease, these patients have less access to psychosocial, behavioral, and/or pharmacologic treatments for alcohol use disorder. Psychosocial and behavioral therapies include 12-step facilitation, brief interventions, cognitive behavioral therapy, and motivational enhancement therapy. In addition to medications approved by the US Food and Drug Administration for alcohol use disorder (disulfiram, naltrexone, and acamprosate), recent efforts to identify potential new treatments have yielded promising candidate pharmacotherapies. Finally, more efforts are needed to integrate treatments across disciplines toward patient-centered approaches in the management of patients with alcohol use disorder and alcoholic liver disease. Published by Elsevier Inc. C1 [Leggio, Lorenzo; Lee, Mary R.] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Bethesda, MD USA. [Leggio, Lorenzo; Lee, Mary R.] NIDA, NIH, Bethesda, MD 20892 USA. [Leggio, Lorenzo] Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Providence, RI 02912 USA. EM lorenzo.leggio@nih.gov; leemary@mail.nih.gov FU National Institutes of Health - National Institute on Alcohol Abuse and Alcoholism [ZIA-AA000218]; National Institutes of Health - National Institute on Drug Abuse [ZIA-AA000218] FX The work was supported by National Institutes of Health intramural funding ZIA-AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology; Principal Investigator: Leggio), jointly supported by the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse. NR 89 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD FEB PY 2017 VL 130 IS 2 BP 124 EP 134 DI 10.1016/j.amjmed.2016.10.004 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EI6RH UT WOS:000392623200022 PM 27984008 ER PT J AU Miller, PE Zhao, D Frazier-Wood, AC Michos, ED Averill, M Sandfort, V Burke, GL Polak, JF Lima, JAC Post, WS Blumenthal, RS Guallar, E Martin, SS AF Miller, P. Elliott Zhao, Di Frazier-Wood, Alexis C. Michos, Erin D. Averill, Michelle Sandfort, Veit Burke, Gregory L. Polak, Joseph F. Lima, Joao A. C. Post, Wendy S. Blumenthal, Roger S. Guallar, Eliseo Martin, Seth S. TI Associations of Coffee, Tea, and Caffeine Intake with Coronary Artery Calcification and Cardiovascular Events SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Caffeine; Cardiovascular events; Coffee; Coronary artery calcium; Tea ID PROSPECTIVE COHORT; COMPUTED-TOMOGRAPHY; BLOOD-PRESSURE; HEART-DISEASE; CONSUMPTION; ATHEROSCLEROSIS; RISK; METAANALYSIS; FLAVONOIDS; ADULTS AB BACKGROUND: Coffee and tea are 2 of the most commonly consumed beverages in the world. The association of coffee and tea intake with coronary artery calcium and major adverse cardiovascular events remains uncertain. METHODS: We examined 6508 ethnically diverse participants with available coffee and tea data from the Multi-Ethnic Study of Atherosclerosis. Intake for each was classified as never, occasional (< 1 cup per day), and regular (>= 1 cup per day). A coronary artery calcium progression ratio was derived from mixed effect regression models using loge(calcium score+1) as the outcome, with coefficients exponentiated to reflect coronary artery calcium progression ratio versus the reference. Cox proportional hazards analyses were used to evaluate the association between beverage intake and incident cardiovascular events. RESULTS: Over a median follow-up of 5.3 years for coronary artery calcium and 11.1 years for cardiovascular events, participants who regularly drank tea (>= 1 cup per day) had a slower progression of coronary artery calcium compared with never drinkers after multivariable adjustment. This correlated with a statistically significant lower incidence of cardiovascular events for >= 1 cup per day tea drinkers (adjusted hazard ratio 0.71; 95% confidence interval 0.53-0.95). Compared with never coffee drinkers, regular coffee intake (>= 1 cup per day) was not statistically associated with coronary artery calcium progression or cardiovascular events (adjusted hazard ratio 0.97; 95% confidence interval 0.78-1.20). Caffeine intake was marginally inversely associated with coronary artery calcium progression. CONCLUSIONS: Moderate tea drinkers had slower progression of coronary artery calcium and reduced risk for cardiovascular events. Future research is needed to understand the potentially protective nature of moderate tea intake. Published by Elsevier Inc. C1 [Miller, P. Elliott] NIH, Dept Crit Care Med, 10 Ctr Dr,Room 2C145, Bethesda, MD 21287 USA. [Miller, P. Elliott; Michos, Erin D.; Post, Wendy S.; Blumenthal, Roger S.; Guallar, Eliseo; Martin, Seth S.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol,Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21205 USA. [Zhao, Di; Post, Wendy S.; Guallar, Eliseo] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Frazier-Wood, Alexis C.] Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Averill, Michelle] Univ Washington, Dept Environm & Occupat Hlth, Seattle, WA 98195 USA. [Sandfort, Veit] NIH, Dept Radiol & Imaging Sci, 10 Ctr Dr,Room 2C145, Bethesda, MD 21287 USA. [Burke, Gregory L.] Wake Forest Sch Med, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC USA. [Polak, Joseph F.] Tufts Univ, Sch Med, Tufts Med Ctr, Dept Radiol, Boston, MA 02111 USA. [Lima, Joao A. C.] Johns Hopkins Univ Hosp, Div Cardiol, Dept Med, Baltimore, MD 21287 USA. EM Elliott.miller@nih.gov FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; National Center for Research Resources [UL1-TR-000040, UL1-TR-001079] FX This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-TR-001079 from the National Center for Research Resources. NR 38 TC 1 Z9 1 U1 12 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD FEB PY 2017 VL 130 IS 2 BP 188 EP + DI 10.1016/j.amjmed.2016.08.038 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA EI6RH UT WOS:000392623200031 PM 27640739 ER PT J AU Gordon, SM Pourmousa, M Sampson, M Sviridov, D Islam, R Perrin, BS Kemeh, G Pastor, RW Remaley, AT AF Gordon, Scott M. Pourmousa, Mohsen Sampson, Maureen Sviridov, Denis Islam, Rafique Perrin, B. Scott, Jr. Kemeh, Georgina Pastor, Richard W. Remaley, Alan T. TI Identification of a novel lipid binding motif in apolipoprotein B by the analysis of hydrophobic cluster domains SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE Lipoprotein; Peptide; Cholesterol efflux; Amphipathic helix; Molecular dynamics simulation; Trilayer ID HIGH-DENSITY-LIPOPROTEIN; MIMETIC PEPTIDE; APO-B; A-I; MEMBRANE CURVATURE; AMPHIPATHIC HELIX; PROTEIN; SEQUENCE; DYNAMICS; MODEL AB Apolipoprotein B (apoB) is a large amphipathic protein that is the structural scaffold for the formation of several classes of lipoproteins involved in lipid transport throughout the body. The goal of the present study was to identify specific domains in the apoB sequence that contribute to its lipid binding properties. A sequence analysis algorithm was developed to identify stretches of hydrophobic amino acids devoid of charged amino adds, which are referred to as hydrophobic cluster domains (HCDs). This analysis identified 78 HCDs in apoB with hydrophobic stretches ranging from 6 to 26 residues. Each HCD was analyzed in silico for secondary structure and lipid binding properties, and a subset was synthesized for experimental evaluation. One HCD peptide, B38, showed high affinity binding to both isolated HDL and LDL, and could exchange between lipoproteins. All-atom molecular dynamics simulations indicate that B38 inserts 3.7 angstrom below the phosphate plane of the bilayer. B38 forms an unusual a-helix with a broad hydrophobic face and polar serine and threonine residues on the opposite face. Based on this structure, we hypothesized that B38 could efflux cholesterol from cells. B38 showed a 12-fold greater activity than the 5A peptide, a bihelical Class A amphipathic helix (EC50 of 0.2658 vs. 3.188 mu M; p < 0.0001), in promoting cholesterol efflux from ABCA1 expressing BHK-1 cells. In conclusion, we have identified novel domains within apoB that contribute to its lipid biding properties. Additionally, we have discovered a unique amphipathic helix design for efficient ABCA1-specific cholesterol efflux. Published by Elsevier B.V. C1 [Gordon, Scott M.; Sampson, Maureen; Sviridov, Denis; Islam, Rafique; Kemeh, Georgina; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. [Pourmousa, Mohsen; Perrin, B. Scott, Jr.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Rockville, MD USA. [Islam, Rafique] George Mason Univ, Sch Syst Biol, Fairfax, VA 22030 USA. RP Gordon, SM (reprint author), NHLBI, Lipoprot Metab Sect, 9000 Rockville Pike Bldg 10,Room 8N224, Bethesda, MD 20892 USA. EM scott.gordon@nih.gov FU National Heart, Lung, and Blood Institute Division of Intramural Research FX This project was funded by the National Heart, Lung, and Blood Institute Division of Intramural Research, and utilized the computational resources of the NIH HPC Biowulf and NHLBI LoBoS clusters. 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. The authors would also like to acknowledge the NHLBI Biophysics Core Facility for training and access to instruments. NR 55 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 EI 0006-3002 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD FEB PY 2017 VL 1859 IS 2 BP 135 EP 145 DI 10.1016/j.bbamem.2016.10.019 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA EI8QI UT WOS:000392772100001 PM 27814978 ER PT J AU Canepa, M Viazzi, F Strait, JB Ameri, P Pontremoli, R Brunelli, C Studenski, S Ferrucci, L Lakatta, EG AlGhatrif, M AF Canepa, Marco Viazzi, Francesca Strait, James B. Ameri, Pietro Pontremoli, Roberto Brunelli, Claudio Studenski, Stephanie Ferrucci, Luigi Lakatta, Edward G. AlGhatrif, Majd TI Longitudinal Association Between Serum Uric Acid and Arterial Stiffness Results From the Baltimore Longitudinal Study of Aging SO HYPERTENSION LA English DT Article DE arterial stiffness; hyperuricemia; longitudinal cohort study; pulse wave velocity; serum uric acid ID PULSE-WAVE VELOCITY; MUSCLE-CELL PROLIFERATION; AORTIC STIFFNESS; BLOOD-PRESSURE; HYPERTENSIVE PATIENTS; INDEPENDENT PREDICTOR; INCIDENT HYPERTENSION; CARDIOVASCULAR RISK; VASCULAR STIFFNESS; HYPERURICEMIA AB Serum uric acid (SUA) has long been associated with increased cardiovascular risk, with arterial stiffness proposed as a mediator. However, evidence on the association between SUA and arterial stiffness is limited to contradicting cross-sectional studies. In this analysis, we examined the longitudinal relationship between SUA and pulse wave velocity, a measure of arterial stiffness, in a community-dwelling population. We studied 446 women and 427 men participating in the BLSA (Baltimore Longitudinal Study of Aging), with 1409 and 1434 observations, respectively, over an average period of 6 years. At baseline, mean ages of women and men were 65 +/- 13 and 68 +/- 13 years; mean SUA, 4.6 +/- 1.1 and 5.7 +/- 1.3 mg/dL; mean pulse wave velocity, 8.1 +/- 1.7 and 8.6 +/- 1.9 m/s, respectively (P<0.0001). In gender-stratified models accounting for age, blood pressure, renal function, metabolic measures, and medications, there was a significant interaction between SUA and follow-up time in men (beta=0.69; P=0.0002) but not in women. Men, but not women, in the highest gender-specific SUA tertile at baseline (SUA >= 6.2 mg/dL in men and SUA >= 4.9 mg/dL in women) had a greater rate of pulse wave velocity increase over time than those in the lowest tertiles (beta=0.997; P=0.012). This gender difference was lost when the distribution of SUA in men and women was made comparable by excluding hyperuricemic men (SUA >= 6.2 mg/dL). In conclusion, higher SUA was associated with greater increase in pulse wave velocity in men but not women; this association was lost when men with SUA >= 6.2 mg/dL were not included, suggesting a threshold for SUA association with arterial stiffness, which is more frequently reached in men. Online Data Supplement C1 [Canepa, Marco; Viazzi, Francesca; Ameri, Pietro; Pontremoli, Roberto; Brunelli, Claudio] Univ Genoa, Dept Internal Med, Genoa, Italy. [Canepa, Marco; Viazzi, Francesca; Ameri, Pietro; Pontremoli, Roberto; Brunelli, Claudio] IRCCS Azienda Osped Univ San Martino IST, Genoa, Italy. [Strait, James B.; Lakatta, Edward G.; AlGhatrif, Majd] NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. [Studenski, Stephanie; Ferrucci, Luigi] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. EM marco.canepa@unige.it FU Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging (USA) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging (USA). NR 44 TC 1 Z9 1 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD FEB PY 2017 VL 69 IS 2 BP 228 EP + DI 10.1161/HYPERTENSIONAHA.116.08114 PG 17 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EI3QE UT WOS:000392405500006 PM 27956574 ER PT J AU Pandey, A Khan, H Newman, AB Lakatta, EG Forman, DE Butler, J Berry, JD AF Pandey, Ambarish Khan, Hassan Newman, Anne B. Lakatta, Edward G. Forman, Daniel E. Butler, Javed Berry, Jarett D. TI Arterial Stiffness and Risk of Overall Heart Failure, Heart Failure With Preserved Ejection Fraction, and Heart Failure With Reduced Ejection Fraction The Health ABC Study (Health, Aging, and Body Composition) SO HYPERTENSION LA English DT Article DE arterial stiffness; ejection fraction; heart failure; hypertension; pulse wave velocity ID LEFT-VENTRICULAR HYPERTROPHY; PULSE-WAVE VELOCITY; CARDIOVASCULAR EVENTS; OLDER-ADULTS; DIASTOLIC DYSFUNCTION; DISEASE; ASSOCIATION; ATHEROSCLEROSIS; EXERCISE; POPULATION AB Higher arterial stiffness is associated with increased risk of atherosclerotic events. However, its contribution toward risk of heart failure (HF) and its subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), independent of other risk factors is not well established. In this study, we included Health ABC study (Health, Aging, and Body Composition) participants without prevalent HF who had arterial stiffness measured as carotid-femoral pulse wave velocity (cf-PWV) at baseline (n=2290). Adjusted Cox-proportional hazards models were constructed to determine the association between continuous and data-derived categorical measures (tertiles) of cf-PWV and incidence of HF and its subtypes (HFpEF [ejection fraction >45%] and HFrEF [ejection fraction <= 45%]). We observed 390 HF events (162 HFpEF and 145 HFrEF events) over 11.4 years of follow-up. In adjusted analysis, higher cf-PWV was associated with greater risk of HF after adjustment for age, sex, ethnicity, mean arterial pressure, and heart rate (hazard ratio [95% confidence interval] for cf-PWV tertile 3 versus tertile 1 [ref] =1.35 [1.05-1.73]). However, this association was not significant after additional adjustment for other cardiovascular risk factors (hazard ratio [95% confidence interval], 1.14 [0.88-1.47]). cf-PWV velocity was also not associated with risk of HFpEF and HFrEF after adjustment for potential confounders (most adjusted hazard ratio [95% confidence interval] for cf-PWV tertile 3 versus tertile 1 [ref]: HFpEF, 1.06 [0.72-1.56]; HFrEF, 1.28 [0.83-1.97]). In conclusion, arterial stiffness, as measured by cf-PWV, is not independently associated with risk of HF or its subtypes after adjustment for traditional cardiovascular risk factors. Online Data Supplement C1 [Pandey, Ambarish; Berry, Jarett D.] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Div Cardiol, Dallas, TX USA. [Berry, Jarett D.] Univ Texas Southwestern Med Ctr Dallas, Dept Clin Sci, Dallas, TX USA. [Khan, Hassan] Emory Univ, Sch Med, Dept Internal Med, Atlanta, GA USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Forman, Daniel E.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Sch Med, Sect Geriatr Cardiol,Div Geriatr, Pittsburgh, PA 15260 USA. [Forman, Daniel E.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Sch Med, Sect Geriatr Cardiol,Div Cardiol, Pittsburgh, PA 15260 USA. [Butler, Javed] SUNY Stony Brook, Sch Med, Dept Internal Med, Div Cardiol, New York, NY USA. EM jarett.berry@utsouthwestern.edu FU Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute of Nursing Research [R01-NR012459] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging. This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and National Institute of Nursing Research grant R01-NR012459. NR 50 TC 0 Z9 0 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD FEB PY 2017 VL 69 IS 2 BP 267 EP + DI 10.1161/HYPERTENSIONAHA.116.08327 PG 12 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EI3QE UT WOS:000392405500011 PM 27993954 ER PT J AU Herrington, W Staplin, N Judge, PK Mafham, M Emberson, J Haynes, R Wheeler, DC Walker, R Tomson, C Agodoa, L Wiecek, A Lewington, S Reith, CA Landray, MJ Baigent, C AF Herrington, William Staplin, Natalie Judge, Parminder K. Mafham, Marion Emberson, Jonathan Haynes, Richard Wheeler, David C. Walker, Robert Tomson, Charlie Agodoa, Larry Wiecek, Andrzej Lewington, Sarah Reith, Christina A. Landray, Martin J. Baigent, Colin CA SHARP Collaborative Grp TI Evidence for Reverse Causality in the Association Between Blood Pressure and Cardiovascular Risk in Patients With Chronic Kidney Disease SO HYPERTENSION LA English DT Article DE blood pressure; chronic kidney disease; epidemiology; vascular disease; troponin ID STAGE RENAL-DISEASE; CARDIAC TROPONIN-T; INCIDENT HEART-FAILURE; LEFT-VENTRICULAR MASS; HEMODIALYSIS-PATIENTS; ALL-CAUSE; INSUFFICIENCY COHORT; NATRIURETIC PEPTIDE; CONTROLLED-TRIAL; MORTALITY AB Among those with moderate-to-advanced chronic kidney disease, the relationship between blood pressure (BP) and cardiovascular disease seems U shaped but is loglinear in apparently healthy adults. The SHARP (Study of Heart and Renal Protection) randomized 9270 patients with chronic kidney disease to ezetimibe/simvastatin versus matching placebo and measured BP at each follow-up visit. Cox regression was used to assess the association between BP and risk of cardiovascular disease among (1) those with a self-reported history of cardiovascular disease and (2) those with no such history and, based on plasma troponin-I concentration, a low probability of subclinical cardiac disease. A total of 8666 participants had a valid baseline BP and troponin-I measurement, and 2188 had at least 1 cardiovascular event during follow-up. After adjustment for relevant confounders, the association between systolic BP and cardiovascular events was U shaped, but among participants without evidence of previous cardiovascular disease, there was a positive loglinear association throughout the range of values studied. Among those with the lowest probability of subclinical cardiac disease, each 10 mm Hg higher systolic BP corresponded to a 27% increased risk of cardiovascular disease (hazard ratio, 1.27; 95% confidence interval, 1.11-1.44). In contrast, the relationship between diastolic BP and cardiovascular risk remained U shaped irrespective of cardiovascular disease history or risk of subclinical disease. In conclusion, the lack of a clear association between systolic BP and cardiovascular risk in this population seems attributable to confounding, suggesting that more intensive systolic BP reduction may be beneficial in such patients. Online Data Supplement C1 [Herrington, William; Staplin, Natalie; Judge, Parminder K.; Mafham, Marion; Emberson, Jonathan; Haynes, Richard; Lewington, Sarah; Reith, Christina A.; Landray, Martin J.; Baigent, Colin] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England. [Herrington, William; Staplin, Natalie; Judge, Parminder K.; Mafham, Marion; Emberson, Jonathan; Haynes, Richard; Lewington, Sarah; Reith, Christina A.; Landray, Martin J.; Baigent, Colin] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England. [Judge, Parminder K.; Emberson, Jonathan; Haynes, Richard; Lewington, Sarah; Baigent, Colin] Univ Oxford, Nuffield Dept Populat Hlth, MRC PHRU, Oxford, England. [Wheeler, David C.] UCL, Ctr Nephrol, London, England. [Walker, Robert] Univ Otago, Dunedin Sch Med, Dunedin, New Zealand. [Tomson, Charlie] Newcastle Upon Tyne Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England. [Agodoa, Larry] NIDDK, NIH, Bethesda, MD USA. [Wiecek, Andrzej] Med Univ Silesia, Dept Nephrol Transplantat & Internal Med, Katowice, Poland. EM colin.baigent@ndph.ox.ac.uk OI Herrington, Will/0000-0003-1172-8243 FU Merck & Co, Inc, Kenilworth, NJ; Australian National Health Medical Research Council; British Heart Foundation; UK Medical Research Council FX The SHARP study (Study of Heart and Renal Protection) was funded by Merck & Co, Inc, Kenilworth, NJ, with additional support from the Australian National Health Medical Research Council, the British Heart Foundation, and the UK Medical Research Council (which supported this analysis). The funders had no involvement in data collection, analysis, interpretation, article writing, or the decision to submit for publication. NR 49 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD FEB PY 2017 VL 69 IS 2 BP 314 EP + DI 10.1161/HYPERTENSIONAHA.116.08386 PG 20 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EI3QE UT WOS:000392405500016 PM 28028192 ER PT J AU Karaczyn, AA Adams, TL Cheng, RYS Matluk, NN Verdi, JM AF Karaczyn, Aldona A. Adams, Tamara L. Cheng, Robert Y. S. Matluk, Nicholas N. Verdi, Joseph M. TI Human NUMB6 Induces Epithelial-Mesenchymal Transition and Enhances Breast Cancer Cells Migration and Invasion SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE NUMB ISOFORMS; NUMB4; NUMB6; EPITHELIAL-MESENCHYMAL TRANSITION; BREAST CANCER CELLS; CELL MIGRATION; CELL INVASION ID E-CADHERIN EXPRESSION; TUMOR PROGRESSION; DISTINCT ROLES; RHO-GTPASES; SNAIL; METASTASIS; PATHWAY; SLUG; CARCINOGENESIS; REPRESSION AB Mammalian NUMB is alternatively spliced generating four isoforms NUMB1-NUMB4 that can function as tumor suppressors. NUMB1-NUMB4 proteins, which normally determine how different cell types develop, are reduced in 210/0 of primary breast tumors. Our previous work has, however, indicated that two novel NUMB isoforms, NUMB5 and NUMB6 have the pro-oncogenic functions. Herein, we address a novel function of human NUMB isoform 6 (NUMB6) in promoting cancer cell migration and invasion. We found that NUMB6 induced expression of embryonic transcription factor Slug, which in turn actively repressed E-cadherin, prompting cells to undergo epithelial-mesenchymal transition (EMT). Low-metastatic breast cancer cells DB-7 stably expressing NUMB6, lost their epithelial phenotype, exhibited migratory and pro-invasive behavior, and ultimately elevated expression of mesenchymal markers. Among these markers, increased vimentin, p-catenin, and fibronectin expression elicited metalloproteinase 9 (MMP9) production. Our results revealed that NUMB6-DB-7 cells have significantly increased level of Akt 1 and Akt2 phosphorylation. Therefore, antagonizing Akt signaling using a chemical inhibitor LY294002, we found that NUMB6-induced Slug expression was reduced, and ultimately accompanied with decreased cell migration and invasion. In summary, this study identified a novel molecular determinant of breast cancer progression, uncovering a potential oncogenic role for the NUMB6 protein in cancer cell migration and invasion, coupled to the maintenance of mesenchymal-like cells. (C) 2016 Wiley Periodicals, Inc. C1 [Karaczyn, Aldona A.; Verdi, Joseph M.] Maine Med Ctr, Res Inst, Ctr Mol Med, 81 Res Dr, Scarborough, ME 04074 USA. [Adams, Tamara L.] Blood Ctr Wisconsin, Milwaukee, WI 53201 USA. [Cheng, Robert Y. S.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Matluk, Nicholas N.] Hlth & Environm Testing Lab, Dept Hlth & Human Serv, Augusta, ME 04333 USA. EM karaca@mmc.org FU Maine Cancer Foundation; Carl Zeiss Microscopy, LLC [P30GM103392]; National Institute of General Medical Sciences; qPCR Bio-Rad [P30GM103465] FX Grant sponsor: Maine Cancer Foundation; Grant sponsor: Carl Zeiss Microscopy, LLC; Grant number: P30GM103392; Grant sponsor: National Institute of General Medical Sciences; Grant sponsor: qPCR Bio-Rad; Grant number: P30GM103465; Grant sponsor: National Institute of General Medical Sciences. NR 46 TC 2 Z9 2 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 EI 1097-4644 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD FEB PY 2017 VL 118 IS 2 BP 237 EP 251 DI 10.1002/jcb.25628 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EI4VO UT WOS:000392491800003 PM 27302072 ER PT J AU Jancel, T Shaw, PA Hallahan, CW Kim, T Freeman, AF Holland, SM Penzak, SR AF Jancel, T. Shaw, P. A. Hallahan, C. W. Kim, T. Freeman, A. F. Holland, S. M. Penzak, S. R. TI Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review SO JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS LA English DT Review DE paediatric; pharmacokinetics; posaconazole; therapeutic drug monitoring ID STEM-CELL TRANSPLANTATION; ANTIFUNGAL PROPHYLAXIS; PHARMACOKINETICS; PLASMA; INFECTION; CHILD; LEUKEMIA; DISEASE; SINGLE; ADULTS AB What is known and objectivePosaconazole is an extended-spectrum triazole antifungal with activity against a variety of clinically significant yeasts and moulds. Posaconazole is not currently approved by the U.S. Food and Drug Administration for use in children younger than 13 years of age. Our primary objective was to describe the dosing and observed trough concentrations with posaconazole oral suspension in paediatric patients at the National Institutes of Health Clinical Center (Bethesda, MD). MethodsThis retrospective single-centre study reviewed paediatric patients younger than 13 years of age initiated on posaconazole oral suspension. Patients were included if they were initiated on posaconazole for prophylaxis or treatment for fungal infections from September 2006 through March 2013 with at least one trough concentration collected after at least 7 days of therapy. Results and discussionA total of 20 male patients were included, of whom 15 (75%) had chronic granulomatous disease. The median age of patients was 65 years (range: 28-107). A total of 79 posaconazole trough concentrations were measured in patients receiving posaconazole as prophylaxis (n = 8) or treatment (n = 12). Posaconazole dose referenced to total body weight ranged from 100 to 492 mg/kg/day. Posaconazole trough concentrations ranged from undetectable (<50 ng/mL) up to 3620 ng/mL and were 500, 700 and 1250 ng/mL in 95%, 60% and 25% of patients, respectively. What is new and conclusionsPatients younger than 13 years of age had highly variable trough concentrations, and recommendations for the appropriate dosing of posaconazole oral suspension remain challenging. Until studies are conducted to determine the appropriate dosing of posaconazole in this patient population, therapeutic drug monitoring should be considered to ensure adequate posaconazole exposure. C1 [Jancel, T.] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Shaw, P. A.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Hallahan, C. W.] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kim, T.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Freeman, A. F.; Holland, S. M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Penzak, S. R.] Univ North Texas Syst, Dept Pharmacotherapy, Coll Pharm, Ft Worth, TX USA. EM timjancel@gmail.com FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This study reflects the views of the authors and should not be construed to represent the views of the US Food and Drug Administration. This research was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 24 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-4727 EI 1365-2710 J9 J CLIN PHARM THER JI J. Clin. Pharm. Ther. PD FEB PY 2017 VL 42 IS 1 BP 75 EP 79 DI 10.1111/jcpt.12483 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI4ZV UT WOS:000392503900011 PM 27982447 ER PT J AU Nehus, EJ Khoury, JC Inge, TH Xiao, N Jenkins, TM Moxey-Mims, MM Mitsnefes, MM AF Nehus, Edward J. Khoury, Jane C. Inge, Thomas H. Xiao, Nianzhou Jenkins, Todd M. Moxey-Mims, Marva M. Mitsnefes, Mark M. TI Kidney outcomes three years after bariatric surgery in severely obese adolescents SO KIDNEY INTERNATIONAL LA English DT Article DE bariatric surgery; kidney disease; severe obesity ID STAGE RENAL-DISEASE; GLOMERULAR-FILTRATION-RATE; POTENTIAL EXPLANATORY FACTORS; SERUM CYSTATIN-C; BODY-MASS INDEX; WEIGHT-LOSS; HEALTH-STATUS; RISK-FACTORS; FOLLOW-UP; POPULATION AB A significant number of severely obese adolescents undergoing bariatric surgery have evidence of early kidney damage. To determine if kidney injury is reversible following bariatric surgery, we investigated renal outcomes in the Teen-Longitudinal Assessment of Bariatric Surgery cohort, a prospective multicenter study of 242 severely obese adolescents undergoing bariatric surgery. Primary outcomes of urine albumin-to-creatinine ratio and cystatin C-based estimated glomerular filtration rate (eGFR) were evaluated preoperatively and up to 3 years following bariatric surgery. At surgery, mean age of participants was 17 years and median body mass index (BMI) was 51 kg/m(2). In those with decreased kidney function at baseline (eGFR under 90 mL/min/1.73m(2)), mean eGFR significantly improved from 76 to 102 mL/min/1.73m(2) at three-year follow-up. Similarly, participants with albuminuria (albumin-to-creatinine ratio of 30 mg/g and more) at baseline demonstrated significant improvement following surgery: geometric mean of ACR was 74 mg/g at baseline and decreased to 17 mg/g at three years. Those with normal renal function and no albuminuria at baseline remained stable throughout the study period. Among individuals with a BMI of 40 kg/m(2) and more at follow-up, increased BMI was associated with significantly lower eGFR, while no association was observed in those with a BMI under 40 kg/m(2). In adjusted analysis, eGFR increased by 3.9 mL/min/1.73m(2) for each 10-unit loss of BMI. Early kidney abnormalities improved following bariatric surgery in adolescents with evidence of preoperative kidney disease. Thus, kidney disease should be considered as a selection criteria for bariatric surgery in severely obese adolescents who fail conventional weight management. C1 [Nehus, Edward J.; Mitsnefes, Mark M.] Cincinnati Childrens Hosp Med Ctr, Div Nephrol & Hypertens, 3333 Burnet Ave,ML 7022, Cincinnati, OH 45229 USA. [Khoury, Jane C.] Cincinnati Childrens Hosp Med Ctr, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA. [Inge, Thomas H.; Jenkins, Todd M.] Cincinnati Childrens Hosp Med Ctr, Div Pediat Gen & Thorac Surg, Cincinnati, OH 45229 USA. [Xiao, Nianzhou] Virginia Commonwealth Univ, Childrens Hosp Richmond, Div Pediat Nephrol & Rheumatol, Richmond, VA USA. [Moxey-Mims, Marva M.] NIDDK, NIH, Bethesda, MD 20892 USA. EM edward.nehus@cchmc.org FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK072493, UM1DK072493, UM1DK095710]; National Institutes of Health [UL1TR000077-04, UL1RR025755, M01-RR00188, UL1RR024153, UL1TR000005, UL1TR000165] FX The Teen-LABS consortium was funded by cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases through grants U01DK072493 (Cincinnati Children's Hospital Medical Center), UM1DK072493 (Cincinnati Children's Hospital Medical Center), and UM1DK095710 (University of Cincinnati). The study also was supported by National Institutes of Health grants UL1TR000077-04 (Cincinnati Children's Hospital Medical Center), UL1RR025755 (Nationwide Children's Hospital), M01-RR00188 (Texan Children's Hospital/Baylor College of Medicine), UL1RR024153 and UL1TR000005 (University of Pittsburgh), and UL1TR000165 (University of Alabama, Birmingham). The funding agency had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript. NR 44 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2017 VL 91 IS 2 BP 451 EP 458 DI 10.1016/j.kint.2016.09.031 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EI6CG UT WOS:000392582000025 PM 27914704 ER PT J AU Torres, VE Abebe, KZ Schrier, RW Perrone, RD Chapman, AB Yu, AS Braun, WE Steinman, TI Brosnahan, G Hogan, MC Rahbari, FF Grantham, JJ Bae, KT Moore, CG Flessner, MF AF Torres, Vicente E. Abebe, Kaleab Z. Schrier, Robert W. Perrone, Ronald D. Chapman, Arlene B. Yu, Alan S. Braun, William E. Steinman, Theodore I. Brosnahan, Godela Hogan, Marie C. Rahbari, Frederic F. Grantham, Jared J. Bae, Kyongtae T. Moore, Charity G. Flessner, Michael F. TI Dietary salt restriction is beneficial to the management of autosomal dominant polycystic kidney disease SO KIDNEY INTERNATIONAL LA English DT Article DE autosomal dominant polycystic kidney disease; CKD progression; kidney volume; low-salt diet; sodium ID SODIUM-INTAKE; CARDIOVASCULAR-DISEASE; URINARY SODIUM; ACE-INHIBITION; BLOOD-PRESSURE; EXCRETION; RENIN; PROGRESSION; CREATININE; TRIALS AB The CRISP study of polycystic kidney disease (PKD) found that urinary sodium excretion associated with the rate of total kidney volume increase. Whether sodium restriction slows the progression of Autosomal Dominant PKD (ADPKD) is not known. To evaluate this we conducted a post hoc analysis of the HALT-PKD clinical trials of renin-angiotensin blockade in patients with ADPKD. Linear mixed models examined whether dietary sodium affected rates of total kidney volume or change in estimated glomerular filtration rate (eGFR) in patients with an eGFR over 60 ml/min/1.73 m(2) (Study A) or the risk for a composite endpoint of 50% reduction in eGFR, end-stage renal disease or death, or the rate of eGFR decline in patients with an eGFR 25-60 ml/min/1.73 m(2) (Study B) all in patients initiated on an under100 mEq sodium diet. During the trial urinary sodium excretion significantly declined by an average of 0.25 and 0.41 mEq/24 hour per month in studies A and B, respectively. In Study A, averaged and time varying urinary sodium excretions were significantly associated with kidney growth (0.43%/year and 0.09%/year, respectively, for each 18 mEq urinary sodium excretion). Averaged urinary sodium excretion was not significantly associated with faster eGFR decline (-0.07 ml/min/1.73m(2)/year for each 18 mEq urinary sodium excretion). In Study B, the averaged but not time-varying urinary sodium excretion significantly associated with increased risk for the composite endpoint (hazard ratio 1.08 for each 18 mEq urinary sodium excretion) and a significantly faster eGFR decline (-0.09 ml/min/1.73m(2)/year for each mEq 18 mEq urinary sodium excretion). Thus, sodium restriction is beneficial in the management of ADPKD. C1 [Torres, Vicente E.; Hogan, Marie C.] Mayo Clin, Coll Med, Rochester, MN USA. [Abebe, Kaleab Z.; Bae, Kyongtae T.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Schrier, Robert W.; Brosnahan, Godela] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Perrone, Ronald D.] Tufts Med Ctr, Boston, MA USA. [Chapman, Arlene B.] Univ Chicago, Chicago, IL 60637 USA. [Yu, Alan S.; Grantham, Jared J.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Braun, William E.] Cleveland Clin, Cleveland, OH 44106 USA. [Steinman, Theodore I.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Rahbari, Frederic F.] Emory Univ, Sch Med, Atlanta, GA USA. [Moore, Charity G.] Carolinas HealthCare Syst, Charlotte, NC USA. [Flessner, Michael F.] NIH, Bldg 10, Bethesda, MD 20892 USA. EM torres.vicente@mayo.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [DK62402, DK082230, DK62411, DK62410, DK62408, DK62401, DK090728]; National Center for Research Resources General Clinical Research Centers [RR000585, RR000039, RR000054, RR000051, RR023940, RR001032]; National Center for Advancing Translational Sciences Clinical and Translational Science Awards [RR024150, TR00135, RR025008, TR000454, RR025752, TR001064, RR025780, TR001082, RR025758, TR001102, RR033179, TR000001, RR024989, TR000439]; Zell Family Foundation; PKD Foundation FX The authors thank the patients involved in the study for their participation and contribution. This work has been supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK62402 to VET, DK082230, to RWS, DK62411, to RDP, DK62410, to CGM, DK62408 to ABC, DK62401 to Washington University in St Louis, and DK090728 to the Mayo Translational PKD Center) and the National Center for Research Resources General Clinical Research Centers (RR000585 to the Mayo Clinic, RR000039 to Emory University, RR000054 to Tufts Medical Center, RR000051 to the University of Colorado, RR023940 to the University of Kansas Medical Center, and RR001032 to Beth Israel Deaconess Medical Center), National Center for Advancing Translational Sciences Clinical and Translational Science Awards (RR024150 and TR00135 to the Mayo Clinic, RR025008 and TR000454 to Emory University, RR025752 and TR001064 to Tufts University, RR025780 and TR001082 to the University of Colorado, RR025758 and TR001102 to Beth Israel Deaconess Medical Center, RR033179 and TR000001 to the University of Kansas Medical Center, and RR024989 and TR000439 to Cleveland Clinic), by funding from the Zell Family Foundation (to the University of Colorado), and by a grant from the PKD Foundation. NR 31 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2017 VL 91 IS 2 BP 493 EP 500 DI 10.1016/j.kint.2016.10.018 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EI6CG UT WOS:000392582000029 PM 27993381 ER PT J AU Lewandowski, LB Schanberg, LE Thielman, N Phuti, A Kalla, AA Okpechi, I Nourse, P Gajjar, P Faller, G Ambaram, P Reuter, H Spittal, G Scott, C AF Lewandowski, L. B. Schanberg, L. E. Thielman, N. Phuti, A. Kalla, A. A. Okpechi, I. Nourse, P. Gajjar, P. Faller, G. Ambaram, P. Reuter, H. Spittal, G. Scott, C. TI Severe disease presentation and poor outcomes among pediatric systemic lupus erythematosus patients in South Africa SO LUPUS LA English DT Article DE Systemic lupus erythematosus; pediatric lupus; Africa; lupus nephritis ID DEVELOPING-COUNTRY; EGYPTIAN CHILDREN; CHILDHOOD LUPUS; RENAL-DISEASE; UNITED-STATES; DAMAGE INDEX; NEPHRITIS; SLE; MORTALITY; RACE AB Background Systemic lupus erythematosus (SLE) is a life-threatening multisystem autoimmune disease that is more severe in patients of African ancestry and children, yet pediatric SLE on the African continent has been understudied. This study describes a cohort of pediatric SLE (PULSE) patients in South Africa. Methods Patients with a diagnosis of SLE (1997 American College of Rheumatology criteria) diagnosed prior to age 19 years in Cape Town, South Africa, were enrolled in this cross-sectional study from September 2013 to December 2014. Information on clinical and serological characteristics was extracted from medical records. Results were compared to a well-described North American pediatric SLE cohort. Results Seventy-two South African patients were enrolled in the study; mean age 11.5 years; 82% were girls. The racial distribution was 68% Coloured, 24% Black, 5% White and 3% Asian/Indian. Most patients presented with severe lupus nephritis documented by renal biopsy (61%). Of patients with lupus nephritis, 63% presented with International Society of Nephrology/Renal Pathology Society class III or IV. Patients in the PULSE cohort were more likely to be treated with cyclophosphamide, methotrexate and azathioprine. The PULSE cohort had high disease activity at diagnosis (mean Systemic Lupus Erythematosus Disease Activity Index-2K (SLEDAI-2K) 20.6). The SLEDAI-2K at enrolment in the PULSE cohort (5.0) did not differ from the North American pediatric SLE cohort (4.8). Sixty-three per cent of the PULSE cohort had end organ damage with Systemic Lupus International Collaborating Clinics Damage Index (SLICC-DI) score >0 (mean SLICC-DI 1.9), compared to 23% in a previously reported US cohort. Within the PULSE cohort, nine (13%) developed end-stage renal disease with six (8%) requiring transplant, strikingly higher than North American peers (transplant rate <1%). Conclusions The PULSE cohort had highly active multiorgan disease at diagnosis and significant disease damage at enrolment in the South African registry. South African patients have severe lupus nephritis and poor renal outcomes compared to North American peers. Our study revealed a severe disease phenotype in the PULSE cohort resulting in poor outcomes in this high-risk population. C1 [Lewandowski, L. B.; Schanberg, L. E.] Duke Univ, Med Ctr, Pediat Rheumatol, Durham, NC 27706 USA. [Lewandowski, L. B.; Thielman, N.] Duke Univ, Med Ctr, Duke Hubert Yeargan Global Hlth, Durham, NC 27706 USA. [Lewandowski, L. B.; Phuti, A.; Nourse, P.; Gajjar, P.; Spittal, G.; Scott, C.] Red Cross War Mem Childrens Hosp, Paediat Rheumatol, Cape Town, South Africa. [Lewandowski, L. B.; Phuti, A.; Kalla, A. A.; Okpechi, I.; Nourse, P.; Gajjar, P.; Spittal, G.; Scott, C.] Univ Cape Town, Cape Town, South Africa. [Kalla, A. A.] Groote Schuur, Rheumatol, Cape Town, South Africa. [Okpechi, I.] Groote Schuur Hosp, Div Nephrol & Hypertens, Cape Town, South Africa. [Faller, G.; Ambaram, P.] Chris Hani Baragwanath Acad Hosp, Paediat Rheumatol, Johannesburg, South Africa. [Faller, G.; Ambaram, P.] Charlotte Maxeke Johannesburg Acad Hosp, Johannesburg, South Africa. [Reuter, H.] Winelands Rheumatol Ctr, Stellenbosch, South Africa. [Reuter, H.] Univ Stellenbosch, Dept Med, Stellenbosch, South Africa. [Lewandowski, L. B.] NIAMSD, NIH, Bethesda, MD 20892 USA. EM laura.lewandowski@nih.gov FU Lupus Foundation of America Early Career Award; T32 Training grant [5T32 AI0007217-31]; Duke Global Health Institute Fieldwork grant; Fogarty International Center of the NIH [R25TW009337]; NIAMS [RC2AR058934]; Friends of CARRA; Arthritis Foundation FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: LL was funded by the Lupus Foundation of America Early Career Award, T32 Training grant 5T32 AI0007217-31, Duke Global Health Institute Fieldwork grant and the Fogarty International Center of the NIH R25TW009337. The CARRA Registry was supported by grants from NIAMS RC2AR058934, Friends of CARRA and the Arthritis Foundation. NR 63 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0961-2033 EI 1477-0962 J9 LUPUS JI Lupus PD FEB PY 2017 VL 26 IS 2 BP 186 EP 194 DI 10.1177/0961203316660625 PG 9 WC Rheumatology SC Rheumatology GA EI6OO UT WOS:000392615400010 ER PT J AU Park, JW Zhao, L Willingham, MC Cheng, SY AF Park, Jeong Won Zhao, Li Willingham, Mark C. Cheng, Sheue-yann TI Loss of tyrosine phosphorylation at Y406 abrogates the tumor suppressor functions of the thyroid hormone receptor SO MOLECULAR CARCINOGENESIS LA English DT Article DE thyroid cancer; thyroid hormone receptor mutant; phosphorylation of thyroid hormone receptor 1; tumor suppressor; xenograft models ID STIMULATING HORMONE; BETA GENE; XENOGRAFT MODELS; BREAST-CANCER; MOUSE MODEL; CARCINOMA; TUMORIGENESIS; NECROSIS; TSH; MUTATIONS AB We have recently identified that phosphorylation at tyrosine (Y)406 is critical for the tumor suppressor functions of the thyroid hormone receptor 1 (TR) in a breast cancer line. However, still unclear is whether the critical tumor suppressor role of phosphorylated Y406 of TR is limited to only breast cancer cells or could be extended to other cell types. In the present studies, we addressed this question by stably expressing TR, a mutated TR oncogene (PV), or a TR mutated at Y406 (TRY406F) in rat PCCL3 thyroid follicular cells and evaluated their tumor characteristics in athymic mice with elevated thyroid stimulating hormone. PCCL3 cells stably expressing PV (PCCL3-PV), TRY406F (PCCL3-TRY406F), or vector only (PCCL3-Neo) developed tumors with sizes in the rank order of TRY406F>PV=Neo, whereas PCCL3 cells expressing TR (PCCL3-TR) barely developed tumors. As evidenced by markedly elevated Ki67, cyclin D1, and p-Rb protein abundance, proliferative activity was high in PV and TRY406F tumors, but low in TR tumors. These results indicate that TR acted as a tumor suppressor in PCCL3 cells, whereas TRY406F and PV had lost tumor suppressor activity. Interestingly, TRY406F tumors had very low necrotic areas with decreased TNF-NFB signaling to lower apoptotic activity. In contrast, PV tumors had prominent large necrotic areas, with no apparent changes in TNF-NFB signaling, indicating distinct oncogenic activities of mutant PV and TRY406F. Thus, the present studies uncovered a novel mechanism by which TR could function as a tumor suppressor through modulation of the TNF-NFB signaling. (c) 2016 Wiley Periodicals, Inc. C1 [Park, Jeong Won; Zhao, Li; Willingham, Mark C.; Cheng, Sheue-yann] NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Intramural Research Program at the Center for Cancer Research; National Cancer Institute; National Institutes of Health FX Grant sponsor: Intramural Research Program at the Center for Cancer Research; Grant sponsor: National Cancer Institute; Grant sponsor: National Institutes of Health NR 41 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD FEB PY 2017 VL 56 IS 2 BP 489 EP 498 DI 10.1002/mc.22511 PG 10 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA EI5GH UT WOS:000392521800016 PM 27254276 ER PT J AU Suboticki, T Ajtic, OM Beleslin-Cokic, BB Nienhold, R Diklic, M Djikic, D Lekovic, D Bulat, T Markovic, D Gotic, M Noguchi, CT Schechter, AN Skoda, RC Cokic, VP AF Suboticki, Tijana Ajtic, Olivera Mitrovic Beleslin-Cokic, Bojana B. Nienhold, Ronny Diklic, Milos Djikic, Dragoslava Lekovic, Danijela Bulat, Tanja Markovic, Dragana Gotic, Mirjana Noguchi, Constance T. Schechter, Alan N. Skoda, Radek C. Cokic, Vladan P. TI Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms SO MOLECULAR CARCINOGENESIS LA English DT Article DE angiogenesis; myeloproliferative neoplasm; HIF-1; VEGF; eNOS ID ENDOTHELIAL GROWTH-FACTOR; INDUCIBLE FACTOR-I; NITRIC-OXIDE; BONE-MARROW; ESSENTIAL THROMBOCYTHEMIA; PROMOTES ANGIOGENESIS; THERAPEUTIC TARGET; TUMOR ANGIOGENESIS; SERUM-LEVELS; VEGF AB It has been shown that angiogenesis and inflammation play an important role in development of most hematological malignancies including the myeloproliferative neoplasm (MPN). The aim of this study was to investigate and correlate the levels of key angiogenic molecules such as hypoxia-inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in peripheral blood and bone marrow cells of MPN patients, along with JAK2V617F mutation allele burden and effects of therapy. HIF-1 and VEGF gene expression were decreased, while eNOS mRNA levels were increased in granulocytes of MPN patients. Furthermore, positively correlated and increased VEGF and eNOS protein levels were in negative correlation with HIF-1 levels in granulocytes of MPN patients. According to immunoblotting, the generally augmented angiogenic factors demonstrated JAK2V617F allele burden dependence only in granulocytes of PMF. The angiogenic factors were largely reduced after hydroxyurea therapy in granulocytes of MPN patients. Levels of eNOS protein expression were stimulated by Calreticulin mutations in granulocytes of essential thrombocythemia. Immunocytochemical analyses of CD34(+) cells showed a more pronounced enhancement of angiogenic factors than in granulocytes. Increased gene expression linked to the proinflammatory TGF and MAPK signaling pathways were detected in CD34(+) cells of MPN patients. In conclusion, the angiogenesis is increased in several cell types of MPN patients supported by the transcriptional activation of inflammation-related target genes, and is not limited to bone marrow stroma cells. It also appears that some of the benefit of hydroxyurea therapy of the MPN is mediated by effects on angiogenic factors. (c) 2016 Wiley Periodicals, Inc. C1 [Suboticki, Tijana; Ajtic, Olivera Mitrovic; Diklic, Milos; Djikic, Dragoslava; Markovic, Dragana; Cokic, Vladan P.] Univ Belgrade, Inst Med Res, Belgrade, Serbia. [Beleslin-Cokic, Bojana B.] Clin Ctr Serbia, Clin Endocrinol Diabet & Metab Dis, Genet Lab, Belgrade, Serbia. [Nienhold, Ronny; Skoda, Radek C.] Univ Basel Hosp, Dept Biomed, Expt Hematol, Basel, Switzerland. [Lekovic, Danijela; Gotic, Mirjana] Clin Ctr Serbia, Clin Hematol, Belgrade, Serbia. [Bulat, Tanja] Univ Belgrade, Inst Nucl Sci Vinca, Belgrade, Serbia. [Gotic, Mirjana] Univ Belgrade, Fac Med, Belgrade, Serbia. [Noguchi, Constance T.; Schechter, Alan N.] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. EM vl@imi.bg.ac.rs FU Serbian Ministry of Education, Science and Technological Development [OI175053]; Swiss National Science Foundation [IZ73Z0_152420]; National Institute of Diabetes and Digestive and Kidney Diseases FX Grant sponsor: Serbian Ministry of Education, Science and Technological Development; Grant number: OI175053; Grant sponsor: Swiss National Science Foundation; Grant number: IZ73Z0_152420; Grant sponsor: National Institute of Diabetes and Digestive and Kidney Diseases NR 46 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD FEB PY 2017 VL 56 IS 2 BP 567 EP 579 DI 10.1002/mc.22517 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA EI5GH UT WOS:000392521800022 PM 27341002 ER PT J AU Zhu, L Almaca, J Dadi, PK Hong, H Sakamoto, W Rossi, M Lee, RJ Vierra, NC Lu, HY Cui, YH McMillin, SM Perry, NA Gurevich, VV Lee, A Kuo, B Leapman, RD Matschinsky, FM Doliba, NM Urs, NM Caron, MG Jacobson, DA Caicedo, A Wess, J AF Zhu, Lu Almaca, Joana Dadi, Prasanna K. Hong, Hao Sakamoto, Wataru Rossi, Mario Lee, Regina J. Vierra, Nicholas C. Lu, Huiyan Cui, Yinghong McMillin, Sara M. Perry, Nicole A. Gurevich, Vsevolod V. Lee, Amy Kuo, Bryan Leapman, Richard D. Matschinsky, Franz M. Doliba, Nicolai M. Urs, Nikhil M. Caron, Marc G. Jacobson, David A. Caicedo, Alejandro Wess, Jurgen TI beta-arrestin-2 is an essential regulator of pancreatic beta-cell function under physiological and pathophysiological conditions SO Nature Communications LA English DT Article ID PROTEIN-KINASE-II; INSULIN-SECRETION; ISLET CELLS; INTRACELLULAR TRAFFICKING; 7-TRANSMEMBRANE RECEPTORS; SIGNALING PATHWAY; GLUCOSE-TOLERANCE; CALCIUM-CHANNELS; GLUCAGON-RELEASE; SYNAPSIN-I AB beta-arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show that inactivation of the beta-arrestin-2 gene, barr2, in beta-cells of adult mice greatly impairs insulin release and glucose tolerance in mice fed with a calorie-rich diet. Both glucose and KCl-induced insulin secretion and calcium responses were profoundly reduced in beta-arrestin-2 (barr2) deficient beta-cells. In human beta-cells, barr2 knockdown abolished glucose-induced insulin secretion. We also show that the presence of barr2 is essential for proper CAMKII function in beta-cells. Importantly, overexpression of barr2 in beta-cells greatly ameliorates the metabolic deficits displayed by mice consuming a high-fat diet. Thus, our data identify barr2 as an important regulator of beta-cell function, which may serve as a new target to improve beta-cell function. C1 [Zhu, Lu; Hong, Hao; Sakamoto, Wataru; Rossi, Mario; Lee, Regina J.; Cui, Yinghong; McMillin, Sara M.; Wess, Jurgen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. [Almaca, Joana; Caicedo, Alejandro] Univ Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Dept Med, Miami, FL 33136 USA. [Dadi, Prasanna K.; Vierra, Nicholas C.; Jacobson, David A.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Hong, Hao] Nanjing Univ Chinese Med, Key Lab Acupuncture & Med Res, Minist Educ, Nanjing 210023, Jiangsu, Peoples R China. [Lu, Huiyan] NIDDK, Mouse Transgen Core Facil, Bethesda, MD 20892 USA. [Perry, Nicole A.; Gurevich, Vsevolod V.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA. [Lee, Amy] Univ Iowa, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA. [Kuo, Bryan; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, Bethesda, MD 20892 USA. [Matschinsky, Franz M.; Doliba, Nicolai M.] Univ Penn, Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. [Urs, Nikhil M.; Caron, Marc G.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov OI Zhu, Lu/0000-0003-2716-4649 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, NIH); ADA grant [7-11-BS-34]; Diabetes Center grant [NIH DK-19525]; NIH grants [DK097392, 5R37-MH-073853, R01DK084321, R21ES025673, R01NS084190, R01DC009433, RO1 GM109955, GM077561, EY011500]; American Heart Association [14POST20380499]; TCM stipend [012062003009K] FX This research was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, NIH), ADA grant 7-11-BS-34 (N.M.D.) and Diabetes Center grant NIH DK-19525 (N.M.D., F.M.M.). D.A.J. and M.G.C. were supported by NIH grants DK097392 and 5R37-MH-073853, respectively. A.C. was funded by NIH grants R01DK084321 and R21ES025673. J.A. is a recipient of a postdoctoral fellowship from the American Heart Association (14POST20380499). H.H. received a stipend from Chinese sources (program to support Traditional Chinese Medicine; TCM stipend No. 012062003009K). A.L. was supported by NIH grants R01NS084190 and R01DC009433. V.V.G. was funded by NIH grants RO1 GM109955, GM077561 and EY011500. We thank Drs Maria Aronova and Guofeng Zhang in the laboratory of Dr R. Leapman (NIBIB, NIH) for their help with the electron microscopic studies, Dr Lingdi Wang (NHLBI, NIH) for her help with the co-immunoprecipitation work, and Drs Johannes Backs and Jutta Krebs-Haupenthal (University of Heidelberg, Heidelberg, Germany) for providing us with the myc-CAMKII adenovirus. The adenoviruses coding for constitutively active and dominant-negative versions of CAMKII (adeno-CA-CAMKII and adeno-KD-CAMKII, respectively) were a gift by Drs Lale Ozcan and Ira Tabas (Columbia University). NR 69 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB 1 PY 2017 VL 8 AR 14295 DI 10.1038/ncomms14295 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ2YF UT WOS:000393076800001 PM 28145434 ER PT J AU D'Souza, G Anantharaman, D Gheit, T Abedi-Ardekani, B Beachler, DC Conway, DI Olshan, AF Wunsch, V Toporcov, TN Ahrens, W Wisniewski, K Merletti, F Boccia, S Tajara, EH Zevallos, JP Levi, JE Weissler, MC Wright, S Scelo, G Mazul, AL Tommasino, M Cadoni, G Brennan, P AF D'Souza, Gypsyamber Anantharaman, Devasena Gheit, Tarik Abedi-Ardekani, Behnoush Beachler, Daniel C. Conway, David I. Olshan, Andrew F. Wunsch-Filho, Victor Toporcov, Tatiana N. Ahrens, Wolfgang Wisniewski, Kathy Merletti, Franco Boccia, Stefania Tajara, Eloiza H. Zevallos, Jose P. Levi, Jose Eduardo Weissler, Mark C. Wright, Sylvia Scelo, Ghislaine Mazul, Angela L. Tommasino, Massimo Cadoni, Gabriella Brennan, Paul TI Effect of HPV on head and neck cancer patient survival, by region and tumor site: A comparison of 1362 cases across three continents (vol 62, pg 20, 2016) SO ORAL ONCOLOGY LA English DT Correction C1 [D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Anantharaman, Devasena; Scelo, Ghislaine; Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, Lyon, France. [Gheit, Tarik; Tommasino, Massimo] Int Agcy Res Canc, Infect & Canc Biol Grp, Lyon, France. [Abedi-Ardekani, Behnoush] Int Agcy Res Canc, Genet Canc Susceptibil Grp, Lyon, France. [Beachler, Daniel C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Conway, David I.] Univ Glasgow, Sch Med Dent & Nursing, Glasgow, Lanark, Scotland. [Olshan, Andrew F.; Wisniewski, Kathy; Mazul, Angela L.] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA. [Wunsch-Filho, Victor; Toporcov, Tatiana N.] Univ Sao Paulo, Sch Publ Hlth, Dept Epidemiol, Sao Paulo, Brazil. [Ahrens, Wolfgang] Leibniz Inst Prevent Res & Epidemiol BIPS, Bremen, Germany. [Ahrens, Wolfgang] Univ Bremen, Inst Stat, Bremen, Germany. [Merletti, Franco] Univ Turin, Dept Med Sci, Turin, Italy. [Boccia, Stefania] Univ Cattolica Sacro Cuore, Fac Med, Inst Publ Hlth, Sect Hyg, Rome, Italy. [Tajara, Eloiza H.] Fac Med Sao Jose do Rio Preto, Dept Mol Biol, Sao Paulo, Brazil. [Zevallos, Jose P.; Weissler, Mark C.] Univ North Carolina Chapel Hill, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC USA. [Levi, Jose Eduardo] Univ Sao Paulo, Inst Trop Med, Virol Lab, Sao Paulo, Brazil. [Wright, Sylvia] Queen Elizabeth Univ Hosp, Dept Pathol, Glasgow, Lanark, Scotland. [Cadoni, Gabriella] Univ Cattolica Sacro Cuore, Fdn Policlin A Gemelli, Inst Otorhinolaryngol, Head & Neck Surg Dept, Rome, Italy. EM gdsouza2@jhu.edu; brennan@iarc.fr NR 1 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD FEB PY 2017 VL 65 BP E1 EP E1 DI 10.1016/j.oraloncology.2016.12.023 PG 1 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA EI6XO UT WOS:000392641100001 PM 28043765 ER PT J AU Eisner, C Kim, S Grill, A Qin, Y Hoerl, M Briggs, J Castrop, H Thiel, M Schnermann, J AF Eisner, Christoph Kim, SooMi Grill, Alexandra Qin, Yan Hoerl, Marion Briggs, Josephine Castrop, Hayo Thiel, Manfred Schnermann, Jurgen TI Profound hypothermia after adenosine kinase inhibition in A1AR-deficient mice suggests a receptor-independent effect of intracellular adenosine SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE Mice; Adenosine; Nucleotides; Hypothermia; Adenosine kinase ID CYTOCHROME-C-OXIDASE; PROTEIN-SYNTHESIS; SPINAL-CORD; RATS; RELEASE; HYPERALGESIA; HEPATOCYTES; INVOLVEMENT; PERFORMANCE; ORGANISMS AB Administration of the nucleoside adenosine has been shown to induce hypothermia in a number of species, an effect mediated predominantly by the adenosine 1 receptor (A1AR) subtype. The present experiments were performed to explore the possibility that the rise of intracellular adenosine levels expected to accompany adenosine administration may contribute to the hypothermic effect of adenosine independent of A1AR activation. Since phosphorylation of adenosine by adenosine kinase (ADK) is causal in the maintenance of low intracellular adenosine, we have examined the effect of ADK inhibition on core body temperature (CBT). Our data show that inhibition of ADK by A-134974 causes a long-lasting deep hypothermia in wild-type mice. Since there was an about 4-fold increase of adenosine plasma levels, experiments were repeated in A1AR-/- mice. ADK inhibition caused deep hypothermia despite the absence of A1AR, although the effect was significantly reduced compared to WT. Furthermore, the dose-dependent hypothermia caused by adenosine administration inWTmice was found to be reduced, but not abolished in A1AR-/- mice. To assess the possible role of A2AR and A3AR activation in our experimental setting, we compared the effects of the agonists CPA (A1AR), CGS21680 (A2AR), and IB-MECA (A3AR) on CBT. Hypothermia induced by CPA was much greater than that caused by CGS21680 or IB-MECA indicating that A1AR activation is the major receptor-dependent pathway for adenosine-induced hypothermia under our experimental conditions. Induction of deep hypothermia by inhibition of ADK, maintenance of this effect in A1AR-/- mice, and maintenance of adenosine-induced hypothermia in A1AR-deficient mice suggest that a receptor-independent action of adenosine requiring intact function of adenosine kinase contributes importantly to the hypothermia induced by adenosine. C1 [Eisner, Christoph; Kim, SooMi; Qin, Yan; Schnermann, Jurgen] NIDDK, Bethesda, MD 20892 USA. [Eisner, Christoph] Univ Heidelberg Hosp, Dept Anesthesiol, Heidelberg, Germany. [Grill, Alexandra; Castrop, Hayo] Univ Regensburg, Inst Physiol, Regensburg, Germany. [Hoerl, Marion] LMU, Dept Anesthesiol, Munich, Germany. [Briggs, Josephine] Natl Ctr Complementary & Integrat Hlth, Bethesda, MD USA. [Thiel, Manfred] Univ Med Mannheim, Dept Anesthesiol & Crit Care, Mannheim, Germany. EM christoph.eisner@med.uni-heidelberg.de NR 33 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 EI 1432-2013 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD FEB PY 2017 VL 469 IS 2 BP 339 EP 347 DI 10.1007/s00424-016-1925-3 PG 9 WC Physiology SC Physiology GA EI6QC UT WOS:000392619600014 PM 27975140 ER PT J AU Harrison, EM Carmack, SA Block, CL Sun, J Anagnostaras, SG Gorman, MR AF Harrison, E. M. Carmack, S. A. Block, C. L. Sun, J. Anagnostaras, S. G. Gorman, M. R. TI Circadian waveform bifurcation, but not phase-shifting, leaves cued fear memory intact SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Circadian; Waveform; Bifurcation; Pavlovian fear conditioning; Learning; Memory ID LONG-TERM POTENTIATION; SUPRACHIASMATIC NUCLEUS; BASOLATERAL AMYGDALA; CONTEXTUAL FEAR; MALE RATS; LIGHT; MICE; HIPPOCAMPUS; RHYTHM; SLEEP AB In mammals, memory acquisition and retrieval can be affected by time of day, as well as by manipulations of the light/dark cycle. Under bifurcation, a manipulation of circadian waveform, two subjective days and nights are experimentally induced in rodents. We examined the effect of bifurcation on Pavlovian fear conditioning, a prominent model of learning and memory. Here we demonstrate that bifurcation of the circadian waveform produces a small deficit in acquisition, but not on retrieval of fear memory. In contrast, repeated phase-shifting in a simulated jet-lag protocol impairs retrieval of memory for cued fear. The results have implications for those attempting to adjust to shift-work or other challenging schedules. (C) 2016 Elsevier Inc. All rights reserved. C1 [Harrison, E. M.; Sun, J.; Gorman, M. R.] Univ San Diego, Ctr Circadian Biol, 9500 Gilman Dr, La Jolla, CA 92093 USA. [Harrison, E. M.; Sun, J.; Anagnostaras, S. G.; Gorman, M. R.] Univ Calif San Diego, Dept Psychol, 9500 Gilman Dr, La Jolla, CA 92093 USA. [Carmack, S. A.] NIDA, Neurobiol Addict Sect, NIH, Baltimore, MD USA. [Block, C. L.] Duke Univ, Dept Psychol & Neurosci, 417 Chapel Dr, Durham, NC 27708 USA. RP Harrison, EM (reprint author), Univ San Diego, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM emharrison@ucsd.edu FU National Institutes of Health [R01 HD036460]; Office of Naval Research [N000141310285] FX The authors would like to thank Antonio Mora and Gil Sanchez for their excellent animal care. Additional thanks go to Qays Poonawala, Jeremy Johnson, Matthew Hermann and Deborah May for their technical assistance. This work was supported by the National Institutes of Health (R01 HD036460) and the Office of Naval Research (N000141310285). NR 49 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD FEB 1 PY 2017 VL 169 BP 106 EP 113 DI 10.1016/j.physbeh.2016.11.033 PG 8 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA EI8RB UT WOS:000392774100015 PM 27890591 ER PT J AU Liu, H Shen, Y Ning, J Qin, J AF Liu, Hao Shen, Yu Ning, Jing Qin, Jing TI Sample size calculations for prevalent cohort designs SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE incident cohort design; length-biased data; prevalent cohort design; sample size determination; survival data ID NONPARAMETRIC-ESTIMATION; SURVIVAL-DATA; COX MODEL; LIKELIHOOD; TRIALS; BIASES; POWER; AIDS AB Cross-sectional prevalent cohort design has drawn considerable interests in the studies of association between risk factors and time-to-event outcome. The sampling scheme in such design gives rise to length-biased data that require specialized analysis strategy but can improve study efficiency. The power and sample size calculation methods are however lacking for studies with prevalent cohort design, and using the formula developed for traditional survival data may overestimate sample size. We derive the sample size formulas that are appropriate for the design of cross-sectional prevalent cohort studies, under the assumptions of exponentially distributed event time and uniform follow-up for cross-sectional prevalent cohort design. We perform numerical and simulation studies to compare the sample size requirements for achieving the same power between prevalent cohort and incident cohort designs. We also use a large prospective prevalent cohort study to demonstrate the procedure. Using rigorous designs and proper analysis tools, the prospective prevalent cohort design can be more efficient than the incident cohort design with the same total sample sizes and study durations. C1 [Liu, Hao] Baylor Coll Med, Dan L Duncan Canc Ctr, Div Biostat, Houston, TX 77030 USA. [Shen, Yu; Ning, Jing] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Qin, Jing] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Liu, H (reprint author), Baylor Coll Med, Dan L Duncan Canc Ctr, Div Biostat, Houston, TX 77030 USA. EM haol@bcm.edu FU National Institutes of Health [CA079466, CA016672, CA126752] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work in this paper was supported in part by the National Institutes of Health (grants CA079466, CA016672, and CA126752). NR 25 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2017 VL 26 IS 1 BP 280 EP 291 DI 10.1177/0962280214544730 PG 12 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA EJ1KK UT WOS:000392968900018 PM 25091809 ER PT J AU Misiak, M Greeno, RV Baptiste, BA Sykora, P Liu, D Cordonnier, S Fang, EF Croteau, DL Mattson, MP Bohr, VA AF Misiak, Magdalena Greeno, Rebeca Vergara Baptiste, Beverly A. Sykora, Peter Liu, Dong Cordonnier, Stephanie Fang, Evandro F. Croteau, Deborah L. Mattson, Mark P. Bohr, Vilhelm A. TI DNA polymerase beta decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer's disease SO AGING CELL LA English DT Article DE DNA repair; DNA damage; DNA polymerase beta; Alzheimer's disease; neurogenesis; olfactory bulb; smell ID BASE-EXCISION-REPAIR; MILD COGNITIVE IMPAIRMENT; AMYLOID-BETA; ISCHEMIC-STROKE; A-BETA; DAMAGE; NEURONS; BRAIN; MICE; NEUROGENESIS AB Alzheimer's disease (AD) involves the progressive degeneration of neurons critical for learning and memory. In addition, patients with AD typically exhibit impaired olfaction associated with neuronal degeneration in the olfactory bulb (OB). Because DNA base excision repair (BER) is reduced in brain cells during normal aging and AD, we determined whether inefficient BER due to reduced DNA polymerase-beta (Pol beta) levels renders OB neurons vulnerable to degeneration in the 3xTgAD mouse model of AD. We interrogated OB histopathology and olfactory function in wild-type and 3xTgAD mice with normal or reduced Pol beta levels. Compared to wild-type control mice, Pol beta heterozygous (Pol beta(+/-)), and 3xTgAD mice, 3xTgAD/Pol beta(+/-) mice exhibited impaired performance in a buried food test of olfaction. Pol beta deficiency did not affect the proliferation of OB neural progenitor cells in the subventricular zone. However, numbers of newly generated neurons were reduced by approximately 25% in Pol beta(+/-) and 3xTgAD mice, and by over 60% in the 3xTgAD/Pol beta(+/-) mice compared to wild-type control mice. Analyses of DNA damage and apoptosis revealed significantly greater degeneration of OB neurons in 3xTgAD/Pol beta(+/-) mice compared to 3xTgAD mice. Levels of amyloid b-peptide (A beta) accumulation in the OB were similar in 3xTgAD and 3xTgAD/Pol beta(+/-) mice, and cultured Pol beta-deficient neurons exhibited increased vulnerability to A beta-induced death. Olfactory deficit is an early sign in human AD, but the mechanism is not yet understood. Our findings in a new AD mouse model demonstrate that diminution of BER can endanger OB neurons, and suggest a mechanism underlying early olfactory impairment in AD. C1 [Misiak, Magdalena; Baptiste, Beverly A.; Sykora, Peter; Cordonnier, Stephanie; Fang, Evandro F.; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Intramural Res Program, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Misiak, Magdalena; Greeno, Rebeca Vergara; Liu, Dong; Cordonnier, Stephanie; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Intramural Res Program, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA.; Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov; bohrv@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institute on Aging. NR 45 TC 0 Z9 0 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD FEB PY 2017 VL 16 IS 1 BP 162 EP 172 DI 10.1111/acel.12541 PG 11 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA EI2AG UT WOS:000392287700015 PM 27686631 ER PT J AU Machado, LB Apolo, AB Steinberg, SM Folio, LR AF Machado, Laura B. Apolo, Andrea B. Steinberg, Seth M. Folio, Les R. TI Radiology Reports With Hyperlinks Improve Target Lesion Selection and Measurement Concordance in Cancer Trials SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE hyperlinks; multimedia; radiology reports; Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; tumor assessment ID REGISTRATION; ONCOLOGISTS; EFFICIENCY; TUMORS; PACS AB OBJECTIVE. Radiology reports often lack the measurements of target lesions that are needed for oncology clinical trials. When available, the measurements in the radiology reports often do not match those in the records used to calculate therapeutic response. This study assessed the clinical value of hyperlinked tumor measurements in multimedia-enhanced radiology reports in the PACS and the inclusion of a radiologist assistant in the process of assessing tumor burden. MATERIALS AND METHODS. We assessed 489 target lesions in 232 CT examinations of 71 patients with metastatic genitourinary cancer enrolled in two therapeutic trials. We analyzed target lesion selection and measurement concordance between oncology records (used to calculate therapeutic response) and two types of radiology reports in the PACS: multimedia-enhanced radiology reports and text-only reports. For statistical tests, we used the Wilcoxon signed rank, Wilcoxon rank sum test, and Fisher method to combine p values from the paired and unpaired results. The Fisher exact test was used to compare overall measurement concordance. RESULTS. Concordance on target lesion selection was greater for multimedia-enhanced radiology reports (78%) than the text-only reports (52%) (p = 0.0050). There was also improved overall measurement concordance with the multimedia-enhanced radiology reports (68%) compared with the text-only reports (38%) (p < 0.0001). CONCLUSION. Compared with text-only reports, hyperlinked multimedia-enhanced radiology reports improved concordance of target lesion selection and measurement with the measurements used to calculate therapeutic response. C1 [Machado, Laura B.; Folio, Les R.] NIH, Radiol & Imaging Sci, Ctr Clin, 9000 Rockville Pike,Bldg 10, Bethesda, MD 20892 USA. [Apolo, Andrea B.] NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, Rockville, MD USA. RP Machado, LB (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, 9000 Rockville Pike,Bldg 10, Bethesda, MD 20892 USA. EM machadolaurab@gmail.com FU Intramural Research Program of the NIH Clinical Center FX This research was supported in part by the Intramural Research Program of the NIH Clinical Center. NR 23 TC 0 Z9 0 U1 1 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2017 VL 208 IS 2 BP W31 EP W37 DI 10.2214/AJR.16.16845 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EI4QQ UT WOS:000392478800001 PM 28112557 ER PT J AU Lindqvist, EK Landgren, O Lund, SH Turesson, I Hultcrantz, M Goldin, L Bjorkholm, M Kristinsson, SY AF Lindqvist, Ebba K. Landgren, Ola Lund, Sigrun H. Turesson, Ingemar Hultcrantz, Malin Goldin, Lynn Bjorkholm, Magnus Kristinsson, Sigurdur Y. TI History of autoimmune disease is associated with impaired survival in multiple myeloma and monoclonal gammopathy of undetermined significance: a population-based study SO ANNALS OF HEMATOLOGY LA English DT Article DE Autoimmunity; Multiple myeloma; MGUS; Survival; Population-based ID UNITED-STATES; 1ST-DEGREE RELATIVES; LONG-TERM; RISK; PATTERNS; COMORBIDITY; DISORDERS; LYMPHOMA; SWEDEN; AGE AB Multiple myeloma (MM) is a plasma cell disorder preceded by monoclonal gammopathy of undetermined significance (MGUS). Incidence of MM and MGUS is higher among patients with autoimmune disease. The aim of this study was to determine whether a history of autoimmunity has an impact on survival in MM and MGUS. Using high-quality national Swedish registries, we identified 8367 patients with MM, 18,768 patients with MGUS, and 110,251 matched control subjects, and obtained information on previous autoimmune disease in patients and controls. Cox regression was used to calculate hazard ratios (HRs) for overall survival with 95 % confidence intervals (CIs). In patients with MM and a prior autoimmune disease, the risk of death was significantly increased, HR = 1.2 (95 % CI 1.2-1.3) compared to MM patients with no history of autoimmunity. In MGUS patients, a prior autoimmune disease was associated with a significantly 1.4-fold elevated risk of death (95 % CI 1.3-1.4). When analyzing different types of autoimmune diseases, a history of ulcerative colitis had a stronger impact on survival in MM than in controls. Our findings that a history of autoimmune disease has a negative impact on survival in MM and MGUS could be due to shared underlying common genetic factors, or that patients with a history of autoimmunity develop more severe cases of MM and MGUS, or cumulative comorbidity in the individual. Our results suggest that more attention should be paid to comorbidity as a prognostic factor in MGUS and MM, and underlines the need for studies aimed at tailoring therapy according to comorbidity. C1 [Lindqvist, Ebba K.; Hultcrantz, Malin; Bjorkholm, Magnus; Kristinsson, Sigurdur Y.] Karolinska Univ Hosp, Div Hematol, Dept Med, S-17176 Stockholm, Sweden. [Lindqvist, Ebba K.; Hultcrantz, Malin; Bjorkholm, Magnus; Kristinsson, Sigurdur Y.] Karolinska Inst, S-17176 Stockholm, Sweden. [Landgren, Ola; Hultcrantz, Malin] Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA. [Lund, Sigrun H.; Kristinsson, Sigurdur Y.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Turesson, Ingemar] Skane Univ Hosp, Dept Hematol & Coagulat Disorders, Malmo, Sweden. [Goldin, Lynn] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Lindqvist, EK (reprint author), Karolinska Univ Hosp, Div Hematol, Dept Med, S-17176 Stockholm, Sweden.; Lindqvist, EK (reprint author), Karolinska Inst, S-17176 Stockholm, Sweden. EM ebba.lindqvist@ki.se FU Swedish Blodcancerfonden; Swedish Cancer Society; Stockholm County Council; Karolinska Institutet; Karolinska Institutet Foundations; University of Iceland; Icelandic Centre for Research (RANNIS); Landspitali University Hospital FX This research was supported by grants from the Swedish Blodcancerfonden, the Swedish Cancer Society, the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Karolinska Institutet Foundations, the University of Iceland Research Fund, Icelandic Centre for Research (RANNIS), and Landspitali University Hospital research Fund. NR 43 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-5555 EI 1432-0584 J9 ANN HEMATOL JI Ann. Hematol. PD FEB PY 2017 VL 96 IS 2 BP 261 EP 269 DI 10.1007/s00277-016-2859-8 PG 9 WC Hematology SC Hematology GA EI2GO UT WOS:000392305100010 PM 27807648 ER PT J AU Konig, N Fiehn, C Wolf, C Schuster, M Costa, EC Tungler, V Alvarez, HA Chara, O Engel, K Goldbach-Mansky, R Gunther, C Lee-Kirsch, MA AF Konig, Nadja Fiehn, Christoph Wolf, Christine Schuster, Max Costa, Emanuel Cura Tungler, Victoria Alvarez, Hugo Ariel Chara, Osvaldo Engel, Kerstin Goldbach-Mansky, Raphaela Gunther, Claudia Lee-Kirsch, Min Ae TI Familial chilblain lupus due to a gain-of-function mutation in STING SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID AICARDI-GOUTIERES-SYNDROME; INNATE IMMUNE-RESPONSE; TREX1; RUXOLITINIB; DISEASE; ERYTHEMATOSUS; UNDERLIES; REVEALS; PATHWAY; SAMHD1 AB Objectives Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREXI or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology. Methods Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-13 reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes. Results In a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase (JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature. Conclusions A heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFNdependent disorders and suggest that JAK inhibition may be of therapeutic value. C1 [Konig, Nadja; Wolf, Christine; Schuster, Max; Tungler, Victoria; Engel, Kerstin; Lee-Kirsch, Min Ae] Tech Univ Dresden, Med Fak Carl Gustav Carus, Dept Pediat, Fetscherstr 74, D-01307 Dresden, Germany. [Fiehn, Christoph] ACURA Akutklin Rheumatol Baden Baden, Baden Baden, Germany. [Costa, Emanuel Cura; Alvarez, Hugo Ariel; Chara, Osvaldo] Univ La Plata, CONICET, Inst Phys Liquids & Biol Syst IFLYSIB, Syst Biol Grp SysBio, La Plata, Argentina. [Chara, Osvaldo] Tech Univ Dresden, Ctr Informat Serv & High Performance Comp, Dresden, Germany. [Goldbach-Mansky, Raphaela] NIAMS, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD USA. [Gunther, Claudia] Tech Univ Dresden, Med Fak Carl Gustav Carus, Dept Dermatol, Dresden, Germany. RP Lee-Kirsch, MA (reprint author), Tech Univ Dresden, Med Fak Carl Gustav Carus, Dept Pediat, Fetscherstr 74, D-01307 Dresden, Germany. EM minae.lee-kirsch@uniklinikum-dresden.de RI Alvarez, Hugo Ariel/E-3707-2016 OI Alvarez, Hugo Ariel/0000-0002-6007-0452 FU Deutsche Forschungsgemeinschaft [LE 1074/3-1, LE 1074/4-1, TU 421/1-2, GU1212/1-1, GU 1212/1-2]; Friede Springer Stiftung; TU Dresden Graduate Academy (greatlipid4all); Deutsche Forschungsgemeinschaft FX Supported by grants from the Deutsche Forschungsgemeinschaft (LE 1074/3-1 and LE 1074/4-1, to MAL-K; TU 421/1-2 to VT, GU1212/1-1 and GU 1212/1-2 to CG), the Friede Springer Stiftung and the TU Dresden Graduate Academy (greatlipid4all) to MAL-K. OC is a career researcher of the Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET) Argentina. The Deep Sequencing Facility of the Biotechnology Center and the Center for Regenerative Therapies Dresden, Technische Universitat Dresden, are funded by the Deutsche Forschungsgemeinschaft. NR 23 TC 4 Z9 4 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD FEB PY 2017 VL 76 IS 2 BP 468 EP 472 DI 10.1136/annrheumdis-2016-209841 PG 5 WC Rheumatology SC Rheumatology GA EI3XT UT WOS:000392426900022 PM 27566796 ER PT J AU Wang, H Romano, G Fedgchin, M Russell, L Sanga, P Kelly, KM Frustaci, ME Thipphawong, J AF Wang, Hao Romano, Gary Fedgchin, Margaret Russell, Lucille Sanga, Panna Kelly, Kathleen M. Frustaci, Mary Ellen Thipphawong, John TI Fulranumab in Patients With Pain Associated With Postherpetic Neuralgia and Postraumatic Neuropathy Efficacy, Safety, and Tolerability Results From a Randomized, Double-blind, Placebo-controlled, Phase-2 Study SO CLINICAL JOURNAL OF PAIN LA English DT Article DE antinerve growth factor; fulranumab; neuropathic pain; postherpetic neuralgia; posttraumatic neuropathy ID LOW-BACK-PAIN; GENERAL-POPULATION; HERPES-ZOSTER; TANEZUMAB; OSTEOARTHRITIS; RELIEF; BURDEN; DRUGS; NGF AB Objective: Fulranumab is an antibody that specifically neutralizes the biological activity of human nerve growth factor. This multicenter, phase-2, randomized, double-blind (DB), placebo-controlled study evaluated the analgesic efficacy and safety of fulranumab in postherpetic neuralgia (PHN) and posttraumatic neuropathy (PTN) patients. Methods: Patients (18 to 80 y) with inadequately controlled moderate-to-severe pain received study medication (subcutaneous injection) every 4 weeks. PHN patients were randomized (3: 2: 2: 3) to receive either placebo or one of 3 doses of fulranumab: 1mg (1 mgQ4wk), 3mg (3 mgQ4wk), or 10 mg (10mgQ4wk). PTN patients were randomized (1: 1) to receive either placebo or fulranumab 10mgQ4wk. Results: The US Food and Drug Administration placed a clinical hold (December 23, 2010) on all trials of antinerve growth factor drugs, including fulranumab, due to identified risks of osteonecrosis or rapidly progressing osteoarthritis; therefore, only 49 (of 150 planned) PHN patients and 34 (of 50 planned) PTN patients completed the DB efficacy evaluation. There was no significant difference (P > 0.05, fulranumab vs. placebo) for change in 7-day average of daily pain intensity scores from DB baseline to end of 12-week DB efficacy phase in PHN or PTN patients (primary endpoint). No significant difference was found with fulranumab versus placebo (P> 0.05) in other efficacy measures in either PHN or PTN patients. The most common treatment-emergent adverse events (> 10% incidence) in PTN patients were sinusitis, carpal tunnel syndrome, and headache, whereas in PHN patients it was arthralgia. Discussion: Fulranumab did not demonstrate efficacy in either PHN or PTN patients, but was generally well-tolerated in this small underpowered and abbreviated study. C1 [Wang, Hao] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Romano, Gary; Fedgchin, Margaret; Russell, Lucille; Sanga, Panna; Kelly, Kathleen M.; Frustaci, Mary Ellen; Thipphawong, John] Janssen Res & Dev LLC, Raritan, NJ USA. RP Thipphawong, J (reprint author), Janssen Res & Dev LLC, 6500 Paseo Padre Blvd, Fremont, CA 94555 USA. EM jthippha@its.jnj.com FU Janssen Research & Development, LLC FX Supported by Janssen Research & Development, LLC. NR 27 TC 0 Z9 0 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0749-8047 EI 1536-5409 J9 CLIN J PAIN JI Clin. J. Pain PD FEB PY 2017 VL 33 IS 2 BP 99 EP 108 DI 10.1097/AJP.0000000000000388 PG 10 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA EI2GS UT WOS:000392305500002 PM 27153360 ER PT J AU Tiniakou, E Mammen, AL AF Tiniakou, Eleni Mammen, Andrew L. TI Idiopathic Inflammatory Myopathies and Malignancy: a Comprehensive Review SO CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY LA English DT Review DE Idiopathic inflammatory myopathies; Malignancy; Myositis-specific antibodies ID INCLUSION-BODY MYOSITIS; CANCER-ASSOCIATED MYOSITIS; POPULATION-BASED COHORT; ONSET POLYMYOSITIS DERMATOMYOSITIS; CHRONIC LYMPHOCYTIC-LEUKEMIA; CONNECTIVE-TISSUE DISEASES; COMPUTER-ASSISTED ANALYSIS; INTERSTITIAL LUNG-DISEASE; ADULT DERMATOMYOSITIS; OVARIAN-CANCER AB The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune diseases (collectively known as myositis) affecting the skeletal muscles as well as other organ systems such as skin, lungs, and joints. The primary forms of myositis include polymyositis (PM), dermatomyositis (PM), and immune-mediated necrotizing myopathy (IMNM). Patients with these diseases experience progressive proximal muscle weakness, have characteristic muscle biopsy findings, and produce autoantibodies that are associated with unique clinical features. One distinguishing feature of these patients is that they are also known to have an increased risk of cancer. Since the first description of the association in 1916, it has been extensively reported in the medical literature. However, there have been significant variations between the different studies with regard to the degree of cancer risk in patients with IIM. These discrepancies can, in part, be attributed to differences in the definition of malignancy-associated myositis used in different studies. In recent years, significant advances have been made in defining specific features of IIM that are associated with the development of malignancy. One of these has been myositis-specific antibodies (MSAs), which are linked to distinct clinical phenotypes and categorize patients into groups with more homogeneous features. Indeed, patients with certain MSAs seem to be at particularly increased risk of malignancy. This review attempts a systematic evaluation of research regarding the association between malignancy and myositis. C1 [Tiniakou, Eleni; Mammen, Andrew L.] Johns Hopkins Univ, Sch Med, Div Rheumatol, Baltimore, MD 21218 USA. [Mammen, Andrew L.] NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Express, NIH, 50 South Dr,Room 1146,Bldg 50,MSC 8024, Bethesda, MD 20892 USA. RP Mammen, AL (reprint author), Johns Hopkins Univ, Sch Med, Div Rheumatol, Baltimore, MD 21218 USA.; 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 Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [T32AR048522] FX Andrew L. Mammen is supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. Eleni Tiniakou is supported by T32AR048522, a training grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 147 TC 0 Z9 0 U1 4 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1080-0549 EI 1559-0267 J9 CLIN REV ALLERG IMMU JI Clin. Rev. Allergy Immunol. PD FEB PY 2017 VL 52 IS 1 BP 20 EP 33 DI 10.1007/s12016-015-8511-x PG 14 WC Allergy; Immunology SC Allergy; Immunology GA EI4UR UT WOS:000392489500002 PM 26429706 ER PT J AU Ruhl, AP Huang, MX Colantuoni, E Lord, RK Dinglas, VD Chong, A Sepulveda, KA Mendez-Tellez, PA Shanholtz, CB Steinwachs, DM Pronovost, PJ Needham, DM AF Ruhl, A. Parker Huang, Minxuan Colantuoni, Elizabeth Lord, Robert K. Dinglas, Victor D. Chong, Alexandra Sepulveda, Kristin A. Mendez-Tellez, Pedro A. Shanholtz, Carl B. Steinwachs, Donald M. Pronovost, Peter J. Needham, Dale M. TI Healthcare Resource Use and Costs in Long-Term Survivors of Acute Respiratory Distress Syndrome: A 5-Year Longitudinal Cohort Study SO CRITICAL CARE MEDICINE LA English DT Article DE critical illness; health care costs; intensive care unit; patient readmission; respiratory distress syndrome; acute ID ACUTE LUNG INJURY; OBSTRUCTIVE PULMONARY-DISEASE; MINIMAL IMPORTANT DIFFERENCE; POST-ACUTE CARE; INTENSIVE-CARE; CRITICAL ILLNESS; SEVERE SEPSIS; PHYSICAL REHABILITATION; MECHANICAL VENTILATION; CRITICALLY-ILL AB Objective: To evaluate the time-varying relationship of annual physical, psychiatric, and quality of life status with subsequent inpatient healthcare resource use and estimated costs. Design: Five-year longitudinal cohort study. Setting: Thirteen ICUs at four teaching hospitals. Patients: One hundred thirty-eight patients surviving greater than or equal to 2 years after acute respiratory distress syndrome. Interventions: None. Measurements and Main Results: Postdischarge inpatient resource use data (e.g., hospitalizations, skilled nursing, and rehabilitation facility stays) were collected via a retrospective structured interview at 2 years, with prospective collection every 4 months thereafter, until 5 years postacute respiratory distress syndrome. Adjusted odds ratios for hospitalization and relative medians for estimated episode of care costs were calculated using marginal longitudinal two-part regression. The median (interquartile range) number of inpatient admission hospitalizations was 4 (2-8), with 114 patients (83%) reporting greater than or equal to one hospital readmission. The median (interquartile range) estimated total inpatient postdischarge costs over 5 years were $58,500 ($19,700-157,800; 90th percentile, $328,083). Better annual physical and quality of life status, but not psychiatric status, were associated with fewer subsequent hospitalizations and lower follow-up costs. For example, greater grip strength (per 6 kg) had an odds ratio (95% CI) of 0.85 (0.73-1.00) for inpatient admission, with 23% lower relative median costs, 0.77 (0.69-0.87). Conclusions: In a multisite cohort of long-term acute respiratory distress syndrome survivors, better annual physical and quality of life status, but not psychiatric status, were associated with fewer hospitalizations and lower healthcare costs. C1 [Ruhl, A. Parker] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Ruhl, A. Parker; Huang, Minxuan; Colantuoni, Elizabeth; Lord, Robert K.; Dinglas, Victor D.; Sepulveda, Kristin A.; Mendez-Tellez, Pedro A.; Pronovost, Peter J.; Needham, Dale M.] Johns Hopkins Univ, Sch Med, Outcomes Crit Illness & Surg OACIS Grp, Baltimore, MD 21218 USA. [Ruhl, A. Parker; Huang, Minxuan; Dinglas, Victor D.; Sepulveda, Kristin A.; Needham, Dale M.] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD 21218 USA. [Colantuoni, Elizabeth] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Lord, Robert K.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Chong, Alexandra] Kent State Univ, Dept Psychol Serv, Kent, OH 44242 USA. [Mendez-Tellez, Pedro A.; Pronovost, Peter J.] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Shanholtz, Carl B.] Univ Maryland, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD 21201 USA. [Steinwachs, Donald M.; Pronovost, Peter J.] Johns Hopkins Univ, Dept Hlth Policy & Management, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. [Needham, Dale M.] Johns Hopkins Univ, Sch Med, Dept Phys Med & Rehabil, Baltimore, MD USA. RP Ruhl, AP (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA.; Ruhl, AP (reprint author), Johns Hopkins Univ, Sch Med, Outcomes Crit Illness & Surg OACIS Grp, Baltimore, MD 21218 USA.; Ruhl, AP (reprint author), Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD 21218 USA. EM parker.ruhl@nih.gov FU National Institutes of Health [P050HL73334, R01HL088045, K24HL088551]; National Institutes of Health (NIH); NIH; NIH-National Heart, Lung, and Blood Institute; Johns Hopkins University; Lehigh Speakers Bureau; Penguin Publishing Book Royalties; Agency for Healthcare Research and Quality; Australian National Health and Medical Research Council; Canadian Institutes of Health FX Supported, in part, by the National Institutes of Health (grant numbers: P050HL73334, R01HL088045, and K24HL088551).; Mr. Lord disclosed that he is the CEO of a startup that works in Health IT Cybersecurity, and as a result, has many relationships, paid and unpaid, in Health IT broadly. However, none of them relate to this work. Dr. Dinglas received support for article research from the National Institutes of Health (NIH). Dr. Mendez-Tellez received support for article research from the NIH. Dr. Shanholtz received support for article research from the NIH. His institution received funding from the NIH-National Heart, Lung, and Blood Institute. Dr. Pronovost received funding from Johns Hopkins University (Employer), Lehigh Speakers Bureau, and Penguin Publishing Book Royalties. Dr. Needham received support for article research from the NIH. His institution received funding from the NIH, Agency for Healthcare Research and Quality, and Australian National Health and Medical Research Council. He received support from a Clinician-Scientist Award from the Canadian Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 50 TC 2 Z9 2 U1 44 U2 44 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2017 VL 45 IS 2 BP 196 EP 204 DI 10.1097/CCM.0000000000002088 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA EI4LF UT WOS:000392464500007 PM 27748659 ER PT J AU Ito, T Jensen, RT AF Ito, Tetsuhide Jensen, Robert T. TI Molecular imaging in neuroendocrine tumors: recent advances, controversies, unresolved issues, and roles in management SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Review DE (68)Gallium PET/CT; carcinoid; pancreatic neuroendocrine tumor; somatostatin; somatostatin receptor scintigraphy ID RECEPTOR RADIONUCLIDE THERAPY; CONSENSUS GUIDELINES UPDATE; GA-68 DOTATATE PET/CT; CELL LUNG-CANCER; GA-68-DOTATATE PET/CT; F-18-FDG PET; ENDOCRINE TUMORS; POSITIVE TUMORS; UNKNOWN PRIMARY; F-18-FLUORODIHYDROXYPHENYLALANINE PET/CT AB Purpose of review The purpose is to review recent advances in molecular imaging of neuroendocrine tumors (NETs), discuss unresolved issues, and review how these advances are affecting clinical management. Recent findings Molecular imaging of NETs underwent a number of important changes in the last few years, leading to some controversies, unresolved issues, and significant changes in clinical management. The most recent changes are reviewed in this article. Particularly important is the rapid replacement in somatostatin receptor scintigraphy of In-111-diethylenetriamine penta-acetic acid-single-photon emission computed tomography/computed tomography (CT) by Ga-68-fluorodopa(F-D) PA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide-PET/CT imaging, which is now approved in many countries including the USA. Numerous studies in many different types of NETs demonstrate the greater sensitivity of Ga-68-DOTA-peptide PET/CT, its high specificity, and its impact on management. Other important developments in somatostatin receptor scintigraphy/molecular imaging include demonstrating the prognostic value of both Ga-68-DOTA-peptide PET/CT and F-18-fluoro-deoxyglucose PET/CT; how their use can be complementary; comparing the sensitivities and usefulness of Ga-68-DOTA-peptide PET/CT and F-18-FDOPA PET/CT; introducing new linkers and radiolabeled ligands such as Cu-64-DOTA-peptides with a long half-life, enhancing utility; and the introduction of somatostatin receptor antagonists which show enhanced uptake by NETs. In addition, novel ligands which interact with other receptors (GLP-1, bombesin, cholecystokinin, gastric inhibitory polpeptide, integrin, chemokines) are described, which show promise in the imaging of both NETs and other tumors. Summary Molecular imaging is now required for all aspects of the management of patients with NETs. Its results are essential not only for the proper diagnostic management of the patient, but also for assessing whether the patient is a candidate for peptide receptor radionuclide therapy with Lu-177 and also for providing prognostic value. C1 [Ito, Tetsuhide] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Fukuoka, Japan. [Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIH, Bldg 10,Room 9C-103, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov FU intramural program on NCI; NIDDK of the NIH FX The research was supported by the intramural program on NCI and NIDDK of the NIH. NR 132 TC 1 Z9 1 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD FEB PY 2017 VL 24 IS 1 BP 15 EP 24 DI 10.1097/MED.0000000000000300 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI0NS UT WOS:000392171800005 PM 27875420 ER PT J AU Chretien, C Fenech, C Lienard, F Grall, S Chevalier, C Chaudy, S Brenachot, X Berges, R Louche, K Stark, R Nedelec, E Laderriere, A Andrews, ZB Benani, A Flockerzi, V Gascuel, J Hartmann, J Moro, C Birnbaumer, L Leloup, C Penicaud, L Fioramonti, X AF Chretien, Chloe Fenech, Claire Lienard, Fabienne Grall, Sylvie Chevalier, Charlene Chaudy, Sylvie Brenachot, Xavier Berges, Raymond Louche, Katie Stark, Romana Nedelec, Emmanuelle Laderriere, Amelie Andrews, Zane B. Benani, Alexandre Flockerzi, Veit Gascuel, Jean Hartmann, Jana Moro, Cedric Birnbaumer, Lutz Leloup, Corinne Penicaud, Luc Fioramonti, Xavier TI Transient Receptor Potential Canonical 3 (TRPC3) Channels Are Required for Hypothalamic Glucose Detection and Energy Homeostasis SO DIABETES LA English DT Article ID ARCUATE NUCLEUS; FOOD-INTAKE; PROOPIOMELANOCORTIN NEURONS; SYNAPTIC-TRANSMISSION; ENDOTHELIAL-CELLS; SKELETAL-MUSCLE; CATION CHANNELS; NEUROPEPTIDE-Y; ION CHANNELS; MOUSE AB The mediobasal hypothalamus (MBH) contains neurons capable of directly detecting metabolic signals such as glucose to control energy homeostasis. Among them, glucose-excited (GE) neurons increase their electrical activity when glucose rises. In view of previous work, we hypothesized that transient receptor potential canonical type 3 (TRPC3) channels are involved in hypothalamic glucose detection and the control of energy homeostasis. To investigate the role of TRPC3, we used constitutive and conditional TRPC3-deficient mouse models. Hypothalamic glucose detection was studied in vivo by measuring food intake and insulin secretion in response to increased brain glucose level. The role of TRPC3 in GE neuron response to glucose was studied by using in vitro calcium imaging on freshly dissociated MBH neurons. We found that whole body and MBH TRPC3-deficient mice have increased body weight and food intake. The anorectic effect of intracerebroventricular glucose and the insulin secretory response to intracarotid glucose injection are blunted in TRPC3-deficient mice. TRPC3 loss of function or pharmacological inhibition blunts calcium responses to glucose in MBH neurons in vitro. Together, the results demonstrate that TRPC3 channels are required for the response to glucose of MBH GE neurons and the central effect of glucose on insulin secretion and food intake. C1 [Chretien, Chloe; Fenech, Claire; Lienard, Fabienne; Grall, Sylvie; Chevalier, Charlene; Chaudy, Sylvie; Brenachot, Xavier; Berges, Raymond; Nedelec, Emmanuelle; Laderriere, Amelie; Benani, Alexandre; Gascuel, Jean; Leloup, Corinne; Penicaud, Luc; Fioramonti, Xavier] Univ Bourgogne Franche Comte, Inst Natl Rech Agron, CNRS, Ctr Sci Gout & Alimentat, Dijon, France. [Louche, Katie; Moro, Cedric] Univ Toulouse, Inst Metab & Cardiovasc Dis, Obes Res Lab, INSERM,UMR1048, Toulouse, France. [Stark, Romana; Andrews, Zane B.] Monash Univ, Biomed Discovery Inst, Metab Dis & Obes Program, Dept Physiol, Clayton, Vic, Australia. [Flockerzi, Veit] Univ Saarland, Expt & Clin Pharmacol & Toxicol, Sch Med, Homburg, Germany. [Hartmann, Jana] Tech Univ Munich, Inst Neurosci, Munich, Germany. [Hartmann, Jana] Tech Univ Munich, Ctr Integrated Prot Sci, Munich, Germany. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Birnbaumer, Lutz] Catholic Univ Argentina, Inst Biomed Res, Buenos Aires, DF, Argentina. RP Fioramonti, X (reprint author), Univ Bourgogne Franche Comte, Inst Natl Rech Agron, CNRS, Ctr Sci Gout & Alimentat, Dijon, France. EM xavier.fioramonti@inra.fr RI Hartmann, Jana/C-1024-2008; OI Andrews, Zane B./0000-0002-9097-7944 FU Institut National de la Recherche Agronomique; L'Agence Nationale de la Recherche [ANR-13-JVS1-0003-01, ANR-11-BSV1-0007]; Deutsche Forschungsgemeinschaft [SFB 894, TRR-152]; National Institutes of Health Intramural Research Program grant [Z01-ES-101684]; Marie Sklodowska-Curie actions-Seventh Framework Programme (CIG NeuROSenS) [PCIG09-GA-2011-293738]; Societe Francophone du Diabete FX C.Chr. was supported by a salary award from Institut National de la Recherche Agronomique. This work was supported by L'Agence Nationale de la Recherche grants ANR-13-JVS1-0003-01 to A.B. and ANR-11-BSV1-0007 to C.L, Deutsche Forschungsgemeinschaft grants SFB 894 to V.F. and TRR-152 to J.H., and National Institutes of Health Intramural Research Program grant Z01-ES-101684 to L.B. This work was also supported by grants from the Marie Sklodowska-Curie actions-Seventh Framework Programme (CIG NeuROSenS PCIG09-GA-2011-293738 to X.F.) and Societe Francophone du Diabete (to X.F.). NR 56 TC 0 Z9 0 U1 5 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD FEB PY 2017 VL 66 IS 2 BP 314 EP 324 DI 10.2337/db16-1114 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI7PS UT WOS:000392691000010 PM 27899482 ER PT J AU Williams, AS Trefts, E Lantier, L Grueter, CA Bracy, DP James, FD Pozzi, A Zent, R Wasserman, DH AF Williams, Ashley S. Trefts, Elijah Lantier, Louise Grueter, Carrie A. Bracy, Deanna P. James, Freyja D. Pozzi, Ambra Zent, Roy Wasserman, David H. TI Integrin-Linked Kinase Is Necessary for the Development of Diet-Induced Hepatic Insulin Resistance SO DIABETES LA English DT Article ID FOCAL ADHESION KINASE; FATTY LIVER-DISEASE; ENDOGENOUS GLUCOSE-PRODUCTION; EXTRACELLULAR-MATRIX; PROTEIN-KINASE; CELL-ADHESION; MICE; ILK; RATS; HEPATOCYTES AB The liver extracellular matrix (ECM) expands with high fat (HF) feeding. This finding led us to address whether receptors for the ECM, integrins, are key to the development of diet-induced hepatic insulin resistance. Integrin-linked kinase (ILK) is a downstream integrin signaling molecule involved in multiple hepatic processes, including those related to differentiation, wound healing, and metabolism. We tested the hypothesis that deletion of ILK in mice on an HF diet would disrupt the ECM-integrin signaling axis, thereby preventing the transformation into the insulin-resistant liver. To determine the role of ILK in hepatic insulin action in vivo, male C57BL/6J ILKlox/lox mice were crossed with Albcre mice to produce a hepatocyte-specific ILK deletion (ILK(lox/lox)Albcre). Results from this study show that hepatic ILK deletion has no effect on insulin action in lean mice but sensitizes the liver to insulin during the challenge of HF feeding. This effect corresponds to changes in the expression and activation of key insulin signaling pathways as well as a greater capacity for hepatic mitochondria! glucose oxidation. This demonstrates that ILK contributes to hepatic insulin resistance and highlights the previously undefined role of integrin signaling in the pathogenesis of diet-induced hepatic insulin resistance. C1 [Williams, Ashley S.; Trefts, Elijah; Lantier, Louise; Bracy, Deanna P.; James, Freyja D.; Pozzi, Ambra; Wasserman, David H.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Lantier, Louise; Wasserman, David H.] Vanderbilt Univ, Mouse Metab Phenotyping Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA. [Grueter, Carrie A.] Vanderbilt Univ, Dept Anesthesiol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Pozzi, Ambra; Zent, Roy] Vanderbilt Univ, Dept Med, Div Nephrol, Nashville, TN USA. [Zent, Roy] Dept Med, Vet Affairs, Nashville, TN USA. RP Williams, AS (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. EM ashley.s.williams@duke.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK095761, R01 DK083187, R01 DK075594, R01 DK069221, R37 DK050277, R01 DK054902, U24 DK059637]; Veterans Affairs Merit Review, Center for Integrated Healthcare, U.S. Department of Veterans Affairs [1I01BX002025-01, 1I01BX002196]; NIDDK (the Diabetes Research and Training Center) [DK20593]; Molecular Endocrinology Training Program at Vanderbilt University FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK095761 to A.P., R01 DK083187 to R.Z., R01 DK075594 to R.Z., R01 DK069221 to R.Z., R37 DK050277 to D.H.W., R01 DK054902 to D.H.W., and U24 DK059637 to D.H.W.) and Veterans Affairs Merit Review, Center for Integrated Healthcare, U.S. Department of Veterans Affairs (1I01BX002025-01 to A.P. and 1I01BX002196 to R.Z.). This work was also supported by NIDDK DK20593 (the Diabetes Research and Training Center) and the Molecular Endocrinology Training Program at Vanderbilt University. NR 49 TC 0 Z9 0 U1 3 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD FEB PY 2017 VL 66 IS 2 BP 325 EP 334 DI 10.2337/db16-0484 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI7PS UT WOS:000392691000011 PM 27899483 ER PT J AU Hu, H Ha, SD Xu, XH AF Hu, Hui Ha, Sandie Xu, Xiaohui TI Ozone and hypertensive disorders of pregnancy in Florida: Identifying critical windows of exposure SO ENVIRONMENTAL RESEARCH LA English DT Article DE Air pollution; Hypertensive disorders of pregnancy; Ozone; Windows of exposure ID AMBIENT AIR-POLLUTION; BLOOD-PRESSURE VARIABILITY; OXIDATIVE STRESS; CARDIOVASCULAR-DISEASE; PARTICULATE MATTER; DIABETES-MELLITUS; GESTATIONAL HYPERTENSION; COMPLICATED PREGNANCIES; PRETERM BIRTH; PREECLAMPSIA AB Introduction: Ozone (03) has been linked to hypertensive disorders of pregnancy (HDP). However, inconsistent results have been reported, and no study has examined the critical exposure windows during pregnancy. Materials and methods: We used Florida birth vital statistics records to investigate the association between HDP and O-3 exposure among 655,529 pregnancies with conception dates between 2005 and 2007. Individual 03 exposure was assessed at mothers' home address at the time of delivery using the Hierarchical Bayesian space-time statistical model. We examined the association during three predefined exposure windows including trimester 1, trimester 2, and trimesters 1 & 2, as well as in each week of the first two trimesters using distributed lag models. Results: Pregnancies with HDP had a higher mean exposure to O-3 (39.07 in trimester 1, 39.02 in trimester 2, and 39.06 in trimesters 1 & 2, unit: ppb) than those without HDP (38.65 in trimester 1, 38.57 in trimester 2, and 38.61 in trimesters 1 &2, unit: ppb). In the adjusted logistic regression model, increased odds of HDP were observed for each 5 ppb increase in O-3 (ORTnrnester1= 1.04, 95% CI: 1.03, 1.06; ORTrimester2= 1.03, 95% CI: 1.02, 1.04; ORTrimester1& 2=1.07, 95% CI: 1.05, 1.08). In the distributed lag models, elevated odds of HDP were observed with increased 03 exposure during the 1st to 24th weeks of gestation, with higher odds during early pregnancy. Conclusions: O-3 exposure during pregnancy is related to increased odds of HDP, and early pregnancy appears to be a potentially critical window of exposure. C1 [Hu, Hui] Univ Florida, Coll Publ Hlth & Hlth Profess, Dept Epidemiol, 2004 Mowry Rd,Room 4224, Gainesville, FL 32610 USA. [Hu, Hui] Univ Florida, Coll Med, 2004 Mowry Rd,Room 4224, Gainesville, FL 32610 USA. [Ha, Sandie] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Bethesda, MD 20892 USA. [Xu, Xiaohui] Texas A&M Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, College Stn, TX USA. RP Hu, H (reprint author), Univ Florida, Coll Publ Hlth & Hlth Profess, Dept Epidemiol, 2004 Mowry Rd,Room 4224, Gainesville, FL 32610 USA.; Hu, H (reprint author), Univ Florida, Coll Med, 2004 Mowry Rd,Room 4224, Gainesville, FL 32610 USA.; Xu, XH (reprint author), Texas A&M Hlth Sci Ctr, Sch Publ Hlth, Dept Epidemiol & Biostat, 205A SRPH Adm Bldg,MS 1266,212 Adriance Lab Rd, College Stn, TX 77843 USA. EM huihu@ufl.edu; xiaohui.xu@sph.tamhsc.edu FU National Institute of Environmental Health Sciences (NIEHS) [K01ES019177]; Intramural Research Program of the Eunice Kennedy Shriner National Institute of Child Health and Human Development (NICHD), National Institutes of Health FX This work was supported by Grant Number K01ES019177 from the National Institute of Environmental Health Sciences (NIEHS), and was partially funded by the Intramural Research Program of the Eunice Kennedy Shriner National Institute of Child Health and Human Development (NICHD), National Institutes of Health. The data were provided by the Bureau of Vital Statistics, Florida Department of Health (DOH). All conclusions are the authors' own and do not necessarily reflect the opinion of the NIEHS or the Florida DOH. NR 56 TC 0 Z9 0 U1 6 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD FEB PY 2017 VL 153 BP 120 EP 125 DI 10.1016/j.envres.2016.12.002 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA EI3CE UT WOS:000392366500016 PM 27940104 ER PT J AU Li, YZ Wu, KJ Yu, SJ Tamargo, IA Wang, Y Greig, NH AF Li, Yazhou Wu, Kou-Jen Yu, Seong-Jin Tamargo, Ian A. Wang, Yun Greig, Nigel H. TI Neurotrophic and neuroprotective effects of oxyntomodulin in neuronal cells and a rat model of stroke SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Oxyntomodulin; Neuroprotection; Stroke; Glucagon-like peptide-1 receptor; Glucagon receptor; Glutamate excitotoxicity; Oxidative stress ID GLUCAGON-LIKE PEPTIDE-1; TRAUMATIC BRAIN-INJURY; PARKINSONS-DISEASE; ISCHEMIC-STROKE; SH-SY5Y CELLS; FOOD-INTAKE; ENERGY-EXPENDITURE; OXIDATIVE STRESS; MOUSE MODEL; RECEPTOR AB Proglucagon-derived peptides, especially glucagon-like peptide-1 (GLP-1) and its long-acting mimetics, have exhibited neuroprotective effects in animal models of stroke. Several of these peptides are in clinical trials for stroke. Oxyntomodulin (OXM) is a proglucagon-derived peptide that co-activates the GLP-1 receptor (GLP-1R) and the glucagon receptor (GCGR). The neuroprotective action of OXM, however, has not been thoroughly investigated. In this study, the neuroprotective effect of OXM was first examined in human neuroblastoma (SH-SY5Y) cells and rat primary cortical neurons. GLP-1R and GCGR antagonists, and inhibitors of various signaling pathways were used in cell culture to characterize the mechanisms of action of OXM. To evaluate translation in vivo, OXM-mediated neuroprotection was assessed in a 60-min, transient middle cerebral artery occlusion (MCAo) rat model of stroke. We found that OXM dose- and time-dependently increased cell viability and protected cells from glutamate toxicity and oxidative stress. These neuroprotective actions of OXM were mainly mediated through the GLP-1 R. OXM induced intracellular CAMP production and activated cAMP-response element-binding protein (CREB). Furthermore, inhibition of the PRA and MAPK pathways, but not inhibition of the PI3K pathway, significantly attenuated the OXM neuroprotective actions. Intracerebroventricular administration of OXM significantly reduced cerebral infarct size and improved locomotor activities in MCAo stroke rats. Therefore, we conclude that OXM is neuroprotective against ischemic brain injury. The mechanisms of action involve induction of intracellular CAMP, activation of PICA and MAPK pathways and phosphorylation of CREB. Published by Elsevier Inc. C1 [Li, Yazhou; Tamargo, Ian A.; Greig, Nigel H.] NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wu, Kou-Jen; Yu, Seong-Jin; Wang, Yun] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Miaoli, Taiwan. RP Li, YZ; Greig, NH (reprint author), Biomed Res Ctr, Room 5C222,251 Bayview Blvd, Baltimore, MD 21224 USA. EM liyaz@mail.nih.gov; greign@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health, Baltimore, MD, USA [AG000333]; National Health Research Institutes, Taiwan FX This research was supported in part by: (i) the Intramural Research Program of the National Institute on Aging Grant #: AG000333, National Institutes of Health, Baltimore, MD, USA, and, (ii) National Health Research Institutes, Taiwan. NR 71 TC 0 Z9 0 U1 9 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD FEB PY 2017 VL 288 BP 104 EP 113 DI 10.1016/j.expneurol.2016.11.010 PG 10 WC Neurosciences SC Neurosciences & Neurology GA EI4JY UT WOS:000392461100010 PM 27856285 ER PT J AU Tamargo, IA Bader, M Li, YZ Yu, SJ Wang, Y Talbot, K DiMarchi, RD Pick, CG Greig, NH AF Tamargo, Ian A. Bader, Miaad Li, Yazhou Yu, Seong-Jin Wang, Yun Talbot, Konrad DiMarchi, Richard D. Pick, Chaim G. Greig, Nigel H. TI Novel GLP-1R/GIPR co-agonist "twincretin" is neuroprotective in cell and rodent models of mild traumatic brain injury SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Traumatic brain injury; Neurodegeneration; Incretin mimetic; Incretin; Glucagon-like peptide-1; Glucose-dependent insulinotropic peptide ID GLUCAGON-LIKE PEPTIDE-1; DEPENDENT INSULINOTROPIC POLYPEPTIDE; REVERSES BEHAVIORAL IMPAIRMENTS; SECONDARY NEURONAL DAMAGE; FOCAL CEREBRAL-ISCHEMIA; PARKINSONS-DISEASE; RECEPTOR AGONIST; ALZHEIMERS-DISEASE; MOUSE MODEL; GENE-EXPRESSION AB Several single incretin receptor agonists that are approved for the treatment of type 2 diabetes mellitus (T2DM) have been shown to be neuroprotective in cell and animal models of neurodegeneration. Recently, a synthetic dual incretin receptor agonist, nicknamed "twincretin," was shown to improve upon the metabolic benefits of single receptor agonists in mouse and monkey models of T2DM. In the current study, the neuroprotective effects of twincretin are probed in cell and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in toddlers, teenagers and the elderly. Twincretin is herein shown to have activity at two different receptors, dose-dependently increase levels of intermediates in the neurotrophic CREB pathway and enhance viability of human neuroblastoma cells exposed to toxic concentrations of glutamate and hydrogen peroxide, insults mimicking the inflammatory conditions in the brain post-mTBI. Additionally, twincretin is shown to improve upon the neurotrophic effects of single incretin receptor agonists in these same cells. Finally, a clinically translatable dose of twincretin, when administered post-mTBI, is shown to fully restore the visual and spatial memory deficits induced by mTBI, as evaluated in a mouse model of weight drop close head injury. These results establish twincretin as a novel neuroprotective agent and suggest that it may improve upon the effects of the single incretin receptor agonists via dual agonism. Published by Elsevier Inc. C1 [Tamargo, Ian A.; Li, Yazhou; Greig, Nigel H.] NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Bader, Miaad; Pick, Chaim G.] Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, Tel Aviv, Israel. [Yu, Seong-Jin; Wang, Yun] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Miaoli, Taiwan. [Talbot, Konrad] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA USA. [DiMarchi, Richard D.] Indiana Univ, Dept Chem, Bloomington, IN 47405 USA. [Pick, Chaim G.] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. RP Tamargo, IA; Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Translat Gerontol Branch, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM iatamargo@gmail.com; Greign@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health [AG000333]; Ari and Regine Aprijaskis Fund at Tel-Aviv University; Israel Science Foundation [108/09] FX This research was supported in part by (i) the Intramural Research Program of the National Institute on Aging, National Institutes of Health, grant number AG000333 (2016), (ii) the Ari and Regine Aprijaskis Fund at Tel-Aviv University, and (iii) a grant from the Israel Science Foundation, grant number 108/09. NR 90 TC 0 Z9 0 U1 8 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD FEB PY 2017 VL 288 BP 176 EP 186 DI 10.1016/j.expneurol.2016.11.005 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EI4JY UT WOS:000392461100017 PM 27845037 ER PT J AU Roy, HK Turzhitsky, V Wali, R Radosevich, AJ Jovanovic, B Della'Zanna, G Umar, A Rubin, DT Goldberg, MJ Bianchi, L De La Cruz, M Bogojevic, A Helenowski, IB Rodriguez, L Chatterton, R Skripkauskas, S Page, K Weber, CR Huang, XK Richmond, E Bergan, RC Backman, V AF Roy, Hemant K. Turzhitsky, Vladimir Wali, Ramesh Radosevich, Andrew J. Jovanovic, Borko Della'Zanna, Gary Umar, Asad Rubin, David T. Goldberg, Michael J. Bianchi, Laura De La Cruz, Mart Bogojevic, Andrej Helenowski, Irene B. Rodriguez, Luz Chatterton, Robert Skripkauskas, Silvia Page, Katherine Weber, Christopher R. Huang, Xiaoke Richmond, Ellen Bergan, Raymond C. Backman, Vadim TI Spectral biomarkers for chemoprevention of colonic neoplasia: a placebo-controlled double-blinded trial with aspirin SO GUT LA English DT Article ID FAMILIAL ADENOMATOUS POLYPOSIS; ANTIINFLAMMATORY DRUG-USE; COLORECTAL-CANCER; RISK STRATIFICATION; ORNITHINE-DECARBOXYLASE; PROTEIN EXPRESSION; GENETIC-VARIANTS; NORMAL MUCOSA; CARCINOGENESIS; PROLIFERATION AB Objective A major impediment to translating chemoprevention to clinical practice has been lack of intermediate biomarkers. We previously reported that rectal interrogation with low-coherence enhanced backscattering spectroscopy (LEBS) detected microarchitectural manifestations of field carcinogenesis. We now wanted to ascertain if reversion of two LEBS markers spectral slope (SPEC) and fractal dimension (FRAC) could serve as a marker for chemopreventive efficacy. Design We conducted a multicentre, prospective, randomised, double-blind placebo-controlled, clinical trial in subjects with a history of colonic neoplasia who manifested altered SPEC/FRAC in histologically normal colonic mucosa. Subjects (n=79) were randomised to 325 mg aspirin or placebo. The primary endpoint changed in FRAC and SPEC spectral markers after 3 months. Mucosal levels of prostaglandin E2 (PGE2) and UDP-glucuronosyltransferase (UGT)1A6 genotypes were planned secondary endpoints. Results At 3 months, the aspirin group manifested alterations in SPEC (48.9%, p=0.055) and FRAC (55.4%, p=0.200) with the direction towards non-neoplastic status. As a measure of aspirin's pharmacological efficacy, we assessed changes in rectal PGE2 levels and noted that it correlated with SPEC and FRAC alterations (R=-0.55, p=0.01 and R=0.57, p=0.009, respectively) whereas there was no significant correlation in placebo specimens. While UGT1A6 subgroup analysis did not achieve statistical significance, the changes in SPEC and FRAC to a less neoplastic direction occurred only in the variant consonant with epidemiological evidence of chemoprevention. Conclusions We provide the first proof of concept, albeit somewhat underpowered, that spectral markers reversion mirrors antineoplastic efficacy providing a potential modality for titration of agent type/dose to optimise chemopreventive strategies in clinical practice. C1 [Roy, Hemant K.; Wali, Ramesh; De La Cruz, Mart] Boston Univ, Med Ctr, Dept Med, Boston, MA USA. [Turzhitsky, Vladimir; Radosevich, Andrew J.; Backman, Vadim] Northwestern Univ, Robert H Lurie Canc Ctr, Dept Biomed Engn, Chicago, IL 60611 USA. [Jovanovic, Borko; Helenowski, Irene B.] Northwestern Univ, Robert H Lurie Canc Ctr, Dept Prevent Med, Chicago, IL 60611 USA. [Della'Zanna, Gary; Umar, Asad; Rodriguez, Luz; Richmond, Ellen] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Rubin, David T.] Univ Chicago, Med Ctr, Dept Med, Chicago, IL 60637 USA. [Goldberg, Michael J.; Bianchi, Laura; Bogojevic, Andrej] NorthShore Univ Hlth Syst, Dept Med, Evanston, IL USA. [Chatterton, Robert] Northwestern Univ, Robert H Lurie Canc Ctr, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Skripkauskas, Silvia; Page, Katherine; Huang, Xiaoke; Bergan, Raymond C.] Northwestern Univ, Robert H Lurie Canc Ctr, Dept Med, Chicago, IL 60611 USA. [Weber, Christopher R.] Univ Chicago, Med Ctr, Dept Pathol, Chicago, IL 60637 USA. RP Roy, HK (reprint author), Boston Univ, Dept Med, Sch Med, 650 Albany St,Suite 526, Boston, MA 02118 USA. EM hkroy@bu.edu FU United States National Institutes of Health [N01-CN-35157] FX This work was supported by funding from the United States National Institutes of Health N01-CN-35157 to RCB and HKR. NR 53 TC 2 Z9 2 U1 5 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD FEB PY 2017 VL 66 IS 2 BP 285 EP 292 DI 10.1136/gutjnl-2015-309996 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EI2CC UT WOS:000392293100012 PM 26503631 ER PT J AU Chen, JD Gottesman, S AF Chen, Jiandong Gottesman, Susan TI Spot 42 Small RNA Regulates Arabinose-Inducible araBAD Promoter Activity by Repressing Synthesis of the High-Affinity Low-Capacity Arabinose Transporter SO JOURNAL OF BACTERIOLOGY LA English DT Article DE regulatory small RNA; posttranscriptional regulation; arabinose transporter; arabinose-inducible promoter ID BINDING SMALL RNAS; P-BAD PROMOTER; ESCHERICHIA-COLI; GENE-EXPRESSION; SOLUBLE-RNAS; HFQ; PROTEIN; SYSTEM; MECHANISM; BACTERIA AB The L-arabinose-inducible araBAD promoter (PBAD) enables tightly controlled and tunable expression of genes of interest in a broad range of bacterial species. It has been used successfully to study bacterial sRNA regulation, where PBAD drives expression of target mRNA translational fusions. Here we report that in Escherichia coli, Spot 42 sRNA regulates PBAD promoter activity by affecting arabinose uptake. We demonstrate that Spot 42 sRNA represses araF, a gene encoding the AraF subunit of the high-affinity low-capacity arabinose transporter AraFGH, through direct base-pairing interactions. We further show that endogenous Spot 42 sRNA is sufficient to repress araF expression under various growth conditions. Finally, we demonstrate this posttranscriptional repression has a biological consequence, decreasing the induction of PBAD at low levels of arabinose. This problem can be circumvented using strategies reported previously for avoiding all-or-none induction behavior, such as through constitutive expression of the low-affinity high-capacity arabinose transporter AraE or induction with a higher concentration of inducers. This work adds araF to the set of Spot 42-regulated genes, in agreement with previous studies suggesting that Spot 42, itself negatively regulated by the cyclic AMP (cAMP) receptor protein-cAMP complex, reinforces the catabolite repression network. IMPORTANCE The bacterial arabinose-inducible system is widely used for titratable control of gene expression. We demonstrate here that a posttranscriptional mechanism mediated by Spot 42 sRNA contributes to the functionality of the PBAD system at subsaturating inducer concentrations by affecting inducer uptake. Our finding extends the inputs into the known transcriptional control for the PBAD system and has implications for improving its usage for tunable gene expression. C1 [Chen, Jiandong; Gottesman, Susan] NCI, Mol Biol Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. EM Gottesms@helix.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD FEB PY 2017 VL 199 IS 3 AR UNSP e00691 DI 10.1128/JB.00691-16 PG 12 WC Microbiology SC Microbiology GA EI4SS UT WOS:000392484200005 ER PT J AU Asher, GN Xie, Y Moaddel, R Sanghvi, M Dossou, KSS Kashuba, ADM Sandler, RS Hawke, RL AF Asher, Gary N. Xie, Ying Moaddel, Ruin Sanghvi, Mitesh Dossou, Katina S. S. Kashuba, Angela D. M. Sandler, Robert S. Hawke, Roy L. TI Randomized Pharmacokinetic Crossover Study Comparing 2 Curcumin Preparations in Plasma and Rectal Tissue of Healthy Human Volunteers SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE curcumin; pharmacokinetics; clinical trial; steady state; human ID CLINICAL UTILITY; IN-VITRO; BIOAVAILABILITY; METABOLISM; APOPTOSIS; CANCER AB Curcumin is poorly absorbed, which is interest in new preparations. However, little is known about variations in its pharmacokinetics and tissue bioavailability between formulations. In this randomized, crossover study we evaluated the relationship between steady-state plasma and rectal tissue curcuminoid concentrations using standard and phosphatidylcholine curcumin extracts. There was no difference in the geometric mean plasma AUCs when adjusted for the 10-fold difference in curcumin dose between the 2 formulations. Phosphatidylcholine curcumin extract yielded only 20% to 30% plasma demethoxycurcumin and bisdemethoxycurcumin conjugates compared to standard extract, yet yielded 20-fold greater hexahydrocurcumin. When adjusting for curcumin dose, tissue curcumin concentrations were 5-fold greater for the phosphatidylcholine extract. Improvements in curcuminoid absorption due to phosphatidylcholine are not uniform across the curcuminoids. Furthermore, curcuminoid exposures in the intestinal mucosa are most likely due to luminal exposure rather than to plasma disposition. Finally, once-daily dosing is sufficient to maintain detectable curcuminoids at steady state in both plasma and rectal tissues. C1 [Asher, Gary N.] Univ N Carolina, Dept Family Med, Sch Med, Chapel Hill, NC USA. [Xie, Ying] Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China. [Moaddel, Ruin; Sanghvi, Mitesh; Dossou, Katina S. S.] NIA, Lab Clin Invest, Div Intramural Res Programs, NIH, Baltimore, MD 21224 USA. [Kashuba, Angela D. M.; Hawke, Roy L.] Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, Eshelman Sch Pharm, Chapel Hill, NC USA. [Sandler, Robert S.] Univ N Carolina, Div Gastroenterol & Hepatol, Sch Med, Chapel Hill, NC USA. RP Asher, GN (reprint author), Univ N Carolina, Dept Family Med, CB 7595, Chapel Hill, NC 27599 USA. EM gasher@med.unc.edu FU National Institutes of Health [KL2TR00084, P50CA106991, P30DK034987, AT003892-03]; Intramural Research Program of the National Institute on Aging FX This work was supported by the National Institutes of Health grants KL2TR00084 (G.N.A.), P50CA106991, P30DK034987, and AT003892-03 (Y.X., R.L.H.). This work was also supported in part by the Intramural Research Program of the National Institute on Aging (M.S., K.S.S.D., R.M.). Meriva was generously supplied by Indena SpA. NR 22 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD FEB PY 2017 VL 57 IS 2 BP 185 EP 193 DI 10.1002/jcph.806 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH8JI UT WOS:000392017700005 PM 27503249 ER PT J AU Sam, WJ Roza, O Hon, YY Alfaro, RM Calis, KA Reynolds, JC Yanovski, JA AF Sam, Wai Johnn Roza, Orsolya Hon, Yuen Yi Alfaro, Raul M. Calis, Karim A. Reynolds, James C. Yanovski, Jack A. TI Effects of SLC22A1 Polymorphisms on Metformin-Induced Reductions in Adiposity and Metformin Pharmacokinetics in Obese Children With Insulin Resistance SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE pharmacokinetics; obesity; pediatric; pharmacogenomics; metformin; weight loss ID TYPE-2 DIABETES-MELLITUS; ORGANIC CATION TRANSPORTERS; BODY-MASS INDEX; CLINICAL PHARMACOKINETICS; POPULATION PHARMACOKINETICS; GLUCOSE-TOLERANCE; GENETIC-VARIATION; HEALTHY-SUBJECTS; RENAL CLEARANCE; DOUBLE-BLIND AB Steady-state population pharmacokinetics of a noncommercial immediate-release metformin (hydrochloride) drug product were characterized in 28 severely obese children with insulin resistance. The concentration-time profiles with double peaks were well described by a 1-compartment model with 2 absorption sites. Mean population apparent clearance (CL/F) was 68.1 L/h, and mean apparent volume of distribution (V/F) was 28.8 L. Body weight was a covariate of CL/F and V/F. Estimated glomerular filtration rate was a significant covariate of CL/F (P < .001). SLC22A1 genotype did not significantly affect metformin pharmacokinetics. The response to 6 months of metformin treatment (HbA(1c), homeostasis model assessment for insulin resistance, fasting insulin, and glucose changes) did not differ between SLC22A1 wild-type subjects and carriers of presumably low-activity SLC22A1 alleles. However, SLC22A1 variant carriers had smaller reductions in percentage of total trunk fat after metformin therapy, although the percentage reduction in trunk fat was small. The median % change in trunk fat was -2.20% (-9.00% to 0.900%) and -1.20% (-2.40% to 7.30%) for the SLC22A1 wild-type subjects and variant carriers, respectively. Future study is needed to evaluate the effects of SLC22A1 polymorphisms on metformin-mediated weight reduction in obese children. C1 [Sam, Wai Johnn; Hon, Yuen Yi; Alfaro, Raul M.; Calis, Karim A.] NIH, Clin Pharmacokinet Res Lab, Ctr Clin, Dept Pharm, Bldg 10, Bethesda, MD 20892 USA. [Roza, Orsolya; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Roza, Orsolya] Univ Szeged, Inst Pharmacognosy, Szeged, Hungary. [Hon, Yuen Yi] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Calis, Karim A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Off Clin Director, NIH, Bethesda, MD USA. [Reynolds, James C.] NIH, Div Nucl Med, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,Hatfield Clin Res Ctr, 10 Ctr Div,Bldg 10,Room 1-3330,MSC 1103, Bethesda, MD 20892 USA. EM jy151@nih.gov FU Intramural Research Program of the National Institutes of Health; Clinical Center Pharmacy Department; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Program in Developmental Endocrinology and Genetics grant from the NICHD [1ZIAHD000641]; National Institute forMinority Health and Health Disparities (NIMHD), NIH FX This work was supported by the Intramural Research Program of the National Institutes of Health, Clinical Center Pharmacy Department and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Program in Developmental Endocrinology and Genetics grant 1ZIAHD000641 from the NICHD, with supplemental funding from the National Institute forMinority Health and Health Disparities (NIMHD), NIH (to Dr. Yanovski). There was no commercial sponsorship. The funding organizations played no role in the design or conduct of the study; the collection, management, analysis, or interpretation of data; or the preparation of the article. NR 48 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD FEB PY 2017 VL 57 IS 2 BP 219 EP 229 DI 10.1002/jcph.796 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH8JI UT WOS:000392017700008 PM 27407018 ER PT J AU Airan, RD Foss, CA Ellens, NPK Wang, YC Mease, RC Farahani, K Pomper, MG AF Airan, Raag D. Foss, Catherine A. Ellens, Nicholas P. K. Wang, Yuchuan Mease, Ronnie C. Farahani, Keyvan Pomper, Martin G. TI MR-Guided Delivery of Hydrophilic Molecular Imaging Agents Across the Blood-Brain Barrier Through Focused Ultrasound SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE MRgFUS; Blood-brain barrier; GCPII; PSMA; NIRF ID GLUTAMATE CARBOXYPEPTIDASE II; MEDIATED DRUG-DELIVERY; PROSTATE-CANCER; MEMBRANE ANTIGEN; PSMA LIGANDS; DISRUPTION; MICROBUBBLES; ASTROCYTES; STRATEGIES; INHIBITORS AB A wide variety of hydrophilic imaging and therapeutic agents are unable to gain access to the central nervous system (CNS) due to the blood-brain barrier (BBB). In particular, unless a particular transporter exists that may transport the agent across the BBB, most agents that are larger than 500 Da or that are hydrophilic will be excluded by the BBB. Glutamate carboxypeptidase II (GCPII), also known as the prostate-specific membrane antigen (PSMA) in the periphery, has been implicated in various neuropsychiatric conditions. As all agents that target GCPII are hydrophilic and thereby excluded from the CNS, we used GCPII as a platform for demonstrating our MR-guided focused ultrasound (MRgFUS) technique for delivery of GCPII/PSMA-specific imaging agents to the brain. Female rats underwent MRgFUS-mediated opening of the BBB. After opening of the BBB, either a radio- or fluorescently labeled ureido-based ligand for GCPII/PSMA was administered intravenously. Brain uptake was assessed for 2-(3-{1-carboxy-5-[(6-[F-18]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ([F-18]DCFPyL) and YC-27, two compounds known to bind GCPII/PSMA with high affinity, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging, respectively. Specificity of ligand binding to GCPII/PSMA in the brain was determined with co-administration of a molar excess of ZJ-43, a compound of the same chemical class but different structure from either [F-18]DCFPyL or YC-27, which competes for GCPII/PSMA binding. Dynamic PET imaging using [F-18]DCFPyL demonstrated that target uptake reached a plateau by similar to 1 h after radiotracer administration, with target/background ratios continuing to increase throughout the course of imaging, from a ratio of similar to 4:1 at 45 min to similar to 7:1 by 80 min. NIRF imaging likewise demonstrated delivery of YC-27 to the brain, with clear visualization of tracer in the brain at 24 h. Tissue uptake of both ligands was greatly diminished by ZJ-43 co-administration, establishing specificity of binding of each to GCPII/PSMA. On gross and histological examination, animals showed no evidence for hemorrhage or other deleterious consequences of MRgFUS. MRgFUS provided safe opening of the BBB to enable specific delivery of two hydrophilic agents to target tissues within the brain. This platform might facilitate imaging and therapy using a variety of agents that have heretofore been excluded from the CNS. C1 [Airan, Raag D.; Foss, Catherine A.; Ellens, Nicholas P. K.; Wang, Yuchuan; Mease, Ronnie C.; Farahani, Keyvan; Pomper, Martin G.] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, 600 N Wolfe St, Baltimore, MD 21205 USA. [Farahani, Keyvan] NCI, NIH, Bethesda, MD 20892 USA. RP Pomper, MG (reprint author), Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, 600 N Wolfe St, Baltimore, MD 21205 USA. EM mpomper@jhmi.edu OI Wang, Yuchuan/0000-0001-5111-6562 FU Philips Healthcare; Walter and Mary Ciceric Foundation; National Institutes of Health [CA134675, CA184228] FX The authors are grateful for grant and in-kind support for this research from Philips Healthcare, the Walter and Mary Ciceric Foundation, and the National Institutes of Health (grant numbers: CA134675, CA184228). The authors also wish to acknowledge the Johns Hopkins Cyclotron Lab for the provision of surplus cGMP [18F]DCFPyL during these studies. NR 38 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD FEB PY 2017 VL 19 IS 1 BP 24 EP 30 DI 10.1007/s11307-016-0985-2 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EI0ZR UT WOS:000392205000004 PM 27481359 ER PT J AU Dutta, D Barr, VA Akpan, I Mittelstadt, PR Singha, LI Samelson, LE Ashwell, JD AF Dutta, Debjani Barr, Valarie A. Akpan, Itoro Mittelstadt, Paul R. Singha, Laishram I. Samelson, Lawrence E. Ashwell, Jonathan D. TI Recruitment of calcineurin to the TCR positively regulates T cell activation SO NATURE IMMUNOLOGY LA English DT Article ID IMMUNOPHILIN-LIGAND COMPLEXES; CYCLOSPORINE-A; ANTIGEN RECEPTOR; TYROSINE KINASE; SIGNALING PATHWAYS; PHOSPHORYLATION; ZAP-70; NFAT; INHIBITION; LFA-1 AB Calcineurin is a phosphatase whose primary targets in T cells are NFAT transcription factors, and inhibition of calcineurin activity by treatment with cyclosporin A (CsA) or FK506 is a cornerstone of immunosuppressive therapies. Here we found that calcineurin was recruited to the T cell antigen receptor (TCR) signaling complex, where it reversed inhibitory phosphorylation of the tyrosine kinase Lck on Ser59 (Lck(S59)). Loss of calcineurin activity impaired phosphorylation of Tyr493 of the tyrosine kinase ZAP-70 (ZAP-70(Y493)), as well as some downstream pathways in a manner consistent with signaling in cells expressing Lck(S59A) (Lck that cannot be phosphorylated) or Lck(S59E) (a phosphomimetic mutant). Notably, CsA inhibited integrin-LFA-1-dependent and NFAT-independent adhesion of T cells to the intercellular adhesion molecule ICAM-1, with little effect on cells expressing mutant Lck. These results provide new understanding of how widely used immunosuppressive drugs interfere with essential processes in the immune response. C1 [Dutta, Debjani; Mittelstadt, Paul R.; Singha, Laishram I.; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. [Barr, Valarie A.; Akpan, Itoro; Samelson, Lawrence E.] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. [Singha, Laishram I.] St Anthonys Coll, Dept Biotechnol, Shillong, Meghalaya, India. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH; Indian Department of Biotechnology, Ministry of Science and Technology FX We thank R. Germain (NIAID) for the DCEK cells and Amphotropic Phoenix packaging cell lines; B. Dong for technical assistance; and S. Koyasu for suggesting that we investigate whether CsA has an effect on the activation of p38 via the alternative pathway. Supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH and the Overseas Associateship funded by the Indian Department of Biotechnology, Ministry of Science and Technology (L.I.S.). NR 40 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2017 VL 18 IS 2 BP 196 EP 204 DI 10.1038/ni.3640 PG 9 WC Immunology SC Immunology GA EI3AE UT WOS:000392360900013 PM 27941787 ER PT J AU Cheng, D Deobagkar-Lele, M Zvezdova, E Choi, S Uehara, S Baup, D Bennett, SC Bull, KR Crockford, TL Ferry, H Warzecha, C Marcellin, M de Peredo, AG Lesourne, R Anzilotti, C Love, PE Cornall, RJ AF Cheng, Daian Deobagkar-Lele, Mukta Zvezdova, Ekaterina Choi, Seeyoung Uehara, Shoji Baup, Delphine Bennett, Sophia C. Bull, Katherine R. Crockford, Tanya L. Ferry, Helen Warzecha, Claude Marcellin, Marlene de Peredo, Anne Gonzalez Lesourne, Renaud Anzilotti, Consuelo Love, Paul E. Cornall, Richard J. TI Themis2 lowers the threshold for B cell activation during positive selection SO NATURE IMMUNOLOGY LA English DT Article ID THYMOCYTE DEVELOPMENT; NEGATIVE SELECTION; LYMPHOCYTES; PROTEIN; DOWNSTREAM; PATHWAY; DETERMINES; EXPRESSION; SURVIVAL; KINASE AB The positive and negative selection of lymphocytes by antigen is central to adaptive immunity and self-tolerance, yet how this is determined by different antigens is not completely understood. We found that thymocyte-selection-associated family member 2 (Themis2) increased the positive selection of B1 cells and germinal center B cells by self and foreign antigens. Themis2 lowered the threshold for B-cell activation by low-avidity, but not high-avidity, antigens. Themis2 constitutively bound the adaptor protein Grb2, src-kinase Lyn and signal transducer phospholipase gamma 2 (PLC-gamma 2), and increased activation of PLC-gamma 2 and its downstream pathways following B cell receptor stimulation. Our findings identify a unique function for Themis2 in differential signaling and provide insight into how B cells discriminate between antigens of different quantity and quality. C1 [Cheng, Daian; Deobagkar-Lele, Mukta; Baup, Delphine; Bennett, Sophia C.; Bull, Katherine R.; Crockford, Tanya L.; Ferry, Helen; Anzilotti, Consuelo; Cornall, Richard J.] Univ Oxford, Nuffield Dept Med, Weatherall Inst Mol Med, MRC Human Immunol Unit, Oxford, England. [Zvezdova, Ekaterina; Choi, Seeyoung; Uehara, Shoji; Warzecha, Claude; Love, Paul E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Hematopoiesis & Lymphocyte Biol, NIH, Bethesda, MD USA. [Marcellin, Marlene; de Peredo, Anne Gonzalez] Inst Pharmacol & Biol Struct, Toulouse, France. [Marcellin, Marlene; de Peredo, Anne Gonzalez] Univ Paul Sabatier, Univ Toulouse, CNRS, Toulouse, France. [Lesourne, Renaud] Ctr Physiopathol Toulouse Purpan, Toulouse, France. [Lesourne, Renaud] INSERM, U1043, CNRS, Toulouse, France. [Cheng, Daian; Deobagkar-Lele, Mukta] Univ Paul Sabatier, Univ Toulouse, Toulouse, France. RP Cornall, RJ (reprint author), Univ Oxford, Nuffield Dept Med, Weatherall Inst Mol Med, MRC Human Immunol Unit, Oxford, England.; Love, PE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Hematopoiesis & Lymphocyte Biol, NIH, Bethesda, MD USA. EM lovep@mail.nih.gov; richard.cornall@ndm.ox.ac.uk RI Lesourne, Renaud/M-1855-2014 FU Medical Research Council; Intramural Research Program of the Eunice Kennedy Shriver, NICHD (PEL: project) [1ZIAHD001803-19]; Wellcome Trust FX We thank the staff of Biomedical Services Unit, Oxford University for animal care and R. Brink (Garvan Institute) for HEL constructs. This work was supported by the Medical Research Council, Intramural Research Program of the Eunice Kennedy Shriver, NICHD (PEL: project number 1ZIAHD001803-19) and the Wellcome Trust (studentship to D.C.). NR 36 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2017 VL 18 IS 2 BP 205 EP 213 DI 10.1038/ni.3642 PG 9 WC Immunology SC Immunology GA EI3AE UT WOS:000392360900014 PM 27992403 ER PT J AU Elmore, JS Dillon-Carter, O Partilla, JS Ellefsen, KN Concheiro, M Suzuki, M Rice, KC Huestis, MA Baumann, MH AF Elmore, Joshua S. Dillon-Carter, Ora Partilla, John S. Ellefsen, Kayla N. Concheiro, Marta Suzuki, Masaki Rice, Kenner C. Huestis, Marilyn A. Baumann, Michael H. TI Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID BATH SALTS; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; DESIGNER DRUG; IN-VITRO; SEROTONIN; ANALOGS; DOPAMINE; RELEASE; HUMANS; BRAIN AB 3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the beta-keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). It is well established that MDMA metabolism produces bioactive metabolites. Here we tested the hypothesis that methylone metabolism in rats can form bioactive metabolites. First, we examined the pharmacokinetics (PKs) of methylone and its metabolites after subcutaneous (sc) methylone administration (3, 6, 12 mg/kg) to male rats fitted with intravenous (iv) catheters for repeated blood sampling. Plasma specimens were assayed by liquid chromatography tandem mass spectrometry to quantify methylone and its phase I metabolites: 3,4-methylenedioxycathinone (MDC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 4-hydroxy-3-methoxy-N-methylcathinone (HMMC). The biological activity of methylone and its metabolites was then compared using in vitro transporter assays and in vivo microdialysis in rat nucleus accumbens. For the PK study, we found that methylone and MDC peaked early (T-max= 15-45 min) and were short lived (t(1/2) = 60-90 min), while HHMC and HMMC peaked later (T-max = 60-120 min) and persisted (t(1/2)= 120-180 min). Area under-the-curve values for methylone and MDC were greater than dose-proportional, suggesting non-linear accumulation. Methylone produced significant locomotor activation, which was correlated with plasma methylone, MDC, and HHMC concentrations. Methylone, MDC, and HHMC were substrate-type releasers at monoamine transporters as determined in vitro, but only methylone and MDC (1, 3 mg/kg, iv) produced significant elevations in brain extracellular dopamine and 5-HT in vivo. Our findings demonstrate that methylone is extensively metabolized in rats, but MDC is the only centrally active metabolite that could contribute to overall effects of the drug in vivo. C1 [Elmore, Joshua S.; Dillon-Carter, Ora; Partilla, John S.; Baumann, Michael H.] NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, 333 Cassell Dr,Suite 4400, Baltimore, MD 21224 USA. [Ellefsen, Kayla N.; Concheiro, Marta; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, 333 Cassell Dr,Suite 4400, Baltimore, MD 21224 USA. [Ellefsen, Kayla N.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Concheiro, Marta] CUNY, Dept Sci, John Jay Coll Criminal Justice, New York, NY 10021 USA. [Suzuki, Masaki; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Intramural Res Program, NIH, 333 Cassell Dr,Suite 4400, Baltimore, MD 21224 USA. RP Baumann, MH (reprint author), NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, 333 Cassell Dr,Suite 4400, Baltimore, MD 21224 USA. EM mbaumann@mail.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX This research was generously supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. The authors declare no conflicts of interest. NR 45 TC 0 Z9 0 U1 12 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2017 VL 42 IS 3 BP 649 EP 660 DI 10.1038/npp.2016.213 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EI0LQ UT WOS:000392166400009 PM 27658484 ER PT J AU Xi, ZX Song, R Li, X Lu, GY Peng, XQ He, Y Bi, GH Sheng, SP Yang, HJ Zhang, HY Li, J Froimowitz, M Gardner, EL AF Xi, Zheng-Xiong Song, Rui Li, Xia Lu, Guan-Yi Peng, Xiao-Qing He, Yi Bi, Guo-Hua Sheng, Siyuan Peter Yang, Hong-Ju Zhang, Haiying Li, Jin Froimowitz, Mark Gardner, Eliot L. TI CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID EXTRACELLULAR DOPAMINE LEVELS; UPTAKE INHIBITORS; RHESUS-MONKEYS; SLOW-ONSET; LONG-DURATION; MEDICATION DEVELOPMENT; POTENTIAL MEDICATIONS; REUPTAKE INHIBITOR; TRANSPORTER; ABUSE AB Agonist-replacement therapies have been successfully used for treatment of opiate and nicotine addiction, but not for cocaine addiction. One of the major obstacles is the cocaine-like addictive potential of the agonists themselves. We report here an atypical dopamine (DA) transporter (DAT) inhibitor, CTDP-32476, that may have translational potential for treating cocaine addiction. In vitro ligand-binding assays suggest that CTDP-32476 is a potent and selective DAT inhibitor and a competitive inhibitor of cocaine binding to the DAT. Systemic administration of CTDP-32476 alone produced a slow-onset, long-lasting increase in extracellular nucleus accumbens DA, locomotion, and brain-stimulation reward. Drug-naive rats did not self-administer CTDP-32476. In a substitution test, cocaine self-administration rats displayed a progressive reduction in CTDP-32476 self-administration with an extinction pattern of drug-taking behavior, suggesting significantly lower addictive potential than cocaine. Pretreatment with CTDP-32476 inhibited cocaine self-administration, cocaine associated cue-induced relapse to drug seeking, and cocaine-enhanced extracellular DA in the nucleus accumbens. These findings suggest that CTDP-32476 is a unique DAT inhibitor that not only could satisfy. 'drug hunger' through its slow-onset long-lasting DAT inhibitor action, but also render subsequent administration of cocaine ineffectual-thus constituting a novel and unique compound with translational potential as an agonist therapy for treatment of cocaine addiction. C1 [Xi, Zheng-Xiong; He, Yi; Bi, Guo-Hua; Sheng, Siyuan Peter; Yang, Hong-Ju; Zhang, Haiying; Gardner, Eliot L.] NIDA, Neuropsychopharmacol Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program, 250 Bayview Blvd, Baltimore, MD 21224 USA. [Song, Rui; Lu, Guan-Yi; Li, Jin] Beijing Inst Pharmacol & Toxicol, State Key Lab Toxicol & Med Countermeasures, Beijing, Peoples R China. [Song, Rui; Lu, Guan-Yi; Li, Jin] Beijing Inst Pharmacol & Toxicol, Beying Key Lab Neuropsychopharmacol, Beijing, Peoples R China. [Li, Xia] Univ Calif San Diego, Sch Med, Dept Psychiat, 9500 Gillman Dr, La Jolla, CA 92093 USA. [Peng, Xiao-Qing] St Elizabeth Hosp, Dept Behav Hlth, Washington, DC USA. [Froimowitz, Mark] Massachusetts Coll Pharm & Hlth Sci, Boston, MA USA. [Froimowitz, Mark] 90 Eastbourne Rd, Newton, MA 02459 USA. RP Xi, ZX (reprint author), NIDA, Intramural Res Program, 250 Bayview Blvd, Baltimore, MD 21224 USA. EM zxi@intra.nida.nih.gov OI Xi, Zheng-Xiong/0000-0001-6482-8104; PENG, XIAOQING/0000-0002-7272-5428 FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, USA; National Basic Research Program of China [2015CB553504]; National Natural Science Foundation of China [81573405]; Beijing Nova Program [xx2014A014] FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, USA, the National Basic Research Program of China (research grant number 2015CB553504), the National Natural Science Foundation of China (#81573405), and the Beijing Nova Program (xx2014A014). The authors declare no conflict of interest. NR 51 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2017 VL 42 IS 3 BP 682 EP 694 DI 10.1038/npp.2016.155 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EI0LQ UT WOS:000392166400012 PM 27534265 ER PT J AU Rose, EJ Salmeron, BJ Ross, TJ Waltz, J Schweitzer, JB Stein, EA AF Rose, Emma Jane Salmeron, Betty Jo Ross, Thomas J. Waltz, James Schweitzer, Julie B. Stein, Elliot A. TI Dissociable Effects of Cocaine Dependence on Reward Processes: The Role of Acute Cocaine and Craving SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID MONETARY REWARD; HUMAN BRAIN; FUNCTIONAL CONNECTIVITY; PREDICTION ERRORS; PREFRONTAL CORTEX; MASS-SPECTROMETRY; LATERAL HABENULA; NEURAL RESPONSES; SENSITIVITY; ADDICTION AB The relative impact of chronic vs acute cocaine on dependence-related variability in reward processing in cocaine-dependent individuals (CD) is not well understood, despite the relevance of such effects to long-term outcomes. To dissociate these effects, CD (N = 15) and healthy controls (HC; N= 15) underwent MRI two times while performing a monetary incentive delay task. Both scans were identical across subjects/groups, except that, in a single-blind, counterbalanced design, CD received intravenous cocaine (30 mg/70 kg) before one session (CD+cocaine) and saline in another (CD+saline). Imaging analyses focused on activity related to anticipatory valence (gain/loss), anticipatory magnitude (small/medium/large), and reinforcing outcomes (successful/unsuccessful). Drug condition (cocaine vs saline) and group (HC vs CD+cocaine or CD+saline) did not influence valence-related activity. However, compared with HC, magnitude-related activity for gains was reduced in CD in the left cingulate gyms post-cocaine and in the left putamen in the abstinence/saline condition. In contrast, magnitude-dependent activity for losses increased in CD vs HC in the right inferior parietal lobe post-cocaine and in the left superior frontal gyms post-saline. Across outcomes (ie, successful and unsuccessful) activity in the right habenula decreased in CD in the abstinence/saline condition vs acute cocaine and HC. Cocaine-dependent variability in outcome- and loss-magnitude activity correlated negatively with ratings of cocaine craving and positively with how high subjects felt during the scanning session. Collectively, these data suggest dissociable effects of acute cocaine on non-drug reward processes, with cocaine consumption partially ameliorating dependence related insensitivity to reinforcing outcomes/liking', but having no discemible effect on dependence-related alterations in incentive salience/ 'wanting'. The relationship of drug-related affective sequelae to non-drug reward processing suggests that CD experience a general alteration of reward function and may be motivated to continue using cocaine for reasons beyond desired drug-related effects. This may have implications for individual differences in treatment efficacy for approaches that rely on reinforcement strategies (eg, contingency management) and for the long-term success of treatment. C1 [Rose, Emma Jane; Salmeron, Betty Jo; Ross, Thomas J.; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD USA. [Rose, Emma Jane] Penn State Univ, Program Translat Res Advers & Neurodev, Bennett Pierce Prevent Res Ctr, Hlth & Human Dev, University Pk, PA 16802 USA. [Waltz, James] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Schweitzer, Julie B.] Univ Calif Davis, Sch Med, Dept Psychiat & Behav Sci, MIND Inst, Sacramento, CA 95817 USA. RP Rose, EJ (reprint author), Penn State Univ, Program Translat Res Advers & Neurodev, Bennett Pierce Prevent Res Ctr, Hlth & Human Dev,Biobehav Hlth 308C, University Pk, PA 16802 USA. EM emmajanerose@psu.edu OI Rose, Emma/0000-0001-5365-4794; Waltz, James/0000-0002-9236-3719 FU National Institute on Drug Abuse-Intramural Research Program FX We gratefully acknowledge Kimberley Slater for her invaluable support and assistance in conducting this study. We also thank NIDA-IRP nursing, recruitment and support staff, and all those individuals who volunteered their time to participate. This work was supported by the National Institute on Drug Abuse-Intramural Research Program. NR 50 TC 0 Z9 0 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2017 VL 42 IS 3 BP 736 EP 747 DI 10.1038/npp.2016.161 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EI0LQ UT WOS:000392166400017 PM 27545986 ER PT J AU Lee, CT Chen, J Kindberg, AA Bendriem, RM Spivak, CE Williams, MP Richie, CT Handreck, A Mallon, BS Lupica, CR Lin, DT Harvey, BK Mash, DC Freed, WJ AF Lee, Chun-Ting Chen, Jia Kindberg, Abigail A. Bendriem, Raphael M. Spivak, Charles E. Williams, Melanie P. Richie, Christopher T. Handreck, Annelie Mallon, Barbara S. Lupica, Carl R. Lin, Da-Ting Harvey, Brandon K. Mash, Deborah C. Freed, William J. TI CYP3A5 Mediates Effects of Cocaine on Human Neocorticogenesis: Studies using an In Vitro 3D Self-Organized hPSC Model with a Single Cortex-Like Unit SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID PLURIPOTENT STEM-CELLS; HUMAN BRAIN; DRUG-METABOLISM; CEREBRAL-CORTEX; NEOCORTEX; EXPOSURE; NEURONS; AUTISM; PROLIFERATION; SCHIZOPHRENIA AB Because of unavoidable confounding variables in the direct study of human subjects, it has been difficult to unravel the effects of prenatal cocaine exposure on the human fetal brain, as well as the cellular and biochemical mechanisms involved. Here, we propose a novel approach using a human pluripotent stem cell (hPSC)-based 3D neocortical organoid model. This model retains essential features of human neocortical development by encompassing a single self-organized neocortical structure, without including an animal-derived gelatinous matrix. We reported previously that prenatal cocaine exposure to rats during the most active period of neural progenitor proliferation induces cytoarchitectural changes in the embryonic neocortex. We also identified a role of CYP450 and consequent oxidative ER stress signaling in these effects. However, because of differences between humans and rodents in neocorticogenesis and brain CYP metabolism, translation of the research findings from the rodent model to human brain development is uncertain. Using hPSC 3D neocortical organoids, we demonstrate that the effects of cocaine are mediated through CYP3A5-induced generation of reactive oxygen species, inhibition of neocortical progenitor cell proliferation, induction of premature neuronal differentiation, and interruption of neural tissue development. Furthermore, knockdown of CYP3A5 reversed these cocaine-induced pathological phenotypes, suggesting CYP3A5 as a therapeutic target to mitigate the deleterious neurodevelopmental effects of prenatal cocaine exposure in humans. Moreover, 3D organoid methodology provides an innovative platform for identifying adverse effects of abused psychostimulants and pharmaceutical agents, and can be adapted for use in neurodevelopmental disorders with genetic etiologies. C1 [Lee, Chun-Ting; Chen, Jia; Kindberg, Abigail A.; Bendriem, Raphael M.; Spivak, Charles E.; Williams, Melanie P.; Richie, Christopher T.; Lupica, Carl R.; Lin, Da-Ting; Harvey, Brandon K.; Freed, William J.] Natl Inst Drug Abuse, IRP, NIH, Baltimore, MD USA. [Lee, Chun-Ting; Mash, Deborah C.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Handreck, Annelie] Univ Vet Med, Dept Pharmacol Toxicol & Pharm, Hannover, Germany. [Mallon, Barbara S.] NINDS, NIH Stem Cell Unit, IRP, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Lee, CT (reprint author), US FDA, Ctr Biol Evaluat & Res, Bldg 52,Room 1121,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Chun-Ting.Lee@fda.hhs.gov FU National Institute on Drug Abuse FX A patent application has been filed for the 3D model (WJ Freed and C-T Lee). This work was supported by the Intramural Research Program of the National Institute on Drug Abuse. NR 46 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2017 VL 42 IS 3 BP 774 EP 784 DI 10.1038/npp.2016.156 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EI0LQ UT WOS:000392166400021 PM 27534267 ER PT J AU Simpson, EA Paukner, A Sclafani, V Kaburu, SSK Suomi, SJ Ferrari, PF AF Simpson, Elizabeth A. Paukner, Annika Sclafani, Valentina Kaburu, Stefano S. K. Suomi, Stephen J. Ferrari, Pier F. TI Acute oxytocin improves memory and gaze following in male but not female nursery-reared infant macaques SO PSYCHOPHARMACOLOGY LA English DT Article DE Infancy; Primate; Individual differences; Intranasal oxytocin; Cognitive; Development ID CEREBROSPINAL-FLUID OXYTOCIN; AUTISM SPECTRUM DISORDER; SEX-DIFFERENCES; SOCIAL-BEHAVIOR; RHESUS-MONKEYS; VISUAL-ATTENTION; JOINT ATTENTION; WORKING-MEMORY; SUPERIOR COLLICULUS; NEWBORN MACAQUES AB Exogenous oxytocin administration is widely reported to improve social cognition in human and nonhuman primate adults. Risk factors of impaired social cognition, however, emerge in infancy. Early interventions-when plasticity is greatest-are critical to reverse negative outcomes. We tested the hypothesis that oxytocin may exert similar positive effects on infant social cognition, as in adults. To test this idea, we assessed the effectiveness of acute, aerosolized oxytocin on two foundational social cognitive skills: working memory (i.e., ability to briefly hold and process information) and social gaze (i.e., tracking the direction of others' gaze) in 1-month-old nursery-reared macaque monkeys (Macaca mulatta). We did not predict sex differences, but we included sex as a factor in our analyses to test whether our effects would be generalizable across both males and females. In a double-blind, placebo-controlled design, we found that females were more socially skilled at baseline compared to males, and that oxytocin improved working memory and gaze following, but only in males. These sex differences, while unexpected, may be due to interactions with gonadal steroids and may be relevant to sexually dimorphic disorders of social cognition, such as male-biased autism spectrum disorder, for which oxytocin has been proposed as a potential treatment. In sum, we report the first evidence that oxytocin may influence primate infant cognitive abilities. Moreover, these behavioral effects appear sexually dimorphic, highlighting the importance of considering sex differences. Oxytocin effects observed in one sex may not be generalizable to the other sex. C1 [Simpson, Elizabeth A.] Univ Miami, Dept Psychol, 5665 Ponce De Leon Blvd, Coral Gables, FL 33124 USA. [Simpson, Elizabeth A.; Paukner, Annika; Sclafani, Valentina; Kaburu, Stefano S. K.; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Poolesville, MD 20837 USA. [Simpson, Elizabeth A.; Sclafani, Valentina; Kaburu, Stefano S. K.; Ferrari, Pier F.] Univ Parma, Dipartimento Neurosci, Parma, Italy. [Sclafani, Valentina] Univ Reading, Sch Psychol & Clin Language Sci, Reading, Berks, England. [Kaburu, Stefano S. K.] Univ Calif Davis, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. [Ferrari, Pier F.] Univ Claude Bernard Lyon, CNRS, Inst Sci Cognit Marc Jeannerod, Lyon, France. RP Simpson, EA (reprint author), Univ Miami, Dept Psychol, 5665 Ponce De Leon Blvd, Coral Gables, FL 33124 USA.; Simpson, EA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Poolesville, MD 20837 USA.; Simpson, EA (reprint author), Univ Parma, Dipartimento Neurosci, Parma, Italy. EM simpsone@miami.edu FU National Institute of Child Health and Human Development, National Institutes of Health [P01HD064653]; James W. McLamore Provost Research Award in Social Sciences, University of Miami; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX We thank the staff and researchers in the Laboratory of Comparative Ethology for help with data collection, Paige Fairman for reliability coding, and Sarah E. Maylott for helpful comments. This work was supported by the National Institute of Child Health and Human Development, National Institutes of Health [P01HD064653 to P.F.F.], a James W. McLamore Provost Research Award in Social Sciences, University of Miami [to E.A.S.], and the Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 63 TC 0 Z9 0 U1 9 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2017 VL 234 IS 3 BP 497 EP 506 DI 10.1007/s00213-016-4480-x PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EI2OW UT WOS:000392328200016 PM 27837331 ER PT J AU Lee, HJ Rao, JS Ertley, RN Chang, LS Rapoport, SI Bazinet, RP AF Lee, Ho-Joo Rao, Jagadeesh S. Ertley, Renee N. Chang, Lisa Rapoport, Stanley I. Bazinet, Richard P. TI Chronic fluoxetine increases cytosolic phospholipase A2 activity and arachidonic acid turnover in brain phospholipids of the unanesthetized rat (Retraction of Vol 190, Pg 103, 2007) SO PSYCHOPHARMACOLOGY LA English DT Retraction C1 [Lee, Ho-Joo; Rao, Jagadeesh S.; Ertley, Renee N.; Chang, Lisa; Rapoport, Stanley I.; Bazinet, Richard P.] NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 9,1S 126, Bethesda, MD 20892 USA. [Bazinet, Richard P.] Univ Toronto, Fac Med, Dept Nutr Sci, FitzGerald Bldg,150 Coll St,Room 306, Toronto, ON M5S 3E2, Canada. RP Bazinet, RP (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 9,1S 126, Bethesda, MD 20892 USA.; Bazinet, RP (reprint author), Univ Toronto, Fac Med, Dept Nutr Sci, FitzGerald Bldg,150 Coll St,Room 306, Toronto, ON M5S 3E2, Canada. EM richard.bazinet@utoronto.ca NR 1 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2017 VL 234 IS 3 BP 523 EP 523 DI 10.1007/s00213-016-4499-z PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EI2OW UT WOS:000392328200019 PM 27999922 ER PT J AU Abdelrahman, RA Chuk, MK Widemann, BC Fox, E Minard, C Weigel, BJ Reid, JM AF Abdelrahman, R. A. Chuk, M. K. Widemann, B. C. Fox, E. Minard, C. Weigel, B. J. Reid, J. M. TI POPULATION PHARMACOKINETIC MODEL OF CABOZANTINIB IN PEDIATRIC PATIENTS WITH RECCURENT OR REFRACTORY SOLID TUMORS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Abdelrahman, R. A.; Reid, J. M.] Mayo Clin, Rochester, MN USA. [Chuk, M. K.; Widemann, B. C.] NCI, Pediat Oncol Branch, CCR, Bethesda, MD 20892 USA. [Fox, E.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Minard, C.] Baylor Coll Med, Houston, TX 77030 USA. [Weigel, B. J.] Univ Minnesota, Minneapolis, MN 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PII-001 BP S54 EP S54 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700186 ER PT J AU Huestis, MA Tyndale, RF AF Huestis, M. A. Tyndale, R. F. TI Designer Drugs 2.0 SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB This "Designer Drugs 2.0" issue of Clinical Pharmacology & Therapeutics focuses on novel psychoactive substances, primarily cannabinoids and cathinones, and the repurposing of established psychoactive compounds (e.g., modafinil, psilocybin, lysergic acid diethylamide, and 3,4-methylenedioxymethamphetamine) that simultaneously offer new pharmacotherapies and pose serious health problems. Novel psychoactive substances were initially used as potent tools to investigate endogenous neurotransmitter systems; for example, synthetic cannabinoids have much higher potency than Delta 9-tetrahydrocannabinol at the cannabinoid receptors. However, they are now being used illicitly as well as being tested for their efficacy in numerous clinical indications. Likewise, previously established psychoactive drugs are being repurposed as treatments for a wide variety of indications where currently approved medications are ineffective. This set of papers examines the arising problems associated with designer drugs (e.g., adverse events, psychosis, rapid new synthesis, abuse liability testing, internet sales, scheduling) as well as the potential therapeutic promises in areas as diverse as cognition enhancement, exercise-mimetics, epilepsy, multiple sclerosis, and posttraumatic stress disorder. C1 [Huestis, M. A.] NIDA, Chem & Drug Metab, IRP, NIH, Baltimore, MD USA. [Huestis, M. A.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Tyndale, R. F.] Univ Toronto, Pharmacogen, Campbell Family Mental Hlth Res Inst, Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Tyndale, R. F.] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada. [Tyndale, R. F.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. RP Tyndale, RF (reprint author), Univ Toronto, Pharmacogen, Campbell Family Mental Hlth Res Inst, Ctr Addict & Mental Hlth, Toronto, ON, Canada.; Tyndale, RF (reprint author), Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada.; Tyndale, RF (reprint author), Univ Toronto, Dept Psychiat, Toronto, ON, Canada. EM r.tyndale@utoronto.ca FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health; PGRN grant [DA020830]; CIHR grant [MOP136937]; Canada Research Chair in Pharmacogenomics (RFT); Campbell Family Mental Health Research Institute of CAMH; CAMH foundation FX We thank Hong Gu and Xia Liang for data analysis assistance. This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health; PGRN grant DA020830, CIHR grant MOP136937, a Canada Research Chair in Pharmacogenomics (RFT), Campbell Family Mental Health Research Institute of CAMH and the CAMH foundation. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 17 TC 0 Z9 0 U1 26 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS 2 BP 152 EP 157 DI 10.1002/cpt.575 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7FS UT WOS:000391938900001 PM 28084644 ER PT J AU Diao, X Huestis, MA AF Diao, X. Huestis, M. A. TI Approaches, Challenges, and Advances in Metabolism of New Synthetic Cannabinoids and Identification of Optimal Urinary Marker Metabolites SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Review ID RESOLUTION MASS-SPECTROMETRY; HUMAN HEPATOCYTES; IN-VITRO; 3-N-BUTYLPHTHALIDE NBP; SMOKING MIXTURES; ILLEGAL PRODUCTS; ALDEHYDE OXIDASE; RECEPTOR AGONIST; DRUG-METABOLISM; 5-FLUORO ANALOG AB We review approaches for determining metabolism of new synthetic cannabinoids (SCs), and challenges and advances in identifying optimal urinary marker metabolites of SC intake. Metabolic patterns of different SC generations are evaluated, and a practical strategy offered for selecting SC urinary marker metabolites. Novel SCs are incubated with human hepatocytes, the most abundant and characteristic metabolites are identified with high-resolution mass spectrometry, and proposed hepatocyte marker metabolites are confirmed in authentic positive urine samples. C1 [Diao, X.; Huestis, M. A.] NIDA, Dept Chem & Drug Metab, IRP, NIH, Baltimore, MD 21224 USA. [Huestis, M. A.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA, Dept Chem & Drug Metab, IRP, NIH, Baltimore, MD 21224 USA.; Huestis, MA (reprint author), Univ Maryland, Sch Med, Baltimore, MD 21201 USA. EM marilyn.huestis@gmail.com NR 75 TC 2 Z9 2 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS 2 BP 239 EP 253 DI 10.1002/cpt.534 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7FS UT WOS:000391938900033 PM 27727455 ER PT J AU Goldman, JL Chung, WH Lee, B Hoetzenecker, W Micheletti, RG Yasuda, SU Margolis, DJ Shear, NH Struewing, JP Pirmohamed, M AF Goldman, J. L. Chung, W-H Lee, B. Hoetzenecker, W. Micheletti, R. G. Yasuda, S. Usdin Margolis, D. J. Shear, N. H. Struewing, J. P. Pirmohamed, M. TI ADVERSE DRUG REACTION CAUSALITY ASSESSMENT TOOLS FOR DRUG-INDUCED STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS: ROOM FOR IMPROVEMENT. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Goldman, J. L.; Lee, B.] Childrens Mercy Hosp, Kansas City, MO 64108 USA. [Chung, W-H] Chang Gung Mem Hosp, Taipei, Taiwan. [Chung, W-H] Chang Gung Mem Hosp, Linkou, Taiwan. [Chung, W-H] Chang Gung Mem Hosp, Keelung, Taiwan. [Hoetzenecker, W.] Univ Zurich, Zurich, Switzerland. [Micheletti, R. G.] Hosp Univ Penn, 3400 Spruce St, Philadelphia, PA 19104 USA. [Yasuda, S. Usdin] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Margolis, D. J.] Univ Penn, Philadelphia, PA 19104 USA. [Shear, N. H.] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Shear, N. H.] Univ Toronto, Toronto, ON, Canada. [Struewing, J. P.] NHGRI, Bethesda, MD 20892 USA. [Pirmohamed, M.] Univ Liverpool, Liverpool, Merseyside, England. 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-037 BP S30 EP S30 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700089 ER PT J AU Mehrotra, S Gopalakrishnan, M Gobburu, J Greer, JM Piekarz, R Karp, JE Pratz, K Rudek, MA AF Mehrotra, S. Gopalakrishnan, M. Gobburu, J. Greer, J. M. Piekarz, R. Karp, J. E. Pratz, K. Rudek, M. A. TI EXPOSURE RESPONSE OF VELIPARIB TO INFORM PHASE 2 TRIAL DESIGN IN REFRACTORY OR RELAPSED PATIENTS WITH HEMATOLOGICAL MALIGNANCIES. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Mehrotra, S.; Gopalakrishnan, M.; Gobburu, J.] Univ Maryland, Ctr Translat Med, Baltimore, MD 21201 USA. [Greer, J. M.; Karp, J. E.; Pratz, K.; Rudek, M. A.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Piekarz, R.] NCI, Rockville, 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PII-095 BP S78 EP S78 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700280 ER PT J AU Machado-Vieira, R Zanetti, MV Otaduy, MC De Sousa, RT Soeiro-de-Souza, MG Costa, AC Carvalho, AF Leite, CC Busatto, GF Zarate, CA Gattaz, WF AF Machado-Vieira, Rodrigo Zanetti, Marcus V. Otaduy, Maria C. De Sousa, Rafael T. Soeiro-de-Souza, Marcio G. Costa, Alana C. Carvalho, Andre F. Leite, Claudia C. Busatto, Geraldo F. Zarate, Carlos A., Jr. Gattaz, Wagner F. TI Increased Brain Lactate During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Drug-Naive Bipolar Disorder A 3-T H-1-MRS Study SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE bipolar disorder; depression; imaging; lactate; lithium; treatment ID MITOCHONDRIALLY MEDIATED PLASTICITY; MAGNETIC-RESONANCE-SPECTROSCOPY; OXIDATIVE STRESS PARAMETERS; RATING-SCALE; COMPLEX; CORTEX; MANIA AB Objective: Mitochondrial dysfunction and energy metabolism impairment are key components in the pathophysiology of bipolar disorder (BD) and may involve a shift from aerobic to anaerobic metabolism. Measurement of brain lactate in vivo using protonmagnetic resonance spectroscopy (H-1-MRS) represents an important tool to evaluate mitochondrial and metabolic dysfunction during mood episodes, as well as to monitor treatment response. To date, very few studies have quantified brain lactate in BD. In addition, no study has longitudinally evaluated lactate using H-1-MRS during depressive episodes or its association with mood stabilizer therapy. This study aimed to evaluate cingulate cortex (CC) lactate using 3-T H-1-MRS during acute depressive episodes in BD and the possible effects induced by lithium monotherapy. Methods: Twenty medication-free outpatients with short length of BD (80% drug-naive) in a current major depressive episode were matched with control subjects. Patients were treated for 6 weeks with lithium monotherapy at therapeutic doses in an open-label trial (blood level, 0.48 +/- 0.19 mmol/L). Cingulate cortex lactate was measured before (week 0) and after lithium therapy (week 6) using H-1-MRS. Antidepressant efficacy was assessed with the 21-item Hamilton Depression Rating Scale as the primary outcome. Results: Subjects with BD depression showed a significantly higher CC lactate in comparison to control subjects. Furthermore, a significant decrease in CC lactate was observed after 6 weeks of lithium treatment compared with baseline (P = 0.002). CC Lactate levels was associated with family history of mood disorders and plasma lithium levels. Conclusions: This is the first report of increased CC lactate in patients with bipolar depression and lower levels after lithium monotherapy for 6 weeks. These findings indicate a shift to anaerobic metabolism and a role for lactate as a state marker during mood episodes. Energy and redox dysfunction may represent key targets for lithium's therapeutic actions. C1 [Machado-Vieira, Rodrigo; Zanetti, Marcus V.; De Sousa, Rafael T.; Soeiro-de-Souza, Marcio G.; Costa, Alana C.; Gattaz, Wagner F.] Univ Sao Paulo, Inst & Dept Psychiat, Lab Neurosci LIM 27, Sao Paulo, Brazil. [Machado-Vieira, Rodrigo; Zanetti, Marcus V.; De Sousa, Rafael T.; Gattaz, Wagner F.] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo, Brazil. [Machado-Vieira, Rodrigo; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Otaduy, Maria C.] Univ Sao Paulo, Inst & Dept Radiol, Lab Magnet Resonance Neuroradiol LIM 44, Sao Paulo, Brazil. [Carvalho, Andre F.] Univ Fed Ceara, Dept Clin Med, Fortaleza, Ceara, Brazil. [Carvalho, Andre F.] Univ Fed Ceara, Fac Med, Translat Psychiat Res Grp, Fortaleza, Ceara, Brazil. [Busatto, Geraldo F.] Univ Sao Paulo, Inst & Dept Psychiat, Lab Psychiat Neuroimaging LIM 21, Sao Paulo, Brazil. RP Machado-Vieira, R (reprint author), NIMH, NIH, Ctr Clin, 10 Ctr Dr,Unit 7SE,Rm 7-5341, Bethesda, MD 20892 USA. EM machadovieirar@gmail.com FU Sao Paulo Research Foundation (FAPESP, Brazil) [2009/14891-9]; Associacao Beneficente Alzira Denise Hertzog da Silva (ABADHS); JNK Empreendimentos e Incorporacoes FX This study was sponsored by Sao Paulo Research Foundation (FAPESP, Brazil, 2009/14891-9, RM-V). The Laboratory of Neuroscience (LIM-27) is also supported by the Associacao Beneficente Alzira Denise Hertzog da Silva (ABADHS) and JNK Empreendimentos e Incorporacoes. NR 32 TC 0 Z9 0 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 2017 VL 37 IS 1 BP 40 EP 45 DI 10.1097/JCP.0000000000000616 PG 6 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA EH5UN UT WOS:000391838500010 PM 27902528 ER PT J AU Muthigi, A George, AK Sidana, A Kongnyuy, M Simon, R Moreno, V Merino, MJ Choyke, PL Turkbey, B Wood, BJ Pinto, PA AF Muthigi, Akhil George, Arvin K. Sidana, Abhinav Kongnyuy, Michael Simon, Richard Moreno, Vanessa Merino, Maria J. Choyke, Peter L. Turkbey, Baris Wood, Bradford J. Pinto, Peter A. TI Missing the Mark: Prostate Cancer Upgrading by Systematic Biopsy over Magnetic Resonance Imaging/Transrectal Ultrasound Fusion Biopsy SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; magnetic resonance imaging; image-guided biopsy; diagnostic imaging; risk ID MRI-TRUS FUSION; TARGETED BIOPSY; GUIDED BIOPSY; MULTIPARAMETRIC MRI; IDENTIFICATION; HETEROGENEITY; GUIDANCE; DIAGNOSIS; GRADE AB Purpose: Multiparametric magnetic resonance imaging and fusion biopsy detect more high risk prostate cancer and less low risk prostate cancer than systematic biopsy. However, there remains a small subset of patients in whom systematic biopsy captures higher grade disease than fusion biopsy. We sought to identify potential mechanisms of the failure of fusion biopsy in the detection of clinically significant prostate cancer. Materials and Methods: We reviewed a prospectively maintained database of patients who underwent multiparametric magnetic resonance imaging followed by fusion biopsy and systematic biopsy from 2007 to 2014. In patients in whom disease was upgraded to clinically significant disease (Gleason 7 or greater) by systematic biopsy over fusion biopsy, independent re-review of magnetic resonance imaging, archived biopsy imaging and whole mount pathology as well as needle coordinate mapping were performed. Multivariate logistic regression analysis was done to determine predictors of upgrading by systematic biopsy. Results: Disease was upgraded based on systematic biopsy over fusion biopsy in 135 of 1,003 patients (13.5%), of whom only 62 (6.2%) were upgraded to intermediate (Gleason 7) and high risk (Gleason 8 or greater) prostate cancer (51 or 5.1% and 11 or 1.1%, respectively). On multivariate analysis lower prostate specific antigen (p < 0.001), higher magnetic resonance imaging prostate volume (p < 0.001) and a lower number of target cores (p = 0.001) were predictors of upgrading by systematic biopsy. Main mechanisms of under grading by fusion biopsy included multiparametric magnetic resonance imaging reader oversight, presence of magnetic resonance imaging invisible cancer, fusion biopsy technique error and intralesion Gleason heterogeneity. Conclusions: Magnetic resonance imaging and fusion biopsy rarely missed clinically significant prostate cancer as only 62 of 1,003 cases (6.2%) were upgraded to clinically significant disease by systematic biopsy. Imaging and biopsy techniques are continually refined. Further studies will help clarify mechanisms of fusion biopsy failure and the patient populations that benefit from systematic biopsy in addition to fusion biopsy. C1 [Muthigi, Akhil; Sidana, Abhinav; Kongnyuy, Michael; Pinto, Peter A.] NIH, Urol Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. [Simon, Richard] NIH, Biometr Res Branch, Bldg 10, Bethesda, MD 20892 USA. [Moreno, Vanessa; Merino, Maria J.] NIH, Pathol Lab, Bethesda, MD 20892 USA. [Choyke, Peter L.; Turkbey, Baris] NIH, Mol Imaging Program, Bldg 10, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [George, Arvin K.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. RP Muthigi, A (reprint author), 10 Ctr Dr,Bldg 10,Room 1-5940, Bethesda, MD 20892 USA. EM akhil.muthigi@nih.gov FU Intramural Research Program of National Institutes of Health; National Cancer Institute; Center for Cancer Research; Center for Interventional Oncology; National Institutes of Health; Foundation for National Institutes of Health from Pfizer Inc.; Doris Duke Charitable Foundation; Alexandria Real Estate Equities Inc.; Howard Hughes Medical Institute FX Supported by the Intramural Research Program of National Institutes of Health, National Cancer Institute, Center for Cancer Research, Center for Interventional Oncology, and the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by National Institutes of Health and contributions to the Foundation for National Institutes of Health from Pfizer Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities Inc., Mr. and Mrs. Joel S. Marcus, the Howard Hughes Medical Institute and other private donors (http://fnih.org/work/education-training-0/medical-research-scholars-pro gram). NR 30 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD FEB PY 2017 VL 197 IS 2 BP 327 EP 333 DI 10.1016/j.juro.2016.08.097 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA EH8YT UT WOS:000392059300023 PM 27582434 ER PT J AU Rawal, S Hinkle, SN Bao, W Zhu, YY Grewal, J Albert, PS Weir, NL Tsai, MY Zhang, CL AF Rawal, Shristi Hinkle, Stefanie N. Bao, Wei Zhu, Yeyi Grewal, Jagteshwar Albert, Paul S. Weir, Natalie L. Tsai, Michael Y. Zhang, Cuilin TI A longitudinal study of iron status during pregnancy and the risk of gestational diabetes: findings from a prospective, multiracial cohort SO DIABETOLOGIA LA English DT Article DE Ferritin; Gestational diabetes mellitus; Hepcidin; Iron overload; Soluble transferrin receptor; sTfR: ferritin ratio ID TRANSFERRIN RECEPTOR; SERUM FERRITIN; MELLITUS; WOMEN; HEPCIDIN; HOMEOSTASIS; HEMOGLOBIN; DEFICIENCY; METABOLISM; MECHANISMS AB Aims/hypothesis The aim of this study was to prospectively and longitudinally investigate maternal iron status during early to mid-pregnancy, and subsequent risk of gestational diabetes mellitus (GDM), using a comprehensive panel of conventional and novel iron biomarkers. Methods A case-control study of 107 women with GDM and 214 controls (matched on age, race/ethnicity and gestational week during blood collection) was conducted within the the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort (2009-2013), a prospective and multiracial pregnancy cohort. Plasma hepcidin, ferritin and soluble transferrin receptor (sTfR) were measured and sTfR:ferritin ratio was derived, twice before GDM diagnosis (gestational weeks 10-14 and 15-26) and at weeks 23-31 and 33-39. GDM diagnosis was ascertained from medical records. Adjusted ORs (aORs) for GDM were estimated using conditional logistic regression analysis, adjusting for demographics, prepregnancy BMI and other major risk factors. Results Hepcidin concentrations during weeks 15-26 were 16% higher among women with GDM vs controls (median 6.4 vs 5.5 ng/ml; p = 0.02 ), and were positively associated with GDM risk; the aOR (95% CI) for highest vs lowest quartile was 2.61 (1.07, 6.36). Ferritin levels were also positively associated with GDM risk; the aOR (95% CI) for highest vs lowest quartile was 2.43 (1.12, 5.28) at weeks 10-14 and 3.95 (1.38, 11.30) at weeks 15-26. The sTfR:ferritin ratio was inversely related to GDM risk; the aOR (95% CI) for highest vs lowest quartile was 0.33 (0.14, 0.80) at weeks 10-14 and 0.15 (0.05, 0.48) at weeks 15-26. Conclusions/interpretation Our findings suggest that elevated iron stores may be involved in the development of GDM from as early as the first trimester. This raises potential concerns for the recommendation of routine iron supplementation among iron-replete pregnant women. C1 [Rawal, Shristi; Hinkle, Stefanie N.; Zhu, Yeyi; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6710B Rockledge Dr,MSC 7004, Bethesda, MD 20817 USA. [Bao, Wei] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Grewal, Jagteshwar] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Off Director, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Weir, Natalie L.; Tsai, Michael Y.] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6710B Rockledge Dr,MSC 7004, Bethesda, MD 20817 USA. EM zhangcu@mail.nih.gov OI Grewal, Jagteshwar/0000-0002-0141-4876 FU NICHD; American Recovery and Reinvestment Act [HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275200800003IC, HHSN275200800014C, HHSN275200800012C, HHSN275200800028C, HHSN275201000009C, HHSN275201000001Z] FX This research was supported by NICHD intramural funding and included American Recovery and Reinvestment Act funding via contract numbers: HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275200800003IC, HHSN275200800014C, HHSN275200800012C, HHSN275200800028C, HHSN275201000009C and HHSN275201000001Z. NR 36 TC 2 Z9 2 U1 15 U2 15 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 FEB PY 2017 VL 60 IS 2 BP 249 EP 257 DI 10.1007/s00125-016-4149-3 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG9EA UT WOS:000391359800005 PM 27830277 ER PT J AU Morales, A Eidinger, D Bruce, AW AF Morales, A. Eidinger, D. Bruce, A. W. TI INTRACAVITARY BACILLUS CALMETTE-GUERIN IN THE TREATMENT OF SUPERFICIAL BLADDER TUMORS SO JOURNAL OF UROLOGY LA English DT Article ID BCG; CANCER; CARCINOMA; MELANOMA; THERAPY AB Patients with recurrent superficial bladder tumors have been treated by vesical and intradermal administration of Bacillus Calmette-Guerin. The pattern of recurrence in 9 patients has been altered favorably. Although the findings are still preliminary they appear to hold promise of a new therapeutic approach to the treatment of a group of neoplasms for which effective therapy is still lacking. C1 Queens Univ, Dept Urol, Kingston, ON, Canada. Queens Univ, Dept Microbiol & Immunol, Kingston, ON, Canada. [Morales, A.] NIH, Lab Immunodiagnosis, Bldg 8,Room 118, Bethesda, MD 20014 USA. RP Morales, A (reprint author), Queens Univ, Etherington Hall, Kingston, ON, Canada. FU Ontario Cancer Foundation [292] FX Supported by the Ontario Cancer Foundation Grant 292. NR 17 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD FEB PY 2017 VL 197 IS 2 SU S BP S142 EP S144 DI 10.1016/j.juro.2016.10.101 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA EH5XA UT WOS:000391845100028 PM 28012770 ER PT J AU Biehl, AJ Katz, JD AF Biehl, Ann J. Katz, James D. TI Pharmacotherapy Pearls for the Geriatrician Focus on Oral Disease-Modifying Antirheumatic Drugs Including Newer Agents SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Geriatrics; DMARDs; Rheumatology; Tofacitinib ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; INHIBITOR TOFACITINIB CP-690,550; RHEUMATOID-ARTHRITIS PATIENTS; INFLAMMATORY-BOWEL-DISEASE; FUNCTIONAL HEALTH LITERACY; JANUS KINASE INHIBITOR; OF-THE-LITERATURE; ELDERLY-PATIENTS; INADEQUATE RESPONSE; ULCERATIVE-COLITIS AB Providing safe and effective pharmacotherapy to the geriatric patients with rheumatological disorders is an ongoing struggle for the rheumatologist and geriatrician alike. Cohesive communication and partnership can improve the care of these patients and subvert adverse outcomes. Disease-modifying antirheumatic drugs, including methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide, and the newest oral agent for treatment of rheumatoid arthritis, tofacitinib, have distinctive monitoring and adverse effect profiles. This article provides the general practitioner or geriatrician with clinically relevant pearls regarding the use of these interventions in older patients. C1 [Biehl, Ann J.] NIH, Dept Pharm, Ctr Clin, 10 Ctr Dr,Room 1C240, Bethesda, MD 20892 USA. [Katz, James D.] NIAMSD, NIH, 6N-216F,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. RP Biehl, AJ (reprint author), NIH, Dept Pharm, Ctr Clin, 10 Ctr Dr,Room 1C240, Bethesda, MD 20892 USA. EM ann.biehl@nih.gov FU Intramural Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) FX This work was supported by the Intramural Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH). NR 100 TC 0 Z9 0 U1 6 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD FEB PY 2017 VL 33 IS 1 BP 1 EP + DI 10.1016/j.cger.2016.08.001 PG 16 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA EG3YN UT WOS:000390980700002 PM 27886691 ER PT J AU Katz, JD Walitt, B AF Katz, James D. Walitt, Brian TI Rheumatic Diseases in Older Adults Preface SO CLINICS IN GERIATRIC MEDICINE LA English DT Editorial Material C1 [Katz, James D.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Walitt, Brian] NIDCR, NINR, NIH, Bethesda, MD USA. RP Katz, JD (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. EM James.katz@nih.gov; brian.walitt@nih.gov NR 2 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 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD FEB PY 2017 VL 33 IS 1 BP IX EP X DI 10.1016/j.cger.2016.10.001 PG 2 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA EG3YN UT WOS:000390980700001 PM 27886701 ER PT J AU Dhillon, RJS Hasni, S AF Dhillon, Robinder J. S. Hasni, Sarfaraz TI Pathogenesis and Management of Sarcopenia SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Sarcopenia; Muscle strength; Muscle atrophy; Frailty; Aging; Senescence; Fall risk; Skeletal muscle mass ID DWELLING OLDER-ADULTS; BODY-COMPOSITION; TRANSFORMING AGENT; MUSCLE MASS; CACHEXIA; DEFINITION; PREVALENCE; DIAGNOSIS; OBESITY; PEOPLE AB Sarcopenia represents a loss of muscle strength and mass in older individuals. Sarcopenia in the elderly has now become a major focus of research and public policy debate due to its impact on morbidity, mortality, and health care expenditure. Despite its clinical importance, sarcopenia remains under-recognized and poorly managed in routine clinical practice. This is, in part, due to a lack of available diagnostic testing and uniform diagnostic criteria. The management of sarcopenia is primarily focused on physical therapy for muscle strengthening and gait training. There are no pharmacologic agents for the treatment of sarcopenia. C1 [Dhillon, Robinder J. S.; Hasni, Sarfaraz] NIAMSD, NIH, 9000 Rockville Pike,Bldg 10,Room 3-2340, Bethesda, MD 20892 USA. RP Hasni, S (reprint author), NIAMSD, NIH, 9000 Rockville Pike,Bldg 10,Room 3-2340, Bethesda, MD 20892 USA. EM hasnisa@mail.nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 57 TC 0 Z9 0 U1 17 U2 17 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD FEB PY 2017 VL 33 IS 1 BP 17 EP + DI 10.1016/j.cger.2016.08.002 PG 11 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA EG3YN UT WOS:000390980700003 PM 27886695 ER PT J AU Acevedo, AT Jackson, A Alter, KE AF Acevedo, Ana T. Jackson, Adrienne Alter, Katharine E. TI Regional Rheumatic Disorders and Rehabilitation in Older Adults SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Regional rheumatic pain syndromes; Geriatric rehabilitation; Rehabilitation medicine ID RANDOMIZED CONTROLLED-TRIALS; PLATELET-RICH PLASMA; KNEE OSTEOARTHRITIS; NERVE-STIMULATION; NEEDLE TENOTOMY; CHRONIC PAIN; ULTRASOUND; INJECTION; PROLOTHERAPY; METAANALYSIS AB Musculoskeletal problems are the most frequently reported complaints among older adults living in the community. The impact of the aging process on skeletal muscles and joints can have a profound effect on the ability of individuals with and without disabilities to function. This article reviews the rehabilitation medicine approach to the evaluation of older adults with regional rheumatic disorders, and the rehabilitation medicine considerations for clinical interventions. Future research considerations are encouraged in order to gain a greater understanding of the subject matter and its impact on the provision of care and patients' quality of life. C1 [Acevedo, Ana T.; Jackson, Adrienne; Alter, Katharine E.] NIH, Dept Rehabil Med, Ctr Clin, 10 Ctr Dr,Bldg 10,CRC,Room 1-1469, Bethesda, MD 20892 USA. RP Acevedo, AT (reprint author), NIH, Dept Rehabil Med, Ctr Clin, 10 Ctr Dr,Bldg 10,CRC,Room 1-1469, Bethesda, MD 20892 USA. EM ana.acevedo@nih.gov NR 64 TC 0 Z9 0 U1 5 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD FEB PY 2017 VL 33 IS 1 BP 53 EP + DI 10.1016/j.cger.2016.08.005 PG 21 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA EG3YN UT WOS:000390980700006 PM 27886698 ER PT J AU Baer, AN Walitt, B AF Baer, Alan N. Walitt, Brian TI Sjogren Syndrome and Other Causes of Sicca in Older Adults SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Sjogren syndrome; Dry eye; Aging; Salivary hypofunction; Xerostomia ID SALIVARY-GLAND ULTRASONOGRAPHY; OF-RHEUMATOLOGY CLASSIFICATION; EUROPEAN CONSENSUS GROUP; HIGHLY SPECIFIC TOOL; DRY EYE; RITUXIMAB TREATMENT; VAGINAL ATROPHY; CLINICAL-TRIAL; DOUBLE-BLIND; DISEASE AB Dry eye and dry mouth symptoms are each reported by up to 30% of persons more than 65 years of age, particularly in women. Medication side effects are the most common contributing factors. The evaluation of these symptoms requires measures of ocular and oral dryness. Sjogren syndrome is the prototypic disease associated with dryness of the eyes and mouth and predominantly affects women in their perimenopausal and postmenopausal years. In addition to topical treatment of the mucosal dryness, patients with Sjogren syndrome may require treatment with systemic immunomodulatory and immunosuppressive agents to manage a variety of extraglandular manifestations. C1 [Baer, Alan N.] Johns Hopkins Univ, Sch Med, Dept Med, Div Rheumatol, 5200 Eastern Ave,Suite 4000,Mason Lord Ctr Tower, Baltimore, MD 21224 USA. [Baer, Alan N.; Walitt, Brian] Natl Inst Dent & Craniofacial Res, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. RP Baer, AN (reprint author), 5200 Eastern Ave,Suite 4000,Mason Lord Ctr Tower, Baltimore, MD 21224 USA. EM alanbaer@jhmi.edu FU Bristol-Myers Squibb; Novartis; Intramural Research Program of the NIH, NIDCR FX Dr A.N. Baer reports consulting fees from Bristol-Myers Squibb and Novartis. This article was supported in part by the Intramural Research Program of the NIH, NIDCR. NR 66 TC 0 Z9 0 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD FEB PY 2017 VL 33 IS 1 BP 87 EP + DI 10.1016/j.cger.2016.08.007 PG 18 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA EG3YN UT WOS:000390980700008 PM 27886700 ER PT J AU Kelly, SP Rosenberg, PS Anderson, WF Andreotti, G Younes, N Cleary, SD Cook, MB AF Kelly, Scott P. Rosenberg, Philip S. Anderson, William F. Andreotti, Gabriella Younes, Naji Cleary, Sean D. Cook, Michael B. TI Trends in the Incidence of Fatal Prostate Cancer in the United States by Race SO EUROPEAN UROLOGY LA English DT Article DE Cancer trends; Cause-specific mortality; Disease progression; Prostate cancer; Prostate-specific antigen ID EUROPEAN-AMERICAN MEN; RACIAL DISPARITIES; AFRICAN-AMERICAN; INCIDENCE RATES; WHITE MEN; MORTALITY; ANTIGEN; SURVEILLANCE; PERIOD; DEATH AB Background: Prostate-specific antigen (PSA) testing has dramatically changed the composition of prostate cancer (PCa), making it difficult to interpret incidence trends. New methods are needed to examine temporal trends in the incidence of clinically significant PCa and whether trends vary by race. Objective: To conduct an in-depth analysis of incidence trends in clinically significant PCa, defined as cases in which PCa was the underlying cause of death within 10 yr of diagnosis. Design, setting, and participants: We extracted incident PCa cases during the period 1975-2002 and associated causes of death and survival through 2012 from nine cancer registries in the population-based Surveillance Epidemiology and End Results program database. Outcome measurements and statistical analysis: We applied joinpoint regression analysis to identify when significant changes in trends occurred and age-period-cohort models to examine longitudinal and cross-sectional trends in the incidence of fatal PCa. Results and limitations: Among 51 680 fatal PCa cases, incidence increased 1% per year prior to 1992, declined 15% per year from 1992 to 1995, and further declined by 5% per year through 2002. Age-specific incidence rates of fatal disease decreased >2% per year among men aged >= 60 yr, yet rates remained relatively stable among men aged <= 55 yr. Fatal disease rates were >2-fold higher in black men compared with white men, a racial disparity that increased to 4.2-fold among younger men. Conclusions: The incidence of fatal PCa substantially declined after widespread PSA screening and treatment advances. Nevertheless, rates of fatal disease among younger men have remained relatively stable, suggesting the need for additional attention to early onset PCa, especially among black men. The persistent black-to-white racial disparity observed in fatal PCa underscores the need for greater understanding of the causes of this difference so that strategies can be implemented to eliminate racial disparities. Patient summary: We assessed how the incidence of ultimately fatal prostate cancer (PCa) changed over time. We found that the incidence of fatal PCa declined by > 50% since the introduction of prostate-specific antigen testing and advances in treatment options; however, incidence rates among younger men remained relatively stable, and younger black men exhibited a 4.2-fold higher risk for fatal disease compared with white men. Published by Elsevier B.V. on behalf of European Association of Urology. C1 [Kelly, Scott P.; Rosenberg, Philip S.; Anderson, William F.; Andreotti, Gabriella; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 7E-106,MSC 9774, Bethesda, MD 20892 USA. [Kelly, Scott P.; Younes, Naji; Cleary, Sean D.] George Washington Univ, Dept Epidemiol & Biostat, Milken Inst Sch Publ Hlth, Washington, DC USA. RP Cook, MB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 7E-106,MSC 9774, Bethesda, MD 20892 USA. EM michael.cook@nih.gov OI Kelly, Scott/0000-0002-0375-1040 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD FX This study was supported entirely by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD. No funding or other financial support was received. NR 30 TC 2 Z9 2 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD FEB PY 2017 VL 71 IS 2 BP 195 EP 201 DI 10.1016/j.eururo.2016.05.011 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA EF8FY UT WOS:000390565700033 PM 27476048 ER PT J AU Gaudinski, MR Milner, JD AF Gaudinski, Martin Robert Milner, Joshua D. TI Atopic Dermatitis and Allergic Urticaria Cutaneous Manifestations of Immunodeficiency SO IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA LA English DT Article DE Atopic dermatitis; Urticaria; Immunodeficiency ID REGULATORY T-CELLS; HYPER-IGE SYNDROME; COMBINED IMMUNE-DEFICIENCY; OMENN-SYNDROME; DIAGNOSTIC-CRITERIA; MUTATIONS; DISEASE; DIFFERENTIATION; AUTOIMMUNITY; IMPAIRMENT AB Atopic dermatitis and allergic urticaria are common conditions of the skin that can also be the presenting symptoms of uncommon diseases. Defects leading to immunodeficiency may be associated with atopic dermatitis or allergic urticaria. Unusually severe or otherwise atypical presentations of atopic dermatitis or allergic urticaria may lead to clinical suspicion of an underlying immunodeficiency. C1 [Gaudinski, Martin Robert; Milner, Joshua D.] NIAID, Genet & Pathogenesis Allergy Sect, 10 Ctr Dr,Bldg 10,Room 11N240A, Bethesda, MD 20814 USA. RP Milner, JD (reprint author), 10 Ctr Dr,NIH Bldg,10CRC 5-3950, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov FU Division of Intramural Research of the NIAID, NIH [ZO1 1ZIAAI001098-02] FX This study was supported by the Division of Intramural Research of the NIAID, NIH (ZO1 1ZIAAI001098-02). NR 40 TC 0 Z9 0 U1 5 U2 5 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 FEB PY 2017 VL 37 IS 1 BP 1 EP + DI 10.1016/j.iac.2016.08.016 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA EG3YT UT WOS:000390981300003 PM 27886899 ER PT J AU Holt, HK Zhang, L Zhao, FH Hu, SY Zhao, XL Zhang, X Pan, QJ Zhang, WH Smith, JS Qiao, YL AF Holt, Hunter K. Zhang, Li Zhao, Fang-Hui Hu, Shang-Ying Zhao, Xue-Lian Zhang, Xun Pan, Qin-Jing Zhang, Wen-Hua Smith, Jennifer S. Qiao, You-Lin TI Evaluation of multiple primary and combination screening strategies in postmenopausal women for detection of cervical cancer in China SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE menopause; HPV DNA testing; cervical cancer; HPV; prevalence; visual inspection with acetic acid; China; cytology ID SQUAMOUS-CELL CARCINOMA; LOW-RESOURCE SETTINGS; HUMAN-PAPILLOMAVIRUS; VISUAL INSPECTION; ACETIC-ACID; INTRAEPITHELIAL NEOPLASIA; DEVELOPING-COUNTRIES; MENOPAUSAL STATUS; POOLED ANALYSIS; BREAST-CANCER AB As China's population ages, the importance of determining prevalence of cervical disease and accurate cervical cancer screening strategies for postmenopausal women is increasing. Seventeen population-based studies were analyzed to determine prevalence of cervical neoplasia in postmenopausal women. All women underwent HPV DNA testing, visual inspection with acetic acid (VIA) and cytology testing. Diagnostic values for primary and combinations screening methods included sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), referral rate and area under curve (AUC) were calculated using directed biopsy or four quadrants biopsy as reference standard. Premenopausal and postmenopausal women had equal HPV infection and cervical neoplasia rates (p>0.05). HPV DNA testing CIN3+ sensitivity, specificity, PPV, NPV, referral rate and AUC were 97.9% (95% CI: 90.2-99.9%), 84.2% (95% CI: 82.8-85.5%), 9.9% (95% CI: 7.4-12.8%), 100% (95% CI: 99.8-100%), 17.2% (95% CI: 15.9-18.7%), 0.911, respectively. VIA values were 41.7% (95% CI: 28.4-55.9%), 94.5% (95% CI: 93.6-95.3%), 11.8% (95% CI: 7.5-17.3%), 98.9% (95% CI: 98.5-99.3%), 6.2% (95% CI: 5.3-7.1%) and 0.681, respectively. Values for VIA with HPV triage were 39.6% (95% CI: 26.6-53.8%), 99.2% (95% CI: 98.8-99.5%), 45.2% (95% CI: 30.8-60.4%), 98.9% (95% CI: 98.5-99.3%), 1.5% (95% CI: 1.1-2.0%) and 0.694, respectively. VIA and HPV DNA co-test values were 100% (95% CI: 94.0-100%), 79.5% (95% CI: 78.0-81.0%), 8.0% (95% CI: 6.0-10.3%), 100% (95% CI: 99.9-100%), 21.9% (95% CI: 20.4-23.4%) and 0.898, respectively. VIA sensitivity decreases significantly in postmenopausal women compared to premenopausal performance. HPV DNA testing maintains performance between pre- and postmenopausal women and is the most accurate primary modality for screening postmenopausal populations in low resource areas of China. What's new? Our study sought to investigate feasible screening strategies for the increasing postmenopausal population in China. There is a similar disease burden in premenopausal and postmenopausal women. VIA had a significant drop in diagnostic performance for postmenopausal women compared to premenopausal diagnostic performance. While HPV DNA testing has the best sensitivity in postmenopausal women and does not have a significant difference in performance between pre- and postmenopausal women. C1 [Holt, Hunter K.; Zhang, Li; Zhao, Fang-Hui; Hu, Shang-Ying; Zhao, Xue-Lian; Zhang, Xun; Pan, Qin-Jing; Zhang, Wen-Hua; Qiao, You-Lin] Chinese Acad Med Sci, Natl Canc Ctr, Canc Hosp, Dept Canc Epidemiol, Beijing, Peoples R China. [Holt, Hunter K.; Zhang, Li; Zhao, Fang-Hui; Hu, Shang-Ying; Zhao, Xue-Lian; Zhang, Xun; Pan, Qin-Jing; Zhang, Wen-Hua; Qiao, You-Lin] Peking Union Med Coll, Beijing, Peoples R China. [Holt, Hunter K.] NIH, Fogarty Int Ctr, UJMT Fogarty Consortium, Bldg 10, Bethesda, MD 20892 USA. [Holt, Hunter K.] Univ Illinois, Chicago Coll Med, Dept Family Med, Chicago, IL USA. [Smith, Jennifer S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Zhao, FH (reprint author), 17 South Panjiayuan Lane,POB 2258, Beijing 100021, Peoples R China. EM Zhaofangh@cicams.ac.cn FU Bill & Melinda Gates Foundation; NIH Fogarty International Center; International Agency for Research on Cancer; Cleveland Clinic FX The authors thank the local doctors and the women who participated in our study from Beijing, Gansu, Guangdong, Jiangsu, Jiangxi, Henan, Shanghai, Shanxi and Xinjiang, as well as the Bill & Melinda Gates Foundation, the NIH Fogarty International Center, the International Agency for Research on Cancer and the Cleveland Clinic for their generous support. NR 43 TC 0 Z9 0 U1 9 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2017 VL 140 IS 3 BP 544 EP 554 DI 10.1002/ijc.30468 PG 11 WC Oncology SC Oncology GA EG0DY UT WOS:000390702500006 PM 27727464 ER PT J AU Felix, AS Bower, JK Pfeiffer, RM Raman, SV Cohn, DE Sherman, ME AF Felix, Ashley S. Bower, Julie K. Pfeiffer, Ruth M. Raman, Subha V. Cohn, David E. Sherman, Mark E. TI High cardiovascular disease mortality after endometrial cancer diagnosis: Results from the Surveillance, Epidemiology, and End Results (SEER) Database SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE uterus neoplasm; cardiovascular disease; competing risk; mortality; survivor ID GYNECOLOGIC-ONCOLOGY-GROUP; BODY-MASS INDEX; UNITED-STATES; DEATH CERTIFICATE; SURVIVAL; RISK; WOMEN; STATISTICS; TRENDS; ADULTS AB Obesity is a strong risk factor for developing endometrial cancer and cardiovascular disease (CVD); consequently, understanding CVD mortality among endometrial cancer survivors is important. We analyzed Surveillance, Epidemiology and End Results Program data for 157,496 endometrial cancer cases diagnosed between 1988 and 2012. We calculated standardized mortality ratios (SMRs) for CVD and all-cause mortality comparing endometrial cancer cases and general population women. We categorized women into one of three prognostic groups (excellent, intermediate and poor) based on tumor characteristics. Cumulative incidence function curves were plotted to visualize absolute mortality risk in the presence of competing risks. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression for cause-specific mortality. Deaths were as follows: endometrial cancer 40.6%, CVD 20.5%, other cancers 18.7% and other causes 20.3%. Women with endometrial cancer were more likely to die from CVD (age-adjusted SMR=8.8, 95% CI=8.7-9.0) and all causes (age-adjusted SMR=15.9, 95% CI=15.8-16.0) compared to general population women. In case-only analyses, higher CVD mortality was associated with older age, Black ethnicity and lack of surgical treatment. Poor prognosis cancers (non-endometrioid histology and late stage) were related to higher mortality from each cause, with the highest HRs observed for endometrial cancer-specific mortality. Among women diagnosed with excellent prognosis tumors (endometrioid, well-differentiated and early stage), absolute risk of CVD mortality surpassed endometrial cancer-specific mortality 5 years after diagnosis. Women diagnosed with common forms of endometrial cancer have a high CVD burden. After diagnosis, cardiovascular health should be emphasized for these women to reduce mortality. What's new? The majority of women who develop endometrial cancer do not die from their cancer; however, the underlying risk factors put them at risk of developing cardiovascular disease (CVD). In this large population-based analysis, CVD mortality was greater among women with endometrial cancer than in the general population. Women diagnosed with excellent prognosis endometrial tumors had a greater absolute risk of dying from CVD than endometrial cancer, whereas women with poor prognosis tumors were at greater risk of dying from endometrial cancer. Women with an endometrial cancer diagnosis should be counseled on cardiovascular health as soon as possible during follow-up care. C1 [Felix, Ashley S.; Bower, Julie K.] Ohio State Univ, Coll Publ Hlth, Div Epidemiol, Columbus, OH 43210 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Raman, Subha V.] Ohio State Univ, Coll Med, Div Cardiovasc Med, Columbus, OH 43210 USA. [Cohn, David E.] Ohio State Univ, Coll Med, Div Gynecol Oncol, Columbus, OH 43210 USA. [Sherman, Mark E.] NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Felix, AS (reprint author), 1841 Neil Ave,300-C Cunz Hall, Columbus, OH 43210 USA. EM Felix.20@osu.Edu NR 44 TC 0 Z9 0 U1 9 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2017 VL 140 IS 3 BP 555 EP 564 DI 10.1002/ijc.30470 PG 10 WC Oncology SC Oncology GA EG0DY UT WOS:000390702500007 PM 27741565 ER PT J AU Trabert, B Eldridge, RC Pfeiffer, RM Shiels, MS Kemp, TJ Guillemette, C Hartge, P Sherman, ME Brinton, LA Black, A Chaturvedi, AK Hildesheim, A Berndt, SI Safaeian, M Pinto, L Wentzensen, N AF Trabert, Britton Eldridge, Ronald C. Pfeiffer, Ruth M. Shiels, Meredith S. Kemp, Troy J. Guillemette, Chantal Hartge, Patricia Sherman, Mark E. Brinton, Louise A. Black, Amanda Chaturvedi, Anil K. Hildesheim, Allan Berndt, Sonja I. Safaeian, Mahboobeh Pinto, Ligia Wentzensen, Nicolas TI Prediagnostic circulating inflammation markers and endometrial cancer risk in the prostate, lung, colorectal and ovarian cancer (PLCO) screening trial SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE endometrial cancer; circulating inflammation markers; prediagnostic; nested case-contro ID POSTMENOPAUSAL WOMEN; PHYSICAL-ACTIVITY; OBESITY; CYTOKINE; IMMUNITY AB Inflammation is proposed to increase risk of developing endometrial cancer, but few prospective epidemiologic studies have investigated the relationship between circulating inflammation markers and endometrial cancer risk. In a nested case-control study within the PLCO Screening Trial we measured serum levels of 64 inflammation-related biomarkers in 284 incident endometrial cancer cases and 284 matched controls. Using multivariable logistic regression inflammation markers were evaluated individually and combined into a cross-validated inflammation score. Of 64 markers, 22 were associated with endometrial cancer risk at p<0.05 and 17 of 22 markers remained associated after multiple testing corrections. After adjusting for BMI and estradiol, SERPINE1 [quartile(Q)4 vs. Q1 odds ratio (OR) (95% confidence interval (CI)), p trend=2.43 (0.94-6.29), 0.03] and VEGFA [2.56 (1.52-4.30), 0.0002] were positively associated with endometrial cancer risk, while CCL3 [0.46 (0.27-0.77), 0.01], IL13 [0.55 (0.33-0.93), 0.01], IL21 [0.52 (0.31-0.87), 0.01], IL1B [0.51 (0.30-0.86), 0.01] and IL23 [0.60 (0.35-1.03), 0.02] were inversely associated with risk. We observed large differences in ORs across BMI-inflammation score categories. Endometrial cancer risk was most pronounced among obese women with the highest inflammation score tertile (T) [10.25 (3.56-29.55) vs. normal BMI/T1]. Several inflammation markers were prospectively associated with endometrial cancer, including adipokines, pro- and anti-inflammatory cytokines, angiogenic factors and acute phase proteins. Inverse associations with anti-inflammatory markers (IL13, IL21), other inflammation markers/mediators (CCL3, IL1B, IL23), and a robust positive association between VEGFA and endometrial cancer risk were independent of BMI and estradiol, suggesting that these factors may influence risk through other mechanisms. What's new? Can circulating inflammation markers predict endometrial cancer? Rising rates of endometrial cancer have been attributed to fewer hysterectomies and more obesity. Inflammation has also been suggested as a contributor, but less evidence supports this association. These authors conducted the most comprehensive evaluation to date of pro- and anti-inflammatory markers in endometrial cancer. While many of the inflammatory marker associations they found disappeared after accounting for BMI or circulating estradiol, they did find an independent association between pro-inflammatory marker VEGFA and endometrial cancer risk. Several anti-inflammatory markers inversely associated with cancer risk as well, independent of BMI and estradiol. C1 [Trabert, Britton; Eldridge, Ronald C.; Pfeiffer, Ruth M.; Shiels, Meredith S.; Hartge, Patricia; Brinton, Louise A.; Black, Amanda; Chaturvedi, Anil K.; Hildesheim, Allan; Berndt, Sonja I.; Safaeian, Mahboobeh; Pinto, Ligia; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kemp, Troy J.; Pinto, Ligia] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, HPV Immunol Lab, Frederick, MD USA. [Guillemette, Chantal] Univ Laval, Fac Pharm, Pharmacogen Lab, CHUQ,Res Ctr, Quebec City, PQ, Canada. [Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Trabert, B (reprint author), 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM britton.trabert@nih.gov FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX Grant sponsors: Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services NR 28 TC 0 Z9 0 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2017 VL 140 IS 3 BP 600 EP 610 DI 10.1002/ijc.30478 PG 11 WC Oncology SC Oncology GA EG0DY UT WOS:000390702500012 PM 27770434 ER PT J AU Schiffman, M Yu, K Zuna, R Terence Dunn, S Zhang, H Walker, J Gold, M Hyun, N Rydzak, G Katki, HA Wentzensen, N AF Schiffman, Mark Yu, Kai Zuna, Rosemary Terence Dunn, S. Zhang, Han Walker, Joan Gold, Michael Hyun, Noorie Rydzak, Greg Katki, Hormuzd A. Wentzensen, Nicolas TI Proof-of-principle study of a novel cervical screening and triage strategy: Computer-analyzed cytology to decide which HPV-positive women are likely to have >= CIN2 SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cervical; cancer; screening; cytology; HPV; automation ID HUMAN-PAPILLOMAVIRUS; CANCER PRECURSORS; INFECTIONS; COLPOSCOPY; MANAGEMENT; TESTS; RISK; END AB A challenge in implementation of sensitive HPV-based screening is limiting unnecessary referrals to colposcopic biopsy. We combined two commonly recommended triage methods: partial HPV typing and reflex cytology, evaluating the possibility of automated cytology. This investigation was based on 1,178 exfoliated cervical specimens collected during the enrollment phase of The Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED, Oklahoma City, OK). We chose a colposcopy clinic population to maximize number of outcomes, for this proof-of-principle cross-sectional study. Residual aliquots of PreservCyt were HPV-typed using Linear Array (LA, Roche Molecular Systems, Pleasanton, CA). High-risk HPV typing data and cytologic results (conventional and automated) were used jointly to predict risk of histologically defined CIN2. We developed a novel computer algorithm that uses the same optical scanning features that are generated by the FocalPoint Slide Profiler (BD, Burlington, NC). We used the Least Absolute Shrinkage and Selection Operator (LASSO) method to build the prediction model based on a training dataset (n=600). In the validation set (n=578), for triage of all HPV-positive women, a cytologic threshold of ASC-US had a sensitivity of 0.94, and specificity of 0.30, in this colposcopy clinic setting. When we chose a threshold for the severity score (generated by the computer algorithm) that had an equal specificity of 0.30, the sensitivity was 0.91. Automated cytology also matched ASC-US when partial HPV typing was added to the triage strategy, and when we re-defined cases as CIN3. If this strategy works in a prospective screening setting, a totally automated screening and triage technology might be possible. What's new? Cervical cancer is caused by infection with a group of high-risk human papillomavirus (HPV) infections. Approximately 90% of HPV infections are however cleared or controlled immunologically within a few years. Risk-stratification of HPV-positive women using cytology has thus been recommended to reduce excessive colposcopy referral and overtreatment that would result from HPV screening alone. In a proof-of-principle study within a colposcopy referral population, here the authors show that automated cytology performs as well as conventionally interpreted cytology for triage of HPV-positive women, whether or not partial HPV typing is included. This raises the possibility of completely automated cervical cancer screening. C1 [Schiffman, Mark; Yu, Kai; Zhang, Han; Hyun, Noorie; Katki, Hormuzd A.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zuna, Rosemary] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Terence Dunn, S.; Walker, Joan] Oklahoma Dept Hlth, Oklahoma City, OK USA. [Gold, Michael] Tulsa Canc Inst, Tulsa, OK USA. [Rydzak, Greg] Informat Management Serv Inc, Calverton, MD USA. RP Schiffman, M (reprint author), NCI, Clin Genet Branch, 9609 Med Ctr Dr, Rockville, MD 20850 USA.; Yu, K (reprint author), NCI, Biostat Branch, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM Schiffmm@mail.Nih.Gov; Yuka@mail.Nih.Gov FU Intramural Research Program of the National Cancer Institute, NCI FX Grant sponsor: Intramural Research Program of the National Cancer Institute, NCI. NR 25 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2017 VL 140 IS 3 BP 718 EP 725 DI 10.1002/ijc.30456 PG 8 WC Oncology SC Oncology GA EG0DY UT WOS:000390702500024 PM 27696414 ER PT J AU Carli, F Silver, JK Feldman, LS McKee, A Gilman, S Gillis, C Scheede-Bergdahl, C Gamsa, A Stout, N Hirsch, B AF Carli, Francesco Silver, Julie K. Feldman, Liane S. McKee, Andrea Gilman, Sean Gillis, Chelsia Scheede-Bergdahl, Celena Gamsa, Ann Stout, Nicole Hirsch, Bradford TI Surgical Prehabilitation in Patients with Cancer State-of-the-Science and Recommendations for Future Research from a Panel of Subject Matter Experts SO PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA LA English DT Article DE Cancer; Surgery; Exercise; Nutrition; Prehabilitation; Anxiety; Outcome ID RANDOMIZED CLINICAL-TRIAL; PREOPERATIVE NUTRITIONAL SUPPORT; FUNCTIONAL EXERCISE CAPACITY; NICOTINE REPLACEMENT THERAPY; PLACEBO-CONTROLLED TRIAL; PHYSICAL-ACTIVITY; SMOKING-CESSATION; ENHANCED-RECOVERY; BREAST-CANCER; COLORECTAL SURGERY AB This review by a 10-member panel of experts in surgical prehabilitation addresses processes that may improve oncologic care. Surgical prehabilitation is the process on the continuum of care that occurs between the time of cancer diagnosis and the beginning of surgical treatment. The panel focused on the current state-of-the-science and recommended future research that would help to identify the elements that enhance preoperative physical, nutritional, and psychological health in anticipation of surgery, mitigate the burden of disease, facilitate the return of patient health status to baseline values, decrease postoperative morbidity, and reduce health care costs. C1 [Carli, Francesco; Gillis, Chelsia; Gamsa, Ann] McGill Univ, Ctr Hlth, Dept Anesthesia, Montreal, PQ, Canada. [Silver, Julie K.] Harvard Med Sch, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Feldman, Liane S.] McGill Univ, Ctr Hlth, Dept Surg, Montreal, PQ, Canada. [McKee, Andrea] Lahey Hosp & Med Ctr, Dept Radiat Oncol, Burlington, MA USA. [Gilman, Sean] McGill Univ, Ctr Hlth, Dept Med, Montreal, PQ, Canada. [Scheede-Bergdahl, Celena] McGill Univ, Dept Kinesiol & Phys Educ, Montreal, PQ, Canada. [Stout, Nicole] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Hirsch, Bradford] Flatiron Hlth, New York, NY USA. RP Carli, F (reprint author), McGill Univ, Ctr Hlth, Montreal Gen Hosp, Dept Anesthesia, 1950 Cedar Ave,Room D10-144, Montreal, PQ H3G 1A4, Canada. EM franco.carli@mcgill.ca FU Peri-Operative Program, a Nonprofit Charitable Foundation, Montreal, Quebec, Canada FX This work was supported by the Peri-Operative Program, a Nonprofit Charitable Foundation, Montreal, Quebec, Canada. NR 78 TC 1 Z9 1 U1 7 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1047-9651 EI 1558-1381 J9 PHYS MED REH CLIN N JI Phys. Med. Rehabil. Clin. N. Am. PD FEB PY 2017 VL 28 IS 1 BP 49 EP + DI 10.1016/j.pmr.2016.09.002 PG 17 WC Rehabilitation SC Rehabilitation GA EG5IW UT WOS:000391078500006 PM 27913000 ER PT J AU de Boer, YS Sherker, AH AF de Boer, Ynto S. Sherker, Averell H. TI Herbal and Dietary Supplement-Induced Liver Injury SO CLINICS IN LIVER DISEASE LA English DT Article DE Herbals; Dietary supplements; Liver; Toxicity; Drug-induced liver injury ID LETTER RETROSPECTIVE REVIEWS; VENO-OCCLUSIVE DISEASE; ADVERSE DRUG-REACTIONS; VENOOCCLUSIVE DISEASE; CAUSALITY ASSESSMENT; UNITED-STATES; BLACK COHOSH; CASE SERIES; NUTRITIONAL SUPPLEMENTS; ALTERNATIVE MEDICINE AB The increase in the use of herbal and dietary supplements (HDSs) over the last decades has been accompanied by an increase in the reports of HDS-associated hepatotoxicity. The spectrum of HDS-induced liver injury is diverse and the outcome may vary from transient liver test increases to fulminant hepatic failure resulting in death or requiring liver transplant. There are no validated standardized tools to establish the diagnosis, but some HDS products have a typical clinical signature that may help to identify HDS-induced liver injury. C1 [de Boer, Ynto S.] NIDDK, Liver Dis Branch, NIH, 10 Ctr Dr, Bethesda, MD 20814 USA. [de Boer, Ynto S.] Vrije Univ Amsterdam, Med Ctr, Dept Gastroenterol & Hepatol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. [Sherker, Averell H.] NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, 6707 Democracy Blvd,Room 6003, Bethesda, MD 20892 USA. RP Sherker, AH (reprint author), NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, 6707 Democracy Blvd,Room 6003, Bethesda, MD 20892 USA. EM averell.sherker@nih.gov OI de Boer, Ynto/0000-0002-4066-7593 FU Intramural NIH HHS [Z99 DK999999] NR 82 TC 1 Z9 1 U1 12 U2 12 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1089-3261 EI 1557-8224 J9 CLIN LIVER DIS JI Clin. Liver Dis. PD FEB PY 2017 VL 21 IS 1 BP 135 EP + DI 10.1016/j.cld.2016.08.010 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG0OA UT WOS:000390730900010 PM 27842768 ER PT J AU Sundaramurthy, S Annamalai, B Samuvel, DJ Shippenberg, TS Jayanthi, LD Ramamoorthy, S AF Sundaramurthy, Santhanalakshmi Annamalai, Balasubramaniam Samuvel, Devadoss J. Shippenberg, Toni S. Jayanthi, Lankupalle D. Ramamoorthy, Sammanda TI Modulation of serotonin transporter function by kappa-opioid receptor ligands SO NEUROPHARMACOLOGY LA English DT Article DE Kappa opioid receptor; Serotonin; Clearance; Serotonin transporter; Phosphorylation; Trafficking ID PROTEIN-KINASE-C; CELL-SURFACE EXPRESSION; AGONIST SALVINORIN-A; NUCLEUS-ACCUMBENS; INTRACELLULAR CALCIUM; DEPENDENT REGULATION; MEDIATED REGULATION; VENTRAL STRIATUM; PLACE PREFERENCE; IN-VIVO AB Kappa opioid receptor (KOR) agonists produce dysphoria and psychotomimesis. While KOR agonists produce pro-depressant-like effects, KOR antagonists produce anti-depressant-like effects in rodent models. The cellular mechanisms and downstream effector(s) by which KOR ligands produce these effects are not clear. KOR agonists modulate serotonin (5-HT) transmission in the brain regions implicated in mood and motivation regulation. Presynaptic serotonin transporter (SERT) activity is critical in the modulation of synaptic 5-HT and, subsequently, in mood disorders. Detailing the molecular events of KOR-linked SERT regulation is important for examining the postulated role of this protein in mood disorders. In this study, we used heterologous expression systems and native tissue preparations to determine the cellular signaling cascades linked to KOR-mediated SERT regulation. KOR agonists U69,593 and U50,488 produced a time and concentration dependent KOR antagonist-reversible decrease in SERT function. KOR-mediated functional down-regulation of SERT is sensitive to CaMKII and Akt inhibition. The U69,593-evoked decrease in SERT activity is associated with a decreased transport V-max, reduced SERT cell surface expression, and increased SERT phosphorylation. Furthermore, KOR activation enhanced SERT internalization and decreased SERT delivery to the membrane. These data demonstrate that KOR activation decreases 5-HT uptake by altering SERT trafficking mechanisms and phosphorylation status to reduce the functional availability of surface SERT. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Sundaramurthy, Santhanalakshmi; Jayanthi, Lankupalle D.; Ramamoorthy, Sammanda] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, R Blackwell Smith Bldg,Room 756A,410 North, Richmond, VA 23298 USA. [Annamalai, Balasubramaniam] Med Univ South Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Samuvel, Devadoss J.] Med Univ South Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [Shippenberg, Toni S.] NIDA, Integrat Neurosci Sect, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Ramamoorthy, S (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, R Blackwell Smith Bldg,Room 756A,410 North, Richmond, VA 23298 USA. EM sammanda.ramamoorthy@vcuhealth.org FU National Institutes of Mental Health [MH083928] FX This work was supported by the National Institutes of Mental Health Grant MH083928, (S.R). NR 77 TC 0 Z9 0 U1 6 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD FEB PY 2017 VL 113 BP 281 EP 292 DI 10.1016/j.neuropharm.2016.10.011 PN A PG 12 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA EF7IB UT WOS:000390502200027 PM 27743931 ER PT J AU Levesque, A Campbell, ANC Pavlicova, M Hu, MC Walker, R McClure, EA Ghitza, UE Bailey, G Stitzer, M Nunes, EV AF Levesque, Annie Campbell, Aimee N. C. Pavlicova, Martina Hu, Mei-Chen Walker, Robrina McClure, Erin A. Ghitza, Udi E. Bailey, Genie Stitzer, Maxine Nunes, Edward V. TI Coping strategies as a mediator of internet-delivered psychosocial treatment: Secondary analysis from a NIDA CTN multisite effectiveness trial SO ADDICTIVE BEHAVIORS LA English DT Article DE Coping strategies; Behavioral therapies; Community reinforcement approach; Substance use disorders; Internet-delivered treatment ID COMMUNITY-REINFORCEMENT APPROACH; COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; SUBSTANCE USE DISORDERS; COCAINE DEPENDENCE; PRIMARY-CARE; SKILLS; ALCOHOL; ACQUISITION; ADDICTION AB Objective: Coping strategies are a predictor of abstinence among patients with substance use disorders. However, little is known regarding, the role of coping strategies in the effectiveness of the Community Reinforcement Approach (CRA). Using data from a 12 week randomized control trial assessing the effectiveness of the Therapeutic Education System (TES); an intemet-delivered version of the CRA combined with contingency management, we tested the role of coping strategies as a mediator of treatment effectiveness. Methods: 507 participants entering 10 outpatient addiction treatment programs received either treatment-as usual (TAU), a counselor-delivered treatment (Arm 1), or reduced TAU plus TES wherein 2 h of TAUper week were replaced by TES (Arm 2). Abstinence from drugs and alcohol was evaluated using urine toxicology and self-report. Coping strategies were measured using the Coping Strategies Scale-Brief Version. Mediation analyses were done following Baron and Kenny's and path analysis approaches. Results: The average baseline coping strategies scores were not significantly different between the two treatment arms. Overall, TES intervention was significantly associated with higher coping strategies scores wheh accounting for baseline scores (F-1,F-1342 = 8.3, p = 0.004). Additionally, higher coping strategies scores at week 12 were associated with an increased likelihood of abstinence during the last 4 weeks of the treatment, while accounting for treatment assignment and baseline abstinence. The effect of TES intervention on abstinence was no longer significant after controlling for coping strategies scores at week 12. Conclusion: Our results support the importance of coping skills as a partial mediator of the effectiveness of an intemet-version of the CRA combined with contingency management. (C) 2016 Published by Elsevier Ltd. C1 [Levesque, Annie] Mt Sinai West Hosp, Dept Psychiat, New York, NY USA. [Campbell, Aimee N. C.; Hu, Mei-Chen; Nunes, Edward V.] Columbia Univ, Med Ctr, New York State Psychiat Inst, Dept Psychiat, New York, NY USA. [Pavlicova, Martina] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Walker, Robrina] Univ Texas Southwestern Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [McClure, Erin A.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. [Ghitza, Udi E.] NIDA, CCTN, Bethesda, MD 20892 USA. [Bailey, Genie] Stanley St Treatment & Resources Inc, Brown Univ, Warren Alpert Med Sch, Dept Psychiat & Human Behav, Fall River, MA USA. [Stitzer, Maxine] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP Levesque, A (reprint author), Mt Sinai West Hosp, 1000 10th Ave,Suite 8C-02, New York, NY 10019 USA. EM alevesque@chpnet.org FU National Drug Abuse Treatment Clinical Trials Network (CTN), NIDA [U10 DA013035, U10 DA015831, U10 DA013034, U10 DA013720, U10 DA013732, U10 DA020024, U10 DA013714, U10 DA015815, U10 DA013045]; NIDA [K24 DA022412, K01 DA036739]; Research in Addiction Medicine Scholars (RAMS) program [R25DA033211]; Fonds de Recherche du Quebec-Sante (FRQS) FX This work was supported by grants from the National Drug Abuse Treatment Clinical Trials Network (CTN), NIDA: U10 DA013035 (EV Nunes, J Rotrosen), U10 DA015831 (KM Carroll, RD Weiss), U10 DA013034 (ML Stitzer, RP Schwartz), U10 DA013720 (J Szapocznik, LR Metsch), U10 DA013732 (T Winhusen), U10 DA020024 (MH Trivedi), U10 DA013714 (DM Donovan, J Roll), U10 DA015815 (JL Sorensen, D McCarty), and U10 DA013045 (W Ling). This work was also supported by NIDA K24 DA022412 (EV Nunes), NIDA K01 DA036739 (EA McClure), by the Research in Addiction Medicine Scholars (RAMS) program, R25DA033211, and by the Fonds de Recherche du Quebec-Sante (FRQS) (A Levesque). NIDA staffs (Udi Ghitza's) participation in this publication arises from his role as a project scientist on a cooperative agreement (this WEB-TX CTN study), which provided the data that were analyzed for this publication, but Udi Ghitza has not had and will not have any programmatic involvement with the non-cooperative agreement grants cited (e.g, the K01,1(24, R25 grants cited). The opinions in this paper are those of the authors and do not represent the official position of the U.S. government NR 35 TC 0 Z9 0 U1 15 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD FEB PY 2017 VL 65 BP 74 EP 80 DI 10.1016/j.addbeh.2016.09.012 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA EF1GT UT WOS:000390074000012 PM 27776269 ER PT J AU Arria, AM Compton, WM AF Arria, Amelia M. Compton, Wilson M. TI Complexities in understanding and addressing the serious public health issues related to the nonmedical use of prescription drugs SO ADDICTIVE BEHAVIORS LA English DT Editorial Material DE Nonmedical use of prescription drugs; Stimulants; Opioid analgesics; Benzodiazepines; Anxiolytics; Sedatives C1 [Arria, Amelia M.] Univ Maryland, Sch Publ Hlth, Ctr Young Adult Hlth & Dev, Dept Behav & Community Hlth, 2387 Sch Publ Hlth Bldg, College Pk, MD 20742 USA. Natl Inst Drug Abuse, NIH, 6001 Executive Blvd,MSC 9581, Bethesda, MD 20892 USA. RP Arria, AM (reprint author), Univ Maryland, Sch Publ Hlth, Ctr Young Adult Hlth & Dev, Dept Behav & Community Hlth, 2387 Sch Publ Hlth Bldg, College Pk, MD 20742 USA. EM aarria@umd.edu; wcompton@nida.nih.gov OI Arria, Amelia/0000-0002-6360-9265 FU Intramural NIH HHS [Z99 DA999999] NR 15 TC 0 Z9 0 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD FEB PY 2017 VL 65 BP 215 EP 217 DI 10.1016/j.addbeh.2016.09.002 PG 3 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA EF1GT UT WOS:000390074000033 PM 27639956 ER PT J AU Tong, ZB Hogberg, H Kuo, D Sakamuru, S Xia, MH Smirnova, L Hartung, T Gerhold, D AF Tong, Zhi-Bin Hogberg, Helena Kuo, David Sakamuru, Srilatha Xia, Menghang Smirnova, Lena Hartung, Thomas Gerhold, David TI Characterization of three human cell line models for high-throughput neuronal cytotoxicity screening SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE LUHMES; SH-SY5Y; neural stem cells; neurotoxicity; neurotoxicant; apoptosis; differentiation ID NEUROBLASTOMA-CELLS; PARKINSONS-DISEASE; OXIDATIVE STRESS; STEM-CELLS; KAPPA-B; NEUROTOXICITY; APOPTOSIS; TOXICITY; DEATH; DIFFERENTIATION AB More than 75 000 man-made chemicals contaminate the environment; many of these have not been tested for toxicities. These chemicals demand quantitative high-throughput screening assays to assess them for causative roles in neurotoxicities, including Parkinson's disease and other neurodegenerative disorders. To facilitate high throughput screening for cytotoxicity to neurons, three human neuronal cellular models were compared: SH-SY5Y neuroblastoma cells, LUHMES conditionally-immortalized dopaminergic neurons, and Neural Stem Cells (NSC) derived from human fetal brain. These three cell lines were evaluated for rapidity and degree of differentiation, and sensitivity to 32 known or candidate neurotoxicants. First, expression of neural differentiation genes was assayed during a 7-day differentiation period. Of the three cell lines, LUHMES showed the highest gene expression of neuronal markers after differentiation. Both in the undifferentiated state and after 7days of neuronal differentiation, LUHMES cells exhibited greater cytotoxic sensitivity to most of 32 suspected or known neurotoxicants than SH-SY5Y or NSCs. LUHMES cells were also unique in being more susceptible to several compounds in the differentiating state than in the undifferentiated state; including known neurotoxicants colchicine, methyl-mercury (II), and vincristine. Gene expression results suggest that differentiating LUHMES cells may be susceptible to apoptosis because they express low levels of anti-apoptotic genes BCL2 and BIRC5/survivin, whereas SH-SY5Y cells may be resistant to apoptosis because they express high levels of BCL2, BIRC5/survivin, and BIRC3 genes. Thus, LUHMES cells exhibited favorable characteristics for neuro-cytotoxicity screening: rapid differentiation into neurons that exhibit high level expression neuronal marker genes, and marked sensitivity of LUHMES cells to known neurotoxicants. Copyright (c) 2016 John Wiley & Sons, Ltd. Three human neuronal cell lines were evaluated as high throughput screening models for neuronal cytotoxicity: SH-SY5Y neuroblastoma cells, LUHMES conditionally-immortalized dopaminergic neurons, and Neural Stem Cells. After 7 days of differentiation, LUHMES expressed the highest levels of neuronal markers. Differentiated LUHMES cells exhibited greater cytotoxic sensitivity to most of 32 suspected or known neurotoxicants than differentiated SH-SY5Y or NSCs, and greater cytotoxic sensitivity to 11 compounds compared to undifferentiated LUHMES cells. C1 [Tong, Zhi-Bin; Kuo, David; Sakamuru, Srilatha; Xia, Menghang; Gerhold, David] NIH, NCATS, 9800 Med Ctr Dr, Rockville, MD 20850 USA. [Hogberg, Helena; Smirnova, Lena; Hartung, Thomas] Johns Hopkins Bloomberg Sch Publ Hlth, CAAT, Baltimore, MD USA. [Hartung, Thomas] Univ Konstanz, POB 600, Constance, Germany. RP Gerhold, D (reprint author), NIH, NCATS, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM david.gerhold@nih.gov FU Tox21 Consortium; N.I.H. Intramural Research Program at NCATS FX The authors are grateful to Dr. Marcel Leist for guidance on LUHMES cells, and John Braisted, Dr. Ruili Huang, and Dr. Yuhong Wang for helpful advice and discussions. These studies were supported by the Tox21 Consortium, and the N.I.H. Intramural Research Program at NCATS. NR 63 TC 2 Z9 2 U1 23 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0260-437X EI 1099-1263 J9 J APPL TOXICOL JI J. Appl. Toxicol. PD FEB PY 2017 VL 37 IS 2 BP 167 EP 180 DI 10.1002/jat.3334 PG 14 WC Toxicology SC Toxicology GA EE9NF UT WOS:000389952700005 PM 27143523 ER PT J AU Ferrucio, B Tiago, M Fannin, RD Liu, LW Gerrish, K Maria-Engler, SS Paules, RS Barros, SBD AF Ferrucio, Bianca Tiago, Manoela Fannin, Richard D. Liu, Liwen Gerrish, Kevin Maria-Engler, Silvya Stuchi Paules, Richard S. de Moraes Barros, Silvia Berlanga TI Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human melanocytes SO TOXICOLOGY IN VITRO LA English DT Article DE Carbaryl; 1-naphthyl-methylcarbamate; Melanocytes; Microarray; Solar radiation; Melanomagenesis ID MICROPHTHALMIA TRANSCRIPTION FACTOR; OXIDATIVE STRESS; GENE-EXPRESSION; DOWN-REGULATION; HUMAN SKIN; MELANOMA; UV; ACTIVATION; PATHWAY; NRF2 AB Carbaryl (1-naphthyl-methylcarbamate), a broad-spectrum insecticide, has recently been associated with the development of cutaneous melanoma in an epidemiological cohort study with U.S. farm workers also exposed to ultraviolet radiation, the main etiologic factor for skin carcinogenesis. We hypothesized that carbaryl exposure may increase deleterious effects of UV solar radiation on skin melanocytes. This study aimed to characterize human melanocytes after individual or combined exposure to carbaryl (100 mu M) and solar radiation (375 mJ/cm(2)). In a microarray analysis, carbaryl, but not solar radiation, induced an oxidative stress response, evidenced by the upregulation of antioxidant genes, such as Hemeoxygenase-1 (HMOX1), and downregulation of Microphtalmia-associated Transcription Factor (MITF), the main regulator of melanocytic activity; results were confirmed by qRT-PCR. Carbaryl and solar radiation induced a gene response suggestive of DNA damage and cell cycle alteration. The expression of CDKNIA, BRCA1/2 and MDM2 genes was notably more intense in the combined treatment group, in a synergistic manner. Flow cytometry assays demonstrated S-phase cell cycle arrest, reduced apoptosis levels and faster induction of cyclobutane pyrimidine dimers (CPD) lesions in carbaryl treated groups. Our data suggests that carbaryl is genotoxic to human melanocytes, especially when associated with solar radiation. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Ferrucio, Bianca; Tiago, Manoela; Maria-Engler, Silvya Stuchi; de Moraes Barros, Silvia Berlanga] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin Chem & Toxicol, Ave Prof Lineu Prestes 580,Bl 17, BR-05508000 Sao Paulo, SP, Brazil. [Fannin, Richard D.; Liu, Liwen; Gerrish, Kevin; Paules, Richard S.] NIEHS, Mol Genom Core Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Ferrucio, Bianca] Planitox, BR-13025320 Campinas, SP, Brazil. [Paules, Richard S.] NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Barros, SBD (reprint author), Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin Chem & Toxicol, Ave Prof Lineu Prestes 580,Bl 17, BR-05508000 Sao Paulo, SP, Brazil. EM biferrucio@usp.br; manoela.santos@usp.br; fannin@niehs.nih.gov; liuliw@niehs.nih.gov; gerrish@niehs.nih.gov; silvya@usp.br; paules@niehs.nih.gov; smbarros@usp.br RI Maria-Engler, Silvya/K-5936-2016 OI Maria-Engler, Silvya/0000-0003-4771-6041 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP [2010/17891-7, 2011/12616-0, 2012/23621-8]; Intramural Research Program of the National Institute of Environmental Health Sciences, NIH FX We thank Prof. Joao Lauro Viana de Camargo, PhD, MD, for contributing to the delineation of this research project and for reviewing this manuscript. We also thank Renata Albuquerque, MSc, for processing of flow cytometry samples; Ms. Laura Wharey for RNA integrity analysis; and Divinomar Severino, PhD, and Mr. Gabriel Mares for the measurement of the solar simulator irradiance. This work was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP [Grant numbers 2010/17891-7, 2011/12616-0 and 2012/23621-8], and by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH. NR 55 TC 0 Z9 0 U1 9 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD FEB PY 2017 VL 38 BP 67 EP 76 DI 10.1016/j.tiv.2016.11.005 PG 10 WC Toxicology SC Toxicology GA ED9CK UT WOS:000389167600009 PM 27829164 ER PT J AU Yaffe, K Freimer, D Chen, HL Asao, K Rosso, A Rubin, S Tranah, G Cummings, S Simonsick, E AF Yaffe, Kristine Freimer, Daniel Chen, Honglei Asao, Keiko Rosso, Andrea Rubin, Susan Tranah, Greg Cummings, Steve Simonsick, Eleanor TI Olfaction and risk of dementia in a biracial cohort of older adults SO NEUROLOGY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; AFRICAN-AMERICANS; APOLIPOPROTEIN-E; RACIAL DISPARITIES; URBAN-COMMUNITY; IDENTIFICATION; ALLELE; CAUCASIANS; CONVERSION AB Objective: Prior studies indicate that olfactory function may be an early marker for cognitive impairment, but the body of evidence has been largely restricted to white populations. Methods: We studied 2,428 community-dwelling black and white older adults (baseline age 70-79 years) without dementia enrolled in the Health, Aging, and Body Composition (Health ABC) study. Olfaction was measured as odor identification (OI) with the 12-item Cross Cultural Smell Identification Test in year 3. We defined incident dementia over 12 years on the basis of hospitalization records, prescription for dementia medication, or 1.5-SD decline in race-stratified global cognition score. We assessed dementia risk associated with OI score (by tertile) using Cox proportional hazards models. All analyses were stratified by race. Results: Poorer OI in older adults without dementia was associated with increased risk of dementia. After adjustment for demographics, medical comorbidities, and lifestyle characteristics, white participants in the poor or moderate OI tertile had greater risk of dementia (adjusted hazard ratio [HR] 3.34, 95% confidence interval [CI] 2.45-4.54; and HR 1.84, 95% CI 1.33-2.54, respectively) compared to those in the good tertile of function. Among blacks, worse OI was associated with an increased risk of dementia, but the magnitude of the effect was weaker (p for interaction 5 0.04) for the poor OI tertile (adjusted HR 2.03, 95% CI 1.44-2.84) and for the moderate tertile (adjusted HR 1.42, 95% CI 0.97-2.10). There was no interaction between OI and APOE e4 and risk of dementia. Conclusions: While the magnitude of the association was stronger in whites, we found that poor OI was associated with increased risk of dementia among both black and white older adults. C1 [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Yaffe, Kristine; Rubin, Susan] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Yaffe, Kristine; Freimer, Daniel] NCIRE Vet Hlth Res Inst, San Francisco, CA 94121 USA. [Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Asao, Keiko] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Rosso, Andrea] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Tranah, Greg; Cummings, Steve] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Simonsick, Eleanor] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA.; Yaffe, K (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA.; Yaffe, K (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.; Yaffe, K (reprint author), San Francisco VA Med Ctr, San Francisco, CA 94121 USA.; Yaffe, K (reprint author), NCIRE Vet Hlth Res Inst, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu OI Chen, Honglei/0000-0003-3446-7779 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, K24-AG031155]; National Institute of Nursing Research [R01-NR012459]; Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences [Z01-ES101986] FX This research was supported by National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, and K24-AG031155; and National Institute of Nursing Research grant R01-NR012459. The study was supported in part by the Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences (Z01-ES101986). NR 46 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 31 PY 2017 VL 88 IS 5 BP 456 EP 462 DI 10.1212/WNL.0000000000003558 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EP4HE UT WOS:000397340800011 PM 28039314 ER PT J AU Siddiqi, OK Elafros, MA Bositis, CM Koralnik, IJ Theodore, WH Okulicz, JF Kalungwana, L Potchen, MJ Sikazwe, I Birbeck, GL AF Siddiqi, Omar K. Elafros, Melissa A. Bositis, Christopher M. Koralnik, Igor J. Theodore, William H. Okulicz, Jason F. Kalungwana, Lisa Potchen, Michael J. Sikazwe, Izukanji Birbeck, Gretchen L. TI New-onset seizure in HIV-infected adult Zambians A search for causes and consequences SO NEUROLOGY LA English DT Article ID ANTIEPILEPTIC DRUG SELECTION; CENTRAL-NERVOUS-SYSTEM; EPSTEIN-BARR-VIRUS; MENINGITIS; GUIDELINES; DIAGNOSIS; EPILEPSY; DISEASE; PEOPLE AB Objective: To identify the etiology of new-onset seizure in HIV-infected Zambian adults and identify risk factors for seizure recurrence. Methods: A prospective cohort study enrolling HIV-infected adults with new-onset seizure within 2 weeks of index seizure obtained clinical, laboratory, and neuroimaging data to determine seizure etiology. Participants were followed to identify risk factors for seizure recurrence. Risk factors for mortality were examined as mortality rates were unexpectedly high. Results: Eighty-one patients with CSF for analysis were enrolled and followed for a median of 306 days (interquartile range 61-636). Most (91%) were at WHO stage III/IV and 66 (81%) had a preseizure Karnofsky score $ 50. Prolonged or multiple seizures occurred in 46 (57%), including 12 (15%) with status epilepticus. Seizure etiologies included CNS opportunistic infections (OI) in 21 (26%), hyponatremia in 23 (28%), and other infections in 8 (10%). OIs included Cryptococcus (17%), JC virus (7%) and 5% each for tuberculosis, cytomegalovirus, and varicella-zoster virus. No etiology could be identified in 16 (20%). Thirty (37%) patients died during follow-up and 20 (25%) had recurrent seizures with survival being the only identifiable risk factor. Conclusions: HIV-infected adults with new-onset seizure in Zambia often have advanced HIV disease with OI being the most frequent seizure etiology. Seizure recurrence is common but no risk factors for recurrence other than survival were identified. These findings suggest an urgent need for immune reconstitution in this population. Initiating treatment for seizure prophylaxis where only enzyme-inducing antiepileptic medications are available could threaten antiretroviral efficacy. C1 [Siddiqi, Omar K.; Koralnik, Igor J.] Beth Israel Deaconess Med Ctr, Dept Neurol, Global Neurol Program, Boston, MA 02215 USA. [Siddiqi, Omar K.; Koralnik, Igor J.] Beth Israel Deaconess Med Ctr, Dept Internal Med, Ctr Virol & Vaccines Res, Boston, MA 02215 USA. [Siddiqi, Omar K.] Univ Zambia, Sch Med UNZA SOM, Dept Internal Med, Lusaka, Zambia. [Elafros, Melissa A.] Michigan State Univ, Coll Human Med, E Lansing, MI 48824 USA. [Bositis, Christopher M.] US Natl Inst Hlth, Greater Lawrence Family Hlth Ctr, Bethesda, MD USA. [Theodore, William H.] US Natl Inst Hlth, Clin Epilepsy Div, Bethesda, MD USA. [Okulicz, Jason F.] San Antonio Mil Med Ctr, HIV Evaluat Unit, Infect Dis Serv, San Antonio, TX USA. [Kalungwana, Lisa] Univ Zambia UNZA, Dept Psychiat, Lusaka, Zambia. [Potchen, Michael J.] Univ Rochester, Dept Imaging Sci, Neuroradiol Div, Rochester, NY 14627 USA. [Birbeck, Gretchen L.] Univ Rochester, Dept Neurol, Strong Epilepsy Ctr, Rochester, NY 14627 USA. [Potchen, Michael J.] Lusaka Apex Med Univ, Dept Radiol, Lusaka, Zambia. [Sikazwe, Izukanji] Lusaka Apex Med Univ, CIDRZ, Lusaka, Zambia. [Birbeck, Gretchen L.] Chikankata Hosp, Epilepsy Care Team, Mazabuka, Zambia. RP Birbeck, GL (reprint author), Univ Rochester, Dept Neurol, Strong Epilepsy Ctr, Rochester, NY 14627 USA.; Birbeck, GL (reprint author), Chikankata Hosp, Epilepsy Care Team, Mazabuka, Zambia. EM gretchen_birbeck@urmc.rochester.edu FU Fogarty International Center; National Institute of Neurological Disorders and Stroke (NINDS) [1R21NS073509]; Spectrum Health; AMA Foundation; Lois C. Walker Endowed Fund for Student Research in the Michigan State University College of Human Medicine; American Academy of Neurology Clinical Research Fellowship; NINDS [R01 047029, 074995]; International League against Epilepsy FX The Fogarty International Center and the National Institute of Neurological Disorders and Stroke (NINDS) supported this work under award 1R21NS073509. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, Department of Defense, or the Departments of the Army, Navy, or Air Force. M.A.E. was supported in part by an MD/PhD Fellowship from Spectrum Health, the AMA Foundation, and the Lois C. Walker Endowed Fund for Student Research in the Michigan State University College of Human Medicine. O.K.S. was supported by an American Academy of Neurology Clinical Research Fellowship. I.J.K. is supported in part by NINDS R01 047029 and 074995. The International League against Epilepsy supported work by W.H.T. NR 22 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 31 PY 2017 VL 88 IS 5 BP 477 EP 482 DI 10.1212/WNL.0000000000003538 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA EP4HE UT WOS:000397340800014 PM 28003499 ER PT J AU Franzin, AM Maruyama, SR Garcia, GR Oliveira, RP Ribeiro, JMC Bishop, R Maia, AAM More, DD Ferreira, BR Santos, IKFM AF Franzin, Alessandra Mara Maruyama, Sandra Regina Garcia, Gustavo Rocha Oliveira, Rosane Pereira Chaves Ribeiro, Jose Marcos Bishop, Richard Mendes Maia, Antonio Augusto More, Daniela Dantas Ferreira, Beatriz Rossetti de Miranda Santos, Isabel Kinney Ferreira TI Immune and biochemical responses in skin differ between bovine hosts genetically susceptible and resistant to the cattle tick Rhipicephalus microplus SO PARASITES & VECTORS LA English DT Article DE Transcriptome; Differentially expressed genes; Bos indicus; Bos taurus; Skin; Rhipicephalus microplus; Salivary glands ID ALLERGIC CONTACT-DERMATITIS; ODORANT-BINDING PROTEIN; BOOPHILUS-MICROPLUS; ATOPIC-DERMATITIS; BOS-TAURUS; PATHOGEN TRANSMISSION; DISTINCT POPULATIONS; AMBLYOMMA-CAJENNENSE; EXPRESSION PATTERNS; CYTOKINE EXPRESSION AB Background: Ticks attach to and penetrate their hosts' skin and inactivate multiple components of host responses in order to acquire a blood meal. Infestation loads with the cattle tick, Rhipicephalus microplus, are heritable: some breeds carry high loads of reproductively successful ticks, whereas in others, few ticks feed and reproduce efficiently. Methods: In order to elucidate the mechanisms that result in the different outcomes of infestations with cattle ticks, we examined global gene expression and inflammation induced by tick bites in skins from one resistant and one susceptible breed of cattle that underwent primary infestations with larvae and nymphs of R. microplus. We also examined the expression profiles of genes encoding secreted tick proteins that mediate parasitism in larvae and nymphs feeding on these breeds. Results: Functional analyses of differentially expressed genes in the skin suggest that allergic contact-like dermatitis develops with ensuing production of IL-6, CXCL-8 and CCL-2 and is sustained by HMGB1, ISG15 and PKR, leading to expression of pro-inflammatory chemokines and cytokines that recruit granulocytes and T lymphocytes. Importantly, this response is delayed in susceptible hosts. Histopathological analyses of infested skins showed inflammatory reactions surrounding tick cement cones that enable attachment in both breeds, but in genetically tick-resistant bovines they destabilized the cone. The transcription data provided insights into tick-mediated activation of basophils, which have previously been shown to be a key to host resistance in model systems. Skin from tick-susceptible bovines expressed more transcripts encoding enzymes that detoxify tissues. Interestingly, these enzymes also produce volatile odoriferous compounds and, accordingly, skin rubbings from tick-susceptible bovines attracted significantly more tick larvae than rubbings from resistant hosts. Moreover, transcripts encoding secreted modulatory molecules by the tick were significantly more abundant in larval and in nymphal salivary glands from ticks feeding on susceptible bovines. Conclusions: Compared with tick-susceptible hosts, genes encoding enzymes producing volatile compounds exhibit significantly lower expression in resistant hosts, which may render them less attractive to larvae; resistant hosts expose ticks to an earlier inflammatory response, which in ticks is associated with significantly lower expression of genes encoding salivary proteins that suppress host immunity, inflammation and coagulation. C1 [Franzin, Alessandra Mara; Maruyama, Sandra Regina; Garcia, Gustavo Rocha; More, Daniela Dantas; de Miranda Santos, Isabel Kinney Ferreira] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto, SP, Brazil. [Oliveira, Rosane Pereira] Univ Illinois, Dept Anim Sci, Urbana, IL 61801 USA. [Chaves Ribeiro, Jose Marcos] NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bishop, Richard] Int Livestock Res Inst, Nairobi, Kenya. [Mendes Maia, Antonio Augusto] Univ Sao Paulo, Sch Anim Sci & Food Technol, Dept Basic Sci, BR-13635900 Pirassununga, SP, Brazil. [Ferreira, Beatriz Rossetti] Univ Sao Paulo, Ribeirao Preto Sch Nursing, Ribeirao Preto, SP, Brazil. [Maruyama, Sandra Regina] Univ Fed Sao Carlos, Dept Genet & Evolut, BR-13565905 Sao Carlos, SP, Brazil. [Oliveira, Rosane Pereira] Univ Calif Davis, Sch Med, Integrat Med Program, Sacramento, CA 95817 USA. [Bishop, Richard] Embrapa Pecuaria Sudeste, BR-13560970 Sao Carlos, SP, Brazil. [More, Daniela Dantas] Washington State Univ, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. RP Santos, IKFM (reprint author), Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto, SP, Brazil. EM imsantos@fmrp.usp.br FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP [2009/53645-3]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPq [490498/2007-8, 471946/2010-9, 300873/2010-7, 559603/2009-6]; Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - CAPES; FAPESP [2012/04087-0, 2009/51212-2] FX This work was supported by the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP (grant number 2009/53645-3 to IKFMS), by the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPq (grant numbers 490498/2007-8, 471946/2010-9, 300873/2010-7 and 559603/2009-6 to IKFMS) and by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. AMF was supported by a scholarship from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - CAPES; SRM. and GRG were supported by scholarships from FAPESP (2012/04087-0 and 2009/51212-2, respectively). Because JMCR is a U.S. government employee and this is a government work, the work is in the public domain in 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. You can establish rights outside of the U.S. subject to a government NR 85 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD JAN 31 PY 2017 VL 10 AR 51 DI 10.1186/s13071-016-1945-z PG 24 WC Parasitology SC Parasitology GA EN9OK UT WOS:000396329300001 PM 28143523 ER PT J AU Cacciottolo, M Wang, X Driscoll, I Woodward, N Saffari, A Reyes, J Serre, ML Vizuete, W Sioutas, C Morgan, TE Gatz, M Chui, HC Shumaker, SA Resnick, SM Espeland, MA Finch, CE Chen, JC AF Cacciottolo, M. Wang, X. Driscoll, I. Woodward, N. Saffari, A. Reyes, J. Serre, M. L. Vizuete, W. Sioutas, C. Morgan, T. E. Gatz, M. Chui, H. C. Shumaker, S. A. Resnick, S. M. Espeland, M. A. Finch, C. E. Chen, J. C. TI Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID HEALTH INITIATIVE MEMORY; POPULATION-BASED COHORT; ALZHEIMERS-DISEASE; ENVIRONMENTAL EXPOSURES; POSTMENOPAUSAL WOMEN; POLLUTION; DEMENTIA; MATTER; NEURODEGENERATION; DECLINE AB Exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of Alzheimer's disease (AD). Neurodegenerative effects of particulate air pollutants were examined in a US-wide cohort of older women from the Women's Health Initiative Memory Study (WHIMS) and in experimental mouse models. Residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE epsilon 4/4 carriers. Female EFAD transgenic mice (5xFAD(+/-)/human APOE epsilon 3 or epsilon 4(+)/(+)) with 225 h exposure to urban nanosized PM (nPM) over 15 weeks showed increased cerebral beta-amyloid by thioflavin S for fibrillary amyloid and by immunocytochemistry for A beta deposits, both exacerbated by APOE epsilon 4. Moreover, nPM exposure increased A beta oligomers, caused selective atrophy of hippocampal CA1 neurites, and decreased the glutamate GluR1 subunit. Wildtype C57BL/6 female mice also showed nPM-induced CA1 atrophy and GluR1 decrease. In vitro nPM exposure of neuroblastoma cells (N2a-APP/swe) increased the pro-amyloidogenic processing of the amyloid precursor protein (APP). We suggest that airborne PM exposure promotes pathological brain aging in older women, with potentially a greater impact in epsilon 4 carriers. The underlying mechanisms may involve increased cerebral Aa production and selective changes in hippocampal CA1 neurons and glutamate receptor subunits. C1 [Cacciottolo, M.; Woodward, N.; Finch, C. E.; Chen, J. C.] Univ Southern Calif, Leonard Davis Sch Gerontol, 2001N Soto St SSB 225P,M-C 9237, Los Angeles, CA 90089 USA. [Wang, X.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Driscoll, I.] Univ Wisconsin, Dept Psychol, Milwaukee, WI 53201 USA. [Saffari, A.] Univ Southern Calif, USC Viterbi Sch Engn, Los Angeles, CA USA. [Reyes, J.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Environm Sci & Engn, Chapel Hill, NC USA. [Gatz, M.] Univ Southern Calif, Dept Psychol, Los Angeles, CA USA. [Gatz, M.] Univ Southern Calif, Keck Sch Med, Memory & Aging Ctr, Los Angeles, CA USA. [Chui, H. C.] Univ Southern Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA USA. [Shumaker, S. A.] Wake Forest Sch Med, Dept Social Sci & Hlth Policy, Windsor, CT USA. [Resnick, S. M.] Natl Inst Aging, Natl Inst Hlth, Lab Behav Neurosci, Baltimore, MD USA. RP Finch, CE; Chen, JC (reprint author), Univ Southern Calif, Leonard Davis Sch Gerontol, 2001N Soto St SSB 225P,M-C 9237, Los Angeles, CA 90089 USA. EM cefinch@usc.edu; jcchen@usc.edu FU National Heart, Lung, and Blood Institute (NIH) [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; Wyeth Pharmaceuticals, St Davids, PA, USA; Wake Forest University; NIH [R01AG033078, R01AG051521, R21AG040753, R21AG040683, R00AG032361]; Cure Alzheimer's Fund; Southern California Environmental Health Sciences Center [5P30ES007048]; [RF1AG054068]; [R21AG0500201] FX The WHI program is funded by the National Heart, Lung, and Blood Institute (NIH) through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. The WHIMS was funded by Wyeth Pharmaceuticals, St Davids, PA, USA, and Wake Forest University. This study was supported by NIH awards R01AG033078, R01AG051521, R21AG040753, R21AG040683 and R00AG032361. This study was supported by awards to J.C. Chen (R01AG033078; RF1AG054068), to I. Driscoll (R00AG032361) and to C. E. Finch (R01AG051521, R21AG040753, R21AG040683, R21AG0500201 and by the Cure Alzheimer's Fund). The research was also supported by the Southern California Environmental Health Sciences Center (5P30ES007048). We are grateful for dedicated efforts by all investigators and staff at the WHI and WHIMS clinical centers, and at the WHI & WHIMS clinical coordinating center:: https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20I nvestigator%20Short%20List.pdf. NR 60 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JAN 31 PY 2017 VL 7 AR e1022 DI 10.1038/tp.2016.280 PG 8 WC Psychiatry SC Psychiatry GA EO1JE UT WOS:000396453800009 PM 28140404 ER PT J AU Golozar, A Khalili, D Etemadi, A Poustchi, H Fazeltabar, A Hosseini, F Kamangar, F Khoshnia, M Islami, F Hadaegh, F Brennan, P Boffetta, P Abnet, CC Dawsey, SM Azizi, F Malekzadeh, R Danaei, G AF Golozar, Asieh Khalili, Davood Etemadi, Arash Poustchi, Hossein Fazeltabar, Akbar Hosseini, Firoozeh Kamangar, Farin Khoshnia, Masoud Islami, Farhad Hadaegh, Farzad Brennan, Paul Boffetta, Paolo Abnet, Christian C. Dawsey, Sanford M. Azizi, Fereidoun Malekzadeh, Reza Danaei, Goodarz TI White rice intake and incidence of type-2 diabetes: analysis of two prospective cohort studies from Iran SO BMC PUBLIC HEALTH LA English DT Article DE Incident type 2 diabetes; Refined carbohydrates; White rice; Low- and middle-income countries; Diet ID GLYCEMIC LOAD; ESOPHAGEAL CANCER; NONCOMMUNICABLE DISEASES; NUTRITION TRANSITION; GOLESTAN COHORT; DIETARY FIBER; JAPANESE MEN; RISK-FACTORS; WOMEN; POPULATION AB Background: Refined grains and white rice have been associated with elevated risk of type 2 diabetes mellitus (T2DM). In this study, we sought to quantify the effect of white rice intake on incident T2DM in two prospective population-based cohort studies from Iran, where white rice is one of the main staple. Methods: We used follow-up data from 9,182 participants from Golestan Cohort Study (GCS, 2004-2007, conducted mainly in rural areas) and 2,173 from Tehran Lipid and Glucose Study (TLGS, 2004-2006) who did not have T2DM and other chronic diseases at baseline. Diet was assessed using validated food frequency questionnaires. Multivariable logistic regression models were used to estimate adjusted odds ratios (ORs) for incident T2DM. Results: We documented 902 new cases of T2DM in GCS and 81 in TLGS. Age-standardized cumulative incidence of T2DM was 9.9% in Golestan and 8.0% in Tehran. Daily white rice intake was significantly higher among residents of Tehran compared to Golestan (median daily intake: 250 vs. 120 grams; P-value < 0.001). After adjustment for potential confounders, there was no significant association between daily white rice intake and incident T2DM in GCS. In TLGS, the adjusted OR (95% confidence interval (CI)) was 2.1 (1.1, 3.9) comparing participants with daily white rice intake of > 250 grams/day to those with < 250. Conclusions: We observed an increased lieklihood of T2DM associated with high white rice intake among residents of Tehran and no association in Golestan. Our findings, if further supported by other studies, have important public health implications especially for countries where white rice is a major staple and diabetes is increasing rapidly incidence is high. Further research is needed to investigate lack of an association between lower levels of white rice intake and T2DM. C1 [Golozar, Asieh; Etemadi, Arash; Poustchi, Hossein; Fazeltabar, Akbar; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Inst, Tehran 14117, Iran. [Golozar, Asieh] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Khalili, Davood; Hadaegh, Farzad] Shahid Beheshti Univ Med Sci, Res Inst Endocrine Sci, Prevent Metab Disorders Res Ctr, Tehran 17413, Iran. [Etemadi, Arash; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20850 USA. [Hosseini, Firoozeh] Shahid Beheshti Univ Med Sci, Res Inst Endocrine Sci, Obes Res Ctr, Nutr & Endocrine Res Ctr, Tehran 17413, Iran. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Baltimore, MD 21251 USA. [Khoshnia, Masoud] Golestan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan 0619, Golestan, Iran. [Islami, Farhad] Amer Canc Soc, Surveillance & Hlth Serv Res, Atlanta, GA 30303 USA. [Brennan, Paul] Int Agcy Res Canc, F-69008 Lyon, France. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY 10029 USA. [Azizi, Fereidoun] Shahid Beheshti Univ Med Sci, Res Inst Endocrine Sci, Endocrine Res Ctr, Tehran 17413, Iran. [Danaei, Goodarz] Harvard Sch Publ Hlth, Dept Global Hlth & Populat, 677 Huntington Ave,Bldg 1, Boston, MA 02115 USA. [Danaei, Goodarz] Harvard Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave,Bldg 1, Boston, MA 02115 USA. [Danaei, Goodarz] SAPHIR, Boston, MA 02132 USA. RP Danaei, G (reprint author), Harvard Sch Publ Hlth, Dept Global Hlth & Populat, 677 Huntington Ave,Bldg 1, Boston, MA 02115 USA.; Danaei, G (reprint author), Harvard Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave,Bldg 1, Boston, MA 02115 USA.; Danaei, G (reprint author), SAPHIR, Boston, MA 02132 USA. EM gdanaei@hsph.harvard.edu FU intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Digestive Disease Research Institute of Tehran University of Medical Sciences [82-603]; International Agency for Research on Cancer; National Research Council of Iran [121]; National Institute of Diabetes and Digestive and Kidney Diseases [DK090435] FX Golestan Cohort Study was supported in part by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Digestive Disease Research Institute of Tehran University of Medical Sciences (82-603) and the International Agency for Research on Cancer. Tehran Lipid and Glucose Study was supported by a grant from the National Research Council of Iran (121), and GD was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (DK090435) (GD). NR 33 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD JAN 31 PY 2017 VL 17 AR 133 DI 10.1186/s12889-016-3999-4 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EK0NY UT WOS:000393624600002 PM 28137245 ER PT J AU Shah, AM Claggett, B Kitzman, D Biering-Sorensen, T Jensen, JS Cheng, S Matsushita, K Konety, S Folsom, AR Mosley, TH Wright, JD Heiss, G Solomon, SD AF Shah, Amil M. Claggett, Brian Kitzman, Dalane Biering-Sorensen, Tor Jensen, Jan Skov Cheng, Susan Matsushita, Kunihiro Konety, Suma Folsom, Aaron R. Mosley, Thomas H. Wright, Jacqueline D. Heiss, Gerardo Solomon, Scott D. TI Contemporary Assessment of Left Ventricular Diastolic Function in Older Adults The Atherosclerosis Risk in Communities Study SO CIRCULATION LA English DT Article DE diastole; echocardiography; epidemiology; heart failure; prognosis ID PRESERVED EJECTION FRACTION; CONGESTIVE-HEART-FAILURE; CARDIOVASCULAR HEALTH; GENERAL-POPULATION; REFERENCE VALUES; AFRICAN-AMERICANS; SYSTOLIC FUNCTION; CARDIAC STRUCTURE; AGE; DYSFUNCTION AB BACKGROUND: Although age-associated changes in left ventricular diastolic function are well recognized, limited data exist characterizing measures of diastolic function in older adults, including both reference ranges reflecting the older adult population and prognostically relevant values for incident heart failure (HF), as well as their associations with circulating biomarkers of HF risk. METHODS: Among 5801 elderly participants in the ARIC study (Atherosclerosis Risk in Communities; age range, 67-90 years; mean age, 76 +/- 5 years; 42% male; 21% black), we determined the continuous association of diastolic measures (tissue Doppler imaging [TDI] e', E/e', and left atrial size) with concomitant N-terminal pro-brain natriuretic peptide and subsequent HF hospitalization or death. We also determined sex-specific 10th and 90th percentile limits for these measures using quantile regression in 401 participants free of prevalent cardiovascular disease and risk factors. RESULTS: Each measure of diastolic function was robustly associated with N-terminal pro-brain natriuretic peptide and incident HF or death. ARIC-based reference limits for TDI e' (4.6 and 5.2 cm/s for septal and lateral TDI e', respectively) were substantially lower than guideline cut points (7 and 10 cm/s, respectively), whereas E/e' and left atrial size demonstrated good agreement with guideline cut points. TDI e' was nonlinearly associated with incident HF or death, with inflection points for risk supportive of ARIC-based limits. ARIC-based limits for diastolic function improved risk discrimination over guideline-based cut points based on the integrated discrimination improvement (P< 0.001) and continuous net reclassification improvement (P< 0.001), reclassifying 42% of the study population as having normal diastolic function. We replicate these findings in the Copenhagen City Heart Study. With these limits, 46% had normal diastolic function and were at low risk of HF hospitalization or death (1%/y over a mean 1.7-year follow-up), 49% had 1 or 2 abnormal measures and were at intermediate risk (2.4%/y), and all 3 diastolic measures were abnormal in 5% who were at high risk (7.5%/y). CONCLUSIONS: Our findings suggest that left ventricular longitudinal relaxation velocity declines as a part of healthy aging and is largely prognostically benign. The use of age-based normative values when considering an elderly population improves the risk discrimination of diastolic measures for incident HF or death. C1 [Shah, Amil M.; Claggett, Brian; Biering-Sorensen, Tor; Cheng, Susan; Solomon, Scott D.] Brigham & Womens Hosp, Div Cardiovascular Med, 75 Francis St, Boston, MA 02445 USA. [Kitzman, Dalane] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Biering-Sorensen, Tor; Jensen, Jan Skov] Univ Copenhagen, Herlev & Gentofte Hosp, Dept Cardiol, Copenhagen, Denmark. [Matsushita, Kunihiro] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Konety, Suma] Univ Minnesota, Div Cardiovasc, Minneapolis, MN 55455 USA. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Div Geriatr & Neurol, Jackson, MS 39216 USA. [Wright, Jacqueline D.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Heiss, Gerardo] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. RP Shah, AM (reprint author), Brigham & Womens Hosp, Div Cardiovascular Med, 75 Francis St, Boston, MA 02445 USA. EM ashah11@partners.org OI Biering-Sorensen, Tor/0000-0003-4209-2778 FU National Heart, Lung, and Blood Institute [HH-SN268201100005C, HHSN268201100006C, HHSN2682011 00007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HH-SN268201100012C, K08HL116792, R00HL107642, R01HL131532]; American Heart Association [14CRP20380422] FX The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HH-SN268201100005C, HHSN268201100006C, HHSN2682011 00007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HH-SN268201100012C). The work for this article was also supported by National Heart, Lung, and Blood Institute grants K08HL116792 (Dr Shah), R00HL107642 (Dr Cheng), and R01HL131532 (Dr Cheng) and American Heart Association grant 14CRP20380422 (Dr Shah). NR 46 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JAN 31 PY 2017 VL 135 IS 5 BP 426 EP + DI 10.1161/CIRCULATIONAHA.116.024825 PG 27 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EK1WJ UT WOS:000393716200005 PM 27927714 ER PT J AU Hoffmann, TJ Passarelli, MN Graff, RE Emami, NC Sakoda, LC Jorgenson, E Habel, LA Shan, J Ranatunga, DK Quesenberry, CP Chao, CR Ghai, NR Aaronson, D Presti, J Nordstrom, T Wang, ZM Berndt, SI Chanock, SJ Mosley, JD Klein, RJ Middha, M Lilja, H Melander, O Kvale, MN Kwok, PY Schaefer, C Risch, N Van Den Eeden, SK Witte, JS AF Hoffmann, Thomas J. Passarelli, Michael N. Graff, Rebecca E. Emami, Nima C. Sakoda, Lori C. Jorgenson, Eric Habel, Laurel A. Shan, Jun Ranatunga, Dilrini K. Quesenberry, Charles P. Chao, Chun R. Ghai, Nirupa R. Aaronson, David Presti, Joseph Nordstrom, Tobias Wang, Zhaoming Berndt, Sonja I. Chanock, Stephen J. Mosley, Jonathan D. Klein, Robert J. Middha, Mridu Lilja, Hans Melander, Olle Kvale, Mark N. Kwok, Pui-Yan Schaefer, Catherine Risch, Neil Van Den Eeden, Stephen K. Witte, John S. TI Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer SO NATURE COMMUNICATIONS LA English DT Article ID GENETIC EPIDEMIOLOGY RESEARCH; AGING GERA COHORT; SUSCEPTIBILITY LOCI; RANDOMIZED PROSTATE; SEQUENCE VARIANTS; SCREENING TRIAL; OVARIAN-CANCER; BREAST-CANCER; ADULT HEALTH; SERUM-LEVELS AB Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa-such as genetics-can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 x 10(-8)) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment. C1 [Hoffmann, Thomas J.; Passarelli, Michael N.; Graff, Rebecca E.; 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 94143 USA. [Sakoda, Lori C.; Jorgenson, Eric; Habel, Laurel A.; Shan, Jun; Ranatunga, Dilrini K.; Quesenberry, Charles P.; Schaefer, Catherine; Risch, Neil; Van Den Eeden, Stephen K.] Kaiser Permanente, Div Res, Oakland, CA 94612 USA. [Chao, Chun R.; Ghai, Nirupa R.] Kaiser Permanente Southern Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA. [Aaronson, David; Presti, Joseph] Kaiser Oakland Med Ctr, Dept Urol, Oakland, CA 94612 USA. [Nordstrom, Tobias] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Wang, Zhaoming; Berndt, Sonja I.; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bethesda, MD 20814 USA. [Mosley, Jonathan D.] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA. [Klein, Robert J.; Middha, Mridu] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA. [Klein, Robert J.; Middha, Mridu; Lilja, Hans] Mem Sloan Kettering Canc Ctr, Dept Lab Med, New York, NY 10065 USA. [Klein, Robert J.; Middha, Mridu; Lilja, Hans] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Klein, Robert J.; Middha, Mridu; Lilja, Hans] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Klein, Robert J.; Middha, Mridu; Lilja, Hans] Univ Oxford, Nuffield Dept Surg Sci, Oxford OX3 7LD, England. [Klein, Robert J.; Middha, Mridu; Lilja, Hans] Lund Univ, Dept Translat Med, S-20502 Malmo, Sweden. [Melander, Olle] Lund Univ, Dept Clin Sci, S-20502 Malmo, Sweden. [Van Den Eeden, Stephen K.; Witte, John S.] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94158 USA. RP Witte, JS (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94158 USA.; Witte, JS (reprint author), Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA.; Van Den Eeden, SK (reprint author), Kaiser Permanente, Div Res, Oakland, CA 94612 USA.; Van Den Eeden, SK; Witte, JS (reprint author), Univ Calif San Francisco, Dept Urol, San Francisco, CA 94158 USA. EM stephen.vandeneeden@kp.org; jwitte@ucsf.edu OI Graff, Rebecca/0000-0003-0316-8303 FU NIH [CA127298, CA088164, CA112355, R01 CA175491]; UCSF Goldberg-Benioff Program in Cancer Translational Biology; Vanderbilt Faculty Research Scholars Fund; National Institute on Aging; National Institute of Mental Health; NIH Common Fund [RC2 AG036607]; Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH; Vanderbilt CTSA [UL1TR000445, RC2GM092618, U01HG004603] FX We are grateful to the Kaiser Permanente Northern California members who have generously agreed to participate in the Kaiser Permanente Research Program on Genes, Environment, and Health, the ProHealth Study and the California Men's Health Study. This work was supported by NIH grants CA127298, CA088164 and CA112355 (J.S.W., M.N.P. and R.E.G.), the UCSF Goldberg-Benioff Program in Cancer Translational Biology (J.S.W.), and a career development award from the Vanderbilt Faculty Research Scholars Fund (J.D.M.). 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.A.S. and N.J.R.). PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. BioVU is supported by institutional funding and by the Vanderbilt CTSA grant UL1TR000445 (NCATS/NIH), RC2GM092618 (NIGMS/OD) and U01HG004603 (NHGRI/NIGMS). The analysis of the Malmo Diet and Cancer cohort was supported by the NIH R01 CA175491. NR 83 TC 0 Z9 0 U1 2 U2 2 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 JAN 31 PY 2017 VL 8 AR 14248 DI 10.1038/ncomms14248 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ1EP UT WOS:000392953600001 PM 28139693 ER PT J AU Li, Q Henry, ER Hofrichter, J Smith, JF Cellmer, T Dunkelberger, EB Metaferia, BB Jones-Straehle, S Boutom, S Christoph, GW Wakefield, TH Link, ME Staton, D Vass, ER Miller, JL Hsieh, MM Tisdale, JF Eaton, WA AF Li, Quan Henry, Eric R. Hofrichter, James Smith, Jeffrey F. Cellmer, Troy Dunkelberger, Emily B. Metaferia, Belhu B. Jones-Straehle, Stacy Boutom, Sarah Christoph, Garrott W. Wakefield, Terri H. Link, Mary E. Staton, Dwayne Vass, Erica R. Miller, Jeffery L. Hsieh, Matthew M. Tisdale, John F. Eaton, William A. TI Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE sickle cell; drugs; hemoglobin S; treatment; screening assay ID HEMOGLOBIN-S POLYMERIZATION; FETAL-HEMOGLOBIN; OXYGEN-AFFINITY; DELAY-TIME; HYDROXYUREA THERAPY; DEOXYHEMOGLOBIN-S; CLINICAL SEVERITY; ANEMIA; GELATION; MECHANISMS AB Although it has been known for more than 60 years that the cause of sickle cell disease is polymerization of a hemoglobin mutant, hydroxyurea is the only drug approved for treatment by the US Food and Drug Administration. This drug, however, is only partially successful, and the discovery of additional drugs that inhibit fiber formation has been hampered by the lack of a sensitive and quantitative cellular assay. Here, we describe such a method in a 96-well plate format that is based on laser-induced polymerization in sickle trait cells and robust, automated image analysis to detect the precise time at which fibers distort ("sickle") the cells. With this kineticmethod, we show that small increases in cell volume to reduce the hemoglobin concentration can result in therapeutic increases in the delay time prior to fiber formation. We also show that, of the two drugs (AES103 and GBT440) in clinical trials that inhibit polymerization by increasing oxygen affinity, one of them (GBT440) also inhibits sickling in the absence of oxygen by two additional mechanisms. C1 [Li, Quan; Henry, Eric R.; Hofrichter, James; Smith, Jeffrey F.; Cellmer, Troy; Dunkelberger, Emily B.; Metaferia, Belhu B.; Jones-Straehle, Stacy; Boutom, Sarah; Christoph, Garrott W.; Eaton, William A.] NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. [Wakefield, Terri H.; Staton, Dwayne; Vass, Erica R.] NIDDK, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Link, Mary E.] NHLBI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Miller, Jeffery L.] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Hsieh, Matthew M.; Tisdale, John F.] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Eaton, WA (reprint author), NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. EM eaton@helix.nih.gov FU intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart Lung and Blood Institute, National Institutes of Health FX We thank Frank A. Ferrone and H. Franklin Bunn for many helpful discussions and H. Franklin Bunn and Carlo Brugnara for their comments and helpful criticisms of the manuscript. We thank Robert Swift of Invenux, LLC for the sample of SCD-101. This work was supported by the intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart Lung and Blood Institute, National Institutes of Health. NR 54 TC 0 Z9 0 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 31 PY 2017 VL 114 IS 5 BP E689 EP E696 DI 10.1073/pnas.1619054114 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4OI UT WOS:000393196300006 PM 28096387 ER PT J AU Bocksteins, E Snyders, DJ Holmgren, M AF Bocksteins, Elke Snyders, Dirk J. Holmgren, Miguel TI Independent movement of the voltage sensors in K(V)2.1/K(V)6.4 heterotetramers SO SCIENTIFIC REPORTS LA English DT Article ID SHAKER K+ CHANNEL; C-TYPE INACTIVATION; POTASSIUM CHANNEL; SODIUM-CHANNELS; GATING CHARGE; CONFORMATIONAL-CHANGES; ACTIVATION GATE; MOLECULAR-BASIS; ALPHA-SUBUNITS; ION CHANNELS AB Heterotetramer voltage-gated K+ (K-V) channels K(V)2.1/K(V)6.4 display a gating charge-voltage (Q(V)) distribution composed by two separate components. We use state dependent chemical accessibility to cysteines substituted in either K(V)2.1 or K(V)6.4 to assess the voltage sensor movements of each subunit. By comparing the voltage dependences of chemical modification and gating charge displacement, here we show that each gating charge component corresponds to a specific subunit forming the heterotetramer. The voltage sensors from K(V)6.4 subunits move at more negative potentials than the voltage sensors belonging to K(V)2.1 subunits. These results indicate that the voltage sensors from the tetrameric channels move independently. In addition, our data shows that 75% of the total charge is attributed to K(V)2.1, while 25% to K(V)6.4. Thus, the most parsimonious model for K(V)2.1/K(V)6.4 channels' stoichiometry is 3:1. C1 [Bocksteins, Elke; Snyders, Dirk J.] Univ Antwerp, Dept Biomed Sci, Lab Mol Biophys Physiol & Pharmacol, Antwerp, Belgium. [Bocksteins, Elke; Holmgren, Miguel] NINDS, Mol Neurophysiol Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Bocksteins, E (reprint author), Univ Antwerp, Dept Biomed Sci, Lab Mol Biophys Physiol & Pharmacol, Antwerp, Belgium.; Bocksteins, E; Holmgren, M (reprint author), NINDS, Mol Neurophysiol Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM elke.bocksteins@uantwerpen.be; holmgren@ninds.nih.gov FU Research Foundation - Flanders (FWO) [FWO-1291913N, FWO-1291916N, FWO-V418013N]; University of Antwerp; Intramural Section Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health FX We thank James S. Trimmer (UC Davis, CA, USA) for the generous gift of the RBG4 vector, and Francisco Bezanilla (University of Chicago, IL, USA), Pablo Miranda Fernandez (NIH, MD, USA) and Jeroen I. Stas (University of Antwerp, Belgium) for insightful discussions. We thank the Section on Instrumentation of the National Institute of Mental Health for assistance. This work was supported by the postdoctoral fellowships FWO-1291913N and FWO-1291916N, and the travel grant FWO-V418013N from the Research Foundation - Flanders (FWO) to E.B., a BOF KP 2015 grant from the University of Antwerp to E.B. and the Intramural Section Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health to M.H. NR 49 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 31 PY 2017 VL 7 AR 41646 DI 10.1038/srep41646 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ3EM UT WOS:000393095400002 PM 28139741 ER PT J AU Gevaert, O Echegaray, S Khuong, A Hoang, CD Shrager, JB Jensen, KC Berry, GJ Guo, HH Lau, C Plevritis, SK Rubin, DL Napel, S Leung, AN AF Gevaert, Olivier Echegaray, Sebastian Khuong, Amanda Hoang, Chuong D. Shrager, Joseph B. Jensen, Kirstin C. Berry, Gerald J. Guo, H. Henry Lau, Charles Plevritis, Sylvia K. Rubin, Daniel L. Napel, Sandy Leung, Ann N. TI Predictive radiogenomics modeling of EGFR mutation status in lung cancer SO SCIENTIFIC REPORTS LA English DT Article ID GROWTH-FACTOR RECEPTOR; IMAGING FEATURES; CLINICAL-TRIALS; KRAS MUTATIONS; ADENOCARCINOMA; ASSOCIATIONS; RADIOMICS; PHENOTYPE; SUBTYPES; IMPACT AB Molecular analysis of the mutation status for EGFR and KRAS are now routine in the management of non-small cell lung cancer. Radiogenomics, the linking of medical images with the genomic properties of human tumors, provides exciting opportunities for non-invasive diagnostics and prognostics. We investigated whether EGFR and KRAS mutation status can be predicted using imaging data. To accomplish this, we studied 186 cases of NSCLC with preoperative thin-slice CT scans. A thoracic radiologist annotated 89 semantic image features of each patient's tumor. Next, we built a decision tree to predict the presence of EGFR and KRAS mutations. We found a statistically significant model for predicting EGFR but not for KRAS mutations. The test set area under the ROC curve for predicting EGFR mutation status was 0.89. The final decision tree used four variables: emphysema, airway abnormality, the percentage of ground glass component and the type of tumor margin. The presence of either of the first two features predicts a wild type status for EGFR while the presence of any ground glass component indicates EGFR mutations. These results show the potential of quantitative imaging to predict molecular properties in a non-invasive manner, as CT imaging is more readily available than biopsies. C1 [Gevaert, Olivier] Stanford Univ, Dept Med, Stanford Ctr Biomed Informat Res, Stanford, CA 94305 USA. [Gevaert, Olivier] Stanford Univ, Dept Biomed Data Sci, Stanford, CA 94305 USA. [Echegaray, Sebastian; Guo, H. Henry; Plevritis, Sylvia K.; Rubin, Daniel L.; Napel, Sandy; Leung, Ann N.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Khuong, Amanda; Hoang, Chuong D.; Shrager, Joseph B.] NCI, Thorac & GI Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Jensen, Kirstin C.; Berry, Gerald J.] Stanford Univ, Med Ctr, Dept Pathol, Stanford, CA 94305 USA. [Jensen, Kirstin C.] Vet Affairs Palo Alto Hlth Care Syst, Pathol & Lab Serv, Palo Alto, CA USA. [Lau, Charles] Stanford Univ, Vet Affairs Palo Alto Hlth Care Syst, Dept Radiol, Palo Alto, CA USA. RP Gevaert, O (reprint author), Stanford Univ, Dept Med, Stanford Ctr Biomed Informat Res, Stanford, CA 94305 USA.; Gevaert, O (reprint author), Stanford Univ, Dept Biomed Data Sci, Stanford, CA 94305 USA. EM olivier.gevaert@stanford.edu FU National Cancer Institute [R01CA160251]; National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health [R01EB020527] FX Research reported in this publication was supported by the National Cancer Institute under Award Number R01CA160251 and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under Award Number R01EB020527. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 37 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 31 PY 2017 VL 7 AR 41674 DI 10.1038/srep41674 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ3EA UT WOS:000393094200001 PM 28139704 ER PT J AU Gao, SG Wolanyk, N Chen, Y Jia, S Hessner, MJ Wang, XJ AF Gao, Shouguo Wolanyk, Nathaniel Chen, Ye Jia, Shuang Hessner, Martin J. Wang, Xujing TI Investigation of coordination and order in transcription regulation of innate and adaptive immunity genes in type 1 diabetes SO BMC Medical Genomics LA English DT Article DE Co-expression network; Network structure; Transcription regulation; Entropy; Type 1 diabetes ID INFLAMMATORY BIOMARKER; NETWORK TOPOLOGY; BIOBREEDING RAT; H-INDEX; EXPRESSION; SIGNATURES; IDENTIFICATION; PATHWAYS; MELLITUS; CELLS AB Background: Type 1 diabetes (T1D) is an autoimmune disease and extensive evidence has indicated a critical role of both the innate and the adaptive arms of immune system in disease development. To date most clinical trials of immunomodulation therapies failed to show efficacy. A number of gene expression studies of T1D have been carried out. However, a systems analysis of the expression variations of the innate and adaptive immunity gene sets, or their co-expression network structures in cohorts at different disease states or of different disease risks, is not available till now. Methods: We utilized data from a large gene expression study that included transcription profiles of control peripheral blood mononuclear cells (PBMC) exposed to plasma of 148 human subjects from four cohorts that included unrelated healthy controls (uHC), recent onset T1D patients (RO-T1D), and healthy siblings of probands that possess high (HRS, High Risk Sibling) or low (LRS, Low Risk Sibling) risk HLA haplotypes. Both weighted and non-weighted co-expression networks were constructed in each cohort separately, and edge weight distribution and the activation of known protein complexes were examined. The co-expression networks of the innate and adaptive immunity genes were further examined in more detail through a number of network measures that included network density, Shannon entropy, h-index, and the scaling exponent. of degree distribution. Pathway analysis was carried out using CoGA, a tool for detecting significant network structural changes of a gene set. Results: Weighted network edge distribution revealed a globally weakened co-expression network induced by the RO-T1D cohort as compared to that by the uHC, suggesting a broad spectrum loss of transcriptional coordination. The two healthy T1D family cohorts (HRS and LRS) induced more active but heterogeneous transcription coordination globally, and among both the innate and the adaptive immunity genes, than the uHC. This finding is consistent with our previous report of these cohorts sharing a heightened innate inflammatory state. The spike-in of IL-1RA to RO-T1D sera improved co-expression network strength of both the innate and the adaptive immunity genes, and enabled a global order recovery in transcription regulation that resulted in significantly increased number of activated protein complexes. Many of the top pathways that showed significant difference in co-expression network structures and order between RO-T1D and uHC have strong links to T1D. Conclusions: Network level analysis of the innate and adaptive immunity genes, and the whole genome, revealed striking cohort-dependent differences in co-expression network structural measures, suggesting their potential in cohort classification and disease-relevant pathway identification. The results demonstrated the advantages of systems analysis in defining molecular signatures as well as in predicting targets in future research. C1 [Gao, Shouguo; Chen, Ye; Wang, Xujing] NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Jia, Shuang; Hessner, Martin J.] Med Coll Wisconsin, Dept Pediat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Jia, Shuang; Hessner, Martin J.] Childrens Hosp Wisconsin, Childrens Res Inst, Max McGee Natl Res Ctr Juvenile Diabet, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Jia, Shuang; Hessner, Martin J.] Med Coll Wisconsin, Human & Mol Genet Ctr, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Wolanyk, Nathaniel] Univ Alabama Birmingham, Dept Phys, 1300 Univ Blvd, Birmingham, AL 35294 USA. RP Wang, XJ (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM xujing.wang@nih.gov FU Intramural Research Program of the NIH, NHLBI; Juvenile Diabetes Research Foundation International [1-2008-1026, 5-2012-220, 17-2012-621, 2-SRA-2015-109-Q-R]; American Diabetes Association [7-12-BS-075]; National Institutes of Health [R01AI078713, DP3DK098161, R01DK080100]; National Institutes of Health (National Center for Advancing Translational Sciences, National Institutes of Health) [8UL1TR000055]; Children's Hospital of Wisconsin Foundation FX This work was partially supported by the Intramural Research Program of the NIH, NHLBI; by The Juvenile Diabetes Research Foundation International (grants 1-2008-1026, 5-2012-220, 17-2012-621, 2-SRA-2015-109-Q-R to MJH); American Diabetes Association (grant 7-12-BS-075 to MJH); National Institutes of Health (grants R01AI078713 to MJH, DP3DK098161 to MJH/CJG, R01DK080100 to XW, and the National Center for Advancing Translational Sciences, National Institutes of Health grant 8UL1TR000055); and The Children's Hospital of Wisconsin Foundation. NR 55 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD JAN 31 PY 2017 VL 10 AR 7 DI 10.1186/s12920-017-0243-8 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA EJ1VA UT WOS:000392997100001 PM 28143555 ER PT J AU Fadda, A Syed, N Mackeh, R Papadopoulou, A Suzuki, S Jithesh, PV Kino, T AF Fadda, Abeer Syed, Najeeb Mackeh, Rafah Papadopoulou, Anna Suzuki, Shigeru Jithesh, Puthen V. Kino, Tomoshige TI Genome-wide Regulatory Roles of the C2H2-type Zinc Finger Protein ZNF764 on the Glucocorticoid Receptor SO SCIENTIFIC REPORTS LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; TRANSCRIPTIONAL ACTIVITY; HORMONE RESISTANCE; CHROMATIN ACCESSIBILITY; STRUCTURAL-ANALYSIS; RESPONSE ELEMENTS; NUCLEAR RECEPTOR; BINDING; KRAB; GENE AB The C2H2-type zinc finger protein ZNF764 acts as an enhancer for several steroid hormone receptors, and haploinsufficiency of this gene may be responsible for tissue resistance to multiple steroid hormones including glucocorticoids observed in a patient with 16p11.2 microdeletion. We examined genome-wide regulatory actions of ZNF764 on the glucocorticoid receptor (GR) in HeLa cells as a model system. ZNF764-and GR-binding sites demonstrated similar distribution in various genomic features. They positioned predominantly around 50-500 kbs from the transcription start sites of their nearby genes, and were closely localized with each other, overlapping in similar to 37% of them. ZNF764 demonstrated differential on/off effects on GR-binding and subsequent mRNA expression: some genes were highly dependent on the presence/absence of ZNF764, but others were not. Pathway analysis revealed that these 3 gene groups were involved in distinct cellular activities. ZNF764 physically interacted with GR at ligand-binding domain through its KRAB domain, and both its physical interaction to GR and zinc finger domain appear to be required for ZNF764 to regulate GR transcriptional activity. Thus, ZNF764 is a cofactor directing GR transcriptional activity toward specific biologic pathways by changing GR binding and transcriptional activity on the glucocorticoid-responsive genes. C1 [Fadda, Abeer; Mackeh, Rafah; Kino, Tomoshige] Sidra Med & Res Ctr, Div Translat Med, Doha, Qatar. [Syed, Najeeb; Jithesh, Puthen V.] Sidra Med & Res Ctr, Div Biomed Informat, Div Translat Med, Doha 26999, Qatar. [Papadopoulou, Anna; Suzuki, Shigeru; Kino, Tomoshige] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Suzuki, Shigeru] Asahikawa Med Univ, Dept Pediat, Asahikawa, Hokkaido 0788510, Japan. RP Kino, T (reprint author), Sidra Med & Res Ctr, Div Translat Med, Doha, Qatar.; Kino, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. EM tkino@sidra.org OI Fadda, Abeer/0000-0002-8489-1335 FU Intramural Research Program of the Sidra Medical and Research Center; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [Z01 HD008732-05 HNT]; Asahikawa Medical University FX We thank Drs. R.M. Evans, G.L. Hager and M.J. Tsai for providing us their plasmids, the Genomic Sequence Center of the National Heart, Lung and Blood Institute for running sequencing samples, Dr. A.H. DeCherney for supporting this study, Dr. W. Chen for valuable discussion and Mr. E.K. Zachman for technical support. This study was funded by the Intramural Research Program of the Sidra Medical and Research Center and that of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Z01 HD008732-05 HNT), National Institutes of Health. A. Papadopoulou and S. Suzuki were supported by a Fulbright Grant and an Internal Grant of the Asahikawa Medical University, respectively. NR 61 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 31 PY 2017 VL 7 AR 41598 DI 10.1038/srep41598 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ1HE UT WOS:000392960300001 PM 28139699 ER PT J AU Jansen, IE Ye, H Heetveld, S Lechler, MC Michels, H Seinstra, RI Lubbe, SJ Drouet, V Lesage, S Majounie, E Gibbs, JR Nalls, MA Ryten, M Botia, JA Vandrovcova, J Simon-Sanchez, J Castillo-Lizardo, M Rizzu, P Blauwendraat, C Chouhan, AK Li, YR Yogi, P Amin, N van Duijn, CM Morris, HR Brice, A Singleton, AB David, DC Nollen, EA Jain, S Shulman, JM Heutink, P AF Jansen, Iris E. Ye, Hui Heetveld, Sasja Lechler, Marie C. Michels, Helen Seinstra, Renee I. Lubbe, Steven J. Drouet, Valerie Lesage, Suzanne Majounie, Elisa Gibbs, J. Raphael Nalls, Mike A. Ryten, Mina Botia, Juan A. Vandrovcova, Jana Simon-Sanchez, Javier Castillo-Lizardo, Melissa Rizzu, Patrizia Blauwendraat, Cornelis Chouhan, Amit K. Li, Yarong Yogi, Puja Amin, Najaf van Duijn, Cornelia M. Morris, Huw R. Brice, Alexis Singleton, Andrew B. David, Della C. Nollen, Ellen A. Jain, Shushant Shulman, Joshua M. Heutink, Peter CA IPGDC TI Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing SO GENOME BIOLOGY LA English DT Article DE Parkinson's disease; Genomics; Whole-exome sequencing; Loss-of-function; Rare variants; Functional screening; Mitochondria; Parkin; alpha-synuclein; Animal model ID RECEPTOR TYROSINE PHOSPHATASE; DOMAIN-CONTAINING 2; ALPHA-SYNUCLEIN; DROSOPHILA MODEL; CAENORHABDITIS-ELEGANS; G-PATCH; ALZHEIMERS-DISEASE; RETROMER COMPLEX; NETWORK ANALYSIS; AXON GUIDANCE AB Background: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. Results: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced alpha-synucleininduced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. Conclusions: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies. C1 [Jansen, Iris E.; Heetveld, Sasja; Lechler, Marie C.; Simon-Sanchez, Javier; Castillo-Lizardo, Melissa; Rizzu, Patrizia; Blauwendraat, Cornelis; David, Della C.; Jain, Shushant; Heutink, Peter] German Ctr Neurodegenerat Dis DZNE, Otfried Muller Str 23, D-72076 Tubingen, Germany. [Jansen, Iris E.; Heutink, Peter] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, NL-1081 HZ Amsterdam, Netherlands. [Ye, Hui; Shulman, Joshua M.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Lechler, Marie C.] Grad Sch Cellular & Mol Neurosci, D-72074 Tubingen, Germany. [Michels, Helen; Seinstra, Renee I.; Nollen, Ellen A.] Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Aging, NL-9700 AD Groningen, Netherlands. [Lubbe, Steven J.; Morris, Huw R.] UCL Inst Neurol, Dept Clin Neurosci, London, England. [Lubbe, Steven J.] Northwestern Univ, Feinberg Sch Med, Ken & Ruth Davee Dept Neurol, Chicago, IL 60611 USA. [Drouet, Valerie; Lesage, Suzanne; Brice, Alexis] UPMC Univ Paris 06, Sorbonne Univ, CNRS, INSERM,U1127,UMR7225,UMR S1127,Inst Cerveau & Moe, Paris, France. [Majounie, Elisa] Cardiff Univ, Inst Psychol Med & Clin Neurosci, MRC Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Gibbs, J. Raphael; Nalls, Mike A.; Singleton, Andrew B.] NIA, Lab Neurogenet, Bethesda, MD 20892 USA. [Ryten, Mina; Botia, Juan A.; Vandrovcova, Jana] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Ryten, Mina] Kings Coll London, Dept Med & Mol Genet, London, England. [Simon-Sanchez, Javier] Univ Tubingen, Hertie Inst Clin Brain Res, Tubingen, Germany. [Chouhan, Amit K.; Li, Yarong; Yogi, Puja; Shulman, Joshua M.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Amin, Najaf; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, Paris, France. [Shulman, Joshua M.] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. [Shulman, Joshua M.] Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA. [Shulman, Joshua M.] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, 1250 Moursund St,1150, Houston, TX 77030 USA. RP Heutink, P (reprint author), German Ctr Neurodegenerat Dis DZNE, Otfried Muller Str 23, D-72076 Tubingen, Germany.; Shulman, JM (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. EM Joshua.Shulman@bcm.edu; Peter.Heutink@dzne.de RI van de Warrenburg, Bart/D-1935-2010; Lubbe, Steven/L-8261-2013; corvol, jean-christophe/I-6387-2012; Revesz, Tamas/A-8732-2010 OI corvol, jean-christophe/0000-0001-7325-0199; Revesz, Tamas/0000-0003-2501-0259 FU Prinses Beatrix Spierfonds; EU joint Program-Neurodegenerative Diseases (JPND): COURAGE-PD; Federal Ministry of Education and Research Germany (BMBF): MitoPD; NIH [K08AG034290, R21NS089854, R01AG033193, U01AG046161, C06RR029965, R01NS037167, R01CA141668, P50NS071674, P30CA125123]; Alzheimer's Association; American Federation for Aging Research; Huffington Foundation; Robert and Renee Belfer Family Foundation; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital; Burroughs Wellcome Fund; Wellcome Trust [076113, 085475, 090355]; Parkinson's UK [8047, J-0804, F1002, F-1201]; Medical Research Council [G0700943, G1100643]; France-Parkinson Association; Roger de Spoelberch Foundation [R12123DD]; French Academy of Sciences; French program "Investissements d'avenir" [ANR-10-IAIHU-06]; Intramural Research Program of the National Institute on Aging; National Institutes of Health; Department of Health and Human Services [ZO1 AG000957]; National Institute of Neurological Disorders and Stroke (NINDS) [Z01-AG000949-02]; National Institute of Environmental Health Sciences [Z01-ES101986]; Department of Defense [W81XWH-09-2-0128]; Michael J Fox Foundation for Parkinson's Research; American Parkinson Disease Association (APDA); Bames Jewish Hospital Foundation; Greater St Louis Chapter of the APDA; Hersenstichting Nederland; German National Genome Network (NGFNplus) [01GS08134]; German Federal Ministry of Education and Research [NGFN 01GR0468]; ERA-NET NEURON [01EW0908]; Helmholtz Alliance Mental Health in an Ageing Society [HA-215]; European Community Framework Programme 7; People Programme; IAPP on novel genetic and phenotypic markers of Parkinson's disease; Essential Tremor [PIAP-GA-2008-230596]; Michael J. Fox Foundation; Abbvie; Avid; Biogen; Bristol-Myers Squibb; Covance; GE Healthcare; Genentech; GlaxoSmithKline; Lilly; Lundbeek; Merck; Meso Scale Discovery; Pfizer; Piramal; Roche; Servier; Teva; UCB; Golub Capital; Assistance Publique Hopitaux de Paris; TRiP at Harvard Medical School [R01GM084947] FX Funding for this study was provided by the Prinses Beatrix Spierfonds (IEJ, PH); the EU joint Program-Neurodegenerative Diseases (JPND): COURAGE-PD (PH, VD, SL, AB); the Federal Ministry of Education and Research Germany (BMBF): MitoPD (PH); NIH grants (K08AG034290, R21NS089854, R01AG033193, U01AG046161, C06RR029965, R01NS037167, R01CA141668, P50NS071674) (JMS, ABS); the Alzheimer's Association (JMS); the American Federation for Aging Research (JMS); Huffington Foundation (JMS); the Robert and Renee Belfer Family Foundation (JMS); the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital (JMS); a Career Award for Medical Scientists from the Burroughs Wellcome Fund (JMS); the Wellcome Trust under awards 076113, 085475, and 090355 (SL, HM), Parkinson's UK (grants 8047, J-0804, F1002, and F-1201) (SL, HM); the Medical Research Council (G0700943 and G1100643) (SL, HM); the France-Parkinson Association (VD, SL, AB); the Roger de Spoelberch Foundation (R12123DD) (VD, SL, AB); the French Academy of Sciences (VD, SL, AB); the French program "Investissements d'avenir" (ANR-10-IAIHU-06) (VD, SL, AB); the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services (ZO1 AG000957) (MN, JRG, ABS), the National Institute of Neurological Disorders and Stroke (NINDS) (Z01-AG000949-02), and the National Institute of Environmental Health Sciences (Z01-ES101986). Department of Defense (award W81XWH-09-2-0128); The Michael J Fox Foundation for Parkinson's Research; American Parkinson Disease Association (APDA); Bames Jewish Hospital Foundation; Greater St Louis Chapter of the APDA; Hersenstichting Nederland; the German National Genome Network (NGFNplus number 01GS08134, German Ministry for Education and Research); the German Federal Ministry of Education and Research (NGFN 01GR0468, PopGen); 01EW0908 in the frame of ERA-NET NEURON and Helmholtz Alliance Mental Health in an Ageing Society (HA-215); European Community Framework Programme 7, People Programme; IAPP on novel genetic and phenotypic markers of Parkinson's disease, and Essential Tremor (MarkMD), contract number PIAP-GA-2008-230596 MarkMD. PPMI - a public-private partnership - is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including Abbvie, Avid, Biogen, Bristol-Myers Squibb, Covance, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeek, Merck, Meso Scale Discovery, Pfizer, Piramal, Roche, Servier, Teva, UCB, and Golub Capital.; The Pathology and Histology Core at Baylor College of Medicine is supported by NIH grant P30CA125123. The DIGPD cohort was sponsored by the Assistance Publique Hopitaux de Paris and founded by the French clinical research hospital program-PHRC (code AOR08010). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (https://hpc.nih.gov/systems/) and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. The TRiP at Harvard Medical School, which provided fly stocks, is supported by R01GM084947. NR 108 TC 2 Z9 2 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD JAN 30 PY 2017 VL 18 AR 22 DI 10.1186/s13059-017-1147-9 PG 26 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EL7UV UT WOS:000394827300003 PM 28137300 ER PT J AU Matsuno, K Orba, Y Maede-White, K Scott, D Feldmann, F Liang, MF Ebihara, H AF Matsuno, Keita Orba, Yasuko Maede-White, Kimberly Scott, Dana Feldmann, Friederike Liang, Mifang Ebihara, Hideki TI Animal Models of Emerging Tick-Borne Phleboviruses: Determining Target Cells in a Lethal Model of SFTSV Infection SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE aged mouse; disease modeling; heartland virus; immunocompromised mouse; mouse; nonhuman primate; severe fever with thrombocytopenia syndrome virus ID THROMBOCYTOPENIA SYNDROME VIRUS; SEVERE FEVER; MOUSE MODEL; RISK-FACTORS; BUNYAVIRUS; PATHOGENESIS; CHINA; IDENTIFICATION; JAPAN AB The pathogenesis of clinical manifestations caused by newly emerging tick-borne phleboviruses [i.e., Severe fever with thrombocytopenia syndrome virus (SFTSV) and Heartland virus (HRTV)], such as severe thrombocytopenia and lymphocytopenia, are not yet fully understood. In the present study, to establish an animal model mimicking the profile of fatal human cases, we examined the susceptibilities of adult mice from 12 strains, aged mice from two strains, and cynomolgus macaques to SFTSV and/or HRTV infections. However, none of these immunocompetent animals developed lethal diseases after infection with SFTSV or HRTV. Thus, we tested a lethal animal model of SFTSV infection using interferon-alpha/beta receptor knock-out (IFNAR(-/-)) mice to identify the target cell(s) of virus infection, as well as lesions that are potentially associated with hematological changes. IbaI-positive macrophages and Pax5-positive immature B cells overlapped with SFTSV-positive cells in the spleen and lymph nodes of IFNAR(-/-) mice, and IbaI- SFTSV-double positive cells were also observed in the liver and kidney, thereby suggesting crucial roles for macrophages in the pathogenesis of SFTSV infection in mice. In the mandibular lymph nodes and spleens of infected mice, we observed extensive necrosis comprising B220-positive B cells, which may be associated with severe lymphocytopenia. The results of this study suggest a resemblance between the IFNAR(-/-) mouse model and lethal infections in humans, as well as roles for multiple cells during pathogenesis in mice. C1 [Matsuno, Keita; Ebihara, Hideki] NIAID, Mol Virol & Host Pathoge Interact Unit, Virol Lab, Div Intramural Res,NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. [Matsuno, Keita] Hokkaido Univ, Microbiol Lab, Grad Sch Vet Med, Sapporo, Hokkaido, Japan. [Matsuno, Keita] Hokkaido Univ, Global Inst Collaborat Res & Educ, Global Stn Zoonosis Control, Sapporo, Hokkaido, Japan. [Orba, Yasuko] Hokkaido Univ, Res Ctr Zoonosis Control, Div Mol Pathobiol, Sapporo, Hokkaido, Japan. [Maede-White, Kimberly; Scott, Dana; Feldmann, Friederike] NIAID, Rocky Mt Vet Branch, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT USA. [Liang, Mifang] China CDC, NHFPC Key Lab Med Virol, Natl Inst Viral Dis Control & Prevent, Beijing, Peoples R China. [Ebihara, Hideki] Mayo Clin, Dept Mol Med, Rochester, MN 55905 USA. RP Ebihara, H (reprint author), NIAID, Mol Virol & Host Pathoge Interact Unit, Virol Lab, Div Intramural Res,NIH,Rocky Mt Labs, Hamilton, MT 59840 USA.; Ebihara, H (reprint author), Mayo Clin, Dept Mol Med, Rochester, MN 55905 USA. EM hidebihara@gmail.com FU Intramural Research Program; US-China Biomedical Collaborative Research on Cancer, Mental Health, Allergy, Immunology and Infectious Diseases; HIV/AIDS; NIH; MEXT/JSPS KAKENHI [JP16749339, JP16H06431, JP16H06429, JP16K21723]; Japan Agency for Medical Research and Development, AMED FX The authors thank the following individuals at RML, DIR, NIAID, and NIII for their help and assistance; Carla Weisend and Brandi Williamson for laboratory assistance; and Martha Thayer for conducting literature searches. The authors would like to thank Enago (www.enago.jp) for the English language review. This study was supported by the Intramural Research Program and US-China Biomedical Collaborative Research on Cancer, Mental Health, Allergy, Immunology and Infectious Diseases including HIV/AIDS and its co-Morbidities of the NIH, MEXT/JSPS KAKENHI Grant Numbers JP16749339, JP16H06431, JP16H06429, and JP16K21723, and Japan Agency for Medical Research and Development, AMED. Any opinions, interpretations, conclusions, and recommendations are those of the authors, and they are not necessarily endorsed by the NIII. NR 29 TC 0 Z9 0 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD JAN 30 PY 2017 VL 8 AR 104 DI 10.3389/fmicb.2017.00104 PG 11 WC Microbiology SC Microbiology GA EI9XS UT WOS:000392863500001 PM 28194148 ER PT J AU Mahiane, SG Laeyendecker, O AF Mahiane, Severin Guy Laeyendecker, Oliver TI Segmented polynomials for incidence rate estimation from prevalence data SO STATISTICS IN MEDICINE LA English DT Article DE incidence rate; mortality; prevalence; segmented polynomials; maximum likelihood estimation; model selection ID AGE-SPECIFIC PREVALENCE; HIV INCIDENCE; DIFFERENTIAL MORTALITY; IRREVERSIBLE DISEASES; SPLINES AB The study considers the problem of estimating incidence of a non remissible infection (or disease) with possibly differential mortality using data from a(several) cross-sectional prevalence survey(s). Fitting segmented polynomial models is proposed to estimate the incidence as a function of age, using the maximum likelihood method. The approach allows automatic search for optimal position of knots, and model selection is performed using the Akaike information criterion. The method is applied to simulated data and to estimate HIV incidence among men in Zimbabwe using data from both the NIMH Project Accept (HPTN 043) and Zimbabwe Demographic Health Surveys (2005-2006). Copyright (C) 2016 John Wiley & Sons, Ltd. C1 [Mahiane, Severin Guy] Avenir Hlth, 41-A New London Turnpike, Glastonbury, CT 06033 USA. [Mahiane, Severin Guy] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Laeyendecker, Oliver] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. RP Mahiane, SG (reprint author), Avenir Hlth, 41-A New London Turnpike, Glastonbury, CT 06033 USA. EM mahianes@yahoo.fr FU Bill and Melinda Gates Foundation; Johns Hopkins University Center for AIDS Research from the National Institute of Allergy And Infectious Diseases [1P30AI094189]; U.S. National Institute of Mental Health [U01MH066687, U01MH066688, U01MH066701, U01MH066702]; Division of AIDS of the U.S. National Institute of Allergy and Infectious Diseases [U01AI068613/UM1A068613, U01AI068617/UM1AI068617, U01AI068619/UM1AI068619]; Office of AIDS Research of the U.S. National Institutes of Health; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was sponsored by Bill and Melinda Gates Foundation, the Johns Hopkins University Center for AIDS Research (Grant Number 1P30AI094189 from the National Institute of Allergy And Infectious Diseases), the U.S. National Institute of Mental Health as a cooperative agreement, through contracts U01MH066687 (Johns Hopkins University - David Celentano, PI); U01MH066688 (Medical University of South Carolina - Michael Sweat, PI); U01MH066701 (University of California, Los Angeles - Thomas J. Coates, PI); and U01MH066702 (University of California, San Francisco - Stephen F. Morin, PI).; In addition, this work was supported as HPTN Protocol 043 through contracts U01AI068613/UM1A068613 (HPTN Network Laboratory-Susan Eshleman, PI); U01AI068617/UM1AI068617 (SCHARP - Deborah Donnell, PI); and U01AI068619/UM1AI068619 (HIV Prevention Trials Network - Sten Vermund/Wafaa El-Sadr, PIs) of the Division of AIDS of the U.S. National Institute of Allergy and Infectious Diseases; and by the Office of AIDS Research of the U.S. National Institutes of Health. Additional support was provided by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Views expressed are those of the authors and not necessarily those of sponsoring agencies. NR 24 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JAN 30 PY 2017 VL 36 IS 2 SI SI BP 334 EP 344 DI 10.1002/sim.7130 PG 11 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA EI9KA UT WOS:000392825500012 PM 27672002 ER PT J AU Ghequire, MGK Kemland, L De Mot, R AF Ghequire, Maarten G. K. Kemland, Lieselore De Mot, Rene TI Novel Immunity Proteins Associated with Colicin M-like Bacteriocins Exhibit Promiscuous Protection in Pseudomonas SO Frontiers in Microbiology LA English DT Article DE colicin M; PmiA; PmiB; pyocin; peptidoglycan; lipid II ID HIGH-AFFINITY; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; AERUGINOSA; RHIZOSPHERE; SELECTIVITY; EXPRESSION; STRAINS; BINDING; PYOCINS AB Bacteriocins related to colicin M, acting via cleavage of the cell wall precursor lipid II, have been characterized in gamma- and beta-proteobacteria. Depending on the species, immunity is provided by either an inner membrane-anchored periplasmic protein or by an integral membrane protein. In Pseudomonas however, the immunity partner of colicin M-like bacteriocins remains unknown. Based on an in silico analysis in pseudomonad genomes, we here identify a gene encoding a putative immunity partner that represents a novel type of integral membrane protein (PmiA, Pseudomonas colicin M-like immunity type A). By heterologous expression of pmiA genes in susceptible strains, we show that immunity to colicin M-like bacteriocins is indeed provided by the cognate PmiA. Sequence homology among PmiA proteins is essentially absent, except for a short motif with a conserved periplasm-exposed aspartate residue. However, PmiA's protective function is not abolished by changing this acidic residue to the uncharged alanine. Immunity by PmiAs appears promiscuous to the extent that PmiA homologs from a clade sharing <40% pairwise amino acid identity, equally provide protection against the bacteriocin linked to the original PmiA. This study shows that multiple immunity factors have evolved independently to silence lipid II-targeting enzymatic bacteriocins. Their relaxed bacteriocin immunization capacity contrasts to the strict specificity of immunity proteins shielding the enzymatic domain of nuclease bacteriocins. The nature of associated immune functions needs consideration when using such natural protein antibiotics or designing novel variants. C1 [Ghequire, Maarten G. K.; Kemland, Lieselore; De Mot, Rene] Katholieke Univ Leuven, Ctr Microbial & Plant Genet, Heverlee, Belgium. [Ghequire, Maarten G. K.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Ghequire, MGK (reprint author), Katholieke Univ Leuven, Ctr Microbial & Plant Genet, Heverlee, Belgium.; Ghequire, MGK (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM maarten.ghequire@biw.kuleuven.be FU FWO-Vlaanderen [12M4615N] FX MG is the recipient of a postdoctoral fellowship from FWO-Vlaanderen (12M4615N). NR 39 TC 1 Z9 1 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD JAN 30 PY 2017 VL 8 AR 93 DI 10.3389/fmicb.2017.00093 PG 9 WC Microbiology SC Microbiology GA EI9WX UT WOS:000392861200001 PM 28194143 ER PT J AU Yasgar, A Titus, SA Wang, YH Danchik, C Yang, SM Vasiliou, V Jadhav, A Maloney, DJ Simeonov, A Martinez, NJ AF Yasgar, Adam Titus, Steven A. Wang, Yuhong Danchik, Carina Yang, Shyh-Ming Vasiliou, Vasilis Jadhav, Ajit Maloney, David J. Simeonov, Anton Martinez, Natalia J. TI A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity SO PLOS ONE LA English DT Article ID MITOCHONDRIAL ALDEHYDE DEHYDROGENASE; CANCER STEM-CELLS; INHIBITOR; ALDH1A1; METABOLISM; RESISTANCE; ALCOHOL; SUPERFAMILY; CONTRIBUTES; METASTASIS AB Aldehyde dehydrogenase enzymes (ALDHs) have a broad spectrum of biological activities through the oxidation of both endogenous and exogenous aldehydes. Increased expression of ALDH1A1 has been identified in a wide-range of human cancer stem cells and is associated with cancer relapse and poor prognosis, raising the potential of ALDH1A1 as a therapeutic target. To facilitate quantitative high-throughput screening (qHTS) campaigns for the discovery, characterization and structure-activity-relationship (SAR) studies of small molecule ALDH1A1 inhibitors with cellular activity, we show herein the miniaturization to 1536-well format and automation of a high-content cell-based ALDEFLUOR assay. We demonstrate the utility of this assay by generating dose-response curves on a comprehensive set of prior art inhibitors as well as hundreds of ALDH1A1 inhibitors synthesized in house. Finally, we established a screening paradigm using a pair of cell lines with low and high ALDH1A1 expression, respectively, to uncover novel cell-active ALDH1A1-specific inhibitors from a collection of over 1,000 small molecules. C1 [Yasgar, Adam; Titus, Steven A.; Wang, Yuhong; Danchik, Carina; Yang, Shyh-Ming; Jadhav, Ajit; Maloney, David J.; Simeonov, Anton; Martinez, Natalia J.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20852 USA. [Vasiliou, Vasilis] Yale Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT USA. RP Simeonov, A; Martinez, NJ (reprint author), NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20852 USA. EM asimeono@mail.nih.gov; natalia.martinez@nih.gov FU National Center for Advancing Translational Sciences; NIH grants [M022057, EY11490] FX This work was supported by the intramural research program (IRP) of the National Center for Advancing Translational Sciences and in part by NIH grants M022057 and EY11490.; This work was supported by the intramural research program of the National Center for Advancing Translational Sciences. We thank Carleen Klumpp-Thomas for assistance with assay automation and the compound management group (Paul Shinn, Danielle Bougie, Crystal McKnight, Misha Itkin, and Zina Itkin) for sourcing, quality control, formatting, and plating all compounds. NR 48 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 27 PY 2017 VL 12 IS 1 AR e0170937 DI 10.1371/journal.pone.0170937 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN7VX UT WOS:000396211400025 PM 28129349 ER PT J AU Wang, TT Sewatanon, J Memoli, MJ Wrammert, J Bournazos, S Bhaumik, SK Pinsky, BA Chokephaibulkit, K Onlamoon, N Pattanapanyasat, K Taubenberger, JK Ahmed, R Ravetch, JV AF Wang, Taia T. Sewatanon, Jaturong Memoli, Matthew J. Wrammert, Jens Bournazos, Stylianos Bhaumik, Siddhartha Kumar Pinsky, Benjamin A. Chokephaibulkit, Kulkanya Onlamoon, Nattawat Pattanapanyasat, Kovit Taubenberger, Jeffery K. Ahmed, Rafi Ravetch, Jeffrey V. TI IgG antibodies to dengue enhanced for Fc gamma RIIIA binding determine disease severity SO SCIENCE LA English DT Article ID VIRUS-INFECTION; HEMORRHAGIC-FEVER; DEPENDENT ENHANCEMENT; IN-VITRO; CORRELATE; RECEPTOR; SEROTYPE; PATHOGENESIS; POLYMORPHISM; MACROPHAGES AB Dengue virus (DENV) infection in the presence of reactive, non-neutralizing immunoglobulin G (IgG) (RNNIg) is the greatest risk factor for dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Progression to DHF/DSS is attributed to antibody-dependent enhancement (ADE); however, because only a fraction of infections occurring in the presence of RNNIg advance to DHF/DSS, the presence of RNNIg alone cannot account for disease severity. We discovered that DHF/DSS patients respond to infection by producing IgGs with enhanced affinity for the activating Fc receptor Fc gamma RIIIA due to afucosylated Fc glycans and IgG1 subclass. RNNIg enriched for afucosylated IgG1 triggered platelet reduction in vivo and was a significant risk factor for thrombocytopenia. Thus, therapeutics and vaccines restricting production of afucosylated, IgG1 RNNIg during infection may prevent ADE of DENV disease. C1 [Wang, Taia T.; Bournazos, Stylianos; Ravetch, Jeffrey V.] Rockefeller Univ, Lab Mol Genet & Immunol, 1230 York Ave, New York, NY 10065 USA. [Wang, Taia T.; Pinsky, Benjamin A.] Stanford Univ, Sch Med, Dept Med, Div Infect Dis & Geog Med, Stanford, CA 94305 USA. [Sewatanon, Jaturong; Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Sewatanon, Jaturong; Wrammert, Jens; Bhaumik, Siddhartha Kumar; Ahmed, Rafi] Emory Univ, Emory Vaccine Ctr, Sch Med, Atlanta, GA 30322 USA. [Sewatanon, Jaturong] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Microbiol, Bangkok 10700, Thailand. [Memoli, Matthew J.; Taubenberger, Jeffery K.] Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Infect Dis Lab, Viral Pathogenesis & Evolut Sect, Bethesda, MD USA. [Wrammert, Jens; Bhaumik, Siddhartha Kumar] Emory Univ, Sch Med, Dept Pediat, Div Infect Dis, Atlanta, GA 30322 USA. [Pinsky, Benjamin A.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Chokephaibulkit, Kulkanya] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Paediat, Bangkok 10700, Thailand. [Onlamoon, Nattawat; Pattanapanyasat, Kovit] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Res & Dev, Bangkok 10700, Thailand. RP Ravetch, JV (reprint author), Rockefeller Univ, Lab Mol Genet & Immunol, 1230 York Ave, New York, NY 10065 USA. EM ravetch@rockefeller.edu FU National Center for Advancing Translational Sciences, NIH [UL1TR001866]; Clinical and Translational Science Award program; NIH [IRO1AI099385]; American Foundation for AIDS Research Mathilde Krim Fellowship in Basic Biomedical Research [109519-60-RKVA]; National Institute of Allergy and Infectious Diseases of the NIH [U19AI111825, U19AI109946, U19AI057266, U01AI115651]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID); NIAID Extramural Clinical Research Acceleration Program; Rockefeller University; Stanford University School of Medicine FX We thank S. Zhang and R. Sherwood at the Cornell Proteomics and Mass Spectrometry Facility for helpful discussions and excellent technical support. The authors also thank the staff of the Stanford Clinical Virology Laboratory for their assistance with dengue virus serologic testing. T.T.W. thanks B. Coller, S. J. Schlesinger, and the Rockefeller University KL2 Clinical Scholars Program for training and support. T.T.W. was supported, in part, by grant UL1TR001866 from the National Center for Advancing Translational Sciences, NIH, and the Clinical and Translational Science Award program. J.S. thanks S. Wang and S. Gunisetty for helping with preparation of sera from patient samples. K.P. was funded by NIH IRO1AI099385. S. B. was supported by an American Foundation for AIDS Research Mathilde Krim Fellowship in Basic Biomedical Research (109519-60-RKVA). Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the NIH under award numbers U19AI111825 (J.V.R.), U19AI109946 (J.V.R.), U19AI057266 (R. A. and J.W.), and U01AI115651 (R. A.). The influenza A virus challenge study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), as well as the NIAID Extramural Clinical Research Acceleration Program. Support and infrastructure were also provided by The Rockefeller University and by Stanford University School of Medicine. Analysis of clinical samples in this work was approved by the Institutional Review Board of Rockefeller University (protocol # TWA-0804) (T.T.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The data presented in this manuscript are in the main paper and in the supplementary materials. NR 38 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JAN 27 PY 2017 VL 355 IS 6323 BP 395 EP + DI 10.1126/science.aai8128 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4FR UT WOS:000393172800039 PM 28126818 ER PT J AU Williams, KM AF Williams, Kirsten M. TI How I treat bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation SO BLOOD LA English DT Review ID VERSUS-HOST-DISEASE; CONSENSUS DEVELOPMENT PROJECT; BONE-MARROW-TRANSPLANTATION; WORKING GROUP-REPORT; AIR-FLOW OBSTRUCTION; LUNG TRANSPLANTATION; EXTRACORPOREAL PHOTOPHERESIS; CLINICAL-TRIALS; RISK-FACTORS; INHALED CORTICOSTEROIDS AB In past years, a diagnosis of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplant (HCT) conferred nearly universal mortality secondary to lack of consensus for diagnostic criteria, poorly understood disease pathogenesis, and very few studies of therapeutic or supportive care interventions. Recently, however, progress has been made in these areas: revised consensus diagnostic guidelines are now available, supportive care has improved, there is greater understanding of potential mechanisms of disease, and prospective trials are being conducted. This article describes these advances and provides suggestions to optimize therapy for patients with BOS after HCT. C1 [Williams, Kirsten M.] Childrens Natl Hlth Syst, Ctr Canc & Blood Disorders, Washington, DC USA. [Williams, Kirsten M.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Williams, KM (reprint author), George Washington Univ, Med Ctr, Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, 111 Michigan Ave NW, Washington, DC 20010 USA. EM kmwillia@cnmc.org OI Williams, Kirsten/0000-0001-9372-5286 FU intramural research program of the National Institutes of Health, National Cancer Institute FX This work was supported in part by the intramural research program of the National Institutes of Health, National Cancer Institute. NR 88 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 26 PY 2017 VL 129 IS 4 BP 448 EP 455 DI 10.1182/blood-2016-08-693507 PG 8 WC Hematology SC Hematology GA EO2MU UT WOS:000396531400010 PM 27856461 ER PT J AU Wacker, D Wang, S McCorvy, JD Betz, RM Venkatakrishnan, AJ Levit, A Lansu, K Schools, ZL Che, T Nichols, DE Shoichet, BK Dror, RO Roth, BL AF Wacker, Daniel Wang, Sheng McCorvy, John D. Betz, Robin M. Venkatakrishnan, A. J. Levit, Anat Lansu, Katherine Schools, Zachary L. Che, Tao Nichols, David E. Shoichet, Brian K. Dror, Ron O. Roth, Bryan L. TI Crystal Structure of an LSD-Bound Human Serotonin Receptor SO CELL LA English DT Article ID LYSERGIC-ACID DIETHYLAMIDE; GENERAL FORCE-FIELD; PROTEIN-COUPLED RECEPTORS; X-RAY CRYSTALLOGRAPHY; FUNCTIONAL SELECTIVITY; MOLECULAR-DYNAMICS; ASSISTED PSYCHOTHERAPY; BETA(2) ADRENOCEPTOR; ATOMIC CHARGES; BINDING AB The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR-a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD's slow binding kinetics may be due to a "lid'' formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD's binding kinetics and selectively dampens LSD-mediated beta-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD's actions at human serotonin receptors. C1 [Wacker, Daniel; Wang, Sheng; McCorvy, John D.; Lansu, Katherine; Schools, Zachary L.; Che, Tao; Roth, Bryan L.] Univ North Carolina Chapel Hill, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Betz, Robin M.; Venkatakrishnan, A. J.; Dror, Ron O.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Betz, Robin M.; Venkatakrishnan, A. J.; Dror, Ron O.] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. [Betz, Robin M.; Venkatakrishnan, A. J.; Dror, Ron O.] Stanford Univ, Inst Computat & Math Engn, Stanford, CA 94305 USA. [Betz, Robin M.; Dror, Ron O.] Stanford Univ, Biophys Program, Stanford, CA 94305 USA. [Levit, Anat; Shoichet, Brian K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. [Nichols, David E.; Roth, Bryan L.] Univ North Carolina Chapel Hill, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ North Carolina Chapel Hill, Sch Med, NIMH, PDSP, Chapel Hill, NC 27599 USA. RP Wacker, D; Roth, BL (reprint author), Univ North Carolina Chapel Hill, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA.; Dror, RO (reprint author), Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA.; Dror, RO (reprint author), Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.; Dror, RO (reprint author), Stanford Univ, Inst Computat & Math Engn, Stanford, CA 94305 USA.; Dror, RO (reprint author), Stanford Univ, Biophys Program, Stanford, CA 94305 USA.; Roth, BL (reprint author), Univ North Carolina Chapel Hill, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA.; Roth, BL (reprint author), Univ North Carolina Chapel Hill, Sch Med, NIMH, PDSP, Chapel Hill, NC 27599 USA. EM dwacker@email.unc.edu; ron.dror@stanford.edu; bryan_roth@med.unc.edu FU NIH [RO1MH61887, U19MH82441]; NIMH Psychoactive Drug Screening Program Contract [GM59957]; Terman Faculty Fellowship; Michael Hooker Distinguished Chair of Pharmacology; National Cancer Institute [P30CA016086]; federal funds from the National Cancer Institute [ACB-12002]; National Institute of General Medical Sciences [AGM-12006]; DOE Office of Science [DE-AC02-06CH11357] FX This work was supported by NIH grants RO1MH61887 and U19MH82441, the NIMH Psychoactive Drug Screening Program Contract (all to B.L.R.), GM59957 (to B.K.S.), a Terman Faculty Fellowship (R.O.D.), and the Michael Hooker Distinguished Chair of Pharmacology (B.L.R.). The CRISPR-generated knockout HEK293 cells were a generous gift from A. Inoue (Tohoku University). We also gratefully acknowledge J. Sondek and S. Endo-Streeter for providing independent structure quality control analysis; M.J. Miley and the UNC macromolecular crystallization core for advice and use of their equipment for crystal harvesting and transport, which is supported by the National Cancer Institute under award number P30CA016086; J. Smith, R. Fischetti, and the staff of GM/CA@APS, which has been funded with federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. NR 87 TC 1 Z9 1 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JAN 26 PY 2017 VL 168 IS 3 BP 377 EP + DI 10.1016/j.cell.2016.12.033 PG 25 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN8KP UT WOS:000396249600008 PM 28129538 ER PT J AU Martin, PL Yin, JJ Seng, V Casey, O Corey, E Morrissey, C Simpson, RM Kelly, K AF Martin, P. L. Yin, J-J Seng, V. Casey, O. Corey, E. Morrissey, C. Simpson, R. M. Kelly, K. TI Androgen deprivation leads to increased carbohydrate metabolism and hexokinase 2-mediated survival in Pten/Tp53-deficient prostate cancer SO ONCOGENE LA English DT Article ID MITOCHONDRIAL HEXOKINASES; MASS-SPECTROMETRY; PTEN; APOPTOSIS; GROWTH; AKT; MECHANISMS; RESISTANCE; TRANSITION; DELETION AB Prostate cancer is characterized by a dependence upon androgen receptor (AR) signaling, and androgen deprivation therapy (ADT) is the accepted treatment for progressive prostate cancer. Although ADT is usually initially effective, acquired resistance termed castrate-resistant prostate cancer (CRPC) develops. PTEN and TP53 are two of the most commonly deleted or mutated genes in prostate cancer, the compound loss of which is enriched in CRPC. To interrogate the metabolic alterations associated with survival following ADT, we used an orthotopic model of Pten/Tp53 null prostate cancer. Metabolite profiles and associated regulators were compared in tumors from androgen-intact mice and in tumors surviving castration. AR inhibition led to changes in the levels of glycolysis and tricarboxylic acid (TCA) cycle pathway intermediates. As anticipated for inhibitory reciprocal feedback between AR and PI3K/AKT signaling pathways, pAKT levels were increased in androgen-deprived tumors. Elevated mitochondrial hexokinase 2 (HK2) levels and enzyme activities also were observed in androgen-deprived tumors, consistent with pAKT-dependent HK2 protein induction and mitochondrial association. Competitive inhibition of HK2-mitochondrial binding in prostate cancer cells led to decreased viability. These data argue for AKT-associated HK2-mediated metabolic reprogramming and mitochondrial association in PI3K-driven prostate cancer as one survival mechanism downstream of AR inhibition. C1 [Martin, P. L.; Yin, J-J; Seng, V.; Casey, O.; Kelly, K.] NCI, Lab Genitourinary Canc Pathogenesis, Ctr Canc Res, NIH, Bldg 37,Room 1068 A, Bethesda, MD 20892 USA. [Corey, E.; Morrissey, C.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Simpson, R. M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Martin, P. L.] Medimmune, Gaithersburg, MD USA. RP Kelly, K (reprint author), NCI, Lab Genitourinary Canc Pathogenesis, Ctr Canc Res, NIH, Bldg 37,Room 1068 A, Bethesda, MD 20892 USA. EM kellyka@mail.nih.gov FU Intramural Research Program; Center for Cancer Research; NCI; Pacific Northwest Prostate Cancer SPORE [P50CA97186]; PO1 NIH [PO1CA085859]; Richard M. LUCAS Foundation FX We appreciated the patients and their families who participated in the Prostate Cancer Donor Program. We thank the investigators Drs Robert Vessella, Celestia Higano, Bruce Montgomery, Evan Yu, Peter Nelson, Paul Lange, Martine Roudier and Lawrence True for their contributions to the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Program. This research was supported by the Intramural Research Program, Center for Cancer Research, NCI and by the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grant (PO1CA085859) and the Richard M. LUCAS Foundation. NR 52 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JAN 26 PY 2017 VL 36 IS 4 BP 525 EP 533 DI 10.1038/onc.2016.223 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA EK8II UT WOS:000394166700009 PM 27375016 ER PT J AU Greer, YE Gao, B Yang, YZ Nussenzweig, A Rubin, JS AF Greer, Yoshimi Endo Gao, Bo Yang, Yingzi Nussenzweig, Andre Rubin, Jeffrey S. TI Lack of Casein Kinase 1 Delta Promotes Genomic Instability - The Accumulation of DNA Damage and Down-Regulation of Checkpoint Kinase 1 SO PLOS ONE LA English DT Article ID MITOTIC SPINDLE FORMATION; BARDET-BIEDL SYNDROME; CELL-CYCLE ARREST; PROTEIN-KINASE; REPLICATION STRESS; BUDDING YEAST; PHOSPHORYLATION; CHK1; CANCER; ACTIVATION AB Casein kinase 1 delta (CK1 delta) is a conserved serine/threonine protein kinase that regulates diverse cellular processes. Mice lacking CK1 delta have a perinatal lethal phenotype and typically weigh 30% less than their wild type littermates. However, the causes of death and small size are unknown. We observed cells with abnormally large nuclei in tissue from Csnk1d null embryos, and multiple centrosomes in mouse embryo fibroblasts (MEFs) deficient in CK1 delta (MEFCsnk1d null). Results from gamma-H2AX staining and the comet assay demonstrated significant DNA damage in MEFCsnk1d null cells. These cells often contain micronuclei, an indicator of genomic instability. Similarly, abrogation of CK1 delta expression in control MEFs stimulated micronuclei formation after doxorubicin treatment, suggesting that CK1 delta loss increases vulnerability to genotoxic stress. Cellular levels of total and activated checkpoint kinase 1 (Chk1), which functions in the DNA damage response and mitotic checkpoints, and its downstream effector, Cdc2/CDK1 kinase, were often decreased in MEFCsnk1d null cells as well as in control MEFs transfected with CK1 delta siRNA. Hydroxyureainduced Chk1 activation, as measured by Ser345 phosphorylation, and nuclear localization also were impaired in MEF cells following siRNA knockdown of CK1 delta. Similar results were observed in the MCF7 human breast cancer cell line. The decreases in phosphorylated Chk1 were rescued by concomitant expression of siRNA-resistant CK1 delta. Experiments with cycloheximide demonstrated that the stability of Chk1 protein was diminished in cells subjected to CK1 delta knockdown. Together, these findings suggest that CK1 delta contributes to the efficient repair of DNA damage and the proper functioning of mitotic checkpoints by maintaining appropriate levels of Chk1. C1 [Greer, Yoshimi Endo; Rubin, Jeffrey S.] NCI, Cellular & Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. [Greer, Yoshimi Endo] NCI, Womens Malignancies Branch, Bethesda, MD 20892 USA. [Gao, Bo; Yang, Yingzi] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Nussenzweig, Andre] NCI, Lab Genome Integr, Bethesda, MD 20892 USA. [Gao, Bo] Univ Hong Kong, Li Ka Shing Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Yang, Yingzi] Harvard Sch Dent Med, Dept Dev Biol, Boston, MA USA. RP Greer, YE; Rubin, JS (reprint author), NCI, Cellular & Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA.; Greer, YE (reprint author), NCI, Womens Malignancies Branch, Bethesda, MD 20892 USA. EM greery@mail.nih.gov; jeff535@verizon.net FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. It paid the salaries of YEG, AN and JSR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 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 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 26 PY 2017 VL 12 IS 1 AR e0170903 DI 10.1371/journal.pone.0170903 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN7IT UT WOS:000396176100027 PM 28125685 ER PT J AU Gong, YH Zhu, YZ Zou, Y Ma, BY Nussinov, R Zhang, QW AF Gong, Yehong Zhu, Yuzhen Zou, Yu Ma, Buyong Nussinov, Ruth Zhang, Qingwen TI Human Neuronal Calcium Sensor-1 Protein Avoids Histidine Residues To Decrease pH Sensitivity SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID BURIED SALT BRIDGES; SWISS-MODEL; SYNAPTIC-TRANSMISSION; BINDING PROTEINS; WATER MODELS; STABILITY; FREQUENIN; MECHANISM; RECEPTOR; NETWORKS AB pH is highly regulated in mammalian central nervous systems. Neuronal calcium sensor-1 (NCS-1) can interact with numerous target proteins. Compared to that in the NCS-1 protein of Caenorhabditis elegans, evolution has avoided the placement of histidine residues at positions 102 and 83 in the NCS-1 protein of humans and Xenopus laevis, possibly to decrease the conformational sensitivity to pH gradients in synaptic processes. We used all-atom molecular dynamics simulations to investigate the effects of amino acid substitutions between species on human NCS-1 by substituting Arg102 and Ser83 for histidine at neutral (R102H and S83H) and acidic pHs (R102H(p) and S83H(p)). Our cumulative 5 mu s simulations revealed that the R102H mutation slightly increases the structural flexibility of loop L2 and the R102H(p) Mutation decreases protein stability. Community network analysis illustrates that the R102H and S83H mutations weaken the interdomain and strengthen the intradomain communications Secondary structure contents in the S83H and S83H(p) mutants are similar to those in the wild type, whereas the global structural stabilities and salt-bridge probabilities decrease. This study highlights the conformational dynamics effects of the R102H and S83H mutations on the local structural flexibility and global stability of NCS-1, whereas protonated histidine decreases the stability of NCS-1. Thus, histidines at positions 102 and 83 may not be compatible with the function of NCS-1 whether in the neutral or protonated state. C1 [Gong, Yehong; Zou, Yu; Zhang, Qingwen] Shanghai Univ Sport, Coll Phys Educ & Training, 399 Chang Hai Rd, Shanghai 200438, Peoples R China. [Zhu, Yuzhen] Shanghai Normal Univ, Coll Phys Educ, 100 Gui Lin Rd, Shanghai 200234, Peoples R China. [Ma, Buyong; Nussinov, Ruth] NCI, Leidos Biomed Res Inc, Canc & Inflammat Program, Basic Sci Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Zhang, QW (reprint author), Shanghai Univ Sport, Coll Phys Educ & Training, 399 Chang Hai Rd, Shanghai 200438, Peoples R China. EM zqw@sus.edu.cn OI Ma, Buyong/0000-0002-7383-719X; Zhang, Qingwen/0000-0002-8885-1066 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Chendi Zhan for helpful discussion. Simulations were performed at the High Performance Computing Server (PowerEdge T710) of Shanghai University of Sport. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 66 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JAN 26 PY 2017 VL 121 IS 3 BP 508 EP 517 DI 10.1021/acs.jpcb.6b11094 PG 10 WC Chemistry, Physical SC Chemistry GA EJ1ZK UT WOS:000393009100007 PM 28030949 ER PT J AU Horstick, EJ Bayleyen, Y Sinclair, JL Burgess, HA AF Horstick, Eric J. Bayleyen, Yared Sinclair, Jennifer L. Burgess, Harold A. TI Search strategy is regulated by somatostatin signaling and deep brain photoreceptors in zebrafish SO BMC BIOLOGY LA English DT Article DE Zebrafish; Search; Motivation; Goal-directed behavior; Non-visual photoreceptor; CRISPR; Orthopedia; Somatostatin; sst1.1; Melanopsin; opn4a ID AREA-RESTRICTED SEARCH; LARVAL ZEBRAFISH; CAENORHABDITIS-ELEGANS; LOCAL SEARCH; SYSTEMATIC SEARCH; PREY CAPTURE; DESERT ANTS; BEHAVIOR; NEURONS; LIGHT AB Background: Animals use sensory cues to efficiently locate resources, but when sensory information is insufficient, they may rely on internally coded search strategies. Despite the importance of search behavior, there is limited understanding of the underlying neural mechanisms in vertebrates. Results: Here, we report that loss of illumination initiates sophisticated light-search behavior in larval zebrafish. Using three-dimensional tracking, we show that at the onset of darkness larvae swim in a helical trajectory that is spatially restricted in the horizontal plane, before gradually transitioning to an outward movement profile. Local and outward swim patterns display characteristic features of area-restricted and roaming search strategies, differentially enhancing phototaxis to nearby and remote sources of light. Retinal signaling is only required to initiate area-restricted search, implying that photoreceptors within the brain drive the transition to the roaming search state. Supporting this, orthopediaA mutant larvae manifest impaired transition to roaming search, a phenotype which is recapitulated by loss of the non-visual opsin opn4a and somatostatin signaling. Conclusion: These findings define distinct neuronal pathways for area-restricted and roaming search behaviors and clarify how internal drives promote goal-directed activity. C1 [Horstick, Eric J.; Bayleyen, Yared; Sinclair, Jennifer L.; Burgess, Harold A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, Bethesda, MD 20892 USA. RP Horstick, EJ; Burgess, HA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, Bethesda, MD 20892 USA. EM eric.horstick@nih.gov; burgessha@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 70 TC 0 Z9 0 U1 7 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD JAN 26 PY 2017 VL 15 AR 4 DI 10.1186/s12915-016-0346-2 PG 16 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EJ1HW UT WOS:000392962100002 PM 28122559 ER PT J AU Michino, M Boateng, CA Donthamsetti, P Yano, H Bakare, OM Bonifazi, A Ellenberger, MP Keck, TM Kumar, V Zhu, C Verma, R Deschamps, JR Javitch, JA Newman, AH Shi, L AF Michino, Mayako Boateng, Comfort A. Donthamsetti, Prashant Yano, Hideaki Bakare, Oluyomi M. Bonifazi, Alessandro Ellenberger, Michael P. Keck, Thomas M. Kumar, Vivek Zhu, Clare Verma, Ravi Deschamps, Jeffrey R. Javitch, Jonathan A. Newman, Amy Hauck Shi, Lei TI Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D-3 Receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; FUNCTIONALIZED LINKING CHAINS; D3 RECEPTOR; FORCE-FIELD; HIGH-AFFINITY; CRYSTAL-STRUCTURE; COCAINE-SEEKING; LIGANDS; ANTAGONISTS; DESIGN AB Both dopamine D-3 receptor (D3R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (R)-enantiomers are antagonists/weak partial agonists, whereas the (S)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond-scale molecular dynamics simulations starting from the inactive state of D3R in complex with these enantiomers. Analysis of the simulation results reveals common structural rearrangements near the ligand binding site induced by the bound (S)-enantiomers, but not by the (R)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agonists may be useful for structure-based design of compounds with tailored efficacy profiles. C1 [Michino, Mayako; Yano, Hideaki; Zhu, Clare; Verma, Ravi; Shi, Lei] Natl Inst Drug Abuse, Computat Chem & Mol Biophys Unit, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. [Boateng, Comfort A.; Bakare, Oluyomi M.; Bonifazi, Alessandro; Ellenberger, Michael P.; Keck, Thomas M.; Kumar, Vivek; Newman, Amy Hauck] Natl Inst Drug Abuse, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. [Keck, Thomas M.] Rowan Univ, Coll Sci & Math, Dept Chem & Biochem, 201 Mullica Hill Rd, Glassboro, NJ 08028 USA. [Keck, Thomas M.] Rowan Univ, Coll Sci & Math, Dept Biomed & Translat Sci, 201 Mullica Hill Rd, Glassboro, NJ 08028 USA. [Donthamsetti, Prashant; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Psychiat, 722 W 168th St, New York, NY 10032 USA. [Donthamsetti, Prashant; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Pharmacol, 722 W 168th St, New York, NY 10032 USA. [Donthamsetti, Prashant; Javitch, Jonathan A.] New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USA. [Deschamps, Jeffrey R.] Naval Res Lab, Code 6930,4555 Overlook Ave, Washington, DC 20375 USA. [Boateng, Comfort A.] High Point Univ, Fred Wilson Sch Pharm, Dept Basic Pharmaceut Sci, One Univ Pkwy, High Point, NC 27268 USA. RP Shi, L (reprint author), Natl Inst Drug Abuse, Computat Chem & Mol Biophys Unit, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA.; Newman, AH (reprint author), Natl Inst Drug Abuse, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov; lei.shi2@nih.gov OI Keck, Thomas M./0000-0003-1845-9373 FU National Institute on Drug Abuse-Intramural Research Program; NLDA through Interagency Agreement [ADA 12003-005]; Naval Research Laboratory; [DA022413]; [MH054137] FX Support for this research was provided to M.M., C.A.B., H.Y., O.M.B., A.B., M.P.E., T.M.K, V.K., C.Z., R.V., A.H.N., and L.S. by the National Institute on Drug Abuse-Intramural Research Program. P.D. and J.A.J. are supported by Grants DA022413 and MH054137. The X-ray crystallographic work was supported by NLDA through Interagency Agreement ADA 12003-005 with the Naval Research Laboratory (J.R.D.). We acknowledge Caitlin Burzynski and Catherine Schweppe for their technical assistance with the binding assays and Ara Abramyan for assistance with analyzing the MD simulation data. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 53 TC 0 Z9 0 U1 5 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JAN 26 PY 2017 VL 60 IS 2 BP 580 EP 593 DI 10.1021/acs.jmedchem.6b01148 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EJ1ZO UT WOS:000393009500004 PM 27983845 ER PT J AU Moler, FW Silverstein, FS Holubkov, R Slomine, BS Christensen, JR Nadkarni, VM Meert, KL Browning, B Pemberton, VL Page, K Gildea, MR Scholefield, BR Shankaran, S Hutchison, JS Berger, JT Ofori-Amanfo, G Newth, CJL Topjian, A Bennett, KS Koch, JD Pham, N Chanani, NK Pineda, JA Harrison, R Dalton, HJ Alten, J Schleien, CL Goodman, DM Zimmerman, JJ Bhalala, US Schwarz, AJ Porter, MB Shah, S Fink, EL McQuillen, P Wu, T Skellett, S Thomas, NJ Nowak, JE Baines, PB Pappachan, J Mathur, M Lloyd, E van der Jagt, EW Dobyns, EL Meyer, MT Sanders, RC Clark, AE Dean, JM AF Moler, F. W. Silverstein, F. S. Holubkov, R. Slomine, B. S. Christensen, J. R. Nadkarni, V. M. Meert, K. L. Browning, B. Pemberton, V. L. Page, K. Gildea, M. R. Scholefield, B. R. Shankaran, S. Hutchison, J. S. Berger, J. T. Ofori-Amanfo, G. Newth, C. J. L. Topjian, A. Bennett, K. S. Koch, J. D. Pham, N. Chanani, N. K. Pineda, J. A. Harrison, R. Dalton, H. J. Alten, J. Schleien, C. L. Goodman, D. M. Zimmerman, J. J. Bhalala, U. S. Schwarz, A. J. Porter, M. B. Shah, S. Fink, E. L. McQuillen, P. Wu, T. Skellett, S. Thomas, N. J. Nowak, J. E. Baines, P. B. Pappachan, J. Mathur, M. Lloyd, E. van der Jagt, E. W. Dobyns, E. L. Meyer, M. T. Sanders, R. C., Jr. Clark, A. E. Dean, J. M. CA THAPCA Trial Investigators TI Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HYPOXIC-ISCHEMIC ENCEPHALOPATHY; EMERGENCY CARDIOVASCULAR CARE; RANDOMIZED-CONTROLLED-TRIAL; AMERICAN-HEART-ASSOCIATION; PEDIATRIC INTENSIVE-CARE; TRAUMATIC BRAIN-INJURY; WHOLE-BODY HYPOTHERMIA; CARDIOPULMONARY-RESUSCITATION; INTERCENTER VARIANCE; MULTICENTER COHORT AB BACKGROUND Targeted temperature management is recommended for comatose adults and children after out-of-hospital cardiac arrest; however, data on temperature management after in-hospital cardiac arrest are limited. METHODS In a trial conducted at 37 children's hospitals, we compared two temperature interventions in children who had had in-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0 degrees C) or therapeutic normothermia (target temperature, 36.8 degrees C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS-II score of at least 70 before the cardiac arrest. RESULTS The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS-II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P=0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS-II score from baseline to 12 months did not differ significantly between the groups (P = 0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did not differ significantly between the hypothermia group and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P = 0.56). The incidences of blood-product use, infection, and serious adverse events, as well as 28-day mortality, did not differ significantly between groups. CONCLUSIONS Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087.) C1 [Moler, F. W.; Silverstein, F. S.] Univ Michigan, Ann Arbor, MI 48109 USA. [Meert, K. L.; Shankaran, S.] Wayne State Univ, Detroit, MI USA. [Holubkov, R.; Browning, B.; Page, K.; Gildea, M. R.; Bennett, K. S.; Clark, A. E.; Dean, J. M.] Univ Utah, Salt Lake City, UT USA. [Slomine, B. S.; Christensen, J. R.] Kennedy Krieger Inst, Baltimore, MD USA. [Slomine, B. S.; Christensen, J. R.] Johns Hopkins Univ, Baltimore, MD USA. [Bhalala, U. S.] Johns Hopkins Childrens Ctr, Baltimore, MD USA. [Pemberton, V. L.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Nadkarni, V. M.; Topjian, A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Fink, E. L.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Thomas, N. J.] Penn State Childrens Hosp, Hershey, PA USA. [Scholefield, B. R.] Birmingham Childrens Hosp, Birmingham, W Midlands, England. [Skellett, S.] Great Ormond St Hosp Sick Children, London, England. [Baines, P. B.] Alder Hey Childrens Hosp, Liverpool, Merseyside, England. [Pappachan, J.] Southampton Univ Hosp, Southampton, Hants, England. [Hutchison, J. S.] Hosp Sick Children, Toronto, ON, Canada. [Berger, J. T.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Ofori-Amanfo, G.] Duke Childrens Hosp, Durham, NC USA. [Newth, C. J. L.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Harrison, R.] Univ Calif Los Angeles, Mattel Childrens Hosp, Los Angeles, CA USA. [Schwarz, A. J.] Childrens Hosp Orange Cty, Orange, CA 92668 USA. [McQuillen, P.] Univ Calif San Francisco, Benioff Childrens Hosp, San Francisco, CA 94143 USA. [Mathur, M.] Loma Linda Univ, Childrens Hosp, Loma Linda, CA 92350 USA. [Koch, J. D.] Univ Texas Southwestern Med Sch, Childrens Med Ctr Dallas, Dallas, TX USA. [Wu, T.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Pham, N.; Chanani, N. K.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Pineda, J. A.] Washington Univ, St Louis, MO USA. [Dalton, H. J.] Phoenix Childrens Hosp, Phoenix, AZ USA. [Alten, J.] Childrens Hosp Alabama, Birmingham, AL USA. [Schleien, C. L.] Columbia Univ, Childrens Hosp New York, Med Ctr, New York, NY USA. [van der Jagt, E. W.] Univ Rochester, Med Ctr, Golisano Childrens Hosp, Rochester, NY 14642 USA. [Goodman, D. M.] Robert Lurie Childrens Hosp Chicago, Chicago, IL USA. [Zimmerman, J. J.] Seattle Childrens Hosp, Seattle, WA USA. [Porter, M. B.] Univ Louisville, Kosair Childrens Hosp, Louisville, KY 40292 USA. [Shah, S.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Nowak, J. E.] Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. [Lloyd, E.] Nationwide Childrens Hosp, Columbus, OH USA. [Dobyns, E. L.] Childrens Hosp Colorado, Aurora, CO USA. [Meyer, M. T.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Sanders, R. C., Jr.] Arkansas Childrens Hosp, 800 Marshall St, Little Rock, AR 72202 USA. RP Moler, FW (reprint author), Univ Michigan Hlth Syst, F-6900 UH S,SPF 5243,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM fmoler@umich.edu FU National Heart, Lung, and Blood Institute [HL094345, HL094339]; THAPCA trials [HD044955, HD050531]; Pediatric Emergency Care Applied Research Network [U03MC00001, U03MC00003, U03MC00006, U03MC00007, U03MC00008]; Collaborative Pediatric Critical Care Research Network [U10HD500009, U10HD050096, U10HD049981, U10HD049945, U10HD049983, U10HD050012, U01HD049934]; National Emergency Medical Services for Children Data Analysis Resource Center Demonstration grant [U07MC09174]; [UL1RR024986]; [UL1TR000433]; [U54HD087011]; [UL1TR000003]; [P30HD040677] FX Supported by grants from the National Heart, Lung, and Blood Institute (HL094345, to Dr. Moler; and HL094339, to Dr. Dean), federal planning grants for the planning of the THAPCA trials (HD044955 and HD050531, both to Dr. Moler), cooperative agreements from the Pediatric Emergency Care Applied Research Network (U03MC00001, U03MC00003, U03MC00006, U03MC00007, and U03MC00008) and the Collaborative Pediatric Critical Care Research Network (U10HD500009, U10HD050096, U10HD049981, U10HD049945, U10HD049983, U10HD050012 and U01HD049934), and a National Emergency Medical Services for Children Data Analysis Resource Center Demonstration grant (U07MC09174). Several centers were supported by supplemental grants or cooperative agreements (UL1RR024986, UL1TR000433, U54HD087011, UL1TR000003, and P30HD040677). NR 40 TC 0 Z9 0 U1 4 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 26 PY 2017 VL 376 IS 4 BP 318 EP 329 DI 10.1056/NEJMoa1610493 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EJ3KR UT WOS:000393111600007 PM 28118559 ER PT J AU Regules, JA Beigel, JH Paolino, KM Voell, J Castellano, AR Hu, Z Munoz, P Moon, JE Ruck, RC Bennett, JW Twomey, PS Gutierrez, RL Remich, SA Hack, HR Wisniewski, ML Josleyn, MD Kwilas, SA Van Deusen, N Mbaya, OT Zhou, Y Stanley, DA Jing, W Smith, KS Shi, M Ledgerwood, JE Graham, BS Sullivan, NJ Jagodzinski, LL Peel, SA Alimonti, JB Hooper, JW Silvera, PM Martin, BK Monath, TP Ramsey, WJ Link, CJ Lane, HC Michael, NL Davey, RT Thomas, SJ AF Regules, J. A. Beigel, J. H. Paolino, K. M. Voell, J. Castellano, A. R. Hu, Z. Munoz, P. Moon, J. E. Ruck, R. C. Bennett, J. W. Twomey, P. S. Gutierrez, R. L. Remich, S. A. Hack, H. R. Wisniewski, M. L. Josleyn, M. D. Kwilas, S. A. Van Deusen, N. Mbaya, O. T. Zhou, Y. Stanley, D. A. Jing, W. Smith, K. S. Shi, M. Ledgerwood, J. E. Graham, B. S. Sullivan, N. J. Jagodzinski, L. L. Peel, S. A. Alimonti, J. B. Hooper, J. W. Silvera, P. M. Martin, B. K. Monath, T. P. Ramsey, W. J. Link, C. J. Lane, H. C. Michael, N. L. Davey, R. T., Jr. Thomas, S. J. CA rVSV G-ZEBOV-GP Study Grp TI A Recombinant Vesicular Stomatitis Virus Ebola Vaccine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NONHUMAN-PRIMATES; MARBURG VIRUSES; VECTORS; PROTECTION; NEUROVIRULENCE; GLYCOPROTEINS; IMMUNIZATION; CHALLENGE AB BACKGROUND The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD. METHODS We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed. RESULTS The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months. CONCLUSIONS This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses. (Funded by the National Institutes of Health and others; rVSV Delta G-ZEBOV-GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408.) C1 [Regules, J. A.; Paolino, K. M.; Castellano, A. R.; Moon, J. E.; Ruck, R. C.; Bennett, J. W.; Twomey, P. S.; Remich, S. A.; Hack, H. R.; Shi, M.; Jagodzinski, L. L.; Peel, S. A.; Michael, N. L.; Thomas, S. J.] Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. [Gutierrez, R. L.] Naval Med Res Ctr, Silver Spring, MD USA. [Beigel, J. H.; Jing, W.] Frederick Natl Lab Canc Res, Leidos Biomed Res, Frederick, MD USA. [Wisniewski, M. L.; Josleyn, M. D.; Kwilas, S. A.; Van Deusen, N.; Smith, K. S.; Hooper, J. W.; Silvera, P. M.] US Army Med Res Inst Infect Dis, Frederick, MD USA. [Voell, J.; Hu, Z.; Munoz, P.; Lane, H. C.; Davey, R. T., Jr.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mbaya, O. T.; Zhou, Y.; Stanley, D. A.; Ledgerwood, J. E.; Graham, B. S.; Sullivan, N. J.] NIAID, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Alimonti, J. B.] Publ Hlth Agcy Canada, Ottawa, ON, Canada. [Martin, B. K.; Monath, T. P.; Ramsey, W. J.; Link, C. J.] BioProtect Syst NewLink Genet, Ames, IA USA. RP Regules, JA (reprint author), Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. EM jason.a.regules.mil@mail.mil FU Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, NIH; National Cancer Institute, NIH [HHSN261200800001E]; Defense Threat Reduction Agency; Joint Vaccine Acquisition Program FX Supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, NIH; the National Cancer Institute, NIH (contract no. HHSN261200800001E); the Defense Threat Reduction Agency; and the Joint Vaccine Acquisition Program. NR 27 TC 4 Z9 4 U1 8 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 26 PY 2017 VL 376 IS 4 BP 330 EP 341 DI 10.1056/NEJMoa1414216 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EJ3KR UT WOS:000393111600008 PM 25830322 ER PT J AU Kasza, KA Ambrose, BK Conway, KP Borek, N Taylor, K Goniewicz, ML Cummings, KM Sharma, E Pearson, JL Green, VR Kaufman, AR Bansal-Travers, M Travers, MJ Kwan, J Tworek, C Cheng, YC Yang, L Pharris-Ciurej, N van Bemmel, DM Backinger, CL Compton, WM Hyland, AJ AF Kasza, Karin A. Ambrose, Bridget K. Conway, Kevin P. Borek, Nicolette Taylor, Kristie Goniewicz, Maciej L. Cummings, K. Michael Sharma, Eva Pearson, Jennifer L. Green, Victoria R. Kaufman, Annette R. Bansal-Travers, Maansi Travers, Mark J. Kwan, Jonathan Tworek, Cindy Cheng, Yu-Ching Yang, Ling Pharris-Ciurej, Nikolas van Bemmel, Dana M. Backinger, Cathy L. Compton, Wilson M. Hyland, Andrew J. TI Tobacco-Product Use by Adults and Youths in the United States in 2013 and 2014 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CIGARETTE SMOKERS; ELECTRONIC CIGARETTES; SMOKELESS TOBACCO; POLYTOBACCO USE; TRENDS; PREVALENCE; CIGARILLO; AWARENESS; SMOKING; SNUS AB BACKGROUND Noncigarette tobacco products are evolving rapidly, with increasing popularity in the United States. METHODS We present prevalence estimates for 12 types of tobacco products, using data from 45,971 adult and youth participants (>= 12 years of age) from Wave 1 (September 2013 through December 2014) of the Population Assessment of Tobacco and Health (PATH) Study, a large, nationally representative, longitudinal study of tobacco use and health in the United States. Participants were asked about their use of cigarettes, e-cigarettes, traditional cigars, cigarillos, filtered cigars, pipe tobacco, hookah, snus pouches, other smokeless tobacco, dissolvable tobacco, bidis, and kreteks. Estimates of the prevalence of use for each product were determined according to use category (e.g., current use or use in the previous 30 days) and demographic subgroup, and the prevalence of multiple-product use was explored. RESULTS More than a quarter (27.6%) of adults were current users of at least one type of tobacco product in 2013 and 2014, although the prevalence varied depending on use category. A total of 8.9% of youths had used a tobacco product in the previous 30 days; 1.6% of youths were daily users. Approximately 40% of tobacco users, adults and youths alike, used multiple tobacco products; cigarettes plus e-cigarettes was the most common combination. Young adults (18 to 24 years of age), male adults and youths, members of racial minorities, and members of sexual minorities generally had higher use of tobacco than their counterparts. CONCLUSIONS During this study, 28% of U.S. adults were current users of tobacco, and 9% of youths had used tobacco in the previous 30 days. Use of multiple products was common among tobacco users. These findings will serve as baseline data to examine between-person differences and within-person changes over time in the use of tobacco products. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration.) C1 [Kasza, Karin A.; Goniewicz, Maciej L.; Bansal-Travers, Maansi; Travers, Mark J.; Hyland, Andrew J.] Roswell Pk Canc Inst, Dept Hlth Behav, Elm & Carlton Sts, Buffalo, NY 14263 USA. [Ambrose, Bridget K.; Borek, Nicolette; Kwan, Jonathan; Tworek, Cindy; Cheng, Yu-Ching; Yang, Ling; Pharris-Ciurej, Nikolas; van Bemmel, Dana M.; Backinger, Cathy L.] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD USA. [Conway, Kevin P.; Green, Victoria R.; Compton, Wilson M.] NIDA, NIH, Bethesda, MD 20892 USA. [Kaufman, Annette R.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Taylor, Kristie; Sharma, Eva] Westat Corp, Rockville, MD USA. [Green, Victoria R.] Kelly Govt Solut, Rockville, MD USA. [Cummings, K. Michael] Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. [Pearson, Jennifer L.] Truth Initiat, Schroeder Inst Tobacco Res & Policy Studies, Washington, DC USA. RP Kasza, KA (reprint author), Roswell Pk Canc Inst, Dept Hlth Behav, Elm & Carlton Sts, Buffalo, NY 14263 USA. EM karin.kasza@roswellpark.org FU National Institute on Drug Abuse, National Institutes of Health; Food and Drug Administration, Department of Health and Human Services [HHSN271201100027C]; Pfizer FX Supported by federal funds from the National Institute on Drug Abuse, National Institutes of Health, and the Food and Drug Administration, Department of Health and Human Services, under a contract (Contract No. HHSN271201100027C) to Westat.; Dr. Cummings reports receiving grant support from Pfizer and fees as a paid expert witness in litigation filed against the tobacco industry; Dr. Goniewicz, receiving fees for serving on an advisory board from Johnson & Johnson and grant support from Pfizer; and Dr. Compton, holding stock in General Electric, the 3M Companies, and Pfizer. No other potential conflict of interest relevant to this article was reported. NR 38 TC 0 Z9 0 U1 3 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 26 PY 2017 VL 376 IS 4 BP 342 EP 353 DI 10.1056/NEJMsa1607538 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EJ3KR UT WOS:000393111600009 PM 28121512 ER PT J AU Zarin, DA Tse, T Williams, RJ Rajakannan, T AF Zarin, Deborah A. Tse, Tony Williams, Rebecca J. Rajakannan, Thiyagu TI Update on Trial Registration 11 Years after the ICMJE Policy Was Established SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIALS; PUBLISHED PRIMARY OUTCOMES; CLINICAL-TRIALS; PUBLICATION BIAS; JOURNAL EDITORS; TRANSPARENCY; STATEMENT; EFFICACY; PROTOCOL; TRUST C1 [Zarin, Deborah A.; Tse, Tony; Williams, Rebecca J.; Rajakannan, Thiyagu] NIH, Natl Lib Med, US Dept HHS, Bldg 10, Bethesda, MD 20892 USA. RP Zarin, DA (reprint author), NIH, Natl Lib Med, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM dzarin@mail.nih.gov OI Tse, Tony/0000-0002-9906-6864 FU Intramural Research Program of the National Library of Medicine, National Institutes of Health FX Supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. NR 43 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 26 PY 2017 VL 376 IS 4 BP 383 EP 391 DI 10.1056/NEJMsr1601330 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EJ3KR UT WOS:000393111600014 PM 28121511 ER PT J AU Bonini, BB Araya, R Quayle, J Evangelista, MS Price, LN Menezes, PR AF Bonini, B. B. Araya, R. Quayle, J. Silva Evangelista, M. Price, LeS. N. Menezes, P. R. TI LATIN-MH: a model for building research capacity within Latin America SO Global Mental Health LA English DT Article DE Capacity building; Latin America; mental health; LATIN-MH ID GLOBAL MENTAL-HEALTH; DISORDERS AB Background. Latin America Treatment and Innovation Network in Mental Health (LATIN-MH) is a research hub located in Brazil and Peru that conducts a research project to help reduce the treatment gap in mental health in Latin America (LA). Besides its research core, LATIN-MH has a Capacity Building (CB) component that aims to help young researchers receive the specific training to contribute to the growing scientific production in mental health in LA. Methods. LATIN-MH proposal in CB includes a series of actions to prepare professionals in the research area. The main proposals are described here, which include online study groups, promotion of scientific meetings, hands-on training in different levels and sharing of information. Results. LATIN-MH CB activities are at its initial stages but the proposed activities were well evaluated by the participants. The first participating fellows who finished their fellowships are contributing elsewhere in the mental treatment and human resources formation area. Conclusion. The repercussion of LATIN-MH actions in CB and its evaluation, particularly on the formation of human resources and dissemination of information, show that the hub is contributing to the critic formation of young researchers and the circulation of important information. C1 [Bonini, B. B.; Quayle, J.; Silva Evangelista, M.; Menezes, P. R.] Univ Sao Paulo, Fac Med, Dept Prevent Med, BR-01246903 Sao Paulo, Brazil. [Araya, R.] London Sch Hyg & Trop Med, Ctr Global Mental Hlth, London, England. [Price, LeS. N.] NIMH, Dept Hlth & Human Serv, NIH, Washington, DC USA. RP Bonini, BB (reprint author), Univ Sao Paulo, Fac Med, Dept Prevent Med, BR-01246903 Sao Paulo, Brazil. EM barbarabbonini@gmail.com FU National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) [U19MH098780] FX The research reported in this publication is supported by the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) under the Award number U19MH098780. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 18 TC 0 Z9 0 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2054-4251 J9 GLOB MENT HEALTH JI Glob. Ment. Health PD JAN 26 PY 2017 VL 4 AR e2 DI 10.1017/gmh.2016.32 PG 10 WC Psychiatry SC Psychiatry GA EI9KB UT WOS:000392825600001 ER PT J AU Baliga, NS Bjorkegren, JLM Boeke, JD Boutros, M Crawford, NPS Dudley, AM Farber, CR Jones, A Levey, AI Lusis, AJ Mak, HC Nadeau, JH Noyes, MB Petretto, E Seyfried, NT Steinmetz, LM Vonesch, SC AF Baliga, Nitin S. Bjoerkegren, Johan L. M. Boeke, Jef D. Boutros, Michael Crawford, Nigel P. S. Dudley, Aimee M. Farber, Charles R. Jones, Allan Levey, Allan I. Lusis, Aldons J. Mak, H. Craig Nadeau, Joseph H. Noyes, Marcus B. Petretto, Enrico Seyfried, Nicholas T. Steinmetz, Lars M. Vonesch, Sibylle C. TI The State of Systems Genetics in 2017 commentary SO CELL SYSTEMS LA English DT Editorial Material ID NETWORKS; REGULATOR; DISEASE; TRAITS AB Cell Systems invited 16 experts to share their views on the field of systems genetics. In questions repeated in the headings, we asked them to define systems genetics, highlight its relevance to researchers outside the field, discuss what makes a strong systems genetics paper, and paint a picture of where the field is heading in the coming years. Their responses, ordered by the journal but otherwise unedited, make it clear that deciphering genotype to phenotype relationships is a central challenge of systems genetics and will require understanding how networks and higher-order properties of biological systems underlie complex traits. In addition, our experts illuminate the applications and relevance of systems genetics to human disease, the gut microbiome, development of tools that connect the global research community, sustainability, drug discovery, patient-specific disease and network models, and personalized treatments. Finally, a table of suggested reading provides a sample of influential work in the field. C1 [Baliga, Nitin S.] Inst Syst Biol, Seattle, WA USA. [Bjoerkegren, Johan L. M.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA. [Bjoerkegren, Johan L. M.] Karolinska Inst, Dept Med Biochem & Biophys, Vasc Biol Unit, Stockholm, Sweden. [Bjoerkegren, Johan L. M.] Univ Tartu, Inst Biomed & Translat Med, Dept Psychol, Tartu, Estonia. [Boeke, Jef D.; Noyes, Marcus B.] NYU, Langone Med Ctr, Inst Syst Genet, New York, NY USA. [Boutros, Michael] German Canc Res Ctr, Heidelberg, Germany. [Boutros, Michael] Heidelberg Univ, Heidelberg, Germany. [Crawford, Nigel P. S.] Natl Inst Hlth, Bethesda, MD USA. [Dudley, Aimee M.; Nadeau, Joseph H.] Pacific Northwest Res Inst, Seattle, WA USA. [Farber, Charles R.] Univ Virginia, Ctr Publ Hlth Gen, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Farber, Charles R.] Univ Virginia, Ctr Publ Hlth Gen, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. [Jones, Allan; Steinmetz, Lars M.; Vonesch, Sibylle C.] European Mol Biol Lab EMBL, Genome Biol Unit, D-69117 Heidelberg, Germany. [Levey, Allan I.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Lusis, Aldons J.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA USA. [Lusis, Aldons J.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA. [Lusis, Aldons J.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. [Mak, H. Craig] Cell Press, Cell Syst, Cambridge, MA 02139 USA. [Petretto, Enrico] Duke Natl Univ Singapore NUS, Sch Med, Cardiovasc & Metab Disorders Program, Singapore, Singapore. [Petretto, Enrico] Duke Natl Univ Singapore NUS, Sch Med, Ctr Computat Biol, Singapore, Singapore. [Seyfried, Nicholas T.] Emory Univ, Sch Med, Dept Biochem & Neurol, Atlanta, GA 30322 USA. [Steinmetz, Lars M.] Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA. [Steinmetz, Lars M.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. RP Mak, HC (reprint author), Cell Press, Cell Syst, Cambridge, MA 02139 USA. EM cmak@cell.com NR 23 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2405-4712 EI 2405-4720 J9 CELL SYST JI Cell Syst. PD JAN 25 PY 2017 VL 4 IS 1 BP 7 EP 15 DI 10.1016/j.cels.2017.01.005 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN1PV UT WOS:000395783200003 PM 28125793 ER PT J AU Winter, JM Gildea, DE Andreas, JP Gatti, DM Williams, KA Lee, M Hu, Y Zhang, SY Mullikin, JC Wolfsberg, TG McDonnell, SK Fogarty, ZC Larson, MC French, AJ Schaid, DJ Thibodeau, SN Churchill, GA Crawford, NPS AF Winter, Jean M. Gildea, Derek E. Andreas, Jonathan P. Gatti, Daniel M. Williams, Kendra A. Lee, Minnkyong Hu, Ying Zhang, Suiyuan Mullikin, James C. Wolfsberg, Tyra G. McDonnell, Shannon K. Fogarty, Zachary C. Larson, Melissa C. French, Amy J. Schaid, Daniel J. Thibodeau, Stephen N. Churchill, Gary A. Crawford, Nigel P. S. CA NISC Comparative Sequencing Progra TI Mapping Complex Traits in a Diversity Outbred F1 Mouse Population Identifies Germline Modifiers of Metastasis in Human Prostate Cancer SO CELL SYSTEMS LA English DT Article ID GENOME-WIDE ASSOCIATION; INTERNATIONAL CONSORTIUM; GENOTYPE IMPUTATION; SCREENING TRIAL; GENETICS; DISEASE; MICE; ADENOCARCINOMA; SUSCEPTIBILITY; VISUALIZATION AB It is unclear how standing genetic variation affects the prognosis of prostate cancer patients. To provide one controlled answer to this problem, we crossed a dominant, penetrant mouse model of prostate cancer to Diversity Outbred mice, a collection of animals that carries over 40 million SNPs. Integration of disease phenotype and SNP variation data in 493 F1 males identified a metastasis modifier locus on Chromosome 8 (LOD = 8.42); further analysis identified the genes Rwdd4, Cenpu, and Casp3 as functional effectors of this locus. Accordingly, analysis of over 5,300 prostate cancer patient samples revealed correlations between the presence of genetic variants at these loci, their expression levels, cancer aggressiveness, and patient survival. We also observed that ectopic overexpression of RWDD4 and CENPU increased the aggressiveness of two human prostate cancer cell lines. In aggregate, our approach demonstrates how well-characterized genetic variation in mice can be harnessed in conjunction with systems genetics approaches to identify and characterize germline modifiers of human disease processes. C1 [Winter, Jean M.; Andreas, Jonathan P.; Williams, Kendra A.; Lee, Minnkyong; Crawford, Nigel P. S.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Gildea, Derek E.; Zhang, Suiyuan; Wolfsberg, Tyra G.] NHGRI, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. [Gatti, Daniel M.; Churchill, Gary A.] Jackson Lab, Bar Harbor, ME 04609 USA. NCI, Ctr Biomed Informat & Informat Technol, NIH, Rockville, MD 20892 USA. [NISC Comparative Sequencing Progra] NHGRI, Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [McDonnell, Shannon K.; Fogarty, Zachary C.; Larson, Melissa C.; Schaid, Daniel J.] Mayo Clin, Coll Med, Dept Hlth Sci Res, 200 First St SW, Rochester, MN 55905 USA. [French, Amy J.; Thibodeau, Stephen N.] Mayo Clin, Coll Med, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN 55905 USA. RP Crawford, NPS (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM crawforn@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute, NIH [HG200366-05]; NIGMS [R01GM070683]; DOD [W81XWH-11-1-0261]; U.S. Public Health Service, NIH [CA151254, CA157881, CA15083]; [U01 CA 89600 (CA-89600)] FX This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, NIH (HG200366-05). D.M.G. and G.A.C. were funded by NIGMS grant R01GM070683. S.K.Mc.D., Z.C.F., M.C.L., A.J.F., D.J.S., and S.N.T. were funded by grants from the DOD (W81XWH-11-1-0261), from the U.S. Public Health Service, NIH (CA151254, CA157881, and CA15083), and U01 CA 89600 (CA-89600). We would like to thank Darla Miller and the University of North Carolina Systems Genetics Core Facility for the assistance with MegaMUGA genotyping and Steven Munger for his advice regarding Seqnature software. We would like to thank Julia Fekecs and Darryl Leja for assistance with image presentation. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD (https://hpc.nih.gov). NR 57 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2405-4712 EI 2405-4720 J9 CELL SYST JI Cell Syst. PD JAN 25 PY 2017 VL 4 IS 1 BP 31 EP + DI 10.1016/j.cels.2016.10.018 PG 21 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN1PV UT WOS:000395783200007 PM 27916600 ER PT J AU Seyfried, NT Dammer, EB Swarup, V Nandakumar, D Duong, DM Yin, LM Deng, Q Nguyen, T Hales, CM Wingo, T Glass, J Gearing, M Thambisetty, M Troncoso, JC Geschwind, DH Lah, JJ Levey, AI AF Seyfried, Nicholas T. Dammer, Eric B. Swarup, Vivek Nandakumar, Divya Duong, Duc M. Yin, Luming Deng, Qiudong Tram Nguyen Hales, Chadwick M. Wingo, Thomas Glass, Jonathan Gearing, Marla Thambisetty, Madhav Troncoso, Juan C. Geschwind, Daniel H. Lah, James J. Levey, Allan I. TI A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer's Disease SO CELL SYSTEMS LA English DT Article ID BLOOD-BRAIN-BARRIER; NEURODEGENERATIVE DISORDERS; MOLECULAR PATHOLOGY; SYSTEMS BIOLOGY; GENE-EXPRESSION; CEREBRAL-CORTEX; CELL-TYPE; FIBRINOGEN; TRANSCRIPTOME; NORMALIZATION AB Here, we report proteomic analyses of 129 human cortical tissues to define changes associated with the asymptomatic and symptomatic stages of Alzheimer's disease (AD). Network analysis revealed 16 modules of co-expressed proteins, 10 of which correlated with AD phenotypes. A subset of modules overlapped with RNA co-expression networks, including those associated with neurons and astroglial cell types, showing altered expression in AD, even in the asymptomatic stages. Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and inflammation. Proteomic modules were validated in an independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases. AD genetic risk loci were concentrated in glial-related modules in the proteome and transcriptome, consistent with their causal role in AD. This multi-network analysis reveals protein- and disease-specific pathways involved in the etiology, initiation, and progression of AD. C1 [Seyfried, Nicholas T.; Dammer, Eric B.; Nandakumar, Divya; Duong, Duc M.; Yin, Luming; Deng, Qiudong; Tram Nguyen] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. [Seyfried, Nicholas T.; Hales, Chadwick M.; Wingo, Thomas; Glass, Jonathan; Lah, James J.; Levey, Allan I.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Swarup, Vivek; Geschwind, Daniel H.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Gearing, Marla] Emory Univ, Sch Med, Dept Expt Pathol, Atlanta, GA 30322 USA. [Thambisetty, Madhav; Troncoso, Juan C.] Johns Hopkins Sch Med, Baltimore, MD 21205 USA. [Thambisetty, Madhav] NIA, NIH, Bethesda, MD 20892 USA. [Wingo, Thomas] Atlanta VA Med Ctr, Div Neurol, Decatur, GA 30033 USA. RP Seyfried, NT (reprint author), Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA.; Seyfried, NT; Levey, AI (reprint author), Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. EM nseyfri@emory.edu; alevey@emory.edu FU Accelerating Medicine Partnership AD [U01AG046161-02]; NINDS Emory Neuroscience Core [P30NS055077]; Johns Hopkins Alzheimer's Disease Research Center [P50AG05146]; Emory Alzheimer's Disease Research Center [P50AG025688]; Biomarkers Across Neurodegenerative Diseases grant [11060]; Alzheimer's Association (ALZ); Alzheimer's Research UK (ARUK); Michael J. Fox Foundation for Parkinson's Research (MJFF); Weston Brain Institute; BrightFocus Foundation [A2015332S]; Intramural Research Program of the NIH, National Institute on Aging FX We are grateful to participants in the Baltimore Longitudinal Study of Aging and Emory brain bank donors for their invaluable contribution. We acknowledge Dr. William Hu (Department of Neurology, Emory School of Medicine) and Drs. Giovanni Coppola (Departments of Psychiatry, UCLA), Chris Gaiteri (Rush University), and Sara Mostafavi (University of British Columbia) for helpful comments and discussion. Support for this study was provided by grants from the Accelerating Medicine Partnership AD (U01AG046161-02), the NINDS Emory Neuroscience Core (P30NS055077), the Johns Hopkins Alzheimer's Disease Research Center(P50AG05146), and the Emory Alzheimer's Disease Research Center (P50AG025688). N.T.S. is supported in part by a Biomarkers Across Neurodegenerative Diseases grant (11060) funded by the Alzheimer's Association (ALZ), Alzheimer's Research UK (ARUK), The Michael J. Fox Foundation for Parkinson's Research (MJFF), and the Weston Brain Institute. J.C.T was also supported by a BrightFocus Foundation (A2015332S). This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 61 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2405-4712 EI 2405-4720 J9 CELL SYST JI Cell Syst. PD JAN 25 PY 2017 VL 4 IS 1 BP 60 EP + DI 10.1016/j.cels.2016.11.006 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN1PV UT WOS:000395783200009 PM 27989508 ER PT J AU Joehanes, R Zhang, XL Huan, TX Yao, C Ying, SX Nguyen, QT Demirkale, CY Feolo, ML Sharopova, NR Sturcke, A Schaeffer, AA Heard-Costa, N Chen, H Liu, PC Wang, R Woodhouse, KA Tanriverdi, K Freedman, JE Raghavachari, N Dupuis, J Johnson, AD O'Donnell, CJ Levy, D Munson, PJ AF Joehanes, Roby Zhang, Xiaoling Huan, Tianxiao Yao, Chen Ying, Sai-xia Quang Tri Nguyen Demirkale, Cumhur Yusuf Feolo, Michael L. Sharopova, Nataliya R. Sturcke, Anne Schaeffer, Alejandro A. Heard-Costa, Nancy Chen, Han Liu, Po-ching Wang, Richard Woodhouse, Kimberly A. Tanriverdi, Kahraman Freedman, Jane E. Raghavachari, Nalini Dupuis, Josee Johnson, Andrew D. O'Donnell, Christopher J. Levy, Daniel Munson, Peter J. TI Integrated genome-wide analysis of expression quantitative trait loci aids interpretation of genomic association studies SO GENOME BIOLOGY LA English DT Article ID CORONARY-ARTERY-DISEASE; LYMPHOBLASTOID CELL-LINES; GENE-EXPRESSION; PLATELET TRANSCRIPTOME; TRANS-EQTLS; WHOLE-BLOOD; IDENTIFICATION; GENOTYPE; HEART; ANNOTATION AB Background: Identification of single nucleotide polymorphisms (SNPs) associated with gene expression levels, known as expression quantitative trait loci (eQTLs), may improve understanding of the functional role of phenotype-associated SNPs in genome-wide association studies (GWAS). The small sample sizes of some previous eQTL studies have limited their statistical power. We conducted an eQTL investigation of microarray-based gene and exon expression levels in whole blood in a cohort of 5257 individuals, exceeding the single cohort size of previous studies by more than a factor of 2. Results: We detected over 19,000 independent lead cis-eQTLs and over 6000 independent lead trans-eQTLs, targeting over 10,000 gene targets (eGenes), with a false discovery rate (FDR) < 5%. Of previously published significant GWAS SNPs, 48% are identified to be significant eQTLs in our study. Some trans-eQTLs point toward novel mechanistic explanations for the association of the SNP with the GWAS-related phenotype. We also identify 59 distinct blocks or clusters of trans-eQTLs, each targeting the expression of sets of six to 229 distinct trans-eGenes. Ten of these sets of target genes are significantly enriched for microRNA targets (FDR < 5%). Many of these clusters are associated in GWAS with multiple phenotypes. Conclusions: These findings provide insights into the molecular regulatory patterns involved in human physiology and pathophysiology. We illustrate the value of our eQTL database in the context of a recent GWAS meta-analysis of coronary artery disease and provide a list of targeted eGenes for 21 of 58 GWAS loci. C1 [Joehanes, Roby; Zhang, Xiaoling; Huan, Tianxiao; Yao, Chen; Dupuis, Josee; Johnson, Andrew D.; O'Donnell, Christopher J.; Levy, Daniel] NHLBI, Framingham Heart Study & Div Intramural Res, NIH, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. [Zhang, Xiaoling; Ying, Sai-xia; Quang Tri Nguyen; Demirkale, Cumhur Yusuf; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. [Joehanes, Roby] Harvard Med Sch, Inst Aging Res Hebrew SeniorLife, Boston, MA USA. [Feolo, Michael L.; Sharopova, Nataliya R.; Sturcke, Anne; Schaeffer, Alejandro A.] NIH, Nat Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Heard-Costa, Nancy] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Chen, Han] Harvard Univ, Sch Publ Hlth, Boston, MA USA. [Liu, Po-ching; Wang, Richard; Woodhouse, Kimberly A.] NIH, DNA Sequencing & Genom Core, Bethesda, MD USA. [Tanriverdi, Kahraman; Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Raghavachari, Nalini] NIA, NIH, Bethesda, MD 20892 USA. [Zhang, Xiaoling; Chen, Han; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [O'Donnell, Christopher J.] Boston VA Healthcare, Dept Med, Cardiol Sect, Boston, MA USA. [Zhang, Xiaoling] Boston Univ, Sch Med, Dept Med, Sect Biomed Genet, Boston, MA 02118 USA. [Munson, Peter J.] NIH, Bldg 12A,Room 2003, Bethesda, MD 20892 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study & Div Intramural Res, NIH, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA.; Munson, PJ (reprint author), NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. EM levyd@nhlbi.nih.gov; munson@mail.nih.gov FU National Institutes of Health [N01-HC-25195]; Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA; Division of Intramural Research, National Heart, Lung, and Blood Institute; Office of Intramural Research, Center for Information Technology, National Institutes of Health, Bethesda, MD, USA; Intramural Research Program of the National Institutes of Health, National Library of Medicine, Bethesda, MD, USA; NIH [U01 DK085526, R01 DK078616] FX The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the by the Office of Intramural Research, Center for Information Technology, National Institutes of Health, Bethesda, MD, USA. The visualization tools and data resources for this project were funded by the Intramural Research Program of the National Institutes of Health, National Library of Medicine, Bethesda, MD, USA. H.C was supported by NIH grant U01 DK085526. J.D. was supported by NIH grants R01 DK078616 and U01 DK085526. NR 62 TC 2 Z9 2 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD JAN 25 PY 2017 VL 18 AR 16 DI 10.1186/s13059-016-1142-6 PG 24 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EL7UT UT WOS:000394827000001 PM 28122634 ER PT J AU Morton, PD Korotcova, L Lewis, BK Bhuvanendran, S Ramachandra, SD Zurakowski, D Zhang, JY Mori, S Frank, JA Jonas, RA Gallo, V Ishibashi, N AF Morton, Paul D. Korotcova, Ludmila Lewis, Bobbi K. Bhuvanendran, Shivaprasad Ramachandra, Shruti D. Zurakowski, David Zhang, Jiangyang Mori, Susumu Frank, Joseph A. Jonas, Richard A. Gallo, Vittorio Ishibashi, Nobuyuki TI Abnormal neurogenesis and cortical growth in congenital heart disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NEURAL STEM-CELLS; WHITE-MATTER INJURY; ADULT HUMAN BRAIN; SUBVENTRICULAR ZONE; NEURODEVELOPMENTAL OUTCOMES; CEREBRAL-CORTEX; HUMAN NEOCORTEX; VASCULAR NICHE; RADIAL GLIA; NEURONS AB Long-term neurological deficits due to immature cortical development are emerging as a major challenge in congenital heart disease (CHD). However, cellular mechanisms underlying dysregulation of perinatal corticogenesis in CHD remain elusive. The subventricular zone (SVZ) represents the largest postnatal niche of neural stem/progenitor cells (NSPCs). We show that the piglet SVZ resembles its human counterpart and displays robust postnatal neurogenesis. We present evidence that SVZ NSPCs migrate to the frontal cortex and differentiate into interneurons in a region-specific manner. Hypoxic exposure of the gyrencephalic piglet brain recapitulates CHD-induced impaired cortical development. Hypoxia reduces proliferation and neurogenesis in the SVZ, which is accompanied by reduced cortical growth. We demonstrate a similar reduction in neuroblasts within the SVZ of human infants born with CHD. Our findings demonstrate that SVZ NSPCs contribute to perinatal corticogenesis and suggest that restoration of SVZ NSPCs' neurogenic potential is a candidate therapeutic target for improving cortical growth in CHD. C1 [Morton, Paul D.; Korotcova, Ludmila; Ramachandra, Shruti D.; Jonas, Richard A.; Gallo, Vittorio; Ishibashi, Nobuyuki] Childrens Natl Hlth Syst, Ctr Neurosci Res, Washington, DC 20010 USA. [Morton, Paul D.; Korotcova, Ludmila; Ramachandra, Shruti D.; Jonas, Richard A.; Ishibashi, Nobuyuki] Childrens Natl Hlth Syst, Childrens Natl Heart Inst, Washington, DC 20010 USA. [Lewis, Bobbi K.] NIH, Frank Lab & Lab Diagnost Radiol Res, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Bhuvanendran, Shivaprasad] Childrens Natl Hlth Syst, Med Genet Res Ctr, Washington, DC 20010 USA. [Zurakowski, David] Harvard Med Sch, Childrens Hosp Boston, Dept Anesthesia, Boston, MA 02115 USA. [Zurakowski, David] Harvard Med Sch, Childrens Hosp Boston, Dept Surg, Boston, MA 02115 USA. [Zhang, Jiangyang; Mori, Susumu] Johns Hopkins Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. [Zhang, Jiangyang; Mori, Susumu] Johns Hopkins Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Jonas, RA; Gallo, V; Ishibashi, N (reprint author), Childrens Natl Hlth Syst, Ctr Neurosci Res, Washington, DC 20010 USA.; Jonas, RA; Ishibashi, N (reprint author), Childrens Natl Hlth Syst, Childrens Natl Heart Inst, Washington, DC 20010 USA. EM rjonas@childrensnational.org; vgallo@childrensnational.org; nishibas@childrensnational.org FU U.S. NIH [R01HL104173, R01HL128546, R01NS045702, R01HD074593, R01NS084957, R01NS086888, P41EB015909]; Intellectual and Developmental Disabilities Research Center [U54 HD090257]; Baier Cardiac Research Fund; Children's Heart Foundation; CRI Neonatal Brain Injury Project; Foglia and Hills families FX This work was supported by the U.S. NIH (R01HL104173 and R01HL128546 to R.A.J.; R01NS045702 to V.G.; R01HD074593 to J.Z.; R01NS084957, R01NS086888, and P41EB015909 to S.M.; and the Intellectual and Developmental Disabilities Research Center grant U54 HD090257 to V.G.), a Baier Cardiac Research Fund to R.A.J., a grant from the Children's Heart Foundation to N.I., the CRI Neonatal Brain Injury Project to V.G. and N.I., and the Foglia and Hills families. NR 67 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JAN 25 PY 2017 VL 9 IS 374 AR eaah7029 DI 10.1126/scitranslmed.aah7029 PG 15 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EL2KH UT WOS:000394448100003 ER PT J AU Faupel-Badger, JM Nelson, DE Izmirlian, G AF Faupel-Badger, Jessica M. Nelson, David E. Izmirlian, Grant TI Career Satisfaction and Perceived Salary Competitiveness among Individuals Who Completed Postdoctoral Research Training in Cancer Prevention SO PLOS ONE LA English DT Article ID BIOMEDICAL-RESEARCH ENTERPRISE; JOB-SATISFACTION; PUBLIC-HEALTH; OUTCOMES; SCIENCES; FACULTY; RECOMMENDATIONS; SCIENTISTS; PREDICTORS; ENGINEERS AB Studies examining career satisfaction of biomedical scientists are limited, especially in the context of prior postdoctoral training. Here we focused on career satisfaction defined as sat-isfaction with one's career trajectory and perceived salary competitiveness among a predominantly Ph. D.-trained population of scientists who completed cancer prevention-related postdoctoral training between 1987-2011. National Cancer Institute (NCI) Cancer Preven-tion Fellowship Program (CPFP) alumni (n = 114), and previous recipients of NCI-spon-sored Ruth L. Kirschstein National Research Service Award (NRSA/F32) postdoctoral fellowships (n = 140) completed online surveys. Associations of career satisfaction and perception of salary competitiveness with demographic, training, and employment-related factors were examined using logistic regression. Overall, 61% reported high levels of satis-faction with their career trajectory to-date. Higher salary (odds ratio [OR] = 2.86, 95% confidence interval [95% CI]: 1.07-7.69) and having more leadership roles (OR = 2.26, 95% CI: 1.04-4.90) were independently associated with higher career satisfaction. Persons with race/ethnicity other than white (OR = 0.40, 95% CI: 0.20-0.82) or age >= 50 (OR = 0.40, 95% CI: 0.17-0.94) had lower career satisfaction levels. There were no statistically signifi-cant differences in career satisfaction levels by gender, scientific discipline, or employment sector. 74% perceived their current salary as competitive, but persons with 5-9, or >= 10 years in their current position reported lower levels (OR = 0.31, 95% CI: 0.15-0.65; and OR = 0.37, 95% CI: 0.16-0.87, respectively), as did individuals in government positions (OR = 0.33, 95% CI: 0.11-0.98). These data add to the understanding of career satisfaction of those with advanced training in biomedical research by examining these measures in rela-tion to prior postdoctoral research training and across multiple career sectors. C1 [Faupel-Badger, Jessica M.] NIGMS, Bethesda, MD 20892 USA. [Nelson, David E.; Izmirlian, Grant] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Faupel-Badger, JM (reprint author), NIGMS, Bethesda, MD 20892 USA. EM badgerje@mail.nih.gov FU NIH Evaluation Set-Aside program; NCI CPFP alumni; NRSA/F32 award FX Authors do not have additional grant funding. This work was funded by the NIH Evaluation Set-Aside program. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We would like to thank all of the NCI CPFP alumni and NRSA/F32 award recipients who took the time to complete the online survey. We also thank employees of Westat, Inc (Kimberley Raue, Sophia Tsakraklides, Atsushi Miyaoka, Maura Spiegelman) for their involvement in design of the survey, collection of data, and preparation of summary report. This work was supported by the NIH Evaluation Set-Aside program award to the NCI Cancer Prevention Fellowship Program, Division of Cancer Prevention and subsequent contract to Westat, Inc. NR 50 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 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 25 PY 2017 VL 12 IS 1 AR e0169859 DI 10.1371/journal.pone.0169859 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN7FK UT WOS:000396167300063 PM 28121985 ER PT J AU Liu, Y Zhou, LJ Wang, J Li, D Ren, WJ Peng, JY Wei, X Xu, T Xin, WJ Pang, RP Li, YY Qin, ZH Murugan, M Mattson, MP Wu, LJ Liu, XG AF Liu, Yong Zhou, Li-Jun Wang, Jun Li, Dai Ren, Wen-Jie Peng, Jiyun Wei, Xiao Xu, Ting Xin, Wen-Jun Pang, Rui-Ping Li, Yong-Yong Qin, Zhi-Hai Murugan, Madhuvika Mattson, Mark P. Wu, Long-Jun Liu, Xian-Guo TI TNF-alpha Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury SO JOURNAL OF NEUROSCIENCE LA English DT Article DE memory deficit; microglia; neuropathic pain; SNI; synaptic plasticity; TNF-alpha ID NECROSIS-FACTOR-ALPHA; LONG-TERM POTENTIATION; LAMINA-I NEURONS; NEUROPATHIC PAIN; WORKING-MEMORY; UP-REGULATION; DORSAL-HORN; NEUROTROPHIC FACTOR; PERSISTENT PAIN; P38 MAPK AB Clinical studies show that chronic pain is accompanied by memory deficits and reduction in hippocampal volume. Experimental studies show that spared nerve injury (SNI) of the sciatic nerve induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn, but impairs LTP in the hippocampus. The opposite changes may contribute to neuropathic pain and memory deficits, respectively. However, the cellular and molecular mechanisms underlying the functional synaptic changes are unclear. Here, we show that the dendrite lengths and spine densities are reduced significantly in hippocampal CA1 pyramidal neurons, but increased in spinal neurokinin-1-positive neurons in mice after SNI, indicating that the excitatory synaptic connectivity is reduced in hippocampus but enhanced in spinal dorsal horn in this neuropathic pain model. Mechanistically, tumor necrosis factor-alpha (TNF-alpha) is upregulated in bilateral hippocampus and in ipsilateral spinal dorsal horn, whereas brain-derived neurotrophic factor (BDNF) is decreased in the hippocampus but increased in the ipsilateral spinal dorsal horn after SNI. Importantly, the SNI-induced opposite changes in synaptic connectivity and BDNF expression are prevented by genetic deletion of TNF receptor 1 in vivo and are mimicked by TNF-alpha in cultured slices. Furthermore, SNI activated microglia in both spinal dorsal horn and hippocampus; pharmacological inhibition or genetic ablation of microglia prevented the region-dependent synaptic changes, neuropathic pain, and memory deficits induced by SNI. The data suggest that neuropathic pain involves different structural synaptic alterations in spinal and hippocampal neurons that are mediated by overproduction of TNF-alpha and microglial activation and may underlie chronic pain and memory deficits. C1 [Liu, Yong; Zhou, Li-Jun; Wang, Jun; Li, Dai; Ren, Wen-Jie; Wei, Xiao; Xu, Ting; Xin, Wen-Jun; Pang, Rui-Ping; Li, Yong-Yong; Liu, Xian-Guo] Sun Yat Sen Univ, Zhongshan Sch Med, Pain Res Ctr, Guangzhou 510080, Guangdong, Peoples R China. [Liu, Yong; Zhou, Li-Jun; Wang, Jun; Li, Dai; Ren, Wen-Jie; Wei, Xiao; Xu, Ting; Xin, Wen-Jun; Pang, Rui-Ping; Li, Yong-Yong; Liu, Xian-Guo] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Physiol, Guangzhou 510080, Guangdong, Peoples R China. [Liu, Yong; Zhou, Li-Jun; Peng, Jiyun; Murugan, Madhuvika; Wu, Long-Jun] Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ 08854 USA. [Liu, Yong; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Qin, Zhi-Hai] Chinese Acad Sci Univ Tokyo Joint Lab Struct Viro, Natl Lab Biomacromol, Beijing 100101, Peoples R China. [Peng, Jiyun; Murugan, Madhuvika; Wu, Long-Jun] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Xin, Wen-Jun; Liu, Xian-Guo] Guangdong Prov Key Lab Brain Funct & Dis, Guangzhou 510080, Guangdong, Peoples R China. RP Liu, XG (reprint author), Sun Yat Sen Univ, Zhongshan Sch Med, Pain Res Ctr, Guangzhou 510080, Guangdong, Peoples R China.; Liu, XG (reprint author), Sun Yat Sen Univ, Zhongshan Sch Med, Dept Physiol, Guangzhou 510080, Guangdong, Peoples R China.; Wu, LJ (reprint author), Rutgers State Univ, Piscataway, NJ 08854 USA. EM lwu@dls.rutgers.edu; liuxg@mail.sysu.edu.cn OI Liu, Yong/0000-0003-1278-7114 FU National Natural Science Foundation of China [U1201223, 81200856, 30970957, 81371198, 31000489]; National Institutes of Health [R01NS088627, R21DE025689]; Intramural Research Program of the National Institute on Aging FX This work was supported by the National Natural Science Foundation of China (Grants U1201223, 81200856, 30970957, 81371198, and 31000489), the National Institutes of Health (Grants R01NS088627 and R21DE025689), and the Intramural Research Program of the National Institute on Aging. We thank Dr. Wen-Biao Gan for providing CX3CR1CreER/+ mice and Huai-Yu Gu for technical support. NR 50 TC 0 Z9 0 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 25 PY 2017 VL 37 IS 4 BP 871 EP 881 DI 10.1523/JNEUROSCI.2235-16.2017 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EJ9TF UT WOS:000393569300012 PM 28123022 ER PT J AU Caprioli, D Venniro, M Zhang, M Bossert, JM Warren, BL Hope, BT Shaham, Y AF Caprioli, Daniele Venniro, Marco Zhang, Michelle Bossert, Jennifer M. Warren, Brandon L. Hope, Bruce T. Shaham, Yavin TI Role of Dorsomedial Striatum Neuronal Ensembles in Incubation of Methamphetamine Craving after Voluntary Abstinence SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Daun02 inactivation; incubation of drug craving; neuronal ensembles; relapse; self-administration; voluntary abstinence ID COCAINE-SEEKING BEHAVIOR; CONTEXT-INDUCED REINSTATEMENT; TIME-DEPENDENT CHANGES; STRESS-INDUCED REINSTATEMENT; TONICALLY ACTIVE NEURONS; PALATABLE FOOD SEEKING; DORSAL STRIATUM; ALCOHOL-SEEKING; SEX-DIFFERENCES; DORSOLATERAL STRIATUM AB We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we studied the role of dorsolateral striatum (DLS) and dorsomedial striatum (DMS) in this incubation. We trained rats to self-administer palatable food pellets (6 d, 6 h/d) and methamphetamine (12 d, 6 h/d). We then assessed relapse to methamphetamine seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent voluntary abstinence ( using a discrete choice procedure between methamphetamine and food; 20 trials/d) for 19 d. We used in situ hybridization to measure the colabeling of the activity marker Fos with Drd1 and Drd2 in DMS and DLS after the tests. Based on the in situ hybridization colabeling results, we tested the causal role of DMS D-1 and D-2 family receptors, and DMS neuronal ensembles in "incubated" methamphetamine seeking, using selective dopamine receptor antagonists (SCH39166 or raclopride) and the Daun02 chemogenetic inactivation procedure, respectively. Methamphetamine seeking was higher after 21 d of voluntary abstinence than after 1 d (incubation of methamphetamine craving). The incubated response was associated with increased Fos expression in DMS but not in DLS; Fos was colabeled with both Drd1 and Drd2. DMS injections of SCH39166 or raclopride selectively decreased methamphetamine seeking after 21 abstinence days. In Fos-lacZ transgenic rats, selective inactivation of relapse test-activated Fos neurons in DMSon abstinence day 18 decreased incubated methamphetamine seeking on day 21. Results demonstrate a role ofDMSdopamine D-1 and D-2 receptors in the incubation of methamphetamine craving after voluntary abstinence and that DMS neuronal ensembles mediate this incubation. C1 [Caprioli, Daniele; Venniro, Marco; Zhang, Michelle; Bossert, Jennifer M.; Warren, Brandon L.; Hope, Bruce T.; Shaham, Yavin] NIDA, Behav Neurosci Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Caprioli, D; Shaham, Y (reprint author), 251 Bayview Blvd,Room 04A505,Suite 200, Baltimore, MD 21224 USA. EM daniele.caprioli@uniroma1.it; yavin.shaham@nih.gov RI Hope, Bruce/A-9223-2010 OI Hope, Bruce/0000-0001-5804-7061 FU Intramural Research Program of the National Institute on Drug Abuse; Brain & Behavior Research Foundation FX The research was supported by the Intramural Research Program of the National Institute on Drug Abuse and a Brain & Behavior Research Foundation (formerly the National Alliance for Research on Schizophrenia and Depression) Distinguished Investigator Grant (to Y.S.). NR 77 TC 1 Z9 1 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 25 PY 2017 VL 37 IS 4 BP 1014 EP 1027 DI 10.1523/JNEUROSCI.3091-16.2017 PG 14 WC Neurosciences SC Neurosciences & Neurology GA EJ9TF UT WOS:000393569300022 PM 28123032 ER PT J AU Cai, W Gao, HY Chu, CC Wang, XY Wang, JQ Zhang, PF Lin, G Li, WG Liu, G Chen, XY AF Cai, Wen Gao, Haiyan Chu, Chengchao Wang, Xiaoyong Wang, Junqing Zhang, Pengfei Lin, Gan Li, Wengang Liu, Gang Chen, Xiaoyuan TI Engineering Phototheranostic Nanoscale Metal-Organic Frameworks for Multimodal Imaging-Guided Cancer Therapy SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article DE metal-organic frameworks (MOFs); indocyanine green; theranostic; bioimaging; photothermal therapy ID INDOCYANINE-GREEN; PHOTOTHERMAL THERAPY; IN-VIVO; DRUG-DELIVERY; MAGNETIC-RESONANCE; TARGETED DELIVERY; GRAPHENE OXIDE; BREAST-CANCER; GOLD NANORODS; PD NANOSHEETS AB Many photoresponsive dyes have been utilized as imaging and photodynamic/photothermal therapy agents. Indocyanine green (ICG) is the only near-infrared region (NIR) organic dye for clinical applications approved by the United States Food and Drug Administration; however, the clinical application of ICG is limited by its poor aqueous solubility, low cancer specificity, and low sensitivity in cancer theranostics. To overcome these issues, a multifunctional nanoplatform based on hyaluronic acid (HA) and ICG-engineered metal-organic framework MIL-100(Fe) nanoparticles (MOF@HA@ICG NPs) was successfully developed for imaging-guided, anticancer photothermal therapy (PTT). The synthesized NPs showed a high loading content of ICG (40%), strong NIR absorbance, and photostability. The in vitro and in vivo imaging showed that the MOF@HA@ICG NPs exhibited greater cellular uptake in CD44-positive MCF-7 cells and enhanced tumor accumulation in xenograft tumors due to their targeting capability, compared to MOF@ICG NPs (non-HA-targeted) and free ICG. The in vitro photothermal toxicity and in vivo PTT treatments demonstrated that MOF@HA@ICG NPs could effectively inhibit the growth of MCF-7 cells/xenograft tumors. These results suggest that MOF@HA@ICG NPs could be served as a new promising theranostic nanoplatform for improved anticancer PTT through cancer-specific and image-guided drug delivery. C1 [Cai, Wen] Xi An Jiao Tong Univ, Hlth Sci Ctr, Sch Basic Med Sci, Inst Med Engn, Xian 710061, Shaanxi, Peoples R China. [Cai, Wen; Gao, Haiyan; Chu, Chengchao; Wang, Xiaoyong; Wang, Junqing; Zhang, Pengfei; Lin, Gan; Li, Wengang; Liu, Gang] Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Ctr Mol Imaging & Translat Med, Xiamen 361102, Fujian, Peoples R China. [Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. RP Liu, G (reprint author), Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Ctr Mol Imaging & Translat Med, Xiamen 361102, Fujian, Peoples R China. EM gangliu.cmitm@xmu.edu.cn OI Wang, Junqing/0000-0002-9091-9891 FU Research Support Program for Young Teachers in Xi'an Jiaotong University [YX1K075]; Major State Basic Research Development Program of China [2014CB744503, 2013CB733802]; National Natural Science Foundation of China [81422023, 51273165, U1505221]; Fundamental Research Funds for the Central Universities [20720160065, 20720150141]; Science Foundation of Fujian Province [2014Y2004, 2014J05098]; Program for New Century Excellent Talents in University, China [NCET-13-0502] FX This project was financially supported by the Research Support Program for Young Teachers in Xi'an Jiaotong University (YX1K075), the Major State Basic Research Development Program of China (2014CB744503 and 2013CB733802), the National Natural Science Foundation of China (81422023, 51273165, and U1505221), the Fundamental Research Funds for the Central Universities (20720160065 and 20720150141), the Science Foundation of Fujian Province (2014Y2004 and 2014J05098), and the Program for New Century Excellent Talents in University, China (NCET-13-0502). NR 63 TC 0 Z9 0 U1 44 U2 44 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1944-8244 J9 ACS APPL MATER INTER JI ACS Appl. Mater. Interfaces PD JAN 25 PY 2017 VL 9 IS 3 BP 2040 EP 2051 DI 10.1021/acsami.6b11579 PG 12 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA EJ0OP UT WOS:000392909500009 PM 28032505 ER PT J AU Fitzgerald, GA Mulligan, C Mindell, JA AF Fitzgerald, Gabriel A. Mulligan, Christopher Mindell, Joseph A. TI A general method for determining secondary active transporter substrate stoichiometry SO ELIFE LA English DT Article ID DEPENDENT DICARBOXYLATE TRANSPORTER; GLUTAMATE TRANSPORTER; COTRANSPORTER; HOMOLOG; K+; MECHANISM; FAMILY AB The number of ions required to drive substrate transport through a secondary active transporter determines the proteins ability to create a substrate gradient, a feature essential to its physiological function, and places fundamental constraints on the transporters mechanism. Stoichiometry is known for a wide array of mammalian transporters, but, due to a lack of readily available tools, not for most of the prokaryotic transporters for which high-resolution structures are available. Here, we describe a general method for using radiolabeled substrate flux assays to determine coupling stoichiometries of electrogenic secondary active transporters reconstituted in proteoliposomes by measuring transporter equilibrium potentials. We demonstrate the utility of this method by determining the coupling stoichiometry of VcINDY, a bacterial Na+-coupled succinate transporter, and further validate it by confirming the coupling stoichiometry of vSGLT, a bacterial sugar transporter. This robust thermodynamic method should be especially useful in probing the mechanisms of transporters with available structures. C1 [Fitzgerald, Gabriel A.; Mulligan, Christopher; Mindell, Joseph A.] NINDS, Membrane Transport Biophys Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Mindell, JA (reprint author), NINDS, Membrane Transport Biophys Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM mindellj@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke FX National Institute of Neurological Disorders and Stroke Intramural Program Joseph A Mindell.; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 27 TC 0 Z9 0 U1 0 U2 0 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JAN 25 PY 2017 VL 6 AR e21016 DI 10.7554/eLife.21016.001 PG 15 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EK9PP UT WOS:000394256700001 ER PT J AU Haft, DH Pierce, PG Mayclin, SJ Sullivan, A Gardberg, AS Abendroth, J Begley, DW Phan, IQ Staker, BL Myler, PJ Marathias, VM Lorimer, DD Edwards, TE AF Haft, Daniel H. Pierce, Phillip G. Mayclin, Stephen J. Sullivan, Amy Gardberg, Anna S. Abendroth, Jan Begley, Darren W. Phan, Isabelle Q. Staker, Bart L. Myler, Peter J. Marathias, Vasilios M. Lorimer, Donald D. Edwards, Thomas E. TI Mycofactocin-associated mycobacterial dehydrogenases with non-exchangeable NAD cofactors SO SCIENTIFIC REPORTS LA English DT Article ID STRUCTURAL GENOMICS CENTER; INFECTIOUS-DISEASE; LIGAND; ENZYME; NMR; PEPTIDE; BINDING; REVEAL; ACIDS; MFTA AB During human infection, Mycobacterium tuberculosis (Mtb) survives the normally bacteriocidal phagosome of macrophages. Mtb and related species may be able to combat this harsh acidic environment which contains reactive oxygen species due to the mycobacterial genomes encoding a large number of dehydrogenases. Typically, dehydrogenase cofactor binding sites are open to solvent, which allows NAD/NADH exchange to support multiple turnover. Interestingly, mycobacterial short chain dehydrogenases/reductases (SDRs) within family TIGR03971 contain an insertion at the NAD binding site. Here we present crystal structures of 9 mycobacterial SDRs in which the insertion buries the NAD cofactor except for a small portion of the nicotinamide ring. Line broadening and STD-NMR experiments did not show NAD or NADH exchange on the NMR timescale. STD-NMR demonstrated binding of the potential substrate carveol, the potential product carvone, the inhibitor tricyclazol, and an external redox partner 2,6-dichloroindophenol (DCIP). Therefore, these SDRs appear to contain a non-exchangeable NAD cofactor and may rely on an external redox partner, rather than cofactor exchange, for multiple turnover. Incidentally, these genes always appear in conjunction with the mftA gene, which encodes the short peptide MftA, and with other genes proposed to convert MftA into the external redox partner mycofactocin. C1 [Haft, Daniel H.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Pierce, Phillip G.; Mayclin, Stephen J.; Sullivan, Amy; Gardberg, Anna S.; Abendroth, Jan; Begley, Darren W.; Phan, Isabelle Q.; Staker, Bart L.; Myler, Peter J.; Marathias, Vasilios M.; Lorimer, Donald D.; Edwards, Thomas E.] Seattle Struct Genom Ctr Infect Dis, Seattle, WA 98109 USA. [Pierce, Phillip G.; Mayclin, Stephen J.; Sullivan, Amy; Gardberg, Anna S.; Abendroth, Jan; Begley, Darren W.; Marathias, Vasilios M.; Lorimer, Donald D.; Edwards, Thomas E.] Beryllium Discovery Corp, 7869 NE Day Rd West, Bainbridge Isl, WA 98110 USA. [Phan, Isabelle Q.; Staker, Bart L.; Myler, Peter J.] Ctr Infect Dis Res, 307 Westlake Ave Nort, Seattle, WA 98109 USA. [Myler, Peter J.] Univ Washington, Dept Med Educ & Biomed Informat, Seattle, WA 98195 USA. [Myler, Peter J.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Begley, Darren W.] Wolfe Labs Inc, 19 Presidential Way, Woburn, MA 01801 USA. RP Haft, DH (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA.; Edwards, TE (reprint author), Seattle Struct Genom Ctr Infect Dis, Seattle, WA 98109 USA.; Edwards, TE (reprint author), Beryllium Discovery Corp, 7869 NE Day Rd West, Bainbridge Isl, WA 98110 USA. EM daniel.haft@nih.gov; tedwards@be4.com FU National Institute of Allergy and Infectious Diseases, National Institute of Health, Department of Health and Human Services [HHSN272201200025C, HHSN272200700057C]; Intramural Research Program of the NIH, National Library of Medicine FX The authors thank the entire SSGCID team as well as D. Smith for assistance with data collection. This research was funded by the National Institute of Allergy and Infectious Diseases, National Institute of Health, Department of Health and Human Services, under Federal Contract number HHSN272201200025C and HHSN272200700057C. D.H. was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 24 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 25 PY 2017 VL 7 AR 41074 DI 10.1038/srep41074 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI6HE UT WOS:000392595300001 PM 28120876 ER PT J AU Fan, WP Lu, N Huang, P Liu, Y Yang, Z Wang, S Yu, GC Liu, YJ Hu, JK He, QJ Qu, JL Wang, TF Chen, XY AF Fan, Wenpei Lu, Nan Huang, Peng Liu, Yi Yang, Zhen Wang, Sheng Yu, Guocan Liu, Yijing Hu, Junkai He, Qianjun Qu, Junle Wang, Tianfu Chen, Xiaoyuan TI Glucose-Responsive Sequential Generation of Hydrogen Peroxide and Nitric Oxide for Synergistic Cancer Starving-Like/Gas Therapy SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE hydrogen peroxide; mesoporous nanomaterials; nitric oxide; synergistic therapy; ultrasound imaging ID MESOPOROUS ORGANOSILICA; NANOPARTICLES; RELEASE; DELIVERY; TUMORS; CELLS; NO; RADIOSENSITIZATION; NANOTECHNOLOGY; HYBRIDIZATION AB Glucose is a key energy supplier and nutrient for tumor growth. Herein, inspired by the glucose oxidase (GOx)assisted conversion of glucose into gluconic acid and toxic H2O2, a novel treatment paradigm of starving- like therapy is developed for significant tumor- killing effects, more effective than conventional starving therapy by only cutting off the energy supply. Furthermore, the generated acidic H2O2 can oxidize l- Arginine (l- Arg) into NO for enhanced gas therapy. By using hollow mesoporous organosilica nanoparticle (HMON) as a biocompatible/biodegradable nanocarrier for the co-delivery of GOx and l- Arg, a novel glucose- responsive nanomedicine (l- Arg- HMON- GOx) has been for the first time constructed for synergistic cancer starving- like/gas therapy without the need of external excitation, which yields a remarkable H2O2-NO cooperative anticancer effect with minimal adverse effect. C1 [Fan, Wenpei; Huang, Peng; Wang, Sheng; He, Qianjun; Wang, Tianfu] Shenzhen Univ, Guangdong Key Lab Biomed Measurements & Ultrasoun, Sch Biomed Engn, Shenzhen 518060, Peoples R China. [Fan, Wenpei; Qu, Junle] Shenzhen Univ, Key Lab Optoelect Devices & Syst, Minist Educ & Guangdong Prov, Coll Optoelect Engn, Shenzhen 518060, Peoples R China. [Fan, Wenpei; Lu, Nan; Liu, Yi; Yang, Zhen; Yu, Guocan; Liu, Yijing; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Hu, Junkai] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. RP Huang, P; Wang, TF (reprint author), Shenzhen Univ, Guangdong Key Lab Biomed Measurements & Ultrasoun, Sch Biomed Engn, Shenzhen 518060, Peoples R China.; Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM peng.huang@szu.edu.cn; tfwang@szu.edu.cn; shawn.chen@nih.gov FU Shenzhen University; National Science Foundation of China [81401465, 51573096, 51602203]; Postdoctoral Science Foundation of China [2016M590808]; Intramural Research Program (IRP) of the NIBIB, NIH FX This project is financially supported by the startup fund from the Shenzhen University, the National Science Foundation of China (grant numbers 81401465, 51573096, and 51602203), the Postdoctoral Science Foundation of China (grant number 2016M590808), and the Intramural Research Program (IRP) of the NIBIB, NIH. NR 37 TC 0 Z9 0 U1 32 U2 32 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD JAN 24 PY 2017 VL 56 IS 5 BP 1229 EP 1233 DI 10.1002/anie.201610682 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA EM0GV UT WOS:000394997700006 PM 27936311 ER PT J AU Lerit, DA Shebelut, CW Lawlor, KJ Rusan, NM Gavis, ER Schedl, P Deshpande, G AF Lerit, Dorothy A. Shebelut, Conrad W. Lawlor, Kristen J. Rusan, Nasser M. Gavis, Elizabeth R. Schedl, Paul Deshpande, Girish TI Germ Cell-less Promotes Centrosome Segregation to Induce Germ Cell Formation SO CELL REPORTS LA English DT Article ID DROSOPHILA EMBRYOS; EXTRA CENTROSOMES; GAMMA-TUBULIN; PROTEIN; LOCALIZATION; BEHAVIOR; NUCLEAR; NANOS; ESTABLISHMENT; EMBRYOGENESIS AB The primordial germ cells (PGCs) specified during embryogenesis serve as progenitors to the adult germline stem cells. In Drosophila, the proper specification and formation of PGCs require both centrosomes and germ plasm, which contains the germline determinants. Centrosomes are microtubule (MT)organizing centers that ensure the faithful segregation of germ plasm into PGCs. To date, mechanisms that modulate centrosome behavior to engineer PGC development have remained elusive. Only one germ plasm component, Germ cell-less (Gcl), is known to play a role in PGC formation. Here, we show that Gcl engineers PGC formation by regulating centrosome dynamics. Loss of gcl leads to aberrant centrosome separation and elaboration of the astral MT network, resulting in inefficient germ plasm segregation and aborted PGC cellularization. Importantly, compromising centrosome separation alone is sufficient to mimic the gcl loss-of-function phenotypes. We conclude Gcl functions as a key regulator of centrosome separation required for proper PGC development. C1 [Lerit, Dorothy A.] Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA 30322 USA. [Shebelut, Conrad W.] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [Lawlor, Kristen J.] Columbia Univ, Dept Neurosci, New York, NY 10032 USA. [Rusan, Nasser M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gavis, Elizabeth R.; Schedl, Paul; Deshpande, Girish] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. [Schedl, Paul] Russian Acad Sci, Inst Gene Biol, Lab Gene Express Regulat Dev, Moscow 119991, Russia. RP Lerit, DA (reprint author), Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA 30322 USA.; Deshpande, G (reprint author), Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. EM dlerit@emory.edu; gdeshpan@princeton.edu FU NIH [R01GM110015, R01GM067758, 1ZIAHL006126, 1K22HK126922-01A1]; Ministry of Education and Science of the Russian Federation [14.B25.31.0022] FX For reagents, we acknowledge the Bloomington Stock Center, Vienna Drosophila Resource Center, and Drs. Ruth Lehmann, Paul Lasko, Tim Megraw, Christine Field, and Greg Rogers. We thank Dr. Gary Laevsky and the Princeton Molecular Biology Confocal Microscopy Facility, a Nikon Center of Excellence. Gordon Grey and Cliff Sonnenbrot provided fly media. This work was supported by NIH grants R01GM110015 to P.S. and G.D., R01GM067758 to E.R.G., 1ZIAHL006126 to N.M.R., and 1K22HK126922-01A1 to D.A.L. P.S. is a recipient of a Ministry of Education and Science of the Russian Federation grant (14.B25.31.0022). NR 32 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JAN 24 PY 2017 VL 18 IS 4 BP 831 EP 839 DI 10.1016/j.celrep.2016.12.074 PG 9 WC Cell Biology SC Cell Biology GA EO1QZ UT WOS:000396474300001 PM 28122234 ER PT J AU Ennis, GE An, Y Resnick, SM Ferrucci, L O'Brien, RJ Moffat, SD AF Ennis, Gilda E. An, Yang Resnick, Susan M. Ferrucci, Luigi O'Brien, Richard J. Moffat, Scott D. TI Long-term cortisol measures predict Alzheimer disease risk SO NEUROLOGY LA English DT Article ID HIPPOCAMPAL DAMAGE; BLOOD-PRESSURE; VARIABILITY; STRESS; DEMENTIA; MEMORY; DEPOSITION; SECRETION; DEFICITS; HORMONES AB Objective: To examine whether long-term measures of cortisol predict Alzheimer disease (AD) risk. Method: We used a prospective longitudinal design to examine whether cortisol dysregulation was related to AD risk. Participants were from the Baltimore Longitudinal Study of Aging (BLSA) and submitted multiple 24-hour urine samples over an average interval of 10.56 years. Urinary free cortisol (UFC) and creatinine (Cr) were measured, and a UFC/Cr ratio was calculated to standardize UFC. To measure cortisol regulation, we used within-person UFC/Cr level (i.e., within-person mean), change in UFC/Cr over time (i.e., within-person slope), and UFC/Cr variability (i.e., within-person coefficient of variation). Cox regression was used to assess whether UFC/Cr measures predicted AD risk. Results: UFC/Cr level and UFC/Cr variability, but not UFC/Cr slope, were significant predictors of AD risk an average of 2.9 years before AD onset. Elevated UFC/Cr level and elevated UFC/Cr variability were related to a 1.31-and 1.38-times increase in AD risk, respectively. In a sensitivity analysis, increased UFC/Cr level and increased UFC/Cr variability predicted increased AD risk an average of 6 years before AD onset. Conclusions: Cortisol dysregulation as manifested by high UFC/Cr level and high UFC/Cr variability may modulate the downstream clinical expression of AD pathology or be a preclinical marker of AD. C1 [Ennis, Gilda E.; Moffat, Scott D.] Georgia Inst Technol, Sch Psychol, Atlanta, GA 30332 USA. [An, Yang; Resnick, Susan M.] Natl Inst Aging, Lab Behav Neurosci, Baltimore, MD USA. [Ferrucci, Luigi] Natl Inst Aging, Longitudinal Studies Sect, Baltimore, MD USA. [O'Brien, Richard J.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. [O'Brien, Richard J.] Duke Univ, Sch Med, Durham, NC 27706 USA. RP Moffat, SD (reprint author), Georgia Inst Technol, Sch Psychol, Atlanta, GA 30332 USA. EM scott.moffat@psych.gatech.edu FU National Institute on Aging of the NIH [R01-AG028466]; Ruth L. Kirschstein Public Health Service training [T32 AG000175]; Intramural Research Program, National Institute on Aging, NIH FX This research was supported by a grant from the National Institute on Aging of the NIH (R01-AG028466; Scott D. Moffat, principal investigator) and a Ruth L. Kirschstein Public Health Service training grant (T32 AG000175). This study was also supported in part by the Intramural Research Program, National Institute on Aging, NIH. NR 40 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 24 PY 2017 VL 88 IS 4 BP 371 EP 378 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EO2ZI UT WOS:000396564200010 PM 27986873 ER PT J AU Turan, TN Nizam, A Lynn, MJ Egan, BM Le, NA Lopes-Virella, MF Hermayer, KL Harrell, J Derdeyn, CP Fiorella, D Janis, LS Lane, B Montgomery, J Chimowitz, MI AF Turan, Tanya N. Nizam, Azhar Lynn, Michael J. Egan, Brent M. Le, Ngoc-Anh Lopes-Virella, Maria F. Hermayer, Kathie L. Harrell, Jamie Derdeyn, Colin P. Fiorella, David Janis, L. Scott Lane, Bethany Montgomery, Jean Chimowitz, Marc I. TI Relationship between risk factor control and vascular events in the SAMMPRIS trial SO NEUROLOGY LA English DT Article ID INTRACRANIAL ARTERIAL-STENOSIS; AGGRESSIVE MEDICAL-MANAGEMENT; PHYSICAL-ACTIVITY; RECURRENT STROKE; BLOOD-PRESSURE; EXERCISE; DISEASE; DESIGN AB Objective: The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study is the first stroke prevention trial to include protocoldriven intensive management of multiple risk factors. In this prespecified analysis, we aimed to investigate the relationship between risk factor control during follow-up and outcome of patients in the medical arm of SAMMPRIS. Methods: Data from SAMMPRIS participants in the medical arm (n = 227) were analyzed. Risk factors were recorded at baseline, 30 days, 4 months, and then every 4 months for a mean followup of 32 months. For each patient, values for all risk factor measures were averaged and dichotomized as in or out of target. Results: Participants who were out of target for systolic blood pressure and physical activity, as well as those with higher mean low-density lipoprotein cholesterol and non-high-density lipoprotein, were more likely to have a recurrent vascular event (stroke, myocardial infarction, or vascular death) at 3 years compared to those who had good risk factor control. In the multivariable analysis, greater physical activity decreased the likelihood of a recurrent stroke, myocardial infarction, or vascular death (odds ratio 0.6, confidence interval 0.4-0.8). Conclusions: Raised blood pressure, cholesterol, and physical inactivity should be aggressively treated in patients with intracranial atherosclerosis to prevent future vascular events. Physical activity, which has not received attention in stroke prevention trials, was the strongest predictor of a good outcome in the medical arm in SAMMPRIS. C1 [Turan, Tanya N.; Lopes-Virella, Maria F.; Hermayer, Kathie L.; Harrell, Jamie; Chimowitz, Marc I.] Med Univ South Carolina, Charleston, SC 29425 USA. [Nizam, Azhar; Lynn, Michael J.; Lane, Bethany; Montgomery, Jean] Emory Univ, Atlanta, GA 30322 USA. [Egan, Brent M.] Univ South Carolina, Sch Med, Greenville, SC USA. [Le, Ngoc-Anh] Atlanta VAMC, Decatur, GA USA. [Derdeyn, Colin P.] Washington Univ, St Louis, MI USA. [Fiorella, David] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Janis, L. Scott] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Turan, TN (reprint author), Med Univ South Carolina, Charleston, SC 29425 USA. EM turan@musc.edu FU US Public Health Service National Institute of Neurologic Disorders and Stroke (NINDS) [U01 NS058728]; NIH [UL1RR029882]; University of Florida [UL1RR029889]; University of Cincinnati [UL1RR029890]; University of California, San Francisco [UL1RR024131]; Investigator-Sponsored Study Program of AstraZeneca; Stryker Neurovascular FX This study was funded by a research grant (U01 NS058728) from the US Public Health Service National Institute of Neurologic Disorders and Stroke (NINDS). In addition, the following Clinical and Translational Science Awards, funded by the NIH, provided local support for the evaluation of patients in the trial: Medical University of South Carolina (UL1RR029882), University of Florida (UL1RR029889), University of Cincinnati (UL1RR029890), and University of California, San Francisco (UL1RR024131). Corporate Support: Stryker Neurovascular (formerly Boston Scientific Neurovascular) provided study devices and supplemental funding for third-party device distribution, site monitoring, and study auditing. This research was also supported by the Investigator-Sponsored Study Program of AstraZeneca, which donated rosuvastatin (Crestor) to study patients. Vendors: INTERVENT provided the lifestyle modification program to the study at a discounted rate. The Regulatory and Clinical Research Institute (RCRI) (Minneapolis, MN) provided assistance in designing the site monitoring processes and performing the site monitoring visits. The VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center (Albuquerque, NM) handled the procurement, labeling, distribution, and inventory management of the study devices and rosuvastatin. Walgreens pharmacies provided study medications except rosuvastatin to patients at a discounted price (paid for by the study). NR 17 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 24 PY 2017 VL 88 IS 4 BP 379 EP 385 DI 10.1212/WNL.0000000000003534 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EO2ZI UT WOS:000396564200011 PM 28003500 ER PT J AU Szaflarski, JP Gloss, D Binder, JR Gaillard, WD Golby, AJ Holland, SK Ojemann, J Spencer, DC Swanson, SJ French, JA Theodore, WH AF Szaflarski, Jerzy P. Gloss, David Binder, Jeffrey R. Gaillard, William D. Golby, Alexandra J. Holland, Scott K. Ojemann, Jeffrey Spencer, David C. Swanson, Sara J. French, Jacqueline A. Theodore, William H. TI Practice guideline summary: Use of fMRI in the presurgical evaluation of patients with epilepsy Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology SO NEUROLOGY LA English DT Article ID TEMPORAL-LOBE EPILEPSY; VERBAL MEMORY DECLINE; LANGUAGE DOMINANCE; WADA TEST; FUNCTIONAL MRI; LATERALIZATION; ACTIVATION; RESECTION; TASK; TOPIRAMATE AB Objective: To assess the diagnostic accuracy and prognostic value of functional MRI (fMRI) in determining lateralization and predicting postsurgical language and memory outcomes. Methods: An 11-member panel evaluated and rated available evidence according to the 2004 American Academy of Neurology process. At least 2 panelists reviewed the full text of 172 articles and selected 37 for data extraction. Case reports, reports with,15 cases, metaanalyses, and editorials were excluded. Results and recommendations: The use of fMRI may be considered an option for lateralizing language functions in place of intracarotid amobarbital procedure (IAP) in patients with medial temporal lobe epilepsy (MTLE; Level C), temporal epilepsy in general (Level C), or extratemporal epilepsy (Level C). For patients with temporal neocortical epilepsy or temporal tumors, the evidence is insufficient (Level U). fMRI may be considered to predict postsurgical language deficits after anterior temporal lobe resection (Level C). The use of fMRI may be considered for lateralizing memory functions in place of IAP in patients with MTLE (Level C) but is of unclear utility in other epilepsy types (Level U). fMRI of verbal memory or language encoding should be considered for predicting verbal memory outcome (Level B). fMRI using nonverbal memory encoding may be considered for predicting visuospatial memory outcomes (Level C). Presurgical fMRI could be an adequate alternative to IAP memory testing for predicting verbal memory outcome (Level C). Clinicians should carefully advise patients of the risks and benefits of fMRI vs IAP during discussions concerning choice of specific modality in each case. C1 [Szaflarski, Jerzy P.] Univ Alabama Birmingham, Dept Neurol, UAB Stn, Birmingham, AL 35294 USA. [Gloss, David] Charleston Area Med Ctr, Dept Neurol, Charleston, WV USA. [Binder, Jeffrey R.; Swanson, Sara J.] Med Coll Wisconsin, Dept Neurol, Milwaukee, WI 53226 USA. [Gaillard, William D.] George Washington Univ, Childrens Natl Med Ctr, Washington, DC USA. [Golby, Alexandra J.] Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA. [Golby, Alexandra J.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Holland, Scott K.] Cincinnati Childrens Hosp Res Fdn, Cincinnati, OH USA. [Ojemann, Jeffrey] Seattle Childrens Hosp, Dept Neurosurg, Seattle, WA USA. [Spencer, David C.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [French, Jacqueline A.] NYU, Dept Neurol, New York, NY 10016 USA. [Theodore, William H.] NINDS, Clin Epilepsy Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Szaflarski, JP (reprint author), Univ Alabama Birmingham, Dept Neurol, UAB Stn, Birmingham, AL 35294 USA. EM guidelines@aan.com FU American Academy of Neurology (AAN) FX This guideline was developed with financial support from the American Academy of Neurology (AAN). Authors who serve as AAN subcommittee members or methodologists (D.G., J.A.F.) were reimbursed by the AAN for expenses related to travel to subcommittee meetings where drafts of manuscripts were reviewed. NR 40 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 24 PY 2017 VL 88 IS 4 BP 395 EP 402 DI 10.1212/WNL.0000000000003532 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EO2ZI UT WOS:000396564200013 PM 28077494 ER PT J AU Velmurugan, G Ramprasath, T Swaminathan, K Mithieux, G Rajendhran, J Dhivakar, M Parthasarathy, A Babu, DDV Thumburaj, LJ Freddy, AJ Dinakaran, V Puhari, SSM Rekha, B Christy, YJ Anusha, S Divya, G Suganya, K Meganathan, B Kalyanaraman, N Vasudevan, V Kamaraj, R Karthik, M Jeyakumar, B Abhishek, A Paul, E Pushpanathan, M Rajmohan, RK Velayutham, K Lyon, AR Ramasamy, S AF Velmurugan, Ganesan Ramprasath, Tharmarajan Swaminathan, Krishnan Mithieux, Gilles Rajendhran, Jeyaprakash Dhivakar, Mani Parthasarathy, Ayothi Babu, D. D. Venkatesh Thumburaj, Leishman John Freddy, Allen J. Dinakaran, Vasudevan Puhari, Shanavas Syed Mohamed Rekha, Balakrishnan Christy, Yacob Jenifer Anusha, Sivakumar Divya, Ganesan Suganya, Kannan Meganathan, Boominathan Kalyanaraman, Narayanan Vasudevan, Varadaraj Kamaraj, Raju Karthik, Maruthan Jeyakumar, Balakrishnan Abhishek, Albert Paul, Eldho Pushpanathan, Muthuirulan Rajmohan, Rajamani Koushick Velayutham, Kumaravel Lyon, Alexander R. Ramasamy, Subbiah TI Gut microbial degradation of organophosphate insecticides-induces glucose intolerance via gluconeogenesis SO GENOME BIOLOGY LA English DT Article DE Organophosphates; Gut microbiota; Diabetes; Glucose intolerance; Acetic acid; Gluconeogenesis; Fecal transplantation; Metatranscriptomics; Metabolomics ID BRAIN NEURAL CIRCUITS; SMALL-INTESTINE; PESTICIDES; HEALTH; ASSAY; RAT; GLUCOSE-6-PHOSPHATASE; ASSOCIATION; HOMEOSTASIS; METABOLISM AB Background: Organophosphates are the most frequently and largely applied insecticide in the world due to their biodegradable nature. Gut microbes were shown to degrade organophosphates and cause intestinal dysfunction. The diabetogenic nature of organophosphates was recently reported but the underlying molecular mechanism is unclear. We aimed to understand the role of gut microbiota in organophosphate-induced hyperglycemia and to unravel the molecular mechanism behind this process. Results: Here we demonstrate a high prevalence of diabetes among people directly exposed to organophosphates in rural India (n = 3080). Correlation and linear regression analysis reveal a strong association between plasma organophosphate residues and HbA1c but no association with acetylcholine esterase was noticed. Chronic treatment of mice with organophosphate for 180 days confirms the induction of glucose intolerance with no significant change in acetylcholine esterase. Further fecal transplantation and culture transplantation experiments confirm the involvement of gut microbiota in organophosphate-induced glucose intolerance. Intestinal metatranscriptomic and host metabolomic analyses reveal that gut microbial organophosphate degradation produces short chain fatty acids like acetic acid, which induces gluconeogenesis and thereby accounts for glucose intolerance. Plasma organophosphate residues are positively correlated with fecal esterase activity and acetate level of human diabetes. Conclusion: Collectively, our results implicate gluconeogenesis as the key mechanism behind organophosphate-induced hyperglycemia, mediated by the organophosphate-degrading potential of gut microbiota. This study reveals the gut microbiome-mediated diabetogenic nature of organophosphates and hence that the usage of these insecticides should be reconsidered. C1 [Velmurugan, Ganesan; Parthasarathy, Ayothi; Babu, D. D. Venkatesh; Rekha, Balakrishnan; Christy, Yacob Jenifer; Anusha, Sivakumar; Meganathan, Boominathan; Karthik, Maruthan; Jeyakumar, Balakrishnan; Rajmohan, Rajamani Koushick; Ramasamy, Subbiah] Madurai Kamaraj Univ, Sch Biol Sci, Ctr Excellence Genom Sci, Dept Mol Biol, Madurai 625021, Tamil Nadu, India. [Ramprasath, Tharmarajan] Georgia State Univ, Ctr Sci Res, Ctr Mol & Translat Med, Atlanta, GA 30303 USA. [Swaminathan, Krishnan] Kovai Med Ctr & Hosp, KMCH Res Fdn, Coimbatore 641014, Tamil Nadu, India. [Mithieux, Gilles] INSERM, U1213, F-69372 Lyon, France. [Rajendhran, Jeyaprakash; Dinakaran, Vasudevan] Madurai Kamaraj Univ, Sch Biol Sci, Ctr Excellence Genom Sci, Dept Genet, Madurai 625021, Tamil Nadu, India. [Dhivakar, Mani; Thumburaj, Leishman John; Kalyanaraman, Narayanan; Kamaraj, Raju] Madurai Kamaraj Univ, Sch Biol Sci, Ctr Excellence Genom Sci, Dept Immunol, Madurai 625021, Tamil Nadu, India. [Freddy, Allen J.] Madras Christian Coll, Dept Zool, Madras 600059, Tamil Nadu, India. [Puhari, Shanavas Syed Mohamed; Divya, Ganesan; Vasudevan, Varadaraj; Abhishek, Albert; Paul, Eldho] Madurai Kamaraj Univ, Sch Biol Sci, Ctr Excellence Genom Sci, Dept Biochem, Madurai 625021, Tamil Nadu, India. [Suganya, Kannan] Madurai Kamaraj Univ, Sch Biol Sci, Ctr Excellence Genom Sci, Dept Microbial Technol, Madurai 625021, Tamil Nadu, India. [Pushpanathan, Muthuirulan] NICHHD, Lab Gene Regulat & Dev, Program Cellular Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Velayutham, Kumaravel] Alpha Hosp & Res Ctr, Inst Diabet & Endocrinol, Madurai 625009, Tamil Nadu, India. [Lyon, Alexander R.] Royal Brompton Hosp, NIHR Cardiovasc Biomed Res Unit, London, England. [Lyon, Alexander R.] Imperial Coll, London, England. RP Velmurugan, G; Ramasamy, S (reprint author), Madurai Kamaraj Univ, Sch Biol Sci, Ctr Excellence Genom Sci, Dept Mol Biol, Madurai 625021, Tamil Nadu, India. EM oomvel@gmail.com; subbiahr@nrcbsmku.org FU DBT-IPLS; DBT-RGYI; UGC-UPE; CAS; CEGS; NRCBS; SERB; DST-PURSE (Govt. of India); CSIR; UGC (Government of India); BHF Intermediate Research Fellowship [FS/11/67/28954]; NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, UK FX This study was funded by DBT-IPLS, -RGYI, UGC-UPE, -CAS, -CEGS, -NRCBS, SERB, and DST-PURSE (Govt. of India). GV is supported by CSIR and UGC (Government of India) through Senior Research Fellowship and Fellowship for Meritorious Students, respectively. ARL is supported by a BHF Intermediate Research Fellowship FS/11/67/28954 and the NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, UK. NR 56 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD JAN 24 PY 2017 VL 18 AR 8 DI 10.1186/s13059-016-1134-6 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EL7UQ UT WOS:000394826700001 PM 28115022 ER PT J AU Lee, HK Kim, HS Kim, JS Kim, YG Park, KH Lee, JH Kim, KH Chang, IY Bae, SC Kim, Y Hong, JT Kehrl, JH Han, SB AF Lee, Hong Kyung Kim, Hyung Sook Kim, Ji Sung Kim, Yong Guk Park, Ki Hwan Lee, Jae Hee Kim, Ki Hun Chang, In Young Bae, Sang-Cheol Kim, Youngsoo Hong, Jin Tae Kehrl, John H. Han, Sang-Bae TI CCL2 deficient mesenchymal stem cells fail to establish long-lasting contact with T cells and no longer ameliorate lupus symptoms SO SCIENTIFIC REPORTS LA English DT Article ID STROMAL CELLS; HEME OXYGENASE-1; DENDRITIC CELLS; NITRIC-OXIDE; MRL/LPR MICE; LYMPH-NODES; IN-VIVO; ERYTHEMATOSUS; ACTIVATION; TRANSPLANTATION AB Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by autoantibody production. Mesenchymal stem cells (MSCs) ameliorate SLE symptoms by targeting T cells, whereas the mechanisms of their efficacy remain incompletely understood. In this study, we show that transfer of human MSCs increased MRL.Fas(lpr) mouse survival, decreased T cell infiltration in the kidneys, and reduced T cell cytokine expression. In vitro, allogeneic mouse MSCs inhibited MRL.Fas(lpr) T cell proliferation and cytokine production. Time-lapse imaging revealed that MSCs recruited MRL.Fas(lpr) T cells establishing long-lasting cellular contacts by enhancing T cell VCAM-1 expression in a CCL2-dependent manner. In contrast, CCL2 deficient MSCs did not induce T cell migration and VCAM-1 expression, resulting in insufficient cell-cell contact. Consequently, CCL2 deficient MSCs did not inhibit IFN-gamma production by T cells and upon transfer no longer prolonged survival of MRL.Fas(lpr) mice. Taken together, our imaging study demonstrates that CCL2 enables the prolonged MSC-T cell interactions needed for sufficient suppression of autoreactive T cells and helps to understand how MSCs ameliorate symptoms in lupus-prone MRL.Fas(lpr) mice. C1 [Lee, Hong Kyung; Kim, Hyung Sook; Kim, Ji Sung; Kim, Yong Guk; Park, Ki Hwan; Lee, Jae Hee; Kim, Ki Hun; Kim, Youngsoo; Hong, Jin Tae; Han, Sang-Bae] Chungbuk Natl Univ, Coll Pharm, Cheongju 28160, Chungbuk, South Korea. [Kim, Hyung Sook; Chang, In Young] Corestem Inc, Gyeonggi 13486, South Korea. [Bae, Sang-Cheol] Hanyang Univ, Hosp Rheumat Dis, Seoul 04763, South Korea. [Kehrl, John H.] NIAID, NIH, Bethesda, MD 20892 USA. RP Han, SB (reprint author), Chungbuk Natl Univ, Coll Pharm, Cheongju 28160, Chungbuk, South Korea. EM shan@chungbuk.ac.kr FU Korean Government [NRF-2008-0062275, KHIDI-HI12C0347, KHIDI-HI15C0778] FX This work was supported by grants funded by the Korean Government (NRF-2008-0062275, KHIDI-HI12C0347, and KHIDI-HI15C0778). NR 56 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 24 PY 2017 VL 7 AR 41258 DI 10.1038/srep41258 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ4PT UT WOS:000393200000001 PM 28117437 ER PT J AU Dalton, G An, SW Al-Juboori, SI Nischan, N Yoon, J Dobrinskikh, E Hilgemann, DW Xie, J Luby-Phelps, K Kohler, JJ Birnbaumer, L Huang, CL AF Dalton, George An, Sung-Wan Al-Juboori, Saif I. Nischan, Nicole Yoon, Joonho Dobrinskikh, Evgenia Hilgemann, Donald W. Xie, Jian Luby-Phelps, Kate Kohler, Jennifer J. Birnbaumer, Lutz Huang, Chou-Long TI Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE soluble klotho; lipid rafts; gangliosides; sialic acids; TRPC6 ID PLASMA-MEMBRANE; TRPV5 CHANNEL; PROTEIN; TRPC6; ACTIVATION; HEART; RAFTS; MODEL AB Soluble klotho, the shed ectodomain of the antiaging membrane protein a-klotho, is a pleiotropic endocrine/paracrine factor with no known receptors and poorly understood mechanism of action. Soluble klotho down-regulates growth factor-driven PI3K signaling, contributing to extension of lifespan, cardioprotection, and tumor inhibition. Here we show that soluble klotho binds membrane lipid rafts. Klotho binding to rafts alters lipid organization, decreases membrane's propensity to form large ordered domains for endocytosis, and down-regulates raft-dependent PI3K/Akt signaling. We identify alpha 2-3-sialyllactose present in the glycan of monosialogangliosides as targets of soluble klotho. alpha 2-3-Sialyllactose is a common motif of glycans. To explain why klotho preferentially targets lipid rafts we show that clustering of gangliosides in lipid rafts is important. In vivo, raft-dependent PI3K signaling is up-regulated in klotho-deficient mouse hearts vs. wild-type hearts. Our results identify ganglioside-enriched lipid rafts to be receptors that mediate soluble klotho regulation of PI3K signaling. Targeting sialic acids may be a general mechanism for pleiotropic actions of soluble klotho. C1 [Dalton, George; An, Sung-Wan; Yoon, Joonho; Xie, Jian; Huang, Chou-Long] Univ Texas Southwestern Med Ctr Dallas, Dept Med, Dallas, TX 75390 USA. [Al-Juboori, Saif I.] Univ Colorado Denver, Dept Elect Engn, Denver, CO 80204 USA. [Nischan, Nicole; Kohler, Jennifer J.] Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Dobrinskikh, Evgenia] Univ Colorado Denver, Dept Med, Denver, CO 80204 USA. [Hilgemann, Donald W.] Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA. [Luby-Phelps, Kate] Univ Texas Southwestern Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA. [Luby-Phelps, Kate] Univ Texas Southwestern Med Ctr Dallas, Live Cell Imaging Core Facil, Dallas, TX 75390 USA. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Birnbaumer, Lutz] Catholic Univ Argentina, Inst Biomed Res, Sch Med Sci, C1107AAZ, Buenos Aires, DF, Argentina. RP Huang, CL (reprint author), Univ Texas Southwestern Med Ctr Dallas, Dept Med, Dallas, TX 75390 USA.; Birnbaumer, L (reprint author), NIEHS, Neurobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA.; Birnbaumer, L (reprint author), Catholic Univ Argentina, Inst Biomed Res, Sch Med Sci, C1107AAZ, Buenos Aires, DF, Argentina. EM Birnbau1@gmail.com; chou-long.huang@utsouthwestern.edu FU NIH [DK85726, DK100605, HL119843]; Intramural Research Program of the NIH [Z01-ES-101684]; Welch Foundation [I-1686]; NIH/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Institute [UL1 TR001082] FX We thank Moshe Levi and Tim Lei for discussion and support, Amberlyn Wands and Janet McCombs for participation in the early stage of the project, and Marc Diamond and Jaime Vaquer-Alicea for provision of the Octet and helpful discussions. This work was supported in part by NIH Grants DK85726, DK100605, and HL119843, the Intramural Research Program of the NIH, Project Z01-ES-101684 (L.B.), Welch Foundation Grant I-1686, and NIH/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Institute Grant UL1 TR001082. NR 31 TC 0 Z9 0 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 24 PY 2017 VL 114 IS 4 BP 752 EP 757 DI 10.1073/pnas.1620301114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI6HV UT WOS:000392597000052 PM 28069944 ER PT J AU Harami, GM Seol, Y In, J Ferencziova, V Martina, M Gyimesi, M Sarlos, K Kovacs, ZJ Nagy, NT Sun, YZ Vellai, T Neuman, KC Kovacs, M AF Harami, Gabor M. Seol, Yeonee In, Junghoon Ferencziova, Veronika Martina, Mate Gyimesi, Mate Sarlos, Kata Kovacs, Zoltan J. Nagy, Nikolett T. Sun, Yuze Vellai, Tibor Neuman, Keir C. Kovacs, Mihaly TI Shuttling along DNA and directed processing of D-loops by RecQ helicase support quality control of homologous recombination SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE RecQ; helicase; magnetic tweezers; single molecule; DNA unwinding ID BLOOMS SYNDROME HELICASE; SINGLE-STRANDED-DNA; ESCHERICHIA-COLI; HRDC DOMAIN; BLM HELICASE; ILLEGITIMATE RECOMBINATION; STRUCTURAL MECHANISMS; REPLICATION FORKS; NS3 HELICASE; E. COLI AB Cells must continuously repair inevitable DNA damage while avoiding the deleterious consequences of imprecise repair. Distinction between legitimate and illegitimate repair processes is thought to be achieved in part through differential recognition and processing of specific noncanonical DNA structures, although the mechanistic basis of discrimination remains poorly defined. Here, we show that Escherichia coli RecQ, a central DNA recombination and repair enzyme, exhibits differential processing of DNA substrates based on their geometry and structure. Through single-molecule and ensemble biophysical experiments, we elucidate how the conserved domain architecture of RecQ supports geometry-dependent shuttling and directed processing of recombination-intermediate [displacement loop (D-loop)] substrates. Our study shows that these activities together suppress illegitimate recombination in vivo, whereas unregulated duplex unwinding is detrimental for recombination precision. Based on these results, we propose a mechanism through which RecQ helicases achieve recombination precision and efficiency. C1 [Harami, Gabor M.; Ferencziova, Veronika; Martina, Mate; Gyimesi, Mate; Sarlos, Kata; Kovacs, Zoltan J.; Nagy, Nikolett T.; Kovacs, Mihaly] Hungarian Acad Sci, Lorand Eotvos Univ, Momentum Motor Enzymol Res Grp, Dept Biochem, H-1117 Budapest, Hungary. [Seol, Yeonee; In, Junghoon; Sun, Yuze; Neuman, Keir C.] NHLBI, Lab Single Mol Biophys, NIH, Bethesda, MD 20892 USA. [Vellai, Tibor] Eotvos Lorand Univ, Dept Genet, H-1117 Budapest, Hungary. [Harami, Gabor M.; Seol, Yeonee] Univ Texas Arlington, Dept Elect Engn, Arlington, TX 76011 USA. RP Kovacs, M (reprint author), Hungarian Acad Sci, Lorand Eotvos Univ, Momentum Motor Enzymol Res Grp, Dept Biochem, H-1117 Budapest, Hungary.; Neuman, KC (reprint author), NHLBI, Lab Single Mol Biophys, NIH, Bethesda, MD 20892 USA. EM neumankc@mail.nih.gov; mihaly.kovacs@ttk.elte.hu RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU Human Frontier Science Program [RGY0072/2010]; Hungarian Academy of Sciences "Momentum" Program [LP2011-006/2011]; Eotvos Lorand University [KMOP-4.2.1/B-10-2011-0002]; National Research, Development and Innovation Office (NKFIH) [K-116072]; NKFIH Grant [ERC_HU 117680]; National Heart, Lung, and Blood Institute, National Institutes of Health, Intramural Research Program [HL001056-07]; Marie Sklodowska-Curie Reintegration Fellowship [H2020-MSCA-IF-2014-657076] FX We are grateful to Dr. Marie-Paule Strub for assistance with protein expression and purification, Dr. Duck-Yeon Lee (National Heart, Lung, and Blood Institute Biochemistry Core) for assistance with mass spectroscopy, and Drs. Hideo Ikeda and Yasuyuki Ogata for providing the YmeI, WL95, and HI1165 E. coli strains. This work was supported by Human Frontier Science Program Grant RGY0072/2010 (to M.K. and K.C.N.); Hungarian Academy of Sciences "Momentum" Program Grant LP2011-006/2011 (to M.K.); Eotvos Lorand University Grant KMOP-4.2.1/B-10-2011-0002; National Research, Development and Innovation Office (NKFIH) Grant K-116072; and NKFIH Grant ERC_HU 117680 (to M.K.). This work was supported in part by National Heart, Lung, and Blood Institute, National Institutes of Health, Intramural Research Program Grant HL001056-07 (to K.C.N.). M.G. is supported by Marie Sklodowska-Curie Reintegration Fellowship H2020-MSCA-IF-2014-657076. NR 63 TC 0 Z9 0 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 24 PY 2017 VL 114 IS 4 BP E466 EP E475 DI 10.1073/pnas.1615439114 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI6HV UT WOS:000392597000004 PM 28069956 ER PT J AU Cong, L Cheng, Y Cawley, NX Murthy, SRK Loh, YP AF Cong, Lin Cheng, Yong Cawley, Niamh X. Murthy, Saravana R. K. Loh, Y. Peng TI A Novel Single Nucleotide T980C Polymorphism in the Human Carboxypeptidase E Gene Results in Loss of Neuroprotective Function SO PLOS ONE LA English DT Article ID ENDOPLASMIC-RETICULUM; OBESITY; DISEASE; STRESS; DEGENERATION; DEFICITS; MOUSE; DEATH AB Report of a human with a homozygous truncating null mutation of the Carboxypeptidase E (CPE) gene with endocrinological and neurological deficits prompted us to search for other mutations in the human CPE gene that might be linked to disease. We searched an EST database and identified from a small population of patients, a novel T to C single nucleotide polymorphism (SNP) in the CPE gene at bp980 of exon 4, herein called TC-CPE. This introduces a tryptophan to arginine (W235R) mutation in the catalytic domain of human CPE protein. Over-expression of TC-CPE in N2A cells, a neuroendocrine cell line, showed that it was synthesized, but was found in lesser amounts compared to over-expressed WT-CPE in these cells. Furthermore, TC-CPE was secreted poorly from these N2A cells. The levels of TC-CPE were significantly increased after the N2A cells were treated with MG132 (a proteasome inhibitor), suggesting that TC-CPE was targeted to proteasomes for degradation in N2A cells. In addition, TC-CPE induced ER stress as demonstrated by the increased expression of CHOP in N2A cells. Double labeling of CPE and calnexin (and ER marker) suggested the accumulation of TC-CPE in the ER, and the accumulation appears to be enhanced by the treatment of MG132 in the cells. Moreover, the secreted levels of TC-CPE were not affected by the treatment of MG132 in the cells. Over-expression studies revealed that while N2A cells transfected with WT-CPE showed reduced cytotoxicity when challenged with H2O2 compared to cells expressing an empty vector, cells transfected with TC-CPE had no effect. Furthermore, WT-CPE condition medium showed protective effect against oxidative stress, but not TC-CPE condition medium. Although co-expression of WT-CPE and TC-CPE in N2A cells resulted in the reduction in secretion of WT-CPE, co-expression of WT-CPE and TC-CPE did not significantly affect the protective effect of WT-CPE. Taken together, we have identified a novel SNP in the CPE gene which results in the loss of its neuroprotective function in cells and may confer neurological disorders in humans. C1 [Cong, Lin] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Gen Surg, Beijing, Peoples R China. [Cong, Lin] Peking Union Med Coll, Beijing, Peoples R China. [Cong, Lin; Cheng, Yong; Cawley, Niamh X.; Murthy, Saravana R. K.; Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA. NR 27 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 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 23 PY 2017 VL 12 IS 1 AR e0170169 DI 10.1371/journal.pone.0170169 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6QR UT WOS:000396129000022 PM 28114332 ER PT J AU Bolton, DL Song, KM Tomaras, GD Rao, S Roederer, M AF Bolton, Diane L. Song, Kaimei Tomaras, Georgia D. Rao, Srinivas Roederer, Mario TI Unique cellular and humoral immunogenicity profiles generated by aerosol, intranasal, or parenteral vaccination in rhesus macaques SO VACCINE LA English DT Article DE Aerosol; Nasal; Vaccine delivery route; Immunogenicity; Rhesus macaque ID ORIGINAL ANTIGENIC SIN; IMMUNE-RESPONSES; NEUTRALIZING ANTIBODIES; MEASLES VACCINATION; IMMUNIZATION; SECRETIONS; GENE; PROTECTION; CHALLENGE; VACCINES AB Respiratory mucosa immunization is capable of eliciting both local and distal mucosal immune responses; it is a potentially powerful yet largely unused modality for vaccination against respiratory diseases. Targeting the lower versus upper airways by aerosol delivery alters the immunogenicity profile of a vaccine, although the full extent of this impact is not well characterized. We set out to define the cellular and humoral response profiles elicited by immunization via intranasal, small aerosol droplets, and large aerosol droplets. We compared responses following adenovirus-vectored vaccination by these routes in macaques, either for the generation of primary immune responses or for the boosting of previously primed systemic responses. Aerosol delivery (4 or 10 mu m diameter droplets, addressing lower or upper airways, respectively) generated the highest magnitude lung CD4 and CD8 T-cell responses, reaching 10-30% vaccine-specific levels in bronchoalveolar lavage cells. In contrast, intranasal delivery was less immunogenic with >10-fold lower peak lung T-cell responses. Systemic (blood) T-cell responses were only observed following 4 pm aerosol (and parenteral) immunization, while all delivery routes elicited similar humoral responses. These data demonstrate distinct immune response profiles with each respiratory tract vaccination modality and suggest that small droplet aerosol offers several immunological advantages over other respiratory routes. Published by Elsevier Ltd. C1 [Bolton, Diane L.; Song, Kaimei; Rao, Srinivas; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Tomaras, Georgia D.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Bolton, Diane L.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. [Bolton, Diane L.] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD 20818 USA. [Rao, Srinivas] SanofiPasteur, 38 Sidney St 370, Cambridge, MA 02139 USA. RP Roederer, M (reprint author), NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM roederer@nih.gov FU Intramural Research Program of the Vaccine Research Center, NIAID, NIH; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-07-2-0067]; U.S. Department of Defense (DOD) [W81XWH-07-2-0067] FX This work was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, NIH and by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DOD). The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense. NR 36 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JAN 23 PY 2017 VL 35 IS 4 BP 639 EP 646 DI 10.1016/j.vaccine.2016.12.008 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EK1XQ UT WOS:000393721500020 PM 28041780 ER PT J AU Leopold, DA Russ, BE AF Leopold, David A. Russ, Brian E. TI Human Neurophysiology: Sampling the Perceptual World SO CURRENT BIOLOGY LA English DT Editorial Material ID NATURAL VISION; VISUAL SPACE; HUMAN BRAIN; REPRESENTATION; CORTEX; NEURONS; MACAQUE C1 [Leopold, David A.; Russ, Brian E.] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, 49 Convent Dr 1E21,MSC 4400, Bethesda, MD 20892 USA. RP Leopold, DA; Russ, BE (reprint author), NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, 49 Convent Dr 1E21,MSC 4400, Bethesda, MD 20892 USA. EM leopoldd@mail.nih.gov; brian.russ@nih.gov NR 18 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD JAN 23 PY 2017 VL 27 IS 2 BP R71 EP R73 DI 10.1016/j.cub.2016.11.051 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EJ0MQ UT WOS:000392904000013 PM 28118593 ER PT J AU Gittelsohn, J Jock, B Redmond, L Fleischhacker, S Eckmann, T Bleich, SN Loh, H Ogburn, E Gadhoke, P Swartz, J Pardilla, M Caballero, B AF Gittelsohn, Joel Jock, Brittany Redmond, Leslie Fleischhacker, Sheila Eckmann, Thomas Bleich, Sara N. Loh, Hong Ogburn, Elizabeth Gadhoke, Preety Swartz, Jacqueline Pardilla, Marla Caballero, Benjamin TI OPREVENT2: Design of a multi-institutional intervention for obesity control and prevention for American Indian adults SO BMC PUBLIC HEALTH LA English DT Article DE Obesity; Adults; Rural; American Indian; Multi-level interventions; Policy; Study design ID PHYSICAL-ACTIVITY; CHILDHOOD OBESITY; SOCIAL NETWORKS; DIETARY-INTAKE; UNITED-STATES; SCHOOL; PATHWAYS; CHILDREN; COMMUNITIES; POPULATIONS AB Background: Obesity and other nutrition-related chronic disease rates are high in American Indian (AI) populations, and an urgent need exists to identify evidence-based strategies for prevention and treatment. Multi-level, multicomponent (MLMC) interventions are needed, but there are significant knowledge gaps on how to deliver these types of interventions in low-income rural AI communities. Methods: OPREVENT2 is a MLMC intervention targeting AI adults living in six rural reservations in New Mexico and Wisconsin. Aiming to prevent and reduce obesity in adults by working at multiple levels of the food and physical activity (PA) environments, OPREVENT2 focuses on evidence-based strategies known to increase access to, demand for, and consumption of healthier foods and beverages, and increase worksite and home-based opportunities for PA. OPREVENT2 works to create systems-level change by partnering with tribal stakeholders, multiple levels of the food and PA environment (food stores, worksites, schools), and the social environment (children as change agents, families, social media). Extensive evaluation will be conducted at each level of the intervention to assess effectiveness via process and impact measures. Discussion: Novel aspects of OPREVENT2 include: active engagement with stakeholders at many levels (policy, institutional, and at multiple levels of the food and PA system); use of community-based strategies to engage policymakers and other key stakeholders (community workshops, action committees); emphasis on both the built environment (intervening with retail food sources) and the social environment. This paper describes the design of the intervention and the evaluation plan of the OPREVENT2. C1 [Gittelsohn, Joel; Jock, Brittany; Redmond, Leslie; Eckmann, Thomas; Loh, Hong; Ogburn, Elizabeth; Swartz, Jacqueline; Pardilla, Marla; Caballero, Benjamin] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, 615 N Wolfe St Suite W2041, Baltimore, MD 21205 USA. [Fleischhacker, Sheila] Natl Inst Diabet Digest & Kidney Dis, Off Nutr Res, Bethesda, MD USA. [Bleich, Sara N.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Gadhoke, Preety] St Johns Univ, Queens, NY USA. RP Gittelsohn, J (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, 615 N Wolfe St Suite W2041, Baltimore, MD 21205 USA. EM jgittel1@jhu.edu FU National Heart, Lung, and Blood Institute [R01HL122150] FX Funding for this study was provided by the National Heart, Lung, and Blood Institute (R01HL122150; J. Gittelsohn). NR 48 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD JAN 23 PY 2017 VL 17 AR 105 DI 10.1186/s12889-017-4018-0 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ0QF UT WOS:000392914500002 PM 28114926 ER PT J AU Jin, TC Chuenchor, W Jiang, JS Cheng, JB Li, YJ Fang, K Huang, M Smith, P Xiao, TS AF Jin, Tengchuan Chuenchor, Watchalee Jiang, Jiansheng Cheng, Jinbo Li, Yajuan Fang, Kang Huang, Mo Smith, Patrick Xiao, Tsan Sam TI Design of an expression system to enhance MBP-mediated crystallization SO SCIENTIFIC REPORTS LA English DT Article ID MALTOSE-BINDING PROTEIN; CASPASE-RECRUITMENT DOMAIN; IN-SITU PROTEOLYSIS; CRYSTAL-STRUCTURE; DEATH DOMAIN; DRIVEN CRYSTALLIZATION; STRUCTURAL INSIGHTS; LYSINE METHYLATION; COMPLEX; RECEPTOR AB Crystallization chaperones have been used to facilitate the crystallization of challenging proteins. Even though the maltose-binding protein (MBP) is one of the most commonly used crystallization chaperones, the design of optimal expression constructs for crystallization of MBP fusion proteins remains a challenge. To increase the success rate of MBP-facilitated crystallization, a series of expression vectors have been designed with either a short flexible linker or a set of rigid helical linkers. Seven death domain superfamily members were tested for crystallization with this set of vectors, six of which had never been crystallized before. All of the seven targets were crystallized, and their structures were determined using at least one of the vectors. Our successful crystallization of all of the targets demonstrates the validity of our approach and expands the arsenal of the crystallization chaperone toolkit, which may be applicable to crystallization of other difficult protein targets, as well as to other crystallization chaperones. C1 [Jin, Tengchuan; Cheng, Jinbo; Li, Yajuan; Fang, Kang] Univ Sci & Technol China, CAS Ctr Excellence Mol Cell Sci, Sch Life Sci,Lab Struct Immunol, CAS Key Lab Innate Immun & Chron Dis, Hefei 230027, Peoples R China. [Jin, Tengchuan; Cheng, Jinbo; Li, Yajuan; Fang, Kang] Univ Sci & Technol China, Med Ctr, Hefei 230027, Peoples R China. [Jin, Tengchuan; Chuenchor, Watchalee; Jiang, Jiansheng; Huang, Mo; Smith, Patrick] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Xiao, Tsan Sam] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. RP Jin, TC (reprint author), Univ Sci & Technol China, CAS Ctr Excellence Mol Cell Sci, Sch Life Sci,Lab Struct Immunol, CAS Key Lab Innate Immun & Chron Dis, Hefei 230027, Peoples R China.; Jin, TC (reprint author), Univ Sci & Technol China, Med Ctr, Hefei 230027, Peoples R China.; Jin, TC (reprint author), NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA.; Xiao, TS (reprint author), Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. EM jint@ustc.edu.cn; tsan.xiao@case.edu FU National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-98CH10886]; Case Research Institute; University Hospitals Case Medical Center; Fundamental Research Funds for the Central Universities; 100 Talents Program of CAS; China Postdoctoral Science Foundation [2015M582007] FX The authors would like to thank Xinhua Ji at the National Cancer Institute for suggestions and discussions, Lars C. Pedersen at the National Institute of Environmental Health Sciences (NIEHS) for providing us the pMAL-MBP wild type and mutant plasmids. X-ray diffraction data were collected at the Advanced Photon Source (APS) GM/CA beamline, which is funded in whole or in part by funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Sciences (Y1-GM-1104). Some data was collected at the National Synchrotron Light Source (NSLS) beamline X-25 at the Brookhaven National Laboratory (BNL). Use of the NSLS is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-98CH10886. We'd like to thank the beamline scientists at both synchrotrons for their assistance. T.S.X. is supported by the Case Research Institute and the University Hospitals Case Medical Center. T.J. is supported by the Fundamental Research Funds for the Central Universities and the 100 Talents Program of CAS. Y.L. is supported by the China Postdoctoral Science Foundation (Grant No.: 2015M582007). NR 58 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 23 PY 2017 VL 7 AR 40991 DI 10.1038/srep40991 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI3RW UT WOS:000392410000001 PM 28112203 ER PT J AU Kim, GY Lee, YM Kwon, JH Jun, HS Chou, J AF Kim, Goo-Young Lee, Young Mok Kwon, Joon Hyun Jun, Hyun Sik Chou, Janice TI Glycogen storage disease type Ib neutrophils exhibit impaired cell adhesion and migration SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Glucose-6-phosphate transporter; CD11 a; CD11 b; Neutrophil adhesion; Migration ID COLONY-STIMULATING FACTOR; GM-CSF; NEUTROPENIA; DYSFUNCTION; GRANULOCYTE; LFA-1; MAC-1; TRANSDUCTION; MECHANISMS; EXPRESSION AB Glycogen storage disease type lb (GSD-Ib), characterized by impaired glucose homeostasis, neutropenia, and neutrophil dysfunction, is an inherited autosomal recessive disorder caused by a deficiency in the glucose-6-phosphate transporter (G6PT). Neutrophils play an essential role in the defense against invading pathogens. The recruitment of neutrophils towards the inflammation sites in response to inflammatory stimuli is a tightly regulated process involving rolling, adhesion, and transmigration. In this study, we investigated the role of G6PT in neutrophil adhesion and migration using in vivo and in vitro models. We showed that the GSD-lb (G6pt(-1-)) mice manifested severe neutropenia in both blood and bone marrow, and treating G6pt(-1-) mice with granulocyte colony-stimulating factor (G-CSF) corrected neutropenia. However, upon thioglycolate challenge, neutrophils from both untreated and G-CSF-treated G6p(-1-)mice exhibited decreased ability to migrate to the peritoneal cavity. In vitro migration and cell adhesion of G6PT-deficient neutrophils were also significantly impaired. Defects in cell migration were not due to enhanced apoptosis or altered fMLP receptor expression. Remarkably, the expression of the 1132 integrins CD11a and CD11b, which are critical for cell adhesion, was greatly decreased in G6PT-deficient neutrophils. This study suggests that deficiencies in G6PT cause impairment in neutrophil adhesion and migration via aberrant expression of (32 integrins, and our finding should facilitate the development of novel therapies for GSD-Ib. (C) 2016 Elsevier Inc. All rights reserved. C1 [Kim, Goo-Young; Lee, Young Mok; Kwon, Joon Hyun; Chou, Janice] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, NIH, Bethesda, MD 20892 USA. [Jun, Hyun Sik] Korea Univ, Dept Biotechnol & Bioinformat, Coll Sci & Technol, Sejong 339700, South Korea. RP Jun, HS (reprint author), Korea Univ, Dept Biotechnol & Bioinformat, Coll Sci & Technol, Sejong 339700, South Korea.; Chou, J (reprint author), Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM toddjun@korea.ac.kr; chouja@mail.nih.gov OI Jun, Hyun Sik/0000-0002-1570-7784 FU Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; "Cooperative Research Program for Agriculture Science & Technology Development" Rural Development Administration, Republic of Korea [PJ011834] FX This work was carried out with the support of the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. Additional support was provided by "Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ011834)" Rural Development Administration, Republic of Korea. NR 31 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 22 PY 2017 VL 482 IS 4 BP 569 EP 574 DI 10.1016/j.bbrc.2016.11.075 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA EK1XB UT WOS:000393720000009 PM 27864142 ER PT J AU Kwong, RY Petersen, SE Schulz-Menger, J Arai, AE Bingham, SE Chen, YC Choi, YL Cury, RC Ferreira, VM Flamm, SD Steel, K Bandettini, WP Martin, ET Nallamshetty, L Neubauer, S Raman, SV Schelbert, EB Valeti, US Cao, JJ Reichek, N Young, AA Fexon, L Pivovarov, M Ferrari, VA Simonetti, OP AF Kwong, Raymond Y. Petersen, Steffen E. Schulz-Menger, Jeanette Arai, Andrew E. Bingham, Scott E. Chen, Yucheng Choi, Yuna L. Cury, Ricardo C. Ferreira, Vanessa M. Flamm, Scott D. Steel, Kevin Bandettini, W. Patricia Martin, Edward T. Nallamshetty, Leelakrishna Neubauer, Stefan Raman, Subha V. Schelbert, Erik B. Valeti, Uma S. Cao, Jie Jane Reichek, Nathaniel Young, Alistair A. Fexon, Lyuba Pivovarov, Misha Ferrari, Victor A. Simonetti, Orlando P. CA Global Cardiovas Magnetic Resonan TI The global cardiovascular magnetic resonance registry (GCMR) of the society for cardiovascular magnetic resonance (SCMR): its goals, rationale, data infrastructure, and current developments SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Registry; Cardiovascular magnetic resonance; Imaging; Patient management; Therapeutic implications ID ACUTE ADVERSE-REACTIONS; EUROCMR REGISTRY; CONTRAST AGENTS; CMR PROTOCOLS; EXPERIENCE; UPDATE AB Background: With multifaceted imaging capabilities, cardiovascular magnetic resonance (CMR) is playing a progressively increasing role in the management of various cardiac conditions. A global registry that harmonizes data from international centers, with participation policies that aim to be open and inclusive of all CMR programs, can support future evidence-based growth in CMR. Methods: The Global CMR Registry (GCMR) was established in 2013 under the auspices of the Society for Cardiovascular Magnetic Resonance (SCMR). The GCMR team has developed a web-based data infrastructure, data use policy and participation agreement, data-harmonizing methods, and site-training tools based on results from an international survey of CMR programs. Results: At present, 17 CMR programs have established a legal agreement to participate in GCMR, amongst them 10 have contributed CMR data, totaling 62,456 studies. There is currently a predominance of CMR centers with more than 10 years of experience (65%), and the majority are located in the United States (63%). The most common clinical indications for CMR have included assessment of cardiomyopathy (21%), myocardial viability (16%), stress CMR perfusion for chest pain syndromes (16%), and evaluation of etiology of arrhythmias or planning of electrophysiological studies (15%) with assessment of cardiomyopathy representing the most rapidly growing indication in the past decade. Most CMR studies involved the use of gadolinium-based contrast media (95%). Conclusions: We present the goals, mission and vision, infrastructure, preliminary results, and challenges of the GCMR. C1 [Kwong, Raymond Y.; Choi, Yuna L.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Kwong, Raymond Y.] Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA. [Petersen, Steffen E.] William Harvey Res Inst, London, England. [Schulz-Menger, Jeanette] Charite, Berlin, Germany. [Arai, Andrew E.; Bandettini, W. Patricia] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Bingham, Scott E.] Revere Hlth, Provo, UT USA. [Chen, Yucheng] West China Hosp, Chengdu, Peoples R China. [Cury, Ricardo C.] Miami Cardiac & Vasc Inst, Miami, FL USA. [Ferreira, Vanessa M.; Neubauer, Stefan] Univ Oxford, Oxford, England. [Flamm, Scott D.] Cleveland Clin, Cleveland, OH 44106 USA. [Steel, Kevin] San Antonio Mil Med Ctr, San Antonio, TX USA. [Martin, Edward T.] Oklahoma Heart Inst, Tulsa, OK USA. [Nallamshetty, Leelakrishna] Univ S Florida, Miami, FL USA. [Raman, Subha V.] Ohio State Univ, Wexner Med Ctr, Cleveland, OH USA. [Schelbert, Erik B.] Univ Pittsburgh, Pittsburgh, PA USA. [Valeti, Uma S.] Univ Minnesota, Minneapolis, MN 55455 USA. [Cao, Jie Jane; Reichek, Nathaniel] St Francis Hosp, New York, NY USA. [Young, Alistair A.] Univ Auckland, Auckland, New Zealand. [Fexon, Lyuba; Pivovarov, Misha] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ferrari, Victor A.] Univ Penn, Philadelphia, PA 19104 USA. [Simonetti, Orlando P.] Ohio State Univ, Columbus, OH 43210 USA. RP Kwong, RY (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA.; Kwong, RY (reprint author), Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA. EM rykwong@partners.org FU SCMR [SCMR_GRANT_001] FX GCMR received seed funding from SCMR (SCMR_GRANT_001) for the development and maintenance of GCMR websites and database infrastructure. NR 9 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JAN 20 PY 2017 VL 19 AR 23 DI 10.1186/s12968-016-0321-7 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EM7FN UT WOS:000395477000001 ER PT J AU Knobler, S Bok, K Gellin, B AF Knobler, Stacey Bok, Karin Gellin, Bruce TI Informing vaccine decision-making: A strategic multi-attribute ranking tool for vaccines-SMART Vaccines 2.0 SO VACCINE LA English DT Editorial Material DE Vaccine; Vaccine decision making; Public health; Global health AB SMART Vaccines 2.0 software is being developed to support decision-making among multiple stakeholders in the process of prioritizing investments to optimize the outcomes of vaccine development and deployment. Vaccines and associated vaccination programs are one of the most successful and effective public health interventions to prevent communicable diseases and vaccine researchers are continually working towards expanding targets for communicable and non-communicable diseases through preventive and therapeutic modes. A growing body of evidence on emerging vaccine technologies, trends in disease burden, costs associated with vaccine development and deployment, and benefits derived from disease prevention through vaccination and a range of other factors can inform decision-making and investment in new and improved vaccines and targeted utilization of already existing vaccines. Recognizing that an array of inputs influences these decisions, the strategic multi-attribute ranking method for vaccines (SMART Vaccines 2.0) is in development as a web-based tool modified from a U. S. Institute of Medicine Committee effort (IOM, 2015) to highlight data needs and create transparency to facilitate dialogue and information-sharing among decision-makers and to optimize the investment of resources leading to improved health outcomes. Current development efforts of the SMART Vaccines 2.0 framework seek to generate a weighted recommendation on vaccine development or vaccination priorities based on population, disease, economic, and vaccine-specific data in combination with individual preference and weights of user-selected attributes incorporating valuations of health, economics, demographics, public concern, scientific and business, programmatic, and political considerations. Further development of the design and utility of the tool is being carried out by the National Vaccine Program Office of the Department of Health and Human Services and the Fogarty International Center of the National Institutes of Health. We aim to demonstrate the utility of SMART Vaccines 2.0 through the engagement of a community of relevant stakeholders and to identify a limited number of pilot projects to determine explicitly defined attribute preferences and the related data and model requirements that are responsive to user needs and able to improve the use of evidence for vaccine-related decision-making and consequential priorities of vaccination options. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Knobler, Stacey] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Bok, Karin; Gellin, Bruce] US Dept Hlth & Human Serv, Natl Vaccine Program Off, Washington, DC USA. RP Knobler, S (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, 16 Ctr Dr,Bldg 16,Room 202, Bethesda, MD 20892 USA. EM stacey.knobler@nih.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JAN 20 PY 2017 VL 35 SU 1 BP A43 EP A45 DI 10.1016/j.vaccine.2016.10.086 PG 3 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EJ5KU UT WOS:000393257700010 PM 28017435 ER PT J AU Shinomiya, K Zaima, K Harada, Y Yasue, M Harikai, N Tokura, K Ito, Y AF Shinomiya, Kazufusa Zaima, Kazumasa Harada, Yukina Yasue, Miho Harikai, Naoki Tokura, Koji Ito, Yoichiro TI Comparison of the peak resolution and the stationary phase retention between the satellite and the planetary motions using the coil satellite centrifuge with counter-current chromatographic separation of 4-methylumbelliferyl sugar derivatives SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 9th International Counter-Current Chromatography Conference (CCC) CY AUG 01-03, 2016 CL Chicago, IL DE Counter-current chromatography; Instrumentation; Coil satellite centrifuge; Partition efficiency; Separation of sugar derivatives ID 2-PHASE SOLVENT SYSTEMS; ROTARY SEALS AB Coil satellite centrifuge (CSC) produces the complex satellite motion consisting of the triplicate rotation of the coiled column around three axes including the sun axis (the angular velocity, omega(1)), the planet axis (omega(2)) and the satellite axis (the central axis of the column) (omega(3)) according to the following formula: omega(1) = omega(2) + omega(3). Improved peak resolution in the separation of 4-methylumbelliferyl sugar derivatives was achieved using the conventional multilayer coiled columns with ethyl acetate/1-butanol/water (3: 2: 5, v/v) for the lower mobile phase at the combination of the rotation speeds (omega(1), omega(2), omega(3)) = (300, 150, 150 rpm), and (1:4:5, v/v) for the upper mobile phase at (300:100:200 rpm). The effect of the satellite motion on the peak resolution and the stationary phase retention was evaluated by each CSC separation with the different rotation speeds of omega(2) and omega(3) under the constant revolution speed at omega(1) = 300 rpm. With the lower mobile phase, almost constant peak resolution and stationary phase retention were yielded regardless of the change of omega(2) and omega(3), while with the upper mobile phase these two values were sensitively varied according to the different combination of omega(2) and omega(3). For example, when omega(2) =147 or 200 rpm is used, no stationary phase was retained in the coiled column while omega(2)=150 rpm could retain enough volume of stationary phase for separation. On the other hand, the combined rotation speeds at (omega(1), omega(2), omega(3)) = (300, 300, 0 rpm) or (300, 0, 300 rpm) produced insufficient peak resolution regardless of the choice of the mobile phase apparently due to the lack of rotation speed except at (300, 0, 300 rpm) with the upper mobile phase. At lower rotation speed of omega(1) = 300 rpm, better peak resolution and stationary phase retention were obtained by the satellite motion (omega(3)) than by the planetary motion (omega(2)), or (omega(3) > omega(2). The effect of the hydrophobicity of the two-phase solvent systems on the stationary phase retention was further examined using the n-hexane/ethyl acetate/1-butanol/methanol/water system at different volume ratios. In the satellite motion at (omega(1), omega(2), omega(3)) = (300, 150, 150 rpm), almost constant stationary phase retention was obtained with the lower mobile phase regardless of the hydrophobicity of the solvent system whereas the stationary phase retention varied according to the volume ratio of the two-phase solvent system for the upper mobile phase. However, stable stationary phase retention was observed with either phase used as the mobile phase.In order to analyze the acceleration acting on the coiled column, an acceleration sensor was set on the column holder by displacing the multilayer column. The combination of the rotation speeds at (300, 100, 200 rpm) showed double loops in the acceleration track, whereas (300, 150, 150 rpm) showed a single loop, and all other combinations showed, complex tracks. The overall results indicate that the satellite motion is seriously affected by the combination of rotation speeds and the hydrophobicity of the two-phase solvent system when the upper phase was used as the mobile phase for separation. (C) 2016 Elsevier B.V. All rights reserved. C1 [Shinomiya, Kazufusa; Zaima, Kazumasa; Harada, Yukina; Yasue, Miho; Harikai, Naoki] Nihon Univ, Sch Pharm, 7-7-1 Narashinodai, Funabashi, Chiba 2748555, Japan. [Tokura, Koji] Nihon Univ, Coll Sci & Technol, 7-24-1 Narashinodai, Funabashi, Chiba 2748501, Japan. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, 10 Ctr Dr,Bldg 10,Room 8N230, Bethesda, MD 20892 USA. RP Shinomiya, K (reprint author), Nihon Univ, Sch Pharm, 7-7-1 Narashinodai, Funabashi, Chiba 2748555, Japan. EM shinomiya.kazufusa@nihon-u.ac.jp FU Intramural NIH HHS [Z99 HL999999] NR 6 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD JAN 20 PY 2017 VL 1481 BP 64 EP 72 DI 10.1016/j.chroma.2016.12.027 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EI7MF UT WOS:000392681400008 PM 28040269 ER PT J AU Cho, YE Lee, MH Song, BJ AF Cho, Young-Eun Lee, Myoung-Hwa Song, Byoung-Joon TI Neuronal Cell Death and Degeneration through Increased Nitroxidative Stress and Tau Phosphorylation in HIV-1 Transgenic Rats SO PLOS ONE LA English DT Article ID VIRUS-ASSOCIATED DEMENTIA; CENTRAL-NERVOUS-SYSTEM; OXIDATIVE STRESS; NEUROCOGNITIVE DISORDERS; ALZHEIMERS-DISEASE; MEDIATED NEURODEGENERATION; MITOCHONDRIAL DYSFUNCTION; CEREBROSPINAL-FLUID; PARKINSONS-DISEASE; EVOLVING DISEASE AB The underlying mechanisms for increased neurodegeneration and neurocognitive deficits in HIV-infected people are unclear. Therefore, this study was aimed to investigate the mechanisms of increased neurodegeneration in 5-month old male HIV-1 Transgenic (Tg) rats compared to the age-and gender-matched wild-type (WT) by evaluating histological changes and biochemical parameters of the key proteins involved in the cell death signaling and apoptosis. Histological and immunohistochemical analyses revealed decreased neuronal cells with elevated astrogliosis in HIV-1 Tg rats compared to WT. Mechanistic studies revealed that increased levels of nitroxidative stress marker proteins such as NADPH-oxidase, cytochrome P450-2E1 (CYP2E1), inducible nitric oxide synthase (iNOS), the stress-activated mitogen-activated protein kinases such as JNK and p38K, activated cell-cycle dependent CDK5, hypoxia-inducible protein-1 alpha, nitrated proteins, hyperphosphorylated tau, and amyloid plaques in HIV-Tg rats were consistently observed in HIV-1 Tg rats. Confocal microscopy and cell viability analyses showed that treatment with an antioxidant N-acetylcysteine or a specific inhibitor of iNOS 1400W significantly prevented the increased apoptosis of neuro-2A cells by HIV-1 Tat or gp120 protein, demonstrating the causal role of HIV-1 mediated nitroxidative stress and protein nitration in promoting neuronal cell death. Immunoprecipitation and immunoblot analysis confirmed nitration of Hsp90, evaluated as an example of nitrated proteins, suggesting possible involvement of nitrated proteins in neuronal damage. Further, activated p-JNK directly binds tau and phosphorylates multiple amino acids, suggesting an important role of p-JNK in tau hyperphosphorylation and tauopathy. These changes were accompanied with elevated levels of many apoptosis-related proteins Bax and cleaved (activated) caspase-3 as well as proinflammatory cytokines including TNF-alpha, IL-6 and MCP-1. Collectively, these results indicate that raised nitroxidative stress accompanied by elevated inflammation, cell death signaling pathway including activated p-JNK, C-terminal C99 amyloid fragment formation and tau hyperphosphorylation are responsible for increased apoptosis of neuronal cells and neurodegeneration in 5-month old HIV-Tg rats. C1 [Cho, Young-Eun; Song, Byoung-Joon] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. [Lee, Myoung-Hwa] NINDS, Off Clin Director, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM bj.song@nih.gov FU Intramural Program of the National Institute on Alcohol Abuse and Alcoholism; National Institute of Neurological Disorders and Stroke; Korea Research Institute of Bioscience and Biotechnology, Republic of Korea (KRIBB) Research Initiative Program (Korean Biomedical Scientist Fellowship Program); Korean Biomedical Scientist Fellowship Program FX This research was supported by the Intramural Program of the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Neurological Disorders and Stroke. Young-Eun Cho was supported by a grant from the Korea Research Institute of Bioscience and Biotechnology, Republic of Korea (KRIBB) Research Initiative Program (Korean Biomedical Scientist Fellowship Program). Drs. Lee and Song are US Government employees and have received our salaries from the National Institutes of Health, while Dr. Cho's salary was provided by the Korean Biomedical Scientist Fellowship Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This research was supported by the Intramural Program of the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Neurological Disorders and Stroke. Young-Eun Cho was supported by a grant from the Korea Research Institute of Bioscience and Biotechnology, Republic of Korea (KRIBB) Research Initiative Program (Korean Biomedical Scientist Fellowship Program). Drs. Lee and Song are US Government employees and have received salaries from the National Institutes of Health, while Dr. Cho's salary was provided by the Korean Biomedical Scientist Fellowship Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors are grateful to the NIH AIDS Reagent Program for providing the recombinant HIV-1 Tat and gp120 proteins. The authors also like to thank Drs. Klaus Gawrisch and Avindra Nath for the support of this project. NR 83 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2017 VL 12 IS 1 AR e0169945 DI 10.1371/journal.pone.0169945 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI3QC UT WOS:000392405300054 PM 28107387 ER PT J AU de Vries, PS Sabater-Lleal, M Chasman, DI Trompet, S Ahluwalia, TS Teumer, A Kleber, ME Chen, MH Wang, JJ Attia, JR Marioni, RE Steri, M Weng, LC Pool, R Grossmann, V Brody, JA Venturini, C Tanaka, T Rose, LM Oldmeadow, C Mazur, J Basu, S Franberg, M Yang, Q Ligthart, S Hottenga, JJ Rumley, A Mulas, A de Craen, AJM Grotevendt, A Taylor, KD Delgado, GE Kifley, A Lopez, LM Berentzen, TL Mangino, M Bandinelli, S Morrison, AC Hamsten, A Tofler, G de Maat, MPM Draisma, HHM Lowe, GD Zoledziewska, M Sattar, N Lackner, KJ Volker, U McKnight, B Huang, J Holliday, EG McEvoy, MA Starr, JM Hysi, PG Hernandez, DG Guan, WH Rivadeneira, F McArdle, WL Slagboom, PE Zeller, T Psaty, BM Uitterlinden, AG de Geus, EJC Stott, DJ Binder, H Hofman, A Franco, OH Rotter, JI Ferrucci, L Spector, TD Deary, IJ Marz, W Greinacher, A Wild, PS Cucca, F Boomsma, DI Watkins, H Tang, WH Ridker, PM Jukema, JW Scott, RJ Mitchell, P Hansen, T O'Donnell, CJ Smith, NL Strachan, DP Dehghan, A AF de Vries, Paul S. Sabater-Lleal, Maria Chasman, Daniel I. Trompet, Stella Ahluwalia, Tarunveer S. Teumer, Alexander Kleber, Marcus E. Chen, Ming-Huei Wang, Jie Jin Attia, John R. Marioni, Riccardo E. Steri, Maristella Weng, Lu-Chen Pool, Rene Grossmann, Vera Brody, Jennifer A. Venturini, Cristina Tanaka, Toshiko Rose, Lynda M. Oldmeadow, Christopher Mazur, Johanna Basu, Saonli Franberg, Mattias Yang, Qiong Ligthart, Symen Hottenga, Jouke J. Rumley, Ann Mulas, Antonella de Craen, Anton J. M. Grotevendt, Anne Taylor, Kent D. Delgado, Graciela E. Kifley, Annette Lopez, Lorna M. Berentzen, Tina L. Mangino, Massimo Bandinelli, Stefania Morrison, Alanna C. Hamsten, Anders Tofler, Geoffrey de Maat, Moniek P. M. Draisma, Harmen H. M. Lowe, Gordon D. Zoledziewska, Magdalena Sattar, Naveed Lackner, Karl J. Voelker, Uwe McKnight, Barbara Huang, Jie Holliday, Elizabeth G. McEvoy, Mark A. Starr, John M. Hysi, Pirro G. Hernandez, Dena G. Guan, Weihua Rivadeneira, Fernando McArdle, Wendy L. Slagboom, P. Eline Zeller, Tanja Psaty, Bruce M. Uitterlinden, Andre G. de Geus, Eco J. C. Stott, David J. Binder, Harald Hofman, Albert Franco, Oscar H. Rotter, Jerome I. Ferrucci, Luigi Spector, Tim D. Deary, Ian J. Maerz, Winfried Greinacher, Andreas Wild, Philipp S. Cucca, Francesco Boomsma, Dorret I. Watkins, Hugh Tang, Weihong Ridker, Paul M. Jukema, Jan W. Scott, Rodney J. Mitchell, Paul Hansen, Torben O'Donnell, Christopher J. Smith, Nicholas L. Strachan, David P. Dehghan, Abbas TI Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study SO PLOS ONE LA English DT Article ID CARDIOVASCULAR-DISEASE; SUSCEPTIBILITY LOCI; GENETIC-VARIANTS; COMMON VARIANTS; METAANALYSIS; CONSORTIUM; IMPUTATION; PRESSURE; INSIGHTS; BIOLOGY AB An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5x10(-8) is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5x10(-8)), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development. C1 [de Vries, Paul S.; Ligthart, Symen; Morrison, Alanna C.; Rivadeneira, Fernando; Uitterlinden, Andre G.; Hofman, Albert; Franco, Oscar H.; Dehghan, Abbas] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [de Vries, Paul S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Sabater-Lleal, Maria; Franberg, Mattias; Hamsten, Anders] Karolinska Inst, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden. [Chasman, Daniel I.; Rose, Lynda M.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Chasman, Daniel I.; Ridker, Paul M.] Harvard Med Sch, Boston, MA USA. [Trompet, Stella; Jukema, Jan W.] Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands. [Trompet, Stella; de Craen, Anton J. M.] Leiden Univ, Dept Gerontol & Geriatr, Med Ctr, Leiden, Netherlands. [Ahluwalia, Tarunveer S.] Steno Diabet Ctr Copenhagen, Gentofte, Denmark. [Ahluwalia, Tarunveer S.] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [Teumer, Alexander] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Kleber, Marcus E.; Delgado, Graciela E.; Maerz, Winfried] Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Ming-Huei; Yang, Qiong; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Populat Sci Branch, Div Intramural Res,NIH, Framingham, MA USA. [Wang, Jie Jin; Kifley, Annette; Mitchell, Paul] Univ Sydney, Dept Ophthalmol, Ctr Vis Res, Sydney, NSW, Australia. [Wang, Jie Jin; Kifley, Annette; Mitchell, Paul] Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia. [Attia, John R.; Oldmeadow, Christopher] Univ Newcastle, Hunter Med Res Inst, Publ Hlth Stream, Newcastle, NSW, Australia. [Attia, John R.; Oldmeadow, Christopher; McEvoy, Mark A.] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW, Australia. [Marioni, Riccardo E.; Lopez, Lorna M.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo E.] Univ Edinburgh, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo E.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Steri, Maristella; Mulas, Antonella; Zoledziewska, Magdalena; Cucca, Francesco] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Weng, Lu-Chen; Tang, Weihong] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Pool, Rene; Hottenga, Jouke J.; Draisma, Harmen H. M.; de Geus, Eco J. C.; Boomsma, Dorret I.] Vrije Univ Amsterdam, Netherlands Twin Register, Dept Biol Psychol, Amsterdam, Netherlands. [Pool, Rene; de Geus, Eco J. C.] Vrije Univ Amsterdam, EMGO Inst, Amsterdam, Netherlands. [Pool, Rene; de Geus, Eco J. C.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Grossmann, Vera] Johannes Gutenberg Univ Mainz, Univ Med Ctr, CTH, Mainz, Germany. [Brody, Jennifer A.] Univ Washington, Dept Med, Seattle, WA USA. [Venturini, Cristina] UCL, Div Infect & Immunol, London, England. [Venturini, Cristina; Mangino, Massimo; Hysi, Pirro G.; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Mazur, Johanna] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Med Biostat Epidemiol & Informat, Mainz, Germany. [Basu, Saonli; Guan, Weihua] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Franberg, Mattias] Stockholm Univ, Dept Numer Anal & Comp Sci, Stockholm, Sweden. [Yang, Qiong] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA USA. [Rumley, Ann] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Grotevendt, Anne] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Taylor, Kent D.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Taylor, Kent D.] Harbor UCLA Med Ctr, Dept Pediat, Div Genom Outcomes, Torrance, CA 90509 USA. [Lopez, Lorna M.] Beaumont Hosp, Royal Coll Surg Ireland, Dept Psychiat, Educ & Res Ctr, Dublin, Ireland. [Lopez, Lorna M.] Univ Coll Dublin, UCD Conway Inst, Ctr Proteome Res, Dublin, Ireland. [Berentzen, Tina L.] Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, Copenhagen, Denmark. [Mangino, Massimo] Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London, England. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Tofler, Geoffrey] Univ Sydney, Royal North Shore Hosp, Sydney, NSW, Australia. [de Maat, Moniek P. M.] Erasmus MC, Dept Hematol, Rotterdam, Netherlands. [Draisma, Harmen H. M.] Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Lowe, Gordon D.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Sattar, Naveed] Fac Med, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Lackner, Karl J.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Clin Chem & Lab Med, Mainz, Germany. [Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Huang, Jie] Wellcome Trust Sanger Inst, Dept Human Genet, Cambridge, England. [Holliday, Elizabeth G.] Univ Newcastle, Hunter Med Res Inst, Publ Hlth Stream, Newcastle, NSW, Australia. [Holliday, Elizabeth G.] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW, Australia. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Hernandez, Dena G.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [McArdle, Wendy L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Slagboom, P. Eline] Leiden Univ, Dept Mol Epidemiol, Med Ctr, Leiden, Netherlands. [Zeller, Tanja] Univ Med Ctr Hamburg Eppendorf, Univ Heart Ctr, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Zeller, Tanja] German Ctr Cardiovascular Res DZHK, Partner Site Hamburg, Hamburg, Germany. [Psaty, Bruce M.] Univ Washington, Dept Med Epidemiol & Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.; Smith, Nicholas L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Stott, David J.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Binder, Harald] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Med Biostat Epidemiol & Informat, Mainz, Germany. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MS USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Div Genom Outcomes, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA. [Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Maerz, Winfried] Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Greinacher, Andreas] Univ Med Greifswald, Inst Immunol & Transfus Med, Greifswald, Germany. [Wild, Philipp S.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Ctr Cardiol, Prevent Cardiol & Prevent Med, Mainz, Germany. [Wild, Philipp S.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, CTH, Mainz, Germany. [Wild, Philipp S.] German Ctr Cardiovasc Res DZHK, Partner Site RhineMain, Mainz, Germany. [Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Radcliffe Dept Med, Dept Cardiovasc Med, Oxford, England. [Jukema, Jan W.] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, Jan W.] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Scott, Rodney J.] Univ Newcastle, Hunter Med Res Inst, Informat Based Med Program, Newcastle, NSW, Australia. [Scott, Rodney J.] Univ Newcastle, Sch Biomed Sci & Pharm, Newcastle, NSW, Australia. [Hansen, Torben] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Dept Vet Affairs, Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Strachan, David P.] St Georges Univ London, Populat Hlth Res Inst, London, England. [Dehghan, Abbas] Imperial Coll London, Dept Epidemiol & Biostat, London, England. RP Dehghan, A (reprint author), Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.; Dehghan, A (reprint author), Imperial Coll London, Dept Epidemiol & Biostat, London, England. EM a.dehghan@imperial.ac.uk RI Wang, Jie Jin/P-1499-2014; OI Wang, Jie Jin/0000-0001-9491-4898; Watkins, Hugh/0000-0002-5287-9016; Ahluwalia, Tarunveer Singh/0000-0002-7464-3354; Sabater Lleal, Maria/0000-0002-0128-379X FU Steno Diabetes Center; Synlab Holding Deutschland GmbH; National Heart, Lung, and Blood Institute [R01HL105756, HL043851, HL080467]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005]; NIH Roadmap for Medical Research; NHLBI [R01HL105756, HL0597367, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL103612, R01HL120393]; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02, 076113/B/04/Z, 079895, 075491/Z/04]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Allergy and Infectious Diseases (NIAID); National Human Genome Research Institute (NHGRI); National Institute of Child Health and Human Development (NICHD); Juvenile Diabetes Research Foundation International (JDRF); Juvenile Diabetes Research Foundation International; National Institute for Health Research Cambridge Biomedical Research Centre; European Commission Framework Programme 6 [018996]; French Ministry of Research; Australian National Health & Medical Research Council, Canberra Australia [974159, 211069, 457349, 512423, 475604, 529912, 529923]; Wellcome Trust, UK; National Institute on Aging (NIA) [R01AG023629]; National Center for Advancing Translational Sciences, CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; National Heart, Lung, and Blood Institute's (NHLBI's) Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc. [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; National Institute of Diabetes and Digestive and Kidney Diseases [K24 DK080140]; National Institute on Aging; National Institute for Neurological Disorders and Stroke [R01 AG033193, NS017950]; GENDINOB; government of Rhineland-Palatinate [AZ 961-386261/733]; Johannes Gutenberg-University of Mainz; Boehringer Ingelheim; PHILIPS Medical Systems; Federal Ministry of Education and Research (BMBF) [01EO1003]; Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336]; Intramural Research Program of the NIH, National Institute on Aging; Biotechnology and Biological Sciences Research Council (BBSRC) [BB/F019394/1]; Age UK; BBSRC; MRC; 6th Framework Program (integrated project Bloodomics) [LSHM-CT-2004-503485]; 7th Framework Program (Atheroremo) of the European Union [201668]; RiskyCAD of the European Union [305739]; INTERREG IV Oberrhein Program [A28]; European Regional Development Fund (ERDF); Wissenschaftsoffensive TMO; Netherlands Organization for Scientific Research (NWO); MagW/ZonMW [904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192]; Center for Medical Systems Biology (CSMB, NWO Genomics); NBIC/BioAssist/RK [2008.024]; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL) [184.021.007]; European Community's Seventh Framework Program (FP7); National Institutes of Health (NIH) [R01D0042157-01A, MH081802, 1RC2 MH089951]; Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health; NWO; European Community Sixth Framework Program [LSHM-CT- 2007-037273]; AstraZeneca; British Heart Foundation; Swedish Research Council; Knut and Alice Wallenberg Foundation; Swedish Heart-Lung Foundation [20130399]; Torsten and Ragnar Soderberg Foundation; Strategic Cardiovascular and Diabetes Programs of Karolinska Institutet; Stockholm County Council; Foundation for Strategic Research; BHF Centre of Research Excellence, Oxford; Ake Wiberg foundation; Tore Nilssons foundation; Magnus Bergvall Foundation; Foundation for Old Servants; European Union's Seventh Framework Programme (FP7) [HEALTH-F2-2009-223004]; Netherlands Consortium of Healthy Aging [NGI: 05060810]; Scottish Executive Chief Scientist Office, Health Services Research Committee [CZG/4/306]; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; NWO grant (veni) [916.12.154]; EUR Fellowship; NIA [NO1-AG-12109]; Sardinian Autonomous Region [cRP3-154]; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg - West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg West Pomerania; Leibniz Supercomputing Centre of the Bavarian Academy of Sciences and Humanities (HLRB) [h1231]; Ministry of Cultural Affairs of the Federal State of Mecklenburg - West Pomerania [03IS2061A]; European Community's Seventh Framework Programme (FP7); National Institute for Health Research (NIHR) Clinical Research Facility at Guy's & St Thomas' NHS Foundation Trust; NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust; King's College London; ERC Advanced Principal Investigator award; National Cancer Institute [CA047988]; Donald W. Reynolds Foundation; Fondation Leducq; Amgen; [U01 DK062418] FX Steno Diabetes Center and Synlab Holding Deutschland GmbH provided support in the form of salaries for authors T.S.A. and W.M. respectively, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. ARIC is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) 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 contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. LITE is supported by HL0597367 from the NHLBI. B58C acknowledges use of phenotype and genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Genotyping for the B58C-WTCCC subset was funded by the Wellcome Trust grant 076113/B/04/Z. The B58C-T1DGC genotyping utilized resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. B58C-T1DGC GWAS data were deposited by the Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge, which is funded by Juvenile Diabetes Research Foundation International, the Wellcome Trust and the National Institute for Health Research Cambridge Biomedical Research Centre; the CIMR is in receipt of a Wellcome Trust Strategic Award (079895). The B58C-GABRIEL genotyping was supported by a contract from the European Commission Framework Programme 6 (018996) and grants from the French Ministry of Research. The BMES has been supported by the Australian National Health & Medical Research Council, Canberra Australia (Grant Numbers 974159, 211069, 457349, 512423, 475604, 529912, and the funding for Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases, CCRE in TCR-Eye, grant ID 529923); In addition, funding by the Wellcome Trust, UK (to A Viswanathan, P McGuffin, P Mitchell, F Topouzis, P Foster) has supported the genotyping costs of the entire BMES population. This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA).; The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The FHS was partially supported by the National Heart, Lung, and Blood Institute's (NHLBI's) Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Partial investigator support was provided by the National Institute of Diabetes and Digestive and Kidney Diseases K24 DK080140 (JB Meigs), the National Institute on Aging and National Institute for Neurological Disorders and Stroke R01 AG033193, NS017950 (S Seshadri). The GOYA Male study was conducted as part of the activities of the Gene-diet Interactions in Obesity project (GENDINOB, www.gendinob.dk) and the MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). We thank the staff of the Copenhagen City Heart Study for their skillful examination of the study subjects in collection of baseline and follow-up data. Tarunveer Singh Ahluwalia received his Postdoctoral Research funding from GENDINOB project and acknowledges the same. The Gutenberg Health Study is funded through the government of Rhineland-Palatinate ("Stiftung Rheinland-Pfalz fur Innovation", contract AZ 961-386261/733), the research programs "Wissen schafft Zukunft" and "Center for Translational Vascular Biology (CTVB)" of the Johannes Gutenberg-University of Mainz, and its contract with Boehringer Ingelheim and PHILIPS Medical Systems, including an unrestricted grant for the Gutenberg Health Study. VG, PSW are funded by the Federal Ministry of Education and Research (BMBF 01EO1003). The InCHIANTI study baseline (1998-2000) was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336); This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The whole genome association study in LBC1936 and LBC1921 was funded by the Biotechnology and Biological Sciences Research Council (BBSRC; Ref. BB/F019394/1). The LBC1936 research was supported by Age UK. The LBC1921 data collection was funded by the BBSRC. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (MR/K026992/1), part of the cross council Lifelong Health and Wellbeing Initiative. Funding from the BBSRC, and MRC is gratefully acknowledged. LURIC has received funding from the 6th Framework Program (integrated project Bloodomics, grant LSHM-CT-2004-503485) and from the 7th Framework Program (Atheroremo, grant agreement number 201668 and RiskyCAD, grant agreement number 305739) of the European Union as well as from the INTERREG IV Oberrhein Program (Project A28, Genetic mechanisms of cardiovascular diseases) with support from the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive TMO.; NTR: Funding was obtained from the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192, Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL, 184.021.007). VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the European Science Foundation (ESF, EU/QLRT-2001-01254), the European Community's Seventh Framework Program (FP7/2007-2013), ENGAGE (HEALTH-F4-2007-201413); the European Science Council (ERC Advanced, 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH, R01D0042157-01A, MH081802, Grand Opportunity grants 1RC2 MH089951). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. PROCARDIS was supported by the European Community Sixth Framework Program (LSHM-CT- 2007-037273), AstraZeneca, the British Heart Foundation, the Wellcome Trust (Contract No. 075491/Z/04), the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Soderberg Foundation, the Strategic Cardiovascular and Diabetes Programs of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council. Jemma C Hopewell and Robert Clarke acknowledge support from the BHF Centre of Research Excellence, Oxford. M.Sabater-Lleal is supported by the Swedish Heart-Lung Foundation (20130399), and acknowledges funding from Ake Wiberg and Tore Nilssons foundations. B.Sennblad acknowledges funding from the Magnus Bergvall Foundation and the Foundation for Old Servants. PROSPER received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no HEALTH-F2-2009-223004. For a part of the genotyping we received funding from the Netherlands Consortium of Healthy Aging (NGI: 05060810). Measurement of serum fibrinogen was supported by a grant from the Scottish Executive Chief Scientist Office, Health Services Research Committee grant number CZG/4/306. Prof. Dr. J.W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (2001 D 032). The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Abbas Dehghan is supported by NWO grant (veni, 916.12.154) and the EUR Fellowship.; The SardiNIA ("ProgeNIA") team was supported by Contract NO1-AG-12109 from the NIA. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging, by Sardinian Autonomous Region (L.R. no. 7/2009) grant cRP3-154, and by grant FaReBio2011 "Farmaci e Reti Biotecnologiche di Qualita". SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg - West Pomerania. Genome- wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg West Pomerania. Computing resources have been made available by the Leibniz Supercomputing Centre of the Bavarian Academy of Sciences and Humanities (HLRB project h1231). The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG and the Cache Campus program of the InterSystems GmbH. This work is also part of the research project Greifswald Approach to Individualized Medicine (GANI_MED). The GANI_MED consortium is funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg - West Pomerania (03IS2061A). TwinsUK. The 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) Clinical Research Facility at Guy's & St Thomas' NHS Foundation Trust and NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. Tim Spector is an NIHR senior Investigator and is holder of an ERC Advanced Principal Investigator award. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. The WGHS is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA047988 from the National Cancer Institute, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. NR 52 TC 0 Z9 0 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2017 VL 12 IS 1 AR e0167742 DI 10.1371/journal.pone.0167742 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI3QC UT WOS:000392405300006 PM 28107422 ER PT J AU Hasenour, CM Ridley, DE James, FD Hughey, CC Donahue, P Viollet, B Foretz, M Young, JD Wasserman, DH AF Hasenour, Clinton M. Ridley, D. Emerson James, Freyja D. Hughey, Curtis C. Donahue, Patrick Viollet, Benoit Foretz, Marc Young, Jamey D. Wasserman, David H. TI Liver AMP-Activated Protein Kinase Is Unnecessary for Gluconeogenesis but Protects Energy State during Nutrient Deprivation SO PLOS ONE LA English DT Article ID ACID CYCLE ACTIVITY; CYTOSOLIC PHOSPHOENOLPYRUVATE CARBOXYKINASE; INHIBITS HEPATIC GLUCONEOGENESIS; SKELETAL-MUSCLE; MITOCHONDRIAL METABOLISM; INSULIN-RESISTANCE; GLUCOSE-PRODUCTION; FATTY LIVER; IN-VIVO; MUSCULAR WORK AB AMPK is an energy sensor that protects cellular energy state by attenuating anabolic and promoting catabolic processes. AMPK signaling is purported to regulate hepatic gluconeogenesis and substrate oxidation; coordination of these processes is vital during nutrient deprivation or pathogenic during overnutrition. Here we directly test hepatic AMPK function in regulating metabolic fluxes that converge to produce glucose and energy in vivo. Flux analysis was applied in mice with a liver-specific deletion of AMPK (L-KO) or floxed control litter mates to assess rates of hepatic glucose producing and citric acid cycle (CAC) fluxes. Fluxes were assessed in short and longterm fasted mice; the latter condition is a nutrient stressor that increases liver AMP/ATP. The flux circuit connecting anaplerosis with gluconeogenesis from the CAC was unaffected by hepatic AMPK deletion in short and long term fasting. Nevertheless, depletion of hepatic ATP was exacerbated in L-KO mice, corresponding to a relative elevation in citrate synthase flux and accumulation of branched-chain amino acid-related metabolites. L-KO mice also had a physiological reduction in flux from glycogen to G6P. These results demonstrate AMPK is unnecessary for maintaining gluconeogenic flux from the CAC yet is critical for stabilizing liver energy state during nutrient deprivation. C1 [Hasenour, Clinton M.; Ridley, D. Emerson; Hughey, Curtis C.; Donahue, Patrick; Young, Jamey D.; Wasserman, David H.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA. [James, Freyja D.; Wasserman, David H.] Vanderbilt Univ, Mouse Metab Phenotyping Ctr, Nashville, TN 37235 USA. [Viollet, Benoit; Foretz, Marc] INSERM, Inst Cochin, U1016, Paris, France. [Viollet, Benoit; Foretz, Marc] CNRS, UMR 8104, Paris, France. [Viollet, Benoit; Foretz, Marc] Univ Paris 05, Sorborne Paris Cite, Paris, France. [Young, Jamey D.] Vanderbilt Univ, Dept Chem & Biomol Engn, Nashville, TN 37235 USA. RP Wasserman, DH (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA.; Wasserman, DH (reprint author), Vanderbilt Univ, Mouse Metab Phenotyping Ctr, Nashville, TN 37235 USA. EM david.wasserman@vanderbilt.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [DK050277, DK059637, DK07563, DK020593]; Canadian Diabetes Association [PF-3-14-4687-CH] FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases through grant numbers DK050277, DK059637, DK07563 and DK020593. This work was also supported by the Canadian Diabetes Association through grant PF-3-14-4687-CH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2017 VL 12 IS 1 AR e0170382 DI 10.1371/journal.pone.0170382 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI3QC UT WOS:000392405300122 PM 28107516 ER PT J AU Marianno, P Abrahao, KP Camarini, R AF Marianno, Priscila Abrahao, Karina Possa Camarini, Rosana TI Environmental Enrichment Blunts Ethanol Consumption after Restraint Stress in C57BL/6 Mice SO PLOS ONE LA English DT Article ID ALCOHOL DEPRIVATION; COCAINE ADDICTION; SOCIAL-ISOLATION; RATS; BEHAVIOR; ANXIETY; MODEL; EXPERIENCE; DRINKING; IMPACT AB Elevated alcohol intake after abstinence is a key feature of the addiction process. Some studies have shown that environmental enrichment (EE) affects ethanol intake and other reinforcing effects. However, different EE protocols may vary in their ability to influence alcohol consumption and stress-induced intake. The present study evaluated whether short (3 h) or continuous (24 h) EE protocols affect ethanol consumption after periods of withdrawal. Mice were challenged with stressful stimuli (24 h isolation and restraint stress) to evaluate the effects of stress on drinking. Male C57BL/6 mice were subjected to a two-bottle choice drinking-in-the-dark paradigm for 15 days (20% ethanol and water, 2 h/day, acquisition phase). Control mice were housed under standard conditions (SC). In the first experiment, one group of mice was housed under EE conditions 24 h/day (EE24h). In the second experiment, the exposure to EE was reduced to 3 h/day (EE3h). After the acquisition phase, the animals were deprived of ethanol for 6 days, followed by 2 h ethanol access once a week. Animals were tested in the elevated plus maze (EPM) during ethanol withdrawal. During the last 2 weeks, the mice were exposed to 24 h ethanol access. A 1-h restraint stress test was performed immediately before the last ethanol exposure. EE24h but not EE3h increased anxiety-like behavior during withdrawal compared to controls. Neither EE24h nor EE3h affected ethanol consumption during the 2 h weekly exposure periods. However, EE24h and EE3h mice that were exposed to acute restraint stress consumed less ethanol than controls during a 24 h ethanol access. These results showed that EE reduces alcohol intake after an acute restraint stress. C1 [Marianno, Priscila; Abrahao, Karina Possa; Camarini, Rosana] Univ Sao Paulo, Inst Ciencias Biomed, Dept Farmacol, Sao Paulo, SP, Brazil. [Abrahao, Karina Possa] NIAAA, Lab Integrat Neurosci, Div Intramural Clin & Biol Res, NIH, Bethesda, MD USA. RP Camarini, R (reprint author), Univ Sao Paulo, Inst Ciencias Biomed, Dept Farmacol, Sao Paulo, SP, Brazil. EM camarini@icb.usp.br OI Camarini, Rosana/0000-0002-8131-6108 FU FAPESP (Sao Paulo Research Foundation) [2015/02397-0, 2011/08280-0]; CNPq (National Council for Scientific and Technological Development) [470070/2012-9]; CAPES (Coordination for the Improvement of Higher Education Personnel) FX The authors thank FAPESP (Sao Paulo Research Foundation) for the research funding (grant # 2015/02397-0) and for scholarship to KPA (grant # 2011/08280-0), CNPq (National Council for Scientific and Technological Development) for the research funding (grant # 470070/2012-9) and CAPES (Coordination for the Improvement of Higher Education Personnel) for the scholarship to PM. RC is research fellow of CNPq. NR 53 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2017 VL 12 IS 1 AR e0170317 DI 10.1371/journal.pone.0170317 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI3QC UT WOS:000392405300106 PM 28107511 ER PT J AU Jones, GT Tromp, G Kuivaniemi, H Gretarsdottir, S Baas, AF Giusti, B Strauss, E van't Hof, FNG Webb, TR Erdman, R Ritchie, MD Elmore, JR Verma, A Pendergrass, S Kullo, IJ Zy, ZY Peissig, PL Gottesman, O Verma, SS Malinowski, J Rasmussen-Torvik, LJ Borthwick, KM Smelser, DT Crosslin, DR de Andrade, M Ryer, EJ McCarty, CA Bottinger, EP Pacheco, JA Crawford, DC Carrell, DS Gerhard, GS Franklin, DP Carey, DJ Phillips, VL Williams, MJA Wei, WH Blair, R Hill, AA Vasudevan, TM Lewis, DR Thomson, IA Krysa, J Hill, GB Roake, J Merriman, TR Oszkinis, G Galora, S Saracini, C Abbate, R Pulli, R Pratesi, C Saratzis, A Verissimo, AR Bumpstead, S Badger, SA Clough, RE Cockerill, G Hafez, H Scott, DJA Futers, TS Romaine, SPR Bridge, K Griffin, KJ Bailey, MA Smith, A Thompson, MM van Bockxmeer, FM Matthiasson, SE Thorleifsson, G Thorsteinsdottir, U Blankensteijn, JD Teijink, JAW Wijmenga, C de Graaf, J Kiemeney, LA Lindholt, JS Hughes, A Bradley, DT Stirrups, K Golledge, J Norman, PE Powell, JT Humphries, SE Hamby, SE Goodall, AH Nelson, CP Sakalihasan, N Courtois, A Ferrell, RE Eriksson, P Folkersen, L Franco-Cereceda, A Eicher, JD Johnson, AD Betsholtz, C Ruusalepp, A Franzen, O Schadt, EE Bjorkegren, JLM Lipovich, L Drolet, AM Verhoeven, EL Zeebregts, CJ Geelkerken, RH van Sambeek, MR van Sterkenburg, SM de Vries, JP Stefansson, K Thompson, JR de Bakker, PIW Deloukas, P Sayers, RD Harrison, SC van Rij, AM Samani, NJ Bown, MJ AF Jones, Gregory T. Tromp, Gerard Kuivaniemi, Helena Gretarsdottir, Solveig Baas, Annette F. Giusti, Betti Strauss, Ewa van't Hof, Femke N. G. Webb, Thomas R. Erdman, Robert Ritchie, Marylyn D. Elmore, James R. Verma, Anurag Pendergrass, Sarah Kullo, Iftikhar J. Zy, Zi Ye Peissig, Peggy L. Gottesman, Omri Verma, Shefali S. Malinowski, Jennifer Rasmussen-Torvik, Laura J. Borthwick, Kenneth M. Smelser, Diane T. Crosslin, David R. de Andrade, Mariza Ryer, Evan J. McCarty, Catherine A. Bottinger, Erwin P. Pacheco, Jennifer A. Crawford, Dana C. Carrell, David S. Gerhard, Glenn S. Franklin, David P. Carey, David J. Phillips, Victoria L. Williams, Michael J. A. Wei, Wenhua Blair, Ross Hill, Andrew A. Vasudevan, Thodor M. Lewis, David R. Thomson, Ian A. Krysa, Jo Hill, Geraldine B. Roake, Justin Merriman, Tony R. Oszkinis, Grzegorz Galora, Silvia Saracini, Claudia Abbate, Rosanna Pulli, Raffaele Pratesi, Carlo Saratzis, Athanasios Verissimo, Ana R. Bumpstead, Suzannah Badger, Stephen A. Clough, Rachel E. Cockerill, Gillian Hafez, Hany Scott, D. Julian A. Futers, T. Simon Romaine, Simon P. R. Bridge, Katherine Griffin, Kathryn J. Bailey, Marc A. Smith, Alberto Thompson, Matthew M. van Bockxmeer, Frank M. Matthiasson, Stefan E. Thorleifsson, Gudmar Thorsteinsdottir, Unnur Blankensteijn, Jan D. Teijink, Joep A. W. Wijmenga, Cisca de Graaf, Jacqueline Kiemeney, Lambertus A. Lindholt, Jes S. Hughes, Anne Bradley, Declan T. Stirrups, Kathleen Golledge, Jonathan Norman, Paul E. Powell, Janet T. Humphries, Steve E. Hamby, Stephen E. Goodall, Alison H. Nelson, Christopher P. Sakalihasan, Natzi Courtois, Audrey Ferrell, Robert E. Eriksson, Per Folkersen, Lasse Franco-Cereceda, Anders Eicher, John D. Johnson, Andrew D. Betsholtz, Christer Ruusalepp, Arno Franzen, Oscar Schadt, Eric E. Bjorkegren, Johan L. M. Lipovich, Leonard Drolet, Anne M. Verhoeven, Eric L. Zeebregts, Clark J. Geelkerken, Robert H. van Sambeek, Marc R. van Sterkenburg, Steven M. de Vries, Jean-Paul Stefansson, Kari Thompson, John R. de Bakker, Paul I. W. Deloukas, Panos Sayers, Robert D. Harrison, Seamus C. van Rij, Andre M. Samani, Nilesh J. Bown, Matthew J. CA Cardiogenics Consortium Int Consortium Blood Pressure TI Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci SO CIRCULATION RESEARCH LA English DT Article DE aortic aneurysm, abdominal; computational biology; genetics; genome-wide association study; matrix metalloproteinases; meta-analysis ID CORONARY-ARTERY-DISEASE; DENSITY-LIPOPROTEIN CHOLESTEROL; ELECTRONIC MEDICAL-RECORDS; CANDIDATE GENE ASSOCIATION; RECEPTOR-RELATED PROTEIN-1; HUMAN PREFRONTAL CORTEX; C-REACTIVE PROTEIN; SUSCEPTIBILITY LOCI; SEQUENCE VARIANT; TRANSCRIPTION FACTORS AB Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease. C1 [Jones, Gregory T.; Phillips, Victoria L.; Wei, Wenhua; Thomson, Ian A.; Krysa, Jo; Hill, Geraldine B.; van Rij, Andre M.] Univ Otago, Dept Surg, Dunedin 9054, New Zealand. [Williams, Michael J. A.] Univ Otago, Dept Med, Dunedin, New Zealand. [Merriman, Tony R.] Univ Otago, Dept Biochem, Dunedin, New Zealand. [Tromp, Gerard; Kuivaniemi, Helena; Erdman, Robert; Borthwick, Kenneth M.; Smelser, Diane T.; Carey, David J.] Geisinger Hlth Syst, Sigfried & Janet Weis Ctr Res, Danville, PA USA. [Ritchie, Marylyn D.; Pendergrass, Sarah] Geisinger Hlth Syst, Biomed & Translat Informat, Danville, PA USA. [Tromp, Gerard; Kuivaniemi, Helena] Univ Stellenbosch, Dept Biomed Sci, Fac Med & Hlth Sci, Div Mol Biol & Human Genet, Tygerberg, South Africa. [Tromp, Gerard; Galora, Silvia; Thorsteinsdottir, Unnur; Ruusalepp, Arno] deCODE Amgen, Reykjavik, Iceland. [Baas, Annette F.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Giusti, Betti; Galora, Silvia; Saracini, Claudia; Abbate, Rosanna; Courtois, Audrey] Univ Florence, Careggi Hosp, Dept Expt & Clin Med, Atherothrombot Dis Ctr, Florence, Italy. [Pulli, Raffaele; Pratesi, Carlo] Univ Florence, Careggi Hosp, Dept Expt & Clin Med, Vasc Surg Unit, Florence, Italy. [Strauss, Ewa] Polish Acad Sci, Inst Human Genet, Fac Nucle Acid Funct, Poznan, Poland. [Strauss, Ewa; Oszkinis, Grzegorz] Poznan Univ Med Sci, Dept Gen & Vasc Surg, Poznan, Poland. [Webb, Thomas R.; Verissimo, Ana R.; Romaine, Simon P. R.; Goodall, Alison H.; Nelson, Christopher P.; Sayers, Robert D.; Harrison, Seamus C.; Samani, Nilesh J.; Bown, Matthew J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Webb, Thomas R.; Verissimo, Ana R.; Goodall, Alison H.; Nelson, Christopher P.; Samani, Nilesh J.; Bown, Matthew J.] Glenfield Gen Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Ritchie, Marylyn D.; Verma, Anurag; Pendergrass, Sarah; Verma, Shefali S.] Penn State Univ, University Pk, PA 16802 USA. [Elmore, James R.; Ryer, Evan J.] Geisinger Med Ctr, Dept Vasc Surg, Danville, PA 17822 USA. [Kullo, Iftikhar J.; Zy, Zi Ye; de Andrade, Mariza] Mayo Clin Rochester, Rochester, MN USA. [Peissig, Peggy L.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Gottesman, Omri; Bottinger, Erwin P.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Franzen, Oscar; Schadt, Eric E.; Bjorkegren, Johan L. M.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Malinowski, Jennifer] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Rasmussen-Torvik, Laura J.; Pacheco, Jennifer A.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Crosslin, David R.] Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Div Res, Duluth, MN USA. [Crawford, Dana C.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Carrell, David S.] Grp Hlth Res Inst, Seattle, WA USA. [Gerhard, Glenn S.] Temple Univ, Sch Med, Dept Med Genet & Mol Biochem, Philadelphia, PA 19122 USA. [Franklin, David P.] Mission Hlth Syst, Mission Clin, Asheville, NC USA. [Blair, Ross; Vasudevan, Thodor M.] Waikato Hosp, Hamilton, New Zealand. [Hill, Andrew A.] Auckland City Hosp, Auckland, New Zealand. [Lewis, David R.; Roake, Justin] Univ Otago, Dept Surg, Christchurch, New Zealand. [Bumpstead, Suzannah] Wellcome Trust Sanger Inst, Genet Complex Traits Humans Grp, Cambridge, England. [Badger, Stephen A.] Queens Univ Belfast, Sch Med, Belfast, Antrim, North Ireland. [Bradley, Declan T.] Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Clough, Rachel E.] Kings Coll London, Dept Vasc Surg, London, England. Kings Coll London, British Heart Fdn Ctr Res Excellence, Cardiovasc Div, Dept Vasc Surg, London, England. [Cockerill, Gillian; Thompson, Matthew M.] St Georges Univ London, Dept Vasc Surg, London, England. [Hafez, Hany] King Faisal Specialist Hosp & Res Ctr, Jeddah, Saudi Arabia. [Scott, D. Julian A.; Futers, T. Simon; Romaine, Simon P. R.; Bridge, Katherine; Griffin, Kathryn J.; Bailey, Marc A.] Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, England. [van Bockxmeer, Frank M.; Norman, Paul E.] Univ Western Australia, Dept Surg, Crawley, Australia. [Matthiasson, Stefan E.] Laekning Med Clin, Reykjavik, Iceland. [Thorsteinsdottir, Unnur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Blankensteijn, Jan D.] Vrije Univ Amsterdam Med Ctr, Dept Vasc Surg, Amsterdam, Netherlands. [Teijink, Joep A. W.] Maastricht Univ, CAPHRI Res Sch, Eindhoven, Netherlands. [Teijink, Joep A. W.; van Sambeek, Marc R.] Catharina Hosp, Dept Vasc Surg, Eindhoven, Netherlands. [Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [de Graaf, Jacqueline; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Lindholt, Jes S.] Odense Univ Hosp, Dept Cardiothorac & Vasc Surg, Elitary Res Ctr Individualized Med Arterial Dis C, Odense, Denmark. [Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. Univ Cambridge, Dept Haematol, Cambridge, England. [Golledge, Jonathan] James Cook Univ, Queensland Res Ctr Peripheral Vasc Dis, Vasc Biol Unit, Townsville, Qld, Australia. [Golledge, Jonathan] James Cook Univ, Dept Vasc & Endovasc Surg, Townsville, Qld, Australia. [Golledge, Jonathan] Townsville Hosp, Townsville, Qld, Australia. [Powell, Janet T.] Imperial Coll London, Dept Surg & Canc, London, England. UCL, Inst Cardiovasc Sci, Cardiovasc Genet, London, England. [Sakalihasan, Natzi] Univ Liege, Surg Res Ctr, GIGA Cardiovasc Sci Unit, Liege, Belgium. [Ferrell, Robert E.] Univ Pittsburgh, Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15260 USA. [Eriksson, Per; Folkersen, Lasse] Karolinska Inst, Dept Med, Ctr Mol Med, Atherosclerosis Res Unit, Stockholm, Sweden. [Franco-Cereceda, Anders] Karolinska Inst, Dept Mol Med & Surg, Cardiothorac Surg Unit, Stockholm, Sweden. [Betsholtz, Christer] Karolinska Inst, Dept Med Biochem & Biophys, Vasc Biol Unit, Stockholm, Sweden. [Bjorkegren, Johan L. M.] Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden. [Folkersen, Lasse] Tech Univ Denmark, Ctr Biol Sequence Anal, Copenhagen, Denmark. [Eicher, John D.; Johnson, Andrew D.] NHLBI, Ctr Populat Studies, Framingham Heart Study, Framingham, MA USA. [Betsholtz, Christer] Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, Uppsala, Sweden. [Bjorkegren, Johan L. M.] Univ Tartu, Inst Biomed & Translat Med, Dept Physiol, Tartu, Estonia. [Ruusalepp, Arno] Tartu Univ Hosp, Dept Cardiac Surg, Tartu, Estonia. [Ruusalepp, Arno; Franzen, Oscar; Bjorkegren, Johan L. M.] Clin Gene Networks AB, Stockholm, Sweden. [Lipovich, Leonard] Wayne State Univ, Dept Neurol, Detroit, MI USA. [Drolet, Anne M.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Verhoeven, Eric L.] Paracelsus Med Univ Nuremberg, Dept Vasc & Endovasc Surg, Nurnberg, Germany. [Zeebregts, Clark J.] Univ Groningen, Univ Med Ctr Groningen, Dept Surg, Div Vasc Surg, Groningen, Netherlands. [Geelkerken, Robert H.] Chirurgencooperatie Oost Nederland, Enschede, Netherlands. [van Sterkenburg, Steven M.] TweeSteden Hosp, Dept Surg, Tilburg, Netherlands. [van Sterkenburg, Steven M.] Rijnstate Ziekenhuis, Dept Vasc Surg, Arnhem, Netherlands. [de Vries, Jean-Paul] St Antonius Hosp, Dept Vasc Surg, Nieuwegein, Netherlands. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia. RP Bown, MJ (reprint author), Univ Leicester, Cardiovasc Sci, Robert Kilpatrick Bldg, Leicester LE2 7LX, Leics, England.; Jones, GT (reprint author), Univ Otago, Dept Surg, Dunedin 9054, New Zealand. EM greg.jones@otago.ac.nz; m.bown@le.ac.uk RI Michael, Williams/C-1759-2008; Webb, Tom/C-6237-2011; OI Michael, Williams/0000-0003-4822-4962; Bailey, Marc/0000-0001-5038-1970 FU Wellcome Trust [076113, 085475]; Health Research Council of New Zealand [08-75, 14-155]; National Heart, Lung, and Blood Institute, National Institutes of Health [HL064310, HL044682]; Pennsylvania Commonwealth Universal Research Enhancement program; Geisinger Clinical Research Fund; American Heart Association; Ben Franklin Technology Development Fund of Pennsylvania; National Institute for Health Research; National Institute of General Medical Sciences [U01HG004438, U01HG004424, U01HG004610, U01HG006375, U01HG004608, U01HG006389, U01HG04599, U01HG006379, U01HG004609, U01HG006388, U01HG04603, U01HG006378, U01HG006385, U01HG006382, U01HG006380]; Netherlands Organization of Scientific Research (NWO) Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative/NWO [050-060-810]; Ente Cassa di Risparmio di Firenze to Fiorgen Foundation, Florence, Italy; Italian Ministry of Health; National Science Centre in Poland [6P05A03921, NN403250440]; Marriot Award for Individualized Medicine; Mayo Center of Individualized Medicine; National Center for Research Resources [UL1 RR024975-01]; National Center for Advancing Translational Sciences [UL1 TR000445-06]; Swedish Research Council; Swedish Heart-Lung Foundation; Leducq Foundation (MIBAVA); British Heart Foundation [PG08/008]; National Institute for Health Research University College London Hospitals Biomedical Research Centre; European Union 6th Framework Programme [LSHM-CT-2006-037593]; BHF clinical training fellowship [FS/11/16/28696]; Astra-Zeneca Translational Science Centre-Karolinska Institutet; University of Tartu (SP1GVARENG); Estonian Research Council [ETF 8853]; Torsten and Ragnar Soderberg Foundation; Knut and Alice Wallenberg Foundation; American Heart Association [A14SFRN20840000]; National Institute of Health [R01HL71207] FX The Welcome Trust Case Control Consortium project was funded by the Wellcome Trust (awards 076113 and 085475). The New Zealand project was funded by the Health Research Council of New Zealand (08-75, 14-155). Recruitment of abdominal aortic aneurysm patients and controls in Belgium, Canada, and Pittsburgh, USA, was funded in part by the National Heart, Lung, and Blood Institute, National Institutes of Health (HL064310 and HL044682). The Geisinger sample collection was funded in part by the Pennsylvania Commonwealth Universal Research Enhancement program, the Geisinger Clinical Research Fund, the American Heart Association, and the Ben Franklin Technology Development Fund of Pennsylvania. The Barts and the Leicester Cardiovascular Biomedical Research Units are funded by the National Institute for Health Research. The eMERGE (electronic Medical Records and Genomics) Network is funded by the National Human Genome Research Institute, with additional funding from the National Institute of General Medical Sciences through the following grants: U01HG004438 to Johns Hopkins University; U01HG004424 to The Broad Institute; U01HG004438 to CIDR; U01HG004610 and U01HG006375 to Group Health Cooperative; U01HG004608 to Marshfield Clinic; U01HG006389 to Essentia Institute of Rural Health; U01HG04599 and U01HG006379 to Mayo Clinic; U01HG004609 and U01HG006388 to Northwestern University; U01HG04603 and U01HG006378 to Vanderbilt University; U01HG006385 to the Coordinating Center; U01HG006382 to Geisinger Health System; U01HG006380 to Icahn School of Medicine Mount Sinai. The generation and management of genome-wide association study (GWAS) data for the Rotterdam Study (control samples for the Dutch GWAS) is supported by the Netherlands Organization of Scientific Research (NWO) Investments (175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative/NWO project nr. 050-060-810. The Italian sample collection were funded by grants from Ente Cassa di Risparmio di Firenze to Fiorgen Foundation, Florence, Italy, and from the Italian Ministry of Health. Sample collections from Poland were funded in part by the National Science Centre in Poland (6P05A03921, NN403250440). The Mayo Vascular Disease Biorepository was funded by a Marriot Award for Individualized Medicine and an Award from the Mayo Center of Individualized Medicine. The Vanderbilt data set(s) were obtained from Vanderbilt University Medical Center's BioVU supported by institutional funding and by the National Center for Research Resources (UL1 RR024975-01, which is now at the National Center for Advancing Translational Sciences, UL1 TR000445-06). The ASAP study (Advanced Study of Aortic Pathology) was supported by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Leducq Foundation (MIBAVA), and a donation by Fredrik Lundberg. S.E. Humphries holds a Chair funded by the British Heart Foundation, and is supported by the British Heart Foundation (BHF; PG08/008) and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The Cardiogenics project was supported by the European Union 6th Framework Programme (LSHM-CT-2006-037593). S.C. Harrison was funded by a BHF clinical training fellowship (FS/11/16/28696).; r The Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task biobank and the generation of the RNASeq data set was funded by Astra-Zeneca Translational Science Centre-Karolinska Institutet, the University of Tartu (SP1GVARENG), the Estonian Research Council (ETF 8853), the Torsten and Ragnar Soderberg Foundation, the Knut and Alice Wallenberg Foundation, the American Heart Association (A14SFRN20840000) and by the National Institute of Health (R01HL71207). NR 228 TC 1 Z9 1 U1 7 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JAN 20 PY 2017 VL 120 IS 2 BP 341 EP + DI 10.1161/CIRCRESAHA.116.308765 PG 104 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA EI1GY UT WOS:000392226200017 PM 27899403 ER PT J AU Mensah, GA Wei, GS Sorlie, PD Fine, LJ Rosenberg, Y Kaufmann, PG Mussolino, ME Hsu, LL Addou, E Engelgau, MM Gordon, D AF Mensah, George A. Wei, Gina S. Sorlie, Paul D. Fine, Lawrence J. Rosenberg, Yves Kaufmann, Peter G. Mussolino, Michael E. Hsu, Lucy L. Addou, Ebyan Engelgau, Michael M. Gordon, David TI Decline in Cardiovascular Mortality Possible Causes and Implications SO CIRCULATION RESEARCH LA English DT Review DE cardiovascular diseases; coronary disease; hypertension; mortality; risk factors ID CORONARY-HEART-DISEASE; MONICA PROJECT POPULATIONS; RISK-FACTOR CHANGES; UNITED-STATES; PRECISION-MEDICINE; YOUNG-ADULTS; TEMPORAL TRENDS; PUBLIC-HEALTH; IMPLEMENTATION SCIENCE; MYOCARDIAL-INFARCTION AB If the control of infectious diseases was the public health success story of the first half of the 20th century, then the decline in mortality from coronary heart disease and stroke has been the success story of the century's past 4 decades. The early phase of this decline in coronary heart disease and stroke was unexpected and controversial when first reported in the mid-1970s, having followed 60 years of gradual increase as the US population aged. However, in 1978, the participants in a conference convened by the National Heart, Lung, and Blood Institute concluded that a significant recent downtick in coronary heart disease and stroke mortality rates had definitely occurred, at least in the US Since 1978, a sharp decline in mortality rates from coronary heart disease and stroke has become unmistakable throughout the industrialized world, with age-adjusted mortality rates having declined to about one third of their 1960s baseline by 2000. Models have shown that this remarkable decline has been fueled by rapid progress in both prevention and treatment, including precipitous declines in cigarette smoking, improvements in hypertension treatment and control, widespread use of statins to lower circulating cholesterol levels, and the development and timely use of thrombolysis and stents in acute coronary syndrome to limit or prevent infarction. However, despite the huge growth in knowledge and advances in prevention and treatment, there remain many questions about this decline. In fact, there is evidence that the rate of decline may have abated and may even be showing early signs of reversal in some population groups. The National Heart, Lung, and Blood Institute, through a request for information, is soliciting input that could inform a follow-up conference on or near the 40th anniversary of the original landmark conference to further explore these trends in cardiovascular mortality in the context of what has come before and what may lie ahead. C1 [Mensah, George A.; Engelgau, Michael M.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wei, Gina S.; Sorlie, Paul D.; Fine, Lawrence J.; Rosenberg, Yves; Kaufmann, Peter G.; Mussolino, Michael E.; Hsu, Lucy L.; Addou, Ebyan; Gordon, David] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kaufmann, Peter G.] Univ Colorado, Denver, CO 80202 USA. RP Mensah, GA (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, Rockledge Ctr 1, 6705 Rockledge Dr,Suite 6070, Bethesda, MD 20892 USA. EM George.Mensah@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 135 TC 0 Z9 0 U1 33 U2 33 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JAN 20 PY 2017 VL 120 IS 2 BP 366 EP 380 DI 10.1161/CIRCRESAHA.116.309115 PG 15 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA EI1GY UT WOS:000392226200019 PM 28104770 ER PT J AU Raja, V Joshi, AS Li, GL Maddipati, KR Greenberg, ML AF Raja, Vaishnavi Joshi, Amit S. Li, Guiling Maddipati, Krishna Rao Greenberg, Miriam L. TI Loss of Cardiolipin Leads to Perturbation of Acetyl-CoA Synthesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PYRUVATE-DEHYDROGENASE BYPASS; SUPPRESSES TEMPERATURE SENSITIVITY; MITOCHONDRIAL IRON HOMEOSTASIS; COENZYME-A SYNTHETASE; SACCHAROMYCES-CEREVISIAE; BARTH-SYNDROME; YEAST MITOCHONDRIA; ESCHERICHIA-COLI; SUPEROXIDE-DISMUTASE; RESPIRATORY-CHAIN AB Cardiolipin (CL), the signature phospholipid of mitochondrial membranes, plays an important role in mitochondrial processes and bioenergetics. CL is synthesized de novo and undergoes remodeling in the mitochondrial membranes. Perturbation of CL remodeling leads to the rare X-linked genetic disorder Barth syndrome, which shows disparities in clinical presentation. Touncover biochemical modifiers that exacerbate CL deficiency, we carried out a synthetic genetic array screen to identify synthetic lethal interactions with the yeast CL synthase mutant crd1 Delta. The results indicated that crd1 Delta is synthetically lethal with mutants in pyruvate dehydrogenase (PDH), which catalyzes the conversion of pyruvate to acetyl-CoA. Acetyl-CoA levels were decreased in the mutant. The synthesis of acetylCoA depends primarily on the PDH-catalyzed conversion of pyruvate in the mitochondria and on the PDH bypass in the cytosol, which synthesizes acetyl-CoA from acetate. Consistent with perturbation of the PDH bypass, crd1 Delta cells grown on acetate as the sole carbon source exhibited decreased growth, decreased acetyl-CoA, and increased intracellular acetate levels resulting from decreased acetyl-CoA synthetase activity. PDH mRNA and protein levels were up-regulated in crd1 Delta cells, but PDH enzyme activity was not increased, indicating that PDH up-regulation did not compensate for defects in the PDH bypass. These findings demonstrate for the first time that CL is required for acetyl-CoA synthesis, which is decreased in CL-deficient cells as a result of a defective PDH bypass pathway. C1 [Raja, Vaishnavi; Joshi, Amit S.; Li, Guiling; Greenberg, Miriam L.] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. [Maddipati, Krishna Rao] Wayne State Univ, Sch Med, Karmanos Canc Inst, Dept Pathol,Bioact Lipids Res Program, Detroit, MI 48202 USA. [Joshi, Amit S.] NIDDK, NIH, Bethesda, MD 20892 USA. [Li, Guiling] Jimei Univ, Coll Food & Biol Engn, Xiamen 361021, Fujian, Peoples R China. RP Greenberg, ML (reprint author), Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. EM mgreenberg@wayne.edu FU National Institutes of Health [HL117880]; Barth Syndrome Foundation; Graduate School of Wayne State University FX This work was supported by National Institutes of Health Grant HL117880, the Barth Syndrome Foundation (to M. L. G.), and the Graduate School of Wayne State University (to V. R.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 80 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 20 PY 2017 VL 292 IS 3 BP 1092 EP 1102 DI 10.1074/jbc.M116.753624 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EI2LL UT WOS:000392318700028 PM 27941023 ER PT J AU Miller, AD De las Heras, M Yu, JY Zhang, FS Liu, SL Vaughan, AE Vaughan, TL Rosadio, R Rocca, S Palmieri, G Goedert, JJ Fujimoto, J Wistuba, II AF Miller, A. Dusty De las Heras, Marcelo Yu, Jingyou Zhang, Fushun Liu, Shan-Lu Vaughan, Andrew E. Vaughan, Thomas L. Rosadio, Raul Rocca, Stefano Palmieri, Giuseppe Goedert, James J. Fujimoto, Junya Wistuba, Ignacio I. TI Evidence against a role for jaagsiekte sheep retrovirus in human lung cancer SO RETROVIROLOGY LA English DT Article DE Jaagsiekte sheep retrovirus; Human lung cancer; Ovine pulmonary adenocarcinoma ID HUMAN BRONCHIOLOALVEOLAR CARCINOMA; RNA TUMOR-VIRUSES; CELL-LINE; HUMAN-SERUM; PULMONARY ADENOCARCINOMA; ENVELOPE PROTEIN; TRANSFORMATION; DNA; VECTORS; CLASSIFICATION AB Background: Jaagsiekte sheep retrovirus (JSRV) causes a contagious lung cancer in sheep and goats that can be transmitted by aerosols produced by infected animals. Virus entry into cells is initiated by binding of the viral envelope (Env) protein to a specific cell-surface receptor, Hyal2. Unlike almost all other retroviruses, the JSRV Env protein is also a potent oncoprotein and is responsible for lung cancer in animals. Of concern, Hyal2 is a functional receptor for JSRV in humans. Results: We show here that JSRV is fully capable of infecting human cells, as measured by its reverse transcription and persistence in the DNA of cultured human cells. Several studies have indicated a role for JSRV in human lung cancer while other studies dispute these results. To further investigate the role of JSRV in human lung cancer, we used highly-specific mouse monoclonal antibodies and a rabbit polyclonal antiserum against JSRV Env to test for JSRV expression in human lung cancer. JSRV Env expression was undetectable in lung cancers from 128 human subjects, including 73 cases of bronchioalveolar carcinoma (BAC; currently reclassified as lung invasive adenocarcinoma with a predominant lepidic component), a lung cancer with histology similar to that found in JSRV-infected sheep. The BAC samples included 8 JSRV DNA-positive samples from subjects residing in Sardinia, Italy, where sheep farming is prevalent and JSRV is present. We also tested for neutralizing antibodies in sera from 138 Peruvians living in an area where sheep farming is prevalent and JSRV is present, 24 of whom were directly exposed to sheep, and found none. Conclusions: We conclude that while JSRV can infect human cells, JSRV plays little if any role in human lung cancer. C1 [Miller, A. Dusty; Vaughan, Andrew E.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Miller, A. Dusty] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [De las Heras, Marcelo] Univ Zaragoza, Dept Anim Pathol, Zaragoza, Spain. [Yu, Jingyou; Liu, Shan-Lu] Ohio State Univ, Ctr Retrovirus Res, Dept Vet Biosci, Columbus, OH 43210 USA. [Yu, Jingyou; Zhang, Fushun; Liu, Shan-Lu] Univ Missouri, Dept Mol Microbiol & Immunol, Bond Life Sci Canter, Columbia, MO USA. [Vaughan, Andrew E.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Rosadio, Raul] Natl Univ San Marcos, Fac Vet, Lima, Peru. [Rocca, Stefano] Univ Sassari, Dept Vet Med, Sassari, Italy. [Palmieri, Giuseppe] CNR, Inst Biomol Chem, Unit Canc Genet, Sassari, Italy. [Goedert, James J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Fujimoto, Junya; Wistuba, Ignacio I.] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA. [Miller, A. Dusty] 17915 Edmundson Rd, Sisters, OR 97759 USA. RP Miller, AD (reprint author), Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA.; Miller, AD (reprint author), Univ Washington, Dept Pathol, Seattle, WA 98195 USA.; Miller, AD (reprint author), 17915 Edmundson Rd, Sisters, OR 97759 USA. EM dmiller@fredhutch.org OI Palmieri, Giuseppe/0000-0002-4350-2276; Miller, Dusty/0000-0002-3736-3660; Liu, Shan-Lu/0000-0003-1620-3817 FU Fred Hutchinson Cancer Research Center; University of Texas Lung Specialized Programs of Research Excellence [P50CA70907]; National Cancer Institute [P30CA016672]; Ohio State University [NIH 1R01AI112381, 1R21AI109464] FX This study was supported by the Fred Hutchinson Cancer Research Center, The University of Texas Lung Specialized Programs of Research Excellence grant (P50CA70907; to I.I.W.), MD Anderson's Institutional Tissue Bank Award (P30CA016672) from the National Cancer Institute, and The Ohio State University grants NIH 1R01AI112381 and 1R21AI109464 (to S.L.L.). NR 39 TC 0 Z9 0 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JAN 20 PY 2017 VL 14 AR 3 DI 10.1186/s12977-017-0329-6 PG 13 WC Virology SC Virology GA EI4DN UT WOS:000392443400001 PM 28107820 ER PT J AU Sulman, EP Ismaila, N Armstrong, TS Tsien, C Batchelor, TT Cloughesy, T Galanis, E Gilbert, M Gondi, V Lovely, M Mehta, M Mumber, MP Sloan, A Chang, SM AF Sulman, Erik P. Ismaila, Nofisat Armstrong, Terri S. Tsien, Christina Batchelor, Tracy T. Cloughesy, Tim Galanis, Evanthia Gilbert, Mark Gondi, Vinai Lovely, Mary Mehta, Minesh Mumber, Matthew P. Sloan, Andrew Chang, Susan M. TI Radiation Therapy for Glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NEWLY-DIAGNOSED GLIOBLASTOMA; RANDOMIZED PHASE-III; RECURRENT MALIGNANT GLIOMA; QUALITY-OF-LIFE; HYPOFRACTIONATED RADIOTHERAPY; ADJUVANT TEMOZOLOMIDE; ANAPLASTIC GLIOMAS; TRIAL; MULTIFORME; BEVACIZUMAB AB Purpose The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on radiation therapy for glioblastoma. Because of its relevance to the ASCO membership, ASCO reviewed the guideline and applied a set of procedures and policies used to critically examine guidelines developed by other organizations. Methods The ASTRO guideline on radiation therapy for glioblastoma was reviewed for developmental rigor by methodologists. An ASCO endorsement panel updated the literature search and reviewed the content and recommendations. Results The ASCO endorsement panel determined that the recommendations from the ASTRO guideline, published in 2016, are clear, thorough, and based on current scientific evidence. ASCO endorsed the ASTRO guideline on radiation therapy for glioblastoma and added qualifying statements. Recommendations Partial-brain fractionated radiotherapy with concurrent and adjuvant temozolomide is the standard of care after biopsy or resection of newly diagnosed glioblastoma in patients up to 70 years of age. Hypofractionated radiotherapy for elderly patients with fair to good performance status is appropriate. The addition of concurrent and adjuvant temozolomide to hypofractionated radiotherapy seems to be safe and efficacious without impairing quality of life for elderly patients with good performance status. Reasonable options for patients with poor performance status include hypofractionated radiotherapy alone, temozolomide alone, or best supportive care. Focal reirradiation represents an option for select patients with recurrent glioblastoma, although this is not supported by prospective randomized evidence. Additional information is available at www.asco.org/glioblastoma-radiotherapy-endorsement and www.asco.org/guidelineswiki. (C) 2016 by American Society of Clinical Oncology C1 [Ismaila, Nofisat] Amer Soc Clin Oncol, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. [Sulman, Erik P.; Armstrong, Terri S.] MD Anderson Canc Ctr, Houston, TX 77030 USA. [Armstrong, Terri S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Tsien, Christina] Washington Univ Phys, St Louis, MO USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cloughesy, Tim] Univ Calif Los Angeles, Los Angeles, CA USA. [Lovely, Mary; Chang, Susan M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Galanis, Evanthia] Mayo Clin, Rochester, MN USA. [Gilbert, Mark] NCI, Bethesda, MD 20892 USA. [Mehta, Minesh] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Gondi, Vinai] Northwestern Med Canc Ctr, Warrenville, IL USA. [Mumber, Matthew P.] Harbin Clin Radiat Oncol, Rome, GA USA. [Sloan, Andrew] Univ Hosp Cleveland Med Ctr, Cleveland, OH USA. RP Sulman, EP (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. EM guidelines@asco.org OI mehta, minesh/0000-0002-4812-5713 FU AbbVie (Inst); Novocure (Inst); Pfizer (Inst); Genentech (Inst); Merck (Inst); Novelos Therapeutics (Inst); Novartis (Inst); Schering-Plough (Inst); Quest Diagnostics (Inst); Agios Pharmaceuticals (Inst); Roche (Inst) FX AbbVie (Inst), Novocure (Inst); Pfizer (Inst); Genentech (Inst), Merck (Inst); Novocure (Inst), Novelos Therapeutics (Inst); Novartis (Inst), Schering-Plough (Inst), Quest Diagnostics (Inst), Agios Pharmaceuticals (Inst), Roche (Inst) NR 40 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2017 VL 35 IS 3 BP 361 EP + DI 10.1200/JCO.2016.70.7562 PG 11 WC Oncology SC Oncology GA EH7PR UT WOS:000391965400014 PM 27893327 ER PT J AU Ma, JT Yang, Q Hwang, SJ Fox, CS Chu, AY AF Ma, Jiantao Yang, Qiong Hwang, Shih-Jen Fox, Caroline S. Chu, Audrey Y. TI Genetic risk score and risk of stage 3 chronic kidney disease SO BMC NEPHROLOGY LA English DT Article DE Genetic risk score; Estimated glomerular filtration rate; Chronic kidney disease ID COMMUNITY-BASED POPULATION; SERUM CREATININE ASSAYS; CARDIOVASCULAR-DISEASE; COMMON; PREDICTION; STATEMENT; TRENDS; CKD AB Background: We developed a genetic risk score (GRS) and examined whether the GRS may predict incident stage 3 chronic kidney disease (CKD) independent of common clinical risk factors. Method: The present study included 2,698 individuals who attended the 15th (1977 to 1979) and the 24th exams (1995 to 1998) in the Framingham Original cohort or the 6th (1995 to 1998) and the 8th exams (2005 to 2008) in the Framingham Offspring cohort. A weighted GRS was constructed combining 53 single nucleotide polymorphisms (SNPs) associated with lower creatinine-based estimated glomerular filtration rate (eGFR). Stage 3 CKD was defined as eGFR <60 mL/min/1.73 m(2), and incident cases were identified at follow-up after excluding prevalent cases at baseline. Results: A total of 292 incident cases and 2,406 non-cases were identified over, on average, 11 years of follow-up. After adjustment for sex, age, cohort, baseline eGFR, hypertension, diabetes, and dipstick proteinuria, the odds ratio of incident stage 3 CKD was 1.37 (95% CI: 1.02-1.83) per 10 alleles of the GRS (P = 0.04). There was no statistically significant difference between the C-statistic without and with inclusion of the GRS (0.783 and 0.785, respectively; P = 0.39). Conclusions: A GRS developed based on 53 SNPs associated with reduced eGFR was prospectively associated with incident stage 3 CKD. However, this score did not substantially improve discrimination of stage 3 CKD beyond the common clinical risk factors. C1 [Ma, Jiantao; Hwang, Shih-Jen; Fox, Caroline S.; Chu, Audrey Y.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Ma, Jiantao; Hwang, Shih-Jen; Fox, Caroline S.; Chu, Audrey Y.] NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Yang, Qiong] Boston Univ, Dept Biostat, Boston, MA 02215 USA. RP Chu, AY (reprint author), Framingham Heart Dis Epidemiol Study, Framingham, MA USA.; Chu, AY (reprint author), NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM audrey.chu@nih.gov FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix for genotyping services [N02-HL-6-4278] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix for genotyping services (Contract No. N02-HL-6-4278). The funding agency plays no role in study design, data collection, analysis, and interpretation. NR 30 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JAN 19 PY 2017 VL 18 AR 32 DI 10.1186/s12882-017-0439-3 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EJ2XR UT WOS:000393075400003 PM 28103844 ER PT J AU Mullooly, M Yang, HP Falk, RT Nyante, SJ Cora, R Pfeiffer, RM Radisky, DC Visscher, DW Hartmann, LC Carter, JM Degnim, AC Stanczyk, FZ Figueroa, JD Garcia-Closas, M Lissowska, J Troester, MA Hewitt, SM Brinton, LA Sherman, ME Gierach, GL AF Mullooly, Maeve Yang, Hannah P. Falk, Roni T. Nyante, Sarah J. Cora, Renata Pfeiffer, Ruth M. Radisky, Derek C. Visscher, Daniel W. Hartmann, Lynn C. Carter, Jodi M. Degnim, Amy C. Stanczyk, Frank Z. Figueroa, Jonine D. Garcia-Closas, Montserrat Lissowska, Jolanta Troester, Melissa A. Hewitt, Stephen M. Brinton, Louise A. Sherman, Mark E. Gierach, Gretchen L. TI Relationship between crown-like structures and sex-steroid hormones in breast adipose tissue and serum among postmenopausal breast cancer patients SO BREAST CANCER RESEARCH LA English DT Article DE Crown-like structures; Estrogens; Hormones; Postmenopausal; Breast cancer ID ELEVATED AROMATASE EXPRESSION; MAMMARY-GLAND INFLAMMATION; OBESE WOMEN; MICE AB Background: Postmenopausal obesity is associated with increased circulating levels of androgens and estrogens and elevated breast cancer risk. Crown-like structures (CLS; microscopic foci of dying adipocytes surrounded by macrophages) are proposed to represent sites of increased aromatization of androgens to estrogens. Accordingly, we examined relationships between CLS and sex-steroid hormones in breast adipose tissue and serum from postmenopausal breast cancer patients. Methods: Formalin-fixed paraffin embedded benign breast tissues collected for research from postmenopausal women (n = 83) diagnosed with invasive breast cancer in the Polish Breast Cancer Study (PBCS) were evaluated. Tissues were immunohistochemically stained for CD68 to determine the presence of CLS per unit area of adipose tissue. Relationships were assessed between CD68 density and CLS and previously reported sex-steroid hormones quantified using radioimmunoassays in serum taken at the time of diagnosis and in fresh frozen adipose tissue taken at the time of surgery. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relationships between hormones (in tertiles) and CLS. Results: CLS were observed in 36% of benign breast tissues, with a higher frequency among obese versus lean women (54% versus 17%, p = 0.03). Detection of CLS was not related to individual hormone levels or breast tumor pathology characteristics. However, detection of CLS was associated with hormone ratios. Compared with women in the highest tertile of estrone: androstenedione ratio in fat, those in the lowest tertile were less likely to have CLS (OR 0.12, 95% CI 0.03-0.59). A similar pattern was observed with estradiol: testosterone ratio in serum and CLS (lowest versus highest tertile, OR 0.18, 95% CI 0.04-0.72). Conclusions: CLS were more frequently identified in the breast fat of obese women and were associated with increased ratios of select estrogens: androgens in the blood and tissues, but not with individual hormones. Additional studies on CLS, tissue and blood hormone levels, and breast cancer risk are needed to understand and confirm these findings. C1 [Mullooly, Maeve; Yang, Hannah P.; Falk, Roni T.; Pfeiffer, Ruth M.; Garcia-Closas, Montserrat; Brinton, Louise A.; Gierach, Gretchen L.] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Mullooly, Maeve] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Nyante, Sarah J.] Univ North Carolina Chapel Hill, Sch Med, Dept Radiol, Chapel Hill, NC USA. [Cora, Renata] MB ASCP, CT ASCP, Stamford, CT USA. [Radisky, Derek C.] Mayo Clin Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. [Visscher, Daniel W.; Hartmann, Lynn C.; Carter, Jodi M.; Degnim, Amy C.] Mayo Clin, Rochester, MN USA. [Stanczyk, Frank Z.] Univ Southern Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA USA. [Figueroa, Jonine D.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Sch Med, Teviot Pl, Edinburgh, Midlothian, Scotland. [Lissowska, Jolanta] Ctr Canc, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] M Sklodowska Curie Inst Oncol, Warsaw, Poland. [Troester, Melissa A.] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA. [Troester, Melissa A.] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Mullooly, M (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA.; Mullooly, M (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. EM maeve.mullooly@nih.gov RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU NCI; Cancer Prevention Fellowship Program (NCI) FX This project was supported by the Intramural Research Program of the NCI and the Cancer Prevention Fellowship Program (NCI). NR 25 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD JAN 19 PY 2017 VL 19 AR 8 DI 10.1186/s13058-016-0791-4 PG 10 WC Oncology SC Oncology GA EK0MZ UT WOS:000393622100001 PM 28103902 ER PT J AU Crandall, JP Tahari, AK Juergens, RA Brahmer, JR Rudin, CM Esposito, G Subramaniam, DS Knopp, MV Hall, NC Gajwani, P Leal, JP Lodge, MA Joo, HO Gabrielson, EW Shankar, LK Wahl, RL AF Crandall, John P. Tahari, Abdel K. Juergens, Rosalyn A. Brahmer, Julie R. Rudin, Charles M. Esposito, Giuseppe Subramaniam, Deepa S. Knopp, Michael V. Hall, Nathan C. Gajwani, Prateek Leal, Jeffrey P. Lodge, Martin A. Joo, H. O. Gabrielson, Edward W. Shankar, Lalitha K. Wahl, Richard L. TI A comparison of FLT to FDG PET/CT in the early assessment of chemotherapy response in stages IB-IIIA resectable NSCLC SO EJNMMI RESEARCH LA English DT Article DE FDG PET/CT; FLT PET/CT; Non-small cell lung cancer; Early treatment response monitoring ID CELL LUNG-CANCER; POSITRON-EMISSION-TOMOGRAPHY; F-18-FDG PET; IMAGING PROLIFERATION; TUMOR RESPONSE; IN-VIVO; KI-67 IMMUNOHISTOCHEMISTRY; EARLY PREDICTION; BREAST-CANCER; CHEMORADIOTHERAPY AB Background: The aim of this study was to compare the percentage change in F-18-fluorothymidine (FLT) standard uptake value (SUV) between baseline and after one cycle of chemotherapy in patients categorized by RECIST 1.1 computed tomography (CT) as responders or non-responders after two cycles of therapy. Change in F-18-fluorodeoxyglucose (FDG) uptake was also compared between these time points. Nine patients with newly diagnosed, operable, non-small cell lung cancer (NSCLC) were imaged with FDG positron emission tomography/CT (PET), FLT PET/CT, and CT at baseline, following one cycle of neoadjuvant therapy (75 mg/m(2) docetaxel + 75 mg/m(2) cisplatin), and again after the second cycle of therapy. All patients had a biopsy prior to enrollment and underwent surgical resection within 4 weeks of post-cycle 2 imaging. Results: Between baseline and post-cycle 1, non-responders had mean SULmax (maximum standard uptake value adjusted for lean body mass) increases of 7.0 and 3.4% for FDG and FLT, respectively. Responders had mean decreases of 44.8 and 32.0% in FDG and FLT SULmax, respectively, between baseline and post-cycle 1 imaging. On post-cycle 1 imaging, primary tumor FDG SUL values were significantly lower in responders than in non-responders (P = 0.016). Primary tumor FLT SUL values did not differ significantly between these groups. Using the change from baseline to post-cycle 1, receiver-operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.94 for FDG and 0.78 for FLT in predicting anatomic tumor response after the second cycle of therapy. Conclusions: Fractional decrease in FDG SULmax from baseline to post-cycle 1 imaging was significantly different between anatomic responders and non-responders, while percentage changes in FLT SULmax were not significantly different between these groups over the same period of time. C1 [Crandall, John P.; Wahl, Richard L.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, 510 S Kingshighway Blvd,Campus Box 8131, St Louis, MO 63110 USA. [Tahari, Abdel K.] King Fahad Specialist Hosp, Dept Med Imaging, POB 15215, Dammam 3144434, Saudi Arabia. [Juergens, Rosalyn A.] McMaster Univ, Juravinski Canc Ctr, 699 Concess St, Hamilton, ON L8V 5C2, Canada. [Brahmer, Julie R.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, 1650 Orleans St,CRB 1 Room G-94, Baltimore, MD 21287 USA. [Rudin, Charles M.] Mem Sloan Kettering Canc Ctr, Dept Med, Div Solid Tumor Oncol, Thorac Oncol Serv, 633 3rd Ave, New York, NY 10017 USA. [Rudin, Charles M.] Weill Cornell Med Coll, 633 3rd Ave, New York, NY 10017 USA. [Esposito, Giuseppe] Georgetown Univ Hosp, Dept Radiol, 3800 Reservoir Rd NW CCC Bldg, Washington, DC 20007 USA. [Subramaniam, Deepa S.] Georgetown Univ Hosp, Dept Med, 3800 Reservoir Rd NW LCCC Bldg,Second Floor Pod B, Washington, DC 20007 USA. [Knopp, Michael V.] Ohio State Univ, Wexner Med Ctr, Dept Radiol, 395 W 12th Ave,Room 430, Columbus, OH 43210 USA. [Hall, Nathan C.] Univ Penn, Perelman Sch Med, Dept Radiol, 116 Donner,HUP 3400 Spruce St, Philadelphia, PA 19104 USA. [Gajwani, Prateek] Johns Hopkins Univ, Sch Med, Johns Hopkins Wilmer Eye Inst, 600 N Wolfe St, Baltimore, MD 21287 USA. [Leal, Jeffrey P.; Lodge, Martin A.; Wahl, Richard L.] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol, Nelson B1-160,600 N Wolfe St, Baltimore, MD 21287 USA. [Joo, H. O.] Catholic Med Ctr, Seoul St Marys Hosp, Dept Nucl Med, Banpo Daero 222, Seoul 06591, South Korea. [Gabrielson, Edward W.] Johns Hopkins Univ, Sch Med, Dept Pathol, 1550 Orleans St,304 CRB 2, Baltimore, MD 21287 USA. [Shankar, Lalitha K.] Natl Canc Inst, 6130 Execut Blvd,MSC 7412, Bethesda, MD 20892 USA. RP Wahl, RL (reprint author), Washington Univ, Sch Med, Mallinckrodt Inst Radiol, 510 S Kingshighway Blvd,Campus Box 8131, St Louis, MO 63110 USA.; Wahl, RL (reprint author), Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol, Nelson B1-160,600 N Wolfe St, Baltimore, MD 21287 USA. EM rwahl@wustl.edu FU National Cancer Institute; National Institutes of Health [N01CM27018, P30CA006973, 1U01CA140204] FX This study was funded by the National Cancer Institute and National Institutes of Health through N01CM27018, P30CA006973, and 1U01CA140204. NR 33 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2191-219X J9 EJNMMI RES JI EJNMMI Res. PD JAN 19 PY 2017 VL 7 AR 8 DI 10.1186/s13550-017-0258-3 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EI5MY UT WOS:000392540200001 PM 28102506 ER PT J AU Ramalingam, D Ziegelbauer, JM AF Ramalingam, Dhivya Ziegelbauer, Joseph M. TI Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses SO SCIENTIFIC REPORTS LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; PRIMARY EFFUSION LYMPHOMA; INFLAMMATORY-CYTOKINE EXPRESSION; HYPER-IGE SYNDROME; SIGNAL-TRANSDUCTION; LYTIC ACTIVATION; PROTEIN; CELLS; ERYTHROPOIETIN; SURVIVIN AB Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs during latency that are processed to yield similar to 25 mature microRNAs (miRNAs). We were interested in identifying cellular networks that were targeted by KSHV-miRNAs and employed network building strategies using validated KSHV miRNA targets. Here, we report the identification of a gene network centering on the transcription factor-signal transducer and activator of transcription 3 (STAT3) that is targeted by KSHV miRNAs. KSHV miRNAs suppressed STAT3 and STAT5 activation and inhibited STAT3-dependent reporter activation upon IL6-treatment. KSHV miRNAs also repressed the induction of antiviral interferon-stimulated genes upon IFN alpha- treatment. Finally, we observed increased lytic reactivation of KSHV from latently infected cells upon STAT3 repression with siRNAs or a small molecule inhibitor. Our data suggest that treatment of infected cells with a STAT3 inhibitor and a viral replication inhibitor, ganciclovir, represents a possible strategy to eliminate latently infected cells without increasing virion production. Together, we show that KSHV miRNAs suppress a network of targets associated with STAT3, deregulate cytokine-mediated gene activation, suppress an interferon response, and influence the transition into the lytic phase of viral replication. C1 [Ramalingam, Dhivya; Ziegelbauer, Joseph M.] NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Ziegelbauer, JM (reprint author), NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. EM ziegelbauerjm@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health [1ZIABC011176] FX We would like to thank Christine Happel of the Ziegelbauer lab for assistance with HUVEC mRNA panels. We also thank Don Ganem for sharing microarray data and along with Chris Sullivan for contributions to initial microarray screening design. We would like to thank former members of the laboratory-Johanna Abend, Philippe Kieffer-Kwon, Jingran Ji, Vera Flowers and Xiaoyan Liu for assistance with the luciferase reporter assays. We would also like to thank Don Ganem for the gift of anti-RTA primary antibody. We are also grateful for the gift of the iSLK mutant cell lines from Rolf Renne. We would like to thank James Darnell for his gift of 4xM67 pTATA TK-Luc plasmid. We would also like to thank Drs. Robert Yarchoan, David Davis, Ashish Lal, and Giovanna Tosato for their critical review of this manuscript. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health [1ZIABC011176]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 62 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 19 PY 2017 VL 7 AR 40813 DI 10.1038/srep40813 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI1FE UT WOS:000392221200001 PM 28102325 ER PT J AU Arce, SC AF Arce, Santiago C. TI Long-Term Oxygen for COPD SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Arce, Santiago C.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Arce, SC (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM arcesantiago@fibertel.com.ar NR 3 TC 0 Z9 0 U1 3 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 19 PY 2017 VL 376 IS 3 BP 286 EP 287 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EI0XO UT WOS:000392199100016 PM 28102646 ER PT J AU Galiatsatos, P AF Galiatsatos, Panagis TI Long-Term Oxygen for COPD SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID LUNG HEALTH C1 [Galiatsatos, Panagis] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Galiatsatos, P (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM panagis.galiatsatos@nih.gov NR 3 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 19 PY 2017 VL 376 IS 3 BP 286 EP 286 DI 10.1056/NEJMc1615074 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EI0XO UT WOS:000392199100015 PM 28102645 ER PT J AU Marconi, C Canobbio, I Bozzi, V Pippucci, T Simonetti, G Melazzini, F Angori, S Martinelli, G Saglio, G Torti, M Pastan, I Seri, M Pecci, A AF Marconi, Caterina Canobbio, Ilaria Bozzi, Valeria Pippucci, Tommaso Simonetti, Giorgia Melazzini, Federica Angori, Silvia Martinelli, Giovanni Saglio, Giuseppe Torti, Mauro Pastan, Ira Seri, Marco Pecci, Alessandro TI 5'UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Article DE ANKRD26 gene; Acute myeloid leukemia; Inherited predisposition to leukemia; Inherited thrombocytopenia ID INHERITED THROMBOCYTOPENIA; MALIGNANCIES; GENE; FORM AB Thrombocytopenia 2 (THC2) is an inherited disorder caused by monoallelic single nucleotide substitutions in the 5'UTR of the ANKRD26 gene. Patients have thrombocytopenia and increased risk of myeloid malignancies, in particular, acute myeloid leukemia (AML). Given the association of variants in the ANKRD26 5'UTR with myeloid neoplasms, we investigated whether, and to what extent, mutations in this region contribute to apparently sporadic AML. To this end, we studied 250 consecutive, non-familial, adult AML patients and screened the first exon of ANKRD26 including the 5'UTR. We found variants in four patients. One patient had the c.-125T>G substitution in the 5'UTR, while three patients carried two different variants in the 5' end of the ANKRD26 coding region (c.3G>A or c.105C>G). Review of medical history showed that the patient carrying the c.-125T>G was actually affected by typical but unrecognized THC2, highlighting that some apparently sporadic AML cases represent the evolution of a well-characterized familial predisposition disorder. As regards the c.3G>A and the c.105C>G, we found that both variants result in the synthesis of N-terminal truncated ANKRD26 isoforms, which are stable and functional in cells, in particular, have a strong ability to activate the MAPK/ERK signaling pathway. Moreover, investigation of one patient with the c.3G>A showed that mutation was associated with strong ANKRD26 overexpression in vivo, which is the proposed mechanism for predisposition to AML in THC2 patients. These data provide evidence that N-terminal ANKRD26 truncating mutations play a potential pathogenetic role in AML. Recognition of AML patients with germline ANKRD26 pathogenetic variants is mandatory for selection of donors for bone marrow transplantation. C1 [Marconi, Caterina; Pippucci, Tommaso; Angori, Silvia; Seri, Marco] Univ Bologna, Med Genet Unit, Dept Med & Surg Sci, Bologna, Italy. [Canobbio, Ilaria; Torti, Mauro] Univ Pavia, Dept Biol & Biotechnol, Labs Biochem, Pavia, Italy. [Bozzi, Valeria; Melazzini, Federica; Pecci, Alessandro] Policlin San Matteo Fdn, IRCCS, Dept Internal Med, Pavia, Italy. [Bozzi, Valeria; Melazzini, Federica; Pecci, Alessandro] Univ Pavia, Pavia, Italy. [Simonetti, Giorgia; Martinelli, Giovanni] Univ Bologna, Inst Hematol L & A Seragnoli, Dept Expt Diagnost & Specialty Med, Bologna, Italy. [Saglio, Giuseppe] Univ Turin, San Luigi Hosp, Dept Clin & Biol Sci, Turin, Italy. [Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Pecci, A (reprint author), Policlin San Matteo Fdn, IRCCS, Dept Internal Med, Pavia, Italy.; Pecci, A (reprint author), Univ Pavia, Pavia, Italy. EM alessandro.pecci@unipv.it FU Telethon Foundation, Italy [GGP10089]; Cariplo Foundation, Italy [2012-0529, 2010-0807]; Italian Ministry of Health [RF-2010-2310098]; ntramural Research Program of the NIH; National Cancer Institute, Center for Cancer Research FX This work was supported in part by grants from the Telethon Foundation, Italy (GGP10089), the Cariplo Foundation, Italy (2012-0529, 2010-0807), the Italian Ministry of Health (RF-2010-2310098), and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 10 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD JAN 18 PY 2017 VL 10 AR 18 DI 10.1186/s13045-016-0382-y PG 4 WC Oncology; Hematology SC Oncology; Hematology GA EO2TS UT WOS:000396549500001 PM 28100250 ER PT J AU Torresen, OK Star, B Jentoft, S Reinar, WB Grove, H Miller, JR Walenz, BP Knight, J Ekholm, JM Peluso, P Edvardsen, RB Tooming-Klunderud, A Skage, M Lien, S Jakobsen, KS Nederbragt, AJ AF Torresen, Ole K. Star, Bastiaan Jentoft, Sissel Reinar, William B. Grove, Harald Miller, Jason R. Walenz, Brian P. Knight, James Ekholm, Jenny M. Peluso, Paul Edvardsen, Rolf B. Tooming-Klunderud, Ave Skage, Morten Lien, Sigbjorn Jakobsen, Kjetill S. Nederbragt, Alexander J. TI An improved genome assembly uncovers prolific tandem repeats in Atlantic cod SO BMC GENOMICS LA English DT Article DE Assembly algorithms; Assembly consolidation; Dinucleotide repeats; Gadus morhua; Heterozygosity; Indel polymorphism; Long-read sequencing technology; Microsatellites; PacBio; Repetitive DNA ID MOLECULE SEQUENCING READS; GADUS-MORHUA; ANNOTATION PIPELINE; PROVIDES INSIGHTS; WIDE ANALYSIS; EVOLUTION; GENERATION; ALIGNMENT; REVEALS; ADAPTATION AB Background: The first Atlantic cod (Gadus morhua) genome assembly published in 2011 was one of the early genome assemblies exclusively based on high-throughput 454 pyrosequencing. Since then, rapid advances in sequencing technologies have led to a multitude of assemblies generated for complex genomes, although many of these are of a fragmented nature with a significant fraction of bases in gaps. The development of long-read sequencing and improved software now enable the generation of more contiguous genome assemblies. Results: By combining data from Illumina, 454 and the longer PacBio sequencing technologies, as well as integrating the results of multiple assembly programs, we have created a substantially improved version of the Atlantic cod genome assembly. The sequence contiguity of this assembly is increased fifty-fold and the proportion of gap-bases has been reduced fifteen-fold. Compared to other vertebrates, the assembly contains an unusual high density of tandem repeats (TRs). Indeed, retrospective analyses reveal that gaps in the first genome assembly were largely associated with these TRs. We show that 21% of the TRs across the assembly, 19% in the promoter regions and 12% in the coding sequences are heterozygous in the sequenced individual. Conclusions: The inclusion of PacBio reads combined with the use of multiple assembly programs drastically improved the Atlantic cod genome assembly by successfully resolving long TRs. The high frequency of heterozygous TRs within or in the vicinity of genes in the genome indicate a considerable standing genomic variation in Atlantic cod populations, which is likely of evolutionary importance. C1 [Torresen, Ole K.; Star, Bastiaan; Jentoft, Sissel; Reinar, William B.; Tooming-Klunderud, Ave; Skage, Morten; Jakobsen, Kjetill S.; Nederbragt, Alexander J.] Univ Oslo, Dept Biosci, Ctr Ecol & Evolutionary Synth, NO-0316 Oslo, Norway. [Jentoft, Sissel] Univ Agder, Dept Nat Sci, NO-4604 Kristiansand, Norway. [Grove, Harald; Lien, Sigbjorn] Norwegian Univ Life Sci, Dept Anim & Aquacultural Sci, Ctr Integrat Genet CIGENE, NO-1432 As, Norway. [Miller, Jason R.] J Craig Venter Inst, 9704 Med Ctr Dr, Rockville, MD 20850 USA. [Walenz, Brian P.] NHGRI, Genome Informat Sect, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. [Knight, James] Yale Univ, Yale Sch Med, New Haven, CT 06520 USA. [Ekholm, Jenny M.; Peluso, Paul] Pacific Biosci, Menlo Pk, CA USA. [Edvardsen, Rolf B.] Nordnes, Inst Marine Res, NO-5817 Bergen, Norway. [Nederbragt, Alexander J.] Univ Oslo, Dept Informat, Biomed Informat Res Grp, NO-0316 Oslo, Norway. RP Torresen, OK; Nederbragt, AJ (reprint author), Univ Oslo, Dept Biosci, Ctr Ecol & Evolutionary Synth, NO-0316 Oslo, Norway.; Nederbragt, AJ (reprint author), Univ Oslo, Dept Informat, Biomed Informat Res Grp, NO-0316 Oslo, Norway. EM o.k.torresen@ibv.uio.no; lex.nederbragt@ibv.uio.no OI Nederbragt, Alexander/0000-0001-5539-0999 FU Research Council of Norway [199806] FX Research Council of Norway project number 199806 to KSJ. NR 117 TC 1 Z9 1 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JAN 18 PY 2017 VL 18 AR 95 DI 10.1186/s12864-016-3448-x PG 23 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EL1KV UT WOS:000394380200002 PM 28100185 ER PT J AU Papanicolaou, A Schetelig, MF Arensburger, P Atkinson, PW Benoit, JB Bourtzis, K Castanera, P Cavanaugh, JP Chao, H Childers, C Curril, I Dinh, H Doddapaneni, H Dolan, A Dugan, S Friedrich, M Gasperi, G Geib, S Georgakilas, G Gibbs, RA Giers, SD Gomulski, LM Gonzalez-Guzman, M Guillem-Amat, A Han, Y Hatzigeorgiou, AG Hernandez-Crespo, P Hughes, DST Jones, JW Karagkouni, D Koskinioti, P Lee, SL Malacrida, AR Manni, M Mathiopoulos, K Meccariello, A Munoz-Torres, M Murali, SC Murphy, TD Muzny, DM Oberhofer, G Ortego, F Paraskevopoulou, MD Poelchau, M Qu, JX Reczko, M Robertson, HM Rosendale, AJ Rosselot, AE Saccone, G Salvemini, M Savini, G Schreiner, P Scolari, F Siciliano, P Sim, SB Tsiamis, G Urena, E Vlachos, IS Werren, JH Wimmer, EA Worley, KC Zacharopoulou, A Richards, S Handler, AM AF Papanicolaou, Alexie Schetelig, Marc F. Arensburger, Peter Atkinson, Peter W. Benoit, Joshua B. Bourtzis, Kostas Castanera, Pedro Cavanaugh, John P. Chao, Hsu Childers, Christopher Curril, Ingrid Dinh, Huyen Doddapaneni, HarshaVardhan Dolan, Amanda Dugan, Shannon Friedrich, Markus Gasperi, Giuliano Geib, Scott Georgakilas, Georgios Gibbs, Richard A. Giers, Sarah D. Gomulski, Ludvik M. Gonzalez-Guzman, Miguel Guillem-Amat, Ana Han, Yi Hatzigeorgiou, Artemis G. Hernandez-Crespo, Pedro Hughes, Daniel S. T. Jones, Jeffery W. Karagkouni, Dimitra Koskinioti, Panagiota Lee, Sandra L. Malacrida, Anna R. Manni, Mose Mathiopoulos, Kostas Meccariello, Angela Munoz-Torres, Monica Murali, Shwetha C. Murphy, Terence D. Muzny, Donna M. Oberhofer, Georg Ortego, Felix Paraskevopoulou, Maria D. Poelchau, Monica Qu, Jiaxin Reczko, Martin Robertson, Hugh M. Rosendale, Andrew J. Rosselot, Andrew E. Saccone, Giuseppe Salvemini, Marco Savini, Grazia Schreiner, Patrick Scolari, Francesca Siciliano, Paolo Sim, Sheina B. Tsiamis, George Urena, Enric Vlachos, Ioannis S. Werren, John H. Wimmer, Ernst A. Worley, Kim C. Zacharopoulou, Antigone Richards, Stephen Handler, Alfred M. TI The whole genome sequence of the Mediterranean fruit fly, Ceratitis capitata (Wiedemann), reveals insights into the biology and adaptive evolution of a highly invasive pest species (vol 17, 192, 2016) SO GENOME BIOLOGY LA English DT Correction C1 [Papanicolaou, Alexie] Univ Western Sydney, Hawkesbury Inst Environm, Sydney, NSW, Australia. [Schetelig, Marc F.] Justus Liebig Univ Giessen, Inst Insect Biotechnol, D-35394 Giessen, Germany. [Arensburger, Peter] Cal Poly Pomona, Dept Sci Biol, Pomona, CA 91768 USA. [Atkinson, Peter W.] Univ Calif Riverside, Dept Entomol, Riverside, CA 92521 USA. [Atkinson, Peter W.] Univ Calif Riverside, Ctr Dis Vector Res, Riverside, CA 92521 USA. [Atkinson, Peter W.; Schreiner, Patrick] Univ Calif Riverside, Interdept Grad Program Genet Genom & Bioinformat, Riverside, CA 92521 USA. [Benoit, Joshua B.; Cavanaugh, John P.; Rosendale, Andrew J.; Rosselot, Andrew E.] Univ Cincinnati, Dept Biol Sci, Cincinnati, OH 45221 USA. [Bourtzis, Kostas] Joint FAO IAEA Programme Nucl Tech Food & Agr, Insect Pest Control Lab, Vienna, Austria. [Bourtzis, Kostas; Tsiamis, George] Univ Patras, Dept Environm & Nat Resources, Agrinion, Greece. [Castanera, Pedro; Gonzalez-Guzman, Miguel; Guillem-Amat, Ana; Hernandez-Crespo, Pedro; Ortego, Felix; Urena, Enric] CSIC, Ctr Invest Biol, Dept Environm Biol, E-28040 Madrid, Spain. [Chao, Hsu; Dinh, Huyen; Doddapaneni, HarshaVardhan; Dugan, Shannon; Gibbs, Richard A.; Han, Yi; Hughes, Daniel S. T.; Lee, Sandra L.; Murali, Shwetha C.; Muzny, Donna M.; Worley, Kim C.; Richards, Stephen] Baylor Coll Med, Human Genome Sequencing Ctr, Dept Human & Mol Genet, Houston, TX 77030 USA. [Childers, Christopher; Munoz-Torres, Monica] USDA, Natl Agr Lib, Beltsville, MD 20705 USA. [Curril, Ingrid; Oberhofer, Georg; Wimmer, Ernst A.] Georg August Univ Gottingen, Johann Friedrich Blumenbach Inst Zool & Anthropol, D-37077 Gottingen, Germany. [Dolan, Amanda; Werren, John H.] Univ Rochester, Dept Biol, Rochester, NY 14627 USA. [Friedrich, Markus] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. [Gasperi, Giuliano; Gomulski, Ludvik M.; Malacrida, Anna R.; Manni, Mose; Savini, Grazia; Scolari, Francesca; Siciliano, Paolo] Univ Pavia, Dept Biol & Biotechnol, I-27100 Pavia, Italy. [Geib, Scott; Sim, Sheina B.] USDA ARS, Pacific Basin Agr Res Ctr, Hilo, HI 96720 USA. [Georgakilas, Georgios; Hatzigeorgiou, Artemis G.; Karagkouni, Dimitra; Paraskevopoulou, Maria D.; Vlachos, Ioannis S.] Univ Thessaly, Dept Elect & Comp Engn, DIANA Lab, Volos 38221, Greece. [Georgakilas, Georgios; Hatzigeorgiou, Artemis G.; Karagkouni, Dimitra; Paraskevopoulou, Maria D.; Vlachos, Ioannis S.] Hellenic Pasteur Inst, Athens 11521, Greece. [Giers, Sarah D.; Robertson, Hugh M.] Univ Illinois, Dept Entomol, Urbana, IL 61801 USA. [Jones, Jeffery W.] Oakland Univ, Dept Biol Sci, Rochester, MI 48309 USA. [Mathiopoulos, Kostas] Univ Thessaly, Dept Biochem & Biotechnol, Larisa, Greece. [Meccariello, Angela; Saccone, Giuseppe; Salvemini, Marco] Univ Naples Federico II, Dept Biol, I-80126 Naples, Italy. [Munoz-Torres, Monica] Lawrence Berkeley Natl Lab, Environm Genom & Syst Biol Div, Berkeley, CA 94720 USA. [Murphy, Terence D.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Reczko, Martin] Biomed Sci Res Ctr Alexander Fleming, Inst Mol Biol & Genet, Athens, Greece. [Zacharopoulou, Antigone] Univ Patras, Dept Biol, Patras, Greece. [Handler, Alfred M.] USDA ARS, Ctr Med Agr & Vet Entomol, 1700 SW 23rd Dr, Gainesville, FL 32608 USA. RP Handler, AM (reprint author), USDA ARS, Ctr Med Agr & Vet Entomol, 1700 SW 23rd Dr, Gainesville, FL 32608 USA. EM al.handler@ars.usda.gov FU U.S. Department of Agriculture (USDA), Agricultural Research Service (ARS); U.S. Department of Agriculture (USDA), Animal and Plant Health Inspection Service (APHIS); U.S. Department of Agriculture (USDA), National Institute of Food and Agriculture (NIFA) [2011-39211-30769]; National Institutes of Health (NIH)-National Human Genome Research Institute (NHGRI) [U54 HG003273]; NIH Intramural Research Program, National Library of Medicine; NIGMS [5R01GM080203]; NHGRI [5R01HG004483]; U.S. Department of Energy [DE-AC02-05CH11231]; MINECO, Spain [AGL2013-42632-R]; European Social Fund; National Strategic Reference Framework-THALES [MIS375869]; U.S. National Science Foundation [DEB 1257053]; USDA-NIFA [2016-67012-24652, 2015-33522-24094]; L.R. Campania [5/02]; FAO/IAEA [16966]; DFG [SCHE 1833/1-1]; LOEWE Center for Insect Biotechnology & Bioresources grant of the Hessen State Ministry of Higher Education, Research and the Arts (HMWK), Germany FX Support of this project was provided by the U.S. Department of Agriculture (USDA), Agricultural Research Service (ARS), Animal and Plant Health Inspection Service (APHIS), and National Institute of Food and Agriculture (NIFA)-Biotechnology Risk Assessment Grants Program (grant #2011-39211-30769 to AMH) for funding the initial phase of this project, and to the National Institutes of Health (NIH)-National Human Genome Research Institute (NHGRI) for funding the medfly genome sequencing, assembly and Maker 2.0 automated annotation as part of the i5K 30 genome pilot project (grant #U54 HG003273 to RAG). The NIH Intramural Research Program, National Library of Medicine funded the NCBI Gnomon annotation and the USDA-National Agricultural Library (NAL) provided support for the WebApollo curation website, with support for manual curation training (to MM-T) provided by NIGMS (grant #5R01GM080203), NHGRI (grant #5R01HG004483), and the U.S. Department of Energy (contract #DE-AC02-05CH11231). Support was provided for: toxin metabolism and insecticide resistance gene studies from MINECO, Spain (AGL2013-42632-R to FO and PH-C); microRNAs, horizontal gene transfer and bacterial contaminant studies from the European Social Fund and National Strategic Reference Framework-THALES (MIS375869 to KB, GT, AGH, and KM) and the U.S. National Science Foundation (DEB 1257053 to JHW); cuticle protein gene studies from USDA-NIFA (grant #2016-67012-24652 to AJR); sex-determination studies from L.R. Campania (grant 5/02, 2008 to GS); male reproduction and sexual differentiation studies from the FAO/IAEA (Technical Contract No: 16966 to GGa) and Cariplo IMPROVE (to FS); and programmed cell death gene studies and genomic data analysis (to MFS) from the Emmy Noether program, DFG (SCHE 1833/1-1) and the LOEWE Center for Insect Biotechnology & Bioresources grant of the Hessen State Ministry of Higher Education, Research and the Arts (HMWK), Germany and from the USDA-NIFA-Biotechnology Risk Assessment Grants Program (grant #2015-33522-24094 to AMH). NR 1 TC 0 Z9 0 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD JAN 18 PY 2017 VL 18 AR 11 DI 10.1186/s13059-017-1155-9 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EL7UM UT WOS:000394826300003 PM 28100280 ER PT J AU Petrovas, C Ferrando-Martinez, S Gerner, MY Casazza, JP Pegu, A Deleage, C Cooper, A Hataye, J Andrews, S Ambrozak, D Estrada, PMD Boritz, E Paris, R Moysi, E Boswell, KL Ruiz-Mateos, E Vagios, I Leal, M Ablanedo-Terrazas, Y Rivero, A Gonzalez-Hernandez, LA McDermott, AB Moir, S Reyes-Teran, G Docobo, F Pantaleo, G Douek, DC Betts, MR Estes, JD Germain, RN Mascola, JR Koup, RA AF Petrovas, Constantinos Ferrando-Martinez, Sara Gerner, Michael Y. Casazza, Joseph P. Pegu, Amarendra Deleage, Claire Cooper, Arik Hataye, Jason Andrews, Sarah Ambrozak, David Del Rio Estrada, Perla M. Boritz, Eli Paris, Robert Moysi, Eirini Boswell, Kristin L. Ruiz-Mateos, Ezequiel Vagios, Ilias Leal, Manuel Ablanedo-Terrazas, Yuria Rivero, Amaranta Alicia Gonzalez-Hernandez, Luz McDermott, Adrian B. Moir, Susan Reyes-Teran, Gustavo Docobo, Fernando Pantaleo, Giuseppe Douek, Daniel C. Betts, Michael R. Estes, Jacob D. Germain, Ronald N. Mascola, John R. Koup, Richard A. TI Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; LYMPHOID-TISSUE; GERMINAL-CENTERS; VIRAL-INFECTION; RNA-SEQ; REPLICATION; EFFECTOR; LYMPHOCYTES; FOLLICLES; ACTIVATION AB Cytolytic CD8 T cells play a crucial role in the control and elimination of virus-infected cells and are a major focus of HIV cure efforts. However, it has been shown that HIV-specific CD8 T cells are infrequently found within germinal centers (GCs), a predominant site of active and latent HIV infection. We demonstrate that HIV infection induces marked changes in the phenotype, frequency, and localization of CD8 T cells within the lymph node (LN). Significantly increased frequencies of CD8 T cells in the B cell follicles and GCs were found in LNs from treated and untreated HIV-infected individuals. This profile was associated with persistent local immune activation but did not appear to be directly related to local viral replication. Follicular CD8 (fCD8) T cells, despite compromised cytokine polyfunctionality, showed good cytolytic potential characterized by high ex vivo expression of granzyme B and perforin. We used an anti-HIV/anti-CD3 bispecific antibody in a redirected killing assay and found that fCD8 T cells had better killing activity than did non-fCD8 T cells. Our results indicate that CD8 T cells with potent cytolytic activity are recruited to GCs during HIV infection and, if appropriately redirected to kill HIV-infected cells, could be an effective component of an HIV cure strategy. C1 [Petrovas, Constantinos; Ferrando-Martinez, Sara; Casazza, Joseph P.; Hataye, Jason; Ambrozak, David; Moysi, Eirini; Boswell, Kristin L.; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gerner, Michael Y.; Germain, Ronald N.] NIAID, Lab Syst Biol, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Pegu, Amarendra; Cooper, Arik; Mascola, John R.] NIAID, Virol Lab, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Deleage, Claire; Estes, Jacob D.] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Leidos Biomed Res Inc, BG 535,POB B, Frederick, MD 21702 USA. [Andrews, Sarah; McDermott, Adrian B.] NIAID, Immunol Core Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Del Rio Estrada, Perla M.; Ablanedo-Terrazas, Yuria; Rivero, Amaranta; Alicia Gonzalez-Hernandez, Luz; Reyes-Teran, Gustavo] Inst Nacl Enfermedades Resp, Dept Invest Enfermedades Infecciosas, Mexico City, DF, Mexico. [Boritz, Eli; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Paris, Robert] Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. [Ruiz-Mateos, Ezequiel; Leal, Manuel; Docobo, Fernando] Univ Seville, Lab Immunovirol, Hosp Univ Virgen Rocio, Inst Biomed Sevilla,CSIC, Seville 41013, Spain. [Vagios, Ilias] Venizeleio Hosp, Dept Histopathol, Iraklion, Crete, Greece. [Moir, Susan] NIAID, Immunoregulat Lab, Bldg 10, Bethesda, MD 20892 USA. [Pantaleo, Giuseppe] Univ Lausanne, Univ Lausanne Hosp, Dept Med, Serv Immunol & Allergy,Serv Infect Dis, CH-1011 Lausanne, Switzerland. [Pantaleo, Giuseppe] Univ Lausanne, Univ Lausanne Hosp, Swiss Vaccine Res Inst, CH-1011 Lausanne, Switzerland. [Betts, Michael R.] Univ Penn, Dept Microbiol, Ctr AIDS Res, Perelman Sch Med, Philadelphia, PA 19104 USA. [Betts, Michael R.] Univ Penn, Inst Immunol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gerner, Michael Y.] Univ Washington, Dept Immunol, Seattle, WA 98109 USA. RP Petrovas, C (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM petrovasc@mail.nih.gov FU VRC, NIAID, NIH; Bill and Melinda Gates Foundation [OPP1032325]; National Cancer Institute, NIH [HHSN261200800001E]; Redes Telematicas de Investigacion Cooperativa en Salud (RETICS; Red de SIDA) [RD12/0017/0029]; Fondo de Investigacion Sanitaria [PI12/02283, PI13/01912, CP08/00172, CPII14/00025] FX This research was supported by the Intramural Research Program of the VRC, NIAID, NIH, and CAVD grant (#OPP1032325) from the Bill and Melinda Gates Foundation (R.A.K.). This project was funded in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Part of the research was also supported by Redes Telematicas de Investigacion Cooperativa en Salud (RETICS; Red de SIDA, RD12/0017/0029) and Fondo de Investigacion Sanitaria (grants PI12/02283 and PI13/01912). E.R.-M. was supported by Fondo de Investigacion Sanitaria (grants CP08/00172 and CPII14/00025). NR 59 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JAN 18 PY 2017 VL 9 IS 373 AR eaag2285 DI 10.1126/scitranslmed.aag2285 PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EL2JX UT WOS:000394447000004 ER PT J AU Pignatelli, M Umanah, GKE Ribeiro, SP Chen, R Karuppagounder, SS Yau, HJ Eacker, S Dawson, VL Dawson, TM Bonci, A AF Pignatelli, Marco Umanah, George Kwabena Essien Ribeiro, Sissi Palma Chen, Rong Karuppagounder, Senthilkumar Senthil Yau, Hau-Jie Eacker, Stephen Dawson, Valina Lynn Dawson, Ted Murray Bonci, Antonello TI Synaptic Plasticity onto Dopamine Neurons Shapes Fear Learning SO NEURON LA English DT Article ID VENTRAL TEGMENTAL AREA; POSTTRAUMATIC-STRESS-DISORDER; LONG-TERM POTENTIATION; AMPA RECEPTORS; CONDITIONED FEAR; COCAINE SEEKING; REWARD; AMYGDALA; MODULATION; EXPRESSION AB Fear learning is a fundamental behavioral process that requires dopamine (DA) release. Experience-dependent synaptic plasticity occurs on DA neurons while anorganism is engagedin aversive experiences. However, whether synaptic plasticity onto DA neurons is causally involved in aversion learning is unknown. Here, we show that a stress priming procedure enhances fear learning by engaging VTA synaptic plasticity. Moreover, we took advantage of the ability of the ATPase Thorase to regulate the internalization of AMPA receptors (AMPARs) in order to selectively manipulate glutamatergic synaptic plasticity on DA neurons. Genetic ablation of Thorase in DAT(+) neurons produced increased AMPAR surface expression and function that lead to impaired induction of both longterm depression (LTD) and long-term potentiation (LTP). Strikingly, animals lacking Thorase inDAT(+) neurons expressed greater associative learning in a fear conditioning paradigm. In conclusion, our data provide a novel, causal link between synaptic plasticity onto DA neurons and fear learning. C1 [Pignatelli, Marco; Ribeiro, Sissi Palma; Yau, Hau-Jie; Bonci, Antonello] Natl Inst Drug Abuse, Synapt Plast Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Dawson, Valina Lynn; Dawson, Ted Murray; Bonci, Antonello] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. [Bonci, Antonello] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Umanah, George Kwabena Essien; Chen, Rong; Karuppagounder, Senthilkumar Senthil; Eacker, Stephen; Dawson, Valina Lynn; Dawson, Ted Murray] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Neuroregenerat & Stem Cell Programs, Baltimore, MD 21205 USA. [Umanah, George Kwabena Essien; Chen, Rong; Karuppagounder, Senthilkumar Senthil; Eacker, Stephen; Dawson, Valina Lynn; Dawson, Ted Murray] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Dawson, Ted Murray] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Dawson, Valina Lynn] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. RP Bonci, A (reprint author), Natl Inst Drug Abuse, Synapt Plast Sect, Intramural Res Program, Baltimore, MD 21224 USA.; Bonci, A (reprint author), Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA.; Bonci, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. EM antonello.bonci@nih.gov FU Intramural Research Program of the National Institute on Drug Abuse (NIDA) at NIH [P50DA000266] FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA) at NIH and grant P50DA000266 (to V.L.D.). We are grateful to Dr. Francois Vautier and Joni McKenzie for assistance with transgenic mouse colonies. NR 66 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JAN 18 PY 2017 VL 93 IS 2 BP 425 EP 440 DI 10.1016/j.neuron.2016.12.030 PG 16 WC Neurosciences SC Neurosciences & Neurology GA EO0ZV UT WOS:000396428200019 PM 28103482 ER PT J AU Clery, S Cumming, BG Nienborg, H AF Clery, Stephane Cumming, Bruce G. Nienborg, Hendrikje TI Decision-Related Activity in Macaque V2 for Fine Disparity Discrimination Is Not Compatible with Optimal Linear Readout SO JOURNAL OF NEUROSCIENCE LA English DT Article DE choice probability; discrimination; disparity; nonhuman primate; readout; V2 ID CHOICE-RELATED ACTIVITY; PRIMARY VISUAL-CORTEX; STEREOSCOPIC DEPTH-PERCEPTION; MIDDLE TEMPORAL AREA; SENSORY NEURONS; EYE-MOVEMENTS; PSYCHOPHYSICAL SENSITIVITY; INTERNEURONAL CORRELATIONS; RESPONSE VARIABILITY; CORRELATED NOISE AB Fine judgments of stereoscopic depth rely mainly on relative judgments of depth (relative binocular disparity) between objects, rather than judgments of the distance to where the eyes are fixating (absolute disparity). In macaques, visual area V2 is the earliest site in the visual processing hierarchy for which neurons selective for relative disparity have been observed (Thomas et al., 2002). Here, we found that, in macaques trained to perform a fine disparity discrimination task, disparity-selective neurons in V2 were highly selective for the task, and their activity correlated with the animals' perceptual decisions (unexplained by the stimulus). This may partially explain similar correlations reported in downstream areas. Although compatible with a perceptual role of these neurons for the task, the interpretation of such decision-related activity is complicated by the effects of interneuronal "noise" correlations between sensory neurons. Recent work has developed simple predictions to differentiate decoding schemes (Pitkow et al., 2015) without needing measures of noise correlations, and found that data from early sensory areas were compatible with optimal linear readout of populations with information limiting correlations. In contrast, our data here deviated significantly from these predictions. We additionally tested this prediction for previously reported results of decision-related activity in V2 for a related task, coarse disparity discrimination (Nienborg and Cumming, 2006), thought to rely on absolute disparity. Although these data followed the predicted pattern, they violated the prediction quantitatively. This suggests that optimal linear decoding of sensory signals is not generally a good predictor of behavior in simple perceptual tasks. C1 [Clery, Stephane; Nienborg, Hendrikje] Univ Tubingen, Werner Reichardt Ctr Integrat Neurosci, Otfried Mueller Str 25, D-72076 Tubingen, Germany. [Cumming, Bruce G.] NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. RP Nienborg, H (reprint author), Univ Tubingen, Werner Reichardt Ctr Integrat Neurosci, Otfried Mueller Str 25, D-72076 Tubingen, Germany. EM hendrikje.nienborg@cin.uni-tuebingen.de FU European Research Council (Project NEUROOPTOGEN) Starting Independent Researcher Grant; National Institutes of Health, National Eye Institute Intramural Research Program FX This work was supported by European Research Council (Project NEUROOPTOGEN) Starting Independent Researcher Grant to H.N. and the National Institutes of Health, National Eye Institute Intramural Research Program. We thank Denise Parker for excellent animal care. NR 62 TC 0 Z9 0 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 18 PY 2017 VL 37 IS 3 BP 715 EP 725 DI 10.1523/JNEUROSCI.2445-16.2017 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EJ9RK UT WOS:000393563900024 PM 28100751 ER PT J AU Hibar, DP Adams, HHH Jahanshad, N Chauhan, G Stein, JL Hofer, E Renteria, ME Bis, JC Arias-Vasquez, A Ikram, MK Desrivieres, S Vernooij, MW Abramovic, L Alhusaini, S Amin, N Andersson, M Arfanakis, K Aribisala, BS Armstrong, NJ Athanasiu, L Axelsson, T Beecham, AH Beiser, A Bernard, M Blanton, SH Bohlken, MM Boks, MP Bralten, J Brickman, AM Carmichael, O Chakravarty, MM Chen, Q Ching, CRK Chouraki, V Cuellar-Partida, G Crivello, F Den Braber, A Doan, NT Ehrlich, S Giddaluru, S Goldman, AL Gottesman, RF Grimm, O Griswold, ME Guadalupe, T Gutman, BA Hass, J Haukvik, UK Hoehn, D Holmes, AJ Hoogman, M Janowitz, D Jia, T Jorgensen, KN Karbalai, N Kasperaviciute, D Kim, S Klein, M Kraemer, B Lee, PH Liewald, DCM Lopez, LM Luciano, M Macare, C Marquand, AF Matarin, M Mather, KA Mattheisen, M McKay, DR Milaneschi, Y Maniega, SM Nho, K Nugent, AC Nyquist, P Loohuis, LMO Oosterlaan, J Papmeyer, M Pirpamer, L Putz, B Ramasamy, A Richards, JS Risacher, SL Roiz-Santianez, R Rommelse, N Ropele, S Rose, EJ Royle, NA Rundek, T Samann, PG Saremi, A Satizabal, CL Schmaal, L Schork, AJ Shen, L Shin, J Shumskaya, E Smith, AV Sprooten, E Strike, LT Teumer, A Tordesillas-Gutierrez, D Toro, R Trabzuni, D Trompet, S Vaidya, D Van der Grond, J Van der Lee, SJ Van der Meer, D Van Donkelaar, MMJ Van Eijk, KR Van Erp, TGM Van Rooij, D Walton, E Westlye, LT Whelan, CD Windham, BG Winkler, AM Wittfeld, K Woldehawariat, G Wolf, C Wolfers, T Yanek, LR Yang, JY Zijdenbos, A Zwiers, MP Agartz, I Almasy, L Ames, D Amouyel, P Andreassen, OA Arepalli, S Assareh, AA Barral, S Bastin, ME Becker, DM Becker, JT Bennett, DA Blangero, J van Bokhoven, H Boomsma, DI Brodaty, H Brouwer, RM Brunner, HG Buckner, RL Buitelaar, JK Bulayeva, KB Cahn, W Calhoun, VD Cannon, DM Cavalleri, GL Cheng, CY Cichon, S Cookson, MR Corvin, A Crespo-Facorro, B Curran, JE Czisch, M Dale, AM Davies, GE De Craen, AJM De Geus, EJC De Jager, PL De Zubicaray, GI Deary, IJ Debette, S DeCarli, C Delanty, N Depondt, C DeStefano, A Dillman, A Djurovic, S Donohoe, G Drevets, WC Duggirala, R Dyer, TD Enzinger, C Erk, S Espeseth, T Fedko, IO Fernandez, G Ferrucci, L Fisher, SE Fleischman, DA Ford, I Fornage, M Foroud, TM Fox, PT Francks, C Fukunaga, M Gibbs, JR Glahn, DC Gollub, RL Goring, HHH Green, RC Gruber, O Gudnason, V Guelfi, S Haberg, AK Hansell, NK Hardy, J Hartman, CA Hashimoto, R Hegenscheid, K Heinz, A Le Hellard, S Hernandez, DG Heslenfeld, DJ Ho, BC Hoekstra, PJ Hoffmann, W Hofman, A Holsboer, F Homuth, G Hosten, N Hottenga, JJ Huentelman, M Pol, HEH Ikeda, M Jack, CR Jenkinson, M Johnson, R Jonsson, EG Jukema, JW Kahn, RS Kanai, R Kloszewska, I Knopman, DS Kochunov, P Kwok, JB Lawrie, SM Lemaitre, H Liu, XM Longo, DL Lopez, OL Lovestone, S Martinez, O Martinot, JL Mattay, VS McDonald, C McIntosh, AM McMahon, FJ McMahon, KL Mecocci, P Melle, I Meyer-Lindenberg, A Mohnke, S Montgomery, GW Morris, DW Mosley, TH Muhleisen, TW Muller-Myhsok, B Nalls, MA Nauck, M Nichols, TE Niessen, WJ Nothen, MM Nyberg, L Ohi, K Olvera, RL Ophoff, RA Pandolfo, M Paus, T Pausova, Z Penninx, BWJH Pike, GB Potkin, SG Psaty, BM Reppermund, S Rietschel, M Roffman, JL Romanczuk-Seiferth, N Rotter, JI Ryten, M Sacco, RL Sachdev, PS Saykin, AJ Schmidt, R Schmidt, H Schofield, PR Sigursson, S Simmons, A Singleton, A Sisodiya, SM Smith, C Smoller, JW Soininen, H Steen, VM Stott, DJ Sussmann, JE Thalamuthu, A Toga, AW Traynor, BJ Troncoso, J Tsolaki, M Tzourio, C Uitterlinden, AG Hernandez, MCV Van der Brug, M van der Lugt, A van der Wee, NJA Van Haren, NEM van't Ent, D Van Tol, MJ Vardarajan, BN Vellas, B Veltman, DJ Volzke, H Walter, H Wardlaw, JM Wassink, TH Weale, ME Weinberger, DR Weiner, MW Wen, W Westman, E White, T Wong, TY Wright, CB Zielke, RH Zonderman, AB Martin, NG Van Duijn, CM Wright, MJ Longstreth, WT Schumann, G Grabe, HJ Franke, B Launer, LJ Medland, SE Seshadri, S Thompson, PM Ikram, MA AF Hibar, Derrek P. Adams, Hieab H. H. Jahanshad, Neda Chauhan, Ganesh Stein, Jason L. Hofer, Edith Renteria, Miguel E. Bis, Joshua C. Arias-Vasquez, Alejandro Ikram, M. Kamran Desrivieres, Sylvane Vernooij, Meike W. Abramovic, Lucija Alhusaini, Saud Amin, Najaf Andersson, Micael Arfanakis, Konstantinos Aribisala, Benjamin S. Armstrong, Nicola J. Athanasiu, Lavinia Axelsson, Tomas Beecham, Ashley H. Beiser, Alexa Bernard, Manon Blanton, Susan H. Bohlken, Marc M. Boks, Marco P. Bralten, Janita Brickman, Adam M. Carmichael, Owen Chakravarty, M. Mallar Chen, Qiang Ching, Christopher R. K. Chouraki, Vincent Cuellar-Partida, Gabriel Crivello, Fabrice Den Braber, Anouk Nhat Trung Doan Ehrlich, Stefan Giddaluru, Sudheer Goldman, Aaron L. Gottesman, Rebecca F. Grimm, Oliver Griswold, Michael E. Guadalupe, Tulio Gutman, Boris A. Hass, Johanna Haukvik, Unn K. Hoehn, David Holmes, Avram J. Hoogman, Martine Janowitz, Deborah Jia, Tianye Jorgensen, Kjetil N. Karbalai, Nazanin Kasperaviciute, Dalia Kim, Sungeun Klein, Marieke Kraemer, Bernd Lee, Phil H. Liewald, David C. M. Lopez, Lorna M. Luciano, Michelle Macare, Christine Marquand, Andre F. Matarin, Mar Mather, Karen A. Mattheisen, Manuel McKay, David R. Milaneschi, Yuri Maniega, Susana Munoz Nho, Kwangsik Nugent, Allison C. Nyquist, Paul Loohuis, Loes M. Olde Oosterlaan, Jaap Papmeyer, Martina Pirpamer, Lukas Puetz, Benno Ramasamy, Adaikalavan Richards, Jennifer S. Risacher, Shannon L. Roiz-Santianez, Roberto Rommelse, Nanda Ropele, Stefan Rose, Emma J. Royle, Natalie A. Rundek, Tatjana Saemann, Philipp G. Saremi, Arvin Satizabal, Claudia L. Schmaal, Lianne Schork, Andrew J. Shen, Li Shin, Jean Shumskaya, Elena Smith, Albert V. Sprooten, Emma Strike, Lachlan T. Teumer, Alexander Tordesillas-Gutierrez, Diana Toro, Roberto Trabzuni, Daniah Trompet, Stella Vaidya, Dhananjay Van der Grond, Jeroen Van der Lee, Sven J. Van der Meer, Dennis Van Donkelaar, Marjolein M. J. Van Eijk, Kristel R. Van Erp, Theo G. M. Van Rooij, Daan Walton, Esther Westlye, Lars T. Whelan, Christopher D. Windham, Beverly G. Winkler, Anderson M. Wittfeld, Katharina Woldehawariat, Girma Wolf, Christiane Wolfers, Thomas Yanek, Lisa R. Yang, Jingyun Zijdenbos, Alex Zwiers, Marcel P. Agartz, Ingrid Almasy, Laura Ames, David Amouyel, Philippe Andreassen, Ole A. Arepalli, Sampath Assareh, Amelia A. Barral, Sandra Bastin, Mark E. Becker, Diane M. Becker, James T. Bennett, David A. Blangero, John van Bokhoven, Hans Boomsma, Dorret I. Brodaty, Henry Brouwer, Rachel M. Brunner, Han G. Buckner, Randy L. Buitelaar, Jan K. Bulayeva, Kazima B. Cahn, Wiepke Calhoun, Vince D. Cannon, Dara M. Cavalleri, Gianpiero L. Cheng, Ching-Yu Cichon, Sven Cookson, Mark R. Corvin, Aiden Crespo-Facorro, Benedicto Curran, Joanne E. Czisch, Michael Dale, Anders M. Davies, Gareth E. De Craen, Anton J. M. De Geus, Eco J. C. De Jager, Philip L. De Zubicaray, Greig I. Deary, Ian J. Debette, Stephanie DeCarli, Charles Delanty, Norman Depondt, Chantal DeStefano, Anita Dillman, Allissa Djurovic, Srdjan Donohoe, Gary Drevets, Wayne C. Duggirala, Ravi Dyer, Thomas D. Enzinger, Christian Erk, Susanne Espeseth, Thomas Fedko, Iryna O. Fernandez, Guillen Ferrucci, Luigi Fisher, Simon E. Fleischman, Debra A. Ford, Ian Fornage, Myriam Foroud, Tatiana M. Fox, Peter T. Francks, Clyde Fukunaga, Masaki Gibbs, J. Raphael Glahn, David C. Gollub, Randy L. Goring, Harald H. H. Green, Robert C. Gruber, Oliver Gudnason, Vilmundur Guelfi, Sebastian Haberg, Asta K. Hansell, Narelle K. Hardy, John Hartman, Catharina A. Hashimoto, Ryota Hegenscheid, Katrin Heinz, Andreas Le Hellard, Stephanie Hernandez, Dena G. Heslenfeld, Dirk J. Ho, Beng-Choon Hoekstra, Pieter J. Hoffmann, Wolfgang Hofman, Albert Holsboer, Florian Homuth, Georg Hosten, Norbert Hottenga, Jouke-Jan Huentelman, Matthew Pol, Hilleke E. Hulshoff Ikeda, Masashi Jack, Clifford R., Jr. Jenkinson, Mark Johnson, Robert Joensson, Erik G. Jukema, J. Wouter Kahn, Rene S. Kanai, Ryota Kloszewska, Iwona Knopman, David S. Kochunov, Peter Kwok, John B. Lawrie, Stephen M. Lemaitre, Herve Liu, Xinmin Longo, Dan L. Lopez, Oscar L. Lovestone, Simon Martinez, Oliver Martinot, Jean-Luc Mattay, Venkata S. McDonald, Colm McIntosh, Andrew M. McMahon, Francis J. McMahon, Katie L. Mecocci, Patrizia Melle, Ingrid Meyer-Lindenberg, Andreas Mohnke, Sebastian Montgomery, Grant W. Morris, Derek W. Mosley, Thomas H. Muhleisen, Thomas W. Mueller-Myhsok, Bertram Nalls, Michael A. Nauck, Matthias Nichols, Thomas E. Niessen, Wiro J. Nothen, Markus M. Nyberg, Lars Ohi, Kazutaka Olvera, Rene L. Ophoff, Roel A. Pandolfo, Massimo Paus, Tomas Pausova, Zdenka Penninx, Brenda W. J. H. Pike, G. Bruce Potkin, Steven G. Psaty, Bruce M. Reppermund, Simone Rietschel, Marcella Roffman, Joshua L. Romanczuk-Seiferth, Nina Rotter, Jerome I. Ryten, Mina Sacco, Ralph L. Sachdev, Perminder S. Saykin, Andrew J. Schmidt, Reinhold Schmidt, Helena Schofield, Peter R. Sigursson, Sigurdur Simmons, Andrew Singleton, Andrew Sisodiya, Sanjay M. Smith, Colin Smoller, Jordan W. Soininen, Hilkka Steen, Vidar M. Stott, David J. Sussmann, Jessika E. Thalamuthu, Anbupalam Toga, Arthur W. Traynor, Bryan J. Troncoso, Juan Tsolaki, Magda Tzourio, Christophe Uitterlinden, Andre G. Hernandez, Maria C. Valdes Van der Brug, Marcel van der Lugt, Aad van der Wee, Nic J. A. Van Haren, Neeltje E. M. van't Ent, Dennis Van Tol, Marie-Jose Vardarajan, Badri N. Vellas, Bruno Veltman, Dick J. Voelzke, Henry Walter, Henrik Wardlaw, Joanna M. Wassink, Thomas H. Weale, Michael E. Weinberger, Daniel R. Weiner, Michael W. Wen, Wei Westman, Eric White, Tonya Wong, Tien Y. Wright, Clinton B. Zielke, Ronald H. Zonderman, Alan B. Martin, Nicholas G. Van Duijn, Cornelia M. Wright, Margaret J. Longstreth, W. T. Schumann, Gunter Grabe, Hans J. Franke, Barbara Launer, Lenore J. Medland, Sarah E. Seshadri, Sudha Thompson, Paul M. Ikram, M. Arfan TI Novel genetic loci associated with hippocampal volume SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; TEMPORAL-LOBE EPILEPSY; SUSCEPTIBILITY LOCI; ALZHEIMERS-DISEASE; BIPOLAR DISORDER; COMMON VARIANTS; BRAIN-REGIONS; MEMORY; SUBFIELDS; METAANALYSIS AB The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. C1 [Hibar, Derrek P.; Jahanshad, Neda; Stein, Jason L.; Ching, Christopher R. K.; Gutman, Boris A.; Saremi, Arvin; Whelan, Christopher D.; Thompson, Paul M.] Univ Southern Calif, Imaging Genet Ctr, USC Mark & Mary Stevens Neuroimaging & Informat I, Keck Sch Med, Marina Del Rey, CA 90292 USA. [Adams, Hieab H. H.; Ikram, M. Kamran; Vernooij, Meike W.; Amin, Najaf; Van der Lee, Sven J.; Uitterlinden, Andre G.; Van Duijn, Cornelia M.; Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands. [Adams, Hieab H. H.; Vernooij, Meike W.; Niessen, Wiro J.; van der Lugt, Aad; White, Tonya; Ikram, M. Arfan] Erasmus MC, Dept Radiol & Nucl Med, NL-3015 CE Rotterdam, Netherlands. [Chauhan, Ganesh; Debette, Stephanie; Tzourio, Christophe] Univ Bordeaux, INSERM Unit U1219, F-33076 Bordeaux, France. [Stein, Jason L.] UNC, Dept Genet, Chapel Hill, NC 27599 USA. [Stein, Jason L.] UNC, UNC Neurosci Ctr, Chapel Hill, NC 27599 USA. [Hofer, Edith; Pirpamer, Lukas; Ropele, Stefan; Enzinger, Christian; Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Auenbruggerpl 22, A-8036 Graz, Austria. [Hofer, Edith] Med Univ Graz, Inst Med Informat Stat & Documentat, Auenbruggerpl 22, A-8036 Graz, Austria. [Renteria, Miguel E.; Cuellar-Partida, Gabriel; Strike, Lachlan T.; Hansell, Narelle K.; Montgomery, Grant W.; Martin, Nicholas G.; Medland, Sarah E.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, 1730 Minor Ave Suite 1360, Seattle, WA 98101 USA. [Arias-Vasquez, Alejandro; Bralten, Janita; Hoogman, Martine; Klein, Marieke; Shumskaya, Elena; Van Donkelaar, Marjolein M. J.; Wolfers, Thomas; van Bokhoven, Hans; Brunner, Han G.; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands. [Arias-Vasquez, Alejandro; Rommelse, Nanda; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 GA Nijmegen, Netherlands. [Arias-Vasquez, Alejandro; Richards, Jennifer S.; Van Rooij, Daan; Buitelaar, Jan K.; Fernandez, Guillen] Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, NL-6525 GA Nijmegen, Netherlands. [Arias-Vasquez, Alejandro; Bralten, Janita; Hoogman, Martine; Klein, Marieke; Marquand, Andre F.; Richards, Jennifer S.; Rommelse, Nanda; Shumskaya, Elena; Van Donkelaar, Marjolein M. J.; Van Rooij, Daan; Wolfers, Thomas; Zwiers, Marcel P.; van Bokhoven, Hans; Brunner, Han G.; Buitelaar, Jan K.; Fernandez, Guillen; Fisher, Simon E.; Francks, Clyde; Franke, Barbara] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands. [Ikram, M. Kamran; Cheng, Ching-Yu; Wong, Tien Y.] Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore 169857, Singapore. [Ikram, M. Kamran; Cheng, Ching-Yu; Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore 168751, Singapore. [Ikram, M. Kamran] Natl Univ Hlth Syst, MACC, Singapore 119228, Singapore. [Ikram, M. Kamran; De Jager, Philip L.] Natl Univ Singapore, Dept Pharmacol, Singapore 119077, Singapore. [Desrivieres, Sylvane; Jia, Tianye; Macare, Christine; Schumann, Gunter] Kings Coll London, MRC SGDP Ctr, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England. [Abramovic, Lucija; Bohlken, Marc M.; Boks, Marco P.; Brouwer, Rachel M.; Cahn, Wiepke; Pol, Hilleke E. Hulshoff; Kahn, Rene S.; Ophoff, Roel A.; Van Haren, Neeltje E. M.] UMC Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CX Utrecht, Netherlands. [Alhusaini, Saud] McGill Univ, Dept Neurol & Neurosurg, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. [Alhusaini, Saud; Whelan, Christopher D.; Cavalleri, Gianpiero L.; Delanty, Norman] Royal Coll Surgeons Ireland, 123 St Stephens Green, Dublin 2, Ireland. [Andersson, Micael; Nyberg, Lars] Umea Univ, Dept Integrat Med Biol, S-90187 Umea, Sweden. [Andersson, Micael; Nyberg, Lars] Umea Univ, Umea Ctr Funct Brain Imaging, S-90187 Umea, Sweden. [Arfanakis, Konstantinos] IIT, Dept Biomed Engn, Chicago, IL 60612 USA. [Arfanakis, Konstantinos; Yang, Jingyun; Bennett, David A.; Fleischman, Debra A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Arfanakis, Konstantinos] Rush Univ, Med Ctr, Dept Diagnost Radiol & Nucl Med, Chicago, IL 60616 USA. [Aribisala, Benjamin S.; Maniega, Susana Munoz; Royle, Natalie A.; Bastin, Mark E.; Hernandez, Dena G.; Wardlaw, Joanna M.] Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh EH4 2XU, Midlothian, Scotland. [Aribisala, Benjamin S.] Lagos State Univ, Dept Comp Sci, PMB 01 LASU, Lagos, Nigeria. [Aribisala, Benjamin S.; Maniega, Susana Munoz; Royle, Natalie A.; Bastin, Mark E.; Hernandez, Dena G.; Wardlaw, Joanna M.] Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Platform Sci Excellence SINAPSE Collaborat, Edinburgh EH16 4SB, Midlothian, Scotland. [Armstrong, Nicola J.; Mather, Karen A.; Assareh, Amelia A.; Brodaty, Henry; Reppermund, Simone; Sachdev, Perminder S.; Thalamuthu, Anbupalam; Wen, Wei] Univ New South Wales, Ctr Healthy Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia. [Armstrong, Nicola J.] Murdoch Univ, Math & Stat, Perth, WA 6150, Australia. [Athanasiu, Lavinia; Nhat Trung Doan; Haukvik, Unn K.; Jorgensen, Kjetil N.; Agartz, Ingrid; Andreassen, Ole A.; Joensson, Erik G.; Melle, Ingrid] Univ Oslo, NORMENT KG Jebsen Ctr, Inst Clin Med, N-0315 Oslo, Norway. [Athanasiu, Lavinia; Westlye, Lars T.; Andreassen, Ole A.; Espeseth, Thomas; Melle, Ingrid] Oslo Univ Hosp, NORMENT KG Jebsen Ctr, Div Mental Hlth & Addict, N-0424 Oslo, Norway. [Axelsson, Tomas] Uppsala Univ, Dept Med Sci Mol Med & Sci Life Lab, Box 1432, SE-75144 Uppsala, Sweden. [Beecham, Ashley H.; Blanton, Susan H.] Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn Dept Human Genet, Miami, FL 33136 USA. [Beecham, Ashley H.; Blanton, Susan H.; Sacco, Ralph L.] Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA. [Beiser, Alexa; Chouraki, Vincent; Satizabal, Claudia L.; Debette, Stephanie; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Beiser, Alexa; DeStefano, Anita] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Beiser, Alexa; Chouraki, Vincent; Satizabal, Claudia L.; DeStefano, Anita; Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, 17 Mt Wayte Ave, Framingham, MA 01703 USA. [Bernard, Manon; Shin, Jean; Pausova, Zdenka] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Brickman, Adam M.; Barral, Sandra; Vardarajan, Badri N.] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, 639 West 1168th St, New York, NY 10032 USA. [Brickman, Adam M.; Barral, Sandra; Vardarajan, Badri N.] Columbia Univ, Med Ctr, GH Sergievsky Ctr, 639 West 1168th St, New York, NY 10032 USA. [Brickman, Adam M.; Barral, Sandra; Vardarajan, Badri N.] Columbia Univ, Med Ctr, Dept Neurol, 639 West 1168th St, New York, NY 10032 USA. [Carmichael, Owen] Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. [Chakravarty, M. Mallar] Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Montreal, PQ H4H 1R3, Canada. [Chakravarty, M. Mallar] McGill Univ, Dept Psychiat & Biomed Engn, Montreal, PQ H3A 2B4, Canada. [Chen, Qiang; Goldman, Aaron L.; Mattay, Venkata S.; Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Ching, Christopher R. K.] Univ Calif Los Angeles, Sch Med, Interdept Neurosci Grad Program, Los Angeles, CA 90095 USA. [Chouraki, Vincent; Amouyel, Philippe] Univ Lille, CHU Lille, INSERM, Inst Pasteur Lille,RID AGE Risk Factors & Mol Det, F-59000 Lille, France. [Crivello, Fabrice] Univ Bordeaux, IMN UMR5293, GIN, CNRS,CEA, 146 Rue Leo Saignat, F-33076 Bordeaux, France. [Den Braber, Anouk; Boomsma, Dorret I.; De Geus, Eco J. C.; Fedko, Iryna O.; Hottenga, Jouke-Jan; van't Ent, Dennis] Vrije Univ Amsterdam, Biol Psychol, Amsterdam Neurosci, NL-1081 BT Amsterdam, Netherlands. [Den Braber, Anouk; Boomsma, Dorret I.; De Geus, Eco J. C.; Fedko, Iryna O.; Hottenga, Jouke-Jan; van't Ent, Dennis] Vrije Univ Amsterdam, Med Ctr, NL-1081 BT Amsterdam, Netherlands. [Ehrlich, Stefan; Walton, Esther] Tech Univ Dresden, Fac Med, Div Psychol & Social Med & Dev Neurosci, D-01307 Dresden, Germany. [Ehrlich, Stefan; Holmes, Avram J.; Lee, Phil H.; Buckner, Randy L.; Gollub, Randy L.; Roffman, Joshua L.; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Ehrlich, Stefan; Gollub, Randy L.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Giddaluru, Sudheer; Djurovic, Srdjan; Le Hellard, Stephanie; Steen, Vidar M.] Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5021 Bergen, Norway. [Giddaluru, Sudheer; Le Hellard, Stephanie; Steen, Vidar M.] Haukeland Hosp, Dr Einar Martens Res Grp Biol Psychiat, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Gottesman, Rebecca F.; Mattay, Venkata S.; Weiner, Michael W.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. [Grimm, Oliver; Meyer-Lindenberg, Andreas; Rietschel, Marcella] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Data Sci, D-68159 Mannheim, Germany. [Griswold, Michael E.] Univ Mississippi, Med Ctr, Dept Data Sci, Jackson, MS 39216 USA. [Guadalupe, Tulio; Fisher, Simon E.; Francks, Clyde] Max Planck Inst Psycholinguist, Language & Genet Dept, NL-6525 XD Nijmegen, Netherlands. [Guadalupe, Tulio] Int Max Planck Res Sch Language Sci, NL-6525 XD Nijmegen, Netherlands. [Hass, Johanna] Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, D-01307 Dresden, Germany. [Haukvik, Unn K.; Jorgensen, Kjetil N.; Agartz, Ingrid] Diakonhjemmet Hosp, Dept Res & Dev, N-0319 Oslo, Norway. [Hoehn, David; Karbalai, Nazanin; Puetz, Benno; Saemann, Philipp G.; Czisch, Michael; Holsboer, Florian; Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Holmes, Avram J.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Janowitz, Deborah; Wittfeld, Katharina; Grabe, Hans J.] Univ Med Greifswald, Dept Psychiat, D-17489 Greifswald, Germany. [Kasperaviciute, Dalia; Matarin, Mar; Sisodiya, Sanjay M.] UCL Inst Neurol, London, England. [Kasperaviciute, Dalia; Matarin, Mar; Sisodiya, Sanjay M.] Epilepsy Soc, St Peter, Bucks, England. [Kasperaviciute, Dalia] Imperial Coll London, Dept Med, London SW7 2AZ, England. [Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Shen, Li; Saykin, Andrew J.] Indiana Univ Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN 46202 USA. [Kim, Sungeun; Nho, Kwangsik; Shen, Li] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA. [Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Shen, Li; Foroud, Tatiana M.; Saykin, Andrew J.] Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA. [Kraemer, Bernd; Gruber, Oliver] Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, D-69120 Heidelberg, Germany. [Lee, Phil H.; Smoller, Jordan W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Lee, Phil H.; De Jager, Philip L.; Gollub, Randy L.; Green, Robert C.; Smoller, Jordan W.] Harvard Med Sch, Boston, MA 02115 USA. [Lee, Phil H.; Smoller, Jordan W.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA 02141 USA. [Lee, Phil H.] Harvard Med Sch, Massachusetts Gen Hosp, Lurie Ctr Autism, Lexington, MA 02421 USA. [Liewald, David C. M.; Lopez, Lorna M.; Luciano, Michelle; Maniega, Susana Munoz; Royle, Natalie A.; Bastin, Mark E.; Deary, Ian J.; Hernandez, Dena G.; McIntosh, Andrew M.; Wardlaw, Joanna M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Marquand, Andre F.; Shumskaya, Elena; Zwiers, Marcel P.] Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, NL-6525 EN Nijmegen, Netherlands. [Matarin, Mar; Ramasamy, Adaikalavan; Trabzuni, Daniah; Gibbs, J. Raphael; Guelfi, Sebastian; Hardy, John; Hernandez, Dena G.; Ryten, Mina] UCL Inst Neurol, Reta Lila Weston Inst, London WC1N 3BG, England. [Matarin, Mar; Ramasamy, Adaikalavan; Trabzuni, Daniah; Gibbs, J. Raphael; Guelfi, Sebastian; Hardy, John; Hernandez, Dena G.; Ryten, Mina] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Mattheisen, Manuel] Aarhus Univ, Dept Biomed, DK-8000 Aarhus, Denmark. [Mattheisen, Manuel] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, DK-8000 Aarhus, Denmark. [Mattheisen, Manuel] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, DK-8000 Copenhagen, Denmark. [Mattheisen, Manuel] Aarhus Univ, iSEQ, Ctr Integrated Sequencing, DK-8000 Aarhus, Denmark. [McKay, David R.; Sprooten, Emma; Winkler, Anderson M.; Glahn, David C.] Yale Univ, Dept Psychiat, New Haven, CT 06511 USA. [McKay, David R.; Sprooten, Emma; Glahn, David C.] Olin Neuropsychiat Res Ctr, Hartford, CT 06114 USA. [Milaneschi, Yuri] VU Univ Med Ctr GGZ inGeest, Dept Psychiat, EMGO Inst Hlth & Care Res, NL-1081 HL Amsterdam, Netherlands. [Milaneschi, Yuri] VU Univ Med Ctr GGZ inGeest, Neurosci Campus Amsterdam, NL-1081 HL Amsterdam, Netherlands. [Nugent, Allison C.; Woldehawariat, Girma; Cannon, Dara M.; Drevets, Wayne C.; Liu, Xinmin; McMahon, Francis J.] NIMH, Human Genet Branch, Intramural Res Program, 35 Convent Dr,Rm 1A202, Bethesda, MD 20892 USA. [Nyquist, Paul] Johns Hopkins, Dept Neurol, Dept Anesthesia Crit Care Med, Dept Neurosurg, USA600 N Wolfe St, Baltimore, MD 21287 USA. [Loohuis, Loes M. Olde; Ophoff, Roel A.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA. [Oosterlaan, Jaap] Vrije Univ Amsterdam, Dept Clin Neuropsychol, NL-1081 HV Amsterdam, Netherlands. [Papmeyer, Martina; Lawrie, Stephen M.; McIntosh, Andrew M.; Sussmann, Jessika E.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland. [Papmeyer, Martina] Univ Bern, Univ Hosp Psychiat, Div Syst Neurosci Psychopathol, Translat Res Ctr, CH-3060 Bern, Switzerland. [Ramasamy, Adaikalavan; Ryten, Mina; Weale, Michael E.] Kings Coll London, Dept Med & Mol Genet, London SE1 9RT, England. [Ramasamy, Adaikalavan] Univ Oxford, Jenner Inst Labs, Oxford OX3 7DQ, England. [Richards, Jennifer S.; Rommelse, Nanda; Buitelaar, Jan K.] Karakter Child & Adolescent Psychiat Univ Ctr, NL-6525 GC Nijmegen, Netherlands. [Roiz-Santianez, Roberto; Crespo-Facorro, Benedicto] Univ Cantabria IDIVAL, Dept Med & Psychiat, Univ Hosp Marques Valdecilla, Sch Med, Santander 39008, Spain. [Roiz-Santianez, Roberto; Tordesillas-Gutierrez, Diana; Crespo-Facorro, Benedicto] CIBERSAM Ctr Invest Biomed Red Salud Mental, Santander 39011, Spain. [Rose, Emma J.; Corvin, Aiden] Trinity Coll Dublin, Psychosis Res Grp, Dept Psychiat, Dublin 2, Ireland. [Rose, Emma J.; Corvin, Aiden] Trinity Coll Dublin, Trinity Translat Med Inst, Dublin 2, Ireland. [Royle, Natalie A.; Bastin, Mark E.; Hernandez, Dena G.; Wardlaw, Joanna M.] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland. [Rundek, Tatjana; Sacco, Ralph L.; Wright, Clinton B.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Rundek, Tatjana; Sacco, Ralph L.; Wright, Clinton B.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA. [Schmaal, Lianne] Orygen, Natl Ctr Excellence Youth Mental Hlth, Melbourne, Vic 3502, Australia. [Schmaal, Lianne] Univ Melbourne, Ctr Youth Mental Hlth, Melbourne, Vic 3502, Australia. [Schmaal, Lianne; Penninx, Brenda W. J. H.; Veltman, Dick J.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, NL-1007 MB Amsterdam, Netherlands. [Schork, Andrew J.] Univ Calif San Diego, Multimodal Imaging Lab, Dept Neurosci, San Diego, CA 92093 USA. [Schork, Andrew J.] Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92161 USA. [Smith, Albert V.; Gudnason, Vilmundur; Sigursson, Sigurdur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Sprooten, Emma] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Strike, Lachlan T.; Hansell, Narelle K.; Wright, Margaret J.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Teumer, Alexander; Hoffmann, Wolfgang; Voelzke, Henry] Univ Med Greifswald, Inst Community Med, D-17489 Greifswald, Germany. [Tordesillas-Gutierrez, Diana] Valdecilla Biomed Res Inst IDIVAL, Neuroimaging Unit, Technol Facilities, Santander 39011, Cantabria, Spain. [Toro, Roberto] Inst Pasteur, F-75015 Paris, France. [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands. [Vaidya, Dhananjay; Yanek, Lisa R.; Becker, Diane M.] Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, 1830 Monument St Suite 8028, Baltimore, MD 21287 USA. [Van der Grond, Jeroen] Leiden Univ, Med Ctr, Dept Radiol, NL-2300 RC Leiden, Netherlands. [Van der Meer, Dennis; Van Rooij, Daan; Hartman, Catharina A.; Hoekstra, Pieter J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 RB Groningen, Netherlands. [Van Eijk, Kristel R.] UMC Utrecht, Brain Ctr Rudolf Magnus, Human Neurogenet Unit, NL-3584 CG Utrecht, Netherlands. [Van Erp, Theo G. M.; Potkin, Steven G.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92617 USA. [Walton, Esther; Westlye, Lars T.; Espeseth, Thomas] Georgia State Univ, Dept Psychol, Atlanta, GA 30302 USA. [Windham, Beverly G.; Mosley, Thomas H.] Univ Oslo, Dept Psychol, NORMENT KG Jebsen Ctr, N-0317 Oslo, Norway. [Winkler, Anderson M.; Jenkinson, Mark; Nichols, Thomas E.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Wittfeld, Katharina; Hoffmann, Wolfgang] Univ Oxford, FMRIB Ctr, Oxford OX3 9DU, England. [Wolf, Christiane] German Ctr Neurodegenerat Dis DZNE Rostock Greifs, D-17487 Greifswald, Germany. [Yang, Jingyun; Bennett, David A.] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, D-97080 Wurzburg, Germany. [Zijdenbos, Alex] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Agartz, Ingrid; Joensson, Erik G.] Biospective Inc, 6100 Ave Royalmount, Montreal, PQ H4P 2R2, Canada. [Almasy, Laura; Blangero, John; Curran, Joanne E.; Duggirala, Ravi; Dyer, Thomas D.; Goring, Harald H. H.] Karolinska Inst, Dept Clin Neurosci, Ctr Psychiat Res, SE-17177 Stockholm, Sweden. [Almasy, Laura] Univ Texas Brownsville, Rio Grande Valley Sch Med, South Texas Diabet & Obes Inst, Brownsville, TX 78250 USA. [Almasy, Laura] Univ Texas, Rio Grande Valley Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX 78250 USA. [Almasy, Laura] Univ Texas San Antonio, Rio Grande Valley Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX 78250 USA. [Almasy, Laura] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ames, David] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA. [Ames, David] Royal Melbourne Hosp, Natl Ageing Res Inst, Parkville, Vic 3052, Australia. [Arepalli, Sampath; Cookson, Mark R.; Dillman, Allissa; Gibbs, J. Raphael; Hernandez, Dena G.; Nalls, Michael A.; Traynor, Bryan J.] Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic 3101, Australia. [Becker, James T.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Brodaty, Henry] Univ Pittsburgh, Dept Psychiat, 3501 Forbes Ave,Suite 830, Pittsburgh, PA 15213 USA. [Brunner, Han G.] Univ New South Wales, Dementia Collaborat Res Centre Assessment & Bette, Sydney, NSW 2052, Australia. [Buckner, Randy L.] Maastricht Univ, Med Ctr, Dept Clin Genet, NL-6200 MD Maastricht, Netherlands. [Buckner, Randy L.] Maastricht Univ, Med Ctr, GROW Sch Oncol & Dev Biol, NL-6200 MD Maastricht, Netherlands. [Bulayeva, Kazima B.] Harvard Univ, Dept Psychol, Ctr Brain Sci, Cambridge, MA 02138 USA. [Calhoun, Vince D.] Dagestan State Univ, Dept Evolut & Genet, Makhachkala 367000, Dagestan, Russia. [Calhoun, Vince D.] Mind Res Network, Albuquerque, NM 87106 USA. [Calhoun, Vince D.] LBERI, Albuquerque, NM 87106 USA. [Cannon, Dara M.; McDonald, Colm] Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA. [Cheng, Ching-Yu; Wong, Tien Y.] Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, Clin Neuroimaging Lab, NCBES Galway Neurosci Ctr,Coll Med Nursing & Hlth, Galway H91 TK33, Ireland. [Cichon, Sven] Natl Univ Singapore, Dept Ophthalmol, Yong Loo Lin Sch Med, Singapore 119077, Singapore. [Cichon, Sven; Muhleisen, Thomas W.; Nothen, Markus M.] Univ Basel, Dept Biome, Div Med Genet, CH-4031 Basel, Switzerland. [Cichon, Sven; Muhleisen, Thomas W.] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany. [Dale, Anders M.] Res Ctr Julich, Inst Neurosci & Med INM 1, D-52425 Julich, Germany. [Dale, Anders M.] Univ Calif San Diego, Ctr Multimodal Imaging & Genet, San Diego, CA 92093 USA. [Davies, Gareth E.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Davies, Gareth E.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Davies, Gareth E.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Davies, Gareth E.] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA. [De Craen, Anton J. M.] Avera Inst Human Genet, Sioux Falls, SD 57108 USA. [De Jager, Philip L.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands. [De Jager, Philip L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Gen, Dept Neurol, Boston, MA 02115 USA. [De Jager, Philip L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Gen, Dept Psychiat, Boston, MA 02115 USA. [De Jager, Philip L.] Harvard Med Sch, Boston, MA 02115 USA. [De Jager, Philip L.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [De Zubicaray, Greig I.] Broad Inst, Cambridge, MA 02142 USA. [Debette, Stephanie] Queensland Univ Technol, Fac Hlth & Inst Hlth & Biomed Innovat, Brisbane, Qld 4059, Australia. [DeCarli, Charles; Martinez, Oliver] Bordeaux Univ Hosp, Dept Neurol, F-33076 Bordeaux, France. [Delanty, Norman] Univ Calif Davis, Imaging Dementia & Aging IDeA Lab, Dept Neurol, 4860 Y St,Suite 3700, Sacramento, CA 95817 USA. [Delanty, Norman] Univ Calif Davis, Ctr Neurosci, 4860 Y St,Suite 3700, Sacramento, CA 95817 USA. [Depondt, Chantal; Pandolfo, Massimo] Beaumont Hosp, Div Neurol, Dublin 9, Ireland. [Djurovic, Srdjan] Univ Libre Bruxelles, Dept Neurol, Hop Erasme, B-1070 Brussels, Belgium. [Donohoe, Gary; Morris, Derek W.] Oslo Univ Hosp, Dept Med Genet, N-0420 Oslo, Norway. [Donohoe, Gary] Natl Univ Ireland Galway, Cognit Genet & Cognit Therapy Grp, Neuroimaging Cognit & Genom Ctr NICOG, Sch Psychol & Discipline Biochem, Galway H91 TK33, Ireland. [Donohoe, Gary] Natl Univ Ireland Galway, Sch Psychol & Discipline Biochem, NCBES Galway Neurosci Ctr, Galway H91 TK33, Ireland. [Drevets, Wayne C.] Trinity Coll Dublin, Neuropsychiat Genet Res Grp, Dept Psychiat, Dublin 8, Ireland. [Drevets, Wayne C.] Trinity Coll Dublin, Trinity Coll, Inst Psychiat, Dublin 8, Ireland. [Erk, Susanne; Heinz, Andreas; Mohnke, Sebastian; Romanczuk-Seiferth, Nina; Walter, Henrik] Janssen Res & Dev LLC, Titusville, NJ 08560 USA. [Ferrucci, Luigi] Charite, Dept Psychiat & Psychotherapy, Campus Charite Mitte,Charite Pl 1, D-10117 Berlin, Germany. [Fleischman, Debra A.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Ford, Ian] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60616 USA. [Ford, Ian] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60616 USA. [Fornage, Myriam] Univ Glasgow, Robertson Ctr Biostat, Glasgow G41 4DQ, Lanark, Scotland. [Foroud, Tatiana M.; Saykin, Andrew J.] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med & Human Genet Ctr, Houston, TX 77030 USA. [Fox, Peter T.; Olvera, Rene L.] Indiana Univ Sch Med, Med & Mol Genet, Indianapolis, IN 46202 USA. [Fukunaga, Masaki] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Green, Robert C.] Natl Inst Physiol Sci, Div Cerebral Integrat, Okazaki, Aichi 4448585, Japan. [Haberg, Asta K.] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Haberg, Asta K.] Norwegian Univ Sci & Technol NTNU, Fac Med, Dept Neurosci, N-7491 Trondheim, Norway. [Hashimoto, Ryota; Ohi, Kazutaka] Univ Trondheim Hosp, Dept Radiol, St Olavs Hosp, N-7030 Trondheim, Norway. [Hashimoto, Ryota] Osaka Univ, Dept Psychiat, Grad Sch Med, Suita, Osaka 5650871, Japan. [Hegenscheid, Katrin; Hosten, Norbert] Osaka Univ, Mol Res Ctr Childrens Mental Dev, United Grad Sch Child Dev, Suita, Osaka 5650871, Japan. [Hernandez, Dena G.] Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, D-17489 Greifswald, Germany. [Heslenfeld, Dirk J.] German Ctr Neurodegenerat Dis DZNE, D-72076 Tubingen, Germany. [Ho, Beng-Choon] Vrije Univ Amsterdam, Dept Psychol, NL-1081 BT Amsterdam, Netherlands. [Holsboer, Florian] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Hofman, Albert; Homuth, Georg] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Huentelman, Matthew] HMNC Brain Hlth, D-80539 Munich, Germany. [Ikeda, Masashi] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17489 Greifswald, Germany. [Jack, Clifford R., Jr.] Translat Genom Res Inst, Neurogen Div, 445N Fifth St, Phoenix, AZ 85004 USA. [Johnson, Robert; Zielke, Ronald H.] Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi 4701192, Japan. [Kanai, Ryota] Mayo Clin, Dept Radiol, Rochester, MN 55905 USA. [Kanai, Ryota] Univ Maryland, Sch Med, NICHD Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA. [Kanai, Ryota] Univ Sussex, Sch Psychol, Brighton BN1 9QH, E Sussex, England. [Kloszewska, Iwona] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. [Knopman, David S.] Araya Brain Imaging, Dept Neuroinformat, Tokyo 1020093, Japan. [Kochunov, Peter] Med Univ Lodz, PL-90419 Lodz, Poland. [Kwok, John B.; Schofield, Peter R.] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Kwok, John B.; Schofield, Peter R.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Catonsville, MD 21228 USA. [Lemaitre, Herve; Martinot, Jean-Luc] Neurosci Res Australia, Randwick, NSW 2031, Australia. [Liu, Xinmin] UNSW, Sch Med Sci, Sydney, NSW 2052, Australia. [Longo, Dan L.] Univ Paris 05, Univ Paris Saclay, INSERM UMR Neuroimaging & Psychiat 1000, Serv Hosp Freric Joliot,Univ Paris Sud,Maison Sol, F-91400 Orsay, France. [Lopez, Oscar L.] Columbia Univ, Med Ctr, New York, NY 10032 USA. [Lovestone, Simon] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Mattay, Venkata S.] Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England. [McMahon, Katie L.; Wright, Margaret J.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Mecocci, Patrizia] Univ Queensland, Ctr Adv Imaging, Brisbane, Qld 4072, Australia. [Mueller-Myhsok, Bertram] Univ Perugia, Dept Med, Sect Gerontol & Geriatr, I-06132 Perugia, Italy. [Mueller-Myhsok, Bertram] Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany. [Nauck, Matthias] Univ Liverpool, Inst Translat Med, Liverpool L69 3BX, Merseyside, England. [Nauck, Matthias] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17489 Greifswald, Germany. [Nichols, Thomas E.] German Ctr Cardiovascular Res DZHK eV, Partner Site Greifswald, D-17475 Greifswald, Germany. [Niessen, Wiro J.] Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England. [Niessen, Wiro J.] Univ Warwick, WMG, Coventry CV4 7AL, W Midlands, England. [Niessen, Wiro J.] Erasmus MC, Dept Med Informat, NL-3015 CE Rotterdam, Netherlands. [Nothen, Markus M.] Delft Univ Technol, Fac Sci Appl, NL-2628 CD Delft, Netherlands. [Paus, Tomas] Univ Bonn, Dept Gen, Life & Brain Ctr, D-53127 Bonn, Germany. [Paus, Tomas] Univ Toronto, Rotman Res Inst, Toronto, ON M6A 2E1, Canada. [Paus, Tomas] Univ Toronto, Dept Psychol, Toronto, ON M5T 1R8, Canada. [Paus, Tomas] Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada. [Pausova, Zdenka] Child Mind Inst, New York, NY 10022 USA. [Pike, G. Bruce] Univ Toronto, Dept Physiol, Toronto, ON M5S 3E2, Canada. [Pike, G. Bruce] Univ Toronto, Dept Nutr Sci, Toronto, ON M5S 3E2, Canada. [Pike, G. Bruce] Univ Calgary, Dept Radiol, Calgary, AB T2N 4N1, Canada. [Psaty, Bruce M.] Univ Calgary, Dept Clin Neurosci, Calgary, AB T2N 4N1, Canada. [Reppermund, Simone] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Reppermund, Simone] Univ Washington, Dept Med, Seattle, WA USA. [Reppermund, Simone] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Reppermund, Simone] USA Grp Hlth Res Inst, Grp Hlth, 1730 Minor Ave Suite 1360, Seattle, WA 98101 USA. [Rotter, Jerome I.] Univ New South Wales, Dept Dev Disabil Neuropsychiat, Sch Psychiat, Sydney, NSW 2052, Australia. [Sacco, Ralph L.; Wright, Clinton B.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst & Pediat, Torrance, CA 90502 USA. [Sachdev, Perminder S.; Wen, Wei] Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Miami, FL 33136 USA. [Schmidt, Helena] Prince Wales Hosp, Neuropsychiat Inst, Randwick, NSW 2031, Australia. [Simmons, Andrew] Med Univ Graz, Inst Mol Biol & Biochem, Harrachgasse 21-3, A-8010 Graz, Austria. [Simmons, Andrew] Kings Coll London, Inst Psychiat, Dept Neuroimaging, London SE5 8AF, England. [Simmons, Andrew] Kings Coll London, Biomed Res Ctr Mental Hlth, London SE5 8AF, England. [Smith, Colin] Kings Coll London, Biomed Res Unit Dementia, London SE5 8AF, England. [Soininen, Hilkka] Univ Edinburgh, Acad Dept Neuropathol, Ctr Clin Brain Sci, MRC Edinburgh Brain Bank, Edinburgh EH16 4SB, Midlothian, Scotland. [Soininen, Hilkka] Univ Eastern Finland, Inst Clin Med, Neurol, FI-70211 Kuopio, Finland. [Stott, David J.] Kuopio Univ Hosp, Neuroctr Neurol, FI-70211 Kuopio, Finland. [Toga, Arthur W.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow G4 0SF, Lanark, Scotland. [Troncoso, Juan] Univ Southern Calif, Lab Neuro Imaging, Inst Neuroimaging & Informat, Keck Sch Med, Los Angeles, CA 90033 USA. [Tsolaki, Magda] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21205 USA. [Tzourio, Christophe] Aristotle Univ Thessaloniki, Dept Neurol 3, G Papanicolaou Hosp, Thessaloniki 57010, Greece. [Uitterlinden, Andre G.] Univ Bordeaux, INSERM, Bordeaux Populat Hlth Res Ctr, UMR1219, F-33000 Bordeaux, France. [Van der Brug, Marcel] Erasmus MC, Dept Internal Med, NL-3015 CE Rotterdam, Netherlands. [van der Wee, Nic J. A.] Genentech Inc, San Francisco, CA 94080 USA. [Van Tol, Marie-Jose] Leiden Univ, Med Ctr, Dept Psychiat, NL-2333 ZA Leiden, Netherlands. [Van Tol, Marie-Jose] Leiden Univ, Med Ctr, Leiden Inst Brain & Cognit, NL-2333 ZA Leiden, Netherlands. [Vellas, Bruno] Univ Groningen, Univ Med Ctr Groningen, Dept Neurosci, NL-9713 AW Groningen, Netherlands. [Wassink, Thomas H.] Univ Toulouse, Dept Internal Med & Geriatr Med, INSERM U1027, F-31024 Toulouse, France. [Weinberger, Daniel R.] Univ Iowa, Carver Coll Med, Dept Psychiat, Iowa City, IA 52242 USA. [Weiner, Michael W.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weiner, Michael W.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Weiner, Michael W.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA. [Westman, Eric] Univ Calif San Francisco, Ctr Imaging Neurodegenerat Dis, San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [White, Tonya] Karolinska Inst, Dept Neurobiol, Care Sci & Soc, SE-14157 Huddinge, Sweden. [Zonderman, Alan B.] Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, NL-3015 CE Rotterdam, Netherlands. [Longstreth, W. T.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Launer, Lenore J.] Univ Washington, Dept Neurol, 325 Ninth Ave, Washington, DC 98104 USA. [Launer, Lenore J.] Univ Washington, Dept Epidemiol, 325 Ninth Ave, Seattle, WA 98104 USA. [Ikram, M. Arfan] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Erasmus MC, Dept Neurol, NL-3015 CE Rotterdam, Netherlands. [Brodaty, Henry; Lovestone, Simon] Univ Pittsburgh, Dept Neurol, 3501 Forbes Ave,Suite 830, Pittsburgh, PA 15213 USA. [Brodaty, Henry] Univ Pittsburgh, Dept Psychol, 3501 Forbes Ave,Suite 830, Pittsburgh, PA 15213 USA. RP Thompson, PM (reprint author), Univ Southern Calif, Imaging Genet Ctr, USC Mark & Mary Stevens Neuroimaging & Informat I, Keck Sch Med, Marina Del Rey, CA 90292 USA.; Thompson, PM (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands.; Ikram, MA (reprint author), Erasmus MC, Dept Radiol & Nucl Med, NL-3015 CE Rotterdam, Netherlands.; Ikram, MA (reprint author), NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM pthomp@usc.edu; m.a.ikram@erasmusmc.nl RI McDonald, Colm/C-1430-2009; Zwiers, Marcel/D-2968-2009; Tzourio, christophe/B-4015-2009; Simmons, Andrew/B-8848-2008; Fernandez, Guillen/B-3771-2009; Franke, Barbara/D-4836-2009; OI Vaidya, Dhananjay/0000-0002-7164-1601; McIntosh, Andrew/0000-0002-0198-4588; Zwiers, Marcel/0000-0001-5483-2935; Tzourio, christophe/0000-0002-6517-2984; Simmons, Andrew/0000-0003-2306-5811; Fernandez, Guillen/0000-0002-5522-0604; Franke, Barbara/0000-0003-4375-6572; Westlye, Lars T./0000-0001-8644-956X; Westman, Eric/0000-0002-3115-2977; Jonsson, Erik/0000-0001-8368-6332 FU Medical Research Council [MC_UU_12013/2, MR/K026992/1]; NIBIB NIH HHS [U54 EB020403]; NIMH NIH HHS [R00 MH102357, T32 MH073526]; NINDS NIH HHS [T32 NS048004]; Wellcome Trust [104036] NR 55 TC 0 Z9 0 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 18 PY 2017 VL 8 AR 13624 DI 10.1038/ncomms13624 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI0HW UT WOS:000392154900001 PM 28098162 ER PT J AU Morawski, PA Qi, CF Bolland, S AF Morawski, Peter A. Qi, Chen-Feng Bolland, Silvia TI Non-pathogenic tissue-resident CD8(+) T cells uniquely accumulate in the brains of lupus-prone mice SO SCIENTIFIC REPORTS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; NECROSIS-FACTOR-ALPHA; INTERCELLULAR-ADHESION MOLECULE-1; COLLAGEN-INDUCED ARTHRITIS; B-CELL; MULTIPLE-SCLEROSIS; AUTOIMMUNE-DISEASE; ERYTHEMATOSUS; AUTOANTIBODIES; INFECTION AB Severe lupus often includes psychiatric and neurological sequelae, although the cellular contributors to CNS disease remain poorly defined. Using intravascular staining to discriminate tissue-localized from blood-borne cells, we find substantial accumulation of CD8(+) T cells relative to other lymphocytes in brain tissue, which correlates with lupus disease and limited neuropathology. This is in contrast to all other affected organs, where infiltrating CD4(+) cells are predominant. Brain-infiltrating CD8(+) T cells represent an activated subset of those found in the periphery, having a resident-memory phenotype (CD69(+) CD122-PD1(+)CD44(+)CD62L(-)) and expressing adhesion molecules (VLA-4(+)LFA-1(+)) complementary to activated brain endothelium. Remarkably, infiltrating CD8(+) T cells do not cause tissue damage in lupus-prone mice, as genetic ablation of these cells via beta 2 m deficiency does not reverse neuropathology, but exacerbates disease both in the brain and globally despite decreased serum IgG levels. Thus, lupus-associated inflammation disrupts the blood-brain barrier in a discriminating way biased in favor of non-pathogenic CD8(+) T cells relative to other infiltrating leukocytes, perhaps preventing further tissue damage in such a sensitive organ. C1 [Morawski, Peter A.; Qi, Chen-Feng; Bolland, Silvia] NIAID, Immunogenet Lab, Div Intramural Res, NIH, Rockville, MD 20852 USA. RP Bolland, S (reprint author), NIAID, Immunogenet Lab, Div Intramural Res, NIH, Rockville, MD 20852 USA. EM sbolland@niaid.nih.gov FU Intramural Research Program of the NIH, NIAID FX We are grateful to Sue Pierce and Geoff Hart for helpful discussion. We thank Bethany Scott for technical assistance, and the Twinbrook II SoBran staff for animal husbandry. This research was supported by the Intramural Research Program of the NIH, NIAID. NR 61 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 18 PY 2017 VL 7 AR 40838 DI 10.1038/srep40838 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI0TJ UT WOS:000392187300001 PM 28098193 ER PT J AU Nagrani, R Mhatre, S Rajaraman, P Chatterjee, N Akbari, MR Boffetta, P Brennan, P Badwe, R Gupta, S Dikshit, R AF Nagrani, Rajini Mhatre, Sharayu Rajaraman, Preetha Chatterjee, Nilanjan Akbari, Mohammad R. Boffetta, Paolo Brennan, Paul Badwe, Rajendra Gupta, Sudeep Dikshit, Rajesh TI Association of Genome-WideAssociation Study (GWAS) Identified SNPs and Risk of Breast Cancer in an Indian Population SO SCIENTIFIC REPORTS LA English DT Article ID WIDE ASSOCIATION; SUSCEPTIBILITY LOCUS; FGFR2 GENE; KAPPA-B; WOMEN; REPLICATION; ALLELES; 6Q25.1 AB To date, no studies have investigated the association of the GWAS-identified SNPs with BC risk in Indian population. We investigated the association of 30 previously reported and replicated BC susceptibility SNPs in 1,204 cases and 1,212 controls from a hospital based case-control study conducted at the Tata Memorial Hospital, Mumbai. As a measure of total susceptibility burden, the polygenic risk score (PRS) for each individual was defined by the weighted sum of genotypes from 21 independent SNPs with weights derived from previously published estimates of association odds-ratios. Logistic regression models were used to assess risk associated with individual SNPs and overall PRS, and stratified by menopausal and receptor status. A total of 11 SNPs from eight genomic regions (FGFR2, 9q31.2, MAP3K, CCND1, ZM1Z1, RAD51L11, ESR1 and UST) showed statistically significant (p-value = 0.05) evidence of association, either overall or when stratified by menopausal status or hormone receptor status. BC SNPs previously identified in Caucasian population showed evidence of replication in the Indian population mainly with respect to risk of postmenopausal and hormone receptor positive BC. C1 [Nagrani, Rajini; Mhatre, Sharayu; Dikshit, Rajesh] Tata Mem Hosp, Ctr Canc Epidemiol, Bombay, Maharashtra, India. [Rajaraman, Preetha; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chatterjee, Nilanjan] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21218 USA. [Chatterjee, Nilanjan] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21218 USA. [Akbari, Mohammad R.] Womens Coll Hosp, Womens Coll Res Inst, Toronto, ON, Canada. [Akbari, Mohammad R.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Boffetta, Paolo] Mt Sinai Hosp, Inst Translat Epidemiol, One Gustave L Levy Pl, New York, NY 10029 USA. [Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, 150 Cours Albert Thomas, F-69372 Lyon, France. [Badwe, Rajendra; Gupta, Sudeep] Tata Mem Hosp, Dept Surg Oncol, Bombay, Maharashtra, India. RP Dikshit, R (reprint author), Tata Mem Hosp, Ctr Canc Epidemiol, Bombay, Maharashtra, India. EM dixr24@hotmail.com OI nagrani, rajini/0000-0002-1708-2319 NR 37 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 18 PY 2017 VL 7 AR 40963 DI 10.1038/srep40963 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI0VE UT WOS:000392192000001 PM 28098224 ER PT J AU Kolev, M Kemper, C AF Kolev, Martin Kemper, Claudia TI Keeping it All Going - Complement Meets Metabolism SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE complement; metabolism; evolution; T cells; metabolic disease ID MEMBRANE COFACTOR PROTEIN; THIOESTER-CONTAINING PROTEINS; T-CELL DIFFERENTIATION; ISCHEMIC BRAIN-INJURY; INNATE IMMUNE-SYSTEM; DIET-INDUCED OBESITY; TOLL-LIKE RECEPTORS; INSULIN-RESISTANCE; EFFECTOR FUNCTION; FERREDOXIN-NADP(H) REDUCTASES AB The complement system is an evolutionary old and crucial component of innate immunity, which is key to the detection and removal of invading pathogens. It was initially discovered as a liver-derived sentinel system circulating in serum, the lymph, and interstitial fluids that mediate the opsonization and lytic killing of bacteria, fungi, and viruses and the initiation of the general inflammatory responses. Although work performed specifically in the last five decades identified complement also as a critical instructor of adaptive immunity-indicating that complement's function is likely broader than initially anticipated-the dominant opinion among researchers and clinicians was that the key complement functions were in principle defined. However, there is now a growing realization that complement activity goes well beyond "classic" immune functions and that this system is also required for normal (neuronal) development and activity and general cell and tissue integrity and homeostasis. Furthermore, the recent discovery that complement activation is not confined to the extracellular space but occurs within cells led to the surprising understanding that complement is involved in the regulation of basic processes of the cell, particularly those of metabolic nature-mostly via novel crosstalks between complement and intracellular sensor, and effector, pathways that had been overlooked because of their spatial separation. These paradigm shifts in the field led to a renaissance in complement research and provide new platforms to now better understand the molecular pathways underlying the wide-reaching effects of complement functions in immunity and beyond. In this review, we will cover the current knowledge about complement's emerging relationship with the cellular metabolism machinery with a focus on the functional differences between serum-circulating versus intracellularly active complement during normal cell survival and induction of effector functions. We will also discuss how taking a closer look into the evolution of key complement components not only made the functional connection between complement and metabolism rather "predictable" but how it may also give clues for the discovery of additional roles for complement in basic cellular processes. C1 [Kolev, Martin; Kemper, Claudia] Kings Coll London, Guys Hosp, Div Transplant Immunol & Mucosal Biol, MRC,Ctr Transplantat, London, England. [Kemper, Claudia] NHLBI, Lab Mol Immunol, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Kolev, M; Kemper, C (reprint author), Kings Coll London, Guys Hosp, Div Transplant Immunol & Mucosal Biol, MRC,Ctr Transplantat, London, England.; Kemper, C (reprint author), NHLBI, Lab Mol Immunol, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM martin.kolev@kcl.ac.uk; claudia.kemper@nih.gov FU MRC Centre grant [MR/J006742/1]; EU; Wellcome Trust Investigator Award; National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London; Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH FX The work in the CK's laboratory is supported by the MRC Centre grant MR/J006742/1, an EU-funded Innovative Medicines Initiative BTCURE (CK), a Wellcome Trust Investigator Award (CK), the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London, and by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH. NR 163 TC 0 Z9 0 U1 12 U2 12 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD JAN 18 PY 2017 VL 8 AR 1 DI 10.3389/fimmu.2017.00001 PG 18 WC Immunology SC Immunology GA EI0DE UT WOS:000392141800001 PM 28149297 ER PT J AU Dutta, M Robertson, SJ Okumura, A Scott, DP Chang, J Weiss, JM Sturdevant, GL Feldmann, F Haddock, E Chiramel, AI Ponia, SS Dougherty, JD Katze, MG Rasmussen, AL Best, SM AF Dutta, Mukta Robertson, Shelly J. Okumura, Atsushi Scott, Dana P. Chang, Jean Weiss, Jeffrey M. Sturdevant, Gail L. Feldmann, Friederike Haddock, Elaine Chiramel, Abhilash I. Ponia, Sanket S. Dougherty, Jonathan D. Katze, Michael G. Rasmussen, Angela L. Best, Sonja M. TI A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection SO CELL REPORTS LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; INNATE ANTIVIRAL RESPONSE; FILOVIRUS INFECTION; HEMORRHAGIC-FEVER; PATHOGENESIS; VP35; MICE; INFLAMMASOME; INHIBITION; ACTIVATION AB The unprecedented 2013-2016 outbreak of Ebola virus (EBOV) resulted in over 11,300 human deaths. Host resistance to RNA viruses requires RIG-I-like receptor (RLR) signaling through the adaptor protein, mitochondrial antiviral signaling protein (MAVS), but the role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here we apply a systems approach to MAVS(-/-) mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through the expression of IFN alpha, regulation of inflammatory responses in the spleen, and prevention of cell death in the liver, with macrophages implicated as a major cell type influencing host resistance. A dominant role for RLR signaling in macrophages was confirmed following conditional MAVS deletion in LysM+ myeloid cells. These findings reveal tissue-specific MAVS-dependent transcriptional pathways associated with resistance to EBOV, and they demonstrate that EBOV adaptation to cause disease in mice involves changes in two distinct events, RLR-MAVS antagonism and suppression of RLR-independent IFN-I responses. C1 [Dutta, Mukta; Okumura, Atsushi; Chang, Jean; Weiss, Jeffrey M.; Katze, Michael G.; Rasmussen, Angela L.] Univ Washington, Sch Med, Dept Microbiol, Seattle, WA 98105 USA. [Robertson, Shelly J.; Okumura, Atsushi; Sturdevant, Gail L.; Haddock, Elaine; Chiramel, Abhilash I.; Ponia, Sanket S.; Dougherty, Jonathan D.; Best, Sonja M.] NIAID, Virol Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. [Okumura, Atsushi; Rasmussen, Angela L.] Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY 10032 USA. [Scott, Dana P.] NIAID, Rocky Mt Lab, Rocky Mt Vet Branch, Hamilton, MT 59840 USA. RP Best, SM (reprint author), NIAID, Virol Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. EM sbest@niaid.nih.gov RI Okumura, Atsushi/E-8012-2015 OI Okumura, Atsushi/0000-0002-7779-3059 FU Division of Intramural Research, NIH, National Institute of Allergy and Infectious Diseases; Center for Research on Diagnostics and Discovery [AI109761] FX Thank you to Nicki Arndt of the RML Veterinary Branch for assistance with animal husbandry and genotyping, Rebecca Rosenke for immunohistochemistry, Dr. Katy Bosio for providing LysM-Cre mice, Dr. Michael Gale for providing MAVS-/- mice, and Dr. Hideki Ebihara for helpful discussions. This work was supported in part by the Division of Intramural Research, NIH, National Institute of Allergy and Infectious Diseases and by the Center for Research on Diagnostics and Discovery grant AI109761. NR 37 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JAN 17 PY 2017 VL 18 IS 3 BP 816 EP 829 DI 10.1016/j.celrep.2016.12.069 PG 14 WC Cell Biology SC Cell Biology GA EO1PO UT WOS:000396470600020 PM 28099857 ER PT J AU Yu, GQ Phillips, S Gail, MH Goedert, JJ Humphrys, MS Ravel, J Ren, YF Caporaso, NE AF Yu, Guoqin Phillips, Stephen Gail, Mitchell H. Goedert, James J. Humphrys, Michael S. Ravel, Jacques Ren, Yanfang Caporaso, Neil E. TI The effect of cigarette smoking on the oral and nasal microbiota SO MICROBIOME LA English DT Article DE Oral cavity; Nasal cavity; Microbiota; 16S rRNA and cigarette smoke ID SUBGINGIVAL MICROBIOTA; NEVER-SMOKERS; DISEASE AB Background: The goal of the study was to investigate whether cigarette smoking alters oral and nasal microbial diversity, composition, and structure. Twenty-three current smokers and 20 never smokers were recruited. From each subject, nine samples including supra and subgingiva plaque scrapes, saliva, swabs from five soft oral tissue sites, and one nasal swab from both the anterior nares were collected. 16S rRNA V3-V4 region was sequenced for microbial profiles. Results: We found that alpha diversity was lower in smokers than in nonsmokers in the buccal mucosa, but in other sample sites, microbial diversity and composition were not significantly different by smoking status. Microbial profiles differed significantly among eight oral sites. Conclusions: This study investigates the effect of cigarette smoking on different sites of the oral cavity and shows a potential effect of cigarette smoking on the buccal mucosa microbiota. The marked heterogeneity of the oral microbial ecosystem that we found may contribute to the stability of the oral microbiota in most sites when facing environmental perturbations such as that caused by cigarette smoking. C1 [Yu, Guoqin; Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 9609 Med Ctr Dr,Room 6E508, Bethesda, MD 20892 USA. [Phillips, Stephen; Ren, Yanfang] Univ Rochester, Eastman Inst Oral Hlth, Rochester, NY USA. [Gail, Mitchell H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Humphrys, Michael S.; Ravel, Jacques] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. RP Yu, GQ (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 9609 Med Ctr Dr,Room 6E508, Bethesda, MD 20892 USA. EM yug3@mail.nih.gov FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. NR 23 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2049-2618 J9 MICROBIOME JI Microbiome PD JAN 17 PY 2017 VL 5 AR 3 DI 10.1186/s40168-016-0226-6 PG 6 WC Microbiology SC Microbiology GA EP3SG UT WOS:000397301400002 PM 28095925 ER PT J AU Pergola, G Di Carlo, P D'Ambrosio, E Gelao, B Fazio, L Papalino, M Monda, A Scozia, G Pietrangelo, B Attrotto, M Apud, JA Chen, Q Mattay, VS Rampino, A Caforio, G Weinberger, DR Blasi, G Bertolino, A AF Pergola, G. Di Carlo, P. D'Ambrosio, E. Gelao, B. Fazio, L. Papalino, M. Monda, A. Scozia, G. Pietrangelo, B. Attrotto, M. Apud, J. A. Chen, Q. Mattay, V. S. Rampino, A. Caforio, G. Weinberger, D. R. Blasi, G. Bertolino, A. TI DRD2 co-expression network and a related polygenic index predict imaging, behavioral and clinical phenotypes linked to schizophrenia SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID WORKING-MEMORY PERFORMANCE; PREFRONTAL CORTEX; GENE-EXPRESSION; DOPAMINE D2; ROBUST REGRESSION; CORTICAL NETWORK; ASSOCIATION; DISORDERS; DYSFUNCTION; RECEPTORS AB Genetic risk for schizophrenia (SCZ) is determined by many genetic loci whose compound biological effects are difficult to determine. We hypothesized that co-expression pathways of SCZ risk genes are associated with system-level brain function and clinical phenotypes of SCZ. We examined genetic variants related to the dopamine D2 receptor gene DRD2 co-expression pathway and associated them with working memory (WM) behavior, the related brain activity and treatment response. Using two independent post-mortem prefrontal messenger RNA (mRNA) data sets (total N = 249), we identified a DRD2 co-expression pathway enriched for SCZ risk genes. Next, we identified non-coding single-nucleotide polymorphisms (SNPs) associated with co-expression of this pathway. These SNPs were associated with regulatory genetic loci in the dorsolateral prefrontal cortex (P < 0.05). We summarized their compound effect on co-expression into a Polygenic Co-expression Index (PCI), which predicted DRD2 pathway co-expression in both mRNA data sets (all P < 0.05). We associated the PCI with brain activity during WM performance in two independent samples of healthy individuals (total N = 368) and 29 patients with SCZ who performed the n-back task. Greater predicted DRD2 pathway prefrontal co-expression was associated with greater prefrontal activity and longer WM reaction times (all corrected P < 0.05), thus indicating inefficient WM processing. Blind prediction of treatment response to antipsychotics in two independent samples of patients with SCZ suggested better clinical course of patientswith greater PCI (total N = 87; P < 0.05). The findings on this DRD2 co-expression pathway are a proof of concept that gene co-expression can parse SCZ risk genes into biological pathways associated with intermediate phenotypes as well as with clinically meaningful information. C1 [Pergola, G.; Di Carlo, P.; D'Ambrosio, E.; Gelao, B.; Fazio, L.; Papalino, M.; Monda, A.; Scozia, G.; Pietrangelo, B.; Attrotto, M.; Rampino, A.; Bertolino, A.] Univ Bari Aldo Moro, Dept Basic Med Sci Neurosci & Sense Organs, Piazza Giulio Cesare 11, I-70120 Bari, Italy. [D'Ambrosio, E.; Mattay, V. S.; Weinberger, D. R.] Lieber Inst Brain Dev, Johns Hopkins Med Campus, Baltimore, MD USA. [Apud, J. A.] NIMH, NIH, Clin & Translat Neurosci Branch, Bethesda, MD 20892 USA. [Mattay, V. S.; Weinberger, D. R.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Mattay, V. S.] Johns Hopkins Sch Med, Dept Radiol, Baltimore, MD USA. [Rampino, A.; Caforio, G.; Blasi, G.; Bertolino, A.] Bari Univ Hosp, Dept Neurosci Sense Organs & Locomot Syst, Inst Psychiat, Bari, Italy. [Weinberger, D. R.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. [Weinberger, D. R.] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD USA. [Weinberger, D. R.] Johns Hopkins Sch Med, Mckusick Nathans Inst Genom Med, Baltimore, MD USA. RP Bertolino, A (reprint author), Univ Bari Aldo Moro, Dept Basic Med Sci Neurosci & Sense Organs, Piazza Giulio Cesare 11, I-70120 Bari, Italy. EM alessandro.bertolino@uniba.it FU 'Capitale Umano ad Alta Qualificazione' grant by Fondazione Con Il Sud; NARSAD [28935]; NIMH Clinical Brain Disorders Branch 'Sibling Study' [95-M-0150] FX We are grateful to Dr Andrew Jaffe, Dr Richard Straub, Dr Gianluca Ursini (Lieber Institute for Brain Development), Dr Nicola Amoroso (Department of Physics, University of Bari Aldo Moro) and Dr Silvia Torretta (Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro) for helpful methodological insights. Data acquisition was made possible by Rita Masellis, Dr Paolo Taurisano, Tiziana Quarto, Dr Raffaella Romano, Dr Annamaria Porcelli, Dr Marina Mancini, Linda Antonucci and Dr Silvia Torretta (Department of Basic Medical Science, Neuroscience, and Sense Organs, University of Bari Aldo Moro). Finally, we gratefully acknowledge the work by Dr Pierluigi Selvaggi, Alessandra Raio, Roberta Passiatore and Dalila Albergo (Department of Basic Medical Science, Neuroscience, and Sense Organs - University of Bari Aldo Moro), who contributed to data analysis. This research has been funded by a 'Capitale Umano ad Alta Qualificazione' grant by Fondazione Con Il Sud and by the NARSAD grant (number: 28935) awarded to Alessandro Bertolino, by the NIMH Clinical Brain Disorders Branch 'Sibling Study' protocol 95-M-0150 awarded to Daniel R. Weinberger, and by the Lieber Institute for Brain Development. The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. NR 60 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 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JAN 17 PY 2017 VL 7 AR e1006 DI 10.1038/tp.2016.253 PG 8 WC Psychiatry SC Psychiatry GA EO1II UT WOS:000396451500006 PM 28094815 ER PT J AU Pan, J Cai, HB AF Pan, Jing Cai, Huaibin TI Opioid system in L-DOPA-induced dyskinesia SO TRANSLATIONAL NEURODEGENERATION LA English DT Review ID LEVODOPA-INDUCED DYSKINESIA; PARKINSONS-DISEASE; BASAL GANGLIA; MOTOR COMPLICATIONS; PRIMATE MODEL; RAT-BRAIN; RECEPTOR; MU; STRIATUM; TRANSMISSION AB L-3,4-Dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) is a major clinical complication in the treatment of Parkinson's disease (PD). This debilitating side effect likely reflects aberrant compensatory responses for a combination of dopaminergic neuron denervation and repeated L-DOPA administration. Abnormal endogenous opioid signal transduction pathways in basal ganglia have been well documented in LID. Opioid receptors have been targeted to alleviate the dyskinesia. However, the exact role of this altered opioid activity is remains under active investigation. In the present review, we discuss the current understanding of opioid signal transduction in the basal ganglia and how the malfunction of opioid signaling contributes to the pathophysiology of LID. Further study of the opioid system in LID may lead to new therapeutic targets and improved treatment of PD patients. C1 [Pan, Jing; Cai, Huaibin] NIA, Transgen Sect, Neurogenet Lab, NIH, Bldg 35,Room 1A112,MSC 3707,35 Convent Dr, Bethesda, MD 20892 USA. RP Cai, HB (reprint author), NIA, Transgen Sect, Neurogenet Lab, NIH, Bldg 35,Room 1A112,MSC 3707,35 Convent Dr, Bethesda, MD 20892 USA. EM caih@mail.nih.gov FU National Institute on Aging [AG000928] FX This review was supported by the intramural research programs of National Institute on Aging (HC, AG000928). NR 55 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2047-9158 J9 TRANSL NEURODEGENER JI Transl. Neurodegener. PD JAN 17 PY 2017 VL 6 AR 1 DI 10.1186/s40035-017-0071-y PG 5 WC Neurosciences SC Neurosciences & Neurology GA EM0XF UT WOS:000395040300001 PM 28105331 ER PT J AU Chen, X Oppenheim, JJ AF Chen, Xin Oppenheim, Joost J. TI Targeting TNFR2, an immune checkpoint stimulator and oncoprotein, is a promising treatment for cancer SO SCIENCE SIGNALING LA English DT Article ID T-REGULATORY-CELLS; EXPRESSION; EXPANSION AB Tumor necrosis factor receptor type II (TNFR2) is expressed both by some cancer cells and by tumor-infiltrating immunosuppressive CD4(+)FoxP3(+) regulatory T cells (T-regs). TNFR2 stimulates the activation and proliferation of T-regs, a major checkpoint of antitumor immune responses, and promotes cancer cell survival and tumor growth. In this issue of Science Signaling, Torrey et al. found that dominant antagonistic antibodies against human TNFR2 may be a potential therapy for ovarian cancer patients by simultaneously suppressing T-reg activity and inducing the death of the cancer cells. C1 [Chen, Xin] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau 999078, Peoples R China. [Chen, Xin; Oppenheim, Joost J.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Chen, X (reprint author), Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau 999078, Peoples R China.; Chen, X; Oppenheim, JJ (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. EM xchen@umac.mo; oppenhej@mail.nih.gov FU U.S. NIH, National Cancer Institute, Center for Cancer Research; University of Macau [SRG2014-00024-ICMS-QRCM, MYRG2016-00023-ICMS-QRCM]; Science and Technology Development Fund [Macao S.A.R.] [014/2015/A1] FX Research in the authors' laboratories is supported in part by the Intramural Research Program of the U.S. NIH, National Cancer Institute, Center for Cancer Research. This project was also funded by University of Macau research grants (SRG2014-00024-ICMS-QRCM and MYRG2016-00023-ICMS-QRCM) and a grant from the Science and Technology Development Fund [Macao S.A.R. (014/2015/A1)]. NR 10 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JAN 17 PY 2017 VL 10 IS 462 AR eaal2328 DI 10.1126/scisignal.aal2328 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EK2VG UT WOS:000393784200001 ER PT J AU Vujkovic-Cvijin, I Deeks, SG AF Vujkovic-Cvijin, Ivan Deeks, Steven G. TI Mucosal Microbes Mitigate Maladies SO IMMUNITY LA English DT Editorial Material ID LACTOBACILLI; ACQUISITION; TRACT AB Understanding the factors that promote or prevent HIV transmission remains a critical component of the global battle against HIV/AIDS. Gosmann et al. (2017) reveal a putative role for the vaginal microbiome in modulating heterosexual transmission of HIV, uncovering a potential strategy for protecting women from acquisition of the virus. C1 [Vujkovic-Cvijin, Ivan] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Deeks, Steven G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Deeks, SG (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM steven.deeks@ucsf.edu OI Vujkovic-Cvijin, Ivan/0000-0002-8611-4900 FU Cancer Research Institute FX I. V.-C. is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute. NR 10 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JAN 17 PY 2017 VL 46 IS 1 BP 1 EP 3 DI 10.1016/j.immuni.2016.12.019 PG 3 WC Immunology SC Immunology GA EJ0RP UT WOS:000392918300001 PM 28099858 ER PT J AU Hickman, HD Pierson, TC AF Hickman, Heather D. Pierson, Theodore C. TI T Cells Take on Zika Virus SO IMMUNITY LA English DT Editorial Material ID DENGUE VIRUS; INFECTION; PEPTIDES AB Although CD8(+) T cells provide protection against many viral infections, their role in Zika virus (ZIKV) immunity has not been extensively examined. In a recent issue of Cell Host & Microbe, Elong Ngono et al. (2017) define antigenic epitopes determining CD8(+) T cell immunity in murine models of ZIKV infection. C1 [Hickman, Heather D.; Pierson, Theodore C.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Pierson, TC (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM piersontc@niaid.nih.gov NR 10 TC 0 Z9 0 U1 6 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JAN 17 PY 2017 VL 46 IS 1 BP 13 EP 14 DI 10.1016/j.immuni.2016.12.020 PG 3 WC Immunology SC Immunology GA EJ0RP UT WOS:000392918300006 PM 28099861 ER PT J AU Grajkowska, LT Ceribelli, M Lau, CM Warren, ME Tiniakou, I Higa, SN Bunin, A Haecker, H Mimy, LA Staudt, LM Reizis, B AF Grajkowska, Lucja T. Ceribelli, Michele Lau, Colleen M. Warren, Margaret E. Tiniakou, Ioanna Higa, Sandra Nakandakari Bunin, Anna Haecker, Hans Mimy, Leonid A. Staudt, Louis M. Reizis, Boris TI Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification SO IMMUNITY LA English DT Article ID TRANSCRIPTION FACTOR E2-2; GERMINAL CENTER; CLONOGENIC PROGENITOR; REPRESSING ID2; STEADY-STATE; B-CELL; SUBSETS; CD8-ALPHA(+); MAINTAINS; ONTOGENY AB The cell fate decision between interferon-producing plasmacytoid DC (pDC) and antigen-presenting classicalDC( cDC) is controlled by the E protein transcription factor TCF4 (E2-2). We report that TCF4 comprises two transcriptional isoforms, both of which are required for optimal pDC development in vitro. The long Tcf4 isoform is expressed specifically in pDCs, and its deletion in mice impaired pDCs development and led to the expansion of non-canonical CD8 + cDCs. The expression of Tcf4 commenced in progenitors and was further upregulated in pDCs, correlating with stage-specific activity of multiple enhancer elements. A conserved enhancer downstream of Tcf4 was required for its upregulation during pDC differentiation, revealing a positive feedback loop. The expression of Tcf4 and the resulting pDC differentiation were selectively sensitive to the inhibition of enhancer-binding BET protein activity. Thus, lineage-specifying function of E proteins is facilitated by lineage-specific isoform expression and by BET-dependent feedback regulation through distal regulatory elements. C1 [Grajkowska, Lucja T.; Lau, Colleen M.; Warren, Margaret E.; Tiniakou, Ioanna; Higa, Sandra Nakandakari; Reizis, Boris] NYU, Dept Pathol, Sch Med, New York, NY 10016 USA. [Grajkowska, Lucja T.; Bunin, Anna; Reizis, Boris] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. [Ceribelli, Michele; Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Ceribelli, Michele] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Warren, Margaret E.] Columbia Univ, Med Ctr, Grad Program Genet & Dev, New York, NY 10032 USA. [Haecker, Hans] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. [Mimy, Leonid A.] MIT, Dept Phys, Cambridge, MA 02139 USA. [Reizis, Boris] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Reizis, B (reprint author), NYU, Dept Pathol, Sch Med, New York, NY 10016 USA.; Reizis, B (reprint author), Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. EM boris.reizis@nyumc.org OI Reizis, Boris/0000-0003-1140-7853 FU NIH [AI072571, AI100853, AI124661] FX We thank S. Kellner for help with cloning sgRNA constructs, N. De Silva and N. Heise for advice, and Y. Zhuang for the Id2 reporter strain. Supported by the NIH grants AI072571 (B.R.), AI100853 (C.M.L.), and AI124661 (M.E.W.). NR 50 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JAN 17 PY 2017 VL 46 IS 1 BP 65 EP 77 DI 10.1016/j.immuni.2016.11.006 PG 13 WC Immunology SC Immunology GA EJ0RP UT WOS:000392918300011 PM 27986456 ER PT J AU Dutzan, N Abusleme, L Bridgeman, H Greenwell-Wild, T Zangerle-Murray, T Fife, ME Bouladoux, N Linley, H Brenchley, L Wemyss, K Calderon, G Hong, BY Break, TJ Bowdish, DME Lionakis, MS Jones, SA Trinchieri, G Diaz, PI Belkaid, Y Konkel, JE Moutsopoulos, NM AF Dutzan, Nicolas Abusleme, Loreto Bridgeman, Hayley Greenwell-Wild, Teresa Zangerle-Murray, Tamsin Fife, Mark E. Bouladoux, Nicolas Linley, Holly Brenchley, Laurie Wemyss, Kelly Calderon, Gloria Hong, Bo-Young Break, Timothy J. Bowdish, Dawn M. E. Lionakis, Michail S. Jones, Simon A. Trinchieri, Giorgio Diaz, Patricia I. Belkaid, Yasmine Konkel, Joanne E. Moutsopoulos, Niki M. TI On-going Mechanical Damage from Mastication Drives Homeostatic Th17 Cell Responses at the Oral Barrier SO IMMUNITY LA English DT Article ID T-HELPER-CELLS; INTESTINAL INFLAMMATION; TRANSCRIPTION-FACTOR; T(H)17 CELLS; BONE LOSS; PERIODONTITIS; DIFFERENTIATION; MICROBIOTA; IL-1-BETA; SECRETION AB Immuno-surveillance networks operating at barrier sites are tuned by local tissue cues to ensure effective immunity. Site-specific commensal bacteria provide key signals ensuring host defense in the skin and gut. However, how the oral microbiome and tissue-specific signals balance immunity and regulation at the gingiva, a key oral barrier, remains minimally explored. In contrast to the skin and gut, we demonstrate that gingiva-resident T helper 17 (Th17) cells developed via a commensal colonization- independent mechanism. Accumulation of Th17 cells at the gingiva was driven in response to the physiological barrier damage that occurs during mastication. Physiological mechanical damage, via induction of interleukin 6 (IL-6) from epithelial cells, tailored effector T cell function, promoting increases in gingival Th17 cell numbers. These data highlight that diverse tissue-specific mechanisms govern education of Th17 cell responses and demonstrate that mechanical damage helps define the immune tone of this important oral barrier. C1 [Dutzan, Nicolas; Abusleme, Loreto; Greenwell-Wild, Teresa; Brenchley, Laurie; Calderon, Gloria; Moutsopoulos, Niki M.] NIDCR, Oral Immun & Inflammat Unit, NIH, Bethesda, MD 20892 USA. [Bridgeman, Hayley; Zangerle-Murray, Tamsin; Wemyss, Kelly; Konkel, Joanne E.] Univ Manchester, Fac Biol Med & Hlth, Manchester M13 9PT, Lancs, England. [Bridgeman, Hayley; Zangerle-Murray, Tamsin; Fife, Mark E.; Linley, Holly; Wemyss, Kelly; Konkel, Joanne E.] Univ Manchester, Manchester Collaborat Ctr Inflammat Res, Manchester M13 9NT, Lancs, England. [Bouladoux, Nicolas; Belkaid, Yasmine] NIAID, Immun Barrier Sites Initiat, NIH, Bethesda, MD 20892 USA. [Bouladoux, Nicolas; Belkaid, Yasmine] NIAID, Parasit Dis Lab, Mucosal Immunol Sect, NIH, Bethesda, MD 20892 USA. [Break, Timothy J.; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, NIH, Bethesda, MD 20892 USA. [Bowdish, Dawn M. E.] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON L8N 3Z5, Canada. [Jones, Simon A.] Cardiff Univ, Inst Infect & Immun, Sch Med, Cardiff CF14 4XN, Wales. [Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hong, Bo-Young; Diaz, Patricia I.] UConn Hlth Ctr, Dept Oral Hlth & Diagnost Sci, Div Periodontol, Farmington, CT 06030 USA. RP Moutsopoulos, NM (reprint author), NIDCR, Oral Immun & Inflammat Unit, NIH, Bethesda, MD 20892 USA.; Konkel, JE (reprint author), Univ Manchester, Fac Biol Med & Hlth, Manchester M13 9PT, Lancs, England.; Konkel, JE (reprint author), Univ Manchester, Manchester Collaborat Ctr Inflammat Res, Manchester M13 9NT, Lancs, England. EM joanne.konkel@manchester.ac.uk; nmoutsopoulos@dir.nidr.nih.gov OI Zangerle Murray, Tamsin/0000-0002-3112-1564 FU intramural program of NIDCR; BBSRC [BB/M025977/1]; Wellcome Trust [097820/Z/11/B, 105610/Z/14/Z]; Manchester Collaborative Centre for Inflammation Research FX This study was funded in part from the intramural program of NIDCR (to N.M.M.), by the BBSRC (BB/M025977/1 to J.E.K.), by the Wellcome Trust (097820/Z/11/B and 105610/Z/14/Z to J.E.K.), and by the Manchester Collaborative Centre for Inflammation Research (to J.E.K). This work was also made possible through use of the University of Manchester Flow Cytometry Core Facility, the Manchester Gnotobiotic Facility (which is supported by the Wellcome Trust [097820/Z/11/B]), the NIAID and NIH Frederick Gnotobiotic facilities, the NIDCR Combined Technical Core, and the NIDCR Veterinary Resource Core. We thank Gnotobiotic Animal Facility staff, in particular V. Taylor (Manchester) and D. Trageser-Cesler and C. Acevedo (NIAID). Wethank Loretta Smith, Robin Winkler-Pickett (both NCI), and Sheila Brown (Manchester) for their help in planning experiments in the Gnotobiotic Facilities. We also thank Dr. J. Grainger for critical review of this manuscript. NR 47 TC 1 Z9 1 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JAN 17 PY 2017 VL 46 IS 1 BP 133 EP 147 DI 10.1016/j.immuni.2016.12.010 PG 15 WC Immunology SC Immunology GA EJ0RP UT WOS:000392918300016 PM 28087239 ER PT J AU Charara, R Forouzanfar, M Naghavi, M Moradi-Lakeh, M Afshin, A Vos, T Daoud, F Wang, HD El Bcheraoui, C Khalil, I Hamadeh, RR Khosravi, A Rahimi-Movaghar, V Khader, Y Al-Hamad, N Obermeyer, CM Rafay, A Asghar, R Rana, SM Shaheen, A Abu-Rmeileh, NME Husseini, A Abu-Raddad, LJ Khoja, T Al Rayess, ZA AlBuhairan, FS Hsairi, M Alomari, MA Ali, R Roshandel, G Terkawi, AS Hamidi, S Refaat, AH Westerman, R Kiadaliri, AA Akanda, AS Ali, SD Bacha, U Badawi, A Bazargan-Hejazi, S Faghmous, IAD Fereshtehnejad, SM Fischer, F Jonas, JB Defo, BK Mehari, A Omer, SB Pourmalek, F Uthman, OA Mokdad, AA Maalouf, FT Abd-Allah, F Akseer, N Arya, D Borschmann, R Brazinova, A Brugha, TS Catala-Lopez, F Degenhardt, L Ferrari, A Haro, JM Horino, M Hornberger, JC Huang, H Kieling, C Kim, D Kim, Y Knudsen, AK Mitchell, PB Patton, G Sagar, R Satpathy, M Savuon, K Seedat, S Shiuem, I Skogen, JC Stein, DJ Tabb, KM Whitefored, HA Yip, P Yonemoto, N Murray, CJL Mokdad, AH AF Charara, Raghid Forouzanfar, Mohammad Naghavi, Mohsen Moradi-Lakeh, Maziar Afshin, Ashkan Vos, Theo Daoud, Farah Wang, Haidong El Bcheraoui, Charbel Khalil, Ibrahim Hamadeh, Randah R. Khosravi, Ardeshir Rahimi-Movaghar, Vafa Khader, Yousef Al-Hamad, Nawal Obermeyer, Carla Makhlouf Rafay, Anwar Asghar, Rana Rana, Saleem M. Shaheen, Amira Abu-Rmeileh, Niveen M. E. Husseini, Abdullatif Abu-Raddad, Laith J. Khoja, Tawfik Al Rayess, Zulfa A. AlBuhairan, Fadia S. Hsairi, Mohamed Alomari, Mahmoud A. Ali, Raghib Roshandel, Gholamreza Terkawi, Abdullah Sulieman Hamidi, Samer Refaat, Amany H. Westerman, Ronny Kiadaliri, Aliasghar Ahmad Akanda, Ali S. Ali, Syed Danish Bacha, Umar Badawi, Alaa Bazargan-Hejazi, Shahrzad Faghmous, Imad A. D. Fereshtehnejad, Seyed-Mohammad Fischer, Florian Jonas, Jost B. Defo, Barthelemy Kuate Mehari, Alem Omer, Saad B. Pourmalek, Farshad Uthman, Olalekan A. Mokdad, Ali A. Maalouf, Fadi T. Abd-Allah, Foad Akseer, Nadia Arya, Dinesh Borschmann, Rohan Brazinova, Alexandra Brugha, Traolach S. Catala-Lopez, Ferran Degenhardt, Louisa Ferrari, Alize Maria Haro, Josep Horino, Masako Hornberger, John C. Huang, Hsiang Kieling, Christian Kim, Daniel Kim, Yunjin Knudsen, Ann Kristin Mitchell, Philip B. Patton, George Sagar, Rajesh Satpathy, Maheswar Savuon, Kim Seedat, Soraya Shiuem, Ivy Skogen, Jens Christoffer Stein, Dan J. Tabb, Karen M. Whitefored, Harvey A. Yip, Paul Yonemoto, Naohiro Murray, Christopher J. L. Mokdad, Ali H. TI The Burden of Mental Disorders in the Eastern Mediterranean Region, 1990-2013 SO PLOS ONE LA English DT Article ID COMMUNITY PSYCHIATRIC SURVEY; GLOBAL BURDEN; HEALTH; PREVALENCE; AFGHANISTAN; POPULATION; DEPRESSION; METAANALYSIS; LEBANON; STRESS AB The Eastern Mediterranean Region (EMR) is witnessing an increase in chronic disorders, including mental illness. With ongoing unrest, this is expected to rise. This is the first study to quantify the burden of mental disorders in the EMR. We used data from the Global Burden of Disease study (GBD) 2013. DALYs (disability-adjusted life years) allow assessment of both premature mortality (years of life lost-YLLs) and nonfatal outcomes (years lived with disability-YLDs). DALYs are computed by adding YLLs and YLDs for each age-sex-country group. In 2013, mental disorders contributed to 5.6% of the total disease burden in the EMR (1894 DALYS/100,000 population): 2519 DALYS/100,000 (2590/100,000 males, 2426/100,000 females) in high-income countries, 1884 DALYS/100,000 (1618/100,000 males, 2157/100,000 females) in middle-income countries, 1607 DALYS/100,000 (1500/100,000 males, 1717/100,000 females) in low-income countries. Females had a greater proportion of burden due to mental disorders than did males of equivalent ages, except for those under 15 years of age. The highest proportion of DALYs occurred in the 25-49 age group, with a peak in the 35-39 years age group (5344 DALYs/100,000). The burden of mental disorders in EMR increased from 1726 DALYs/100,000 in 1990 to 1912 DALYs/100,000 in 2013 (10.8% increase). Within the mental disorders group in EMR, depressive disorders accounted for most DALYs, followed by anxiety disorders. Among EMR countries, Palestine had the largest burden of mental disorders. Nearly all EMR countries had a higher mental disorder burden compared to the global level. Our findings call for EMR ministries of health to increase provision of mental health services and to address the stigma of mental illness. Moreover, our results showing the accelerating burden of mental health are alarming as the region is seeing an increased level of instability. Indeed, mental health problems, if not properly addressed, will lead to an increased burden of diseases in the region. C1 [Charara, Raghid; Forouzanfar, Mohammad; Naghavi, Mohsen; Moradi-Lakeh, Maziar; Afshin, Ashkan; Vos, Theo; Daoud, Farah; Wang, Haidong; El Bcheraoui, Charbel; Khalil, Ibrahim; Terkawi, Abdullah Sulieman; Ferrari, Alize; Murray, Christopher J. L.; Mokdad, Ali H.] Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. [Moradi-Lakeh, Maziar] Iran Univ Med Sci, Dept Community Med, Prevent Med & Publ Hlth Res Ctr, Tehran, Iran. [Hamadeh, Randah R.] Arabian Gulf Univ, Manama, Bahrain. [Khosravi, Ardeshir] Iranian Minist Hlth & Med Educ, Tehran, Iran. [Rahimi-Movaghar, Vafa] Univ Tehran Med Sci, Sina Trauma & Surg Res Ctr, Tehran, Iran. [Khader, Yousef] Jordan Univ Sci & Technol, Irbid, Jordan. [Al-Hamad, Nawal] Publ Author Food & Nutr, Kuwait, Kuwait. [Obermeyer, Carla Makhlouf] Amer Univ Beirut, Fac Hlth Sci, Ctr Res Populat & Hlth, Beirut, Lebanon. [Rafay, Anwar; Rana, Saleem M.] Contech Int Hlth Consultants, Lahore, Pakistan. [Asghar, Rana] South Asian Publ Hlth Forum, Islamabad, Pakistan. [Shaheen, Amira] An Najah Univ, Dept Publ Hlth, Nablus, Israel. [Abu-Rmeileh, Niveen M. E.; Husseini, Abdullatif] Birzeit Univ, Inst Community & Publ Hlth, Ramallah, Israel. [Abu-Raddad, Laith J.] Harvard Univ, Boston, MA 02115 USA. [Abu-Raddad, Laith J.] Weill Cornell Med Coll Qatar, Infect Dis Epidemiol Grp, Doha, Qatar. [Khoja, Tawfik] Hlth Ministers Council Cooperat Council States, Riyadh, Saudi Arabia. [Al Rayess, Zulfa A.] Saudi Ctr Evidence Based Healthcare, Riyadh, Saudi Arabia. [AlBuhairan, Fadia S.] King Saud bin Abdulaziz Univ Hlth Sci, King Abdullah Specialized Childrens Hosp, Riyadh, Saudi Arabia. [Hsairi, Mohamed] Fac Sci Tunis, Minist Hlth Tunisia, Tunis, Tunisia. [Alomari, Mahmoud A.] Jordan Univ Sci & Technol, Div Phys Therapy, Dept Rehabil Sci, Irbid, Jordan. [Ali, Raghib] Univ Oxford, Oxford, England. [Roshandel, Gholamreza] Golestan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan, Iran. [Terkawi, Abdullah Sulieman] Univ Virginia, Dept Anesthesiol, Charlottesville, VA USA. [Terkawi, Abdullah Sulieman] King Fahad Med City, Dept Anesthesiol, Riyadh, Saudi Arabia. [Terkawi, Abdullah Sulieman] OUTCOMES RES Consortium, Cleveland, OH USA. [Hamidi, Samer] Hamdan Bin Mohammed Smart Univ, Dubai, U Arab Emirates. [Refaat, Amany H.] Suez Canal Univ, Ismailia, Egypt. [Refaat, Amany H.] Walden Univ, Minneapolis, MN USA. [Westerman, Ronny] Fed Inst Populat Res, Wiesbaden, Germany. [Kiadaliri, Aliasghar Ahmad] Lund Univ, Dept Clin Sci Lund, Orthoped, Clin Epidemiol Unit, Lund, Sweden. [Akanda, Ali S.] Univ Rhode Isl, Kingston, RI 02881 USA. [Ali, Syed Danish] SIR Consultants, Sindh, Pakistan. [Bacha, Umar] Univ Management & Technol, Sch Hlth Sci, Lahore, Pakistan. [Badawi, Alaa] Publ Hlth Agcy Canada, Toronto, ON, Canada. [Bazargan-Hejazi, Shahrzad] Charles R Drew Univ Med & Sci, Dept Psychiat, Los Angeles, CA 90059 USA. [Bazargan-Hejazi, Shahrzad] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Faghmous, Imad A. D.] Univ Tehran Med Sci, Tehran, Iran. [Faghmous, Imad A. D.] London Sch Hyg & Trop Med, London, England. [Fereshtehnejad, Seyed-Mohammad] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. [Fischer, Florian] Univ Bielefeld, Bielefeld, Germany. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Heidelberg, Germany. [Defo, Barthelemy Kuate] Univ Montreal, Sch Publ Hlth, Dept Social & Prevent Med, Montreal, PQ, Canada. [Mehari, Alem] Howard Univ, Coll Med, Washington, DC USA. [Omer, Saad B.] Emory Univ, Atlanta, GA 30322 USA. [Pourmalek, Farshad] Univ British Columbia, Vancouver, BC, Canada. [Uthman, Olalekan A.] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Warwick Ctr Appl Hlth Res & Delivery WCAHRD, Coventry, W Midlands, England. [Mokdad, Ali A.] Univ Texas Southwestern, Dallas, TX USA. [Maalouf, Fadi T.] Amer Univ Beirut, Dept Psychiat, Beirut, Lebanon. [Abd-Allah, Foad] Cairo Univ, Dept Neurol, Cairo, Egypt. [Akseer, Nadia] Hosp Sick Children, Toronto, ON, Canada. [Akseer, Nadia] Univ Toronto, Toronto, ON, Canada. [Arya, Dinesh] Northern Terr Dept Hlth, Darwin, NT, Australia. [Borschmann, Rohan] Murdoch Childrens Res Inst, Ctr Adolescent Hlth, Melbourne, Vic, Australia. [Brazinova, Alexandra] Trnava Univ, Trnava, Slovakia. [Brugha, Traolach S.] Univ Leicester, Leicester, Leics, England. [Catala-Lopez, Ferran] Univ Valencia, Dept Med, Valencia, Spain. [Catala-Lopez, Ferran] INCLIVA Hlth Res Inst, Valencia, Spain. [Catala-Lopez, Ferran] CIBERSAM, Valencia, Spain. [Degenhardt, Louisa] Univ New South Wales, Natl Drug & Alcohol Res Ctr, Sydney, NSW, Australia. [Ferrari, Alize] Univ Queensland, Sch Publ Hlth, Herston, Qld, Australia. [Ferrari, Alize] Queensland Ctr Mental Hlth Res, Wacol, Qld, Australia. [Maria Haro, Josep] Parc Sanitari St Joan Deu CIBERSAM, St Boi De Llobregat, Spain. [Horino, Masako] Nevada Div Behav & Publ Hlth, Carson City, NV USA. [Hornberger, John C.] NIH, Bethesda, MD 20892 USA. [Hornberger, John C.] Cedar Associates, Menlo Pk, CA USA. [Huang, Hsiang] Cambridge Hlth Alliance, Cambridge, MA USA. [Kieling, Christian] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Kim, Daniel] Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA. [Kim, Yunjin] Southern Univ Coll, Johor Baharu, Malaysia. [Knudsen, Ann Kristin] Norwegian Inst Publ Hlth, Ctr Dis Burden, Bergen, Norway. [Mitchell, Philip B.] Univ New South Wales, Sch Psychiat, Sydney, NSW, Australia. [Patton, George] Univ Melbourne, Dept Paediat, Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Sagar, Rajesh] All India Inst Med Sci, Dept Psychiat, New Delhi, India. [Satpathy, Maheswar] Utkal Univ, UGC Ctr Adv Studies Psychol, Bhubaneswar, Odisha, India. [Savuon, Kim] Minist Hlth, Dept Hosp Serv, Phnom Penh, Cambodia. [Savuon, Kim] Mental Hlth Assoc Cambodia, Phnom Penh, Cambodia. [Seedat, Soraya] Univ Stellenbosch, Dept Psychiat, Stellenbosch, South Africa. [Shiuem, Ivy] Northumbria Univ, Hlth & Life Sci, Newcastle Upon Tyne, Tyne & Wear, England. [Skogen, Jens Christoffer] Norwegian Inst Publ Hlth, Domain Mental & Phys Hlth, Bergen, Norway. [Skogen, Jens Christoffer] Stavanger Univ Hosp, Ctr Alcohol & Drug Res, Stavanger, Norway. [Stein, Dan J.] Univ Cape Town, Dept Psychiat, Cape Town, South Africa. [Stein, Dan J.] MRC Unit Risk & Resilience Mental Disorders, Cape Town, South Africa. [Tabb, Karen M.] Univ Illinois, Sch Social Work, Champaign, IL USA. [Whitefored, Harvey A.] Univ Queensland, Brisbane, Qld, Australia. [Yip, Paul] Univ Hong Kong, Ctr Suicide Res & Prevent, Pok Fu Lam, Hong Kong, Peoples R China. [Yip, Paul] Univ Hong Kong, Social Work & Social Adm Dept, Pok Fu Lam, Hong Kong, Peoples R China. [Yonemoto, Naohiro] Kyoto Univ, Dept Biostat, Sch Publ Hlth, Kyoto, Japan. RP Mokdad, AH (reprint author), Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. EM mokdaa@uw.edu RI Altirkawi, Khalid/D-7302-2017; A. Kiadaliri, Aliasghar/E-8685-2017; OI Altirkawi, Khalid/0000-0002-7331-4196; A. Kiadaliri, Aliasghar/0000-0002-4254-9099; Catala-Lopez, Ferran/0000-0002-3833-9312; Degenhardt, Louisa/0000-0002-8513-2218; Husseini, Abdullatif/0000-0001-8767-5956 FU Bill and Melinda Gates Foundation FX The funding source was the Bill and Melinda Gates Foundation. The funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials. We would like to declare the following commercial affiliations: Dr. Anwar Rafay is employed by Contech International health consultants. Syed Danish Ali is employed by SIR Consultants. NR 83 TC 0 Z9 0 U1 15 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 17 PY 2017 VL 12 IS 1 AR e0169575 DI 10.1371/journal.pone.0169575 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI3EK UT WOS:000392372300025 PM 28095477 ER PT J AU Tu, ZW Bayazit, MB Liu, HB Zhang, JJ Busayavalasa, K Risal, S Shao, JC Satyanarayana, A Coppola, V Tessarollo, L Singh, M Zheng, CW Han, CS Chen, ZJ Kaldis, P Gustafsson, JA Liu, K AF Tu, Zhaowei Bayazit, Mustafa Bilal Liu, Hongbin Zhang, Jingjing Busayavalasa, Kiran Risal, Sanjiv Shao, Jingchen Satyanarayana, Ande Coppola, Vincenzo Tessarollo, Lino Singh, Meenakshi Zheng, Chunwei Han, Chunsheng Chen, Zijiang Kaldis, Philipp Gustafsson, Jan-Ake Liu, Kui TI Speedy A-Cdk2 binding mediates initial telomere-nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE meiosis; telomere; Speedy A; Cdk2; germ cells ID CELL-CYCLE REGULATOR; MAMMALIAN MEIOSIS; PROTEIN; MICE; DYNAMICS; PROLIFERATION; LOCALIZATION; CHROMOSOMES; OOCYTES; ARREST AB Telomere attachment to the nuclear envelope (NE) is a prerequisite for chromosomemovement duringmeiotic prophase I that is required for pairing of homologous chromosomes, synapsis, and homologous recombination. Here we show that Speedy A, a noncanonical activator of cyclin-dependent kinases (Cdks), is specifically localized to telomeres in prophase I male and female germ cells in mice, and plays an essential role in the telomere-NE attachment. Deletion of Spdya in mice disrupts telomere-NE attachment, and this impairs homologous pairing and synapsis and leads to zygotene arrest in male and female germ cells. In addition, we have identified a telomere localization domain on Speedy A covering the distal N terminus and the Cdk2-binding Ringo domain, and this domain is essential for the localization of Speedy A to telomeres. Furthermore, we found that the binding of Cdk2 to Speedy A is indispensable for Cdk2' s localization on telomeres, suggesting that Speedy A and Cdk2 might be the initial components that are recruited to the NE for forming the meiotic telomere complex. However, Speedy A-Cdk2-mediated telomere-NE attachment is independent of Cdk2 activation. Our results thus indicate that Speedy A and Cdk2 might mediate the initial telomere-NE attachment for the efficient assembly of the telomere complex that is essential for meiotic prophase I progression. C1 [Tu, Zhaowei; Bayazit, Mustafa Bilal; Zhang, Jingjing; Busayavalasa, Kiran; Risal, Sanjiv; Shao, Jingchen; Singh, Meenakshi; Liu, Kui] Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden. [Liu, Hongbin; Chen, Zijiang; Liu, Kui] Shandong Univ, Minist Educ, Key Lab Reprod Endocrinol, Jinan 250001, Peoples R China. [Satyanarayana, Ande; Coppola, Vincenzo; Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Zheng, Chunwei; Han, Chunsheng] Chinese Acad Sci, Inst Zool, State Key Lab Stem Cell & Reprod Biol, Beijing 100101, Peoples R China. [Kaldis, Philipp] ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore. [Kaldis, Philipp] Natl Univ Singapore, Dept Biochem, Singapore 117599, Singapore. [Gustafsson, Jan-Ake] Univ Houston, Ctr Nucl Receptors & Cell Signaling, Houston, TX 77204 USA. [Satyanarayana, Ande] Georgia Regents Univ, Ctr Canc, Dept Biochem & Mol Biol, Mol Oncol & Biomarkers Program, Augusta, GA 30912 USA. [Satyanarayana, Ande] Georgia Regents Univ, Dept Pathol, Program Pulm Vasc Dis, Vasc Biol Ctr, Augusta, GA 30912 USA. [Coppola, Vincenzo] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. RP Liu, K (reprint author), Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.; Liu, K (reprint author), Shandong Univ, Minist Educ, Key Lab Reprod Endocrinol, Jinan 250001, Peoples R China.; Kaldis, P (reprint author), ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore.; Kaldis, P (reprint author), Natl Univ Singapore, Dept Biochem, Singapore 117599, Singapore.; Gustafsson, JA (reprint author), Univ Houston, Ctr Nucl Receptors & Cell Signaling, Houston, TX 77204 USA. EM kaldis@imcb.a-star.edu.sg; jgustafs@central.uh.edu; kui.liu@gu.se FU Jane and Dan Olssons Foundation; LUA/ALF-medel Vastra Gotalandsregionen; AFA Insurance; Swedish Research Council; Swedish Cancer Foundation, Sweden; Biomedical Research Council of A*STAR (Agency for Science, Technology, and Research), Singapore; Robert A. Welch Foundation Grant [E-0004] FX We thank Dr. Yoshinori Watanabe from the University of Tokyo, Japan for providing the TERB1 and MAJIN antibodies. We also acknowledge the Centre for Cellular Imaging at University of Gothenburg. This study was supported by grants from the Jane and Dan Olssons Foundation, the LUA/ALF-medel Vastra Gotalandsregionen, AFA Insurance, the Swedish Research Council, and the Swedish Cancer Foundation, Sweden (all to K.L.). P.K. was supported by the Biomedical Research Council of A*STAR (Agency for Science, Technology, and Research), Singapore. J.-A.G. was supported by Robert A. Welch Foundation Grant E-0004. NR 38 TC 0 Z9 0 U1 3 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 17 PY 2017 VL 114 IS 3 BP 592 EP 597 DI 10.1073/pnas.1618465114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH9MQ UT WOS:000392095800053 PM 28031483 ER PT J AU Le Nouen, C McCarty, T Brown, M Smith, ML Lleras, R Dolan, MA Mehedi, M Yang, LJ Luongo, C Liang, B Munir, S DiNapoli, JM Mueller, S Wimmer, E Collins, PL Buchholz, UJ AF Le Nouen, Cyril McCarty, Thomas Brown, Michael Smith, Melissa Laird Lleras, Roberto Dolan, Michael A. Mehedi, Masfique Yang, Lijuan Luongo, Cindy Liang, Bo Munir, Shirin DiNapoli, Joshua M. Mueller, Steffen Wimmer, Eckard Collins, Peter L. Buchholz, Ursula J. TI Genetic stability of genome-scale deoptimized RNA virus vaccine candidates under selective pressure SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE negative-strand RNA virus; respiratory syncytial virus; live attenuated vaccine; codon pair deoptimization; genetic stability ID RESPIRATORY SYNCYTIAL VIRUS; CODON-PAIR BIAS; MOLECULAR-DYNAMICS; INFLUENZA-VIRUS; M2-1 PROTEIN; ATTENUATION; FITNESS; TRANSCRIPTION; OPTIMIZATION; REDUCTION AB Recoding viral genomes by numerous synonymous but suboptimal substitutions provides live attenuated vaccine candidates. These vaccine candidates should have a low risk of deattenuation because of the many changes involved. However, their genetic stability under selective pressure is largely unknown. We evaluated phenotypic reversion of deoptimized human respiratory syncytial virus (RSV) vaccine candidates in the context of strong selective pressure. Codon pair deoptimized (CPD) versions of RSV were attenuated and temperature-sensitive. During serial passage at progressively increasing temperature, a CPD RSV containing 2,692 synonymous mutations in 9 of 11 ORFs did not lose temperature sensitivity, remained genetically stable, and was restricted at temperatures of 34 degrees C/35 degrees C and above. However, a CPD RSV containing 1,378 synonymous mutations solely in the polymerase L ORF quickly lost substantial attenuation. Comprehensive sequence analysis of virus populations identified many different potentially deattenuating mutations in the L ORF as well as, surprisingly, many appearing in other ORFs. Phenotypic analysis revealed that either of two competing mutations in the virus transcription antitermination factor M2-1, outside of the CPD area, substantially reversed defective transcription of the CPD L gene and substantially restored virus fitness in vitro and in case of one of these twomutations, also in vivo. Paradoxically, the introduction into Min L of one mutation each in the M2-1, N, P, and L proteins resulted in a virus with increased attenuation in vivo but increased immunogenicity. Thus, in addition to providing insights on the adaptability of genome-scale deoptimized RNA viruses, stability studies can yield improved synthetic RNA virus vaccine candidates. C1 [Le Nouen, Cyril; McCarty, Thomas; Mehedi, Masfique; Yang, Lijuan; Luongo, Cindy; Liang, Bo; Munir, Shirin; DiNapoli, Joshua M.; Collins, Peter L.; Buchholz, Ursula J.] NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Brown, Michael; Smith, Melissa Laird; Lleras, Roberto] Pacific Biosci Inc, Menlo Pk, CA 94025 USA. [Dolan, Michael A.] NIAID, Bioinformat & Computat Biosci Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mueller, Steffen] Codagenix Inc, Stony Brook, NY 11790 USA. [Wimmer, Eckard] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. [Smith, Melissa Laird] Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA. [DiNapoli, Joshua M.] Sanofi Pasteur Biol LLC, North Amer Res Dept, Cambridge, MA 02139 USA. RP Le Nouen, C (reprint author), NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Wimmer, E (reprint author), SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. EM lenouenc@niaid.nih.gov; Eckard.Wimmer@stonybrook.edu FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH (C.L.N., T.M., M.A.D., M.M., L.Y., C.L., B.L., S. Munir, J.M.D., P.L.C., and U.J.B.). NR 34 TC 0 Z9 0 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 17 PY 2017 VL 114 IS 3 BP E386 EP E395 DI 10.1073/pnas.1619242114 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH9MQ UT WOS:000392095800015 PM 28049853 ER PT J AU Arbyn, M Xu, L Verdoodt, F Cuzick, J Szarewski, A Belinson, JL Wentzensen, N Gage, JC Khan, MJ AF Arbyn, Marc Xu, Lan Verdoodt, Freija Cuzick, Jack Szarewski, Anne Belinson, Jerome L. Wentzensen, Nicolas Gage, Julia C. Khan, Michelle J. TI Genotyping for Human Papillomavirus Types 16 and 18 in Women With Minor Cervical Lesions SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID ATYPICAL SQUAMOUS-CELLS; DIAGNOSTIC-TEST ACCURACY; HYBRID CAPTURE 2; ASC-US CYTOLOGY; RISK HPV TEST; INTRAEPITHELIAL NEOPLASIA; UNDETERMINED SIGNIFICANCE; SYSTEMATIC REVIEWS; ABNORMAL SMEARS; UTERINE CERVIX AB Background: High-risk human papillomavirus (hrHPV) testing to triage women with minor cervical lesions generates many referrals. Purpose: To evaluate the accuracy of genotyping for HPV types 16 and 18 and its utility as a second triage step after hrHPV testing in women with minor cervical lesions. Data Sources: Searches of 4 bibliographic databases, without language restrictions, from 1 January 1999 to 1 February 2016. Study Selection: Studies involving women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL) who were triaged with tests for hrHPV and HPV 16/18 to find cervical intraepithelial neoplasia (grade >= 2 [CIN2+] or grade >= 3 [CIN3+]). Data Extraction: Independent study selection, extraction of data, and quality assessment by 2 reviewers. Data Synthesis: Twenty-four moderate-to good-quality studies involving 8587 women with ASC-US and 5284 with LSIL were found. The pooled sensitivity of HPV 16/18 genotyping for CIN3+ was about 70% for women with either ASC-US or LSIL. The pooled specificity (with a threshold of grade <2 CIN) was 83% (95% CI, 80% to 86%) for women with ASC-US and 76% (CI, 74% to 79%) for those with LSIL. The average risk for CIN3+ was 17% and 19% in HPV 16/18-positive women with ASC-US and LSIL, respectively, and was 5% in hrHPV-positive but HPV 16/18-negative women with either ASC-US or LSIL. Limitation: Methodological and technical heterogeneity among studies; insufficient data to assess accuracy of separate assays. Conclusion: Testing for HPV 16/18 to triage women with minor abnormal cytology is poorly sensitive but may be useful as a second triage test after hrHPV testing, with direct referral if the woman is positive for HPV 16/18. Whether colposcopy or repeated testing is recommended for hrHPV-positive but HPV 16/18-negative women depends on local decision thresholds that can be derived from pretest-posttest probability plots. C1 Sci Inst Publ Hlth, Brussels, Belgium. Queen Mary Univ London, London, England. Cleveland Clin, Cleveland, OH 44106 USA. NCI, Bethesda, MD 20892 USA. Kaiser Permanente Northern Calif, San Leandro, CA USA. [Arbyn, Marc; Xu, Lan; Verdoodt, Freija] Sci Inst Publ Hlth, Belgian Canc Ctr, Canc Epidemiol Unit, J Wytsmanst 14, B-1050 Brussels, Belgium. [Cuzick, Jack] Queen Mary Univ London, Wolfson Inst Prevent Med, Ctr Canc Prevent, Charterhouse Sq, London EC1M 6BQ, England. [Belinson, Jerome L.] Cleveland Clin, Womens Hlth Inst, 9500 Euclid Ave,A81, Cleveland, OH 44118 USA. [Wentzensen, Nicolas; Gage, Julia C.] NCI, Div Canc Epidemiol & Genet, 609 Med Ctr Dr, Bethesda, MD 20892 USA. [Khan, Michelle J.] Kaiser Permanente Northern Calif, Dept Obstet & Gynecol, 2500 Merced St, San Leandro, CA 94577 USA. RP Arbyn, M (reprint author), Sci Inst Publ Hlth, Belgian Canc Ctr, Canc Epidemiol Unit, J Wytsmanst 14, B-1050 Brussels, Belgium. EM marc.arbyn@wiv-isp.be FU Belgian Foundation Against Cancer, Brussels, Belgium; European Commission through the COHEAHR Network [603019]; 7th Framework Programme of DG Research (Brussels, Belgium); Joint Action CANCON; European Union in the framework of the Health Programme; Medizinische Hochschule of Hannover (Hannover, Germany); National Institute of Allergy and Infectious Diseases of the National Institutes of Health [5T32AI065388-05]; National Institutes of Health/National Center for Research Resources University of California San Francisco-Clinical and Translational Science Institute Strategic Opportunities Support program [UL1 RR024131]; Agency for Healthcare Research and Quality [K12 HS023009] FX Drs. Arbyn and Verdoodt and Ms. Xu were supported by the Belgian Foundation Against Cancer, Brussels, Belgium; the European Commission through the COHEAHR Network (grant no. 603019), coordinated by the Free University of Amsterdam (Amsterdam, the Netherlands), funded by the 7th Framework Programme of DG Research (Brussels, Belgium); the Joint Action CANCON, which has received funding from the European Union in the framework of the Health Programme (2008-13); and the Medizinische Hochschule of Hannover (Hannover, Germany). Dr. Khan was supported by training grant 5T32AI065388-05 from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, institutional grant UL1 RR024131 through the National Institutes of Health/National Center for Research Resources University of California San Francisco-Clinical and Translational Science Institute Strategic Opportunities Support program, and mentored career development award K12 HS023009 through the Agency for Healthcare Research and Quality. NR 54 TC 0 Z9 0 U1 2 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 17 PY 2017 VL 166 IS 2 BP 118 EP + DI 10.7326/M15-2735 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EH5WB UT WOS:000391842600016 PM 27842420 ER PT J AU Mattison, JA Colman, RJ Beasley, TM Allison, DB Kemnitz, JW Roth, GS Ingram, DK Weindruch, R de Cabo, R Anderson, RM AF Mattison, Julie A. Colman, Ricki J. Beasley, T. Mark Allison, David B. Kemnitz, Joseph W. Roth, George S. Ingram, Donald K. Weindruch, Richard de Cabo, Rafael Anderson, Rozalyn M. TI Caloric restriction improves health and survival of rhesus monkeys SO NATURE COMMUNICATIONS LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; MACAQUES MACACA-MULATTA; DIETARY RESTRICTION; NONHUMAN-PRIMATES; ENERGY-EXPENDITURE; DIABETES-MELLITUS; BODY-COMPOSITION; LIFE-SPAN; AGE; DISEASE AB Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species but its impact in nonhuman primates has been controversial. In the late 1980s two parallel studies were initiated to determine the effect of CR in rhesus monkeys. The University of Wisconsin study reported a significant positive impact of CR on survival, but the National Institute on Aging study detected no significant survival effect. Here we present a direct comparison of longitudinal data from both studies including survival, bodyweight, food intake, fasting glucose levels and age-related morbidity. We describe differences in study design that could contribute to differences in outcomes, and we report species specificity in the impact of CR in terms of optimal onset and diet. Taken together these data confirm that health benefits of CR are conserved in monkeys and suggest that CR mechanisms are likely translatable to human health. C1 [Mattison, Julie A.; de Cabo, Rafael] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Colman, Ricki J.; Kemnitz, Joseph W.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. [Beasley, T. Mark; Allison, David B.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Beasley, T. Mark] Birmingham Atlanta Vet Adm Hosp, Geriatr Res Educ & Clin Ctr, Birmingham, AL 35233 USA. [Kemnitz, Joseph W.] Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53792 USA. [Roth, George S.] GeroScience, Pylesville, MD 21323 USA. [Ingram, Donald K.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Weindruch, Richard; Anderson, Rozalyn M.] Univ Wisconsin, Dept Med, Madison, WI 53792 USA. [Weindruch, Richard; Anderson, Rozalyn M.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI 53705 USA. RP de Cabo, R (reprint author), NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA.; Anderson, RM (reprint author), Univ Wisconsin, Dept Med, Madison, WI 53792 USA.; Anderson, RM (reprint author), William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI 53705 USA. EM decabora@grc.nia.nih.gov; rmanderson5@wisc.edu FU NIH [P01AG011915, R01AG040178, R01AG037000]; Department of Medicine, School of Medicine and Public Health UW Madison; NCRR/ORIP grants [P51RR000167/P51OD011106]; NIA [HHSN-263-2013-00026C]; Intramural Research Program of the NIH, National Institute on Aging FX Thanks to animal care and research staff at both facilities including Scott Baum, Julie Adriansjach, Saverio Capuano, Casey Fitz, Heather Simmons at UW, and Rick Herbert, Edward Tilmont, Kelli Vaughan, Mark Szarowicz, Amanda Evans, Danielle Sedlak, Mark Bryant and Matt Starost at NIA for their tireless efforts and stalwart commitment over the years. Funding for the UW study was provided by NIH grants P01AG011915, R01AG040178, R01AG037000, and the Department of Medicine, School of Medicine and Public Health UW Madison. This publication was made possible in part by NCRR/ORIP grants P51RR000167/P51OD011106 to the Wisconsin National Primate Research Center, University of Wisconsin-Madison and the use of resources and facilities at the William S. Middleton Memorial Veterans Hospital, Madison, WI. The internet Primate Aging Database is funded by contract HHSN-263-2013-00026C from the NIA. The NIA study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 54 TC 1 Z9 1 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 17 PY 2017 VL 8 AR 14063 DI 10.1038/ncomms14063 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH7GE UT WOS:000391940100001 PM 28094793 ER PT J AU Tschirhart, T Kim, E McKay, R Ueda, H Wu, HC Pottash, AE Zargar, A Negrete, A Shiloach, J Payne, GF Bentley, WE AF Tschirhart, Tanya Kim, Eunkyoung McKay, Ryan Ueda, Hana Wu, Hsuan-Chen Pottash, Alex Eli Zargar, Amin Negrete, Alejandro Shiloach, Joseph Payne, Gregory F. Bentley, William E. TI Electronic control of gene expression and cell behaviour in Escherichia coli through redox signalling SO NATURE COMMUNICATIONS LA English DT Article ID SUPEROXIDE RESPONSE REGULON; BIOCHEMICAL OXYGEN-DEMAND; MICROBIAL FUEL-CELLS; BETA-GALACTOSIDASE; SOXR; COMMUNICATION; SYSTEMS; GLUCOSE; PROTEIN; LIGHT AB The ability to interconvert information between electronic and ionic modalities has transformed our ability to record and actuate biological function. Synthetic biology offers the potential to expand communication 'bandwidth' by using biomolecules and providing electrochemical access to redox-based cell signals and behaviours. While engineered cells have transmitted molecular information to electronic devices, the potential for bidirectional communication stands largely untapped. Here we present a simple electrogenetic device that uses redox biomolecules to carry electronic information to engineered bacterial cells in order to control transcription from a simple synthetic gene circuit. Electronic actuation of the native transcriptional regulator SoxR and transcription from the PsoxS promoter allows cell response that is quick, reversible and dependent on the amplitude and frequency of the imposed electronic signals. Further, induction of bacterial motility and population based cell-to-cell communication demonstrates the versatility of our approach and potential to drive intricate biological behaviours. C1 [Tschirhart, Tanya; Kim, Eunkyoung; McKay, Ryan; Ueda, Hana; Wu, Hsuan-Chen; Pottash, Alex Eli; Payne, Gregory F.; Bentley, William E.] Univ Maryland, Inst Biosci & Biotechnol Res, 4291 Fieldhouse Dr,5112 Plant Sci Bldg, College Pk, MD 20742 USA. [McKay, Ryan; Pottash, Alex Eli; Zargar, Amin; Payne, Gregory F.; Bentley, William E.] Univ Maryland, Fischell Dept Bioengn, 8228 Paint Branch Dr,2330 Jeong H Kim Engn Bldg, College Pk, MD 20742 USA. [Ueda, Hana] Univ Maryland, Dept Math, 4176 Campus Dr,William E Kirwan Hall, College Pk, MD 20742 USA. [Negrete, Alejandro; Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, 14 Serv Rd West, Bethesda, MD 20892 USA. RP Bentley, WE (reprint author), Univ Maryland, Inst Biosci & Biotechnol Res, 4291 Fieldhouse Dr,5112 Plant Sci Bldg, College Pk, MD 20742 USA.; Bentley, WE (reprint author), Univ Maryland, Fischell Dept Bioengn, 8228 Paint Branch Dr,2330 Jeong H Kim Engn Bldg, College Pk, MD 20742 USA. EM bentley@umd.edu FU Defense Threat Reduction Agency (DTRA) [HDTRA1-13-1-00037]; National Science Foundation [CBET 1160005, CBET 1264509]; NSF EAPSI fellowship FX We would like to acknowledge funding provided for this work by the Defense Threat Reduction Agency (DTRA, HDTRA1-13-1-00037) and the National Science Foundation (CBET 1160005 and CBET 1264509), and the NSF EAPSI fellowship to T. (Gordonov) Tschirhart. We would like to thank Dr James A. Imlay for helpful conversations. NR 63 TC 0 Z9 0 U1 34 U2 34 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 JAN 17 PY 2017 VL 8 AR 14030 DI 10.1038/ncomms14030 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH7GC UT WOS:000391939900001 PM 28094788 ER PT J AU Sizdahkhani, S Feldman, MJ Piazza, MG Ksendzovsky, A Edwards, NA Ray-Chaudhury, A Maric, D Merrill, MJ Pacak, K Zhuang, ZP Chittiboina, P AF Sizdahkhani, Saman Feldman, Michael J. Piazza, Martin G. Ksendzovsky, Alexander Edwards, Nancy A. Ray-Chaudhury, Abhik Maric, Dragan Merrill, Marsha J. Pacak, Karel Zhuang, Zhengping Chittiboina, Prashant TI Somatostatin receptor expression on von Hippel-Lindau-associated hemangioblastomas offers novel therapeutic target SO SCIENTIFIC REPORTS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; TUMOR-SUPPRESSOR PROTEIN; CELLS IN-VITRO; NEUROENDOCRINE TUMORS; DISEASE; OCTREOTIDE; CANCER; GENE; APOPTOSIS; ANALOGS AB Von Hippel-Lindau (VHL)-associated hemangioblastomas (VHL-HB) arise in the central nervous system (CNS), and are a leading cause of morbidity and mortality in VHL disease. Currently, surgical resection is the most effective way to manage symptomatic VHL-HBs. Surgically unresectable VHL-HBs or those in frail patients are challenging problems. Therapies targeting oncologic and vascular endothelial growth factor (VEGF) pathways have failed to demonstrate tumor control. Our experience and previous reports on VHL-HB avidity to somatostatin analogues suggested somatostatin receptor (SSTR) expression in VHL-HBs, offering an alternative therapeutic strategy. We explored this possibility by demonstrating consistent histologic expression of SSTR1, 2a, 4, and 5 in VHL-HBs. We found that somatostatin analogue octreotide induces apoptosis in VHL-HB stromal cells in a dose-dependent fashion by BAX - caspase-3 pathway unrelated to canonical VHL pathway. When administered to a patient with unresectable symptomatic suprasellar hemangioblastoma, octreotide resulted in tumor volume reduction, symptom stabilization, and tumor cytopenia on repeat Ga-68-DOTA-TATE positron emission tomography (PET) within 6 months, suggesting tumor infarction. We conclude that VHL-HBs harbor multiple SSTR subtypes that offer actionable chemo-therapeutic strategy for management of symptomatic, unresectable tumors by somatostatin analogue therapy. C1 [Sizdahkhani, Saman; Feldman, Michael J.; Piazza, Martin G.; Ksendzovsky, Alexander; Edwards, Nancy A.; Ray-Chaudhury, Abhik; Merrill, Marsha J.; Zhuang, Zhengping; Chittiboina, Prashant] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Ksendzovsky, Alexander] Univ Virginia Hlth Syst, Dept Neurosurg, Charlottesville, VA USA. [Maric, Dragan] NINDS, Flow Cytometry Core, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Pacak, Karel] NICHHD, Sect Med Neuroendocrinol, NIH, Bethesda, MD 20892 USA. RP Chittiboina, P (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM Prashant.Chittiboina@nih.gov FU NIH Intramural Research Program at the National Institute of Neurological Disorders and Stroke [ZIA NS003053-09] FX We would like to acknowledge Dr. Martha Quezado for her assistance with neuropathological analysis. P. Chittiboina received grant ZIA NS003053-09 from the NIH Intramural Research Program at the National Institute of Neurological Disorders and Stroke. NR 49 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 17 PY 2017 VL 7 AR 40822 DI 10.1038/srep40822 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH8WA UT WOS:000392052200001 PM 28094316 ER PT J AU Radtke, AJ Anderson, CF Riteau, N Rausch, K Scaria, P Kelnhofer, ER Howard, RF Sher, A Germain, RN Duffy, P AF Radtke, Andrea J. Anderson, Charles F. Riteau, Nicolas Rausch, Kelly Scaria, Puthupparampil Kelnhofer, Emily R. Howard, Randall F. Sher, Alan Germain, Ronald N. Duffy, Patrick TI Adjuvant and carrier protein-dependent T-cell priming promotes a robust antibody response against the Plasmodium falciparum Pfs25 vaccine candidate SO SCIENTIFIC REPORTS LA English DT Article ID TRANSMISSION-BLOCKING VACCINES; GERMINAL-CENTER FORMATION; LIVED PLASMA-CELLS; MALARIA VACCINE; ENHANCING IMMUNOGENICITY; CONJUGATE VACCINES; HUMORAL IMMUNITY; ANTIGEN; CENTERS; DIFFERENTIATION AB Humoral immune responses have the potential to maintain protective antibody levels for years due to the immunoglobulin-secreting activity of long-lived plasma cells (LLPCs). However, many subunit vaccines under development fail to generate robust LLPC responses, and therefore a variety of strategies are being employed to overcome this limitation, including conjugation to carrier proteins and/or formulation with potent adjuvants. Pfs25, an antigen expressed on malaria zygotes and ookinetes, is a leading transmission blocking vaccine (TBV) candidate for Plasmodium falciparum. Currently, the conjugate vaccine Pfs25-EPA/Alhydrogel is in Phase 1 clinical trials in the USA and Africa. Thus far, it has proven to be safe and immunogenic, but it is expected that a more potent formulation will be required to establish antibody titers that persist for several malaria transmission seasons. We sought to determine the contribution of carrier determinants and adjuvants in promoting high-titer, long-lived antibody responses against Pfs25. We found that both adjuvants and carrier proteins influence the magnitude and capacity of Pfs25-specific humoral responses to remain above a protective level. Furthermore, a liposomal adjuvant with QS21 and a TLR4 agonist (GLA-LSQ) was especially effective at inducing T follicular helper (Tfh) and LLPC responses to Pfs25 when coupled to immunogenic carrier proteins. C1 [Radtke, Andrea J.; Germain, Ronald N.] NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Anderson, Charles F.; Rausch, Kelly; Scaria, Puthupparampil; Kelnhofer, Emily R.; Duffy, Patrick] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Riteau, Nicolas; Sher, Alan] NIAID, Lab Parasit Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Howard, Randall F.] Infect Dis Res Inst, Seattle, WA USA. RP Anderson, CF (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. EM cfanderson@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bill & Melinda Gates Foundation [OPP1055855] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. We are grateful to the NIAID Flow Cytometry Facility and Animal Care Branch for major contributions to this work. We would like to thank Dr. Marc Jenkins for sharing his laboratory's custom script and for Dr. Bastian Angermann for executing this script in R, Lynn Lambert and Sachy Orr-Gonzalez for animal procedures, Chris Rowe and Beth Chen for conjugation, and Olga Muratova for membrane feeding assays. This research was supported in part with funding (to Steve Reed, IDRI) from the Bill & Melinda Gates Foundation under grant OPP1055855. NR 51 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 16 PY 2017 VL 7 AR 40312 DI 10.1038/srep40312 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH6HN UT WOS:000391873900001 PM 28091576 ER PT J AU Vogtmann, E Chen, J Amir, A Shi, JX Abnet, CC Nelson, H Knight, R Chia, N Sinha, R AF Vogtmann, Emily Chen, Jun Amir, Amnon Shi, Jianxin Abnet, Christian C. Nelson, Heidi Knight, Rob Chia, Nicholas Sinha, Rashmi TI Comparison of Collection Methods for Fecal Samples in Microbiome Studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE feces; microbiota; specimen collection ID HUMAN GUT; STORAGE-CONDITIONS; COLORECTAL-CANCER; DNA EXTRACTION; BACTERIAL; SEQUENCE; DATABASE; STOOL AB Prospective cohort studies are needed to assess the relationship between the fecal microbiome and human health and disease. To evaluate fecal collection methods, we determined technical reproducibility, stability at ambient temperature, and accuracy of 5 fecal collection methods (no additive, 95% ethanol, RNAlater Stabilization Solution, fecal occult blood test cards, and fecal immunochemical test tubes). Fifty-two healthy volunteers provided fecal samples at the Mayo Clinic in Rochester, Minnesota, in 2014. One set from each sample collection method was frozen immediately, and a second set was incubated at room temperature for 96 hours and then frozen. Intraclass correlation coefficients (ICCs) were calculated for the relative abundance of 3 phyla, 2 alpha diversity metrics, and 4 beta diversity metrics. Technical reproducibility was high, with ICCs for duplicate fecal samples between 0.64 and 1.00. Stability for most methods was generally high, although the ICCs were below 0.60 for 95% ethanol in metrics that were more sensitive to relative abundance. When compared with fecal samples that were frozen immediately, the ICCs were below 0.60 for the metrics that were sensitive to relative abundance; however, the remaining 2 alpha diversity and 3 beta diversitymetrics were all relatively accurate, with ICCs above 0.60. In conclusion, all fecal sample collection methods appear relatively reproducible, stable, and accurate. Future studies could use these collection methods for microbiome analyses. C1 [Vogtmann, Emily; Abnet, Christian C.; Sinha, Rashmi] NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Vogtmann, Emily] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Chen, Jun; Nelson, Heidi; Chia, Nicholas] Mayo Clin, Ctr Individualized Med, Microbiome Program, Rochester, MN USA. [Chen, Jun; Chia, Nicholas] Mayo Clin, Hlth Sci Res, Rochester, MN USA. [Amir, Amnon; Knight, Rob] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Shi, Jianxin] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Nelson, Heidi; Chia, Nicholas] Mayo Clin, Dept Surg, Rochester, MN USA. [Knight, Rob] Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA. [Chia, Nicholas] Mayo Coll, Biomed Engn & Physiol, Rochester, MN USA. RP Vogtmann, E (reprint author), NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr MSC 9768, Bethesda, MD 20892 USA. EM emily.vogtmann@nih.gov FU National Cancer Institute at the National Institutes of Health; Gerstner Family Career Development Awards; Mayo Clinic Center for Individualized Medicine; National Institutes of Health [1R01CA179243]; Howard Hughes Medical Institute; Sloan Foundation FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health; the Gerstner Family Career Development Awards and Mayo Clinic Center for Individualized Medicine (to J.C.); a grant from the National Institutes of Health (1R01CA179243 to N.C.); and the Howard Hughes Medical Institute and the Sloan Foundation awards (to R.K.). NR 36 TC 0 Z9 0 U1 1 U2 1 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 JAN 15 PY 2017 VL 185 IS 2 BP 115 EP 123 DI 10.1093/aje/kww177 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EP2WM UT WOS:000397244300005 PM 27986704 ER PT J AU Gulick, RM Wilkin, TJ Chen, YQ Landovitz, RJ Amico, KR Young, AM Richardson, P Marzinke, MA Hendrix, CW Eshleman, SH McGowan, I Cottle, LM Andrade, A Marcus, C Klingman, KL Chege, W Rinehart, AR Rooney, JF Andrew, P Salata, RA Magnus, M Farley, JE Liu, A Frank, I Ho, K Santana, J Stekler, JD McCauley, M Mayer, KH AF Gulick, Roy M. Wilkin, Timothy J. Chen, Ying Q. Landovitz, Raphael J. Amico, K. Rivet Young, Alicia M. Richardson, Paul Marzinke, Mark A. Hendrix, Craig W. Eshleman, Susan H. McGowan, Ian Cottle, Leslie M. Andrade, Adriana Marcus, Cheryl Klingman, Karin L. Chege, Wairimu Rinehart, Alex R. Rooney, James F. Andrew, Philip Salata, Robert A. Magnus, Manya Farley, Jason E. Liu, Albert Frank, Ian Ho, Ken Santana, Jorge Stekler, Joanne D. McCauley, Marybeth Mayer, Kenneth H. TI Phase 2 Study of the Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Men Who Have Sex With Men (HPTN 069/ACTG A5305) SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; PrEP; men who have sex with men (MSM); maraviroc; phase 2 clinical trial ID RANDOMIZED CLINICAL-TRIAL; PLACEBO-CONTROLLED TRIAL; PREEXPOSURE PROPHYLAXIS; AFRICAN WOMEN; DOUBLE-BLIND; EFFICACY; EMTRICITABINE/TENOFOVIR; PHARMACOKINETICS; ANTAGONIST; ADHERENCE AB Background. Maraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis. Methods. Phase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with >= 1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat. Results. Among 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [ 95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations. Conclusions. MVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis. C1 [Gulick, Roy M.; Wilkin, Timothy J.] Weill Cornell Med, Dept Med, New York, NY USA. [Chen, Ying Q.; Young, Alicia M.; Cottle, Leslie M.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, 1124 Columbia St, Seattle, WA 98104 USA. [Stekler, Joanne D.] Univ Washington, Dept Med, Seattle, WA USA. [Landovitz, Raphael J.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Rooney, James F.] Gilead Sci, Foster City, CA USA. [Liu, Albert] San Francisco Dept Publ Hlth, Bridge HIV, San Francisco, CA USA. [Amico, K. Rivet] Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. [Richardson, Paul; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Marzinke, Mark A.; Hendrix, Craig W.; Andrade, Adriana] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Farley, Jason E.] Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. [Klingman, Karin L.] NIAID, HIV Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Chege, Wairimu] NIAID, Clin Prevent Res Branch, Prevent Sci Program, Div Aids,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [McGowan, Ian; Ho, Ken] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15260 USA. [Frank, Ian] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Marcus, Cheryl] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Rinehart, Alex R.] ViiV Healthcare, Durham, NC USA. [Andrew, Philip] FHI 360, Durham, NC USA. [Salata, Robert A.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Magnus, Manya] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Epidemiol & Biostat, Washington, DC USA. [McCauley, Marybeth] FHI 360, Washington, DC USA. [Santana, Jorge] Univ Puerto Rico, Sch Med, Dept Med, San Juan, PR 00936 USA. [Mayer, Kenneth H.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Fenway Hlth, Boston, MA USA. RP Gulick, RM (reprint author), Weill Cornell Med, Div Infect Dis, Box 125,1300 York Ave, New York, NY 10065 USA. EM rgulick@med.cornell.edu FU DAIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health through the HPTN [UM1-AI068619, UM1-AI068613, UM1-AI068617]; AIDS Clinical Trials Group [UM1-AI-068636] FX This work was supported by DAIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health through the HPTN (grants UM1-AI068619, UM1-AI068613, and UM1-AI068617) and the AIDS Clinical Trials Group (grant UM1-AI-068636). Gilead Sciences and ViiV Healthcare provided study drugs. NR 35 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2017 VL 215 IS 2 BP 238 EP 246 DI 10.1093/infdis/jiw525 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP2HN UT WOS:000397204100011 PM 27811319 ER PT J AU Kundakovic, M Jiang, Y Kavanagh, DH Dincer, A Brown, L Pothula, V Zharovsky, E Park, R Jacobov, R Magro, I Kassim, B Wiseman, J Dang, K Sieberts, SK Roussos, P Fromer, M Harris, B Lipska, BK Peters, MA Sklar, P Akbarian, S AF Kundakovic, Marija Jiang, Yan Kavanagh, David H. Dincer, Aslihan Brown, Leanne Pothula, Venu Zharovsky, Elizabeth Park, Royce Jacobov, Rivka Magro, Isabelle Kassim, Bibi Wiseman, Jennifer Dang, Kristen Sieberts, Solveig K. Roussos, Panos Fromer, Menachem Harris, Brent Lipska, Barbara K. Peters, Mette A. Sklar, Pamela Akbarian, Schahram TI Practical Guidelines for High-Resolution Epigenomic Profiling of Nucleosomal Histones in Postmortem Human Brain Tissue SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Cell type specific; ChIP-seq; Epigenomics; Postmortem human brain; PsychENCODE; Schizophrenia ID CHIP-SEQ; DNA-METHYLATION; SCHIZOPHRENIA; CHROMATIN; IMMUNOPRECIPITATION; DYNAMICS AB BACKGROUND: The nervous system may include more than 100 residue-specific posttranslational modifications of histones forming the nucleosome core that are often regulated in cell-type-specific manner. On a genome-wide scale, some of the histone posttranslational modification landscapes show significant overlap with the genetic risk architecture for several psychiatric disorders, fueling PsychENCODE and other large-scale efforts to comprehensively map neuronal and nonneuronal epigenomes in hundreds of specimens. However, practical guidelines for efficient generation of histone chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) datasets from postmortem brains are needed. METHODS: Protocols and quality controls are given for the following: 1) extraction, purification, and NeuN neuronal marker immunotagging of nuclei from adult human cerebral cortex; 2) fluorescence-activated nuclei sorting; 3) preparation of chromatin by micrococcal nuclease digest; 4) ChIP for open chromatin-associated histone methylation and acetylation; and 5) generation and sequencing of ChIP-seq libraries. RESULTS: We present a ChIP-seq pipeline for epigenome mapping in the neuronal and nonneuronal nuclei from the postmortem brain. This includes a stepwise system of quality controls and user-friendly data presentation platforms. CONCLUSIONS: Our practical guidelines will be useful for projects aimed at histone posttranslational modification mapping in chromatin extracted from hundreds of postmortem brain samples in cell-type-specific manner. C1 [Kundakovic, Marija; Jiang, Yan; Kavanagh, David H.; Dincer, Aslihan; Brown, Leanne; Pothula, Venu; Zharovsky, Elizabeth; Park, Royce; Jacobov, Rivka; Magro, Isabelle; Kassim, Bibi; Wiseman, Jennifer; Roussos, Panos; Fromer, Menachem; Sklar, Pamela; Akbarian, Schahram] Icahn Sch Med Mt Sinai, Dept Psychiat, Friedman Brain Inst, New York, NY 10029 USA. [Kundakovic, Marija; Jiang, Yan; Kavanagh, David H.; Dincer, Aslihan; Brown, Leanne; Pothula, Venu; Zharovsky, Elizabeth; Park, Royce; Jacobov, Rivka; Magro, Isabelle; Kassim, Bibi; Wiseman, Jennifer; Roussos, Panos; Fromer, Menachem; Sklar, Pamela; Akbarian, Schahram] Icahn Sch Med Mt Sinai, Dept Neurosci, Friedman Brain Inst, New York, NY 10029 USA. [Kavanagh, David H.; Dincer, Aslihan; Roussos, Panos; Fromer, Menachem; Sklar, Pamela] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Dang, Kristen; Sieberts, Solveig K.; Peters, Mette A.] Sage Bionetworks, Seattle, WA USA. [Harris, Brent] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA. [Harris, Brent; Lipska, Barbara K.] NIMH, Human Brain Collect Core, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Kundakovic, Marija] Fordham Univ, Dept Biol Sci, Bronx, NY 10458 USA. RP Akbarian, S (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, 1470 Madison Ave,Hess CSM Room 9-105, New York, NY 10029 USA.; Akbarian, S (reprint author), Icahn Sch Med Mt Sinai, Dept Neurosci, 1470 Madison Ave,Hess CSM Room 9-105, New York, NY 10029 USA. EM Schahram.akbarian@mssm.edu RI Lipska, Barbara/E-4569-2017 FU National Institutes of Health [U01 MH103392, P50MH096890]; National Alliance for Research on Schizophrenia and Depression Young Investigator Grants from the Brain & Behavior Research Foundation FX This work was supported by National Institutes of Health Grant No. U01 MH103392. MK and YJ were supported, in part, by National Alliance for Research on Schizophrenia and Depression Young Investigator Grants from the Brain & Behavior Research Foundation, and YJ by National Institutes of Health Grant No. P50MH096890. NR 36 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2017 VL 81 IS 2 BP 162 EP 170 DI 10.1016/j.biopsych.2016.03.1048 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EO2JY UT WOS:000396524000014 PM 27113501 ER PT J AU Sereti, I Krebs, SJ Phanuphak, N Fletcher, JL Slike, B Pinyakorn, S O'Connell, RJ Rupert, A Chomont, N Valcour, V Kim, JH Robb, ML Michael, NL Douek, DC Ananworanich, J Utay, NS AF Sereti, Irini Krebs, Shelly J. Phanuphak, Nittaya Fletcher, James L. Slike, Bonnie Pinyakorn, Suteeraporn O'Connell, Robert J. Rupert, Adam Chomont, Nicolas Valcour, Victor Kim, Jerome H. Robb, Merlin L. Michael, Nelson L. Douek, Daniel C. Ananworanich, Jintanat Utay, Netanya S. CA RV254 SEARCH 010 Protocol Teams RV304 SEARCH 013 Protocol Teams SEARCH 011 Protocol Teams TI Persistent, Albeit Reduced, Chronic Inflammation in Persons Starting Antiretroviral Therapy in Acute HIV Infection SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE acute HIV infection; antiretroviral therapy; inflammation; monocyte activation; sIL-6R ID MONOCYTE ACTIVATION; PREDICT MORTALITY; IMMUNE ACTIVATION; D-DIMER; AIDS; INTERLEUKIN-6; COAGULATION; DISEASE; MARKERS; RISK AB Background. Serious non-AIDS events cause substantial disease and death despite human immunodeficiency virus (HIV) suppression with antiretroviral therapy (ART). Biomarkers of inflammation, coagulation cascade activation, and fibrosis predict these end-organ events. We aimed to determine whether ART initiation during acute HIV infection would attenuate changes in these biomarker levels. Methods. Plasma samples were obtained from participants starting ART during acute or chronic HIV infection and from HIV-uninfected participants from Bangkok, Thailand. Biomarkers of inflammation (C-reactive protein [CRP], interleukin 6, soluble interleukin 6 receptor [sIL-6R], soluble gp130, tumor necrosis factor [TNF]), enterocyte turnover (intestinal fatty acid binding protein [I-FABP]), lipopolysaccharide-induced monocyte activation (soluble CD14 [sCD14]), coagulation cascade activation [D-dimer], and fibrosis (hyaluronic acid [HA]) were measured at baseline and through 96 weeks of ART. Results. CRP, TNF, sIL-6R, I-FABP, sCD14, D-dimer, and HA levels were elevated in acute HIV infection. Early ART was associated with increased I-FABP levels but normalization of TNF, sIL-6R, and D-dimer levels. CRP, sCD14, and HA levels decreased during ART but remained elevated compared with HIV-uninfected participants. Higher sCD14, CRP, and D-dimer levels were associated with higher peripheral blood mononuclear cell and gut integrated HIV DNA levels. Decreases in sCD14 and CRP levels were correlated with increases in CD4 T-cell counts. Conclusions. ART initiated in early acute HIV infection was associated with normalization of the coagulation cascade and several systemic inflammatory biomarkers, but the acute-phase response, enterocyte turnover, monocyte activation, and fibrosis biomarkers remained elevated. Additional interventions to attenuate inflammation may be needed to optimize clinical outcomes in persons with HIV infection. C1 [Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Douek, Daniel C.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Krebs, Shelly J.; Slike, Bonnie; Pinyakorn, Suteeraporn; O'Connell, Robert J.; Kim, Jerome H.; Robb, Merlin L.; Michael, Nelson L.; Ananworanich, Jintanat] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Krebs, Shelly J.; Slike, Bonnie; Pinyakorn, Suteeraporn; O'Connell, Robert J.; Kim, Jerome H.; Robb, Merlin L.; Michael, Nelson L.; Ananworanich, Jintanat] US Mil, HIV Res Program, Walter Reed Army Inst Res, Silver Spring, MD USA. [Rupert, Adam] Frederick Natl Lab Canc Res, AIDS Monitoring Lab, Leidos Biomed Res, Frederick, MD USA. [Valcour, Victor] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, Sandler Neurosci Ctr, San Francisco, CA 94143 USA. [Utay, Netanya S.] Univ Texas Med Branch, Div Infect Dis, Dept Internal Med, 301 Univ Blvd,Rte 0435, Galveston, TX 77555 USA. [Phanuphak, Nittaya; Fletcher, James L.; Ananworanich, Jintanat] Thai Red Cross AIDS Res Ctr, SEARCH, Bangkok, Thailand. [O'Connell, Robert J.] US Army Med Component, Dept Retrovirol, Armed Forces Res Inst Med Sci, Bangkok, Thailand. [Chomont, Nicolas] Univ Montreal, CHUM, Ctr Rech, Montreal, PQ H3C 3J7, Canada. [Chomont, Nicolas] Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ H3C 3J7, Canada. [Kim, Jerome H.] SNU Res Pk, Int Vaccine Inst, Seoul, South Korea. RP Utay, NS (reprint author), Univ Texas Med Branch, Div Infect Dis, Dept Internal Med, 301 Univ Blvd,Rte 0435, Galveston, TX 77555 USA. EM neutay@utmb.edu FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; Henry M. Jackson Foundation for the Advancement of Military Medicine [W81XWH-11-2-0174]; US Department of Defense [W81XWH-11-2-0174]; National Institutes of Health [R01MH095613, R01NS061696]; Government Pharmaceutical Organization (GPO), Thailand; Gilead; Merck; ViiV Healthcare FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; by a cooperative agreement (W81XWH-11-2-0174) between The Henry M. Jackson Foundation for the Advancement of Military Medicine and the US Department of Defense; and by the National Institutes of Health (grants R01MH095613 and R01NS061696 to SEARCH 010 and SEARCH 011, respectively). The Government Pharmaceutical Organization (GPO), Thailand, Gilead, Merck and ViiV Healthcare provided support for antiretroviral medications. NR 33 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JAN 15 PY 2017 VL 64 IS 2 BP 124 EP 131 DI 10.1093/cid/ciw683 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP1GB UT WOS:000397132300009 PM 27737952 ER PT J AU Rosenke, K Adjemian, J Munster, VJ Strong, JE Sprecher, A Feldmann, H de Wit, E AF Rosenke, Kyle Adjemian, Jennifer Munster, Vincent J. Strong, James E. Sprecher, Armand Feldmann, Heinz de Wit, Emmie TI Is Plasmodium Species Parasitemia Really Associated With Increased Survival in Ebola Virus-Infected Patients? SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Rosenke, Kyle; Munster, Vincent J.; Feldmann, Heinz; de Wit, Emmie] NIAID, Lab Virol, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Adjemian, Jennifer] NIAID, Epidemiol Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Adjemian, Jennifer] US PHS, Commissioned Corps, Rockville, MD USA. [Strong, James E.] Publ Hlth Agcy Canada, Special Pathogens Program, Winnipeg, MB, Canada. [Sprecher, Armand] Medecins Sans Frontieres, Operat Ctr Brussels, Brussels, Belgium. RP de Wit, E (reprint author), 903 South 4th St, Hamilton, MT 59840 USA. EM emmie.dewit@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JAN 15 PY 2017 VL 64 IS 2 BP 231 EP + PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP1GB UT WOS:000397132300032 ER PT J AU Rosenke, K Adjemian, J Munster, VJ Strong, JE Sprecher, A Feldmann, H de Wit, E AF Rosenke, Kyle Adjemian, Jennifer Munster, Vincent J. Strong, James E. Sprecher, Armand Feldmann, Heinz de Wit, Emmie TI Is Plasmodium Species Parasitemia Really Associated With Increased Survival in Ebola Virus-Infected Patients? Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Rosenke, Kyle; Munster, Vincent J.; Feldmann, Heinz; de Wit, Emmie] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Adjemian, Jennifer] NIAID, Epidemiol Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Adjemian, Jennifer] US PHS, Commissioned Corps, Rockville, MD USA. [Strong, James E.] Publ Hlth Agcy Canada, Special Pathogens Program, Winnipeg, MB, Canada. [Sprecher, Armand] Medecins Sans Frontieres, Operat Ctr Brussels, Brussels, Belgium. RP de Wit, E (reprint author), 903 South 4th St, Hamilton, MT 59840 USA. EM emmie.dewit@nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JAN 15 PY 2017 VL 64 IS 2 BP 232 EP 232 DI 10.1093/cid/ciw734 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP1GB UT WOS:000397132300034 PM 27986680 ER PT J AU Jensen, RE Moinpour, CM Potosky, AL Lobo, T Hahn, EA Hays, RD Cella, D Smith, AW Wu, XC Keegan, THM Paddock, LE Stroup, AM Eton, DT AF Jensen, Roxanne E. Moinpour, Carol M. Potosky, Arnold L. Lobo, Tania Hahn, Elizabeth A. Hays, Ron D. Cella, David Smith, Ashley Wilder Wu, Xiao-Cheng Keegan, Theresa H. M. Paddock, Lisa E. Stroup, Antoinette M. Eton, David T. TI Responsiveness of 8 Patient-Reported Outcomes Measurement Information System (PROMIS) Measures in a Large, Community-Based Cancer Study Cohort SO CANCER LA English DT Article DE oncology; patient-reported outcomes; responsiveness; validation studies ID MINIMALLY IMPORTANT DIFFERENCES; COOPERATIVE-ONCOLOGY-GROUP; FUNCTIONAL ASSESSMENT; MEANINGFUL CHANGE; VALIDATION; VALIDITY AB BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) was a National Institutes of Health-funded initiative to develop measures of symptoms and function. Responsiveness is the degree to which a measure can detect underlying changes over time. The objective of the current study was to document the responsiveness of 8 PROMIS measures in a large, population-based cancer cohort. METHODS: The Measuring Your Health study recruited 2968 patients who were diagnosed with 1 of 7 cancers between 2010 and 2012 through 4 Surveillance, Epidemiology, and End Results registries. Participants completed a baseline survey (6-13 months after diagnosis) and a 6-month follow-up survey. Changes in 8 PROMIS scores were compared with global ratings of transition, changes in performance status, and clinical events. RESULTS: Measures were responsive to 6-month declines and improvements in performance status with small to large effect sizes (ES) (Cohen d=0.34-0.71; P<.01). Mean changes and effect sizes were larger for participants who reported declines compared with those who reported improvements. Small-to-medium ES were observed in patients who reported being "a little" worse (d=0.31-0.56), and medium-to-large ES were observed in those who reported being "a lot" worse (d=0.53-0.72). Hospitalized participants reported significant score increases, resulting in worsening of pain (d=0.51), fatigue (d=0.35), and depression (d=0.57; all P<.01). Cancer recurrence and progression were associated with smaller increases in pain, fatigue, and sleep disturbance (d=0.22-0.27). CONCLUSIONS: The current results indicated that all 8 PROMIS measures were sensitive to patient-perceived worsening and improvement and to major clinical events. These findings will be able to inform the design and interpretation of future research studies and clinical initiatives administering PROMIS measures. (C) 2016 American Cancer Society. C1 [Jensen, Roxanne E.; Potosky, Arnold L.] Georgetown Univ, Dept Oncol, Washington, DC USA. [Jensen, Roxanne E.; Potosky, Arnold L.; Lobo, Tania] Lombardi Comprehens Canc Ctr, Canc Prevent & Control Program, Washington, DC USA. [Moinpour, Carol M.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Hahn, Elizabeth A.; Cella, David] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Hays, Ron D.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Smith, Ashley Wilder] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Wu, Xiao-Cheng] Lousiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, Louisiana Tumor Registry, New Orleans, LA USA. [Keegan, Theresa H. M.] Univ Calif Davis, Sch Med, Div Hematol & Oncol, Dept Internal Med, Sacramento, CA 95817 USA. [Paddock, Lisa E.; Stroup, Antoinette M.] New Jersey Dept Hlth, Canc Epidemiol Serv, Trenton, NJ USA. [Paddock, Lisa E.] Rutgers Sch Publ Hlth, New Brunswick, NJ USA. [Paddock, Lisa E.] Canc Inst New Jersey, New Brunswick, NJ USA. [Eton, David T.] Mayo Clin, Div Hlth Care Policy & Res, Dept Hlth Sci Res, Rochester, MN USA. RP Jensen, RE (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Canc Prevent & Control Program, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM rj222@georgetown.edu FU National Institutes of Health (NIH) [U01 AR057971, P30 CA051008]; National Center for Research Resources; National Center for Advancing Translational Sciences; NIH through the Clinical and Translational Science Awards Program [KL2 TR000102] FX This work was supported by grants from the National Institutes of Health (NIH) (U01 AR057971 [to R.E.J., T.L., A.L.P, and C.M.M.] and P30 CA051008 [to R.E.J., T.L., and A.L.P.]); the National Center for Research Resources, the National Center for Advancing Translational Sciences, and the NIH through the Clinical and Translational Science Awards Program (KL2 TR000102 [to R.E.J.]) NR 24 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JAN 15 PY 2017 VL 123 IS 2 BP 327 EP 335 DI 10.1002/cncr.30354 PG 9 WC Oncology SC Oncology GA EL6GU UT WOS:000394719200020 PM 27696377 ER PT J AU Halpern, MT Urato, MP Kent, EE AF Halpern, Michael T. Urato, Matthew P. Kent, Erin E. TI The Health Care Experience of Patients With Cancer During the Last Year of Life: Analysis of the SEER-CAHPS Data Set SO CANCER LA English DT Article DE cancer; Consumer Assessment of Healthcare Providers and Systems (CAHPS); Medicare; patient satisfaction; Surveillance, Epidemiology and End Results (SEER); surveys ID FEE-FOR-SERVICE; QUALITY-OF-CARE; PALLIATIVE CARE; ONCOLOGY CARE; END; MEDICARE; OUTCOMES; PLANS; CHEMOTHERAPY; SATISFACTION AB BACKGROUND: Providing high-quality medical care for individuals with cancer during their last year of life involves a range of challenges. An important component of high-quality care during this critical period is ensuring optimal patient satisfaction. The objective of the current study was to assess factors influencing health care ratings among individuals with cancer within 1 year before death. METHODS: The current study used the Surveillance, Epidemiology, and End Results (SEER)-Consumer Assessment of Healthcare Providers and Systems (CAHPS) data set, a new data resource linking patient-reported information from the CAHPS Medicare Survey with clinical information from the National Cancer Institute's SEER program. The study included 5102 Medicare beneficiaries diagnosed with cancer who completed CAHPS between 1998 and 2011 within 1 year before their death. Multivariable logistic regression analyses examined associations between patient demographic and insurance characteristics with 9 measures of health care experience. RESULTS: Patients with higher general or mental health status were significantly more likely to indicate excellent experience with nearly all measures examined. Sex, race/ethnicity, and education also were found to be significant predictors for certain ratings. Greater time before death predicted an increased likelihood of higher ratings for health plan and specialist physician. Clinical characteristics were found to have few significant associations with experience of care. Individuals in fee-for-service Medicare plans (vs Medicare Advantage) had a greater likelihood of excellent experience with health plans, getting care quickly, and getting needed care. CONCLUSIONS: Among patients with cancer within 1 year before death, experience with health plans, physicians, and medical care were found to be associated with sociodemographic, insurance, and clinical characteristics. These findings provide guidance for the development of programs to improve the experience of care among individuals with cancer. (C) 2016 American Cancer Society. C1 [Halpern, Michael T.; Urato, Matthew P.] RTI Int, Res Triangle Pk, NC USA. [Halpern, Michael T.] Temple Univ, Coll Publ Hlth, Dept Hlth Serv Adm & Policy, Ritter Annex 533,1301 Cecil B Moore Ave, Philadelphia, PA 19122 USA. [Kent, Erin E.] NCI, Outcomes Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. RP Halpern, MT (reprint author), Temple Univ, Coll Publ Hlth, Dept Hlth Serv Adm & Policy, Ritter Annex 533,1301 Cecil B Moore Ave, Philadelphia, PA 19122 USA. EM michael.halpern@temple.edu OI Halpern, Michael/0000-0001-8514-6313 FU National Cancer Institute [HHSN261201000166U, HHSN261201500132U] FX Funded by a research contract from the National Cancer Institute (contract number HHSN261201000166U and HHSN261201500132U). NR 33 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JAN 15 PY 2017 VL 123 IS 2 BP 336 EP 344 DI 10.1002/cncr.30319 PG 9 WC Oncology SC Oncology GA EL6GU UT WOS:000394719200021 PM 27654842 ER PT J AU Hasumi, H Hasumi, Y Baba, M Nishi, H Furuya, M Vocke, CD Lang, M Irie, N Esumi, C Merino, MJ Kawahara, T Isono, Y Makiyama, K Warner, AC Haines, DC Wei, MH Zbar, B Hagenau, H Feigenbaum, L Kondo, K Nakaigawa, N Yao, M Metwalli, AR Linehan, WM Schmidt, LS AF Hasumi, Hisashi Hasumi, Yukiko Baba, Masaya Nishi, Hafumi Furuya, Mitsuko Vocke, Cathy D. Lang, Martin Irie, Nobuko Esumi, Chiharu Merino, Maria J. Kawahara, Takashi Isono, Yasuhiro Makiyama, Kazuhide Warner, Andrew C. Haines, Diana C. Wei, Ming-Hui Zbar, Berton Hagenau, Herbert Feigenbaum, Lionel Kondo, Keiichi Nakaigawa, Noboru Yao, Masahiro Metwalli, Adam R. Linehan, W. Marston Schmidt, Laura S. TI H255Y and K508R missense mutations in tumour suppressor folliculin (FLCN) promote kidney cell proliferation SO HUMAN MOLECULAR GENETICS LA English DT Article ID BIRT-HOGG-DUBE; BHD GENE; MTOR ACTIVATION; RENAL TUMORS; PROTEIN; FNIP1; TUMORIGENESIS; INACTIVATION; ROLES; AMPK AB Germline H255Y and K508R missense mutations in the folliculin (FLCN) gene have been identified in patients with bilateral multifocal (BMF) kidney tumours and clinical manifestations of Birt-Hogg-Dube (BHD) syndrome, or with BMF kidney tumours as the only manifestation; however, their impact on FLCN function remains to be determined. In order to determine if FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation leading to pathogenicity, we generated mouse models expressing these mutants using BAC recombineering technology and investigated their ability to rescue the multi-cystic phenotype of Flcn-deficient mouse kidneys. Flcn H255Y mutant transgene expression in kidney-targeted Flcn knockout mice did not rescue the multi-cystic kidney phenotype. However, expression of the Flcn K508R mutant transgene partially, but not completely, abrogated the phenotype. Notably, expression of the Flcn K508R mutant transgene in heterozygous Flcn knockout mice resulted in development of multi-cystic kidneys and cardiac hypertrophy in some mice. These results demonstrate that both FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation, but to different degrees. Based on the phenotypes of our preclinical models, the FLCN H255Y mutant protein has lost it tumour suppressive function leading to the clinical manifestations of BHD, whereas the FLCN K508R mutant protein may have a dominant negative effect on the function of wild-type FLCN in regulating kidney cell proliferation and, therefore, act as an oncoprotein. These findings may provide mechanistic insight into the role of FLCN in regulating kidney cell proliferation and facilitate the development of novel therapeutics for FLCN-deficient kidney cancer. C1 [Hasumi, Hisashi; Hasumi, Yukiko; Baba, Masaya; Vocke, Cathy D.; Lang, Martin; Wei, Ming-Hui; Zbar, Berton; Metwalli, Adam R.; Linehan, W. Marston; Schmidt, Laura S.] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hasumi, Hisashi; Kawahara, Takashi; Makiyama, Kazuhide; Kondo, Keiichi; Nakaigawa, Noboru; Yao, Masahiro] Yokohama City Univ, Dept Urol & Mol Genet, Yokohama, Kanagawa, Japan. [Baba, Masaya; Irie, Nobuko; Esumi, Chiharu] Kumamoto Univ, Int Res Ctr Med Sci, Kumamoto, Japan. [Nishi, Hafumi] Tohoku Univ, Dept Appl Informat Sci, Sendai, Miyagi, Japan. [Furuya, Mitsuko] Yokohama City Univ, Dept Mol Pathol, Yokohama, Kanagawa, Japan. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Warner, Andrew C.; Haines, Diana C.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Pathol Histotechnol Lab, Frederick, MD USA. [Hagenau, Herbert; Feigenbaum, Lionel] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Lab Anim Sci Program, Frederick, MD USA. [Schmidt, Laura S.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Basic Sci Program, Frederick, MD USA. [Isono, Yasuhiro] Yokohama City Univ, Dept Otorhinolaryngol Head & Neck Surg, Yokohama, Kanagawa, Japan. RP Schmidt, LS (reprint author), NCI, Urol Oncol Branch, NIH, Bldg 10 CRC Room 1W-3961,10 Ctr Dr MSC 1107, Bethesda, MD 20892 USA. EM schmidtl@mail.nih.gov FU Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001 E]; JSPS KAKENHI [15604475, 15551829]; Fondazione Italiana Ricerca sul Cancro, 'Fellowship For Abroad' FX This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under Contract HHSN261200800001 E. (LSS) M.B. was supported by JSPS KAKENHI Grant Number 15604475 and 15551829. M.L. was supported by an annual outbound fellowship from Fondazione Italiana Ricerca sul Cancro, 'Fellowship For Abroad 2011'. NR 31 TC 0 Z9 0 U1 0 U2 0 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 JAN 15 PY 2017 VL 26 IS 2 BP 354 EP 366 DI 10.1093/hmg/ddw392 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EP0GX UT WOS:000397066400010 PM 28007907 ER PT J AU Springelkamp, H Iglesias, AI Mishra, A Hohn, R Wojciechowski, R Khawaja, AP Nag, A Wang, YX Wang, JJ Cuellar-Partida, G Gibson, J Bailey, JNC Vithana, EN Gharahkhani, P Boutin, T Ramdas, WD Zeller, T Luben, RN Yonova-Doing, E Viswanathan, AC Yazar, S Cree, AJ Haines, JL Koh, JY Souzeau, E Wilson, JF Amin, N Muller, C Venturini, C Kearns, LS Kang, JH Tham, YC Zhou, T van Leeuwen, EM Nickels, S Sanfilippo, P Liao, JM van der Linde, H Zhao, WT van Koolwijk, LME Zheng, L Rivadeneira, F Baskaran, M van der Lee, SJ Perera, S de Jong, PTVM Oostra, BA Uitterlinden, AG Fan, Q Hofman, A Tai, ES Vingerling, JR Sim, XL Wolfs, RCW Teo, YY Lemij, HG Khor, CC Willemsen, R Lackner, KJ Aung, T Jansonius, NM Montgomery, G Wild, PS Young, TL Burdon, KP Hysi, PG Pasquale, LR Wong, TY Klaver, CCW Hewitt, AW Jonas, JB Mitchell, P Lotery, AJ Foster, PJ Vitart, V Pfeiffer, N Craig, JE Mackey, DA Hammond, CJ Wiggs, JL Cheng, CY van Duijn, CM MacGregor, S AF Springelkamp, Henriet Iglesias, Adriana I. Mishra, Aniket Hoehn, Rene Wojciechowski, Robert Khawaja, Anthony P. Nag, Abhishek Wang, Ya Xing Wang, Jie Jin Cuellar-Partida, Gabriel Gibson, Jane Bailey, Jessica N. Cooke Vithana, Eranga N. Gharahkhani, Puya Boutin, Thibaud Ramdas, Wishal D. Zeller, Tanja Luben, Robert N. Yonova-Doing, Ekaterina Viswanathan, Ananth C. Yazar, Seyhan Cree, Angela J. Haines, Jonathan L. Koh, Jia Yu Souzeau, Emmanuelle Wilson, James F. Amin, Najaf Mueller, Christian Venturini, Cristina Kearns, Lisa S. Kang, Jae Hee Tham, Yih Chung Zhou, Tiger van Leeuwen, Elisabeth M. Nickels, Stefan Sanfilippo, Paul Liao, Jiemin van der Linde, Herma Zhao, Wanting van Koolwijk, Leonieke M. E. Zheng, Li Rivadeneira, Fernando Baskaran, Mani van der Lee, Sven J. Perera, Shamira de Jong, Paulus T. V. M. Oostra, Ben A. Uitterlinden, Andre G. Fan, Qiao Hofman, Albert Tai, E-Shyong Vingerling, Johannes R. Sim, Xueling Wolfs, Roger C. W. Teo, Yik Ying Lemij, Hans G. Khor, Chiea Chuen Willemsen, Rob Lackner, Karl J. Aung, Tin Jansonius, Nomdo M. Montgomery, Grant Wild, Philipp S. Young, Terri L. Burdon, Kathryn P. Hysi, Pirro G. Pasquale, Louis R. Wong, Tien Yin Klaver, Caroline C. W. Hewitt, Alex W. Jonas, Jost B. Mitchell, Paul Lotery, Andrew J. Foster, Paul J. Vitart, Veronique Pfeiffer, Norbert Craig, Jamie E. Mackey, David A. Hammond, Christopher J. Wiggs, Janey L. Cheng, Ching-Yu van Duijn, Cornelia M. MacGregor, Stuart CA NEIGHBORHOOD Consortium TI New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; POPULATION-BASED EPIDEMIOLOGY; SUSCEPTIBILITY LOCI; COMMON VARIANTS; IDENTIFIES 5; RISK; PROSTATE; PROTEIN; CANCER; P53 AB Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk. C1 [Springelkamp, Henriet; van Koolwijk, Leonieke M. E.; Rivadeneira, Fernando; van der Lee, Sven J.; Uitterlinden, Andre G.; Hofman, Albert; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Springelkamp, Henriet; Ramdas, Wishal D.; Vingerling, Johannes R.; Wolfs, Roger C. W.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Iglesias, Adriana I.; Oostra, Ben A.; Willemsen, Rob] Erasmus MC, Dept Clin Sci, Rotterdam, Netherlands. [Mishra, Aniket; Cuellar-Partida, Gabriel; Gharahkhani, Puya; MacGregor, Stuart] Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Stat Genet, Brisbane, Qld, Australia. [Mishra, Aniket] Vrije Univ Amsterdam, Ctr Neurogenom & Cognit Res, Dept Complex Trait Genet, Amsterdam, Netherlands. [Hoehn, Rene] Univ Bern, Univ Hosp Bern, Inselspital, Dept Ophthalmol, Bern, Switzerland. [Hoehn, Rene; Nickels, Stefan; Pfeiffer, Norbert] Univ Med Ctr Mainz, Dept Ophthalmol, Mainz, Germany. [Wojciechowski, Robert] Natl Human Genome Res Inst NIH, Computat & Stat Genom Branch, Baltimore, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wojciechowski, Robert] Johns Hopkins Sch Med, Wilmer Eye Inst, Baltimore, MD USA. [Khawaja, Anthony P.; Viswanathan, Ananth C.; Foster, Paul J.] Moorfields Eye Hosp NHS Fdn Trust, NIHR Biomed Res Ctr, London, England. [Khawaja, Anthony P.; Viswanathan, Ananth C.; Foster, Paul J.] UCL, Inst Ophthalmol, London, England. [Nag, Abhishek; Yonova-Doing, Ekaterina; Hammond, Christopher J.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Wang, Ya Xing] Capital Med Univ, Beijing Tongren Hosp, Beijing Tongren Eye Ctr, Beijing Inst Ophthalmol, Beijing, Peoples R China. [Wang, Ya Xing] Beijing Ophthalmol & Visual Sci Key Lab, Beijing, Peoples R China. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Ctr Vis Res, Dept Ophthalmol, Sydney, NSW, Australia. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia. [Gibson, Jane] Univ Southampton, Fac Nat & Environm Sci, Ctr Biol Sci, Southampton, Hants, England. [Bailey, Jessica N. Cooke; Haines, Jonathan L.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Vithana, Eranga N.; Koh, Jia Yu; Tham, Yih Chung; Liao, Jiemin; Zhao, Wanting; Zheng, Li; Baskaran, Mani; Perera, Shamira; Fan, Qiao; Khor, Chiea Chuen; Aung, Tin; Wong, Tien Yin; Cheng, Ching-Yu] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Zhao, Wanting; Perera, Shamira; Tai, E-Shyong] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. [Vithana, Eranga N.; Tham, Yih Chung; Liao, Jiemin; Baskaran, Mani; Aung, Tin; Wong, Tien Yin; Cheng, Ching-Yu] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore. [Boutin, Thibaud; Wilson, James F.; Vitart, Veronique] Univ Edinburgh, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland. [Zeller, Tanja; Mueller, Christian] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany. [Zeller, Tanja; Mueller, Christian] German Ctr Cardiovasc Res DZHK, Partner Site Hamburg, Hamburg, Germany. [Luben, Robert N.] Univ Cambridge, Sch Clin Med, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge, England. [Yazar, Seyhan; Sanfilippo, Paul; Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA, Australia. [Cree, Angela J.; Lotery, Andrew J.] Univ Southampton, Fac Med, Clin & Expt Sci, Southampton, Hants, England. [Souzeau, Emmanuelle; Zhou, Tiger; Craig, Jamie E.] Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA, Australia. [Wilson, James F.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh EH8 9YL, Midlothian, Scotland. [Kearns, Lisa S.; Sanfilippo, Paul; Hewitt, Alex W.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Kang, Jae Hee; Pasquale, Louis R.] Brigham & Womens Hosp, Dept Med, Div Network Med, Boston, MA USA. [Zheng, Li; Khor, Chiea Chuen] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.; Hofman, Albert] Netherlands Genom Initiat, Netherlands Consortium Healthy Ageing, The Hague, Netherlands. [de Jong, Paulus T. V. M.] Acad Med Ctr, Dept Ophthalmol, Amsterdam, Netherlands. Leiden Univ, Med Ctr, Dept Ophthalmol, Leiden, Netherlands. [de Jong, Paulus T. V. M.] Netherlands Inst Neurosci KNAW, Amsterdam, Netherlands. [Tai, E-Shyong] Natl Univ Singapore, Dept Med, Singapore, Singapore. [Tai, E-Shyong] Natl Univ Hlth Syst, Singapore, Singapore. [Tai, E-Shyong; Sim, Xueling; Teo, Yik Ying] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Tai, E-Shyong; Sim, Xueling; Teo, Yik Ying] Natl Univ Hlth Syst, Singapore, Singapore. [Teo, Yik Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore. [Lemij, Hans G.] Rotterdam Eye Hosp, Glaucoma Serv, Rotterdam, Netherlands. [Khor, Chiea Chuen] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore. [Lackner, Karl J.] Univ Med Ctr Mainz, Inst Clin Chem, Mainz, Germany. [Lackner, Karl J.] Univ Med Ctr Mainz, Lab Med, Mainz, Germany. [Jansonius, Nomdo M.] Univ Groningen, Univ Med Ctr Groningen, Dept Ophthalmol, Groningen, Netherlands. [Montgomery, Grant] Queensland Inst Med Res, Dept Mol Epidemiol, Brisbane, Qld, Australia. [Wild, Philipp S.] Univ Med Ctr Mainz, Prevent Cardiol & Prevent Med Ctr Cardiol, Mainz, Germany. Univ Med Ctr Mainz, Ctr Thrombosis & Hemostasis, Mainz, Germany. [Wild, Philipp S.] German Ctr Cardiovasc Res DZHK, Partner Site RhineMain, Mainz, Germany. [Young, Terri L.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Burdon, Kathryn P.; Hewitt, Alex W.; Mackey, David A.] Univ Tasmania, Menzies Res Inst Tasmania, Sch Med, Hobart, Tas, Australia. [Pasquale, Louis R.; Wiggs, Janey L.] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. [Pasquale, Louis R.; Wiggs, Janey L.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Heidelberg, Germany. RP MacGregor, S (reprint author), Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Stuart MacGregor Stat Genet, Brisbane, Qld, Australia. EM Stuart.MacGregor@qimrberghofer.edu.au RI Mackey, David/H-5340-2014 OI Mackey, David/0000-0001-7914-4709 FU National Institutes of Health/National Eye Institute (NIH/NEI) [1R01EY018246-01]; NIH/NEI [R01 EY014685]; Research to Prevent Blindness, Inc.; University of Wisconsin School of Medicine and Public Health Centennial Scholars Fund; Australian National Health & Medical Research Council (NH&MRC), Canberra Australia [974159, 211069, 457349, 512423, 475604, 529912]; Centre for Clinical Research Excellence (Translational Clinical Research in Major Eye Diseases) [519923]; NH&MRC research fellowships [358702, 632909]; Wellcome Trust, UK as part of Wellcome Trust Case Control Consortium 2 [085475/B/08/Z, 085475/Z/08/Z, 076113]; UK and Eire Glaucoma Society; International Glaucoma Association; Royal College of Ophthalmologists; National Institutes of Health [NIH R01 EY022305]; NEI [K08EY022943]; MRC HGU "QTL in Health and Disease" core programme FX Terri L. Young, MD, MBA is supported by National Institutes of Health/National Eye Institute (NIH/NEI) 1R01EY018246-01, NIH/NEI R01 EY014685, Research to Prevent Blindness, Inc. and The University of Wisconsin School of Medicine and Public Health Centennial Scholars Fund.; Blue Mountains Eye Study was supported by the Australian National Health & Medical Research Council (NH&MRC), Canberra Australia (974159, 211069, 457349, 512423, 475604, 529912); the Centre for Clinical Research Excellence (Translational Clinical Research in Major Eye Diseases, 519923); NH&MRC research fellowships (358702, 632909 to J.J.W); and the Wellcome Trust, UK as part of Wellcome Trust Case Control Consortium 2 (A. Viswanathan, P. McGuffin, P. Mitchell, F. Topouzis, P. Foster) for genotyping costs of the entire BMES population (085475/B/08/Z, 085475/Z/08/Z, 076113).; The Southampton acknowledges funding from the UK and Eire Glaucoma Society and the International Glaucoma Association (in association with the Royal College of Ophthalmologists). EY015473 (LRP) supported generation of the cohort at risk for POAG in Nurses Health Study (NHS, UM1 CA186107) and Health Professionals Followup Study (HPFS, UM1 CA167552).; HG004728 (LRP) supported genotyping in a subset of the Neighborhood consortium, specifically NHS, HPFS and Massachusetts Eye and Ear Infirmary (MEEI) cases and controls. We acknowledge funding from National Institutes of Health NIH R01 EY022305 (JLW) and NEI grant K08EY022943 (RW).; Genetic analyses for the Orkney Complex Disease Study (ORCADES) were supported by the MRC HGU "QTL in Health and Disease" core programme. NR 72 TC 0 Z9 0 U1 1 U2 1 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 JAN 15 PY 2017 VL 26 IS 2 BP 438 EP 453 DI 10.1093/hmg/ddw399 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EP0GX UT WOS:000397066400017 PM 28073927 ER PT J AU Seow, WJ Matsuo, K Hsiung, CA Shiraishi, K Song, MS Kim, HN Wong, MP Hong, YC Hosgood, HD Wang, ZM Chang, IS Wang, JC Chatterjee, N Tucker, M Wei, H Mitsudomi, T Zheng, W Kim, JH Zhou, BS Caporaso, NE Albanes, D Shin, MH Chung, LP An, SJ Wang, P Zheng, H Yatabe, Y Zhang, XC Kim, YT Shu, XO Kim, YC Bassig, BA Chang, J Ho, JCM Ji, BT Kubo, M Daigo, Y Ito, H Momozawa, Y Ashikawa, K Kamatani, Y Honda, T Sakamoto, H Kunitoh, H Tsuta, K Watanabe, SI Nokihara, H Miyagi, Y Nakayama, H Matsumoto, S Tsuboi, M Goto, K Yin, ZH Shi, JX Takahashi, A Goto, A Minamiya, Y Shimizu, K Tanaka, K Wu, TC Wei, FS Wong, JYY Matsuda, F Su, J Kim, YH Oh, IJ Song, FJ Lee, VHF Su, WC Chen, YM Chang, GC Chen, KY Huang, MS Yang, PC Lin, HC Xiang, YB Seow, A Park, JY Kweon, SS Chen, CJ Li, HX Gao, YT Wu, C Qian, BY Lu, DR Liu, JJ Jeon, HS Hsiao, CF Sung, JS Tsai, YH Jung, YJ Guo, H Hu, ZB Wang, WC Chung, CC Lawrence, C Burdett, L Yeager, M Jacobs, KB Hutchinson, A Berndt, SI He, XZ Wu, W Wang, JW Li, YQ Choi, JE Park, KH Sung, SW Liu, L Kang, CH Hu, LM Chen, CH Yang, TY Xu, J Guan, P Tan, W Wang, CL Sihoe, ADL Chen, Y Choi, YY Hung, JY Kim, JS Yoon, HI Cai, QY Lin, CC Park, IK Xu, P Dong, J Kim, C He, QC Perng, RP Chen, CY Vermeulen, R Wu, JJ Lim, WY Chen, KC Chan, JKC Chu, MJ Li, YJ Li, JH Chen, HY Yu, CJ Jin, L Lo, YL Chen, YH Fraumeni, JF Liu, J Yamaji, T Yang, Y Hicks, B Wyatt, K Li, SA Dai, JC Ma, HX Jin, GF Song, B Wang, ZH Cheng, SS Li, XL Ren, YW Cui, P Iwasaki, M Shimazu, T Tsugane, S Zhu, JJ Jiang, GN Fei, K Wu, GP Chien, LH Chen, HL Su, YC Tsai, FY Chen, YS Yu, JM Stevens, VL Laird-Offringa, IA Marconett, CN Lin, DX Chen, KX Wu, YL Landi, MT Shen, HB Rothman, N Kohno, T Chanock, SJ Lan, Q AF Seow, Wei Jie Matsuo, Keitaro Hsiung, Chao Agnes Shiraishi, Kouya Song, Minsun Kim, Hee Nam Wong, Maria Pik Hong, Yun-Chul Hosgood, H. Dean, III Wang, Zhaoming Chang, I-Shou Wang, Jiu-Cun Chatterjee, Nilanjan Tucker, Margaret Wei, Hu Mitsudomi, Tetsuya Zheng, Wei Kim, Jin Hee Zhou, Baosen Caporaso, Neil E. Albanes, Demetrius Shin, Min-Ho Chung, Lap Ping An, She-Juan Wang, Ping Zheng, Hong Yatabe, Yasushi Zhang, Xu-Chao Kim, Young Tae Shu, Xiao-Ou Kim, Young-Chul Bassig, Bryan A. Chang, Jiang Ho, James Chung Man Ji, Bu-Tian Kubo, Michiaki Daigo, Yataro Ito, Hidemi Momozawa, Yukihide Ashikawa, Kyota Kamatani, Yoichiro Honda, Takayuki Sakamoto, Hiromi Kunitoh, Hideo Tsuta, Koji Watanabe, Shun-Ichi Nokihara, Hiroshi Miyagi, Yohei Nakayama, Haruhiko Matsumoto, Shingo Tsuboi, Masahiro Goto, Koichi Yin, Zhihua Shi, Jianxin Takahashi, Atsushi Goto, Akiteru Minamiya, Yoshihiro Shimizu, Kimihiro Tanaka, Kazumi Wu, Tangchun Wei, Fusheng Wong, Jason Y. Y. Matsuda, Fumihiko Su, Jian Kim, Yeul Hong Oh, In-Jae Song, Fengju Lee, Victor Ho Fun Su, Wu-Chou Chen, Yuh-Min Chang, Gee-Chen Chen, Kuan-Yu Huang, Ming-Shyan Yang, Pan-Chyr Lin, Hsien-Chih Xiang, Yong-Bing Seow, Adeline Park, Jae Yong Kweon, Sun-Seog Chen, Chien-Jen Li, Haixin Gao, Yu-Tang Wu, Chen Qian, Biyun Lu, Daru Liu, Jianjun Jeon, Hyo-Sung Hsiao, Chin-Fu Sung, Jae Sook Tsai, Ying-Huang Jung, Yoo Jin Guo, Huan Hu, Zhibin Wang, Wen-Chang Chung, Charles C. Lawrence, Charles Burdett, Laurie Yeager, Meredith Jacobs, Kevin B. Hutchinson, Amy Berndt, Sonja I. He, Xingzhou Wu, Wei Wang, Junwen Li, Yuqing Choi, Jin Eun Park, Kyong Hwa Sung, Sook Whan Liu, Li Kang, Chang Hyun Hu, Lingmin Chen, Chung-Hsing Yang, Tsung-Ying Xu, Jun Guan, Peng Tan, Wen Wang, Chih-Liang Sihoe, Alan Dart Loon Chen, Ying Choi, Yi Young Hung, Jen-Yu Kim, Jun Suk Yoon, Ho-Il Cai, Qiuyin Lin, Chien-Chung Park, In Kyu Xu, Ping Dong, Jing Kim, Christopher He, Qincheng Perng, Reury-Perng Chen, Chih-Yi Vermeulen, Roel Wu, Junjie Lim, Wei-Yen Chen, Kun-Chieh Chan, John K. C. Chu, Minjie Li, Yao-Jen Li, Jihua Chen, Hongyan Yu, Chong-Jen Jin, Li Lo, Yen-Li Chen, Ying-Hsiang Fraumeni, Joseph F., Jr. Liu, Jie Yamaji, Taiki Yang, Yang Hicks, Belynda Wyatt, Kathleen Li, Shengchao A. Dai, Juncheng Ma, Hongxia Jin, Guangfu Song, Bao Wang, Zhehai Cheng, Sensen Li, Xuelian Ren, Yangwu Cui, Ping Iwasaki, Motoki Shimazu, Taichi Tsugane, Shoichiro Zhu, Junjie Jiang, Gening Fei, Ke Wu, Guoping Chien, Li-Hsin Chen, Hui-Ling Su, Yu-Chun Tsai, Fang-Yu Chen, Yi-Song Yu, Jinming Stevens, Victoria L. Laird-Offringa, Ite A. Marconett, Crystal N. Lin, Dongxin Chen, Kexin Wu, Yi-Long Landi, Maria Teresa Shen, Hongbing Rothman, Nathaniel Kohno, Takashi Chanock, Stephen J. Lan, Qing TI Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations SO HUMAN MOLECULAR GENETICS LA English DT Article ID GROWTH-FACTOR-RECEPTOR; GENOME-WIDE ASSOCIATION; CANCER RISK; JAPANESE POPULATION; BIOPSY SPECIMENS; GENETIC-VARIANTS; POLYMORPHISMS; METAANALYSIS; CHINESE; 15Q25 AB To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 X 10(-8)), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications. C1 [Seow, Wei Jie; Song, Minsun; Wang, Zhaoming; Chatterjee, Nilanjan; Tucker, Margaret; Wei, Hu; Caporaso, Neil E.; Albanes, Demetrius; Bassig, Bryan A.; Ji, Bu-Tian; Shi, Jianxin; Wong, Jason Y. Y.; Chung, Charles C.; Burdett, Laurie; Yeager, Meredith; Jacobs, Kevin B.; Hutchinson, Amy; Berndt, Sonja I.; Kim, Christopher; Fraumeni, Joseph F., Jr.; Hicks, Belynda; Wyatt, Kathleen; Li, Shengchao A.; Landi, Maria Teresa; Rothman, Nathaniel; Chanock, Stephen J.; Lan, Qing] NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Seow, Wei Jie; Seow, Adeline; Liu, Jianjun; Chen, Ying] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Matsuo, Keitaro] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan. [Hsiung, Chao Agnes; Lin, Hsien-Chih; Hsiao, Chin-Fu; Lo, Yen-Li; Chen, Ying-Hsiang; Chien, Li-Hsin; Chen, Hui-Ling; Su, Yu-Chun; Chen, Yi-Song] Natl Hlth Res Inst, Inst Populat Hlth Sci, Zhunan, Taiwan. [Shiraishi, Kouya; Honda, Takayuki; Kohno, Takashi] Natl Canc Ctr, Div Genome Biol, Tokyo, Japan. [Song, Minsun] Sookmyung Womens Univ, Dept Stat, Seoul, South Korea. [Kim, Hee Nam; Shin, Min-Ho; Kweon, Sun-Seog] Chonnam Natl Univ, Sch Med, Dept Prevent Med, Gwangju, South Korea. [Wong, Maria Pik; Chung, Lap Ping] Univ Hong Kong, Queen Mary Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Hosgood, H. Dean, III] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Wang, Zhaoming] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale, Memphis, TN 38105 USA. [Hong, Yun-Chul; Chang, I-Shou; Chen, Chung-Hsing; Tsai, Fang-Yu] Natl Hlth Res Inst, Natl Inst Canc Res, Zhunan, Taiwan. [Wang, Jiu-Cun; Lu, Daru; Wu, Junjie; Chen, Hongyan; Jin, Li] Fudan Univ, Sch Life Sci, Minist Educ, Key Lab Contemporary Anthropol, Shanghai, Peoples R China. [Wang, Jiu-Cun; Lu, Daru; Wu, Junjie; Chen, Hongyan; Jin, Li] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai, Peoples R China. [Mitsudomi, Tetsuya] Kinki Univ, Sch Med, Div Thorac Surg, Sayama, Osaka, Japan. [Zheng, Wei; Shu, Xiao-Ou; Cai, Qiuyin] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Zheng, Wei; Shu, Xiao-Ou; Cai, Qiuyin] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Kim, Jin Hee] Sejong Univ, Dept Integrat Biosci & Biotechnol, Seoul, South Korea. [Zhou, Baosen; Yin, Zhihua; Wu, Wei; Guan, Peng; He, Qincheng; Li, Xuelian; Ren, Yangwu] China Med Univ, Sch Publ Hlth, Dept Epidemiol, Shenyang, Peoples R China. [An, She-Juan; Zhang, Xu-Chao; Su, Jian; Wu, Yi-Long] Guangdong Acad Med Sci, Guangdong Gen Hosp, Med Res Ctr, Guangdong Lung Canc Inst, Guangzhou, Guangdong, Peoples R China. [An, She-Juan; Zhang, Xu-Chao; Su, Jian; Wu, Yi-Long] Guangdong Acad Med Sci, Guangdong Gen Hosp, Ctr Canc, Guangzhou, Guangdong, Peoples R China. [Wang, Ping] Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Key Lab Canc Prevent & Therapy, Dept Radiotherapy, Tianjin, Peoples R China. [Zheng, Hong; Song, Fengju; Li, Haixin; Qian, Biyun; Hutchinson, Amy; Cui, Ping; Chen, Kexin] Tianjin Med Univ Canc Inst & Hosp, Dept Epidemiol & Biostat, Tianjin, Peoples R China. [Yatabe, Yasushi] Aichi Canc Ctr, Dept Pathol & Mol Diagnost, Cent Hosp, Nagoya, Aichi, Japan. [Kim, Young Tae; Jung, Yoo Jin; Kang, Chang Hyun; Park, In Kyu] Seoul Natl Univ, Coll Med, Canc Res Inst, Dept Thorac & Cardiovasc Surg, Seoul, South Korea. [Kim, Young-Chul; Oh, In-Jae] Chonnam Natl Univ, Hwasun Hosp, Lung & Esophageal Canc Clin, Hwasun Eup, South Korea. [Kim, Young-Chul; Oh, In-Jae] Chonnam Natl Univ, Sch Med, Dept Internal Med, Gwangju, South Korea. [Chang, Jiang] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Etiol & Carcinogenesis, Beijing, Peoples R China. [Chang, Jiang] Peking Union Med Coll, Beijing, Peoples R China. [Ho, James Chung Man] Univ Hong Kong, Dept Med, Queen Mary Hosp, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China. [Kubo, Michiaki; Momozawa, Yukihide; Ashikawa, Kyota] RIKEN, Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa, Japan. [Daigo, Yataro] Univ Tokyo, Inst Med Sci, Res Hosp, Ctr Antibody & Vaccine Therapy, Tokyo, Japan. [Daigo, Yataro] Shiga Univ Med Sci, Ctr Canc, Otsu, Shiga, Japan. [Ito, Hidemi] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Kamatani, Yoichiro; Takahashi, Atsushi] RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan. [Sakamoto, Hiromi] Natl Canc Ctr, Res Inst, Div Genet, Tokyo, Japan. [Kunitoh, Hideo] Japanese Red Cross Med Ctr, Dept Med Oncol, Tokyo, Japan. [Tsuta, Koji] Natl Canc Ctr, Dept Pathol, Tokyo, Japan. [Watanabe, Shun-Ichi] Natl Canc Ctr, Div Thorac Surg, Tokyo, Japan. [Nokihara, Hiroshi] Natl Canc Ctr, Dept Thorac Oncol, Tokyo, Japan. [Miyagi, Yohei] Kanagawa Canc Ctr Res Inst, Mol Pathol & Genet Div, Kanagawa, Japan. [Nakayama, Haruhiko] Kanagawa Canc Ctr, Dept Thorac Surg, Kanagawa, Japan. [Matsumoto, Shingo] Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr EPOC, Div Translat Res, Kashiwa, Chiba, Japan. [Tsuboi, Masahiro] Natl Canc Ctr Hosp East, Dept Thorac Surg, Kashiwa, Chiba, Japan. [Goto, Koichi] Natl Canc Ctr Hosp East, Dept Thorac Oncol, Kashiwa, Chiba, Japan. [Goto, Akiteru] Akita Univ, Grad Sch Med, Dept Cellular & Organ Pathol, Akita, Japan. [Goto, Akiteru] Akita Univ, Grad Sch Med, Dept Thorac Surg, Akita, Japan. [Shimizu, Kimihiro; Tanaka, Kazumi] Gunma Univ Hosp, Dept Integrat Ctr Gen Surg, Gunma, Japan. [Wu, Tangchun; Guo, Huan] Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Occupat & Environm Hlth, Wuhan, Peoples R China. [Wu, Tangchun; Guo, Huan] Huazhong Univ Sci & Technol, Tongji Med Coll, Minist Educ, Key Lab Environm & Hlth, Wuhan, Peoples R China. [Wei, Fusheng; Wu, Guoping] China Natl Environm Monitoring Ctr, Beijing, Peoples R China. [Matsuda, Fumihiko] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto, Japan. [Kim, Yeul Hong; Sung, Jae Sook; Park, Kyong Hwa] Korea Univ, Anam Hosp, Coll Med, Dept Internal Med,Div Oncol Hematol, Seoul, South Korea. [Lee, Victor Ho Fun] Univ Hong Kong, Queen Mary Hosp, Dept Clin Oncol, Hong Kong, Hong Kong, Peoples R China. [Su, Wu-Chou; Lin, Chien-Chung] Natl Cheng Kung Univ, Coll Med, Natl Cheng Kung Univ Hosp, Dept Internal Med, Tainan, Taiwan. [Chen, Yuh-Min] Taipei Vet Gen Hosp, Dept Chest Med, Taipei, Taiwan. [Chen, Yuh-Min] Taipei Med Univ, Coll Med Sci & Technol, Taipei, Taiwan. [Chang, Gee-Chen] Natl Yang Ming Univ, Fac Med, Sch Med, Taipei, Taiwan. [Chang, Gee-Chen; Yang, Tsung-Ying; Chen, Kun-Chieh] Taichung Vet Gen Hosp, Dept Internal Med, Div Chest Med, Taichung, Taiwan. [Chen, Kuan-Yu] Natl Taiwan Univ, Natl Taiwan Univ Hosp, Dept Internal Med, Div Pulm Med, Taipei, Taiwan. [Chen, Kuan-Yu] Natl Taiwan Univ, Coll Med, Taipei, Taiwan. [Huang, Ming-Shyan; Hung, Jen-Yu] Kaohsiung Med Univ, Sch Med, Kaohsiung Med Univ Hosp, Dept Internal Med, Kaohsiung, Taiwan. [Yang, Pan-Chyr; Yu, Chong-Jen] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan. [Xiang, Yong-Bing; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Park, Jae Yong] Kyungpook Natl Univ, Med Ctr, Lung Canc Ctr, Daegu, South Korea. [Chen, Chien-Jen; Li, Yao-Jen] Acad Sinica, Genom Res Ctr, Taipei, Taiwan. [Wu, Chen; Tan, Wen; Lin, Dongxin] Chinese Acad Med Sci, Dept Etiol & Carcinogenesis, Beijing, Peoples R China. [Wu, Chen; Tan, Wen; Lin, Dongxin] Chinese Acad Med Sci, Canc Inst & Hosp, State Key Lab Mol Oncol, Beijing, Peoples R China. [Wu, Chen; Tan, Wen; Lin, Dongxin] Peking Union Med Coll, Beijing, Peoples R China. [Liu, Jianjun] Genome Inst Singapore, Dept Human Genet, Singapore, Singapore. [Liu, Jianjun] Anhui Med Univ, Sch Life Sci, Hefei, Peoples R China. [Jeon, Hyo-Sung; Choi, Jin Eun; Choi, Yi Young] Kyungpook Natl Univ, Med Ctr, Canc Res Ctr, Daegu, South Korea. [Tsai, Ying-Huang] Chiayi Chang Gung Mem Hosp, Div Pulm & Crit Care Med, Chiayi, Taiwan. [Hu, Zhibin; Dai, Juncheng; Ma, Hongxia; Jin, Guangfu; Shen, Hongbing] Nanjing Med Univ, Sch Publ Hlth, Collaborat Innovat Ctr Canc Personalized Med, Dept Epidemiol & Biostat,Jiangsu Key Lab Canc Bio, Nanjing, Peoples R China. [Wang, Wen-Chang] Taipei Med Univ, Coll Med Sci & Technol, Program Translat Med, Taipei, Taiwan. [Chung, Charles C.; Burdett, Laurie; Yeager, Meredith; Jacobs, Kevin B.; Hutchinson, Amy; Hicks, Belynda; Wyatt, Kathleen; Li, Shengchao A.] Leidos Biomed Res Inc, Canc Genom Res Lab, Gaithersburg, MD USA. [Lawrence, Charles] Westat Corp, Rockville, MD USA. [He, Xingzhou] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. [Wang, Junwen] Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ USA. [Wang, Junwen] Mayo Clin, Ctr Individualized Med, Scottsdale, AZ USA. [Sung, Sook Whan] Catholic Univ Korea, Seoul St Marys Hosp, Dept Thorac & Cardiovasc Surg, Seoul, South Korea. [Liu, Li] Huazhong Univ Sci & Technol, Union Hosp, Ctr Canc, Dept Oncol, Wuhan, Peoples R China. [Hu, Lingmin; Dong, Jing; Chu, Minjie] Nanjing Med Univ, Minist Educ, Key Lab Modern Toxicol, Nanjing, Peoples R China. [Hu, Lingmin; Dong, Jing; Chu, Minjie] Nanjing Med Univ, Jiangsu Key Lab Canc Biomarkers Prevent & Treat, Nanjing, Peoples R China. [Xu, Jun] Univ Hong Kong, Fac Med, Li Ka Shing, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. [Guan, Peng; Li, Xuelian; Ren, Yangwu] Univ Liaoning Prov, Key Lab Canc Etiol & Intervent, Shenyang, Peoples R China. [Kweon, Sun-Seog] Chonnam Natl Univ Hwasun, Hwasun Hosp, Jeonnam Reg Canc Ctr, Hwasun, South Korea. [Wang, Chih-Liang] Chang Gung Mem Hosp, Dept Pulm & Crit Care, Taoyuan, Taiwan. [Sihoe, Alan Dart Loon] Univ Hong Kong, Fac Med, Li Ka Shing, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Kim, Jun Suk] Korea Univ Guro Hosp, Coll Med, Dept Internal Med, Div Med Oncol, Seoul, South Korea. [Yoon, Ho-Il] Seoul Natl Univ, Bundang Hosp, Dept Internal Med, Seongnam, South Korea. [Xu, Ping] Staff Worker Hosp, Wuhan Iron & Steel Grp Corp, Dept Oncol, Wuhan, Peoples R China. [Perng, Reury-Perng] Taipei Vet Gen Hosp, Chest Dept, Taipei, Taiwan. [Chen, Chih-Yi] Chung Shan Med Univ, Inst Med, Taichung, Taiwan. [Chen, Chih-Yi] Chung Shan Med Univ Hosp, Dept Surg, Div Thorac Surg, Taichung, Taiwan. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, Utrecht, Netherlands. [Lim, Wei-Yen] Agcy Integrated Care, Singapore, Singapore. [Chan, John K. C.] Queen Elizabeth Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Li, Jihua] Qujing Ctr Dis Control & Prevent, Qujing, Peoples R China. [Liu, Jie; Song, Bao; Wang, Zhehai; Cheng, Sensen; Yu, Jinming] Shandong Acad Med Sci, Shandong Canc Hosp & Inst, Dept Oncol, Jinan, Peoples R China. [Yamaji, Taiki; Iwasaki, Motoki; Shimazu, Taichi; Tsugane, Shoichiro] Natl Canc Ctr, Ctr Publ Hlth Sci, Epidemiol & Prevent Grp, Tokyo, Japan. [Yang, Yang; Zhu, Junjie; Jiang, Gening; Fei, Ke] Shanghai Pulm Hosp, Shanghai, Peoples R China. [Stevens, Victoria L.] Amer Canc Soc, Lab Serv, Atlanta, GA 30329 USA. [Laird-Offringa, Ite A.; Marconett, Crystal N.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Surg,Dept Biochem & Mol Med, Los Angeles, CA 90033 USA. [Shen, Hongbing] Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol, Nanjing, Peoples R China. [Li, Yuqing] Canc Prevent Inst Calif, Fremont, CA USA. RP Seow, WJ (reprint author), Tahir Fdn Bldg,12 Sci Dr 2,09-01H, Singapore 117549, Singapore. EM ephswj@nus.edu.sg RI Jin, Li/C-1468-2009 OI Jin, Li/0000-0002-4546-2415 FU Ministry of Education, Science, Sports, Culture and Technology of Japan; Ministry Health, Labor and Welfare of Japan; Health and Labor Sciences Research Grants for Research on Applying Health Technology from the Ministry of Health, Labor and Welfare of Japan; National Cancer Center Research and Development Fund; National Research Foundation of Korea (NRF) grant - Korea government (MEST) [2011-0016106]; National Project for Personalized Genomic Medicine, Ministry for Health & Welfare, Republic of Korea [A111218-11-GM04]; Program for Changjiang Scholars and Innovative Research Team in University in China [IRT_14R40]; National Science & Technology Pillar Program [2011BAI09B00]; MOE 111 Project [B13016]; National Natural Science Foundation of China [30772531, 81272618, 81272293, 81102194]; Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine [2012A061400006]; Special Fund for Research in the Public Interest from the National Health and Family Planning Commission of PRC [201402031]; Ministry of Science and Technology, Taiwan [MOST 103-2325-B-400-023, 104-2325-B-400-012]; Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development [15ck0106096h0002]; Management Expenses Grants from the Government to the National Cancer Center for Biobank [26-A-1]; Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government; National Cancer Center Research and Development Fund [23-A-31[toku], 26-A-2]; Ministry of Health, Labour and Welfare of Japan; National Research Program on Genomic Medicine in Taiwan [DOH99-TD-G-111-028]; National Research Program for Biopharmaceuticals in Taiwan [MOST 103-2325-B-400-023, MOHW 103-TDUPB-211-144003]; Bioinformatics Core Facility for Translational Medicine and Biotechnology Development [MOST 104-2319-B-400-002]; Jinan Science Research Project Foundation [201102051]; National Key Scientific and Technological Project [2011ZX09307-001-04]; State Key Program of National Natural Science of China [81230067]; National Research Foundation of Korea (NRF) grant - Korea government (MSIP) [NRF-2014R1A2A2A05003665]; Sookmyung Women's University Research Grants, Korea [1-1603-2048]; Agency for Science, Technology and Research (A*STAR), Singapore; US National Institute of Health [1U19CA148127-01]; intramural program of the US National Institutes of Health/National Cancer Institute; National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea [0720550-2, A010250]; National Key Basic Research and Development Program [2011CB503800]; Liaoning Provincial Department of Education [LS2010168]; China Medical Board [00726]; Foundation of Guangdong Science and Technology Department [2006B60101010, 2007A032000002, 2011A030400010]; Guangzhou Science and Information Technology Bureau [2011Y2-00014]; Chinese Lung Cancer Research Foundation; Natural Science Foundation of Guangdong Province [S2011010000792]; Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT), China [IRT1076]; Tianjin Cancer Institute and Hospital; National Foundation for Cancer Research (US); Ministry of Health [201002007]; Ministry of Science and Technology [2011BAI09B00]; National S&T Major Special Project [2011ZX09102-010-01]; China National High-Tech Research and Development Program [2012AA02A517, 2012AA02A518]; National Science Foundation of China [30890034]; National Basic Research Program [2012CB944600]; Scientific and Technological Support Plans from Jiangsu Province [BE2010715]; China National High-Tech Research and Development Program Grant [2009AA022705]; Priority Academic Program Development of Jiangsu Higher Education Institution; National Key Basic Research Program Grant [2011CB503805]; National Medical Research Council Singapore grant [NMRC/0897/2004, NMRC/1075/2006]; Agency for Science, Technology and Research (A*STAR) of Singapore; National Science Council, Taiwan [NSC 100-2319-B-400-001]; National Institutes of Health [R37 CA70867]; National Cancer Institute intramural research program, including NCI Intramural Research Program [N02 CP1101066]; Ministry of Health, Labor, and Welfare for Research on Applying Health Technology; Ministry of Education, Science, Sports, Culture and - Technology of Japan; NCI [R01-CA121210, NO1-CN-25514, NO1-CN-25522, NO1-CN-25515, NO1-CN-25512, NO1-CN25513, NO1-CN-25516, NO1-CN-25511, NO1-CN25524, NO1-CN25518, NO1-CN75022, NO1-CN-25476, NO1-CN-25404]; General Research Fund of Research Grant Council, Hong Kong [781511M]; Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics; U.S. Public Health Service from the NCI [N01-CN-45165, N01-RC-45035, N01-RC-37004]; NIH Genes, Environment and Health Initiative (GEI) [HG-06-033-NCI-01, RO1HL091172-01] FX This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry Health, Labor and Welfare of Japan, by Health and Labor Sciences Research Grants for Research on Applying Health Technology from the Ministry of Health, Labor and Welfare of Japan, by the National Cancer Center Research and Development Fund, the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (grant No. 2011-0016106), a grant of the National Project for Personalized Genomic Medicine, Ministry for Health & Welfare, Republic of Korea (A111218-11-GM04), the Program for Changjiang Scholars and Innovative Research Team in University in China (IRT_14R40 to K.C.), the National Science & Technology Pillar Program (2011BAI09B00), MOE 111 Project (B13016), the National Natural Science Foundation of China (No. 30772531, and 81272618), Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine (No. 2012A061400006), Special Fund for Research in the Public Interest from the National Health and Family Planning Commission of PRC (No. 201402031), and the Ministry of Science and Technology, Taiwan (MOST 103-2325-B-400-023 & 104-2325-B-400-012). The Japan Lung Cancer Study (JLCS) was supported in part by the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development (15ck0106096h0002) and the Management Expenses Grants from the Government to the National Cancer Center (26-A-1) for Biobank. BioBank Japan was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government. The Japan Public Health Center-based prospective Study (the JPHC Study) was supported by the National Cancer Center Research and Development Fund (23-A-31[toku] and 26-A-2) (since 2011) and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010). The Taiwan GELAC Study (Genetic Epidemiological Study for Lung AdenoCarcinoma) was supported by grants from the National Research Program on Genomic Medicine in Taiwan (DOH99-TD-G-111-028), the National Research Program for Biopharmaceuticals in Taiwan (MOHW 103-TDUPB-211-144003, MOST 103-2325-B-400-023) and the Bioinformatics Core Facility for Translational Medicine and Biotechnology Development (MOST 104-2319-B-400-002). This work was also supported by the Jinan Science Research Project Foundation (201102051), the National Key Scientific and Technological Project (2011ZX09307-001-04), the National Natural Science Foundation of China (No. 81272293), the State Key Program of National Natural Science of China (81230067), the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. NRF-2014R1A2A2A05003665), Sookmyung Women's University Research Grants, Korea (1-1603-2048), Agency for Science, Technology and Research (A*STAR), Singapore and the US National Institute of Health Grant (1U19CA148127-01).; The overall GWAS project was supported by the intramural program of the US National Institutes of Health/National Cancer Institute. The following is a list of grants by study center: SKLCS (Y.T.K.)-National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2011-0016106). (J.C.) This work was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (grant no. 0720550-2). (J.S.S) -grant number is A010250. WLCS (T.W.)-National Key Basic Research and Development Program (2011CB503800). SLCS (B.Z.)-National Nature Science Foundation of China (81102194). Liaoning Provincial Department of Education (LS2010168). China Medical Board (00726). GDS (Y.L.W.)-Foundation of Guangdong Science and Technology Department (2006B60101010, 2007A032000002, 2011A030400010). Guangzhou Science and Information Technology Bureau (2011Y2-00014). Chinese Lung Cancer Research Foundation, National Natural Science Foundation of China (81101549). Natural Science Foundation of Guangdong Province (S2011010000792). TLCS (K.C., B.Q)-Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT), China (IRT1076). Tianjin Cancer Institute and Hospital. National Foundation for Cancer Research (US). FLCS (J.C.W., D.R., L.J.)-Ministry of Health (201002007). Ministry of Science and Technology (2011BAI09B00). National S&T Major Special Project (2011ZX09102-010-01). China National High-Tech Research and Development Program (2012AA02A517, 2012AA02A518). National Science Foundation of China (30890034). National Basic Research Program (2012CB944600). Scientific and Technological Support Plans from Jiangsu Province (BE2010715). NLCS (H.S.)-China National High-Tech Research and Development Program Grant (2009AA022705). Priority Academic Program Development of Jiangsu Higher Education Institution. National Key Basic Research Program Grant (2011CB503805). GEL-S (A.S.)-National Medical Research Council Singapore grant (NMRC/0897/2004, NMRC/1075/2006). (J. Liu)-Agency for Science, Technology and Research (A*STAR) of Singapore. GELAC (C.A.H.)-National Research Program on Genomic Medicine in Taiwan (DOH98-TDG-111-015). National Research Program for Biopharmaceuticals in Taiwan (DOH 100-TD-PB-111-TM013). National Science Council, Taiwan (NSC 100-2319-B-400-001). YLCS (Q.L.)-Supported by the intramural program of U.S. National Institutes of Health, National Cancer Institute. SWHS (W.Z., W-H.C., N.R.)-The work was supported by a grant from the National Institutes of Health (R37 CA70867) and the National Cancer Institute intramural research program, including NCI Intramural Research Program contract (N02 CP1101066). JLCS (K.M., T.K.)-Grants-in-Aid from the Ministry of Health, Labor, and Welfare for Research on Applying Health Technology and for the 3rd-term Comprehensive 10-year Strategy for Cancer Control; by the National Cancer Center Research and Development Fund; by Grant-in-Aid for Scientific Research on Priority Areas and on Innovative Area from the Ministry of Education, Science, Sports, Culture and - Technology of Japan. (W.P.)-NCI R01-CA121210. HKS (J.W.)-General Research Fund of Research Grant Council, Hong Kong (781511M).; The Environment and Genetics in Lung Cancer Etiology (EAGLE), Prostate, Lung, Colon, Ovary Screening Trial (PLCO), and Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) studies were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics. ATBC was also supported by U.S. Public Health Service contracts (N01-CN-45165, N01-RC-45035, and N01-RC-37004) from the NCI. PLCO was also supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University (NO1-CN-25522), the Pacific Health Research Institute (NO1-CN-25515), the Henry Ford Health System (NO1-CN-25512), the University of Minnesota, (NO1-CN25513), Washington University (NO1-CN-25516), the University of Pittsburgh (NO1-CN-25511), the University of Utah (NO1-CN25524), the Marshfield Clinic Research Foundation (NO1-CN25518), the University of Alabama at Birmingham (NO1-CN75022), Westat, Inc. (NO1-CN-25476), and the University of California, Los Angeles (NO1-CN-25404). The Cancer Prevention Study-II (CPS-II) Nutrition Cohort was supported by the American Cancer Society. The NIH Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research. NR 55 TC 0 Z9 0 U1 2 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 JAN 15 PY 2017 VL 26 IS 2 BP 454 EP 465 DI 10.1093/hmg/ddw414 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EP0GX UT WOS:000397066400018 PM 28025329 ER PT J AU Han, SY Ko, A Kitano, H Choi, CH Lee, MS Seo, J Fukuoka, J Kim, SY Hewitt, SM Chung, JY Song, J AF Han, Su Yeon Ko, Aram Kitano, Haruhisa Choi, Chel Hun Lee, Min-Sik Seo, Jinho Fukuoka, Junya Kim, Soo-Youl Hewitt, Stephen M. Chung, Joon-Yong Song, Jaewhan TI Molecular Chaperone HSP90 Is Necessary to Prevent Cellular Senescence via Lysosomal Degradation of p14ARF SO CANCER RESEARCH LA English DT Article ID HEAT-SHOCK-PROTEIN; LUNG-CANCER; MEDIATED AUTOPHAGY; TUMOR-SUPPRESSOR; QUALITY-CONTROL; COMPLEX; GELDANAMYCIN; DESTABILIZATION; ACTIVATION; INHIBITORS AB The tumor suppressor function of p14ARF is regulated at a posttranslational level via mechanisms yet to be fully understood. Here, we report the identification of an unconventional p14ARF degradation pathway induced by the chaperone HSP90 in association with the E3 ubiquitin ligase C-terminus of HSP70-interacting protein (CHIP). The ternary complex of HSP90, CHIP, and p14ARF was required to induce the lysosomal degradation of p14ARF by an ubiquitination-independent but LAMP2A-dependent mechanism. Depletion of HSP90 or CHIP induced p14ARF-dependent senescence in human fibroblasts. Premature senescence observed in cells genetically deficient in CHIP was rescued in cells that were doubly deficient in CHIP and p14ARF. Notably, non-small cell lung cancer cells (NSCLC) positive for p14ARF were sensitive to treatment with the HSP90 inhibitor geldanamycin. Furthermore, overexpression of HSP90 and CHIP with a concomitant loss of p14ARF correlated with poor prognosis in patients with NSCLC. Our findings identify a relationship between p14ARF and its chaperones that suggest new therapeutic strategies in cancers that overexpress HSP90. (C) 2016 AACR. C1 [Han, Su Yeon; Ko, Aram; Lee, Min-Sik; Seo, Jinho; Song, Jaewhan] Yonsei Univ, Dept Biochem, Coll Life Sci & Biotechnol, Seoul, South Korea. [Kitano, Haruhisa; Choi, Chel Hun; Hewitt, Stephen M.; Chung, Joon-Yong] NCI, Expt Pathol Lab, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Kitano, Haruhisa] Shiga Univ Med Sci, Dept Thorac Surg, Otsu, Shiga, Japan. [Choi, Chel Hun] Sungkyunkwan Univ, Dept Obstet & Gynecol, Samsung Med Ctr, Sch Med, Seoul, South Korea. [Fukuoka, Junya] Nagasaki Univ, Dept Pathol, Grad Sch Biomed Sci, Nagasaki, Japan. [Kim, Soo-Youl] Natl Canc Ctr, Res Inst, Div Canc Biol, Canc Cell & Mol Biol, Goyang, South Korea. RP Song, J (reprint author), Yonsei Univ, Dept Biochem, Seoul 120749, South Korea. EM jso678@yonsei.ac.kr FU Basic Science Research Program of the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning [2014R1A1A1002589]; Creative Research Initiative Program of NRF - Ministry of Science, ICT and Future Planning [2015R1A3A2066581]; National Cancer Center, Korea [NCC-1420300] FX This work was supported by grants from the Basic Science Research Program of the National Research Foundation of Korea (NRF; 2014R1A1A1002589 to S. Han and A. Ko) and Creative Research Initiative Program of NRF (2015R1A3A2066581 to J. Song) funded by the Ministry of Science, ICT and Future Planning, and from the National Cancer Center, Korea (NCC-1420300 to J. Song). NR 50 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2017 VL 77 IS 2 BP 343 EP 354 DI 10.1158/0008-5472.CAN-16-0613 PG 12 WC Oncology SC Oncology GA EJ4MF UT WOS:000393190600014 PM 27793846 ER PT J AU Chmielecki, J Bailey, M He, J Elvin, J Vergilio, JA Ramkissoon, S Suh, J Frampton, GM Sun, JX Morley, S Spritz, D Ali, S Gay, L Erlich, RL Ross, JS Buxhaku, J Davies, H Faso, V Germain, A Glanville, B Miller, VA Stephens, PJ Janeway, KA Maris, JM Meshinchi, S Pugh, TJ Shern, JF Lipson, D AF Chmielecki, Juliann Bailey, Mark He, Jie Elvin, Julia Vergilio, Jo-Anne Ramkissoon, Shakti Suh, James Frampton, Garrett M. Sun, James X. Morley, Samantha Spritz, Daniel Ali, Siraj Gay, Laurie Erlich, Rachel L. Ross, Jeffrey S. Buxhaku, Joana Davies, Hilary Faso, Vinny Germain, Alexis Glanville, Blair Miller, Vincent A. Stephens, Philip J. Janeway, Katherine A. Maris, John M. Meshinchi, Soheil Pugh, Trevor J. Shern, Jack F. Lipson, Doron TI Genomic Profiling of a Large Set of Diverse Pediatric Cancers Identifies Known and Novel Mutations across Tumor Spectra SO CANCER RESEARCH LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; CHILDRENS ONCOLOGY GROUP; PROGNOSTIC-SIGNIFICANCE; CHILDHOOD-AML; WIDE ANALYSIS; LUNG-CANCER; FUSION; FLT3 AB Pediatric cancers are generally characterized by low mutational burden and few recurrently mutated genes. Recent studies suggest that genomic alterations may help guide treatment decisions and clinical trial selection. Here, we describe genomic profiles from 1,215 pediatric tumors representing sarcomas, extracranial embryonal tumors, brain tumors, hematologic malignancies, carcinomas, and gonadal tumors. Comparable published datasets identified similar frequencies of clinically relevant alterations, validating this dataset as biologically relevant. We identified novel ALK fusions in a neuroblastoma (BEND5-ALK) and an astrocytoma (PPP1CB-ALK), novel BRAF fusions in an astrocytoma (BCAS1-BRAF) and a ganglioglioma (TMEM106B-BRAF), and a novel PAX3-GLI2 fusion in a rhabdomyosarcoma. Previously characterized ALK, NTRK1, and PAX3 fusions were observed in unexpected malignancies, challenging the "disease-specific" alterations paradigm. Finally, we identified recurrent variants of unknown significance in MLL3 and PRSS1 predicted to have functional impact. Data from these 1,215 tumors are publicly available for discovery and validation. (C) 2017 AACR. C1 [Chmielecki, Juliann; Bailey, Mark; He, Jie; Elvin, Julia; Vergilio, Jo-Anne; Ramkissoon, Shakti; Suh, James; Frampton, Garrett M.; Sun, James X.; Morley, Samantha; Spritz, Daniel; Ali, Siraj; Gay, Laurie; Erlich, Rachel L.; Ross, Jeffrey S.; Buxhaku, Joana; Davies, Hilary; Faso, Vinny; Germain, Alexis; Glanville, Blair; Miller, Vincent A.; Stephens, Philip J.; Lipson, Doron] Fdn Med, 150 Second St,1st Floor, Cambridge, MA 02141 USA. [Ross, Jeffrey S.] Albany Med Coll, Albany, NY 12208 USA. [Janeway, Katherine A.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Janeway, Katherine A.] Harvard Med Sch, Pediat, Boston, MA USA. [Maris, John M.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Maris, John M.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. [Maris, John M.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Meshinchi, Soheil] Univ Washington, Fred Hutchinson Canc Res Ctr, Sch Med, Seattle, WA 98195 USA. [Pugh, Trevor J.] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Pugh, Trevor J.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Shern, Jack F.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lipson, D (reprint author), Fdn Med, 150 Second St,1st Floor, Cambridge, MA 02141 USA. EM dlipson@foundationmedicine.com FU Foundation Medicine FX J. Chmielecki, M. Bailey, and J.A. Elvin have ownership interest (including patents) in Foundation Medicine. S. Ramkissoon is a consultant/advisory board member for Bristol-Meyers Squibb. J. Suh has received speakers bureau honoraria from Genentech. G.M. Frampton is a scientist at and has ownership interest (including patents) in Foundation Medicine. S.M. Ali has ownership interest (including patents) in Foundation Medicine. L. Gay is a senior scientist at and has ownership interest (including patents) in Foundation Medicine. R. Erlich is Senior Director, at Biomedical Informatics and has ownership interest (including patents) in Foundation Medicine. J. S. Ross is Medical Director at and reports receiving a commercial research grant from Foundation Medicine. J. Buxhaku is client services representative at Joana Buxhaku. V. Miller is Chief Medical Officer at Foundation Medicine, Inc. P.J. Stephens is CSO at and has ownership interest (including patents) in Foundation Medicine. D. Lipson is vice president at and has ownership interest (including patents) in Foundation Medicine. No potential conflicts of interest were disclosed by the other authors. NR 50 TC 0 Z9 0 U1 0 U2 0 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 JAN 15 PY 2017 VL 77 IS 2 BP 509 EP 519 DI 10.1158/0008-5472.CAN-16-1106 PG 11 WC Oncology SC Oncology GA EJ4MF UT WOS:000393190600028 PM 28069802 ER PT J AU Del Brutto, OH Nash, TE White, AC Rajshekhar, V Wilkins, PP Singh, G Vasquez, CM Salgado, P Gilman, RH Garcia, HH AF Del Brutto, O. H. Nash, T. E. White, A. C., Jr. Rajshekhar, V. Wilkins, P. P. Singh, G. Vasquez, C. M. Salgado, P. Gilman, R. H. Garcia, H. H. TI Revised diagnostic criteria for neurocysticercosis SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Review DE Cysticercosis; Neurocysticercosis; Taenia solium; Diagnostic criteria, epilepsy, intracranial hypertension ID INTRAVENTRICULAR NEUROCYSTICERCOSIS; TAENIA-SOLIUM; ANTIPARASITIC THERAPY; BRUNS-SYNDROME; VENTRICULAR NEUROCYSTICERCOSIS; CYSTICERCUS GRANULOMA; TAPEWORM CARRIERS; COLLOID CYST; SEIZURES; EPILEPSY AB Background: A unified set of criteria for neurocysticercosis (NCC) has helped to standardize its diagnosis in different settings. Methods: Cysticercosis experts were convened to update current diagnostic criteria for NCC according to two principles: neuroimaging studies are essential for diagnosis, and all other information provides indirect evidence favoring the diagnosis. Recent diagnostic advances were incorporated to this revised set. Results: This revised set is structured in absolute, neuroimaging and clinical/exposure criteria. Absolute criteria include: histological confirmation of parasites, evidence of subretinal cysts, and demonstration of the scolex within a cyst. Neuroimaging criteria are categorized as major (cystic lesions without scolex, enhancing lesions, multilobulated cysts, and calcifications), confirmative (resolution of cysts after cysticidal drug therapy, spontaneous resolution of single enhancing lesions, and migrating ventricular cysts on sequential neuroimaging studies) and minor (hydrocephalus and leptomeningeal enhancement). Clinical/exposure criteria include: detection of anticysticercal antibodies or cysticercal antigens by well-standardized tests, systemic cysticercosis, evidence of a household Taenia carrier, suggestive clinical manifestations, and residency in endemic areas. Besides patients having absolute criteria, definitive diagnosis can be made in those having two major neuroimaging criteria (or one major plus one confirmative criteria) plus exposure. For patients presenting with one major and one minor neuroimaging criteria plus exposure, definitive diagnosis of NCC requires the exclusion of confounding pathologies. Probable diagnosis is reserved for individuals presenting with one neuroimaging criteria plus strong evidence of exposure. Conclusions: This revised set of diagnostic criteria provides simpler definitions and may facilitate its more uniform and widespread applicability in different scenarios. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Del Brutto, O. H.] Univ Espiritu Santo Ecuador, Sch Med, Guayaquil, Ecuador. [Nash, T. E.] NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [White, A. C., Jr.] Univ Texas Med Branch, Dept Internal Med, Div Infect Dis, Galveston, TX 77555 USA. [Rajshekhar, V.] Christian Med Coll & Hosp, Dept Neurol Sci, Vellore, Tamil Nadu, India. [Wilkins, P. P.] Parasitol Serv, Marathon, FL USA. [Singh, G.] Dayanand Med Coll, Dept Neurol, Ludhiana, Punjab, India. [Vasquez, C. M.] Inst Natl Ciencias Neurol, Dept Neurosurg, Lima, Peru. [Salgado, P.] Natl Inst Neurol & Neurosurg Manuel Velasco Suare, Neuroimaging Unit, Mexico City, DF, Mexico. [Gilman, R. H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Garcia, H. H.] Ctr Global Hlth, Tumbes, Peru. [Garcia, H. H.] Univ Peruana Cayetano Heredia, Sch Sci, Dept Microbiol, Lima, Peru. [Garcia, H. H.] Inst Natl Ciencias Neurol, Cysticercosis Unit, Jr Ancash 1271, Lima 1, Peru. RP Garcia, HH (reprint author), Inst Natl Ciencias Neurol, Cysticercosis Unit, Jr Ancash 1271, Lima 1, Peru. EM hgarcia@jhsph.edu FU FIC NIH HHS [D43 TW001140]; Wellcome Trust [091077] NR 73 TC 2 Z9 2 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD JAN 15 PY 2017 VL 372 BP 202 EP 210 DI 10.1016/j.jns.2016.11.045 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EJ1WZ UT WOS:000393002500040 PM 28017213 ER PT J AU Dunnick, JK Morgan, DL Elmore, SA Gerrish, K Pandiri, A Ton, TV Shockley, KR Merrick, BA AF Dunnick, J. K. Morgan, D. L. Elmore, S. A. Gerrish, K. Pandiri, A. Ton, T. V. Shockley, K. R. Merrick, B. A. TI Tetrabromobisphenol A activates the hepatic interferon pathway in rats SO TOXICOLOGY LETTERS LA English DT Article DE Tetrabromobisphenol A; Toxicogenomics; Microarray; Interferon response transcripts; Pathway analysis ID STIMULATED GENES; IMMUNE-RESPONSE; FLAME-RETARDANT; BISPHENOL-A; PROBE LEVEL; BREAST-MILK; CANCER; EXPRESSION; LIVER; METABOLISM AB Tetrabromobisphenol A (TBBPA) is a widely used flame retardant in printed circuit boards, paper, and textiles. In a two-year study, TBBPA showed evidence of uterine tumors in female Wistar-Han rats and liver and colon tumors in B6C3F1 mice. In order to gain further insight into early gene and pathway changes leading to cancer, we exposed female Wistar Han rats to TBBPA at 0, 25, 250, or 1000 mg/kg (oral gavage in corn oil, 5x/week) for 13 weeks. Because at the end of the TBBPA exposure period, there were no treatment-related effects on body weights, liver or uterus lesions, and liver and uterine organ weights were within 10% of controls, only the high dose animals were analyzed. Analysis of the hepatic and uterine transcriptomes showed TBBPA-induced changes primarily in the liver (1000 mg/kg), with 159 transcripts corresponding to 132 genes differentially expressed compared to controls (FDR = 0.05). Pathway analysis showed activation of interferon (IFN) and metabolic networks. TBBPA induced few molecular changes in the uterus. Activation of the interferon pathway in the liver occurred after 13-weeks of TBBPA exposure, and with longer term TBBPA exposure this may lead to immunomodulatory changes that contribute to carcinogenic processes. Published by Elsevier Ireland Ltd. C1 [Dunnick, J. K.] NIEHS, Toxicol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Morgan, D. L.] NIEHS, NTP Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Elmore, S. A.; Pandiri, A.; Ton, T. V.] NIEHS, Cellular & Mol Pathol, POB 12233, Res Triangle Pk, NC 27709 USA. [Gerrish, K.] NIEHS, Mol Genom Core, POB 12233, Res Triangle Pk, NC 27709 USA. [Shockley, K. R.] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Merrick, B. A.] NIEHS, Biomol Screening Branch, POB 12233, Res Triangle Pk, NC 27709 USA. RP Dunnick, JK (reprint author), NIEHS, Toxicol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM dunnickj@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX This research was supported [in part] by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. We thank M. Cesta, NIEHS, and G. Knudson, NCI for their review of this manuscript. NR 65 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 EI 1879-3169 J9 TOXICOL LETT JI Toxicol. Lett. PD JAN 15 PY 2017 VL 266 BP 32 EP 41 DI 10.1016/j.toxlet.2016.11.019 PG 10 WC Toxicology SC Toxicology GA EJ9FG UT WOS:000393531400004 PM 27914987 ER PT J AU de Wilde, AH Falzarano, D Zevenhoven-Dobbe, JC Beugeling, C Fett, C Martellaro, C Posthuma, CC Feldmann, H Perlman, S Snijder, EJ AF de Wilde, Adriaan H. Falzarano, Darryl Zevenhoven-Dobbe, Jessika C. Beugeling, Corrine Fett, Craig Martellaro, Cynthia Posthuma, Clara C. Feldmann, Heinz Perlman, Stanley Snijder, Eric J. TI Alisporivir inhibits MERS- and SARS-coronavirus replication in cell culture, but not SARS-coronavirus infection in a mouse model SO VIRUS RESEARCH LA English DT Article ID RESPIRATORY SYNDROME CORONAVIRUS; GENOTYPE 1 INFECTION; HEPATITIS-C; CYCLOSPORINE-A; IN-VITRO; CYCLOPHILIN INHIBITORS; VIRUS; RIBAVIRIN; INTERFERON; COMBINATION AB Currently, there is no registered treatment for infections with emerging zoonotic coronaviruses like SARS- and MERS-coronavirus. We here report that in cultured cells low-micromolar concentrations of alisporivir, a non-immunosuppressive cyclosporin A-analog, inhibit the replication of four different coronaviruses, including MERS- and SARS-coronavirus. Ribavirin was found to further potentiate the antiviral effect of alisporivir in these cell culture-based infection models, but this combination treatment was unable to improve the outcome of SARS-CoV infection in a mouse model. Nevertheless, our data provide a basis to further explore the potential of Cyp inhibitors as host-directed, broad-spectrum inhibitors of coronavirus replication. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). C1 [de Wilde, Adriaan H.; Zevenhoven-Dobbe, Jessika C.; Beugeling, Corrine; Posthuma, Clara C.; Snijder, Eric J.] Leiden Univ, Dept Med Microbiol, Mol Virol Lab, Med Ctr, Leiden, Netherlands. [Falzarano, Darryl; Martellaro, Cynthia; Feldmann, Heinz] NIAID, NIH, Hamilton, MT USA. [Fett, Craig; Perlman, Stanley] Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. RP de Wilde, AH; Snijder, EJ (reprint author), Leiden Univ, Dept Med Microbiol, Mol Virol Lab, Med Ctr, Leiden, Netherlands. EM A.H.de_Wilde@lumc.nl; E.J.Snijder@lumc.nl FU Council for Chemical Sciences (CW) of the Netherlands Organization for Scientific Research (NWO) through TOP grant [700.57.301]; Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Disease (NIAID); Novartis (Basel, Switzerland) FX We thank Dr. Frauke Fischer, Dr. Nikolai Naoumov (Novartis, Switzerland) and Dr. Gregoire Vuagniaux (DebioPharm, Switzerland) for helpful discussions and providing alisporivir. We thank Dr. Michael Cooper and Coljames Cummings (Global Emerging Infections Surveillance and Response Systems, Armed Forces Health Surveillance Branch, Silver Spring, MD, USA) and the Naval Medical Research Unit-3 in Cairo, Egypt, for providing MERS-CoV isolate N3/Jordan, Dr. Ron Fouchier (Erasmus Medical Center Rotterdam, The Netherlands) for sharing MERS-CoV isolate EMC/2012, and Dr. Luis Enjuanes, National Center of Biotechnology (CNB-CSIC), Spain) for providing SARS-CoV strain MA-15. We are grateful to Dr. Pieter Hiemstra (Dept. of Pulmonology, LUMC) for sharing HAE cell cultures, to Renate Verhoosel, Dennis Ninaber, and Diede Oudshoorn for technical assistance. We thank Dr. Dirk Jochmans and Dr. Johan Neyts (KU Leuven, Belgium) for helpful discussions. This research was supported in part by the Council for Chemical Sciences (CW) of the Netherlands Organization for Scientific Research (NWO) through TOP grant 700.57.301, as well as by the Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Disease (NIAID) and Novartis (Basel, Switzerland). All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee at the University of Iowa. NR 44 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD JAN 15 PY 2017 VL 228 BP 7 EP 13 DI 10.1016/j.virusres.2016.11.011 PG 7 WC Virology SC Virology GA EJ2CR UT WOS:000393018000002 PM 27840112 ER PT J AU Pavana, RK Choudhary, S Bastian, A Ihnat, MA Bai, R Hamel, E Gangjee, A AF Pavana, Roheeth Kumar Choudhary, Shruti Bastian, Anja Ihnat, Michael A. Bai, Ruoli Hamel, Ernest Gangjee, Aleem TI Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo [3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple -acting angiokinase inhibition as antitumor agents SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Antiangiogenic; Combination chemotherapy; Receptor tyrosine kinase inhibitors; Multitargeted agents; Microtubule targeting agents ID RECEPTOR TYROSINE KINASE; CELL LUNG-CANCER; ENDOTHELIAL GROWTH-FACTOR; BREAST-CANCER; COLCHICINE SITE; ANGIOGENESIS INHIBITOR; ANTIANGIOGENIC AGENTS; BIOLOGICAL EVALUATION; TUMOR HETEROGENEITY; DRUG-RESISTANCE AB The utility of cytostatic antiangiogenic agents (AA) in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of AA with microtubule targeting agents (MTAs) have been particularly successful. The discovery, synthesis and biological evaluations of a series of 7-benzyl-N-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds which inhibit proangiogenic receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor-beta (PDGFR-beta) and epidermal growth factor receptor (EGFR), along with microtubule targeting in single molecules are described. These compounds also inhibited blood vessel formation in the chicken chorioallantoic membrane (CAM) assay, and some potently inhibited tubulin assembly (with activity comparable to that of combretastatin A-4 (CA)). In addition, some of the analogs circumvent the most clinically relevant tumor resistance mechanisms (P-glycoprotein and beta-III tubulin expression) to microtubule targeting agents (MTA). These MTAs bind at the colchicine site on tubulin. Two analogs displayed two to three digit nanomolar GI(50) values across the entire NCI 60 tumor cell panel and one of these, compound 7, freely water soluble as its HCI salt, afforded excellent in vivo antitumor activity against an orthotopic triple negative 4T1 breast cancer model and was superior to doxorubicin. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Pavana, Roheeth Kumar; Choudhary, Shruti; Gangjee, Aleem] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA. [Bastian, Anja] Univ Oklahoma, Coll Med, Dept Physiol, Oklahoma City, OK 73104 USA. [Ihnat, Michael A.] Univ Oklahoma, Dept Pharmaceut Sci, Coll Pharm, Oklahoma City, OK 73117 USA. [Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. RP Gangjee, A (reprint author), Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA. EM gangjee@duq.edu RI Pavana, Roheeth/F-5839-2017 OI Pavana, Roheeth/0000-0001-6256-3683 FU National Institutes of Health; NCI [CA136944, CA142868]; NSF [NMR: CHE 0614785]; Duquesne University Adrian Van Kaam Chair in Scholarly Excellence FX We gratefully acknowledge the NCI for performing the in vitro antitumor evaluation in their 60 tumor cell line panel. This work was supported, in part, by the National Institutes of Health and NCI grants CA136944 (A.G.) and CA142868 (A.G.), NSF equipment grant for NMR instrumentation (NMR: CHE 0614785) and Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (A.G.). NR 61 TC 0 Z9 0 U1 5 U2 5 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 JAN 15 PY 2017 VL 25 IS 2 BP 545 EP 556 DI 10.1016/j.bmc.2016.11.026 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA EJ0NO UT WOS:000392906500010 PM 27894589 ER PT J AU Yao, ZH Qin, ZF Liang-Liang, H Wang, XL Dai, Y Qin, L Gonzalez, FJ Ye, WC Yao, XS AF Yao, Zhi-Hong Qin, Zi-Fei Liang-Liang, H. Wang, Xin-Luan Dai, Yi Qin, Ling Gonzalez, Frank J. Ye, Wen-Cai Yao, Xin-Sheng TI Identification, bioactivity evaluation and pharmacokinetics of multiple components in rat serum after oral administration of Xian-Ling-Gu-Bao capsule by ultra performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Xian-Ling-Gu-Bao capsule; Main prototypes; Bioactivity evaluation; Pharmacokinetics; Rat serum; UPLC/Q-TOF-MS ID TRADITIONAL CHINESE MEDICINE; CHEMICAL-CONSTITUENTS; ASPEROSAPONIN VI; MS/MS METHOD; LC-MS/MS; IN-VIVO; PLASMA; METABOLITES; BIOAVAILABILITY; DECOCTION AB The Xian-Ling-Gu-Bao capsule (XLGB) is a famous traditional Chinese medicine prescription (TCMP), which has proven effective in osteoporosis treatment. However, due to the lack of a dynamic XLGB profile, the in vivo pharmacokinetics of multiple bioactive components within this medicine remains unknown. In the present study, ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS) identified a total of eighteen prototypes (using reference standards) in rat serum after oral administration of XLGB. These prototypes were subsequently evaluated to ascertain their effects on the proliferation and alkaline phosphatase activity of UMR106 cells and the adipogenesis of 3T3-L1 cells. Furthermore, a rapid and sensitive UPLC/Q-TOF-MS method was developed and validated for simultaneous quantitative analysis of 11 prototypes in rat serum. Chromatographic separation was achieved using a Waters Acquity BEH C18 column (2.1 x 100 mm, 1.7 mu m) and linear gradient elution employing a mobile phase consisting of water and acetonitrile (both containing 0.1% formic acid). All calibration curves showed excellent linearity (r(2) >0.99) within the sampling ranges considered. The assay was accurate, precise and reproducible, as demonstrated by the obtained intra- and inter-day precisions (less than 12.3%) and accuracies (between -12.7% and 11.0%), and the matrix effects, extraction recoveries and stabilities were all satisfactory. Moreover, pharmacokinetic parameters were calculated from the plasma concentration-time data. Compared to single-compound dosing, significantly enhanced responses were obtained when several analytes were administered simultaneously, indicating possible drug-drug interactions among the complex ingredients of TCMP. This work provides an experimental baseline regarding the clinical applications and medicinal effectiveness of XLGB in the treatment of osteoporosis. (C) 2016 Elsevier B.V. All rights reserved. C1 [Yao, Zhi-Hong; Qin, Zi-Fei; Liang-Liang, H.; Dai, Yi; Ye, Wen-Cai; Yao, Xin-Sheng] Jinan Univ, Coll Pharm, Guangzhou 510632, Guangdong, Peoples R China. [Wang, Xin-Luan; Qin, Ling] Chinese Univ Hong Kong, Dept Orthopaed & Traumatol, Musculoskeletal Res Lab, Shatin, Hong Kong, Peoples R China. [Wang, Xin-Luan; Qin, Ling] Chinese Acad Sci, Shenzhen Inst Adv Technol, Inst Biomed & Hlth Engn, Translat Med R&D Ctr, Shenzhen 518057, Peoples R China. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Yao, ZH; Dai, Y (reprint author), Jinan Univ, Coll Pharm, Guangzhou 510632, Guangdong, Peoples R China. EM tyaozh@jnu.edu.cn; daiyi1004@163.com FU Major Project for International Cooperation and Exchange of the National Natural Science Foundation of China [81220108028]; National Natural Science Foundation of China [81073003]; National Major Scientific and Technological Special Project for Significant New Drugs Development of China [2011ZX09201-201-05]; Natural Science Foundation of Guangdong Province [S2013010012373]; Science and Technology Projects of Guangdong Province [2011B031700068] FX The work was supported by the Major Project for International Cooperation and Exchange of the National Natural Science Foundation of China (Grant No. 81220108028), the Project of National Natural Science Foundation of China (Grant No. 81073003), the National Major Scientific and Technological Special Project for Significant New Drugs Development of China (Grant No. 2011ZX09201-201-05), the Project of Natural Science Foundation of Guangdong Province (Grant No. S2013010012373) and the Science and Technology Projects of Guangdong Province (Grant No. 2011B031700068). The authors would like to thank their colleague Feng-Juan Tu, Ph.D., for supplying the reference standards. NR 36 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 EI 1873-376X J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 15 PY 2017 VL 1041 BP 104 EP 112 DI 10.1016/j.jchromb.2016.12.026 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EI8TR UT WOS:000392781500013 PM 28033584 ER PT J AU Tan, CY Wandu, WS Lee, RS Hinshaw, SH Klinman, DM Wawrousek, E Gery, I AF Tan, Cuiyan Wandu, Wambui S. Lee, R. Steven Hinshaw, Samuel H. Klinman, Dennis M. Wawrousek, Eric Gery, Igal TI Shedding New Light on the Process of "Licensing" for Pathogenicity by Th Lymphocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; NEO-SELF ANTIGEN; ADOPTIVE TRANSFER; EFFECTOR-CELLS; TLR LIGANDS; UVEORETINITIS; ACTIVATION; ANTIBODIES AB Th cells sensitized against autoantigens acquire pathogenicity following two sequential events, namely activation by their target Ag and a process named "licensing." In this study, we analyzed these processes in a transgenic mouse system in which TCR-transgenic Th cells specific to hen egg lysozyme (HEL) are adoptively transferred to recipients and induce inflammation in eyes expressing HEL. Our data show that the notion that the lung is the organ where "licensing" for pathogenicity takes place is based on biased data collected with cells injected i.v., a route in which most transferred cells enter via the lung. Thus, we found that when donor cells were activated in vitro and injected intraperitoneally, or were activated in vivo, they migrated simultaneously to the lung, spleen, and other tested organs. In all, tested organs donor cells undergo "licensing" for pathogenicity, consisting of vigorous increase in number and changes in expression levels of inflammation-related genes, monitored by both flow cytometry and microarray analysis. After reaching peak numbers, around day 3, the "licensed" donor cells migrate to the circulation and initiate inflammation in the HEL-expressing recipient eyes. Importantly, the kinetics of increase in number and of changes in gene expression by the donor cells were similar in lung, spleen, and other tested organs of the recipient mice. Furthermore, the total numbers of donor cells in the spleen at their peaks were 10-to 100-fold larger in the spleen than in the lung, contradicting the notion that the lung is the organ where "licensing" takes place. C1 [Tan, Cuiyan; Wandu, Wambui S.; Hinshaw, Samuel H.; Gery, Igal] NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N208, Bethesda, MD 20892 USA. [Lee, R. Steven; Wawrousek, Eric] NEI, Genet Engn Core, NIH, Bethesda, MD 20892 USA. [Klinman, Dennis M.] NCI, Canc & Inflammat Program, NIH, Frederick, MD 21702 USA. RP Gery, I (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N208, Bethesda, MD 20892 USA. EM geryi@nei.nih.gov OI Lee, Robert/0000-0003-0836-5314 FU Intramural Program of the National Eye Institute, National Institutes of Health FX This work was supported by the Intramural Program of the National Eye Institute, National Institutes of Health. NR 24 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2017 VL 198 IS 2 BP 681 EP 690 DI 10.4049/jimmunol.1502108 PG 10 WC Immunology SC Immunology GA EI3PZ UT WOS:000392405000017 PM 27986906 ER PT J AU Veres, TZ Kopcsanyi, T van Panhuys, N Gerner, MY Liu, ZD Rantakari, P Dunkel, J Miyasaka, M Salmi, M Jalkanen, S Germain, RN AF Veres, Tibor Z. Kopcsanyi, Tamas van Panhuys, Nicholas Gerner, Michael Y. Liu, Zhiduo Rantakari, Pia Dunkel, Johannes Miyasaka, Masayuki Salmi, Marko Jalkanen, Sirpa Germain, Ronald N. TI Allergen-Induced CD4(+) T Cell Cytokine Production within Airway Mucosal Dendritic Cell-T Cell Clusters Drives the Local Recruitment of Myeloid Effector Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INNATE LYMPHOID-CELLS; DUST MITE ALLERGEN; IN-VIVO; MYCOBACTERIAL GRANULOMAS; ANTIGEN PRESENTATION; EPITHELIAL-CELLS; INFLAMMATION; ASTHMA; LUNG; RESPONSES AB Allergic asthma develops in the mucosal tissue of small bronchi. At these sites, local cytokine production by Th2/Th17 cells is believed to be critical for the development of tissue eosinophilia/neutrophilia. Using the mouse trachea as a relevant model of human small airways, we performed advanced in vivo dynamic and in situ static imaging to visualize individual cytokine-producing T cells in the airway mucosa and to define their immediate cellular environment. Upon allergen sensitization, newly recruited CD4(+) T cells formed discrete Ag-driven clusters with dendritic cells (DCs). Within T cell-DC clusters, a small fraction of CD4(+) T cells produced IL-13 or IL-17 following prolonged Ag-specific interactions with DCs. As a result of local Th2 cytokine signaling, eosinophils were recruited into these clusters. Neutrophils also infiltrated these clusters in a T cell-dependent manner, but their mucosal distribution was more diffuse. Our findings reveal the focal nature of allergen-driven responses in the airways and define multiple steps with potential for interference with the progression of asthmatic pathology. C1 [Veres, Tibor Z.; Kopcsanyi, Tamas; Rantakari, Pia; Dunkel, Johannes; Miyasaka, Masayuki; Salmi, Marko; Jalkanen, Sirpa] Univ Turku, MediC Res Lab, Tykistokatu 6A, FIN-20520 Turku, Finland. [Veres, Tibor Z.; van Panhuys, Nicholas; Gerner, Michael Y.; Liu, Zhiduo; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [van Panhuys, Nicholas] Sidra Med & Res Ctr, Doha, Qatar. [Miyasaka, Masayuki] Osaka Univ, World Premier Int Immunol Frontier Res Ctr, Osaka 5650871, Japan. [Salmi, Marko; Jalkanen, Sirpa] Univ Turku, Dept Med Microbiol & Immunol, FIN-20520 Turku, Finland. RP Veres, TZ (reprint author), Univ Turku, MediC Res Lab, Tykistokatu 6A, FIN-20520 Turku, Finland.; Germain, RN (reprint author), NIAID, NIH, 9000 Rockville Pike,Bldg 4 Room 126A MSC 0421, Bethesda, MD 20892 USA. EM tibor.veres@utu.fi; rgermain@nih.gov OI Miyasaka, Masayuki/0000-0001-6122-5201; Rantakari, Pia/0000-0003-1638-5075 FU Academy of Finland; Sigrid Juselius Foundation; University of Turku; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Academy of Finland, the Sigrid Juselius Foundation, the University of Turku, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 57 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2017 VL 198 IS 2 BP 895 EP 907 DI 10.4049/jimmunol.1601448 PG 13 WC Immunology SC Immunology GA EI3PZ UT WOS:000392405000038 PM 27903737 ER PT J AU Baird, MA Billington, N Wang, AB Adelstein, RS Sellers, JR Fischer, RS Waterman, CM AF Baird, Michelle A. Billington, Neil Wang, Aibing Adelstein, Robert S. Sellers, James R. Fischer, Robert S. Waterman, Clare M. TI Local pulsatile contractions are an intrinsic property of the myosin 2A motor in the cortical cytoskeleton of adherent cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID LIGHT CHAIN KINASE; II ISOFORMS; DORSAL CLOSURE; F-ACTIN; EPITHELIAL MORPHOGENESIS; KINETIC CHARACTERIZATION; APICAL CONSTRICTION; FUNCTIONAL DOMAINS; MIGRATING CELLS; SHAPE CHANGE AB The role of nonmuscle myosin 2 (NM2) pulsatile dynamics in generating contractile forces required for developmental morphogenesis has been characterized, but whether these pulsatile contractions are an intrinsic property of all actomyosin networks is not known. Here we used live-cell fluorescence imaging to show that transient, local assembly of NM2A "pulses" occurs in the cortical cytoskeleton of single adherent cells of mesenchymal, epithelial, and sarcoma origin, independent of developmental signaling cues and cell-cell or cell-ECM interactions. We show that pulses in the cortical cytoskeleton require Rho-associated kinase-or myosin light chain kinase (MLCK) activity, increases in cytosolic calcium, and NM2 ATPase activity. Surprisingly, we find that cortical cytoskeleton pulses specifically require the head domain of NM2A, as they do not occur with either NM2B or a 2B-head-2A-tail chimera. Our results thus suggest that pulsatile contractions in the cortical cytoskeleton are an intrinsic property of the NM2A motor that may mediate its role in homeostatic maintenance of tension in the cortical cytoskeleton of adherent cells. C1 [Baird, Michelle A.; Billington, Neil; Sellers, James R.; Fischer, Robert S.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Wang, Aibing; Adelstein, Robert S.] NHLBI, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [Wang, Aibing] Hunan Agr Univ, Coll Vet Med, Changsha 410128, Hunan, Peoples R China. RP Waterman, CM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. EM watermancm@nhlbi.nih.gov FU Intramural Program of the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD FX We thank the Hammer lab at the National Heart, Lung and Blood Institute for helpful discussion and reagents; Hye Kim, Callie Miller, and Lance Davidson's lab at the University of Pittsburgh for software and discussion; Mike Davidson at Florida State University for reagents; Colleen Skau for assistance with MEF preparations; William Shin for work on the Waterman Lab microscopes; and Schwanna Thacker for administrative assistance. We thank the Electron Microscopy Core Facility of the National Heart, Lung and Blood Institute for support, advice, and use of facilities. This work was supported by the Intramural Program of the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD. NR 67 TC 0 Z9 0 U1 1 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 JAN 15 PY 2017 VL 28 IS 2 BP 240 EP 251 DI 10.1091/mbc.E16-05-0335 PG 12 WC Cell Biology SC Cell Biology GA EI4WI UT WOS:000392493900003 PM 27881665 ER PT J AU Offerdahl, DK Dorward, DW Hansen, BT Bloom, ME AF Offerdahl, Danielle K. Dorward, David W. Hansen, Bryan T. Bloom, Marshall E. TI Cytoarchitecture of Zika virus infection in human neuroblastoma and Aedes albopictus cell lines SO VIROLOGY LA English DT Article DE Flavivirus; Zika virus; Human neuroblastoma; SK-N-SH; Aedes albopictus; C6/36; Electron microscopy; Electron tomography ID 3-DIMENSIONAL ARCHITECTURE; MOSQUITO CELLS; ENDOPLASMIC-RETICULUM; SEXUAL TRANSMISSION; REPLICATION SITES; DENGUE-2 VIRUS; ELECTRON; AEGYPTI; MATURATION; RNA AB The Zika virus (ZIKV) pandemic is a global concern due to its role in the development of congenital anomalies of the central nervous system. This mosquito-borne flavivirus alternates between mammalian and mosquito hosts, but information about the biogenesis of ZIKV is limited. Using a human neuroblastoma cell line (SK-N-SH) and an Aedes albopictus mosquito cell line (C6/36), we characterized ZIKV infection by immunofluorescence, transmission electron microscopy (TEM), and electron tomography (ET) to better understand infection in these disparate host cells. ZIKV replicated well in both cell lines, but infected SK-N-SH cells suffered a lytic crisis. Flaviviruses scavenge host cell membranes to serve as replication platforms and ZIKV showed the hallmarks of this process. Via TEM, we identified virus particles and 60-100 nm spherular vesicles. ET revealed these vesicular replication compartments contain smaller 20-30 nm spherular structures. Our studies indicate that SK-N-SH and C6/36 cells are relevant models for viral cytoarchitecture study. C1 [Offerdahl, Danielle K.; Bloom, Marshall E.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Dorward, David W.; Hansen, Bryan T.] NIAID, Microscopy Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Bloom, ME (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM mbloom@nih.gov FU Intramural Research Program of NIH/NIAID, United States FX These studies were supported by the Intramural Research Program of NIH/NIAID, United States. NR 46 TC 1 Z9 1 U1 5 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 15 PY 2017 VL 501 BP 54 EP 62 DI 10.1016/j.virol.2016.11.002 PG 9 WC Virology SC Virology GA EI1UG UT WOS:000392263000006 PM 27863275 ER PT J AU Reynolds, SE Earl, PL Minai, M Moore, I Moss, B AF Reynolds, Sara E. Earl, Patricia L. Minai, Mahnaz Moore, Ian Moss, Bernard TI A homolog of the variola virus B22 membrane protein contributes to ectromelia virus pathogenicity in the mouse footpad model SO VIROLOGY LA English DT Article DE Poxvirus; Viral pathogenicity; Host defense; Innate immunity; T cells; Ectromelia virus ID LETHAL MOUSEPOX; INBRED MICE AB Most poxviruses encode a homolog of a similar to 200,000-kDa membrane protein originally identified in variola virus. We investigated the importance of the ectromelia virus (ECTV) homolog C15 in a natural infection model. In cultured mouse cells, the replication of a mutant virus with stop codons near the N-terminus (ECTV-C15Stop) was indistinguishable from a control virus (ECTV-C15Rev). However, for a range of doses injected into the footpads of BALB/c mice there was less mortality with the mutant. Similar virus loads were present at the site of infection with mutant or control virus whereas there was less ECTV-C15Stop in popliteal and inguinal lymph nodes, spleen and liver indicating decreased virus spread and replication. The latter results were supported by immunohistochemical analyses. Decreased spread was evidently due to immune modulatory activity of C15, rather than to an intrinsic viral function, as the survival of infected mice depended on CD4+ and CDS+ T cells. C1 [Reynolds, Sara E.; Earl, Patricia L.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Reynolds, Sara E.] Fairleigh Dickinson Univ, 285 Madison Ave, Madison, NJ 07940 USA. [Minai, Mahnaz; Moore, Ian] NIAID, Comparat Med Branch, Infect Dis Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID, NIH FX We thank Catherine Cotter for assistance with tissue culture and Jeffrey Americo for help with digital PCR. The Comparative Medicine Branch provided animal care including daily weight measurements. The research was supported by the Division of Intramural Research, NIAID, NIH. S.R. carried out research while a Ph.D. candidate in the Department of Cell Biology and Molecular Genetics at the University of Maryland, College Park, MD. NR 18 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 15 PY 2017 VL 501 BP 107 EP 114 DI 10.1016/j.virol.2016.11.010 PG 8 WC Virology SC Virology GA EI1UG UT WOS:000392263000013 PM 27898336 ER PT J AU Croteau-Chonka, DC Qiu, WL Martinez, FD Strunk, RC Lemanske, RF Liu, AH Gilliland, FD Millstein, J Gauderman, WJ Ober, C Krishnan, JA White, SR Naureckas, ET Nicolae, DL Barnes, KC London, SJ Barraza-Villarreal, A Careyl, VJ Weiss, ST Raby, BA AF Croteau-Chonka, Damien C. Qiu, Weiliang Martinez, Fernando D. Strunk, Robert C. Lemanske, Robert F., Jr. Liu, Andrew H. Gilliland, Frank D. Millstein, Joshua Gauderman, W. James Ober, Carole Krishnan, Jerry A. White, Steven R. Naureckas, Edward T. Nicolae, Dan L. Barnes, Kathleen C. London, Stephanie J. Barraza-Villarreal, Albino Careyl, Vincent J. Weiss, Scott T. Raby, Benjamin A. CA Asthma BioRepository Integrative G TI Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE genomics; gene expression; asthma; exacerbation; blood ID CHILDHOOD ASTHMA; IMMUNE-RESPONSES; TRANSCRIPTOME; PHENOTYPES; INFLAMMATION; BIOLOGY AB Rationale: Maintaining optimal symptom control remains the primary objective of asthma treatment. Better understanding of the biologic underpinnings of asthma control may lead to the development of improved clinical and pharmaceutical approaches. Objectives: To identify molecular pathways and interrelated genes whose differential expression was associated with asthma control. Methods: We performed gene set enrichment analyses of asthma control in 1,170 adults with asthma, each with gene expression data derived from either whole blood (WB) or unstimulated CD4(+) T lymphocytes (CD4), and a self-reported asthma control score representing either the preceding 6 months (chronic) or 7 days (acute). Our study comprised a discovery WB cohort (n = 245, chronic) and three independent, nonoverlapping replication cohorts: a second WB set (n = 448, acute) and two CD4 sets (n = 300, chronic; n = 77, acute). Measurements and Main Results: In the WB discovery cohort, we found significant overrepresentation of genes associated with asthma control in 1,106 gene sets from the Molecular Signatures Database (false discovery rate, <5%). Of these, 583 (53%) replicated in at least one replication cohort (false discovery rate, <25%). Suboptimal control was associated with signatures of eosinophilic and granulocytic inflammatory signals, whereas optimal control signatures were enriched for immature lymphocytic patterns. These signatures included two related biologic processes related to activation by TREM-1 (triggering receptor expressed on myeloid cells 1) and lipopolysaccharide. Conclusions: Together, these results demonstrate the existence of specific, reproducible transcriptomic components in blood that vary with degree of asthma control and implicate a novel biologic target (TREM-1). C1 [Croteau-Chonka, Damien C.; Qiu, Weiliang; Careyl, Vincent J.; Weiss, Scott T.; Raby, Benjamin A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Raby, Benjamin A.] Brigham & Womens Hosp, Dept Med, Pulm Genet Ctr, 75 Francis St, Boston, MA 02115 USA. [Raby, Benjamin A.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. [Raby, Benjamin A.] Harvard Med Sch, Boston, MA 02115 USA. [Martinez, Fernando D.] Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA. [Martinez, Fernando D.] Univ Arizona, Inst BIO5, Tucson, AZ USA. [Strunk, Robert C.] Washington Univ, Sch Med, Dept Pediat, Div Allergy Immunol & Pulm Med, St Louis, MO 63110 USA. [Lemanske, Robert F., Jr.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Liu, Andrew H.] Natl Jewish Hlth, Dept Pediat, Div Allergy & Clin Immunol, Denver, CO USA. [Liu, Andrew H.] Univ Colorado, Sch Med, Denver, CO USA. [Gilliland, Frank D.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Div Environm Hlth, Los Angeles, CA USA. [Millstein, Joshua; Gauderman, W. James] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Div Biostat, Los Angeles, CA USA. [Ober, Carole; Nicolae, Dan L.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [White, Steven R.; Naureckas, Edward T.] Univ Chicago, Dept Med, Sect Pulm & Crit Care Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Nicolae, Dan L.] Univ Chicago, Dept Med, Med Genet Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Krishnan, Jerry A.] Univ Illinois, Dept Med, Div Pulm Crit Care Sleep & Allergy, Chicago, IL USA. [Barnes, Kathleen C.] Johns Hopkins Univ, Dept Med, Div Clin Immunol & Allergy, Baltimore, MD USA. [London, Stephanie J.] NIEHS, Div Intramural Res, US Dept HHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Barraza-Villarreal, Albino] Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [Weiss, Scott T.] Partners Hlth Care, Partners HealthCare Personalized Med, Boston, MA USA. RP Croteau-Chonka, DC (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.; Croteau-Chonka, DC (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM damien.croteau-chonka@channing.harvard.edu OI London, Stephanie/0000-0003-4911-5290 FU NHLBI at the National Institutes of Health [America Recovery and Reinvestment Act "Grand Opportunity"] [RC2 HL101543, R01 HL086601, T32 HL007427, K01 HL127265]; National Institutes of Health Intramural Research Program at the National Institute of Environmental Health Sciences FX Supported by extramural grants from the NHLBI at the National Institutes of Health (RC2 HL101543 [America Recovery and Reinvestment Act "Grand Opportunity"], R01 HL086601, T32 HL007427, and K01 HL127265); and by the National Institutes of Health Intramural Research Program at the National Institute of Environmental Health Sciences (S.J.L.). NR 35 TC 0 Z9 0 U1 3 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JAN 15 PY 2017 VL 195 IS 2 BP 179 EP 188 DI 10.1164/rccm.201601-0107OC PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EH6TR UT WOS:000391907300010 PM 27494826 ER PT J AU Parr, CL Magnus, MC Karlstad, O Haugen, M Refsum, H Ueland, PM McCann, A Nafstadm, P Haberg, SE Nystad, W London, SJ AF Parr, Christine L. Magnus, Maria C. Karlstad, Oystein Haugen, Margaretha Refsum, Helga Ueland, Per M. McCann, Adrian Nafstadm, Per Haberg, Siri E. Nystad, Wenche London, Stephanie J. TI Maternal Folate Intake during Pregnancy and Childhood Asthma in a Population-based Cohort SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE folic acid; children's asthma development; birth cohort; epidemiology; maternal diet ID FOLIC-ACID SUPPLEMENTS; NORWEGIAN MOTHER; RESPIRATORY HEALTH; RISK; CHILDREN; WOMEN; ATOPY; MOBA; FORTIFICATION; METAANALYSIS AB Rationale: A potential adverse effect of high folate intake during pregnancy on children's asthma development remains controversial. Objectives: To prospectively investigate folate intake from both food and supplements during pregnancy and asthma at age 7 years when the diagnosis is more reliable than at preschool age. Methods: This study included eligible children born 2002-2006 from the Norwegian Mother and Child Cohort Study, a population based pregnancy cohort, linked to the Norwegian Prescription Database. Current asthma at age 7 was defined by asthma medications dispensed at least twice in the year (1,901 cases; n = 39,846) or by maternal questionnaire report (1,624 cases; n = 28,872). Maternal folate intake was assessed with a food frequency questionnaire validated against plasma folate. We used log-binomial and multinomial regression to calculate adjusted relative risks with 95% confidence intervals. Measurements and Main Results: Risk of asthma was increased in the highest versus lowest quintile of total folate intake with an adjusted relative risk of 1.23 (95% confidence interval, 1.06-1.44) that was similar for maternally reported asthma. Mothers in the highest quintile had a relatively high intake of food folate (median, 308; interquartile range, 241-366 mu g/d) and nearly, all took at least 400 mu g/d of supplemental folic acid (median, 500; interquartile range, 400-600 mu g/d). Conclusions: In this large prospective population-based cohort with essentially complete follow-up, pregnant women taking supplemental folic acid at or above the recommended dose, combined with a diet rich in folate, reach a total folate intake level associated with a slightly increased risk of asthma in children. C1 [Parr, Christine L.; Magnus, Maria C.; Karlstad, Oystein; Nafstadm, Per; Haberg, Siri E.; Nystad, Wenche] Norwegian Inst Publ Hlth, Dept Mental & Phys Hlth, Oslo, Norway. [Haugen, Margaretha] Norwegian Inst Publ Hlth, Dept Exposure & Risk Assessment, Oslo, Norway. [Parr, Christine L.; London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Magnus, Maria C.] Univ Bristol, Med Res Council Integrat Epidemiol Unit, Bristol, Avon, England. [Magnus, Maria C.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Refsum, Helga] Univ Oslo, Dept Nutr, Inst Basic Med Sci, Oslo, Norway. [Nafstadm, Per] Univ Oslo, Dept Community Med, Oslo, Norway. [Ueland, Per M.] Univ Bergen, Dept Clin Sci, Bergen, Norway. [Ueland, Per M.] Haukeland Hosp, Lab Clin Biochem, Bergen, Norway. [McCann, Adrian] Bevital AS, Bergen, Norway. RP Parr, CL (reprint author), Norwegian Inst Publ Hlth, POB 4404 Nydalen, N-0403 Oslo, Norway. EM christine-louise.parr@fhi.no OI London, Stephanie/0000-0003-4911-5290 FU National Institutes of Health (National Institute of Environmental Health Sciences) [N01-ES-75558]; National Institutes of Health (National Institute of Neurological Disorders and Stroke) [UO1 NS 047537-01, UO1 NS 047537-06A1]; Norwegian Research Council/FUGE program [151918/S10]; Norwegian Research Council [221097]; Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [ES49019] FX The data collection in the Norwegian Mother and Child Cohort Study is supported by the National Institutes of Health (National Institute of Environmental Health Sciences contract number N01-ES-75558, National Institute of Neurological Disorders and Stroke grant UO1 NS 047537-01 and UO1 NS 047537-06A1) and the Norwegian Research Council/FUGE program (grant number 151918/S10). This work was also supported by the Norwegian Research Council (grant number 221097, W.N.) and the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (ES49019, S.J.L.). The funders of the study had no role in study design, data collection, data analysis and interpretation, writing of the report, or the decision to submit the article for publication. NR 39 TC 1 Z9 1 U1 3 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JAN 15 PY 2017 VL 195 IS 2 BP 221 EP 228 DI 10.1164/rccm.201604-078800 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EH6TR UT WOS:000391907300015 PM 27518161 ER EF