FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Folweiler, KA Bondi, CO Ogunsanya, EA LaPorte, MJ Leary, JB Radabaugh, HL Monaco, CM Kline, AE AF Folweiler, Kaitlin A. Bondi, Corina O. Ogunsanya, Elizabeth A. LaPorte, Megan J. Leary, Jacob B. Radabaugh, Hannah L. Monaco, Christina M. Kline, Anthony E. TI Combining the Antipsychotic Drug Haloperidol and Environmental Enrichment after Traumatic Brain Injury Is a Double-Edged Sword SO JOURNAL OF NEUROTRAUMA LA English DT Article DE antipsychotic drugs; behavioral outcome; controlled cortical impact; environmental enrichment; functional recovery; learning and memory; Morris water maze; traumatic brain injury ID CONTROLLED CORTICAL IMPACT; WATER MAZE PERFORMANCE; RAT CEREBRAL-CORTEX; COGNITIVE FUNCTION; ATYPICAL ANTIPSYCHOTICS; LIPID-PEROXIDATION; WORKING-MEMORY; UNITED-STATES; IN-VIVO; RECOVERY AB Environmental enrichment (EE) confers significant benefits after experimental traumatic brain injury (TBI). In contrast, the antipsychotic drug (APD) haloperidol (HAL) exerts deleterious effects on neurobehavioral and cognitive recovery. Neurorehabilitation and management of agitation, however, are integral components of the treatment strategy for patients with TBI. Hence, the goal of this study was to determine how the two therapeutic approaches interact and influence motor and cognitive recovery. Anesthetized adult male rats received a controlled cortical impact (2.8mmtissue deformation at 4 m/sec) or sham injury and then were provided HAL (0.5 mg/kg; intraperitoneally [IP]) or vehicle (VEH; 1 mL/kg; IP) commencing 24 h after surgery and once daily for 19 days while housed in EE or standard (STD) conditions. Beam balance/walk and Morris water maze performance were assessed on post-injury days 1-5 and 14-19, respectively, followed immediately by quantification of cortical lesion volumes. The data revealed both expected and unexpected findings. It was not surprising that the TBI groups receiving EE performed significantly better than those in STD housing and that the TBI + STD + HAL group performed worse than the TBI + STD + VEH group (p < 0.05). What was surprising was that the therapeutic effects of EE were greatly reduced by concomitant administration of HAL. No differences in cortical lesion volumes were observed among the groups (p > 0.05). The potential clinical implications of these findings suggest that administering HAL to patients undergoing neurorehabilitation may be a double-edged sword because agitation must be controlled before rehabilitation can be safely initiated and executed, but its use may compromise therapeutic efficacy. C1 [Folweiler, Kaitlin A.; Bondi, Corina O.; Ogunsanya, Elizabeth A.; LaPorte, Megan J.; Leary, Jacob B.; Radabaugh, Hannah L.; Monaco, Christina M.; Kline, Anthony E.] Univ Pittsburgh, Phys Med & Rehabil, Pittsburgh, PA USA. [Folweiler, Kaitlin A.; Bondi, Corina O.; Ogunsanya, Elizabeth A.; LaPorte, Megan J.; Leary, Jacob B.; Radabaugh, Hannah L.; Monaco, Christina M.; Kline, Anthony E.] Univ Pittsburgh, Safar Ctr Resuscitat Res, Pittsburgh, PA USA. [Bondi, Corina O.] Univ Pittsburgh, Neurobiol, Pittsburgh, PA USA. [Kline, Anthony E.] Univ Pittsburgh, Crit Care Med, Pittsburgh, PA USA. [Kline, Anthony E.] Univ Pittsburgh, Psychol, Pittsburgh, PA USA. [Kline, Anthony E.] Univ Pittsburgh, Ctr Neurosci, Pittsburgh, PA 15260 USA. [Kline, Anthony E.] Univ Pittsburgh, Ctr Neural Basis Cognit, Pittsburgh, PA 15260 USA. [Folweiler, Kaitlin A.] Univ Penn, Dept Neurosci, Philadelphia, PA 19104 USA. [Folweiler, Kaitlin A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Leary, Jacob B.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Monaco, Christina M.] Philadelphia Coll Osteopath Med, Philadelphia, PA USA. RP Kline, AE (reprint author), Univ Pittsburgh, Safar Ctr Resuscitat Res, Dept Phys Med & Rehabil, 3471 Fifth Ave,Suite 201, Pittsburgh, PA 15213 USA.; Kline, AE (reprint author), Univ Pittsburgh, Safar Ctr Resuscitat Res, Dept Crit Care Med, 3471 Fifth Ave,Suite 201, Pittsburgh, PA 15213 USA.; Kline, AE (reprint author), Univ Pittsburgh, Safar Ctr Resuscitat Res, Dept Psychol, 3471 Fifth Ave,Suite 201, Pittsburgh, PA 15213 USA. EM klineae@upmc.edu FU National Institutes of Health [R01NS060005, R01HD069620, HD069620-S1, R01NS084967]; University of Pittsburgh Physicians / UPMC Academic Foundation FX This work was supported, in part, by the National Institutes of Health grants R01NS060005, R01HD069620, HD069620-S1, R01NS084967 (AEK) and the University of Pittsburgh Physicians / UPMC Academic Foundation (COB). NR 83 TC 0 Z9 0 U1 4 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JAN 15 PY 2017 VL 34 IS 2 BP 451 EP + DI 10.1089/neu.2016.4417 PG 9 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EH4QD UT WOS:000391754800021 PM 26975872 ER PT J AU Chen, G Shin, YW Taylor, PA Glen, DR Reynolds, RC Israel, RB Cox, RW AF Chen, Gang Shin, Yong Wook Taylor, Paul A. Glen, Daniel R. Reynolds, Richard C. Israel, Robert B. Cox, Robert W. TI Untangling the relatedness among correlations, Part I: Nonparametric approaches to inter-subject correlation analysis at the group level (vol 142, pg 248, 2016) SO NEUROIMAGE LA English DT Correction C1 [Chen, Gang; Taylor, Paul A.; Glen, Daniel R.; Reynolds, Richard C.; Cox, Robert W.] NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Shin, Yong Wook] Univ Ulsan, Coll Med, Dept Psychiat, Asan Med Ctr, 88 Olymp Ro 43 Gil, Seoul 05535, South Korea. [Israel, Robert B.] Univ British Columbia, Dept Math, Vancouver, BC, Canada. RP Chen, G (reprint author), NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA.; Shin, YW (reprint author), Univ Ulsan, Coll Med, Dept Psychiat, Asan Med Ctr, 88 Olymp Ro 43 Gil, Seoul 05535, South Korea. EM gangchen@mail.nih.gov; shaman_korea@mac.com NR 5 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 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2017 VL 145 BP 130 EP 132 DI 10.1016/j.neuroimage.2016.10.021 PN A PG 3 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EG7QF UT WOS:000391243200011 PM 28340982 ER PT J AU Steele, VR Rao, V Calhoun, VD Kiehl, KA AF Steele, Vaughn R. Rao, Vikram Calhoun, Vince D. Kiehl, Kent A. TI Machine learning of structural magnetic resonance imaging predicts psychopathic traits in adolescent offenders SO NEUROIMAGE LA English DT Article DE Prediction; Voxel-based morphometry; SVM; Psychopathy ID CALLOUS-UNEMOTIONAL TRAITS; BIPOLAR DISORDER; GRAY-MATTER; CONDUCT PROBLEMS; VIOLENCE; CLASSIFICATION; SCHIZOPHRENIA; CHILDREN; REARREST; FMRI AB Classification models are becoming useful tools for finding patterns in neuroimaging data sets that are not observable to the naked eye. Many of these models are applied to discriminating clinical groups such as schizophrenic patients from healthy controls or from patients with bipolar disorder. A more nuanced model might be to discriminate between levels of personality traits. Here, as a proof of concept, we take an initial step toward developing prediction models to differentiate individuals based on a personality disorder: psychopathy. We included three groups of adolescent participants: incarcerated youth with elevated psychopathic traits (i.e., callous and unemotional traits and conduct disordered traits; n = 71), incarcerated youth with low psychopathic traits (n = 72), and non-incarcerated youth as healthy controls (n = 21). Support vector machine (SVM) learning models were developed to separate these groups using an out-of-sample cross-validation method on voxel-based morphometry (VBM) data. Regions of interest from the paralimbic system, identified in an independent forensic sample, were successful in differentiating youth groups. Models seeking to classify incarcerated individuals to have high or low psychopathic traits achieved 69.23% overall accuracy. As expected, accuracy increased in models differentiating healthy controls from individuals with high psychopathic traits (82.61%) and low psychopathic traits (80.65%). Here we have laid the foundation for using neural correlates of personality traits to identify group membership within and beyond psychopathy. This is only the first step, of many, toward prediction models using neural measures as a proxy for personality traits. As these methods are improved, prediction models with neural measures of personality traits could have far-reaching impact on diagnosis, treatment, and prediction of future behavior. (C) 2015 Elsevier Inc. All rights reserved. C1 [Steele, Vaughn R.] NIDA, Intramural Res Program, Neuroimaging Res Branch, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Steele, Vaughn R.; Rao, Vikram; Calhoun, Vince D.; Kiehl, Kent A.] Nonprofit Mind Res Network MRN, Albuquerque, NM USA. [Steele, Vaughn R.; Rao, Vikram; Calhoun, Vince D.; Kiehl, Kent A.] Lovelace Biomed & Environm Res Inst LBERI, Albuquerque, NM USA. [Steele, Vaughn R.; Kiehl, Kent A.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. [Calhoun, Vince D.] Univ New Mexico, Sch Med, Dept Psychiat, Albuquerque, NM 87131 USA. [Calhoun, Vince D.; Kiehl, Kent A.] Univ New Mexico, Dept Neurosci, Albuquerque, NM 87131 USA. RP Steele, VR (reprint author), NIDA, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA.; Kiehl, KA (reprint author), Mind Res Network, 1101 Yale Blvd NE, Albuquerque, NM 87106 USA. EM vaughn.r.steele@gmail.com; kkiehl@mrn.org FU National Institute of Mental Health (NIMH) [1R01MH071896]; National Institute of Biomedical Imaging and Bioengineering (NIBIB) [1R01EB006841]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [1R01HD082257] FX This study was funded by the National Institute of Mental Health (NIMH) grant 1R01MH071896 (K.A.K., PI), the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant 1R01EB006841 (V.D.C., PI), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grant 1R01HD082257 (K.A.K., PI). We thank Ebany Martinez-Finley, J. Michael Maurer, and Prashanth Nyalakanti for their contributions. We gratefully acknowledge the staff and inmates of the New Mexico Corrections Department for without their generous cooperation, this work could not have been completed. NR 70 TC 0 Z9 0 U1 20 U2 20 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2017 VL 145 SI SI BP 265 EP 273 DI 10.1016/j.neuroimage.2015.12.013 PN B PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EG3WU UT WOS:000390976200012 PM 26690808 ER PT J AU Lindquist, MA Krishnan, A Lopez-Sola, M Jepma, M Woo, CW Koban, L Roy, M Atlas, LY Schmidt, L Chang, LJ Losin, EAR Eisenbarth, H Ashar, YK Delk, E Wager, TD AF Lindquist, Martin A. Krishnan, Anjali Lopez-Sola, Marina Jepma, Marieke Woo, Choong-Wan Koban, Leonie Roy, Mathieu Atlas, Lauren Y. Schmidt, Liane Chang, Luke J. Losin, Elizabeth A. Reynolds Eisenbarth, Hedwig Ashar, Yoni K. Delk, Elizabeth Wager, Tor D. TI Group-regularized individual prediction: theory and application to pain SO NEUROIMAGE LA English DT Article DE Machine leaming; Statistical learning; Pain; MVPA; Empirical Bayes; Prediction; fMRI; Mega-analysis; Meta-analysis; Shrinkage ID VENTRAL TEMPORAL CORTEX; HUMAN BRAIN ACTIVITY; PATTERN-ANALYSIS; FUNCTIONAL CONNECTIVITY; NEURAL REPRESENTATIONS; PHYSICAL PAIN; FMRI; ACTIVATION; CLASSIFICATION; MEMORY AB Multivariate pattern analysis (MVPA) has become an important tool for identifying brain representations of psychological processes and clinical outcomes using fMRI and related methods. Such methods can be used to predict or 'decode' psychological states in individual subjects. Single-subject MVPA approaches, however, are limited by the amount and quality of individual-subject data. In spite of higher spatial resolution, predictive accuracy from single-subject data often does not exceed what can be accomplished using coarser, group-level maps, because single-subject patterns are trained on limited amounts of often-noisy data. Here, we present a method that combines population-level priors, in the form of biomarker patterns developed on prior samples, with single-subject MVPA maps to improve single-subject prediction. Theoretical results and simulations motivate a weighting based on the relative variances of biomarker-based prediction based on population-level predictive maps from prior groups and individual-subject, cross-validated prediction. Empirical results predicting pain using brain activity on a trial-by-trial basis (single-trial prediction) across 6 studies (N = 180 participants) confirm the theoretical predictions. Regularization based on a population-level biomarker in this case, the Neurologic Pain Signature (NPS) improved single-subject prediction accuracy compared with idiographic maps based on the individuals' data alone. The regularization scheme that we propose, which we term group-regularized individual prediction (GRIP), can be applied broadly to within-person MVPA-based prediction. We also show how GRIP can be used to evaluate data quality and provide benchmarks for the appropriateness of population-level maps like the NPS for a given individual or study. (C) 2015 Elsevier Inc. All rights reserved. C1 [Lindquist, Martin A.] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Krishnan, Anjali; Lopez-Sola, Marina; Jepma, Marieke; Woo, Choong-Wan; Koban, Leonie; Chang, Luke J.; Losin, Elizabeth A. Reynolds; Eisenbarth, Hedwig; Ashar, Yoni K.; Delk, Elizabeth; Wager, Tor D.] Univ Colorado Boulder, 345 UCB, Boulder, CO 80309 USA. [Roy, Mathieu] Concordia Univ, Chicago, IL USA. [Atlas, Lauren Y.] NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA. [Losin, Elizabeth A. Reynolds] Univ Miami, Coral Gables, FL 33124 USA. [Krishnan, Anjali] CUNY Brooklyn Coll, Brooklyn, NY 11210 USA. [Schmidt, Liane] INSEAD, Fontainebleau, France. [Schmidt, Liane] Ecole Normale Super, Cognit Neurosci Lab, Dept Cognit Sci, INSERM,U960, Paris, France. RP Wager, TD (reprint author), Univ Colorado Boulder, Dept Psychol & Neurosci, 345 UCB, Boulder, CO 80309 USA. EM tor.wager@colorado.edu OI KOBAN, LEONIE/0000-0002-3121-6491 FU NIH [R01DA035484, 2R01MH076136, R01DA027794, R01 EB016061, P41 E8015909] FX Author note: We are grateful for the funding support of NIH, which supported this work under grants R01DA035484 (TDW), 2R01MH076136 (TDW), R01DA027794 (TDW), R01 EB016061 (MAL) and P41 E8015909 (MAL). NR 66 TC 2 Z9 2 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 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2017 VL 145 SI SI BP 274 EP 287 DI 10.1016/j.neuroimage.2015.10.074 PN B PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EG3WU UT WOS:000390976200013 PM 26592808 ER PT J AU Thompson, PM Andreassen, OA Arias-Vasquez, A Bearden, CE Boedhoe, PS Brouwer, RM Buckner, RL Buitelaar, JK Bulayeva, KB Cannon, DM Cohen, RA Conrod, PJ Dale, AM Deary, IJ Dennis, EL de Reus, MA Desrivieres, S Dima, D Donohoe, G Fisher, SE Fouche, JP Francks, C Frangou, S Franke, B Ganjgahi, H Garavan, H Glahn, DC Grabe, HJ Guadalupe, T Gutman, BA Hashimoto, R Hibar, DP Holland, D Hoogman, M Pol, HEH Hosten, N Jahanshad, N Kelly, S Kochunov, P Kremen, WS Lee, PH Mackey, S Martin, NG Mazoyer, B McDonald, C Medland, SE Morey, RA Nichols, TE Paus, T Pausova, Z Schmaal, L Schumann, G Shen, L Sisodiya, SM Smit, DJA Smoller, JW Stein, DJ Stein, JL Toro, R Turner, JA van den Heuvel, MP van den Heuvel, OL van Erp, TGM van Rooij, D Veltman, DJ Walter, H Wang, YL Wardlaw, JM Whelan, CD Wright, MJ Ye, JP AF Thompson, Paul M. Andreassen, Ole A. Arias-Vasquez, Alejandro Bearden, Carrie E. Boedhoe, Premika S. Brouwer, Rachel M. Buckner, Randy L. Buitelaar, Jan K. Bulayeva, Kazima B. Cannon, Dara M. Cohen, Ronald A. Conrod, Patricia J. Dale, Anders M. Deary, Ian J. Dennis, Emily L. de Reus, Marcel A. Desrivieres, Sylvane Dima, Danai Donohoe, Gary Fisher, Simon E. Fouche, Jean-Paul Francks, Clyde Frangou, Sophia Franke, Barbara Ganjgahi, Habib Garavan, Hugh Glahn, David C. Grabe, Hans J. Guadalupe, Tulio Gutman, Boris A. Hashimoto, Ryota Hibar, Derrek P. Holland, Dominic Hoogman, Martine Pol, Hilleke E. Hulshoff Hosten, Norbert Jahanshad, Neda Kelly, Sinead Kochunov, Peter Kremen, William S. Lee, Phil H. Mackey, Scott Martin, Nicholas G. Mazoyer, Bernard McDonald, Colm Medland, Sarah E. Morey, Rajendra A. Nichols, Thomas E. Paus, Tomas Pausova, Zdenka Schmaal, Lianne Schumann, Gunter Shen, Li Sisodiya, Sanjay M. Smit, Dirk J. A. Smoller, Jordan W. Stein, Dan J. Stein, Jason L. Toro, Roberto Turner, Jessica A. van den Heuvel, Martijn P. van den Heuvel, Odile L. van Erp, Theo G. M. van Rooij, Daan Veltman, Dick J. Walter, Henrik Wang, Yalin Wardlaw, Joanna M. Whelan, Christopher D. Wright, Margaret J. Ye, Jieping CA ENIGMA Consortium TI ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide SO NEUROIMAGE LA English DT Article ID GENOME-WIDE ASSOCIATION; 22Q11.2 DELETION SYNDROME; CORTICAL SURFACE-AREA; ALZHEIMERS-DISEASE; WHITE-MATTER; CHRONIC-SCHIZOPHRENIA; HERITABILITY ANALYSIS; GENETIC ASSOCIATIONS; SUSCEPTIBILITY LOCI; CANDIDATE GENES AB In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) - a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date - of schizophrenia and major depression - ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others(1), ENIGMA's genomic screens - now numbering over 30,000 MRI scans - have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants and genetic variants in general - may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures - from tens of thousands of people - that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far. (C) 2015 The Authors. Published by Elsevier Inc. C1 [Thompson, Paul M.; Dennis, Emily L.; Gutman, Boris A.; Hibar, Derrek P.; Jahanshad, Neda; Kelly, Sinead; Stein, Jason L.; Whelan, Christopher D.] Univ Southern Calif, Keck Sch Med, Mark & Mary Stevens Inst Neuroimaging & Informat, Imaging Genet Ctr, Marina Del Rey, CA 90292 USA. [Andreassen, Ole A.] Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, N-0315 Oslo, Norway. [Andreassen, Ole A.] Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, N-0315 Oslo, Norway. [Arias-Vasquez, Alejandro] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Donders Ctr Cognit Neurosci, NL-6525 Nijmegen, Netherlands. [Arias-Vasquez, Alejandro] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Donders Ctr Cognit Neurosci, NL-6525 Nijmegen, Netherlands. [Arias-Vasquez, Alejandro] Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Donders Ctr Cognit Neurosci, NL-6525 Nijmegen, Netherlands. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA. [Boedhoe, Premika S.; van den Heuvel, Odile L.; Veltman, Dick J.] Vrije Univ Amsterdam, Med Ctr, Dept Anat & Neurosci, Amsterdam, Netherlands. [Brouwer, Rachel M.; de Reus, Marcel A.; Pol, Hilleke E. Hulshoff; van den Heuvel, Martijn P.] UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, NL-3584 CX Utrecht, Netherlands. [Buckner, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Buitelaar, Jan K.; Fisher, Simon E.; Francks, Clyde; Franke, Barbara; Hoogman, Martine; van Rooij, Daan] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, NL-6500 HB Nijmegen, Netherlands. [Buitelaar, Jan K.] Harvard Univ, Dept Psychol, Ctr Brain Sci, 33 Kirkland St, Cambridge, MA 02138 USA. [Bulayeva, Kazima B.] Russian Acad Sci, NI Vavilov Inst Gen Genet, Gubkin Str 3, Moscow 119991, Russia. [Cannon, Dara M.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Cannon, Dara M.; McDonald, Colm] Natl Univ Ireland Galway, Coll Med Nursing & Hlth Sci, NCBES Galway Neurosci Ctr, Neuroimaging & Cognit Genom Ctr NICOG,Clin Neuroi, Galway H91 TK33, Ireland. [Cohen, Ronald A.] Univ Florida, Inst Aging, Gainesville, FL 32611 USA. [Conrod, Patricia J.] Univ London, Kings Coll London, Sect Addict, Dept Psychol Med & Psychiat, London, England. [Dale, Anders M.; Holland, Dominic] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Dale, Anders M.; Holland, Dominic] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Dale, Anders M.; Holland, Dominic; Kremen, William S.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Dale, Anders M.; Holland, Dominic] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA. [Thompson, Paul M.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92093 USA. [Thompson, Paul M.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92093 USA. [Thompson, Paul M.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA. [Thompson, Paul M.] Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92093 USA. [Deary, Ian J.; Wardlaw, Joanna M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Desrivieres, Sylvane; Schumann, Gunter] Kings Coll London, Inst Psychiat, MRC SGDP Ctr, London SE5 8AF, England. [Dima, Danai] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England. [Dima, Danai; Frangou, Sophia] Icahn Sch Med Mt Sinai, Dept Psychiat, Clin Neurosci Studies CNS Ctr, New York, NY 10029 USA. [Donohoe, Gary] Natl Univ Ireland, Sch Psychol, Neuroimaging & Cognit Genom Ctr NICOG, Galway, Ireland. [Fisher, Simon E.; Francks, Clyde; Guadalupe, Tulio] Max Planck Inst Psycholinguist, Language & Genet Dept, NL-6525 XD Nijmegen, Netherlands. [Fouche, Jean-Paul; Stein, Dan J.] Univ Cape Town, Dept Psychiat & Mental Hlth, Cape Town, South Africa. [Franke, Barbara; Hoogman, Martine] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 Nijmegen, Netherlands. [Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 Nijmegen, Netherlands. [Ganjgahi, Habib] Univ Warwick, Dept Stat, Coventry, W Midlands, England. [Garavan, Hugh; Mackey, Scott] Univ Vermont, Dept Psychiat, Burlington, VT 05401 USA. [Glahn, David C.] Yale Univ, Dept Psychiat, New Haven, CT 06511 USA. [Glahn, David C.] Olin Neuropsychiat Res Ctr, Hartford, CT 06114 USA. [Grabe, Hans J.] Univ Med Greifswald, Dept Psychiat, D-17489 Greifswald, Germany. [Grabe, Hans J.] HELIOS Hosp, Dept Psychiat & Psychotherapy, D-18435 Stralsund, Germany. [Guadalupe, Tulio] Int Max Planck Res Sch Language Sci, NL-6525 XD Nijmegen, Netherlands. [Hashimoto, Ryota] Osaka Univ, United Grad Sch Child Dev, Mol Res Ctr Childrens Mental Dev, Suita, Osaka, Japan. [Hosten, Norbert] Univ Med Greifswald, Dept Radiol, D-17475 Greifswald, Germany. [Kochunov, Peter] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Lee, Phil H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Lee, Phil H.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Lee, Phil H.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Mazoyer, Bernard] Univ Bordeaux, CEA, CNRS, UMR5296,Grp Imagerie Neurofonct, Bordeaux, France. [Martin, Nicholas G.; Medland, Sarah E.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Morey, Rajendra A.] Duke Univ, Duke Inst Brain Sci, Durham, NC 27710 USA. [Nichols, Thomas E.] Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England. [Nichols, Thomas E.] Univ Warwick, WMG, Coventry CV4 7AL, W Midlands, England. [Nichols, Thomas E.] Univ Oxford, FMRIB Ctr, Oxford OX3 9DU, England. [Paus, Tomas] Baycrest, Rotman Res Inst, Toronto, ON, Canada. [Paus, Tomas] Univ Toronto, Dept Psychol, Toronto, ON, Canada. [Paus, Tomas] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Paus, Tomas] Child Mind Inst, New York, NY USA. [Pausova, Zdenka] Univ Toronto, Hosp Sick Children, Toronto, ON, Canada. [Pausova, Zdenka] Univ Toronto, Dept Physiol, Toronto, ON, Canada. [Pausova, Zdenka] Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada. [Shen, Li] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Ctr Neuroimaging, 355 W 16th St,Suite 4100, Indianapolis, IN 46202 USA. [Shen, Li] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, 355 W 16th St,Suite 4100, Indianapolis, IN 46202 USA. [Sisodiya, Sanjay M.] UCL Inst Neurol, Dept Clin & Expt Epilepsy, London WC1N 3BG, England. [Sisodiya, Sanjay M.] Epilepsy Soc, Gerrards Cross, Bucks, England. [Smit, Dirk J. A.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Stein, Dan J.] MRC Res Unit Anxiety & Stress Disorders, Stellenbosch, South Africa. [Stein, Jason L.] UCLA Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA. [Toro, Roberto] Inst Pasteur, F-75015 Paris, France. [Turner, Jessica A.] Georgia State Univ, Dept Psychol, Atlanta, GA 30302 USA. [Turner, Jessica A.] Georgia State Univ, Dept Neurosci, Atlanta, GA 30302 USA. [Boedhoe, Premika S.; Schmaal, Lianne; van den Heuvel, Odile L.; Veltman, Dick J.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Boedhoe, Premika S.; Schmaal, Lianne; Smit, Dirk J. A.; van den Heuvel, Odile L.; Veltman, Dick J.] VU VUMC, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [van Erp, Theo G. M.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92617 USA. [Walter, Henrik] Charite, CCM, Dept Psychiat & Psychotherapy, D-10117 Berlin, Germany. [Wang, Yalin] Arizona State Univ, Sch Comp Informat & Decis Syst Engn, Tempe, AZ 85281 USA. [Wardlaw, Joanna M.] Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh EH4 2XU, Midlothian, Scotland. [Wardlaw, Joanna M.] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH4 2XU, Midlothian, Scotland. [Wright, Margaret J.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Ye, Jieping] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Ye, Jieping] Univ Michigan, Dept Elect Engn & Comp Sci, Ann Arbor, MI 48109 USA. RP Thompson, PM (reprint author), Univ Southern Calif, Keck Sch Med, Mark & Mary Stevens Inst Neuroimaging & Informat, Imaging Genet Ctr, Marina Del Rey, CA 90292 USA.; Thompson, PM (reprint author), Univ Calif San Diego, Dept Neurosci, San Diego, CA 92093 USA.; Thompson, PM (reprint author), Univ Calif San Diego, Dept Radiol, San Diego, CA 92093 USA.; Thompson, PM (reprint author), Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.; Thompson, PM (reprint author), Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92093 USA. RI McDonald, Colm/C-1430-2009; Franke, Barbara/D-4836-2009; OI Franke, Barbara/0000-0003-4375-6572; Donohoe, Gary/0000-0003-3037-7426; Wright, Margaret/0000-0001-7133-4970; Shen, Li/0000-0002-5443-0503; Medland, Sarah/0000-0003-1382-380X FU NIH Institutes [U54 EB 020403]; NIBIB FX This work was supported in part by a Consortium grant (U54 EB 020403) from the NIH Institutes contributing to the Big Data to Knowledge (BD2K) Initiative, including the NIBIB. Funding for individual consortium authors is listed in Hibar et al., Nature, 2015 and in other papers cited here. This paper was collaboratively written on Google Docs by all authors, over a period of several weeks. We thank Josh Faskowitz for making Fig. 3, the ENIGMA "roadmap". NR 123 TC 2 Z9 3 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 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2017 VL 145 SI SI BP 389 EP 408 DI 10.1016/j.neuroimage.2015.11.057 PN B PG 20 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EG3WU UT WOS:000390976200022 PM 26658930 ER PT J AU McCormack, VA Menya, D Munishi, MO Dzamalala, C Gasmelseed, N Roux, ML Assefa, M Osano, O Watts, M Mwasamwaja, AO Mmbaga, BT Murphy, G Abnet, CC Dawsey, SM Schuz, J AF McCormack, V. A. Menya, D. Munishi, M. O. Dzamalala, C. Gasmelseed, N. Roux, M. Leon Assefa, M. Osano, O. Watts, M. Mwasamwaja, A. O. Mmbaga, B. T. Murphy, G. Abnet, C. C. Dawsey, S. M. Schuz, J. TI Informing etiologic research priorities for squamous cell esophageal cancer in Africa: A review of setting-specific exposures to known and putative risk factors SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE Africa; esophageal cancer; risk factors ID AROMATIC-HYDROCARBON EXPOSURE; SOUTH-AFRICA; WESTERN KENYA; HUMAN-PAPILLOMAVIRUS; GASTRIC CANCERS; BOMET DISTRICT; HIV-INFECTION; ORAL HYGIENE; YOUNG-PEOPLE; ADDIS-ABABA AB Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in most Eastern and Southern African countries, but its etiology has been understudied to date. To inform its research agenda, we undertook a review to identify, of the ESCC risk factors which have been established or strongly suggested worldwide, those with a high prevalence or high exposure levels in any ESCC-affected African setting and the sources thereof. We found that for almost all ESCC risk factors known to date, including tobacco, alcohol, hot beverage consumption, nitrosamines and both inhaled and ingested PAHs, there is evidence of population groups with raised exposures, the sources of which vary greatly between cultures across the ESCC corridor. Research encompassing these risk factors is warranted and is likely to identify primary prevention strategies. C1 [McCormack, V. A.; Roux, M. Leon; Schuz, J.] Int Agcy Res Canc, Sect Environm & Radiat, 150 Cours Albert Thomas, F-69372 Lyon 08, France. [Menya, D.] Moi Univ, Sch Publ Hlth, Eldoret, Kenya. [Munishi, M. O.; Mwasamwaja, A. O.; Mmbaga, B. T.] Kilimanjaro Clin Res Inst, Moshi, Tanzania. [Dzamalala, C.] Univ Malawi, Coll Med, Blantyre, Malawi. [Dzamalala, C.] Malawi Canc Registry, Blantyre, Malawi. [Gasmelseed, N.] Univ Gezira, Natl Canc Inst, Wad Madani, Sudan. [Gasmelseed, N.] Univ Hafr Al Batin, Fac Sci, Hafar al Batin, Saudi Arabia. [Assefa, M.] Univ Addis Ababa, Radiotherapy Ctr, Addis Ababa, Ethiopia. [Osano, O.] Univ Eldoret, Sch Environm Studies, Eldoret, Kenya. [Watts, M.] British Geol Survey, Ctr Environm Geochem, Inorgan Chem, Nottingham, England. [Mwasamwaja, A. O.; Mmbaga, B. T.] Kilimanjaro Christian Med Ctr, Moshi, Tanzania. [Murphy, G.; Abnet, C. C.; Dawsey, S. M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP McCormack, VA (reprint author), Int Agcy Res Canc, Sect Environm & Radiat, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM mccormackv@iarc.fr RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU IARC FX Grant sponsor: IARC NR 106 TC 0 Z9 0 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2017 VL 140 IS 2 BP 259 EP 271 DI 10.1002/ijc.30292 PG 13 WC Oncology SC Oncology GA EG0EI UT WOS:000390703600001 PM 27466161 ER PT J AU Elliott, EG Trinh, P Ma, XM Leaderer, BP Ward, MH Deziel, NC AF Elliott, Elise G. Trinh, Pauline Ma, Xiaomei Leaderer, Brian P. Ward, Mary H. Deziel, Nicole C. TI Unconventional oil and gas development and risk of childhood leukemia: Assessing the evidence SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Air pollution; Carcinogens; Hydraulic fracturing; Shale; Wastewater; Water contamination ID BARNETT SHALE REGION; ACUTE LYMPHOBLASTIC-LEUKEMIA; HYDRAULIC FRACTURING FLUIDS; AIR-POLLUTANT EMISSIONS; SENTINEL HEALTH EVENTS; DRINKING-WATER WELLS; TAKE-HOME EXPOSURE; NATURAL-GAS; MARCELLUS SHALE; METHANE EMISSIONS AB The widespread distribution of unconventional oil and gas (UO&G) wells and other facilities in the United States potentially exposes millions of people to air and water pollutants, including known or suspected carcinogens. Childhood leukemia is a particular concern because of the disease severity, vulnerable population, and short disease latency. A comprehensive review of carcinogens and leukemogens associated with UO&G development is not available and could inform future exposure monitoring studies and human health assessments. The objective of this analysis was to assess the evidence of carcinogenicity of water contaminants and air pollutants related to UO&G development. We obtained a list of 1177 chemicals in hydraulic fracturing fluids and wastewater from the U.S. Environmental Protection Agency and constructed a list of 143 UO&G-related air pollutants through a review of scientific papers published through 2015 using PubMed and ProQuest databases. We assessed carcinogenicity and evidence of increased risk for leukemia/lymphoma of these chemicals using International Agency for Research on Cancer (IARC) monographs. The majority of compounds (>80%) were not evaluated by IARC and therefore could not be reviewed. Of the 111 potential water contaminants and 29 potential air pollutants evaluated by IARC (119 unique compounds), 49 water and 20 air pollutants were known, probable, or possible human carcinogens (55 unique compounds). A total of 17 water and 11 air pollutants (20 unique compounds) had evidence of increased risk for leukemia/lymphoma, including benzene, 1,3-butadiene, cadmium, diesel exhaust, and several polycyclic aromatic hydrocarbons. Though information on the carcinogenicity of compounds associated with UO&G development was limited, our assessment identified 20 known or suspected carcinogens that could be measured in future studies to advance exposure and risk assessments of cancer-causing agents. Our findings support the need for investigation into the relationship between UO&G development and risk of cancer in general and childhood leukemia in particular. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Elliott, Elise G.; Trinh, Pauline; Ma, Xiaomei; Leaderer, Brian P.; Deziel, Nicole C.] Yale Univ, Yale Sch Publ Hlth, 60 Coll St, New Haven, CT 06520 USA. [Ward, Mary H.] NCI, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. RP Deziel, NC (reprint author), Yale Sch Publ Hlth, 60 Coll St, New Haven, CT 06520 USA. EM nicole.deziel@yale.edu NR 125 TC 0 Z9 0 U1 27 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD JAN 15 PY 2017 VL 576 BP 138 EP 147 DI 10.1016/j.scitotenv.2016.10.072 PG 10 WC Environmental Sciences SC Environmental Sciences & Ecology GA EG3SJ UT WOS:000390964700013 PM 27783932 ER PT J AU Mendola, P Sundaram, R Louis, GMB Sun, LP Wallace, ME Smarr, MM Sherman, S Zhu, YY Ying, Q Liu, DP AF Mendola, Pauline Sundaram, Rajeshwari Louis, Germaine M. Buck Sun, Liping Wallace, Maeve E. Smarr, Melissa M. Sherman, Seth Zhu, Yeyi Ying, Qi Liu, Danping TI Proximity to major roadways and prospectively-measured time-to-pregnancy and infertility SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Infertility; Time-to-pregnancy; Major roadways; Traffic ID AIR-POLLUTION; RESIDENTIAL PROXIMITY; PROSPECTIVE COHORT; SEMEN QUALITY; TRAFFIC NOISE; HUMAN SPERM; EXPOSURE; FERTILITY; IMPACT; MORTALITY AB We aimed to study the potential impact of proximity to major roadways on time-to-pregnancy and infertility in couples attempting pregnancy in the Longitudinal Investigation of Fertility and Environment (LIFE) study (20052009), a population-based, prospective cohort study. Couples attempting pregnancy (n = 500) were enrolled and followed prospectively until pregnancy or 12 months of trying and 393 couples (78%) had complete data and full follow-up. Time-to-pregnancy was based on a standard protocol using fertility monitors, tracking estrone-3-glucuonide and luteinizing hormone, and pregnancy test kits to detect human chorionic gonadotropin (hCG). The fecundability odds ratio (FOR) and 95% confidence interval (CI) were estimated using proportional odds models. Infertility was defined as 12 months of trying to conceive without an hCG pregnancy and the relative risk (RR) and 95% CI were estimated with log-binomial regression. Final models were adjusted for age, parity, study site, and salivary alpha-amylase, a stress marker. Infertile couples (53/393; 14%) tended to live closer to major roadways on average than fertile couples (689 m vs. 843 m, respectively) but the difference was not statistically significant. The likelihood of pregnancy was increased 3% for every 200 m further away the couples residence was from a major roadway (FOR = 1.03; CI = 1.01-1.06). Infertility also appeared elevated at moderate distances compared to 1000 m or greater, but estimates lacked precision. Our findings suggest that proximity to major roadways may be related to reductions in fecundity. Prospective data from larger populations is warranted to corroborate these findings. Published by Elsevier B.V. C1 [Mendola, Pauline; Sundaram, Rajeshwari; Louis, Germaine M. Buck; Wallace, Maeve E.; Smarr, Melissa M.; Zhu, Yeyi; Liu, Danping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, 6710B Rockledge Dr,Room 3119,MSC 7004, Bethesda, MD 20892 USA. [Sun, Liping] Glotech Inc, 1801 Res Blvd 605, Rockville, MD 20850 USA. [Sherman, Seth] Emmes Corp, 401 N Washington St 700, Rockville, MD 20850 USA. [Ying, Qi] Texas A&M Univ, 401 Joe Routt Blvd, College Stn, TX 77843 USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, 6710B Rockledge Dr,Room 3119,MSC 7004, Bethesda, MD 20892 USA. EM pauline.mendola@nih.gov OI Sherman, Seth/0000-0003-3667-9898; Mendola, Pauline/0000-0001-5330-2844; Sundaram, Rajeshwari/0000-0002-6918-5002 FU Intramural Research Program of the Eunice Kennedy Shriver National Institutes of Child Health and Human Development (LIFE study) [N01-HD-3-3355, N01-HD-#-3356, N01-HD-3-3358]; Air Quality and Reproductive Health Study [HHSN275200800002I, HHSN27500008] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institutes of Child Health and Human Development (LIFE study contract nos. #N01-HD-3-3355, N01-HD-#-3356, N0I-HD-3-3358 and the Air Quality and Reproductive Health Study Contract No. HHSN275200800002I, Task Order No. HHSN27500008). All manuscripts undergo institute clearance but the funding source is not responsible for study design; collection, analysis and interpretation of data; writing of the report, or the decision to submit the manuscript. NR 36 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD JAN 15 PY 2017 VL 576 BP 172 EP 177 DI 10.1016/j.scitotenv.2016.10.038 PG 6 WC Environmental Sciences SC Environmental Sciences & Ecology GA EG3SJ UT WOS:000390964700016 PM 27783935 ER PT J AU Taylor, SF Bhati, MT Dubin, MJ Hawkins, JM Lisanby, SH Morales, O Reti, IM Sampson, S Short, EB Spino, C Watcharotone, K Wright, J AF Taylor, Stephan F. Bhati, Mahendra T. Dubin, Marc J. Hawkins, John M. Lisanby, Sarah H. Morales, Oscar Reti, Irving M. Sampson, Shirlene Short, E. Baron Spino, Catherine Watcharotone, Kuanwong Wright, Jesse TI A naturalistic, multi-site study of repetitive transcranial magnetic stimulation therapy for depression SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Dorsolateral prefrontal cortex; Neuromodulation; Registry; Brain ID TREATING MAJOR DEPRESSION; TREATMENT-RESISTANT DEPRESSION; RANDOMIZED CONTROLLED-TRIAL; BRAIN-STIMULATION; METAANALYSIS; DISORDER; EFFICACY; RISK; RTMS; SAFETY AB Background: Repetitive transcranial magnetic stimulation (rTMS) was approved in 2008 in the United States, and there are relatively few studies describing its use in regular clinical practice since approval. Methods: From April 2011 to October 2014, ten sites within the National Network of Depression Centers (NNDC) provided data on 62 evaluable patients with a depressive episode. Treatment was determined naturalistically. Response was assessed by the Quick Inventory of Depressive Symptoms, Self-Report (QIDSSR) as the primary outcome, and the Patient Health Questionnaire-9 (PHQ-9) and the clinician-rated Clinical Global Impression (CGI) as secondary depression measures. Results: Enrolled patients exhibited significant treatment resistance, with 70.2% reporting more than 4 prior depressive episodes. Most patients received treatment with standard parameters (10 Hz over the left dorsolateral prefrontal cortex), although 22.6% of the patients received 1 or 5 Hz stimulation at some point. Over 6 weeks of treatment, response and remission rates were 29.4% and 5.9%, respectively, for the QIDS-SR; 39.2% and 15.7%, respectively, for the PHQ-9; and 50.9% and 17.9%, respectively, for the CGI. Moderator analyses revealed no effect of prior depressive episodes, history of ECT or gender, although early life stress predicted a better response to rTMS therapy. Limitations: The study was an open-label, registry trial, with relatively coarse clinical data, reflecting practice only in academic, depression-specialty centers. Because of the relatively small size and heterogeneity of the sample, type 2 errors are possible and positive findings are in need of replication. Conclusion: rTMS demonstrates effectiveness in clinical practice within the NNDC, although remission rates appear slightly lower in comparison with other recent naturalistic studies. C1 [Taylor, Stephan F.; Spino, Catherine; Watcharotone, Kuanwong] Univ Michigan, Ann Arbor, MI 48109 USA. [Bhati, Mahendra T.] Univ Penn, Philadelphia, PA 19104 USA. [Dubin, Marc J.] Weill Cornell Med Coll, New York, NY USA. [Hawkins, John M.] Univ Cincinnati, Linder Ctr, Cincinnati, OH USA. [Lisanby, Sarah H.] Duke Univ, Durham, NC USA. [Lisanby, Sarah H.] NIMH, Bethesda, MD 20892 USA. [Morales, Oscar] Harvard Univ, McLean Hosp, Cambridge, MA 02138 USA. [Reti, Irving M.] Johns Hopkins Univ, Baltimore, MD USA. [Sampson, Shirlene] Mayo Clin, Rochester, MN USA. [Short, E. Baron] Med Univ South Carolina, Charleston, SC 29425 USA. [Wright, Jesse] Univ Louisville, Louisville, KY 40292 USA. RP Taylor, SF (reprint author), Dept Psychiat, Rachel Upjohn Bldg,4250 Plymouth Rd, Ann Arbor, MI 48109 USA. EM sftaylor@umich.edu FU National Network of Depression Centers; University of Michigan Department of Psychiatry; Michigan Institute for Clinical and Health Research [UL1TR000433] FX This research was supported by The National Network of Depression Centers, The University of Michigan Department of Psychiatry and The Michigan Institute for Clinical and Health Research (UL1TR000433). NR 36 TC 0 Z9 0 U1 12 U2 12 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 JAN 15 PY 2017 VL 208 BP 284 EP 290 DI 10.1016/j.jad.2016.08.049 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EG0OR UT WOS:000390732600042 PM 27794252 ER PT J AU Bernert, RA Luckenbaugh, DA Duncan, WC Iwata, NG Ballard, ED Zarate, CA AF Bernert, Rebecca A. Luckenbaugh, David A. Duncan, Wallace C. Iwata, Naomi G. Ballard, Elizabeth D. Zarate, Carlos A. TI Sleep architecture parameters as a putative biomarker of suicidal ideation in treatment-resistant depression SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Sleep architecture; Suicide risk; Depression; Bipolar disorder; Treatment-resistance ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL THERAPY; BIPOLAR DISORDER; METABOLIC SYNDROME; MENTAL-DISORDERS; INSOMNIA; RISK; HOPELESSNESS; METAANALYSIS; DISTURBANCE AB Background: Disturbed sleep may confer risk for suicidal behaviors. Polysomnographic (PSG) sleep parameters have not been systematically evaluated in association with suicidal ideation (SI) among individuals with treatment-resistant depression (TRD). Methods: This secondary data analysis included 54 TRD individuals (N=30 with major depressive disorder (MDD) and N=24 with bipolar depression (BD)). PSG sleep parameters included Sleep Efficiency (SE), Total Sleep Time (TST), Wakefulness After Sleep Onset (WASO), REM percent/latency, and non-REM (NREM) Sleep Stages 1-4. The Hamilton Depression Rating Scale (HAM-D) was used to group participants according to presence or absence of SI. Sleep abnormalities were hypothesized among those with current SI. ANOVA analyses were conducted before (Model 1) and after adjusting for depression (Model 2) and diagnostic variables (Model 3). Results: Significant differences in PSG parameters were observed in Model 1; those with SI had less NREM Stage 4 sleep (p <.05). After adjusting for central covariates, Models 2 and 3 revealed significantly less NREM Stage 4 sleep, lower SE (P <.05), and higher WASO (P <.05) among those with SI. BD participants with SI also had less NREM Stage 4 and more NREM Stage 1 sleep. Limitations: 1) a predominantly white sample; 2) exclusion of imminent suicide risk; 3) concomitant mood stabilizer use among BD patients; and 4) single-item SI assessment. Conclusions: Independent of depression severity, SI was associated with less NREM Stage 4 sleep, and higher nocturnal wakefulness across diagnostic groups. Sleep may warrant further investigation in the pathogenesis of suicide risk, particularly in TRD, where risk may be heightened. C1 [Bernert, Rebecca A.; Iwata, Naomi G.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Suicide Prevent Res Lab, Stanford, CA 94305 USA. [Luckenbaugh, David A.; Duncan, Wallace C.; Ballard, Elizabeth D.; Zarate, Carlos A.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Bernert, RA (reprint author), Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Suicide Prevent Res Lab, Stanford, CA 94305 USA. EM rbernert@stanford.edu NR 72 TC 0 Z9 0 U1 10 U2 10 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 JAN 15 PY 2017 VL 208 BP 309 EP 315 DI 10.1016/j.jad.2016.08.050 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EG0OR UT WOS:000390732600045 PM 27810712 ER PT J AU Pennybaker, SJ Niciu, MJ Luckenbaugh, DA Zarate, CA AF Pennybaker, Steven J. Niciu, Mark J. Luckenbaugh, David A. Zarate, Carlos A., Jr. TI Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Major depressive disorder; Bipolar depression; Treatment-resistant depression; Ketamine; NMDA receptor antagonist; Antidepressant; Glutamatergic modulator ID MAJOR DEPRESSIVE DISORDER; D-ASPARTATE ANTAGONIST; TREATMENT-RESISTANT DEPRESSION; STAR-ASTERISK-D; ADD-ON TRIAL; BIPOLAR DEPRESSION; ALCOHOL DEPENDENCE; FAMILY-HISTORY; DOUBLE-BLIND; RECEPTOR ANTAGONISTS AB Background: Antidepressant response to a single subanesthetic dose infusion of the glutamatergic modulator ketamine is transient in most depressed patients; however, a minority continue to experience an extended response. This study examined depressive symptoms and potential clinical predictors of extended response to ketamine in subjects with mood disorders. Methods: Subjects were diagnosed with either major depressive disorder (MDD) or bipolar depression. All subjects were treatment-resistant and experiencing a major depressive episode of at least moderate severity. MDD subjects were unmedicated and those with bipolar depression were receiving therapeutic-dose lithium or valproate. All subjects received a single 0.5 mg/kg ketamine infusion. Data were collected pre-infusion (baseline) and at days one, 14, and 28 post-infusion. Results: Twelve of 93 (12.9%) participants continued to meet response criteria (50% reduction in Montgomery-Asberg Depression Rating Scale (MADRS) score) at two weeks. All depressive symptoms assessed by the MADRS were improved at two weeks in ketamine responders except for sleep duration/depth. A positive family history of alcohol use disorder in a first-degree relative (FHP) and greater dissociation during the infusion were associated with better antidepressant response at two weeks. Improved measures of apparent sadness, reported sadness, inability to feel, and difficulty concentrating at day 1 correlated most strongly with antidepressant effects at two weeks. Limitations: Post-hoc design, small sample size, diagnostic heterogeneity. Conclusions: Static (FHP) and dynamic (improved depressive symptoms) factors may be clinically useful in predicting whether a patient will have an extended response to ketamine. C1 [Pennybaker, Steven J.; Niciu, Mark J.; Luckenbaugh, David A.; Zarate, Carlos A., Jr.] NIMH, NIH, Expt Therapeut & Pathophysiol Branch, Bldg 10 CRC,10 Ctr Dr, Bethesda, MD 20892 USA. [Pennybaker, Steven J.] Johns Hopkins Univ, Sch Med, 600 N Wolfe St, Baltimore, MD 21287 USA. RP Zarate, CA (reprint author), NIMH, NIH, Expt Therapeut & Pathophysiol Branch, Bldg 10 CRC,10 Ctr Dr, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [00088699, 04-M-0222]; Brain and Behavior Research Foundation (NARSAD); Brain & Behavior Mood Disorders Research Award; NIH FX This work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; NCT#00088699, protocol 04-M-0222, substudies 2-4), by a Brain and Behavior Research Foundation (NARSAD) Independent Investigator to Dr. Zarate, and by a Brain & Behavior Mood Disorders Research Award to Dr. Zarate. The research was also made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and by generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors.These funding sources had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 60 TC 0 Z9 0 U1 31 U2 31 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 JAN 15 PY 2017 VL 208 BP 560 EP 566 DI 10.1016/j.jad.2016.10.026 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EG0OR UT WOS:000390732600080 PM 27839782 ER PT J AU Grabowski, JM Gulia-Nuss, M Kuhn, RJ Hill, CA AF Grabowski, Jeffrey M. Gulia-Nuss, Monika Kuhn, Richard J. Hill, Catherine A. TI RNAi reveals proteins for metabolism and protein processing associated with Langat virus infection in Ixodes scapularis (black-legged tick) ISE6 cells SO PARASITES & VECTORS LA English DT Article DE Ixodes scapularis; Tick-borne disease; Flavivirus; Langat; ISE6; RNAi; Functional studies; Metabolism; Protein-processing ID HEPATITIS-C-VIRUS; DENGUE VIRUS; FLAVIVIRUS INFECTION; BORNE FLAVIVIRUS; LYME-DISEASE; FUMARYLACETOACETATE HYDROLASE; CRYSTAL-STRUCTURE; OXIDATIVE STRESS; WEST-NILE; INHIBITION AB Background: Tick-borne flaviviruses (TBFs) cause thousands of human cases of encephalitis worldwide each year, with some TBF infections progressing to hemorrhagic fever. TBFs are of medical and veterinary importance and strategies to reduce flavivirus transmission by the tick vector may have significant application. Analyses of the proteome of ISE6 cells derived from the black legged tick, Ixodes scapularis infected with the TBF, Langat virus (LGTV), have provided insights into proteins and cellular processes involved with LGTV infection. Methods: RNA interference (RNAi)-induced knockdown of transcripts was used to investigate the role of ten tick proteins in the LGTV infection cycle in ISE6 cells. LGTV-infected cells were separately transfected with dsRNA corresponding to each gene of interest and the effect on LGTV genome replication and release of infectious virus was assessed by RT-qPCR and plaque assays, respectively. Results: RNAi-induced knockdown of transcripts for two enzymes that likely function in amino acid, carbohydrate, lipid, terpenoid/polykeytide and vitamin metabolism, and a transcript for one protein of unknown function were associated with decreased replication of the LGTV genome and release of infectious virus from cells. The knockdown of transcripts for five enzymes predicted to function in metabolism, a protein likely associated with folding, sorting and degradation, and a protein of unknown function was associated with a decrease only in the amount of infectious LGTV released from cells. Conclusions: These data suggest tick proteins potentially associated with metabolism and protein processing may be involved in LGTV infection of ISE6 cells. Our study provides information to begin to elucidate the function of these proteins and identify targets for the development of new interventions aimed at controlling the transmission of TBFs. C1 [Grabowski, Jeffrey M.; Gulia-Nuss, Monika; Hill, Catherine A.] Purdue Univ, Coll Agr, Dept Entomol, 901 W State St, W Lafayette, IN 47907 USA. [Grabowski, Jeffrey M.; Kuhn, Richard J.] Purdue Univ, Markey Ctr Struct Biol, Dept Biol Sci, Coll Sci, 915 W State St, W Lafayette, IN 47907 USA. [Kuhn, Richard J.; Hill, Catherine A.] Purdue Univ, Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN 47907 USA. [Grabowski, Jeffrey M.] NIAID, NIH, Rocky Mt Labs, Lab Virol,Biol Vector Borne Viruses Sect, 903 S 4th St, Hamilton, MT 59840 USA. [Gulia-Nuss, Monika] Univ Nevada, Dept Biochem & Mol Biol, Coll Agr Biotechnol & Nat Resources, 1664 N Virginia St, Reno, NV 89503 USA. RP Hill, CA (reprint author), Purdue Univ, Coll Agr, Dept Entomol, 901 W State St, W Lafayette, IN 47907 USA.; Hill, CA (reprint author), Purdue Univ, Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN 47907 USA. EM hillca@purdue.edu FU NSF Graduate Research Fellowship [DGE-1333468]; Indiana Clinical and Translational Science Institute Pre-doctoral Training Program [NIH/NCATS-ICTSI TL1 TR000162]; Entomological Society of America, Monsanto Research Grant FX JMG was supported by an NSF Graduate Research Fellowship (Program DGE-1333468) and the Indiana Clinical and Translational Science Institute Pre-doctoral Training Program (NIH/NCATS-ICTSI TL1 TR000162). Research funds provided by the Entomological Society of America, Monsanto Research Grant Award to JMG are gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 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 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD JAN 13 PY 2017 VL 10 AR 24 DI 10.1186/s13071-016-1944-0 PG 14 WC Parasitology SC Parasitology GA EN9MR UT WOS:000396324800001 PM 28086865 ER PT J AU Esser, L Zhou, F Pluchino, KM Shiloach, J Ma, JC Tang, W Gutierrez, C Zhang, A Shukla, S Madigan, JP Zhou, TQ Kwong, PD Ambudkar, SV Gottesman, MM Xia, D AF Esser, Lothar Zhou, Fei Pluchino, Kristen M. Shiloach, Joseph Ma, Jichun Tang, Wai-kwan Gutierrez, Camilo Zhang, Alex Shukla, Suneet Madigan, James P. Zhou, Tongqing Kwong, Peter D. Ambudkar, Suresh V. Gottesman, Michael M. Xia, Di TI Structures of the Multidrug Transporter P-glycoprotein Reveal Asymmetric ATP Binding and the Mechanism of Polyspecificity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ABC TRANSPORTER; DRUG-BINDING; CRYSTAL-STRUCTURE; CATALYTIC CYCLE; NUCLEOTIDE; RESISTANCE; SITES; FLEXIBILITY; HYDROLYSIS; STATE AB P-glycoprotein (P-gp) is a polyspecific ATP-dependent transporter linked to multidrug resistance in cancer; it plays important roles in determining the pharmacokinetics of many drugs. Understanding the structural basis of P-gp, substrate polyspecificity has been hampered by its intrinsic flexibility, which is facilitated by a 75-residue linker that connects the two halves of P-gp. Here we constructed a mutant murine P-gp with a shortened linker to facilitate structural determination. Despite dramatic reduction in rhodamine 123 and calcein-AM transport, the linker-shortened mutant P-gp possesses basal ATPase activity and binds ATP only in its N-terminal nucleotide-binding domain. Nine independently determined structures of wild type, the linker mutant, and a methylated P-gp at up to 3.3 angstrom resolution display significant movements of individual transmembrane domain helices, which correlated with the opening and closing motion of the two halves of P-gp. The open-and-close motion alters the surface topology of P-gp within the drug-binding pocket, providing a mechanistic explanation for the polyspecificity of P-gp in substrate interactions. C1 [Esser, Lothar; Zhou, Fei; Pluchino, Kristen M.; Ma, Jichun; Tang, Wai-kwan; Gutierrez, Camilo; Zhang, Alex; Shukla, Suneet; Madigan, James P.; Ambudkar, Suresh V.; Gottesman, Michael M.; Xia, Di] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37,Rm 2122C,37 Convent Dr, Bethesda, MD 20892 USA. [Shiloach, Joseph] NIDDK, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. [Zhou, Tongqing; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Rm 2122C,37 Convent Dr, Bethesda, MD 20892 USA. EM xiad@mail.nih.gov FU Intramural Research Program of the NCI, Center for Cancer Research, National Institutes of Health FX This work was supported by the Intramural Research Program of the NCI, Center for Cancer Research, National Institutes of Health. 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 61 TC 0 Z9 0 U1 7 U2 7 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 13 PY 2017 VL 292 IS 2 BP 446 EP + DI 10.1074/jbc.M116.755884 PG 28 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EI2KN UT WOS:000392316100004 PM 27864369 ER PT J AU Beg, I Minton, AP Islam, A Hassan, MI Ahmad, F AF Beg, Ilyas Minton, Allen P. Islam, Asimul Hassan, Md. Imtaiyaz Ahmad, Faizan TI The pH Dependence of Saccharides' Influence on Thermal Denaturation of Two Model Proteins Supports an Excluded Volume Model for Stabilization Generalized to Allow for Intramolecular Electrostatic Interactions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GUANIDINE-HYDROCHLORIDE; TREHALOSE SYNTHESIS; ORGANIC OSMOLYTES; CHARGE-DENSITY; IN-VITRO; STABILITY; THERMOTOLERANCE; POLYELECTROLYTE; ACQUISITION; EQUILIBRIA AB The reversible thermal denaturation of apo alpha-lactalbumin (alpha-LA) and lysozyme was measured in the absence and presence of multiple concentrations of each of seven saccharides (glucose, galactose, fructose, sucrose, trehalose, raffinose, and stachyose) at multiple pH values. It was observed that with increasing pH, the absolute stability of alpha-LA decreased, whereas the stabilizing effect per mole of all saccharides increased, and that the absolute stability of lysozyme increased, whereas the stabilizing effect per mole of all saccharides decreased. All of the data may be accounted for quantitatively by straightforward electrostatic generalization of a previously introduced coarse-grained model for stabilization of proteins by sugars. C1 [Beg, Ilyas; Islam, Asimul; Hassan, Md. Imtaiyaz; Ahmad, Faizan] Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi 110025, India. [Minton, Allen P.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Ahmad, F (reprint author), Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi 110025, India.; Minton, AP (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM minton@helix.nih.gov; fahmad@jmi.ac.in OI Minton, Allen/0000-0001-8459-1247 FU Council of Scientific and Industrial Research, India [37(1603)/13/EMRII, 37(1604)/13/EMRII)]; National Institutes of Health Intramural Research Program of the NIDDK FX This work was supported by Council of Scientific and Industrial Research, India, Research Grants 37(1603)/13/EMRII and 37(1604)/13/EMRII) (to F. A. and A. I.) and the National Institutes of Health Intramural Research Program of the NIDDK (to A. P. M). 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 35 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 13 PY 2017 VL 292 IS 2 BP 505 EP + DI 10.1074/jbc.M116.757302 PG 27 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EI2KN UT WOS:000392316100008 PM 27909048 ER PT J AU Bullock, A Burrows, NR Narva, AS Sheff, K Hora, I Lekiachvili, A Cain, H Espey, D AF Bullock, Ann Burrows, Nilka Rios Narva, Andrew S. Sheff, Karen Hora, Israel Lekiachvili, Akaki Cain, Hannah Espey, David TI Vital Signs: Decrease in Incidence of Diabetes-Related End-Stage Renal Disease among American Indians/Alaska Natives - United States, 1996-2013 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID KIDNEY-DISEASE; NEPHROPATHY; MELLITUS; OUTCOMES; CARE AB Background: American Indians and Alaska Natives (AI/AN) have the highest diabetes prevalence among any racial/ethnic group in the United States. Among AI/AN, diabetes accounts for 69% of new cases of end-stage renal disease (ESRD), defined as kidney failure treated with dialysis or transplantation. During 1982-1996, diabetes-related ESRD (ESRD-D) in AI/AN increased substantially and disproportionately compared with other racial/ethnic groups. Methods: Data from the U.S. Renal Data System, the Indian Health Service (IHS), the National Health Interview Survey, and the U.S. Census were used to calculate ESRD-D incidence rates by race/ethnicity among U.S. adults aged =18 years during 1996-2013 and in the diabetic population during 2006-2013. Rates were age-adjusted based on the 2000 U.S. standard population. IHS clinical data from the Diabetes Cares and Outcomes Audit were analyzed for diabetes management measures in AI/AN. Results: Among AI/AN adults, age-adjusted ESRD-D rates per 100,000 population decreased 54%, from 57.3 in 1996 to 26.5 in 2013. Although rates for adults in other racial/ethnic groups also decreased during this period, AI/AN had the steepest decline. Among AI/AN with diabetes, ESRD-D incidence decreased during 2006-2013 and, by 2013, was the same as that for whites. Measures related to the assessment and treatment of ESRD-D risk factors also showed more improvement during this period in AI/AN than in the general population. Conclusion and Implications for Public Health Practice: Despite well-documented health and socioeconomic disparities among AI/AN, ESRD-D incidence rates among this population have decreased substantially since 1996. This decline followed implementation by the IHS of public health and population management approaches to diabetes accompanied by improvements in clinical care beginning in the mid-1980s. These approaches might be a useful model for diabetes management in other health care systems, especially those serving populations at high risk. C1 [Bullock, Ann; Sheff, Karen] Indian Hlth Serv, Div Diabet Treatment & Prevent, Rockville, MD USA. [Burrows, Nilka Rios; Hora, Israel] CDC, Div Diabet Translat, Atlanta, GA 30333 USA. [Narva, Andrew S.] NIDDK, NIH, Bethesda, MD 20892 USA. [Lekiachvili, Akaki; Espey, David] CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Cain, Hannah] CDC, Off State Tribal Local & Terr Support, Atlanta, GA 30333 USA. RP Burrows, NR (reprint author), CDC, Div Diabet Translat, Atlanta, GA 30333 USA. EM NRios@cdc.gov NR 19 TC 0 Z9 0 U1 3 U2 3 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD JAN 13 PY 2017 VL 66 IS 1 BP 26 EP 32 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EI2YO UT WOS:000392356300006 PM 28081061 ER PT J AU Chung, YW Ahmad, F Tang, Y Hockman, SC Kee, HJ Berger, K Guirguis, E Choi, YH Schimel, DM Aponte, AM Park, S Degerman, E Manganiello, VC AF Chung, Youn Wook Ahmad, Faiyaz Tang, Yan Hockman, Steven C. Kee, Hyun Jung Berger, Karin Guirguis, Emilia Choi, Young Hun Schimel, Dan M. Aponte, Angel M. Park, Sunhee Degerman, Eva Manganiello, Vincent C. TI White to beige conversion in PDE3B KO adipose tissue through activation of AMPK signaling and mitochondrial function SO SCIENTIFIC REPORTS LA English DT Article ID DEPENDENT PROTEIN-KINASE; FATTY-ACID OXIDATION; BROWN ADIPOCYTE DIFFERENTIATION; ENERGY HOMEOSTASIS; TRANSCRIPTIONAL CONTROL; ADAPTIVE THERMOGENESIS; INSULIN-RESISTANCE; 3T3-L1 ADIPOCYTES; METABOLIC-CONTROL; TUMOR-SUPPRESSOR AB Understanding mechanisms by which a population of beige adipocytes is increased in white adipose tissue (WAT) reflects a potential strategy in the fight against obesity and diabetes. Cyclic adenosine monophosphate (cAMP) is very important in the development of the beige phenotype and activation of its thermogenic program. To study effects of cyclic nucleotides on energy homeostatic mechanisms, mice were generated by targeted inactivation of cyclic nucleotide phosphodiesterase 3b (Pde3b) gene, which encodes PDE3B, an enzyme that catalyzes hydrolysis of cAMP and cGMP and is highly expressed in tissues that regulate energy homeostasis, including adipose tissue, liver, and pancreas. In epididymal white adipose tissue (eWAT) of PDE3B KO mice on a SvJ129 background, cAMP/protein kinase A (PKA) and AMP-activated protein kinase (AMPK) signaling pathways are activated, resulting in "browning" phenotype, with a smaller increases in body weight under high-fat diet, smaller fat deposits, increased beta-oxidation of fatty acids (FAO) and oxygen consumption. Results reported here suggest that PDE3B and/or its downstream signaling partners might be important regulators of energy metabolism in adipose tissue, and potential therapeutic targets for treating obesity, diabetes and their associated metabolic disorders. C1 [Chung, Youn Wook; Ahmad, Faiyaz; Tang, Yan; Hockman, Steven C.; Guirguis, Emilia; Choi, Young Hun; Park, Sunhee; Manganiello, Vincent C.] NHLBI, CPB, NIH, Bldg 10, Bethesda, MD 20892 USA. [Chung, Youn Wook] Yonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, Seoul 03722, South Korea. [Kee, Hyun Jung] Yonsei Univ, Dept Surg, Coll Med, Seoul 03722, South Korea. [Berger, Karin; Degerman, Eva] Lund Univ, Dept Expt Med Sci, Ctr Diabet, S-22184 Lund, Sweden. [Schimel, Dan M.] NIH, NIH MRI Res Facil, Bldg 10, Bethesda, MD 20892 USA. [Aponte, Angel M.] NHLBI, Prote Core Facil, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Chung, YW (reprint author), NHLBI, CPB, NIH, Bldg 10, Bethesda, MD 20892 USA.; Chung, YW (reprint author), Yonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, Seoul 03722, South Korea. EM chungyw@yuhs.ac FU Intramural Research Programs (NIH/NHLBI); Intramural Research Programs (NIDDK); Basic Science Research Program through the National Research Foundation of Korea (NRF); Ministry of Education [NRF-2015R1D1A1A01057981]; Swedish Diabetes Society; Albert Pahlsson Foundation [DIA 2014-031, DIA 2014-2832] FX We thank Dr. Bruce M. Spiegelman for providing PGC-1 alpha adenovirus, which was used to infect H4IIE hepatoma cells to produce PGC-1 alpha protein. We also acknowledge the NIDDK Mouse Metabolism Core for indirect calorimetry data. This work was supported in part by the Intramural Research Programs (NIH/NHLBI and NIDDK). Y.W.C. was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2015R1D1A1A01057981). K.B. and E.D. were supported by the Swedish Diabetes Society and the Albert Pahlsson Foundation, DIA 2014-031 and DIA 2014-2832, respectively. Dr. Manganiello died prior to completion of the manuscript. Joel Moss, a long-time colleague, assisted with review of the data and completion of the manuscript. NR 102 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 13 PY 2017 VL 7 AR 40445 DI 10.1038/srep40445 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI0NZ UT WOS:000392172500001 PM 28084425 ER PT J AU Ghitza, UE AF Ghitza, Udi E. TI Commentary: Addictions Neuroclinical Assessment: A Neuroscience-Based Framework for Addictive Disorders SO FRONTIERS IN PSYCHIATRY LA English DT Editorial Material DE addiction; addictive disorders; addiction treatment; drug abuse; drug abuse treatment; personalized medicine; precision medicine; substance abuse ID RDOC C1 [Ghitza, Udi E.] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. RP Ghitza, UE (reprint author), NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. EM ghitzau@nida.nih.gov FU Center for the Clinical Trials Network, NIDA FX UG is a Health Scientist Administrator, Program Official, at the Center for the Clinical Trials Network, NIDA, which is the funding agency for the National Drug Abuse Treatment Clinical Trials Network. This commentary was supported through UG's duties as a Health Scientist Administrator. NR 10 TC 0 Z9 0 U1 6 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-0640 J9 FRONT PSYCHIATRY JI Front. Psychiatry PD JAN 13 PY 2017 VL 8 AR 2 DI 10.3389/fpsyt.2017.00002 PG 3 WC Psychiatry SC Psychiatry GA EH5JO UT WOS:000391809400001 PM 28133452 ER PT J AU Barrett, AJ AF Barrett, Austin John TI Transplant biomarkers ready for the clinic? SO BLOOD LA English DT Editorial Material ID VERSUS-HOST-DISEASE; T-CELLS; GVHD; ST2 C1 [Barrett, Austin John] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Barrett, AJ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 3 U2 3 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 12 PY 2017 VL 129 IS 2 BP 137 EP 139 DI 10.1182/blood-2016-11-751842 PG 5 WC Hematology SC Hematology GA EO2LO UT WOS:000396528200004 PM 28082289 ER PT J AU Iwamura, C Bouladoux, N Belkaid, Y Sher, A Jankovic, D AF Iwamura, Chiaki Bouladoux, Nicolas Belkaid, Yasmine Sher, Alan Jankovic, Dragana TI Sensing of the microbiota by NOD1 in mesenchymal stromal cells regulates murine hematopoiesis SO BLOOD LA English DT Article ID GUT MICROBIOTA; STEM-CELLS; BACTERIAL-INFECTION; IMMUNE-SYSTEM; PEPTIDOGLYCAN; DISEASE AB The microbiota is known to influence the generation of hematopoietic progenitors, although the pathways underlying this process are still poorly understood. NOD1 and NOD2 are intracellular sensors for both Gram-positive and Gram-negative bacteria, but their role in steady-state hematopoiesis has never been characterized. We observed that stimulation with NOD1 or NOD2 ligand had no effect on the survival/ proliferation of hematopoietic precursors. Nonetheless, NOD1, but not NOD2, ligand induced expression of multiple hematopoietic cytokines (interleukin-7 [IL-7], Flt3L, stem cell factor [SCF], ThPO, and IL-6) from bone marrow mesenchymal stromal cells (MSCs) in vitro. Moreover, in vivo administration of NOD1 ligand to germ-free mice restored the numbers of hematopoietic stem cells and precursors in bone marrow as well as serum concentrations of IL-7, Flt3L, SCF, and ThPO to the levels displayed by specific pathogen-free control animals. Based on these findings, we propose that NOD1 signaling in MSCs serves as an important pathway underlying the requirement for microbiota in the maintenance of steady-state hematopoiesis. This function is distinct from that triggered by lipopolysaccharide in both its broad effects on multiple progenitors and specific targeting of MSCs as cytokine producing intermediates. C1 [Iwamura, Chiaki; Sher, Alan; Jankovic, Dragana] NIAID, Immunobiol Sect, Parasit Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bouladoux, Nicolas; Belkaid, Yasmine] NIAID, Microbiome Program, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bouladoux, Nicolas; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Jankovic, D (reprint author), BG33 RM 1W10A3,33 North Dr, Bethesda, MD 20814 USA. EM djankovic@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Uehara Memorial Foundation FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by a fellowship from the Uehara Memorial Foundation (C.I.). NR 22 TC 1 Z9 1 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 12 PY 2017 VL 129 IS 2 BP 171 EP 176 DI 10.1182/blood-2016-06-723742 PG 6 WC Hematology SC Hematology GA EO2LO UT WOS:000396528200013 PM 27799160 ER PT J AU Kim, J Bowlby, R Mungall, AJ Robertson, AG Odze, RD Cherniack, AD Shih, J Pedamallu, CS Cibulskis, C Dunford, A Meier, SR Kim, J Raphael, BJ Wu, HT Wong, AM Willis, JE Bass, AJ Derks, S Garman, K McCall, SJ Wiznerowicz, M Pantazi, A Parfenov, M Thorsson, V Shmulevich, I Dhankani, V Miller, M Sakai, R Wang, K Schultz, N Shen, R Arora, A Weinhold, N Sanchez-Vega, F Kelsen, DP Zhang, J Felau, I Demchok, J Rabkin, CS Camargo, MC Zenklusen, JC Bowen, J Leraas, K Lichtenberg, TM Curtis, C Seoane, JA Ojesina, AI Beer, DG Gulley, ML Pennathur, A Luketich, JD Zhou, ZR Weisenberger, DJ Akbani, R Lee, JS Liu, W Mills, GB Zhang, W Reid, BJ Hinoue, T Laird, PW Shen, H Piazuelo, MB Schneider, BG McLellan, M Taylor-Weiner, A Cibulskis, C Lawrence, M Cibulskis, K Stewart, C Getz, G Lander, E Gabriel, SB Ding, L McLellan, MD Miller, CA Appelbaum, EL Cordes, MG Fronick, CC Fulton, LA Mardis, ER Wilson, RK Schmidt, HK Fulton, RS Ally, A Balasundaram, M Bowlby, R Carlsen, R Chuah, E Dhalla, N Holt, RA Jones, SJM Kasaian, K Brooks, D Li, HI Ma, Y Marra, MA Mayo, M Moore, RA Mungall, AJ Mungall, KL Robertson, AG Schein, JE Sipahimalani, P Tam, A Thiessen, N Wong, T Cherniack, AD Shih, J Pedamallu, CS Beroukhim, R Bullman, S Cibulskis, C Murray, BA Saksena, G Schumacher, SE Gabriel, S Meyerson, M Hadjipanayis, A Kucherlapati, R Pantazi, A Parfenov, M Ren, X Park, PJ Lee, S Kucherlapati, M Yang, LX Baylin, SB Hoadley, KA Weisenberger, DJ Bootwalla, MS Lai, PH Van den Berg, DJ Berrios, M Holbrook, A Akbani, R Hwang, JE Jang, HJ Liu, WB Weinstein, JN Lee, JS Lu, YL Sohn, BH Mills, G Seth, S Protopopov, A Bristow, CA Mahadeshwar, HS Tang, JB Song, XZ Zhang, JH Laird, PW Hinoue, T Shen, H Cho, J Defrietas, T Frazer, S Gehlenborg, N Heiman, DI Lawrence, MS Lin, P Meier, SR Noble, MS Voet, D Zhang, HL Kim, J Polak, P Saksena, G Chin, L Getz, G Wong, AM Raphael, BJ Wu, HT Lee, S Park, PJ Yang, LX Thorsson, V Bernard, B Iype, L Miller, M Reynolds, SM Shmulevich, I Dhankani, V Abeshouse, A Arora, A Armenia, J Kundra, R Ladanyi, M Kjong-Van Lehmann Gao, J Sander, C Schultz, N Sanchez-Vega, F Shen, RL Weinhold, N Chakravarty, D Zhang, HX Radenbaugh, A Hegde, A Akbani, R Liu, WB Weinstein, JN Chin, L Bristow, CA Lu, YL Penny, R Crain, D Gardner, J Curley, E Mallery, D Morris, S Paulauskis, J Shelton, T Shelton, C Bowen, J Frick, J Gastier-Foster, JM Gerken, M Leraas, KM Lichtenberg, TM Ramirez, NC Wise, L Zmuda, E Tarvin, K Saller, C Park, YS Button, M Carvalho, AL Reis, RM Matsushita, MM Lucchesi, F de Oliveira, AT Le, X Paklina, O Setdikova, G Lee, JH Bennett, J Iacocca, M Huelsenbeck-Dill, L Potapova, CO Voronina, O Liu, O Fulidou, V Cates, C Sharp, A Behera, M Force, S Khuri, F Owonikoko, T Pickens, A Ramalingam, S Sica, G Dinjens, W van Nistelrooij, A Wijnhoven, B Sandusky, G Stepa, S Crain, D Paulauskis, J Penny, R Gardner, J Mallery, D Morris, S Shelton, T Shelton, C Curley, E Juhl, IH Zornig, C Kwon, SY Kelsen, D Kim, GHK Bartlett, J Parfitt, J Chetty, R Darling, G Knox, J Wong, R El-Zimaity, H Liu, G Boussioutas, A Park, DY Kemp, R Carlotti, CG Tirapelli, DPD Saggioro, FP Sankarankutty, AK Noushmehr, H dos Santos, JS Trevisan, FA Eschbacher, J Eschbacher, J Dubina, M Mozgovoy, E Carey, F Chalmers, S Forgie, I Godwin, A Reilly, C Madan, R Naima, Z Ferrer-Torres, D Vinco, M Dhir, R Luketich, J Pennathur, A Ajani, JA McCall, SJ Janjigian, Y Kelsen, D Ladanyi, M Tang, L Camargo, MC Ajani, JA Cheong, JH Chudamani, S Liu, J Lolla, L Naresh, R Pihl, T Sun, Q Wan, YH Wu, Y Demchok, JA Felau, I Ferguson, ML Shaw, KRM Sheth, M Tarnuzzer, R Wang, ZN Yang, LM Zenklusen, JC Hutter, CM Sofia, HJ Zhang, JS AF Kim, Jihun Bowlby, Reanne Mungall, Andrew J. Robertson, A. Gordon Odze, Robert D. Cherniack, Andrew D. Shih, Juliann Pedamallu, Chandra Sekhar Cibulskis, Carrie Dunford, Andrew Meier, Samuel R. Kim, Jaegil Raphael, Benjamin J. Wu, Hsin-Ta Wong, Alexandra M. Willis, Joseph E. Bass, Adam J. Derks, Sarah Garman, Katherine McCall, Shannon J. Wiznerowicz, Maciej Pantazi, Angeliki Parfenov, Michael Thorsson, Vesteinn Shmulevich, Ilya Dhankani, Varsha Miller, Michael Sakai, Ryo Wang, Kenneth Schultz, Nikolaus Shen, Ronglai Arora, Arshi Weinhold, Nils Sanchez-Vega, Francisco Kelsen, David P. Zhang, Julia Felau, Ina Demchok, John Rabkin, Charles S. Camargo, M. Constanza Zenklusen, Jean Claude Bowen, Jay Leraas, Kristen Lichtenberg, Tara M. Curtis, Christina Seoane, Jose A. Ojesina, Akinyemi I. Beer, David G. Gulley, Margaret L. Pennathur, Arjun Luketich, James D. Zhou, Zhongren Weisenberger, Daniel J. Akbani, Rehan Lee, Ju-Seog Liu, Wenbin Mills, Gordon B. Zhang, Wei Reid, Brian J. Hinoue, Toshinori Laird, Peter W. Shen, Hui Piazuelo, M. Blanca Schneider, Barbara G. McLellan, Michael Taylor-Weiner, Amaro Cibulskis, Carrie Lawrence, Michael Cibulskis, Kristian Stewart, Chip Getz, Gad Lander, Eric Gabriel, Stacey B. Ding, Li McLellan, Michael D. Miller, Christopher A. Appelbaum, Elizabeth L. Cordes, Matthew G. Fronick, Catrina C. Fulton, Lucinda A. Mardis, Elaine R. Wilson, Richard K. Schmidt, Heather K. Fulton, Robert S. Ally, Adrian Balasundaram, Miruna Bowlby, Reanne Carlsen, Rebecca Chuah, Eric Dhalla, Noreen Holt, Robert A. Jones, Steven J. M. Kasaian, Katayoon Brooks, Denise Li, Haiyan I. Ma, Yussanne Marra, Marco A. Mayo, Michael Moore, Richard A. Mungall, Andrew J. Mungall, Karen L. Robertson, A. Gordon Schein, Jacqueline E. Sipahimalani, Payal Tam, Angela Thiessen, Nina Wong, Tina Cherniack, Andrew D. Shih, Juliann Pedamallu, Chandra Sekhar Beroukhim, Rameen Bullman, Susan Cibulskis, Carrie Murray, Bradley A. Saksena, Gordon Schumacher, Steven E. Gabriel, Stacey Meyerson, Matthew Hadjipanayis, Angela Kucherlapati, Raju Pantazi, Angeliki Parfenov, Michael Ren, Xiaojia Park, Peter J. Lee, Semin Kucherlapati, Melanie Yang, Lixing Baylin, Stephen B. Hoadley, Katherine A. Weisenberger, Daniel J. Bootwalla, Moiz S. Lai, Phillip H. Van den Berg, David J. Berrios, Mario Holbrook, Andrea Akbani, Rehan Hwang, Jun-Eul Jang, Hee-Jin Liu, Wenbin Weinstein, John N. Lee, Ju-Seog Lu, Yiling Sohn, Bo Hwa Mills, Gordon Seth, Sahil Protopopov, Alexei Bristow, Christopher A. Mahadeshwar, Harshad S. Tang, Jiabin Song, Xingzhi Zhang, Jianhua Laird, Peter W. Hinoue, Toshinori Shen, Hui Cho, Juok Defrietas, Timothy Frazer, Scott Gehlenborg, Nils Heiman, David I. Lawrence, Michael S. Lin, Pei Meier, Samuel R. Noble, Michael S. Doug Voet Zhang, Hailei Kim, Jaegil Polak, Paz Saksena, Gordon Chin, Lynda Getz, Gad Wong, Alexandra M. Raphael, Benjamin J. Wu, Hsin-Ta Lee, Semin Park, Peter J. Yang, Lixing Thorsson, Vesteinn Bernard, Brady Iype, Lisa Miller, Michael Reynolds, Sheila M. Shmulevich, Ilya Dhankani, Varsha Abeshouse, Adam Arora, Arshi Armenia, Joshua Kundra, Ritika Ladanyi, Marc Kjong-Van Lehmann Gao, Jianjiong Sander, Chris Schultz, Nikolaus Sanchez-Vega, Francisco Shen, Ronglai Weinhold, Nils Chakravarty, Debyani Zhang, Hongxin Radenbaugh, Amie Hegde, Apruva Akbani, Rehan Liu, Wenbin Weinstein, John N. Chin, Lynda Bristow, Christopher A. Lu, Yiling Penny, Robert Crain, Daniel Gardner, Johanna Curley, Erin Mallery, David Morris, Scott Paulauskis, Joseph Shelton, Troy Shelton, Candace Bowen, Jay Frick, Jessica Gastier-Foster, Julie M. Gerken, Mark Leraas, Kristen M. Lichtenberg, Tara M. Ramirez, Nilsa C. Wise, Lisa Zmuda, Erik Tarvin, Katherine Saller, Charles Park, Young Soo Button, Michael Carvalho, Andre L. Reis, Rui Manuel Matsushita, Marcus Medeiros Lucchesi, Fabiano de Oliveira, Antonio Talvane Le, Xuan Paklina, Oxana Setdikova, Galiya Lee, Jae-Hyuck Bennett, Joseph Iacocca, Mary Huelsenbeck-Dill, Lori Potapova, Cureline Olga Voronina, Olga Liu, Ouida Fulidou, Victoria Cates, Crystal Sharp, Alexis Behera, Madhusmitara Force, Seth Khuri, Fadio Owonikoko, Taofeek Pickens, Allan Ramalingam, Suresh Sica, Gabriel Dinjens, Winand van Nistelrooij, Anna Wijnhoven, Bas Sandusky, George Stepa, Serghei Crain, Daniel Paulauskis, Joseph Penny, Robert Gardner, Johanna Mallery, David Morris, Scott Shelton, Troy Shelton, Candace Curley, Erin Juhl, Invidumed Hartmut Zornig, Carsten Kwon, Sun Young Kelsen, David Kim, Goyang Hark Kyun Bartlett, John Parfitt, Jeremy Chetty, Runjan Darling, Gail Knox, Jennifer Wong, Rebecca El-Zimaity, Haila Liu, Geoffrey Boussioutas, Alex Park, Do Young Kemp, Rafael Carlotti, Carlos Gilberto, Jr. da Cunha Tirapelli, Daniela Pretti Saggioro, Fabiano Pinto Sankarankutty, Ajith Kumar Noushmehr, Houtan dos Santos, Jose Sebastiao Trevisan, Felipe Amstalden Eschbacher, Jennifer Eschbacher, Jennifer Dubina, Michael Mozgovoy, Eugene Carey, Frank Chalmers, Sally Forgie, Ian Godwin, Andrew Reilly, Colleen Madan, Rashna Naima, Zaid Ferrer-Torres, Daysha Rathmell, W. Kimryn Dhir, Rajiv Luketich, James Pennathur, Arjun Ajani, Jaffer A. McCall, Shannon J. Janjigian, Yelena Kelsen, David Ladanyi, Marc Tang, Laura Camargo, M. Constanza Ajani, Jaffer A. Cheong, Jae-Ho Chudamani, Sudha Liu, Jai Lolla, Laxmi Naresh, Rashi Pihl, Todd Sun, Qiang Wan, Yunhu Wu, Ye Demchok, John A. Felau, Ina Ferguson, Martin L. Shaw, Kenna R. Mills sheth, Margi Tarnuzzer, Roy Wang, Zhining Yang, Liming Zenklusen, Jean Claude Hutter, Carolyn M. Sofia, Heidi J. Zhang, Jiashan CA Canc Genome Atlas Res Network TI Integrated genomic characterization of oesophageal carcinoma SO NATURE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; HUMAN CANCER; ESOPHAGOGASTRIC JUNCTION; STRUCTURAL VARIATIONS; LINEAGE-SURVIVAL; SEQUENCING DATA; ADENOCARCINOMA; GENES; LUNG; IDENTIFICATION AB Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies. C1 [Kim, Jihun; Park, Young Soo] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 05505, South Korea. [Ally, Adrian; Balasundaram, Miruna; Carlsen, Rebecca; Chuah, Eric; Dhalla, Noreen; Holt, Robert A.; Jones, Steven J. M.; Kasaian, Katayoon; Brooks, Denise; Li, Haiyan I.; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Karen L.; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Thiessen, Nina; Wong, Tina] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Odze, Robert D.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Odze, Robert D.; Meyerson, Matthew] Harvard Med Sch, Dept Pathol, Boston, MA 02215 USA. [Cherniack, Andrew D.; Pedamallu, Chandra Sekhar; Dunford, Andrew; Taylor-Weiner, Amaro; Lawrence, Michael; Cibulskis, Kristian; Stewart, Chip; Lander, Eric; Gabriel, Stacey B.; Cherniack, Andrew D.; Pedamallu, Chandra Sekhar; Beroukhim, Rameen; Bullman, Susan; Murray, Bradley A.; Schumacher, Steven E.; Gabriel, Stacey; Cho, Juok; Defrietas, Timothy; Frazer, Scott; Gehlenborg, Nils; Heiman, David I.; Lawrence, Michael S.; Lin, Pei; Noble, Michael S.; Doug Voet; Zhang, Hailei; Polak, Paz] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Pedamallu, Chandra Sekhar; Bass, Adam J.; Derks, Sarah; Cherniack, Andrew D.; Beroukhim, Rameen; Bullman, Susan; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Raphael, Benjamin J.; Wu, Hsin-Ta; Wong, Alexandra M.] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA. [Raphael, Benjamin J.; Wu, Hsin-Ta; Wong, Alexandra M.] Brown Univ, Ctr Computat Mol Biol, Providence, RI 02912 USA. [Willis, Joseph E.] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Willis, Joseph E.] Case Med Ctr, Dept Pathol, Cleveland, OH 44106 USA. [Bass, Adam J.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Derks, Sarah] Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Garman, Katherine; Cates, Crystal; Sharp, Alexis] Duke Univ, Dept Pathol, Durham, NC 27710 USA. [Wiznerowicz, Maciej] Int Inst Mol Oncol, PL-60203 Poznan, Poland. [Wiznerowicz, Maciej] Greater Poland Canc Ctr, PL-61866 Poznan, Poland. [Wiznerowicz, Maciej] Poznan Univ Med Sci, PL-61866 Poznan, Poland. [Hadjipanayis, Angela; Kucherlapati, Raju; Ren, Xiaojia; Kucherlapati, Melanie] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Ren, Xiaojia; Protopopov, Alexei] KEW Grp Inc, Cambridge, MA 02139 USA. [Thorsson, Vesteinn; Bernard, Brady; Iype, Lisa; Reynolds, Sheila M.] Inst Syst Biol, Seattle, WA 98109 USA. [Sakai, Ryo] Katholieke Univ Leuven, Dept Elect Engn ESAT STADIUS, Leuven, Belgium. [Sakai, Ryo] Katholieke Univ Leuven, iMinds Med IT, B-3001 Leuven, Belgium. [Wang, Kenneth] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA. [Schultz, Nikolaus; Armenia, Joshua; Kundra, Ritika; Gao, Jianjiong; Chakravarty, Debyani; Zhang, Hongxin] Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, New York, NY 10065 USA. [Shen, Ronglai] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Abeshouse, Adam; Kjong-Van Lehmann; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Kelsen, David P.; Janjigian, Yelena] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Zhang, Julia; Demchok, John; Demchok, John A.; Ferguson, Martin L.; Shaw, Kenna R. Mills; sheth, Margi; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zhang, Jiashan] NCI, Bethesda, MD 20892 USA. [Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Leraas, Kristen; Frick, Jessica; Gastier-Foster, Julie M.; Gerken, Mark; Leraas, Kristen M.; Ramirez, Nilsa C.; Wise, Lisa; Zmuda, Erik] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA. [Curtis, Christina; Seoane, Jose A.] Stanford Univ, Sch Med, Div Oncol, Dept Med, Stanford, CA 94305 USA. [Curtis, Christina; Seoane, Jose A.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Ojesina, Akinyemi I.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. [Ojesina, Akinyemi I.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Beer, David G.; Ferrer-Torres, Daysha] Univ Michigan, Ctr Comprehens Canc, Dept Thorac Surg, Ann Arbor, MI 48109 USA. [Gulley, Margaret L.] Univ North Carolina Chapel Hill, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Luketich, James D.; Luketich, James] Univ Pittsburgh, Med Ctr, Sch Med, Dept Cardiothorac Surg, Pittsburgh, PA 15213 USA. [Zhou, Zhongren] Univ Rochester, Dept Pathol & Lab Med, Rochester, NY 14642 USA. [Weisenberger, Daniel J.] Univ Southern Calif, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA. [Liu, Wenbin; Weinstein, John N.; Hegde, Apruva] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Lee, Ju-Seog; Mills, Gordon B.; Mills, Gordon] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Zhang, Wei] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Reid, Brian J.] Fred Hutchinson Canc Res Ctr, North Seattle, WA 98109 USA. [Hinoue, Toshinori] Van Andel Res Inst, Ctr Epigenet, Grand Rapids, MI 49503 USA. [Piazuelo, M. Blanca; Schneider, Barbara G.] Vanderbilt Univ, Med Ctr, Div Gastroenterol, Dept Med, Nashville, TN 37232 USA. [McLellan, Michael; Ding, Li; McLellan, Michael D.; Miller, Christopher A.; Appelbaum, Elizabeth L.; Cordes, Matthew G.; Fronick, Catrina C.; Fulton, Lucinda A.; Mardis, Elaine R.; Wilson, Richard K.; Schmidt, Heather K.; Fulton, Robert S.] Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA. [Taylor-Weiner, Amaro; Lee, Semin; Gehlenborg, Nils] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA. [Polak, Paz] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ding, Li] Washington Univ, Sch Med, Dept Med, St Louis, MO 63108 USA. [Beroukhim, Rameen] Harvard Med Sch, Dept Med, Boston, MA 02215 USA. [Schumacher, Steven E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Hadjipanayis, Angela; Kucherlapati, Raju; Kucherlapati, Melanie] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Baylin, Stephen B.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Canc Biol Div, Baltimore, MD 21231 USA. [Hoadley, Katherine A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA. [Bootwalla, Moiz S.; Lai, Phillip H.; Berrios, Mario; Holbrook, Andrea] USC, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Van den Berg, David J.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hwang, Jun-Eul; Jang, Hee-Jin; Lee, Ju-Seog; Sohn, Bo Hwa] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Inst Personalized Canc Treatment, Houston, TX 77030 USA. [Hwang, Jun-Eul] Chonnam Natl Univ, Sch Med, Dept Hematooncol, Kwangju, South Korea. [Seth, Sahil; Protopopov, Alexei; Mahadeshwar, Harshad S.; Tang, Jiabin; Song, Xingzhi; Zhang, Jianhua] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Inst Appl Canc Sci, Houston, TX 77054 USA. [Weinstein, John N.; Le, Xuan; Tang, Laura] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Radenbaugh, Amie] Univ Calif Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA. [Gardner, Johanna; Morris, Scott; Paulauskis, Joseph; Shelton, Troy] Int Genom Consortium, Phoenix, AZ 85004 USA. [Tarvin, Katherine; Saller, Charles] Analyt Biol Serv Inc, Wilmington, DE 19801 USA. [Button, Michael] Asterand Biosci, Detroit, MI 48202 USA. [Carvalho, Andre L.; Reis, Rui Manuel] Barretos Canc Hosp, Mol Oncol Res Ctr, Sao Paulo, Brazil. [Reis, Rui Manuel] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, Braga, Portugal. [Matsushita, Marcus Medeiros] Barretos Canc Hosp, Dept Pathol, Sao Paulo, Brazil. [Lucchesi, Fabiano] Barretos Canc Hosp, Dept Radiol, Sao Paulo, Brazil. [de Oliveira, Antonio Talvane] Barretos Canc Hosp, Dept Surg, Sao Paulo, Brazil. [Le, Xuan] BioreclamationIVT, Dept Res Pathol, Chestertown, MD 21620 USA. [Paklina, Oxana; Setdikova, Galiya] Botkin Municipal Clin, Moscow 125284, Russia. [Lee, Jae-Hyuck] Chonnam Natl Univ, Sch Med, Dept Pathol, Hwasun, South Korea. [Bennett, Joseph; Iacocca, Mary; Huelsenbeck-Dill, Lori] Christiana Care Hlth Syst, Helen F Graham Canc Ctr & Res Inst, Newark, DE 19713 USA. [Potapova, Cureline Olga; Voronina, Olga; Liu, Ouida; Fulidou, Victoria] Cureline Inc, San Francisco, CA 94080 USA. [Behera, Madhusmitara; Force, Seth; Khuri, Fadio; Owonikoko, Taofeek; Pickens, Allan; Ramalingam, Suresh; Sica, Gabriel] Emory Univ, Atlanta, GA 30322 USA. [Behera, Madhusmitara; Force, Seth; Khuri, Fadio; Owonikoko, Taofeek; Pickens, Allan; Ramalingam, Suresh; Sica, Gabriel] Winship Canc Inst, Atlanta, GA 30322 USA. [Dinjens, Winand] Univ Med Ctr, Erasmus MC Canc Inst, Dept Pathol, NL-3000 CA Rotterdam, Netherlands. [van Nistelrooij, Anna; Wijnhoven, Bas] Univ Med Ctr Rotterdam, Erasmus MC Canc Inst, Dept Surg, NL-3000 CA Rotterdam, Netherlands. [van Nistelrooij, Anna] Univ Med Ctr Rotterdam, Erasmus MC Canc Inst, Dept Pathol, NL-3000 CA Rotterdam, Netherlands. [Sandusky, George] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. [Stepa, Serghei] Inst Oncol Moldova, Kishinev, Moldova. [Juhl, Invidumed Hartmut] Indivumed GmbH, D-20251 Hamburg, Germany. [Zornig, Carsten] Israelit Krankenhaus Hamburg, D-22297 Hamburg, Germany. [Kwon, Sun Young] Keimyung Univ, Sch Med, Dept Pathol, Daegu, South Korea. [Kim, Goyang Hark Kyun] Natl Canc Ctr, Ctr Gastr Canc, Goyang, South Korea. [Bartlett, John] Ontario Inst Canc Res, Ontario Tumour Bank, Toronto, ON M5G 0A3, Canada. [Parfitt, Jeremy] London Hlth Sci Ctr, Ontario Tumour Bank, London, ON N6A 5A5, Canada. [Chetty, Runjan; Darling, Gail; Knox, Jennifer; Wong, Rebecca; El-Zimaity, Haila; Liu, Geoffrey] Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada. [Boussioutas, Alex] Univ Melbourne, Sir Peter MacCallum Canc Dept Oncol, Melbourne, Vic 3002, Australia. [Park, Do Young] Pusan Natl Univ, Sch Med, Dept Pathol, Pusan, South Korea. [Kemp, Rafael; Carlotti, Carlos Gilberto, Jr.; da Cunha Tirapelli, Daniela Pretti; Sankarankutty, Ajith Kumar; dos Santos, Jose Sebastiao; Trevisan, Felipe Amstalden] Univ Sao Paulo, Ribeirao Preto Med School FMRP, Dept Surg & Anat, BR-14049900 Sao Paulo, Brazil. [Saggioro, Fabiano Pinto] Univ Sao Paulo, Ribeirao Preto Med School FMRP, Dept Pathol, BR-14049900 Sao Paulo, Brazil. [Noushmehr, Houtan] Univ Sao Paulo, Ribeirao Preto Med School FMRP, Dept Genet, BR-14049900 Sao Paulo, Brazil. [Eschbacher, Jennifer] St Josephs Hosp, Dept Pathol, Phoenix, AZ 85013 USA. [Dubina, Michael; Mozgovoy, Eugene] St Petersburg Acad Univ, RAS, St Petersburg 194021, Russia. [Carey, Frank; Chalmers, Sally; Forgie, Ian] Univ Dundee, Ninewells Hosp & Med Sch, Tayside Tissue Bank, Dundee DD1 9SY, Scotland. [Godwin, Andrew; Reilly, Colleen; Madan, Rashna; Naima, Zaid] Univ Kansas, Med Ctr, Kansas City, KS 66160 USA. [Ferrer-Torres, Daysha] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Rathmell, W. Kimryn] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Dept Med, Chapel Hill, NC 27599 USA. [Dhir, Rajiv] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Ajani, Jaffer A.] Univ Texas MD Anderson Canc Ctr, Dept GI Med Oncol, Houston, TX 77030 USA. [Cheong, Jae-Ho] Yonsei Univ, Coll Med, Dept Surg, Seoul 120752, South Korea. [Chudamani, Sudha; Liu, Jai; Lolla, Laxmi; Wu, Ye] Leidos Biomed, Rockville, MD 20850 USA. [Naresh, Rashi; Pihl, Todd; Sun, Qiang; Wan, Yunhu] CSRA Inc, Falls Church, VA 22042 USA. [Hutter, Carolyn M.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Bass, AJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Bass, AJ (reprint author), Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA.; Thorsson, V (reprint author), Inst Syst Biol, Seattle, WA 98109 USA. EM adam_bass@dfci.harvard.edu; Vesteinn.Thorsson@systemsbiology.org RI Carlotti, Carlos/C-1608-2012; OI Carlotti, Carlos/0000-0002-7055-0564; Reis, Rui/0000-0002-9639-7940 FU Intramural Research Program; United States National Institutes of Health [5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273, P30CA16672] FX We are grateful to all patients who contributed to this study, to K. Hoadley and R. Kucherlapati for scientific editing, and to J. Zhang and I. Felau for administrative support. This work was supported by the Intramural Research Program and the following grants from the United States National Institutes of Health: 5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, and U54HG003273, P30CA16672. NR 58 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 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JAN 12 PY 2017 VL 541 IS 7636 BP 169 EP + DI 10.1038/nature20805 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6PI UT WOS:000396125500030 ER PT J AU Qiang, W Yau, WM Lu, JX Collinge, J Tycko, R AF Qiang, Wei Yau, Wai-Ming Lu, Jun-Xia Collinge, John Tycko, Robert TI Structural variation in amyloid-beta fibrils from Alzheimer's disease clinical subtypes SO NATURE LA English DT Article ID ATOMIC-RESOLUTION STRUCTURE; PRION STRAINS; POLYMORPHISM; MODEL; MICE AB Aggregation of amyloid-beta peptides into fibrils or other self-assembled states is central to the pathogenesis of Alzheimer's disease. Fibrils formed in vitro by 40- and 42-residue amyloid-beta peptides (A beta 40 and A beta 42) are polymorphic, with variations in molecular structure that depend on fibril growth conditions(1-12). Recent experiments(1,13-16) suggest that variations in amyloid-beta fibril structure in vivo may correlate with variations in Alzheimer's disease phenotype, in analogy to distinct prion strains that are associated with different clinical and pathological phenotypes(17-19). Here we investigate correlations between structural variation and Alzheimer's disease phenotype using solid-state nuclear magnetic resonance (ssNMR) measurements on A beta 40 and A beta 42 fibrils prepared by seeded growth from extracts of Alzheimer's disease brain cortex. We compared two atypical Alzheimer's disease clinical subtypes-the rapidly progressive form (r-AD) and the posterior cortical atrophy variant (PCA-AD)-with a typical prolonged-duration form (t-AD). On the basis of ssNMR data from 37 cortical tissue samples from 18 individuals, we find that a single A beta 40 fibril structure is most abundant in samples from patients with t-AD and PCA-AD, whereas A beta 40 fibrils from r-AD samples exhibit a significantly greater proportion of additional structures. Data for A beta 42 fibrils indicate structural heterogeneity in most samples from all patient categories, with at least two prevalent structures. These results demonstrate the existence of a specific predominant A beta 40 fibril structure in t-AD and PCA-AD, suggest that r-AD may relate to additional fibril structures and indicate that there is a qualitative difference between A beta 40 and A beta 42 aggregates in the brain tissue of patients with Alzheimer's disease. C1 [Qiang, Wei; Yau, Wai-Ming; Lu, Jun-Xia; Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Collinge, John] UCL Inst Neurol, MRC Prion Unit, London WC1N 3BG, England. [Collinge, John] UCL Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England. [Qiang, Wei] SUNY Binghamton, Dept Chem, Binghamton, NY 13902 USA. [Lu, Jun-Xia] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA.; Collinge, J (reprint author), UCL Inst Neurol, MRC Prion Unit, London WC1N 3BG, England.; Collinge, J (reprint author), UCL Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England. EM jc@prion.ucl.ac.uk; robertty@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases of the US National Institutes of Health; UK Medical Research Council; National Institute of Health Research (NIHR) UCLH/UCL Biomedical Research Centre; Reta Lila Weston Trust for Medical Research; Progressive Supranuclear Palsy [Europe] Association; Medical Research Council FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the US National Institutes of Health, by the UK Medical Research Council and by the National Institute of Health Research (NIHR) UCLH/UCL Biomedical Research Centre. We are grateful for the assistance of S. Mead, O. Avwenagha, and J. Wadsworth at the MRC Prion Unit in selection and processing of tissue samples. We thank UK neurologists for referral of rapidly progressive dementias to the NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery (NHNN), University College London Hospitals NHS Foundation Trust (UCLH). We thank the Queen Square Brain Bank for Neurological Disorders (supported by the Reta Lila Weston Trust for Medical Research, the Progressive Supranuclear Palsy [Europe] Association and the Medical Research Council) at the UCL Institute of Neurology, for provision of the human brain tissue samples. We thank all patients and their families for consent to use tissues in research. NR 30 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 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JAN 12 PY 2017 VL 541 IS 7636 BP 217 EP + DI 10.1038/nature20814 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6PI UT WOS:000396125500041 PM 28052060 ER PT J AU Stagno, JR Liu, Y Bhandari, YR Conrad, CE Panja, S Swain, M Fan, L Nelson, G Li, C Wendel, DR White, TA Coe, JD Wiedorn, MO Knoska, J Oberthuer, D Tuckey, RA Yu, P Dyba, M Tarasov, SG Weierstall, U Grant, TD Schwieters, CD Zhang, J Ferre-D'Amare, AR Fromme, P Draper, DE Liang, M Hunter, MS Boutet, S Tan, K Zuo, X Ji, X Barty, A Zatsepin, NA Chapman, HN Spence, JCH Woodson, SA Wang, YX AF Stagno, J. R. Liu, Y. Bhandari, Y. R. Conrad, C. E. Panja, S. Swain, M. Fan, L. Nelson, G. Li, C. Wendel, D. R. White, T. A. Coe, J. D. Wiedorn, M. O. Knoska, J. Oberthuer, D. Tuckey, R. A. Yu, P. Dyba, M. Tarasov, S. G. Weierstall, U. Grant, T. D. Schwieters, C. D. Zhang, J. Ferre-D'Amare, A. R. Fromme, P. Draper, D. E. Liang, M. Hunter, M. S. Boutet, S. Tan, K. Zuo, X. Ji, X. Barty, A. Zatsepin, N. A. Chapman, H. N. Spence, J. C. H. Woodson, S. A. Wang, Y. -X. TI Structures of riboswitch RNA reaction states by mix-and-inject XFEL serial crystallography SO NATURE LA English DT Article ID X-RAY-DIFFRACTION; PHOTOACTIVE YELLOW PROTEIN; STANDARD ATOMIC VOLUMES; FEMTOSECOND CRYSTALLOGRAPHY; BINDING RIBOSWITCHES; MOLECULAR-STRUCTURE; ADENINE RIBOSWITCH; GENETIC-CONTROL; SCATTERING DATA; LIGAND AB Riboswitches are structural RNA elements that are generally located in the 5' untranslated region of messenger RNA. During regulation of gene expression, ligand binding to the aptamer domain of a riboswitch triggers a signal to the downstream expression platform(1-3). A complete understanding of the structural basis of this mechanism requires the ability to study structural changes over time(4). Here we use femtosecond X-ray free electron laser (XFEL) pulses(5,6) to obtain structural measurements from crystals so small that diffusion of a ligand can be timed to initiate a reaction before diffraction. We demonstrate this approach by determining four structures of the adenine riboswitch aptamer domain during the course of a reaction, involving two unbound apo structures, one ligand-bound intermediate, and the final ligand-bound conformation. These structures support a reaction mechanism model with at least four states and illustrate the structural basis of signal transmission. The three-way junction and the P1 switch helix of the two apo conformers are notably different from those in the ligand-bound conformation. Our time-resolved crystallographic measurements with a 10-second delay captured the structure of an intermediate with changes in the binding pocket that accommodate the ligand. With at least a 10-minute delay, the RNA molecules were fully converted to the ligand-bound state, in which the substantial conformational changes resulted in conversion of the space group. Such notable changes in crystallo highlight the important opportunities that micro-and nanocrystals may offer in these and similar time-resolved diffraction studies. Together, these results demonstrate the potential of 'mix-and-inject' time-resolved serial crystallography to study biochemically important interactions between biomacromolecules and ligands, including those that involve large conformational changes. C1 [Stagno, J. R.; Liu, Y.; Bhandari, Y. R.; Swain, M.; Wendel, D. R.; Tuckey, R. A.; Yu, P.; Dyba, M.; Tarasov, S. G.; Wang, Y. -X.] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Conrad, C. E.; Coe, J. D.; Fromme, P.] Arizona State Univ, Dept Biochem, Tempe, AZ 85287 USA. [Conrad, C. E.; Coe, J. D.; Weierstall, U.; Fromme, P.; Zatsepin, N. A.; Spence, J. C. H.] Arizona State Univ, Biodesign Inst, Ctr Appl Struct Discovery, Tempe, AZ 85287 USA. [Panja, S.; Woodson, S. A.] Johns Hopkins Univ, Dept Biophys, Baltimore, MD 21218 USA. [Fan, L.] NCI, Small Angle Xray Scattering Core Facil, Ctr Canc Res, Frederick, MD 21702 USA. [Nelson, G.; Li, C.; Weierstall, U.; Zatsepin, N. A.; Spence, J. C. H.] Arizona State Univ, Dept Phys, Tempe, AZ 85287 USA. [White, T. A.; Wiedorn, M. O.; Knoska, J.; Oberthuer, D.; Barty, A.; Chapman, H. N.] Deutsch Elektronen Synchrotron DESY, Ctr Free Electron Laser Sci, Notkestr 85, D-22607 Hamburg, Germany. [Wiedorn, M. O.; Knoska, J.; Chapman, H. N.] Univ Hamburg, Dept Phys, Luruper Chaussee 149, D-22607 Hamburg, Germany. [Grant, T. D.] Hauptmann Woodward Med Res Inst, Buffalo, NY 14203 USA. [Schwieters, C. D.] NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Zhang, J.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Ferre-D'Amare, A. R.] NHLBI, Lab RNA Biophys & Cellular Physiol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Draper, D. E.] Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. [Liang, M.; Hunter, M. S.; Boutet, S.] SLAC Natl Accelerator Lab, Linac Coherent Light Source, Menlo Pk, CA 94025 USA. [Tan, K.] Argonne Natl Lab, Adv Photon Source, Struct Biol Ctr, Biosci Div, Argonne, IL 60439 USA. [Zuo, X.] Argonne Natl Lab, Adv Photon Source, Xray Sci Div, Argonne, IL 60439 USA. [Ji, X.] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Wang, YX (reprint author), NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM wangyunx@mail.nih.gov FU LCLS Ultrafast Science Instruments (LUSI) project - US Department of Energy, Office of Basic Energy Sciences; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]; NSF-STC "BioXFEL" [NSF-1231306]; NIH Intramural Research Program of NCI; NIH Intramural Research Program of CIT; NIH Intramural Research Program of NHLBI; NIH Intramural Research Program of US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]; European Research Council [ERC-2013-SyG 609920]; BMBF [05K16GU1] FX Portions of this research were carried out at the Linac Coherent Light Source, a National User Facility operated by Stanford University on behalf of the US Department of Energy, Office of Basic Energy Sciences. The CXI instrument was funded by the LCLS Ultrafast Science Instruments (LUSI) project funded by the US Department of Energy, Office of Basic Energy Sciences. Use of the Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. We thank J. Strathern and M. Dunne for their support and S. Wakatsuki for discussions. This work is supported in part by the NSF-STC "BioXFEL" (NSF-1231306), the NIH Intramural Research Programs of NCI, CIT, NHLBI, and the US Department of Energy, Office of Biological and Environmental Research under Contract DE-AC02-06CH11357, the European Research Council, "Frontiers in Attosecond X-ray Science: Imaging and Spectroscopy (AXSIS)", ERC-2013-SyG 609920, and the BMBF through project 05K16GU1. NR 55 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 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JAN 12 PY 2017 VL 541 IS 7636 BP 242 EP + DI 10.1038/nature20599 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6PI UT WOS:000396125500046 PM 27841871 ER PT J AU Zhang, Q Lenardo, MJ Baltimore, D AF Zhang, Qian Lenardo, Michael J. Baltimore, David TI 30 Years of NF-kappa B: A Blossoming of Relevance to Human Pathobiology SO CELL LA English DT Review ID HERPES-SIMPLEX ENCEPHALITIS; HYPOHIDROTIC ECTODERMAL DYSPLASIA; COMMON VARIABLE IMMUNODEFICIENCY; PYOGENIC BACTERIAL-INFECTIONS; BETA-BINDING PROTEIN; DEFICIENT MICE; LYMPHOCYTE-ACTIVATION; ANTIGEN-RECEPTOR; IMMUNE-SYSTEM; FRONTOMETAPHYSEAL DYSPLASIA AB NF-kappa B was discovered 30 years ago as a rapidly inducible transcription factor. Since that time, it has been found to have a broad role in gene induction in diverse cellular responses, particularly throughout the immune system. Here, we summarize elaborate regulatory pathways involving this transcription factor and use recent discoveries in human genetic diseases to place specific proteins within their relevant medical and biological contexts. C1 [Zhang, Qian] Sidra Med & Res Ctr, Dept Translat Med, Doha, Qatar. [Lenardo, Michael J.] NIAID, Mol Dev Immune Syst Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lenardo, Michael J.] NIAID, NIAID Clin Genom Program, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Baltimore, David] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. RP Lenardo, MJ (reprint author), NIAID, Mol Dev Immune Syst Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Lenardo, MJ (reprint author), NIAID, NIAID Clin Genom Program, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lenardo@nih.gov FU Intramural Research Program of the NIAID; Intramural Research Program of the NIH FX We apologize to the many hundreds of colleagues over the past 30 years whose work has created this rich tapestry of science but could not be cited due to space limitations. We thank Sankar Ghosh for critically reading the manuscript. This work was supported by the Intramural Research Program of the NIAID, NIH. NR 138 TC 1 Z9 1 U1 1 U2 1 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 12 PY 2017 VL 168 IS 1-2 BP 37 EP 57 DI 10.1016/j.cell.2016.12.012 PG 21 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN8JM UT WOS:000396246700010 PM 28086098 ER PT J AU Tenente, IM Hayes, MN Ignatius, MS McCarthy, K Yohe, M Sindiri, S Gryder, B Oliveira, ML Ramakrishnan, A Tang, Q Chen, EY Nielsen, GP Khan, J Langenau, DM AF Tenente, Ines M. Hayes, Madeline N. Ignatius, Myron S. McCarthy, Karin Yohe, Marielle Sindiri, Sivasish Gryder, Berkley Oliveira, Mariana L. Ramakrishnan, Ashwin Tang, Qin Chen, Eleanor Y. Nielsen, G. Petur Khan, Javed Langenau, David M. TI Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma SO ELIFE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHILDRENS ONCOLOGY GROUP; ACUTE MYELOID-LEUKEMIA; GENOME-WIDE BINDING; SKELETAL-MUSCLE; EMBRYONAL RHABDOMYOSARCOMA; TRANSGENIC ZEBRAFISH; CELL TRANSPLANTATION; SELF-RENEWAL; SATELLITE CELL AB Rhabdomyosarcoma (RMS) is a pediatric malignacy of muscle with myogenic regulatory transcription factors MYOD and MYF5 being expressed in this disease. Consensus in the field has been that expression of these factors likely reflects the target cell of transformation rather than being required for continued tumor growth. Here, we used a transgenic zebrafish model to show that Myf5 is sufficient to confer tumor-propagating potential to RMS cells and caused tumors to initiate earlier and have higher penetrance. Analysis of human RMS revealed that MYF5 and MYOD are mutually-exclusively expressed and each is required for sustained tumor growth. ChIP-seq and mechanistic studies in human RMS uncovered that MYF5 and MYOD bind common DNA regulatory elements to alter transcription of genes that regulate muscle development and cell cycle progression. Our data support unappreciated and dominant oncogenic roles for MYF5 and MYOD convergence on common transcriptional targets to regulate human RMS growth. C1 [Tenente, Ines M.; Hayes, Madeline N.; Ignatius, Myron S.; McCarthy, Karin; Oliveira, Mariana L.; Ramakrishnan, Ashwin; Tang, Qin; Langenau, David M.] Massachusetts Gen Hosp, Mol Pathol Canc Ctr & Regenerat Med, Boston, MA 02114 USA. [Tenente, Ines M.; Hayes, Madeline N.; Ignatius, Myron S.; McCarthy, Karin; Oliveira, Mariana L.; Ramakrishnan, Ashwin; Tang, Qin; Langenau, David M.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Tenente, Ines M.] Univ Porto, Abel Salazar Biomed Sci Inst, GABBA Program, Oporto, Portugal. [Ignatius, Myron S.] Greehey Childrens Canc Res Inst, Mol Med, San Antonio, TX USA. [Yohe, Marielle; Sindiri, Sivasish; Gryder, Berkley; Khan, Javed] NCI, Adv Technol Ctr, Pediat Oncol Branch, Oncogen Sec, Gaithersburg, MD USA. [Oliveira, Mariana L.] Univ Lisbon, Fac Med, Inst Mol Med, Lisbon, Portugal. [Chen, Eleanor Y.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Nielsen, G. Petur] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Langenau, DM (reprint author), Massachusetts Gen Hosp, Mol Pathol Canc Ctr & Regenerat Med, Boston, MA 02114 USA.; Langenau, DM (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM dlangenau@mgh.harvard.edu RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU National Institutes of Health [R01CA154923, U54CA168512]; Fundacao para a Ciencia e a Tecnologia; China Scholarship Council; Alex's Lemonade Stand Foundation for Childhood Cancer; Saint Baldrick's Foundation; NIH Office of the Director [R24OD016761] FX National Institutes of Health Ines M Tenente; Fundacao para a Ciencia e a Tecnologia Myron S Ignatius David M Langenau; China Scholarship Council Qin Tang; Alex's Lemonade Stand Foundation for Childhood Cancer David M Langena; Saint Baldrick's Foundation David M Langenau; National Institutes of Health R01CA154923 David M Langenau; National Institutes of Health U54CA168512 David M Langenau; NIH Office of the Director R24OD016761 David M Langenau; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 80 TC 0 Z9 0 U1 3 U2 3 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 12 PY 2017 VL 6 AR e19214 DI 10.7554/eLife.19214 PG 24 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EJ7RN UT WOS:000393420000001 ER PT J AU Pardo, LM Li, WQ Hwang, SJ Verkouteren, JAC Hofman, A Uitterlinden, AG Kraft, P Turman, C Han, JL Cho, E Murabito, JM Levy, D Qureshi, AA Nijsten, T AF Pardo, Luba M. Li, Wen-Qing Hwang, Shih-Jen Verkouteren, Joris A. C. Hofman, Albert Uitterlinden, Andre G. Kraft, Peter Turman, Constance Han, Jiali Cho, Eunyoung Murabito, Joanne M. Levy, Daniel Qureshi, Abrar A. Nijsten, Tamar TI Genome-Wide Association Studies of Multiple Keratinocyte Cancers SO PLOS ONE LA English DT Article ID BASAL-CELL CARCINOMA; NONMELANOMA SKIN CANCERS; PIGMENTATION TRAITS; METAANALYSIS; RISK; NETHERLANDS; DESIGN; HEART; LOCI; GENE AB There is strong evidence for a role of environmental risk factors involved in susceptibility to develop multiple keratinocyte cancers (mKCs), but whether genes are also involved in mKCs susceptibility has not been thoroughly investigated. We investigated whether single nucleotide polymorphisms (SNPs) are associated with susceptibility for mKCs. A genome-wide association study (GWAS) of 1,666 cases with mKCs and 1,950 cases with single KC (sKCs; controls) from Harvard cohorts (the Nurses' Health Study [ NHS], NHS II, and the Health Professionals Follow-Up Study) and the Framingham Heart Study was carried-out using over 8 million SNPs (stage-1). We sought to replicate the most significant statistical associations (p-value <= 5.5x10(-6)) in an independent cohort of 574 mKCs and 872 sKCs from the Rotterdam Study. In the discovery stage, 40 SNPs with suggestive associations (p-value <= 5.5x10(-6)) were identified, with eight independent SNPs tagging all 40 SNPs. The most significant SNP was located at chromosome 9 (rs7468390; p-value = 3.92x10(-7)). In stage-2, none of these SNPs replicated and only two of them were associated with mKCs in the same direction in the combined meta-analysis. We tested the associations for 19 previously reported basal cell carcinoma-related SNPs (candidate gene association analysis), and found that rs1805007 (MC1R locus) was significantly associated with risk of mKCs (p-value = 2.80x10(-4)). Although the suggestive SNPs with susceptibility for mKCs were not replicated, we found that previously identified BCC variants may also be associated with mKC, which the most significant association (rs1805007) located at the MC1R gene. C1 [Pardo, Luba M.; Verkouteren, Joris A. C.; Nijsten, Tamar] Erasmus MC Canc Inst, Dept Dermatol, Rotterdam, Netherlands. [Li, Wen-Qing; Cho, Eunyoung; Qureshi, Abrar A.] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02912 USA. [Li, Wen-Qing; Cho, Eunyoung; Qureshi, Abrar A.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Hwang, Shih-Jen; Murabito, Joanne M.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Hwang, Shih-Jen; Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA. [Hofman, Albert] Erasmus MC Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Uitterlinden, Andre G.] Erasmus MC Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Kraft, Peter; Turman, Constance] Harvard Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA. [Kraft, Peter; Han, Jiali; Cho, Eunyoung; Qureshi, Abrar A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Kraft, Peter; Han, Jiali; Cho, Eunyoung; Qureshi, Abrar A.] Harvard Med Sch, Boston, MA USA. [Han, Jiali] Indiana Univ, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Bloomington, IN 47405 USA. [Han, Jiali] Indiana Univ, Melvin & Bren Simon Canc Ctr, Bloomington, IN 47405 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02215 USA. RP Nijsten, T (reprint author), Erasmus MC Canc Inst, Dept Dermatol, Rotterdam, Netherlands.; Qureshi, AA (reprint author), Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02912 USA.; Qureshi, AA (reprint author), Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA.; Qureshi, AA (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.; Qureshi, AA (reprint author), Harvard Med Sch, Boston, MA USA. EM abrar_qureshi@brown.edu; t.nijsten@erasmusmc.nl FU Vidi Grant of ZonMw [91711315]; Erasmus Medical Center; Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative (NGI); Netherlands Organisation for Scientific Research (NOW); Netherlands Organization for the Health Research and Development (ZonMw); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; National Institutes of Health [N01-HC-25195]; Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; NIH [UM1 CA186107, P01 CA87969, R01 CA49449, UM1 CA176726, R01 CA67262, UM1 CA167552, CA122838, CA055075, CA100264, CA093459]; Erasmus University, Rotterdam FX The study is funded by a Vidi Grant of ZonMw (nr. 91711315). The Rotterdam Study is supported by Erasmus Medical Center and Erasmus University, Rotterdam; the Research Institute for Diseases in the Elderly; The Netherlands Genomics Initiative (NGI); The Netherlands Organisation for Scientific Research (NOW); The Netherlands Organization for the Health Research and Development (ZonMw); The Ministry of Education, Culture and Science; The Ministry for Health, Welfare and Sports; The European Commission (DG XII), and the Municipality of Rotterdam. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. The study was also supported by NIH grants UM1 CA186107, P01 CA87969, R01 CA49449, UM1 CA176726, R01 CA67262, UM1 CA167552, CA122838, CA055075, CA100264, and CA093459. NR 33 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 12 PY 2017 VL 12 IS 1 AR e0169873 DI 10.1371/journal.pone.0169873 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH7JQ UT WOS:000391949500095 PM 28081215 ER PT J AU Kuboki, R Sugase-Miyamoto, Y Matsumoto, N Richmond, BJ Shidara, M AF Kuboki, Ryosuke Sugase-Miyamoto, Yasuko Matsumoto, Narihisa Richmond, Barry J. Shidara, Munetaka TI Information Accumulation over Time in Monkey Inferior Temporal Cortex Neurons Explains Pattern Recognition Reaction Time under Visual Noise SO FRONTIERS IN INTEGRATIVE NEUROSCIENCE LA English DT Article DE inferior temporal cortex; information theory; pattern recognition; visual noise; behavioral latency; rhesus monkey ID TWO-DIMENSIONAL PATTERNS; INFEROTEMPORAL CORTEX; OBJECT RECOGNITION; SINGLE UNITS; PROGRESS; VISION; DISCRIMINATION; CATEGORIZATION; RESPONSES; POSITION AB We recognize objects even when they are partially degraded by visual noise. We studied the relation between the amount of visual noise (5, 10, 15, 20, or 25%) degrading 8 black-and-white stimuli and stimulus identification in 2 monkeys performing a sequential delayed match-to-sample task. We measured the accuracy and speed with which matching stimuli were identified. The performance decreased slightly (errors increased) as the amount of visual noise increased for both monkeys. The performance remained above 80% correct, even with 25% noise. However, the reaction times markedly increased as the noise increased, indicating that the monkeys took progressively longer to decide what the correct response would be as the amount of visual noise increased, showing that the monkeys trade time to maintain accuracy. Thus, as time unfolds the monkeys act as if they are accumulating the information and/or testing hypotheses about whether the test stimulus is likely to be a match for the sample being held in short-term memory. We recorded responses from 13 single neurons in area TE of the 2 monkeys. We found that stimulus-selective information in the neuronal responses began accumulating when the match stimulus appeared. We found that the greater the amount of noise obscuring the test stimulus, the more slowly stimulus-related information by the 13 neurons accumulated. The noise induced slowing was about the same for both behavior and information. These data are consistent with the hypothesis that area TE neuron population carries information about stimulus identity that accumulates over time in such a manner that it progressively overcomes the signal degradation imposed by adding visual noise. C1 [Kuboki, Ryosuke; Shidara, Munetaka] Univ Tsukuba, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki, Japan. [Sugase-Miyamoto, Yasuko; Matsumoto, Narihisa] Natl Inst Adv Ind Sci & Technol, Human Informat Res Inst, Tsukuba, Ibaraki, Japan. [Richmond, Barry J.] NIMH, Neuropsychol Lab, Bldg 9, Bethesda, MD 20892 USA. [Shidara, Munetaka] Univ Tsukuba, Fac Med, Tsukuba, Ibaraki, Japan. RP Shidara, M (reprint author), Univ Tsukuba, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki, Japan.; Shidara, M (reprint author), Univ Tsukuba, Fac Med, Tsukuba, Ibaraki, Japan. EM mshidara@md.tsukuba.ac.jp FU IRP/NIMH/USA; MEXT/JSPS KAKENHI [23650105, JP16H01684]; New Energy and Industrial Technology Development Organization (NEDO) FX We would like to thank Dr. Zheng Liu for data recording. This work was supported by IRP/NIMH/USA and MEXT/JSPS KAKENHI Grant Number 23650105, JP16H01684, and the New Energy and Industrial Technology Development Organization (NEDO). NR 34 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND EI 1662-5145 J9 FRONT INTEGR NEUROSC JI Front. Integr. Neurosci. PD JAN 12 PY 2017 VL 10 AR 43 DI 10.3389/fnint.2016.00043 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EH6GM UT WOS:000391870900001 ER PT J AU Hudson, KL Collins, FS AF Hudson, Kathy L. Collins, Francis S. TI The 21st Century Cures Act - A View from the NIH SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Hudson, Kathy L.; Collins, Francis S.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Hudson, KL (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 1 Z9 1 U1 2 U2 2 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 12 PY 2017 VL 376 IS 2 BP 111 EP 113 DI 10.1056/NEJMp1615745 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EI0XI UT WOS:000392198400005 PM 27959585 ER PT J AU Powers, SW Coffey, CS Chamberlin, LA Ecklund, DJ Klingner, EA Yankey, JW Korbee, LL Porter, LL Hershey, AD AF Powers, Scott W. Coffey, Christopher S. Chamberlin, Leigh A. Ecklund, Dixie J. Klingner, Elizabeth A. Yankey, Jon W. Korbee, Leslie L. Porter, Linda L. Hershey, Andrew D. CA CHAMP Investigators TI Trial of Amitriptyline, Topiramate, and Placebo for Pediatric Migraine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PHARMACOLOGICAL-TREATMENT; ADOLESCENT MIGRAINE; PREVENTION CHAMP; CHILDHOOD; CHILDREN; HEADACHE; PREVALENCE; DISABILITY; EFFICACY; AGE AB BACKGROUND Which, medication, if any, to use to prevent the headache of pediatric migraine has not been established. METHODS We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2: 2: 1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment. RESULTS A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P = 0.26; topiramate vs. placebo, P = 0.48; amitriptyline vs. topiramate, P = 0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt. CONCLUSIONS There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281). C1 [Powers, Scott W.; Hershey, Andrew D.] Univ Cincinnati, Dept Pediat, Coll Med, Cincinnati, OH 45221 USA. [Powers, Scott W.; Chamberlin, Leigh A.] Cincinnati Childrens Hosp Med Ctr, Div Behav Med & Clin Psychol, Cincinnati, OH 45229 USA. [Korbee, Leslie L.] Cincinnati Childrens Hosp Med Ctr, Off Clin & Translat Res, Cincinnati, OH 45229 USA. [Hershey, Andrew D.] Cincinnati Childrens Hosp Med Ctr, Div Neurol, Cincinnati, OH 45229 USA. [Coffey, Christopher S.; Ecklund, Dixie J.; Klingner, Elizabeth A.; Yankey, Jon W.] Univ Iowa, Dept Biostat, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA. [Porter, Linda L.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Powers, SW (reprint author), Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave,MLC 7039, Cincinnati, OH 45229 USA. EM scott.powers@cchmc.org FU National Institutes of Health FX Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281). NR 25 TC 6 Z9 6 U1 15 U2 15 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 12 PY 2017 VL 376 IS 2 BP 115 EP 124 DI 10.1056/NEJMoa1610384 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EI0XI UT WOS:000392198400006 PM 27788026 ER PT J AU Hao, M Bryant, SH Wang, YL AF Hao, Ming Bryant, Stephen H. Wang, Yanli TI Predicting drug-target interactionsby dual-network integrated logistic matrix factorization SO SCIENTIFIC REPORTS LA English DT Article ID DATABASE; IDENTIFICATION; INFORMATION AB In this work, we propose a dual-network integrated logistic matrix factorization (DNILMF) algorithm to predict potential drug-target interactions (DTI). The prediction procedure consists of four steps: (1) inferring new drug/target profiles and constructing profile kernel matrix; (2) diffusing drug profile kernel matrix with drug structure kernel matrix; (3) diffusing target profile kernel matrix with target sequence kernel matrix; and (4) building DNILMF model and smoothing new drug/target predictions based on their neighbors. We compare our algorithm with the state-of-the-art method based on the benchmark dataset. Results indicate that the DNILMF algorithm outperforms the previously reported approaches in terms of AUPR (area under precision-recall curve) and AUC (area under curve of receiver operating characteristic) based on the 5 trials of 10-fold cross-validation. We conclude that the performance improvement depends on not only the proposed objective function, but also the used nonlinear diffusion technique which is important but under studied in the DTI prediction field. In addition, we also compile a new DTI dataset for increasing the diversity of currently available benchmark datasets. The top prediction results for the new dataset are confirmed by experimental studies or supported by other computational research. C1 [Hao, Ming; Bryant, Stephen H.; Wang, Yanli] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 38 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 JAN 12 PY 2017 VL 7 AR 40376 DI 10.1038/srep40376 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH3KI UT WOS:000391670100001 PM 28079135 ER PT J AU Li, Y Wang, HB Wang, K Hu, QL Yao, Q Shen, YQ Yu, GC Tang, GP AF Li, Yang Wang, Hebin Wang, Kai Hu, Qinglian Yao, Qi Shen, Youqing Yu, Guocan Tang, Guping TI Targeted Co-delivery of PTX and TR3 siRNA by PTP Peptide Modified Dendrimer for the Treatment of Pancreatic Cancer SO SMALL LA English DT Article ID SYSTEMICALLY ADMINISTERED SIRNA; MESOPOROUS SILICA NANOPARTICLES; POLYMER HYBRID NANOPARTICLES; NEGATIVE BREAST-CANCER; COMBINATION THERAPY; ANTICANCER DRUG; DOXORUBICIN; MICELLES; CELLS; PACLITAXEL C1 [Li, Yang; Wang, Hebin; Wang, Kai; Yao, Qi; Tang, Guping] Zhejiang Univ, Dept Chem, Inst Chem Biol & Pharmaceut Chem, Hangzhou 310028, Zhejiang, Peoples R China. [Wang, Hebin] Tarim Univ, Coll Life Sci, Alar 843300, Peoples R China. [Hu, Qinglian] Zhejiang Univ Technol, Coll Biotechnol & Bioengn, Hangzhou 310032, Zhejiang, Peoples R China. [Shen, Youqing] Zhejiang Univ, Ctr Bionanoengn, Hangzhou 310027, Zhejiang, Peoples R China. [Shen, Youqing] Zhejiang Univ, Dept Chem & Biol Engn, State Key Lab Chem Engn, Hangzhou 310027, Zhejiang, Peoples R China. [Yu, Guocan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Tang, GP (reprint author), Zhejiang Univ, Dept Chem, Inst Chem Biol & Pharmaceut Chem, Hangzhou 310028, Zhejiang, Peoples R China.; Yu, GC (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM guocan.yu@nih.gov; tangguping@zju.edu.cn FU National Basic Research Program of China [2014CB931900] FX Y.L. and H.W. contributed equally to this work. This research was funded by the National Basic Research Program of China (Grant No. 2014CB931900). Animal care and handling procedures were in agreement with the guidelines evaluated and approved by the ethics committee of Zhejiang University. Study protocols involving animals were approved by the Zhejiang University Animal Care and Use Committee. NR 48 TC 0 Z9 0 U1 9 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1613-6810 EI 1613-6829 J9 SMALL JI Small PD JAN 11 PY 2017 VL 13 IS 2 AR UNSP 1602697 DI 10.1002/smll.201602697 PG 9 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 EO2ZM UT WOS:000396564600016 ER PT J AU De Ravin, SS Li, LH Wu, XL Choi, U Allen, C Koontz, S Lee, J Theobald-Whiting, N Chu, J Garofalo, M Sweeney, C Kardava, L Moir, S Viley, A Natarajan, P Su, L Kuhns, D Zarember, KA Peshwa, MV Malech, HL AF De Ravin, Suk See Li, Linhong Wu, Xiaolin Choi, Uimook Allen, Cornell Koontz, Sherry Lee, Janet Theobald-Whiting, Narda Chu, Jessica Garofalo, Mary Sweeney, Colin Kardava, Lela Moir, Susan Viley, Angelia Natarajan, Pachai Su, Ling Kuhns, Douglas Zarember, Kol A. Peshwa, Madhusudan V. Malech, Harry L. TI CRISPR-Cas9 gene repair of hematopoietic stem cells from patients with X-linked chronic granulomatous disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; B-CELLS; THERAPY; EXPRESSION; NUCLEASES; MUTATION; IMMUNITY AB Gene repair of CD34(+) hematopoietic stem and progenitor cells (HSPCs) may avoid problems associated with gene therapy, such as vector-related mutagenesis and dysregulated transgene expression. We used CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 (CRISPR-associated 9) to repair a mutation in the CYBB gene of CD34(+) HSPCs from patients with the immunodeficiency disorder X-linked chronic granulomatous disease (X-CGD). Sequence-confirmed repair of >20% of HSPCs from X-CGD patients restored the function of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and superoxide radical production in myeloid cells differentiated from these progenitor cells in vitro. Transplant of gene-repaired X-CGD HSPCs into NOD (nonobese diabetic) SCID (severe combined immunodeficient) gamma c(-/-) mice resulted in efficient engraftment and production of functional mature human myeloid and lymphoid cells for up to 5 months. Whole-exome sequencing detected no indels outside of the CYBB gene after gene correction. CRISPR-mediated gene editing of HSPCs may be applicable to other CGD mutations and other monogenic disorders of the hematopoietic system. C1 [De Ravin, Suk See; Choi, Uimook; Koontz, Sherry; Lee, Janet; Theobald-Whiting, Narda; Chu, Jessica; Garofalo, Mary; Sweeney, Colin; Kuhns, Douglas; Zarember, Kol A.; Malech, Harry L.] NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Li, Linhong; Allen, Cornell; Viley, Angelia; Natarajan, Pachai; Peshwa, Madhusudan V.] MaxCyte Inc, Gaithersburg, MD 20878 USA. [Wu, Xiaolin; Su, Ling] Leidos Biomed Res Inc, Canc Res Technol Program, Frederick, MD 21701 USA. [Kardava, Lela; Moir, Susan] NIAID, Lab Immunoregulat, NIH, Bethesda, MD USA. RP De Ravin, SS; Malech, HL (reprint author), NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. EM sderavin@niaid.nih.gov; hmalech@nih.gov FU Intramural Research Program of NIAID, NIH [Z01-A1-00644, Z01-A1-00988]; Maryland Stem Cell Research Fund [2015-MSCRFP-1752] FX This research was supported by the Intramural Research Program of NIAID, NIH (Intramural project numbers Z01-A1-00644 and Z01-A1-00988) and the Maryland Stem Cell Research Fund (#2015-MSCRFP-1752). NR 31 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 11 PY 2017 VL 9 IS 372 AR eaah3480 DI 10.1126/scitranslmed.aah3480 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EL2JK UT WOS:000394445700006 ER PT J AU Gonzalez-Suarez, AD Nash, AI Garcia-Olivares, J Torres-Salazar, D AF Gonzalez-Suarez, Aneysis D. Nash, Abigail I. Garcia-Olivares, Jennie Torres-Salazar, Delany TI Emerging Evidence for a Direct Link between EAAT-Associated Anion Channels and Neurological Disorders SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material ID GLUTAMATE TRANSPORTER EAAT1; CHLORIDE CHANNEL; EPISODIC ATAXIA; MUTATION; ASTROCYTES C1 [Gonzalez-Suarez, Aneysis D.] Yale Univ, Sch Med, Interdept Neurosci Program, New Haven, CT 06510 USA. [Nash, Abigail I.; Garcia-Olivares, Jennie; Torres-Salazar, Delany] NIMH, NIH, Bethesda, MD 20892 USA. RP Torres-Salazar, D (reprint author), NIMH, Lab Mol & Cellular Neurobiol, NIH, 35 Convent Dr,Room 3A-207, Bethesda, MD 20892 USA. EM delany.torressalazar@nih.gov OI Torres-Salazar, Delany/0000-0002-6789-9810 NR 21 TC 0 Z9 0 U1 0 U2 0 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 11 PY 2017 VL 37 IS 2 BP 241 EP 243 DI 10.1523/JNEUROSCI.2947-16.2017 PG 3 WC Neurosciences SC Neurosciences & Neurology GA EJ9CZ UT WOS:000393525500003 PM 28077704 ER PT J AU Hoest, C Seidman, JC Lee, G Platts-Mills, JA Ali, A Olortegui, MP Bessong, P Chandyo, R Babji, S Mohan, VR Mondal, D Mahfuz, M Mduma, ER Nyathi, E Abreu, C Miller, MA Pan, W Mason, CJ Knobler, SL AF Hoest, Christel Seidman, Jessica C. Lee, Gwenyth Platts-Mills, James A. Ali, Asad Paredes Olortegui, Maribel Bessong, Pascal Chandyo, Ram Babji, Sudhir Mohan, Venkata Raghava Mondal, Dinesh Mahfuz, Mustafa Mduma, Estomih R. Nyathi, Emanuel Abreu, Claudia Miller, Mark A. Pan, William Mason, Carl J. Knobler, Stacey L. CA MAL-ED Network Investigators TI Vaccine coverage and adherence to EPI schedules in eight resource poor settings in the MAL-ED cohort study SO VACCINE LA English DT Article DE Public health; Vaccine coverage; Vaccine timing; EPI; Socioeconomic factors; Measles ID IMMUNIZATION COVERAGE; ENTERIC INFECTIONS; BIRTH COHORT; SOUTH-AFRICA; RISK-FACTORS; TIMELINESS; POLIO; SITE; MALNUTRITION; NETWORK AB Background: Launched in 1974, the Expanded Program on Immunization (EPI) is estimated to prevent two-three million deaths annually from polio, diphtheria, tuberculosis, pertussis, measles, and tetanus. Additional lives could be saved through better understanding what influences adherence to the EPI schedule in specific settings. Methods: The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study followed cohorts in eight sites in South Asia, Africa, and South America and monitored vaccine receipt over the first two years of life for the children enrolled in the study. Vaccination histories were obtained monthly from vaccination cards, local clinic records and/or caregiver reports. Vaccination histories were compared against the prescribed EPI schedules for each country, and coverage rates were examined in relation to the timing of vaccination. The influence of socioeconomic factors on vaccine timing and coverage was also considered. Results: Coverage rates for EPI vaccines varied between sites and by type of vaccine; overall, coverage was highest in the Nepal and Bangladesh sites and lowest in the Tanzania and Brazil sites. Bacillus Calmette-Guerin coverage was high across all sites, 87-100%, whereas measles vaccination rates ranged widely, 73-100%. Significant delays between the scheduled administration age and actual vaccination date were present in all sites, especially for measles vaccine where less than 40% were administered on schedule. A range of socioeconomic factors were significantly associated with vaccination status in study children but these results were largely site-specific. Conclusions: Our findings highlight the need to improve measles vaccination rates and reduce delayed vaccination to achieve EPI targets related to the establishment of herd immunity and reduction in disease transmission. (C) 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license. C1 [Hoest, Christel; Seidman, Jessica C.; Miller, Mark A.; Knobler, Stacey L.] Natl Inst Hlth, Fogarty Int Ctr, Div Int Epidemiol & Populat Studies Fogarty, 16 Ctr Dr,Bldg 16,Room 202, Bethesda, MD 20892 USA. [Lee, Gwenyth] Johns Hopkins Univ, Dept Int Hlth, Baltimore, MD 21205 USA. [Platts-Mills, James A.] Univ Virginia, Div Infect Dis & Int Hlth, POB 801340,345 Crispell Dr,Carter Harrison Bldg, Charlottesville, VA 22908 USA. [Ali, Asad] Aga Khan Univ, Dept Pediat & Child Hlth, Stadium Rd, Karachi, Pakistan. [Paredes Olortegui, Maribel] Asociac Benef Proyectos Informat Sauld Med & Agr, Ramirez Hurtado 622, Iquitos, Peru. [Bessong, Pascal] Univ Venda, HIV AIDS & Global Hlth Res Programme, ZA-0950 Thohoyandou, South Africa. [Chandyo, Ram] Tribhuvan Univ, Inst Med, Dept Child Hlth, Kathmandu, Nepal. [Chandyo, Ram] Univ Bergen, Ctr Int Hlth, POB 7800, N-5020 Bergen, Norway. [Babji, Sudhir; Mohan, Venkata Raghava] Christian Med Coll & Hosp, Dept Community Hlth, Dept Gastrointestinal Sci, Vellore 632004, Tamil Nadu, India. [Mondal, Dinesh; Mahfuz, Mustafa] Int Ctr Diarrhoeal Dis Res, Nutr & Clin Serv Div, 68 Shaheed Tajuddin Ahmed Sarani, Dhaka 1212, Bangladesh. [Mduma, Estomih R.] Haydom Lutheran Hosp, POB 9041, Haydom, Manyara Region, Tanzania. [Abreu, Claudia; MAL-ED Network Investigators] Univ Fed Ceara, Fac Med, Inst Biomed, Dept Fisiol & Farmacol, Rua Coronel Nunes Melo 1315,CP 3229, BR-60430270 Fortaleza, Ceara, Brazil. [Pan, William] Duke Univ, Dept Environm Sci & Policy, Durham, NC USA. [Pan, William] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Mason, Carl J.] Armed Forces Res Inst Med Sci, Bangkok, Thailand. RP Hoest, C (reprint author), Natl Inst Hlth, Fogarty Int Ctr, Div Int Epidemiol & Populat Studies Fogarty, 16 Ctr Dr,Bldg 16,Room 202, Bethesda, MD 20892 USA. EM christel.host@nih.gov OI Ali, Syed Asad/0000-0001-5274-7665 FU Bill & Melinda Gates Foundation; Foundation for the NIH; National Institutes of Health, Fogarty International Center FX The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the NIH, and the National Institutes of Health, Fogarty International Center. 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 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JAN 11 PY 2017 VL 35 IS 3 BP 443 EP 451 DI 10.1016/j.vaccine.2016.11.075 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EJ2AK UT WOS:000393011900006 PM 27998640 ER PT J AU Kim, S Kahn, P Robinson, AB Lang, B Shulman, A Oberle, EJ Schikler, K Curran, ML Barillas-Arias, L Spencer, CH Rider, LG Huber, AM AF Kim, Susan Kahn, Philip Robinson, Angela B. Lang, Bianca Shulman, Andrew Oberle, Edward. J. Schikler, Kenneth Curran, Megan Lea Barillas-Arias, Lilliana Spencer, Charles H. Rider, Lisa G. Huber, Adam M. TI Childhood Arthritis and Rheumatology Research Alliance consensus clinical treatment plans for juvenile dermatomyositis with skin predominant disease SO Pediatric Rheumatology LA English DT Article DE Dermatomyositis; Childhood Type; Therapeutics; Child; Adolescent; Amyopathic ID CUTANEOUS ASSESSMENT-TOOL; IDIOPATHIC INFLAMMATORY MYOPATHIES; AMYOPATHIC DERMATOMYOSITIS; SINE MYOSITIS; CORE SET; RELIABILITY; VALIDATION; ADULT; HYPERTENSION; INVOLVEMENT AB Background: Juvenile dermatomyositis (JDM) is the most common form of the idiopathic inflammatory myopathies in children. A subset of children have the rash of JDM without significant weakness, and the optimal treatments for these children are unknown. The goal of this study was to describe the development of consensus clinical treatment plans (CTPs) for children with JDM who have active skin rashes, without significant muscle involvement, referred to as skin predominant JDM in this manuscript. Methods: The Children's Arthritis and Rheumatology Research Alliance (CARRA) is a North American consortium of pediatric rheumatology health care providers. CARRA members collaborated to determine consensus on typical treatments for JDM patients with skin findings without significant weakness, to develop CTPs for this subgroup of patients. We used a combination of Delphi surveys and nominal group consensus meetings to develop these CTPs. Results: Consensus was reached on patient characteristics and outcome assessment, and CTPs were developed and finalized for patients with skin predominant JDM. Treatment option A included hydroxychloroquine alone, Treatment option B included hydroxychloroquine and methotrexate, and Treatment option C included hydroxychloroquine, methotrexate and corticosteroids. Conclusions: Three CTPs were developed for use in children with skin predominant JDM, which reflect typical treatment approaches. These are not considered to be specific recommendations or standard of care. Using the CARRA network and prospective data collection, we will be able to apply statistical methods in the future to allow comparisons of JDM patients following these consensus treatment plans. C1 [Kim, Susan] Univ Calif San Francisco, Benioff Childrens Hosp, Div Pediat Rheumatol, 550 16th St, San Francisco, CA 94143 USA. [Kahn, Philip] NYU, Langone Med Ctr, Div Pediat Rheumatol, 550 First Ave, New York, NY USA. [Robinson, Angela B.] Rainbow Babies & Childrens Hosp, Pediat Rheumatol, 11100 Euclid Ave MS6008B, Cleveland, OH USA. [Lang, Bianca; Huber, Adam M.] IWK Hlth Ctr, Dept Pediat, 5980 Univ Ave, Halifax, NS, Canada. [Lang, Bianca; Huber, Adam M.] Dalhousie Univ, 5980 Univ Ave, Halifax, NS, Canada. [Shulman, Andrew] Childrens Hosp Orange Cty, Pediat Rheumatol, 1201 W La Veta Ave, Irvine, CA USA. [Oberle, Edward. J.; Spencer, Charles H.] Nationwide Childrens Hosp, Res Inst, Dept Pediat, 700 Childrens Dr, Columbus, OH USA. [Schikler, Kenneth] Univ Louisville, Div Adolescent Med, Dept Pediat, Sch Med, 571 South Floyd St, Louisville, KY USA. [Schikler, Kenneth] Univ Louisville, Div Pediat Rheumatol, Dept Pediat, Sch Med, 571 South Floyd St, Louisville, KY USA. [Curran, Megan Lea] Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60611 USA. [Curran, Megan Lea] Ann & Robert H Lurie Childrens Hosp Chicago, Div Rheumatol, 225 E Chicago Ave, Chicago, IL 60611 USA. [Barillas-Arias, Lilliana] Albany Med Ctr, Dept Pediat, Rheumatol, 43 New Scotland Ave, Albany, NY USA. [Rider, Lisa G.] NIEHS, Environm Autoimmun Grp, Clin Res Branch, NIH, 10 Ctr Dr, Bethesda, MD USA. RP Kim, S (reprint author), Univ Calif San Francisco, Benioff Childrens Hosp, Div Pediat Rheumatol, 550 16th St, San Francisco, CA 94143 USA. EM Susan.kim@ucsf.edu FU Arthritis Foundation; NIAMS; Duke Clinical Research Institute; WASIE Foundation; CureJM; National Institutes of Health, National Institute of Environmental Health Sciences FX CARRA is supported in part by grants from the Arthritis Foundation, NIAMS, Duke Clinical Research Institute, the WASIE Foundation, and CureJM. Dr. Rider is supported in part by the intramural research program of the National Institutes of Health, National Institute of Environmental Health Sciences. We thank Dr. Alison Ehrlich for critical reading of the manuscript. We also would like to thank our PeDRA collaborators and Dermatology Colleagues who helped to review and distribute the survey, including Dr. Shielagh Maguiness, Dr. Ruth Ann Vleugels, Dr. Jennifer Huang, Dr. Yvonne Chiu, Dr. Michele Ramien, Dr. Jerome Coulombe, MD, Dr. Regina-Celeste Ahmad, Dr. Lisa M. Arkin and Dr. Reagan Hunt. Mitali Dave is acknowledged for her insights and contribution as a parent of a child with JDM to our CTP development, as well as Dr. Fatma Dedeoglu, Dr. Andrew Eichenfield, Dr. Donald Goldsmith, Dr. Peri Pepmueller, Dr. Kathryn Phillippi, Dr. Kara Schmidt, Dr. Rosie Scuccimarri and Dr. Amy Woodward were active participants in the development of this CTP. NR 38 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 1546-0096 J9 PEDIATR RHEUMATOL JI Pediatr. Rheumatol. PD JAN 11 PY 2017 VL 15 AR 1 DI 10.1186/s12969-016-0134-0 PG 8 WC Pediatrics; Rheumatology SC Pediatrics; Rheumatology GA EJ1TL UT WOS:000392993000001 PM 28077146 ER PT J AU Pashakhanloo, F Herzka, DA Mori, S Zviman, M Halperin, H Gai, N Bluemke, DA Trayanova, NA McVeigh, ER AF Pashakhanloo, Farhad Herzka, Daniel A. Mori, Susumu Zviman, Muz Halperin, Henry Gai, Neville Bluemke, David A. Trayanova, Natalia A. McVeigh, Elliot R. TI Submillimeter diffusion tensor imaging and late gadolinium enhancement cardiovascular magnetic resonance of chronic myocardial infarction SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Myocardial infarction; Fiber structure; Microstructural remodeling; Diffusion tensor imaging; Late gadolinium enhancement ID HEART-DISEASE; CARDIAC ELECTROPHYSIOLOGY; HISTOLOGICAL VALIDATION; FIBER ARCHITECTURE; BORDER ZONE; MRI; ORIENTATION; MODELS; RECONSTRUCTION; ANISOTROPY AB Background: Knowledge of the three-dimensional (3D) infarct structure and fiber orientation remodeling is essential for complete understanding of infarct pathophysiology and post-infarction electromechanical functioning of the heart. Accurate imaging of infarct microstructure necessitates imaging techniques that produce high image spatial resolution and high signal-to-noise ratio (SNR). The aim of this study is to provide detailed reconstruction of 3D chronic infarcts in order to characterize the infarct microstructural remodeling in porcine and human hearts. Methods: We employed a customized diffusion tensor imaging (DTI) technique in conjunction with late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) on a 3T clinical scanner to image, at submillimeter resolution, myofiber orientation and scar structure in eight chronically infarcted porcine hearts ex vivo. Systematic quantification of local microstructure was performed and the chronic infarct remodeling was characterized at different levels of wall thickness and scar transmurality. Further, a human heart with myocardial infarction was imaged using the same DTI sequence. Results: The SNR of non-diffusion-weighted images was > 100 in the infarcted and control hearts. Mean diffusivity and fractional anisotropy (FA) demonstrated a 43% increase, and a 35% decrease respectively, inside the scar tissue. Despite this, the majority of the scar showed anisotropic structure with FA higher than an isotropic liquid. The analysis revealed that the primary eigenvector orientation at the infarcted wall on average followed the pattern of original fiber orientation (imbrication angle mean: 1.96 +/- 11.03 degrees vs. 0.84 +/- 1.47 degrees, p = 0.61, and inclination angle range: 111.0 +/- 10.7 degrees vs. 112.5 +/- 6.8 degrees, p = 0.61, infarcted/control wall), but at a higher transmural gradient of inclination angle that increased with scar transmurality (r = 0.36) and the inverse of wall thickness (r = 0.59). Further, the infarcted wall exhibited a significant increase in both the proportion of left-handed epicardial eigenvectors, and in the angle incoherency. The infarcted human heart demonstrated preservation of primary eigenvector orientation at the thinned region of infarct, consistent with the findings in the porcine hearts. Conclusions: The application of high-resolution DTI and LGE-CMR revealed the detailed organization of anisotropic infarct structure at a chronic state. This information enhances our understanding of chronic post-infarction remodeling in large animal and human hearts. C1 [Pashakhanloo, Farhad; Herzka, Daniel A.; Trayanova, Natalia A.; McVeigh, Elliot R.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. [Mori, Susumu] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Zviman, Muz; Halperin, Henry; McVeigh, Elliot R.] Johns Hopkins Univ, Dept Med, Baltimore, MD 21218 USA. [Gai, Neville; Bluemke, David A.] NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [McVeigh, Elliot R.] Univ Calif San Diego, Dept Bioengn, 9500 Gilman Dr MC0412, San Diego, CA 92093 USA. [McVeigh, Elliot R.] Univ Calif San Diego, Dept Med, 9500 Gilman Dr MC0412, San Diego, CA 92093 USA. [McVeigh, Elliot R.] Univ Calif San Diego, Dept Radiol, 9500 Gilman Dr MC0412, San Diego, CA 92093 USA. RP McVeigh, ER (reprint author), Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA.; McVeigh, ER (reprint author), Johns Hopkins Univ, Dept Med, Baltimore, MD 21218 USA.; McVeigh, ER (reprint author), Univ Calif San Diego, Dept Bioengn, 9500 Gilman Dr MC0412, San Diego, CA 92093 USA.; McVeigh, ER (reprint author), Univ Calif San Diego, Dept Med, 9500 Gilman Dr MC0412, San Diego, CA 92093 USA.; McVeigh, ER (reprint author), Univ Calif San Diego, Dept Radiol, 9500 Gilman Dr MC0412, San Diego, CA 92093 USA. EM emcveigh@ucsd.edu FU National Institutes of Health (NIH) [DP1HL123271]; NIH intramural research program FX The authors acknowledge support by the National Institutes of Health (NIH) Pioneer Award (DP1HL123271) to NT, and the NIH intramural research program. NR 45 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 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JAN 11 PY 2017 VL 19 AR 9 DI 10.1186/s12968-016-0317-3 PG 14 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EI7IC UT WOS:000392670000001 PM 28122618 ER PT J AU Monroe, A Nakigozi, G Ddaaki, W Bazaale, JM Gray, RH Wawer, MJ Reynolds, SJ Kennedy, CE Chang, LW AF Monroe, April Nakigozi, Gertrude Ddaaki, William Bazaale, Jeremiah Mulamba Gray, Ronald H. Wawer, Maria J. Reynolds, Steven J. Kennedy, Caitlin E. Chang, Larry W. TI Qualitative insights into implementation, processes, and outcomes of a randomized trial on peer support and HIV care engagement in Rakai, Uganda SO BMC INFECTIOUS DISEASES LA English DT Article DE HIV; Pre-ART; Peer support; Randomized controlled trial; Qualitative research; Linkage; Uganda; Mixed methods research; Implementation science ID BEHAVIORAL SKILLS MODEL; ANTIRETROVIRAL THERAPY; RETENTION; TRANSMISSION; PREVENTION; INITIATION; ADHERENCE; SETTINGS; LINKAGE AB Background: People living with human immunodeficiency virus (HIV) who have not yet initiated antiretroviral therapy (ART) can benefit from being engaged in care and utilizing preventive interventions. Community-based peer support may be an effective approach to promote these important HIV services. Methods: After conducting a randomized trial of the impact of peer support on pre-ART outcomes, we conducted a qualitative evaluation to better understand trial implementation, processes, and results. Overall, 75 participants, including trial participants (clients), peer supporters, and clinic staff, participated in 41 in-depth interviews and 6 focus group discussions. A situated Information Motivation, and Behavioral skills model of behavior change was used to develop semi-structured interview and focus group guides. Transcripts were coded and thematically synthesized. Results: We found that participant narratives were generally consistent with the theoretical model, indicating that peer support improved information, motivation, and behavioral skills, leading to increased engagement in pre-ART care. Clients described how peer supporters reinforced health messages and helped them better understand complicated health information. Peer supporters also helped clients navigate the health system, develop support networks, and identify strategies for remembering medication and clinic appointments. Some peer supporters adopted roles beyond visiting patients, serving as a bridge between the client and his or her family, community, and health system. Qualitative results demonstrated plausible processes by which peer support improved client engagement in care, cotrimoxazole use, and safe water vessel use. Challenges identified included insufficient messaging surrounding ART initiation, lack of care continuity after ART initiation, rare breaches in confidentiality, and structural challenges. Conclusions: The evaluation found largely positive perceptions of the peer intervention across stakeholders and provided valuable information to inform uptake and scalability of the intervention. Study findings also suggest several areas for improvement for future implementation of pre-ART peer support programs. C1 [Monroe, April; Kennedy, Caitlin E.; Chang, Larry W.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. [Nakigozi, Gertrude; Ddaaki, William; Bazaale, Jeremiah Mulamba] Rakai Hlth Sci Program, Rakai, Uganda. [Gray, Ronald H.; Wawer, Maria J.; Chang, Larry W.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, Immunoregulat Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Reynolds, Steven J.; Chang, Larry W.] Johns Hopkins Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. RP Chang, LW (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA.; Chang, LW (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA.; Chang, LW (reprint author), Johns Hopkins Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. EM lchang8@jhmi.edu FU National Institute of Mental Health, National Institutes of Health [K23MH086338]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institute of Health; Johns Hopkins University Center for AIDS Research [P30AI094189] FX This study was supported by The National Institute of Mental Health, National Institutes of Health (K23MH086338), the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institute of Health, and the Johns Hopkins University Center for AIDS Research (P30AI094189). NR 24 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 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JAN 10 PY 2017 VL 17 AR 54 DI 10.1186/s12879-016-2156-0 PG 9 WC Infectious Diseases SC Infectious Diseases GA EP4IV UT WOS:000397345100005 PM 28068935 ER PT J AU Soreq, L Rose, J Soreq, E Hardy, J Trabzuni, D Cookson, MR Smith, C Ryten, M Patani, R Ule, J AF Soreq, Lilach Rose, Jamie Soreq, Eyal Hardy, John Trabzuni, Daniah Cookson, Mark R. Smith, Colin Ryten, Mina Patani, Rickie Ule, Jernej CA UK Brain Expression Consortium North Amer Brain Expression Consor TI Major Shifts in Glial Regional Identity Are a Transcriptional Hallmark of Human Brain Aging SO CELL REPORTS LA English DT Article ID ALZHEIMERS-DISEASE; GENE-EXPRESSION; TRANSGENIC MICE; CEREBRAL-CORTEX; WHITE-MATTER; OLIGODENDROCYTES; MICROGLIA; NEURONS; CELLS; NEURODEGENERATION AB Gene expression studies suggest that aging of the human brain is determined by a complex interplay of molecular events, although both its region-and cell-type-specific consequences remain poorly understood. Here, we extensively characterized aging-altered gene expression changes across ten human brain regions from 480 individuals ranging in age from 16 to 106 years. We show that astrocyte-and oligodendrocyte-specific genes, but not neuron-specific genes, shift their regional expression patterns upon aging, particularly in the hippocampus and substantia nigra, while the expression of microglia-and endothelial-specific genes increase in all brain regions. In line with these changes, high-resolution immunohistochemistry demonstrated decreased numbers of oligodendrocytes and of neuronal subpopulations in the aging brain cortex. Finally, glial-specific genes predict age with greater precision than neuron-specific genes, thus highlighting the need for greater mechanistic understanding of neuron-glia interactions in aging and late-life diseases. C1 [Soreq, Lilach; Hardy, John; Trabzuni, Daniah; Ryten, Mina; Patani, Rickie; Ule, Jernej] UCL, Inst Neurol, London WC1N 3BG, England. [Soreq, Lilach; Patani, Rickie; Ule, Jernej] Francis Crick Inst, 1 Midland Rd, London NW1 1AT, England. [Rose, Jamie; Smith, Colin] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh Brain Bank, MRC,Acad Neuropathol, Edinburgh EH16 4SB, Midlothian, Scotland. [Soreq, Eyal] Imperial Coll, Div Brain Sci, Computat Cognit & Clin NeuroImaging Lab, London SW7 2AZ, England. [Hardy, John; Patani, Rickie] UCL ION, Reta Lila Weston Inst Neurol Studies, 1 Wakefield St, London WC1N 1PJ, England. [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 12713, Saudi Arabia. [Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Patani, Rickie] Univ Edinburgh, Euan MacDonald Ctr MND, Edinburgh EH8 9YL, Midlothian, Scotland. [Ryten, Mina] Kings Coll London, Guys Hosp, Dept Med & Mol Genet, London SE1 9RT, England. [Patani, Rickie] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 1TN, England. RP Patani, R; Ule, J (reprint author), UCL, Inst Neurol, London WC1N 3BG, England.; Patani, R; Ule, J (reprint author), Francis Crick Inst, 1 Midland Rd, London NW1 1AT, England.; Patani, R (reprint author), UCL ION, Reta Lila Weston Inst Neurol Studies, 1 Wakefield St, London WC1N 1PJ, England.; Patani, R (reprint author), Univ Edinburgh, Euan MacDonald Ctr MND, Edinburgh EH8 9YL, Midlothian, Scotland.; Patani, R (reprint author), Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 1TN, England. EM rickie.patani@ucl.ac.uk; j.ule@ucl.ac.uk FU European Research Council [617837]; Marie Curie Intra European Fellowship [330430]; Alzheimer's Society [172065, 534121]; Francis Crick Institute; Cancer Research UK [FC001002]; UK Medical Research Council [FC001002]; Wellcome Trust [FC001002]; UK Medical Research Council (MRC) through the MRC Sudden Death Brain Bank; Intramural Research Program of the US National Institute on Aging, NIH, Department of Health and Human Services [ZO1 AG000947]; King Faisal Specialist Hospital and Research Centre, Saudi Arabia; US National Institute of Neurological Disorders and Stroke [U24 NS072026]; National Institute on Aging [P30 AG19610]; Arizona Department of Health Services [211002]; Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]; Michael J. Fox Foundation for Parkinson's Research; Intramural Research Program of the NIH, National Institute on Aging; [G0901254]; [G0802462] FX This work was supported by the European Research Council (617837-Translate) to J.U.; the Marie Curie Intra European Fellowship (330430-PRANA), and the Alzheimer's Society for Junior Investigator award (award 172065, project 534121) to L.S.; the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001002), the UK Medical Research Council (FC001002); the Wellcome Trust (FC001002); the UK Medical Research Council (MRC) through the MRC Sudden Death Brain Bank to C.S.; a project grant (G0901254) to J.H.and a training fellowship (G0802462) to M.R.; and in part by the Intramural Research Program of the US National Institute on Aging, NIH, Department of Health and Human Services (project ZO1 AG000947). R.P. is a Wellcome Trust Intermediate Clinical Fellow (101149/Z/13/A) and an Anne Rowling Fellow in Regenerative Neurology. D.T.was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia. We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona, for the provision of human biospecimens. The Brain and Body Donation Program is supported by the US National Institute of Neurological Disorders and Stroke (U24 NS072026 to the National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 to the Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002 to the Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J.Fox Foundation for Parkinson's Research. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 44 TC 1 Z9 1 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JAN 10 PY 2017 VL 18 IS 2 BP 557 EP 570 DI 10.1016/j.celrep.2016.12.011 PG 14 WC Cell Biology SC Cell Biology GA EO1OQ UT WOS:000396468200023 PM 28076797 ER PT J AU McGarry, A McDermott, M Kieburtz, K de Blieck, EA Beal, F Marder, K Ross, C Shoulson, I Gilbert, P Mallonee, WM Guttman, M Wojcieszek, J Kumar, R LeDoux, MS Jenkins, M Rosas, HD Nance, M Biglan, K Como, P Dubinsky, RM Shannon, KM O'Suilleabhain, P Chou, K Walker, F Martin, W Wheelock, VL McCusker, E Jankovic, J Singer, C Sanchez-Ramos, J Scott, B Suchowersky, O Factor, SA Higgins, DS Molho, E Revilla, F Caviness, JN Friedman, JH Perlmutter, JS Feigin, A Anderson, K Rodriguez, R McFarland, NR Margolis, RL Farbman, ES Raymond, LA Suski, V Kostyk, S Colcher, A Seeberger, L Epping, E Esmail, S Diaz, N Fung, WLA Diamond, A Frank, S Hanna, P Hermanowicz, N Dure, LS Cudkowicz, M AF McGarry, Andrew McDermott, Michael Kieburtz, Karl de Blieck, Elisabeth A. Beal, Flint Marder, Karen Ross, Christopher Shoulson, Ira Gilbert, Peter Mallonee, William M. Guttman, Mark Wojcieszek, Joanne Kumar, Rajeev LeDoux, Mark S. Jenkins, Mary Rosas, H. Diana Nance, Martha Biglan, Kevin Como, Peter Dubinsky, Richard M. Shannon, Kathleen M. O'Suilleabhain, Padraig Chou, Kelvin Walker, Francis Martin, Wayne Wheelock, Vicki L. McCusker, Elizabeth Jankovic, Joseph Singer, Carlos Sanchez-Ramos, Juan Scott, Burton Suchowersky, Oksana Factor, Stewart A. Higgins, Donald S., Jr. Molho, Eric Revilla, Fredy Caviness, John N. Friedman, Joseph H. Perlmutter, Joel S. Feigin, Andrew Anderson, Karen Rodriguez, Ramon McFarland, Nikolaus R. Margolis, Russell L. Farbman, Eric S. Raymond, Lynn A. Suski, Valerie Kostyk, Sandra Colcher, Amy Seeberger, Lauren Epping, Eric Esmail, Sherali Diaz, Nancy Fung, Wai Lun Alan Diamond, Alan Frank, Samuel Hanna, Philip Hermanowicz, Neal Dure, Leon S. Cudkowicz, Merit CA Huntington Study Grp 2CARE TI A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease SO NEUROLOGY LA English DT Article ID TRANSGENIC MOUSE MODEL; ENERGY-METABOLISM; CLINICAL-TRIALS; IN-VIVO; Q(10); CREATINE; IMPAIRMENT; REMACEMIDE; DEFECTS; MICE AB Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD. ClinicalTrials.gov identifier: NCT00608881. Classification of evidence: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD. Neurology (R) 2017;88:152-159 C1 [McGarry, Andrew] Rowan Univ, Cooper Univ Healthcare, Camden, NJ 08102 USA. [McDermott, Michael; Kieburtz, Karl; de Blieck, Elisabeth A.; Biglan, Kevin; Como, Peter] Univ Rochester, Rochester, NY 14627 USA. [Beal, Flint] Weill Cornell Med Ctr, New York, NY USA. [Marder, Karen] Columbia Presbyterian Med Ctr, New York, NY 10032 USA. [Ross, Christopher] Johns Hopkins Med Ctr, Baltimore, MD USA. [Shoulson, Ira; Anderson, Karen] Georgetown Univ, Washington, DC USA. [Gilbert, Peter] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Mallonee, William M.] Hereditary Neurol Dis Ctr, Wichita, KS USA. [Guttman, Mark] Ctr Movement Disorders, Toronto, ON, Canada. [Wojcieszek, Joanne] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Kumar, Rajeev] Colorado Neurol Inst, Englewood, CO USA. [LeDoux, Mark S.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Jenkins, Mary] London Hlth Sci Ctr, London, ON, Canada. [Rosas, H. Diana] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nance, Martha] Struthers Parkinsons Ctr, Minneapolis, MN USA. [Dubinsky, Richard M.] Univ Kansas Med Ctr, Kansas City, KS USA. [Shannon, Kathleen M.] Rush Univ Med Ctr, Chicago, IL USA. [O'Suilleabhain, Padraig] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Chou, Kelvin] Univ Michigan, Ann Arbor, MI 48109 USA. [Walker, Francis] Wake Forest Univ, Winston Salem, NC 27109 USA. [Martin, Wayne] Univ Alberta, Edmonton, AB, Canada. [Wheelock, Vicki L.] Univ Calif Davis, Sacramento, CA 95817 USA. [McCusker, Elizabeth] Westmead Hosp, Westmead, NSW, Australia. [Jankovic, Joseph] Baylor Coll Med, Houston, TX 77030 USA. [Singer, Carlos] Univ Miami, Miller Sch Med, Coral Gables, FL 33124 USA. [Sanchez-Ramos, Juan] Univ S Florida, Tampa, FL USA. [Scott, Burton] Duke Univ, Durham, NC USA. [Suchowersky, Oksana] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Factor, Stewart A.] Emory Univ, Sch Med, Atlanta, GA USA. [Higgins, Donald S., Jr.; Molho, Eric] Albany Med Coll, Albany, NY 12208 USA. [Revilla, Fredy] Univ Cincinnati, Cincinnati, OH 45221 USA. [Caviness, John N.] Mayo Clin Arizona, Scottsdale, AZ USA. [Friedman, Joseph H.] Butler Hosp, Providence, RI 02906 USA. [Perlmutter, Joel S.] Washington Univ, St Louis, MO USA. [Feigin, Andrew] Feinstein Inst Med Res, Manhasset, NY USA. [Rodriguez, Ramon; McFarland, Nikolaus R.] Univ Florida, Gainesville, FL USA. [Margolis, Russell L.] Johns Hopkins Univ, Baltimore, MD USA. [Farbman, Eric S.] Univ Nevada, Sch Med, Reno, NV 89557 USA. [Raymond, Lynn A.] Univ British Columbia, Vancouver, BC, Canada. [Suski, Valerie] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Kostyk, Sandra] Ohio State Univ, Columbus, OH 43210 USA. [Colcher, Amy] Cooper Univ Hlth Syst, Camden, NJ USA. [Seeberger, Lauren] Idaho Elks Rehabil Hosp, Boise, ID USA. [Epping, Eric] Univ Iowa, Iowa City, IA USA. [Esmail, Sherali] North York Gen Hosp 1, Toronto, ON, Canada. [Diaz, Nancy] St Lukes Hosp, Allentown, PA USA. [Fung, Wai Lun Alan] Univ Toronto, North York Gen Hosp 2, Toronto, ON M5S 1A1, Canada. [Diamond, Alan] Washington Reg Med Ctr, Fayetteville, AR USA. [Frank, Samuel] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Hanna, Philip] NJ Neurosci Inst, Edison, NJ USA. [Hermanowicz, Neal] Univ Calif Irvine, Irvine, CA 92717 USA. [Dure, Leon S.] Univ Alabama Birmingham, Birmingham, AL USA. [Cudkowicz, Merit] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP McGarry, A (reprint author), Rowan Univ, Cooper Univ Healthcare, Camden, NJ 08102 USA. EM mcgarry-andrew@cooperhealth.edu RI Raymond, Lynn/A-6664-2010 OI Raymond, Lynn/0000-0002-8610-1042 FU National Institute of Neurological Disorders and Stroke [NS052592, NS052619] FX Study funded by National Institute of Neurological Disorders and Stroke (grants NS052592 and NS052619). NR 34 TC 2 Z9 2 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 10 PY 2017 VL 88 IS 2 BP 152 EP 159 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EO2YH UT WOS:000396561500011 PM 27913695 ER PT J AU Cnaan, A Shinnar, S Arya, R Adamson, PC Clark, PO Dlugos, D Hirtz, DG Masur, D Glauser, TA AF Cnaan, Avital Shinnar, Shlomo Arya, Ravindra Adamson, Peter C. Clark, Peggy O. Dlugos, Dennis Hirtz, Deborah G. Masur, David Glauser, Tracy A. CA Childhood Absence Epilepsy Study TI Second monotherapy in childhood absence epilepsy SO NEUROLOGY LA English DT Article ID CENSORED SURVIVAL-DATA; TONIC-CLONIC SEIZURES; INITIAL MONOTHERAPY; ANTIEPILEPTIC DRUG; ONSET EPILEPSY; VALPROIC ACID; OUTCOMES; CARBAMAZEPINE; ETHOSUXIMIDE; LAMOTRIGINE AB Objective: To determine optimal second monotherapy for children with childhood absence epilepsy (CAE) experiencing initial treatment failure. Methods: Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16-20 and month 12 visits after randomization. Secondary study outcome was percentage of participants experiencing attentional dysfunction at these visits. Results: A total of 208 children were enrolled, randomized, and received second therapy. At both week 16-20 visit and month 12 visit, ethosuximide's (63%, 57%) and valproic acid's (65%, 49%) freedom from failure proportions were similar to each other and higher than lamotrigine's (45%, 36%, p = 0.051 and p = 0.062). At both time points, ethosuximide and valproic acid had superior seizure control compared to lamotrigine (p < 0.0001). At both the week 16-20 and month 12 visits, attentional dysfunction was numerically more common with valproic acid than with ethosuximide or lamotrigine. For each medication, second monotherapy freedom from failure proportions demonstrated noninferiority to initial monotherapy freedom from failure proportions. Conclusions: As second monotherapy, ethosuximide and valproic acid, demonstrated higher freedom from failure proportions and greater efficacy than lamotrigine; valproic acid was associated with more attentional dysfunction. Ethosuximide is the optimal second monotherapy for children with CAE not responding to initial therapy with other medications. C1 [Cnaan, Avital] Childrens Natl Hlth Syst, Washington, DC USA. [Shinnar, Shlomo; Masur, David] Albert Einstein Coll Med, Montefiore Med Ctr, New York, NY USA. [Arya, Ravindra; Clark, Peggy O.; Glauser, Tracy A.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Arya, Ravindra; Clark, Peggy O.; Glauser, Tracy A.] Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. [Adamson, Peter C.; Dlugos, Dennis] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Adamson, Peter C.; Dlugos, Dennis] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Hirtz, Deborah G.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP Cnaan, A (reprint author), Childrens Natl Hlth Syst, Washington, DC USA. EM acnaan@trinds.com FU NIH [U01-NS045911, U01-NS045803] FX Supported by NIH (U01-NS045911 and U01-NS045803). NR 25 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 10 PY 2017 VL 88 IS 2 BP 182 EP 190 DI 10.1212/WNL.0000000000003480 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EO2YH UT WOS:000396561500016 PM 27986874 ER PT J AU Liu, S Zhang, F Shugart, YY Yang, L Li, X Liu, Z Sun, N Yang, C Guo, X Shi, J Wang, L Cheng, L Zhang, K Yang, T Xu, Y AF Liu, S. Zhang, F. Shugart, Y. Y. Yang, L. Li, X. Liu, Z. Sun, N. Yang, C. Guo, X. Shi, J. Wang, L. Cheng, L. Zhang, K. Yang, T. Xu, Y. TI The early growth response protein 1-miR-30a-5p-neurogenic differentiation factor 1 axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID POTENTIAL PERIPHERAL MARKER; PREFRONTAL CORTEX; GENE-EXPRESSION; MICROARRAY ANALYSIS; MICRORNA EXPRESSION; EARLY INTERVENTION; MONONUCLEAR-CELLS; TEMPORAL CORTEX; HUMAN-DISEASE; C-ELEGANS AB To date, diagnosis of schizophrenia is still based on clinical interviews and careful observations, which is subjective and variable, and can lead to misdiagnosis and/or delay in diagnosis. As early intervention in schizophrenia is important in improving outcomes, objective tests that can be used for schizophrenia diagnosis or treatment monitoring are thus in great need. MicroRNAs (miRNAs) negatively regulate target gene expression and their biogenesis is tightly controlled by various factors including transcription factors (TFs). Dysregulation of miRNAs in brain tissue and peripheral blood mononuclear cells (PBMNCs) from patients with schizophrenia has been well documented, but analysis of the sensitivity and specificity for potential diagnostic utility of these alternations is limited. In this study, we explored the TF-miRNA-30-target gene axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring. Using bioinformatics analysis, we retrieved all TFs that control the biogenesis of miRNA 30 members as well as all target genes that are regulated by miRNA-30 members. Further, reverse transcription-quantitative PCR analysis revealed that the early growth response protein 1 (EGR1) and miR-30a-5p were remarkably downregulated, whereas neurogenic differentiation factor 1 (NEUROD1) was significantly upregulated in PBMNCs from patients in acute psychotic state. Antipsychotics treatment resulted in the elevation of EGR1 and miR-30a-5p but the reduction of NEUROD1. Receiver operating characteristic analysis showed that the EGR1-miR-30a-5p-NEUROD1 axis possessed significantly greater diagnostic value than miR-30a-5p alone. Our data suggest the EGR1-miR-30a-5p-NEUROD1 axis might serve as a promising biomarker for diagnosis and treatment monitoring for those patients in acute psychotic state. C1 [Liu, S.; Li, X.; Liu, Z.; Sun, N.; Yang, C.; Guo, X.; Shi, J.; Wang, L.; Cheng, L.; Zhang, K.; Xu, Y.] Shanxi Med Univ, Hosp 1, Dept Psychiat, Taiyuan, Peoples R China. [Zhang, F.] Wuxi Mental Hlth Ctr, Wuxi, Peoples R China. [Shugart, Y. Y.] NIMH, Unit Stat Genom, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Yang, L.; Yang, T.] Shanxi Med Univ, Dept Biochem & Mol Biol, Taiyuan 030001, Peoples R China. [Guo, X.; Shi, J.; Wang, L.; Cheng, L.; Zhang, K.; Xu, Y.] Shanxi Med Univ, Clin Med Coll 1, Taiyuan, Peoples R China. RP Yang, T (reprint author), Shanxi Med Univ, Dept Biochem & Mol Biol, Taiyuan 030001, Peoples R China.; Xu, Y (reprint author), Shanxi Med Univ, Clin Med Coll 1, Hosp 1, Dept Psychiat, Taiyuan 030001, Peoples R China. EM yangtao056cn@126.com; xuyongshanxi@sina.com FU National Natural Science Foundation of China [81271482, 81471364, 81571319]; Program for New Century Excellent Talents [NCET-121036]; Construction Plan for Shanxi Science & Technology Infrastructure Platforms [2015091002-0102]; Natural Science Foundation of Shanxi [201601D021150]; Doctoral Fund of Shanxi Medical University [03201314]; Intramural Research Program of National Institute of Mental Health, National Institutes of Health [MH002929-04] FX We sincerely thank all the subjects for their support and participation in this study. We are indebted to staff at the blood lab who helped collect blood samples. This work was supported by the National Natural Science Foundation of China (81271482, 81471364 and 81571319); the Program for New Century Excellent Talents (NCET-121036); the Construction Plan for Shanxi Science & Technology Infrastructure Platforms (2015091002-0102); Natural Science Foundation of Shanxi (201601D021150); and the Doctoral Fund of Shanxi Medical University (03201314). Shugart was supported by the Intramural Research Program of National Institute of Mental Health, National Institutes of Health (MH002929-04). NR 47 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 10 PY 2017 VL 7 AR e998 DI 10.1038/tp.2016.268 PG 7 WC Psychiatry SC Psychiatry GA EO1IA UT WOS:000396450700006 PM 28072411 ER PT J AU McEvoy, JW Martin, SS Dardari, ZA Miedema, MD Sandfort, V Yeboah, J Budoff, MJ Goff, DC Psaty, BM Post, WS Nasir, K Blumenthal, RS Blaha, MJ AF McEvoy, John W. Martin, Seth S. Dardari, Zeina A. Miedema, Michael D. Sandfort, Veit Yeboah, Joseph Budoff, Matthew J. Goff, David C., Jr. Psaty, Bruce M. Post, Wendy S. Nasir, Khurram Blumenthal, Roger S. Blaha, Michael J. TI Coronary Artery Calcium to Guide a Personalized Risk-Based Approach to Initiation and Intensification of Antihypertensive Therapy SO CIRCULATION LA English DT Article DE antihypertensive therapy; cardiovascular disease risk; coronary artery calcium; systolic blood pressure ID BLOOD-PRESSURE; CARDIOVASCULAR RISK; RANDOMIZED-TRIALS; HEART-DISEASE; ATHEROSCLEROSIS; INDIVIDUALS; HYPERTENSION; METAANALYSIS; POPULATION; PREVENTION AB BACKGROUND: The use of atherosclerotic cardiovascular disease (ASCVD) risk to personalize systolic blood pressure (SBP) treatment goals is a topic of increasing interest. Therefore, we studied whether coronary artery calcium (CAC) can further guide the allocation of anti-hypertensive treatment intensity. METHODS: We included 3733 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with SBP between 120 and 179 mm Hg. Within subgroups categorized by both SBP (120-139 mm Hg, 140-159 mm Hg, and 160-179 mm Hg) and estimated 10-year ASCVD risk (using the American College of Cardiology/American Heart Assocation pooled-cohort equations), we compared multivariable-adjusted hazard ratios for the composite outcome of incident ASCVD or heart failure after further stratifying by CAC (0, 1-100, or >100). We estimated 10-year number-needed-to-treat for an intensive SBP goal of 120 mm Hg by applying the treatment benefit recorded in meta-analyses to event rates within CAC strata. RESULTS: The mean age was 65 years, and 642 composite events took place over a median of 10.2 years. In persons with SBP <160 mm Hg, CAC stratified risk for events. For example, among those with an ASCVD risk of <15% and who had an SBP of either 120 to 139 mm Hg or 140 to 159 mm Hg, respectively, we found increasing hazard ratios for events with CAC 1 to 100 (1.7 [95% confidence interval, 1.0-2.6] or 2.0 [1.1-3.8]) and CAC >100 (3.0 [1.8-5.0] or 5.7 [2.9-11.0]), all relative to CAC= 0. There appeared to be no statistical association between CAC and events when SBP was 160 to 179 mm Hg, irrespective of ASCVD risk level. Estimated 10-year number-needed-to-treat for a SBP goal of 120mmHg varied substantially according to CAC levels when predicted ASCVD risk <15% and SBP <160mmHg (eg, 10-year number-needed-to-treat of 99 for CAC= 0 and 24 for CAC>100, when SBP 120-139mm Hg). However, few participants with ASCVD risk <5% had elevated CAC. Furthermore, 10-year number-needed-to-treat estimates were consistently low and varied less among CAC strata when SBP was 160 to 179 mm Hg or when ASCVD risk was >= 15% at any SBP level. CONCLUSIONS: Combined CAC imaging and assessment of global ASCVD risk has the potential to guide personalized SBP goals (eg, choosing a traditional goal of 140 or a more intensive goal of 120 mm Hg), particularly among adults with an estimated ASCVD risk of 5% to 15% and prehypertension or mild hypertension. C1 [McEvoy, John W.; Martin, Seth S.; Dardari, Zeina A.; Post, Wendy S.; Nasir, Khurram; Blumenthal, Roger S.; Blaha, Michael J.] Johns Hopkins Univ, Sch Med, Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA. [Miedema, Michael D.] Minneapolis Heart Inst, Minneapolis, MN USA. [Miedema, Michael D.] Minneapolis Heart Inst Fdn, Minneapolis, MN USA. [Sandfort, Veit] NIH, Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. [Yeboah, Joseph] Wake Forest Baptist Hlth, Heart & Vasc Ctr Excellence, Winston Salem, NC USA. [Budoff, Matthew J.] Harbor UCLA, Los Angeles Biomed Res Inst, Torrance, CA USA. [Goff, David C., Jr.] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Nasir, Khurram] Baptist Hlth South Florida, Ctr Healthcare Adv & Outcomes, South Miami, FL USA. [Nasir, Khurram] Baptist Hlth South Florida, Miami Cardiac & Vasc Inst, South Miami, FL USA. RP McEvoy, JW (reprint author), Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Blalock 524C,600 N Wolfe St, Baltimore, MD 21287 USA. EM jmcevoy1@jhmi.edu FU National Heart, Lung, and Blood Institute [HHS-N268201500003I, 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 HHS-N268201500003I, 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 grants UL1-TR-000040 and UL1-TR-001079 from the National Center for Research Resources. NR 34 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 10 PY 2017 VL 135 IS 2 BP 153 EP + DI 10.1161/CIRCULATIONAHA.116.025471 PG 30 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EI2AW UT WOS:000392289500012 PM 27881560 ER PT J AU Bruno, RD Fleming, JM George, AL Boulanger, CA Schedin, P Smith, GH AF Bruno, Robert D. Fleming, Jodie M. George, Andrea L. Boulanger, Corinne A. Schedin, Pepper Smith, Gilbert H. TI Mammary extracellular matrix directs differentiation of testicular and embryonic stem cells to form functional mammary glands in vivo SO SCIENTIFIC REPORTS LA English DT Article ID BREAST-CANCER; EPITHELIAL PROGENITOR; MICROENVIRONMENT; PREGNANCY; EXPRESSION; PHENOTYPE; BEHAVIOR; CULTURE; GENES; FATE AB Previously, we demonstrated the ability of the normal mammary microenvironment (niche) to direct non-mammary cells including testicular and embryonic stem cells (ESCs) to adopt a mammary epithelial cell (MEC) fate. These studies relied upon the interaction of transplanted normal MECs with non-mammary cells within the mammary fat-pads of recipient mice that had their endogenous epithelium removed. Here, we tested whether acellular mammary extracellular matrix (mECM) preparations are sufficient to direct differentiation of testicular-derived cells and ESCs to form functional mammary epithelial trees in vivo. We found that mECMs isolated from adult mice and rats were sufficient to redirect testicular derived cells to produce normal mammary epithelial trees within epithelial divested mouse mammary fat-pads. Conversely, ECMs isolated from omental fat and lung did not redirect testicular cells to a MEC fate, indicating the necessity of tissue specific components of the mECM. mECM preparations also completely inhibited teratoma formation from ESC inoculations. Further, a phenotypically normal ductal outgrowth resulted from a single inoculation of ESCs and mECM. To the best of our knowledge, this is the first demonstration of a tissue specific ECM driving differentiation of cells to form a functional tissue in vivo. C1 [Bruno, Robert D.] Old Dominion Univ, Coll Hlth Sci, Sch Med Diagnost & Translat Sci, Norfolk, VA 23529 USA. [Fleming, Jodie M.] North Carolina Cent Univ, Dept Biol & Biomed Sci, Durham, NC 27707 USA. [George, Andrea L.; Boulanger, Corinne A.; Smith, Gilbert H.] NCI, Mammary Stem Cell Biol Sect, Basic Res Lab, CCR,NIH, Bethesda, MD 20892 USA. [Schedin, Pepper] Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. RP Smith, GH (reprint author), NCI, Mammary Stem Cell Biol Sect, Basic Res Lab, CCR,NIH, Bethesda, MD 20892 USA. EM smithg@mail.nih.gov FU NCI NIH HHS [R01 CA169175] NR 35 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 10 PY 2017 VL 7 AR 40196 DI 10.1038/srep40196 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI1LF UT WOS:000392238100001 PM 28071703 ER PT J AU Siersbaek, M Varticovski, L Yang, ST Baek, S Nielsen, R Mandrup, S Hager, GL Chung, JH Grontved, L AF Siersbaek, Majken Varticovski, Lyuba Yang, Shutong Baek, Songjoon Nielsen, Ronni Mandrup, Susanne Hager, Gordon L. Chung, Jay H. Grontved, Lars TI High fat diet-induced changes of mouse hepatic transcription and enhancer activity can be reversed by subsequent weight loss SO SCIENTIFIC REPORTS LA English DT Article ID REACTOME PATHWAY KNOWLEDGEBASE; CONTAINING 2 GENE; LIVER-DISEASE; CHROMATIN ACCESSIBILITY; DEFICIENCY PROTECTS; INDUCED OBESITY; C57BL/6J MICE; EXPRESSION PROFILES; HUMAN GENOME; RNA-SEQ AB Epigenetic factors have been suggested to play an important role in metabolic memory by trapping and maintaining initial metabolic changes within the transcriptional regulatory machinery. In this study we fed mice a high fat diet (HFD) for seven weeks followed by additional five weeks of chow, to identify HFD-mediated changes to the hepatic transcriptional program that may persist after weight loss. Mice fed a HFD displayed increased fasting insulin levels, hepatosteatosis and major changes in hepatic gene transcription associated with modulation of H3K27Ac at enhancers, but no significant changes in chromatin accessibility, indicating that HFD-regulated gene transcription is primarily controlled by modulating the activity of pre-established enhancers. After return to the same body weight as chow fed control mice, the fasting insulin, glucose, and hepatic triglyceride levels were fully restored to normal levels. Moreover, HFD-regulated H3K27Ac and mRNA levels returned to similar levels as control mice. These data demonstrates that the transcription regulatory landscape in the liver induced by HFD is highly dynamic and can be reversed by weight loss. This provides hope for efficient treatment of early obesity-associated changes to hepatic complications by simple weight loss intervention without persistent reprograming of the liver transcriptome. C1 [Siersbaek, Majken; Nielsen, Ronni; Mandrup, Susanne; Grontved, Lars] Univ Southern Denmark, Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark. [Varticovski, Lyuba; Baek, Songjoon; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yang, Shutong; Chung, Jay H.] NHLBI, Lab Obes & Aging Res, Genet & Dev Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Grontved, L (reprint author), Univ Southern Denmark, Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark. EM larsgr@bmb.sdu.dk OI Grontved, Lars/0000-0002-6735-8483 FU Danish Independent Research Council; VILLUM Foundation FX This study was supported by a research grant to LG from the Danish Independent Research Council. Furthermore, the work was supported by the VILLUM Foundation to the VILLUM Center for Bioanalytical Sciences at University of Southern Denmark. NR 60 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 10 PY 2017 VL 7 AR 40220 DI 10.1038/srep40220 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI1LV UT WOS:000392239800001 PM 28071704 ER PT J AU Dogan, RI Kim, S Chatr-Aryamontri, A Chang, CS Oughtred, R Rust, J Wilbur, WJ Comeau, DC Dolinski, K Tyers, M AF Dogan, Rezarta Islamaj Kim, Sun Chatr-aryamontri, Andrew Chang, Christie S. Oughtred, Rose Rust, Jennifer Wilbur, W. John Comeau, Donald C. Dolinski, Kara Tyers, Mike TI The BioC-BioGRID corpus: full text articles annotated for curation of protein-protein and genetic interactions SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID BIOLOGY; CHALLENGE; COMMUNITY AB A great deal of information on the molecular genetics and biochemistry of model organisms has been reported in the scientific literature. However, this data is typically described in free text form and is not readily amenable to computational analyses. To this end, the BioGRID database systematically curates the biomedical literature for genetic and protein interaction data. This data is provided in a standardized computationally tractable format and includes structured annotation of experimental evidence. BioGRID curation necessarily involves substantial human effort by expert curators who must read each publication to extract the relevant information. Computational text-mining methods offer the potential to augment and accelerate manual curation. To facilitate the development of practical text-mining strategies, a new challenge was organized in BioCreative V for the BioC task, the collaborative Biocurator Assistant Task. This was a noncompetitive, cooperative task in which the participants worked together to build BioCcompatible modules into an integrated pipeline to assist BioGRID curators. As an integral part of this task, a test collection of full text articles was developed that contained both biological entity annotations (gene/protein and organism/species) and molecular interaction annotations (protein-protein and genetic interactions (PPIs and GIs)). This collection, which we call the BioC-BioGRID corpus, was annotated by four BioGRID curators over three rounds of annotation and contains 120 full text articles curated in a dataset representing two major model organisms, namely budding yeast and human. The BioC-BioGRID corpus contains annotations for 6409 mentions of genes and their Entrez Gene IDs, 186 mentions of organism names and their NCBI Taxonomy IDs, 1867 mentions of PPIs and 701 annotations of PPI experimental evidence statements, 856 mentions of GIs and 399 annotations of GI evidence statements. The purpose, characteristics and possible future uses of the BioC-BioGRID corpus are detailed in this report. C1 [Dogan, Rezarta Islamaj; Kim, Sun; Wilbur, W. John; Comeau, Donald C.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Chatr-aryamontri, Andrew; Tyers, Mike] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada. [Chang, Christie S.; Oughtred, Rose; Rust, Jennifer; Dolinski, Kara] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Tyers, Mike] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. RP Dogan, RI (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM Rezarta.Islamaj@nih.gov FU NIH, National Library of Medicine; National Institutes of Health [R01OD010929, R24OD011194] FX Intramural Research Program of the NIH, National Library of Medicine to R.I.D., S.K., W.J.W. and D.C.C.; National Institutes of Health R01OD010929 to M.T. and K.D., National Institutes of Health R24OD011194 to K.D. and M.T. NR 24 TC 0 Z9 0 U1 6 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD JAN 10 PY 2017 AR baw147 DI 10.1093/database/baw147 PG 11 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA EH0ZQ UT WOS:000391493500001 ER PT J AU El Kennani, S Adrait, A Shaytan, AK Khochbin, S Bruley, C Panchenko, AR Landsman, D Pflieger, D Govin, J AF El Kennani, Sara Adrait, Annie Shaytan, Alexey K. Khochbin, Saadi Bruley, Christophe Panchenko, Anna R. Landsman, David Pflieger, Delphine Govin, Jerome TI MS_HistoneDB, a manually curated resource for proteomic analysis of human and mouse histones SO EPIGENETICS & CHROMATIN LA English DT Article DE Histone; Histone variants; Chromatin; Mass spectrometry; Proteomics ID DOWN MASS-SPECTROMETRY; INACTIVE X-CHROMOSOME; CENP-A; MESSENGER-RNA; MAMMALIAN SPERMIOGENESIS; H1-LIKE PROTEIN; GENE-EXPRESSION; CHROMATIN-STRUCTURE; SEQUENCE-ANALYSIS; VARIANT H2A.BBD AB Background: Histones and histone variants are essential components of the nuclear chromatin. While mass spectrometry has opened a large window to their characterization and functional studies, their identification from proteomic data remains challenging. Indeed, the current interpretation of mass spectrometry data relies on public databases which are either not exhaustive (Swiss-Prot) or contain many redundant entries (UniProtKB or NCBI). Currently, no protein database is ideally suited for the analysis of histones and the complex array of mammalian histone variants. Results: We propose two proteomics-oriented manually curated databases for mouse and human histone variants. We manually curated >1700 gene, transcript and protein entries to produce a non-redundant list of 83 mouse and 85 human histones. These entries were annotated in accordance with the current nomenclature and unified with the "HistoneDB2.0 with Variants" database. This resource is provided in a format that can be directly read by programs used for mass spectrometry data interpretation. In addition, it was used to interpret mass spectrometry data acquired on histones extracted from mouse testis. Several histone variants, which had so far only been inferred by homology or detected at the RNA level, were detected by mass spectrometry, confirming the existence of their protein form. Conclusions: Mouse and human histone entries were collected from different databases and subsequently curated to produce a non-redundant protein-centric resource, MS_HistoneDB. It is dedicated to the proteomic study of histones in mouse and human and will hopefully facilitate the identification and functional study of histone variants. C1 [El Kennani, Sara; Adrait, Annie; Bruley, Christophe; Pflieger, Delphine; Govin, Jerome] Univ Grenoble Alpes, INSERM, CEA, BIG,FR,CNRS,BGE 3425,U1038, Grenoble, France. [Shaytan, Alexey K.; Panchenko, Anna R.; Landsman, David] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Khochbin, Saadi] Univ Grenoble Alpes, Inst Adv Biosci, INSERM, CNRS,UMR 5309,U1209, Grenoble, France. RP Pflieger, D; Govin, J (reprint author), Univ Grenoble Alpes, INSERM, CEA, BIG,FR,CNRS,BGE 3425,U1038, Grenoble, France. EM Delphine.Pflieger@cea.fr; Jerome.Govin@inserm.fr RI Shaytan, Alexey/D-7306-2012; OI Shaytan, Alexey/0000-0003-0312-938X; Govin, Jerome/0000-0001-5511-6965 FU Fond d'Intervention of the University Grenoble Alpes; Agence Nationale de la Recherche [ANR-11-PDOC-0011]; European Union FP7 Marie Curie Action "Career Integration Grant" [304003]; French National Research Agency [ANR-10-INBS-08]; Intramural Research Program of the National Library of Medicine, National Institutes of Health FX This work was supported by the Fond d'Intervention of the University Grenoble Alpes (to JG), the Agence Nationale de la Recherche (ANR-11-PDOC-0011 to JG), and the European Union FP7 Marie Curie Action "Career Integration Grant" (304003 to JG). This study also received financial support from the French National Research Agency ANR-10-INBS-08 ProFI, Proteomics French Infrastructure. This research was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. NR 131 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8935 J9 EPIGENET CHROMATIN JI Epigenetics Chromatin PD JAN 10 PY 2017 VL 10 AR 2 DI 10.1186/s13072-016-0109-x PG 18 WC Genetics & Heredity SC Genetics & Heredity GA EH1HE UT WOS:000391513800001 PM 28096900 ER PT J AU Volkow, ND Compton, WM Wargo, EM AF Volkow, Nora D. Compton, Wilson M. Wargo, Eric M. TI The Risks of Marijuana Use During Pregnancy SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Volkow, Nora D.; Compton, Wilson M.; Wargo, Eric M.] NIDA, NIH, Bethesda, MD 20892 USA. RP Wargo, EM (reprint author), NIDA, Off Sci Policy & Commun, Sci Policy Branch, 6001 Execut Blvd,Room 5235, Bethesda, MD 20892 USA. EM wargoem@nida.nih.gov NR 6 TC 0 Z9 0 U1 11 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 10 PY 2017 VL 317 IS 2 BP 129 EP 130 DI 10.1001/jama.2016.18612 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EH5PV UT WOS:000391826200009 PM 27992628 ER PT J AU Mills, JL AF Mills, James L. TI Strategies for Preventing Folate-Related Neural Tube Defects Supplements, Fortified Foods, or Both? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID FOLIC-ACID FORTIFICATION; UNITED-STATES; TRENDS; EUROPE C1 [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Epidemiol Branch, 6710B Bldg,Room 3117, Bethesda, MD 20892 USA. RP Mills, JL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Epidemiol Branch, 6710B Bldg,Room 3117, Bethesda, MD 20892 USA. EM jamesmills@nih.gov FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 15 TC 0 Z9 0 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 10 PY 2017 VL 317 IS 2 BP 144 EP 145 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EH5PV UT WOS:000391826200016 PM 28097344 ER PT J AU Forouzanfar, MH Liu, P Roth, GA Ng, M Biryukov, S Marczak, L Alexander, L Estep, K Abate, KH Akinyemiju, TF Ali, R Alvis-Guzman, N Azzopardi, P Banerjee, A Barnighausen, T Basu, A Bekele, T Bennett, DA Biadgilign, S Catala-Lopez, F Feigin, VL Fernandes, JC Fischer, F Gebru, AA Gona, P Gupta, R Hankey, GJ Jonas, JB Judd, SE Khang, YH Khosravi, A Kim, YJ Kimokoti, RW Kokubo, Y Kolte, D Lopez, A Lotufo, PA Malekzadeh, R Melaku, YA Mensah, GA Misganaw, A Mokdad, AH Moran, AE Nawaz, H Neal, B Ngalesoni, FN Ohkubo, T Pourmalek, F Rafay, A Rai, RK Rojas-Rueda, D Sampson, UK Santos, IS Sawhney, M Schutte, AE Sepanlou, SG Shifa, GT Shiue, I Tedla, BA Thrift, AG Tonelli, M Truelsen, T Tsilimparis, N Ukwaja, KN Uthman, OA Vasankari, T Venketasubramanian, N Vlassov, VV Vos, T Westerman, R Yan, LJL Yano, Y Yonemoto, N Zaki, MES Murray, CJL AF Forouzanfar, Mohammad H. Liu, Patrick Roth, Gregory A. Ng, Marie Biryukov, Stan Marczak, Laurie Alexander, Lily Estep, Kara Abate, Kalkidan Hassen Akinyemiju, Tomi F. Ali, Raghib Alvis-Guzman, Nelson Azzopardi, Peter Banerjee, Amitava Baernighausen, Till Basu, Arindam Bekele, Tolesa Bennett, Derrick A. Biadgilign, Sibhatu Catala-Lopez, Ferran Feigin, Valery L. Fernandes, Joao C. Fischer, Florian Gebru, Alemseged Aregay Gona, Philimon Gupta, Rajeev Hankey, Graeme J. Jonas, Jost B. Judd, Suzanne E. Khang, Young-Ho Khosravi, Ardeshir Kim, Yun Jin Kimokoti, Ruth W. Kokubo, Yoshihiro Kolte, Dhaval Lopez, Alan Lotufo, Paulo A. Malekzadeh, Reza Melaku, Yohannes Adama Mensah, George A. Misganaw, Awoke Mokdad, Ali H. Moran, Andrew E. Nawaz, Haseeb Neal, Bruce Ngalesoni, Frida Namnyak Ohkubo, Takayoshi Pourmalek, Farshad Rafay, Anwar Rai, Rajesh Kumar Rojas-Rueda, David Sampson, Uchechukwu K. Santos, Itamar S. Sawhney, Monika Schutte, Aletta E. Sepanlou, Sadaf G. Shifa, Girma Temam Shiue, Ivy Tedla, Bemnet Amare Thrift, Amanda G. Tonelli, Marcello Truelsen, Thomas Tsilimparis, Nikolaos Ukwaja, Kingsley Nnanna Uthman, Olalekan A. Vasankari, Tommi Venketasubramanian, Narayanaswamy Vlassov, Vasiliy Victorovich Vos, Theo Westerman, Ronny Yan, Lijing L. Yano, Yuichiro Yonemoto, Naohiro Zaki, Maysaa El Sayed Murray, Christopher J. L. TI Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; RISK-FACTORS; ARTERIAL STIFFNESS; KIDNEY-DISEASE; AGE; METAANALYSIS; MORTALITY; PROGRESSION; PREVALENCE AB IMPORTANCE Elevated systolic blood (SBP) pressure is a leading global health risk. Quantifying the levels of SBP is important to guide prevention policies and interventions. OBJECTIVE To estimate the association between SBP of at least 110 to 115 mm Hg and SBP of 140 mm Hg or higher and the burden of different causes of death and disability by age and sex for 195 countries and territories, 1990-2015. DESIGN A comparative risk assessment of health loss related to SBP. Estimated distribution of SBP was based on 844 studies from 154 countries (published 1980-2015) of 8.69 million participants. Spatiotemporal Gaussian process regression was used to generate estimates of mean SBP and adjusted variance for each age, sex, country, and year. Diseases with sufficient evidence for a causal relationship with high SBP (eg, ischemic heart disease, ischemic stroke, and hemorrhagic stroke) were included in the primary analysis. MAIN OUTCOMES AND MEASURES Mean SBP level, cause-specific deaths, and health burden related to SBP (>110-115mmHg and also >= 140 mm Hg) by age, sex, country, and year. RESULTS Between 1990-2015, the rate of SBP of at least 110 to 115 mm Hg increased from 73 119 (95% uncertainty interval [UI], 67 949-78 241) to 81 373 (95% UI, 76 814-85 770) per 100000, and SBP of 140 mm Hg or higher increased from 17 307 (95% UI, 17 117-17 492) to 20526 (95% UI, 20283-20746) per 100000. The estimated annual death rate per 100000 associated with SBP of at least 110 to 115 mm Hg increased from 135.6 (95% UI, 122.4-148.1) to 145.2 (95% UI 130.3-159.9) and the rate for SBP of 140 mm Hg or higher increased from 97.9 (95% UI, 87.5-108.1) to 106.3 (95% UI, 94.6-118.1). Loss of disability-adjusted life-years (DALYs) associated with SBP of at least 110 to 115 mm Hg increased from 148 million (95% UI, 134-162 million) to 211 million (95% UI, 193-231 million), and for SBP of 140 mm Hg or higher, the loss increased from 5.2 million (95% UI, 4.6-5.7 million) to 7.8 million (95% UI, 7.0-8.7 million). The largest numbers of SBP-related deathswere caused by ischemic heart disease (4.9 million [95% UI, 4.0-5.7 million]; 54.5%), hemorrhagic stroke (2.0million [95% UI, 1.6-2.3 million]; 58.3%), and ischemic stroke (1.5 million [95% UI, 1.2-1.8 million]; 50.0%). In 2015, China, India, Russia, Indonesia, and the United States accounted for more than half of the global DALYs related to SBP of at least 110 to 115 mm Hg. CONCLUSIONS AND RELEVANCE In international surveys, although there is uncertainty in some estimates, the rate of elevated SBP (>= 110-115 and >= 140 mm Hg) increased substantially between 1990 and 2015, and DALYs and deaths associated with elevated SBP also increased. Projections based on this sample suggest that in 2015, an estimated 3.5 billion adults had SBP of at least 110 to 115 mm Hg and 874 million adults had SBP of 140 mm Hg or higher. Copyright 2016 American Medical Association. All rights reserved. C1 [Forouzanfar, Mohammad H.; Liu, Patrick; Roth, Gregory A.; Ng, Marie; Biryukov, Stan; Marczak, Laurie; Alexander, Lily; Estep, Kara; Misganaw, Awoke; Mokdad, Ali H.; Vos, Theo; Murray, Christopher J. L.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Abate, Kalkidan Hassen] Jimma Univ, Jimma, Ethiopia. [Akinyemiju, Tomi F.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Ali, Raghib; Bennett, Derrick A.] Univ Oxford, Oxford, England. [Alvis-Guzman, Nelson] Univ Cartagena, Cartagena Indias, Colombia. [Azzopardi, Peter] Ctr Adolescent Hlth, Parkville, Vic, Australia. [Azzopardi, Peter] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. [Banerjee, Amitava] UCL, Farr Inst Hlth Informat Res, London, England. [Baernighausen, Till] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Baernighausen, Till] Wellcome Trust Africa Ctr Hlth & Populat Studies, Mtubatuba, Kwazulu Natal, South Africa. [Basu, Arindam] Univ Canterbury, Sch Hlth Sci, Christchurch, New Zealand. [Bekele, Tolesa] Madawalabu Univ, Bale Goba, Ethiopia. [Catala-Lopez, Ferran] Univ Valencia, INCLIVA Hlth Res Inst, Valencia, Spain. [Catala-Lopez, Ferran] CIBERSAM, Dept Med, Valencia, Spain. [Catala-Lopez, Ferran] Ottawa Hosp Res Inst, Program Epidemiol, Ottawa, ON, Canada. [Feigin, Valery L.] Auckland Univ Technol, Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Fernandes, Joao C.] Univ Coimbra, Fac Med, IBILI Inst Biomed Imaging & Life Sci, Pharmacol & Expt Therapeut, Coimbra, Portugal. [Fischer, Florian] Univ Bielefeld, Bielefeld, Germany. [Gebru, Alemseged Aregay] Mekelle Univ, Kilte Awlaelo I Hlth & Demog Surveillance Syst, Mekelle, Ethiopia. [Gona, Philimon] Univ Massachusetts, Boston, MA 02125 USA. [Gupta, Rajeev] Eternal Heart Care Ctr, Res Inst, Jaipur, Rajasthan, India. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia. [Hankey, Graeme J.] Harry Perkins Inst Med Res, Nedlands, WA, Australia. [Hankey, Graeme J.] Western Australian Neurosci Res Inst, Nedlands, WA, Australia. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Judd, Suzanne E.] Univ Alabama Birmingham, Birmingham, AL USA. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Khosravi, Ardeshir] Iranian Minist Hlth & Med Educ, Tehran, Iran. [Kim, Yun Jin] Southern Univ Coll, Johor Baharu, Malaysia. [Kimokoti, Ruth W.] Simmons Coll, Boston, MA USA. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan. [Kolte, Dhaval] Brown Univ, Rhode Isl Hosp, Providence, RI 02912 USA. [Lopez, Alan] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Melbourne, QLD, Australia. [Lotufo, Paulo A.] Univ Sao Paulo, Sao Paulo, Brazil. [Malekzadeh, Reza; Sepanlou, Sadaf G.] Univ Tehran Med Sci, Digest Dis Res Inst, Tehran, Iran. [Melaku, Yohannes Adama] Mekelle Univ, Sch Publ Hlth, Mekelle, Ethiopia. [Melaku, Yohannes Adama] Univ Adelaide, Sch Med, Adelaide, SA, Australia. [Mensah, George A.] NHLBI, NIH, Ctr Translat Res & Implementat Sci, Bethesda, MD 20892 USA. [Moran, Andrew E.] Columbia Univ, New York, NY USA. [Nawaz, Haseeb] Southern Illinois Univ, Springfield, IL USA. [Neal, Bruce] George Inst Global Hlth, Sydney, NSW, Australia. [Neal, Bruce] Univ Sydney, Sydney, NSW, Australia. [Neal, Bruce] Royal Prince Alfred Hosp, Sydney, NSW, Australia. [Neal, Bruce] Imperial Coll London, London, England. [Ngalesoni, Frida Namnyak] Minist Hlth & Social Welf, Dar Es Salaam, Tanzania. [Ohkubo, Takayoshi] Teikyo Univ, Sch Med, Tokyo, Japan. [Pourmalek, Farshad] Univ British Columbia, Vancouver, BC, Canada. [Rafay, Anwar] Contech Sch Publ Hlth, Lahore, Punjab, Pakistan. [Rai, Rajesh Kumar] Soc Hlth & Demog Surveillance, Suri, India. [Rojas-Rueda, David] ISGlobal, Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Sampson, Uchechukwu K.] NHLBI, NIH, Bethesda, MD USA. [Santos, Itamar S.] Univ Sao Paulo, Dept Internal Med, Sao Paulo, Brazil. [Sawhney, Monika] Marshall Univ, Huntington, WV USA. [Schutte, Aletta E.] North West Univ, HART, South African Med Res Council, Potchefstroom, South Africa. [Shifa, Girma Temam] Arba Minch Univ, Arba Minch, SNNPR, Ethiopia. [Shifa, Girma Temam] Univ Addis Ababa, Addis Ababa, Ethiopia. [Shiue, Ivy] Northumbria Univ, Fac Hlth & Life Sci, Newcastle Upon Tyne, Tyne & Wear, England. [Shiue, Ivy] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Tedla, Bemnet Amare] Univ Gondar, Gondar, Ethiopia. [Tedla, Bemnet Amare] James Cook Univ, Cairns, Queensland, Australia. [Thrift, Amanda G.] Monash Univ, Sch Clin Sci Monash Hlth, Melbourne, Vic, Australia. [Tonelli, Marcello] Univ Calgary, Calgary, AB, Canada. [Truelsen, Thomas] Univ Copenhagen, Dept Neurol, Copenhagen, Denmark. [Tsilimparis, Nikolaos] Univ Heart Ctr Hamburg, Hamburg, Germany. [Ukwaja, Kingsley Nnanna] Fed Teaching Hosp, Dept Internal Med, Abakaliki, Nigeria. [Uthman, Olalekan A.] Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England. [Vasankari, Tommi] UKK Inst Hlth Promot Res, Tampere, Finland. [Venketasubramanian, Narayanaswamy] Raffles Hosp, Raffles Neurosci Ctr, Singapore, Singapore. [Vlassov, Vasiliy Victorovich] Natl Res Univ, Higher Sch Econ, Moscow, Russia. [Westerman, Ronny] Fed Inst Populat Res, Wiesbaden, Germany. [Westerman, Ronny] German Natl Cohort Consortium, Heidelberg, Germany. [Yan, Lijing L.] Duke Kunshan Univ, Global Hlth Res Ctr, Kunshan, Peoples R China. [Yano, Yuichiro] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Yonemoto, Naohiro] Natl Ctr Neurol & Psychiat, Kodaira, Tokyo, Japan. [Zaki, Maysaa El Sayed] Mansoura Fac Med, Mansoura, Egypt. RP Murray, CJL (reprint author), Inst Hlth Metr & Evaluat, 2301 Fifth Ave,Ste 600, Seattle, WA 98121 USA. EM cjlm@uw.edu RI Tonelli, Marcello/B-3028-2009; Lotufo, Paulo/A-9843-2008; Hankey, Graeme /H-4968-2014; OI Lotufo, Paulo/0000-0002-4856-8450; Hankey, Graeme /0000-0002-6044-7328; Catala-Lopez, Ferran/0000-0002-3833-9312 FU Bill and Melinda Gates Foundation FX This research was supported by funding from the Bill and Melinda Gates Foundation. NR 53 TC 2 Z9 2 U1 14 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 10 PY 2017 VL 317 IS 2 BP 165 EP 182 DI 10.1001/jama.2016.19043 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA EH5PV UT WOS:000391826200019 PM 28097354 ER PT J AU Compton, WM Han, B Hughes, A Jones, CM Blanco, C AF Compton, Wilson M. Han, Beth Hughes, Arthur Jones, Christopher M. Blanco, Carlos TI Use of Marijuana for Medical Purposes Among Adults in the United States SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Compton, Wilson M.; Blanco, Carlos] Natl Inst Drug Abuse, 6001 Execut Blvd,MSC 9589, Bethesda, MD 20892 USA. [Han, Beth; Hughes, Arthur] Subst Abuse & Mental Hlth Serv Adm, Rockville, MD USA. [Jones, Christopher M.] US Dept HHS, Off Assistant Secretary Planning & Evaluat, Washington, DC 20201 USA. RP Compton, WM (reprint author), Natl Inst Drug Abuse, 6001 Execut Blvd,MSC 9589, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov FU Substance Abuse and Mental Health Services Administration; National Institute on Drug Abuse of the National Institutes of Health; Office of the Assistant Secretary for Planning and Evaluation of the US Department of Health and Human Services FX The National Survey on Drug Use and Health was supported by contracts from the Substance Abuse and Mental Health Services Administration. This study was jointly sponsored by the National Institute on Drug Abuse of the National Institutes of Health, the Substance Abuse and Mental Health Services Administration, and the Office of the Assistant Secretary for Planning and Evaluation of the US Department of Health and Human Services. NR 4 TC 0 Z9 0 U1 27 U2 27 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 10 PY 2017 VL 317 IS 2 BP 209 EP 211 DI 10.1001/jama.2016.18900 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EH5PV UT WOS:000391826200024 PM 27992636 ER PT J AU Wallace, BD Berman, Z Mueller, GA Lin, YF Chang, T Andres, SN Wojtaszek, JL DeRose, EF Appel, CD London, RE Yan, S Williams, RS AF Wallace, Bret D. Berman, Zachary Mueller, Geoffrey A. Lin, Yunfeng Chang, Timothy Andres, Sara N. Wojtaszek, Jessica L. DeRose, Eugene F. Appel, C. Denise London, Robert E. Yan, Shan Williams, R. Scott TI APE2 Zf-GRF facilitates 3 '-5 ' resection of DNA damage following oxidative stress SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE oxidative stress; APE2; Zf-GRF; crystallography; Xenopus laevis ID CELL NUCLEAR ANTIGEN; SACCHAROMYCES-CEREVISIAE; ABASIC ENDONUCLEASE; GENOME INTEGRITY; EXONUCLEASE-III; REPAIR PATHWAYS; PROTEIN MIMICRY; ZINC-FINGERS; YEAST APN2; COMPLEX AB The Xenopus laevis APE2 (apurinic/apyrimidinic endonuclease 2) nuclease participates in 3'-5' nucleolytic resection of oxidative DNA damage and activation of the ATR-Chk1 DNA damage response (DDR) pathway via ill-defined mechanisms. Here we report that APE2 resection activity is regulated by DNA interactions in its Zf-GRF domain, a region sharing high homology with DDR proteins Topoisomerase 3 alpha(TOP3 alpha) and NEIL3 (Nei-like DNA glycosylase 3), as well as transcription and RNA regulatory proteins, such as TTF2 (transcription termination factor 2), TFIIS, and RPB9. Biochemical and NMR results establish the nucleic acid-binding activity of the Zf-GRF domain. Moreover, an APE2 Zf-GRF X-ray structure and small-angle X-ray scattering analyses show that the Zf-GRF fold is typified by a crescent-shaped ssDNA binding claw that is flexibly appended to an APE2 endonuclease/ exonuclease/phosphatase (EEP) catalytic core. Structure-guided Zf-GRF mutations impact APE2 DNA binding and 3'-5' exonuclease processing, and also prevent efficient APE2-dependent RPA recruitment to damaged chromatin and activation of the ATR-Chk1 DDR pathway in response to oxidative stress in Xenopus egg extracts. Collectively, our data unveil the APE2 Zf-GRF domain as a nucleic acid interaction module in the regulation of a key single-strand break resection function of APE2, and also reveal topologic similarity of the Zf-GRF to the zinc ribbon domains of TFIIS and RPB9. C1 [Wallace, Bret D.; Mueller, Geoffrey A.; Chang, Timothy; Andres, Sara N.; Wojtaszek, Jessica L.; DeRose, Eugene F.; Appel, C. Denise; London, Robert E.; Williams, R. Scott] NIEHS, Genome Integr & Struct Biol Lab, Dept Hlth & Human Serv, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Berman, Zachary; Lin, Yunfeng; Yan, Shan] Univ N Carolina, Dept Biol Sci, Charlotte, NC 28223 USA. RP Williams, RS (reprint author), NIEHS, Genome Integr & Struct Biol Lab, Dept Hlth & Human Serv, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.; Yan, S (reprint author), Univ N Carolina, Dept Biol Sci, Charlotte, NC 28223 USA. EM shan.yan@uncc.edu; williamsrs@niehs.nih.gov FU University of North Carolina at Charlotte; National Institute of General Medical Sciences of the National Institutes of Health (NIH) [R15 GM101571, R15 GM114713]; DOE's Office of Biological and Environmental Research; NIH Project MINOS [R01 GM105404]; DOE, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; NIH Intramural Program; NIEHS [1Z01ES102765, 1Z01ES050111] FX We thank Drs. Matthew Michael, Karlene Cimprich, and Howard Lindsay for reagents; Jason Williams of the National Institute of Environmental Health Sciences (NIEHS) protein microcharacterization core for mass spectrometry analysis, and Lars Pedersen of the NIEHS X-ray crystallography core for help with X- ray data collection. We also thank Drs. Robin Stanley and Jun Zhang for comments on the manuscript. This study was supported in part by funds provided by University of North Carolina at Charlotte and the National Institute of General Medical Sciences of the National Institutes of Health (NIH; Grants R15 GM101571 and R15 GM114713) to S.Y. The SAXS experiments were conducted at the Advanced Light Source, a national user facility operated by Lawrence Berkeley National Laboratory on behalf of the Department of Energy (DOE), Office of Basic Energy Sciences, through the Integrated Diffraction Analysis Technologies program, supported by the DOE's Office of Biological and Environmental Research. Additional support came from the NIH Project MINOS (Grant R01 GM105404). X-ray crystallographic data were collected at Southeast Regional Collaborative Access Team beamline 22-ID at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the DOE, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. This research was also supported by the NIH Intramural Program and the NIEHS (Grants 1Z01ES102765, to R.S.W., and 1Z01ES050111, to R.E.L.). NR 56 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 10 PY 2017 VL 114 IS 2 BP 304 EP 309 DI 10.1073/pnas.1610011114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH0FR UT WOS:000391439300043 PM 28028224 ER PT J AU Garten, M Mosgaard, LD Bornschlogl, T Dieudonne, S Bassereau, P Toombes, GES AF Garten, Matthias Mosgaard, Lars D. Bornschloegl, Thomas Dieudonne, Stephane Bassereau, Patricia Toombes, Gilman E. S. TI Whole-GUV patch-clamping SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE giant unilamellar vesicle; patch clamp; electrophysiology; biomimetic system; lipid-glass interaction ID GIANT UNILAMELLAR VESICLES; LIPID-BILAYER; MECHANOSENSITIVE CHANNELS; XENOPUS OOCYTES; CHAIN-LENGTH; K+ CHANNELS; MEMBRANE; ACTIVATION; MICROSCOPY; CELLS AB Studying how the membrane modulates ion channel and transporter activity is challenging because cells actively regulate membrane properties, whereas existing in vitro systems have limitations, such as residual solvent and unphysiologically high membrane tension. Cell-sized giant unilamellar vesicles (GUVs) would be ideal for in vitro electrophysiology, but efforts to measure the membrane current of intact GUVs have been unsuccessful. In this work, two challenges for obtaining the "whole-GUV" patch-clamp configuration were identified and resolved. First, unless the patch pipette and GUV pressures are precisely matched in the GUV-attached configuration, breaking the patch membrane also ruptures the GUV. Second, GUVs shrink irreversibly because the membrane/glass adhesion creating the high-resistance seal (> 1 G Omega) continuously pulls membrane into the pipette. In contrast, for cell-derived giant plasma membrane vesicles (GPMVs), breaking the patch membrane allows the GPMV contents to passivate the pipette surface, thereby dynamically blocking membrane spreading in the whole-GMPV mode. To mimic this dynamic passivation mechanism, beta-casein was encapsulated into GUVs, yielding a stable, high-resistance, whole-GUV configuration for a range of membrane compositions. Specific membrane capacitance measurements confirmed that the membranes were truly solvent-free and that membrane tension could be controlled over a physiological range. Finally, the potential for ion transport studies was tested using the model ion channel, gramicidin, and voltage-clamp fluorometry measurements were performed with a voltage-dependent fluorophore/ quencher pair. Whole-GUV patch-clamping allows ion transport and other voltage-dependent processes to be studied while controlling membrane composition, tension, and shape. C1 [Garten, Matthias; Bornschloegl, Thomas; Bassereau, Patricia] PSL Res Univ, CNRS, Inst Curie, Lab Phys Chim Curie,UMR 168, F-75005 Paris, France. [Garten, Matthias; Bornschloegl, Thomas; Bassereau, Patricia] Univ Paris 06, Sorbonne Univ, F-75005 Paris, France. [Garten, Matthias] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Integrat Biophys, NIH, Bethesda, MD 20892 USA. [Mosgaard, Lars D.] Univ Copenhagen, Niels Bohr Inst, DK-2100 Copenhagen, Denmark. [Dieudonne, Stephane] Inst Biol Ecole Normale Super, INSERM U1024, F-75005 Paris, France. [Dieudonne, Stephane; Toombes, Gilman E. S.] CNRS, UMR 8197, F-75005 Paris, France. [Toombes, Gilman E. S.] NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Toombes, GES (reprint author), NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM gilman.toombes@nih.gov OI Garten, Matthias/0000-0002-8660-1039 FU Agence Nationale de la Recherche [BLAN-0057-01]; European Commission (NoE SoftComp); Universite Pierre et Marie Curie (Dynamique des Systemes Complexes) [FED21]; Intramural Research Program of the NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke; Institut Curie International PhD Fellowship; Marie Curie International Incoming Fellowship; Universite Pierre et Marie Curie FX We thank Jacques Prost, Sophie Aimon, John Manzi, Johnathan Bradley, Loic Auvrey, Rumiana Dimova, and Jan Behrends for helpful discussions and suggestions. P.B. belongs to the CNRS consortium CellTiss. This work was supported by the Agence Nationale de la Recherche (Grant BLAN-0057-01), the European Commission (NoE SoftComp), the Universite Pierre et Marie Curie (FED21, Dynamique des Systemes Complexes), the Intramural Research Program of the NIH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Neurological Disorders and Stroke. M.G. acknowledges support from the Institut Curie International PhD Fellowship, and G.E.S.T. was supported by a Marie Curie International Incoming Fellowship and the Universite Pierre et Marie Curie. NR 52 TC 0 Z9 0 U1 11 U2 11 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 10 PY 2017 VL 114 IS 2 BP 328 EP 333 DI 10.1073/pnas.1609142114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH0FR UT WOS:000391439300047 PM 28003462 ER PT J AU Linsley, JW Hsu, IU Groom, L Yarotskyy, V Lavorato, M Horstick, EJ Linsley, D Wang, WJ Franzini-Armstrong, C Dirksen, RT Kuwada, JY AF Linsley, Jeremy W. Hsu, I-Uen Groom, Linda Yarotskyy, Viktor Lavorato, Manuela Horstick, Eric J. Linsley, Drew Wang, Wenjia Franzini-Armstrong, Clara Dirksen, Robert T. Kuwada, John Y. TI Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE zebrafish; skeletal muscle; excitation-contraction coupling; dihydropyridine receptor; Native American myopathy ID II-III-LOOP; MALIGNANT HYPERTHERMIA SUSCEPTIBILITY; DIHYDROPYRIDINE-RECEPTOR ARRAYS; SKELETAL-MUSCLE; RYANODINE RECEPTOR; SARCOPLASMIC-RETICULUM; RELEASE CHANNEL; CALCIUM-RELEASE; MUTATION; ZEBRAFISH AB Skeletalmuscle contractions are initiated by an increase in Ca2+ released during excitation-contraction (EC) coupling, and defects in EC coupling are associated with human myopathies. EC coupling requires communication between voltage-sensing dihydropyridine receptors (DHPRs) in transverse tubule membrane and Ca2+ release channel ryanodine receptor 1 (RyR1) in the sarcoplasmic reticulum (SR). Stac3 protein (SH3 and cysteine-rich domain 3) is an essential component of the EC coupling apparatus and a mutation in human STAC3 causes the debilitating Native Americanmyopathy (NAM), but the nature of how Stac3 acts on the DHPR and/or RyR1 is unknown. Using electron microscopy, electrophysiology, and dynamic imaging of zebrafish muscle fibers, we find significantly reduced DHPR levels, functionality, and stability in stac3 mutants. Furthermore, stac3(NAM) myofibers exhibited increased caffeine-induced Ca2+ release across a wide range of concentrations in the absence of altered caffeine sensitivity as well as increased Ca2+ in internal stores, which is consistent with increased SR luminal Ca2+. These findings define critical roles for Stac3 in EC coupling and human disease. C1 [Linsley, Jeremy W.; Kuwada, John Y.] Univ Michigan, Cell & Mol Biol Program, Ann Arbor, MI 48109 USA. [Linsley, Jeremy W.; Hsu, I-Uen; Horstick, Eric J.; Wang, Wenjia; Kuwada, John Y.] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Groom, Linda; Yarotskyy, Viktor; Dirksen, Robert T.] Univ Rochester, Med Ctr, Dept Pharmacol & Physiol, Rochester, NY 14642 USA. [Lavorato, Manuela; Franzini-Armstrong, Clara] Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. [Horstick, Eric J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, Bethesda, MD 20892 USA. [Linsley, Drew] Brown Univ, Dept Cognit Linguist & Psychol Sci, Providence, RI 02912 USA. RP Kuwada, JY (reprint author), Univ Michigan, Cell & Mol Biol Program, Ann Arbor, MI 48109 USA.; Kuwada, JY (reprint author), Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA.; Dirksen, RT (reprint author), Univ Rochester, Med Ctr, Dept Pharmacol & Physiol, Rochester, NY 14642 USA.; Franzini-Armstrong, C (reprint author), Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. EM armstroc@mail.med.upenn.edu; robert_dirksen@urmc.rochester.edu; kuwada@umich.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health [R01-AR-063056]; Rackham Merit Fellowship (University of Michigan); NIGMS [T32 GM007315]; NIAMS [AR059646, AR053349, AR060831, 2P01 AR 052354-06A1] FX We thank Alex Migda, Matthew Lacey, Sean Lowe, Hoaxing Xu, and Richard Hume for technical assistance and discussions. Research was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health Grant R01-AR-063056 (to J.Y.K.); Grants NIAMS AR059646 and AR053349 (to R.T.D.); Grant NIAMS AR060831 (to V.Y.); and Grant NIAMS 2P01 AR 052354-06A1, PI: P. D. Allen (to C.F.-A.). J.W.L. was supported in part by a Rackham Merit Fellowship (University of Michigan) and NIGMS (Grant T32 GM007315). NR 43 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 10 PY 2017 VL 114 IS 2 BP E228 EP E236 DI 10.1073/pnas.1619238114 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH0FR UT WOS:000391439300015 PM 28003463 ER PT J AU Clarke, GM Rockett, K Kivinen, K Hubbart, C Jeffreys, AE Rowlands, K Jallow, M Conway, DJ Bojang, KA Pinder, M Usen, S Sisay-Joof, F Sirugo, G Toure, O Thera, MA Konate, S Sissoko, S Niangaly, A Poudiougou, B Mangano, VD Bougouma, EC Sirima, SB Modioano, D Amenga-Etego, LN Ghansah, A Koram, KA Wilson, MD Enimil, A Evans, J Amodu, OK Olaniyan, S Apinjoh, T Mugri, R Ndi, A Ndila, CM Uyoga, S Macharia, A Peshu, N Williams, TN Manjurano, A Sepulveda, N Clark, TG Riley, E Drakeley, C Reyburn, H Nyirongo, V Kachala, D Molyneux, M Dunstan, SJ Phu, NH Quyen, NN Thai, CQ Hien, TT Manning, L Laman, M Siba, P Karunajeewa, H Allen, S Allen, A Davis, TME Michon, P Mueller, I Molloy, SF Campino, S Kerasidou, A Cornelius, VJ Hart, L Shah, SS Band, G Spencer, CCA Agbenyega, T Achidi, E Doumbo, OK Farrar, J Marsh, K Taylor, T Kwaitkowski, DP AF Clarke, Geraldine M. Rockett, Kirk Kivinen, Katja Hubbart, Christina Jeffreys, Anna E. Rowlands, Kate Jallow, Muminatou Conway, David J. Bojang, Kalifa A. Pinder, Margaret Usen, Stanley Sisay-Joof, Fatoumatta Sirugo, Giorgio Toure, Ousmane Thera, Mahamadou A. Konate, Salimata Sissoko, Sibiry Niangaly, Amadou Poudiougou, Belco Mangano, Valentina D. Bougouma, Edith C. Sirima, Sodiomon B. Modioano, David Amenga-Etego, Lucas N. Ghansah, Anita Koram, Kwadwo A. Wilson, Michael D. Enimil, Anthony Evans, Jennifer Amodu, Olukemi K. Olaniyan, Subulade Apinjoh, Tobias Mugri, Regina Ndi, Andre Ndila, Carolyne M. Uyoga, Sophie Macharia, Alexander Peshu, Norbert Williams, Thomas N. Manjurano, Alphaxard Sepulveda, Nuno Clark, Taane G. Riley, Eleanor Drakeley, Chris Reyburn, Hugh Nyirongo, Vysaul Kachala, David Molyneux, Malcolm Dunstan, Sarah J. Nguyen Hoan Phu Nguyen Ngoc Quyen Cao Quang Thai Tran Tinh Hien Manning, Laurens Laman, Moses Siba, Peter Karunajeewa, Harin Allen, Steve Allen, Angela Davis, Timothy M. E. Michon, Pascal Mueller, Ivo Molloy, SIle F. Campino, Susan Kerasidou, Angeliki Cornelius, Victoria J. Hart, Lee Shah, Shivang S. Band, Gavin Spencer, Chris C. A. Agbenyega, Tsiri Achidi, Eric Doumbo, Ogobara K. Farrar, Jeremy Marsh, Kevin Taylor, Terrie Kwaitkowski, Dominic P. CA MalariaGEn Consortium TI Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia SO ELIFE LA English DT Article ID PLASMODIUM-FALCIPARUM TRANSMISSION; SEX-LINKED LOCUS; NATURAL-SELECTION; WEST-AFRICA; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE DEFICIENCY; DEHYDROGENASE-DEFICIENCY; LINKAGE DISEQUILIBRIUM; HETEROZYGOTE ADVANTAGE; 2 AREAS; CHILDREN AB Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effect has proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individuals level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations. C1 [Clarke, Geraldine M.; Rockett, Kirk; Hubbart, Christina; Jeffreys, Anna E.; Rowlands, Kate; Molloy, SIle F.; Kerasidou, Angeliki; Cornelius, Victoria J.; Hart, Lee; Shah, Shivang S.; Band, Gavin; Spencer, Chris C. A.; Kwaitkowski, Dominic P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Clarke, Geraldine M.; Rockett, Kirk; Cornelius, Victoria J.; Band, Gavin; Kwaitkowski, Dominic P.] Univ Oxford, MRC, Ctr Genom & Global Hlth, Oxford, England. [Rockett, Kirk; Kivinen, Katja; Campino, Susan; Kwaitkowski, Dominic P.; MalariaGEn Consortium] Wellcome Trust Sanger Inst, Cambridge, England. [Jallow, Muminatou; Conway, David J.; Bojang, Kalifa A.; Pinder, Margaret; Usen, Stanley; Sisay-Joof, Fatoumatta; Sirugo, Giorgio] Med Res Council Gambia, Fajara, Gambia. [Jallow, Muminatou] Edward Small Teaching Hosp, Independence Dr, Banjul, Gambia. [Conway, David J.; Clark, Taane G.] London Sch Hyg & Trop Med, Dept Pathogen Mol Biol, London, England. [Toure, Ousmane; Thera, Mahamadou A.; Konate, Salimata; Sissoko, Sibiry; Niangaly, Amadou; Poudiougou, Belco; Doumbo, Ogobara K.] Univ Bamako, Malaria Res & Training Ctr, Bamako, Mali. [Mangano, Valentina D.; Modioano, David] Univ Roma La Sapienza, Rome, Italy. [Bougouma, Edith C.; Sirima, Sodiomon B.] CNRFP, Ouagadougou, Burkina Faso. [Amenga-Etego, Lucas N.] Navrongo Hlth Res Ctr, Navrongo, Ghana. [Ghansah, Anita; Koram, Kwadwo A.; Wilson, Michael D.] Univ Ghana, Noguchi Mem Inst Med Res, Accra, Ghana. [Enimil, Anthony; Agbenyega, Tsiri] Komfo Anoyke Teaching Hosp, Kumasi, Ghana. [Evans, Jennifer] Bernhard Nocht Inst Trop Med, Dept Mol Med, Hamburg, Germany. [Evans, Jennifer] Kumasi Ctr Collaborat Res, Kumasi, Ghana. [Amodu, Olukemi K.; Olaniyan, Subulade] Univ Ibadan, Ibadan, Nigeria. [Apinjoh, Tobias] Univ Buea, Dept Biochem & Mol Biol, Buea, Cameroon. [Mugri, Regina; Ndi, Andre; Achidi, Eric] Univ Buea, Dept Med Lab Sci, Buea, Cameroon. [Ndila, Carolyne M.; Uyoga, Sophie; Macharia, Alexander; Peshu, Norbert; Williams, Thomas N.; Marsh, Kevin] KEMRI Wellcome Trust Res Programme, Kilifi, Kenya. [Williams, Thomas N.] Imperial Coll, Fac Med, Dept Med, London, England. [Manjurano, Alphaxard; Drakeley, Chris; Reyburn, Hugh] Kilimanjaro Christian Med Coll, Joint Malaria Programme, Moshi, Tanzania. [Manjurano, Alphaxard; Sepulveda, Nuno; Clark, Taane G.; Riley, Eleanor; Drakeley, Chris; Reyburn, Hugh] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England. [Nyirongo, Vysaul; Molyneux, Malcolm] Univ Malawi, Malawi Liverpool Wellcome Trust Clin Res Programm, Blantyre, Malawi. [Kachala, David; Nguyen Hoan Phu; Nguyen Ngoc Quyen; Cao Quang Thai; Tran Tinh Hien; Farrar, Jeremy] Univ Oxford, Clin Res Unit, Ho Chi Minh City, Vietnam. [Molyneux, Malcolm] Univ Liverpool Liverpool Sch Trop Med, Pembroke Pl, Liverpool, Merseyside, England. [Dunstan, Sarah J.] Univ Melbourne, Peter Doherty Inst Infect & Immun, Melbourne, Vic, Australia. [Nguyen Hoan Phu; Cao Quang Thai; Tran Tinh Hien] Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Tran Tinh Hien; Manning, Laurens; Laman, Moses; Siba, Peter; Michon, Pascal; Mueller, Ivo] Papua New Guinea Inst Med Res, Goroka, Papua N Guinea. [Karunajeewa, Harin; Davis, Timothy M. E.] Univ Western Australia, Perth, WA, Australia. [Allen, Steve] Swansea Univ, Swansea, W Glam, Wales. [Allen, Angela] Univ Oxford, Weatherall Inst Mol Med, Oxford, England. [Michon, Pascal] Divine Word Univ, Fac Med & Hlth Sci, Madang, Papua N Guinea. [Mueller, Ivo] Walter & Eliza Hall Inst Med Res, Melbourne, Vic, Australia. [Mueller, Ivo] Barcelona Ctr Int Hlth Res, Barcelona, Spain. [Kerasidou, Angeliki] Univ Oxford, Ethox Ctr, Nuffield Dept Populat Hlth, Oxford, England. [Shah, Shivang S.] NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Agbenyega, Tsiri] Kwame Nkrumah Univ Sci & Technol, Kumasi, Ghana. [Farrar, Jeremy] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England. [Taylor, Terrie] Univ Malawi, Blantyre Malaria Project, Coll Med, Blantyre, Malawi. RP Clarke, GM; Rockett, K; Kwaitkowski, DP (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.; Clarke, GM; Rockett, K; Kwaitkowski, DP (reprint author), Univ Oxford, MRC, Ctr Genom & Global Hlth, Oxford, England.; Rockett, K; Kwaitkowski, DP (reprint author), Wellcome Trust Sanger Inst, Cambridge, England. EM gclarke@well.ox.ac.uk; krockett@well.ox.ac.uk; dominic@well.ox.ac.uk RI Manning, Laurens/H-5360-2014; OI Manning, Laurens/0000-0003-4334-5351; Kwiatkowski, Dominic/0000-0002-5023-0176 FU Wellcome Trust [090770/Z/09/Z, 097364/Z/11/Z, 076934/Z/05/Z, 091758/Z/10/Z, 084538, 089276/Z/09/Z, 077383/Z/05/Z, 090532/Z/09/Z, 077012/Z/05/Z, 087285, 096527]; Foundation for the National Institutes of Health [566]; European Commission [LSHP-CT-2004-503578, SANTE/2004/078-607]; National Institute of Allergy and Infectious Diseases; European and Developing Countries Clinical Trials Partnership; National Health and Medical Research Council; Fogarty International Center; Seventh Framework Programme [242095]; Royal Australasian College of Physicians; Medical Research Council [G9901439, G0600718, G0600230, G19/9] FX Wellcome Trust 090770/Z/09/Z Geraldine M Clarke Kirk Rockett Katja Kivinen Christina Hubbart Anna EJeffreys Kate Rowlands Sile F Molloy Angeliki Kerasidou Victoria JCornelius Lee Hart Gavin Band Chris CA Spencer Dominic P Kwiatkowski; Foundation for the National Institutes of Health Billand Melinda Gates Foundation Grand Challenges in Global Health 566 Geraldine M Clarke Kirk Rockett Katja Kivinen Christina Hubbart Anna E Jeffreys Kate Rowlands Muminatou Jallow David J Conway Kalifa A Bojang Margaret Pinder Stanley Usen Fatoumatta Sisay-Joof Giorgio Sirugo Ousmane Toure Mahamadou A Thera Salimata Konate Sibiry Sissoko Amadou Niangaly Belco Poudiougou Valentina D Mangano Edith C Bougouma Sodiomon BSirima David Modiano Lucas N Amenga-Etego Anita Ghansah Kwadwo A Koram Michael D Wilson Anthony Enimil Jennifer Evans Olukemi K Amodu Subulade Olaniyan Tobias Apinjoh Regina Mugri Andre Ndi Carolyne M Ndila Sophie Uyoga Alexander Macharia Norbert Peshu Thomas N Williams Alphaxard Manjurano Nuno Sepulveda Taane G Clark Eleanor Riley Chris Drakeley Hugh Reyburn Vysaul Nyirongo David Kachala Malcolm Molyneux Sarah J Dunstan Nguyen Hoan Phu Nguyen Ngoc Quyen Cao Quang Thai Tran Tinh Hien Laurens Manning Moses Laman Peter Siba Harin Karunajeewa Steve Allen Angela Allen Timothy ME Davis Pascal Michon Ivo Mueller Sile F Molloy Susana Campino Angeliki Kerasidou Victoria J Cornelius Lee Hart Shivang S Shah Gavin Band Chris CA Spencer Tsiri Agbenyega Eric Achidi Ogobara K Doumbo Jeremy Farrar Kevin Marsh Terrie Taylor Dominic P Kwiatkowski; Wellcome Trust 097364/Z/11/Z (Spencer) Chris CA Spencer; European Commission LSHP-CT-2004-503578 (Nigeria) Olukemi K Amodu Subulade Olaniyan; National Institute of Allergy and Infectious Diseases Ousmane Toure Mahamadou A Thera Salimata Konate Sibiry Sissoko Amadou Niangaly Belco Poudiougou; European Commission Europaid: SANTE/2004/078-607 Alphaxard Manjurano Nuno Sepulveda Taane G Clark EleanorRiley Chris Drakeley Hugh Reyburn Timothy ME Davis; European and Developing Countries Clinical Trials Partnership Eric Achidi; National Health and Medical Research Council Laurens Manning Timothy ME Davis; Fogarty International Center Moses Laman; Seventh Framework Programme 242095 Thomas N Williams Eric Achidi; Wellcome Trust 076934/Z/05/Z and 091758/Z/10/Z Sophie Uyoga Alexander Macharia Thomas N Williams; Wellcome Trust 084538 Carolyne M Ndila; Wellcome Trust KEMRI Core Support Carolyne M Ndila Sophie Uyoga Alexander Macharia Norbert Peshu Thomas N Williams Kevin Marsh; Wellcome Trust WT Major Overseas Program in Vietnam 089276/Z/09/Z David Kachala Nguyen Hoan Phu Nguyen Ngoc Quyen Cao Quang Thai Tran Tinh Hien Jeremy Farrar; Royal Australasian College of Physicians Laurens Manning; Wellcome Trust MalariaGEN Project 077383/Z/05/Z Geraldine M Clarke Kirk Rockett Christina Hubbart Anna E Jeffreys Kate Rowlands Muminatou Jallow David J Conway Kalifa A Bojang Margaret Pinder Stanley Usen Fatoumatta Sisay-Joof Giorgio Sirugo Ousmane Toure Mahamadou A Thera Salimata Konate Sibiry Sissoko Amadou Niangaly Belco Poudiougou Valentina D Mangano Edith C Bougouma Sodiomon BSirima David Modiano Lucas N Amenga-Etego Anita Ghansah Kwadwo A Koram Michael DWilson Anthony Enimil Jennifer Evans Olukemi K Amodu Subulade Olaniyan Tobias Apinjoh Regina Mugri Andre Ndi Carolyne M Ndila Sophie Uyoga Alexander Macharia Norbert Peshu Thomas N Williams Alphaxard Manjurano Nuno Sepulveda Taane G Clark Eleanor Riley Chris Drakeley Hugh Reyburn Vysaul Nyirongo David Kachala Malcolm Molyneux Sarah J Dunstan Nguyen Hoan Phu Nguyen Ngoc Quyen Cao Quang Thai Tran Tinh Hien Laurens Manning Moses Laman Peter Siba Harin Karunajeewa Steve Allen Angela Allen Timothy ME Davis Pascal Michon Ivo Mueller Sile F Molloy Susana Campino Angeliki Kerasidou Victoria J Cornelius Lee Hart Shivang S Shah Gavin Band Chris CA Spencer Tsiri Agbenyega Eric Achidi Ogobara K Doumbo Jeremy Farrar Kevin Marsh Terrie Taylor Dominic P Kwiatkowsk; Wellcome Trust WT Centre for Human Genetic Core 090532/Z/09/Z Geraldine M Clarke Kirk Rockett Christina Hubbart Anna E Jeffreys Kate Rowlands Sile F Molloy Angeliki Kerasidou Victoria J Cornelius Lee Hart Shivang S Shah Gavin Band Chris CA Spencer Dominic P Kwiatkowski; Wellcome Trust WT SangerInstitute Core 077012/Z/05/Z Katja Kivinen Susana Campino Dominic P Kwiatkowski; Wellcome Trust 087285;096527 Angeliki Kerasidou; Medical Research Council Tanzania Joint Collaboration G9901439 Alphaxard Manjurano Nuno Sepulveda Taane G Clark Eleanor Riley Chris Drakeley Hugh Reyburn Timothy ME Davis; Medical Research Council G0600718; G0600230 Kirk Rockett Dominic P Kwiatkowsk; Medical Research Council G19/9 Dominic P Kwiatkowski NR 66 TC 1 Z9 1 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 9 PY 2017 VL 6 AR e15085 DI 10.7554/eLIFE.15085 PG 30 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EJ7FS UT WOS:000393387700001 ER PT J AU Lederman, RJ Greenbaum, AB Rogers, T Khan, JM Fusari, M Chen, MY AF Lederman, Robert J. Greenbaum, Adam B. Rogers, Toby Khan, Jaffar M. Fusari, Melissa Chen, Marcus Y. TI Anatomic Suitability for Transcaval Access Based on Computed Tomography SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Review DE aorto-caval; caval-aortic; computed tomography; structural heart disease; transcatheter aortic valve replacement; transcatheter electrosurgery; transcaval ID AORTIC ACCESS AB Transcaval access has been used successfully for over 200 transcatheter aortic valve replacements, large-bore percutaneous left ventricular assist devices, and thoracic endovascular aortic aneurysm repairs. This review teaches how to plan transcaval access and closure based on computed tomography. The main planning goals are to: 1) identify calcium-free crossing targets in the abdominal aorta along with optimal fluoroscopic projection angles and level with respect to lumbar vertebrae; 2) identify obstacles such as interposed bowel or pedunculated aortic atheroma; 3) plan covered stent bailout; and 4) identify jeopardized vascular branches such as renal arteries that might be obstructed by bailout covered stents if employed. The aorta and inferior vena cava are segmented (sculpted) using an image reconstruction workstation and crossing targets are highlighted. Important measurements such as aortic lumen diameter and target distance from renal arteries, aortoiliac bifurcation, and right femoral vein puncture site are reported to assist the operator. The proposed classification for transcaval feasibility has been revised, making some previously unfavorable candidates now feasible or favorable based on procedural success to date. Transcaval access allows percutaneous introduction of large devices into the aorta despite small or diseased iliofemoral arteries. By following these simplified procedures, both operators and imaging specialists can easily prepare comprehensive treatment plans. (C) 2017 by the American College of Cardiology Foundation. Published by Elsevier. All rights reserved. C1 [Lederman, Robert J.; Rogers, Toby; Khan, Jaffar M.; Chen, Marcus Y.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Greenbaum, Adam B.] Henry Ford Hlth Syst, Div Cardiol, Ctr Struct Heart Dis, Detroit, MI USA. [Fusari, Melissa] Edwards Lifesci, Irvine, CA USA. EM lederman@nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health [Z01-HL006040] FX From the Cardiovascular and Pulmonary Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland; Center for Structural Heart Disease, Division of Cardiology, Henry Ford Health System, Detroit, Michigan; and Edwards Lifesciences, Irvine, California. The study was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Z01-HL006040. Drs. Lederman, Rogers, and Greenbaum are listed as inventors on patent applications, assigned to their employers, related to transcaval access and closure. Dr. Greenbaum has served as a physician proctor for Edwards Lifesciences, Medtronic, and St. Jude Medical. Mr. Khan has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Fusari is a full-time employee of and surgeon proctor for Edwards Lifesciences. Dr. Chen is the National Heart, Lung, and Blood Institute core lab director for transcaval access. NR 4 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD JAN 9 PY 2017 VL 10 IS 1 BP 1 EP 10 DI 10.1016/j.jcin.2016.09.002 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI6RP UT WOS:000392624100003 PM 28057275 ER PT J AU Veschi, V Liu, ZH Voss, TC Ozbun, L Gryder, B Yan, CH Hu, Y Ma, AQ Jin, J Mazur, SJ Lam, N Souza, BK Giannini, G Hager, GL Arrowsmith, CH Khan, J Appella, E Thiele, CJ AF Veschi, Veronica Liu, Zhihui Voss, Ty C. Ozbun, Laurent Gryder, Berkley Yan, Chunhua Hu, Ying Ma, Anqi Jin, Jian Mazur, Sharlyn J. Lam, Norris Souza, Barbara K. Giannini, Giuseppe Hager, Gordon L. Arrowsmith, Cheryl H. Khan, Javed Appella, Ettore Thiele, Carol J. TI Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma SO CANCER CELL LA English DT Article ID PR-SET7 HISTONE METHYLTRANSFERASE; CELL-CYCLE; SUPPRESSOR GENES; EXPRESSION; TUMORS; DIFFERENTIATION; METHYLATION; MOLECULE; CANCER; DISCOVERY AB Given the paucity of druggable mutations in high-risk neuroblastoma (NB), we undertook chromatin-focused small interfering RNA and chemical screens to uncover epigenetic regulators critical for the differentiation block in high-risk NB. High-content Opera imaging identified 53 genes whose loss of expression led to a decrease in NB cell proliferation and 16 also induced differentiation. From these, the secondary chemical screen identified SETD8, the H4(K20me1) methyltransferase, as a druggable NB target. Functional studies revealed that SETD8 ablation rescued the pro-apoptotic and cell-cycle arrest functions of p53 by decreasing p53(K382me1) leading to activation of the p53 canonical pathway. In pre-clinical xenograft NB models, genetic or pharmacological (UNC0379) SETD8 inhibition conferred a significant survival advantage, providing evidence for SETD8 as a therapeutic target in NB. C1 [Veschi, Veronica; Liu, Zhihui; Lam, Norris; Souza, Barbara K.; Thiele, Carol J.] NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, Ctr Canc Res,CRC, 1-3940,10 Ctr Dr MSC 1105, Bethesda, MD 20892 USA. [Voss, Ty C.; Ozbun, Laurent] NCI, High Throughput Imaging Facil, Ctr Canc Res, Bethesda, MD 20892 USA. [Gryder, Berkley; Khan, Javed] NCI, Oncogen Sect, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Yan, Chunhua; Hu, Ying] NCI, Ctr Biomed Informat & Informat Technol, Ctr Canc Res, Rockville, MD 20850 USA. [Ma, Anqi; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, Oncol Sci Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Arrowsmith, Cheryl H.] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada. [Mazur, Sharlyn J.; Appella, Ettore] NCI, Chem Immunol Sect, Cell Biol Lab, Bethesda, MD 20892 USA. [Hager, Gordon L.] NIH, Lab Receptor Biol & Gene Express, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Giannini, Giuseppe] Univ Roma La Sapienza, Dept Mol Med, Fdn Cenci Bolognetti, Ist Pasteur, I-00161 Rome, Italy. RP Thiele, CJ (reprint author), NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, Ctr Canc Res,CRC, 1-3940,10 Ctr Dr MSC 1105, Bethesda, MD 20892 USA. EM ct47a@nih.gov RI Khan, Javed/P-9157-2014; OI Khan, Javed/0000-0002-5858-0488; Veschi, Veronica/0000-0002-6379-7366 FU St. Baldrick's Foundation; AbbVie; Bayer Pharma AG; Boehringer Ingelheim; Canada Foundation for Innovation; Eshelman Institute for Innovation; Genome Canada through the Ontario Genomics Institute; Innovative Medicines Initiative (EU/EFPIA) [115766]; Janssen; Merck; Novartis Pharma AG; Ontario Ministry of Economic Development and Innovation; Pfizer; Sao Paulo Research Foundation-FAPESP; Takeda; Wellcome Trust; AIRC [IG17734]; MIUR PRIN; Center for Cancer Research, NCI, as part of the Intramural Research Program, NIH FX We are grateful to Drs. G. Pegoraro (High-Throughput Imaging Facility, CCR) and D. Wei (Urologic Oncology Branch, CCR) for technical assistance, to Dr. N. Caplen for her critical review, and to Drs. M. Aladjem and D. Banerjee for insightful discussions. Studies on the epigenetic siRNA screen were funded by a grant from the St. Baldrick's Foundation to C.J.T. and Z.L. SGC is a registered charity (1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through the Ontario Genomics Institute, the Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant no. 115766), Janssen, Merck, Novartis Pharma AG, the Ontario Ministry of Economic Development and Innovation, Pfizer, Sao Paulo Research Foundation-FAPESP, Takeda, and the Wellcome Trust. G.G. was funded by AIRC IG17734; MIUR PRIN 2015. This work is supported by the Center for Cancer Research, NCI, as part of the Intramural Research Program, NIH. NR 46 TC 0 Z9 0 U1 6 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD JAN 9 PY 2017 VL 31 IS 1 BP 50 EP 63 DI 10.1016/j.ccell.2016.12.002 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EH6RJ UT WOS:000391901300006 PM 28073004 ER PT J AU Hayashi, T Lombaert, IMA Hauser, BR Patel, VN Hoffman, MP AF Hayashi, Toru Lombaert, Isabelle M. A. Hauser, Belinda R. Patel, Vaishali N. Hoffman, Matthew P. TI Exosomal MicroRNA Transport from Salivary Mesenchyme Regulates Epithelial Progenitor Expansion during Organogenesis SO DEVELOPMENTAL CELL LA English DT Article ID GLAND BRANCHING MORPHOGENESIS; EXTRACELLULAR VESICLES; CELLS; CANCER; INFORMATION; MECHANISMS; MEMBRANE; RELEASE; MIRNAS AB Epithelial-mesenchymal interactions involve fundamental communication between tissues during organogenesis and are primarily regulated by growth factors and extracellular matrix. It is unclear whether RNA-containing exosomes are mobile genetic signals regulating epithelial-mesenchymal interactions. Here we identify that exosomes loaded with mesenchyme-specific mature microRNA contribute mobile genetic signals from mesenchyme to epithelium. The mature mesenchymal miR-133b-3p, loaded into exosomes, was transported from mesenchyme to the salivary epithelium, which did not express primary miR-133b-3p. Knockdown of miR-133b-3p in culture decreased endbud morphogenesis, reduced proliferation of epithelial KIT+ progenitors, and increased expression of a target gene, Disco-interacting protein 2 homolog B (Dip2b). DIP2B, which is involved in DNA methylation, was localized with 5-methylcytosine in the prophase nucleus of a subset of KIT+ progenitors during mitosis. In summary, exosomal transport of miR-133b-3p from mesenchyme to epithelium decreases DIP2B, which may function as an epigenetic regulator of genes responsible for KIT+ progenitor expansion during organogenesis. C1 [Hayashi, Toru; Lombaert, Isabelle M. A.; Hauser, Belinda R.; Patel, Vaishali N.; Hoffman, Matthew P.] Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Sect, NIH, Bethesda, MD 20892 USA. [Hayashi, Toru] Asahi Univ, Sch Dent, Dept Pharmacol, 1851 Hozumi, Mizuho, Gifu 5010296, Japan. [Lombaert, Isabelle M. A.] Univ Michigan, Sch Dent, Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Lombaert, Isabelle M. A.] Univ Michigan, Biointerfaces Inst, Ann Arbor, MI 48109 USA. RP Hoffman, MP (reprint author), Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Sect, NIH, Bethesda, MD 20892 USA. EM mhoffman@mail.nih.gov FU Intramural Research Program of the National Institute of Dental and Craniofacial Research at the NIH; JSPS [JP15K11060, JP15K20370]; Sumitomo Foundation FX The authors would like to thank the NIDCR Combined Technical Research Core for FACS analysis, Daniel Martin for bioinformatics analysis, Kelly Ten Hagen for critical reading of the manuscript, and Masanori Kashimata at Asahi University for technical support. This research was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research at the NIH and by JSPS KAKENHI grants JP15K11060 and JP15K20370, and by a grant for Basic Science Research Projects from The Sumitomo Foundation. NR 40 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD JAN 9 PY 2017 VL 40 IS 1 BP 95 EP 103 DI 10.1016/j.devcel.2016.12.001 PG 9 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA EH6RA UT WOS:000391900400011 PM 28041903 ER PT J AU Caglayan, M Horton, JK Dai, DP Stefanick, DF Wilson, SH AF Caglayan, Melike Horton, Julie K. Dai, Da-Peng Stefanick, Donna F. Wilson, Samuel H. TI Oxidized nucleotide insertion by pol beta confounds ligation during base excision repair SO NATURE COMMUNICATIONS LA English DT Article ID DNA-POLYMERASE-BETA; OXIDATIVE STRESS; APRATAXIN DEFICIENCY; HYDROGEN-PEROXIDE; MAMMALIAN-CELLS; NUCLEIC-ACIDS; STRAND BREAK; ACTIVE-SITE; LIGASE I; DAMAGE AB Oxidative stress in cells can lead to accumulation of reactive oxygen species and oxidation of DNA precursors. Oxidized purine nucleotides can be inserted into DNA during replication and repair. The main pathway for correcting oxidized bases in DNA is base excision repair (BER), and in vertebrates DNA polymerase beta (pol beta) provides gap filling and tailoring functions. Here we report that the DNA ligation step of BER is compromised after pol beta insertion of oxidized purine nucleotides into the BER intermediate in vitro. These results suggest the possibility that BER mediated toxic strand breaks are produced in cells under oxidative stress conditions. We observe enhanced cytotoxicity in oxidizing-agent treated pol beta expressing mouse fibroblasts, suggesting formation of DNA strand breaks under these treatment conditions. Increased cytotoxicity following MTH1 knockout or treatment with MTH1 inhibitor suggests the oxidation of precursor nucleotides. C1 [Caglayan, Melike; Horton, Julie K.; Dai, Da-Peng; Stefanick, Donna F.; Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES050158, Z01 ES050159] FX We thank Rajendra Prasad, David Shock, Akira Sassa, Nadezhda Dyrkheeva, Alan Tomkinson (Univ. of New Mexico) and Stephen Lloyd (OHSU) for gifts of purified proteins used in this study. We thank Carl Bortner for his advice with Flow Cytometry and Natalie Gassman for helpful discussion. This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Project numbers Z01 ES050158 and Z01 ES050159). 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 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 9 PY 2017 VL 8 AR 14045 DI 10.1038/ncomms14045 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG9GA UT WOS:000391365700001 PM 28067232 ER PT J AU Lin, HH Yin, XY Xie, ZJ Lunetta, KL Lubitz, SA Larson, MG Ko, D Magnani, JW Mendelson, MM Liu, CY McManus, DD Levy, D Ellinor, PT Benjamin, EJ AF Lin, Honghuang Yin, Xiaoyan Xie, Zhijun Lunetta, Kathryn L. Lubitz, Steven A. Larson, Martin G. Ko, Darae Magnani, Jared W. Mendelson, Michael M. Liu, Chunyu McManus, David D. Levy, Daniel Ellinor, Patrick T. Benjamin, Emelia J. TI Methylome-wide Association Study of Atrial Fibrillation in Framingham Heart Study SO SCIENTIFIC REPORTS LA English DT Article ID SMOOTH-MUSCLE-CELLS; DNA METHYLATION; RISK-FACTORS; ALCOHOL-CONSUMPTION; GENE-EXPRESSION; FOLLOW-UP; PROTEIN; PREVALENCE; MORTALITY; DISEASE AB Atrial fibrillation (AF) is the most common cardiac arrhythmia, but little is known about the molecular mechanisms associated with AF arrhythmogenesis. DNA methylation is an important epigenetic mechanism that regulates gene expression and downstream biological processes. We hypothesize that DNA methylation might play an important role in the susceptibility to develop AF. A total of 2,639 participants from the Offspring Cohort of Framingham Heart Study were enrolled in the current study. These participants included 183 participants with prevalent AF and 220 with incident AF during up to 9 years follow up. Genome-wide methylation was profiled using the Illumina Infinium HumanMethylation450 BeadChip on blood-derived DNA collected during the eighth examination cycle (2005-2008). Two CpG sites were significantly associated with prevalent AF, and five CpGs were associated with incident AF after correction for multiple testing (FDR < 0.05). Fourteen previously reported genome-wide significant AF-related SNP were each associated with at least one CpG site; the most significant association was rs6490029 at the CUX2 locus and cg10833066 (P = 9.5 x 10(-279)). In summary, we performed genome-wide methylation profiling in a community-based cohort and identified seven methylation signatures associated with AF. Our study suggests that DNA methylation might play an important role in AF arrhythmogenesis. C1 [Lin, Honghuang; Yin, Xiaoyan; Lunetta, Kathryn L.; Larson, Martin G.; Liu, Chunyu; Levy, Daniel; Benjamin, Emelia J.] NHLBI, Framingham, MA 01702 USA. [Lin, Honghuang; Yin, Xiaoyan; Lunetta, Kathryn L.; Larson, Martin G.; Liu, Chunyu; Levy, Daniel; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA 01702 USA. [Lin, Honghuang; Xie, Zhijun] Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. [Xie, Zhijun] Zhejiang Chinese Med Univ, TCM Clin Basis Inst, Hangzhou, Zhejiang, Peoples R China. [Lunetta, Kathryn L.; Liu, Chunyu] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Magnani, Jared W.] Univ Pittsburgh, Dept Med, UPMC Heart & Vasc Inst, Div Cardiol, Pittsburgh, PA USA. [Ko, Darae; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Mendelson, Michael M.; Liu, Chunyu; Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Mendelson, Michael M.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [McManus, David D.] Univ Massachusetts, Sch Med, Med & Quantitat Hlth Sci, Worcester, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Lin, HH (reprint author), NHLBI, Framingham, MA 01702 USA.; Lin, HH (reprint author), Boston Univ, Framingham Heart Study, Framingham, MA 01702 USA.; Lin, HH (reprint author), Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. EM hhlin@bu.edu OI Mendelson, Michael/0000-0001-7590-3958 FU National Institutes of Health [N01-HC-25195, HHSN268 201500001I, K24HL105780]; Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health; NIH [2RO1HL092577, 1R01HL128914, K23HL114724]; American Heart Association [13EIA14220013]; Fondation Leducq [14CVD01]; Doris Duke Charitable Foundation [2014105, 2015084]; Tommy Kaplan Fund, Department of Cardiology, Boston Children's Hospital FX The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195; HHSN268 201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, and by a Director's Challenge Award, National Institutes of Health (DL, PI). This project also was supported by NIH grants to Drs. Ellinor, Benjamin, and Lunetta (2RO1HL092577) and Benjamin and Ellinor (1R01HL128914). Dr. Ellinor is supported by grants from the National Institutes of Health (K24HL105780), an Established Investigator Award from the American Heart Association (13EIA14220013) and by support from the Fondation Leducq (14CVD01). Dr. Lubitz is supported by NIH grants K23HL114724. This work was supported by Grant 2014105 and Grant 2015084 from the Doris Duke Charitable Foundation. Dr. Mendelson is partly supported by a family foundation award from the Tommy Kaplan Fund, Department of Cardiology, Boston Children's Hospital. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. NR 54 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 9 PY 2017 VL 7 AR 40377 DI 10.1038/srep40377 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG9IR UT WOS:000391372800001 PM 28067321 ER PT J AU Thomason, ME Scheinost, D Manning, JH Grove, LE Hect, J Marshall, N Hernandez-Andrade, E Berman, S Pappas, A Yeo, L Hassan, SS Constable, RT Ment, LR Romero, R AF Thomason, Moriah E. Scheinost, Dustin Manning, Janessa H. Grove, Lauren E. Hect, Jasmine Marshall, Narcis Hernandez-Andrade, Edgar Berman, Susan Pappas, Athina Yeo, Lami Hassan, Sonia S. Constable, R. Todd Ment, Laura R. Romero, Roberto TI Weak functional connectivity in the human fetal brain prior to preterm birth SO SCIENTIFIC REPORTS LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; RESTING-STATE NETWORKS; WHITE-MATTER LESIONS; FRAGILE-X-SYNDROME; INTRINSIC CONNECTIVITY; HEMODYNAMIC-RESPONSES; NEURAL CONNECTIVITY; COGNITIVE FUNCTION; WILLIAMS-SYNDROME AB It has been suggested that neurological problems more frequent in those born preterm are expressed prior to birth, but owing to technical limitations, this has been difficult to test in humans. We applied novel fetal resting-state functional MRI to measure brain function in 32 human fetuses in utero and found that systems-level neural functional connectivity was diminished in fetuses that would subsequently be born preterm. Neural connectivity was reduced in a left-hemisphere pre-language region, and the degree to which connectivity of this left language region extended to right-hemisphere homologs was positively associated with the time elapsed between fMRI assessment and delivery. These results provide the first evidence that altered functional connectivity in the preterm brain is identifiable before birth. They suggest that neurodevelopmental disorders associated with preterm birth may result from neurological insults that begin in utero. C1 [Thomason, Moriah E.; Manning, Janessa H.; Grove, Lauren E.; Hect, Jasmine; Marshall, Narcis] Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI 48202 USA. [Thomason, Moriah E.; Pappas, Athina] Wayne State Univ, Dept Pediat, Sch Med, Detroit, MI 48202 USA. [Thomason, Moriah E.; Manning, Janessa H.; Grove, Lauren E.; Marshall, Narcis; Hernandez-Andrade, Edgar; Pappas, Athina; Yeo, Lami; Hassan, Sonia S.; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Thomason, Moriah E.; Manning, Janessa H.; Grove, Lauren E.; Marshall, Narcis; Hernandez-Andrade, Edgar; Pappas, Athina; Yeo, Lami; Hassan, Sonia S.; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Thomason, Moriah E.] Univ Michigan, Survey Res Ctr, Inst Social Res, Ann Arbor, MI 48104 USA. [Scheinost, Dustin; Constable, R. Todd] Yale Sch Med, Dept Radiol & Biomed Imaging, New Haven, CT 06520 USA. [Hernandez-Andrade, Edgar; Berman, Susan; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Constable, R. Todd] Yale Sch Med, Dept Neurosurg, New Haven, CT 06520 USA. [Ment, Laura R.] Yale Sch Med, Dept Pediat, New Haven, CT 06520 USA. [Ment, Laura R.] Yale Sch Med, Dept Neurol, New Haven, CT 06520 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med, Detroit, MI 48202 USA. [Romero, Roberto] Univ Michigan, Sch Med, Dept Obstet & Gynecol, Ann Arbor, MI 48104 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48825 USA. RP Thomason, ME (reprint author), Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI 48202 USA.; Thomason, ME (reprint author), Wayne State Univ, Dept Pediat, Sch Med, Detroit, MI 48202 USA.; Thomason, ME (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA.; Thomason, ME (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA.; Thomason, ME (reprint author), Univ Michigan, Survey Res Ctr, Inst Social Res, Ann Arbor, MI 48104 USA. EM moriaht@gmail.com FU National Institutes of Health [MH110793, ES026022]; NARSAD; NIH [HHSN 275201300006 C] FX This project was supported by awards to M.E.T. from the National Institutes of Health, MH110793 and ES026022, and by a NARSAD Young Investigator Award. This project was also supported in part by NIH contract HHSN 275201300006 C. The authors thank Pavan Jella, Saige Rutherford, Sophia Neuenfeldt, and Ki-Jana Malone for their assistance in acquiring the scan data; Farrah Elrahal, Jamie Pierce, Jordan Boeve, Gillian Grace Spitzley, Sydney Rooks, and Joi Webb for their assistance in participant recruitment, screening, and conducting behavioral testing; and Tarek Bazzi, Alison Li, Kassem Soufan, and Baldish Oberoi for their help with data processing. The authors also thank participant families who generously shared their time. NR 88 TC 1 Z9 1 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 9 PY 2017 VL 7 AR 39286 DI 10.1038/srep39286 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG9MQ UT WOS:000391383500001 PM 28067865 ER PT J AU Wu, C Xu, G Tsai, SYA Freed, WJ Lee, CT AF Wu, Chun Xu, Gang Tsai, Shang-Yi A. Freed, William J. Lee, Chun-Ting TI Transcriptional profiles of type 2 diabetes in human skeletal muscle reveal insulin resistance, metabolic defects, apoptosis, and molecular signatures of immune activation in response to infections SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Transcriptome; Type 2 diabetes; Insulin resistance; Metabolic defects; Immune activation ID GENES; INFLAMMATION; MELLITUS; PACKAGE; RISK AB Skeletal muscle insulin resistance is considered to be the primary defect involved in type 2 diabetes mellitus (T2DM). Despite transcriptome studies in limited T2DM human subjects suggesting an association of T2DM with impaired oxidative phosphorylation in muscle, its molecular pathogenesis remains largely unknown. To identify dysregulated genes and gene networks that are associated with T2DM in human skeletal muscle, we examined expression patterns of 56,318 transcribed genes on 92 T2DM cases and 184 gender-, age- and race-matched non-diabetic controls from the Genotype-Tissue Expression (GTEx) database. RNA-Sequencing data suggest that diabetic skeletal muscle is characterized by decreased expression of genes that are related to insulin resistance (1RS2, MTOR, SLC2A4, and PPARA), carbohydrate, energy, and amino acid metabolism pathways (NDUFSI, NDUFA10, NDUFB4, NDUFB5, NDUFA5, NDUFB10, SDHB, SDHC, ATP5H, ATP5A, and ATP5J). Up-regulated genes in T2DM are mainly enriched in apoptosis pathways (TP53, GADD45A, TNFRSF10B, TP53A1P1, and PMAIP1), and notably include immune-related pathways suggestive of a response to various infectious diseases (C2, CFB, C4A, C4B, C1S, C1R, C3, HLA-DRA, HLA-DMA, HLA-DOA, and HLA-DPB1). These results confirm the essential regulation of impaired insulin signaling and oxidative phosphorylation in the muscle of T2DM patients, and provide novel molecular insights into the pathophysiological mechanisms of T2DM. (C) 2016 Elsevier Inc. All rights reserved. C1 [Wu, Chun] Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, 1951 NW 7th Ave,Suite 240, Miami, FL 33136 USA. [Xu, Gang] Univ Miami, Miller Sch Med, Div Biostat, Dept Publ Hlth Sci, Miami, FL 33136 USA. [Tsai, Shang-Yi A.; Freed, William J.] NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD 21244 USA. [Freed, William J.] Lebanon Valley Coll, Dept Biol, Annville, PA 17003 USA. [Lee, Chun-Ting] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. EM c.wu6@med.miami.edu; Chun-Ting.Lee@fda.hhs.gov OI Wu, Chun/0000-0003-2858-8064 NR 24 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 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 8 PY 2017 VL 482 IS 2 BP 282 EP 288 DI 10.1016/j.bbrc.2016.11.055 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA EI7PJ UT WOS:000392690100015 PM 27847319 ER PT J AU Taylor, LJ Strebel, K AF Taylor, Louis J. Strebel, Klaus TI Pyviko: an automated Python tool to design gene knockouts in complex viruses with overlapping genes SO BMC MICROBIOLOGY LA English DT Software Review DE Virus; Knockout virus; Mutation; Overprinting; Bioinformatics; Cloning; Viral mutant; Knockout; Pyviko AB Background: Gene knockouts are a common tool used to study gene function in various organisms. However, designing gene knockouts is complicated in viruses, which frequently contain sequences that code for multiple overlapping genes. Designing mutants that can be traced by the creation of new or elimination of existing restriction sites further compounds the difficulty in experimental design of knockouts of overlapping genes. While software is available to rapidly identify restriction sites in a given nucleotide sequence, no existing software addresses experimental design of mutations involving multiple overlapping amino acid sequences in generating gene knockouts. Results: Pyviko performed well on a test set of over 240,000 gene pairs collected from viral genomes deposited in the National Center for Biotechnology Information Nucleotide database, identifying a point mutation which added a premature stop codon within the first 20 codons of the target gene in 93.2% of all tested gene-overprinted gene pairs. This shows that Pyviko can be used successfully in a wide variety of contexts to facilitate the molecular cloning and study of viral overprinted genes. Conclusions: Pyviko is an extensible and intuitive Python tool for designing knockouts of overlapping genes. Freely available as both a Python package and a web-based interface (http://louiejtaylor.github.io/pyViKO/), Pyviko simplifies the experimental design of gene knockouts in complex viruses with overlapping genes. C1 [Taylor, Louis J.; Strebel, Klaus] NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Taylor, Louis J.] Univ Penn, Perelman Sch Med, Cell & Mol Biol Grad Grp, Philadelphia, PA 19104 USA. RP Taylor, LJ (reprint author), NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Taylor, LJ (reprint author), Univ Penn, Perelman Sch Med, Cell & Mol Biol Grad Grp, Philadelphia, PA 19104 USA. EM louist@upenn.edu OI Taylor, Louis/0000-0002-6993-5838 FU Intramural Research Program of the NIH, NIAID [1 Z01 AI000669]; NIH Post-baccalaureate Fellowship FX This work was supported by the Intramural Research Program of the NIH, NIAID (KS: 1 Z01 AI000669) and by an NIH Post-baccalaureate Fellowship (LJT). NR 23 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 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD JAN 7 PY 2017 VL 17 AR 12 DI 10.1186/s12866-016-0920-3 PG 6 WC Microbiology SC Microbiology GA EH6OG UT WOS:000391892000004 PM 28061810 ER PT J AU Kodati, S Palmore, TN Spellman, FA Cunningham, D Weistrop, B Sen, HN AF Kodati, Shilpa Palmore, Tara N. Spellman, Frank A. Cunningham, Denise Weistrop, Benjamin Sen, H. Nida TI Bilateral posterior uveitis associated with Zika virus infection SO LANCET LA English DT Editorial Material C1 [Kodati, Shilpa; Cunningham, Denise; Sen, H. Nida] NEI, Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. [Palmore, Tara N.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Spellman, Frank A.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Spellman, Frank A.] Retina Grp Washington, Washington, DC USA. [Weistrop, Benjamin] New York Med Coll, Valhalla, NY 10595 USA. RP Sen, HN (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM senh@nei.nih.gov NR 5 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JAN 7 PY 2017 VL 389 IS 10064 BP 125 EP 126 DI 10.1016/S0140-6736(16)32518-1 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EG7VH UT WOS:000391264000044 PM 27939402 ER PT J AU Symons, R Cork, TE Sahbaee, P Fuld, MK Kappler, S Folio, LR Bluemke, DA Pourmorteza, A AF Symons, Rolf Cork, Tyler E. Sahbaee, Pooyan Fuld, Matthew K. Kappler, Steffen Folio, Les R. Bluemke, David A. Pourmorteza, Amir TI Low-dose lung cancer screening with photon-counting CT: a feasibility study SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE computed tomography; photon-counting CT; lung imaging; lung cancer screening; ground-glass nodule; emphysema; low-contrast detectability ID COMPUTED-TOMOGRAPHY; CHEST CT; DETECTOR; NODULES; SYSTEM; MODEL AB To evaluate the feasibility of using a whole-body photon-counting detector (PCD) CT scanner for low-dose lung cancer screening compared to a conventional energy integrating detector (EID) system. Radiation dose-matched EID and PCD scans of the COPDGene 2 phantom were acquired at different radiation dose levels (CTDIvol: 3.0, 1.5, and 0.75 mGy) and different tube voltages (120, 100, and 80 kVp). EID and PCD images were compared for quantitative Hounsfield unit (HU) accuracy, noise levels, and contrast-to-noise ratios (CNR) for detection of ground-glass nodules (GGN) and emphysema. The PCD HU accuracy was better than EID for water at all scan parameters. PCD HU stability for lung, GGN and emphysema regions were superior to EID and PCD attenuation values were more reproducible than EID for all scan parameters (all P < 0.01), while HUs for lung, GGN and emphysema ROIs changed significantly for EID with decreasing dose (all P < 0.001). PCD showed lower noise levels at the lowest dose setting at 120, 100 and 80 kVp (15.2 +/- 0.3 HU versus 15.8 +/- 0.2 HU, P = 0.03; 16.1 +/- 0.3 HU versus 18.0 +/- 0.4 HU, P = 0.003; and 16.1 +/- 0.3 HU versus 17.9 +/- 0.3 HU, P = 0.001, respectively), resulting in superior CNR for evaluation of GGNs and emphysema at 100 and 80 kVp. PCD provided better HU stability for lung, ground-glass, and emphysema-equivalent foams at lower radiation dose settings with better reproducibility than EID. Additionally, PCD showed up to 10% less noise, and 11% higher CNR at 0.75 mGy for both 100 and 80 kVp. PCD technology may help reduce radiation exposure in lung cancer screening while maintaining diagnostic quality. C1 [Symons, Rolf; Cork, Tyler E.; Folio, Les R.; Bluemke, David A.; Pourmorteza, Amir] NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Sahbaee, Pooyan; Fuld, Matthew K.] Siemens Med Solut, Malvern, PA USA. [Kappler, Steffen] Siemens Healthcare GmbH, Forchheim, Germany. RP Pourmorteza, A (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM amir.pourmorteza@nih.gov FU NIH intramural research program [ZIACL090019, ZIAEB000072]; Siemens Medical Systems (Forchheim, Germany) FX This study was supported by the NIH intramural research program (ZIACL090019; ZIAEB000072), and in part by a collaborative research agreement with Siemens Medical Systems (Forchheim, Germany). Authors who are not employees of or consultants for Siemens had control of inclusion of any data and information that might present a conflict of interest for the authors who are employed by Siemens. NR 28 TC 0 Z9 0 U1 1 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JAN 7 PY 2017 VL 62 IS 1 BP 202 EP 213 DI 10.1088/1361-6560/62/1/202 PG 12 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EH1ZT UT WOS:000391567700004 PM 27991453 ER PT J AU Lee, S Chowell, G AF Lee, Sunmi Chowell, Gerardo TI Exploring optimal control strategies in seasonally varying flu-like epidemics SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Influenza transmission dynamics; Seasonally varying transmission rate; Optimal control theory; Vaccination and treatment strategies ID PANDEMIC INFLUENZA; DRUG-USE; TRANSMISSION; IMPACT AB The impact of optimal control strategies in the context of seasonally varying infectious disease transmission remains a wide open research area. We investigate optimal control strategies for flu-like epidemics using an SIR (susceptible-infectious-recovered) type epidemic model where the transmission rate varies seasonally Specifically, we explore optimal control strategies using time-dependent treatment and vaccination as control functions alone or in combination. Optimal strategies and associated epidemic outcomes are contrasted for epidemics with constant and seasonal transmission rates. Our results show that the epidemic outcomes assessed in terms of the timing and size of seasonal epidemics subject to optimal control strategies are highly sensitive to various parameters including R-0, the timing of the introduction of the initial number of infectious individuals into the population, the time at which interventions start, and the strength of the seasonal forcing that modulates the time-dependent transmission rate. Findings highlight the difficult challenge in predicting short-term epidemic impact in the context of seasonally varying infectious disease transmission with some interventions scenarios exhibiting larger epidemic size compared to scenarios without control interventions. C1 [Lee, Sunmi] Kyung Hee Univ, Dept Appl Math, Yongin, South Korea. [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Lee, S (reprint author), Kyung Hee Univ, Dept Appl Math, Yongin, South Korea. EM sunmilee@khu.ac.kr FU National Research Foundation of Korea (NRF) - Korean government (MSIP) [20152194] FX This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. 20152194). The authors would like to thank the anonymous reviewers for their valuable comments and suggestions to improve our manuscript. NR 35 TC 0 Z9 0 U1 7 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 EI 1095-8541 J9 J THEOR BIOL JI J. Theor. Biol. PD JAN 7 PY 2017 VL 412 BP 36 EP 47 DI 10.1016/j.jtbi.2016.09.023 PG 12 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA EG5KA UT WOS:000391081500005 PM 27693366 ER PT J AU Togias, A Cooper, SF Acebal, ML Assa'ad, A Baker, JR Beck, LA Block, J Byrd-Bredbenner, C Chan, ES Eichenfield, LF Fleischer, DM Fuchs, GJ Furuta, GT Greenhawt, MJ Gupta, RS Habich, M Jones, SM Keaton, K Muraro, A Plaut, M Rosenwasser, LJ Rotrosen, D Sampson, HA Schneider, LC Sicherer, SH Sidbury, R Spergel, J Stukus, DR Venter, C Boyce, JA AF Togias, Alkis Cooper, Susan F. Acebal, Maria L. Assa'ad, Amal Baker, James R. Beck, Lisa A. Block, Julie Byrd-Bredbenner, Carol Chan, Edmond S. Eichenfield, Lawrence F. Fleischer, David M. Fuchs, George J., III Furuta, Glenn T. Greenhawt, Matthew J. Gupta, Ruchi S. Habich, Michele Jones, Stacie M. Keaton, Kari Muraro, Antonella Plaut, Marshall Rosenwasser, Lanny J. Rotrosen, Daniel Sampson, Hugh A. Schneider, Lynda C. Sicherer, Scott H. Sidbury, Robert Spergel, Jonathan Stukus, David R. Venter, Carina Boyce, Joshua A. TI Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel SO ALLERGY ASTHMA AND CLINICAL IMMUNOLOGY LA English DT Article DE Food; Peanut; Allergy; Prevention; Guidelines ID FOOD ALLERGY; NUTRITIONAL INTERVENTIONS; ANAPHYLACTIC REACTIONS; GRADING QUALITY; PREVALENCE; INFANTS; CONSUMPTION; RECOMMENDATIONS; FEASIBILITY; FATALITIES AB Background: Food allergy is an important public health problem because it affects children and adults, can be severe and even life-threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. A recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanut-containing foods beginning in infancy. Objectives: Prompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy. Results: The addendum provides 3 separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanut-containing foods in the health care provider's office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation. Conclusions: Guidelines have been developed for early introduction of peanut-containing foods into the diets of infants at various risk levels for peanut allergy. C1 [Togias, Alkis; Cooper, Susan F.; Plaut, Marshall; Rotrosen, Daniel] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Acebal, Maria L.] Board Directors, Food Allergy Res & Educ, Mclean, VA USA. [Assa'ad, Amal] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH USA. [Baker, James R.] Food Allergy Res & Educ, Mclean, VA USA. [Baker, James R.] Univ Michigan Hlth Syst, Div Allergy & Clin Immunol, Ann Arbor, MI USA. [Beck, Lisa A.] Univ Rochester, Med Ctr, Dept Dermatol, Rochester, NY 14627 USA. [Block, Julie] Natl Eczema Assoc, San Rafael, CA USA. [Byrd-Bredbenner, Carol] Rutgers State Univ, Dept Nutr Sci, Fredericton, NB, Canada. [Chan, Edmond S.] Univ British Columbia, BC Childrens Hosp, Dept Pediat, Div Allergy & Immunol, Vancouver, BC, Canada. [Eichenfield, Lawrence F.] Univ Calif San Diego, Sch Med, Rady Childrens Hosp, Dept Dermatol, San Diego, CA 92103 USA. [Eichenfield, Lawrence F.] Univ Calif San Diego, Sch Med, Rady Childrens Hosp, Dept Pediat, San Diego, CA 92103 USA. [Fleischer, David M.; Greenhawt, Matthew J.] Univ Colorado Denver, Sch Med, Sect Allergy & Immunol, Dept Pediat,Childrens Hosp Colorado, Aurora, CO USA. [Fuchs, George J., III] Univ Kentucky, Coll Med, Div Gastroenterol Hepatol & Nutr, Dept Pediat,Coll Med,Kentucky Childrens Hosp, Lexington, KY USA. [Furuta, Glenn T.] Childrens Hosp Colorado, Digest Hlth Inst, Aurora, CO USA. [Gupta, Ruchi S.] Northwestern Univ, Div Acad Gen Pediat & Primary Care, Ann & Robert H Lurie Childrens Hosp Chicago, Dept Pediat,Feinberg Sch Med, Chicago, IL 60611 USA. [Habich, Michele] Cent DuPage Hosp, Northwestern Med, Winfield, IL USA. [Jones, Stacie M.] Univ Arkansas Med Sci, Arkansas Childrens Hosp, Dept Pediat, Div Allergy & Immunol, Little Rock, AR 72205 USA. [Keaton, Kari] Metro DC Food Allergy Support Grp, Rockville, MD USA. [Muraro, Antonella] Padua Univ Hosp, Dept Women & Child Hlth, Food Allergy Referral Ctr, Padua, Italy. [Rosenwasser, Lanny J.] Univ Missouri, Sch Med, Kansas City, MO 64110 USA. [Sampson, Hugh A.] Harvard Med Sch, Dept Pediat, Div Allergy & Immunol, Boston, MA USA. [Schneider, Lynda C.] Icahn Sch Med Mt Sinai, Div Pediat Allergy & Immunol, New York, NY 10029 USA. [Sicherer, Scott H.] Boston Childrens Hosp, Div Allergy & Immunol, Boston, MA USA. [Sidbury, Robert] Univ Washington, Sch Med, Dept Pediat, Div Dermatol,Seattle Childrens Hosp, Seattle, WA 98195 USA. [Spergel, Jonathan] Univ Penn, Div Allergy & Immunol, Dept Pediat, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Stukus, David R.] Ohio State Univ, Dept Pediat, Sect Allergy & Immunol, Nationwide Childrens Hosp,Coll Med, Columbus, OH 43210 USA. [Venter, Carina] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA. [Boyce, Joshua A.] Harvard Med Sch, Dept Med, Boston, MA USA. [Boyce, Joshua A.] Harvard Med Sch, Dept Pediat, Boston, MA USA. RP Cooper, SF (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM coopersu@niaid.nih.gov FU DBV Technologies; Aimmune; Stanford Foundation; TEVA Pharmaceuticals; GlaxoSmithKline; National Institutes of Health (NIH); Astellas; Food Allergy Research & Education (FARE); ACAAI; Pfizer; Sanofi; Mead Johnson; Nestle; Monsanto Company; Nestle Nutrition Institute; Aimmune Therapeutics; Agency for Healthcare Research and Quality [1K08HS024599-01]; Reach MD; Thermo Fisher Scientific; California Society for Allergy and Immunology; Allergy and Asthma Network; New England Society for Allergy; UCLA/Harbor Heiner Lectureship; Medscape; Western Michigan School of Medicine; Canadian Society of Allergy and Clinical Immunology; Pennsylvania Society for Allergy and Immunology; NIH; FARE; Mylan LLC; Grand Rounds; NIH/NIAID; Aimmune Technologies; National Peanut Board; Kansas City Allergy Society; Mercy Children's Hospital; Riley Children's Hospital; Southwester Medical School-Children's Medical Center; European Academy of Allergy & Clinical Immunology; New York Allergy Asthma Society; University of Iowa Paul M. Seebohm Lectureship in Allergy; Iowa Society of Allergy, Asthma, and Immunology; Meda; Menarini; NIAID; Immune Tolerance Network; HAL Allergy; Epidermolysis Bullosa Research Partnership; Taiwanese Dermatological Society; Dartmouth College; Florida Allergy Society FX A. Assa'ad received travel support from the American College of Allergy, Asthma & Immunology (ACAAI); was an elected member of the Board of Directors for the American Academy of Allergy, Asthma, & Immunology (AAAAI) from March 2012 to March 2016; has consultant arrangements with Aimmune; is employed by Cincinnati Children's Hospital Medical Center; has received grants from DBV Technologies, Aimmune, Stanford Foundation, TEVA Pharmaceuticals, GlaxoSmithKline, the National Institutes of Health (NIH), Astellas, and Food Allergy Research & Education (FARE); and has received payment for lectures from the ACAAI. C. Byrd-Bredbenner and G.J. Fuchs III have received travel support from the NIH/National Institute of Allergy and Infectious Disease (NIAID). E.S. Chan has received travel support from the NIAID, has received grants from DBV Technologies, and has received payment for lectures from Pfizer, Sanofi, Mead Johnson, and Nestle. D.M. Fleischer has received travel support from the NIAID; is a board member for the National Peanut Board, the FAACT Medical Advisory Board, and the FARE Medical Advisory Board; has consultant arrangements with Adamis Pharmaceuticals Corporation, INSYS Therapeutics, DBV Technologies, Aimmune Therapeutics, Intrommune Therapeutics, and Kaleo Pharma; is employed by University Physicians; has received grants from Monsanto Company, Nestle Nutrition Institute, DBV Technologies, and Aimmune Therapeutics; has received payment for lectures from Nestle Nutrition Institute; and has received royalties from UpToDate. M.J. Greenhawt has received a grant from the Agency for Healthcare Research and Quality (1K08HS024599-01, Career Development Award); has received travel support from the NIAID and the Joint Taskforce on Allergy Practice Parameters; has a board membership with the National Peanut Board; has consultant arrangements with Adamis Pharmaceuticals, the Canadian Transportation Agency, Nutricia, Nestle/Gerber, Aimmune, Kaleo Pharmaceutical, and Monsanto; is an Associate Editor for the Annals of Allergy, Asthma, and Immunology; has received payment for lectures from the ACAAI, Reach MD, Thermo Fisher Scientific, the California Society for Allergy and Immunology, the Allergy and Asthma Network, the New England Society for Allergy, UCLA/Harbor Heiner Lectureship, Medscape, the Western Michigan School of Medicine, the Canadian Society of Allergy and Clinical Immunology, and the Pennsylvania Society for Allergy and Immunology. R.S. Gupta has consultant arrangements with BEFORE Brands and DBV Technologies; has received grants from the NIH, FARE, and Mylan LLC; has received payment for lectures from Grand Rounds; and has received royalties from Createspace Independent Publishing Platform. S.M. Jones is on the Research Advisory Board for FARE; is on the Scientific Advisory Board for Aimmune; has consultant arrangements with Stallergenes; has received grants from the NIH/NIAID (Consortium of Food Allergy Research and Immune Tolerance Network-IMPACT Trial), FARE, Aimmune Technologies, DBV Technologies, and the National Peanut Board; has received payment for lectures from the Kansas City Allergy Society, Mercy Children's Hospital, Riley Children's Hospital, Southwester Medical School-Children's Medical Center, the European Academy of Allergy & Clinical Immunology, the New York Allergy & Asthma Society, the University of Iowa Paul M. Seebohm Lectureship in Allergy, and the Iowa Society of Allergy, Asthma, and Immunology. A.; Muraro has consultant arrangements with Meda, Novartis, and Menarini; is employed by Padua University Hospital; and has received payment for lectures from Meda and Menarini. L.J. Rosenwasser is a board member for the World Allergy Organization. H.A. Sampson has consultant arrangements with Allertein Therapeutics, Genentech/Roche, Sanofi, Stallergenes, Danone, and Merck; is employed part time as Chief Scientific Officer for DBV Technologies; has received grants from the NIAID and the Immune Tolerance Network; has received royalties from UpToDate and Elsevier; has been offered stock options in DBV Technologies; and is chairman of PhARF Award Selection Committee for Thermo Fisher. L.C. Schneider is on the Medical Advisory Board for FARE, has received a grant from DBV Technologies, and has received stock/stock options in Antera Therapeutics. S.H. Sicherer has received grants from the NIAID, FARE, and HAL Allergy; has received royalties from UpToDate; and is serving as Associate Editor for the Journal of Allergy and Clinical Immunology: In Practice. R. Sidbury has received travel support from the NIH and the Hawaii Dermatology Seminar, has consultant arrangements with Anacor, has provided expert witness testimony on behalf of Roche in Accutane-inflammatory bowel disease cases, has received a grant from Epidermolysis Bullosa Research Partnership, has received payment for lectures from the Taiwanese Dermatological Society, and has received royalties from UpToDate. J. Spergel has consultant arrangements with DBV Technologies and Danone; has received grants from DBV Technologies, Aimmune Therapeutics, and the NIH; has received payment for lectures for Dartmouth College, the ACAAI, and the Florida Allergy Society; and has received stock/stock options in DBV Technologies. D.R. Stukus has received payment for lectures from the ACAAI. C. Venter has consultant arrangements with Danone and Nestle, has received payment for lectures from Mead Johnson, and has received travel support from Thermo Fisher. The rest of the authors declare that they have no relevant competing interests. NR 28 TC 1 Z9 1 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1710-1484 EI 1710-1492 J9 ALLERGY ASTHMA CL IM JI Allerg Asthma Clin. Immunol. PD JAN 6 PY 2017 VL 13 AR 1 DI 10.1186/s13223-016-0175-4 PG 20 WC Allergy; Immunology SC Allergy; Immunology GA EL6CZ UT WOS:000394709300001 ER PT J AU Togias, A Cooper, SF Acebal, ML Assa'ad, A Baker, JR Beck, LA Block, J Byrd-Bredbenner, C Chan, ES Eichenfield, LF Fleischer, DM Fuchs, GJ Furuta, GT Greenhawt, MJ Gupta, RS Habich, M Jones, SM Keaton, K Muraro, A Plaut, M Rosenwasser, LJ Rotrosen, D Sampson, HA Schneider, LC Sicherer, SH Sidbury, R Spergel, J Stukus, DR Venter, C Boyce, JA AF Togias, Alkis Cooper, Susan F. Acebal, Maria L. Assa'ad, Amal Baker, James R., Jr. Beck, Lisa A. Block, Julie Byrd-Bredbenner, Carol Chan, Edmond S. Eichenfield, Lawrence F. Fleischer, David M. Fuchs, George J., III Furuta, Glenn T. Greenhawt, Matthew J. Gupta, Ruchi S. Habich, Michele Jones, Stacie M. Keaton, Kari Muraro, Antonella Plaut, Marshall Rosenwasser, Lanny J. Rotrosen, Daniel Sampson, Hugh A. Schneider, Lynda C. Sicherer, Scott H. Sidbury, Robert Spergel, Jonathan Stukus, David R. Venter, Carina Boyce, Joshua A. TI Addendum guidelines for the prevention of peanut allergy in the United States: Report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel SO WORLD ALLERGY ORGANIZATION JOURNAL LA English DT Article DE Food; Peanut; Allergy; Prevention; Guidelines ID FOOD ALLERGY; NUTRITIONAL INTERVENTIONS; ANAPHYLACTIC REACTIONS; GRADING QUALITY; PREVALENCE; INFANTS; CONSUMPTION; RECOMMENDATIONS; FEASIBILITY; FATALITIES AB Background: Food allergy is an important public health problem because it affects children and adults, can be severe and even life-threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. A recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanut-containing foods beginning in infancy. Objectives: Prompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy. Results: The addendum provides 3 separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanut-containing foods in the health care provider's office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation. Conclusions: Guidelines have been developed for early introduction of peanut-containing foods into the diets of infants at various risk levels for peanut allergy. C1 [Togias, Alkis; Cooper, Susan F.; Plaut, Marshall; Rotrosen, Daniel] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Acebal, Maria L.; Baker, James R., Jr.] Food Allergy Res & Educ, Mclean, VA USA. [Assa'ad, Amal] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH USA. [Baker, James R., Jr.] Univ Michigan Hlth Syst, Div Allergy & Clin Immunol, Ann Arbor, MI USA. [Beck, Lisa A.] Univ Rochester, Med Ctr, Dept Dermatol, New York, NY USA. [Block, Julie] Natl Eczema Assoc, San Rafael, CA USA. [Byrd-Bredbenner, Carol] Rutgers State Univ, Dept Nutr Sci, Fredericton, NB, Canada. [Chan, Edmond S.] Univ British Columbia, Div Allergy & Immunol, Dept Pediat, BC Childrens Hosp, Vancouver, BC, Canada. [Eichenfield, Lawrence F.] Univ Calif San Diego, Sch Med, Dept Pediat, Rady Childrens Hosp, San Diego, CA 92103 USA. [Eichenfield, Lawrence F.] Univ Calif San Diego, Sch Med, Dept Pediat, Rady Childrens Hosp, San Diego, CA 92103 USA. [Fleischer, David M.; Greenhawt, Matthew J.] Univ Colorado Denver, Sch Med, Childrens Hosp Colorado, Sect Allergy & Immunol,Dept Pediat, Aurora, CO USA. [Fuchs, George J., III] Univ Kentucky, Coll Med, Dept Pediat, Div Gastroenterol Hepatol & Nutr,Kentucky Childre, Lexington, KY USA. [Furuta, Glenn T.] Childrens Hosp Colorado, Digest Hlth Inst, Aurora, CO USA. [Furuta, Glenn T.] Univ Colorado Denver, Sch Med, Sect Pediat Gastroenterol, Aurora, CO USA. [Gupta, Ruchi S.] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Div Acad Gen Pediat & Primary Care, Chicago, IL 60611 USA. [Gupta, Ruchi S.] Northwestern Univ, Feinberg Sch Med, Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Habich, Michele] Cent DuPage Hosp, Northwestern Med, Winfield, IL USA. [Jones, Stacie M.] Univ Arkansas Med Sci, Arkansas Childrens Hosp, Dept Pediat, Div Allergy & Immunol, Little Rock, AR 72205 USA. [Keaton, Kari] Metro DC Food Allergy Support Grp, Rockville, MD USA. [Muraro, Antonella] Padua Univ Hosp, Dept Women & Child Hlth, Food Allergy Referral Ctr, Padua, Italy. [Rosenwasser, Lanny J.] Univ Missouri, Sch Med, Kansas City, MO 64108 USA. [Sampson, Hugh A.] Harvard Med Sch, Dept Pediat, Div Allergy & Immunol, Boston, MA USA. [Sicherer, Scott H.] Icahn Sch Med Mt Sinai, Div Pediat Allergy & Immunol, New York, NY 10029 USA. [Schneider, Lynda C.] Boston Childrens Hosp, Div Allergy & Immunol, Boston, MA USA. [Sidbury, Robert] Univ Washington, Sch Med, Dept Pediat, Div Dermatol,Seattle Childrens Hosp, Seattle, WA 98195 USA. [Spergel, Jonathan] Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Div Allergy & Immunol,Perelman Sch Med, Philadelphia, PA 19104 USA. [Stukus, David R.] Ohio State Univ, Coll Med, Dept Pediat, Sect Allergy & Immunol,Nationwide Childrens Hosp, Columbus, OH 43210 USA. [Venter, Carina] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA. [Boyce, Joshua A.] Harvard Med Sch, Dept Med, Boston, MA USA. [Boyce, Joshua A.] Harvard Med Sch, Dept Pediat, Boston, MA USA. RP Cooper, SF (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM coopersu@niaid.nih.gov NR 28 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 1939-4551 J9 WORLD ALLERGY ORGAN JI World Allergy Organ. J. PD JAN 6 PY 2017 VL 10 AR 1 DI 10.1186/s40413-016-0137-9 PG 18 WC Allergy SC Allergy GA EO4UU UT WOS:000396690600001 ER PT J AU Van de Velde, LA Subramanian, C Smith, AM Barron, L Qualls, JE Neale, G Alfonso-Pecchio, A Jackowski, S Rock, CO Wynn, TA Murray, PJ AF Van de Velde, Lee-Ann Subramanian, Chitra Smith, Amber M. Barron, Luke Qualls, Joseph E. Neale, Geoffrey Alfonso-Pecchio, Adolfo Jackowski, Suzanne Rock, Charles O. Wynn, Thomas A. Murray, Peter J. TI T Cells Encountering Myeloid Cells Programmed for Amino Acid-dependent Immunosuppression Use Rictor/mTORC2 Protein for Proliferative Checkpoint Decisions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NITRIC-OXIDE-SYNTHASE; L-ARGININE METABOLISM; DENDRITIC CELLS; ACTIVATION; MACROPHAGES; MTOR; INTERLEUKIN-2; SCHISTOSOMIASIS; DIFFERENTIATION; AVAILABILITY AB Modulation of T cell proliferation and function by immunoregulatory myeloid cells are an essential means of preventing self-reactivity and restoring tissue homeostasis. Consumption of amino acids such as arginine and tryptophan by immunoregulatory macrophages is one pathway that suppresses local T cell proliferation. Using a reduced complexity in vitro macrophage-T cell co-culture system, we show that macrophage arginase-1 is the only factor required by M2 macrophages to block T cells in G1, and this effect is mediated by L-arginine elimination rather than metabolite generation. Tracking how T cells adjust their metabolism when deprived of arginine revealed the significance of macrophage-mediated arginine deprivation to T cells. We found mTORC1 activity was unaffected in the initial G1 block. After 2 days of arginine deprivation, mTORC1 activity declined paralleling a selective down-regulation of SREBP target gene expression, whereas mRNAs involved in glycolysis, gluconeogenesis, and T cell activation were unaffected. Cell cycle arrest was reversible at any point by exogenous arginine, suggesting starved T cells remain poised awaiting nutrients. Arginine deprivation-induced cell cycle arrest was mediated in part by Rictor/mTORC2, providing evidence that this nutrient recognition pathway is a central component of how T cells measure environmental arginine. C1 [Van de Velde, Lee-Ann; Subramanian, Chitra; Smith, Amber M.; Qualls, Joseph E.; Alfonso-Pecchio, Adolfo; Jackowski, Suzanne; Rock, Charles O.; Murray, Peter J.] St Jude Childrens Res Hosp, Dept Infect Dis, Mail Stop 320,262 Danny Thomas Pl, Memphis, TN 38105 USA. [Van de Velde, Lee-Ann; Smith, Amber M.; Qualls, Joseph E.; Murray, Peter J.] St Jude Childrens Res Hosp, Dept Immunol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Neale, Geoffrey] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Barron, Luke; Wynn, Thomas A.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Qualls, Joseph E.] Cincinnati Childrens Hosp Med Ctr, Div Infect Dis, Cincinnati, OH 45229 USA. RP Murray, PJ (reprint author), St Jude Childrens Res Hosp, Dept Infect Dis, Mail Stop 320,262 Danny Thomas Pl, Memphis, TN 38105 USA. EM peter.murray@stjude.org FU National Institutes of Health [AI062921, CA138064]; Cancer Center Core Grant [P30 CA21765]; American Lebanese Syrian Associated Charities; National Institutes of Health Intramural Program FX This work was supported by National Institutes of Health Grants AI062921 (to P. J. M.) and CA138064 (to J. E. Q.), Cancer Center Core Grant P30 CA21765, the American Lebanese Syrian Associated Charities, and the National Institutes of Health Intramural Program. 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 60 TC 2 Z9 2 U1 3 U2 3 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 6 PY 2017 VL 292 IS 1 BP 15 EP 30 DI 10.1074/jbc.M116.766238 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EH2DQ UT WOS:000391578000002 PM 27903651 ER PT J AU Hamo, CE Klem, I Rao, SV Songco, V Najjar, S Lakatta, EG Raman, SV Harrington, RA Heitner, JF AF Hamo, Carine E. Klem, Igor Rao, Sunil V. Songco, Vincent Najjar, Samer Lakatta, Edward G. Raman, Subha V. Harrington, Robert A. Heitner, John F. TI The Systematic Evaluation of Identifying the Infarct Related Artery Utilizing Cardiac Magnetic Resonance in Patients Presenting with ST-Elevation Myocardial Infarction SO PLOS ONE LA English DT Article ID PERCUTANEOUS CORONARY INTERVENTION; RANDOMIZED CONTROLLED-TRIAL; MULTIVESSEL DISEASE; REVASCULARIZATION; CONTRAST; ERYTHROPOIETIN; VISUALIZATION; METAANALYSIS; ANGIOPLASTY; GUIDELINES AB Background Identification of the infarct-related artery (IRA) in patients with STEMI using coronary angiography (CA) is often based on the ECG and can be challenging in patients with severe multi-vessel disease. The current study aimed to determine how often percutaneous intervention (PCI) is performed in a coronary artery different from the artery supplying the territory of acute infarction on cardiac magnetic resonance imaging (CMR). Methods We evaluated 113 patients from the Reduction of infarct Expansion and Ventricular remodeling with Erythropoetin After Large myocardial infarction (REVEAL) trial, who underwent CMR within 4+2 days of revascularization. Blinded reviewers interpreted CA to determine the IRA and CMR to determine the location of infarction on a 17-segment model. In patients with multiple infarcts on CMR, acuity was determined with T2-weighted imaging and/or evidence of microvascular obstruction. Results A total of 5 (4%) patients were found to have a mismatch between the IRA identified on CMR and CA. In 4/5 cases, there were multiple infarcts noted on CMR. Thirteen patients (11.5%) had multiple infarcts in separate territories on CMR with 4 patients (3.5%) having multiple acute infarcts and 9 patients (8%) having both acute and chronic infarcts. Conclusions In this select population of patients, the identification of the IRA by CA was incorrect in 4% of patients presenting with STEMI. Four patients with a mismatch had an acute infarction in more than one coronary artery territory on CMR. The role of CMR in patients presenting with STEMI with multi-vessel disease on CA deserves further investigation. C1 [Hamo, Carine E.] Stony Brook Univ Hosp, Dept Med, Stony Brook, NY USA. [Klem, Igor; Rao, Sunil V.] Duke Clin Res Inst, Durham, NC USA. [Songco, Vincent; Heitner, John F.] New York Methodist Hosp, Div Cardiol, Brooklyn, NY 11215 USA. [Najjar, Samer] MedStar Hlth Res Inst, Washington, DC USA. [Najjar, Samer; Lakatta, Edward G.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Raman, Subha V.] Ohio State Univ, Div Cardiovasc Med, Columbus, OH 43210 USA. [Harrington, Robert A.] Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. RP Heitner, JF (reprint author), New York Methodist Hosp, Div Cardiol, Brooklyn, NY 11215 USA. EM jfh9003@nyp.org FU Intramural Research Program of the National Institute on Aging, the National Institutes of Health, Bethesda, MD, USA FX This work was supported by the Intramural Research Program of the National Institute on Aging, the National Institutes of Health, Bethesda, MD, USA. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00378352. NR 27 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 6 PY 2017 VL 12 IS 1 AR e0619108 DI 10.1371/journal.pone.0169108 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH3AX UT WOS:000391641500054 PM 28060863 ER PT J AU Johns, LE Ferguson, KK McElrath, TF Mukherjee, B Seely, EW Meeker, JD AF Johns, Lauren E. Ferguson, Kelly K. McElrath, Thomas F. Mukherjee, Bhramar Seely, Ellen W. Meeker, John D. TI Longitudinal Profiles of Thyroid Hormone Parameters in Pregnancy and Associations with Preterm Birth SO PLOS ONE LA English DT Article ID POPULATION-BASED COHORT; SUBCLINICAL HYPOTHYROIDISM; INFLAMMATORY CYTOKINES; FUNCTION TESTS; 1ST TRIMESTER; DELIVERY; RISK; OUTCOMES; DYSFUNCTION; GESTATION AB Introduction Overt thyroid disease in pregnancy is associated with numerous maternal and neonatal complications including preterm birth. Less is known about the contribution of trimester-specific subclinical alterations in individual thyroid hormones, especially in late gestation, on the risk of preterm birth. Herein, we examined the associations between subclinical changes in maternal thyroid hormone concentrations (TSH, total T3, free and total T4), measured at multiple time points in pregnancy, and the odds of preterm birth in pregnant women without clinical thyroid disease. Participants and Methods Data were obtained from pregnant women participating in a nested case-control study of preterm birth within on ongoing birth cohort study at Brigham and Women's Hospital in Boston, MA (N = 439; 116 cases and 323 controls). We measured thyroid hormones in plasma collected at up to four time points in pregnancy (median = 10, 18, 26, and 35 weeks). We used multivariate logistic regression models stratified by study visit of sample collection to examine associations. To reveal potential biological pathways, we also explored these relationships by obstetric presentation of preterm birth (e.g., spontaneous preterm delivery) that have been previously hypothesized to share common underlying mechanisms. Results In samples collected at median 10 and 26 weeks of gestation, we found inverse associations between FT4 and the odds of overall preterm birth (odds ratio [OR] = 0.57, 95% confidence interval (CI) = 0.33, 1.00; and OR = 0.53, 95% CI = 0.34, 0.84, respectively). Positive associations were detected for total T3 at these same time points (OR = 2.52, 95% CI = 1.20, 5.31; and OR = 3.40, 95% CI = 1.56, 7.40, respectively). These effect estimates were stronger for spontaneous preterm birth. Conclusions Our results suggest that subclinical alterations in individual maternal thyroid hormones may influence the risk of preterm birth, and the strength of these associations vary by gestational age. C1 [Johns, Lauren E.; Ferguson, Kelly K.; Meeker, John D.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Ferguson, Kelly K.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [McElrath, Thomas F.] Harvard Med Sch, Brigham & Womens Hosp, Div Maternal & Fetal Med, Boston, MA USA. [Mukherjee, Bhramar] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Seely, Ellen W.] Harvard Med Sch, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA USA. RP Meeker, JD (reprint author), Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. EM meekerj@umich.edu OI Ferguson, Kelly/0000-0001-8467-3250 FU Abbott Diagnostics; National Institute of Environmental Health Sciences, National Institutes of Health [R01ES018872, P42ES017198, P01E5022844, P30ES017885, T32ES007062]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX Subject recruitment and sample collection was originally funded by Abbott Diagnostics. Funding was also provided by the National Institute of Environmental Health Sciences, National Institutes of Health (grants R01ES018872, P42ES017198, P01E5022844, P30ES017885, and T32ES007062). Funding support for KKF was provided by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 0 Z9 0 U1 8 U2 8 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 6 PY 2017 VL 12 IS 1 AR e0169542 DI 10.1371/journal.pone.0169542 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH3AX UT WOS:000391641500107 PM 28060899 ER PT J AU Kelly, K Balk, SP AF Kelly, Kathleen Balk, Steven P. TI Reprogramming to resist SO SCIENCE LA English DT Editorial Material ID NEUROENDOCRINE PROSTATE-CANCER C1 [Kelly, Kathleen] NCI, Lab Genitourinary Canc Pathogenesis, Ctr Canc Res, Bethesda, MD 20892 USA. [Balk, Steven P.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Balk, Steven P.] Beth Israel Deaconess Med Ctr, Ctr Canc, Boston, MA 02215 USA. [Balk, Steven P.] Harvard Med Sch, Boston, MA 02215 USA. RP Kelly, K (reprint author), NCI, Lab Genitourinary Canc Pathogenesis, Ctr Canc Res, Bethesda, MD 20892 USA. EM kellyka@mail.nih.gov NR 13 TC 0 Z9 0 U1 3 U2 3 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 6 PY 2017 VL 355 IS 6320 BP 29 EP 30 DI 10.1126/science.aam5355 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH4KK UT WOS:000391739900034 PM 28059730 ER PT J AU Passos, DO Li, M Yang, RB Rebensburg, SV Ghirlando, R Jeon, Y Shkriabai, N Kvaratskhelia, M Craigie, R Lyumkis, D AF Passos, Dario Oliveira Li, Min Yang, Renbin Rebensburg, Stephanie V. Ghirlando, Rodolfo Jeon, Youngmin Shkriabai, Nikoloz Kvaratskhelia, Mamuka Craigie, Robert Lyumkis, Dmitry TI Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome SO SCIENCE LA English DT Article ID DNA-BINDING; CRYSTAL-STRUCTURE; INTEGRASE STRUCTURE; CATALYTIC DOMAIN; GENETIC ANALYSES; TARGET; PROTEIN; INHIBITION; MECHANISM; RESIDUES AB Like all retroviruses, HIV-1 irreversibly inserts a viral DNA (vDNA) copy of its RNA genome into host target DNA (tDNA). The intasome, a higher-order nucleoprotein complex composed of viral integrase (IN) and the ends of linear vDNA, mediates integration. Productive integration into host chromatin results in the formation of the strand transfer complex (STC) containing catalytically joined vDNA and tDNA. HIV-1 intasomes have been refractory to high-resolution structural studies. We used a soluble IN fusion protein to facilitate structural studies, through which we present a high-resolution cryo-electron microscopy (cryo-EM) structure of the core tetrameric HIV-1 STC and a higher-order form that adopts carboxyl-terminal domain rearrangements. The distinct STC structures highlight how HIV-1 can use the common retroviral intasome core architecture to accommodate different IN domain modules for assembly. C1 [Passos, Dario Oliveira; Jeon, Youngmin; Lyumkis, Dmitry] Salk Inst Biol Studies, Genet Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Passos, Dario Oliveira; Jeon, Youngmin; Lyumkis, Dmitry] Salk Inst Biol Studies, Helmsley Ctr Genom Med, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Li, Min; Yang, Renbin; Ghirlando, Rodolfo; Craigie, Robert] NIDDK, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. [Rebensburg, Stephanie V.; Shkriabai, Nikoloz; Kvaratskhelia, Mamuka] Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Rebensburg, Stephanie V.; Shkriabai, Nikoloz; Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. RP Lyumkis, D (reprint author), Salk Inst Biol Studies, Genet Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA.; Lyumkis, D (reprint author), Salk Inst Biol Studies, Helmsley Ctr Genom Med, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM dlyumkis@salk.edu FU NIH [P50 GM103368, R01 AI062520, P41 GM103331]; Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]; National Institute of Diabetes and Digestive Diseases of the NIH; Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX D.L. acknowledges support from NIH grant P50 GM103368 and the Leona M. and Harry B. Helmsley Charitable Trust grant 2012-PG-MED002. R.C. is supported by the Intramural Program of the National Institute of Diabetes and Digestive Diseases of the NIH and by the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH. These studies were also partly supported by NIH grant R01 AI062520 to M.K. Molecular graphics and analyses were performed with the University of California, San Francisco, Chimera package (supported by NIH grant P41 GM103331). We thank B. Anderson and J.-C. Ducom for help with EM data collection and network infrastructure, F. Dwyer for computational support, G. Lander and M. Herzik for help with ensemble refinements, and A. Engelman and M. Gellert for critical review of the manuscript. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. The EM maps of STC and STCIBD are deposited into the Electron Microscopy Data Bank under accession codes EMD-8481 and EMD-8483, respectively. The STC model is deposited into the Protein Data Bank under ID 5U1C. The STC model ensemble and the composite model of the higher-order STCIBD oligomers are available upon request. NR 35 TC 2 Z9 2 U1 8 U2 8 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 6 PY 2017 VL 355 IS 6320 BP 89 EP 92 DI 10.1126/science.aah5163 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH4KK UT WOS:000391739900049 PM 28059769 ER PT J AU Pardo, CA Farmer, CA Thurm, A Shebl, FM Ilieva, J Kalra, S Swedo, S AF Pardo, Carlos A. Farmer, Cristan A. Thurm, Audrey Shebl, Fatma M. Ilieva, Jorjetta Kalra, Simran Swedo, Susan TI Serum and cerebrospinal fluid immune mediators in children with autistic disorder: a longitudinal study SO MOLECULAR AUTISM LA English DT Article DE Autism; Immune; CSF; Chemokine; Cytokine; Growth factor ID EPIDERMAL-GROWTH-FACTOR; SPECTRUM DISORDER; CYTOKINE LEVELS; SOLUBLE CD40; MOUSE MODEL; BRAIN; INFLAMMATION; NEUROINFLAMMATION; DISEASE; INTERLEUKIN-15 AB Background: The causes of autism likely involve genetic and environmental factors that influence neurobiological changes and the neurological and behavioral features of the disorder. Immune factors and inflammation are hypothesized pathogenic influences, but have not been examined longitudinally. Methods: In a cohort of 104 participants with autism, we performed an assessment of immune mediators such as cytokines, chemokines, or growth factors in serum and cerebrospinal fluid (n = 67) to determine potential influences of such mediators in autism. Results: As compared with 54 typically developing controls, we found no evidence of differences in the blood profile of immune mediators supportive of active systemic inflammation mechanisms in participants with autism. Some modulators of immune function (e.g., EGF and soluble CD40 ligand) were increased in the autism group; however, no evidence of group differences in traditional markers of active inflammation (e.g., IL-6, TNFa, IL-1 beta) were observed in the serum. Further, within-subject stability (measured by estimated intraclass correlations) of most analytes was low, indicating that a single measurement is not a reliable prospective indicator of concentration for most analytes. Additionally, in participants with autism, there was little correspondence between the blood and CSF profiles of cytokines, chemokines, and growth factors, suggesting that peripheral markers may not optimally reflect the immune status of the central nervous system. Although the relatively high fraction of intrathecal production of selected chemokines involved in monocyte/microglia function may suggest a possible relationship with the homeostatic role of microglia, control data are needed for further interpretation of its relevance in autism. Conclusions: These longitudinal observations fail to provide support for the hypothesized role of disturbances in the expression of circulating cytokines and chemokines as an indicator of systemic inflammation in autism. ClinicalTrials. gov, NCT00298246. C1 [Pardo, Carlos A.; Ilieva, Jorjetta] Johns Hopkins Univ Sch Med, 627 Pathology Bld 6000 North Wolfe St, Baltimore, MD 21287 USA. [Farmer, Cristan A.; Thurm, Audrey; Kalra, Simran; Swedo, Susan] Natl Inst Mental Hlth, Pediatr & Dev Neurosci, Bethesda, MD USA. [Shebl, Fatma M.] Yale Univ, Yale Sch Publ Hlth, New Haven, CT USA. RP Pardo, CA (reprint author), Johns Hopkins Univ Sch Med, 627 Pathology Bld 6000 North Wolfe St, Baltimore, MD 21287 USA. EM cpardov1@jhmi.edu FU National Institute of Mental Health of the National Institutes of Health [ZIA MH002914]; Bart McLean Fund for Neuroimmunology Research; Johns Hopkins Project Restore FX This work was supported by the Intramural Research Program (ZIA MH002914) of the National Institute of Mental Health of the National Institutes of Health, and the Pardo lab is supported by the Bart McLean Fund for Neuroimmunology Research and Johns Hopkins Project Restore. NR 76 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 2040-2392 J9 MOL AUTISM JI Mol. Autism PD JAN 5 PY 2017 VL 8 DI 10.1186/s13229-016-0115-7 PG 14 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA EP0RH UT WOS:000397093900001 ER PT J AU Nickerson, ML Witte, N Im, KM Turan, S Owens, C Misner, K Tsang, SX Cai, Z Wu, S Dean, M Costello, JC Theodorescu, D AF Nickerson, M. L. Witte, N. Im, K. M. Turan, S. Owens, C. Misner, K. Tsang, S. X. Cai, Z. Wu, S. Dean, M. Costello, J. C. Theodorescu, D. TI Molecular analysis of urothelial cancer cell lines for modeling tumor biology and drug response SO ONCOGENE LA English DT Article ID INVASIVE BLADDER-CANCER; WHOLE-GENOME; IMPACT ANALYSIS; ANNOTATION; IDENTIFICATION; VISUALIZATION; SENSITIVITY; RESOURCE; GENES; CHEMOSENSITIVITY AB The utility of tumor-derived cell lines is dependent on their ability to recapitulate underlying genomic aberrations and primary tumor biology. Here, we sequenced the exomes of 25 bladder cancer (BCa) cell lines and compared mutations, copy number alterations (CNAs), gene expression and drug response to BCa patient profiles in The Cancer Genome Atlas (TCGA). We observed a mutation pattern associated with altered CpGs and APOBEC-family cytosine deaminases similar to mutation signatures derived from somatic alterations in muscle-invasive (Ml) primary tumors, highlighting a major mechanism(s) contributing to cancer associated alterations in the BCa cell line exomes. Non-silent sequence alterations were confirmed in 76 cancer-associated genes, including mutations that likely activate oncogenes TERT and PIK3CA, and alter chromatin-associated proteins (MLL3, ARID1A, CHD6 and KDM6A) and established BCa genes (TP53, RB1, CDKN2A and TSC1). We identified alterations in signaling pathways and proteins with related functions, including the PI3K/mTOR pathway, altered in 60% of lines; BRCA DNA repair, 44%; and SYNE1-SYNE2, 60%. Homozygous deletions of chromosome 9p21 are known to target the cell cycle regulators CDKN2A and CDKN2B. This loci was commonly lost in BCa cell lines and we show the deletions extended to the polyamine enzyme methylthioadenosine (MTA) phosphorylase (MTAP) in 36% of lines, transcription factor DMRTA1 (27%) and antiviral interferon epsilon (IFNE, 19%). Overall, the BCa cell line genomic aberrations were concordant with those found in BCa patient tumors. We used gene expression and copy number data to infer pathway activities for cell lines, then used the inferred pathway activities to build a predictive model of cisplatin response. When applied to platinum-treated patients gathered from TCGA, the model predicted treatment-specific response. Together, these data and analysis represent a valuable community resource to model basic tumor biology and to study the pharmacogenomics of BCa. C1 [Nickerson, M. L.; Turan, S.; Misner, K.; Dean, M.] NCI, Canc & Inflammat Program, NIH, Frederick, MD 21701 USA. [Witte, N.; Costello, J. C.] Univ Colorado, Computat Biosci Program, Aurora, CO USA. [Im, K. M.] Data Sci Genom LLC, Ellicott City, MD USA. [Owens, C.; Theodorescu, D.] Univ Colorado, Dept Surg Urol, Aurora, CO USA. [Tsang, S. X.] BGI Shenzhen, Shenzhen, Peoples R China. [Cai, Z.; Wu, S.] Shenzhen Second Peoples Hosp, Shenzhen, Peoples R China. [Costello, J. C.; Theodorescu, D.] Univ Colorado, Dept Pharmacol, Anschutz Med Campus,12801 E 17th Ave, Aurora, CO 80045 USA. [Costello, J. C.; Theodorescu, D.] Univ Colorado, Ctr Comprehens Canc, Anschutz Med Campus,13001 E 17th Pl,F-434, Aurora, CO 80045 USA. RP Costello, JC (reprint author), Univ Colorado, Dept Pharmacol, Anschutz Med Campus,12801 E 17th Ave, Aurora, CO 80045 USA.; Theodorescu, D (reprint author), Univ Colorado, Ctr Comprehens Canc, Anschutz Med Campus,13001 E 17th Pl,F-434, Aurora, CO 80045 USA. EM james.costello@ucdenver.edu; dan.theodorescu@ucdenver.edu FU NIH [CA143971, CA075115]; Intramural Research Program of the NIH; National Cancer Institute, Center for Cancer Research; National Library of Medicine T15 training grant [LM009451]; Shenzhen municipal science and technology project [CXZZ20140826163906370] FX We would like to thank Dr Neeraj Agarwal for providing the TERT experimental data. This work was in part supported by NIH grants CA143971 and CA075115 for DT; Intramural Research Program of the NIH, the National Cancer Institute, Center for Cancer Research for MLN and MD; National Library of Medicine T15 training grant LM009451 for NW; Shenzhen municipal science and technology project CXZZ20140826163906370 for SW. NR 56 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 5 PY 2017 VL 36 IS 1 BP 35 EP 46 DI 10.1038/onc.2016.172 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA EK6XJ UT WOS:000394069100004 PM 27270441 ER PT J AU Liu, Z Lam, N Wang, E Virden, RA Pawel, B Attiyeh, EF Maris, JM Thiele, CJ AF Liu, Z. Lam, N. Wang, E. Virden, R. A. Pawel, B. Attiyeh, E. F. Maris, J. M. Thiele, C. J. TI Identification of CASZ1 NES reveals potential mechanisms for loss of CASZ1 tumor suppressor activity in neuroblastoma SO ONCOGENE LA English DT Article ID NUCLEAR EXPORT SIGNALS; TRANSCRIPTION FACTOR; P53 TETRAMERIZATION; GENE-EXPRESSION; CRM1 INHIBITOR; DNA-DAMAGE; IN-VIVO; PROTEIN; LOCALIZATION; PHOSPHORYLATION AB As a transcription factor, localization to the nucleus and the recruitment of cofactors to regulate gene transcription is essential. Nuclear localization and nucleosome remodeling and histone deacetylase (NuRD) complex binding are required for the zinc-finger transcription factor CASZ1 to function as a neuroblastoma (NB) tumor suppressor. However, the critical amino acids (AAs) that are required for CASZ1 interaction with NuRD complex and the regulation of CASZ1 subcellular localization have not been characterized. Through alanine scanning, immunofluorescence cell staining and co-immunoprecipitation, we define a critical region at the CASZ1 N terminus (AAs 23-40) that mediates the CASZ1b nuclear localization and NuRD interaction. Furthermore, we identified a nuclear export signal (NES) at the N terminus (AAs 176-192) that contributes to CASZ1 nuclear-cytoplasmic shuttling in a chromosomal maintenance 1 -dependent manner. An analysis of CASZ1 protein expression in a primary NB tissue microarray shows that high nuclear CASZ1 staining is detected in tumor samples from NB patients with good prognosis. In contrast, cytoplasmic-restricted CASZ1 staining or low nuclear CASZ1 staining is found in tumor samples from patients with poor prognosis. These findings provide insight into mechanisms by which CASZ1 regulates transcription, and suggests that regulation of CASZ1 subcellular localization may impact its function in normal development and pathologic conditions such as NB tumorigenesis. C1 [Liu, Z.; Lam, N.; Wang, E.; Virden, R. A.; Thiele, C. J.] NCI, Pediat Oncol Branch, 9000 Rockville Pike,Bldg 10,Room 1W-3940,MSC 1105, Bethesda, MD 20892 USA. [Pawel, B.; Attiyeh, E. F.; Maris, J. M.] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Thiele, CJ (reprint author), NCI, Pediat Oncol Branch, 9000 Rockville Pike,Bldg 10,Room 1W-3940,MSC 1105, Bethesda, MD 20892 USA. EM thielec@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX We thank Dr Gregory Wray from the Institute for Genome Sciences and Policy, Duke University for generously providing the tyrosine hydroxylase promoter-pGL4.1-luc (TH-Luc) construct; Nisha Pawer and Neeraj Prasad of the POB, NCI for making the CASZ1b and mutant-EGFP constructs. We appreciate the insightful discussions with Drs Dinah Singer and David Levens of the CCR, NCI on this study. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute and Center for Cancer Research. NR 52 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 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JAN 5 PY 2017 VL 36 IS 1 BP 97 EP 109 DI 10.1038/onc.2016.179 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA EK6XJ UT WOS:000394069100009 PM 27270431 ER PT J AU van Rooij, FJA Qayyum, R Smith, AV Zhou, Y Trompet, S Tanaka, T Keller, MF Chang, LC Schmidt, H Yang, ML Chen, MH Hayes, J Johnson, AD Yanek, LR Mueller, C Lange, L Floyd, JS Ghanbari, M Zonderman, AB Jukema, JW Hofman, A van Duijn, CM Desch, KC Saba, Y Ozel, AB Snively, BM Wu, JY Schmidt, R Fornage, M Klein, RJ Fox, CS Matsuda, K Kamatani, N Wild, PS Stott, DJ Ford, I Slagboom, PE Yang, J Chu, AY Lambert, AJ Uitterlinden, AG Franco, OH Hofer, E Ginsburg, D Hu, B Keating, B Schick, UM Brody, JA Li, JZ Chen, Z Zeller, T Guralnik, JM Chasman, DI Peters, LL Kubo, M Becker, DM Li, J Eiriksdottir, G Rotter, JI Levy, D Grossmann, V Patel, KV Chen, CH Ridker, PM Tang, H Launer, LJ Rice, KM Li-Gao, R Ferrucci, L Evans, MK Choudhuri, A Trompouki, E Abraham, BJ Yang, S Takahashi, A Kamatani, Y Kooperberg, C Harris, TB Jee, SH Coresh, J Tsai, FJ Longo, DL Chen, YT Felix, JF Yang, Q Psaty, BM Boerwinkle, E Becker, LC Mook-Kanamori, DO Wilson, JG Gudnason, V O'Donnell, CJ Dehghan, A Cupples, LA Nalls, MA Morris, AP Okada, Y Reiner, AP Zon, LI Ganesh, SK AF van Rooij, Frank J. A. Qayyum, Rehan Smith, Albert V. Zhou, Yi Trompet, Stella Tanaka, Toshiko Keller, Margaux F. Chang, Li-Ching Schmidt, Helena Yang, Min-Lee Chen, Ming-Huei Hayes, James Johnson, Andrew D. Yanek, Lisa R. Mueller, Christian Lange, Leslie Floyd, James S. Ghanbari, Mohsen Zonderman, Alan B. Jukema, J. Wouter Hofman, Albert van Duijn, Cornelia M. Desch, Karl C. Saba, Yasaman Ozel, Ayse B. Snively, Beverly M. Wu, Jer-Yuarn Schmidt, Reinhold Fornage, Myriam Klein, Robert J. Fox, Caroline S. Matsuda, Koichi Kamatani, Naoyuki Wild, Philipp S. Stott, David J. Ford, Ian Slagboom, P. Eline Yang, Jaden Chu, Audrey Y. Lambert, Amy J. Uitterlinden, Andre G. Franco, Oscar H. Hofer, Edith Ginsburg, David Hu, Bella Keating, Brendan Schick, Ursula M. Brody, Jennifer A. Li, Jun Z. Chen, Zhao Zeller, Tanja Guralnik, Jack M. Chasman, Daniel I. Peters, Luanne L. Kubo, Michiaki Becker, Diane M. Li, Jin Eiriksdottir, Gudny Rotter, Jerome I. Levy, Daniel Grossmann, Vera Patel, Kushang V. Chen, Chien-Hsiun Ridker, Paul M. Tang, Hua Launer, Lenore J. Rice, Kenneth M. Li-Gao, Ruifang Ferrucci, Luigi Evans, Michelle K. Choudhuri, Avik Trompouki, Eirini Abraham, Brian J. Yang, Song Takahashi, Atsushi Kamatani, Yoichiro Kooperberg, Charles Harris, Tamara B. Jee, Sun Ha Coresh, Josef Tsai, Fuu-Jen Longo, Dan L. Chen, Yuan-Tsong Felix, Janine F. Yang, Qiong Psaty, Bruce M. Boerwinkle, Eric Becker, Lewis C. Mook-Kanamori, Dennis O. Wilson, James G. Gudnason, Vilmundur O'Donnell, Christopher J. Dehghan, Abbas Cupples, L. Adrienne Nalls, Michael A. Morris, Andrew P. Okada, Yukinori Reiner, Alexander P. Zon, Leonard I. Ganesh, Santhi K. CA BioBank Japan Project TI Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID RED-BLOOD-CELL; TRANSETHNIC METAANALYSIS; AFRICAN-AMERICANS; STEM-CELLS; ASSOCIATION; PROTEIN; HEMOGLOBIN; LINKAGE; DIFFERENTIATION; MICROARRAY AB Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits. C1 [van Rooij, Frank J. A.; Ghanbari, Mohsen; Hofman, Albert; van Duijn, Cornelia M.; Uitterlinden, Andre G.; Franco, Oscar H.; Felix, Janine F.; Dehghan, Abbas] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Qayyum, Rehan; Yanek, Lisa R.; Becker, Diane M.; Becker, Lewis C.] Johns Hopkins Univ, Sch Med, GeneSTAR Res Program, Baltimore, MD 21287 USA. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Smith, Albert V.; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, IS-210 Kopavogur, Iceland. [Zhou, Yi; Hu, Bella; Choudhuri, Avik; Yang, Song; Zon, Leonard I.] Harvard Univ, Harvard Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Zhou, Yi; Hu, Bella; Choudhuri, Avik; Trompouki, Eirini; Yang, Song; Zon, Leonard I.] Harvard Med Sch, Harvard Stem Cell Inst, Childrens Hosp Boston, Pediat Hematol Oncol DFCI,Stem Cell Program, Boston, MA 02115 USA. [Zhou, Yi; Hu, Bella; Choudhuri, Avik; Trompouki, Eirini; Yang, Song; Zon, Leonard I.] Harvard Med Sch, Harvard Stem Cell Inst, Childrens Hosp Boston, Pediat Hematol Oncol DFCI,Div Hematol Oncol, Boston, MA 02115 USA. [Zhou, Yi; Hu, Bella; Choudhuri, Avik; Trompouki, Eirini; Yang, Song; Zon, Leonard I.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 AC Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 AC Leiden, Netherlands. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. [Keller, Margaux F.; Nalls, Michael A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Chang, Li-Ching; Wu, Jer-Yuarn; Chen, Chien-Hsiun; Chen, Yuan-Tsong] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. [Schmidt, Helena; Saba, Yasaman] Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, A-8010 Graz, Austria. [Yang, Min-Lee; Ganesh, Santhi K.] Univ Michigan, Dept Human Genet, Dept Internal Med, Div Cardiovasc Med, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Ming-Huei; Johnson, Andrew D.; Fox, Caroline S.; Levy, Daniel; Yang, Qiong; O'Donnell, Christopher J.; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Populat Sci Branch, Div Intramural Res,NIH, Framingham, MA 01702 USA. [Hayes, James; Klein, Robert J.; Zeller, Tanja] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Icahn Inst Multiscale Biol, New York, NY 10029 USA. [Mueller, Christian; Zeller, Tanja] Univ Heart Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, D-20246 Hamburg, Germany. [Lange, Leslie] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Floyd, James S.; Brody, Jennifer A.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Ghanbari, Mohsen] Mashhad Univ Med Sci, Sch Med, Dept Genet, Mashhad 91375345, Iran. [Zonderman, Alan B.; Patel, Kushang V.] NIA, NIH, Bethesda, MD 20892 USA. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Desch, Karl C.; Ozel, Ayse B.; Ginsburg, David; Li, Jun Z.] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Snively, Beverly M.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA. [Wu, Jer-Yuarn; Chen, Chien-Hsiun; Tsai, Fuu-Jen] China Med Univ, Sch Chinese Med, Taichung 40402, Taiwan. [Schmidt, Reinhold; Hofer, Edith] Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, A-8010 Graz, Austria. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA. [Matsuda, Koichi] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Mol Med, Tokyo 1088639, Japan. [Kamatani, Naoyuki; Takahashi, Atsushi; Kamatani, Yoichiro; Okada, Yukinori] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa 2300045, Japan. [Wild, Philipp S.; Grossmann, Vera] Univ Med Ctr Mainz, CTH, D-55131 Mainz, Germany. [Wild, Philipp S.] German Ctr Cardiovasc Res DZHK, Partner Site RhineMain, Mainz, Germany. [Wild, Philipp S.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Ctr Cardiol, Prevent Cardiol & Prevent Med, D-55131 Mainz, Germany. [Stott, David J.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow G12 8QQ, Lanark, Scotland. [Slagboom, P. Eline] Leiden Univ, Med Ctr, Sect Mol Epidemiol, Dept Med Stat & Bioinformat, NL-2300 AC Leiden, Netherlands. [Yang, Jaden] Stanford Univ, Sch Med, Quantitat Sci Unit, Palo Alto, CA 94304 USA. [Chu, Audrey Y.; Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Chu, Audrey Y.; Chasman, Daniel I.; Ridker, Paul M.] Harvard Med Sch, Boston, MA 02215 USA. [Lambert, Amy J.; Peters, Luanne L.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Hofer, Edith] Med Univ Graz, Inst Med Informat Stat & Documentat, A-8010 Graz, Austria. [Keating, Brendan] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Keating, Brendan] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA. [Schick, Ursula M.; Reiner, Alexander P.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA. [Schick, Ursula M.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Chen, Zhao] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Dept Epidemiol & Biostat, Tucson, AZ 85724 USA. [Mueller, Christian] German Ctr Cardiovasc Res DZHK, Partner Site Hamburg, D-20246 Hamburg, Germany. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Chasman, Daniel I.] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Chasman, Daniel I.; Ridker, Paul M.] Harvard Med Sch, Boston, MA 02115 USA. [Kubo, Michiaki] RIKEN Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa 2300045, Japan. [Li, Jin] Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Palo Alto, CA 94304 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, LABioMed, Inst Translat Genom & Populat Sci, Dept Pediat, Torrance, CA 90502 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, LABioMed, Inst Translat Genom & Populat Sci, Dept Med, Torrance, CA 90502 USA. [Ridker, Paul M.] Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Tang, Hua] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Li-Gao, Ruifang; Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2300 AC Leiden, Netherlands. [Evans, Michelle K.] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Bethesda, MD 20892 USA. [Trompouki, Eirini] Max Planck Inst Immunobiol & Epigenet, D-79108 Freiburg, Germany. [Abraham, Brian J.] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. [Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Biostat & Biomath, Seattle, WA 98109 USA. [Jee, Sun Ha] Yonsei Univ, Grad Sch Publ Hlth, Inst Hlth Promot, Seoul 03722, South Korea. [Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, George W Comstock Ctr Publ Hlth Res & Prevent, Comstock Ctr & Cardiovasc Epidemiol, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [Longo, Dan L.] NIA, Lab Genet & Genom, NIH, Baltimore, MD 21225 USA. [Yang, Qiong; Cupples, L. Adrienne] Boston Univ Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Mook-Kanamori, Dennis O.] King Faisal Specialist Hosp & Res Ctr, Epidemiol Sect, Dept BESC, Riyadh, Saudi Arabia. [Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, NL-2300 AC Leiden, Netherlands. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Dehghan, Abbas] Imperial Coll, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Biostat & Epidemiol, London W2 1PG, England. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Block F,Waterhouse Bldg,1-5 Brownlow St, Liverpool L69 3GL, Merseyside, England. [Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England. [Okada, Yukinori] Osaka Univ, Grad Sch Med, Dept Stat Genet, Suita, Osaka 5650871, Japan. [Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Ganesh, SK (reprint author), Univ Michigan, Dept Human Genet, Dept Internal Med, Div Cardiovasc Med, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM sganesh@umich.edu RI Floyd, James/G-7563-2015 FU manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access project - Johnson Johnson FX B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access project funded by Johnson & Johnson. NR 67 TC 0 Z9 0 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN 5 PY 2017 VL 100 IS 1 BP 51 EP 63 DI 10.1016/j.ajhg.2016.11.016 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA EH6UX UT WOS:000391910500005 PM 28017375 ER PT J AU Chao, HT Davids, M Burke, E Pappas, JG Rosenfeld, JA McCarty, AJ Davis, T Wolfe, L Toro, C Tifft, C Xia, F Stong, N Johnson, TK Warr, CG Yamamoto, S Adams, DR Markello, TC Gahl, WA Bellen, HJ Wangler, MF Malicdan, MCV AF Chao, Hsiao-Tuan Davids, Mariska Burke, Elizabeth Pappas, John G. Rosenfeld, Jill A. McCarty, Alexandra J. Davis, Taylor Wolfe, Lynne Toro, Camilo Tifft, Cynthia Xia, Fan Stong, Nicholas Johnson, Travis K. Warr, Coral G. Yamamoto, Shinya Adams, David R. Markello, Thomas C. Gahl, William A. Bellen, Hugo J. Wangler, Michael F. Malicdan, May Christine V. CA Undiag Dis Network TI A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID LINKED MENTAL-RETARDATION; INTELLECTUAL DISABILITY; NEURONAL DIFFERENTIATION; TRANSCRIPTION FACTORS; TRUNCATING MUTATIONS; ABNORMAL GENITALIA; GENE; DROSOPHILA; ARX; FAMILY AB Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations. C1 [Chao, Hsiao-Tuan] Baylor Coll Med, Dept Pediat, Sect Child Neurol, Houston, TX 77030 USA. [Chao, Hsiao-Tuan; Yamamoto, Shinya; Bellen, Hugo J.; Wangler, Michael F.] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA. [Davids, Mariska; McCarty, Alexandra J.; Wolfe, Lynne; Toro, Camilo; Tifft, Cynthia; Adams, David R.; Markello, Thomas C.; Gahl, William A.; Malicdan, May Christine V.] NHGRI, Undiagnosed Dis Program, NIH Common Fund, Off Director,NIH, Bethesda, MD 20892 USA. [Burke, Elizabeth; Davis, Taylor; Wolfe, Lynne; Toro, Camilo; Tifft, Cynthia; Adams, David R.; Markello, Thomas C.; Gahl, William A.; Malicdan, May Christine V.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Pappas, John G.] NYU, Dept Pediat, Langone Med Ctr, New York, NY 10016 USA. [Rosenfeld, Jill A.; Xia, Fan; Yamamoto, Shinya; Bellen, Hugo J.; Wangler, Michael F.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Xia, Fan] Baylor Genet Labs, Houston, TX 77030 USA. [Stong, Nicholas] Columbia Univ, Inst Genom Med, New York, NY 10032 USA. [Johnson, Travis K.; Warr, Coral G.] Monash Univ, Sch Biol Sci, Melbourne, Vic 3800, Australia. [Yamamoto, Shinya; Bellen, Hugo J.] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. [Yamamoto, Shinya; Bellen, Hugo J.; Wangler, Michael F.] Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA. [Bellen, Hugo J.] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA. RP Wangler, MF (reprint author), Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA.; Malicdan, MCV (reprint author), NHGRI, Undiagnosed Dis Program, NIH Common Fund, Off Director,NIH, Bethesda, MD 20892 USA.; Malicdan, MCV (reprint author), NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA.; Wangler, MF (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. EM mw147467@bcm.edu; maychristine.malicdan@nih.gov OI Pappas, John/0000-0001-5625-2598 FU NIH [U54NS093793, R24OD022005, R01GM067858, U01HG007709]; Intramural Research Program of the National Human Genome Research Institute; Common Fund of the NIH Office of the Director; Wellcome Trust FX We thank the families and clinical staff at the Undiagnosed Diseases Program (UDP), Baylor College of Medicine (BCM), and New York University for participating in this study. This work was supported in part by NIH grants U54NS093793, R24OD022005, and R01GM067858 to H.J.B, by the Intramural Research Program of the National Human Genome Research Institute, and by the Common Fund of the NIH Office of the Director. H.J.B. is an investigator of the Howard Hughes Medical Institute (HHMI). F.X. and J.A.R. are supported by NIH grant U01HG007709. The Department of Molecular and Human Genetics at BCM derives revenue from the clinical exome sequencing offered at Baylor Genetics. We are thankful for the technical assistance provided by Y. Huang (NIH UDP Translational Laboratory) for Sanger sequencing; A. Weech (NIH UDP Translational Laboratory) for input on protein modeling; H. Pan (HHMI, BCM) for fly embryo injections; S. Nagarkar-Jaiswal, P. Lee, Y. He, J. Li, Z. Wang, Q. Gao, and L. Wang (BCM) for creating the 15,000 MIMIC insertion stocks; and W. Lin (BCM) for T2A-GAL4 conversion. We thank the Bloomington Drosophila Stock Center, Drosophila Genomics and Genetic Resources, and FIyORF for numerous stocks and the Developmental Studies Hybridoma Bank for antibodies. This study made use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available at http://decipher.sanger.ac.uk and via email at decipher@sanger.ac.uk. Funding for the project was provided by the Wellcome Trust. NR 56 TC 1 Z9 1 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN 5 PY 2017 VL 100 IS 1 BP 128 EP 137 DI 10.1016/j.ajhg.2016.11.018 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA EH6UX UT WOS:000391910500011 PM 28017372 ER PT J AU Wang, H Russell, LJ Kelly, KM Wang, S Thipphawong, J AF Wang, Hao Russell, Lucille J. Kelly, Kathleen M. Wang, Steven Thipphawong, John TI Fulranumab in patients with interstitial cystitis/bladder pain syndrome: observations from a randomized, double-blind, placebo-controlled study SO BMC UROLOGY LA English DT Article DE Fulranumab; Pain; Analgesia; Interstitial cystitis; Bladder ID NERVE GROWTH-FACTOR; CYSTITIS/PAINFUL BLADDER SYNDROME; PROOF-OF-CONCEPT; NEUROPATHIC PAIN; CLINICAL-TRIAL; EFFICACY; SAFETY; MANAGEMENT; TANEZUMAB; PREVALENCE AB Background: This study was designed to evaluate the efficacy and safety of fulranumab, a fully human monoclonal antibody directed against nerve growth factor (NGF), for pain relief in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). Methods: In this multicenter, double-blind study, adults with IC/BPS (i.e., interstitial cystitis symptom index [ ICSI] total score >= 8) accompanied by chronic, moderate-to-severe pain were randomized to fulranumab 9 mg or matching placebo, administered subcutaneously at weeks 1, 5, and 9. The primary efficacy endpoint was change from baseline to study endpoint (week 12 or at withdrawal) in average daily pain intensity score. Key secondary endpoints included change from baseline to study endpoint in worst pain intensity score, ICSI total score, Pelvic Pain and Urgency/Frequency total score, Patient Perception of Bladder Condition score, and global response assessment. Results: This study was terminated prematurely based on concern that this class may be associated with rapidly progressing osteoarthritis or osteonecrosis. Thirty-one patients (of the targeted 70 patients) were randomized, 17 to placebo and 14 to fulranumab, with 15 and 10 patients, respectively, receiving all 3 doses of double-blind treatment. In ANOVA analyses, there was no statistically significant difference between treatment groups for the primary endpoint (LS mean difference [95% CI] vs. placebo, -0.2 [-1.52, 1.10]) or any of the secondary endpoints. Fulranumab was well tolerated, with no patient discontinuing due to an adverse event or experiencing a joint-related serious adverse event over a 26-week follow-up period. No events related to the neurologic or motor systems were reported. Conclusions: Efficacy was not demonstrated in the present study with the single dose tested and a limited sample size, leading to lack of statistical power. These findings do not exclude the possibility that fulranumab would provide clinical benefit in a larger study and/or specific populations (phenotypes) in this difficult to treat pain condition. C1 [Russell, Lucille J.; Kelly, Kathleen M.; Wang, Steven; Thipphawong, John] Janssen Res & Dev LLC, Raritan, NJ 08869 USA. [Wang, Hao] NINDS, Off Translat Res, Bethesda, MD USA. RP Thipphawong, J (reprint author), Janssen Res & Dev LLC, Raritan, NJ 08869 USA. EM JThippha@its.jnj.com FU Janssen Research & Development, LLC FX This study was funded by Janssen Research & Development, LLC. NR 35 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 1471-2490 J9 BMC UROL JI BMC Urol. PD JAN 5 PY 2017 VL 17 AR 2 DI 10.1186/s12894-016-0193-z PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EH2ZR UT WOS:000391637800002 PM 28056917 ER PT J AU Jiang, ZP Heinrich, F McGlinchey, RP Gruschus, JM Lee, JC AF Jiang, Zhiping Heinrich, Frank McGlinchey, Ryan P. Gruschus, James M. Lee, Jennifer C. TI Segmental Deuteration of alpha-Synuclein for Neutron Reflectometry on Tethered Bilayers SO JOURNAL OF PHYSICAL CHEMISTRY LETTERS LA English DT Article ID PARKINSONS-DISEASE; LIPID MEMBRANES; IN-VITRO; BINDING; FLUORESCENCE; SPECTROSCOPY; REFLECTIVITY; AGGREGATION; BIOPHYSICS; SCATTERING AB Neutron reflectometry (NR) is uniquely suited for studying protein interaction with phospholipid bilayers along the bilayer normal on an angstrom scale. However, NR on its own cannot discern specific membrane-bound regions due to a lack of scattering contrast within a protein. Here we report the successful coupling of native chemical ligation (NCL) and NR to study a-synuclein (alpha-syn), a membrane-binding neuronal protein central in Parkinson's disease. Two alpha-syn variants were generated where either the first 86 or last 54 residues are deuterated, allowing for region-specific contrast within the protein and the identification of membrane interacting residues by NR Residues 1-86 are positioned at the hydrocarbon/headgroup interface of the outer leaflet, whereas the density distribution of the 54 C-terminal residues ranges from the hydrocarbon region to the aqueous environment. Coupling of NCL and NR should have broad utility in studies of membrane protein folding. C1 [Jiang, Zhiping; McGlinchey, Ryan P.; Gruschus, James M.; Lee, Jennifer C.] NHLBI, Lab Prot Conformat & Dynam, NIH, Bethesda, MD 20892 USA. [Heinrich, Frank] Carnegie Mellon Univ, Dept Phys, Pittsburgh, PA 15213 USA. [Heinrich, Frank] NIST, Gaithersburg, MD 20899 USA. RP Lee, JC (reprint author), NHLBI, Lab Prot Conformat & Dynam, NIH, Bethesda, MD 20892 USA. EM leej4@mail.nih.gov RI Heinrich, Frank/A-5339-2010 OI Heinrich, Frank/0000-0002-8579-553X FU Intramural Research Program at the NIH, NHLBI; NIST IMS program "Precision Measurements for Integral Membrane Proteins" FX This work is supported by the Intramural Research Program at the NIH, NHLBI and by the NIST IMS program "Precision Measurements for Integral Membrane Proteins". NR was performed on the NG-7 reflectometer at the NIST Neutron Center for Neutron Research and the NIST Center for Nanoscale Science and Technology. Parts of this research were performed at the NHLBI Biophysics (CD and DLS) and Biochemistry (ES-MS) Cores. We thank Nico Tjandra for the use of 800 MHz Bruker spectrometer. Certain commercial materials, equipment, and instruments are identified in this work to describe the experimental procedure as completely as possible. In no case does such an identification imply a recommendation or endorsement by NIST, nor does it imply that the materials, equipment, or instrument identified are necessarily the best available for the purpose. NR 42 TC 0 Z9 0 U1 9 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7185 J9 J PHYS CHEM LETT JI J. Phys. Chem. Lett. PD JAN 5 PY 2017 VL 8 IS 1 BP 29 EP 34 DI 10.1021/acs.jpclett.6b02304 PG 6 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Atomic, Molecular & Chemical SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EH3EJ UT WOS:000391653200005 PM 27936328 ER PT J AU Saloustros, E Liu, SS Mertz, EL Bhattacharyya, N Starost, MF Salpea, P Nesterova, M Collins, M Leikin, S Stratakis, CA AF Saloustros, Emmanouil Liu, Sisi Mertz, Edward L. Bhattacharyya, Nisan Starost, Matthew F. Salpea, Paraskevi Nesterova, Maria Collins, Michael Leikin, Sergey Stratakis, Constantine A. TI Celecoxib treatment of fibrous dysplasia (FD) in a human FD cell line and FD-like lesions in mice with protein kinase A (PKA) defects SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Cyclic AMP; Prostaglandin E2; Cyclooxygenase-2 (COX-2); Bone tumors; McCune-Albright syndrome; Carney complex ID TOTAL HIP-ARTHROPLASTY; CARNEY COMPLEX; CYCLIC-AMP; OSTEOBLAST LINEAGE; BONE; CANCER; PRKAR1A; MUTATIONS; ALPHA; DIFFERENTIATION AB Osteochondromyxomas (OMX) in the context of Carney complex (CNC) and fibrous dysplasia (FD)-like lesions (FDLL) in mice, as well as isolated myxomas in humans may be caused by inactivation of PRKAR1A, the gene coding for the type 1a regulatory subunit (R1 a) of cAMP dependent protein kinase (PKA). OMXs and FDLL in mice lacking Prkar1 alpha grow from abnormal proliferation of adult bone stromal cells (aBSCs). Prkarla and Prkaca (coding for C alpha) haploinsufficiency leads to COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of aBSC5. Celecoxib is a cyclooxygenase-2 (COX2) inhibitor. We hypothesized that COX-2 inhibition may have an effect in FD and FDLL. In vitro treatment of a human cell line prepared from a FD patient with Celecoxib resulted in decreased PGE2 and cell proliferation. Treatment of mice haploinsufficient for R1 alpha and C alpha with 1500 mg/ kg Celecoxib led to decreased PGE2 and proliferation and increased apoptosis, with a corresponding gene expression profile, resulting in dramatic reduction of tumor growth. Furthermore, the treatment improved the organization of cortical bone that was adjacent to the tumor. We conclude that, in vitro and in vivo, Celecoxib had an inhibitory effect on FD cell proliferation and in mouse FDLL structure, respectively. We speculate that COX-2 inhibitors offer an attractive alternative to current treatments for benign tumors such as OMX and FD that, apart from tumor suppression, may mechanically stabilize affected bones. Published by Elsevier Ireland Ltd. C1 [Saloustros, Emmanouil; Liu, Sisi; Salpea, Paraskevi; Nesterova, Maria; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet SEGEN, NIH, Bethesda, MD 20892 USA. [Mertz, Edward L.; Leikin, Sergey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Phys Biochem, Off Sci Director, NIH, Bethesda, MD 20892 USA. [Bhattacharyya, Nisan; Collins, Michael] NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Starost, Matthew F.] NIH, ORS, DVR, OD, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHD, SEGEN, PDEGEN, NIH,Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 1-3330,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov OI Saloustros, Emmanouil /0000-0002-0485-0120 FU Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD USA [Z01-HD008920-01]; Hellenic Society of Medical Oncology FX This work was supported by the Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) (Z01-HD008920-01), Bethesda, MD 20892 USA and a grant by the Hellenic Society of Medical Oncology (to Dr. Saloustros). NR 47 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JAN 5 PY 2017 VL 439 IS C BP 165 EP 174 DI 10.1016/j.mce.2016.08.004 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EH3CX UT WOS:000391647800018 PM 27498419 ER PT J AU Habib, T Sadoun, A Nader, N Suzuki, S Liu, W Jithesh, PV Kino, T AF Habib, Tanwir Sadoun, Ameera Nader, Nancy Suzuki, Shigeru Liu, Wei Jithesh, Puthen V. Kino, Tomoshige TI AKT1 has dual actions on the glucocorticoid receptor by cooperating with 14-3-3 SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Histone modification; Nuclear translocation; Phosphorylation; Protein-protein interaction; Transcriptomics ID ACUTE LYMPHOBLASTIC-LEUKEMIA; TRANSCRIPTIONAL ACTIVITY; SUBCELLULAR-LOCALIZATION; SIGNALING PATHWAY; INDUCED APOPTOSIS; SKELETAL-MUSCLE; BINDING DOMAINS; NUCLEAR EXPORT; PHOSPHORYLATION; PROTEIN AB Glucocorticoids are important therapeutic compounds for acute lymphoblastic leukemia (ALL). AIM or the protein kinase B is frequently activated in ALL, and contributes to the development of glucocorticoid resistance. We examined impact of AKT1 on glucocorticoid receptor (GR)-induced transcriptional activity in cooperation with phospho-serine/threonine-binding protein 14-3-3. AKT1 has two distinct actions on GR transcriptional activity, one through segregation of GR in the cytoplasm by phosphorylating GR at Ser-134 and subsequent association of 14-3-3, and the other through direct modulation of GR transcriptional activity in the nucleus. For the latter, AKT1 and 14-3-3 are attracted to DNA -bound GR, accompanied by AKT1-dependent p300 phosphorylation, H3S10 phosphorylation and H3K14 acetylation at the DNA site. These two actions of AKT1 regulate distinct sets of glucocorticoid-responsive genes. Our results suggest that specific inhibition of the AKT1/14-3-3 activity on the cytoplasmic retention of GR may be a promising target for treating glucocorticoid resistance observed in ALL (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Habib, Tanwir; Jithesh, Puthen V.] Sidra Med & Res Ctr, Div Syst Biol, Out Patient Clin, POB 26999,Al Luqta St,Educ City North Campus, Doha, Qatar. [Sadoun, Ameera; Kino, Tomoshige] Sidra Med & Res Ctr, Div Translat Med, Out Patient Clin, POB 26999,Al Luqta St,Educ City North Campus, Doha, Qatar. [Nader, Nancy] Weill Cornell Univ Qatar, Physiol & Biophys, POB 24144,Al Luqta St,Educ City North Campus, Doha, Qatar. [Suzuki, Shigeru; Kino, Tomoshige] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bldg 10,Rm 1-3140,10 Ctr Dr MSC 1109, Bethesda, MD 20892 USA. [Suzuki, Shigeru] Asahikawa Med Univ, Dept Pediat, Asahikawa, Hokkaido 0788510, Japan. [Liu, Wei] Sidra Med & Res Ctr, Div Genom Core, Out Patient Clin, POB 26999,Al Luqta St,Educ City North Campus, Doha, Qatar. RP Kino, T (reprint author), Sidra Med & Res Ctr, Div Translat Med, Out Patient Clin, POB 26999,Al Luqta St,Educ City North Campus, Doha, Qatar. EM thabib@sidra.org; asadoun@sidra.org; nan2017@qatar-med.cornell.edu; shige5p@asahikawa-med.ac.jp; wliu@sidra.org; pjithesh@sidra.org; tkino@sidra.org OI Jithesh, Puthen Veettil/0000-0001-7747-0930; Kino, Tomoshige/0000-0003-0220-9396 FU Intramural Research Program of the Sidra Medical and Research Center, Doha, Qatar; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD [Z01 HD008732-05 HNT] FX This study was funded by the Intramural Research Program of the Sidra Medical and Research Center, Doha, Qatar, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Z01 HD008732-05 HNT), National Institutes of Health, Bethesda, MD. NR 62 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JAN 5 PY 2017 VL 439 IS C BP 431 EP 443 DI 10.1016/j.mce.2016.10.002 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EH3CX UT WOS:000391647800044 PM 27717743 ER PT J AU Hanif, A Edin, ML Zeldin, DC Morisseau, C Falck, JR Nayeem, MA AF Hanif, Ahmad Edin, Matthew L. Zeldin, Darryl C. Morisseau, Christophe Falck, John R. Nayeem, Mohammed A. TI Vascular Endothelial Over-Expression of Human Soluble Epoxide Hydrolase (Tie2-sEH Tr) Attenuates Coronary Reactive Hyperemia in Mice: Role of Oxylipins and omega-Hydroxylases SO PLOS ONE LA English DT Article ID BLOOD-PRESSURE REGULATION; NITRIC-OXIDE SYNTHASE; SMOOTH-MUSCLE-CELLS; EPOXYEICOSATRIENOIC ACIDS; CARDIAC-HYPERTROPHY; PPAR-GAMMA; RECEPTORS; ACTIVATION; CHANNELS; DISEASE AB Cytochromes P450 metabolize arachidonic acid (AA) into two vasoactive oxylipins with opposing biologic effects: epoxyeicosatrienoic acids (EETs) and omega-(omega)-terminal hydroxyeicosatetraenoic acids (HETEs). EETs have numerous beneficial physiological effects, including vasodilation and protection against ischemia/reperfusion injury, whereas omega-terminal HETEs induce vasoconstriction and vascular dysfunction. We evaluated the effect of these oxylipins on post-ischemic vasodilation known as coronary reactive hyperemia (CRH). CRH prevents the potential harm associated with transient ischemia. The beneficial effects of EETs are reduced after their hydrolysis to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). omega-terminal HETEs are formed by omega-hydroxylase family members. The relationship among endothelial over-expression of sEH (Tie2-sEH Tr), the changes in oxylipins it may produce, the pharmacologic inhibition of omega-hydroxylases, activation of PPAR gamma, and CRH response to a brief ischemia is not known. We hypothesized that CRH is attenuated in isolated mouse hearts with endothelial sEH over-expression through modulation of oxylipin profiles, whereas both inhibition of omega-hydroxylases and activation of PPAR gamma enhance CRH. Compared to WT mice, Tie2-sEH Tr mice had decreased CRH, including repayment volume, repayment duration, and repayment/debt ratio (P < 0.05), whereas inhibition of omega-hydroxylases increased these same CRH parameters in Tie2-sEH Tr mice. Inhibition of sEH with t-AUCB reversed the decreased CRH in Tie2-sEH Tr mice. Endothelial over expression of sEH significantly changed oxylipin profiles, including decreases in DHETs, mid-chain HETEs, and prostaglandins (P < 0.05). Treatment with rosiglitazone, PPAR gamma-agonist, enhanced CRH (P < 0.05) in both Tie2-sEH Tr and wild type (WT) mice. These data demonstrate that endothelial over-expression of sEH (through changing the oxylipin profiles) attenuates CRH, whereas inhibition of omega-hydroxylases and activation of PPAR gamma enhance it. C1 [Hanif, Ahmad; Nayeem, Mohammed A.] West Virginia Univ, Ctr Basic & Translat Stroke Res, Sch Pharm, Basic Pharmaceut Sci, Morgantown, WV 26506 USA. [Edin, Matthew L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Morisseau, Christophe] Univ Calif Davis, 1 Shields Ave, Davis, CA 95616 USA. [Falck, John R.] Univ Texas Southwestern Med Ctr Dallas, Biochem, Dallas, TX 75390 USA. RP Nayeem, MA (reprint author), West Virginia Univ, Ctr Basic & Translat Stroke Res, Sch Pharm, Basic Pharmaceut Sci, Morgantown, WV 26506 USA. EM mnayeem@hsc.wvu.edu FU National Institutes of Health [HL-114559)]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES025034] FX This work was supported by National Institutes of Health (HL-114559) to MAN, and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES025034 to DCZ). 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 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 5 PY 2017 VL 12 IS 1 AR e0169584 DI 10.1371/journal.pone.0169584 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH3AE UT WOS:000391639100056 PM 28056085 ER PT J AU Mangino, M Roederer, M Beddall, MH Nestle, FO Spector, TD AF Mangino, Massimo Roederer, Mario Beddall, Margaret H. Nestle, Frank O. Spector, Tim D. TI Innate and adaptive immune traits are differentially affected by genetic and environmental factors SO NATURE COMMUNICATIONS LA English DT Article ID SYSTEM; AUTOIMMUNITY; DISEASE; TWIN AB The diversity and activity of leukocytes is controlled by genetic and environmental influences to maintain balanced immune responses. However, the relative contribution of environmental compared with genetic factors that affect variations in immune traits is unknown. Here we analyse 23,394 immune phenotypes in 497 adult female twins. 76% of these traits show a predominantly heritable influence, whereas 24% are mostly influenced by environment. These data highlight the importance of shared childhood environmental influences such as diet, infections or microbes in shaping immune homeostasis for monocytes, B1 cells, gamma delta Tcells and NKT cells, whereas dendritic cells, B2 cells, CD4(+) T and CD8(+) T cells are more influenced by genetics. Although leukocyte subsets are influenced by genetics and environment, adaptive immune traits are more affected by genetics, whereas innate immune traits are more affected by environment. C1 [Mangino, Massimo; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Mangino, Massimo; Nestle, Frank O.] Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London SE1 9RT, England. [Roederer, Mario; Beddall, Margaret H.] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20817 USA. [Nestle, Frank O.] Kings Coll London, St Johns Inst Dermatol, Cutaneous Med Unit, London SE1 9RT, England. RP Nestle, FO (reprint author), Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London SE1 9RT, England.; Roederer, M (reprint author), NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20817 USA.; Nestle, FO (reprint author), Kings Coll London, St Johns Inst Dermatol, Cutaneous Med Unit, London SE1 9RT, England. EM roederer@nih.gov; frank.nestle@kcl.ac.uk NR 12 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 JAN 5 PY 2017 VL 8 AR 13850 DI 10.1038/ncomms13850 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG6SQ UT WOS:000391176900001 PM 28054551 ER PT J AU Angmo, S Tripathi, N Abbat, S Sharma, S Singh, SS Halder, A Yadav, K Shukla, G Sandhir, R Rishi, V Bharatam, PV Yadav, H Singhal, NK AF Angmo, Stanzin Tripathi, Neha Abbat, Sheenu Sharma, Shailesh Singh, Shelley Sardul Halder, Avishek Yadav, Kamalendra Shukla, Geeta Sandhir, Rajat Rishi, Vikas Bharatam, Prasad V. Yadav, Hariom Singhal, Nitin Kumar TI Identification of Guanosine 5 '-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway SO SCIENTIFIC REPORTS LA English DT Article ID INFLAMMATION-INDUCED ANEMIA; CHRONIC DISEASE; DEFICIENCY ANEMIA; PEPTIDE HEPCIDIN; MOUSE MODEL; METABOLISM; EXPRESSION; GENE; INTERNALIZATION; MOLECULES AB Hepcidin, a peptide hormone, is a key regulator in mammalian iron homeostasis. Increased level of hepcidin due to inflammatory conditions stimulates the ferroportin (FPN) transporter internalization, impairing the iron absorption; clinically manifested as anemia of inflammation (AI). Inhibiting hepcidin-mediated FPN degradation is proposed as an important strategy to combat AI. A systematic approach involving in silico, in vitro, ex vivo and in vivo studies is employed to identify hepcidin-binding agents. The virtual screening of 68,752 natural compounds via molecular docking resulted into identification of guanosine 5'-diphosphate (GDP) as a promising hepcidin-binding agent. The molecular dynamics simulations helped to identify the important hepcidin residues involved in stabilization of hepcidin-GDP complex. The results gave a preliminary indication that GDP may possibly inhibit the hepcidin-FPN interactions. The in vitro studies revealed that GDP caused FPN stabilization (FPN-GFP cell lines) and increased the FPN-mediated cellular iron efflux (HepG2 and Caco-2 cells). Interestingly, the co-administration of GDP and ferrous sulphate (FeSO4) ameliorated the turpentine-induced AI in mice (indicated by increased haemoglobin level, serum iron, FPN expression and decreased ferritin level). These results suggest that GDP a promising natural small-molecule inhibitor that targets Hepcidin-FPN complex may be incorporated with iron supplement regimens to ameliorate AI. C1 [Angmo, Stanzin; Sharma, Shailesh; Singh, Shelley Sardul; Yadav, Kamalendra; Rishi, Vikas; Singhal, Nitin Kumar] Natl Agrifood Biotechnol Inst, Sas Nagar, Punjab, India. [Tripathi, Neha; Abbat, Sheenu; Bharatam, Prasad V.] NIPER, Sect 67, Sas Nagar, Punjab, India. [Halder, Avishek; Sandhir, Rajat] Panjab Univ, Dept Biochem, Chandigarh, India. [Shukla, Geeta] Panjab Univ, Dept Microbiol, Chandigarh, Punjab, India. [Yadav, Hariom] NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Singhal, NK (reprint author), Natl Agrifood Biotechnol Inst, Sas Nagar, Punjab, India.; Yadav, H (reprint author), NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM yadav@mail.nih.gov; nitin@nabi.res.in OI Yadav, Hariom/0000-0003-4504-1597 FU Department of Science and Technology (DST); Council of Scientific and Industrial Research, New Delhi, India; Department of Biotechnology (DBT); CSIR; University Grants Commission (UGC) FX Authors thank the Department of Science and Technology (DST) and the Council of Scientific and Industrial Research, New Delhi, India for financial support. Stanzin Angmo, Neha Tripathi, Sheenu Abbat and Avishek Halder thank Department of Biotechnology (DBT), CSIR and University Grants Commission (UGC) for their fellowships. NR 45 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 5 PY 2017 VL 7 AR 40097 DI 10.1038/srep40097 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG9NK UT WOS:000391385500001 PM 28054602 ER PT J AU Barski, A Cuddapah, S Kartashov, AV Liu, C Imamichi, H Yang, WJ Peng, WQ Lane, HC Zhao, KJ AF Barski, Artem Cuddapah, Suresh Kartashov, Andrey V. Liu, Chong Imamichi, Hiromi Yang, Wenjing Peng, Weiqun Lane, H. Clifford Zhao, Keji TI Rapid Recall Ability of Memory T cells is Encoded in their Epigenome SO SCIENTIFIC REPORTS LA English DT Article ID CYTOKINE GENE-EXPRESSION; TRANSCRIPTION FACTOR; CHIP-SEQ; HELPER-CELLS; HUMAN GENOME; RNA-SEQ; DIFFERENTIATION; ELEMENTS; ANTIGEN; LOCUS AB Even though T-cell receptor (TCR) stimulation together with co-stimulation is sufficient for the activation of both naive and memory T cells, the memory cells are capable of producing lineage specific cytokines much more rapidly than the naive cells. The mechanisms behind this rapid recall response of the memory cells are still not completely understood. Here, we performed epigenetic profiling of human resting naive, central and effector memory T cells using ChIP-Seq and found that unlike the naive cells, the regulatory elements of the cytokine genes in the memory T cells are marked by activating histone modifications even in the resting state. Therefore, the ability to induce expression of rapid recall genes upon activation is associated with the deposition of positive histone modifications during memory T cell differentiation. We propose a model of T cell memory, in which immunological memory state is encoded epigenetically, through poising and transcriptional memory. C1 [Barski, Artem; Kartashov, Andrey V.; Liu, Chong] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA. [Barski, Artem; Kartashov, Andrey V.; Liu, Chong] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Barski, Artem; Kartashov, Andrey V.; Liu, Chong] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA. [Cuddapah, Suresh] NYU, Sch Med, Dept Environm Med, Tuxedo Pk, NY 10987 USA. [Imamichi, Hiromi; Lane, H. Clifford] NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Yang, Wenjing; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Barski, A (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA.; Barski, A (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA.; Barski, A (reprint author), Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA.; Zhao, KJ (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM artem.barski@cchmc.org; zhaok@nhlbi.nih.gov FU NIH Director's New Innovator Award [DP2 GM119134]; NIH R01 grants [ES023174, ES024727]; NIH P30 grant [DK078392]; Division of Intramural Research of NHLBI; Division of Intramural Research of NIAID FX Authors thank David Hildeman (CCHMC) for critically reading the manuscript. This research was supported in part by NIH Director's New Innovator Award to AB DP2 GM119134, NIH R01 grants ES023174 and ES024727 to SC, P30 grant DK078392 and Divisions of Intramural Research of NHLBI and NIAID. NR 54 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 5 PY 2017 VL 7 AR 39785 DI 10.1038/srep39785 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG6UT UT WOS:000391182500001 PM 28054639 ER PT J AU Del Bello, F Bonifazi, A Giannella, M Giorgioni, G Piergentili, A Petrelli, R Cifani, C Di Bonaventura, MVM Keck, TM Mazzolari, A Vistoli, G Cilia, A Poggesi, E Matucci, R Quaglia, W AF Del Bello, Fabio Bonifazi, Alessandro Giannella, Mario Giorgioni, Gianfabio Piergentili, Alessandro Petrelli, Riccardo Cifani, Carlo Di Bonaventura, Maria Vittoria Micioni Keck, Thomas M. Mazzolari, Angelica Vistoli, Giulio Cilia, Antonio Poggesi, Elena Matucci, Rosanna Quaglia, Wilma TI The replacement of the 2-methoxy substituent of N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-ami ne improves the selectivity for 5-HT1A receptor over alpha(1)-adrenoceptor and D-2-like receptor subtypes SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE 5-HT1A receptor; alpha(1)-Adrenoceptor subtypes; D-2-like receptor subtypes; Selective 5-HT1A receptor agonists; Docking studies; Anxiolytic effect ID CENTRAL-NERVOUS-SYSTEM; ADRENERGIC-RECEPTOR; 1,4-DIOXANE RING; LIGANDS; ANTAGONISTS; SEROTONIN; DERIVATIVES; BINDING; POTENT; DOPAMINE AB N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine (3) is a potent 5-HT1A receptor and alpha(1d)-adrenoceptor (alpha(1d)-AR) ligand. Analogues 5-10 were rationally designed and prepared to evaluate whether electronic and/or lipophilic properties of substituents in the ortho position of its phenoxy moiety exert any favorable effects on the affinity/activity at 5-HT1A, receptor and improve selectivity over alpha(1)-ARs. To rationalize the experimental observations and derive information about receptor-ligand interactions of the reported ligands, docking studies, using 5-HT1A and alpha(1d)-AR models generated by homology techniques, and a retrospective computational study were performed. The results highlighted that proper substituents in position 2 of the phenoxy moiety of 3 selectively address the ligands toward 5-HT1A receptor with respect to alpha(1)-ARs and D-2-like receptor subtypes. Methoxymethylenoxy derivative 9 showed the best 5-HT1A selectivity profile and the highest potency at 5-HT1A receptor, behaving as a partial agonist. Finally, 9, tested in light/dark exploration test in mice, significantly reduced anxiety-linked behaviors. Therefore, it may be considered a lead for the design of partial agonists potentially useful in the treatment of disorders in which 5-HT1A receptor is involved. (C) 2016 Elsevier Masson SAS. All rights reserved. C1 [Del Bello, Fabio; Bonifazi, Alessandro; Giannella, Mario; Giorgioni, Gianfabio; Piergentili, Alessandro; Petrelli, Riccardo; Cifani, Carlo; Di Bonaventura, Maria Vittoria Micioni; Quaglia, Wilma] Univ Camerino, Scuola Sci Farmaco & Prod Salute, Via S Agostino 1, I-62032 Camerino, Italy. [Bonifazi, Alessandro; Keck, Thomas M.] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. [Keck, Thomas M.] Rowan Univ, Dept Chem & Biochem, Coll Sci & Math, 201 Mullica Hill Rd, Glassboro, NJ 08028 USA. [Keck, Thomas M.] Rowan Univ, Dept Biomed & Translat Sci, Coll Sci & Math, 201 Mullica Hill Rd, Glassboro, NJ 08028 USA. [Mazzolari, Angelica; Vistoli, Giulio] Univ Milan, Dipartimento Sci Farmaceut, Via Mangiagalli 25, I-20133 Milan, Italy. [Cilia, Antonio; Poggesi, Elena] Recordati SpA, Drug Discovery, Via Civitali 1, I-20148 Milan, Italy. [Matucci, Rosanna] Univ Firenze, Dipartimento Neurosci Psicol Area Farmaco & Salut, Sez Farmacol & Tossicol, Viale Pieraccini 6, I-50139 Florence, Italy. RP Quaglia, W (reprint author), Univ Camerino, Scuola Sci Farmaco & Prod Salute, Via S Agostino 1, I-62032 Camerino, Italy. EM wilma.quaglia@unicam.it FU University of Camerino (Fondo di Ateneo per la Ricerca); NIDA-IRP funds FX This work was supported by grants from the University of Camerino (Fondo di Ateneo per la Ricerca 2014-2015) and by NIDA-IRP funds (AB, TMK). We express our gratitude to Dr Amy H. Newman and Michael P. Ellenberger for their suggestions and comments for this manuscript. NR 41 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD JAN 5 PY 2017 VL 125 BP 233 EP 244 DI 10.1016/j.ejmech.2016.09.026 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EF7FX UT WOS:000390496600016 PM 27662034 ER PT J AU Jatoi, I Anderson, WF AF Jatoi, Ismail Anderson, William F. TI Breast-Cancer Tumor Size and Screening Effectiveness SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID OVERDIAGNOSIS C1 [Jatoi, Ismail] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Anderson, William F.] NCI, Bethesda, MD 20892 USA. RP Jatoi, I (reprint author), Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. EM jatoi@uthscsa.edu OI Brentnall, Adam/0000-0001-6327-4357 NR 3 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 5 PY 2017 VL 376 IS 1 BP 93 EP 93 DI 10.1056/NEJMc1614282 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EG6SS UT WOS:000391177100022 PM 28060474 ER PT J AU Welch, HG Prorok, PC Kramer, BS AF Welch, H. Gilbert Prorok, Philip C. Kramer, Barnett S. TI Breast-Cancer Tumor Size and Screening Effectiveness REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Welch, H. Gilbert] Dartmouth Inst Hlth Policy & Clin Practice, Hanover, NH 03755 USA. [Prorok, Philip C.; Kramer, Barnett S.] NCI, Bethesda, MD 20892 USA. RP Welch, HG (reprint author), Dartmouth Inst Hlth Policy & Clin Practice, Hanover, NH 03755 USA. EM h.gilbert.welch@dartmouth.edu NR 3 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 5 PY 2017 VL 376 IS 1 BP 94 EP 95 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EG6SS UT WOS:000391177100025 PM 28052230 ER PT J AU Nogueira, MAF Peer, CJ Nguyen, J McCalla, A Helman, L Figg, WD AF Ferraz Nogueira Filho, Marco A. Peer, Cody J. Nguyen, Jeffers McCalla, Amy Helman, Lee Figg, William D. TI A simple and rapid UHPLC-MS/MS method for the quantitation of the dual aurora kinase A/B inhibitor SCH-1473759 in murine plasma SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Aurora kinases; UHPLC-MS/MS pharmacokinetics; Mice ID SMALL-MOLECULE INHIBITOR; CELL-DIVISION; B KINASE; CHROMOSOMAL PASSENGERS; SELECTIVE INHIBITOR; PHASE-II; ALISERTIB; AZD1152; TUMORS; CANCER AB The Aurora kinase family facilitates cell division through various processes and is overexpressed in a wide variety of human cancers, leading to aneuploidy. For that reason, these enzymes are currently targets of a rising class of anticancer drugs, with some molecules already in therapeutic use. In this study, a new UHPLC-MS/MS method was developed and validated to quantitate a new pan Aurora kinase inhibitor still in preclinical development, SCH-1473759. This bioanalytical method employed a liquid-liquid extraction from plasma using ethyl acetate before evaporation. Calibration range encompassed 0.5-2500 ng/mL. The inter- and intra-day accuracy and precision were assessed over five quality control levels; all within limits required by the FDA guidelines. Assay applicability was demonstrated in a first-in-animals study with oral administration, where the maximum plasma concentration (34 ng/mL) occurred at 1 h, the half-life (1 h) was consistent with a previous IV study, and oral bioavailability was poor (F=0.002). (C) 2016 Published by Elsevier B.V. C1 [Ferraz Nogueira Filho, Marco A.; Peer, Cody J.; Nguyen, Jeffers; Figg, William D.] NCI, Clin Pharmacol Program, Off Clin Director, Bethesda, MD 20892 USA. [Ferraz Nogueira Filho, Marco A.] Minist Educ Brazil, CAPES Fdn, Brasilia, DF, Brazil. [McCalla, Amy; Helman, Lee] NCI, Mol Oncol Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), Clin Pharmacol Program, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov NR 19 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JAN 5 PY 2017 VL 132 BP 223 EP 226 DI 10.1016/j.jpba.2016.10.003 PG 4 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA ED7DK UT WOS:000389015700030 ER PT J AU Agarwala, R Barrett, T Beck, J Benson, DA Bollin, C Bolton, E Bourexis, D Brister, JR Bryant, SH Canese, K Charowhas, C Clark, K DiCuccio, M Dondoshansky, I Feolo, M Funk, K Geer, LY Gorelenkov, V Hlavina, W Hoeppner, M Holmes, B Johnson, M Khotomlianski, V Kimchi, A Kimelman, M Kitts, P Klimke, W Krasnov, S Kuznetsov, A Landrum, MJ Landsman, D Lee, JM Lipman, DJ Lu, ZY Madden, TL Madej, T Marchler-Bauer, A Karsch-Mizrachi, I Murphy, T Orris, R Ostell, J O'Sullivan, C Palanigobu, V Panchenko, AR Phan, L Pruitt, KD Rodarmer, K Rubinstein, W Sayers, EW Schneider, V Schoch, CL Schuler, GD Sherry, ST Sirotkin, K Siyan, K Slotta, D Soboleva, A Soussov, V Starchenko, G Tatusova, T Todorov, K Trawick, BW Vakatov, D Wang, YL Ward, M Wilbur, WJ Yaschenko, E Zbicz, K AF Agarwala, Richa Barrett, Tanya Beck, Jeff Benson, Dennis A. Bollin, Colleen Bolton, Evan Bourexis, Devon Brister, J. Rodney Bryant, Stephen H. Canese, Kathi Charowhas, Chad Clark, Karen DiCuccio, Michael Dondoshansky, Ilya Feolo, Michael Funk, Kathryn Geer, Lewis Y. Gorelenkov, Viatcheslav Hlavina, Wratko Hoeppner, Marilu Holmes, Brad Johnson, Mark Khotomlianski, Viatcheslav Kimchi, Avi Kimelman, Michael Kitts, Paul Klimke, William Krasnov, Sergey Kuznetsov, Anatoliy Landrum, Melissa J. Landsman, David Lee, Jennifer M. Lipman, David J. Lu, Zhiyong Madden, Thomas L. Madej, Tom Marchler-Bauer, Aron Karsch-Mizrachi, Ilene Murphy, Terence Orris, Rebecca Ostell, James O'Sullivan, Christopher Palanigobu, Vasuki Panchenko, Anna R. Phan, Lon Pruitt, Kim D. Rodarmer, Kurt Rubinstein, Wendy Sayers, Eric W. Schneider, Valerie Schoch, Conrad L. Schuler, Gregory D. Sherry, Stephen T. Sirotkin, Karl Siyan, Karanjit Slotta, Douglas Soboleva, Alexandra Soussov, Vladimir Starchenko, Grigory Tatusova, TatianaA. Todorov, Kamen Trawick, Bart W. Vakatov, Denis Wang, Yanli Ward, Minghong Wilbur, W. John Yaschenko, Eugene Zbicz, Kerry CA NCBI Resource Coordinators TI Database Resources of the National Center for Biotechnology SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SEQUENCE; TOOL AB The National Center for Biotechnology Information (NCBI) provides a large suite of online resources for biological information and data, including the GenBank((R)) nucleic acid sequence database and the PubMed database of citations and abstracts for published life science journals. The Entrez system provides search and retrieval operations for most of these data from 37 distinct databases. The E-utilities serve as the programming interface for the Entrez system. Augmenting many of the Web applications are custom implementations of the BLAST program optimized to search specialized data sets. New resources released in the past year include iCn3D, MutaBind, and the Antimicrobial Resistance Gene Reference Database; and resources that were updated in the past year include My Bibliography, SciENcv, the Pathogen Detection Project, Assembly, Genome, the Genome Data Viewer, BLAST and PubChem. All of these resources can be accessed through the NCBI home page at www.ncbi.nlm.nih.gov. C1 [Sayers, Eric W.; NCBI Resource Coordinators] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. RP Sayers, EW (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM sayers@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 11 TC 0 Z9 0 U1 1 U2 1 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 JAN 4 PY 2017 VL 45 IS D1 BP D12 EP D17 DI 10.1093/nar/gkw1071 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500002 ER PT J AU Benson, DA Cavanaugh, M Clark, K Karsch-Mizrachi, I Lipman, DJ Ostell, J Sayers, EW AF Benson, Dennis A. Cavanaugh, Mark Clark, Karen Karsch-Mizrachi, Ilene Lipman, David J. Ostell, James Sayers, Eric W. TI GenBank SO NUCLEIC ACIDS RESEARCH LA English DT Article ID NCBI TAXONOMY DATABASE; SINGLE-MOLECULE; DNA; ARCHIVE; GENOMES; BLAST AB GenBank((R)) (www.ncbi.nlm.nih.gov/genbank/) is a comprehensive database that contains publicly available nucleotide sequences for 370 000 formally described species. These sequences are obtained primarily through submissions from individual laboratories and batch submissions from large-scale sequencing projects, including whole genome shotgun (WGS) and environmental sampling projects. Most submissions are made using the web-based BankIt or the NCBI Submission Portal. GenBank staff assign accession numbers upon data receipt. Daily data exchange with the European Nucleotide Archive (ENA) and the DNA Data Bank of Japan (DDBJ) ensures worldwide coverage. GenBank is accessible through the NCBI Nucleotide database, which links to related information such as taxonomy, genomes ,protein sequences and structures, and biomedical journal literature in PubMed. BLAST provides sequence similarity searches of GenBank and other sequence databases. Complete bimonthly releases and daily updates of the GenBank database are available by FTP. Recent updates include changes to policies regarding sequence identifiers, an improved 16S submission wizard, targeted loci studies, the ability to submit methylation and BioNano mapping files, and a database of anti-microbial resistance genes. C1 [Benson, Dennis A.; Cavanaugh, Mark; Clark, Karen; Karsch-Mizrachi, Ilene; Lipman, David J.; Ostell, James; Sayers, Eric W.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. RP Sayers, EW (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM sayers@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 19 TC 1 Z9 1 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 JAN 4 PY 2017 VL 45 IS D1 BP D37 EP D42 DI 10.1093/nar/gkw1070 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500006 PM 27899564 ER PT J AU Nguyen, DT Mathias, S Bologa, C Brunak, S Fernandez, N Gaulton, A Hersey, A Holmes, J Jensen, LJ Karlsson, A Liu, GX Ma'ayan, A Mandava, G Mani, S Mehta, S Overington, J Patel, J Rouillard, AD Schurer, S Sheils, T Simeonov, A Sklar, LA Southall, N Ursu, O Vidovic, D Waller, A Yang, J Jadhav, A Oprea, TI Guha, R AF Dac-Trung Nguyen Mathias, Stephen Bologa, Cristian Brunak, Soren Fernandez, Nicolas Gaulton, Anna Hersey, Anne Holmes, Jayme Jensen, Lars Juhl Karlsson, Anneli Liu, Guixia Ma'ayan, Avi Mandava, Geetha Mani, Subramani Mehta, Saurabh Overington, John Patel, Juhee Rouillard, Andrew D. Schurer, Stephan Sheils, Timothy Simeonov, Anton Sklar, Larry A. Southall, Noel Ursu, Oleg Vidovic, Dusica Waller, Anna Yang, Jeremy Jadhav, Ajit Oprea, Tudor I. Guha, Rajarshi TI Pharos: Collating protein information to shed light on the druggable genome SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DATABASE; ONTOLOGY; TARGETS; BIOLOGY; UPDATE AB The 'druggable genome' encompasses several protein families, but only a subset of targets within them have attracted significant research attention and thus have information about them publicly available. The Illuminating the Druggable Genome (IDG) program was initiated in 2014, has the goal of developing experimental techniques and a Knowledge Management Center (KMC) that would collect and organize information about protein targets from four families, representing the most common druggable targets with an emphasis on understudied proteins. Here, we describe two resources developed by the KMC: the Target Central Resource Database (TCRD) which collates many heterogeneous gene/protein datasets and Pharos (https://pharos.nih.gov), a multimodal web interface that presents the data from TCRD. We briefly describe the types and sources of data considered by the KMC and then highlight features of the Pharos interface designed to enable intuitive access to the IDG knowledgebase. The aim of Pharos is to encourage 'serendipitous browsing', whereby related, relevant information is made easily discoverable. We conclude by describing two use cases that highlight the utility of Pharos and TCRD. C1 [Dac-Trung Nguyen; Mandava, Geetha; Sheils, Timothy; Simeonov, Anton; Southall, Noel; Jadhav, Ajit; Guha, Rajarshi] Natl Ctr Advancing Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. [Fernandez, Nicolas; Ma'ayan, Avi; Rouillard, Andrew D.] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, Mt Sinai Ctr Bioinformat, One Gustave L Levy Pl,Box 1603, New York, NY 10029 USA. [Mathias, Stephen; Bologa, Cristian; Holmes, Jayme; Liu, Guixia; Mani, Subramani; Patel, Juhee; Sklar, Larry A.; Ursu, Oleg; Waller, Anna; Yang, Jeremy; Oprea, Tudor I.] Univ New Mexico, Sch Med, Translat Informat Div, Albuquerque, NM 87131 USA. [Sklar, Larry A.; Waller, Anna] Univ New Mexico, Ctr Canc, Ctr Mol Discovery, Albuquerque, NM 87131 USA. [Mehta, Saurabh; Schurer, Stephan; Vidovic, Dusica] Univ Miami, Ctr Computat Sci, Coral Gables, FL 33146 USA. [Mehta, Saurabh] Delhi Technol Univ, Dept Appl Chem, Delhi 110042, India. [Schurer, Stephan; Vidovic, Dusica] Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL 33136 USA. [Brunak, Soren; Jensen, Lars Juhl] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Prot Res, DK-2200 Copenhagen, Denmark. [Gaulton, Anna; Hersey, Anne] European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Hinxton CB10 1SD, Cambs, England. [Liu, Guixia] East China Univ Sci & Technol, Dept Pharmaceut Sci, Shanghai, Peoples R China. [Patel, Juhee] Univ New Mexico, Sch Med, BA MD Program, Albuquerque, NM 87131 USA. [Karlsson, Anneli; Overington, John] BenevolentAI, 40 Churchway, London NW1 1LW, England. RP Guha, R (reprint author), Natl Ctr Advancing Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA.; Oprea, TI (reprint author), Univ New Mexico, Sch Med, Translat Informat Div, Albuquerque, NM 87131 USA. EM toprea@salud.unm.edu; guhar@mail.nih.gov OI Overington, John/0000-0002-5859-1064 FU National Institutes of Health (NIH) Common Fund [CA189205]; NIH Common Fund [CA189201]; Novo Nordisk Foundation [NNF14CC0001]; NIH FX National Institutes of Health (NIH) Common Fund [CA189205 to T.O.]; NIH Common Fund [CA189201 to A.M.]; Novo Nordisk Foundation [NNF14CC0001 to S.B. and L.J.J.]. Intramural Research Program, NCATS [DTN, GM, TS, AS, NS, AJ, RG]. Funding for open access charge: NIH. NR 22 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 JAN 4 PY 2017 VL 45 IS D1 BP D995 EP D1002 DI 10.1093/nar/gkw1072 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500137 PM 27903890 ER PT J AU Finn, RD Attwood, TK Babbitt, PC Bateman, A Bork, P Bridge, AJ Chang, HY Dosztanyi, Z El-Gebali, S Fraser, M Gough, J Haft, D Holliday, GL Huang, HZ Huang, XS Letunic, I Lopez, R Lu, SN Marchler-Bauer, A Mi, HY Mistry, J Natale, DA Necci, M Nuka, G Orengo, CA Park, Y Pesseat, S Piovesan, D Potter, SC Rawlings, ND Redaschi, N Richardson, L Rivoire, C Sangrador-Vegas, A Sigrist, C Sillitoe, I Smithers, B Squizzato, S Sutton, G Thanki, N Thomas, PD Tosatto, SCE Wu, CH Xenarios, I Yeh, LS Young, SY Mitchell, AL AF Finn, Robert D. Attwood, Teresa K. Babbitt, Patricia C. Bateman, Alex Bork, Peer Bridge, Alan J. Chang, Hsin-Yu Dosztanyi, Zsuzsanna El-Gebali, Sara Fraser, Matthew Gough, Julian Haft, David Holliday, Gemma L. Huang, Hongzhan Huang, Xiaosong Letunic, Ivica Lopez, Rodrigo Lu, Shennan Marchler-Bauer, Aron Mi, Huaiyu Mistry, Jaina Natale, Darren A. Necci, Marco Nuka, Gift Orengo, Christine A. Park, Youngmi Pesseat, Sebastien Piovesan, Damiano Potter, Simon C. Rawlings, Neil D. Redaschi, Nicole Richardson, Lorna Rivoire, Catherine Sangrador-Vegas, Amaia Sigrist, Christian Sillitoe, Ian Smithers, Ben Squizzato, Silvano Sutton, Granger Thanki, Narmada Thomas, Paul D. Tosatto, Silvio C. E. Wu, Cathy H. Xenarios, Ioannis Yeh, Lai-Su Young, Siew-Yit Mitchell, Alex L. TI InterPro in 2017-beyond protein family and domain annotations SO NUCLEIC ACIDS RESEARCH LA English DT Article ID METABOLIC PATHWAYS; DATABASE; RESOURCE; GENOME; CLASSIFICATION; DISORDER; GENE; PREDICTION; SEQUENCES; SYSTEM AB InterPro (http://www.ebi.ac.uk/interpro/) is a freely available database used to classify protein sequences into families and to predict the presence of important domains and sites. InterProScan is the underlying software that allows both protein and nucleic acid sequences to be searched against InterPro's predictive models, which are provided by its member databases. Here, we report recent developments with InterPro and its associated software, in-cluding the addition of two new databases (SFLD and CDD), and the functionality to include residue-level annotation and prediction of intrinsic disorder. These developments enrich the annotations provided by InterPro, increase the overall number of residues annotated and allow more specific functional inferences. C1 [Finn, Robert D.; Bateman, Alex; Chang, Hsin-Yu; El-Gebali, Sara; Fraser, Matthew; Lopez, Rodrigo; Mistry, Jaina; Nuka, Gift; Park, Youngmi; Pesseat, Sebastien; Potter, Simon C.; Rawlings, Neil D.; Richardson, Lorna; Sangrador-Vegas, Amaia; Squizzato, Silvano; Young, Siew-Yit; Mitchell, Alex L.] EBI, EMBL, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England. [Attwood, Teresa K.] Univ Manchester, Sch Comp Sci, Manchester, Lancs, England. [Babbitt, Patricia C.; Holliday, Gemma L.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Bork, Peer] European Mol Biol Lab, Biocomp, Meyerhofstasse 1, D-69117 Heidelberg, Germany. [Bridge, Alan J.; Redaschi, Nicole; Rivoire, Catherine; Sigrist, Christian; Xenarios, Ioannis] CMU, SIB, Swiss Prot Grp, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland. [Dosztanyi, Zsuzsanna] Eotvos Lorand Univ, Dept Biochem, MTA ELTE Lendulet Bioinformat Res Grp, Pazmany Peter Setany 1-C, Budapest, Hungary. [Gough, Julian; Smithers, Ben] Univ Bristol, Dept Comp Sci, Woodland Rd, Bristol BS8 1UB, Avon, England. [Haft, David; Sutton, Granger] J Craig Venter Inst, Bioinformat Dept, 9714 Med Ctr Dr, Rockville, MD 20850 USA. [Huang, Hongzhan; Wu, Cathy H.] Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19711 USA. [Huang, Xiaosong; Mi, Huaiyu; Thomas, Paul D.] Univ Southern Calif, Dept Prevent Med, Div Bioinformat, Los Angeles, CA 90033 USA. [Letunic, Ivica] Biobyte Solut GmbH, Bothestr 142, D-69126 Heidelberg, Germany. [Lu, Shennan; Marchler-Bauer, Aron; Thanki, Narmada] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH Bldg,38A,8600 Rockville Pike, Bethesda, MD 20894 USA. [Natale, Darren A.; Yeh, Lai-Su] Georgetown Univ, Med Ctr, 3300 Whitehaven St NW, Washington, DC 20007 USA. [Necci, Marco; Piovesan, Damiano; Tosatto, Silvio C. E.] Univ Padua, Dept Biomed Sci, Via U Bassi 58-B, I-35131 Padua, Italy. [Necci, Marco; Piovesan, Damiano; Tosatto, Silvio C. E.] Univ Padua, CRIBI Biotech Ctr, Via U Bassi 58-B, I-35131 Padua, Italy. [Orengo, Christine A.; Sillitoe, Ian] UCL, Struct & Mol Biol, Darwin Bldg, London WC1E 6BT, England. [Tosatto, Silvio C. E.] CNR, Inst Neurosci, Via U Bassi 58-B, I-35131 Padua, Italy. RP Finn, RD (reprint author), EBI, EMBL, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England. EM rdf@ebi.ac.uk OI Bridge, Alan/0000-0003-2148-9135 FU BBSRC [BB/L024136/1, BB/N00521X/1]; Wellcome Trust [108433/Z/15/Z]; National Sciences Foundation [DBI 1458808]; Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS; COST Action [BM1405]; European Molecular Biology Laboratories core funds; Research Councils UK FX BBSRC [BB/L024136/1, BB/N00521X/1]; Wellcome Trust [108433/Z/15/Z]; National Sciences Foundation [DBI 1458808]; Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS; COST Action [BM1405]; European Molecular Biology Laboratories core funds. Funding for open access charge: Research Councils UK. NR 47 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 JAN 4 PY 2017 VL 45 IS D1 BP D190 EP D199 DI 10.1093/nar/gkw1107 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500029 PM 27899635 ER PT J AU Galperin, MY Fernandez-Suarez, XM Rigden, DJ AF Galperin, Michael Y. Fernandez-Suarez, Xose M. Rigden, Daniel J. TI The 24th annual Nucleic Acids Research database issue: a look back and upcoming changes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PROTEIN FAMILIES DATABASE; MODEL ORGANISM DATABASE; GENOME DATABASE; FUNCTIONAL ANNOTATIONS; INFORMATION RESOURCE; INTERACTION NETWORKS; ANALYSIS TOOLS; THE DATABASE; 2016 UPDATE; DATA-BANK AB This year's Database Issue of Nucleic Acids Re-search contains 152 papers that include descriptions of 54 new databases and update papers on 98 databases, of which 16 have not been previously featured in NAR. As always, these databases cover a broad range of molecular biology subjects, including genome structure, gene expression and its regulation, proteins, protein domains, and protein-protein interactions. Following the recent trend, an increasing number of new and established databases deal with the issues of human health, from cancer causing mutations to drugs and drug targets. In accordance with this trend, three recently compiled databases that have been selected by NAR reviewers and editors as `breakthrough' contributions, DENOVODB, the Monarch Initiative, and Open Targets, cover human de novo gene variants, disease-related phenotypes in model organisms, and a bioinformatics platform for therapeutic target identification and validation, respectively. We expect these databases to attract the attention of numerous researchers working in various areas of genetics and genomics. Looking back at the past 12 years, we present here the 'golden set' of databases that have consistently served as authoritative, comprehensive, and convenient data resources widely used by the entire community and offer some lessons on what makes a successful database. The Database Issue is freely available online at the https://academic.oup.com/narwebsite. An updated version of the NAR Molecular Biology Database Collection is available at http://www.oxfordjournals.org/nar/database/a/. C1 [Galperin, Michael Y.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Fernandez-Suarez, Xose M.] Thermo Fisher Sci, Inchinnan Business Pk, Paisley PA4 9RF, Renfrew, Scotland. [Rigden, Daniel J.] Univ Liverpool, Inst Integrat Biol, Crown St, Liverpool L69 7ZB, Merseyside, England. RP Galperin, MY (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA.; Rigden, DJ (reprint author), Univ Liverpool, Inst Integrat Biol, Crown St, Liverpool L69 7ZB, Merseyside, England. EM nardatabase@gmail.com; drigden@liv.ac.uk OI Galperin, Michael/0000-0002-2265-5572 FU NIH Intramural Research Program at the National Library of Medicine FX The NIH Intramural Research Program at the National Library of Medicine (to M.Y.G.). The open access publication charge for this paper has been waived by Oxford University Press. NR 116 TC 0 Z9 0 U1 1 U2 1 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 JAN 4 PY 2017 VL 45 IS D1 BP D1 EP D11 DI 10.1093/nar/gkw1188 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500001 PM 28053160 ER PT J AU Grazziotin, AL Koonin, EV Kristensen, DM AF Grazziotin, Ana Laura Koonin, Eugene V. Kristensen, David M. TI Prokaryotic Virus Orthologous Groups (pVOGs): a resource for comparative genomics and protein family annotation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID STRANDED DNA VIRUSES; VIRAL GENOMES; CLUSTERS; BACTERIOPHAGES; EVOLUTION; GENES; CLASSIFICATION; RECONSTRUCTION; METAGENOMES; REPERTOIRE AB Viruses are the most abundant and diverse biological entities on earth, and while most of this diversity remains completely unexplored, advances in genome sequencing have provided unprecedented glimpses into the virosphere. The Prokaryotic Virus Orthologous Groups (pVOGs, formerly called Phage Orthologous Groups, POGs) resource has aided in this task over the past decade by using automated methods to keep pace with the rapid increase in genomic data. The uses of pVOGs include functional annotation of viral proteins, identification of genes and viruses in uncharacterized DNA samples, phylogenetic analysis, large-scale comparative genomics projects, and more. The pVOGs database represents a comprehensive set of orthologous gene families shared across multiple complete genomes of viruses that infect bacterial or archaeal hosts (viruses of eukaryotes will be added at a future date). The pVOGs are constructed within the Clusters of Orthologous Groups (COGs) framework that is widely used for orthology identification in prokaryotes. Since the previous release of the POGs, the size has tripled to nearly 3000 genomes and 300 000 proteins, and the number of conserved orthologous groups doubled to 9518. User-friendly webpages are available, including multiple sequence alignments and HMM profiles for each VOG. These changes provide major improvements to the pVOGs database, at a time of rapid advances in virus genomics. The pVOGs database is hosted jointly at the University of Iowa at http://dmk-brain.ecn.uiowa.edu/pVOGs and the NCBI at ftp://ftp.ncbi.nlm.nih.gov/pub/kristensen/pVOGs/home.html. C1 [Grazziotin, Ana Laura; Kristensen, David M.] Univ Iowa, Dept Biomed Engn, Coll Engn, Iowa City, IA 52242 USA. [Koonin, Eugene V.; Kristensen, David M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Kristensen, DM (reprint author), Univ Iowa, Dept Biomed Engn, Coll Engn, Iowa City, IA 52242 USA.; Kristensen, DM (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM david-kristensen@uiowa.edu FU Department of Biomedical Engineering at the University of Iowa (Iowa City, USA); Intramural Research Program of the National Library of Medicine at the National Institutes of Health (NIH) (Bethesda, USA); NIH FX D.M.K. and A.L.G. are supported by the Department of Biomedical Engineering at the University of Iowa (Iowa City, USA). E.V.K. is supported by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health (NIH) (Bethesda, USA). Funding for open access charge: NIH. NR 50 TC 0 Z9 0 U1 3 U2 3 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 JAN 4 PY 2017 VL 45 IS D1 BP D491 EP D498 DI 10.1093/nar/gkw975 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500070 PM 27789703 ER PT J AU Hatcher, EL Zhdanov, SA Bao, YM Blinkova, O Nawrocki, EP Ostapchuck, Y Schaffer, AA Brister, JR AF Hatcher, Eneida L. Zhdanov, Sergey A. Bao, Yiming Blinkova, Olga Nawrocki, Eric P. Ostapchuck, Yuri Schaffer, Alejandro A. Brister, J. Rodney TI Virus Variation Resource - improved response to emergent viral outbreaks SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GROUP-A ROTAVIRUSES; WEST NILE VIRUS; GENOME ANNOTATION; BIOTECHNOLOGY INFORMATION; NATIONAL CENTER; SEQUENCE; DATABASE; WEB; CLASSIFICATION AB The Virus Variation Resource is a value-added viral sequence data resource hosted by the National Center for Biotechnology Information. The resource is located at http://www.ncbi.nlm.nih.gov/genome/viruses/variation/ and includes modules for seven viral groups: influenza virus, Dengue virus, West Nile virus, Ebolavirus, MERS coronavirus, Rotavirus A and Zika virus. Each module is supported by pipelines that scan newly released GenBank records, annotate genes and proteins and parse sample descriptors and then map them to controlled vocabulary. These processes in turn support a purpose-built search interface where users can select sequences based on standardized gene, protein and metadata terms. Once sequences are selected, a suite of tools for downloading data, multi-sequence alignment and tree building supports a variety of user directed activities. This manuscript describes a series of features and functionalities recently added to the Virus Variation Resource. C1 [Hatcher, Eneida L.; Zhdanov, Sergey A.; Bao, Yiming; Blinkova, Olga; Nawrocki, Eric P.; Ostapchuck, Yuri; Schaffer, Alejandro A.; Brister, J. Rodney] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Brister, JR (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM jamesbr@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health; National Library of Medicine FX Intramural Research Program of the National Institutes of Health; National Library of Medicine. Funding for open access charge: Intramural Research Program of the National Institutes of Health; National Library of Medicine. NR 32 TC 0 Z9 0 U1 1 U2 1 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 JAN 4 PY 2017 VL 45 IS D1 BP D482 EP D490 DI 10.1093/nar/gkw1065 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500069 PM 27899678 ER PT J AU Kristensen, DM Wolf, YI Koonin, EV AF Kristensen, David M. Wolf, Yuri I. Koonin, Eugene V. TI ATGC database and ATGC-COGs: an updated resource for micro- and macro-evolutionary studies of prokaryotic genomes and protein family annotation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MAXIMUM-LIKELIHOOD; ARCHAEAL GENOMES; BACTERIAL; GENES; ISLANDS; SYSTEMS; SEARCH; BLAST; TREES; LIFE AB The Alignable Tight Genomic Clusters (ATGCs) database is a collection of closely related bacterial and archaeal genomes that provides several tools to aid research into evolutionary processes in the microbialworld. Each ATGC is a taxonomy-independent cluster of 2 or more completely sequenced genomes that meet the objective criteria of a high degree of local gene order (synteny) and a small number of synonymous substitutions in the protein-coding genes. As such, each ATGC is suited for analysis of microevolutionary variations within a cohesive group of organisms (e.g. species), whereas the entire collection of ATGCs is useful for macroevolutionary studies. The ATGC database includes many forms of pre-computed data, in particular ATGC-COGs (Clusters of Orthologous Genes), multiple sequence alignments, a set of 'index' orthologs representing the most well-conserved members of each ATGC-COG, the phylogenetic tree of the organisms within each ATGC, etc. Although the ATGC database contains several million proteins from thousands of genomes organized into hundreds of clusters (roughly a 4-fold increase since the last version of the ATGC database), it is now built with completely automated methods and will be regularly updated following new releases of the NCBI RefSeq database. The ATGC database is hosted jointly at the University of Iowa at dmk-brain.ecn.uiowa.edu/ATGC/ and the NCBI at ftp.ncbi.nlm.nih.gov/pub/kristensen/ATGC/atgc_home.html. C1 [Kristensen, David M.] Univ Iowa, Dept Biomed Engn, Iowa City, IA 52242 USA. [Kristensen, David M.; Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Kristensen, DM (reprint author), Univ Iowa, Dept Biomed Engn, Iowa City, IA 52242 USA.; Kristensen, DM (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM david-kristensen@uiowa.edu FU Intramural Research Program of the U.S. National Institutes of Health at the National Library of Medicine; Department of Biomedical Engineering at the University of Iowa (IowaCity, USA); NIH FX Intramural Research Program of the U.S. National Institutes of Health at the National Library of Medicine (to D.M.K. and E.V.K.); Department of Biomedical Engineering at the University of Iowa (IowaCity, USA) (to D.M.K.). Funding for open access charge: NIH. NR 41 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 JAN 4 PY 2017 VL 45 IS D1 BP D210 EP D218 DI 10.1093/nar/gkw934 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500032 PM 28053163 ER PT J AU Lea, IA Gong, H Paleja, A Rashid, A Fostel, J AF Lea, Isabel A. Gong, Hui Paleja, Anand Rashid, Asif Fostel, Jennifer TI CEBS: a comprehensive annotated database of toxicological data SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BIOLOGICAL-SYSTEMS; RAT-LIVER; DESIGN; TOXICOGENOMICS; METABOLITES; MICROARRAY; TOXICITY; ASSAYS AB The Chemical Effects in Biological Systems database (CEBS) is a comprehensive and unique toxicology resource that compiles individual and summary animal data from the National Toxicology Program (NTP) testing program and other depositors into a single electronic repository. CEBS has undergone significant updates in recent years and currently contains over 11 000 test articles (exposure agents) and over 8000 studies including all available NTP car-cinogenicity, short-term toxicity and genetic toxicity studies. Study data provided to CEBS are manually curated, accessioned and subject to quality assurance review prior to release to ensure high quality. The CEBS database has two main components: data collection and data delivery. To accommodate the breadth of data produced by NTP, the CEBS data collection component is an integrated relational design that allows the flexibility to capture any type of electronic data ( to date). The data delivery component of the database comprises a series of dedicated user interface tables containing pre-processed data that support each component of the user interface. The user interface has been updated to include a series of nine Guided Search tools that allow access to NTP summary and conclusion data and larger non-NTP datasets. The CEBS database can be accessed online at http://www.niehs.nih.gov/research/resources/databases/cebs/. C1 [Lea, Isabel A.; Gong, Hui; Paleja, Anand; Rashid, Asif] ASRCFed Vistronix, 430 Davis Dr,Suite 260, Morrisville, NC 27569 USA. [Fostel, Jennifer] NIEHS, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. RP Lea, IA (reprint author), ASRCFed Vistronix, 430 Davis Dr,Suite 260, Morrisville, NC 27569 USA.; Fostel, J (reprint author), NIEHS, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM Isabel.lea@nih.gov; fostel@niehs.nih.gov FU ASRC Federal Vistronix under National Institute of Environmental Health Sciences (NIEHS) [HHSN31620120054W, HHSN273201000063U GS06F0629Z]; National Institute of Environmental Health Sciences FX ASRC Federal Vistronix under National Institute of Environmental Health Sciences (NIEHS) contracts 'Support for Toxicological Data for the National Toxicology Program (NTP)' [HHSN31620120054W and HHSN273201000063U GS06F0629Z]. Funding for open access charge: National Institute of Environmental Health Sciences. NR 25 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 JAN 4 PY 2017 VL 45 IS D1 BP D964 EP D971 DI 10.1093/nar/gkw1077 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500133 PM 27899660 ER PT J AU MacArthur, J Bowler, E Cerezo, M Gil, L Hall, P Hastings, E Junkins, H McMahon, A Milano, A Morales, J Pendlington, ZM Welter, D Burdett, T Hindorff, L Flicek, P Cunningham, F Parkinson, H AF MacArthur, Jacqueline Bowler, Emily Cerezo, Maria Gil, Laurent Hall, Peggy Hastings, Emma Junkins, Heather McMahon, Aoife Milano, Annalisa Morales, Joannella Pendlington, Zoe May Welter, Danielle Burdett, Tony Hindorff, Lucia Flicek, Paul Cunningham, Fiona Parkinson, Helen TI The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog) SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DIABETES SUSCEPTIBILITY; LOCI; METAANALYSIS; UPDATE; VARIANTS; DISEASES; DATABASE; INSIGHT; TRAITS; RISK AB The NHGRI-EBI GWAS Catalog has provided data from published genome-wide association studies since 2008. In 2015, the database was redesigned and relocated to EMBL-EBI. The new infrastructure includes a new graphical user interface (www.ebi.ac.uk/gwas/), ontology supported search functionality and an improved curation interface. These developments have improved the data release frequency by increasing automation of curation and providing scaling improvements. The range of available Catalog data has also been extended with structured ancestry and recruitment information added for all studies. The infrastructure improvements also support scaling for larger arrays, exome and sequencing studies, allowing the Catalog to adapt to the needs of evolving study design, genotyping technologies and user needs in the future. C1 [MacArthur, Jacqueline; Bowler, Emily; Cerezo, Maria; Gil, Laurent; Hastings, Emma; McMahon, Aoife; Milano, Annalisa; Morales, Joannella; Pendlington, Zoe May; Welter, Danielle; Burdett, Tony; Flicek, Paul; Cunningham, Fiona; Parkinson, Helen] European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England. [Hall, Peggy; Junkins, Heather; Hindorff, Lucia] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. RP Parkinson, H (reprint author), European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England. EM parkinson@ebi.ac.uk OI Welter, Danielle/0000-0003-1058-2668 FU National Human Genome Research Institute; National Heart, Lung and Blood Institute; National Institutes of Health Common Fund [U54-HG004028, U41-HG006104, U41-HG007823]; European Molecular Biology Laboratory; National Institutes of Health FX National Human Genome Research Institute, National Heart, Lung and Blood Institute; National Institutes of Health Common Fund [U54-HG004028, U41-HG006104, U41-HG007823]; European Molecular Biology Laboratory; L.H., P.H. and H.J. are employees of the National Human Genome Research Institute. Funding for open access charge: National Institutes of Health. NR 21 TC 1 Z9 1 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 JAN 4 PY 2017 VL 45 IS D1 BP D896 EP D901 DI 10.1093/nar/gkw1133 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500124 PM 27899670 ER PT J AU Marchler-Bauer, A Bo, Y Han, LY He, JE Lanczycki, CJ Lu, SN Chitsaz, F Derbyshire, MK Geer, RC Gonzales, NR Gwadz, M Hurwitz, DI Lu, F Marchler, GH Song, JS Thanki, N Wang, ZX Yamashita, RA Zhang, DC Zheng, CJ Geer, LY Bryant, SH AF Marchler-Bauer, Aron Bo, Yu Han, Lianyi He, Jane Lanczycki, Christopher J. Lu, Shennan Chitsaz, Farideh Derbyshire, Myra K. Geer, Renata C. Gonzales, Noreen R. Gwadz, Marc Hurwitz, David I. Lu, Fu Marchler, Gabriele H. Song, James S. Thanki, Narmada Wang, Zhouxi Yamashita, Roxanne A. Zhang, Dachuan Zheng, Chanjuan Geer, Lewis Y. Bryant, Stephen H. TI CDD/SPARCLE: functional classification of proteins via subfamily domain architectures SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DATABASE AB NCBI's Conserved Domain Database (CDD) aims at annotating biomolecular sequences with the location of evolutionarily conserved protein domain footprints, and functional sites inferred from such footprints. An archive of pre-computed domain annotation is maintained for proteins tracked by NCBI's Entrez database, and live search services are offered as well. CDD curation staff supplements a comprehensive collection of protein domain and protein family models, which have been imported from external providers, with representations of selected domain families that are curated in-house and organized into hierarchical classifications of functionally distinct families and sub-families. CDD also supports comparative analyses of protein families via conserved domain architectures, and a recent curation effort focuses on providing functional characterizations of distinct subfamily architectures using SPARCLE: Subfamily Protein Architecture Labeling Engine. C1 [Marchler-Bauer, Aron; Bo, Yu; Han, Lianyi; He, Jane; Lanczycki, Christopher J.; Lu, Shennan; Chitsaz, Farideh; Derbyshire, Myra K.; Geer, Renata C.; Gonzales, Noreen R.; Gwadz, Marc; Hurwitz, David I.; Lu, Fu; Marchler, Gabriele H.; Song, James S.; Thanki, Narmada; Wang, Zhouxi; Yamashita, Roxanne A.; Zhang, Dachuan; Zheng, Chanjuan; Geer, Lewis Y.; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38 A,Room 8N805,8600 Rockville Pike, Bethesda, MD 20894 USA. RP Marchler-Bauer, A (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38 A,Room 8N805,8600 Rockville Pike, Bethesda, MD 20894 USA. EM bauer@ncbi.nlm.nih.gov FU Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS; Intramural Research Program of the National Library of Medicine, National Institutes of Health FX Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS. Funding for open access charge: Intramural Research Program of the National Library of Medicine, National Institutes of Health. NR 9 TC 0 Z9 0 U1 5 U2 5 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 JAN 4 PY 2017 VL 45 IS D1 BP D200 EP D203 DI 10.1093/nar/gkw1129 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500030 PM 27899674 ER PT J AU Van Doorslaer, K Li, Z Xirasagar, S Maes, P Kaminsky, D Liou, D Sun, Q Kaur, R Huyen, Y McBride, AA AF Van Doorslaer, Koenraad Li, Zhiwen Xirasagar, Sandhya Maes, Piet Kaminsky, David Liou, David Sun, Qiang Kaur, Ramandeep Huyen, Yentram McBride, Alison A. TI The Papillomavirus Episteme: a major update to the papillomavirus sequence database SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CAPSID PROTEIN; E7 PROTEINS; E5 PROTEINS; CLASSIFICATION; E6; LOCALIZATION; PERFORMANCE; EXPRESSION AB The Papillomavirus Episteme (PaVE) is a database of curated papillomavirus genomic sequences, accompanied by web-based sequence analysis tools. This update describes the addition of major new features. The papillomavirus genomes within PaVE have been further annotated, and now includes the major spliced mRNA transcripts. Viral genes and transcripts can be visualized on both linear and circular genome browsers. Evolutionary relationships among PaVE reference protein sequences can be analysed using multiple sequence alignments and phylogenetic trees. To assist in viral discovery, PaVE offers a typing tool; a simplified algorithm to determine whether a newly sequenced virus is novel. PaVE also now contains an image library containing gross clinical and histopathological images of papillomavirus infected lesions. Database URL: https://pave.niaid.nih.gov/. C1 [Van Doorslaer, Koenraad; McBride, Alison A.] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Viral Dis Lab, IDNA Tumor Virus Sect, Bethesda, MD 20989 USA. [Li, Zhiwen; Xirasagar, Sandhya; Kaminsky, David; Liou, David; Sun, Qiang; Kaur, Ramandeep; Huyen, Yentram] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Bioinformat & Computat Biosciences Branch, Off Cyber Infrastructure & Computat Biol, Bethesda, MD 20989 USA. [Maes, Piet] Katholieke Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, Lab Clin Virol, B-3000 Leuven, Belgium. RP McBride, AA (reprint author), Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Viral Dis Lab, IDNA Tumor Virus Sect, Bethesda, MD 20989 USA.; McBride, AA (reprint author), Univ Arizona, Sch Anim & Comparat Biomed Sci, Koenraad Doorslaer, Tucson, AZ USA.; McBride, AA (reprint author), Intel Corp, Yentram Huyen, Amer Hlth & Life Sci Solut & Strategy, Fairfax, VA USA. EM amcbride@nih.gov FU Intramural Research Program of the National Institutes of Allergy and Infectious Diseases [1ZIAAI001071]; BCBB Support Services Contract-National Institutes of Allergy and Infectious Diseases, National Institutes of Health [GS35F0373X]; National Institutes of Allergy and Infectious Diseases [1ZIAAI001071] FX Intramural Research Program [1ZIAAI001071] of the National Institutes of Allergy and Infectious Diseases; BCBB Support Services Contract [GS35F0373X] funded by the National Institutes of Allergy and Infectious Diseases, National Institutes of Health. Funding for open access charge: National Institutes of Allergy and Infectious Diseases [1ZIAAI001071]. NR 46 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 JAN 4 PY 2017 VL 45 IS D1 BP D499 EP D506 DI 10.1093/nar/gkw879 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500071 PM 28053164 ER PT J AU Wang, YL Bryant, SH Cheng, TJ Wang, JY Gindulyte, A Shoemaker, BA Thiessen, PA He, SQ Zhang, J AF Wang, Yanli Bryant, Stephen H. Cheng, Tiejun Wang, Jiyao Gindulyte, Asta Shoemaker, Benjamin A. Thiessen, Paul A. He, Siqian Zhang, Jian TI PubChem BioAssay: 2017 update SO NUCLEIC ACIDS RESEARCH LA English DT Article ID 6-PHOSPHOGLUCONATE DEHYDROGENASE; TUMOR-GROWTH; DNA-REPAIR; DATABASE; PROTEIN; DISCOVERY; SCREENS; PHARMACOLOGY; INFORMATION; RECEPTORS AB PubChem's BioAssay database (https://pubchem.ncbi.nlm.nih.gov) has served as a public repository for small-molecule and RNAi screening data since 2004 providing open access of its data content to the community. PubChem accepts data submission from worldwide researchers at academia, industry and government agencies. PubChem also collaborates with other chemical biology database stake-holders with data exchange. With over a decade's development effort, it becomes an important information resource supporting drug discovery and chemical biology research. To facilitate data discovery, PubChem is integrated with all other databases at NCBI. In this work, we provide an update for the PubChem BioAssay database describing several recent development including added sources of research data, redesigned BioAssay record page, new BioAssay classification browser and new features in the Upload system facilitating data sharing. C1 [Wang, Yanli; Bryant, Stephen H.; Cheng, Tiejun; Wang, Jiyao; Gindulyte, Asta; Shoemaker, Benjamin A.; Thiessen, Paul A.; He, Siqian; Zhang, Jian] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Wang, YL; Bryant, SH (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Library of Medicine (NLM); National Center for Biotechnology Information (NCBI) FX Intramural Research Program of the National Institutes of Health (NIH); National Library of Medicine (NLM). Funding for open access charge: National Center for Biotechnology Information (NCBI). NR 38 TC 1 Z9 1 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 JAN 4 PY 2017 VL 45 IS D1 BP D955 EP D963 DI 10.1093/nar/gkw1118 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500132 PM 27899599 ER PT J AU Wong, KM Langlais, K Tobias, GS Fletcher-Hoppe, C Krasnewich, D Leeds, HS Rodriguez, LL Godynskiy, G Schneider, VA Ramos, EM Sherry, ST AF Wong, Kira M. Langlais, Kristofor Tobias, Geoffrey S. Fletcher-Hoppe, Colette Krasnewich, Donna Leeds, Hilary S. Rodriguez, Laura Lyman Godynskiy, Georgy Schneider, Valerie A. Ramos, Erin M. Sherry, Stephen T. TI The dbGaP data browser: a new tool for browsing dbGaP controlled-access genomic data SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PHENOTYPES; GENOTYPES; ARCHIVE AB The database of Genotypes and Phenotypes (dbGaP) Data Browser (https://www.ncbi.nlm.nih.gov/gap/ddb/) was developed in response to requests from the scientific community for a resource that enable view-only access to summary-level information and individual-level genotype and sequence data associated with phenotypic features maintained in the controlled-access tier of dbGaP. Until now, the dbGaP controlled-access environment required investigators to submit a data access request, wait for Data Access Committee review, download each data set and locally examine them for potentially relevant information. Existing unrestricted-access genomic data browsing resources (e.g.http://evs.gs.washington.edu/EVS/,http://exac.broadinstitute.org/) provide only summary statistics or aggregate allele frequencies. The dbGaP Data Browser serves as a third solution, providing researchers with view-only access to a compilation of individual-level data from general research use (GRU) studies through a simplified controlled-access process. The National Institutes of Health (NIH) will continue to improve the Browser in response to user feedback and believes that this tool may decrease unnecessary download requests, while still facilitating responsible genomic data-sharing. C1 [Wong, Kira M.; Fletcher-Hoppe, Colette; Rodriguez, Laura Lyman; Ramos, Erin M.] Natl Human Genome Res Inst, Natl Inst Hlth, Bethesda, MD 20814 USA. [Langlais, Kristofor; Leeds, Hilary S.] Natl Inst Hlth, Off Sci Policy, Bethesda, MD 20814 USA. [Tobias, Geoffrey S.] Natl Canc Inst, Natl Inst Hlth, Bethesda, MD 20892 USA. [Krasnewich, Donna] Natl Inst Gen Med Sci, Natl Inst Hlth, Bethesda, MD 20892 USA. [Godynskiy, Georgy; Schneider, Valerie A.; Sherry, Stephen T.] Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Ramos, EM (reprint author), Natl Human Genome Res Inst, Natl Inst Hlth, Bethesda, MD 20814 USA.; Sherry, ST (reprint author), Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM ramoser@mail.nih.gov; sherry@ncbi.nlm.nih.gov FU Intramural Research Program of the National Library of Medicine at the National Institutes of Health (NIH); Intramural Research Program of the National Institutes of Health, National Library of Medicine FX Intramural Research Program of the National Library of Medicine at the National Institutes of Health (NIH) [in part]. Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. 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 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 4 PY 2017 VL 45 IS D1 BP D819 EP D826 DI 10.1093/nar/gkw1139 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500114 PM 27899644 ER PT J AU Tejeda, HA Wu, J Kornspun, AR Pignatelli, M Kashtelyan, V Krashes, MJ Lowell, BB Carlezon, WA Bonci, A AF Tejeda, Hugo A. Wu, Jocelyn Kornspun, Alana R. Pignatelli, Marco Kashtelyan, Vadim Krashes, Michael J. Lowell, Brad B. Carlezon, William A., Jr. Bonci, Antonello TI Pathway-and Cell-Specific Kappa-Opioid Receptor Modulation of Excitation-Inhibition Balance Differentially Gates D1 and D2 Accumbens Neuron Activity SO NEURON LA English DT Article ID LONG-TERM DEPRESSION; MESSENGER-RNA EXPRESSION; NUCLEUS-ACCUMBENS; DOPAMINE NEURONS; PROJECTION NEURONS; SPINY NEURONS; SYNAPTIC-TRANSMISSION; PARKINSONS-DISEASE; COCAINE REWARD; PLACE AVERSION AB Endogenous dynorphin signaling via the kappa-opioid receptor (KOR) in the nucleus accumbens (NAcc) powerfully mediates negative affective states and stress reactivity. Excitatory inputs from the hippocampus and amygdala play a fundamental role in shaping the activity of both NAcc D1 and D2 MSNs, which encode positive and negative motivational valences, respectively. However, a circuit-based mechanism by which KOR modulation of excitation-inhibition balance modifies D1 and D2 MSN activity is lacking. Here, we provide a comprehensive synaptic framework wherein presynaptic KOR inhibition decreases the excitatory drive of D1 MSN activity by the amygdala, but not the hippocampus. Conversely, presynaptic inhibition by KORs of inhibitory synapses on D2 MSNs enhances integration of excitatory drive by the amygdala and hippocampus. In conclusion, we describe a circuit-based mechanism showing differential gating of afferent control of D1 and D2 MSN activity by KORs in a pathway-specific manner. C1 [Tejeda, Hugo A.; Wu, Jocelyn; Kornspun, Alana R.; Pignatelli, Marco; Krashes, Michael J.; Bonci, Antonello] NIDA, Synapt Plast Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Kashtelyan, Vadim] NIDA, Neuronal Networks Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Krashes, Michael J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Lowell, Brad B.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Carlezon, William A., Jr.] Harvard Med Sch, McLean Hosp, Dept Psychiat, Behav Genet Lab, Belmont, MA 02578 USA. [Bonci, Antonello] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. RP Bonci, A (reprint author), NIDA, Synapt Plast Sect, Intramural Res Program, Baltimore, MD 21224 USA.; Bonci, A (reprint author), Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. EM antonello.bonci@nih.gov FU NIDA Intramural Research Program; NIH; NIDDK [R01 DK096010, R01 DK089044, R01 DK071051, R01 DK075632] FX We thank members of the Bonci laboratory, Drs. Alex Hoffman, Carl Lupica, and Roy Wise, for helpful discussions. We thank Drs. Yeka Aponte and Zheng-Xiong Xi for sharing equipment. We thank Dr. Marisela Morales for reagents, resources, and guidance on FG and radioactive in situ hybridization experiments. We thank Drs. Carlos Mejias-Aponte, Bing Liu, and Hui-Ling Wang for assistance with FG and radioactive in situ hybridization experiments. We thanks Drs. Robert Steiner and Sasha Kauffman for generously providing KOR cDNA. We thank Drs. Bruce Cohen, Anita Bechtholt, and Ashlee Van't Veer for their roles in developing KOR-floxed mice. This work was funded by the NIDA Intramural Research Program and grants to B.B.L. from the NIH and NIDDK (R01 DK096010, R01 DK089044, R01 DK071051, and R01 DK075632). NR 60 TC 0 Z9 0 U1 1 U2 1 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 4 PY 2017 VL 93 IS 1 BP 147 EP 163 DI 10.1016/j.neuron.2016.12.005 PG 17 WC Neurosciences SC Neurosciences & Neurology GA EO0ZR UT WOS:000396427800015 PM 28056342 ER PT J AU Hong, SG Yada, RC Choi, K Carpentier, A Liang, TJ Merling, RK Sweeney, CL Malech, HL Jung, M Corat, MAF AlJanahi, AA Lin, YS Liu, HM Tunc, I Wang, XJ Palisoc, M Pittaluga, S Boehm, M Winkler, T Zou, JZ Dunbar, CE AF Hong, So Gun Yada, Ravi Chandra Choi, Kyujoo Carpentier, Arnaud Liang, T. Jake Merling, Randall K. Sweeney, Colin L. Malech, Harry L. Jung, Moonjung Corat, Marcus A. F. AlJanahi, Aisha A. Lin, Yongshun Liu, Huimin Tunc, Ilker Wang, Xujing Palisoc, Maryknoll Pittaluga, Stefania Boehm, Manfred Winkler, Thomas Zou, Jizhong Dunbar, Cynthia E. TI Rhesus iPSC Safe Harbor Gene-Editing Platform for Stable Expression of Transgenes in Differentiated Cells of All Germ Layers SO MOLECULAR THERAPY LA English DT Article ID EMBRYONIC STEM-CELLS; NONHUMAN PRIMATE MODEL; CAS9 NUCLEASES; AAVS1 LOCUS; CRISPR/CAS9; SPECIFICITY; MONKEY; THERAPY; DISEASE; INTEGRATION AB Nonhuman primate (NHP) induced pluripotent stem cells (iPSCs) offer the opportunity to investigate the safety, feasibility, and efficacy of proposed iPSC-derived cellular delivery in clinically relevant in vivo models. However, there is need for stable, robust, and safe labeling methods for NHP iPSCs and their differentiated lineages to study survival, proliferation, tissue integration, and biodistribution following transplantation. Here we investigate the utility of the adenoassociated virus integration site 1 (AAVS1) as a safe harbor for the addition of transgenes in our rhesus macaque iPSC (RhiPSC) model. A clinically relevant marker gene, human truncated CD19 (h Delta CD19), or GFP was inserted into the AAVS1 site in RhiPSCs using the CRISPR/Cas9 system. Genetically modified RhiPSCs maintained normal karyotype and pluripotency, and these clones were able to further differentiate into all three germ layers in vitro and in vivo. In contrast to transgene delivery using randomly integrating viral vectors, AAVS1 targeting allowed stable transgene expression following differentiation. Off -target mutations were observed in some edited clones, highlighting the importance of careful characterization of these cells prior to downstream applications. Genetically marked RhiPSCs will be useful to further advance clinically relevant models for iPSC-based cell therapies. C1 [Hong, So Gun; Yada, Ravi Chandra; Choi, Kyujoo; Jung, Moonjung; Corat, Marcus A. F.; AlJanahi, Aisha A.; Winkler, Thomas; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Carpentier, Arnaud; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Merling, Randall K.; Sweeney, Colin L.; Malech, Harry L.] NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Corat, Marcus A. F.] Univ Estadual Campinas, Multidisciplinar Ctr Biol Res, BR-13083877 Campinas, SP, Brazil. [AlJanahi, Aisha A.] Georgetown Univ, Dept Chem & Mol & Cellular Biol, Washington, DC 20057 USA. [Lin, Yongshun; Liu, Huimin; Zou, Jizhong] NHLBI, iPSC Core, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. [Tunc, Ilker; Wang, Xujing] NHLBI, Syst Biol Core, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Palisoc, Maryknoll; Pittaluga, Stefania] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Boehm, Manfred] NHLBI, Lab Cardiovasc Regenerat Med, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Hong, SG (reprint author), NHLBI, NIH, Bld 10-CRC,Room 3-3216,9000 Rockville Pike, Bethesda, MD 20892 USA. EM sogun.hong@nih.gov FU Division of Intramural Research at the National Heart, Lung and Blood Institute (NHLBI) at the NIH FX This research was supported by funding from the Division of Intramural Research at the National Heart, Lung and Blood Institute (NHLBI) at the NIH. We thank Gianpietro Dotti for sharing the pCDH-iCasp9-2A-h ACD19 lentiviral vector. We thank the NHLBI Pathology core for tissue processing and Building 50 staff for provision of excellent animal care. We also thank Shiqin Judy Yu for assisting with the iPSC culture, Macallister Harris for his support during the Southern blot analysis, and Alec Nicholls for feedback on neural stem cell staining. NR 44 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD JAN 4 PY 2017 VL 25 IS 1 BP 44 EP 53 DI 10.1016/j.ymthe.2016.10.007 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA EH6RM UT WOS:000391901600007 PM 28129126 ER PT J AU Abdelmegeed, MA Choi, Y Godlewski, G Ha, SK Banerjee, A Jang, S Song, BJ AF Abdelmegeed, Mohamed A. Choi, Youngshim Godlewski, Grzegorz Ha, Seung-Kwon Banerjee, Atrayee Jang, Sehwan Song, Byoung-Joon TI Cytochrome P450-2E1 promotes fast food-mediated hepatic fibrosis SO SCIENTIFIC REPORTS LA English DT Article ID NONALCOHOLIC FATTY LIVER; ENDOPLASMIC-RETICULUM STRESS; METABOLIC SYNDROME; OXIDATIVE STRESS; STELLATE CELLS; STEATOHEPATITIS; MICE; CHOLESTEROL; DISEASE; CYP2E1 AB Cytochrome P450-2E1 (CYP2E1) increases oxidative stress. High hepatic cholesterol causes nonalcoholic steatohepatitis (NASH) and fibrosis. Thus, we aimed to study the role of CYP2E1 in promoting liver fibrosis by high cholesterol-containing fast-food (FF). Male wild-type (WT) and Cyp2e1-null mice were fed standard chow or FF for 2, 12, and 24 weeks. Various parameters of liver fibrosis and potential mechanisms such as oxidative and endoplasmic reticulum (ER) stress, inflammation, and insulin resistance (IR) were studied. Indirect calorimetry was also used to determine metabolic parameters. Liver histology showed that only WT fed FF (WT-FF) developed NASH and fibrosis. Hepatic levels of fibrosis protein markers were significantly increased in WT-FF. The nitroxidative stress marker iNOS, but not CYP2E1, was significantly elevated only in FF-fed WT. Serum endotoxin, TLR-4 levels, and inflammatory markers were highest in WT-FF. FAS, PPAR-alpha, PPAR-gamma, and CB1-R were markedly altered in WT-FF. Electron microscopy and immunoblot analyses showed significantly higher levels of ER stress in FF-fed WT. Indirect calorimetry showed that Cyp2e1-null-mice fed FF exhibited consistently higher total energy expenditure (TEE) than their corresponding WT. These results demonstrate that CYP2E1 is important in fast food-mediated liver fibrosis by promoting nitroxidative and ER stress, endotoxemia, inflammation, IR, and low TEE. C1 [Abdelmegeed, Mohamed A.; Choi, Youngshim; Ha, Seung-Kwon; Banerjee, Atrayee; Jang, Sehwan; Song, Byoung-Joon] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. [Godlewski, Grzegorz] NIAAA, Lab Physiol Studies, Bethesda, MD 20892 USA. RP Abdelmegeed, MA; Song, BJ (reprint author), NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. EM abdelmegeedm@mail.nih.gov; bj.song@nih.gov FU Intramural Research Program of National Institute on Alcohol Abuse and Alcoholism; Korean Biomedical Scientist Fellowship Program from Korea Research Institute of Bioscience and Biotechnology, Republic of Korea FX This research was supported by the Intramural Research Program of National Institute on Alcohol Abuse and Alcoholism. Youngshim Choi was supported by the Korean Biomedical Scientist Fellowship Program from Korea Research Institute of Bioscience and Biotechnology, Republic of Korea. NR 47 TC 1 Z9 1 U1 8 U2 8 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 4 PY 2017 VL 7 AR 39764 DI 10.1038/srep39764 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG6BU UT WOS:000391129600001 PM 28051126 ER PT J AU Kumarasamy, S Solanki, S Atolagbe, OT Joe, B Birnbaumer, L Vazquez, G AF Kumarasamy, Sivarajan Solanki, Sumeet Atolagbe, Oluwatomisin T. Joe, Bina Birnbaumer, Lutz Vazquez, Guillermo TI Deep Transcriptomic Profiling of M1 Macrophages Lacking Trpc3 SO SCIENTIFIC REPORTS LA English DT Article ID ATHEROSCLEROTIC PLAQUES; NETRIN-1; CHANNELS; RETENTION; SURVIVAL; DISEASE; GENE; KEGG AB In previous studies using mice with macrophage-specific loss of TRPC3 we found a significant, selective effect of TRPC3 on the biology of M1, or inflammatory macrophages. Whereas activation of some components of the unfolded protein response and the pro-apoptotic mediators CamkII and Stat1 was impaired in Trpc3-deficient M1 cells, gathering insight about other molecular signatures within macrophages that might be affected by Trpc3 expression requires an alternative approach. In the present study we conducted RNA-seq analysis to interrogate the transcriptome of M1 macrophages derived from mice with macrophage-specific loss of TRPC3 and their littermate controls. We identified 160 significantly differentially expressed genes between the two groups, of which 62 were upregulated and 98 downregulated in control vs. Trpc3-deficient M1 macrophages. Gene ontology analysis revealed enrichment in processes associated to cellular movement and lipid signaling, whereas the enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways included networks for calcium signaling and cell adhesion molecules, among others. This is the first deep transcriptomic analysis of macrophages in the context of Trpc3 deficiency and the data presented constitutes a unique resource to further explore functions of TRPC3 in macrophage biology. C1 [Kumarasamy, Sivarajan; Solanki, Sumeet; Atolagbe, Oluwatomisin T.; Joe, Bina; Vazquez, Guillermo] Univ Toledo, Dept Physiol & Pharmacol, Coll Med & Life Sci, Hlth Sci Campus,3000 Transverse Dr, Toledo, OH 43614 USA. [Kumarasamy, Sivarajan; Solanki, Sumeet; Atolagbe, Oluwatomisin T.; Joe, Bina; Vazquez, Guillermo] Univ Toledo, Ctr Hypertens & Personalized Med, Coll Med & Life Sci, Hlth Sci Campus,3000 Transverse Dr, Toledo, OH 43614 USA. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. [Birnbaumer, Lutz] Inst Biomed Res BIOMED UCA CONICET, Fac Med Sci, Av Alicia Moreau de Justo 1600,C1107AFF, Buenos Aires, DF, Argentina. RP Vazquez, G (reprint author), Univ Toledo, Dept Physiol & Pharmacol, Coll Med & Life Sci, Hlth Sci Campus,3000 Transverse Dr, Toledo, OH 43614 USA.; Vazquez, G (reprint author), Univ Toledo, Ctr Hypertens & Personalized Med, Coll Med & Life Sci, Hlth Sci Campus,3000 Transverse Dr, Toledo, OH 43614 USA. EM Guillermo.Vazquez@utoledo.edu FU NIH [R01HL111877-04, HL-076709, HL-112641, HL-020176]; Intramural Research Program of the NIH [Z01-ES101684] FX This work was supported by NIH grant R01HL111877-04 to G.V., HL-076709, HL-112641 and HL-020176 to B.J., and by the Intramural Research Program of the NIH ( project Z01-ES101684 to L.B.). NR 23 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 4 PY 2017 VL 7 AR 39867 DI 10.1038/srep39867 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG6YW UT WOS:000391193200001 PM 28051144 ER PT J AU Journy, NMY Lee, C Harbron, RW McHugh, K Pearce, MS de Gonzalez, AB AF Journy, Neige M. Y. Lee, Choonsik Harbron, Richard W. McHugh, Kieran Pearce, Mark S. de Gonzalez, Amy Berrington TI Projected cancer risks potentially related to past, current, and future practices in paediatric CT in the United Kingdom, 1990-2020 SO BRITISH JOURNAL OF CANCER LA English DT Article DE computed tomography; public health; paediatrics; radiation exposures; risk assessment; cancer ID ATOMIC-BOMB SURVIVORS; COMPUTED-TOMOGRAPHY; RADIATION-EXPOSURE; SUBSEQUENT RISK; DOSE REDUCTION; BRAIN-TUMORS; SCANS; LEUKEMIA; CHILDHOOD; IMPACT AB Background: To project risks of developing cancer and the number of cases potentially induced by past, current, and future computed tomography (CT) scans performed in the United Kingdom in individuals aged <20 years. Methods: Organ doses were estimated from surveys of individual scan parameters and CT protocols used in the United Kingdom. Frequencies of scans were estimated from the NHS Diagnostic Imaging Dataset. Excess lifetime risks (ELRs) of radiation-related cancer were calculated as cumulative lifetime risks, accounting for survival probabilities, using the RadRAT risk assessment tool. Results: In 2000-2008, ELRs ranged from 0.3 to 1 per 1000 head scans and 1 to 5 per 1000 non-head scans. ELRs per scan were reduced by 50-70% in 2000-2008 compared with 1990-1995, subsequent to dose reduction over time. The 130 750 scans performed in 2015 in the United Kingdom were projected to induce 64 (90% uncertainty interval (UI): 38-113) future cancers. Current practices would lead to about 300 (90% UI: 230-680) future cancers induced by scans performed in 2016-2020. Conclusions: Absolute excess risks from single exposures would be low compared with background risks, but even small increases in annual CT rates over the next years would substantially increase the number of potential subsequent cancers. C1 [Journy, Neige M. Y.; Lee, Choonsik; de Gonzalez, Amy Berrington] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,MSC 9776, Bethesda, MD 20892 USA. [Harbron, Richard W.; Pearce, Mark S.] Newcastle Univ, Inst Hlth & Soc, Royal Victoria Infirm, Queen Victoria Rd, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Harbron, Richard W.; Pearce, Mark S.] Newcastle Univ, NIHR Hlth Protect Res Unit Chem & Radiat Threats, Newcastle Upon Tyne, Tyne & Wear, England. [McHugh, Kieran] Great Ormond St Hosp Sick Children, Great Ormond St, London WC1N 3JH, England. RP Journy, NMY (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,MSC 9776, Bethesda, MD 20892 USA. EM neige.journy@nih.gov FU US National Cancer Institute intramural research program; UK Department of Health; Cancer Research UK FX This study used data from the Diagnostic Imaging Dataset released by the National Health Service (NHS) England. We thank the NHS England for providing us detailed data on frequencies of paediatric CT scans. The interpretation and reporting of these data are the sole responsibility of the authors and do not necessarily reflect the view of the NHS. Likewise, the views expressed by the authors do not necessarily reflect those of the National Institute for Health Research (NIHR), the Department of Health or Public Health England, to which MSP and RWH are affiliated or collaborate with. The estimated frequencies of CT scans provided in this paper might differ from official statistics because we applied our own methodology to handle missing data on patients' characteristics. This study was financially supported by the US National Cancer Institute intramural research program, the UK Department of Health, and Cancer Research UK. The funding sources and sponsor had no role in 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 47 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 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 3 PY 2017 VL 116 IS 1 BP 109 EP 116 DI 10.1038/bjc.2016.351 PG 8 WC Oncology SC Oncology GA EL1VE UT WOS:000394408700016 PM 27824812 ER PT J AU Wang, PY Li, J Walcott, FL Kang, JG Starost, MF Talagala, SL Zhuang, J Park, JH Huffstutler, RD Bryla, CM Mai, PL Pollak, M Annunziata, CM Savage, SA Fojo, AT Hwang, PM AF Wang, Ping-Yuan Li, Jie Walcott, Farzana L. Kang, Ju-Gyeong Starost, Matthew F. Talagala, S. Lalith Zhuang, Jie Park, Ji-Hoon Huffstutler, Rebecca D. Bryla, Christina M. Mai, Phuong L. Pollak, Michael Annunziata, Christina M. Savage, Sharon A. Fojo, Antonio Tito Hwang, Paul M. TI Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID B-CELL LYMPHOMA; OXIDATIVE STRESS; MUTANT P53; METFORMIN; METABOLISM; MUTATIONS; ACTIVATION; GENERATION; MICE; DNA AB Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder caused by germline mutations in TP53 that can lead to increased mitochondrial metabolism in patients. However, the implications of altered mitochondrial function for tumorigenesis in LFS are unclear. Here, we have reported that genetic or pharmacologic disruption of mitochondrial respiration improves cancer-free survival in a mouse model of LFS that expresses mutant p53. Mechanistically, inhibition of mitochondrial function increased autophagy and decreased the aberrant proliferation signaling caused by mutant p53. In a pilot study, LFS patients treated with metformin exhibited decreases in mitochondrial activity concomitant with activation of antiproliferation signaling, thus reproducing the effects of disrupting mitochondrial function observed in LFS mice. These observations indicate that a commonly prescribed diabetic medicine can restrain mitochondrial metabolism and tumorigenesis in an LFS model, supporting its further consideration for cancer prevention in LFS patients. C1 [Wang, Ping-Yuan; Li, Jie; Kang, Ju-Gyeong; Zhuang, Jie; Park, Ji-Hoon; Huffstutler, Rebecca D.; Hwang, Paul M.] NHLBI, Ctr Mol Med, NIH, Bldg 10 CRC,Room 5-5330, Bethesda, MD 20892 USA. [Walcott, Farzana L.; Mai, Phuong L.; Savage, Sharon A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Walcott, Farzana L.] George Washington Univ, Dept Internal Med, Washington, DC USA. [Starost, Matthew F.] NIH, Div Vet Resources, Bldg 10, Bethesda, MD 20892 USA. [Talagala, S. Lalith] NINDS, NIH MRI Res Facil, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bryla, Christina M.; Annunziata, Christina M.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Pollak, Michael] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Pollak, Michael] McGill Univ, Dept Med, Montreal, PQ, Canada. [Fojo, Antonio Tito] Columbia Univ, Med Ctr, Div Hematol Oncol, New York, NY USA. EM hwangp@mail.nih.gov FU Division of Intramural Research, NHLBI-NIH [HL005101] FX This work was supported by the Division of Intramural Research, NHLBI-NIH (HL005101 to P.M. Hwang). We thank J. Stolinski, R. Hill, and H. Merkle for MRS studies; J. Chavez, R. Fleischmann, A. Merriweather, and C. King for pathology services; T. Finkel for helpful comments and the Polg+/mut mouse created by T.A. Prolla; M.A. Waclawiw for advice with statistical analysis; and N.A. Long and W.M. Kamp for technical and editorial assistance. NR 27 TC 1 Z9 1 U1 3 U2 3 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 JAN 3 PY 2017 VL 127 IS 1 BP 132 EP 136 DI 10.1172/JCI88668 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EI1UK UT WOS:000392271300017 PM 27869650 ER PT J AU Kim, W Khan, SK Gvozdenovic-Jeremic, J Kim, Y Dahlman, J Kim, H Park, O Ishitani, T Jho, EH Gao, B Yang, Y AF Kim, Wantae Khan, Sanjoy Kumar Gvozdenovic-Jeremic, Jelena Kim, Youngeun Dahlman, Jason Kim, Hanjun Park, Ogyi Ishitani, Tohru Jho, Eek-Hoon Gao, Bin Yang, Yingzi TI Hippo signaling interactions with Wnt/beta-catenin and Notch signaling repress liver tumorigenesis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID STEM-CELL PROLIFERATION; HUMAN HEPATOCELLULAR-CARCINOMA; BETA-CATENIN; ADHERENS JUNCTIONS; STAT3 ACTIVATION; DUAL FUNCTIONS; GAMMA-CATENIN; SIZE-CONTROL; IN-VIVO; KAPPA-B AB Malignant tumors develop through multiple steps of initiation and progression, and tumor initiation is of singular importance in tumor prevention, diagnosis, and treatment. However, the molecular mechanism whereby a signaling network of interacting pathways restrains proliferation in normal cells and prevents tumor initiation is still poorly understood. Here, we have reported that the Hippo, Wnt/beta-catenin, and Notch pathways form an interacting network to maintain liver size and suppress hepatocellular carcinoma (HCC). Ablation of the mammalian Hippo kinases Mst1 and Mst2 in liver led to rapid HCC formation and activated Yes-associated protein/WW domain containing transcription regulator 1 (YAP/TAZ), STAT3, Wnt/beta-catenin, and Notch signaling. Previous work has shown that abnormal activation of these downstream pathways can lead to HCC. Rigorous genetic experiments revealed that Notch signaling forms a positive feedback loop with the Hippo signaling effector YAP/TAZ to promote severe hepatomegaly and rapid HCC initiation and progression. Surprisingly, we found that Wnt/beta-catenin signaling activation suppressed HCC formation by inhibiting the positive feedback loop between YAP/TAZ and Notch signaling. Furthermore, we found that STAT3 in hepatocytes is dispensable for HCC formation when mammalian sterile 20-like kinase 1 and 2 (Mst1 and Mst2) were removed. The molecular network we have identified provides insights into HCC molecular classifications and therapeutic developments for the treatment of liver tumors caused by distinct genetic mutations. C1 [Kim, Wantae; Khan, Sanjoy Kumar; Gvozdenovic-Jeremic, Jelena; Dahlman, Jason; Kim, Hanjun; Yang, Yingzi] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Kim, Wantae; Khan, Sanjoy Kumar; Kim, Hanjun; Yang, Yingzi] Harvard Sch Dent Med, Dept Dev Biol, 188 Longwood Ave, Boston, MA 02115 USA. [Kim, Youngeun; Jho, Eek-Hoon] Univ Seoul, Dept Life Sci, Seoul, South Korea. [Park, Ogyi; Gao, Bin] NIAAA, Sect Liver Biol, NIH, Bethesda, MD USA. [Ishitani, Tohru] Kyushu Univ, Med Inst Bioregulat, Div Cell Regulat Syst, Fukuoka, Japan. EM yingzi_yang@hsdm.harvard.edu FU intramural research program of the NHGRI; HSDM; Korean Visiting Scientist Training Award (KVSTA) fellowship from the Korean Health Industry Development Institute (KHIDI) [HI13C1274, HI13C1276]; National R&D Program for Cancer Control of the Ministry of Health and Welfare of Korea [1420060] FX We thank members of the Yang laboratory for stimulating discussions and J. Jiang for reagents (University of Texas Southwestern Medical Center, Dallas, Texas). This study was supported by grants from the intramural research program of the NHGRI and the HSDM and by a Korean Visiting Scientist Training Award (KVSTA) fellowship from the Korean Health Industry Development Institute (KHIDI) (HI13C1274, to WK and HI13C1276, to HK). This research was partially supported by the National R&D Program for Cancer Control of the Ministry of Health and Welfare of Korea (1420060, to EHJ). NR 82 TC 0 Z9 0 U1 3 U2 3 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 JAN 3 PY 2017 VL 127 IS 1 BP 137 EP 152 DI 10.1172/JCI88486 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EI1UK UT WOS:000392271300018 PM 27869648 ER PT J AU Keir, LS Firth, R Aponik, L Feitelberg, D Sakimoto, S Aguilar, E Welsh, GI Richards, A Usui, Y Satchell, SC Kuzmuk, V Coward, RJ Goult, J Bull, KR Sharma, R Bharti, K Westenskow, PD Michael, IP Saleem, MA Friedlander, M AF Keir, Lindsay S. Firth, Rachel Aponik, Lyndsey Feitelberg, Daniel Sakimoto, Susumu Aguilar, Edith Welsh, Gavin I. Richards, Anna Usui, Yoshihiko Satchell, Simon C. Kuzmuk, Valeryia Coward, Richard J. Goult, Jonathan Bull, Katherine R. Sharma, Ruchi Bharti, Kapil Westenskow, Peter D. Michael, Iacovos P. Saleem, Moin A. Friedlander, Martin TI VEGF regulates local inhibitory complement proteins in the eye and kidney SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; RETINAL-PIGMENT EPITHELIUM; MEMBRANE-ATTACK-COMPLEX; HEMOLYTIC-UREMIC SYNDROME; MACULAR DEGENERATION; FACTOR-H; GEOGRAPHIC ATROPHY; IN-VITRO; MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS; CHOROIDAL NEOVASCULARIZATION AB Outer retinal and renal glomerular functions rely on specialized vasculature maintained by VEGF that is produced by neighboring epithelial cells, the retinal pigment epithelium (RPE) and podocytes, respectively. Dysregulation of RPE- and podocyte-derived VEGF is associated with neovascularization in wet age-related macular degeneration (ARMD), choriocapillaris degeneration, and glomerular thrombotic microangiopathy (TMA). Since complement activation and genetic variants in inhibitory complement factor H (CFH) are also features of both ARMD and TMA, we hypothesized that VEGF and CFH interact. Here, we demonstrated that VEGF inhibition decreases local CFH and other complement regulators in the eye and kidney through reduced VEGFR2/PKC-alpha/CREB signaling. Patient podocytes and RPE cells carrying disease-associated CFH genetic variants had more alternative complement pathway deposits than controls. These deposits were increased by VEGF antagonism, a common wet ARMD treatment, suggesting that VEGF inhibition could reduce cellular complement regulatory capacity. VEGF antagonism also increased markers of endothelial cell activation, which was partially reduced by genetic complement inhibition. Together, these results suggest that VEGF protects the retinal and glomerular microvasculature, not only through VEGFR2-mediated vasculotrophism, but also through modulation of local complement proteins that could protect against complement-mediated damage. Though further study is warranted, these findings could be relevant for patients receiving VEGF antagonists. C1 [Keir, Lindsay S.; Aponik, Lyndsey; Feitelberg, Daniel; Sakimoto, Susumu; Aguilar, Edith; Usui, Yoshihiko; Westenskow, Peter D.; Friedlander, Martin] Scripps Res Inst, Dept Cell & Mol Biol, La Jolla, CA 92037 USA. [Keir, Lindsay S.; Firth, Rachel; Welsh, Gavin I.; Satchell, Simon C.; Kuzmuk, Valeryia; Coward, Richard J.; Saleem, Moin A.] Univ Bristol, Sch Clin Sci, Acad Renal Unit, Bristol, Avon, England. [Richards, Anna] Univ Edinburgh, Queens Med Res Inst, Edinburgh, Midlothian, Scotland. [Usui, Yoshihiko] Tokyo Med Univ Hosp, Tokyo, Japan. [Goult, Jonathan; Bull, Katherine R.] Univ Oxford, Ctr Cellular & Mol Physiol, Oxford OX1 2JD, England. [Sharma, Ruchi; Bharti, Kapil] NEI, NIH, Bethesda, MD 20892 USA. [Westenskow, Peter D.] Lowy Med Res Inst, La Jolla, CA USA. [Michael, Iacovos P.] Ecole Polytech Fed Lausanne, Lausanne, Switzerland. EM m.saleem@bristol.ac.uk; friedlan@scripps.edu FU medical research council clinical research training fellowship [G0901987]; University of Bristol MRC Centenary award; NIHR clinical lecturer post; Wellcome Trust intermediate clinical training fellowship [WT085226]; National Eye Institute of the NIH [EY011254]; Lowy Medical Research Institute FX We would like to thank all collaborators who provided samples and reagents as listed in the manuscript; the Wolfson biomedical imaging facility at the University of Bristol; the flow cytometry facility at the Scripps Research Institute; Lea Scheppke, Salome Murinello, and Alys Belcher for review of the manuscript; and Stacey Moreno, Carli Wittgrove, Mauricio Rosenfeld, and Lan Ni for excellent technical assistance. LSK was funded by a medical research council clinical research training fellowship (G0901987), a University of Bristol MRC Centenary award, and an NIHR clinical lecturer post. AR was funded by a Wellcome Trust intermediate clinical training fellowship (WT085226; 2009-2014). This work was also funded by grants to MF from the National Eye Institute of the NIH (EY011254) and the Lowy Medical Research Institute. NR 92 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 JAN 3 PY 2017 VL 127 IS 1 BP 199 EP 214 DI 10.1172/JCI86418 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EI1UK UT WOS:000392271300022 PM 27918307 ER PT J AU Mace, EM Bigley, V Gunesch, JT Chinn, IK Angelo, LS Care, MA Maisuria, S Keller, MD Togi, S Watkin, LB LaRosa, DF Jhangiani, SN Muzny, DM Stray-Pedersen, A Akdemir, ZC Smith, JB Hernandez-Sanabria, M Le, DT Hogg, GD Cao, TN Freud, AG Szymanski, EP Savic, S Collin, M Cant, AJ Gibbs, RA Holland, SM Caligiuri, MA Ozato, K Paust, S Doody, GM Lupski, JR Orange, JS AF Mace, Emily M. Bigley, Venetia Gunesch, Justin T. Chinn, Ivan K. Angelo, Laura S. Care, Matthew A. Maisuria, Sheetal Keller, Michael D. Togi, Sumihito Watkin, Levi B. LaRosa, David F. Jhangiani, Shalini N. Muzny, Donna M. Stray-Pedersen, Asbjorg Akdemir, Zeynep Coban Smith, Jansen B. Hernandez-Sanabria, Mayra Le, Duy T. Hogg, Graham D. Cao, Tram N. Freud, Aharon G. Szymanski, Eva P. Savic, Sinisa Collin, Matthew Cant, Andrew J. Gibbs, Richard A. Holland, Steven M. Caligiuri, Michael A. Ozato, Keiko Paust, Silke Doody, Gina M. Lupski, James R. Orange, Jordan S. TI Biallelic mutations in IRF8 impair human NK cell maturation and function SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NATURAL-KILLER-CELLS; SEQUENCE-BINDING-PROTEIN; LEUKEMIA-LIKE SYNDROME; T-CELL; TRANSCRIPTION FACTOR; IN-VIVO; DENDRITIC CELLS; B-CELL; IMMUNOLOGICAL SYNAPSE; SIGNALING PATHWAYS AB Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature CD56(dim) NK cells and an increase in the frequency of the immature CD56(bright) NK cells, and this impairment in terminal maturation was also observed in Irf8(-/-), but not Irf8(+/-), mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense. C1 [Mace, Emily M.; Gunesch, Justin T.; Chinn, Ivan K.; Angelo, Laura S.; Watkin, Levi B.; Smith, Jansen B.; Hernandez-Sanabria, Mayra; Le, Duy T.; Hogg, Graham D.; Cao, Tram N.; Orange, Jordan S.] Texas Childrens Hosp, Ctr Human Immunobiol, Houston, TX 77030 USA. [Mace, Emily M.; Chinn, Ivan K.; Lupski, James R.; Orange, Jordan S.] Baylor Coll Med, Dept Pediat, Houston, TX USA. [Mace, Emily M.; Gunesch, Justin T.; Orange, Jordan S.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX USA. [Bigley, Venetia; Collin, Matthew] Univ Newcastle, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Chinn, Ivan K.; Jhangiani, Shalini N.; Muzny, Donna M.; Stray-Pedersen, Asbjorg; Akdemir, Zeynep Coban; Gibbs, Richard A.; Lupski, James R.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Care, Matthew A.; Doody, Gina M.] Univ Leeds, Leeds Inst Canc & Pathol, Sect Expt Haematol, Leeds, W Yorkshire, England. [Maisuria, Sheetal] St James Univ Hosp, Dept Clin Immunol & Allergy, Leeds, W Yorkshire, England. [Keller, Michael D.] Childrens Natl Hlth Syst, Ctr Canc & Immunol Res, Div Allergy & Immunol, Washington, DC USA. [Togi, Sumihito; Ozato, Keiko] NIH, Natl Inst Child Hlth & Human Dev, Lab Mol Growth Regulat, Program Genom Differentiat, Bethesda, MD 20892 USA. [LaRosa, David F.] Univ Penn, Childrens Hosp, Sch Med, Philadelphia Res Inst,Dept Pediat, Philadelphia, PA 19104 USA. [Stray-Pedersen, Asbjorg; Akdemir, Zeynep Coban; Lupski, James R.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Freud, Aharon G.; Paust, Silke] Ohio State Univ, Dept Pathol, Div Hematopathol, Columbus, OH 43210 USA. [Freud, Aharon G.; Caligiuri, Michael A.] Ohio State Univ, James Canc Hosp & Solove Res Ctr, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Szymanski, Eva P.; Holland, Steven M.] NIH, NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Cant, Andrew J.] Great North Childrens Hosp, Dept Paediat Immunol & Bone Marrow Transplantat, Newcastle Upon Tyne, Tyne & Wear, England. [Caligiuri, Michael A.] Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA. [Paust, Silke; Orange, Jordan S.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. EM orange@bcm.edu FU Genomic and RNA Profiling Core at Baylor College of Medicine; NIH-National Institute of Allergy and Infectious Diseases grants [R01AI067946, R01 AI120989]; Jeffrey Modell Foundation; NIH (National Human Genome Research Institute/National Heart, Lung, and Blood Institute) [U54HG006542] FX The authors thank all the patients and their families, particularly the proband's, for their engagement in this study. The authors also thank Linda Monaco-Shawver for technical assistance. This project was supported by the Genomic and RNA Profiling Core at Baylor College of Medicine and the expert assistance of the core director, Lisa D. White, and Mylinh Bernardi. This work was supported by NIH-National Institute of Allergy and Infectious Diseases grants R01AI067946 and R01 AI120989 to JSO, the Jeffrey Modell Foundation, and NIH (National Human Genome Research Institute/National Heart, Lung, and Blood Institute) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics. NR 75 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 JAN 3 PY 2017 VL 127 IS 1 BP 306 EP 320 DI 10.1172/JCI86276 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EI1UK UT WOS:000392271300030 PM 27893462 ER PT J AU Cao, J Tyburczy, ME Moss, J Darling, TN Widlund, HR Kwiatkowski, DJ AF Cao, Juxiang Tyburczy, Magdalena E. Moss, Joel Darling, Thomas N. Widlund, Hans R. Kwiatkowski, David J. TI Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GLYCOGEN-SYNTHASE KINASE-3; TRANSCRIPTION FACTOR LEF-1; B16 MELANOMA-CELLS; BETA-CATENIN; NEURAL CREST; TSC1-TSC2 COMPLEX; SIGNALING PATHWAY; HUMAN MELANOCYTES; PROTEIN; MITF AB Tuberous sclerosis complex (TSC) is an autosomal dominant tumor-suppressor gene syndrome caused by inactivating mutations in either TSC1 or TSC2, and the TSC protein complex is an essential regulator of mTOR complex 1 (mTORC1). Patients with TSC develop hypomelanotic macules (white spots), but the molecular mechanisms underlying their formation are not fully characterized. Using human primary melanocytes and a highly pigmented melanoma cell line, we demonstrate that reduced expression of either TSC1 or TSC2 causes reduced pigmentation through mTORC1 activation, which results in hyperactivation of glycogen synthase kinase 3 beta (GSK3 beta), followed by phosphorylation of and loss of beta-catenin from the nucleus, thereby reducing expression of microphthalmia-associated transcription factor (MITF), and subsequent reductions in tyrosinase and other genes required for melanogenesis. Genetic suppression or pharmacological inhibition of this signaling cascade at multiple levels restored pigmentation. Importantly, primary melanocytes isolated from hypomelanotic macules from 6 patients with TSC all exhibited reduced TSC2 protein expression, and 1 culture showed biallelic mutation in TSC2, one of which was germline and the second acquired in the melanocytes of the hypomelanotic macule. These findings indicate that the TSC/mTORC1/AKT/GSK3 beta/beta-catenin/MITF axis plays a central role in regulating melanogenesis. Interventions that enhance or diminish mTORC1 activity or other nodes in this pathway in melanocytes could potentially modulate pigment production. C1 [Cao, Juxiang; Tyburczy, Magdalena E.; Kwiatkowski, David J.] Brigham & Womens Hosp, Harvard Med Sch, Dept Med, Div Pulm & Crit Care Med & Genet, Boston, MA 02115 USA. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Darling, Thomas N.] Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. [Widlund, Hans R.] Brigham & Womens Hosp, Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. EM dk@rics.bwh.harvard.edu FU National Cancer Institute (NCI), NIH [1P01CA120964, R01AR062080]; Intramural Research Program of the NHLBI, NIH FX We thank Brendan Manning's laboratory (T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA) for providing TSC2-knockdown cells, cDNA constructs, and GSK3 beta inhibitors and Ken Inoki for providing beta-catenin constructs. We also thank the members of DJK's laboratory for helpful comments and suggestions. This work was supported by grants from the National Cancer Institute (NCI), NIH (1P01CA120964, to DJK and R01AR062080, to TND). JM was supported by the Intramural Research Program of the NHLBI, NIH. NR 94 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 JAN 3 PY 2017 VL 127 IS 1 BP 349 EP 364 DI 10.1172/JCI84262 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EI1UK UT WOS:000392271300033 PM 27918305 ER PT J AU Lu, SS Grigoryan, H Edmands, WMB Hu, W Iavarone, AT Hubbard, A Rothman, N Vermeulen, R Lan, Q Rappaport, SM AF Lu, Sixin S. Grigoryan, Hasmik Edmands, William M. B. Hu, Wei Iavarone, Anthony T. Hubbard, Alan Rothman, Nathaniel Vermeulen, Roel Lan, Qing Rappaport, Stephen M. TI Profiling the Serum Albumin Cys34 Adductome of Solid Fuel Users in Xuanwei and Fuyuan, China SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID LUNG-CANCER RISK; COAL COMBUSTION EMISSIONS; HOUSEHOLD AIR-POLLUTION; HUMAN PLASMA; EXPOSURE; WEI; GLUTATHIONE; GENOTYPES; COUNTIES; TISSUES AB Xuanwei and Fuyuan counties in China have the highest lung cancer rates in the world due to household air pollution from combustion of smoky coal for cooking and heating. To discover potential biomarkers of indoor combustion products, we profiled adducts at the Cys34 locus of human serum albumin (HSA) in 29 nonsmoking Xuanwei and Fuyuan females who used smoky coal, smokeless coal, or wood and 10 local controls who used electricity or gas fuel. Our untargeted "adductomics" method detected 50 tryptic peptides of HSA, containing Cys34 and prominent post-translational modifications. Putative adducts included Cys34 oxidation products, mixed disulfides, rearrangements, and truncations. The most significant differences in adduct levels across fuel types were observed for S-glutathione (S-GSH) and S-gamma-glutamylcysteine (S-gamma-GluCys), both of which were present at lower levels in subjects exposed to combustion products than in controls. After adjustment for age and personal measurements of airborne benzo(a)pyrene, the largest reductions in levels of S-GSH and S-gamma-GluCys relative to controls were observed for users of smoky coal, compared to users, of smokeless coal and wood. These results point to possible depletion of GSH, an essential antioxidant, and its precursor gamma-GluCys in nonsmoking females exposed to indoor-combustion products in Xuanwei and Fuyuan, China. C1 [Lu, Sixin S.] Univ Calif Berkeley, Coll Nat Resources, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Grigoryan, Hasmik; Edmands, William M. B.; Rappaport, Stephen M.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Hu, Wei; Rothman, Nathaniel; Lan, Qing] NCI, US Dept HHS, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Iavarone, Anthony T.] Univ Calif Berkeley, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA. [Hubbard, Alan] Univ Calif Berkeley, Sch Publ Hlth, Div Biostat, Berkeley, CA 94720 USA. [Vermeulen, Roel] Univ Utrecht, Div Environm Epidemiol, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands. RP Rappaport, SM (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. EM srappaport@berkeley.edu RI Vermeulen, Roel/F-8037-2011; OI Vermeulen, Roel/0000-0003-4082-8163; Lu, Sixin/0000-0001-9951-1721 FU National Cancer Institute of the U.S. National Institutes of Health; National Institute for Environmental Health Sciences [U54ES016115, R44ES022360]; [R33CA191159] FX This work was supported by Grant R33CA191159 and by the intramural program of the National Cancer Institute of the U.S. National Institutes of Health. The authors also acknowledge support from Grants U54ES016115 and R44ES022360 from the National Institute for Environmental Health Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 42 TC 0 Z9 0 U1 9 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD JAN 3 PY 2017 VL 51 IS 1 BP 46 EP 57 DI 10.1021/acs.est.6b03955 PG 12 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA EG8ZR UT WOS:000391346900007 PM 27936627 ER PT J AU Esposito, G Manian, N Truzzi, A Bornstein, MH AF Esposito, Gianluca Manian, Nanmathi Truzzi, Anna Bornstein, Marc H. TI Response to Infant Cry in Clinically Depressed and Non-Depressed Mothers SO PLOS ONE LA English DT Article ID OXYTOCIN RECEPTOR GENE; MATERNAL SENSITIVITY; POSTNATAL DEPRESSION; POSTPARTUM DEPRESSION; ATTACHMENT SECURITY; PARENTING BEHAVIOR; CHRONOLOGICAL AGE; MEDIATING ROLE; DISTRESS; METAANALYSIS AB Background Bowlby and Ainsworth hypothesized that maternal responsiveness is displayed in the context of infant distress. Depressed mothers are less responsive to infant distress vocalizations (cry) than non-depressed mothers. The present study focuses on acoustical components of infant cry that give rise to responsive caregiving in clinically depressed (n = 30) compared with non-depressed mothers (n = 30) in the natural setting of the home. Methods Analyses of infant and mother behaviors followed three paths: (1) tests of group differences in acoustic characteristics of infant cry, (2) tests of group differences of mothers' behaviors during their infant's crying, and (3) tree-based modeling to ascertain which variable(s) best predict maternal behaviors during infant cry. Results (1) Infants of depressed mothers cried as frequently and for equal durations as infants of non-depressed mothers; however, infants of depressed mothers cried with a higher fundamental frequency (fO) and in a more restricted range of fO. (2) Depressed mothers fed, rocked, and touched their crying infants less than non-depressed mothers, and depressed mothers were less responsive to their infants overall. (3) Novel tree-based analyses confirmed that depressed mothers engaged in less caregiving during their infants' cry and indicated that depressed mothers responded only to cries at higher fOs and shorter durations. Older non-depressed mothers were the most interactive with infants. Conclusions Clinical depression affects maternal responsiveness during infant cry, leading to patterns of action that appear poorly attuned to infant needs. C1 [Esposito, Gianluca; Truzzi, Anna] Univ Trento, Dept Psychol & Cognit Sci, Rovereto, Trentino, Italy. [Esposito, Gianluca] Nanyang Technol Univ, Sch Humanities & Social Sci, Div Psychol, Singapore, Singapore. [Manian, Nanmathi] Westat Corp, Rockville, MD USA. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Bethesda, MD USA. RP Esposito, G (reprint author), Univ Trento, Dept Psychol & Cognit Sci, Rovereto, Trentino, Italy.; Esposito, G (reprint author), Nanyang Technol Univ, Sch Humanities & Social Sci, Div Psychol, Singapore, Singapore.; Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Bethesda, MD USA. EM gianluca.esposito@unitn.it; Marc_H_Bornstein@nih.gov FU FP7 PEOPLE-Marie Curie Career Integration Grants [GA-2013-630166]; Intramural Research Program of the NIH, NICHD; Westat, a commercial company FX This research was supported by grants from the FP7 PEOPLE-Marie Curie Career Integration Grants (GA-2013-630166) and the Intramural Research Program of the NIH, NICHD. Westat, a commercial company, provided financial support in the form of salary for author NM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 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 3 PY 2017 VL 12 IS 1 AR e0169066 DI 10.1371/journal.pone.0169066 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH2QJ UT WOS:000391612300105 PM 28046020 ER PT J AU Peavey, MC Reynolds, CL Szwarc, MM Gibbons, WE Valdese, CT DeMayo, FJ Lydon, JP AF Peavey, Mary C. Reynolds, Corey L. Szwarc, Maria M. Gibbons, William E. Valdese, Cecilia T. DeMayo, Francesco J. Lydon, John P. TI Three-Dimensional High-Frequency Ultrasonography for Early Detection and Characterization of Embryo Implantation Site Development in the Mouse SO PLOS ONE LA English DT Article ID RECURRENT PREGNANCY LOSS; ULTRASOUND; GROWTH; MICE; SCIENCE; MODELS; CANCER; 3RS AB Ultrasonography is a powerful tool to non-invasively monitor in real time the development of the human fetus in utero. Although genetically engineered mice have served as valuable in vivo models to study both embryo implantation and pregnancy progression, such studies usually require sacrifice of parous mice for subsequent phenotypic analysis. To address this issue, we used three-dimensional (3-D) reconstruction in silico of high-frequency ultrasound (HFUS) imaging data for early detection and characterization of murine embryo implantation sites and their development in utero. With HFUS imaging followed by 3-D reconstruction, we were able to precisely quantify embryo implantation site number and embryonic developmental progression in pregnant C57BL6J/129S mice from as early as 5.5 days post coitus (d.p.c.) through to 9.5 d.p.c. using a VisualSonics Vevo 2100 (MS550S) transducer. In addition to measurements of implantation site number, location, volume and spacing, embryo viability via cardiac activity monitoring was also achieved. A total of 12 dams were imaged with HFUS with approximately 100 embryos examined per embryonic day. For the post implantation period (5.5 to 8.5 d.p.c.), 3-D reconstruction of the gravid uterus in mesh or solid overlay format enabled visual representation in silico of implantation site location, number, spacing distances, and site volume within each uterine horn. Therefore, this short technical report describes the feasibility of using 3-D HFUS imaging for early detection and analysis of post-implantation events in the pregnant mouse with the ability to longitudinally monitor the development of these early pregnancy events in a non-invasive manner. As genetically engineered mice continue to be used to characterize female reproductive phenotypes, we believe this reliable and non-invasive method to detect, quantify, and characterize early implantation events will prove to be an invaluable investigative tool for the study of female infertility and subfertility phenotypes based on a defective uterus. C1 [Peavey, Mary C.; Szwarc, Maria M.; Lydon, John P.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Peavey, Mary C.; Gibbons, William E.; Valdese, Cecilia T.] Baylor Coll Med, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Houston, TX 77030 USA. [Reynolds, Corey L.] Baylor Coll Med, Mouse Phenotyping Core, Houston, TX 77030 USA. [DeMayo, Francesco J.] NIEHS, Reprod & Dev Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. RP Lydon, JP (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.; DeMayo, FJ (reprint author), NIEHS, Reprod & Dev Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM francesco.demayo@nih.gov; jlydon@bcm.tmc.edu FU NIH/NICHD [RO1: HD-042311]; Burroughs Wellcome Fund; NIH [U54 HG006348] FX This project was supported by NIH/NICHD RO1: HD-042311 (to JPL) and the Burroughs Wellcome Fund (to FJD). Ultrasound imaging was conducted in the Mouse Phenotyping Core at Baylor College of Medicine with funding from the NIH (U54 HG006348). 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 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 3 PY 2017 VL 12 IS 1 AR e0169312 DI 10.1371/journal.pone.0169312 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH2QJ UT WOS:000391612300164 PM 28046063 ER PT J AU Slike, BM Creegan, M Marovich, M Ngauy, V AF Slike, Bonnie M. Creegan, Matthew Marovich, Mary Ngauy, Viseth TI Humoral Immunity to Primary Smallpox Vaccination: Impact of Childhood versus Adult Immunization on Vaccinia Vector Vaccine Development in Military Populations SO PLOS ONE LA English DT Article ID PREEXISTING POXVIRUS IMMUNITY; HIV-1 NEUTRALIZING ANTIBODIES; IMMUNOLOGICAL RESPONSE; HVTN 503/PHAMBILI; DENDRITIC CELLS; SOUTH-AFRICA; PHASE 2H; MVA-B; VIRUS; HIV/AIDS AB Modified Vaccinia virus has been shown to be a safe and immunogenic vector platform for delivery of HIV vaccines. Use of this vector is of particular importance to the military, with the implementation of a large scale smallpox vaccination campaign in 2002 in active duty and key civilian personnel in response to potential bioterrorist activities. Humoral immunity to smallpox vaccination was previously shown to be long lasting (up to 75 years) and protective. However, using vaccinia-vectored vaccine delivery for other diseases on a background of anti-vector antibodies (i.e. pre-existing immunity) may limit their use as a vaccine platform, especially in the military. In this pilot study, we examined the durability of vaccinia antibody responses in adult primary vaccinees in a healthy military population using a standard ELISA assay and a novel dendritic cell neutralization assay. We found binding and neutralizing antibody (NAb) responses to vaccinia waned after 5-10 years in a group of 475 active duty military, born after 1972, who were vaccinated as adults with Dryvax (R). These responses decreased from a geometric mean titer (GMT) of 250 to baseline (<20) after 1020 years post vaccination. This contrasted with a comparator group of adults, ages 35-49, who were vaccinated with Dryvax (R) as children. In the childhood vaccinees, titers persisted for >30 years with a GMT of 210 (range 112-3234). This data suggests limited durability of antibody responses in adult vaccinees compared to those vaccinated in childhood and further that adult vaccinia recipients may benefit similarly from receipt of a vaccinia based vaccine as those who are vaccinia na ve. Our findings may have implications for the smallpox vaccination schedule and support the ongoing development of this promising viral vector in a military vaccination program. C1 [Slike, Bonnie M.; Creegan, Matthew] US Mil HIV Res Program, Silver Spring, MD USA. [Slike, Bonnie M.; Creegan, Matthew] Henry M Jackson Adv Mil Med, Bethesda, MD USA. [Marovich, Mary] NIAID, Div Aids, Bethesda, MD USA. [Ngauy, Viseth] Tripler Army Med Ctr, Honolulu, HI 96859 USA. RP Ngauy, V (reprint author), Tripler Army Med Ctr, Honolulu, HI 96859 USA. EM Viseth.ngauy.mil@mail.mil FU Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-07-2-0067]; U.S. Department of Defense [W81XWH-07-2-0067]; Infectious Disease Clinical Research Program (IDCRP); Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) [Y1-AI-5072]; Military Vaccine Program (MILVAX) FX This work was supported 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, the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), under Inter-Agency Agreement Y1-AI-5072, and the Military Vaccine Program (MILVAX). The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or DoD. NR 34 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 3 PY 2017 VL 12 IS 1 AR e0169247 DI 10.1371/journal.pone.0169247 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH2QJ UT WOS:000391612300152 PM 28046039 ER PT J AU Rabkin, CS Goedert, JJ AF Rabkin, Charles S. Goedert, James J. TI Chronic Hepatitis and Non-Hodgkin Lymphoma Among People With HIV: Implications for Screening, Treatment, and Prevention SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID ANTIRETROVIRAL THERAPY; C VIRUS; COHORT; RISK; METAANALYSIS; INFECTION; ERA C1 [Rabkin, Charles S.; Goedert, James J.] NCI, Bethesda, MD 20892 USA. [Rabkin, Charles S.; Goedert, James J.] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. RP Rabkin, CS (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 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 3 PY 2017 VL 166 IS 1 BP 69 EP + DI 10.7326/M16-2340 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EH0QD UT WOS:000391467900010 PM 27750296 ER PT J AU Xu, ZL Langie, SAS De Boever, P Taylor, JA Niu, L AF Xu, Zongli Langie, Sabine A. S. De Boever, Patrick Taylor, Jack A. Niu, Liang TI RELIC: a novel dye-bias correction method for Illumina Methylation BeadChip SO BMC GENOMICS LA English DT Article DE RELIC; DNA methylation; Dye-bias correction; Illumina HumanMethylation450; Illumina MethylationEPIC; Data preprocessing ID PROBE DESIGN BIAS; NORMALIZATION; ARRAY; QUANTILE AB Background: The Illumina Infinium HumanMethylation450 BeadChip and its successor, Infinium MethylationEPIC BeadChip, have been extensively utilized in epigenome-wide association studies. Both arrays use two fluorescent dyes (Cy3-green/Cy5-red) to measure methylation level at CpG sites. However, performance difference between dyes can result in biased estimates of methylation levels. Results: Here we describe a novel method, called REgression on Logarithm of Internal Control probes (RELIC) to correct for dye bias on whole array by utilizing the intensity values of paired internal control probes that monitor the two color channels. We evaluate the method in several datasets against other widely used dye-bias correction methods. Results on data quality improvement showed that RELIC correction statistically significantly outperforms alternative dye-bias correction methods. We incorporated the method into the R package ENmix, which is freely available from the Bioconductor website(https://www.bioconductor.org/packages/release/bioc/html/ENmix.html). Conclusions: RELIC is an efficient and robust method to correct for dye-bias in Illumina Methylation BeadChip data. It outperforms other alternative methods and conveniently implemented in R package ENmix to facilitate DNA methylation studies. C1 [Xu, Zongli; Taylor, Jack A.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. [Langie, Sabine A. S.; De Boever, Patrick] Flemish Inst Technol Res VITO, Environm Risk & Hlth Unit, Mol, Belgium. [Langie, Sabine A. S.; De Boever, Patrick] Hasselt Univ, Fac Sci, Diepenbeek, Belgium. [Taylor, Jack A.] Natl Inst Environm Hlth Sci, Epigenet & Stem Cell Biol Lab, NIH, Res Triangle Pk, NC USA. [Niu, Liang] Univ Cincinnati, Coll Med, Dept Environm Hlth, Div Biostat & Bioinformat, Cincinnati, OH 45267 USA. RP Niu, L (reprint author), Univ Cincinnati, Coll Med, Dept Environm Hlth, Div Biostat & Bioinformat, Cincinnati, OH 45267 USA. EM niulg@ucmail.uc.edu OI xu, zongli/0000-0002-9034-8902; taylor, jack/0000-0001-5303-6398 FU Center for Environmental Genetics grant (National Institute of Environmental Health Sciences) [P30-ES00606]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES049033, Z01 ES049032]; VITO-FWO post-doctoral fellowship [12L5216N] FX This work was supported by the Center for Environmental Genetics grant (National Institute of Environmental Health Sciences award P30-ES00606), Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES049033, and Z01 ES049032), and VITO-FWO post-doctoral fellowship (12L5216N). NR 14 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 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JAN 3 PY 2017 VL 18 AR 4 DI 10.1186/s12864-016-3426-3 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EG8UG UT WOS:000391332000004 PM 28049437 ER PT J AU Karyadi, DM Geybels, MS Karlins, E Decker, B Mcntosh, L Hutchinson, A Kolb, S McDonnell, SK Hicks, B Middha, S FitzGerald, LM DeRycke, MS Yeager, M Schaid, DJ Chanock, SJ Thibodeau, SN Bernd, SI Stanford, JL Ostrander, EA AF Karyadi, Danielle M. Geybels, Milan S. Karlins, Eric Decker, Brennan Mcntosh, Laura Hutchinson, Amy Kolb, Suzanne McDonnell, Shannon K. Hicks, Belynda Middha, Sumit FitzGerald, Liesel M. DeRycke, Melissa S. Yeager, Meredith Schaid, Daniel J. Chanock, Stephen J. Thibodeau, Stephen N. Bernd, Sonja I. Stanford, Janet L. Ostrander, Elaine A. TI Whole exome sequencing in 75 high-risk families with validation and replication in independent case-control studies identifies TANGO2, OR5H14, and CHAD as new prostate cancer susceptibility genes SO ONCOTARGET LA English DT Article DE whole exome sequencing; cancer susceptibility; high-risk families; case-control association; prostate cancer ID GENOME-WIDE SCAN; INTERNATIONAL CONSORTIUM; METABOLIC CRISES; MUTATIONS; LINKAGE; GENETICS; AGGRESSIVENESS; ASSOCIATION; FRAMEWORK; VARIANTS AB Prostate cancer (PCa) susceptibility is defined by a continuum from rare, high-penetrance to common, low-penetrance alleles. Research to date has concentrated on identification of variants at the ends of that continuum. Taking an alternate approach, we focused on the important but elusive class of low-frequency, moderately penetrant variants by performing disease model-based variant filtering of whole exome sequence data from 75 hereditary PCa families. Analysis of 341 candidate risk variants identified nine variants significantly associated with increased PCa risk in a population-based, case-control study of 2,495 men. In an independent nested case-control study of 7,121 men, there was risk association evidence for TANGO2 p. Ser17Ter and the established HOXB13 p. Gly84Glu variant. Meta-analysis combining the case-control studies identified two additional variants suggestively associated with risk, OR5H14 p. Met59Val and CHAD p. Ala342Asp. The TANGO2 and HOXB13 variants co-occurred in cases more often than expected by chance and never in controls. Finally, TANGO2 p. Ser17Ter was associated with aggressive disease in both case-control studies separately. Our analyses identified three new PCa susceptibility alleles in the TANGO2, OR5H14 and CHAD genes that not only segregate in multiple high-risk families but are also of importance in altering disease risk for men from the general population. This is the first successful study to utilize sequencing in high-risk families for the express purpose of identifying low-frequency, moderately penetrant PCa risk mutations. C1 [Karyadi, Danielle M.; Karlins, Eric; Decker, Brennan; Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Geybels, Milan S.; Mcntosh, Laura; Kolb, Suzanne; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Karlins, Eric; Hutchinson, Amy; Hicks, Belynda; Yeager, Meredith; Chanock, Stephen J.; Bernd, Sonja I.] NCI, NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [McDonnell, Shannon K.; Middha, Sumit; Schaid, Daniel J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [FitzGerald, Liesel M.] Univ Tasmania, Menzies Inst Med Res, Hobart, Tas, Australia. [DeRycke, Melissa S.; Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Ostrander, EA (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Decker, Brennan/0000-0003-4516-7421; Ostrander, Elaine/0000-0001-6075-9738 FU Intramural Program of the National Human Genome Research Institute; National Cancer Institute; National Cancer Institute, NIH [R01 CA056678, R01 CA092579, R01 CA080122, U01 CA89600]; Fred Hutchinson Cancer Research Center; Prostate Cancer Foundation; Dutch Cancer Society Fellowship [BUIT 2014-6645]; NIH [HHSN268200782096C] FX This work was supported by the Intramural Program of the National Human Genome Research Institute (D.M. Karyadi, E. Karlins, B. Decker, E. A. Ostrander) and National Cancer Institute (E. Karlins, A. Hutchinson, B. Hicks, M. Yeager, S.J. Chanock, S. I. Berndt), by grants from the National Cancer Institute, NIH (R01 CA056678, R01 CA092579, and R01 CA080122 to J.L. Stanford; U01 CA89600 to S.N. Thibodeau) with additional support from the Fred Hutchinson Cancer Research Center and the Prostate Cancer Foundation and by a Dutch Cancer Society Fellowship (BUIT 2014-6645 to M. Geybels). The Center for Inherited Disease Research, which provided sequencing services for 19 families, is funded through a contact from NIH to The Johns Hopkins University (contract number HHSN268200782096C). Sequencing of the 56 families at Mayo Clinic was supported by a grant from the National Cancer Institute, NIH (U01 CA89600). NR 38 TC 0 Z9 0 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JAN 3 PY 2017 VL 8 IS 1 BP 1495 EP 1507 DI 10.18632/oncotarget.13646 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EH1DH UT WOS:000391503300116 PM 27902461 ER PT J AU Pope, HG Khalsa, JH Bhasin, S AF Pope, Harrison G., Jr. Khalsa, Jag H. Bhasin, Shalender TI Body Image Disorders and Abuse of Anabolic-Androgenic Steroids Among Men SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID MUSCLE DYSMORPHIA; USERS C1 [Pope, Harrison G., Jr.] Harvard Med Sch, McLean Hosp, Biol Psychiat Lab, Belmont, MA USA. [Khalsa, Jag H.] NIDA, Med Consequences Branch, Div Therapeut & Med Consequences, NIH, Bethesda, MD 20892 USA. [Bhasin, Shalender] Harvard Med Sch, Brigham & Womens Hosp, Res Program Mens Hlth Aging & Metab, 221 Longwood Ave, Boston, MA 02115 USA. RP Bhasin, S (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Res Program Mens Hlth Aging & Metab, 221 Longwood Ave, Boston, MA 02115 USA. EM sbhasin@bwh.harvard.edu NR 10 TC 0 Z9 0 U1 10 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 3 PY 2017 VL 317 IS 1 BP 23 EP 24 DI 10.1001/jama.2016.17441 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EG4JE UT WOS:000391009100011 PM 27930760 ER PT J AU Himelstein, AL Foster, JC Khatcheressian, JL Roberts, JD Seisler, DK Novotny, PJ Qin, R Go, RS Grubbs, SS O'Connor, T Velasco, MR Weckstein, D O'Mara, A Loprinzi, CL Shapiro, CL AF Himelstein, Andrew L. Foster, Jared C. Khatcheressian, James L. Roberts, John D. Seisler, Drew K. Novotny, Paul J. Qin, Rui Go, Ronald S. Grubbs, Stephen S. O'Connor, Tracey Velasco, Mario R., Jr. Weckstein, Douglas O'Mara, Ann Loprinzi, Charles L. Shapiro, Charles L. TI Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PLACEBO-CONTROLLED TRIAL; BREAST-CANCER; PREVENTION; CARCINOMA; PHASE-3 AB IMPORTANCE Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. OBJECTIVE To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. DESIGN, SETTING, PARTICIPANTS Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014. INTERVENTIONS Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years. MAIN OUTCOMES AND MEASURES The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). RESULTS Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3%[1-sided 95% CI, -4% to infinity]; P<.001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks. CONCLUSIONS AND RELEVANCE Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option. C1 [Himelstein, Andrew L.; Grubbs, Stephen S.] Canc Ctr & Res Inst, 4701 Ogletown Stanton Rd,Ste 3400, Newark, DE 19713 USA. [Foster, Jared C.; Seisler, Drew K.; Novotny, Paul J.; Qin, Rui] Mayo Clin, Alliance Stat & Data Ctr, Rochester, MN USA. [Khatcheressian, James L.] Virginia Canc Inst, Richmond, VA USA. [Roberts, John D.] VCU Massey Canc Ctr, Richmond, VA USA. [Roberts, John D.] Yale Univ, New Haven, CT USA. [Qin, Rui] Regeneron Pharmaceut, Basking Ridge, NJ USA. [Go, Ronald S.] Gundersen Hlth Syst, La Crosse, WI USA. [Go, Ronald S.; Loprinzi, Charles L.] Mayo Clin, Rochester, MN USA. [Grubbs, Stephen S.] Amer Soc Clin Oncol, Alexandria, VA USA. [O'Connor, Tracey] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Velasco, Mario R., Jr.] Decatur Mem Hosp, Decatur, IL USA. [Weckstein, Douglas] New Hampshire Oncol Hematol PA, Hooksett, NH USA. [O'Mara, Ann] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Shapiro, Charles L.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. RP Himelstein, AL (reprint author), Canc Ctr & Res Inst, 4701 Ogletown Stanton Rd,Ste 3400, Newark, DE 19713 USA. EM ahimelstein@cbg.org FU National Cancer Institute, National Institutes of Health [UG1CA189823, U10CA016359, U10CA037404, U10CA037447, U10CA059518, U10CA180790, U10CA045418, U10CA180866, UG1CA189819]; National Center for Advancing Translational Sciences, National Institutes of Health [UL1TR001070] FX This research was supported by grants UG1CA189823 (awarded to the Alliance for Clinical Trials in Oncology), U10CA016359, U10CA037404, U10CA037447, U10CA059518, U10CA180790, U10CA045418, U10CA180866, and UG1CA189819 from the National Cancer Institute, National Institutes of Health. The C-terminal telopeptide assays were supported by grant UL1TR001070 from the National Center for Advancing Translational Sciences, National Institutes of Health. NR 19 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 3 PY 2017 VL 317 IS 1 BP 48 EP 58 DI 10.1001/jama.2016.19425 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EG4JE UT WOS:000391009100019 PM 28030702 ER PT J AU Soethoudt, M Grether, U Fingerle, J Grim, TW Fezza, F de Petrocellis, L Ullmer, C Rothenhausler, B Perret, C van Gils, N Finlay, D MacDonald, C Chicca, A Gens, MD Stuart, J de Vries, H Mastrangelo, N Xia, LZ Alachouzos, G Baggelaar, MP Martella, A Mock, ED Deng, H Heitman, LH Connor, M Di Marzo, V Gertsch, J Lichtman, AH Maccarrone, M Pacher, P Glass, M van der Stelt, M AF Soethoudt, Marjolein Grether, Uwe Fingerle, Juergen Grim, Travis W. Fezza, Filomena de Petrocellis, Luciano Ullmer, Christoph Rothenhausler, Benno Perret, Camille van Gils, Noortje Finlay, David MacDonald, Christa Chicca, Andrea Gens, Marianela Dalghi Stuart, Jordyn de Vries, Henk Mastrangelo, Nicolina Xia, Lizi Alachouzos, Georgios Baggelaar, Marc P. Martella, Andrea Mock, Elliot D. Deng, Hui Heitman, Laura H. Connor, Mark Di Marzo, Vincenzo Gertsch, Jurg Lichtman, Aron H. Maccarrone, Mauro Pacher, Pal Glass, Michelle van der Stelt, Mario TI Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity SO NATURE COMMUNICATIONS LA English DT Article ID HEPATIC ISCHEMIA/REPERFUSION INJURY; DIACYLGLYCEROL LIPASE-ALPHA; ENDOCANNABINOID SYSTEM; MOLECULAR CHARACTERIZATION; BIOLOGICAL EVALUATION; TRICYCLIC PYRAZOLES; THERAPEUTIC TARGET; IN-VIVO; ANANDAMIDE; INHIBITION AB The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CB2R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB2R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB2R agonists to study the role of CB2R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research. C1 [Soethoudt, Marjolein; Alachouzos, Georgios; Baggelaar, Marc P.; Martella, Andrea; Mock, Elliot D.; Deng, Hui; van der Stelt, Mario] Leiden Univ, Leiden Inst Chem, Dept Mol Physiol, Einsteinweg 55, NL-2333 CC Leiden, Netherlands. [Soethoudt, Marjolein; van Gils, Noortje; de Vries, Henk; Xia, Lizi; Heitman, Laura H.] Leiden Univ, Leiden Acad Ctr Drug Res, Dept Med Chem, Einsteinweg 55, NL-2333 CC Leiden, Netherlands. [Grether, Uwe; Ullmer, Christoph; Rothenhausler, Benno; Perret, Camille] F Hoffmann La Roche Inc, Roche Innovat Ctr Basel, Grenzachterstr 124, CH-4070 Basel, Switzerland. [Fingerle, Juergen] Univ Tubingen, NMI, Dept Biochem, Markwiesenstr 55, D-72770 Reutlingen, Germany. [Grim, Travis W.; Lichtman, Aron H.] Dept Pharmacol & Toxicol, 1220 East Broad St,POB 980613, Richmond, VA 23298 USA. [Fezza, Filomena] Univ Roma Tor Vergata, Dept Expt Med & Surg, Via Montpellier 1, I-00133 Rome, Italy. [Fezza, Filomena; Maccarrone, Mauro] IRCCS Santa Lucia Fdn, European Ctr Brain Res, Via Fosso Fiorano 65, I-00143 Rome, Italy. [de Petrocellis, Luciano; Di Marzo, Vincenzo] CNR, Endocannabinoid Res Grp, Inst Biomol Chem, Via Campi Flegrei 34, I-80078 Pozzuoli, Italy. [Finlay, David; MacDonald, Christa; Glass, Michelle] Univ Auckland, Fac Med & Hlth Sci, Dept Pharmacol & Clin Pharmacol, 85 Pk Rd, Auckland 1023, New Zealand. [Chicca, Andrea; Gens, Marianela Dalghi; Gertsch, Jurg] Univ Bern, Inst Biochem & Mol Med, Buhlstr 28, CH-3012 Bern, Switzerland. [Stuart, Jordyn; Connor, Mark] Macquarie Univ, Fac Med & Hlth Sci, Dept Biomed Sci, N Ryde, NSW 2109, Australia. [Mastrangelo, Nicolina; Martella, Andrea; Maccarrone, Mauro] Campus Biomed Univ Rome, Dept Med, Via Alvaro del Portillo 21, I-00128 Rome, Italy. [Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. RP van der Stelt, M (reprint author), Leiden Univ, Leiden Inst Chem, Dept Mol Physiol, Einsteinweg 55, NL-2333 CC Leiden, Netherlands.; Glass, M (reprint author), Univ Auckland, Fac Med & Hlth Sci, Dept Pharmacol & Clin Pharmacol, 85 Pk Rd, Auckland 1023, New Zealand.; Pacher, P (reprint author), NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. EM pacher@mail.nih.gov; m.glass@auckland.ac.nz; m.van.der.stelt@chem.leidenuniv.nl OI Connor, Mark/0000-0003-2538-2001; Glass, Michelle/0000-0002-5997-6898 FU ECHO-STIP grant from Dutch Research Council-Chemical Sciences; RPF program; Ministero dell'Istruzione, dell'Universita e della Ricerca (PRIN grant); Intramural Research Program of NIH/NIAAA; NIH [P30 DA033934, T32DA007027] FX This paper is dedicated to Prof Dr Raphael Mechoulam, the founder of cannabinoid research. M.S., L.H.H. and M.v.d.S. were supported by an ECHO-STIP grant from the Dutch Research Council-Chemical Sciences. A.M. was supported by the RPF program. Partial support from Ministero dell'Istruzione, dell'Universita e della Ricerca (PRIN 2010-2011 grant to M.M.) is gratefully acknowledged. P.P. was supported by the Intramural Research Program of NIH/NIAAA. Mark Rau (laboratory J.G.) is acknowledged for measuring AEA uptake inhibition. Pharmacokinetics in vivo laboratories, Drug Disposition and Safety laboratories. Pharmaceutical Sciences pRED and F. Hoffmann-La Roche Ltd, Basel, Switzerland are acknowledged for performing the in vitro DMPK and in vivo studies. T.W.G and A.H.L were supported by NIH grants P30 DA033934 and T32DA007027. 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 JAN 3 PY 2017 VL 8 AR 13958 DI 10.1038/ncomms13958 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG5CS UT WOS:000391061700001 PM 28045021 ER PT J AU Mahmoodi, BK Cushman, M Naess, IA Allison, MA Bos, WJ Braekkan, SK Cannegieter, SC Gansevoort, RT Gona, PN Hammerstrom, J Hansen, JB Heckbert, S Holst, AG Lakoski, SG Lutsey, PL Manson, JE Martin, LW Matsushita, K Meijer, K Overvad, K Prescott, E Puurunen, M Rossouw, JE Sang, YY Severinsen, MT ten Berg, J Folsom, AR Zakai, NA AF Mahmoodi, Bakhtawar K. Cushman, Mary Naess, Inger Anne Allison, Matthew A. Bos, Willem Jan Braekkan, Sigrid K. Cannegieter, Suzanne C. Gansevoort, Ron T. Gona, Philimon N. Hammerstrom, Jens Hansen, John-Bjarne Heckbert, Susan Holst, Anders G. Lakoski, Susan G. Lutsey, Pamela L. Manson, JoAnn E. Martin, Lisa W. Matsushita, Kunihiro Meijer, Karina Overvad, Kim Prescott, Eva Puurunen, Marja Rossouw, Jacques E. Sang, Yingying Severinsen, Marianne T. ten Berg, Jur Folsom, Aaron R. Zakai, Neil A. TI Association of Traditional Cardiovascular Risk Factors With Venous Thromboembolism An Individual Participant Data Meta-Analysis of Prospective Studies SO CIRCULATION LA English DT Article DE cardiovascular disease; diabetes mellitus; hyperlipidemia; hypertension; risk factors; smoking; venous thromboembolism ID DIABETES-MELLITUS; WOMENS HEALTH; THROMBOSIS; POPULATION; DISEASE; TROMSO; MORTALITY; ARTERIAL AB BACKGROUND: Much controversy surrounds the association of traditional cardiovascular disease risk factors with venous thromboembolism (VTE). METHODS: We performed an individual level random-effect meta-analysis including 9 prospective studies with measured baseline cardiovascular disease risk factors and validated VTE events. Definitions were harmonized across studies. Traditional cardiovascular disease risk factors were modeled categorically and continuously using restricted cubic splines. Estimates were obtained for overall VTE, provoked VTE (ie, VTE occurring in the presence of 1 or more established VTE risk factors), and unprovoked VTE, pulmonary embolism, and deep-vein thrombosis. RESULTS: The studies included 244 865 participants with 4910 VTE events occurring during a mean follow-up of 4.7 to 19.7 years per study. Age, sex, and body mass index-adjusted hazard ratios for overall VTE were 0.98 (95% confidence interval [CI]: 0.89-1.07) for hypertension, 0.97 (95% CI: 0.88-1.08) for hyperlipidemia, 1.01 (95% CI: 0.89-1.15) for diabetes mellitus, and 1.19 (95% CI: 1.08-1.32) for current smoking. After full adjustment, these estimates were numerically similar. When modeled continuously, an inverse association was observed for systolic blood pressure (hazard ratio= 0.79 [95% CI: 0.68-0.92] at systolic blood pressure 160 vs 110 mm Hg) but not for diastolic blood pressure or lipid measures with VTE. An important finding from VTE subtype analyses was that cigarette smoking was associated with provoked but not unprovoked VTE. Fully adjusted hazard ratios for the associations of current smoking with provoked and unprovoked VTE were 1.36 (95% CI: 1.22-1.52) and 1.08 (95% CI: 0.90-1.29), respectively. CONCLUSIONS: Except for the association between cigarette smoking and provoked VTE, which is potentially mediated through comorbid conditions such as cancer, the modifiable traditional cardiovascular disease risk factors are not associated with increased VTE risk. Higher systolic blood pressure showed an inverse association with VTE. C1 [Mahmoodi, Bakhtawar K.; Bos, Willem Jan; ten Berg, Jur] St Antonius Hosp, Dept Cardiol & Internal Med, Nieuwegein, Netherlands. [Mahmoodi, Bakhtawar K.; Meijer, Karina] Univ Groningen, Univ Med Ctr Groningen, Dept Haematol, NL-9700 AB Groningen, Netherlands. [Cushman, Mary; Zakai, Neil A.] Univ Vermont, Dept Med, Burlington, VT 05405 USA. [Cushman, Mary; Zakai, Neil A.] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Naess, Inger Anne; Hammerstrom, Jens] Univ Trondheim Hosp, Dept Hematol, Trondheim, Norway. [Allison, Matthew A.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Braekkan, Sigrid K.; Hansen, John-Bjarne] Univ Tromso, Dept Clin Med, KG Jebsen Thrombosis Res & Expertise Ctr, N-9001 Tromso, Norway. [Cannegieter, Suzanne C.] Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2300 RA Leiden, Netherlands. [Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9700 AB Groningen, Netherlands. [Gona, Philimon N.] Univ Massachusetts, Dept Exercise & Hlth Sci, Boston, MA 02125 USA. [Heckbert, Susan] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Holst, Anders G.] Rigshosp, Copenhagen Univ Hosp, Mol Cardiol Lab, Copenhagen, Denmark. [Lakoski, Susan G.] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent & Cardiol, Houston, TX 77030 USA. [Lutsey, Pamela L.; Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Manson, JoAnn E.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Martin, Lisa W.] George Washington Univ, Sch Med & Hlth Sci, Div Cardiol, Washington, DC 20052 USA. [Matsushita, Kunihiro; Sang, Yingying] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Overvad, Kim] Aarhus Univ, Epidemiol Sect, Dept Publ Hlth, DK-8000 Aarhus C, Denmark. [Overvad, Kim] Aalborg Univ Hosp, Dept Cardiol, Aalborg, Denmark. [Prescott, Eva] Univ Copenhagen, Dept Cardiol, Bispebjerg Hosp, DK-1168 Copenhagen, Denmark. [Puurunen, Marja] Boston Univ, Sch Med, Framingham Heart Study, Boston, MA 02215 USA. [Rossouw, Jacques E.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Severinsen, Marianne T.] Aalborg Univ Hosp, Dept Hematol, Aalborg, Denmark. RP Mahmoodi, BK (reprint author), St Antonius Hosp, Dept Cardiol, Koekoekslaan 1, NL-3435 CM Nieuwegein, Netherlands. EM b.k.mahmoodi@umcg.nl FU Sint Antonius Hospital's research fund [10000] FX Individual studies were supported by a variety of sources for enrollment and data collection, including laboratory measurements and follow-up (online-only Data Supplement). The current meta analysis was sponsored by a small grant (<$10000) provided by the Sint Antonius Hospital's research fund. The sponsors had no role in the study design, analysis, data interpretation, or writing of the article. Dr Mahmoodi had full access to the output and estimates of the studies and performed the meta-analysis of the estimates; individual-level data were accessible by the representing coauthor of the individual studies. All authors had final responsibility for the decision to submit for publication. NR 31 TC 1 Z9 1 U1 4 U2 4 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 3 PY 2017 VL 135 IS 1 BP 7 EP + DI 10.1161/CIRCULATIONAHA.116.024507 PG 56 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF8ED UT WOS:000390560700005 PM 27831499 ER PT J AU Kovacs, ZI Kim, S Jikaria, N Qureshi, F Milo, B Lewis, BK Bresler, M Burks, SR Frank, JA AF Kovacs, Zsofia I. Kim, Saejeong Jikaria, Neekita Qureshi, Farhan Milo, Blerta Lewis, Bobbi K. Bresler, Michele Burks, Scott R. Frank, Joseph A. TI Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pulsed focused ultrasound; microbubbles; blood-brain barrier; sterile inflammation; magnetic resonance imaging ID FOCAL CEREBRAL-ISCHEMIA; MONOCYTE CHEMOATTRACTANT PROTEIN-1; NF-KAPPA-B; CONTRAST AGENT; IN-VIVO; ACTIVATED CHANNELS; DRUG-DELIVERY; IMMUNE-SYSTEM; MOUSE MODEL; INJURY AB MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFa indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NF kappa B pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL+ neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68(+) macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials. C1 [Kovacs, Zsofia I.; Kim, Saejeong; Jikaria, Neekita; Qureshi, Farhan; Milo, Blerta; Lewis, Bobbi K.; Bresler, Michele; Burks, Scott R.; Frank, Joseph A.] NIH, Frank Lab, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Kovacs, Zsofia I.; Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Kovacs, ZI (reprint author), NIH, Frank Lab, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA.; Kovacs, ZI (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. EM zsofia.kovacs@nih.gov; jf5z@nih.gov FU Intramural Research Programs of the Clinical Center; National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health FX This research was funded by the Intramural Research Programs of the Clinical Center and the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health. NR 88 TC 0 Z9 0 U1 13 U2 13 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 3 PY 2017 VL 114 IS 1 BP E75 EP E84 DI 10.1073/pnas.1614777114 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG5OM UT WOS:000391093700009 PM 27994152 ER PT J AU Petrie, RJ Harlin, HM Korsak, LIT Yamada, KM AF Petrie, Ryan J. Harlin, Heather M. Korsak, Lulu I. T. Yamada, Kenneth M. TI Activating the nuclear piston mechanism of 3D migration in tumor cells SO JOURNAL OF CELL BIOLOGY LA English DT Article ID PROTEOLYSIS; ADHESION; MATRIX; MODES; METASTASIS; PLASTICITY; MOTILITY; INVASION; MT1-MMP; FORCE AB Primary human fibroblasts have the remarkable ability to use their nucleus like a piston, switching from low-to high-pressure protrusions in response to the surrounding three-dimensional (3D) matrix. Although migrating tumor cells can also change how they migrate in response to the 3D matrix, it is not clear if they can switch between high-and low-pressure protrusions like primary fibroblasts. We report that unlike primary fibroblasts, the nuclear piston is not active in fibrosarcoma cells. Protease inhibition rescued the nuclear piston mechanism in polarized HT1080 and SW684 cells and generated compartmentalized pressure. Achieving compartmentalized pressure required the nucleoskeleton-cytoskeleton linker protein nesprin 3, actomyosin contractility, and integrin-mediated adhesion, consistent with lobopodia-based fibroblast migration. In addition, this activation of the nuclear piston mechanism slowed the 3D movement of HT1080 cells. Together, these data indicate that inhibiting protease activity during polarized tumor cell 3D migration is sufficient to restore the nuclear piston migration mechanism with compartmentalized pressure characteristic of nonmalignant cells. C1 [Petrie, Ryan J.; Harlin, Heather M.; Korsak, Lulu I. T.] Drexel Univ, Dept Biol, Philadelphia, PA 19104 USA. [Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Petrie, RJ (reprint author), Drexel Univ, Dept Biol, Philadelphia, PA 19104 USA. EM rjp336@drexel.edu FU Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research; College of Arts and Sciences of Drexel University; Department of Biology of Drexel University FX Work in K.M. Yamada's laboratory is supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research. R.J. Petrie is supported by startup funds from the College of Arts and Sciences and the Department of Biology of Drexel University. NR 30 TC 0 Z9 0 U1 7 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JAN 2 PY 2017 VL 216 IS 1 BP 93 EP 100 DI 10.1083/jcb.201605097 PG 8 WC Cell Biology SC Cell Biology GA EI5TD UT WOS:000392556800016 PM 27998990 ER PT J AU Liu, LK Choudhary, V Toulmay, A Prinz, WA AF Liu, Li-Ka Choudhary, Vineet Toulmay, Alexandre Prinz, William A. TI An inducible ER-Golgi tether facilitates ceramide transport to alleviate lipotoxicity SO JOURNAL OF CELL BIOLOGY LA English DT Article ID NUCLEUS-VACUOLE JUNCTIONS; MEMBRANE CONTACT SITES; SACCHAROMYCES-CEREVISIAE; ENDOPLASMIC-RETICULUM; LIPID TRANSFER; EXTENDED SYNAPTOTAGMINS; SPHINGOLIPID SYNTHESIS; ALKALINE CERAMIDASE; ELECTRON-MICROSCOPY; INSULIN-RESISTANCE AB Ceramides are key intermediates in sphingolipid biosynthesis and potent signaling molecules. However, excess ceramide is toxic, causing growth arrest and apoptosis. In this study, we identify a novel mechanism by which cells prevent the toxic accumulation of ceramides; they facilitate nonvesicular ceramide transfer from the endoplasmic reticulum (ER) to the Golgi complex, where ceramides are converted to complex sphingolipids. We find that the yeast protein Nvi2p promotes the nonvesicular transfer of ceramides from the ER to the Golgi complex. The protein is a tether that generates close contacts between these compartments and may directly transport ceramide. Nvi2p normally resides at contacts between the ER and other organelles, but during ER stress, it relocalizes to and increases ER Golgi contacts. ER Golgi contacts fail to form during ER stress in cells lacking Nvi2p. Our findings demonstrate that cells regulate ER Golgi contacts in response to stress and reveal that nonvesicular ceramide transfer out of the ER prevents the buildup of toxic amounts of ceramides. C1 [Liu, Li-Ka; Choudhary, Vineet; Toulmay, Alexandre; Prinz, William A.] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Toulmay, A; Prinz, WA (reprint author), NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM toulmayal@niddk.nih.gov; prinzw@helix.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 59 TC 1 Z9 1 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JAN 2 PY 2017 VL 216 IS 1 BP 131 EP 147 DI 10.1083/jcb.201606059 PG 17 WC Cell Biology SC Cell Biology GA EI5TD UT WOS:000392556800019 PM 28011845 ER PT J AU Perera, L Beard, WA Pedersen, LG Wilson, SH AF Perera, Lalith Beard, William A. Pedersen, Lee G. Wilson, Samuel H. TI Hiding in Plain Sight: The Bimetallic Magnesium Covalent Bond in Enzyme Active Sites SO INORGANIC CHEMISTRY LA English DT Article ID PARTICLE MESH EWALD; CATALYTIC COMPLEX; MECHANISM; ARGINASE; MG-2(2+); CLUSTER; IONS AB The transfer of phosphate groups is an essential function of many intracellular biological enzymes. The transfer is in many cases facilitated by a protein scaffold involving two closely spaced magnesium "ions". It has long been a mystery how these "ions" can retain their closely spaced positions throughout enzymatic phosphate transfer: Coulomb's law would dictate large repulsive forces between these ions at the observed distances. Here we show, however, that the electron density can be borrowed from nearby electron-rich oxygens to populate a bonding molecular orbital that is largely localized between the magnesium "ions". The result is that the Mg-Mg core of these phosphate transfer enzymes is surprisingly similar to a metastable [Mg-2](2+) ion in the gas phase, an ion that has been identified experimentally and studied with high-level quantum-mechanical calculations. This similarity is confirmed by comparative computations of the electron densities of [Mg-2](2+) in the gas phase and the Mg-Mg core in the structures derived from QM/MM studies of high-resolution X-ray crystal structures. That there is a level of covalent bonding between the two Mg "ions" at the core of these enzymes is a novel concept that enables an improved vision of how these enzymes function at the molecular level. The concept is broader than magnesium-other biologically relevant metals (e.g., Mn and Zn) can also form similar stabilizing covalent Me-Me bonds in both organometallic and inorganic crystals. C1 [Perera, Lalith; Beard, William A.; Pedersen, Lee G.; Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Pedersen, Lee G.] Univ North Carolina Chapel Hill, Dept Chem, POB 3290, Chapel Hill, NC 27517 USA. RP Pedersen, LG; Wilson, SH (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.; Pedersen, LG (reprint author), Univ North Carolina Chapel Hill, Dept Chem, POB 3290, Chapel Hill, NC 27517 USA. EM pedersen@ad.unc.edu; wilson5@niehs.nih.gov FU Research Projects in Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES043010, Z01-ES050158, Z01-ES050159]; National Institutes of Health [U19CA105010] FX This research was supported by Research Projects Z01-ES043010 (to L.P.) and Z01-ES050158 and Z01-ES050159 (to S.H.W.) in the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences and in association with National Institutes of Health Grant U19CA105010. NR 30 TC 0 Z9 0 U1 9 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0020-1669 EI 1520-510X J9 INORG CHEM JI Inorg. Chem. PD JAN 2 PY 2017 VL 56 IS 1 BP 313 EP 320 DI 10.1021/acs.inorgchem.6b02189 PG 8 WC Chemistry, Inorganic & Nuclear SC Chemistry GA EG7SJ UT WOS:000391248900036 PM 27976880 ER PT J AU Levin, MJ Lindsey, JC Kaplan, SS Schimana, W Lawrence, J McNeal, MM Bwakura-Dangarembizi, M Ogwu, A Mpabalwani, EM Sato, P Siberry, G Nelson, M Hille, D Weinberg, GA Weinberg, A AF Levin, Myron J. Lindsey, Jane C. Kaplan, Susan S. Schimana, Werner Lawrence, Jody McNeal, Monica M. Bwakura-Dangarembizi, Mutsa Ogwu, Anthony Mpabalwani, Evans M. Sato, Paul Siberry, George Nelson, Margaret Hille, Darcy Weinberg, Geoffrey A. Weinberg, Adriana TI Safety and immunogenicity of a live attenuated pentavalent rotavirus vaccine in HIV-exposed infants with or without HIV infection in Africa SO AIDS LA English DT Article DE HIV exposed; HIV infection; immunogenicity; infants; rotavirus; rotavirus vaccine; safety ID ACTIVE-ANTIRETROVIRAL-THERAPY; TREATMENT STRATEGIES; ACQUIRED ROTAVIRUS; ANTIBODY-RESPONSES; UNINFECTED INFANTS; DIARRHEAL DISEASE; CHILDREN; IMMUNODEFICIENCY; MEASLES; PROTECTION AB Objective:Although many HIV-infected (HIV+) and HIV-exposed but uninfected (HEU) infants have received live rotavirus vaccines since the WHO recommended universal administration of these vaccines to infants, there has been limited prospective information on their safety and immunogenicity in either group of infants.Design/methods:We performed a randomized, double-blinded, placebo-controlled trial of the safety and immunogenicity of oral pentavalent rotavirus vaccine (RV5) administered to HIV+ and HEU infants in four African countries. Ninety-three percent of HIV+ infants were receiving antiretroviral therapy prior to vaccination. Participants were followed for safety. Immune responses were measured 14 days after three doses of RV5, including serum antirotavirus neutralizing and IgA antibodies, IgA antibody in stool, and antirotavirus memory B and T-cell FluoroSpot. Shedding of RV5 in stool was monitored.Results:A total of 76 HIV+ and 126 HEU infants were enrolled from 2009 to 2013. No significant differences were found in adverse event rates, including grade 3 events, between RV5 and placebo recipients, for either HIV+ or HEU infants. The proportion of antirotavirus IgA responders (at least three-fold increase from baseline) after RV5 administration was 81% in both HIV+ and HEU infants, which was approximately 2.5-fold higher than in placebo recipients (P<0.001). Neutralizing antibody responses to three of five serotypes were significantly higher after RV5 regardless of HIV status, and those of HIV+ infants were equal or greater than responses of HEU infants to all five serotypes. Only one HIV+ RV5 recipient had RV5 isolated from stool.Conclusion:RV5 was immunogenic in both HIV+ and HEU infants and no safety signals were observed. C1 [Levin, Myron J.; Weinberg, Adriana] Univ Colorado Anschutz Med Campus, Dept Pediat, Sect Pediat Infect Dis, Aurora, CO USA. [Levin, Myron J.] Univ Colorado Anschutz Med Campus, Dept Med, Sect Pediat Infect Dis, Aurora, CO USA. [Lindsey, Jane C.] Harvard Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. [Kaplan, Susan S.; Nelson, Margaret; Hille, Darcy] Merck & Co Inc, Kenilworth, NJ USA. [Schimana, Werner] Municipal Munich, Dept Hlth & Environm, Sect Hlth Promot, Munich, Germany. [Lawrence, Jody] Pfizer Inc, Collegeville, PA USA. [McNeal, Monica M.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Infect Dis, Cincinnati, OH 45229 USA. [Bwakura-Dangarembizi, Mutsa] Univ Zimbabwe, Coll Hlth Sci, Dept Paediat & Child Hlth, Harare, Zimbabwe. [Ogwu, Anthony] Harvard AIDS Inst, Gaborone, Botswana. [Ogwu, Anthony] Trinity Med Ctr, Port Adelaide, SA, Australia. [Mpabalwani, Evans M.] Univ Teaching Hosp, Dept Pediat & Child Hlth, Lusaka, Zambia. [Sato, Paul] NIAID, Maternal Adolescent & Pediat Res Branch, NIH, Rockville, MD USA. [Sato, Paul] NIH, Off AIDS Res, Bethesda, MD USA. [Siberry, George] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD USA. [Weinberg, Geoffrey A.] Univ Rochester, Sch Med & Dent, Dept Pediat, Rochester, NY 14642 USA. [Weinberg, Adriana] Univ Colorado Anschutz Med Campus, Dept Med, Sect Pediat Infect Dis, Aurora, CO USA. [Weinberg, Adriana] Univ Colorado Anschutz Med Campus, Dept Pathol, Sect Pediat Infect Dis, Aurora, CO USA. RP Levin, MJ (reprint author), Univ Colorado Anschutz Med Campus, 401 Mail Stop C227,1784 Racine St, Aurora, CO 80045 USA. EM myron.levin@ucdenver.edu FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH); Merck Co., Inc.; Merck & Co., Inc., Kenilworth, NJ, USA FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACTLOC), UM1AI068616 (IMPAACT SDMC), and UM1AI106716 (IMPAACT LC), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.; Merck & Co., Inc. provided financial support. In addition, Barbara Heckman BS (Frontier Science and Technology Research Foundation, Inc., 4033 Maple RD., Amherst, NY 14226, USA) helped with study conduct and manuscript preparation, Michelle Brown (Merck & Co., Inc.) contributed to the protocol development, and Jon Stek (Merck & Co., Inc.) for assistance in preparing the manuscript.; Funding for this research was provided by Merck & Co., Inc., Kenilworth, NJ, USA (sponsor) in conjunction with the International Maternal, Pediatric, and Adolescent AIDS Clinical Trials Network (IMPAACT) of the National Institute of Allergy and Infectious Diseases, NIH; National Institute of Mental Health, NIH; and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 51 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 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JAN 2 PY 2017 VL 31 IS 1 BP 49 EP 59 DI 10.1097/QAD.0000000000001258 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EF3QY UT WOS:000390240700006 PM 27662551 ER PT J AU Wilson, ML Fleming, KA AF Wilson, Michael L. Fleming, Kenneth A. TI Improving Global Access to Diagnostic Testing More Steps Forward SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Editorial Material C1 [Wilson, Michael L.] Denver Hlth, Dept Pathol & Lab Serv, Denver, CO 80204 USA. [Wilson, Michael L.] Univ Colorado, Sch Med, Dept Pathol, Aurora, CO 80045 USA. [Fleming, Kenneth A.] NCI, Ctr Global Hlth, Washington, DC USA. [Fleming, Kenneth A.] Univ Oxford, Green Templeton Coll, Oxford, England. RP Wilson, ML (reprint author), Denver Hlth, Dept Pathol & Lab Serv, Denver, CO 80204 USA.; Wilson, ML (reprint author), Univ Colorado, Sch Med, Dept Pathol, Aurora, CO 80045 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JAN PY 2017 VL 147 IS 1 BP 6 EP 7 DI 10.1093/AJCP/AQW219 PG 2 WC Pathology SC Pathology GA EP0QI UT WOS:000397091400001 PM 28171911 ER PT J AU Fleming, KA Naidoo, M Wilson, M Flanigan, J Horton, S Kuti, M Looi, LM Price, C Ru, K Ghafur, A Wang, JX Lago, N AF Fleming, Kenneth A. Naidoo, Mahendra Wilson, Michael Flanigan, John Horton, Susan Kuti, Modupe Looi, Lai Meng Price, Chris Ru, Kun Ghafur, Abdul Wang, Jianxiang Lago, Nestor TI An Essential Pathology Package for Low- and Middle-Income Countries SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Review DE Low-income countries; Middle-income countries; Africa; Asia; Essential pathology services; Hospital laboratory services ID SUB-SAHARAN AFRICA; LABORATORY ACCREDITATION; HEALTH; MEDICINE; QUALITY; COST AB Objectives: We review the current status of pathology services in low-and middle-income countries and propose an "essential pathology package" along with estimated costs. The purpose is to provide guidance to policy makers as countries move toward universal health care systems. Methods: Five key themes were reviewed using existing literature (role of leadership; education, training, and continuing professional development; technology; accreditation, management, and quality standards; and reimbursement systems). A tiered system is described, building on existing proposals. The economic analysis draws on the very limited published studies, combined with expert opinion. Results: Countries have underinvested in pathology services, with detrimental effects on health care. The equipment needs for a tier 1 laboratory in a primary health facility are modest ($ 2-$ 5,000), compared with $ 150,000 to $ 200,000 in a district hospital, and higher in a referral hospital (depending on tests undertaken). Access to a national (or regional) specialized laboratory undertaking disease surveillance and registry is important. Recurrent costs of appropriate laboratories in district and referral hospitals are around 6% of the hospital budget in midsized hospitals and likely decline in the largest hospitals. Primary health facilities rely largely on single-use tests. Conclusions: Pathology is an essential component of good universal health care. C1 [Fleming, Kenneth A.; Naidoo, Mahendra; Flanigan, John] NCI, Ctr Global Hlth, Washington, DC USA. [Fleming, Kenneth A.] Green Templeton Coll, 43 Woodstock Rd, Oxford OX2 6HG, England. [Price, Chris] Univ Oxford, Nuffield Dept Primary Care Hlth Sci, Oxford, England. [Wilson, Michael] Univ Colorado, Sch Med, Dept Pathol, Denver, CO 80262 USA. [Wilson, Michael] Denver Hlth, Dept Pathol & Lab Serv, Denver, CO USA. [Horton, Susan] Univ Waterloo, Global Hlth Econ, Waterloo, ON, Canada. [Kuti, Modupe] Univ Ibadan, Coll Med, Dept Chem Pathol, Ibadan, Nigeria. [Kuti, Modupe] Univ Coll Hosp, Ibadan, Nigeria. [Looi, Lai Meng] Univ Malaya, Dept Pathol, Fac Med, Kuala Lumpur, Malaysia. [Ru, Kun] Chinese Acad Med Sci, Dept Pathol & Lab Med, Beijing, Peoples R China. [Wang, Jianxiang] Chinese Acad Med Sci, Inst Hematol, Beijing, Peoples R China. [Ghafur, Abdul] Apollo Hosp, Chennai, Tamil Nadu, India. [Lago, Nestor] Univ Buenos Aires, Dept Pathol, Buenos Aires, DF, Argentina. RP Fleming, KA (reprint author), Green Templeton Coll, 43 Woodstock Rd, Oxford OX2 6HG, England. EM kenneth.fleming@medsci.ox.ac.uk NR 55 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JAN PY 2017 VL 147 IS 1 BP 15 EP 32 DI 10.1093/AJCP/AQW143 PG 18 WC Pathology SC Pathology GA EP0QI UT WOS:000397091400003 PM 28158414 ER PT J AU Datta, M Via, L Chen, W Baish, J Xu, L Barry, C Jain, R AF Datta, Meenal Via, Laura Chen, Wei Baish, James Xu, Lei Barry, Clfton Jain, Rakesh TI Mathematical Model of Oxygen Transport in Tuberculosis Granulomas SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Engineering and Physical Sciences in Oncology CY JUN 25-28, 2016 CL Boston, MA SP Amer Assoc Canc Res C1 [Datta, Meenal; Chen, Wei; Xu, Lei; Jain, Rakesh] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Via, Laura; Barry, Clfton] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Baish, James] Bucknell Univ, Lewisburg, PA 17837 USA. NR 0 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 PY 2017 VL 77 SU 2 MA B59 DI 10.1158/1538-7445.EPSO16-B59 PG 2 WC Oncology SC Oncology GA EQ1WJ UT WOS:000397860000093 ER PT J AU Lee, JA Ayat, N Tandle, A Lu, ZR Camphausen, K AF Lee, Jennifer A. Ayat, Nadia Tandle, Anita Lu, Zheng-Rong Camphausen, Kevin TI Silencing of DNA repair proteins with ECO/siRNA nanoparticles for the enhancement of radiation response in glioblastoma SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Engineering and Physical Sciences in Oncology CY JUN 25-28, 2016 CL Boston, MA SP Amer Assoc Canc Res C1 [Lee, Jennifer A.; Tandle, Anita; Camphausen, Kevin] NCI, Bethesda, MD USA. [Ayat, Nadia; Lu, Zheng-Rong] Case Western Reserve Univ, Cleveland, OH USA. NR 0 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 PY 2017 VL 77 SU 2 MA B42 DI 10.1158/1538-7445.EPSO16-B42 PG 2 WC Oncology SC Oncology GA EQ1WJ UT WOS:000397860000082 ER PT J AU Zeldow, B Kim, S McSherry, G Cotton, MF Jean-Philippe, P Violari, A Bobat, R Nachman, S Mofenson, LM Madhi, SA Mitchell, C AF Zeldow, B. Kim, S. McSherry, G. Cotton, M. F. Jean-Philippe, P. Violari, A. Bobat, R. Nachman, S. Mofenson, L. M. Madhi, S. A. Mitchell, C. TI Use of antiretrovirals in HIV-infected children in a tuberculosis prevention trial: IMPAACT P1041 SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Article DE TB; perinatal HIV infection; antiretroviral therapy; mortality ID MARGINAL STRUCTURAL MODELS; SOUTH-AFRICAN CHILDREN; CHILDHOOD TUBERCULOSIS; ISONIAZID PROPHYLAXIS; THERAPY; INFANTS; BURDEN; IMPACT; HAART; EPIDEMIOLOGY AB SETTING: International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1041, a tuberculosis (TB) prevention trial conducted among children enrolled from 2004 to 2008 during South Africa's roll-out of combination antiretroviral therapy (ART). OBJECTIVE: To estimate TB incidence and mortality and the effect of ART. DESIGN: Children were pre-screened to exclude TB disease and exposure, actively screened 3-monthly for TB exposure and symptoms, and provided post-exposure isoniazid prophylaxis therapy (IPT). TB diagnoses were definite, probable, or possible, and mortality all cause. Testing was at the 5% significance level. RESULTS: In 539 children (aged 3-4 months) followed up for a median of 74 weeks (interquartile range [IQR] 48-116), incidence/100 person-years (py) was 10.67 (95%CI 8.47-13.26) for any TB and 2.89 (95%CI 1.85-4.31) for definite/probable TB. Any TB incidence was respectively 9.39, 13.59, and 9.83/100 py before, <180 days after, and >= 180 days after ART initiation. Adjusted analysis showed a non-significant increase in any TB (HR 1.32, 95%CI 0.71-2.52, P = 0.38) and a significant reduction in mortality (HR 0.39, 95%CI 0.17-0.82, P = 0.017) following ART initiation. CONCLUSIONS: ART reduced mortality but not TB incidence in human immunodeficiency virus (HIV) infected children in IMPAACT P1041, possibly attributable to active screening for TB exposure and symptoms with post-exposure IPT. Research into this as a strategy for TB prevention in high HIV-TB burden settings may be warranted. C1 [Zeldow, B.; Kim, S.] Harvard Sch Publ Hlth, Ctr Biostat AIDS Res, 655 Huntington Ave, Boston, MA 02115 USA. [Kim, S.] Rutgers Sch Publ Hlth, Dept Biostat, Newark, NJ USA. [McSherry, G.] Penn State Univ, Coll Med, Hershey, PA USA. [Cotton, M. F.] Univ Stellenbosch, Dept Paediat & Child Hlth, Tygerberg, South Africa. [Jean-Philippe, P.] Henry Jackson Fdn, Nat Inst Allergy & Infect Dis, Bethesda, MD USA. [Violari, A.] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Bobat, R.] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Dept Paediat & Child Hlth, Durban, South Africa. [Nachman, S.] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Mofenson, L. M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD USA. [Mofenson, L. M.] Elizabeth Glaser Pediat AIDS Fdn, Washington, DC USA. [Madhi, S. A.] Univ Witwatersrand, MRC, Resp & Meningeal Pathogens Res Unit, Johannesburg, South Africa. [Mitchell, C.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. RP Kim, S (reprint author), Harvard Sch Publ Hlth, Ctr Biostat AIDS Res, 655 Huntington Ave, Boston, MA 02115 USA. EM skim@sdac.harvard.edu FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health, Bethesda, MD, USA [AI068632]; Statistical and Data Analysis Center at the Harvard School of Public Health, Boston, MA, USA under NIAID cooperative agreements; IMPAACT Group [1 U01 AI068616]; NIAID; NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network (NICHD) [N01-DK-9-001/HHSN267200800001C]; NIAID [HHSN272200800014C]; Secure the Future Fund, a philanthropy program - Bristol-Myers Squibb, New York, NY, USA; Pediatric AIDS Clinical Trials Group [5 U01 AI41110] FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group was provided by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health, Bethesda, MD, USA (AI068632). This work was supported by the Statistical and Data Analysis Center at the Harvard School of Public Health, Boston, MA, USA, under NIAID cooperative agreements with the Pediatric AIDS Clinical Trials Group (5 U01 AI41110) and the IMPAACT Group (1 U01 AI068616). Support for the sites was provided by NIAID and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network (NICHD contract number N01-DK-9-001/HHSN267200800001C). Support for PJP comes from NIAID Contract No. HHSN272200800014C. The study was also funded by a grant from the Secure the Future Fund, a philanthropy program sponsored by Bristol-Myers Squibb, New York, NY, USA. NR 26 TC 0 Z9 0 U1 0 U2 0 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 EI 1815-7920 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD JAN PY 2017 VL 21 IS 1 BP 38 EP 45 DI 10.5588/ijtld.16.0149 PG 8 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA EP7JH UT WOS:000397553600009 PM 28157463 ER PT J AU Kumar, NP Velayutham, B Nair, D Babu, S AF Kumar, N. P. Velayutham, B. Nair, D. Babu, S. TI Angiopoietins as biomarkers of disease severity and bacterial burden in pulmonary tuberculosis SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Article DE tuberculosis; angiopoietins angiogenesis; lymphangiogenesis ID ENDOTHELIAL GROWTH-FACTOR; ANGIOGENESIS; GRANULOMA; SERUM; PERMEABILITY; INFLAMMATION; ACTIVATION AB BACKGROUND: Circulating angiogenic factors of the vascular endothelial growth factor family are important biomarkers of disease severity in pulmonary tuberculosis (PTB). However, the role of angiopoietins, which are also involved in angiogenesis, in PTB is not known. OBJECTIVE AND DESIGN: To examine the association of circulating angiopoietins with TB disease or latent tuberculous infection (LTBI), we examined the systemic levels of angiopoietin (Ang) 1, Ang 2 and Tie-2 receptor in individuals with PTB (n = 44), LTBI (n = 44) or no tuberculous infection (NTBI) (n = 44). RESULTS: Circulating levels of Ang-1, Ang-2 and Tie-2 were significantly higher in PTB than in individuals with LTBI or NTBI. Moreover, Ang-1, Ang-2 and Tie-2 levels were significantly higher in PTB with bilateral disease. The levels of these factors also exhibited a significant positive relationship with bacterial burdens in P 1B. Receiver operating characteristics curve analysis revealed Ang-2 as a marker distinguishing PTB from L1BI or NTBI. Finally, the circulating levels of Ang-1, Ang-2 and Tie-2 were significantly reduced following antituberculosis chemotherapy. CONCLUSIONS: Our data demonstrate that PTB is associated with elevated levels of circulating angiopoietins, possibly reflecting endothelial dysfunction. In addition, Ang-2 could prove useful as a biomarker to monitor disease severity, bacterial burden and therapeutic responses. C1 [Kumar, N. P.; Babu, S.] Int Ctr Excellence Res, Natl Inst Res TB, 1 Sathiyamoorthy Rd Chetput, Chennai 600031, Tamil Nadu, India. [Velayutham, B.; Nair, D.] Natl Inst Res TB, Chennai, Tamil Nadu, India. [Babu, S.] NIH, Natl Inst Allergy & Infect Dis, Parasit Dis Lab, Bldg 10, Bethesda, MD 20892 USA. RP Kumar, NP (reprint author), Int Ctr Excellence Res, Natl Inst Res TB, 1 Sathiyamoorthy Rd Chetput, Chennai 600031, Tamil Nadu, India. EM pavankumarn@nirt.res.in FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA FX The Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, supported this work. NR 26 TC 0 Z9 0 U1 0 U2 0 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 EI 1815-7920 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD JAN PY 2017 VL 21 IS 1 BP 93 EP 99 DI 10.5588/ijfld.16.0565 PG 7 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA EP7JH UT WOS:000397553600017 PM 28157471 ER PT J AU Koonin, EV Zhang, F AF Koonin, Eugene V. Zhang, Feng TI Coupling immunity and programmed cell suicide in prokaryotes: Life-or-death choices SO BIOESSAYS LA English DT Article DE genotoxic stress sensing; immunity; programmed cell death; virus-host coevolution ID CRISPR-CAS SYSTEMS; RESTRICTION-MODIFICATION SYSTEMS; TOXIN-ANTITOXIN SYSTEMS; SHORT PALINDROMIC REPEATS; PRRC-ANTICODON NUCLEASE; TRANSFER-RNA REPAIR; ADAPTIVE IMMUNITY; DEFENSE SYSTEMS; FUNCTIONAL-CHARACTERIZATION; MODIFICATION ENZYMES AB Host-pathogen arms race is a universal, central aspect of the evolution of life. Most organisms evolved several distinct yet interacting strategies of anti-pathogen defense including resistance to parasite invasion, innate and adaptive immunity, and programmed cell death (PCD). The PCD is the means of last resort, a suicidal response to infection that is activated when resistance and immunity fail. An infected cell faces a decision between active defense and altruistic suicide or dormancy induction, depending on whether immunity is "deemed" capable of preventing parasite reproduction and consequent infection of other cells. In bacteria and archaea, immunity genes typically colocalize with PCD modules, such as toxins-antitoxins, suggestive of immunity-PCD coupling, likely mediated by shared proteins that sense damage and "predict" the outcome of infections. In type VI CRISPR-Cas systems, the same enzyme that inactivates the target RNA might execute cell suicide, in a case of ultimate integration of immunity and PCD. C1 [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA USA. [Zhang, Feng] MIT, Dept Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Zhang, Feng] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Zhang, Feng] Dept Brain & Cognit Sci, Cambridge, MA USA. [Zhang, Feng] Dept Biol Engn, Cambridge, MA USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 95 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0265-9247 EI 1521-1878 J9 BIOESSAYS JI Bioessays PD JAN PY 2017 VL 39 IS 1 AR UNSP 1600186 DI 10.1002/bies.201600186 PG 9 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA EO7TB UT WOS:000396891900013 ER PT J AU Fleming, KA Naidoo, M Wilson, M Flanigan, J Horton, S Kuti, M Looi, LM Price, C Ru, K Ghafur, A Wang, JX Lago, N AF Fleming, Kenneth A. Naidoo, Mahendra Wilson, Michael Flanigan, John Horton, Susan Kuti, Modupe Looi, Lai Meng Price, Chris Ru, Kun Ghafur, Abdul Wang, Jianxiang Lago, Nestor TI An Essential Pathology Package for Low- and Middle-Income Countries SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Review DE Low-income countries; Middle-income countries; Africa; Asia; Essential pathology services; Hospital laboratory services ID SUB-SAHARAN AFRICA; LABORATORY ACCREDITATION; MEDICINE; QUALITY; COSTS AB Objectives: We review the current status of pathology services in low- and middle-income countries and propose an "essential pathology package" along with estimated costs. The purpose is to provide guidance to policy makers as countries move toward universal health care systems. Methods: Five key themes were reviewed using existing literature (role of leadership; education, training, and continuing professional development; technology; accreditation, management, and quality standards; and reimbursement systems). A tiered system is described, building on existing proposals. The economic analysis draws on the very limited published studies, combined with expert opinion. Results: Countries have underinvested in pathology services, with detrimental effects on health care. The equipment needs for a tier 1 laboratory in a primary health facility are modest ($ 2-$ 5,000), compared with $ 150,000 to $ 200,000 in a district hospital, and higher in a referral hospital (depending on tests undertaken). Access to a national (or regional) specialized laboratory undertaking disease surveillance and registry is important. Recurrent costs of appropriate laboratories in district and referral hospitals are around 6% of the hospital budget in midsized hospitals and likely decline in the largest hospitals. Primary health facilities rely largely on single-use tests. Conclusions: Pathology is an essential component of good universal health care. C1 [Fleming, Kenneth A.; Naidoo, Mahendra; Flanigan, John] NCI, Ctr Global Hlth, Washington, DC USA. [Fleming, Kenneth A.] Univ Oxford, Green Templeton Coll, Oxford, England. [Price, Chris] Univ Oxford, Nuffield Dept Primary Care Hlth Sci, Oxford, England. [Wilson, Michael] Univ Colorado, Sch Med, Dept Pathol, Denver, CO 80262 USA. [Wilson, Michael] Denver Hlth, Dept Pathol & Lab Serv, Denver, CO USA. [Horton, Susan] Univ Waterloo, Global Hlth Econ, Waterloo, ON, Canada. [Kuti, Modupe] Univ Ibadan, Coll Med, Dept Chem Pathol, Ibadan, Nigeria. [Kuti, Modupe] Univ Coll Hosp, Ibadan, Nigeria. [Looi, Lai Meng] Univ Malaya, Dept Pathol, Fac Med, Kuala Lumpur, Malaysia. [Ru, Kun] Chinese Acad Med Sci, Dept Pathol & Lab Med, Beijing, Peoples R China. [Wang, Jianxiang] Chinese Acad Med Sci, Inst Hematol, Beijing, Peoples R China. [Ghafur, Abdul] Apollo Hosp, Madras, Tamil Nadu, India. [Lago, Nestor] Univ Buenos Aires, Dept Pathol, Buenos Aires, DF, Argentina. RP Fleming, KA (reprint author), Green Templeton Coll, 43 Woodstock Rd, Oxford OX2 6HG, England. EM kenneth.fleming@medsci.ox.ac.uk NR 53 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JAN PY 2017 VL 147 IS 1 BP 15 EP 32 DI 10.1093/AJCP/AQW143 PG 18 WC Pathology SC Pathology GA EP2PV UT WOS:000397226500003 ER PT J AU Smith, E Master, Z AF Smith, Elise Master, Zubin TI Best Practice to Order Authors in Multi/Interdisciplinary Health Sciences Research Publications SO ACCOUNTABILITY IN RESEARCH-POLICIES AND QUALITY ASSURANCE LA English DT Article DE Authorship; ethics and public policy; multidisciplinary research teams; publication; publication ethics; research integrity; responsible conduct of research ID RESPONSIBLE CONDUCT; SCIENTIFIC MISCONDUCT; EQUAL CONTRIBUTIONS; MEDICAL JOURNALS; CREDIT; CONTRIBUTORS; CRITERIA; ETHICS; BIOETHICS; ARTICLES AB Misunderstanding and disputes about authorship are commonplace among members of multi/interdisciplinary health research teams. If left unmanaged and unresolved, these conflicts can undermine knowledge sharing and collaboration, obscure accountability for research, and contribute to the incorrect attribution of credit. To mitigate these issues, certain researchers suggest quantitative authorship distributions schemes (e.g., point systems), while others wish to replace or minimize the importance of authorship by using contributorshipa system based on authors' self-reporting contributions. While both methods have advantages, we argue that authorship and contributorship will most likely continue to coexist for multiple ethical and practical reasons. In this article, we develop a five-step best practice that incorporates the distribution of both contributorship and authorship for multi/interdisciplinary research. This procedure involves continuous dialogue and the use of a detailed contributorship taxonomy ending with a declaration explaining contributorship, which is used to justify authorship order. Institutions can introduce this approach in responsible conduct of research training as it promotes greater fairness, trust, and collegiality among team members and ultimately reduces confusion and facilitates resolution of time-consuming disagreements. C1 [Smith, Elise; Master, Zubin] Univ Montreal, Dept Social & Prevent Med, Bioeth Programs, Montreal, PQ, Canada. [Smith, Elise] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Master, Zubin] Albany Med Coll, Alden March Bioeth Inst, 47 New Scotland Ave,MC 153, Albany, NY 12208 USA. RP Master, Z (reprint author), Albany Med Coll, Alden March Bioeth Inst, 47 New Scotland Ave,MC 153, Albany, NY 12208 USA. EM zubin@zubsplace.com FU Committee on Publication Ethics; Social Sciences and Humanities Research Council; University of Montreal, Montreal, Canada FX A research grant from the Committee on Publication Ethics (Master) partly funded this project. In addition, Smith was supported by scholarships from the Social Sciences and Humanities Research Council (Joseph-Armand Bombardier Ph.D. Scholarship) and the University of Montreal, Montreal, Canada. NR 92 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 0898-9621 EI 1545-5815 J9 ACCOUNT RES JI Account. Res. PY 2017 VL 24 IS 4 BP 243 EP 267 DI 10.1080/08989621.2017.1287567 PG 25 WC Medical Ethics SC Medical Ethics GA EN0MS UT WOS:000395704700004 PM 28128975 ER PT J AU Spencer, RG Cortese, BD Lukas, VA Pleshko, N AF Spencer, Richard G. Cortese, Benjamin D. Lukas, Vanessa A. Pleshko, Nancy TI Point Estimates of Test Sensitivity and Specificity from Sample Means and Variances SO AMERICAN STATISTICIAN LA English DT Article DE Diagnostic markers; Discriminant tests; Test characteristics AB In a wide variety of biomedical and clinical research studies, sample statistics from diagnostic marker measurements are presented as a means of distinguishing between two populations, such as with and without disease. Intuitively, a larger difference between themean values of a marker for the two populations, and a smaller spread of values within each population, should lead to more reliable classification rules based on this marker. We formalize this intuitive notion by deriving practical, new, closed-form expressions for the sensitivity and specificity of three different discriminant tests defined in terms of the sample means and standard deviations of diagnosticmarkermeasurements. The three discriminant tests evaluated are based, respectively, on the Euclidean distance and theMahalanobis distance between means, and a likelihood ratio analysis. Expressions for the effects of measurement error are also presented. Our final expressions assume that the diagnostic markers follow independent normal distributions for the two populations, although it will be clear that other known distributions may be similarly analyzed. We then discuss applications drawn from the medical literature, although the formalism is clearly not restricted to that application. C1 [Spencer, Richard G.; Lukas, Vanessa A.] NIH, Magnet Resonance Imaging & Spect Sect, Natl Inst Aging, Baltimore, MD USA. [Cortese, Benjamin D.] Syracuse Univ, Dept Math, Syracuse, NY USA. [Pleshko, Nancy] Temple Univ, Dept Bioengn, Tissue Imaging & Spect Lab, Philadelphia, PA USA. RP Spencer, RG (reprint author), NIH, Magnet Resonance Imaging & Spect Sect, Natl Inst Aging, Intramural Res Program, BRC 04B-116, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM spencer@helix.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging FX This work was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 15 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0003-1305 EI 1537-2731 J9 AM STAT JI Am. Stat. PY 2017 VL 71 IS 1 BP 81 EP 87 DI 10.1080/00031305.2016.1239589 PG 7 WC Statistics & Probability SC Mathematics GA EP2PR UT WOS:000397226100015 ER PT J AU Ossandon, M Balsam, J Bruck, HA Kalpakis, K Rasooly, A AF Ossandon, Miguel Balsam, Joshua Bruck, Hugh Alan Kalpakis, Konstantinos Rasooly, Avraham TI A computational streak mode cytometry biosensor for rare cell analysis SO ANALYST LA English DT Article ID SMART-PHONE; TRACKING; MICROSCOPY; CANCER; ARRAY; FLOW; AIR AB Streak mode imaging flow cytometry for rare cell detection involves imaging moving fluorescently labeled cells in the video mode with a CCD camera. The path of the moving cells results in a "streak", whose length is proportional to the exposure time. The dynamic imaging conditions introduce detection challenges (e.g., images with high signal-to-noise ratio (SNR) backgrounds), especially for enumerating cells using low resolution webcams or smartphone cameras suitable for point of care testing (POCT). To overcome the imaging challenges, a new approach called a "computational biosensor" was developed. It involves combining biosensing hardware with computational algorithms to "computationally transduce" measureable signals from events captured by the hardware. The computational biosensor quantifies potential cells based on the streak intensity, length and relative location of the streaks in consecutive frames. Cell identification consists of three parts: (1) finding streaks, (2) identifying candidate cells, and (3) filtering out spurious cells to identify true cells. Samples of 1 cell per mL were analyzed in batch sizes of 30 mL at flow rates of 10 mL min(1) and imaged at 4 frames per second (fps). The detected cells were annotated, and the SNR was calculated. For images with SNR greater than 4.4 dB, the total detected cells (TD) compared with ground truth (GT) are 98%, while 66% were detected for low SNR. For true positive cells detected compared with ground truth (TP/GT), 91% were detected for high SNR. This demonstrated the new analytical capabilities of the computational biosensor to enumerate rare cells in large volumes not possible with current technologies. C1 [Ossandon, Miguel; Rasooly, Avraham] NCI, Rockville, MD 20850 USA. [Ossandon, Miguel; Kalpakis, Konstantinos] Univers Maryland Baltimore Cty, Baltimore, MD USA. [Balsam, Joshua; Bruck, Hugh Alan] Univ Maryland, College Pk, MD 20742 USA. RP Rasooly, A (reprint author), NCI, Rockville, MD 20850 USA. EM ossandom@mail.nih.gov FU National Cancer Institute (NCI) FX This work was supported by the National Cancer Institute (NCI). NR 24 TC 0 Z9 0 U1 0 U2 0 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0003-2654 EI 1364-5528 J9 ANALYST JI Analyst PY 2017 VL 142 IS 4 BP 641 EP 648 DI 10.1039/c6an02517j PG 8 WC Chemistry, Analytical SC Chemistry GA EM9RP UT WOS:000395649100012 ER PT S AU Jaffe, ES AF Jaffe, Elaine S. BE Abbas, AK Aster, JC Feany, MB TI The Microscope as a Tool for Disease Discovery-A Personal Voyage SO ANNUAL REVIEW OF PATHOLOGY: MECHANISMS OF DISEASE, VOL 12 SE Annual Review of Pathology-Mechanisms of Disease LA English DT Review; Book Chapter DE malignant lymphoma; B cells; T cells; molecular diagnosis; molecular oncology; cell of origin ID B-CELL LYMPHOMA; NON-HODGKINS-LYMPHOMA; GRAY-ZONE LYMPHOMA; HEALTH-ORGANIZATION CLASSIFICATION; IMMUNOGLOBULIN-GENE REARRANGEMENTS; REED-STERNBERG CELLS; RED-BLOOD-CELLS; C-MYC GENE; FOLLICULAR LYMPHOMA; LYMPHOCYTIC LYMPHOMA AB This review reflects the trajectory of my career in hematopathology, and my personal reflections on scientific advances in the field. During the course of more than 40 years, the approach to classification of hematological malignancies has evolved from descriptive approaches, based on either cytological or clinical features, to a modern approach, which incorporates cutting-edge technologies. My philosophy has focused on defining individual diseases, an approach that can best lead to an understanding of molecular pathogenesis. To quote Carolus Linnaeus (1, p. 19), the father of taxonomy, "The first step in wisdom is to know the things themselves; this notion consists in having a true idea of the objects; objects are distinguished and known by classifying them methodically and giving them appropriate names. Therefore, classification and name-giving will be the foundation of our science." C1 [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov NR 131 TC 0 Z9 0 U1 0 U2 0 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 1553-4006 J9 ANNU REV PATHOL-MECH JI Annu. Rev. Pathol.-Mech Dis. PY 2017 VL 12 BP 1 EP 24 DI 10.1146/annurev-pathol-052016-100351 PG 24 WC Pathology SC Pathology GA BG9PJ UT WOS:000393554200001 PM 27959631 ER PT S AU Baseler, L Chertow, DS Johnson, KM Feldmann, H Morens, DM AF Baseler, Laura Chertow, Daniel S. Johnson, Karl M. Feldmann, Heinz Morens, David M. BE Abbas, AK Aster, JC Feany, MB TI The Pathogenesis of Ebola Virus Disease SO ANNUAL REVIEW OF PATHOLOGY: MECHANISMS OF DISEASE, VOL 12 SE Annual Review of Pathology-Mechanisms of Disease LA English DT Review; Book Chapter DE Ebola; ebolavirus; epidemic; filovirus; viral disease pathogenesis; viral hemorrhagic fever ID DENDRITIC CELL MATURATION; AFRICAN-GREEN MONKEYS; HEMORRHAGIC-FEVER; SIERRA-LEONE; ZAIRE-EBOLAVIRUS; GUINEA-PIGS; NONHUMAN-PRIMATES; RHESUS-MONKEYS; MARBURG-VIRUS; VP35 PROTEIN AB For almost 50 years, ebolaviruses and related filoviruses have been repeatedly reemerging across the vast equatorial belt of the African continent to cause epidemics of highly fatal hemorrhagic fever. The 2013-2015 West African epidemic, by far the most geographically extensive, most fatal, and longest lasting epidemic in Ebola's history, presented an enormous international public health challenge, but it also provided insights into Ebola's pathogenesis and natural history, clinical expression, treatment, prevention, and control. Growing understanding of ebolavirus pathogenetic mechanisms and important new clinical observations of the disease course provide fresh clues about prevention and treatment approaches. Although viral cytopathology and immune-mediated cell damage in ebolavirus disease often result in severe compromise of multiple organs, tissue repair and organ function recovery can be expected if patients receive supportive care with fluids and electrolytes; maintenance of oxygenation and tissue perfusion; and respiratory, renal, and cardiovascular support. Major challenges for managing future Ebola epidemics include establishment of early and aggressive epidemic control and earlier and better patient care and treatment in remote, resource-poor areas where Ebola typically reemerges. In addition, it will be important to further develop Ebola vaccines and to adopt policies for their use in epidemic and pre-epidemic situations. C1 [Baseler, Laura] Univ Texas MD Anderson Canc Ctr, Dept Vet Med & Surg, Houston, TX 77030 USA. [Chertow, Daniel S.] NIAID, Dept Crit Care Med, Ctr Clin, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Johnson, Karl M.] Ctr Dis Control & Prevent, Special Pathogens Branch, Placitas, NM 87043 USA. [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. [Morens, David M.] NIAID, Off Director, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, Off Director, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dm270q@nih.gov NR 176 TC 0 Z9 0 U1 7 U2 7 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 1553-4006 J9 ANNU REV PATHOL-MECH JI Annu. Rev. Pathol.-Mech Dis. PY 2017 VL 12 BP 387 EP 418 DI 10.1146/annurev-pathol-052016-100506 PG 32 WC Pathology SC Pathology GA BG9PJ UT WOS:000393554200015 PM 27959626 ER PT S AU Metcalfe, DD Mekori, YA AF Metcalfe, Dean D. Mekori, Yoseph A. BE Abbas, AK Aster, JC Feany, MB TI Pathogenesis and Pathology of Mastocytosis SO ANNUAL REVIEW OF PATHOLOGY: MECHANISMS OF DISEASE, VOL 12 SE Annual Review of Pathology-Mechanisms of Disease LA English DT Review; Book Chapter DE KIT; mast cells; mast cell mediators; mastocytosis ID MAST-CELL DISEASE; ADVANCED SYSTEMIC MASTOCYTOSIS; BONE-MARROW HISTOPATHOLOGY; TYROSINE KINASE INHIBITORS; CATALYTIC DOMAIN MUTATIONS; KIT-ACTIVATING MUTATION; SERUM TRYPTASE LEVELS; RECEPTOR-ALPHA CHAIN; PROTOONCOGENE C-KIT; URTICARIA PIGMENTOSA AB Systemic mastocytosis is a clonal disorder of mast cells that may variably present with characteristic skin lesions, episodes of mast cell mediator release, and disturbances of hematopoiesis. No curative therapy presently exists. Conventional management has relied on agents that antagonize mediators released by mast cells, inhibit mediator secretion, or modulate mast cell proliferation. Recent advances in the molecular understanding of the pathophysiology of systemic mastocytosis have provided new therapeutic considerations, including new and novel tyrosine kinase inhibitors. C1 [Metcalfe, Dean D.] NIAID, Lab Allerg Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mekori, Yoseph A.] Tel Hai Coll, IL-1220800 Upper Galilee, Israel. [Mekori, Yoseph A.] Meir Med Ctr, IL-44281 Kefar Sava, Israel. [Mekori, Yoseph A.] Tel Aviv Univ, Sackler Sch Med, IL-6997801 Tel Aviv, Israel. RP Metcalfe, DD (reprint author), NIAID, Lab Allerg Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dmetcalfe@niaid.nih.gov; ymekori@telhai.ac.il NR 129 TC 0 Z9 0 U1 1 U2 1 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 1553-4006 J9 ANNU REV PATHOL-MECH JI Annu. Rev. Pathol.-Mech Dis. PY 2017 VL 12 BP 487 EP 514 DI 10.1146/annurev-pathol-052016-100312 PG 28 WC Pathology SC Pathology GA BG9PJ UT WOS:000393554200018 PM 28135563 ER PT S AU Insel, PA Amara, SG Blaschke, TF Meyer, UA AF Insel, Paul A. Amara, Susan G. Blaschke, Terrence F. Meyer, Urs A. BE Insel, PA TI Introduction to the Theme "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology" SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 57 SE Annual Review of Pharmacology and Toxicology LA English DT Review; Book Chapter ID NEURODEGENERATIVE DISEASES AB Major advances in scientific discovery and insights can result from the development and use of new techniques, as exemplified by the work of Solomon Snyder, who writes a prefatory article in this volume. The Editors have chosen "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology" as the Theme for a number of articles in this volume. These include ones that review the development and use of new experimental tools and approaches (e. g., nanobodies and techniques to explore protein-protein interactions), new types of therapeutics (e. g., aptamers and antisense oligonucleotides), and systems pharmacology, which assembles (big) data derived from omics studies together with information regarding drugs and patients. The application of these new methods and therapeutic approaches has the potential to have a major impact on basic and clinical research in pharmacology and toxicology as well as on patient care. C1 [Insel, Paul A.] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Insel, Paul A.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Amara, Susan G.] NIMH, Bethesda, MD 20892 USA. [Blaschke, Terrence F.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Meyer, Urs A.] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland. RP Insel, PA (reprint author), Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA.; Insel, PA (reprint author), Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. NR 15 TC 0 Z9 0 U1 1 U2 1 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0457-7 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2017 VL 57 BP 13 EP 17 DI 10.1146/annurev-pharmtox-091616-023708 PG 5 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BH0QN UT WOS:000396044800002 PM 27732830 ER PT S AU Hutson, PH Clark, JA Cross, AJ AF Hutson, P. H. Clark, J. A. Cross, A. J. BE Insel, PA TI CNS Target Identification and Validation: Avoiding the Valley of Death or Naive Optimism? SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 57 SE Annual Review of Pharmacology and Toxicology LA English DT Review; Book Chapter DE drug discovery; drug development; neurology; psychiatry; translational research ID MAJOR DEPRESSIVE DISORDER; P NK1 RECEPTOR; PDE9 INHIBITOR PF-04447943; PLURIPOTENT STEM-CELLS; PARKINSONS-DISEASE; DRUG DISCOVERY; ALZHEIMERS-DISEASE; ANIMAL-MODELS; HUNTINGTONS-DISEASE; COGNITIVE FUNCTION AB There are many challenges along the path to the approval of new drugs to treat CNS disorders, one of the greatest areas of unmet medical need with a large societal burden and health-care impact. Unfortunately, over the past two decades, few CNS drug approvals have succeeded, leading many pharmaceutical companies to deprioritize this therapeutic area. The reasons for the failures in CNS drug discovery are likely to be multifactorial. However, selecting the most biologically plausible molecular targets that are relevant to the disorder is a critical first step to improve the probability of success. In this review, we outline previous methods for identifying and validating novel targets for CNS drug discovery, and, cognizant of previous failures, we discuss potential new strategies that may improve the probability of success of developing novel treatments for CNS disorders. C1 [Hutson, P. H.] Teva Pharmaceut, CNS Discovery, Neurobiol, W Chester, PA 19380 USA. [Clark, J. A.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Cross, A. J.] AstraZeneca, Neurosci Innovat Med, Cambridge, MA 01239 USA. RP Hutson, PH (reprint author), Teva Pharmaceut, CNS Discovery, Neurobiol, W Chester, PA 19380 USA. EM peter.hutson@tevapharm.com; Janet.Clark@nih.gov; alan.cross@azneuro.com NR 115 TC 1 Z9 1 U1 0 U2 0 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0457-7 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2017 VL 57 BP 171 EP 187 DI 10.1146/annurev-pharmtox-010716-104624 PG 17 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BH0QN UT WOS:000396044800010 PM 27575715 ER PT S AU Xie, L Draizen, EJ Bourne, PE AF Xie, Lei Draizen, Eli J. Bourne, Philip E. BE Insel, PA TI Harnessing Big Data for Systems Pharmacology SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 57 SE Annual Review of Pharmacology and Toxicology LA English DT Review; Book Chapter DE cloud computing; data science; machine learning; semantic web; computational modeling; systems biology; systems pharmacology modeling; NIH Commons ID GENOME-SCALE MODELS; SEMANTIC WEB TECHNOLOGIES; NEED EXACT SOLVERS; COMPRESSIVE GENOMICS; CLEARER STANDARDS; LIFE SCIENCES; DRUG TARGETS; NETWORK; BIOLOGY; DISEASE AB Systems pharmacology aims to holistically understand mechanisms of drug actions to support drug discovery and clinical practice. Systems pharmacology modeling (SPM) is data driven. It integrates an exponentially growing amount of data at multiple scales (genetic, molecular, cellular, organismal, and environmental). The goal of SPM is to develop mechanistic or predictive multiscale models that are interpretable and actionable. The current explosions in genomics and other omics data, as well as the tremendous advances in big data technologies, have already enabled biologists to generate novel hypotheses and gain new knowledge through computational models of genome-wide, heterogeneous, and dynamic data sets. More work is needed to interpret and predict a drug response phenotype, which is dependent on many known and unknown factors. To gain a comprehensive understanding of drug actions, SPM requires close collaborations between domain experts from diverse fields and integration of heterogeneous models from biophysics, mathematics, statistics, machine learning, and semantic webs. This creates challenges in model management, model integration, model translation, and knowledge integration. In this review, we discuss several emergent issues in SPM and potential solutions using big data technology and analytics. The concurrent development of high-throughput techniques, cloud computing, data science, and the semantic web will likely allow SPM to be findable, accessible, interoperable, reusable, reliable, interpretable, and actionable. C1 [Xie, Lei] CUNY, Hunter Coll, Dept Comp Sci, New York, NY 10065 USA. [Xie, Lei] CUNY, Grad Ctr, New York, NY 10016 USA. [Draizen, Eli J.; Bourne, Philip E.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Draizen, Eli J.] Boston Univ, Program Bioinformat, Boston, MA 02215 USA. [Bourne, Philip E.] NIH, Off Director, Bethesda, MD 20894 USA. RP Xie, L (reprint author), CUNY, Hunter Coll, Dept Comp Sci, New York, NY 10065 USA.; Xie, L (reprint author), CUNY, Grad Ctr, New York, NY 10016 USA. EM lei.xie@hunter.cuny.edu; philip.bourne@nih.gov NR 89 TC 2 Z9 2 U1 1 U2 1 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0457-7 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2017 VL 57 BP 245 EP 262 DI 10.1146/annurev-pharmtox-010716-104659 PG 18 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BH0QN UT WOS:000396044800013 PM 27814027 ER PT S AU Volkow, ND Hampson, AJ Baler, RD AF Volkow, Nora D. Hampson, Aidan J. Baler, Ruben D. BE Insel, PA TI Don't Worry, Be Happy: Endocannabinoids and Cannabis at the Intersection of Stress and Reward SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 57 SE Annual Review of Pharmacology and Toxicology LA English DT Review; Book Chapter DE cannabis; marijuana; endocannabinoids; THC; stress; reward ID POSITRON-EMISSION-TOMOGRAPHY; VENTRAL TEGMENTAL AREA; ACID AMIDE HYDROLASE; METABOTROPIC GLUTAMATE RECEPTORS; CB1 RECEPTOR; TYPE-1 RECEPTOR; MOUSE-BRAIN; INDUCED ANALGESIA; DOPAMINE FUNCTION; ENDOGENOUS CANNABINOIDS AB Cannabis enables and enhances the subjective sense of well-being by stimulating the endocannabinoid system (ECS), which plays a key role in modulating the response to stress, reward, and their interactions. However, over time, repeated activation of the ECS by cannabis can trigger neuroadaptations that may impair the sensitivity to stress and reward. This effect, in vulnerable individuals, can lead to addiction and other adverse consequences. The recent shift toward legalization of medical or recreational cannabis has renewed interest in investigating the physiological role of the ECS as well as the potential health effects, both adverse and beneficial, of cannabis. Here we review our current understanding of the ECS and its complex physiological roles. We discuss the implications of this understanding vis-a-vis the ECS's modulation of stress and reward and its relevance to mental disorders in which these processes are disrupted (i. e., addiction, depression, posttraumatic stress disorder, schizophrenia), along with the therapeutic potential of strategies to manipulate the ECS for these conditions. C1 [Volkow, Nora D.; Hampson, Aidan J.; Baler, Ruben D.] NIDA, NIH, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, NIH, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 171 TC 0 Z9 0 U1 8 U2 8 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0457-7 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2017 VL 57 BP 285 EP 308 DI 10.1146/annurev-pharmtox-010716-104615 PG 24 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BH0QN UT WOS:000396044800015 PM 27618739 ER PT S AU Vannella, KM Wynn, TA AF Vannella, Kevin M. Wynn, Thomas A. BE Julius, D TI Mechanisms of Organ Injury and Repair by Macrophages SO ANNUAL REVIEW OF PHYSIOLOGY, VOL 79 SE Annual Review of Physiology LA English DT Review; Book Chapter DE fibrosis; pulmonary; hepatic; cardiovascular; gut; brain ID TISSUE-RESIDENT MACROPHAGES; ALTERNATIVELY ACTIVATED MACROPHAGES; SKELETAL-MUSCLE REGENERATION; ERYTHRO-MYELOID PROGENITOR; CENTRAL-NERVOUS-SYSTEM; MURINE LIVER FIBROSIS; SPINAL-CORD-INJURY; GROWTH-FACTOR; ALVEOLAR MACROPHAGES; ALZHEIMERS-DISEASE AB Macrophages regulate tissue regeneration following injury. They can worsen tissue injury by producing reactive oxygen species and other toxic mediators that disrupt cell metabolism, induce apoptosis, and exacerbate ischemic injury. However, they also produce a variety of growth factors, such as IGF-1, VEGF-alpha, TGF-beta, and Wnt proteins that regulate epithelial and endothelial cell proliferation, myofibroblast activation, stem and tissue progenitor cell differentiation, and angiogenesis. Proresolving macrophages in turn restore tissue homeostasis by functioning as anti-inflammatory cells, and macrophage-derived matrix metalloproteinases regulate fibrin and collagen turnover. However, dysregulated macrophage function impairs wound healing and contributes to the development of fibrosis. Consequently, the mechanisms that regulate these different macrophage activation states have become active areas of research. In this review, we discuss the common and unique mechanisms by which macrophages instruct tissue repair in the liver, nervous system, heart, lung, skeletal muscle, and intestine and illustrate how macrophages might be exploited therapeutically. C1 [Vannella, Kevin M.; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Vannella, KM (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kevin.vannella@nih.gov; twynn@niaid.nih.gov NR 125 TC 0 Z9 0 U1 3 U2 3 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0066-4278 BN 978-0-8243-0379-2 J9 ANNU REV PHYSIOL JI Annu. Rev. Physiol. PY 2017 VL 79 BP 593 EP 617 DI 10.1146/annurev-physiol-022516-034356 PG 25 WC Physiology SC Physiology GA BH0QP UT WOS:000396049000026 PM 27959618 ER PT S AU Sheeran, P Klein, WMP Rothman, AJ AF Sheeran, Paschal Klein, William M. P. Rothman, Alexander J. BE Fiske, ST TI Health Behavior Change: Moving from Observation to Intervention SO ANNUAL REVIEW OF PSYCHOLOGY, VOL 68 SE Annual Review of Psychology LA English DT Review; Book Chapter DE experimental medicine; interventions; trials; theory; construct; correlational data ID RANDOMIZED CONTROLLED-TRIAL; PHYSICAL-ACTIVITY INTERVENTIONS; IMPLEMENTATION INTENTIONS; SELF-AFFIRMATION; SMOKING-CESSATION; PUBLIC-HEALTH; DRINKING BEHAVIOR; CONSORT STATEMENT; REGULATORY FOCUS; DECISION-MAKING AB How can progress in research on health behavior change be accelerated? Experimental medicine (EM) offers an approach that can help investigators specify the research questions that need to be addressed and the evidence needed to test those questions. Whereas current research draws predominantly on multiple overlapping theories resting largely on correlational evidence, the EM approach emphasizes experimental tests of targets or mechanisms of change and programmatic research on which targets change health behaviors and which techniques change those targets. There is evidence that engaging particular targets promotes behavior change; however, systematic studies are needed to identify and validate targets and to discover when and how targets are best engaged. The EM approach promises progress in answering the key question that will enable the science of health behavior change to improve public health: What strategies are effective in promoting behavior change, for whom, and under what circumstances? C1 [Sheeran, Paschal] Univ N Carolina, Dept Psychol & Neurosci, Chapel Hill, NC 27599 USA. [Klein, William M. P.] NCI, Behav Res Program, Bethesda, MD 20892 USA. [Rothman, Alexander J.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. RP Sheeran, P (reprint author), Univ N Carolina, Dept Psychol & Neurosci, Chapel Hill, NC 27599 USA. EM psheeran@email.unc.edu NR 158 TC 2 Z9 2 U1 0 U2 0 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0066-4308 BN 978-0-8243-0268-9 J9 ANNU REV PSYCHOL JI Annu. Rev. Psychol PY 2017 VL 68 BP 573 EP 600 DI 10.1146/annurev-psych-010416-044007 PG 28 WC Psychology; Psychology, Multidisciplinary SC Psychology GA BH0QL UT WOS:000396040000023 PM 27618942 ER PT J AU Greer, S Han, T Dieguez, C McLean, N Saer, R Reis, I Levi, J Marquez, VE AF Greer, Sheldon Han, Tieran Dieguez, Cristina McLean, Nicola Saer, Rafael Reis, Isildinha Levi, Joe Marquez, Victor E. TI Enzyme-Driven Chemo-and Radiation-Therapy with 12 Pyrimidine Nucleoside Analogs Not Yet in the Clinic SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Article DE Chemotherapy; radiosensitization; activation of prodrugs; dCkinase; cytidine deaminase; dCMPdeaminase; uridine/cytidine kinase; pyrimidine nucleoside analogs ID DNA METHYLTRANSFERASE INHIBITOR; TARGET-DIRECTED THERAPIES; EXPLOIT HIGH-LEVELS; CYTIDINE DEAMINASE; METHYLATION INHIBITOR; CYTOSINE-ARABINOSIDE; CANCER-CELLS; E-CADHERIN; IN-VITRO; DEOXYCYTIDYLATE DEAMINASE AB Enzymatic activity from tumor and adjacent normal tissue of 200 patients involving deoxycytidine kinase (dCK), uridine/cytidine kinase (U/CK), cytidine deaminase (CD) and deoxycytidylate deaminase (dCMPD) was quantified. Patients with brain (17), colon (24), and breast (30) tumors, 53, 67, and 73%, respectively, had an elevated T/N value (Specific Activity of tumor/Specific Activity of normal tissue) involving dCK and dCMPD suggesting chemotherapy with 5-fluorodeoxycytidine (5-FdC) alone or in combination with thymidine plus deoxytetra-hydrouridine, or with the radiosensitizer, 5-chlorodeoxycytidine (5-CldC) plus tetrahydrouridine (H4U). Among patients with colon (19) and pancreatic tumors (40), 53 and 68 %, respectively, displayed T/N values >4 for CD suggesting chemotherapy with 5-FdC, 4-N-methylamino-5-FdC, 5-trifluoromethyldeoxycytidine and radiosensitization with 5-CldC, 4-N-methylamino-5-CldC, 5-iododeoxycytidine and 5-bromodeoxycytidine. The percent of patients with tumors with a T/N value >4 for U/CK in lung (72), colon (23) and breast (28) was 47, 61 and 68, respectively, suggesting zebularine (plus thymidine) treatment for tumors involving gene silencing. Evidence is presented that the 4-N-alkylamino-dC substituted nucleosides and those with large 5-substitutions are activated only via CD to thymidine kinase (TK) using end-points of cytotoxicity and/or radiosensitization: H4U, the inhibitor of CD is an antagonist, cells with low CD or no TK are resistant to the analogs, the end points are indifferent to the dCK status of cells, they are poor substrates for dCK and good substrates for CD, whereas 5-FdC and 5-CldC are good substrates for both enzymes. The analogs present opportunities for Collateral Sensitivity for 5-azacytidine and gemcitabine resistant tumors. C1 [Greer, Sheldon; Dieguez, Cristina; Saer, Rafael] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA. [Greer, Sheldon] Univ Miami, Miller Sch Med, Dept Biochem & Mol Biol, Miami, FL 33136 USA. [Greer, Sheldon; McLean, Nicola] Univ Miami, Miller Sch Med, Dept Radiat Oncol, Miami, FL 33136 USA. [Greer, Sheldon; Han, Tieran] Univ Miami, Miller Sch Med, Sylvester Canc Ctr, Coral Gables, FL 33124 USA. [Reis, Isildinha] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Coral Gables, FL 33124 USA. [Levi, Joe] Univ Miami, Miller Sch Med, Dept Surg, Coral Gables, FL 33124 USA. [Marquez, Victor E.] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Greer, S (reprint author), Univ Miami, Miller Sch Med, Dept Microbiol Immunol R138, 1600 NW 10th Ave, Miami, FL 33136 USA. EM sgreer@miami.edu FU NIH STTR [CA79279-02]; Women's Cancer Association; Intramural Research Program of the NIH, NCI, Center for Cancer Research FX This study was supported mainly by NIH STTR grant CA79279-02 to Dr. Greer, Professor of Microbiology/Immunology; Biochemistry/Molecular Biology and Radiation Oncology and CSO of Halogenetics Inc. and, in part, by a grant from the Women's Cancer Association. Contributors to the Sylvester Cancer Center of Miami, FL and the Rumbaugh-Goodwin Cancer Center of Plantation FL are acknowledged. This research was supported, in part, by the Intramural Research Program of the NIH, NCI, Center for Cancer Research to Dr. Victor E. Marquez. This paper is dedicated to the memory of Dr. Eckhard Podack, who served as Chairman of Microbiology/Immunology at the University of Miami, Miller School of Medicine for many creative years His dedication to make an impact in Life Science and the Cancer Problem, which he achieved, was an inspiration to all who were close to him-and he made many feel close to him. NR 76 TC 0 Z9 0 U1 1 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 EI 1875-5992 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PY 2017 VL 17 IS 2 BP 250 EP 264 DI 10.2174/1871520616666161013145853 PG 15 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA EP2YY UT WOS:000397250800010 PM 27745548 ER PT J AU Funderburg, NT Xu, DH Playford, MP Joshi, AA Andrade, A Kuritzkes, DR Lederman, MM Mehta, NN AF Funderburg, Nicholas T. Xu, Dihua Playford, Martin P. Joshi, Aditya A. Andrade, Adriana Kuritzkes, Daniel R. Lederman, Michael M. Mehta, Nehal N. TI Treatment of HIV infection with a raltegravir-based regimen increases LDL levels, but improves HDL cholesterol efflux capacity SO ANTIVIRAL THERAPY LA English DT Article ID ANTIRETROVIRAL THERAPY ACTG; MONOCYTE ACTIVATION; VASCULAR-DISEASE; SOLUBLE CD14; NAIVE; INFLAMMATION; INDIVIDUALS; DRIVE AB Background: Persons infected with HIV often have altered lipid profiles that may be affected by antiretroviral therapies (ART). Traditional lipid measurements may be insufficient to assess cardiovascular disease (CVD) risk in this population. Methods: We report results from 39 ART-naive participants in a substudy of A5248, a single-arm study of raltegravir, emtricitabine/tenofovir administration. Samples were collected at baseline, 12, 24 and 48 weeks after ART initiation. We performed advanced lipid phenotyping using nuclear magnetic resonance spectroscopy (Liposcience, Raleigh, NC, USA) for lipid particle size and number, and examined high-density lipoprotein (HDL) function measuring reverse cholesterol transport using J774 macrophages. Results: We report significant increases in total cholesterol (13 mg/dl; P<0.001) and low-density lipoprotein (LDL; 8 mg/dl; P=0.03), with no change in triglycerides and without an increase in LDL particle number (P>0.1 all time points). HDL levels were increased over baseline levels at all time points (P<0.003), but reached a peak at week 12 and subsequently declined. HDL particle numbers also increased from baseline (P<0.002) and HDL function improved at week 48 (7% increase in efflux capacity; P<0.001). Oxidized LDL (oxLDL) levels decreased by week 12, but rose subsequently, and were not different from baseline at later time points. Conclusions: HDL increases were associated with increases in beneficial HDL particles and HDL cholesterol efflux capacity, which may reduce future CVD events. Persistent inflammation in these HIV+ participants, may be a cause or consequence of oxLDL levels, and may contribute to declining levels of HDL over time. C1 [Funderburg, Nicholas T.] Ohio State Univ, Div Med Lab Sci, Sch Hlth & Rehabil Sci, Columbus, OH 43210 USA. [Xu, Dihua; Playford, Martin P.; Joshi, Aditya A.; Mehta, Nehal N.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Andrade, Adriana] Johns Hopkins Univ, Div Infect Dis, Baltimore, MD USA. [Kuritzkes, Daniel R.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Lederman, Michael M.] Case Western Reserve Univ, Dept Med, Univ Hosp Case Med Ctr, Ctr AIDS Res,Div Infect Dis & HIV Med, Cleveland, OH 44106 USA. RP Mehta, NN (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov FU National Institutes of Health [AI-07164, AI-67039, AI-68636, R00HL108743, R56HL126563]; Fasenmyer Foundation (Cleveland, OH, USA); Center for AIDS Research at Case Western Reserve University [AI-36219]; NIH Intramural Grant from the NHLBI [HL006193-01]; National Institute of Allergy and Infectious Diseases [U01AI068636]; National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR) FX This work was supported by grants from the National Institutes of Health (grant numbers AI-07164, AI-67039, AI-68636, R00HL108743, R56HL126563), the Fasenmyer Foundation (Cleveland, OH, USA), the Center for AIDS Research at Case Western Reserve University AI-36219 and an NIH Intramural Grant from the NHLBI to NNM (HL006193-01).; The project described was supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases and supported by National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. NR 20 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2017 VL 22 IS 1 BP 71 EP 75 DI 10.3851/IMP3091 PG 5 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA EO1ZV UT WOS:000396497300008 PM 27740536 ER PT J AU Lee, M Gouskova, NA Feuer, EJ Fine, JP AF Lee, Minjung Gouskova, Natalia A. Feuer, Eric J. Fine, Jason P. TI On the choice of time scales in competing risks predictions SO BIOSTATISTICS LA English DT Article DE Cumulative incidence function; Disease registry data; Left truncation; Multiple time scales; Population risk; Proportional hazards model ID MODEL; SURVIVAL; CANCER AB In the standard analysis of competing risks data, proportional hazards models are fit to the cause-specific hazard functions for all causes on the same time scale. These regression analyses are the foundation for predictions of cause-specific cumulative incidence functions based on combining the estimated cause-specific hazard functions. However, in predictions arising from disease registries, where only subjects with disease enter the database, disease-related mortality may be more naturally modeled on the time since diagnosis time scale while death from other causes may be more naturally modeled on the age time scale. The single time scale methodology may be biased if an incorrect time scale is employed for one of the causes and an alternative methodology is not available. We propose inferences for the cumulative incidence function in which regression models for the cause-specific hazard functions may be specified on different time scales. Using the disease registry data, the analysis of other cause mortality on the age scale requires left truncating the event time at the age of disease diagnosis, complicating the analysis. In addition, standard Martingale theory is not applicable when combining regression models on different time scales. We establish that the covariate conditional predictions are consistent and asymptotically normal using empirical process techniques and propose consistent variance estimators for constructing confidence intervals. Simulation studies show that the proposed two time scales method performs well, outperforming the single time-scale predictions when the time scale is misspecified. The methods are illustrated with stage III colon cancer data obtained from the Surveillance, Epidemiology, and End Results program of National Cancer Institute. C1 [Lee, Minjung] Kangwon Natl Univ, Dept Stat, Chunchon 24341, South Korea. [Gouskova, Natalia A.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Feuer, Eric J.] Natl Canc Inst, Div Canc Control & Populat Studies, Stat Res & Applicat Branch, Bethesda, MD 20892 USA. [Fine, Jason P.] Univ N Carolina, Dept Biostat & Dept Stat, Chapel Hill, NC 27599 USA. RP Lee, M (reprint author), Kangwon Natl Univ, Dept Stat, Chunchon 24341, South Korea. EM minjung.lee09@gmail.com FU Kangwon National University FX This study was supported by 2016 Research Grant from Kangwon National University. NR 19 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD JAN PY 2017 VL 18 IS 1 BP 15 EP 31 DI 10.1093/biostatistics/kxw024 PG 17 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA EP0FX UT WOS:000397063700002 PM 27335117 ER PT J AU Zhu, H Ning, J Shen, Y Qin, J AF Zhu, Hong Ning, Jing Shen, Yu Qin, Jing TI Semiparametric density ratio modeling of survival data from a prevalent cohort SO BIOSTATISTICS LA English DT Article DE Conditional pairwise likelihood; Density ratio model; Left-truncated right-censored data; Prevalent sampling; Profile likelihood ID REGRESSION-ANALYSIS; PROFILE LIKELIHOOD; TRUNCATED DATA AB In this article, we consider methods for assessing covariate effects on survival outcome in the target population when data are collected under prevalent sampling. We investigate a flexible semiparametric density ratio model without the constraints of the constant disease incidence rate and discrete covariates as required in Shen and others 2012. For inference, we introduce two likelihood approaches with distinct computational algorithms. We first develop a full likelihood approach to obtain the most efficient estimators by an iterative algorithm. Under the density ratio model, we exploit the invariance property of uncensored failure times from the prevalent cohort and also propose a computationally convenient estimation procedure that uses a conditional pairwise likelihood. The empirical performance and efficiency of the two approaches are evaluated through simulation studies. The proposed methods are applied to the Surveillance, Epidemiology, and End Results Medicare linked data for women diagnosed with stage IV breast cancer. C1 [Zhu, Hong] Univ Texas Southwestern Med Ctr Dallas, Dept Clin Sci, Div Biostat, Dallas, TX 75390 USA. [Ning, Jing; Shen, Yu] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Qin, Jing] Natl Inst Allergy & Infect Dis, Biostat Res Branch, Bethesda, MD 20892 USA. RP Zhu, H (reprint author), Univ Texas Southwestern Med Ctr Dallas, Dept Clin Sci, Div Biostat, Dallas, TX 75390 USA. EM hong.zhu@utsouthwestern.edu FU National Institutes of Health; Cancer Center Support Grant from the National Cancer Institute [2P30CA142543]; National Cancer Institute [R01CA193878, R01CA07466, P30CA016672] FX National Institutes of Health; the Cancer Center Support Grant from the National Cancer Institute (2P30CA142543, to H.Z.) awarded to the Harold C. Simmons Cancer Center at the University of Texas Southwestern Medical Center; the National Cancer Institute (R01CA193878, R01CA07466 and P30CA016672, J.N. and Y.S.). NR 15 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD JAN PY 2017 VL 18 IS 1 BP 62 EP 75 DI 10.1093/biostatistics/kxw028 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA EP0FX UT WOS:000397063700005 PM 27354710 ER PT J AU Hamilton, DH David, JM Dominguez, C Palena, C AF Hamilton, Duane H. David, Justin M. Dominguez, Charli Palena, Claudia TI Development of Cancer Vaccines Targeting Brachyury, a Transcription Factor Associated with Tumor Epithelial-Mesenchymal Transition SO CELLS TISSUES ORGANS LA English DT Article; Proceedings Paper CT International EMT Meeting CY OCT 11-14, 2015 CL Melbourne, AUSTRALIA DE Epithelial-mesenchymal transition; Brachyury; Cancer vaccines; Immune resistance ID CELL LUNG-CANCER; EGFR INHIBITOR RESISTANCE; HUMAN CARCINOMA-CELLS; PHASE-I TRIAL; AUTOPHAGY INDUCTION; MESODERM FORMATION; PROSTATE-CANCER; MEDIATED LYSIS; IMMUNE ATTACK; T-GENE AB Epithelial-mesenchymal transition (EMT) is recognized as a relevant process during the progression of carcinomas towards metastatic disease. Epithelial cancer cells undergoing an EMT program may acquire mesenchymal features, motility, invasiveness, and resistance to a variety of anticancer therapeutics. Preventing or reverting the EMT process in carcinomas has the potential to minimize tumor dissemination and the emergence of therapeutic resistance. One of the strategies currently under investigation to target tumor cells undergoing EMT is the generation of a sustained immune response directed against an essential molecular driver of the process. This review focuses on the current development of immune-mediated anticancer interventions aimed at targeting a transcription factor, brachyury, associated with human tumor EMT. Also presented here is a summary of recent studies demonstrating a role for EMT in tumor resistance to immune effector cytotoxicity, and the study of novel strategies aimed at reverting the EMT to be used in combination with immune-mediated anticancer interventions. (C) 2017 S. Karger AG, Basel C1 [Hamilton, Duane H.; David, Justin M.; Dominguez, Charli; Palena, Claudia] Natl Inst Hlth, Natl Canc Inst, Ctr Canc Res, Lab Tumor Immunol & Biol, 10 Ctr Dr,Room 8B14,Bethesda, Bethesda, MD 20892 USA. RP Palena, C (reprint author), Natl Inst Hlth, Natl Canc Inst, Ctr Canc Res, Lab Tumor Immunol & Biol, 10 Ctr Dr,Room 8B14,Bethesda, Bethesda, MD 20892 USA. EM palenac@mail.nih.gov FU NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research FX This research was supported by funds of the NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research. NR 70 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1422-6405 EI 1422-6421 J9 CELLS TISSUES ORGANS JI Cells Tissues Organs PY 2017 VL 203 IS 2 BP 128 EP 138 DI 10.1159/000446495 PG 11 WC Anatomy & Morphology; Cell Biology; Developmental Biology SC Anatomy & Morphology; Cell Biology; Developmental Biology GA EL9EM UT WOS:000394922500007 PM 28214895 ER PT J AU Strong, SL Silson, EH Gouws, AD Morland, AB McKeefry, DJ AF Strong, Samantha L. Silson, Edward H. Gouws, Andre D. Morland, Antony B. McKeefry, Declan J. TI A Direct Demonstration of Functional Differences between Subdivisions of Human V5/MT+ SO CEREBRAL CORTEX LA English DT Article DE fMRI; psychophysics; transcranial magnetic stimulation; V5/MT+ ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN VISUAL-CORTEX; SUPERIOR TEMPORAL SULCUS; OPTIC FLOW STIMULI; MT PLUS COMPLEX; PURSUIT EYE-MOVEMENTS; CORTICAL AREAS MT; MST NEURONS; HUMAN BRAIN; EXTRASTRIATE CORTEX AB Two subdivisions of human V5/MT+: one located posteriorly (MT/TO-1) and the other more anteriorly (MST/TO-2) were identified in human participants using functional magnetic resonance imaging on the basis of their representations of the ipsilateral versus contralateral visual field. These subdivisions were then targeted for disruption by the application of repetitive transcranial magnetic stimulation (rTMS). The rTMS was delivered to cortical areas while participants performed direction discrimination tasks involving 3 different types of moving stimuli defined by the translational, radial, or rotational motion of dot patterns. For translational motion, performance was significantly reduced relative to baseline when rTMS was applied to both MT/TO-1 and MST/TO-2. For radial motion, there was a differential effect between MT/TO-1 and MST/TO-2, with only disruption of the latter area affecting performance. The rTMS failed to reveal a complete dissociation between MT/TO-1 and MST/TO-2 in terms of their contribution to the perception of rotational motion. On the basis of these results, MT/TO-1 and MST/TO-2 appear to be functionally distinct subdivisions of hV5/MT+. While both areas appear to be implicated in the processing of translational motion, only the anterior region (MST/TO-2) makes a causal contribution to the perception of radial motion. C1 [Strong, Samantha L.; McKeefry, Declan J.] Univ Bradford, Sch Optometry & Vis Sci, Bradford BD7 1DP, W Yorkshire, England. [Strong, Samantha L.; Silson, Edward H.; Gouws, Andre D.; Morland, Antony B.] Univ York, Dept Psychol, York Neuroimaging Ctr, York YO10 5DD, N Yorkshire, England. [Silson, Edward H.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Morland, Antony B.] Univ York, Hull York Med Sch, Ctr Neurosci, York YO10 5DD, N Yorkshire, England. RP McKeefry, DJ (reprint author), Univ Bradford, Sch Optometry & Vis Sci, Bradford BD7 1DP, W Yorkshire, England. EM d.mckeefry@bradford.ac.uk FU BBSRC award [BB/N003012/1] FX BBSRC award (BB/N003012/1). NR 71 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 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD JAN PY 2017 VL 27 IS 1 BP 1 EP 10 DI 10.1093/cercor/bhw362 PG 10 WC Neurosciences SC Neurosciences & Neurology GA EP0GI UT WOS:000397064800001 PM 28365777 ER PT J AU Zavala, B Damera, S Dong, JW Lungu, C Brown, P Zaghloul, KA AF Zavala, Baltazar Damera, Srikanth Dong, Jian Wilson Lungu, Codrin Brown, Peter Zaghloul, Kareem A. TI Human Subthalamic Nucleus Theta and Beta Oscillations Entrain Neuronal Firing During Sensorimotor Conflict SO CEREBRAL CORTEX LA English DT Article DE conflict; deep brain stimulation; impulsivity; inhibition; theta oscillations ID DEEP BRAIN-STIMULATION; ANTERIOR CINGULATE CORTEX; FIELD POTENTIAL ACTIVITY; INFERIOR FRONTAL GYRUS; STOP-SIGNAL TASK; PARKINSONS-DISEASE; BASAL GANGLIA; RESPONSE-INHIBITION; DECISION-MAKING; IMPULSE CONTROL AB Recent evidence has suggested that prefrontal cortical structures may inhibit impulsive actions during conflict through activation of the subthalamic nucleus (STN). Consistent with this hypothesis, deep brain stimulation to the STN has been associated with altered prefrontal cortical activity and impaired response inhibition. The interactions between oscillatory activity in the STN and its presumably antikinetic neuronal spiking, however, remain poorly understood. Here, we simultaneously recorded intraoperative local field potential and spiking activity from the human STN as participants performed a sensorimotor action selection task involving conflict. We identified several STN neuronal response types that exhibited different temporal dynamics during the task. Some neurons showed early, cue-related firing rate increases that remained elevated longer during high conflict trials, whereas other neurons showed late, movement-related firing rate increases. Notably, the high conflict trials were associated with an entrainment of individual neurons by theta-and beta-band oscillations, both of which have been observed in cortical structures involved in response inhibition. Our data suggest that frequency-specific activity in the beta and theta bands influence STN firing to inhibit impulsivity during conflict. C1 [Zavala, Baltazar; Damera, Srikanth; Dong, Jian Wilson; Zaghloul, Kareem A.] NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 3D20,10 Ctr Dr, Bethesda, MD 20892 USA. [Lungu, Codrin] NINDS, Off Clin Director, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Zavala, Baltazar; Brown, Peter] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurol, Expt Neurol Grp, Oxford OX3 9DU, England. [Brown, Peter] Univ Oxford, MRC, Brain Network Dynam Unit, Oxford OX1 3TH, England. RP Zaghloul, KA (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 3D20,10 Ctr Dr, Bethesda, MD 20892 USA. EM kareem.zaghloul@nih.gov FU National Institutes of Health; Medical Research Council; National Institute for Health Research Oxford Biomedical Research Centre FX This work was supported by the National Institutes of Health Intramural Research Program (B.Z., S.D., J.D., C.L., and K.Z.) as well as by the Medical Research Council (P.B.) and the National Institute for Health Research Oxford Biomedical Research Centre (P.B.). NR 72 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD JAN PY 2017 VL 27 IS 1 BP 496 EP 508 DI 10.1093/cercor/bhv244 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EP0GI UT WOS:000397064800040 PM 26494798 ER PT J AU Roccella, EJ AF Roccella, Edward J. TI Giants in Chest Medicine Claude Lenfant, MD SO CHEST LA English DT Biographical-Item ID CLINICAL-PRACTICE; BLOOD-PRESSURE C1 [Roccella, Edward J.] NHLBI, Natl High Blood Pressure Educ Program, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Roccella, EJ (reprint author), NHLBI, Natl High Blood Pressure Educ Program, NIH, Bldg 10, Bethesda, MD 20892 USA. EM eroccella@cox.net NR 21 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD JAN PY 2017 VL 151 IS 1 BP 11 EP 13 DI 10.1016/j.chest.2016.09.048 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EO0HE UT WOS:000396378100009 PM 28065248 ER PT J AU Balk, RA Kadri, SS Cao, Z Robinson, SB Lipkin, C Bozzette, SA AF Balk, Robert A. Kadri, Sameer S. Cao, Zhun Robinson, Scott B. Lipkin, Craig Bozzette, Samuel A. TI Effect of Procalcitonin Testing on Health-care Utilization and Costs in Critically Ill Patients in the United States SO CHEST LA English DT Article DE antibiotic use; cost of care; intensive care unit; procalcitonin; sepsis ID RESPIRATORY-TRACT INFECTIONS; RANDOMIZED CONTROLLED-TRIAL; GUIDED ANTIBIOTIC-THERAPY; SEPTIC SHOCK; SEVERE SEPSIS; BACTERIAL-INFECTION; SERUM PROCALCITONIN; METAANALYSIS; ALGORITHMS; DURATION AB BACKGROUND: There is a growing use of procalcitonin (PCT) to facilitate the diagnosis and management of severe sepsis. We investigated the impact of one to two PCT determinations on ICU day 1 on health-care utilization and cost in a large research database. METHODS: A retrospective, propensity score-matched multivariable analysis was performed on the Premier Healthcare Database for patients admitted to the ICU with one to two PCT evaluations on day 1 of ICU admission vs patients who did not have PCT testing. RESULTS: A total of 33,569 PCT-managed patients were compared with 98,543 propensity score-matched non-PCT patients. In multivariable regression analysis, PCT utilization was associated with significantly decreased total length of stay (11.6 days [95% CI, 11.4 to 11.7] vs 12.7 days [95% CI, 12.6 to 12.8]; 95% CI for difference, 1 to 1.3; P < .001) and ICU length of stay (5.1 days [95% CI, 5.1 to 5.2] vs 5.3 days [95% CI, 5.3 to 5.4]; 95% CI for difference, 0.1 to 0.3; P < .03), and lower hospital costs ($30,454 [95% CI, 29,968 to 31,033] vs $33,213 [95% CI, 32,964 to 33,556); 95% CI for difference, 2,159 to 3,321; P < .001). There was significantly less total antibiotic exposure (16.2 days [95% CI, 16.1 to 16.5] vs 16.9 days [95% CI, 16.8 to 17.1]; 95% CI for difference, -0.9 to 0.4; P = 0.006) in PCT-managed patients. Patients in the PCT group were more likely to be discharged to home (44.1% [95% CI, 43.7 to 44.6] vs 41.3% [95% CI, 41 to 41.6]; 95% CI for difference, 2.3 to 3.3; P = .006). Mortality was not different in an analysis including the 96% of patients who had an independent measure of mortality risk available (19.1% [95% CI, 18.7 to 19.4] vs 19.1% [95% CI, 18.9 to 19.3]; 95% CI for difference, -0.5 to 0.4; P = .93). CONCLUSIONS: Use of PCT testing on the first day of ICU admission was associated with significantly lower hospital and ICU lengths of stay, as well as decreased total, ICU, and pharmacy cost of care. Further elucidation of clinical outcomes requires additional data. C1 [Balk, Robert A.] Rush Med Coll, Div Pulm & Crit Care Med, Chicago, IL 60612 USA. Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Bozzette, Samuel A.] BioMerieux USA, Med Affairs Amer East Asia & Global Hlth Econ & O, Durham, NC USA. [Bozzette, Samuel A.] Univ Calif San Diego, Med & Int Relat, San Diego, CA 92103 USA. [Bozzette, Samuel A.] Univ N Carolina, Hlth Policy & Management, Raleigh, NC USA. [Cao, Zhun; Robinson, Scott B.; Lipkin, Craig] Premier Res Serv Inc, Charlotte, NC USA. [Kadri, Sameer S.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Balk, RA (reprint author), Rush Univ, Med Ctr, Div Pulm & Crit Care Med, 1725 W Harrison St,Ste 054, Chicago, IL 60612 USA. EM rbalk@rush.edu FU bioMerieux USA FX This study was funded by bioMerieux USA. NR 33 TC 2 Z9 2 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD JAN PY 2017 VL 151 IS 1 BP 23 EP 33 DI 10.1016/j.chest.2016.06.046 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EO0HE UT WOS:000396378100014 PM 27568580 ER PT J AU Small, AM Mehta, NN Rader, DJ AF Small, Aeron M. Mehta, Nehal N. Rader, Daniel J. TI The Role of Emerging Biomarkers in Unraveling the Complex Biology Underlying Associations between HDL Cholesterol and Cardiovascular Diseases SO CLINICAL CHEMISTRY LA English DT Editorial Material ID INFLAMMATION; GLYCA; RISK; EVENTS C1 [Small, Aeron M.; Rader, Daniel J.] Univ Penn, Dept Med, Hosp Univ Penn, Div Cardiol,Perelman Sch Med, Philadelphia, PA 19104 USA. [Mehta, Nehal N.] NHLBI, Cardiovasc & Pulm Branch, Bldg 10, Bethesda, MD 20892 USA. [Rader, Daniel J.] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Rader, DJ (reprint author), Univ Penn, Smilow Ctr Translat Res 11 125, Perelman Sch Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. 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 JAN PY 2017 VL 63 IS 1 BP 27 EP 29 DI 10.1373/clinchem.2016.267922 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM1AE UT WOS:000395048800006 PM 27815309 ER PT J AU Karathanasis, SK Freeman, LA Gordon, SM Remaley, AT AF Karathanasis, Sotirios K. Freeman, Lita A. Gordon, Scott M. Remaley, Alan T. TI The Changing Face of HDL and the Best Way to Measure It SO CLINICAL CHEMISTRY LA English DT Review ID HIGH-DENSITY-LIPOPROTEIN; CORONARY-ARTERY-DISEASE; CHOLESTEROL EFFLUX CAPACITY; TRYPANOSOME LYTIC FACTOR; ISCHEMIC-HEART-DISEASE; APOLIPOPROTEIN-A-I; CHRONIC KIDNEY-DISEASE; NITRIC-OXIDE SYNTHASE; ACUTE MYOCARDIAL-INFARCTION; HAPTOGLOBIN-RELATED PROTEIN AB BACKGROUND: HDL cholesterol (HDL-C) is a commonly used lipid biomarker for assessing cardiovascular health. While a central focus has been placed on the role of HDL in the reverse cholesterol transport (RCT) process, our appreciation for the other cardioprotective properties of HDL continues to expand with further investigation into the structure and function of HDL and its specific subfractions. The development of novel assays is empowering the research community to assess different aspects of HDL function, which at some point may evolve into new diagnostic tests. CONTENT: This review discusses our current understanding of the formation and maturation of HDL particles via RCT, as well as the newly recognized roles of HDL outside RCT. The antioxidative, antiinflammatory, andapoptotic, anti thrombotic, and infective, and vasoprotective effects of HDL are all discussed, as are the related methodologies for assessing these different aspects of HDL function. We elaborate on the importance of protein and lipid composition of HDL in health and disease and highlight potential new diagnostic assays based on these parameters. SUMMARY: Although multiple epidemiologic studies have confirmed that HDL-C is a strong negative risk marker for cardiovascular disease, several clinical and experimental studies have yielded inconsistent results on the direct role of HDL-C as an antiatherogenic factor. As of yet, our increased understanding of HDL biology has not been translated into successful new therapies, but will undoubtedly depend on the development of alternative ways for measuring HDL besides its cholesterol content. (C) 2016 American Association for Clinical Chemistry C1 [Karathanasis, Sotirios K.] MedImmune, Cardiovasc & Metab Dis Sect, Gaithersburg, MD USA. [Freeman, Lita A.; Gordon, Scott M.; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Cardiovasc Pulm Branch, NIH, Bldg 10,Rm 2C433, Bethesda, MD 20814 USA. RP Remaley, AT (reprint author), NHLBI, Lipoprot Metab Sect, Cardiovasc Pulm Branch, NIH, Bldg 10,Rm 2C433, Bethesda, MD 20814 USA. EM aremaley1@nhlbi.nih.gov FU Medlmmune; CRADA Research Grant; intramural National Heart, Lung and Blood Institute of the NIH; MedImmune on LCAT FX Medical writing support was funded by Medlmmune. L.A. Freeman, intramural National Heart, Lung and Blood Institute of the NIH; S.M. Gordon, intramural National Heart, Lung and Blood Institute of the NIH; A.T. Remaley, CRADA Research Grant with MedImmune on LCAT and intramural National Heart, Lung and Blood Institute of the NIH. NR 196 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 JAN PY 2017 VL 63 IS 1 BP 196 EP 210 DI 10.1373/clinchem.2016.257725 PG 15 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM1AE UT WOS:000395048800028 PM 27879324 ER PT J AU Salahudeen, AA Patel, MI Baas, P Curran, WJ Bradley, JD Gandara, DR Goss, GD Mok, TS Ramalingam, SS Vokes, EE Malik, SM Wakelee, HA AF Salahudeen, Ameen Abdulla Patel, Manali I. Baas, Paul Curran, Walter J. Bradley, Jeffrey D. Gandara, David R. Goss, Glenwood D. Mok, Tony S. Ramalingam, Suresh S. Vokes, Everett E. Malik, Shakun M. Wakelee, Heather A. TI Overview of Thoracic Oncology Trials in Cooperative Groups Around the Globe SO CLINICAL LUNG CANCER LA English DT Review DE Cooperative group; Mesothelioma; NCTN; NSCLC; SCLC ID CELL LUNG-CANCER; DOUBLE-BLIND; OPEN-LABEL; CHEMOTHERAPY; MULTICENTER; ERLOTINIB; ADENOCARCINOMA; GEFITINIB; THERAPY; PLACEBO AB Survival rates of patients with either early and advanced stage non small-cell lung cancer (NSCLC) have improved with newer systemic therapy and radiation techniques, including combination regimens, targeted therapies, and immunotherapies. The cancer cooperative groups have historically played a critical role in the advancement of NSCLC therapy. Annually, representatives from cooperative groups worldwide convene at the International Lung Cancer Congress (ILCC). In summer 2015, the ILCC reached its 16th anniversary. This article highlights the NSCLC studies presented by participating groups in 2015. (C) 2016 Elsevier Inc. All rights reserved. C1 [Salahudeen, Ameen Abdulla; Patel, Manali I.; Ramalingam, Suresh S.; Wakelee, Heather A.] Emory Univ, Sch Med, Winship Canc Inst, Hematol & Med Oncol, Atlanta, GA 30322 USA. [Curran, Walter J.] Emory Univ, Sch Med, Winship Canc Inst, Radiat Oncol, Atlanta, GA USA. [Baas, Paul] Univ Amsterdam AMC UvA, Antoni van Leeuwenhoek Hosp NKI AVL, Netherlands Canc Inst, Thorac Oncol,Fac Med, Amsterdam, Netherlands. [Bradley, Jeffrey D.] Washington Univ, Sch Med, S Lee Kling Ctr Proton Therapy, St Louis, MO USA. [Gandara, David R.] Univ Calif Davis, Ctr Comprehens Canc, Thorac Oncol Program, Davis, CA USA. [Goss, Glenwood D.] Univ Ottawa, Div Oncol, Dept Med, Ottawa, ON, Canada. [Mok, Tony S.] Chinese Med Univ Hong Kong, Dept Clin Oncol, Shatin, Hong Kong, Peoples R China. [Vokes, Everett E.] Univ Chicago, Sch Med, Dept Med, Chicago, IL 60637 USA. [Malik, Shakun M.] NCI, Clin Invest Branch, CTEP, DCTD,NIH, Rockville, MD USA. RP Wakelee, HA (reprint author), Stanford Univ, Dept Med, 875 Blake Wilbur Dr,Room 2233, Stanford, CA 94305 USA.; Wakelee, HA (reprint author), Stanford Univ, Dept Oncol, 875 Blake Wilbur Dr,Room 2233, Stanford, CA 94305 USA. EM hwakelee@stanford.edu FU NCI NIH HHS [U10 CA180833, U10 CA180888] NR 17 TC 1 Z9 1 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1525-7304 EI 1938-0690 J9 CLIN LUNG CANCER JI Clin. Lung Cancer PD JAN PY 2017 VL 18 IS 1 BP 5 EP 12 DI 10.1016/j.cllc.2016.06.007 PG 8 WC Oncology SC Oncology GA EK7AW UT WOS:000394078900002 PM 27473736 ER PT J AU Cai, YT Zijlema, WL Doiron, D Blangiardo, M Burton, PR Fortier, I Gaye, A Gulliver, J de Hoogh, K Hveem, K Mbatchou, S Morley, DW Stolk, RP Elliott, P Hansell, AL Hodgson, S AF Cai, Yutong Zijlema, Wilma L. Doiron, Dany Blangiardo, Marta Burton, Paul R. Fortier, Isabel Gaye, Amadou Gulliver, John de Hoogh, Kees Hveem, Kristian Mbatchou, Stephane Morley, David W. Stolk, Ronald P. Elliott, Paul Hansell, Anna L. Hodgson, Susan TI Ambient air pollution, traffic noise and adult asthma prevalence: a BioSHaRE approach SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article ID RESPIRATORY HEALTH; ENVIRONMENTAL NOISE; ALLERGIC RHINITIS; EXPOSURE; NO2; COHORT; ROAD; ESCAPE; EUROPE; IMPACT AB We investigated the effects of both ambient air pollution and traffic noise on adult asthma prevalence, using harmonised data from three European cohort studies established in 2006-2013 (HUNT3, Lifelines and UK Biobank). Residential exposures to ambient air pollution (particulate matter with aerodynamic diameter <= 10 mu m (PM10) and nitrogen dioxide (NO2)) were estimated by a pan-European Land Use Regression model for 2007. Traffic noise for 2009 was modelled at home addresses by adapting a standardised noise assessment framework (CNOSSOS-EU). A cross-sectional analysis of 646 731 participants aged >= 20 years was undertaken using DataSHIELD to pool data for individual-level analysis via a "compute to the data" approach. Multivariate logistic regression models were fitted to assess the effects of each exposure on lifetime and current asthma prevalence. PM10 or NO2 higher by 10 mu g center dot m-3 was associated with 12.8% (95% CI 9.5-16.3%) and 1.9% (95% CI 1.1-2.8%) higher lifetime asthma prevalence, respectively, independent of confounders. Effects were larger in those aged. 50 years, ever-smokers and less educated. Noise exposure was not significantly associated with asthma prevalence. This study suggests that long-term ambient PM10 exposure is associated with asthma prevalence in western European adults. Traffic noise is not associated with asthma prevalence, but its potential to impact on asthma exacerbations needs further investigation. C1 [Cai, Yutong; Blangiardo, Marta; Morley, David W.; Elliott, Paul; Hansell, Anna L.; Hodgson, Susan] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, IMRC PHE Ctr Environm & Hlth, London, England. [Zijlema, Wilma L.; Stolk, Ronald P.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Doiron, Dany; Mbatchou, Stephane] McGill Univ Hlth Ctr & Dept Med, McGill Univ, Res Inst, Montreal, PQ, Canada. [Burton, Paul R.] Univ Bristol, Data Knowledge D2K Res Grp, Bristol, Avon, England. [Burton, Paul R.] Publ Populat Project Genom & Soc P3G, Montreal, PQ, Canada. [Gaye, Amadou] Natl Human Genome Res Inst, Cardiovascular & Inflammatory Dis Genom Branch, Metab, Bethesda, MD USA. [de Hoogh, Kees] Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [de Hoogh, Kees] Univ Basel, Basel, Switzerland. [Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Trondheim, Norway. [Hansell, Anna L.] Imperial Coll Healthcare NHS Trust, Directorate Publ Hlth & Primary Care, London, England. [Cai, Yutong] Sch Publ Hlth, Dept Epidemiol & Biostatist, Imperial Coll London, MRC PHE Ctr Environm & Hlth, St Marys Campus,Pl, Norfolk, VA USA. RP Cai, YT (reprint author), Sch Publ Hlth, Dept Epidemiol & Biostatist, Imperial Coll London, MRC PHE Ctr Environm & Hlth, St Marys Campus,Pl, Norfolk, VA USA. EM yutong.cai@imperial.ac.uk FU European Union [261433]; UK Medical Research Council (MRC); Wellcome Trust; MRC; BBMRI-LPC (European Union Seventh Framework Programme: I3 grant); Netherlands Organisation of Scientific Research NWO [175.010.2007.006]; Economic Structure Enhancing Fund (FES) of the Dutch government; Ministry of Economic Affairs; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; Northern Netherlands Collaboration of Provinces (SNN); Province of Groningen; University Medical Center Groningen; University of Groningen; Dutch Kidney Foundation; Dutch Diabetes Research Foundation; Welsh Assembly Government; British Heart Foundation; Diabetes UK; European Union Seventh Framework Programme (FP7) [211250]; Public Health England (PHE) [MR/L01341X/1]; Imperial College Healthcare National Health Service Trust; Imperial College London Biomedical Research Centre; NIHR Health Protection Research Unit on the Health Effects of Environmental Hazards [HPRU-2012-10030-KCL]; MRC-PHE Centre for Environment and Health FX The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement 261433 (Biobank Standardisation and Harmonisation for Research Excellence in the European Union (BioSHaRE)). BioSHaRE is engaged in a Bioresource Research Impact Factor (BRIF) policy pilot study (www.bioshare.eu/content/bioresource-impact-factor). DataSHIELD development is also partly funded under a strategic award from the UK Medical Research Council (MRC) and Wellcome Trust underpinning the ALSPAC (Avon Longitudinal Study of Parents and Children) project, and the Welsh and Scottish Farr Institutes funded by MRC, BBMRI-LPC (European Union Seventh Framework Programme: I3 grant). The Lifelines Cohort Study, and generation and management of genomewide association studies genotype data for the Lifelines Cohort Study, is supported by the Netherlands Organisation of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. Lifelines is a facility that is open for all researchers. Information on application and data access procedures is summarised at www.lifelines.nl. UK Biobank was established by the Wellcome Trust medical charity, MRC, Dept of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The ESCAPE (European Study of Cohorts for Air Pollution Effects) project has received funding from the European Union Seventh Framework Programme (FP7/2007-2011) under grant agreement 211250. The MRC-PHE Centre for Environment and Health is funded by the MRC and Public Health England (PHE) (MR/L01341X/1). P. Elliott is a National Institute for Health Research (NIHR) Senior Investigator and acknowledges support from the Imperial College Healthcare National Health Service Trust and Imperial College London Biomedical Research Centre, the NIHR Health Protection Research Unit on the Health Effects of Environmental Hazards (HPRU-2012-10030-KCL), and the MRC-PHE Centre for Environment and Health. Funding information for this article has been deposited with the Open Funder Registry. NR 41 TC 0 Z9 0 U1 1 U2 1 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD JAN PY 2017 VL 49 IS 1 AR 1502127 DI 10.1183/13993003.02127-2015 PG 10 WC Respiratory System SC Respiratory System GA EP5MU UT WOS:000397423500003 ER PT J AU Khincha, PP Bertuch, AA Agarwal, S Townsley, DM Young, NS Keel, S Shimamura, A Boulad, F Simoneau, T Justino, H Kuo, C Artandi, S McCaslin, C Cox, DW Chaffee, S Collins, BF Giri, N Alter, BP Raghu, G Savage, SA AF Khincha, Payal P. Bertuch, Alison A. Agarwal, Suneet Townsley, Danielle M. Young, Neal S. Keel, Sioban Shimamura, Akiko Boulad, Farid Simoneau, Tregony Justino, Henri Kuo, Christin Artandi, Steven McCaslin, Charles Cox, Des W. Chaffee, Sara Collins, Bridget F. Giri, Neelam Alter, Blanche P. Raghu, Ganesh Savage, Sharon A. TI Pulmonary arteriovenous malformations: an uncharacterised phenotype of dyskeratosis congenita and related telomere biology disorders SO EUROPEAN RESPIRATORY JOURNAL LA English DT Letter ID HEPATOPULMONARY SYNDROME; FISTULAS C1 [Khincha, Payal P.; Giri, Neelam; Alter, Blanche P.; Savage, Sharon A.] NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, NIH, Bethesda, MD 20892 USA. [Bertuch, Alison A.; Justino, Henri] Baylor Coll Med, Houston, TX 77030 USA. [Agarwal, Suneet; Shimamura, Akiko] Boston Childrens Hosp, Div Haematol Oncol, Boston, MA USA. [Townsley, Danielle M.; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Keel, Sioban] Univ Washington, Dept Med, Div Haematol, Seattle, WA 98195 USA. [Boulad, Farid] Mem Sloan Kettering Canc Ctr, Dept Paediat, Paediat Oncol & Bone Marrow Transplant Serv, 1275 York Ave, New York, NY 10021 USA. [Simoneau, Tregony] Connecticut Childrens Med Ctr, Dept Pulmonol, Hartford, CT USA. [Kuo, Christin] Lucile Packard Childrens Hosp Stanford, Dept Pulmonol, Palo Alto, CA USA. [Artandi, Steven] Stanford Univ, Sch Med, Canc Biol Program, Palo Alto, CA 94304 USA. [McCaslin, Charles] Helen DeVos Childrens Hosp, Grand Rapids, MI USA. [Cox, Des W.] Our Ladys Childrens Hosp, Paediat Resp Med, Dublin, Ireland. [Chaffee, Sara] Childrens Hosp Dartmouth, Dartmouth Hitchcock Med Ctr, Paediat Haematol Oncol, Lebanon, NH USA. [Collins, Bridget F.; Raghu, Ganesh] Univ Washington, Ctr Interstitial Lung Dis, Dept Med, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. RP Khincha, PP (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E562,MSC 9772, Bethesda, MD 20892 USA. EM khinchapp@mail.nih.gov FU National Cancer Institute (Rockville, MD, USA); National Institutes of Health (NIH; Bethesda, MD, USA); National Heart, Lung and Blood Institute, NIH; Translational Research Program at Boston Children's Hospital (Boston, MA, USA) FX This work was supported by the intramural research programme of the National Cancer Institute (Rockville, MD, USA), National Institutes of Health (NIH; Bethesda, MD, USA), the National Heart, Lung and Blood Institute, NIH and the Translational Research Program at Boston Children's Hospital (Boston, MA, USA). Funding information for this article has been deposited with Open Funder Registry. NR 15 TC 1 Z9 1 U1 1 U2 1 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD JAN PY 2017 VL 49 IS 1 AR 1601640 DI 10.1183/13993003.01640-2016 PG 4 WC Respiratory System SC Respiratory System GA EP5MU UT WOS:000397423500036 ER PT J AU Brooks, KM George, JM Kumar, P AF Brooks, Kristina M. George, Jomy M. Kumar, Parag TI Drug interactions in HIV treatment: complementary & alternative medicines and over-the-counter products SO EXPERT REVIEW OF CLINICAL PHARMACOLOGY LA English DT Review DE Antiretrovirals; complementary and alternative medicines (CAMs); drug interactions; herbals; HIV; over-the-counter (OTC); pharmacokinetics; supplements ID ST-JOHNS-WORT; HUMAN-IMMUNODEFICIENCY-VIRUS; PREGNANE-X-RECEPTOR; GOLDENSEAL HYDRASTIS-CANADENSIS; ACTIVE ANTIRETROVIRAL THERAPY; PROTEASE INHIBITOR INDINAVIR; CYTOCHROME-P450 3A ACTIVITY; AFRICAN HERBAL MEDICINES; KAVA PIPER-METHYSTICUM; SEVILLE ORANGE JUICE AB Introduction: Use of complementary and alternative medicines (CAMs) and over-the-counter (OTC) medications are very common among HIV-infected patients. These products can cause clinically significant drug-drug interactions (DDIs) with antiretroviral (ARV) medications, thereby increasing risk for negative outcomes such as toxicity or loss of virologic control. Areas covered: This article provides an updated review of the different mechanisms by which CAM and OTC products are implicated in DDIs with ARV medications. Expert commentary: Much of the literature published to date involves studies of CAMs interacting with older ARV agents via the cytochrome P450 (CYP450) system. However, the HIV treatment and prevention arsenal is continually evolving. Furthermore, our elucidation of the role of non-CYP450 mediated DDIs with ARV medications is greatly increasing. Therefore, clinicians are well served to understand the various mechanisms and extent by which new ARV therapies may be involved in drug interactions with CAMs and OTC medications. C1 [Brooks, Kristina M.; George, Jomy M.; Kumar, Parag] NIH, Clin Pharmacokinet Res Unit, Clin Ctr Pharm Dept, 10 Ctr Dr Bldg 10,Rm 1C-230G, Bethesda, MD 20892 USA. RP Kumar, P (reprint author), NIH, Clin Pharmacokinet Res Unit, Clin Ctr Pharm Dept, 10 Ctr Dr Bldg 10,Rm 1C-230G, Bethesda, MD 20892 USA. EM Parag.kumar@nih.gov NR 166 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 1751-2433 EI 1751-2441 J9 EXPERT REV CLIN PHAR JI Expert Rev. Clin. Pharmacol. PY 2017 VL 10 IS 1 BP 59 EP 79 DI 10.1080/17512433.2017.1246180 PG 21 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL3MG UT WOS:000394522600007 PM 27715369 ER PT J AU Ke, SZ Chen, SZ Dong, ZH Hong, CS Zhang, Q Tang, L Yang, PG Zhai, J Yan, HX Shen, F Zhuang, ZG Wen, W Wang, HY AF Ke, Shizhong Chen, Shuzhen Dong, Zihui Hong, Christopher S. Zhang, Qi Tang, Liang Yang, Pinghua Zhai, Jian Yan, Hexin Shen, Feng Zhuang, Zhengping Wen, Wen Wang, Hongyang TI Erythrocytosis in Hepatocellular Carcinoma Portends Poor Prognosis by Respiratory Dysfunction Secondary to Mitochondrial DNA Mutations SO HEPATOLOGY LA English DT Article ID ERYTHROPOIETIN RECEPTOR; COMPLEX-I; BREAST-CANCER; DOUBLE-BLIND; EXPRESSION; CELLS; CARDIOMYOPATHY; ENCEPHALOPATHY; DIAGNOSIS; APOPTOSIS AB Erythrocytosis is a common paraneoplastic syndrome associated with hepatocellular carcinoma. Although increased erythropoietin (EPO) is found in these patients, the clinical significance and molecular mechanisms underlying this observation are unclear. We demonstrate an inverse relationship between EPO production and overall prognosis in our cohort of 664 patients as well as in data from The Cancer Genome Atlas. In the subset of hepatocellular carcinoma patients with erythrocytosis, we identified somatic mutations of mitochondrial DNA, resulting in impairment of respiratory metabolism, which sequentially led to depletion of a-ketoglutarate, stabilization of hypoxia inducible factor-alpha, and expression of target genes such as EPO. Cell lines and patient-derived xenograft models were used to demonstrate that EPO promoted cancer stem cell self-renewal and expansion in an autocrine/paracrine manner through enhanced Janus kinase/signal transducer and activator of transcription signaling both in vitro and in vivo. Furthermore, to explore the therapeutic targeting of EPO-induced tumor changes, we found that blocking EPO signaling with soluble EPO receptor extracellular domain Fc fusion protein could inhibit tumor growth both in vitro and in vivo. Conclusion: These findings suggest clinical and therapeutic implications for erythrocytosis in hepatocellular carcinoma. There is an underlying link between mitochondrial function and hypoxia inducible factor alpha signaling, revealing a mechanism of erythrocytosis in a subset of hepatocellular carcinoma patients who may benefit from treatment involving EPO signaling interference. C1 [Ke, Shizhong; Wang, Hongyang] Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Shanghai Canc Inst State Key Lab Oncogenes & Rel, Shanghai, Peoples R China. [Chen, Shuzhen; Dong, Zihui; Tang, Liang; Yan, Hexin; Wen, Wen] Second Mil Med Univ, Natl Ctr Liver Canc, Shanghai, Peoples R China. [Chen, Shuzhen; Dong, Zihui; Tang, Liang; Yan, Hexin; Wen, Wen; Wang, Hongyang] Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Int Cooperat Lab Signal Transduct, 225 Changhai Rd, Shanghai 200438, Peoples R China. [Hong, Christopher S.] NIH, Surg Neurol Branch, Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Yang, Pinghua; Shen, Feng] Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Dept Hepat Surg, Shanghai, Peoples R China. [Zhai, Jian] Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Dept Int Radiol, Shanghai, Peoples R China. [Wang, Hongyang] Second Mil Med Univ, Minist Educ MOE Key Lab Signaling Regulat & Targe, Shanghai, Peoples R China. [Hong, Christopher S.] Yale Sch Med, Dept Neurosurg, New Haven, CT USA. RP Wen, W; Wang, HY (reprint author), Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Int Cooperat Lab Signal Transduct, 225 Changhai Rd, Shanghai 200438, Peoples R China. EM wenwen_smmu@163.com; hywangk@vip.sina.com FU National Natural Science Foundation of China [81370061, 81521091, 81572896]; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12010201-XDA12020102] FX Supported by the National Natural Science Foundation of China (81370061, 81521091, and 81572896) and Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No.XDA12010201-XDA12020102. NR 49 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 JAN PY 2017 VL 65 IS 1 BP 134 EP 151 DI 10.1002/hep.28889 PG 18 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP3RE UT WOS:000397298600014 PM 27774607 ER PT J AU Navarro, VJ Khan, I Bjornsson, E Seeff, LB Serrano, J Hoofnagle, JH AF Navarro, Victor J. Khan, Ikhlas Bjoernsson, Einar Seeff, Leonard B. Serrano, Jose Hoofnagle, Jay H. TI Liver Injury From Herbal and Dietary Supplements SO HEPATOLOGY LA English DT Review ID ANABOLIC-ANDROGENIC STEROIDS; GREEN TEA; OXYELITE PRO; PLANT-MATERIAL; UNITED-STATES; HEPATOTOXICITY; EXPERIENCE; TRENDS; SAFETY AB Herbal and dietary supplements (HDS) are used increasingly both in the United States and worldwide, and HDS-induced liver injury in the United States has increased proportionally. Current challenges in the diagnosis and management of HDS-induced liver injury were the focus of a 2-day research symposium sponsored by the American Association for the Study of Liver Disease and the National Institutes of Health. HDS-induced liver injury now accounts for 20% of cases of hepatotoxicity in the United States based on research data. The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements. Anabolic steroids marketed as bodybuilding supplements typically induce a prolonged cholestatic but ultimately self-limiting liver injury that has a distinctive serum biochemical as well as histological phenotype. Green tea extract and many other products, in contrast, tend to cause an acute hepatitis-like injury. Currently, however, the majority of cases of HDS-associated liver injury are due to multi-ingredient nutritional supplements, and the component responsible for the toxicity is usually unknown or can only be suspected. HDS-induced liver injury presents many clinical and research challenges in diagnosis, identification of the responsible constituents, treatment, and prevention. Also important are improvements in regulatory oversight of nonprescription products to guarantee their constituents and ensure purity and safety. The confident identification of injurious ingredients within HDS will require strategic alignments among clinicians, chemists, and toxicologists. The ultimate goal should be to prohibit or more closely regulate potentially injurious ingredients and thus promote public safety. C1 [Navarro, Victor J.; Seeff, Leonard B.] Einstein Healthcare Network, Div Hepatol, Philadelphia, PA USA. [Khan, Ikhlas] Univ Mississippi, Sch Pharm, Dept Pharmacognosy, Jackson, MS USA. [Bjoernsson, Einar] Natl Univ Hosp Iceland, Reykjavik, Iceland. [Bjoernsson, Einar] Univ Iceland, Fac Med, Reykjavik, Iceland. [Serrano, Jose; Hoofnagle, Jay H.] Natl Inst Hlth, Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Res Branch, Bethesda, MD USA. RP Navarro, VJ (reprint author), Einstein Med Ctr, Div Hepatol, 5401 Old York Rd,Suite 505, Philadelphia, PA 19141 USA. EM Navarrov@einstein.edu FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); American Association for the Study of Liver Diseases; Office of Dietary Supplements, Office of the Director, NIH; National Center for Complementary and Integrative Health, NIH; National Institute of Environmental Health Services, NIH; US Department of Agriculture; Centers for Disease Control and Prevention FX This summary is based upon the research symposium Liver Injury From Herbal and Dietary Supplements, held May 4-5, 2015, in Bethesda, MD, which was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), in collaboration with the American Association for the Study of Liver Diseases with support from the Office of Dietary Supplements, Office of the Director, NIH; the National Center for Complementary and Integrative Health, NIH; the National Institute of Environmental Health Services, NIH; the US Department of Agriculture; and the Centers for Disease Control and Prevention, with a special contribution by The National Center for Natural Products Research, School of Pharmacy, University of Mississippi (University, MS). NR 47 TC 1 Z9 1 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 JAN PY 2017 VL 65 IS 1 BP 363 EP 373 DI 10.1002/hep.28813 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP3RE UT WOS:000397298600031 PM 27677775 ER PT J AU Fontana, RJ Engle, RE Purcell, RH Lee, WM AF Fontana, Robert J. Engle, Ronald E. Purcell, Robert H. Lee, William M. TI Hepatitis E in Decompensated Alcoholic Cirrhosis REPLY SO HEPATOLOGY LA English DT Letter ID E VIRUS-INFECTION C1 [Fontana, Robert J.] Univ Michigan, Med Ctr, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI USA. [Engle, Ronald E.; Purcell, Robert H.] NIAID, Bethesda, MD USA. [Lee, William M.] Univ Texas Southwestern, Dallas, TX USA. RP Fontana, RJ (reprint author), Univ Michigan, Med Ctr, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI USA. FU Bristol-Myers Squibb; Janssen; Gilead; Merck; Ocera; Exalenz FX Dr. Fontana received grants from Bristol-Myers Squibb, Janssen, and Gilead. Dr. Lee consults for Novartis and Sanofi and received grants from Bristol-Myers Squibb, Gilead, Merck, Ocera, and Exalenz. NR 5 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 JAN PY 2017 VL 65 IS 1 BP 389 EP 390 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP3RE UT WOS:000397298600038 PM 27616011 ER PT J AU Boyce, AM Collins, MT Tosi, LL Gafni, RI AF Boyce, Alison M. Collins, Michael T. Tosi, Laura L. Gafni, Rachel I. TI A Subtrochanteric Femoral Stress Fracture following Bisphosphonate Treatment in an Adolescent Girl SO HORMONE RESEARCH IN PAEDIATRICS LA English DT Article DE Atypical subtrochanteric and diaphyseal femoral fractures; Bisphosphonates ID DIAPHYSEAL FRACTURES; SHAFT; FEMUR; DXA AB Atypical subtrochanteric and diaphyseal femoral fractures (AFFs) have emerged as a potential complication of bisphosphonate treatment in adults. Despite increasing off-label use of bisphosphonates in children and adolescents for a variety of skeletal disorders, there have been no reports of AFFs in children or adolescents outside of the osteogenesis imperfecta population. We present the case of a 16-year-old girl who developed a subtrochanteric femoral stress fracture following pamidronate treatment for idiopathic juvenile osteoporosis. (C) 2016 S. Karger AG, Basel C1 [Boyce, Alison M.; Collins, Michael T.; Gafni, Rachel I.] NIDCR, Sect Skeletal Disorders & Mineral Homeostasis, Craniofacial & Skeletal Dis Branch, NIH, 30 Convent Dr Bldg 30,Room 228 MSC 4320, Bethesda, MD 20892 USA. [Boyce, Alison M.; Tosi, Laura L.] Childrens Natl Hlth Syst, Bone Hlth Program, Div Orthopaed & Sports Med, Washington, DC USA. [Boyce, Alison M.] Childrens Natl Hlth Syst, Div Endocrinol & Diabet, Washington, DC USA. RP Boyce, AM (reprint author), NIDCR, Sect Skeletal Disorders & Mineral Homeostasis, Craniofacial & Skeletal Dis Branch, NIH, 30 Convent Dr Bldg 30,Room 228 MSC 4320, Bethesda, MD 20892 USA. EM boyceam@mail.nih.gov FU Intramural NIH HHS [Z99 DE999999] NR 14 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1663-2818 EI 1663-2826 J9 HORM RES PAEDIAT JI Horm. Res. Paediatr. PY 2017 VL 87 IS 1 BP 69 EP 72 DI 10.1159/000447425 PG 4 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA EN3GG UT WOS:000395896400010 PM 27379824 ER PT J AU Kamal, A Sinha, A Hutfless, SM Afghani, E Faghih, M Khashab, MA Lennon, AM Yadav, D Makary, MA Andersen, DK Kalloo, AN Singh, VK AF Kamal, Ayesha Sinha, Amitasha Hutfless, Susan M. Afghani, Elham Faghih, Mahya Khashab, Mouen A. Lennon, Anne Marie Yadav, Dhiraj Makary, Martin A. Andersen, Dana K. Kalloo, Anthony N. Singh, Vikesh K. TI Hospital admission volume does not impact the in-hospital mortality of acute pancreatitis SO HPB LA English DT Article ID ORGAN FAILURE; UNITED-STATES; NECROTIZING PANCREATITIS; DYNAMIC NATURE; CLINICAL-DATA; CO-MORBIDITY; RISK; EPIDEMIOLOGY; DYSFUNCTION; PERSISTENT AB Background: Multiple factors influence mortality in Acute Pancreatitis (AP). Methods: To evaluate the association of demographic, clinical, and hospital factors with the in-hospital mortality of AP using a population-based administrative database. The Maryland HSCRC database was queried for adult (>= 18 years) admissions with primary diagnosis of AP between 1/94-12/10. Organ failure (OF), interventions, hospital characteristics and referral status were evaluated. Results: There were 72,601 AP admissions across 48 hospitals in Maryland with 885 (1.2%) deaths. A total of 1657 (2.3%) were transfer patients, of whom 101 (6.1%) died. Multisystem OF was present in 1078 (1.5%), of whom 306 (28.4%) died. On univariable analysis, age, male gender, transfer status, comorbidity, OF, all interventions, and all hospital characteristics were significantly associated with mortality; however, only age, transfer status, OF, interventions, and large hospital size were significant in the adjusted analysis. Patients with commercial health insurance had significantly less mortality than those with other forms of insurance (OR 0.65, 95% Cl: 0.52, 0.82, p = 0.0002). Conclusion: OF is the strongest predictor of mortality in AP after adjusting for demographic, clinical, and hospital characteristics. Admission to HV or teaching hospital has no survival benefit in AP after adjusting for OF and transfer status. C1 [Makary, Martin A.; Kalloo, Anthony N.; Singh, Vikesh K.] Johns Hopkins Univ, Sch Med, Pancreatitis Ctr, Baltimore, MD USA. [Kamal, Ayesha; Sinha, Amitasha; Hutfless, Susan M.; Faghih, Mahya; Khashab, Mouen A.; Lennon, Anne Marie; Kalloo, Anthony N.; Singh, Vikesh K.] Johns Hopkins Univ, Sch Med, Div Gastroenterol, Baltimore, MD USA. [Makary, Martin A.] Johns Hopkins Univ, Sch Med, Dept Surg, Div Surg Oncol, Baltimore, MD 21205 USA. [Yadav, Dhiraj] Univ Pittsburgh, Div Gastroenterol, Sch Med, Pittsburgh, PA USA. [Andersen, Dana K.] NIDDK, NIH, Bethesda, MD 20892 USA. [Afghani, Elham] Cedars Sinai Med Ctr, Ctr Digest Dis, Los Angeles, CA 90048 USA. RP Singh, VK (reprint author), Johns Hopkins Univ Hosp, Div Gastroenterol, 1830 E Monument St,Room 428, Baltimore, MD 21205 USA. EM vsingh1@jhmi.edu NR 50 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1365-182X EI 1477-2574 J9 HPB JI HPB PD JAN PY 2017 VL 19 IS 1 BP 21 EP 28 DI 10.1016/j.hpb.2016.10.013 PG 8 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA EK8RZ UT WOS:000394193100005 PM 27887788 ER PT J AU Farag, A Lu, L Roth, HR Liu, JM Turkbey, E Summers, RM AF Farag, Amal Lu, Le Roth, Holger R. Liu, Jiamin Turkbey, Evrim Summers, Ronald M. TI A Bottom-Up Approach for Pancreas Segmentation Using Cascaded Superpixels and (Deep) Image Patch Labeling SO IEEE TRANSACTIONS ON IMAGE PROCESSING LA English DT Article DE Abdominal computed tomography (CT); deep convolutional neural networks; dense image patch labeling; cascaded random forest; pancreas segmentation ID FEATURES; ALGORITHM; NETWORKS AB Robust organ segmentation is a prerequisite for computer-aided diagnosis, quantitative imaging analysis, pathology detection, and surgical assistance. For organs with high anatomical variability (e.g., the pancreas), previous segmentation approaches report low accuracies, compared with well-studied organs, such as the liver or heart. We present an automated bottom-up approach for pancreas segmentation in abdominal computed tomography (CT) scans. The method generates a hierarchical cascade of information propagation by classifying image patches at different resolutions and cascading (segments) superpixels. The system contains four steps: 1) decomposition of CT slice images into a set of disjoint boundary-preserving superpixels; 2) computation of pancreas class probability maps via dense patch labeling; 3) superpixel classification by pooling both intensity and probability features to form empirical statistics in cascaded random forest frameworks; and 4) simple connectivity based post-processing. Dense image patch labeling is conducted using two methods: efficient random forest classification on image histogram, location and texture features; and more expensive (but more accurate) deep convolutional neural network classification, on larger image windows (i.e., with more spatial contexts). Over-segmented 2 - D CT slices by the simple linear iterative clustering approach are adopted through model/parameter calibration and labeled at the superpixel level for positive (pancreas) or negative (non-pancreas or background) classes. The proposed method is evaluated on a data set of 80 manually segmented CT volumes, using six-fold cross-validation. Its performance equals or surpasses other state-of-the-art methods (evaluated by " leave-one-patient-out"), with a dice coefficient of 70.7% and Jaccard index of 57.9%. In addition, the computational efficiency has improved significantly, requiring a mere 6 similar to 8 min per testing case, versus >= 10 h for other methods. The segmentation framework using deep patch labeling confidences is also more numerically stable, as reflected in the smaller performance metric standard deviations. Finally, we implement a multi-atlas label fusion (MALF) approach for pancreas segmentation using the same data set. Under six-fold cross-validation, our bottom-up segmentation method significantly outperforms its MALF counterpart: 70.7 +/- 13.0% versus 52.51 +/- 20.84% in dice coefficients. C1 [Farag, Amal; Lu, Le; Liu, Jiamin; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Lu, Le; Summers, Ronald M.] NIH, Clin Image Proc Serv, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Roth, Holger R.] Nagoya Univ, Nagoya, Aichi 4648602, Japan. [Turkbey, Evrim] NIH, Clin Image Proc Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Turkbey, Evrim] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. RP Lu, L (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM le.lu@nih.gov; rms@nih.gov OI Lu, Le/0000-0002-6799-9416 FU National Institutes of Health Clinical Center FX This work was supported by the Intramural Research Program of the National Institutes of Health Clinical Center. The associate editor coordinating the review of this manuscript and approving it for publication was Prof. Chunming Li. NR 49 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 1057-7149 EI 1941-0042 J9 IEEE T IMAGE PROCESS JI IEEE Trans. Image Process. PD JAN PY 2017 VL 26 IS 1 BP 386 EP 399 DI 10.1109/TIP.2016.2624198 PG 14 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA EP2OB UT WOS:000397221700004 ER PT J AU Vila, A Dapas, JI Rivero, CV Bocanegra, F Furnari, RF Hsu, AP Holland, SM AF Vila, Andrea Dapas, Juan I. Rivero, Cynthia V. Bocanegra, Florencia Furnari, Roberto F. Hsu, Amy P. Holland, Steven M. TI Multiple Opportunistic Infections in a Woman with GATA2 Mutation SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE GATA2 mutation; MonoMAC syndrome; monocytopenia; GATA2 deficiency ID ACUTE MYELOID-LEUKEMIA; SPORADIC MONOCYTOPENIA; AUTOSOMAL-DOMINANT; MONOMAC SYNDROME; DEFICIENCY; CELL AB GATA2 deficiency is a genetic disorder caused by inherited or sporadic haploinsufficient mutations in the GATA2 gene. Patients have abnormalities in hematopoiesis, lymphangiogenesis and immunity; encompassing a broad range of clinical syndromes, mainly characterized by monocytopenia, B and NK cell cytopenia, severe or recurrent infections, and a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). We report a case of an Argentinean woman who presented with multiple opportunistic infections as her first manifestation of GATA2 deficiency. (C) 2016 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. C1 [Vila, Andrea; Dapas, Juan I.; Rivero, Cynthia V.] Hosp Italiano Mendoza, Dept Infect Dis, Ave Acceso Este 1070, San Jose, Mendoza, Argentina. [Bocanegra, Florencia; Furnari, Roberto F.] Hosp Italiano Mendoza, Dept Internal Med, Ave Acceso Este 1070, San Jose, Mendoza, Argentina. [Hsu, Amy P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Vila, A (reprint author), Hosp Italiano Mendoza, Ave Acceso Este Lateral Norte 1070,CP 5519, San Jose, Mendoza, Argentina. EM santander@arlink.net.ar FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA FX This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 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 1201-9712 EI 1878-3511 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD JAN PY 2017 VL 54 BP 89 EP 91 DI 10.1016/j.ijid.2016.11.408 PG 3 WC Infectious Diseases SC Infectious Diseases GA EO0YY UT WOS:000396425800020 PM 27894982 ER PT J AU Togias, A Cooper, SF Acebal, ML Assa'ad, A Baker, JR Beck, LA Block, J Byrd-Bredbenner, C Chan, ES Eichenfield, LF Fleischer, DM Fuchs, GJ Furuta, GT Greenhawt, MJ Gupta, RS Habich, M Jones, SM Keaton, K Muraro, A Plaut, M Rosenwasser, LJ Rotrosen, D Sampson, HA Schneider, LC Sicherer, SH Sidbury, R Spergel, J Stukus, DR Venter, C Boyce, JA AF Togias, Alkis Cooper, Susan F. Acebal, Maria L. Assa'ad, Amal Baker, James R., Jr. Beck, Lisa A. Block, Julie Byrd-Bredbenner, Carol Chan, Edmond S. Eichenfield, Lawrence F. Fleischer, David M. Fuchs, George J., III Furuta, Glenn T. Greenhawt, Matthew J. Gupta, Ruchi S. Habich, Michele Jones, Stacie M. Keaton, Kari Muraro, Antonella Plaut, Marshall Rosenwasser, Lanny J. Rotrosen, Daniel Sampson, Hugh A. Schneider, Lynda C. Sicherer, Scott H. Sidbury, Robert Spergel, Jonathan Stukus, David R. Venter, Carina Boyce, Joshua A. TI Addendum guidelines for the prevention of peanut allergy in the United States: Report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Food; peanut; allergy; prevention; guidelines ID FOOD ALLERGY; NUTRITIONAL INTERVENTIONS; ANAPHYLACTIC REACTIONS; GRADING QUALITY; HIGH-RISK; INFANTS; PREVALENCE; CONSUMPTION; RECOMMENDATIONS; FEASIBILITY AB Background: Food allergy is an important public health problem because it affects children and adults, can be severe and even life-threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. A recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanut-containing foods beginning in infancy. Objectives: Prompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy. Results: The addendum provides 3 separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanut-containing foods in the health care provider's office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation. Conclusions: Guidelines have been developed for early introduction of peanut-containing foods into the diets of infants at various risk levels for peanut allergy. C1 [Togias, Alkis; Cooper, Susan F.; Plaut, Marshall; Rotrosen, Daniel] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Acebal, Maria L.] Food Allergy Res & Educ, Board Directors, Mclean, VA 22102 USA. [Assa'ad, Amal] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45221 USA. [Baker, James R., Jr.] Food Allergy Res & Educ, Ann Arbor, MI 22102 USA. [Baker, James R., Jr.] Univ Michigan Hlth Syst, Div Allergy & Clin Immunol, Ann Arbor, MI USA. [Beck, Lisa A.] Univ Rochester, Med Ctr, Dept Dermatol, Rochester, NY 14627 USA. [Block, Julie] Natl Eczema Assoc, San Rafael, CA USA. [Byrd-Bredbenner, Carol] Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08903 USA. [Chan, Edmond S.] Univ British Columbia, BC Childrens Hosp, Dept Pediat, Div Allergy & Immunol, Vancouver, WA USA. [Eichenfield, Lawrence F.] Univ Calif San Diego, Rady Childrens Hosp, San Diego Sch Med, Dept Dermatol, San Diego, CA 92103 USA. [Eichenfield, Lawrence F.] Univ Calif San Diego, Rady Childrens Hosp, San Diego Sch Med, Dept Pediat, San Diego, CA 92103 USA. [Fleischer, David M.; Greenhawt, Matthew J.] Univ Colorado, Denver Sch Med, Childrens Hosp Colorado, Dept Pediat,Sect Allergy & Immunol, Aurora, CO USA. [Fuchs, George J., III] Univ Kentucky, Coll Med, Kentucky Childrens Hosp, Dept Pediat,Div Gastroenterol Hepatol & Nutr, Lexington, KY 40506 USA. [Furuta, Glenn T.] Childrens Hosp Colorado, Digest Hlth Inst, Aurora, CO 80045 USA. [Furuta, Glenn T.] Univ Colorado, Denver Sch Med, Sect Pediat Gastroenterol, Aurora, CO 80045 USA. [Gupta, Ruchi S.] Northwestern Univ, Dept Pediat, Div Acad Gen Pediat & Primary Care, Chicago, IL 60611 USA. [Gupta, Ruchi S.] Northwestern Univ, Ann & Robert H Lurie Childrens Hosp Chicago, Feinberg Sch Med, Chicago, IL 60611 USA. [Habich, Michele] Cent DuPage Hosp, Northwestern Med, Winfield, KS USA. [Jones, Stacie M.] Univ Arkansas Med Sci, Dept Pediat, Div Allergy & Immunol, Arkansas Childrens Hosp, Little Rock, AR 72205 USA. [Keaton, Kari] Metro DC Food Allergy Support Grp, Rockville, MD 20850 USA. [Muraro, Antonella] Padua Univ Hosp, Dept Women & Child Hlth, Food Allergy Referral Ctr, Padua, Italy. [Rosenwasser, Lanny J.] Univ Missouri Kansas City, Sch Med, Kansas City, KS 64110 USA. [Sampson, Hugh A.] Icahn Sch Med Mt Sinai, Dept Pediat, Div Allergy & Immunol, New York, NY 10029 USA. [Sicherer, Scott H.] Icahn Sch Med Mt Sinai, Div Pediat Allergy & Immunol, New York, NY 10029 USA. [Schneider, Lynda C.] Boston Childrens Hosp, Div Allergy & Immunol, Boston, MA 02115 USA. [Sidbury, Robert] Univ Washington, Sch Med, Dept Pediat, Seattle Childrens Hosp,Div Dermatol, Seattle, WA 98195 USA. [Spergel, Jonathan] Univ Penn, Perelman Sch Med, Childrens Hosp Philadelphia, Div Allergy & Immunol,Dept Pediat, Philadelphia, PA 19104 USA. [Stukus, David R.] Ohio State Univ, Coll Med, Nationwide Childrens Hosp, Dept Pediat,Sect Allergy & Immunol, Columbus, OH 43210 USA. [Venter, Carina] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA. [Boyce, Joshua A.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Boyce, Joshua A.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. RP Cooper, SF (reprint author), NIAID, Div Allergy Immunol & Transplantat, NIH, 5601 Fishers Lane,Room 7C28, Rockville, MD 20892 USA. EM coopersu@niaid.nih.gov FU DBV Technologies; Aimmune; Stanford Foundation; TEVA Pharmaceuticals; GlaxoSmithKline; National Institutes of Health (NIH); Astellas; Food Allergy Research & Education (FARE); Monsanto Company; Nestle Nutrition Institute; Aimmune Therapeutics; Agency for Healthcare Research and Quality [1K08HS024599-01]; NIH; FARE; Mylan LLC; NIH/NIAID (Consortium of Food Allergy Research and Immune Tolerance Network IMPACT Trial); National Peanut Board; NIAID; Immune Tolerance Network; HAL Allergy; ACAAI; Pfizer; Sanofi; Mead Johnson; Nestle; Grand Rounds; Kansas City Allergy Society; Mercy Children's Hospital; Riley Children's Hospital; Southwester Medical School Children's Medical Center; European Academy of Allergy & Clinical Immunology; New York Allergy Asthma Society; University of Iowa Paul M. Seebohm Lectureship in Allergy; Iowa Society of Allergy; Asthma; Immunology; Taiwanese Dermatological Society; Dartmouth College; Florida Allergy Society FX A. Assa' ad received travel support from the American College of Allergy, Asthma & Immunology (ACAAI); was an elected member of the Board of Directors for the American Academy of Allergy, Asthma, & Immunology (AAAAI) from March 2012 to March 2016; has consultant arrangements with Aimmune; is employed by Cincinnati Children's Hospital Medical Center; has received grants from DBV Technologies, Aimmune, Stanford Foundation, TEVA Pharmaceuticals, GlaxoSmithKline, the National Institutes of Health (NIH), Astellas, and Food Allergy Research & Education (FARE); and has received payment for lectures from the ACAAI. C. Byrd-Bredbenner and G. J. Fuchs III have received travel support from the NIH/National Institute of Allergy and Infectious Disease (MAID). E. S. Chan has received travel support from the NIAID, has received grants from DBV Technologies, and has received payment for lectures from Pfizer, Sanofi, Mead Johnson, and Nestle. D. M. Fleischer has received travel support from the NIAID; is a board member for the National Peanut Board, the FAACT Medical Advisory Board, and the FARE Medical Advisory Board; has consultant arrangements with Adamis Pharmaceuticals Corporation, INSYS Therapeutics, DBV Technologies, Aimmune Therapeutics, Intrommune Therapeutics, and Kaleo Pharma; is employed by University Physicians; has received grants from Monsanto Company, Nestle Nutrition Institute, DBV Technologies, and Aimmune Therapeutics; has received payment for lectures from Nestle Nutrition Institute; and has received royalties from UpToDate. M. J. Greenhawt has received a grant from the Agency for Healthcare Research and Quality (1K08HS024599-01, Career Development Award); has received travel support from the MAID and the Joint Taskforce on Allergy Practice Parameters; has a board membership with the National Peanut Board; has consultant arrangements with Adamis Pharmaceuticals, the Canadian Transportation Agency, Nutricia, Nestle/Gerber, Aimmune, Kaleo Pharmaceutical, and Monsanto; is an Associate Editor for the Annals of Allergy, Asthma, and Immunology; has received payment for lectures from the ACAAI, Reach MD, Thermo Fisher Scientific, the California Society for Allergy and Immunology, the Allergy and Asthma Network, the New England Society for Allergy, UCLA/Harbor Heiner Lectureship, Medscape, the Western Michigan School of Medicine, the Canadian Society of Allergy and Clinical Immunology, and the Pennsylvania Society for Allergy and Immunology. R. S. Gupta has consultant arrangements with BEFORE Brands and DBV Technologies; has received grants from the NIH, FARE, and Mylan LLC; has received payment for lectures from Grand Rounds; and has received royalties from Createspace Independent Publishing Platform. S. M. Jones is on the Research Advisory Board for FARE; is on the Scientific Advisory Board for Aimmune; has consultant arrangements with Stallergenes; has received grants from the NIH/NIAID (Consortium of Food Allergy Research and Immune Tolerance Network IMPACT Trial), FARE, Aimmune Technologies, DBV Technologies, and the National Peanut Board; has received payment for lectures from the Kansas City Allergy Society, Mercy Children's Hospital, Riley Children's Hospital, Southwester Medical School Children's Medical Center, the European Academy of Allergy & Clinical Immunology, the New York Allergy & Asthma Society, the University of Iowa Paul M. Seebohm Lectureship in Allergy, and the Iowa Society of Allergy, Asthma, and Immunology. A.; Muraro has consultant arrangements with Meda, Novartis, and Menarini; is employed by Padua University Hospital; and has received payment for lectures from Meda and Menarini. L. J. Rosenwasser is a board member for the World Allergy Organization H A Sampson has consultant arrangements with Allertein Therapeutics, Genentech/Roche, Sanofi, Stallergenes, Danone, and Merck; is employed part time as Chief Scientific Officer for DBV Technologies; has received grants from the NIAID and the Immune Tolerance Network; has received royalties from UpToDate and Elsevier; has been offered stock options in DBV Technologies; and is chairman of PhARF Award Selection Committee for Thermo Fisher. L. C. Schneider is on the Medical Advisory Board for FARE, has received a grant from DBV Technologies, and has received stock/stock options in Antera Therapeutics. S. H. Sicherer has received grants from the NIAID, FARE, and HAL Allergy; has received royalties from UpToDate; and is serving as Associate Editor for the Journal of Allergy and Clinical Immunology: In Practice. R. Sidbury has received travel support from the NIH and the Hawaii Dermatology Seminar, has consultant arrangements with Anacor, has provided expert witness testimony on behalf of Roche in Accutane inflammatory bowel disease cases, has received a grant from Epidermolysis Bullosa Research Partnership, has received payment for lectures from the Taiwanese Dermatological Society, and has received royalties from UpToDate. J. Spergel has consultant arrangements with DBV Technologies and Danone; has received grants from DBV Technologies, Aimmune Therapeutics, and the NIH; has received payment for lectures for Dartmouth College, the ACAAI, and the Florida Allergy Society; and has received stock/stock options in DBV Technologies. D. R. Stukus has received payment for lectures from the ACAAI. C. Venter has consultant arrangements with Danone and Nestle, has received payment for lectures from Mead Johnson, and has received travel support from Thermo Fisher. The rest of the authors declare that they have no relevant conflicts of interest. NR 29 TC 2 Z9 2 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JAN PY 2017 VL 139 IS 1 BP 29 EP 44 DI 10.1016/j.jaci.2016.10.010 PG 16 WC Allergy; Immunology SC Allergy; Immunology GA EK5WM UT WOS:000393996800004 PM 28065278 ER PT J AU Kennedy, EA Connolly, J Hourihane, JO Fallon, PG McLean, WHI Murray, D Jo, JH Segre, JA Kong, HH Irvine, AD AF Kennedy, Elizabeth A. Connolly, Jennifer Hourihane, Jonathan O'B. Fallon, Padraic G. McLean, W. H. Irwin Murray, Deirdre Jo, Jay-Hyun Segre, Julia A. Kong, Heidi H. Irvine, Alan D. TI Skin microbiome before development of atopic dermatitis: Early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Staphylococcus aureus; atopic dermatitis; skin; microbiome; longitudinal birth cohort; 16S sequencing ID PARTY DIAGNOSTIC-CRITERIA; HAY-FEVER; ALLERGIC SENSITIZATION; CESAREAN DELIVERY; BODY HABITATS; CHILDREN; CELLS; DISEASE; AUREUS; LIFE AB Background: Disease flares of established atopic dermatitis (AD) are generally associated with a low-diversity skin microbiota and Staphylococcus aureus dominance. The temporal transition of the skin microbiome between early infancy and the dysbiosis of established AD is unknown. Methods: We randomly selected 50 children from the Cork Babies After SCOPE: Evaluating the Longitudinal Impact Using Neurological andNutritional Endpoints (BASELINE) longitudinal birth cohort for microbiome sampling at 3 points in the first 6 months of life at 4 skin sites relevant to AD: the antecubital and popliteal fossae, nasal tip, and cheek. We identified 10 infants with AD and compared them with 10 randomly selected control infants with no AD. We performed bacterial 16S ribosomal RNA sequencing and analysis directly from clinical samples. Results: Bacterial community structures and diversity shifted over time, suggesting that age strongly affects the skin microbiome in infants. Unlike established AD, these patients with infantile AD did not have noticeably dysbiotic communities before or with disease and were not colonized by S aureus. In comparing patients and control subjects, infants who had affected skin at month 12 had statistically significant differences in bacterial communities on the antecubital fossa at month 2 compared with infants who were unaffected at month 12. In particular, commensal staphylococci were significantly less abundant in infants affected at month 12, suggesting that this genus might protect against the later development of AD. Conclusions: This study suggests that 12-month-old infants with AD were not colonized with S aureus before having AD. Additional studies are needed to confirm whether colonization with commensal staphylococci modulates skin immunity and attenuates development of AD. C1 [Kennedy, Elizabeth A.; Jo, Jay-Hyun; Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Connolly, Jennifer; Hourihane, Jonathan O'B.; Murray, Deirdre] Univ Coll, Paediat & Child Hlth, Cork, Ireland. [Fallon, Padraic G.; Irvine, Alan D.] Cork Univ Matern Hosp, Irish Ctr Fetal & Neonatal Translat INFANT Res, Cork, Ireland. [Fallon, Padraic G.; Irvine, Alan D.] Trin Coll Dublin, Med Clin, Dublin, Ireland. [Irvine, Alan D.] Univ Dundee, Natl Childrens Res Ctr, Dundee DD1 4HN, Scotland. [Irvine, Alan D.] Univ Dundee, Paediat Dermatol, Our Ladys Childrens Hosp Crumlin, Dundee DD1 4HN, Scotland. [McLean, W. H. Irwin] Univ Dundee, Dermatol & Genet Med, Dundee DD1 4HN, Scotland. [Segre, Julia A.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. RP Irvine, AD (reprint author), Our Ladys Childrens Hosp Crumlin, Natl Childrens Res Ctr, Dublin 12, Ireland.; Kong, HH (reprint author), NCI, Dermatol Branch, CCR, NIH, 10 Ctr Dr,Bldg 10-MSC 1908, Bethesda, MD 20892 USA. EM konghe@mail.nih.gov; irvinea@tcd.ie FU National Children's Research Centre (NCRC), Dublin, Ireland; NCRC; UK Food Standards Agency (FSA); Intramural Research Program of the National Institutes of Health's National Cancer Institute; National Human Genome Research Institute; Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea [HI15C1095] FX A.D.I. is funded by the National Children's Research Centre (NCRC), Dublin, Ireland. The NCRC is the primary funding source for the ongoing Cork BASELINE birth cohort. Additional support came from the UK Food Standards Agency (FSA). The work was also supported by the Intramural Research Program of the National Institutes of Health's National Cancer Institute (to E.A.K., J.-H.J., and H.H.K.) and the National Human Genome Research Institute (to J.A.S.). J.-H.J. is also supported by a grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI15C1095). NR 44 TC 1 Z9 1 U1 3 U2 3 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 JAN PY 2017 VL 139 IS 1 BP 166 EP 172 DI 10.1016/j.jaci.2016.07.029 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA EK5WM UT WOS:000393996800018 PM 27609659 ER PT J AU Meyer, ML Palta, P Tanaka, H Deal, JA Wright, J Knopman, DS Griswold, ME Mosley, TH Heiss, G AF Meyer, Michelle L. Palta, Priya Tanaka, Hirofumi Deal, Jennifer A. Wright, Jacqueline Knopman, David S. Griswold, Michael E. Mosley, Thomas H. Heiss, Gerardo TI Association of Central Arterial Stiffness and Pressure Pulsatility with Mild Cognitive Impairment and Dementia: The Atherosclerosis Risk in Communities Study-Neurocognitive Study (ARIC-NCS) SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Alzheimer's disease; brain; cognition; dementia; mild cognitive impairment; pulse wave velocity ID PULSE-WAVE VELOCITY; SMALL-VESSEL DISEASE; VASCULAR DEMENTIA; ALZHEIMERS-DISEASE; OLDER-ADULTS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; PHYSICAL-ACTIVITY; UNITED-STATES; NINDS-AIREN AB Background: The association of central arterial stiffness and pressure pulsatility with mild cognitive impairment (MCI) and dementia is not well characterized in the population-based setting. Objective: The aim of this study was to quantify the cross-sectional association of arterial stiffness and pressure pulsatility with MCI and dementia among 4,461 older white and black adults from the population-based Atherosclerosis Risk in Communities Study-Neurocognitive Study. Methods: We used race-stratified multinomial logistic regression to evaluate associations of percentile cut points of carotidfemoral pulse wave velocity, central systolic blood pressure, central pulse pressure, and pulse pressure amplification with MCI and dementia versus no cognitive impairment. Results: Among whites, those with carotid-femoral pulse wave velocity or central systolic blood pressure >= 75th percentile had a higher prevalence of MCI compared to participants < 75th percentile (conditional odds ratio (OR); 95% confidence interval (CI): 1.27 (1.02, 1.56) and 1.28 (1.04, 1.57), respectively) and those with central pulse pressure >= 25th percentile had a higher prevalence of MCI (OR 1.27 (95% CI: 1.03, 1.58)) and dementia (OR 1.76 (95% CI: 1.06, 2.92) compared to participants < 75th percentile. Also among whites, those with pulse pressure amplification <= 25th percentile had a higher prevalence of dementia compared to participants > 25th percentile (OR 1.65; (95% CI: 1.01, 2.70). Weaker associations were seen among black participants. Conclusion: Higher arterial stiffness and pulsatility were associated with MCI and dementia in white participants. Longitudinal characterization of the observed associations is warranted to assess whether arterial stiffness and pressure pulsatility predict MCI and dementia among older adults. C1 [Meyer, Michelle L.; Palta, Priya; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Tanaka, Hirofumi] Univ Texas Austin, Dept Kinesiol & Hlth Educ, Austin, TX 78712 USA. [Deal, Jennifer A.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Wright, Jacqueline] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Knopman, David S.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Griswold, Michael E.] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. RP Meyer, ML (reprint author), Univ N Carolina, Dept Emergency Med, 170 Manning Dr, Chapel Hill, NC 27599 USA. EM michelle_meyer@med.unc.edu FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; NHLBI T32 training grant [HL-007055] FX The authors thank the staff and participants of the ARIC study for their important contributions. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data was collected by U01 HL096812, HL096814, HL096899, HL096902, and HL096917 with previous brain MRI examinations funded by R01-HL70825. MLM was supported by the NHLBI T32 training grant HL-007055. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. NR 59 TC 0 Z9 0 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1387-2877 EI 1875-8908 J9 J ALZHEIMERS DIS JI J. Alzheimers Dis. PY 2017 VL 57 IS 1 BP 195 EP 204 DI 10.3233/JAD-161041 PG 10 WC Neurosciences SC Neurosciences & Neurology GA EN8SQ UT WOS:000396270500017 PM 28222517 ER PT J AU Faruque, MU Chen, GJ Doumatey, AP Zhou, J Huang, HX Shriner, D Adeyemo, AA Rotimi, CN Dunston, GM AF Faruque, Mezbah U. Chen, Guanjie Doumatey, Ayo P. Zhou, Jie Huang, Hanxia Shriner, Daniel Adeyemo, Adebowale A. Rotimi, Charles N. Dunston, Georgia M. TI Transferability of genome-wide associated loci for asthma in African Americans SO JOURNAL OF ASTHMA LA English DT Article DE Asthma; replication; single nucleotide polymorphism; genetic association; African Americans; IL33; ethnicity ID POPULATION DIFFERENTIATION; GENETIC ASSOCIATION; UNITED-STATES; DISEASE; REPLICATION; IL-33; VARIANTS; CELLS; STRATIFICATION; METAANALYSIS AB Objective: Transferability of significantly associated loci or GWAS hits adds credibility to genotype-disease associations and provides evidence for generalizability across different ancestral populations. We sought evidence of association of known asthma-associated single nucleotide polymorphisms (SNPs) in an African American population. Methods: Subjects comprised 661 participants (261 asthma cases and 400 controls) from the Howard University Family Study. Forty-eight SNPs previously reported to be associated with asthma by GWAS were selected for testing. We adopted a combined strategy by first adopting an exact approach where we looked-up only the reported index SNP. For those index SNPs missing form our dataset, we used a local approach that examined all the regional SNPs in LD with the index SNP. Results: Out of the 48 SNPs, our cohort had genotype data available for 27, which were examined for exact replication. Of these, two SNPs were found positively associated with asthma. These included: rs10508372 (OR = 1.567 [95%CI, 1.133-2.167], P = 0.0066) and rs2378383 (OR = 2.147 [95%CI, 1.149-4.013], P = 0.0166), located on chromosomal bands 10p14 and 9q21.31, respectively. Local replication of the remaining 21 loci showed association at two chromosomal loci (9p24.1-rs2381413 and 6p21.32-rs3132947; Bonferroni-corrected P values: 0.0033 and 0.0197, respectively). Of note, multiple SNPs in LD with rs2381413 located upstream of IL33 were significantly associated with asthma. Conclusions: This study has successfully transferred four reported asthma-associated loci in an independent African American population. Identification of several asthma-associated SNPs in the upstream of the IL33, a gene previously implicated in allergic inflammation of asthmatic airway, supports the generalizability of this finding. C1 [Faruque, Mezbah U.; Dunston, Georgia M.] Howard Univ, Coll Med, Natl Human Genome Ctr, Washington, DC 20059 USA. [Chen, Guanjie; Doumatey, Ayo P.; Zhou, Jie; Huang, Hanxia; Shriner, Daniel; Adeyemo, Adebowale A.; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Faruque, MU (reprint author), Howard Univ, Ctr Canc, 2041 Georgia Ave,NW,Rm 612, Washington, DC 20060 USA. EM mfaruque@howard.edu FU MBRS/SCORE Program of the National Institute of General Medical Sciences, National Institutes of Health (NIH) [S06GM008016-320107, S06GM008016-380111]; National Center for Research Resources (NCRR), NIH [2M01RR010284]; RCMI Program at Howard University - Division of Research Infrastructure, NCRR, NIH [RR003048]; Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH); National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the NIH [Z01HG200362] FX The Howard University Family Study (HUFS) was supported by grants S06GM008016-320107 to C.N.R. and S06GM008016-380111 to A.A.A., both from the MBRS/SCORE Program of the National Institute of General Medical Sciences, National Institutes of Health (NIH). Participant enrollment for the HUFS was carried out at the Howard University General Clinical Research Center, which is supported by grant 2M01RR010284 from the National Center for Research Resources (NCRR), NIH. This research was supported in part by the RCMI Program at Howard University funded by the Division of Research Infrastructure, NCRR, NIH (RR003048) and by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the NIH (Z01HG200362). NR 54 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 0277-0903 EI 1532-4303 J9 J ASTHMA JI J. Asthma PY 2017 VL 54 IS 1 BP 1 EP 8 DI 10.1080/02770903.2016.1188941 PG 8 WC Allergy; Respiratory System SC Allergy; Respiratory System GA EM1FZ UT WOS:000395064800001 PM 27177148 ER PT J AU Radin, RG Sjaarda, LA Perkins, NJ Silver, RM Chen, Z Lesher, LL Galai, N Wactawski-Wende, J Mumford, SL Schisterman, EF AF Radin, Rose G. Sjaarda, Lindsey A. Perkins, Neil J. Silver, Robert M. Chen, Zhen Lesher, Laurie L. Galai, Noya Wactawski-Wende, Jean Mumford, Sunni L. Schisterman, Enrique F. TI Low-Dose Aspirin and Sporadic Anovulation in the EAGeR Randomized Trial SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID IN-VITRO FERTILIZATION; PROSTAGLANDIN SYNTHETASE INHIBITORS; DOUBLE-BLIND; BLOOD-FLOW; EMBRYO-TRANSFER; OVARIAN RESPONSIVENESS; EUMENORRHEIC WOMEN; MENSTRUAL-CYCLE; PREGNANCY; UTERINE AB Context: Among women with a single, recent pregnancy loss, daily preconception low-dose aspirin (LDA) increased the live birth rate with no effect on pregnancy loss. Ovulation is a potentialmechanism underlying this effect. Objective: Weestimated the effect of LDA on the per-cycle risk of anovulation among eumenorrheic women. Design: Multicenter, randomized, double-blind, placebo-controlled trial of daily LDA on reproductive outcomes. Preconception follow-up lasted 1 to 6 menstrual cycles (ClinicalTrials. gov, NCT00467363). Setting: Four US medical centers during 2007 to 2011. Patients or Other Participants: Healthy women (n = 1214), age 18 to 40, were attempting pregnancy, had regular menstrual cycles (21 to 42 days), and had a history of 1 to 2 documented pregnancy losses, <= 2 live births, and no infertility. All participants completed at least 1 menstrual cycle of follow-up; none withdrew due to adverse events. Intervention: Aspirin (81 mg) daily for 1 to 6 menstrual cycles. Main Outcome Measure: Per-cycle risk of anovulation, defined as the absence of both a positive spot-urine pregnancy test and a luteinizing hormone (LH) peak (2.5-fold increase in daily urinary LH). Hypothesis formulation preceded data collection. Results: Among4340cycles, LDAwasnotassociatedwithanovulation(LDA: 13.4%, placebo: 11.1%; riskratio= 1.16, 95% confidence interval, 0.88 to 1.52). Results were similar among women with a single, recent loss. Conclusions: Daily LDA had no effect on anovulation among women with a history of 1 to 2 pregnancy losses. LDA may affect fertility via other pathways, and these warrant further study. C1 [Radin, Rose G.; Sjaarda, Lindsey A.; Perkins, Neil J.; Mumford, Sunni L.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20817 USA. [Silver, Robert M.; Lesher, Laurie L.] Univ Utah, Hlth Sci Ctr, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Chen, Zhen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20817 USA. [Galai, Noya] Univ Haifa, Dept Stat, IL-3498838 Haifa, Israel. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14228 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6710B Rockledge Dr, Bethesda, MD 20817 USA. EM schistee@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland [HHSN267200603423, HHSN267200603424, HHSN267200603426] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract Nos. HHSN267200603423, HHSN267200603424, and HHSN267200603426). NR 51 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 JAN PY 2017 VL 102 IS 1 BP 86 EP 92 DI 10.1210/jc.2016-2095 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0IV UT WOS:000397071900012 PM 27754808 ER PT J AU Bernard, V Kherra, S Francou, B Fagart, J Viengchareun, S Guechot, J Ladjouze, A Guiochon-Mantel, A Korach, KS Binart, N Lombes, M Christin-Maitre, S AF Bernard, Valerie Kherra, Sakina Francou, Bruno Fagart, Jerome Viengchareun, Say Guechot, Jerome Ladjouze, Asmahane Guiochon-Mantel, Anne Korach, Kenneth S. Binart, Nadine Lombes, Marc Christin-Maitre, Sophie TI Familial Multiplicity of Estrogen Insensitivity Associated With a Loss-of-Function ESR1 Mutation SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RECEPTOR KNOCKOUT MICE; HUMAN-DISEASE; GENE; FEMALE; ALPHA; GUBERNACULUM; DISRUPTION; DEFICIENCY; RESISTANCE; CLONING AB Context: Estrogens influence many physiological processes in mammals, including reproduction. Estrogen peripheral actions are mainly mediated through estrogen receptors (ERs) a and b, encoded by ESR1 and ESR2 genes, respectively. Objective: The study's aim was to describe a family in which 3 members presented with estrogen insensitivity. Design and Setting: Clinical evaluation and genetic and mutational analysis were performed in an academic medical center. Patients and Interventions: An ESR1 mutation was identified in 2 sisters and 1 brother, originating from a consanguineous Algerian family, who did not enter puberty and presented with delayed bone maturation consistent with estrogen insensitivity. The 2 sisters had enlarged multicystic ovaries. Hormonal evaluation as well as genetic and mutational analysis were performed. Results: Hormonal evaluation revealed extremely high plasma 17b-estradiol (>50-fold normal range) associated with elevated gonadotropin levels (greater than threefold normal range), highly suggestive of estrogen resistance. The 3 affected patients carried a homozygous mutation of a highly conserved arginine 394 for which histidine was substituted through an autosomal recessive mode of transmission. Structural and functional analysis of the mutant ERa revealed strongly reduced transcriptional activity and the inability to securely anchor the activating hormone, estradiol, compared with wild-type ERa. A group of other potential ER activating ligands were tested, but none overcame the estrogen insensitivity in these patients. Conclusion: Description and analysis of this family of patients with mutant ERa provide additional clinical findings toward identification and characterization of what was previously thought to be a highly rare clinical condition. C1 [Bernard, Valerie; Francou, Bruno; Fagart, Jerome; Viengchareun, Say; Guiochon-Mantel, Anne; Binart, Nadine; Lombes, Marc] Univ Paris Saclay, Fac Med Paris Sud, INSERM 1185, F-94270 Le Kremlin Bicetre, France. [Kherra, Sakina] Hop Nafissa Hamoud, Serv Pediat, Algiers 16040, Algeria. [Francou, Bruno; Guiochon-Mantel, Anne] CHU Bicetre, Hop Univ Paris Sud, AP HP, Serv Genet Mol Pharmacogenet & Hormonol, F-94270 Le Kremlin Bicetre, France. [Lombes, Marc] CHU Bicetre, Hop Univ Paris Sud, AP HP, Serv Endocrinol & Malad Reprod, F-94270 Le Kremlin Bicetre, France. [Guechot, Jerome] Hop Univ Est Parisien, AP HP, Lab Hormonol, Pole Biol Med & Pathol, Site St Antoine, F-75012 Paris, France. [Ladjouze, Asmahane] Hop Bab El Oued, Serv Pediat, Algiers 16040, Algeria. [Korach, Kenneth S.] NIEHS, Reprod & Dev Biol Lab, NIH, Durham, NC 27709 USA. [Christin-Maitre, Sophie] Hop St Antoine, AP HP, Serv Endocrinol & Malad Reprod, F-75012 Paris, France. [Christin-Maitre, Sophie] Univ Paris 06, INSERM 933, F-75011 Paris, France. RP Christin-Maitre, S (reprint author), Univ Paris 06, Hop St Antoine, AP HP, Serv Endocrinol & Malad Reprod,Ctr Malad Endocrin, 184 Rue Faubourg St Antoine, F-75011 Paris, France. EM sophie.christin-maitre@aphp.fr FU INSERM; Universite Paris Sud; Division of Intramural Research, National Institute of Environmental Health Sciences/National Institutes of Health [1ZIAES70065] FX This work was supported by grants from INSERM and Universite Paris Sud. V.B. was a recipient of a fellowship (Poste d'accueil-Plan Cancer 2014-2019) from INSERM. K.S.K. received funding from the Division of Intramural Research, National Institute of Environmental Health Sciences/National Institutes of Health (grant no. 1ZIAES70065). NR 24 TC 1 Z9 1 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 JAN PY 2017 VL 102 IS 1 BP 93 EP 99 DI 10.1210/jc.2016-2749 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0IV UT WOS:000397071900013 PM 27754803 ER PT J AU Nockel, P Babic, B Millo, C Herscovitch, P Patel, D Nilubol, N Sadowski, SM Cochran, C Gorden, P Kebebew, E AF Nockel, Pavel Babic, Bruna Millo, Corina Herscovitch, Peter Patel, Dhaval Nilubol, Naris Sadowski, Samira M. Cochran, Craig Gorden, Phillip Kebebew, Electron TI Localization of Insulinoma Using Ga-68-DOTATATE PET/CT Scan SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NEUROENDOCRINE TUMORS AB Context: Reliable localization of insulinoma is critical for successful treatment. Objective: This study compared the accuracy of (68)Gallium DOTA-(Tyr3)-octreotate (Ga-DOTATATE) positron emission tomography (PET)/computed tomography (CT) to anatomic imaging modalities, selective arterial secretagogue injection (SASI), and intraoperative ultrasound (IO ultrasound) and palpation for localizing insulinoma in patients who were biochemically cured. Design, Setting, and Patients: We conducted a retrospective analysis of 31 patients who had an insulinoma. The results of CT, magnetic resonance imaging (MRI), ultrasound, IO ultrasound, Ga-68-DOTATATE PET/CT, SASI, and operative findings were analyzed. Intervention, Main Outcome Measures, and Results: The insulinomas were correctly localized in 17 out of 31 (55%) patients by CT, in 17 out of 28 (61%) by MRI, in 6 out of 28 (21%) by ultrasound, and in 9 out of 10 (90%) by Ga-68-DOTATATE. In 29 of 31 patients (93.5%) who had IO ultrasound, an insulinoma was successfully localized. Thirty patients underwent SASI, and the insulinoma was regionalized in 28 out of 30 patients (93%). In 19 out of 23 patients (83%), manual palpation identified insulinoma. In patients who had all 4 noninvasive imaging studies, CT was concordant with Ga-68-DOTATATE in 6 out of 9 patients (67%), MRI in 8 out of 9 (78%), ultrasound in 0 out of 9; the lesion was only seen by Ga-68-DOTATATE in 1 out of 9 (11%). Conclusions Ga-68-DOTATATE PET/CT identifies most insulinomas and may be considered as an adjunct imaging study when all imaging studies are negative and when a minimally invasive surgical approach is planned. C1 [Nockel, Pavel; Babic, Bruna; Patel, Dhaval; Nilubol, Naris; Kebebew, Electron] Natl Canc Inst, Natl Inst Hlth, Endocrine Oncol Branch, Bethesda, MD 20892 USA. [Millo, Corina; Herscovitch, Peter] Natl Inst Hlth, Ctr Clin, Positron Emiss Tomog Dept, Bethesda, MD 20892 USA. [Cochran, Craig; Gorden, Phillip] Natl Inst Hlth, Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD 20892 USA. [Sadowski, Samira M.] Univ Hosp Geneva, Thorac & Endocrine Surg, CH-1211 Geneva, Switzerland. RP Nockel, P (reprint author), Natl Canc Inst, Natl Inst Hlth, Endocrine Oncol Branch, Bethesda, MD 20892 USA. FU intramural research program of the Center for Cancer Research, National Cancer Institute FX This research was supported, in part, by the intramural research program of the Center for Cancer Research, National Cancer Institute. NR 19 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 JAN PY 2017 VL 102 IS 1 BP 195 EP 199 DI 10.1210/jc.2016-3445 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0IV UT WOS:000397071900024 PM 27805844 ER PT J AU Vinales, KL Schlogl, M Piaggi, P Hohenadel, M Graham, A Bonfiglio, S Krakoff, J Thearle, MS AF Vinales, Karyne Lima Schlogl, Mathias Piaggi, Paolo Hohenadel, Maximilian Graham, Alexis Bonfiglio, Susan Krakoff, Jonathan Thearle, Marie S. TI The Consistency in Macronutrient Oxidation and the Role for Epinephrine in the Response to Fasting and Overfeeding SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID SYMPATHETIC-NERVOUS-SYSTEM; BROWN ADIPOSE-TISSUE; ENERGY-EXPENDITURE; FOOD-INTAKE; CARBOHYDRATE OXIDATION; RESPIRATORY CHAMBER; CALORIC RESTRICTION; PIMA-INDIANS; BODY-WEIGHT; NOREPINEPHRINE AB Context: In humans, dietary vs intraindividual determinants of macronutrient oxidation preference and the role of the sympathetic nervous system (SNS) during short-term overfeeding and fasting are unclear. Objective: To understand the influence on metabolic changes of diet and SNS during 24 hours of overfeeding. Design, Setting, Participants, and Interventions: While residing on a clinical research unit, 64 participants with normal glucose regulation were assessed during energy balance, fasting, and four 24-hour overfeeding diets, given in random order. The overfeeding diets contained 200% of energy requirements and varied macronutrient proportions: (1) standard (50% carbohydrate, 20% protein, and 30% fat); (2) 75% carbohydrate; (3) 60% fat; and (4) 3% protein. Main Outcome Measures: Twenty-four-hour energy expenditure (EE) and macronutrient oxidation rates were measured in an indirect calorimeter during the dietary interventions, with concomitant measurement of urinary catecholamines and free cortisol. Results: EE decreased with fasting (27.7% 64.8%; P, 0.0001) and increased with overfeeding. The smallest increase occurred during consumption of the diet with 3% protein (2.7% +/- 4.5%; P = 0.001) and the greatest during the diet with 75% carbohydrate (13.8 6 5.7%; P, 0.0001). Approximately 60% of macronutrient oxidation was determined by diet and 20% by intrinsic factors (P < 0.0001). Only urinary epinephrine differed between fasting and overfeeding diets (Delta = 2.25 +/- 2.9 mu g/24h; P < 0.0001). During fasting, higher urinary epinephrine concentrations correlated with smaller reductions in EE (rho = 0.34; P = 0.01). Conclusions: Independent from dietary macronutrient proportions, there is a strong individual contribution to fuel preference that remains consistent across diets. Higher urinary epinephrine levels may reflect the importance of epinephrine in maintaining EE during fasting. C1 [Vinales, Karyne Lima; Schlogl, Mathias; Piaggi, Paolo; Hohenadel, Maximilian; Bonfiglio, Susan; Krakoff, Jonathan; Thearle, Marie S.] Natl Inst Diabet & Digest & Kidney Dis, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ 85014 USA. [Schlogl, Mathias] Univ Zurich Hosp, Dept Geriatr & Aging Res, CH-8091 Zurich, Switzerland. [Graham, Alexis] Johns Hopkins Sch Med, Baltimore, MD 21205 USA. RP Vinales, KL (reprint author), Natl Inst Diabet & Digest & Kidney Dis, 4212 N 16th St, Phoenix, AZ 85016 USA. EM karyne.vinales@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 34 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 JAN PY 2017 VL 102 IS 1 BP 279 EP 289 DI 10.1210/jc.2016-3006 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0IV UT WOS:000397071900033 PM 27820654 ER PT J AU Kowalczyk, WJ Wehring, HJ Burton, G Raley, H Feldman, S Heishman, SJ Kelly, DL AF Kowalczyk, William J. Wehring, Heidi J. Burton, George Raley, Heather Feldman, Stephanie Heishman, Stephen J. Kelly, Deanna L. TI Predictors of the Perception of Smoking Health Risks in Smokers With or Without Schizophrenia SO JOURNAL OF DUAL DIAGNOSIS LA English DT Article DE Schizophrenia; cigarette smoking; health risks; perception ID BIPOLAR DISORDER; ADULT SMOKERS; QUIT SMOKING; QUESTIONNAIRE; MOTIVATION; CESSATION AB Objective: This study sought to examine the predictors of health risk perception in smokers with or without schizophrenia. Methods: The health risk subscale from the Smoking Consequences Questionnaire was dichotomized and used to measure health risk perception in smokers with (n D 67) and without schizophrenia (n = 100). A backward stepwise logistic regression was conducted using variables associated at the bivariate level to determine multivariate predictors. Results: Overall, 62.5% of smokers without schizophrenia and 40.3% of smokers with schizophrenia completely recognize the health risks of smoking (p <= .01). Multivariate predictors for smokers without schizophrenia included: sex (Exp (B) = .3; p < .05), Smoking Consequences Questionnaire state enhancement (Exp (B) = .69; p < .01), and craving relief (Exp (B) = 1.8; p < .01). Among smokers with schizophrenia, predictors were education (Exp (B) = .7; p < .05), nicotine dependence (Exp (B) = .5; p < .01), motivation to quit (Exp (B) = 1.8; p <.01), and Smoking Consequences Questionnaire craving relief (Exp (B) = 1.8; p < .01). Conclusions: There was overlap and differences between predictors in smokers with and without schizophrenia. Commonly used techniques for education on the health consequences of cigarettes may work in smokers with schizophrenia, but intervention efforts specifically tailored to smokers with schizophrenia might be more efficacious. C1 [Kowalczyk, William J.; Burton, George; Heishman, Stephen J.] NIDA, Intramural Res Program, Baltimore, MD USA. [Wehring, Heidi J.; Raley, Heather; Feldman, Stephanie; Kelly, Deanna L.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Box 21247, Baltimore, MD 21228 USA. RP Wehring, HJ (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Box 21247, Baltimore, MD 21228 USA. EM hwehring@mprc.umaryland.edu FU Intramural Research Program of the National Institutes of Health; National Institute on Drug Abuse (NIDA); NIDA Residential Research Support Services Contract [HHSN271200599091CADB (N01DA-5-9909)]; NIDA FX Funding for this study was provided by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse (NIDA), and NIDA Residential Research Support Services Contract HHSN271200599091CADB (N01DA-5-9909 Kelly, PI). Both NIDA funds and personnel supported the design, study methods, and analysis of this study. NR 27 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1550-4263 EI 1550-4271 J9 J DUAL DIAGN JI J. Dual Diagn. PY 2017 VL 13 IS 1 BP 29 EP 35 DI 10.1080/15504263.2016.1260190 PG 7 WC Psychology, Clinical; Substance Abuse; Psychiatry SC Psychology; Substance Abuse; Psychiatry GA EP2UA UT WOS:000397237700005 PM 27858591 ER PT J AU Wehring, HJ Heishman, SJ McMahon, RP Liu, F Feldman, S Raley, H Weiner, E Kelly, DL AF Wehring, Heidi J. Heishman, Stephen J. McMahon, Robert P. Liu, Fang Feldman, Stephanie Raley, Heather Weiner, Elaine Kelly, Deanna L. TI Antipsychotic Treatment and Tobacco Craving in People With Schizophrenia SO JOURNAL OF DUAL DIAGNOSIS LA English DT Article DE Tobacco; craving; schizophrenia; antipsychotic ID FAGERSTROM TOLERANCE QUESTIONNAIRE; NICOTINE DEPENDENCE; SMOKING-BEHAVIOR; REDUCES SMOKING; HEAVY SMOKERS; USE DISORDER; HALOPERIDOL; CLOZAPINE; DSM-5; ARIPIPRAZOLE AB Objective: Nicotine dependence is high in schizophrenia, and craving is known to impact relapse during quit attempts. Methods: We compared tobacco craving in smokers with schizophrenia treated with different antipsychotics. Results: Mean craving scores were lowest in participants receiving first-generation antipsychotics, although these differences were not statistically significant. Craving with clozapine was not lower than with other antipsychotics. Conclusions: Further research is needed to determine whether differences in craving exist between antipsychotic classes. C1 [Wehring, Heidi J.; McMahon, Robert P.; Liu, Fang; Feldman, Stephanie; Raley, Heather; Weiner, Elaine; Kelly, Deanna L.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21228 USA. [Heishman, Stephen J.] NIDA, NIH, Intramural Res Program, Baltimore, MD USA. RP Wehring, HJ (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21228 USA. EM hwehring@mprc.umaryland.edu FU National Institute on Drug Abuse (NIDA) Residential Research Services Contract [HHSN271200599091CADB (N01DA-5-9909)] FX This study was funded in part by the National Institute on Drug Abuse (NIDA) Residential Research Services Contract HHSN271200599091CADB (N01DA-5-9909 Kelly, PI). NR 47 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1550-4263 EI 1550-4271 J9 J DUAL DIAGN JI J. Dual Diagn. PY 2017 VL 13 IS 1 BP 36 EP 42 DI 10.1080/15504263.2017.1288946 PG 7 WC Psychology, Clinical; Substance Abuse; Psychiatry SC Psychology; Substance Abuse; Psychiatry GA EP2UA UT WOS:000397237700006 PM 28166471 ER PT J AU Pierce, KK Whitehead, SS Kirkpatrick, BD Grier, PL Jarvis, A Kenney, H Carmolli, MP Reynolds, C Tibery, CM Lovchik, J Janiak, A Luke, CJ Durbin, AP Pletnev, AG AF Pierce, Kristen K. Whitehead, Stephen S. Kirkpatrick, Beth D. Grier, Palmtama L. Jarvis, Adrienne Kenney, Heather Carmolli, Marya P. Reynolds, Cynthia Tibery, Cecilia M. Lovchik, Janece Janiak, Anna Luke, Catherine J. Durbin, Anna P. Pletnev, Alexander G. TI A Live Attenuated Chimeric West Nile Virus Vaccine, rWN/DEN4 Delta 30, Is Well Tolerated and Immunogenic in Flavivirus-Naive Older Adult Volunteers SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE West Nile virus; vaccine; flavivirus ID UNITED-STATES; INFECTION; CANDIDATE; GENOTYPE; MONKEYS AB West Nile virus (WNV) is a major cause of mosquito-borne illness in the United States. Human disease ranges from mild febrile illness to severe fatal neurologic infection. Adults aged > 60 years are more susceptible to neuroinvasive disease accompanied by a high mortality rate or long-lasting neurologic sequelae. A chimeric live attenuated West Nile virus vaccine, rWN/DEN4 Delta 30, was shown to be safe and immunogenic in healthy adults aged 18-50 years. This study evaluated rWN/DEN4 Delta 30 in flavivirus-naive adults aged 50-65 years and found it to be safe and immunogenic. Outbreaks of WNV infection tend to be unpredictable, and a safe and effective vaccine will be an important public health tool. C1 [Pierce, Kristen K.; Kirkpatrick, Beth D.; Jarvis, Adrienne; Carmolli, Marya P.; Reynolds, Cynthia] Univ Vermont, Robert Larner MD Coll Med, Burlington, VT 05405 USA. [Whitehead, Stephen S.; Kenney, Heather; Luke, Catherine J.; Pletnev, Alexander G.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Grier, Palmtama L.; Tibery, Cecilia M.; Lovchik, Janece; Janiak, Anna; Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD USA. RP Pierce, KK (reprint author), Univ Vermont, Coll Med, Dept Med, Vaccine Testing Ctr, 89 Beaumont Ave,Given Bldg C205, Burlington, VT 05405 USA. EM kristen.pierce@uvmhealth.org FU National Institute of Allergy and Infectious Disease Intramural Research Program, National Institutes of Health [HHSN272200900010C] FX This work was supported by the National Institute of Allergy and Infectious Disease Intramural Research Program, National Institutes of Health (contract HHSN272200900010C). NR 15 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 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 1 PY 2017 VL 215 IS 1 BP 52 EP 55 DI 10.1093/infdis/jiw501 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP2HH UT WOS:000397203500010 PM 28077583 ER PT J AU Nyombayire, J Anzala, O Gazzard, B Karita, E Bergin, P Hayes, P Kopycinski, J Omosa-Manyonyi, G Jackson, A Bizimana, J Farah, B Sayeed, E Parks, CL Inoue, M Hironaka, T Hara, H Shu, T Matano, T Dally, L Barin, B Park, H Gilmour, J Lombardo, A Excler, JL Fast, P Laufer, DS Cox, JH AF Nyombayire, Julien Anzala, Omu Gazzard, Brian Karita, Etienne Bergin, Philip Hayes, Peter Kopycinski, Jakub Omosa-Manyonyi, Gloria Jackson, Akil Bizimana, Jean Farah, Bashir Sayeed, Eddy Parks, Christopher L. Inoue, Makoto Hironaka, Takashi Hara, Hiroto Shu, Tsugumine Matano, Tetsuro Dally, Len Barin, Burc Park, Harriet Gilmour, Jill Lombardo, Angela Excler, Jean-Louis Fast, Patricia Laufer, Dagna S. Cox, Josephine H. CA S001 Study Team TI First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus-Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE replication competent; Sendai virus vector; HIV-1 vaccine; intranasal delivery; immunogenicity; adenovirus 35; prime-boost; mucosal responses ID IMMUNE-RESPONSES; MUCOSAL VACCINES; CLINICAL-TRIALS; YOUNG-CHILDREN; DNA; INFECTION; GENE; DELIVERY; CANDIDATES; PROTEIN AB Background. We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)-vectored, human immunodeficiency virus type 1 (HIV-1) vaccine. Methods. Sixty-five HIV-1-uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 primeboost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12: 4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35-vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (S(L)A); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (S(H)A); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (AS(H)); and priming and boosting with a higher-dose SeV-Gag given intranasally (SHSH). Results. All vaccine regimens were well tolerated. Gag-specific IFN-gamma enzyme-linked immunospot-determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (S(L)A and S(H)A) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeVGag (55% and 59 spot-forming units, respectively); responses persisted for >= 8 months after completion of the prime-boost regimen. Functional CD8(+) T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the S(L)A and S(H)A groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T-cell counts in the AS(H) group. In contrast, the highest Gag-specific antibody titers were seen in the AS(H) group. Mucosal antibody responses were sporadic. Conclusions. SeV-Gag primed functional, durable HIV-specific T-cell responses and boosted antibody responses. The prime-boost sequence appears to determine which arm of the immune response is stimulated. C1 [Nyombayire, Julien; Karita, Etienne; Bizimana, Jean] Projet San Francisco, Kigali, Rwanda. [Anzala, Omu; Omosa-Manyonyi, Gloria; Farah, Bashir] Kenya AIDS Vaccine Initiat Inst Clin Res, Nairobi, Kenya. [Gazzard, Brian; Jackson, Akil] Chelsea & Westminster Healthcare NHS Fdn Trust, London, England. [Bergin, Philip; Hayes, Peter; Kopycinski, Jakub; Gilmour, Jill] Int AIDS Vaccine Initiat, Human Immunol Lab, London, England. [Sayeed, Eddy; Parks, Christopher L.; Park, Harriet; Lombardo, Angela; Excler, Jean-Louis; Fast, Patricia; Laufer, Dagna S.; Cox, Josephine H.] Int AIDS Vaccine Initiat, 125 Broad St,9th Fl, New York, NY 10004 USA. [Dally, Len; Barin, Burc] Emmes Corp, Rockville, MD USA. [Inoue, Makoto; Hironaka, Takashi; Hara, Hiroto; Shu, Tsugumine] ID Pharma, Tsukuba, Ibaraki, Japan. [Matano, Tetsuro] Univ Tokyo, Tokyo, Japan. [Matano, Tetsuro] Natl Inst Infect Dis, Tokyo, Japan. [Excler, Jean-Louis] Int Vaccine Inst, Seoul, South Korea. [Cox, Josephine H.] NIAID, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Laufer, DS (reprint author), Int AIDS Vaccine Initiat, 125 Broad St,9th Fl, New York, NY 10004 USA. EM dlaufer@iavi.org FU United States Agency for International Development (USAID); Ministry of Finance of Japan; World Bank; Bill and Melinda Gates Foundation; Ministry of Foreign Affairs of Denmark; Irish Aid; Ministry of Foreign Affairs of the Netherlands; Norwegian Agency for Development Cooperation; United Kingdom Department for International Development FX This work was supported by the United States Agency for International Development (USAID), the Ministry of Finance of Japan in partnership with the World Bank; the Bill and Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan, in partnership with the World Bank; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation and the United Kingdom Department for International Development. The full list of IAVI donors is available at: http://www.iavi.org. NR 51 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 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 1 PY 2017 VL 215 IS 1 BP 95 EP 104 DI 10.1093/infdis/jiw500 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP2HH UT WOS:000397203500016 PM 28077588 ER PT J AU Hobbs, CV Anderson, C Neal, J Sahu, T Conteh, S Voza, T Langhorne, J Borkowsky, W Duffy, PE AF Hobbs, Charlotte V. Anderson, Charles Neal, Jillian Sahu, Tejram Conteh, Solomon Voza, Tatiana Langhorne, Jean Borkowsky, William Duffy, Patrick E. TI Trimethoprim-Sulfamethoxazole Prophylaxis During Live Malaria Sporozoite Immunization Induces Long-Lived, Homologous, and Heterologous Protective Immunity Against Sporozoite Challenge SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; malaria; antiretroviral therapy; liver stages; eradication; children; trimethoprim-sulfamethoxazole; immunity ID STAGE PLASMODIUM PARASITES; T-CELL RESPONSES; COTRIMOXAZOLE PROPHYLAXIS; PROTRACTED PROTECTION; FALCIPARUM; YOELII; MICE; VACCINATION; INHIBITORS; INFECTION AB Trimethoprim-sulfamethoxazole (TMP-SMX) is widely used in malaria-endemic areas in human immunodeficiency virus (HIV)-infected children and HIV-uninfected, HIV-exposed children as opportunistic infection prophylaxis. Despite the known effects that TMP-SMX has in reducing clinical malaria, its impact on development of malaria-specific immunity in these children remains poorly understood. Using rodent malaria models, we previously showed that TMP-SMX, at prophylactic doses, can arrest liver stage development of malaria parasites and speculated that TMP-SMX prophylaxis during repeated malaria exposures would induce protective long-lived sterile immunity targeting pre-erythrocytic stage parasites in mice. Using the same models, we now demonstrate that repeated exposures to malaria parasites during TMP-SMX administration induces stage-specific and long-lived pre-erythrocytic protective anti-malarial immunity, mediated primarily by CD8(+) T-cells. Given the HIV infection and malaria coepidemic in sub-Saharan Africa, clinical studies aimed at determining the optimum duration of TMP-SMX prophylaxis in HIV-infected or HIV-exposed children must account for the potential anti-infection immunity effect of TMP-SMX prophylaxis. C1 [Hobbs, Charlotte V.; Anderson, Charles; Neal, Jillian; Sahu, Tejram; Conteh, Solomon; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Hobbs, Charlotte V.] Univ Mississippi, Med Ctr, Dept Microbiol, Batson Childrens Hosp, Jackson, MS 39216 USA. [Hobbs, Charlotte V.; Borkowsky, William] NYU, Sch Med, Dept Pediat, Div Infect Dis & Immunol, New York, NY 10003 USA. [Voza, Tatiana] CUNY, New York City Coll Technol, Dept Biol Sci, New York, NY 10021 USA. [Langhorne, Jean] Francis Crick Inst, Mill Hill Lab, London, England. RP Hobbs, CV (reprint author), Dept Pediat, Div Infect Dis, 2500 N State St, Jackson, MS 39216 USA.; Hobbs, CV (reprint author), Dept Microbiol, 2500 N State St, Jackson, MS 39216 USA. EM chobbs@umc.edu FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. NR 49 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 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 1 PY 2017 VL 215 IS 1 BP 122 EP 130 DI 10.1093/infdis/jiw482 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP2HH UT WOS:000397203500019 PM 28077589 ER PT J AU Togias, A Cooper, SF Acebal, ML Assa'ad, A Baker, JR Beck, LA Block, J Byrd-Bredbenner, C Chan, ES Eichenfield, LF Fleischer, DM Fuchs, GJ Furuta, GT Greenhawt, MJ Gupta, RS Habich, M Jones, SM Keaton, K Muraro, A Plaut, M Rosenwasser, LJ Rotrosen, D Sampson, HA Schneider, LC Sicherer, SH Sidbury, R Spergel, J Stukus, DR Venter, C Boyce, JA AF Togias, Alkis Cooper, Susan F. Acebal, Maria L. Assa'ad, Amal Baker, James R. jr Beck, Lisa A. Block, Julie Byrd-Bredbenner, Carol Chan, Edmond S. Eichenfield, Lawrence F. Fleischer, David M. Fuchs, George J., III Furuta, Glenn T. Greenhawt, Matthew J. Gupta, Ruchi S. Habich, Michele Jones, Stacie M. Keaton, Kari Muraro, Antonella Plaut, Marshall Rosenwasser, Lanny J. Rotrosen, Daniel Sampson, Hugh A. Schneider, Lynda C. Sicherer, Scott H. Sidbury, Robert Spergel, Jonathan Stukus, David R. Venter, Carina Boyce, Joshua A. TI Addendum Guidelines for the Prevention of Peanut Allergy in the United States: Report of the National Institute of Allergy and Infectious Diseases-Sponsored Expert Panel SO JOURNAL OF PEDIATRIC NURSING-NURSING CARE OF CHILDREN & FAMILIES LA English DT Article DE Food; peanut; allergy; prevention; guidelines ID NUTRITIONAL INTERVENTIONS; ANAPHYLACTIC REACTIONS; GRADING QUALITY; HIGH-RISK; INFANTS; RECOMMENDATIONS; CONSUMPTION; FATALITIES; STRENGTH; CHILDREN AB Background: Food allergy is an important public health problem because it affects children and adults, can be severe and even life-threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. A recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanut-containing foods beginning in infancy. Objectives: Prompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy. Results: The addendum provides 3 separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanut-containing foods in the health care provider's office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation. Conclusions: Guidelines have been developed for early introduction of peanut-containing foods into the diets of infants at various risk levels for peanut allergy. Published by Elsevier Inc. C1 [Togias, Alkis; Cooper, Susan F.; Plaut, Marshall; Rotrosen, Daniel] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Acebal, Maria L.] Board Directors, Food Allergy Res & Educ, Mclean, VA USA. [Assa'ad, Amal] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH USA. [Baker, James R. jr] Food Allergy Res & Educ, Mclean, VA USA. [Baker, James R. jr] Univ Michigan Hlth Syst, Div Allergy & Clin Immunol, Ann Arbor, MI USA. [Beck, Lisa A.] Univ Rochester, Med Ctr, Dept Dermatol, Rochester, NY 14627 USA. [Block, Julie] Natl Eczema Assoc, San Rafael, CA USA. [Byrd-Bredbenner, Carol] Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ USA. [Chan, Edmond S.] Univ British Columbia, Div Allergy & Immunol, Dept Pediat, BC Childrens Hosp, Vancouver, BC, Canada. [Eichenfield, Lawrence F.] Univ Calif San Diego, San Diego Sch Med, Rady Childrens Hosp, Dept Dermatol, San Diego, CA 92103 USA. [Eichenfield, Lawrence F.] Univ Calif San Diego, San Diego Sch Med, Rady Childrens Hosp, Dept Pediat, San Diego, CA 92103 USA. [Fleischer, David M.; Greenhawt, Matthew J.] Univ Colorado Denver, Sch Med, Childrens Hosp Colorado, Sect Allergy & Immunol,Dept Pediat, Aurora, CO USA. [Fuchs, George J., III] Univ Kentucky, Coll Med, Div Gastroenterol Hepatol & Nutr, Dept Pediat,Kentucky Childrens Hosp, Lexington, KY USA. [Furuta, Glenn T.] Childrens Hosp Colorado, Digest Hlth Inst, Aurora, CO USA. [Furuta, Glenn T.] Univ Colorado Denver, Sch Med, Sect Pediat Gastroenterol, Aurora, CO USA. [Gupta, Ruchi S.] Northwestern Univ, Dept Pediat, Div Acad Gen Pediat & Primary Care, Feinberg Sch Med, Chicago, IL 60611 USA. [Gupta, Ruchi S.] Northwestern Univ, Ann & Robert H Lurie Childrens Hosp Chicago, Feinberg Sch Med, Chicago, IL 60611 USA. [Habich, Michele] Cent DuPage Hosp, Northwestern Med, Winfield, IL USA. [Jones, Stacie M.] Univ Arkansas Med Sci, Arkansas Childrens Hosp, Div Allergy & Immunol, Dept Pediat, Little Rock, AR 72205 USA. [Keaton, Kari] Metro DC Food Allergy Support Grp, Rockville, MD USA. [Muraro, Antonella] Padua Univ Hosp, Food Allergy Referral Ctr, Dept Women & Child Hlth, Padua, Italy. [Sicherer, Scott H.] Icahn Sch Med Mt Sinai, Div Pediat Allergy & Immunol, New York, NY 10029 USA. [Rosenwasser, Lanny J.] Univ Missouri, Sch Med, Kansas City, MO 64108 USA. [Sampson, Hugh A.] Icahn Sch Med Mt Sinai, Div Allergy & Immunol, Dept Pediat, New York, NY 10029 USA. [Schneider, Lynda C.] Boston Childrens Hosp, Div Allergy & Immunol, Boston, MA USA. [Sidbury, Robert] Univ Washington, Sch Med, Dept Pediat, Div Dermatol,Seattle Childrens Hosp, Seattle, WA 98195 USA. [Spergel, Jonathan] Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Div Allergy & Immunol,Perelman Sch Med, Philadelphia, PA 19104 USA. [Stukus, David R.] Ohio State Univ, Coll Med, Dept Pediat, Sect Allergy & Immunol,Nationwide Childrens Hosp, Columbus, OH 43210 USA. [Venter, Carina] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA. [Boyce, Joshua A.] Harvard Med Sch, Dept Med, Boston, MA USA. [Boyce, Joshua A.] Harvard Med Sch, Dept Pediat, Boston, MA USA. RP Cooper, SF (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM coopersu@niaid.nih.gov FU American College of Allergy, Asthma & Immunology (ACAAI); DBV Technologies; Aimmune; Stanford Foundation; TEVA Pharmaceuticals; GlaxoSmithKline; National Institutes of Health (NIH); Astellas; Food Allergy Research & Education (FARE); ACAAI. C. Byrd-Bredbenner; NIH/National Institute of Allergy and Infectious Disease (NIAID); NIAID; Pfizer; Sanofi; Monsanto Company; Nestle Nutrition Institute; Aimmune Therapeutics; Agency for Healthcare Research and Quality [1K08HS024599-01]; Joint Taskforce on Allergy Practice Parameters; NIH; FARE; Mylan LLC; Grand Rounds; Meda and Menarini; HAL Allergy; Epidermolysis Bullosa Research Partnership; Taiwanese Dermatological Society FX Disclosure of potential conflict of interest: A. Assa'ad received travel support from the American College of Allergy, Asthma & Immunology (ACAAI); was an elected member of the Board of Directors for the American Academy of Allergy, Asthma, & Immunology (AAAAI) from March 2012 to March 2016; has consultant arrangements with Aimmune; is employed by Cincinnati Children's Hospital Medical Center; has received grants from DBV Technologies, Aimmune, Stanford Foundation, TEVA Pharmaceuticals, GlaxoSmithKline, the National Institutes of Health (NIH), Astellas, and Food Allergy Research & Education (FARE); and has received payment for lectures from the ACAAI. C. Byrd-Bredbenner and G. J. Fuchs III have received travel support from the NIH/National Institute of Allergy and Infectious Disease (NIAID). E. S. Chan has received travel support from the NIAID, has received grants from DBV Technologies, and has received payment for lectures from Pfizer, Sanofi, Mead Johnson, and Nestle. D. M. Fleischer has received travel support from the NIAID; is a board member for the National Peanut Board, the FAACT Medical Advisory Board, and the FARE Medical Advisory Board; has consultant arrangements with Adamis Pharmaceuticals Corporation, INSYS Therapeutics, DBV Technologies, Aimmune Therapeutics, Intrommune Therapeutics, and Kaleo Pharma; is employed by University Physicians; has received grants from Monsanto Company, Nestle Nutrition Institute, DBV Technologies, and Aimmune Therapeutics; has received payment for lectures from Nestle Nutrition Institute; and has received royalties from UpToDate. M. J. Greenhawt has received a grant from the Agency for Healthcare Research and Quality (1K08HS024599-01, Career Development Award); has received travel support from the NIAID and the Joint Taskforce on Allergy Practice Parameters; has a board membership with the National Peanut Board; has consultant arrangements with Adamis Pharmaceuticals, the Canadian Transportation Agency, Nutricia, Nestle/Gerber, Aimmune, Kaleo Pharmaceutical, and Monsanto; is an Associate Editor for the Annals of Allergy, Asthma, and Immunology; has received payment for lectures from the ACAAI, Reach MD, Thermo Fisher Scientific, the California Society for Allergy and Immunology, the Allergy and Asthma Network, the New England Society for Allergy, UCLA/Harbor Heiner Lectureship, Medscape, the Western Michigan School of Medicine, the Canadian Society of Allergy and Clinical Immunology, and the Pennsylvania Society for Allergy and Immunology. R. S. Gupta has consultant arrangements with BEFORE Brands and DBV Technologies; has received grants from the NIH, FARE, and Mylan LLC; has received payment for lectures from Grand Rounds; and has received royalties from Createspace Independent Publishing Platform. S. M. Jones is on the Research Advisory Board for FARE; is on the Scientific Advisory Board for Aimmune; has consultant arrangements with Stallergenes; has received grants from the NIH/NIAID (Consortium of Food Allergy Research and Immune Tolerance Network-IMPACT Trial), FARE, Aimmune Technologies, DBVTechnologies, and the National Peanut Board; has received payment for lectures from the Kansas City Allergy Society, Mercy Children's Hospital, Riley Children's Hospital, Southwester Medical School-Children's Medical Center, the European Academy of Allergy & Clinical Immunology, the New York Allergy & Asthma Society, the University of Iowa Paul M. Seebohm Lectureship in Allergy, and the Iowa Society of Allergy, Asthma, and Immunology. A.; Muraro has consultant arrangements with Meda, Novartis, and Menarini; is employed by Padua University Hospital; and has received payment for lectures from Meda and Menarini. L. J. Rosenwasser is a board member for the World Allergy Organization. H. A. Sampson has consultant arrangements with Allertein Therapeutics, Genentech/Roche, Sanofi, Stallergenes, Danone, and Merck; is employed part time as Chief Scientific Officer for DBV Technologies; has received grants from the NIAID and the Immune Tolerance Network; has received royalties from UpToDate and Elsevier; has been offered stock options in DBV Technologies; and is chairman of PhARF Award Selection Committee for Thermo Fisher. L C. Schneider is on the Medical Advisory Board for FARE, has received a grant from DBV Technologies, and has received stock/stock options in Antera Therapeutics. S. H. Sicherer has received grants from the NIAID, FARE, and HAL Allergy; has received royalties from UpToDate; and is serving as Associate Editor for the Journal of Allergy and Clinical Immunology: In Practice. R. Sidbury has received travel support from the NIH and the Hawaii Dermatology Seminar, has consultant arrangements with Anacor, has provided expert witness testimony on behalf of Roche in Accutane-inflammatory bowel disease cases, has received a grant from Epidermolysis Bullosa Research Partnership, has received payment for lectures from the Taiwanese Dermatological Society, and has received royalties from UpToDate. J. Spergel has consultant arrangements with DBV Technologies and Danone; has received grants from DBV Technologies, Aimmune Therapeutics, and the NIH; has received payment for lectures for Dartmouth College, the ACAAI, and the Florida Allergy Society; and has received stock/stock options in DBV Technologies. D. R. Stukus has received payment for lectures from the ACAAI. C. Venter has consultant arrangements with Danone and Nestle, has received payment for lectures from Mead Johnson, and has received travel support from Thermo Fisher. The rest of the authors declare that they have no relevant conflicts of interest. NR 29 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 0882-5963 J9 J PEDIATR NURS JI J. Pediatr. Nurs. PD JAN-FEB PY 2017 VL 32 BP 91 EP 98 DI 10.1016/j.pedn.2016.12.006 PG 8 WC Nursing; Pediatrics SC Nursing; Pediatrics GA EM5MS UT WOS:000395356300019 PM 28137368 ER PT J AU Walker, V AF Walker, Verma TI Implementing a 3D printing service in a biomedical library SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article ID SURGERY AB Three-dimensional (3D) printing is opening new opportunities in biomedicine by enabling creative problem solving, faster prototyping of ideas, advances in tissue engineering, and customized patient solutions. The National Institutes of Health (NIH) Library purchased a Makerbot Replicator 2 3D printer to give scientists a chance to try out this technology. To launch the service, the library offered training, conducted a survey on service model preferences, and tracked usage and class attendance. 3D printing was very popular, with new lab equipment prototypes being the most common model type. Most survey respondents indicated they would use the service again and be willing to pay for models. There was high interest in training for 3D modeling, which has a steep learning curve. 3D printers also require significant care and repairs. NIH scientists are using 3D printing to improve their research, and it is opening new avenues for problem solving in labs. Several scientists found the 3D printer so helpful they bought one for their labs. Having a printer in a central and open location like a library can help scientists, doctors, and students learn how to use this technology in their work. C1 [Walker, Verma] NIH Lib, Off Res Serv, NIH, Bldg 10,B1L306F,MSC 1150, Bethesda, MD 20892 USA. RP Walker, V (reprint author), NIH Lib, Off Res Serv, NIH, Bldg 10,B1L306F,MSC 1150, Bethesda, MD 20892 USA. EM walkerve@mail.nih.gov NR 24 TC 0 Z9 0 U1 2 U2 2 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD JAN PY 2017 VL 105 IS 1 BP 55 EP 60 DI 10.5195/jmla.2017.107 PG 6 WC Information Science & Library Science SC Information Science & Library Science GA EO0LZ UT WOS:000396390600010 PM 28096747 ER PT J AU Greenberg, SJ AF Greenberg, Stephen J. TI History matters SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Editorial Material C1 [Greenberg, Stephen J.] Natl Lib Med, Publ Serv, Hist Med Div, NIH, Bethesda, MD 20894 USA. RP Greenberg, SJ (reprint author), Natl Lib Med, Publ Serv, Hist Med Div, NIH, Bethesda, MD 20894 USA. EM greenbes@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 4 TC 0 Z9 0 U1 0 U2 0 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD JAN PY 2017 VL 105 IS 1 BP 89 EP 90 DI 10.5195/jmla.2017.112 PG 2 WC Information Science & Library Science SC Information Science & Library Science GA EO0LZ UT WOS:000396390600016 PM 28096753 ER PT J AU Proano, A Xu, ZY Caligiuri, P Mollura, DJ Gilman, RH AF Proano, Alvaro Xu, Ziyue Caligiuri, Philip Mollura, Daniel J. Gilman, Robert H. CA TB Working Grp Peru TI Computer automated algorithm to evaluate cavitary lesions in adults with pulmonary tuberculosis SO JOURNAL OF THORACIC DISEASE LA English DT Letter ID DRUG-SUSCEPTIBILITY ASSAY; MICROSCOPIC-OBSERVATION C1 [Proano, Alvaro] Univ Peruana Cayetano Heredia, Sch Med, Fac Med Alberto Hurtado, Av El Mastil 387 Apt 602-1, Lima, Peru. [Proano, Alvaro; Gilman, Robert H.] Univ Peruana Cayetano Heredia, Fac Sci, Res & Dev Labs, Lab TB Infect Dis, Lima, Peru. [Xu, Ziyue; Mollura, Daniel J.] NIH, CIDI, Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. [Caligiuri, Philip] Univ Utah, Sch Med, Dept Radiol & Imaging Sci, Salt Lake City, UT USA. [Gilman, Robert H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Program Global Dis Epidemiol & Control, Baltimore, MD USA. RP Proano, A (reprint author), Univ Peruana Cayetano Heredia, Sch Med, Fac Med Alberto Hurtado, Av El Mastil 387 Apt 602-1, Lima, Peru.; Gilman, RH (reprint author), Johns Hopkins Med Inst, Dept Int Hlth, Bloomberg Sch Publ Hlth, 615 N Wolfe St,Rm W5515, Baltimore, MD 21205 USA. EM alvaro.proano.f@upch.pe; gilmanbob@gmail.com OI Proano, Alvaro/0000-0002-4057-7686; Comina, German/0000-0003-2114-0486 FU CIDI; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health [5D43TW006581, 5R21AI094143-02, 5D43TW009349-03] FX This research is supported by CIDI, the intramural research program of the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB). It also received support from the National Institutes of Health (5D43TW006581 "Infectious Diseases Training Program in Peru", 5R21AI094143-02 " Cougha rapid indicator of response to therapy in pulmonary TB", and 5D43TW009349-03" Inter-American Training for Innovations in Emerging Infectious Diseases"). NR 11 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 JAN PY 2017 VL 9 IS 1 BP E93 EP E96 DI 10.21037/jtd.2017.01.35 PG 4 WC Respiratory System SC Respiratory System GA EO1XN UT WOS:000396491300019 PM 28203447 ER PT J AU Bouska, A Zhang, W Gong, Q Iqbal, J Scuto, A Vose, J Ludvigsen, M Fu, K Weisenburger, DD Greiner, TC Gascoyne, RD Rosenwald, A Ott, G Campo, E Rimsza, LM Delabie, J Jaffe, ES Braziel, RM Connors, JM Wu, CI Staudt, LM Amore, FD McKeithan, TW Chan, WC AF Bouska, A. Zhang, W. Gong, Q. Iqbal, J. Scuto, A. Vose, J. Ludvigsen, M. Fu, K. Weisenburger, D. D. Greiner, T. C. Gascoyne, R. D. Rosenwald, A. Ott, G. Campo, E. Rimsza, L. M. Delabie, J. Jaffe, E. S. Braziel, R. M. Connors, J. M. Wu, C-I Staudt, L. M. Amore, F. D. McKeithan, T. W. Chan, W. C. TI Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma SO LEUKEMIA LA English DT Article ID B-CELL LYMPHOMA; SOMATIC MUTATIONS; EZH2 MUTATIONS; CLONAL EVOLUTION; CARD11 MUTATIONS; EXPRESSION; PATHOGENESIS; SURVIVAL; FREQUENT; TARGET AB Follicular lymphoma (FL) is typically an indolent disease, but 30-40% of FL cases transform into an aggressive lymphoma (tFL) with a poor prognosis. To identify the genetic changes that drive this transformation, we sequenced the exomes of 12 cases with paired FL and tFL biopsies and identified 45 recurrently mutated genes in the FL-tFL data set and 39 in the tFL cases. We selected 496 genes of potential importance in transformation and sequenced them in 23 additional tFL cases. Integration of the mutation data with copy-number abnormality (CNA) data provided complementary information. We found recurrent mutations of miR-142, which has not been previously been reported to be mutated in FL/tFL. The genes most frequently mutated in tFL included KMT2D (MLL2), CREBBP, EZH2, BCL2 and MEF2B. Many recurrently mutated genes are involved in epigenetic regulation, the Janus-activated kinase-signal transducer and activator of transcription (STAT) or the nuclear factor-kappa B pathways, immune surveillance and cell cycle regulation or are TFs involved in B-cell development. Of particular interest are mutations and CNAs affecting S1P-activated pathways through S1PR1 or S1PR2, which likely regulate lymphoma cell migration and survival outside of follicles. Our custom gene enrichment panel provides high depth of coverage for the study of clonal evolution or divergence. C1 [Bouska, A.; Zhang, W.; Iqbal, J.; Fu, K.; Greiner, T. C.] Univ Nebraska Med Ctr, Pathol & Microbiol, Omaha, NE USA. [Gong, Q.; Scuto, A.; Weisenburger, D. D.; McKeithan, T. W.; Chan, W. C.] City Hope Natl Med Ctr, Dept Pathol, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Vose, J.] Univ Nebraska Med Ctr, Div Hematol & Oncol, Omaha, NE USA. [Ludvigsen, M.] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [Gascoyne, R. D.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC, Canada. [Rosenwald, A.] Univ Wurzburg, Inst Pathol, Wurzburg, Germany. [Rosenwald, A.] Comprehens Canc Ctr Mainfranken, Wurzburg, Germany. [Ott, G.] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Ott, G.] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Campo, E.] Univ Barcelona, Hosp Clin, Hematopathol Unit, IDIBAPS, Barcelona, Spain. [Rimsza, L. M.] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Delabie, J.] Univ Toronto, Dept Pathol, Toronto, ON, Canada. [Jaffe, E. S.] NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Braziel, R. M.] Oregon Hlth & Sci Univ, Portland, OR USA. [Connors, J. M.] British Columbia Canc Agcy, Div Med Oncol, Vancouver, BC, Canada. [Wu, C-I] Chinese Acad Sci, Beijing Inst Genom, Beijing, Peoples R China. [Wu, C-I] Univ Chicago, Dept Ecol & Evolut, 940 E 57th St, Chicago, IL 60637 USA. [Staudt, L. M.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Amore, F. D.] Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark. RP Chan, WC (reprint author), City Hope Natl Med Ctr, Dept Pathol, 1500 East Duarte Rd, Duarte, CA 91010 USA. EM jochan@coh.org OI Campo, elias/0000-0001-9850-9793 FU Lymphoma Research Foundation Follicular Lymphoma initiative; Lymphoma SPORE [P50CA136411-01-(NCI)]; University of Nebraska Foundation; NCRR [1S10RR027754-01, 5P20RR016469, RR018788-08]; National Institute for General Medical Science (NIGMS) [8P20GM103427, GM103471-09]; National Cancer Institute of the National Institutes of Health [P30CA033572] FX This work was supported by the Lymphoma Research Foundation Follicular Lymphoma initiative (to WCC), Lymphoma SPORE P50CA136411-01-(NCI) (to WCC) and a grant for Global Engagement from the University of Nebraska Foundation (to WCC). The University of Nebraska DNA Sequencing Core receives partial support from the NCRR (1S10RR027754-01, 5P20RR016469, RR018788-08) and the National Institute for General Medical Science (NIGMS) (8P20GM103427, GM103471-09). Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under award number P30CA033572 and included work performed in the Bioinformatics Core. Thanks to Adam Cornish and Robert J Boissy for initial sequencing analysis assistance. NR 51 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD JAN PY 2017 VL 31 IS 1 BP 83 EP 91 DI 10.1038/leu.2016.175 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA EK6UD UT WOS:000394058700011 PM 27389057 ER PT J AU Hegde, ML Bohr, VA Mitra, S AF Hegde, Muralidhar L. Bohr, Vilhelm A. Mitra, Sankar TI DNA damage responses in central nervous system and age-associated neurodegeneration SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Editorial Material ID STRAND BREAK REPAIR; ATAXIA-TELANGIECTASIA; ALZHEIMERS-DISEASE; COCKAYNE-SYNDROME; EXCISION-REPAIR; BRAIN; INSTABILITY; DEFICIENCY; INTEGRITY; MUTATION C1 [Hegde, Muralidhar L.; Mitra, Sankar] Houston Methodist Res Inst, Dept Radiat Oncol, Houston, TX 77030 USA. [Hegde, Muralidhar L.] Houston Methodist Neurol Inst, Houston, TX 77030 USA. [Hegde, Muralidhar L.; Mitra, Sankar] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Hegde, ML (reprint author), 6550 Fannin St, Houston, TX 77030 USA. FU National institute of Health, USA [R01 NS088645, IRP-NIH/NIA, R01 CA CA158910] FX M.L.H. (R01 NS088645), V.A.B. (IRP-NIH/NIA) and S.A. (R01 CA CA158910) acknowledge the National institute of Health, USA for the support of their research program. NR 25 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 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD JAN PY 2017 VL 161 SI SI BP 1 EP 3 DI 10.1016/j.mad.2017.01.010 PN A PG 3 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA EP0JQ UT WOS:000397074000001 PM 28212866 ER PT J AU Hou, YJ Song, HD Croteau, DL Akbari, M Bohr, VA AF Hou, Yujun Song, Hyundong Croteau, Deborah L. Akbari, Mansour Bohr, Vilhelm A. TI Genome instability in Alzheimer disease SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE DNA damage; DNA repair; Alzheimer's disease ID BASE-EXCISION-REPAIR; MILD COGNITIVE IMPAIRMENT; OXIDATIVE DNA-DAMAGE; AMYLOID PRECURSOR PROTEIN; MITOCHONDRIAL CASCADE HYPOTHESIS; CYTOCHROME-OXIDASE ACTIVITY; HUMAN NEUROBLASTOMA-CELLS; DOUBLE-STRAND BREAKS; SMOOTH-MUSCLE-CELLS; MOUSE MODEL AB Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis of sporadic AD (sAD) is more complex and variants of several genes are associated with an increased lifetime risk of AD. Nuclear and mitochondrial DNA integrity is pivotal during neuronal development, maintenance and function. DNA damage and alterations in cellular DNA repair capacity have been implicated in the aging process and in age-associated neurodegenerative diseases, including AD. These findings are supported by research using animal models of AD and in DNA repair deficient animal models. In recent years, novel mechanisms linking DNA damage to neuronal dysfunction have been identified and have led to the development of noninvasive treatment strategies. Further investigations into the molecular mechanisms connecting DNA damage to AD pathology may help to develop novel treatment strategies for this debilitating disease. Here we provide an overview of the role of genome instability and DNA repair deficiency in AD pathology and discuss research strategies that include genome instability as a component. Published by Elsevier Ireland Ltd. C1 [Hou, Yujun; Song, Hyundong; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Akbari, Mansour] Univ Copenhagen, Ctr Hlth Aging, SUND, Copenhagen, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU Intramural Research Program of National Institute on Aging, National Institutes of Health FX This work was supported entirely by Intramural Research Program of National Institute on Aging, National Institutes of Health. We thank Qiping Lu and Stephanie Cordonnier for critically reading the manuscript. NR 216 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 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD JAN PY 2017 VL 161 SI SI BP 83 EP 94 DI 10.1016/j.mad.2016.04.005 PN A PG 12 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA EP0JQ UT WOS:000397074000007 PM 27105872 ER PT J AU Shin, HW Ryu, HS Kim, J Kim, MJ Hallett, M Chung, SJ AF Shin, Hae-Won Ryu, Ho-Sung Kim, Juyeon Kim, Mi-Jung Hallett, Mark Chung, Sun Ju TI Sensory Tricks for Cervical Levodopa-induced Dyskinesia in Patients with Parkinson's Disease SO MOVEMENT DISORDERS CLINICAL PRACTICE LA English DT Article DE Parkinson's disease; levodopa-induced dyskinesia; cervical dystonia; sensory tricks ID CLINICAL CHARACTERISTICS; DYSTONIA AB Choreiform or dystonic movement in the craniocervical region can occur as levodopa-induced dyskinesia (LID). "Sensory tricks" are various alleviating maneuvers for the relief of abnormal postures in patients who have idiopathic focal dystonia, particularly those who have cervical dystonia. The authors report on three men with Parkinson's disease who had been receiving levodopa for more than 3 years and presented with involuntary neck movements during the drug on period. In all three patients, cervical LIDs appeared during the drug on period and completely disappeared during the drug off period. The effects of using sensory tricks to markedly improve the symptoms of cervical LID were studied. In all patients, the cervical LIDs improved more efficiently when sensory tricks were performed on the patient by another person (passive tricks) than by the patient himself (self-sensory tricks). The unique features of the sensory tricks for cervical LID in the current patients may be important clinical evidence of abnormal sensorimotor integration in patients who have PD with LID. C1 [Shin, Hae-Won] Chung Ang Univ, Coll Med, Dept Neurol, Seoul, South Korea. [Ryu, Ho-Sung; Kim, Juyeon; Chung, Sun Ju] Univ Ulsan, Coll Med, Dept Neurol, Asan Med Ctr, 88 Olymp Ro 43 Gil, Seoul 138736, South Korea. [Kim, Mi-Jung] Univ Ulsan, Coll Med, Hlth Screening & Promot Ctr, Asan Med Ctr, Seoul, South Korea. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Chung, SJ (reprint author), Univ Ulsan, Coll Med, Dept Neurol, Asan Med Ctr, 88 Olymp Ro 43 Gil, Seoul 138736, South Korea. EM sjchung@amc.seoul.kr FU Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea [HI14C2206] FX This work was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI14C2206). The authors report no conflicts of interest. NR 9 TC 1 Z9 1 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2330-1619 J9 MOV DISORD CLIN PRAC JI MOV. DISORD. CLIN. PRACT. PD JAN-FEB PY 2017 VL 4 IS 1 BP 138 EP 140 DI 10.1002/mdc3.12363 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA EO0EF UT WOS:000396370400029 ER PT J AU Kwon-Chung, KJ Bennett, JE Wickes, BL Meyer, W Cuomo, CA Wollenburg, KR Bicanic, TA Castaneda, E Chang, YC Chen, JH Cogliati, M Dromer, F Ellis, D Filler, SG Fisher, MC Harrison, TS Holland, SM Kohno, S Kronstad, JW Lazera, M Levitz, SM Lionakis, MS May, RC Ngamskulrongroj, P Pappas, PG Perfect, JR Rickerts, V Sorrell, TC Walsh, TJ Williamson, PR Xu, JP Zelazny, AM Casadevall, A AF Kwon-Chung, Kyung J. Bennett, John E. Wickes, Brian L. Meyer, Wieland Cuomo, Christina A. Wollenburg, Kurt R. Bicanic, Tihana A. Castaneda, Elizabeth Chang, Yun C. Chen, Jianghan Cogliati, Massimo Dromer, Francoise Ellis, David Filler, Scott G. Fisher, Matthew C. Harrison, Thomas S. Holland, Steven M. Kohno, Shigeru Kronstad, James W. Lazera, Marcia Levitz, Stuart M. Lionakis, Michail S. May, Robin C. Ngamskulrongroj, Popchai Pappas, Peter G. Perfect, John R. Rickerts, Volker Sorrell, Tania C. Walsh, Thomas J. Williamson, Peter R. Xu, Jianping Zelazny, Adrian M. Casadevall, Arturo TI The Case for Adopting the "Species Complex" Nomenclature for the Etiologic Agents of Cryptococcosis SO MSPHERE LA English DT Article DE Cryptococcosis; Cryptococcus gattii; Cryptococcus neoformans; clade; genetic diversity; new nomenclature; species complex ID NEOFORMANS; GATTII; FUNGI; POPULATION; HIV/AIDS; REVEALS; HYBRID AB Cryptococcosis is a potentially lethal disease of humans/animals caused by Cryptococcus neoformans and Cryptococcus gattii. Distinction between the two species is based on phenotypic and genotypic characteristics. Recently, it was proposed that C. neoformans be divided into two species and C. gattii into five species based on a phylogenetic analysis of 115 isolates. While this proposal adds to the knowledge about the genetic diversity and population structure of cryptococcosis agents, the published genotypes of 2,606 strains have already revealed more genetic diversity than is encompassed by seven species. Naming every clade as a separate species at this juncture will lead to continuing nomenclatural instability. In the absence of biological differences between clades and no consensus about how DNA sequence alone can delineate a species, we recommend using "Cryptococcus neoformans species complex" and "C. gattii species complex" as a practical intermediate step, rather than creating more species. This strategy recognizes genetic diversity without creating confusion. C1 [Kwon-Chung, Kyung J.; Bennett, John E.; Chang, Yun C.; Holland, Steven M.; Lionakis, Michail S.; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Wickes, Brian L.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Meyer, Wieland] Univ Sydney, Mol Mycol Res Lab, Sydney, NSW, Australia. [Meyer, Wieland; Sorrell, Tania C.] Westmead Inst Med Res, Westmead, NSW, Australia. [Cuomo, Christina A.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Wollenburg, Kurt R.] NIAID, Off Cyber Infrastruct & Computat Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bicanic, Tihana A.; Harrison, Thomas S.] St Georges Univ London, Inst Infect & Immun, London, England. [Castaneda, Elizabeth] Colombia Inst Nacl Salud, Bogota, Colombia. [Chen, Jianghan] Second Mil Med Univ, Changzheng Hosp, Mycol Ctr, Shanghai, Peoples R China. [Cogliati, Massimo] Univ Milan, Dipartimento Sci Biomed Salute, Milan, Italy. [Dromer, Francoise] Inst Pasteur, Mol Mycol Unit, Paris, France. [Ellis, David] Univ Adelaide, Sch Biol Sci, Adelaide, SA, Australia. [Filler, Scott G.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Los Angeles, CA USA. [Fisher, Matthew C.] Imperial Coll London, Dept Infect Dis Epidemiol, London, England. [Kohno, Shigeru] Nagasaki Univ, Nagasaki, Japan. [Kronstad, James W.] Univ British Columbia, Michael Smith Labs, Vancouver, BC, Canada. [Lazera, Marcia] Fiocruz MS, Inst Nacl Infectol Evandro Chagas, Rio De Janeiro, Brazil. [Levitz, Stuart M.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [May, Robin C.] Univ Birmingham, Inst Microbiol & Infect, Birmingham, W Midlands, England. [May, Robin C.] Univ Birmingham, Sch Biosci, Birmingham, W Midlands, England. [Ngamskulrongroj, Popchai] Mahidol Univ, Siriraj Hosp, Fac Med, Bangkok, Thailand. [Pappas, Peter G.] Univ Alabama Birmingham, Div Infect Dis, Birmingham, AL USA. [Perfect, John R.] Duke Univ, Sch Med, Durham, NC USA. [Rickerts, Volker] Robert Koch Inst, Berlin, Germany. [Sorrell, Tania C.] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW, Australia. [Walsh, Thomas J.] Weill Cornell Med, Dept Med, New York, NY USA. [Walsh, Thomas J.] Weill Cornell Med, Dept Pediat, New York, NY USA. [Walsh, Thomas J.] Weill Cornell Med, Dept Microbiol & Immunol, New York, NY USA. [Xu, Jianping] McMaster Univ, Dept Biol, Hamilton, ON, Canada. [Xu, Jianping] Hainan Med Coll, Haikou, Hainan, Peoples R China. [Zelazny, Adrian M.] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Casadevall, Arturo] Johns Hopkins Sch Med, Baltimore, MD USA. RP Kwon-Chung, KJ (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM june_kwon-chung@nih.gov FU intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; NHMRC [APP1031943]; European Research Council under the European Union's Seventh Framework Program (FP); ERC [614562]; Royal Society Wolfson Research Merit Award; Lister Institute Prize Fellowship FX This work was supported by funds from the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, to K.J.K.-C., J.E.B., Y.C.C., S.M.H., M.L., and P.R.W. and an NHMRC grant, APP1031943, to W.M. and T.C.S. R.C.M. is supported by the European Research Council under the European Union's Seventh Framework Program (FP/2007-2013) and ERC grant agreement no. 614562 and by a Royal Society Wolfson Research Merit Award and a Lister Institute Prize Fellowship. T.C.S. is a Sydney Medical School Foundation Fellow. NR 40 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2379-5042 J9 MSPHERE JI mSphere PD JAN PY 2017 VL 2 IS 1 AR e00357-16 DI 10.1128/mSphere.00357-16 PG 7 WC Microbiology SC Microbiology GA EL3WL UT WOS:000394549900019 ER PT J AU Mahic, M Mjaaland, S Bovelstad, HM Gunnes, N Susser, E Bresnahan, M Oyen, AS Levin, B Che, X Hirtz, D Reichborn-Kjennerud, T Schjolberg, S Roth, C Magnus, P Stoltenberg, C Suren, P Hornig, M Lipkin, WI AF Mahic, Milada Mjaaland, Siri Bovelstad, Hege Marie Gunnes, Nina Susser, Ezra Bresnahan, Michaeline Oyen, Anne-Siri Levin, Bruce Che, Xiaoyu Hirtz, Deborah Reichborn-Kjennerud, Ted Schjolberg, Synnve Roth, Christine Magnus, Per Stoltenberg, Camilla Suren, Pal Hornig, Mady Lipkin, W. Ian TI Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring SO MSPHERE LA English DT Article DE autism; birth cohort; herpes simplex virus; infection; prenatal; serology ID EPSTEIN-BARR-VIRUS; CONGENITAL TOXOPLASMOSIS; INTRAUTERINE INFECTION; INFLAMMATORY CYTOKINES; AUTOIMMUNE-DISEASES; TYPE-2 INFECTION; AMNIOTIC-FLUID; PRETERM BIRTH; FETAL-DEATH; PREGNANCY AB Maternal infections during pregnancy are associated with risk of neuro-developmental disorders, including autism spectrum disorders (ASDs). Proposed pathogenetic mechanisms include fetal infection, placental inflammation, and maternal cytokines or antibodies that cross the placenta. The Autism Birth Cohort comprises mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaire screening, referrals, and linkages to a national patient registry, 442 mothers of children with ASD were identified, and 464 frequency-matched controls were selected. Immunoglobulin G (IgG) antibodies to Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), and HSV-2 in plasma collected at midpregnancy and after delivery were measured by multiplexed immunoassays. High levels of HSV-2 IgG antibodies in maternal midpregnancy plasma were associated with increased risk of ASD in male offspring (an increase in HSV-2 IgG levels from 240 to 640 arbitrary units/ml was associated with an odds ratio of 2.07; 95% confidence interval, 1.06 to 4.06; P = 0.03) when adjusted for parity and child's birth year. No association was found between ASD and the presence of IgG antibodies to Toxoplasma gondii, rubella virus, CMV, or HSV-1. Additional studies are needed to test for replicability of risk and specificity of the sex effect and to examine risk associated with other infections. IMPORTANCE The cause (or causes) of most cases of autism spectrum disorder is unknown. Evidence from epidemiological studies and work in animal models of neurodevelopmental disorders suggest that both genetic and environmental factors may be implicated. The latter include gestational infection and immune activation. In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy. C1 [Mahic, Milada; Mjaaland, Siri; Che, Xiaoyu; Hornig, Mady; Lipkin, W. Ian] Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY 10027 USA. [Mahic, Milada; Mjaaland, Siri; Bovelstad, Hege Marie; Gunnes, Nina; Oyen, Anne-Siri; Reichborn-Kjennerud, Ted; Schjolberg, Synnve; Roth, Christine; Magnus, Per; Stoltenberg, Camilla; Suren, Pal] Norwegian Inst Publ Hlth, Oslo, Norway. [Susser, Ezra; Bresnahan, Michaeline; Hornig, Mady; Lipkin, W. Ian] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY 10027 USA. [Susser, Ezra; Bresnahan, Michaeline] Columbia Univ, New York State Psychiat Inst, New York, NY USA. [Levin, Bruce] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Hirtz, Deborah] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Reichborn-Kjennerud, Ted] Univ Oslo, Inst Clin Med, Oslo, Norway. [Roth, Christine] Lovisenberg Hosp, Nic Waals Inst, Oslo, Norway. [Stoltenberg, Camilla] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Hirtz, Deborah] Univ Vermont, Coll Med, Dept Pediat Neurol, Burlington, VT USA. RP Lipkin, WI (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY 10027 USA.; Lipkin, WI (reprint author), Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY 10027 USA. EM wil2001@cumc.columbia.edu FU National Institutes of Health [NS47537, NS086122]; Jane Botsford Johnson foundation; Simons Foundation Autism Research Initiative; Norwegian Ministry of Health and Care Services; Norwegian Ministry of Education and Research; Research Council of Norway [189457, 190694, 196452] FX This work was supported by National Institutes of Health grants NS47537 and NS086122 (all authors), the Jane Botsford Johnson foundation (all authors), the Simons Foundation Autism Research Initiative (all authors), the Norwegian Ministry of Health and Care Services (M.M., S.M., H.M.B., N.G., A.-S.O., T.R.-K., S.S., C.R., P.M., C.S., and P.S.), the Norwegian Ministry of Education and Research (M.M., S.M., H.M.B., N.G., A.-S.O., T.R.-K., S.S., C.R., P.M., C.S., and P.S.), and Research Council of Norway grants 189457, 190694, and 196452 (M.M., S.M., H.M.B., N.G., A.-S.O., T.R.-K., S.S., C.R., P.M., C.S., and P.S.). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 69 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 2379-5042 J9 MSPHERE JI mSphere PD JAN PY 2017 VL 2 IS 1 AR e00016-17 DI 10.1128/mSphere.00016-17 PG 10 WC Microbiology SC Microbiology GA EL3WL UT WOS:000394549900005 ER PT J AU Song, KH Cho, H Kim, S Lee, HJ Oh, SJ Woo, SR Hong, SO Jang, HS Noh, KH Choi, CH Chung, JY Hewitt, SM Kim, JH Son, M Kim, SH Lee, BI Park, HC Bae, YK Kim, TW AF Song, K-H Cho, H. Kim, S. Lee, H-J Oh, S. J. Woo, S. R. Hong, S-O Jang, H. S. Noh, K. H. Choi, C. H. Chung, J-Y Hewitt, S. M. Kim, J-H Son, M. Kim, S-H Lee, B. I. Park, H-C Bae, Y-K Kim, T. W. TI API5 confers cancer stem cell-like properties through the FGF2-NANOG axis SO ONCOGENESIS LA English DT Article ID CERVICAL-CANCER; IMMUNE EVASION; SMALL-MOLECULE; APOPTOSIS; AAC-11; GROWTH; OVEREXPRESSION; IDENTIFICATION; EXPRESSION; INHIBITOR AB Immune selection drives the evolution of tumor cells toward an immune-resistant and cancer stem cell (CSC)-like phenotype. We reported that apoptosis inhibitor-5 (API5) acts as an immune escape factor, which has a significant role in controlling immune resistance to antigen-specific T cells, but its functional association with CSC-like properties remains largely unknown. In this study, we demonstrated for the first time that API5 confers CSC-like properties, including NANOG expression, the frequency of CD44-positive cells and sphere-forming capacity. Critically, these CSC-like properties mediated by API5 are dependent on FGFR1 signaling, which is triggered by E2F1-dependent FGF2 expression. Furthermore, we uncovered the FGF2-NANOG molecular axis as a downstream component of API5 signaling that is conserved in cervical cancer patients. Finally, we found that the blockade of FGFR signaling is an effective strategy to control API5(high) human cancer. Thus, our findings reveal a crucial role of API5 in linking immune resistance and CSC-like properties, and provide the rationale for its therapeutic application for the treatment of API5(+) refractory tumors. C1 [Song, K-H; Lee, H-J; Oh, S. J.; Woo, S. R.; Hong, S-O; Jang, H. S.; Noh, K. H.; Bae, Y-K; Kim, T. W.] Korea Univ, Grad Sch Med, Dept Biomed Sci, Lab Tumor Immunol, Seoul, South Korea. [Song, K-H; Lee, H-J; Oh, S. J.; Woo, S. R.; Hong, S-O; Jang, H. S.; Noh, K. H.; Kim, T. W.] Korea Univ, Dept Biochem, Coll Med, Seoul, South Korea. [Song, K-H; Lee, H-J; Oh, S. J.; Jang, H. S.; Kim, T. W.] Korea Univ, Dept Biomed Sci, Coll Med, Seoul, South Korea. [Cho, H.; Chung, J-Y; Hewitt, S. M.] NCI, Expt Pathol Lab, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Cho, H.; Kim, J-H] Yonsei Univ, Coll Med, Gangnam Severance Hosp, Dept Obstet & Gynecol, Seoul, South Korea. [Cho, H.; Kim, J-H] Yonsei Univ, Coll Med, Inst Womens Life Med Sci, Seoul, South Korea. [Kim, S.; Park, H-C] Korea Univ, Grad Sch Med, Ansan, South Korea. [Choi, C. H.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Obstet & Gynecol, Seoul, South Korea. [Son, M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Kim, S-H] KRIBB, Immunotherapy Res Ctr, Daejeon, South Korea. [Lee, B. I.] Natl Canc Ctr, Res Inst, Div Convergence Technol, Biomol Funct Res Branch, Goyang, South Korea. [Bae, Y-K] Natl Canc Ctr, Res Inst, Div Canc Biol, Comparat Biomed Res Branch, Goyang, South Korea. RP Bae, YK (reprint author), Natl Canc Ctr, Res Inst, Div Canc Biol, Comparat Biomed Res Branch, 323 Ilsan Ro, Goyang Si 10408, Gyeonggi Do, South Korea.; Kim, TW (reprint author), Korea Univ, Coll Med, Lab Tumor Immunol, Room 319,Moonsook Med Hall,73 Inchon Ro, Seoul 02841, South Korea. EM zebra@ncc.re.kr; twkim0421@korea.ac.kr FU National Research Foundation of Korea [NRF-2014R1A2A1A10054205, NRF-2013M3A9D3045881] FX This work was funded by the National Research Foundation of Korea (NRF-2014R1A2A1A10054205 and NRF-2013M3A9D3045881). NR 32 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 2157-9024 J9 ONCOGENESIS JI Oncogenesis PD JAN PY 2017 VL 6 AR e285 DI 10.1038/oncsis.2016.87 PG 13 WC Oncology SC Oncology GA EO1AI UT WOS:000396429500009 PM 28092370 ER PT J AU Dolinska, MB Kus, NJ Farney, SK Wingfield, PT Brooks, BP Sergeev, YV AF Dolinska, Monika B. Kus, Nicole J. Farney, S. Katie Wingfield, Paul T. Brooks, Brian P. Sergeev, Yuri V. TI Oculocutaneous albinism type 1: link between mutations, tyrosinase conformational stability, and enzymatic activity SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE oculocutaneous albinism; tyrosinase; genetic mutations; protein structure; protein stability; protein unfolding; protein purification ID HERMANSKY-PUDLAK-SYNDROME; RECESSIVE OCULAR ALBINISM; ENDOPLASMIC-RETICULUM; KOREAN PATIENTS; GENE-MUTATIONS; HUMAN HOMOLOG; MOUSE; LOCUS; FORM; OCA1 AB Oculocutaneous albinism type 1 ( OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. Two subtypes of OCA1 have been described: severe OCA1A with complete absence of tyrosinase activity and less severe OCA1B with residual tyrosinase activity. Here, we characterize the recombinant human tyrosinase intramelanosomal domain and mutant variants, which mimic genetic changes in both subtypes of OCA1 patients. Proteins were prepared using site-directed mutagenesis, expressed in insect larvae, purified by chromatography, and characterized by enzymatic activities, tryptophan fluorescence, and Gibbs free energy changes. The OCA1A mutants showed very low protein expression and protein yield and are enzymatically inactive. Mutants mimicking OCA1B were biochemically similar to the wild type, but exhibited lower specific activities and protein stabilities. The results are consistent with clinical data, which indicates that OCA1A mutations inactivate tyrosinase and result in severe phenotype, while OCA1B mutations partially inactivate tyrosinase and result in OCA1B albinism. C1 [Dolinska, Monika B.; Kus, Nicole J.; Farney, S. Katie; Brooks, Brian P.; Sergeev, Yuri V.] NEI, NIH, Bethesda, MD 20892 USA. [Wingfield, Paul T.] Natl Inst Artritis & Musculoskeletal & Skin Dis, NIH, Bethesda, MD USA. RP Sergeev, YV (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM sergeevy@nei.nih.gov NR 59 TC 0 Z9 0 U1 3 U2 3 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD JAN PY 2017 VL 30 IS 1 BP 41 EP 52 DI 10.1111/pcmr.12546 PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA EK5HJ UT WOS:000393957200008 PM 27775880 ER PT J AU Gao, Y Cao, ZJ Yang, X Abdelmegeed, MA Sun, JC Chen, S Beger, RD Davis, K Salminen, WF Song, BJ Mendrick, DL Yu, LR AF Gao, Yuan Cao, Zhijun Yang, Xi Abdelmegeed, Mohamed A. Sun, Jinchun Chen, Si Beger, Richard D. Davis, Kelly Salminen, William F. Song, Byoung-Joon Mendrick, Donna L. Yu, Li-Rong TI Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Acetaminophen; Heme oxygenase 1 (HMOX1); Hepatotoxicity; MS ID MITOCHONDRIAL PERMEABILITY TRANSITION; UNITED-STATES; IN-VIVO; QUANTITATIVE PROTEOMICS; THERAPEUTIC TARGET; OXIDATIVE STRESS; PROTEIN ADDUCT; MOUSE-LIVER; TOXICITY; RATS AB Purpose: Overdose of acetaminophen (APAP) is a major cause of acute liver failure. This study was aimed to identify pathways related to hepatotoxicity and potential biomarkers of liver injury. Experimental design: Rats were treated with low (100 mg/kg) and high (1250 mg/kg) doses of APAP, and liver tissues at 6 and 24 h post-treatment were analyzed using a proteomic approach of 16O/18O labeling and 2D-LC-MS/MS. Results: Molecular pathways evolved progressively from scattered and less significant perturbations to more focused and significant alterations in a dose-and time-dependent manner upon APAP treatment. Imbalanced expression of hemeoxygenase 1 (HMOX1) and biliverdin reductase A (BLVRA) was associated with hepatotoxicity. Protein abundance changes of a total of 31 proteins were uniquely correlated to liver damage, among which a dramatic increase of HMOX1 levels in plasma was observed. Liver injury-associated significant elevation of plasma HMOX1 was further validated in mice treated with APAP. Conclusions and clinical relevance: This study unveiled molecular changes associated with APAP-induced liver toxicity at the pathway levels and identified HMOX1 as a potential plasma biomarker of liver injury. C1 [Gao, Yuan; Cao, Zhijun; Yang, Xi; Sun, Jinchun; Beger, Richard D.; Salminen, William F.; Mendrick, Donna L.; Yu, Li-Rong] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Abdelmegeed, Mohamed A.; Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD USA. [Chen, Si] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Davis, Kelly] US FDA, Toxicol Pathol Associates, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Yu, LR (reprint author), US FDA, Biomarkers & Alternat Models Branch, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 233, Jefferson, AR 72079 USA. EM Lirong.Yu@fda.hhs.gov FU National Center for Toxicological Research, U.S. Food and Drug Administration (NCTR/FDA), Jefferson, Arkansas; National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland FX This study was supported with funds from the National Center for Toxicological Research, U.S. Food and Drug Administration (NCTR/FDA), Jefferson, Arkansas, and in part with the Intramural funds from National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland. The information in this article is not a formal dissemination of information by FDA and does not represent agency position or policy. NR 72 TC 0 Z9 0 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1862-8346 EI 1862-8354 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD JAN PY 2017 VL 11 IS 1-2 AR UNSP 1600123 DI 10.1002/prca.201600123 PG 17 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO0NM UT WOS:000396394800008 ER PT J AU Gru, AA Jaffe, ES AF Gru, Alejandro A. Jaffe, Elaine S. TI The Landscape of Cutaneous Lymphomas in 2016, An Introduction SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Editorial Material ID B-CELL LYMPHOMA; MYCOSIS-FUNGOIDES; SEZARY-SYNDROME; CLASSIFICATION; NEOPLASMS; PAPULOSIS C1 [Gru, Alejandro A.] Univ Virginia, Charlottesville, VA USA. [Jaffe, Elaine S.] Ctr Canc Res, NCI, Pathol Lab, Hematopathol Sect, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), Ctr Canc Res, NCI, Pathol Lab, Hematopathol Sect, Bethesda, MD 20892 USA. NR 19 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 0740-2570 EI 1930-1111 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD JAN PY 2017 VL 34 IS 1 BP 1 EP 2 DI 10.1053/j.semdp.2016.11.010 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA EP1VI UT WOS:000397172000001 PM 27989527 ER PT J AU Gru, AA Jaffe, ES AF Gru, Alejandro A. Jaffe, Elaine S. TI Cutaneous EBV-related lymphoproliferative disorders SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE Extranodal NW-cell lymphoma; EBV plus mucocutaneous ulcer; Hydroa vacciniforme; Chronic active EBV infection ID EPSTEIN-BARR-VIRUS; NK/T-CELL LYMPHOMA; POSITIVE MUCOCUTANEOUS ULCER; VACCINIFORME-LIKE LYMPHOMA; OF-THE-LITERATURE; CATENIN GENE-MUTATIONS; PERIPHERAL T-CELL; ANGIOCENTRIC IMMUNOPROLIFERATIVE LESIONS; COMPARATIVE GENOMIC HYBRIDIZATION; ORGAN TRANSPLANT RECIPIENTS AB This article will focus on the cutaneous lymphoproliferative disorders associated with EBV, with an emphasis on the upcoming changes in the revised 4th Edition of the WHO classification of tumors of the hematopoietic system, many of which deal with cutaneous disorders derived from NK-cells or T-cells. Extranodal NK/T-cell lymphoma usually presents in the upper aerodigestive tract, but can involve the skin secondarily. EBV-associated T- and NK-cell lymphoproliferative disorders (LPD) in the pediatric age group include the systemic diseases, chronic active EBV infection (CAEBV) and systemic EBV+ T-cell lymphoma of childhood. Hydroa vacciniforme (HV)-like LPD is a primarily cutaneous form of CAEBV and encompasses the lesions previously referred to as HV and HV-like lymphoma (HVLL). All the T/NK-cellEBV-associated diseases occur with higher frequency in Asians, and indigenous populations from Central and South America and Mexico. Among the B-cell EBV-associated LPD two major changes have been introduced in the WHO. The previously designated EBV-positive diffuse large B-cell lymphoma (EBVDLBCL) of the elderly, has been changed to EBV-DLBCL with 'not otherwise specified' as a modifier (NOS). A new addition to the WHO system is the more recently identified EBV+ mucocutaneous ulcer, which involves skin and mucosal-associated sites. (C) 2017 Elsevier Inc. All rights reserved. C1 [Gru, Alejandro A.] Univ Virginia, Hematopathol Sect, Pathol & Dermatol, Charlottesville, VA 22903 USA. [Gru, Alejandro A.] Univ Virginia, Dermatopathol Sect, Pathol & Dermatol, Charlottesville, VA USA. [Jaffe, Elaine S.] Natl Canc Inst, Hematopathol, Bethesda, MD USA. RP Gru, AA (reprint author), Univ Virginia, Hematopathol Sect, Pathol & Dermatol, Charlottesville, VA 22903 USA.; Gru, AA (reprint author), Univ Virginia, Dermatopathol Sect, Pathol & Dermatol, Charlottesville, VA USA. EM aag4b@virginia.edu NR 222 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 0740-2570 EI 1930-1111 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD JAN PY 2017 VL 34 IS 1 BP 60 EP 75 DI 10.1053/j.semdp.2016.11.003 PG 16 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA EP1VI UT WOS:000397172000007 PM 27988064 ER PT J AU Bellucci, G Chernyak, S Hoffman, M Deshpande, G Dal Monte, O Knutson, KM Grafman, J Krueger, F AF Bellucci, Gabriele Chernyak, Sergey Hoffman, Morris Deshpande, Gopikrishna Dal Monte, Olga Knutson, Kristine M. Grafman, Jordan Krueger, Frank TI Effective connectivity of brain regions underlying third-party punishment: Functional MRI and Granger causality evidence SO SOCIAL NEUROSCIENCE LA English DT Article DE Third-party punishment; social cognition; prefrontal cortex; temporal pole; effective connectivity ID EVENT-RELATED FMRI; MEDIAL PREFRONTAL CORTEX; NEURAL BASIS; SOCIAL COGNITION; TEXT COMPREHENSION; DECISION-MAKING; JUSTICE; NORMS; METAANALYSIS; INTUITIONS AB Third-party punishment (TPP) for norm violations is an essential deterrent in large-scale human societies, and builds on two essential cognitive functions: evaluating legal responsibility and determining appropriate punishment. Despite converging evidence that TPP is mediated by a specific set of brain regions, little is known about their effective connectivity (direction and strength of connections). Applying parametric event-related functional MRI in conjunction with multivariate Granger causality analysis, we asked healthy participants to estimate how much punishment a hypothetical perpetrator deserves for intentionally committing criminal offenses varying in levels of harm. Our results confirmed that TPP legal decisions are based on two domain-general networks: the mentalizing network for evaluating legal responsibility and the central-executive network for determining appropriate punishment. Further, temporal pole (TP) and dorsomedial prefrontal cortex (PFC) emerged as hubs of the mentalizing network, uniquely generating converging output connections to ventromedial PFC, temporo-parietal junction, and posterior cingulate. In particular, dorsomedial PFC received inputs only from TP and both its activation and its connectivity to dorsolateral PFC correlated with degree of punishment. This supports the hypothesis that dorsomedial PFC acts as the driver of the TPP activation pattern, leading to the decision on the appropriate punishment. In conclusion, these results advance our understanding of the organizational elements of the TPP brain networks and provide better insights into the mental states of judges and jurors tasked with blaming and punishing legal wrongs. C1 [Bellucci, Gabriele; Chernyak, Sergey; Krueger, Frank] George Mason Univ, Mol Neurosci Dept, Fairfax, VA 22030 USA. [Bellucci, Gabriele] Humboldt Univ, Berlin Sch Mind & Brain, Berlin, Germany. [Hoffman, Morris] Second Judicial Dist, Denver, CO USA. [Hoffman, Morris] John D & Catherine T MacArthur Fdn Res Network La, Nashville, TN USA. [Deshpande, Gopikrishna] Auburn Univ, Dept Elect & Comp Engn, AU MRI Res Ctr, Auburn, AL 36849 USA. [Deshpande, Gopikrishna] Auburn Univ, Dept Psychol, Auburn, AL 36849 USA. [Dal Monte, Olga] Yale Univ, Dept Psychol, New Haven, CT USA. [Knutson, Kristine M.] NINDS, Behav Neurol Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Grafman, Jordan] Rehabil Inst Chicago, Brain Injury Res Program, Chicago, IL 60611 USA. [Krueger, Frank] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. RP Krueger, F (reprint author), George Mason Univ, Dept Psychol, Mol Neurosci Dept, 4400 Univ Dr,Mail Stop 2A1, Fairfax, VA 22030 USA. EM FKrueger@gmu.edu FU Intramural Research Program of the CNS/ NINDS/ NIH FX The work was supported by the Intramural Research Program of the CNS/ NINDS/ NIH. NR 71 TC 0 Z9 0 U1 4 U2 4 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1747-0919 EI 1747-0927 J9 SOC NEUROSCI-UK JI Soc. Neurosci. PY 2017 VL 12 IS 2 BP 124 EP 134 DI 10.1080/17470919.2016.1153518 PG 11 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA EM1ST UT WOS:000395098000003 PM 26942651 ER PT J AU Rigo, P De Pisapia, N Bornstein, MH Putnick, DL Serra, M Esposito, G Venuti, P AF Rigo, Paola De Pisapia, Nicola Bornstein, Marc H. Putnick, Diane L. Serra, Mauro Esposito, Gianluca Venuti, Paola TI Brain processes in women and men in response to emotive sounds SO SOCIAL NEUROSCIENCE LA English DT Article DE Infant and adult crying; adult sensitivity; behavior; default mode network ID STIMULUS-INDEPENDENT THOUGHT; DEFAULT MODE NETWORK; SEX-DIFFERENCES; RESTING-STATE; PHYSIOLOGICAL REACTIVITY; SELF-REFLECTION; WORKING-MEMORY; INFANT CRIES; BABY-CRY; TASK AB Adult appropriate responding to salient infant signals is vital to child healthy psychological development. Here we investigated how infant crying, relative to other emotive sounds of infant laughing or adult crying, captures adults' brain resources. In a sample of nulliparous women and men, we investigated the effects of different sounds on cerebral activation of the default mode network (DMN) and reaction times (RTs) while listeners engaged in self-referential decision and syllabic counting tasks, which, respectively, require the activation or deactivation of the DMN. Sounds affect women and men differently. In women, infant crying deactivated the DMN during the self-referential decision task; in men, female adult crying interfered with the DMN during the syllabic counting task. These findings point to different brain processes underlying responsiveness to crying in women and men and show that cerebral activation is modulated by situational contexts in which crying occurs. C1 [Rigo, Paola; De Pisapia, Nicola; Serra, Mauro; Esposito, Gianluca; Venuti, Paola] Univ Trento, Dept Psychol & Cognit Sci, Via Matteo Ben 5-B, Trento, Italy. [Rigo, Paola; Bornstein, Marc H.; Putnick, Diane L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Esposito, Gianluca] Nanyang Technol Univ, Div Psychol, Singapore, Singapore. RP Rigo, P (reprint author), Univ Trento, Dept Psychol & Cognit Sci, Via Matteo Ben 5-B, Trento, Italy. EM paola.rigo@unitn.it OI Putnick, Diane/0000-0002-6323-749X; De Pisapia, Nicola/0000-0002-1089-8841 FU Intramural Research Program of the NIH, NICHD FX This research was partially supported by the Intramural Research Program of the NIH, NICHD. NR 80 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1747-0919 EI 1747-0927 J9 SOC NEUROSCI-UK JI Soc. Neurosci. PY 2017 VL 12 IS 2 BP 150 EP 162 DI 10.1080/17470919.2016.1150341 PG 13 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA EM1ST UT WOS:000395098000005 PM 26905380 ER PT J AU Hunsberger, S Proschan, MA AF Hunsberger, Sally Proschan, Michael A. TI Simple Approaches to Analyzing Self-Controlled Case Series (SCCS) Data SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Case control; Guillain-Barre Syndrome; Scan statistics; Vaccine studies ID GUILLAIN-BARRE-SYNDROME; INFLUENZA VACCINE; ASSOCIATION AB Adverse events that occur at moderate rates can be identified during the development of vaccines. When large populations are vaccinated, new rare adverse events can be observed. Determining whether an observed adverse event is related to a vaccine poses statistical issues. Cohort studies can be biased when comparing vaccinated and unvaccinated cohorts. In self-controlled case series designs, each case acts as his or her own control, eliminating the potential bias between vaccinated and unvaccinated participants in a cohort study. The comparison is whether there is an excess of events close to the time of vaccination versus later in time fromthe vaccination. In this design, one must specify a time point where the excess risk from the vaccine is thought to be over. We explore the effect of misspecifying this time point and develop analysis methods that do not require the specification of the time point. Power and Type I error rates of different analysis methods are simulated. C1 [Hunsberger, Sally; Proschan, Michael A.] NIAID, Biostat Res Branch, Rockville, MD 20852 USA. RP Hunsberger, S (reprint author), NIAID, Biostat Res Branch, Rockville, MD 20852 USA. EM sallyh@mail.nih.gov NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PY 2017 VL 9 IS 1 BP 65 EP 72 DI 10.1080/19466315.2016.1206034 PG 8 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA EP3BV UT WOS:000397258400007 ER PT J AU Song, KH Fan, AC Hinkle, JJ Newman, J Borden, MA Harvey, BK AF Song, Kang-Ho Fan, Alexander C. Hinkle, Joshua J. Newman, Joshua Borden, Mark A. Harvey, Brandon K. TI Microbubble gas volume: A unifying dose parameter in blood-brain barrier opening by focused ultrasound SO THERANOSTICS LA English DT Article DE ultrasound contrast agent; drug delivery; gene therapy; pharmacokinetics ID IN-VIVO; ADENOASSOCIATED VIRUS; TARGETED DELIVERY; DRUG-DELIVERY; GENE-THERAPY; DISRUPTION; DEPENDENCE; MICE; PERSISTENCE; SIZE AB Focused ultrasound with microbubbles is being developed to transiently, locally and noninvasively open the blood-brain barrier (BBB) for improved pharmaceutical delivery. Prior work has demonstrated that, for a given concentration dose, microbubble size affects both the intravascular circulation persistence and extent of BBB opening. When matched to gas volume dose, however, the circulation half-life was found to be independent of microbubble size. In order to determine whether this holds true for BBB opening as well, we independently measured the effects of microbubble size (2 vs. 6 mu m diameter) and concentration, covering a range of overlapping gas volume doses (1-40 mu L/kg). We first demonstrated precise targeting and a linear dose-response of Evans Blue dye extravasation to the rat striatum for a set of constant microbubble and ultrasound parameters. We found that dye extravasation increased linearly with gas volume dose, with data points from both microbubble sizes collapsing to a single line. A linear trend was observed for both the initial sonication (R-2=0.90) and a second sonication on the contralateral side (R-2=0.68). Based on these results, we conclude that microbubble gas volume dose, not size, determines the extent of BBB opening by focused ultrasound (1 MHz, similar to 0.5 MPa at the focus). This result may simplify planning for focused ultrasound treatments by constraining the protocol to a single microbubble parameter - gas volume dose - which gives equivalent results for varying size distributions. Finally, using optimal parameters determined for Evan Blue, we demonstrated gene delivery and expression using a viral vector, dsAAV1-CMV-EGFP, one week after BBB disruption, which allowed us to qualitatively evaluate neuronal health. C1 [Song, Kang-Ho; Fan, Alexander C.; Borden, Mark A.] Univ Colorado, Dept Mech Engn, 1111 Engn Dr, Boulder, CO 80309 USA. [Song, Kang-Ho; Fan, Alexander C.; Hinkle, Joshua J.; Newman, Joshua; Harvey, Brandon K.] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. RP Borden, MA (reprint author), Univ Colorado, Dept Mech Engn, 1111 Engn Dr, Boulder, CO 80309 USA.; Harvey, BK (reprint author), Natl Inst Drug Abuse, Glia Neuron Interact Unit, Suite 200,Room 06A729,251 Bayview Blvd, Baltimore, MD 21224 USA. EM mark.borden@colorado.edu; bharvey@mail.nih.gov FU University of Colorado Boulder; Intramural Research Program at the National Institute on Drug Abuse FX This work was supported by the University of Colorado Boulder and the Intramural Research Program at the National Institute on Drug Abuse. We would like to thank Mr. Pyry Koivula, Julie Necarsulmer and Dr. Yajun Zhang for lending their expertise in animal procedures, and Dr. Leslie Whitaker for assistance with vibratome preparation of brain slices. NR 27 TC 0 Z9 0 U1 1 U2 1 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2017 VL 7 IS 1 BP 144 EP 152 DI 10.7150/thno.15987 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO2VK UT WOS:000396553900013 PM 28042323 ER PT J AU Yang, XY Wang, Z Zhang, FW Zhu, GZ Song, JB Teng, GJ Niu, G Chen, XY AF Yang, Xiangyu Wang, Zhe Zhang, Fuwu Zhu, Guizhi Song, Jibin Teng, Gao-Jun Niu, Gang Chen, Xiaoyuan TI Mapping Sentinel Lymph Node Metastasis by Dual-probe Optical Imaging SO THERANOSTICS LA English DT Article DE metastasis; sentinel lymph node; optical imaging; hyaluronic acid; EGFR; HER2 ID BREAST-CANCER; MOLECULAR-MECHANISMS; PROSTATE-CANCER; RECEPTOR; BIOPSY; CARCINOMA; LYVE-1; LYMPHANGIOGENESIS; NANOPARTICLES; HYALURONAN AB Purpose: Sentinel lymph node biopsy (SLNB) has emerged as the preferred standard procedure in patients with breast cancer, melanoma and other types of cancer. Herein, we developed a method to intra-operatively map SLNs and differentiate tumor metastases within SLNs at the same time, with the aim to provide more accurate and real-time intraoperative guidance. Experimental Design: Hyaluronic acid (HA), a ligand of lymphatic vessel endothelial hyaluronan receptor (LYVE)-1, is employed as a SLN mapping agent after being conjugated with a near-infrared fluorophore (Cy5.5). Different sized HAs (5, 10 and 20K) were tested in normal mice and mice with localized inflammation to optimize LN retention time and signal to background ratio. Cetuximab, an antibody against epidermal growth factor receptor (EGFR), and trastuzumab, an antibody against human epidermal growth factor receptor 2 (HER2), were labeled with near-infrared fluorophore (IRDye800) for detecting metastatic tumors. LN metastasis model was developed by hock injection of firefly luciferase engineered human head neck squamous carcinoma cancer UM-SCC-22B cells or human ovarian cancer SKOV-3 cells. The metastases within LNs were confirmed by bioluminescence imaging (BLI). IRDye800-Antibodies were intravenously administered 24 h before local administration of Cy5.5-HA. Optical imaging was then performed to identify nodal metastases. Results: Binding of HA with LYVE-1 was confirmed by ELISA and fluorescence staining. HA with a size of 10K was chosen based on the favorable migration and retention profile. After sequential administration of IRDye800-antibodies intravenously and Cy5.5-HA locally to a mouse model with LN metastases and fluorescence optical imaging, partially metastasized LNs were successfully distinguished from un-metastasized LNs and fully tumor occupied LNs, based on the different signal patterns. Conclusions: Fluorophore conjugated HA is a potential lymphatic mapping agent for SLNB. Dual-tracer imaging with the combination of lymphatic mapping agents and tumor targeting agents can identify tumor metastases within SLNs, thus may provide accurate and real-time intra-operative guidance to spare the time spent waiting for a biopsy result. C1 [Yang, Xiangyu; Teng, Gao-Jun] Southeast Univ, Zhongda Hosp, Sch Med, Dept Radiol,Jiangsu Key Lab Mol Imaging & Funct I, Nanjing 210009, Jiangsu, Peoples R China. [Yang, Xiangyu; Wang, Zhe; Zhang, Fuwu; Zhu, Guizhi; Song, Jibin; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Teng, GJ (reprint author), 87 Dingjiaqiao Rd, Nanjing 210009, Jiangsu, Peoples R China.; Niu, G; Chen, XY (reprint author), 35A Convent Dr Rm GD959, Bethesda, MD 20892 USA. EM gjteng@vip.sina.com; niug@mail.nih.gov; shawn.chen@nih.gov FU Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX The research was supported by the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 44 TC 0 Z9 0 U1 3 U2 3 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2017 VL 7 IS 1 BP 153 EP 163 DI 10.7150/thno.17085 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO2VK UT WOS:000396553900014 PM 28042324 ER PT J AU Yu, Y Sikorski, P Smith, M Bowman-Gholston, C Cacciabeve, N Nelson, KE Pieper, R AF Yu, Yanbao Sikorski, Patricia Smith, Madeline Bowman-Gholston, Cynthia Cacciabeve, Nicolas Nelson, Karen E. Pieper, Rembert TI Comprehensive Metaproteomic Analyses of Urine in the Presence and Absence of Neutrophil-Associated Inflammation in the Urinary Tract SO THERANOSTICS LA English DT Article DE urine; clinical proteomics; urothelial cells; label-free quantitation; urinary tract infection; neutrophils; inflammation; network analysis; shotgun proteomics; urine sediment ID HOST-PATHOGEN INTERACTIONS; MASS-SPECTROMETRY; BIOMARKER DISCOVERY; PROTEOMIC ANALYSIS; SAMPLE PREPARATION; BLADDER-CANCER; QUANTITATIVE PROTEOMICS; CLINICAL PROTEOMICS; INFECTION; PROTEINS AB Inflammation in the urinary tract results in a urinary proteome characterized by a high dynamic range of protein concentrations and high variability in protein content. This proteome encompasses plasma proteins not resorbed by renal tubular uptake, renal secretion products, proteins of immune cells and erythrocytes derived from trans-urothelial migration and vascular leakage, respectively, and exfoliating urothelial and squamous epithelial cells. We examined how such proteins partition into soluble urine (SU) and urinary pellet (UP) fractions by analyzing 33 urine specimens 12 of which were associated with a urinary tract infection (UTI). Using mass spectrometry-based metaproteomic approaches, we identified 5,327 non-redundant human proteins, 2,638 and 4,379 of which were associated with SU and UP fractions, respectively, and 1,206 non-redundant protein orthology groups derived from pathogenic and commensal organisms of the urogenital tract. Differences between the SU and UP proteomes were influenced by local inflammation, supported by respective comparisons with 12 healthy control urine proteomes. Clustering analyses showed that SU and UP fractions had proteomic signatures discerning UTIs, vascular injury, and epithelial cell exfoliation from the control group to varying degrees. Cases of UTI revealed clusters of proteins produced by activated neutrophils. Network analysis supported the central role of neutrophil effector proteins in the defense against invading pathogens associated with subsequent coagulation and wound repair processes. Our study expands the existing knowledge of the urinary proteome under perturbed conditions, and should be useful as reference dataset in the search of biomarkers. C1 [Yu, Yanbao; Sikorski, Patricia; Smith, Madeline; Nelson, Karen E.; Pieper, Rembert] J Craig Venter Inst, 9714 Med Ctr Dr, Rockville, MD 20850 USA. [Bowman-Gholston, Cynthia] Quest Diagnost Shady Grove Adventist Hosp, 9901 Med Ctr Dr, Rockville, MD 20850 USA. [Cacciabeve, Nicolas] Adv Pathol Associates LLC, Shady Grove Adventist Hosp, 9901 Med Ctr Dr, Rockville, MD 20850 USA. [Sikorski, Patricia] NIAID, Parasit Dis Lab, NIH, 4 Mem Dr, Bethesda, MD 20892 USA. [Sikorski, Patricia] Georgetown Univ, Dept Microbiol & Immunol, 3900 Reservoir Rd,NW, Washington, DC 20057 USA. RP Yu, Y; Pieper, R (reprint author), J Craig Venter Inst, 9714 Med Ctr Dr, Rockville, MD 20850 USA. EM yayu@jcvi.org; rpieper@jcvi.org OI Yu, Yanbao/0000-0003-2994-1974 FU National Institute of General Medical Sciences, National Institutes of Health [5R01GM103598-02]; J. Craig Venter Institute FX We thank the National Institute of General Medical Sciences, National Institutes of Health, via grant 5R01GM103598-02, the J. Craig Venter Institute, and Dr. J. Craig Venter for funding the study. We thank the Ruggles Family Foundation for a contribution to fund the mass spectrometer used for the research. We thank Tamara Tsitrin for technical assistance in the laboratory, Dr. Harinder Singh for assistance with bioinformatics analyses, and David Haft for discussions on network analysis methods. The funding bodies did not have a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript. NR 63 TC 1 Z9 1 U1 0 U2 0 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2017 VL 7 IS 2 BP 238 EP 252 DI 10.7150/thno.16086 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO2WE UT WOS:000396555900001 PM 28042331 ER PT J AU Sun, XL Yan, XF Jacobson, O Sun, WJ Wang, ZT Tong, X Xia, YQ Ling, DS Chen, XY AF Sun, Xiaolian Yan, Xuefeng Jacobson, Orit Sun, Wenjing Wang, Zhantong Tong, Xiao Xia, Yuqiong Ling, Daishun Chen, Xiaoyuan TI Improved Tumor Uptake by Optimizing Liposome Based RES Blockade Strategy SO THERANOSTICS LA English DT Article DE Reticuloendothelial system; Nanoparticle; Liposome blockade; Positron Emission Tomography; Enhanced tumor uptake ID DRUG-DELIVERY SYSTEMS; RETICULOENDOTHELIAL SYSTEM; CANCER-THERAPY; CLINICAL-APPLICATIONS; NANOPARTICLES; NANOMEDICINE; CLEARANCE; VESICLES AB Minimizing the sequestration of nanomaterials (NMs) by the reticuloendothelial system (RES) can enhance the circulation time of NMs, and thus increase their tumor-specific accumulation. Liposomes are generally regarded as safe (GRAS) agents that can block the RES reversibly and temporarily. With the help of positron emission tomography (PET), we monitored the in vivo tissue distribution of Cu-64-labeled 40 x 10 nm gold nanorods (Au NRs) after pretreatment with liposomes. We systematically studied the effectiveness of liposome administration by comparing (1) differently charged liposomes; (2) different liposome doses; and (3) varying time intervals between liposome dose and NR dose. By pre-injecting 400 mu mol/kg positively charged liposomes into mice 5 h before the Au NRs, the liver and spleen uptakes of Au NRs decreased by 30% and 53%, respectively. Significantly, U87MG tumor uptake of Au NRs increased from 11.5 +/- 1.1 % ID/g to 16.1 +/- 1.3 % ID/g at 27 h post-injection. Quantitative PET imaging is a valuable tool to understand the fate of NMs in vivo and cationic liposomal pretreatment is a viable approach to reduce RES clearance, prolong circulation, and improve tumor uptake. C1 [Sun, Xiaolian; Sun, Wenjing; Wang, Zhantong] Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361102, Peoples R China. [Sun, Xiaolian; Sun, Wenjing; Wang, Zhantong; Chen, Xiaoyuan] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361102, Peoples R China. [Sun, Xiaolian; Yan, Xuefeng; Jacobson, Orit; Wang, Zhantong; Tong, Xiao; Xia, Yuqiong; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomedicine LOMIN, NIH, Bethesda, MD 20892 USA. [Ling, Daishun] Zhejiang Univ, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Zhejiang, Peoples R China. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomedicine LOMIN, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov RI Ling, Daishun/J-4736-2014 OI Ling, Daishun/0000-0002-6814-7370 FU National Key Research and Development Program of China [2016YFA0203600]; National Natural Science Foundation of China [51502251, 81571743]; Fundamental Research Funds for Xiamen University [20720160067]; Science Foundation of Fujian Province [2014Y2004]; Intramural Research Program (IRP), National Institute of Biomedical Imaging (NIBIB), National Institutes of Health (NIH) FX This work was supported in part, by the National Key Research and Development Program of China (2016YFA0203600), National Natural Science Foundation of China (51502251, 81571743), Fundamental Research Funds for Xiamen University (20720160067), Science Foundation of Fujian Province (2014Y2004), and the Intramural Research Program (IRP), National Institute of Biomedical Imaging (NIBIB), National Institutes of Health (NIH). NR 38 TC 0 Z9 0 U1 4 U2 4 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2017 VL 7 IS 2 BP 319 EP 328 DI 10.7150/thno.18078 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO2WE UT WOS:000396555900007 PM 28042337 ER PT J AU Yang, SX Polley, EC Nguyen, D AF Yang, Sherry X. Polley, Eric C. Nguyen, Dat TI Association of gamma H2AX at Diagnosis with Chemotherapy Outcome in Patients with Breast Cancer SO THERANOSTICS LA English DT Article DE breast cancer; chemotherapy; gamma H2AX expression; overall survival; standard therapy ID CLINICAL-PRACTICE GUIDELINES; DNA-DAMAGE; AMERICAN SOCIETY; ONCOLOGY; THERAPY; RECOMMENDATIONS; METAANALYSIS; EXPRESSION; RELEVANCE; TAMOXIFEN AB gamma H2AX plays a role in DNA damage response signaling and facilitates the repair of DNA double strand breaks. However, it remains unknown whether constitutive tumor gamma H2AX expression is associated with treatment outcome in patients. gamma H2AX status was detected in primary tumors from 24% of 826 patients with stage I, II and III breast cancer by immunohistochemistry; overall survival was analyzed by Kaplan-Meier method. At median follow-up of 176 months (range 13 282 months), we found substantial survival heterogeneity in gamma H2AX-positive patients (P=0.002) among uniform treatment groups including radiation or endocrine therapy alone and no-treatment, as well as chemotherapy alone (being worst), in contrast to gamma H2AX-negative patients (P=0.2). In the chemotherapy group (n=118), median survival was 63 months (95% confidence interval [CI], 29-83) in patients with gamma H2AX-positive tumors compared with 170 months (95% CI 94-235) in those with gamma H2AX-negative tumors (P=0.0017). gamma H2AX remained a poor prognosis factor in the group by multivariable analysis (adjusted hazard ratio 2.12, P=0.009). Our data demonstrate that constitutive gamma H2AX positivity is significantly associated with survival heterogeneity in patients among uniform treatment groups, and its expression at diagnosis independently predicts poor chemotherapy outcome in breast cancer. C1 [Yang, Sherry X.; Nguyen, Dat] NCI, Natl Clin Target Validat Lab, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Polley, Eric C.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. RP Yang, SX (reprint author), 37 Convent Dr,Bldg 37,Room 1048, Bethesda, MD 20892 USA. EM Sherry.Yang@nih.gov FU Division of Cancer Treatment and Diagnosis (DCTD); National Cancer Institute, National Institutes of Health FX Supported in part by Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute, National Institutes of Health. We would like to thank patients who donated their breast cancer specimens for research, and the CBCTR physicians, pathologists and staff who acquired specimens and established the database. We are very grateful to the National Cancer Institute Cancer Diagnosis Program in DCTD for its design of the prognostic breast cancer tissue microarray and providing guidance. NR 30 TC 0 Z9 0 U1 0 U2 0 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2017 VL 7 IS 4 BP 945 EP 951 DI 10.7150/thno.19102 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO2XP UT WOS:000396559600012 PM 28382166 ER PT J AU Kim, YH Min, KH Wang, ZT Kim, JH Jacobson, O Huang, P Zhu, GZ Liu, YJ Yung, B Niu, G Chen, XY AF Kim, Young-Hwa Min, Kyung Hyun Wang, Zhantong Kim, Jihoon Jacobson, Orit Huang, Peng Zhu, Guizhi Liu, Yijing Yung, Bryant Niu, Gang Chen, Xiaoyuan TI Development of Sialic Acid-coated Nanoparticles for Targeting Cancer and Efficient Evasion of the Immune System SO THERANOSTICS LA English DT Article DE sialic acid (N-acetylneuraminic acid, Neu5Ac); anti-recognition effect; evading phagocytosis; lectin targeting; molecular imaging; positron emission tomography (PET) ID PROTEIN-TYROSINE PHOSPHATASES; POLYETHYLENE-GLYCOL; FACTOR-H; BINDING-SITE; CELLS; COMPLEMENT; DELIVERY; GLYCOSAMINOGLYCANS; DISCRIMINATION; MACROPHAGES AB Evading the reticuloendothelial system (RES) remains a critical challenge in the development of efficient delivery and diagnostic systems for cancer. Sialic acid (N-acetylneuraminic acid, Neu5Ac) is recognized as a "self" marker by major serum protein complement factor H and shows reduced interaction with the innate immune system via sialic acid-binding immunoglobulin-like lectin (Siglec), which is known as one of the significant regulators of phagocytic evasion. Accordingly, we prepared different surface-modified gold nanoparticles (AuNPs) and investigated the effects of sialic acid on cellular and immune responses of nanoparticles in vitro and in vivo. Sialic acid modification not only facilitates evasion of the RES by suppressing the immune response, but also enhances tumor accumulation via its active targeting ability. Therefore, sialic acid modification presents a promising strategy to advance nanotechnology towards the prospect of clinical translation. C1 [Kim, Young-Hwa; Min, Kyung Hyun; Wang, Zhantong; Kim, Jihoon; Jacobson, Orit; Zhu, Guizhi; Liu, Yijing; Yung, Bryant; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Huang, Peng] Shenzhen Univ, Sch Biomed Engn, Guangdong Key Lab Biomed Measurements & Ultrasoun, Shenzhen 518060, Peoples R China. RP Niu, G; Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM Gang.Niu@nih.gov; shawn.chen@nih.gov FU KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program); Korea Research Institute of Bioscience and Biotechnology, Republic of Korea; Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Global Innovative Research Center (GiRC) Program of the National Research Foundation of Korea [2012K1A1A2A01055811] FX This work was supported by a grant from the KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea, and the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). This research was also supported by the Global Innovative Research Center (GiRC) Program (2012K1A1A2A01055811) of the National Research Foundation of Korea. NR 44 TC 0 Z9 0 U1 2 U2 2 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2017 VL 7 IS 4 BP 962 EP 973 DI 10.7150/thno.19061 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO2XP UT WOS:000396559600014 PM 28382168 ER PT J AU Jiang, Y Cao, Y Wang, YB Li, W Liu, XY Lv, YX Li, XL Mi, J AF Jiang, Yang Cao, Yuan Wang, Yongbin Li, Wei Liu, Xinyi Lv, Yixuan Li, Xiaoling Mi, Jun TI Cysteine transporter SLC3A1 promotes breast cancer tumorigenesis SO THERANOSTICS LA English DT Article DE solute carrier SLC3A1; breast cancer; ROS; cysteine; PDK1 ID CYSTINE TRANSPORTER; CELL-PROLIFERATION; REDOX REGULATION; IN-VIVO; EXPRESSION; PROTEIN; SYSTEM; KIDNEY; SULFASALAZINE; INACTIVATION AB Cysteine is an essential amino acid for infants, aged people as well as patients with metabolic disorders. Although the thiol group of cysteine side chain is active in oxidative reactions, the role of cysteine in cancer remains largely unknown. Here, we report that the expression level of the solute carrier family 3, member 1 (SLC3A1), the cysteine carrier, tightly correlated with clinical stages and patients' survival. Elevated SLC3A1 expression accelerated the cysteine uptake and the accumulation of reductive glutathione (GSH), leading to reduced reactive oxygen species (ROS). ROS increased the stability and activity of PP2Ac, resulting in decreased AKT activity. Hence, SLC3A1 activated the AKT signaling through inhibiting PP2A phosphatase activity. Consistently, overexpression of SLC3A1 enhanced tumorigenesis of breast cancer cells, whereas blocking SLC3A1 either with specific siRNA or SLC3A1 specific inhibitor sulfasalazine suppressed tumor growth and also abolished dietary NAC-promoted tumor growth. Collectively, our data demonstrate that SLC3A1 promotes cysteine uptake and determines cellular response to antioxidant N-acetylcysteine, suggesting SLC3A1 is a potential therapeutic target for breast cancer. C1 [Jiang, Yang; Cao, Yuan; Wang, Yongbin; Liu, Xinyi; Lv, Yixuan; Mi, Jun] Shanghai Jiao Tong Univ, Sch Med, Chinese Minist Educ, Key Lab Cell Differentiat & Apoptosis, 280 South Choongqing Rd, Shanghai 200025, Peoples R China. [Jiang, Yang] Dalian Med Univ, Inst Canc Stem Cell, 9 West South Lvshun Rd, Dalian 116044, Liaoning, Peoples R China. [Li, Wei] Soochow Univ, Affiliated Hosp 1, 188 Shizi Rd, Suzhou 215006, Jiangsu, Peoples R China. [Li, Xiaoling] NIEHS, NIH, 111 TW Alexander Dr,Rall Bldg, Res Triangle Pk, NC 27709 USA. RP Mi, J (reprint author), Shanghai Jiao Tong Univ, Sch Med, Chinese Minist Educ, Key Lab Cell Differentiat & Apoptosis, 280 South Choongqing Rd, Shanghai 200025, Peoples R China. EM jmei@sjtu.edu.cn FU National Program on Key Basic Research Project (973 Program) [2012CB910102]; Shanghai Committee of Science and Technology [11DZ2260200]; National Science Foundation of China [81372194, 81572300] FX We are grateful to Dr. Zhaoyuan Hou and Dr. Xuemei Tong (Shanghai Jiao Tong University School of Medicine) for valuable discussions. This study was supported by grants from the National Program on Key Basic Research Project (973 Program) (2012CB910102), the Shanghai Committee of Science and Technology (11DZ2260200), and the National Science Foundation of China (81372194) (81572300) to Dr. Mi. NR 34 TC 0 Z9 0 U1 0 U2 0 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2017 VL 7 IS 4 BP 1036 EP 1046 DI 10.7150/thno.18005 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO2XP UT WOS:000396559600020 PM 28382174 ER PT J AU Eisenberg, MH Street, RL Persky, S AF Eisenberg, Miriam H. Street, Richard L., Jr. Persky, Susan TI "It runs in my family ... ": The association of perceived family history with body dissatisfaction and weight bias internalization among overweight women SO WOMEN & HEALTH LA English DT Article DE Biological attributions for weight; body acceptance; family history of overweight; race; weight bias internalization ID OBESITY; STIGMA; PEOPLE; SIZE; DISORDER; IMAGE; GIRLS; GAIN; WELL AB Aspects of poor body acceptance (BA), such as internalized weight bias and dissatisfaction with one's shape and size, are the strongest predictors of disordered eating and are associated with reduced engagement in healthy behaviors. Perceiving oneself as having a family history of overweight (PFH) could boost BA by increasing attributions for inherited, biological causes of weight. A community sample of 289 women who were overweight from the Washington, DC metropolitan area who were dissatisfied with their current weight (68% Black; 32% White) enrolled in this study in 2012. PFH of overweight was associated with decreased internalized weight bias among white women and marginally increased body shape satisfaction generally. The relationship between PFH and BA was not explained by biological attributions for weight. Perceptions that overweight runs in one's family can be protective with respect to BA. This is suggestive of the potential benefit of integrating family-based approaches into weight management interventions. C1 [Eisenberg, Miriam H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B13B, Rockville, MD 20892 USA. [Street, Richard L., Jr.] Texas A&M Univ, Dept Commun, College Stn, TX USA. [Street, Richard L., Jr.] Baylor Coll Med, Dept Med, Houston Ctr Qual Care & Utilizat Studies, Sect Hlth Serv Res, Houston, TX 77030 USA. [Persky, Susan] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Eisenberg, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B13B, Rockville, MD 20892 USA. EM miriam.eisenberg@nih.gov OI Eisenberg, Miriam/0000-0002-7133-8805 FU National Human Genome Research Institute, National Institutes of Health; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. M.H.E's time was also partially supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. This work is based on data collected in the Immersive Virtual Environment Testing Area of the Social and Behavioral Research Branch, NHGRI, NIH. NR 43 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0363-0242 EI 1541-0331 J9 WOMEN HEALTH JI Women Health PY 2017 VL 57 IS 4 BP 478 EP 493 DI 10.1080/03630242.2016.1170095 PG 16 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA EP3XN UT WOS:000397315100005 PM 27015259 ER PT J AU Hibbert, D Aboshaiqah, AE Sienko, KA Forestell, D Harb, AW Yousuf, SA Kelley, PW Brennan, PF Serrant, L Leary, A AF Hibbert, Denise Aboshaiqah, Ahmad E. Sienko, Kathy A. Forestell, Debra Harb, Adel W. Yousuf, Shadia A. Kelley, Patricia W. Brennan, Patricia F. Serrant, Laura Leary, Alison TI Advancing Nursing Practice: The Emergence of the Role of Advanced Practice Nurse in Saudi Arabia SO ANNALS OF SAUDI MEDICINE LA English DT Article ID SPECIALIST AB BACKGROUND: The roots of advanced practice nursing (APN) can be traced back to the 1890s, but the nurse practitioner (NP) emerged in Western countries during the 1960s in response to the unmet healthcare needs of populations in rural areas. These early NPs utilized the medical model of care to assess, diagnose and treat. Nursing has since grown as a profession, with its own unique and distinguishable, holistic, science-based knowledge, which is complementary within the multidisciplinary team. Today, APNs demonstrate nursing expertise in clinical practice, education, research and leadership, and are no longer perceived as "physician replacements" or assistants. Saudi Arabia has yet to define, legislate or regulate APN. AIMS: This article aims to disseminate information from a Saudi APN thought leadership meeting, to chronicle the history of APN within Saudi Arabia, while identifying strategies for moving forward. CONCLUSION: It is important to build an APN model based on Saudi healthcare culture and patient population needs, while recognizing global historical underpinnings. Ensuring that nursing continues to distinguish itself from other healthcare professions, while securing a seat at the multidisciplinary healthcare table will be instrumental in advancing the practice of nursing. C1 [Hibbert, Denise] King Faisal Specialist Hosp & Res Ctr, Colorectal Therapy Unit, POB 3354, Riyadh 11211, Saudi Arabia. [Aboshaiqah, Ahmad E.] King Saud Univ, Coll Nursing, Riyadh, Saudi Arabia. [Sienko, Kathy A.] Aldara Hosp & Med Ctr, Nursing Affairs, Riyadh, Saudi Arabia. [Forestell, Debra] King Faisal Specialist Hosp & Res Ctr, Dept Nursing, Riyadh, Saudi Arabia. [Harb, Adel W.] Secur Forces Hosp Program, Dept Nursing, Riyadh, Saudi Arabia. [Yousuf, Shadia A.] King Abdulaziz Univ, Fac Nursing, Jeddah, Saudi Arabia. [Kelley, Patricia W.] Duquesne Univ, Fac Nursing, Pittsburgh, PA 15219 USA. [Brennan, Patricia F.] NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Serrant, Laura] Sheffield Hallam Univ, Fac Hlth & Wellbeing, Dept Nursing, Sheffield, S Yorkshire, England. [Leary, Alison] London South Bank Univ, Dept Hlth & Social Care, London, England. RP Hibbert, D (reprint author), King Faisal Specialist Hosp & Res Ctr, Colorectal Therapy Unit, POB 3354, Riyadh 11211, Saudi Arabia. EM denisehibbert@gmail.com NR 37 TC 0 Z9 0 U1 1 U2 1 PU K FAISAL SPEC HOSP RES CENTRE PI RIYADH PA PUBLICATIONS OFFICE PO BOX 3354, RIYADH 11211, SAUDI ARABIA SN 0256-4947 EI 1319-9226 J9 ANN SAUDI MED JI Ann. Saudi Med. PD JAN-FEB PY 2017 VL 37 IS 1 BP 72 EP 78 DI 10.5144/0256-4947.2017.72 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA EO4QE UT WOS:000396678600011 PM 28151460 ER PT J AU Epel, B Halpern, HJ AF Epel, Boris Halpern, Howard J. TI Imaging SO EMAGRES LA English DT Article DE electron paramagnetic resonance; imaging; oxygen imaging; pH imaging; redox imaging; image reconstruction; EPR instrumentation; EPR methodology; spin probes ID ELECTRON-PARAMAGNETIC-RESONANCE; NUCLEAR-MAGNETIC-RESONANCE; TIME-DOMAIN EPR; IN-VIVO; SPIN-PROBE; NONINVASIVE MEASUREMENT; TUMOR OXYGENATION; TRITYL RADICALS; CYCLING HYPOXIA; 250 MHZ AB EPR imaging is a well-established method for the study of the spatial distribution and the local environment of electron paramagnetic centers (PC) and spin probes. Although conceptually similar to nuclear MRI, EPR imaging did not receive widespread use due to relatively low availability of endogenous electron PC, especially in vivo. However, the development of injectable spin probes sensitive to various physiological parameters allowed EPR imaging to become a valuable tool for preclinical studies. One of the most important applications of modern EPR imaging is in vivo oximetry. Partial oxygen pressure (pO(2)) levels in tumors are major determinants of the response to cancer therapy and thus need thorough investigation. Other areas of EPR imaging application are imaging pH, thio-redox potentials, and polymer degradation. C1 [Epel, Boris] Univ Chicago, Dept Radiat & Cellular Oncol, Ctr EPR Imaging Vivo Physiol, Chicago, IL 60637 USA. Univ Chicago, NIBIB, NIH, Ctr EPR Imaging In Vivo Physiol, Chicago, IL 60637 USA. RP Epel, B (reprint author), Univ Chicago, Dept Radiat & Cellular Oncol, Ctr EPR Imaging Vivo Physiol, Chicago, IL 60637 USA. FU NIH [P41 EB 002034, R01 CA 098575, R50 CA211408] FX This work was supported by NIH grants P41 EB 002034, R01 CA 098575 and R50 CA211408. NR 101 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2055-6101 J9 EMAGRES JI eMagRes PY 2017 VL 6 IS 1 BP 149 EP 160 DI 10.1002/9780470034590.emrstm1512 PG 12 WC Spectroscopy SC Spectroscopy GA EO3RJ UT WOS:000396611600010 ER PT J AU Veronese, P Bogana, G Cerutti, A Yeo, L Romero, R Gervasi, MT AF Veronese, Paola Bogana, Gianna Cerutti, Alessia Yeo, Lami Romero, Roberto Gervasi, Maria Teresa TI A Prospective Study of the Use of Fetal Intelligent Navigation Echocardiography (FINE) to Obtain Standard Fetal Echocardiography Views SO FETAL DIAGNOSIS AND THERAPY LA English DT Article DE 4D ultrasound; Cardiac screening; Fetal heart; Prenatal diagnosis; Spatiotemporal image correlation; STIC; STICLoop (TM); Ultrasound; Virtual Intelligent Sonographer Assistance; VIS-Assistance (R) ID SPATIOTEMPORAL IMAGE CORRELATION; CONGENITAL HEART-DISEASE; ACQUIRE CARDIAC VOLUMES; PRENATAL-DIAGNOSIS; 4-DIMENSIONAL ULTRASOUND; GREAT-ARTERIES; 3-DIMENSIONAL ULTRASOUND; INTERVENTRICULAR SEPTUM; SONOGRAPHIC EXAMINATION; ANTENATAL DIAGNOSIS AB Objective: To evaluate the performance of Fetal Intelligent Navigation Echocardiography (FINE) applied to spatiotemporal image correlation (STIC) volume datasets of the normal fetal heart in generating standard fetal echocardiography views. Methods: In this prospective cohort study of patients with normal fetal hearts (19-30 gestational weeks), one or more STIC volume datasets were obtained of the apical four chamber view. Each STIC volume successfully obtained was evaluated by STICLoop (TM) to determine its appropriateness before applying the FINE method. Visualization rates for standard fetal echocardiography views using diagnostic planes and/or Virtual Intelligent Sonographer Assistance (VIS-Assistance (R)) were calculated. Results: One or more STIC volumes (total n = 463) were obtained from 246 patients. A single STIC volume per patient was analyzed using the FINE method. In normal cases, FINE was able to generate nine fetal echocardiography views using: (1) diagnostic planes in 76-100% of the cases, (2) VIS-Assistance (R) in 96-100% of the cases, and (3) a combination of diagnostic planes and/or VISAssistance (R) in 96-100% of the cases. Conclusion: FINE applied to STIC volumes can successfully generate nine standard fetal echocardiography views in 96-100% of cases in the 2nd and 3rd trimesters. This suggests that the technology can be used as a method of screening for congenital heart disease. (C) 2016 S. Karger AG, Basel C1 [Veronese, Paola; Bogana, Gianna; Gervasi, Maria Teresa] AOP, Dept Womens & Childrens Hlth, Unit Maternal Fetal Med, Padua, Italy. [Cerutti, Alessia] AOP, Dept Womens & Childrens Hlth, Unit Pediat Cardiol, Padua, Italy. [Yeo, Lami; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Yeo, Lami; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Yeo, Lami] Wayne State Univ, Hutzel Womens Hosp, Sch Med, Detroit Med Ctr, Detroit, MI 48202 USA. [Yeo, Lami] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. RP Yeo, L (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS Hutzel Womens Hosp, 3990 John R 4 Brush, Detroit, MI 48201 USA. EM lyeo@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Department of Health and Human Services (NICHD/NIH/DHHS) FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Department of Health and Human Services (NICHD/NIH/DHHS). NR 71 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1015-3837 EI 1421-9964 J9 FETAL DIAGN THER JI Fetal Diagn. Ther. PY 2017 VL 41 IS 2 BP 89 EP 99 DI 10.1159/000446982 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EO0KN UT WOS:000396386800002 PM 27309391 ER PT J AU Hooker, GW Umstead, KL Lewis, KL Koehly, LK Biesecker, LG Biesecker, BB AF Hooker, Gillian W. Umstead, Kendall L. Lewis, Katie L. Koehly, Laura K. Biesecker, Leslie G. Biesecker, Barbara B. TI Engagement and communication among participants in the ClinSeq Genomic Sequencing Study SO GENETICS IN MEDICINE LA English DT Article ID PRECAUTION ADOPTION PROCESS; 1ST-DEGREE RELATIVES; PATIENT ENGAGEMENT; RANDOMIZED-TRIAL; DECISION AID; CANCER; RISK; IMPACT; BEHAVIOR; DISEASE AB Purpose: As clinical genome sequencing expand its reach, understanding how individuals engage with this process are of critical importance. In this study, we aimed to describe internal engagement and its correlates among a ClinSeq cohort of adults consented to genome sequencing and receipt of results. Methods: This study was framed using the precaution adoption process model (PAPM), in which knowledge predicts engagement and engagement predicts subsequent behaviors. Prior to receipt of sequencing results, 630 participants in the study completed a baseline survey. Engagement was assessed as the frequency with which participants thought about their participation in ClinSeq since enrollment. Results: Results were consistent with the PAPM: those with higher genomics knowledge reported higher engagement (r = 0.13, P = 0.001) and those who were more engaged reported more frequent communication with their physicians (r = 0.28, P < 0.001) and family members (r = 0.35, P < 0.001) about ClinSeq. Characteristics of those with higher engagement included poorer overall health (r = -0.13, P = 0.002), greater seeking of health information (r = 0.16, P < 0.001), and more recent study enrollment (r = -0.21, P < 0.001). Conclusion: These data support the importance of internal engagement in communication related to genomic sequencing. C1 [Hooker, Gillian W.; Umstead, Kendall L.; Biesecker, Barbara B.] NHGRI, Genet Serv Res Unit, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Lewis, Katie L.; Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Koehly, Laura K.] NHGRI, Social Network Methods Sect, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Hooker, Gillian W.] NextGxDx Inc, Franklin, TN USA. RP Biesecker, BB (reprint author), NHGRI, Genet Serv Res Unit, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. EM barbarab@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health FX The authors thank the dedicated ClinSeq participants who completed the baseline survey. This research was funded by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. An earlier version of this analysis was presented by Dr Hooker at the National Society of Genetic Counselors in Anaheim, California, October 2013. NR 38 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 JAN PY 2017 VL 19 IS 1 BP 98 EP 103 DI 10.1038/gim.2016.71 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA EH6VD UT WOS:000391911100014 PM 27763633 ER PT J AU Chandler, RJ Williams, IM Gibson, AL Davidson, CD Incao, AA Hubbard, BT Porter, FD Pavan, WJ Venditti, CP AF Chandler, Randy J. Williams, Ian M. Gibson, Alana L. Davidson, Cristin D. Incao, Arturo A. Hubbard, Brandon T. Porter, Forbes D. Pavan, William J. Venditti, Charles P. TI Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1 SO HUMAN MOLECULAR GENETICS LA English DT Article ID SPINAL MUSCULAR-ATROPHY; CHOLESTEROL HOMEOSTASIS; NPC1 PROTEIN; MOUSE MODELS; DELIVERY; NEURODEGENERATION; TRAFFICKING; NEURONS; CYCLODEXTRIN; PROGRESSION AB Niemann-Pick disease, type C1 (NPC1) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. A murine model of NPC1 disease (Npc1(-/-)) displays a rapidly progressing form of NPC1 disease which is characterized by weight loss, ataxia, increased cholesterol storage, loss of cerebellar Purkinje neurons and early lethality. To test the potential efficacy of gene therapy for NPC1, we constructed adeno-associated virus serotype 9 (AAV9) vectors to deliver the NPC1 gene under the transcriptional control of the neuronal-specific (CamKII) or a ubiquitous (EF1a) promoter. The Npc1(-/-) mice that received a single dose of AAV9-CamKII-NPC1 as neonates (2.6 x 10(11)GC) or at weaning (1.3 x 10(12)GC), and the mice that received a single dose of AAV9-EF1a-NPC1 at weaning (1.2 x 10(12)GC), exhibited an increased life span, characterized by delayed weight loss and diminished motor decline. Cholesterol storage and Purkinje neuron loss were also reduced in the central nervous system of AAV9 treated Npc1(-/-) mice. Treatment with AAV9-EF1a-NPC1, as compared to AAV9-CamKII-NPC1, resulted in significantly increased survival (mean survival increased from 69 days to 166 and 97 days, respectively) and growth, and reduced hepatic-cholesterol accumulation. Our results provide the first demonstration that gene therapy may represent a therapeutic option for NPC1 patients and suggest that extraneuronal NPC1 expression can further augment the lifespan of the Npc1(-/-) mice after systemic AAV gene delivery. C1 [Chandler, Randy J.; Hubbard, Brandon T.; Venditti, Charles P.] NHGRI, Med Genom & Metab Genet Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Williams, Ian M.; Porter, Forbes D.] NICHHD, Eunice Kennedy Shriver, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gibson, Alana L.; Incao, Arturo A.; Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Davidson, Cristin D.] Albert Einstein Coll Med, Intellectual & Dev Disabil Res Ctr, Rose F Kennedy Ctr, Dominick P Purpura Dept Neurosci, Bronx, NY 10467 USA. RP Pavan, WJ (reprint author), NHGRI, Genet Dis Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA.; Venditti, CP (reprint author), NHGRI, Med Genom & Metab Genet Branch, NIH, Bldg 10 Room 7N248A, Bethesda, MD 20892 USA. EM bpavan@mail.nih.gov; venditti@mail.nih.gov RI Davidson, Cristin/F-4889-2017 OI Davidson, Cristin/0000-0002-5508-8113 FU Intramural Research Program of the National Human Genome Research Institute; Intramural Research Program of the National Institute of Child Health and Human Development; Support of Accelerated Research for Niemann-Pick C (Dana's Angels Research Trust, The Hide & Seek Foundation for Lysosomal Disease Research, Fight NPC); Liferay Foundation; Ara Parseghian Medical Research Foundation (APMRF) FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute, the Intramural Research Program of the National Institute of Child Health and Human Development, Support of Accelerated Research for Niemann-Pick C (Dana's Angels Research Trust, The Hide & Seek Foundation for Lysosomal Disease Research, Fight NPC), Liferay Foundation and Ara Parseghian Medical Research Foundation (APMRF). NR 45 TC 1 Z9 1 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 1 PY 2017 VL 26 IS 1 BP 52 EP 64 DI 10.1093/hmg/ddw367 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EP0GG UT WOS:000397064600005 PM 27798114 ER PT J AU Akins, MR Berk-Rauch, HE Kwan, KY Mitchell, ME Shepard, KA Korsak, LIT Stackpole, EE Warner-Schmidt, JL Sestan, N Cameron, HA Fallon, JR AF Akins, Michael R. Berk-Rauch, Hanna E. Kwan, Kenneth Y. Mitchell, Molly E. Shepard, Katherine A. Korsak, Lulu I. T. Stackpole, Emily E. Warner-Schmidt, Jennifer L. Sestan, Nenad Cameron, Heather A. Fallon, Justin R. TI Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains SO HUMAN MOLECULAR GENETICS LA English DT Article ID OLFACTORY MARKER PROTEIN; MENTAL-RETARDATION; PRESYNAPTIC FMRP; RECEPTOR NEURONS; SENSORY NEURONS; BETA-CATENIN; MOUSE MODEL; RATS; MICE; BULB AB Local mRNA translation in growing axons allows for rapid and precise regulation of protein expression in response to extrinsic stimuli. However, the role of local translation in mature CNS axons is unknown. Such a mechanism requires the presence of translational machinery and associated mRNAs in circuit-integrated brain axons. Here we use a combination of genetic, quantitative imaging and super-resolution microscopy approaches to show that mature axons in the mammalian brain contain ribosomes, the translational regulator FMRP and a subset of FMRP mRNA targets. This axonal translational machinery is associated with Fragile X granules (FXGs), which are restricted to axons in a stereotyped subset of brain circuits. FXGs and associated axonal translational machinery are present in hippocampus in humans as old as 57 years. This FXG-associated axonal translational machinery is present in adult rats, even when adult neurogenesis is blocked. In contrast, in mouse this machinery is only observed in juvenile hippocampal axons. This differential developmental expression was specific to the hippocampus, as both mice and rats exhibit FXGs in mature axons in the adult olfactory system. Experiments in Fmr1 null mice show that FMRP regulates axonal protein expression but is not required for axonal transport of ribosomes or its target mRNAs. Axonal translational machinery is thus a feature of adult CNS neurons. Regulation of this machinery by FMRP could support complex behaviours in humans throughout life. C1 [Akins, Michael R.; Mitchell, Molly E.; Shepard, Katherine A.; Korsak, Lulu I. T.] Drexel Univ, Dept Biol, Philadelphia, PA 19104 USA. [Akins, Michael R.; Berk-Rauch, Hanna E.; Stackpole, Emily E.; Fallon, Justin R.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Kwan, Kenneth Y.; Sestan, Nenad] Yale Sch Med, Dept Neurosci, New Haven, CT USA. [Kwan, Kenneth Y.; Sestan, Nenad] Yale Sch Med, Kavli Inst Neurosci, New Haven, CT USA. [Warner-Schmidt, Jennifer L.] Rockefeller Univ, Lab Mol & Cellular Neurosci, 1230 York Ave, New York, NY 10021 USA. [Cameron, Heather A.] NIMH, Sect Neuroplast, NIH, Bethesda, MD 20892 USA. [Kwan, Kenneth Y.] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Kwan, Kenneth Y.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. RP Akins, MR (reprint author), PISB 319,3245 Chestnut St, Philadelphia, PA 19104 USA. EM Michael.R.Akins@drexel.edu FU National Institutes of Health [R00 MH090237, R00 MH096939, P50 MH106934, U01 MH103339, R01 MH109904, R01 HD052083]; NIH, National Institute of Mental Health [ZIAMH002784] FX This work was supported by National Institutes of Health grants R00 MH090237 to MRA; R00 MH096939 to KYK; P50 MH106934, U01 MH103339, R01 MH109904 to NS; and R01 HD052083 to JRF. HAC was funded by the Intramural Program of the NIH, National Institute of Mental Health. Grant Number: ZIAMH002784. NR 70 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 1 PY 2017 VL 26 IS 1 BP 192 EP 209 DI 10.1093/hmg/ddw381 PG 18 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EP0GG UT WOS:000397064600016 PM 28082376 ER PT J AU Heymann, J Winkler, CA Hoek, M Susztak, K Kopp, JB AF Heymann, Jurgen Winkler, Cheryl A. Hoek, Maarten Susztak, Katalin Kopp, Jeffrey B. TI Therapeutics for APOL1 nephropathies: putting out the fire in the podocyte SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Review DE chronic kidney disease; focal segmental glomerulosclerosis; glomerulosclerosis; inflammation; podocytes ID ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; CHRONIC KIDNEY-DISEASE; RISK VARIANTS; AFRICAN-AMERICANS; PATHOGENESIS; INHIBITORS; POTASSIUM; ASSOCIATE; KINASES AB APOL1 nephropathies comprise a range of clinical and pathologic syndromes, which can be summarized as focal segmental glomerulosclerosis, in various guises, and arterionephrosclerosis, otherwise known as hypertensive kidney diseases. Current therapies for these conditions may achieve therapeutic targets, reduction in proteinuria and control of blood pressure, respectively, but often fail to halt the progressive decline in kidney function. It appears that current therapies fail to address certain underlying critical pathologic processes that are driven, particularly in podocytes and microvascular cells, by the APOL1 renal risk genetic variants. Mechanisms hypothesized to be responsible for APOL1 variant-associated cell injury can be summarized in five domains: increased APOL1 gene expression, activation of inflammasomes, activation of protein kinase R, electrolyte flux across plasma or intracellular membranes, and altered endolysosomal trafficking associated with endoplasmic reticulum stress. We briefly review the available evidence for these five mechanisms and suggest possible novel therapeutic approaches. C1 [Heymann, Jurgen; Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. [Winkler, Cheryl A.] NCI, Mol Genet Epidemiol Sect, Basic Res Lab,NIH, Basic Sci Program,Leidos Biomed Res,Frederick Nat, Frederick, MD 21701 USA. [Hoek, Maarten] Merck & Co Inc, Merck Res Labs, Kenilworth, NJ USA. [Susztak, Katalin] Univ Penn, Sch Med, Dept Med, Renal Electrolyte & Hypertens Div,Perelman Sch Me, Philadelphia, PA 19104 USA. RP Kopp, JB (reprint author), NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. EM Jbkopp@nih.gov FU NIDDK, NIH; NIDDK Intramural Research Program [ZO1 DK043308, RO1 DK105821]; Intramural Research Program of the NCI, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN26120080001E] FX This work was supported by NIDDK, NIH, including the NIDDK Intramural Research Program under ZO1 DK043308 and RO1 DK105821 to K.S. The work was also supported by Intramural Research Program of the NCI, Center for Cancer Research, in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. 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 appreciate the willingness of members of our laboratories to allow us to reference data that have only been published in abstract form. NR 43 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD JAN PY 2017 VL 32 SU 1 BP 65 EP 70 DI 10.1093/ndt/gfw402 PG 6 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA EO9RZ UT WOS:000397027100009 ER PT J AU Juberg, DR Knudsen, TB Sander, M Beck, NB Faustman, EM Mendrick, DL Fowle, JR Hartung, T Tice, RR Lemazurier, E Becker, RA Fitzpatrick, SC Daston, GP Harrill, A Hines, RN Keller, DA Lipscomb, JC Watson, D Bahadori, T Crofton, KM AF Juberg, Daland R. Knudsen, Thomas B. Sander, Miriam Beck, Nancy B. Faustman, Elaine M. Mendrick, Donna L. Fowle, John R., III Hartung, Thomas Tice, Raymond R. Lemazurier, Emmanuel Becker, Richard A. Fitzpatrick, Suzanne Compton Daston, George P. Harrill, Alison Hines, Ronald N. Keller, Douglas A. Lipscomb, John C. Watson, David Bahadori, Tina Crofton, Kevin M. TI FutureTox III: Bridges for Translation SO TOXICOLOGICAL SCIENCES LA English DT Article DE predictive toxicology; in vitro and alternatives; regulatory/policy; risk assessment; testing alternatives ID ESTROGEN-RECEPTOR; RISK-ASSESSMENT; TOXICITY; 21ST-CENTURY; TOXICOLOGY; EXPOSURE; CHEMICALS; VISION; MODELS; PRIORITIZATION AB Future Tox III, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2015. Building upon Future Tox I and II, Future Tox III was focused on developing the high throughput risk assessment paradigm and taking the science of in vitro data and in silico models forward to explore the question-what progress is being made to address challenges in implementing the emerging big-data toolbox for risk assessment and regulatory decision-making. This article reports on the outcome of the workshop including 2 examples of where advancements in predictive toxicology approaches are being applied within Federal agencies, where opportunities remain within the exposome and AOP domains, and how collectively the toxicology community across multiple sectors can continue to bridge the translation from historical approaches to Tox21 implementation relative to risk assessment and regulatory decision-making. C1 [Juberg, Daland R.] Dow AgroSci, Indianapolis, IN 46268 USA. [Knudsen, Thomas B.; Hines, Ronald N.; Crofton, Kevin M.] US EPA, Res Triangle Pk, NC 27711 USA. [Sander, Miriam] Page One Editorial Serv, Boulder, CO USA. [Beck, Nancy B.; Becker, Richard A.] Amer Chem Council, Washington, DC USA. [Faustman, Elaine M.] Univ Washington, Seattle, WA 98195 USA. [Mendrick, Donna L.] US FDA, Silver Spring, MD USA. [Fowle, John R., III] Sci Inform LLC, Pittsboro, NC USA. [Hartung, Thomas] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Tice, Raymond R.] NIEHS, Natl Toxicol Program, Durham, NC USA. [Lemazurier, Emmanuel] INERIS Chron Risk Div, Verneeuil En Halatte, France. [Fitzpatrick, Suzanne Compton] US FDA, College Pk, MD USA. [Daston, George P.] Procter & Gamble Co, Cincinnati, OH USA. [Harrill, Alison] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Keller, Douglas A.] Sanofi, Bridgewater, NJ USA. [Lipscomb, John C.] US EPA, Cincinnati, OH 45268 USA. [Watson, David] Lhasa Ltd, Leeds, W Yorkshire, England. [Bahadori, Tina] US EPA, Washington, DC 20460 USA. RP Juberg, DR (reprint author), Dow AgroSci, Indianapolis, IN 46268 USA. EM drjuberg@dow.com FU Society of Toxicology; Scientific Liaison Coalition; American Chemistry Council; Dow AgroSciences, LLC; Hamner Institutes for Health Sciences; Human Toxicology Project Consortium; Humane Society of the United States; National Institute of Environmental Health Sciences; U.S. Food and Drug Administration, Office of the Chief Scientist; National Center for Toxicological Reseach; Bayer Crop Science; NSF International; Syngenta Crop Protection LLC; TERA Center; University of Cincinnati; ToxServices; American Academy of Clinical Toxicology; American College of Toxicology; CAAT; Johns Hopkins Center for Alternatives to Animal Testing (CAAT); In Sphero; Lhasa Limited; Ramboll Environ; Safety Pharmacology Society; Society of Toxicologic Pathology; Teratology Society FX FutureTox III Sponsors included Society of Toxicology, Scientific Liaison Coalition, the American Chemistry Council, Dow AgroSciences, LLC, The Hamner Institutes for Health Sciences, Human Toxicology Project Consortium, The Humane Society of the United States, National Institute of Environmental Health Sciences, U.S. Food and Drug Administration, Office of the Chief Scientist and the National Center for Toxicological Reseach, Bayer Crop Science, NSF International, Syngenta Crop Protection LLC, TERA Center, University of Cincinnati, ToxServices, American Academy of Clinical Toxicology, American College of Toxicology, CAAT, Johns Hopkins Center for Alternatives to Animal Testing (CAAT), In Sphero, Lhasa Limited, Ramboll Environ, Safety Pharmacology Society, Society of Toxicologic Pathology, The Teratology Society. NR 41 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD JAN PY 2017 VL 155 IS 1 BP 22 EP 31 DI 10.1093/toxsci/kfw194 PG 10 WC Toxicology SC Toxicology GA EO9XL UT WOS:000397041300003 PM 27780885 ER PT J AU Ben-Avraham, D Karasik, D Verghese, J Lunetta, KL Smith, JA Eicher, JD Vered, R Deelen, J Arnold, AM Buchman, AS Tanaka, T Faul, JD Nethander, M Fornage, M Adams, HH Matteini, AM Callisaya, ML Smith, AV Yu, L De Jager, PL Evans, DA Gudnason, V Hofman, A Pattie, A Corley, J Launer, LJ Knopman, DS Parimi, N Turner, ST Bandinelli, S Beekman, M Gutman, D Sharvit, L Mooijaart, SP Liewald, DC Houwing-Duistermaat, JJ Ohlsson, C Moed, M Verlinden, VJ Mellstrom, D van der Geest, JN Karlsson, M Hernandez, D McWhirter, R Liu, YM Thomson, R Tranah, GJ Uitterlinden, AG Weir, DR Zhao, W Starr, JM Johnson, AD Ikram, MA Bennett, DA Cummings, SR Deary, IJ Harris, TB Kardia, SLR Mosley, TH Srikanth, VK Windham, BG Newman, AB Walston, JD Davies, G Evans, DS Slagboom, EP Ferrucci, L Kiel, DP Murabito, JM Atzmon, G AF Ben-Avraham, Dan Karasik, David Verghese, Joe Lunetta, Kathryn L. Smith, Jennifer A. Eicher, John D. Vered, Rotem Deelen, Joris Arnold, Alice M. Buchman, Aron S. Tanaka, Toshiko Faul, Jessica D. Nethander, Maria Fornage, Myriam Adams, Hieab H. Matteini, Amy M. Callisaya, Michele L. Smith, Albert V. Yu, Lei De Jager, Philip L. Evans, Denis A. Gudnason, Vilmundur Hofman, Albert Pattie, Alison Corley, Janie Launer, Lenore J. Knopman, Davis S. Parimi, Neeta Turner, Stephen T. Bandinelli, Stefania Beekman, Marian Gutman, Danielle Sharvit, Lital Mooijaart, Simon P. Liewald, David C. Houwing-Duistermaat, Jeanine J. Ohlsson, Claes Moed, Matthijs Verlinden, Vincent J. Mellstrom, Dan van der Geest, Jos N. Karlsson, Magnus Hernandez, Dena McWhirter, Rebekah Liu, Yongmei Thomson, Russell Tranah, Gregory J. Uitterlinden, Andre G. Weir, David R. Zhao, Wei Starr, John M. Johnson, Andrew D. Ikram, M. Arfan Bennett, David A. Cummings, Steven R. Deary, Ian J. Harris, Tamara B. Kardia, Sharon L. R. Mosley, Thomas H. Srikanth, Velandai K. Windham, Beverly G. Newman, Ann B. Walston, Jeremy D. Davies, Gail Evans, Daniel S. Slagboom, Eline P. Ferrucci, Luigi Kiel, Douglas P. Murabito, Joanne M. Atzmon, Gil TI The complex genetics of gait speed: genome-wide meta-analysis approach SO AGING-US LA English DT Article DE gait speed; meta-analysis; aging; GWAS ID QUANTITATIVE TRAIT LOCI; LOWER-EXTREMITY FUNCTION; TRANSCRIPT ISOFORM VARIATION; HUMAN PREFRONTAL CORTEX; MAXIMAL WALKING SPEED; OLDER WOMEN; WHOLE-BLOOD; PHYSICAL PERFORMANCE; REGULATORY VARIATION; MULTIPLE TISSUES AB Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta- analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging. C1 [Ben-Avraham, Dan; Atzmon, Gil] Albert Einstein Coll Med, Dept Med & Genet, Bronx, NY 10461 USA. [Karasik, David; Kiel, Douglas P.] Beth Israel Deaconess Med Ctr, Dept Med, Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA. [Karasik, David; Kiel, Douglas P.] Harvard Med Sch, Boston, MA 02131 USA. [Karasik, David] Bar Ilan Univ, Fac Med Galilee, Safed, Israel. [Verghese, Joe] Albert Einstein Coll Med, Montefiore Einstein Ctr Aging Brain, Integrated Div Cognit & Motor Aging Neurol, Bronx, NY 10461 USA. [Verghese, Joe] Albert Einstein Coll Med, Montefiore Einstein Ctr Aging Brain, Integrated Div Geriatr Med, Bronx, NY 10461 USA. [Lunetta, Kathryn L.; Eicher, John D.; Johnson, Andrew D.; Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Smith, Jennifer A.; Zhao, Wei; Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Eicher, John D.; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Framingham, MA 01702 USA. [Vered, Rotem] Univ Haifa, Dept Psychol, Haifa, Israel. [Deelen, Joris; Beekman, Marian; Moed, Matthijs; Slagboom, Eline P.] Leiden Univ, Med Ctr, Mol Epidemiol, Leiden, Netherlands. [Deelen, Joris] Max Planck Inst Biol Ageing, Cologne, Germany. [Arnold, Alice M.] Univ Washington, Dept Biostat, Seattle, WA 98115 USA. [Buchman, Aron S.; Yu, Lei; Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60614 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Faul, Jessica D.; Weir, David R.] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI 48104 USA. [Nethander, Maria] Univ Gothenburg, Sahlgrenska Acad, Bioinformat Core Facil, Gothenburg, Sweden. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Adams, Hieab H.; Hofman, Albert; Verlinden, Vincent J.; Ikram, M. Arfan] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Adams, Hieab H.; Ikram, M. Arfan] Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands. [Matteini, Amy M.; Walston, Jeremy D.] Johns Hopkins Med Inst, Div Geriatr Med, Baltimore, MD 21224 USA. [Callisaya, Michele L.; Srikanth, Velandai K.] Cent Clin Sch Frankston, Peninsula Clin Sch, Peninsula Hlth, Med, Melbourne, Vic, Australia. [Callisaya, Michele L.; McWhirter, Rebekah; Thomson, Russell; Srikanth, Velandai K.] Univ Tasmania, Inst Med Res, Hobart, Tas, Australia. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Iceland Heart Assoc, IS-101 Reykjavik, Iceland. [De Jager, Philip L.] Broad Inst Harvard & MIT, Cambridge, MA 02139 USA. [De Jager, Philip L.] Brigham & Womens Hosp, Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. [Evans, Denis A.] Rush Univ, Med Ctr, Rush Inst Hlth Aging, Chicago, IL 60612 USA. [Evans, Denis A.] Rush Univ, Med Ctr, Dept Internal Med, Chicago, IL 60612 USA. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Pattie, Alison; Corley, Janie; Deary, Ian J.; Davies, Gail] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Knopman, Davis S.] Mayo Clin, Rochester, MN 55905 USA. [Parimi, Neeta; Tranah, Gregory J.; Cummings, Steven R.; Evans, Daniel S.] Calif Pacific Med Ctr Res Inst, San Francisco, CA 94107 USA. [Turner, Stephen T.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN 55905 USA. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Mooijaart, Simon P.] Leiden Univ, Med Ctr, Gerontol & Geriatr, Leiden, Netherlands. [Liewald, David C.; Starr, John M.; Deary, Ian J.; Davies, Gail] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland. [Houwing-Duistermaat, Jeanine J.] Leiden Univ, Med Ctr, Genet Stat, Leiden, Netherlands. [Houwing-Duistermaat, Jeanine J.] Univ Leeds, Dept Stat, Leeds LS2 9JT, W Yorkshire, England. [Ohlsson, Claes; Mellstrom, Dan] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med & Clin Nutr, Gothenburg, Sweden. [van der Geest, Jos N.] Erasmus MC, Dept Neurosci, Rotterdam, Netherlands. [Karlsson, Magnus] Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Lund, Sweden. [Hernandez, Dena] NIA, Lab Neurogenet, Bethesda, MD 20892 USA. [Liu, Yongmei] Wake Forest Univ, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Thomson, Russell] Univ Western Sydney, Sch Comp Engn & Math, Penrith, NSW 1797, Australia. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Uitterlinden, Andre G.] NCHA, NGI, Rotterdam, Netherlands. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland. [Mosley, Thomas H.; Windham, Beverly G.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Newman, Ann B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Kiel, Douglas P.] Broad Inst Harvard & MIT, Boston, MA 02131 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Sect Gen Internal Med, Boston, MA 02118 USA. [Gutman, Danielle; Sharvit, Lital; Atzmon, Gil] Univ Haifa, Fac Nat Sci, Dept Human Biol, Haifa, Israel. RP Atzmon, G (reprint author), Albert Einstein Coll Med, Dept Med & Genet, Bronx, NY 10461 USA.; Murabito, JM (reprint author), NHLBI, Framingham Heart Study, Framingham, MA 01702 USA.; Murabito, JM (reprint author), Boston Univ, Sch Med, Dept Med, Sect Gen Internal Med, Boston, MA 02118 USA.; Atzmon, G (reprint author), Univ Haifa, Fac Nat Sci, Dept Human Biol, Haifa, Israel. EM murabito@bu.edu; gil.atzmon@einstein.yu.edu FU NIH [N01-AG-1-2100, 271201200022C, R01-HL093029]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005, HHSN268200782096C]; NIH Roadmap for Medical Research; Intramural Research Program of the NIH, National Institute on Aging; NHLBI [HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [AG023629]; CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; NIA [R01AG29451, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1, RC2 AG036495, RC4 AG039029]; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc [N02-HL-64278]; Robert Dawson Evans Endowment; Framingham Heart Study; NIAMS [RO1 AR41398]; National Institute on Aging [NIA U01AG009740]; "targeted project" by the Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336]; UK Biotechnology and Biological Sciences Research Council (BBSRC); Royal Society; Chief Scientist Office of the Scottish Government; Research Into Ageing; BBSRC; Medical Research Council (MRC); National Institutes of Health; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Research Resources (NCRR); NIH Roadmap for Medical Research [U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01AG027810, UL1 RR024140]; MrOS ancillary study 'Replication of candidate gene associations and bone strength phenotype in MrOS' [R01-AR051124]; National Institute on Aging grants [P30AG10161, R01AG17917, R01AG15819, R01AG30146, R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576]; Illinois Department of Public Health [R01NS078009]; Translational Genomics Research Institute; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation [050-060-810]; 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; Dutch Technology Foundation STW; Ministry of Economic Affairs; ZonMW [916.13.054]; National Health and Medical Research Council (NHMRC) of Australia; National Institutes of Health (NIH) USA; National Heart, Lung and Blood Institute [HL054457, HL087660, HL119443]; National Institute of Neurological Disorders and Stroke [NS041558]; European Union's Seventh Framework Programme (FP7) [259679]; Innovation-Oriented Research Program on Genomics [IGE05007]; Centre for Medical Systems Biology; Netherlands Consortium for Healthy Ageing [050-060-810]; Netherlands Organization for Scientific Research (NWO); Unilever Colworth; BBMRI-NL; Dutch government [NWO 184.021.007]; Swedish Research Council; Swedish government (under the Avtal om Lakarutbildning och Medicinsk Forskning [Agreement for Medical Education and Research]); Lundberg Foundation; Torsten Soderberg Foundation; Novo Nordisk Foundation; Knut and Alice Wallenberg Foundation; Erasmus Medical Center Rotterdam; Erasmus University, Rotterdam; [RC2ARO58973] FX This study has been funded by NIH contracts N01-AG1-2100 and 271201200022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study.; The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. This project was also partially supported from NIH grant R01-HL093029.; The BLSA was supported by the Intramural Research Program of the NIH, National Institute on Aging.; The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of CHS investigators and institutions can be found at http://chs-nhlbi.org/. 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 Framingham Heart Study phenotype-genotype analyses were supported by NIA R01AG29451 (JMM, KLL). The Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study Contract No. N01-HC-25195 and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-64278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using 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. The investigators thank the participants and the staff for their support of the Framingham Heart Study. Dr Kiel's effort was supported by NIAMS grant RO1 AR41398.; This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.; HRS is supported by the National Institute on Aging (NIA U01AG009740). Genotyping was funded separately by NIA (RC2 AG036495, RC4 AG039029). Our genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the Genetics Coordinating Center at the University of Washington.; 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).; We thank the cohort participants and team members who contributed to these studies. Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK The Disconnected Mind project). Genotyping of the cohorts was funded by the BBSRC. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged.; The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute on Aging (NIA), the National Center for Research Resources (NCRR), and NIH Roadmap for Medical Research under the following grant numbers: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01AG027810, and UL1 RR024140. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the MrOS ancillary study 'Replication of candidate gene associations and bone strength phenotype in MrOS' under the grant number R01-AR051124. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the MrOS ancillary study 'GWAS in MrOS and SOF' under the grant number RC2ARO58973.; The data from the Rush Alzheimer's Disease Center used in these analyses was supported by National Institute on Aging grants P30AG10161, R01AG17917, R01AG15819, R01AG30146, the Illinois Department of Public Health, R01NS078009 and the Translational Genomics Research Institute.; The generation and management of GWAS genotype data for the Rotterdam Study are 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. This research is supported by the Dutch Technology Foundation STW, which is part of the NWO, and which is partly funded by the Ministry of Economic Affairs. MAI is supported by ZonMW grant number 916.13.054.; The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576.; All participants and research staff who took part in TASCOG are duly acknowledged, in addition to funding bodies including the National Health and Medical Research Council (NHMRC) of Australia, and the National Institutes of Health (NIH) USA.; Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the National Heart, Lung and Blood Institute (HL054457, HL087660, HL119443) and the National Institute of Neurological Disorders and Stroke (NS041558) of the National Institutes of Health. Genotyping was performed at the Mayo Clinic (S.T.T, Mariza de Andrade, Julie Cunningham) and was made possible by the University of Texas Health Sciences Center (Eric Boerwinkle, Megan Grove-Gaona). We would also like to thank the families that participated in the GENOA study.; The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement number 259679. This study was financially supported by the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology and the Netherlands Consortium for Healthy Ageing (grant 050060-810), all in the framework of the Netherlands Genomics Initiative, Netherlands Organization for Scientific Research (NWO), by Unilever Colworth and by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007).; This study was supported by the Swedish Research Council and by grants from the Swedish government (under the Avtal om Lakarutbildning och Medicinsk Forskning [Agreement for Medical Education and Research]), the Lundberg Foundation, the Torsten Soderberg Foundation, the Novo Nordisk Foundation and the Knut and Alice Wallenberg Foundation. NR 192 TC 0 Z9 0 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1945-4589 J9 AGING-US JI Aging-US PD JAN PY 2017 VL 9 IS 1 BP 209 EP 246 PG 38 WC Cell Biology SC Cell Biology GA EK8JW UT WOS:000394170800016 PM 28077804 ER PT J AU Mayer, JE Fontelo, P AF Mayer, Jonathan E. Fontelo, Paul TI Meta-analysis on the effect of text message reminders for HIV-related compliance SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE HIV; AIDS; compliance; text message; cell phones ID RANDOMIZED CONTROLLED-TRIAL; ANTIRETROVIRAL THERAPY ADHERENCE; MOBILE PHONE REMINDERS; SERVICE SMS TEXTS; APPOINTMENT REMINDERS; RURAL UGANDA; HIGHER RISK; CARE; INTERVENTION; SUPPORT AB For the treatment of HIV, compliance in regard to appointment attendance and medication usage is critical. Various methods have been attempted to increased HIV care compliance, and a method that has inspired many published studies is text message reminders. We conducted a meta-analysis of the literature from inception through May 2016 using the following databases: Pubmed, Embase, CINAHL, Web of Science, and Cochrane. Examples of terms used in the search included exploded versions of "HIV, "AIDS", "cell phone","SMS", "text message", "reminder". After abstract and manuscript review, articles were discussed with co-author and included based on consensus. We excluded qualitative analyses, observational studies without an intervention, and studies without a control or pre-intervention group. We used random-effects models to calculate odds ratios (OR) and standardized mean differences (SMDs) for the text message intervention. Thirty-four unique studies were found and included in the meta-analysis. For the seven articles relating to non-attendance, text message reminders significantly reduced the rates of nonattendance (OR, 0.66; 95% CI, 0.48-0.92; P = .01; I-2 = 52%). For the 20 articles on drug adherence, text message reminders significantly increased adherence (SMD, 0.87; 95% CI, 0.06-1.68; P = .04; I-2 = 99%). For the 11 articles with physiologic measures (CD4 count or viral load), text message reminders led to significant improvement (SMD, 1.53; 95% CI, 0.52-2.55; P = .003; I-2 = 99%). This meta-analysis reveals that text message reminders are a promising intervention that can be used to increase HIV care compliance when logistically feasible. Further study should focus on which populations benefit the most from this intervention, and successful implementers could create an established technological infrastructure for other clinics to adopt when seeking to boost compliance. C1 [Mayer, Jonathan E.] Johns Hopkins Univ, Sch Med, Johns Hopkins Bayview Med Ctr, Dept Med, 5200 Eastern Ave,Room 342, Baltimore, MD 21224 USA. [Fontelo, Paul] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD USA. RP Mayer, JE (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Bayview Med Ctr, Dept Med, 5200 Eastern Ave,Room 342, Baltimore, MD 21224 USA. EM jem361@mail.harvard.edu FU Intramural Research Program of the National Institutes of Health (NIH); National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM), and Lister Hill National Center for Biomedical Communications (LHNCBC). The views and opinions of the authors expressed herein do not necessarily state or reflect those of the National Library of Medicine, National Institutes of Health or the US Department of Health and Human Services. NR 54 TC 0 Z9 0 U1 4 U2 4 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PY 2017 VL 29 IS 4 BP 409 EP 417 DI 10.1080/09540121.2016.1214674 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA EL4UL UT WOS:000394616300001 PM 27477580 ER PT J AU Zablotsky, B Colpe, LJ Pringle, BA Kogan, MD Rice, C Blumberg, SJ AF Zablotsky, Benjamin Colpe, Lisa J. Pringle, Beverly A. Kogan, Michael D. Rice, Catherine Blumberg, Stephen J. TI Age of Parental Concern, Diagnosis, and Service Initiation Among Children With Autism Spectrum Disorder SO AJIDD-AMERICAN JOURNAL ON INTELLECTUAL AND DEVELOPMENTAL DISABILITIES LA English DT Article DE autism spectrum disorder; national surveys; diagnosis; epidemiology ID 1ST CONCERNS; IDENTIFICATION; TODDLERS; ACCESS; SURVEILLANCE; SEVERITY; CARE AB Children with autism spectrum disorder (ASD) require substantial support to address the core symptoms of ASD and co-occurring behavioral/developmental conditions. This study explores the early diagnostic experiences of school-aged children with ASD using survey data from a large probability-based national sample. Multivariate linear regressions were used to examine age when parent reported developmental concern to doctor, received ASD diagnosis, and first obtained services. Children whose parents had concerns about their child's verbal communication reported earlier ages for all outcomes when compared to children of parents who did not have verbal communication concerns. Children whose parents had concerns about their child's nonverbal communication or unusual gestures/ movements received an earlier diagnosis than children whose parents did not have these specific concerns. C1 [Zablotsky, Benjamin; Blumberg, Stephen J.] Natl Ctr Hlth Stat, Hyattsville, MD USA. [Colpe, Lisa J.; Pringle, Beverly A.] Natl Inst Mental Hlth, Bethesda, MD USA. [Kogan, Michael D.] Maternal & Child Hlth Bur, Ottawa, ON, Canada. [Rice, Catherine] Emory Univ, Atlanta, GA 30322 USA. RP Zablotsky, B (reprint author), Natl Ctr Hlth Stat, Hyattsville, MD USA. EM bzablotsky@cdc.gov NR 46 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC INTELLECTUAL DEVELOPMENTAL DISABILITIES PI WASHINGTON PA 444 N CAPITOL ST, NW STE 846, WASHINGTON, DC 20001-1512 USA SN 1944-7515 EI 1944-7558 J9 AJIDD-AM J INTELLECT JI AJIDD-Am. J. Intellect. Dev. Disabil. PD JAN PY 2017 VL 122 IS 1 BP 49 EP 61 DI 10.1352/1944-7558-122.1.49 PG 13 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA EO2LM UT WOS:000396528000004 PM 28095057 ER PT J AU Doernberg, S Hull, SC AF Doernberg, Sam Hull, Sara Chandros TI Harms of Deception in FMR1 Premutation Genotype-Driven Recruitment SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 [Doernberg, Sam; Hull, Sara Chandros] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Hull, Sara Chandros] NHGRI, Bethesda, MD 20892 USA. RP Hull, SC (reprint author), NIH, Dept Clin Bioeth, Bldg 10,Suite 1C118,10 Ctr Dr,MSC 1156, Bethesda, MD 20892 USA. EM shull@mail.nih.gov NR 8 TC 0 Z9 0 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2017 VL 17 IS 4 BP 62 EP 63 DI 10.1080/15265161.2017.1284920 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EO9JS UT WOS:000397005600025 PM 28328354 ER PT J AU Doussau, A Hanmer, CB AF Doussau, Adelaide Hanmer, Clark B. TI A Rationale for Relaxing the Requirement to Undergo a Noncurative Chemotherapy for Advanced Cancer in a Phase I Immunotherapy Trial SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 [Doussau, Adelaide] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Doussau, A (reprint author), McGill Univ, Biomed Eth Unit, Montreal, PQ, Canada. EM adelaide.doussau@mail.mcgill.ca NR 4 TC 0 Z9 0 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2017 VL 17 IS 4 BP 68 EP 69 DI 10.1080/15265161.2017.1284922 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EO9JS UT WOS:000397005600028 PM 28328363 ER PT J AU Collier, E Danis, M AF Collier, Elaine Danis, Marion TI Participation of Citizen Scientists in Clinical Research and Access to Research Ethics Consultation SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material AB This case teaches us two important lessons. The first pertains to the valuable input that patients, prospective and active research participants, and others can provide to the research enterprise. The second pertains to the value of allowing patients as well as prospective and active research participants to request research ethics consultations. C1 [Collier, Elaine] Natl Ctr Adv Translat Sci, 6701 Democracy Blvd, Bethesda, MD 20892 USA. [Danis, Marion] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Collier, E (reprint author), Natl Ctr Adv Translat Sci, 6701 Democracy Blvd, Bethesda, MD 20892 USA. EM ec5x@nih.gov FU Office of Director, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH); intramural program of the NIH, particularly the Department of Bioethics at the NIH FX This work was funded in part by the Office of Director, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), and by the intramural program of the NIH, particularly the Department of Bioethics at the NIH. NR 9 TC 0 Z9 0 U1 2 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2017 VL 17 IS 4 BP 70 EP 72 DI 10.1080/15265161.2017.1284933 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EO9JS UT WOS:000397005600029 PM 28328379 ER PT J AU Thomas-White, KJ Kliethermes, S Rickey, L Lukacz, ES Richter, HE Moalli, P Zimmem, P Norton, P Kusek, JW Wolfe, AJ Brubaker, L AF Thomas-White, Krystal J. Kliethermes, Stephanie Rickey, Leslie Lukacz, Emily S. Richter, Holly E. Moalli, Pamela Zimmem, Philippe Norton, Peggy Kusek, John W. Wolfe, Alan J. Brubaker, Linda CA Natl Inst Diabet Digestive Kidney TI Evaluation of the urinary microbiota of women with uncomplicated stress urinary incontinence SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE bladder; estrogen; microbiome; stress urinary incontinence; urgency urinary incontinence ID ADULT FEMALE BLADDER; OVERACTIVE BLADDER; INFECTION; ESTROGEN; BACTERIA; WEIGHT AB BACKGROUND: Female urinary microbiota are associated with urgency urinary incontinence and response to medication. The urinary microbiota of women with stress urinary incontinence has not been described. OBJECTIVE: We sought to study the cross-sectional relationships between urinary microbiota features and demographic and clinical characteristics of women undergoing stress urinary incontinence surgery. STUDY DESIGN: Preoperative urine specimens were collected from women without urinary tract infection and were available from 197 women (174 voided, 23 catheterized) enrolled in a multicenter prospective randomized trial, the Value of Urodynamic Evaluation study. Demographic and clinical variables were obtained including stress and urgency urinary incontinence symptoms, menopausal status, and hormone use. The bacterial composition of the urine was qualitatively assessed by sequencing the bacterial 16S ribosomal RNA gene. Phylogenetic relatedness and microbial alpha diversity were compared to demographics and symptoms using generalized estimating equation models. RESULTS: The majority of 197 urine samples (86%) had detectable bacterial DNA. Bacterial diversity was significantly associated with higher body mass index (P =.02); increased Medical, Epidemiologic, and Social Aspects of Aging urge index score (P =.04); and hormonal status (P <.001). No associations were detected with stress urinary incontinence symptoms. Increased diversity was also associated with a concomitant lower frequency of Lactobacillus in hormone-negative women. CONCLUSION: Women undergoing stress urinary incontinence surgery have detectable urinary microbiota. This cross-sectional analysis revealed that increased diversity of the microbiota was associated with urgency urinary incontinence symptoms, hormonal status, and body mass index. In contrast, the female urinary microbiota were not associated with stress urinary incontinence symptoms. C1 [Thomas-White, Krystal J.; Wolfe, Alan J.] Loyola Univ, Dept Microbiol & Immunol, Chicago, IL USA. [Brubaker, Linda] Loyola Univ, Stritch Sch Med, Dept Obstet, Chicago, IL USA. [Brubaker, Linda] Loyola Univ, Stritch Sch Med, Dept Gynecol, Chicago, IL USA. [Brubaker, Linda] Loyola Univ, Stritch Sch Med, Dept Urol, Chicago, IL USA. [Kliethermes, Stephanie] Loyola Univ Chicago, Stritch Sch Med, Dept Med, Maywood, IL USA. [Kliethermes, Stephanie] Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL USA. [Rickey, Leslie] Yale Univ, Dept Urol, New Haven, CT USA. [Lukacz, Emily S.] Univ Calif San Diego, Dept Reprod Med, San Diego, CA USA. [Lukacz, Emily S.] Univ Calif San Diego Hlth Syst, San Diego, CA USA. [Richter, Holly E.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL USA. [Moalli, Pamela] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Zimmem, Philippe] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Norton, Peggy] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Kusek, John W.] Natl Inst Hlth, Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. RP Wolfe, AJ (reprint author), Loyola Univ, Dept Microbiol & Immunol, Chicago, IL USA. EM awolfe@luc.edu FU National Institutes of Health (NIH) [U01 DK58229, R21 DK097435]; Department of Health and Human Services [1G20RR030939-1]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01 DK58229, U01 DK58225, U01 DK58231, U01 DK58234, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, U01 DK60401]; Office of Research in Women's Health; NIH [NCT00803959] FX Supported by National Institutes of Health (NIH) grants U01 DK58229 and R21 DK097435 (to A.J.W. and L.B.). Loyola University Chicago Stritch School of Medicine's research computing facility was developed through grant funds awarded by the Department of Health and Human Services as award number 1G20RR030939-1. Our funding sources had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Urinary Incontinence Treatment Network and investigators were supported by cooperative agreements from the NIDDK, U01 DK58225, U01 DK58229, U01 DK58231, U01 DK58234, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, and U01 DK60401. Support was also provided by the Office of Research in Women's Health, NIH. Registered at www. clinicaltrials. gov as NCT00803959. NR 33 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 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2017 VL 216 IS 1 AR 55.e1 DI 10.1016/j.ajog.2016.07.049 PG 16 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EO0II UT WOS:000396381100014 ER PT J AU Baker, KC Dettmer, AM AF Baker, Kate C. Dettmer, Amanda M. TI The Well-Being of Laboratory Non-Human Primates INTRODUCTION SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Editorial Material DE pair housing; psychological well-being; chronic stress; behavioral management; primate ID RHESUS MACAQUES; MACACA-MULATTA; HAIR CORTISOL; FULL-CONTACT; BENEFITS; MONKEYS AB The well-being of non-human primates in captivity is of joint concern to scientists, veterinarians, colony managers, caretakers, and researchers working with non-human primates in biomedical research. With increased regulatory, accreditation, and research focus on optimizing the use of social housing for laboratory primates, as well as the advent of techniques to assess indices of chronic stress and related measures of well-being, there is no better time to present the most current advances in the field of non-human primate behavioral management. The collective body of research presented here was inspired in part by a 2014 symposium entitled, "Chronic Hormones and Demographic Variables: Center-Wide Studies on Non-Human Primate Well-Being" held at the American Society of Primatologists' 37th Annual Meeting in Decatur, GA. By aiming to target readership with scientific and/or management oversight of captive primate behavioral management programs, this special issue provides badly-needed guidance for implementing social housing programs in a research environment and leverages collaboration across multiple facilities to address key components of behavioral management, explore refinements in how well-being can be measured, and identify the interrelationships between varying indices. (C) 2016 Wiley Periodicals, Inc. C1 [Baker, Kate C.] Tulane Natl Primate Res Ctr, Div Vet Med, Covington, LA USA. [Dettmer, Amanda M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Poolesville, MD USA. RP Dettmer, AM (reprint author), NICHD, Comparat Ethol Lab, NIH, POB 529, Poolesville, MD 20837 USA. EM dettmera@mail.nih.gov NR 16 TC 1 Z9 1 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD JAN PY 2017 VL 79 IS 1 AR UNSP e22520 DI 10.1002/ajp.22520 PG 5 WC Zoology SC Zoology GA EL5LB UT WOS:000394661500001 ER PT J AU Dettmer, AM Rosenberg, K Menard, MT El-Mallah, SN Woodward, RA Suomi, SJ Meyer, JS AF Dettmer, Amanda M. Rosenberg, Kendra Menard, Mark T. El-Mallah, Saif N. Woodward, Ruth A. Suomi, Stephen J. Meyer, Jerrold S. TI Differential Relationships Between Chronic Hormone Profiles in Pregnancy and Maternal Investment in Rhesus Monkey Mothers With Hair Loss in the Neonatal Period SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE hair loss; alopecia; pregnancy; infant growth; maternal investment ID MACACA-MULATTA; CORTISOL CONCENTRATIONS; STRESS; MACAQUES; BIOMARKER; ALOPECIA AB Hair loss is commonly used as an indicator of well being in primate facilities, yet it has been shown to also occur in otherwise healthy pregnant and postpartum females. There is significant variability in the incidence of hair loss during these important developmental periods, reasons for which remain unclear. We studied female rhesus monkeys (Macaca mulatta, n = 47) with and without hair loss in pregnancy/postpartum. We hypothesized that, similar to previously published reports, pregnancy would result in an increased likelihood of hair loss, and that hair loss would be correlated with higher hair cortisol concentrations (HCCs). We further hypothesized that hair loss among pregnant females is related to differential maternal investment. We studied a subset of monkeys (n = 26) from mid-to-late pregnancy through peak lactation, some of which exhibited hair loss in the perinatal period (n = 15), and some of which did not (n = 11). We examined fetal measurements, infant birth weight, infant growth rate, and milk yield volume (MYV) in the first 30 days as indices of investment. We found that pregnant monkeys showed a greater incidence of hair loss across the study year (x((2))(2) = 6.55, P = 0.038), and that mothers with hair loss had significantly higher HCCs in pregnancy than those without (F-(2,F-28) = 3.8, P = 0.017, eta(2)(p) = 0.21). HCCs in pregnancy were correlated with severity of hair loss in the neonatal period (r((37)) = 0.42, P = 0.008). Moreover, HCCs in pregnancy were positively correlated with infant birth weight (r((12)) = 0.56, P = 0.038), infant growth rate (r((12)) = 0.64, P = 0.014), and MYV((r(11)) = 0.85, P < 0.001) for alopecic but not non-alopecic mothers. These mothers did not differ in fetal measurements, infant birth weight/growth rate, or MYV. Our results suggest that hair loss in some monkeys, especially during the birthing season, may be a signal of greater physiological stress during pregnancy and differential investment by mothers to their offspring. (C) 2015 Wiley Periodicals, Inc. C1 [Dettmer, Amanda M.; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Poolesville, MD USA. [Rosenberg, Kendra; Menard, Mark T.; El-Mallah, Saif N.; Meyer, Jerrold S.] Univ Massachusetts, Dept Psychol, Tobin Hall, Amherst, MA 01003 USA. [Woodward, Ruth A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Res Anim Management Branch, Div Intramural Res, NIH, Poolesville, MD USA. RP Dettmer, AM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, POB 529, Dickerson, MD 20837 USA. EM dettmera@mail.nih.gov FU NIH [R24OD011180-15] FX Contract grant sponsor: NIH; contract grant number: R24OD011180-15. NR 35 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD JAN PY 2017 VL 79 IS 1 AR UNSP e22489 DI 10.1002/ajp.22489 PG 8 WC Zoology SC Zoology GA EL5LB UT WOS:000394661500004 ER PT J AU Peterson, EJ Worlein, JM Lee, GH Dettmer, AM Varner, EK Novak, MA AF Peterson, Emily J. Worlein, Julie M. Lee, Grace H. Dettmer, Amanda M. Varner, Elana K. Novak, Melinda A. TI Rhesus Macaques (Macaca mulatta) With Self-Injurious Behavior Show Less Behavioral Anxiety During the Human Intruder Test SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE self-injury; rhesus macaques; anxiety; human intruder test; blunted affect ID NONHUMAN-PRIMATES; STEREOTYPIC BEHAVIOR; RELOCATION STRESS; SUICIDE ATTEMPTS; MONKEYS; MODEL; ADOLESCENTS; ENVIRONMENT; DEPRESSION; CORTISOL AB Self-injurious behavior (SIB) has been linked to anxiety in the human literature, but relatively few studies have explored this link in rhesus macaques. A widely used behavioral assessment of anxiety, the human intruder test (HIT), employs the mildly stressful stimulus of an unfamiliar experimenter to assess anxious behavior in macaques. The HIT was conducted on 59 (20 male) laboratory housed rhesus macaques, 30 with a record of SIB (10 male). If monkeys with SIB have a more anxious phenotype, they should show stronger reactions to the HIT. However, contrary to our predictions, monkeys with SIB did not show higher levels of anxious behavior compared to controls. They spent significantly less time showing anxious behavior and displayed little aggression in response to the stare of the intruder. SIB and control monkeys did not differ in a range score (number of unique behaviors expressed per phase); however, SIB monkeys had a lower change score (total number of behaviors expressed including repetitions) than controls. In general, monkeys that paced regardless of SIB status, showed a reduction in pacing when the intruder entered the room. Possible explanations for the failure of SIB monkeys to show increased anxiety in the HIT include greater exposure of SIB monkeys to unfamiliar humans because of their condition, evidence for a subtype of SIB which is not anxiety related, and/or the presence of comorbid depressive-like symptoms. (C) 2016 Wiley Periodicals, Inc. C1 [Peterson, Emily J.] Univ Massachusetts, Neurosci & Behav Grad Program, Amherst, MA 01003 USA. [Worlein, Julie M.; Lee, Grace H.] Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Dettmer, Amanda M.] NICHD, Lab Comparat Ethol, NIH Anim Ctr, NIH, Poolesville, MD USA. [Varner, Elana K.; Novak, Melinda A.] Univ Massachusetts, Dept Psychol & Brain Sci, 135 Hicks Way, Amherst, MA 01003 USA. RP Novak, MA (reprint author), Univ Massachusetts, Dept Psychol & Brain Sci, 135 Hicks Way, Amherst, MA 01003 USA. EM mnovak@psych.umass.edu FU National Institutes of Health [R24-OD11180] FX Contract grant sponsor: National Institutes of Health; contract grant number: R24-OD11180. NR 32 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD JAN PY 2017 VL 79 IS 1 AR UNSP e22569 DI 10.1002/ajp.22569 PG 8 WC Zoology SC Zoology GA EL5LB UT WOS:000394661500011 ER PT J AU Capparelli, EV Bricker-Ford, R Rogers, MJ McKerrow, JH Reed, SL AF Capparelli, Edmund V. Bricker-Ford, Robin Rogers, M. John McKerrow, James H. Reed, Sharon L. TI Phase I Clinical Trial Results of Auranofin, a Novel Antiparasitic Agent SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article DE auranofin; phase I trial; antiparasitic agents ID ENTAMOEBA-HISTOLYTICA; DRUG; MECHANISM AB Under an NIH priority to identify new drugs to treat class B parasitic agents, we performed high-throughput screens, which identified the activity of auranofin (Ridaura) against Entamoeba histolytica and Giardia intestinalis, major causes of water- and foodborne outbreaks. Auranofin, an orally administered, gold (Au)-containing compound that was approved by the FDA in 1985 for treatment of rheumatoid arthritis, was effective in vitro and in vivo against E. histolytica and both metronidazole-sensitive and -resistant strains of Giardia. We now report the results of an NIH-sponsored phase I trial to characterize the pharmacokinetics (PK) and safety of auranofin in healthy volunteers using modern techniques to measure gold levels. Subjects received orally 6 mg (p. o.) of auranofin daily, the recommended dose for rheumatoid arthritis, for 7 days and were followed for 126 days. Treatment-associated adverse events were reported by 47% of the subjects, but all were mild and resolved without treatment. The mean gold maximum concentration in plasma (C-max) at day 7 was 0.312 mu g/ml and the half-life (t(1/2)) 35 days, so steadystate blood levels would not be reached in short-term therapy. The highest concentration of gold, 13 mu M (auranofin equivalent), or more than 25 x the 50% inhibitory concentration (IC50) for E. histolytica and 4 x that for Giardia, was in feces at 7 days. Modeling of higher doses (9 and 21 mg/day) was performed for systemic parasitic infections, and plasma gold levels of 0.4 to 1.0 mu g/ml were reached after 14 days of treatment at 21 mg/day. This phase I trial supports the idea of the safety of auranofin and provides important PK data to support its potential use as a broadspectrum antiparasitic drug. C1 [Capparelli, Edmund V.; Bricker-Ford, Robin; McKerrow, James H.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Rogers, M. John] NIH, Div Microbiol & Infect Dis, Bldg 10, Bethesda, MD 20892 USA. [Reed, Sharon L.] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA. [Reed, Sharon L.] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA. RP Reed, SL (reprint author), Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA.; Reed, SL (reprint author), Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA. EM slreed@ucsd.edu FU National Institutes of Health [HHSN272200800024C, UO1 A1077822, UO1 AI110435] FX This work was supported by the National Institutes of Health (Study DMID 12-0101 under Phase 1 Unit Contract Number HHSN272200800024C to S.L.R., UO1 A1077822 to S.L.R. and J.H.M., and UO1 AI110435 to S.L.R.). NR 22 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2017 VL 61 IS 1 AR e01947- 16 DI 10.1128/AAC.01947-16 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA EK7HC UT WOS:000394095800051 ER PT J AU Rudramurthy, SM Seyedmousavi, S Dhaliwal, M Chakrabarti, A Meis, JF Mouton, JW AF Rudramurthy, Shivaprakash M. Seyedmousavi, Seyedmojtaba Dhaliwal, Manpreet Chakrabarti, Arunaloke Meis, Jacques F. Mouton, Johan W. TI Pharmacodynamics of Voriconazole against Wild-Type and Azole-Resistant Aspergillus flavus Isolates in a Nonneutropenic Murine Model of Disseminated Aspergillosis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article DE voriconazole; Aspergillus flavus; azole resistance; pharmacokinetics; pharmacodynamics ID INVASIVE ASPERGILLOSIS; AMPHOTERICIN-B; HUMAN PATHOGEN; FUMIGATUS; SUSCEPTIBILITY; ISAVUCONAZOLE; PHARMACOKINETICS; ANIDULAFUNGIN; MUTATIONS; STRAINS AB Invasive aspergillosis (IA) due to Aspergillus flavus is associated with high mortality. Although voriconazole (VRC) is widely recommended as the first-line treatment for IA, emergence of azole resistance in Aspergillus spp. is translating to treatment failure. We evaluated the efficacy of voriconazole in a nonneutropenic murine model of disseminated A. flavus infection using two voriconazole-resistant isolates (one harboring the Y319H substitution in the cyp51C gene) and two wild-type isolates without mutations. All isolates exhibited a dose-response relationship, and voriconazole treatment improved mouse survival in a dose-dependent manner. At 40 mg/kg of body weight, 100% efficacy was observed for 1 susceptible isolate and 1 resistant isolate (with mutation), whereas for another susceptible isolate and resistant isolate (without mutation), survival rates were 81% and 72%, respectively. The Hill equation with a variable slope fitted the relationship between the area under the concentration-time curve (AUC)/MIC ratio and 14-day survival well for each strain. An F test showed the 50% effective doses to be significantly different from each other (P = 0.0023). However, contrary to expectation, there was a significant difference in exposure-response relationships between strains, and it appeared that the susceptible strains required a relatively higher exposure than the resistant ones to result in the same treatment effect, the 50% effective pharmacokinetic/pharmacodynamic (PK/PD) index (EI50) required being negatively and log-linearly related to the MIC (P = 0.04). We conclude that the efficacy of voriconazole depended on drug exposure and the voriconazole MIC of the isolates, but lower exposures are required for strains with higher MICs. These findings may have profound significance in clinical practice with respect to dosing and drug choice. C1 [Rudramurthy, Shivaprakash M.; Dhaliwal, Manpreet; Chakrabarti, Arunaloke] Postgrad Inst Med Educ & Res PGIMER, Dept Med Microbiol, Chandigarh, India. [Seyedmousavi, Seyedmojtaba; Mouton, Johan W.] Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands. [Seyedmousavi, Seyedmojtaba; Meis, Jacques F.; Mouton, Johan W.] Radboudumc, Dept Med Microbiol, Nijmegen, Netherlands. [Meis, Jacques F.] Canisius Wilhelmina Hosp, Dept Med Microbiol & Infect Dis, Nijmegen, Netherlands. [Seyedmousavi, Seyedmojtaba] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Rudramurthy, SM (reprint author), Postgrad Inst Med Educ & Res PGIMER, Dept Med Microbiol, Chandigarh, India. EM mrshivprakash@yahoo.com FU Indian Council of Medical Research, New Delhi; Astellas Pharma B.V; Astellas; Basilea; Gilead Sciences; Merck; Pfizer; United Medical FX This study was supported in part by Indian Council of Medical Research, New Delhi.; As potential conflicts of interest, S.S has received a research grant from Astellas Pharma B.V. J.F.M. and J.W.M have served as consultants to and have received research grants from Astellas, Basilea, Gilead Sciences, Merck, Pfizer, and United Medical. All other authors have no conflicts of interest. NR 34 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 JAN PY 2017 VL 61 IS 1 AR e01491-16 DI 10.1128/AAC.01491-16 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA EK7HC UT WOS:000394095800027 ER PT J AU Malloy, LC Orbach, Y Lamb, ME Walker, AG AF Malloy, Lindsay C. Orbach, Yael Lamb, Michael E. Walker, Anne Graffam TI "How" and "Why" prompts in forensic investigative interviews with preschool children SO APPLIED DEVELOPMENTAL SCIENCE LA English DT Article ID WH-QUESTIONS; SEXUAL-ABUSE; YOUNG-CHILDREN; ACQUISITION AB Although young children may frequently be asked How and Why questions, it is unclear whether they have the ability to respond well enough to justify the use of these words during investigative interviews. The range of possible uses and interpretations of the words How and Why makes it critical to examine their use when communicatively immature children are interviewed. In this study, police interviews of 3- to 5-year-old suspected victims of sexual abuse (n=49) were examined. The use of How/Why prompts by interviewers and children's responses to interviewers' How/Why prompts were coded. How/Why prompts represented 22% of all interviewer prompts. Of all details provided by children, however, 8.5% were in response to How/Why prompts. In addition, children provided the information sought in response to only 20% of the interviewers' How/Why prompts, whereas uninformative responses were relatively common. Children responded to more How/Why prompts with the information sought by interviewers as they grew older. The findings suggest that How/Why prompts may not be particularly effective when interviewing preschool children. C1 [Malloy, Lindsay C.] Florida Int Univ, Miami, FL 33199 USA. [Orbach, Yael] NICHHD, Bethesda, MD 20892 USA. [Lamb, Michael E.] Univ Cambridge, Cambridge, England. RP Lamb, ME (reprint author), Univ Cambridge, Dept Psychol, Free Sch Lane, Cambridge CB2 3RQ, England. EM mel37@cam.ac.uk NR 38 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1088-8691 EI 1532-480X J9 APPL DEV SCI JI Appl. Dev. Sci. PY 2017 VL 21 IS 1 BP 58 EP 66 DI 10.1080/10888691.2016.1158652 PG 9 WC Psychology, Developmental SC Psychology GA EL9WL UT WOS:000394970700005 ER PT J AU Kim, JK Lee, HM Park, KS Shin, DM Kim, TS Kim, YS Suh, HW Kim, SY Kim, IS Kim, JM Son, JW Sohn, KM Jung, SS Chung, C Han, SB Yang, CS Jo, EK AF Kim, Jin Kyung Lee, Hye-Mi Park, Ki-Sun Shin, Dong-Min Kim, Tae Sung Kim, Yi Sak Suh, Hyun-Woo Kim, Soo Yeon Kim, In Soo Kim, Jin-Man Son, Ji-Woong Sohn, Kyung Mok Jung, Sung Soo Chung, Chaeuk Han, Sang-Bae Yang, Chul-Su Jo, Eun-Kyeong TI MIR144* inhibits antimicrobial responses against Mycobacterium tuberculosis in human monocytes and macrophages by targeting the autophagy protein DRAM2 SO AUTOPHAGY LA English DT Article DE AMPK; DRAM2; MIR144*; Mycobacterium tuberculosis; tuberculosis ID PHAGOSOME MATURATION; IMMUNE-RESPONSE; DEFENSE; PATHWAY; MICRORNA; EXPRESSION; ROLES; MODULATOR; BACTERIA; RUBICON AB Autophagy is an important antimicrobial effector process that defends against Mycobacterium tuberculosis (Mtb), the human pathogen causing tuberculosis (TB). MicroRNAs (miRNAs), endogenous noncoding RNAs, are involved in various biological functions and act as post-transcriptional regulators to target mRNAs. The process by which miRNAs affect antibacterial autophagy and host defense mechanisms against Mtb infections in human monocytes and macrophages is largely uncharacterized. In this study, we show that Mtb significantly induces the expression of MIR144*/hsa-miR-144-5p, which targets the 3-untranslated region of DRAM2 (DNA damage regulated autophagy modulator 2) in human monocytes and macrophages. Mtb infection downregulated, whereas the autophagy activators upregulated, DRAM2 expression in human monocytes and macrophages by activating AMP-activated protein kinase. In addition, overexpression of MIR144* decreased DRAM2 expression and formation of autophagosomes in human monocytes, whereas inhibition of MIR144* had the opposite effect. Moreover, the levels of MIR144* were elevated, whereas DRAM2 levels were reduced, in human peripheral blood cells and tissues in TB patients, indicating the clinical significance of MIR144* and DRAM2 in human TB. Notably, DRAM2 interacted with BECN1 and UVRAG, essential components of the autophagic machinery, leading to displacement of RUBCN from the BECN1 complex and enhancement of Ptdlns3K activity. Furthermore, MIR144* and DRAM2 were critically involved in phagosomal maturation and enhanced antimicrobial effects against Mtb. Our findings identify a previously unrecognized role of human MIR144* in the inhibition of antibacterial autophagy and the innate host immune response to Mtb. Additionally, these data reveal that DRAM2 is a key coordinator of autophagy activation that enhances antimicrobial activity against Mtb. C1 [Kim, Jin Kyung; Lee, Hye-Mi; Shin, Dong-Min; Kim, Tae Sung; Kim, Yi Sak; Suh, Hyun-Woo; Kim, Soo Yeon; Kim, In Soo; Jo, Eun-Kyeong] Chungnam Natl Univ, Sch Med, Dept Microbiol, Daejeon, South Korea. [Kim, Jin Kyung; Kim, Tae Sung; Kim, Yi Sak; Suh, Hyun-Woo; Kim, Soo Yeon; Kim, Jin-Man; Jo, Eun-Kyeong] Chungnam Natl Univ, Sch Med, Dept Med Sci, Daejeon, South Korea. [Park, Ki-Sun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. [Kim, Jin-Man] Chungnam Natl Univ, Sch Med, Dept Pathol, Daejeon, South Korea. [Son, Ji-Woong] Konyang Univ, Dept Internal Med, Daejeon, South Korea. [Sohn, Kyung Mok] Chungnam Natl Univ, Sch Med, Dept Internal Med, Div Infect Dis, Daejeon, South Korea. [Jung, Sung Soo; Chung, Chaeuk] Chungnam Natl Univ, Sch Med, Dept Internal Med, Div Pulm & Crit Care, Daejeon, South Korea. [Han, Sang-Bae] Chungbuk Natl Univ, Coll Pharm, Cheongju, South Korea. [Yang, Chul-Su] Hanyang Univ, Dept Mol & Life Sci, Ansan, South Korea. RP Yang, CS (reprint author), Chungnam Natl Univ, Sch Med, Dept Microbiol & Med Sci, 6 Munhwa Dong, Daejeon 301747, South Korea. EM chulsuyang@hanyang.ac.kr FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2013R1A1A2058116]; Korea Science & Engineering Foundation through the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI); Ministry of Health & Welfare, Republic of Korea at Chungnam National University [HI15C0395]; National Research Foundation of Korea (NRF) - Korea government (MSIP) [2011-0030049]; Chungnam National University FX This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A2058116) and Korea Science & Engineering Foundation through the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C0395) at Chungnam National University. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2011-0030049). This work was also supported by a research fund (2015) of Chungnam National University. NR 66 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PY 2017 VL 13 IS 2 BP 423 EP 441 DI 10.1080/15548627.2016.1241922 PG 19 WC Cell Biology SC Cell Biology GA EM2CY UT WOS:000395125200015 PM 27764573 ER PT J AU Fang, EF Bohr, VA AF Fang, Evandro F. Bohr, Vilhelm A. TI NAD(+): The convergence of DNA repair and mitophagy SO AUTOPHAGY LA English DT Editorial Material DE ataxia telangiectasia; ATM; autophagy; DNA damage; mitophagy AB ATM is a 350kDa serine/threonine kinase best known for its role in DNA repair and multiple cellular homeostasis pathways. Mutation in ATM causes the disease ataxia telangiectasia (A-T) with clinical features including ataxia, severe cerebellar atrophy and Purkinje cell loss. In a cross-species study, using primary rat neurons, the roundworm C. elegans, and a mouse model of A-T, we showed that loss of ATM induces mitochondrial dysfunction and compromised mitophagy due to NAD(+) insufficiency. Remarkably, NAD(+) repletion mitigates both the DNA repair defect and mitochondrial dysfunction in ATM-deficient neurons. In C. elegans, NAD(+) repletion can clear accumulated dysfunctional mitochondria through restoration of compromised mitophagy via upregulation of DCT-1. Thus, NAD(+) ties together DNA repair and mitophagy in neuroprotection and intimates immediate translational applications for A-T and related neurodegenerative DNA repair-deficient diseases. C1 [Fang, Evandro F.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, 215 Bayview Blvd, Baltimore, MD 21224 USA. RP Fang, EF; Bohr, VA (reprint author), NIA, NIH, 215 Bayview Blvd, Baltimore, MD 21224 USA. EM Evandro.fang@nih.gov; vbohr@nih.gov FU Intramural Research Program of the NIH; National Institute on Aging, including NIA intra-laboratory grant FX This research was supported by the Intramural Research Program of the NIH (VAB), National Institute on Aging, including a 2014-2015 NIA intra-laboratory grant (EFF, VAB). NR 0 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PY 2017 VL 13 IS 2 BP 442 EP 443 DI 10.1080/15548627.2016.1257467 PG 2 WC Cell Biology SC Cell Biology GA EM2CY UT WOS:000395125200016 PM 27929719 ER PT J AU Schliep, KC Chen, Z Stanford, JB Xie, Y Mumford, SL Hammoud, AO Johnstone, EB Dorais, JK Varner, MW Louis, GMB Peterson, CM AF Schliep, K. C. Chen, Z. Stanford, J. B. Xie, Y. Mumford, S. L. Hammoud, A. O. Johnstone, E. Boiman Dorais, J. K. Varner, M. W. Louis, G. M. Buck Peterson, C. M. TI Endometriosis diagnosis and staging by operating surgeon and expert review using multiple diagnostic tools: an inter-rater agreement study SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Review DE Endometriosis; epidemiology; histology; laparoscopy; magnetic resonance imaging; reliability ID ESHRE GUIDELINE; PELVIC PAIN; LAPAROSCOPY; RELIABILITY; WOMEN; ACCURACY AB Objective To determine agreement on endometriosis diagnosis between real-time laparoscopy and subsequent expert review of digital images, operative reports, magnetic resonance imaging (MRI), and histopathology, viewed sequentially. Design Inter-rater agreement study. Setting Five urban surgical centres. Population Women, aged 18-44 years, who underwent a laparoscopy regardless of clinical indication. A random sample of 105 women with and 43 women without a postoperative endometriosis diagnosis was obtained from the ENDO study. Methods Laparoscopies were diagnosed, digitally recorded, and reassessed. Main outcome measures Inter-observer agreement of endometriosis diagnosis and staging according to the revised American Society for Reproductive Medicine criteria. Prevalence and bias- adjusted kappa values (kappa) were calculated for diagnosis, and weighted kappa values were calculated for staging. Results Surgeons and expert reviewers had substantial agreement on diagnosis and staging after viewing digital images (n = 148; mean kappa = 0.67, range 0.61-0.69; mean kappa = 0.64, range 0.53-0.78, respectively) and after additionally viewing operative reports n = 148; mean kappa = 0.88, range 0.85-0.89; mean kappa = 0.85, range 0.84-0.86, respectively). Although additionally viewing MRI findings (n = 36) did not greatly impact agreement, agreement substantially decreased after viewing histological findings (n = 67), with expert reviewers changing their assessment from a positive to a negative diagnosis in up to 20% of cases. Conclusion Although these findings suggest that misclassification bias in the diagnosis or staging of endometriosis via visualised disease is minimal, they should alert gynaecologists who review operative images in order to make decisions on endometriosis treatment that operative reports/drawings and histopathology, but not necessarily MRI, will improve their ability to make sound judgments. C1 [Schliep, K. C.; Chen, Z.; Xie, Y.; Mumford, S. L.; Louis, G. M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. [Schliep, K. C.; Stanford, J. B.] Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT USA. [Hammoud, A. O.; Johnstone, E. Boiman; Dorais, J. K.; Varner, M. W.; Peterson, C. M.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. RP Schliep, KC (reprint author), Univ Utah, Div Publ Hlth, Dept Family & Prevent Med, 375 Chipeta Way,Suite A, Salt Lake City, UT 84108 USA. EM karen.schliep@utah.edu OI Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [NO1-DK-6-3428, NO1-DK-6-3427, 10001 406-02] FX Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001 406-02). NR 25 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1470-0328 EI 1471-0528 J9 BJOG-INT J OBSTET GY JI BJOG PD JAN PY 2017 VL 124 IS 2 SI SI BP 220 EP 229 DI 10.1111/1471-0528.13854 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EO0HI UT WOS:000396378500009 PM 26435386 ER PT J AU Klein, HG AF Klein, Harvey G. TI The red cell storage lesion(s): of dogs and men SO BLOOD TRANSFUSION LA English DT Review DE transfusion; storage lesion; red blood cells; canine model ID OLDER STORED-BLOOD; EXCHANGE-TRANSFUSION; CANINE PNEUMONIA; PATHOPHYSIOLOGY; METAANALYSIS; MORTALITY; OUTCOMES; IMPROVE; SAFETY; UNITS AB The advent of preservative solutions permitted refrigerated storage of red blood cells. However, the convenience of having red blood cell inventories was accompanied by a disadvantage. Red cells undergo numerous physical and metabolic changes during cold storage, the "storage lesion(s)". Whereas controlled clinical trials have not confirmed the clinical importance of such changes, ethical and operational issues have prevented careful study of the oldest stored red blood cells. Suggestions of toxicity from meta-analyses motivated us to develop pre-clinical canine models to compare the freshest vs the oldest red blood cells. Our model of canine pneumonia with red blood cell transfusion indicated that the oldest red blood cells increased mortality, that the severity of pneumonia is important, but that the dose of transfused red blood cells is not. Washing the oldest red blood cells reduces mortality by removing senescent cells and remnants, whereas washing fresher cells increases mortality by damaging the red blood cell membrane. An opposite effect was found in a model of haemorrhagic shock with reperfusion injury. Physiological studies indicate that release of iron from old cells is a primary mechanism of toxicity during infection, whereas scavenging of cell-free haemoglobin may be beneficial during reperfusion injury. Intravenous iron appears to have toxicity equivalent to old red blood cells in the pneumonia model, suggesting that intravenous iron and old red blood cells should be administered with caution to infected patients. C1 [Klein, Harvey G.] NIH, Dept Transfus Med, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Klein, HG (reprint author), NIH, Dept Transfus Med, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hklein@cc.nih.gov FU National Institutes of Health FX These studies were performed in collaboration with Drs. Charles Natanson, Steven Solomon, Irene CortesPuch, Dong Wang, Kenneth Remy, and Jungfen Sun. The studies were supported by intramural research funding, the Intramural Research Program, and the National Institutes of Health. NR 19 TC 0 Z9 0 U1 0 U2 0 PU SIMTI SERVIZI SRL PI MILAN PA VIA DESIDERIO 21, MILAN, 20131, ITALY SN 1723-2007 J9 BLOOD TRANSFUS-ITALY JI Blood Transf. PY 2017 VL 15 IS 2 BP 107 EP 111 DI 10.2450/2017.0306-16 PG 5 WC Hematology SC Hematology GA EM7QP UT WOS:000395507700003 PM 28263166 ER PT J AU Harburg, L McCormack, E Kenney, K Moore, C Yang, K Vos, P Jacobs, B Madden, CJ Diaz-Arrastia, R Bogoslovsky, T AF Harburg, Leah McCormack, Erin Kenney, Kimbra Moore, Carol Yang, Kelly Vos, Pieter Jacobs, Bram Madden, Christopher J. Diaz-Arrastia, Ramon Bogoslovsky, Tanya TI Reliability of the NINDS common data elements cranial tomography (CT) rating variables for traumatic brain injury (TBI) SO BRAIN INJURY LA English DT Article DE Traumatic brain injury; common data elements; cranial tomography; CT scanning; head trauma ID SEVERE HEAD-INJURY; PROGRESSION; HEMORRHAGE; PREDICTION; CONTUSION; CLASSIFICATION; VALIDATION; EDEMA; TRIAL; SCAN AB Background: Non-contrast head computer tomography (CT) is widely used to evaluate eligibility of patients after acute traumatic brain injury (TBI) for clinical trials. The NINDS Common Data Elements (CDEs) TBI were developed to standardize collection of CT variables. The objectives of this study were to train research assistants (RAs) to rate CDEs and then to evaluate their performance. The aim was to assess inter-rater reliability (IRR) of CDEs between trained RAs and a neurologist and to evaluate applicability of CDEs in acute and sub-acute TBI to test the feasibility of using CDE CT ratings in future trials and ultimately in clinical practice. The second aim was to confirm that the ratings of CDEs reflect pathophysiological events after TBI.Methods and results: First, a manual was developed for application of the CDEs, which was used to rate brain CTs (n = 100). An excellent agreement was found in combined kappas between RAs on admission and on 24-hour follow-up CTs (Iota = 0.803 and 0.787, respectively). Good IRR (kappa > 0.61) was shown for six CDEs on admissions and for seven CDEs on follow-up CTs. Low IRR (kappa < 0.4) was determined for five CDEs on admission and for four CDEs on follow-up CT. Combined IRR of each assistant with the neurologist were good on admission (Iota = 0.613 and 0.787) and excellent on follow-up CT (Iota = 0.906 and 0.977). Second, Principal Component Analysis (PCA) was applied to cluster the rated CDEs (n = 255) and five major components were found that explain 53% of the variance.Conclusions: CT CDEs are useful in clinical studies of TBI. Trained RAs can reliably collect variables. PCA identifies CDE clusters with clinical and biologic plausibility.Abbreviations: RA, research assistant; CT, Cranial Tomography; TBI, Traumatic Brain Injury; CDE, Common Data Elements; IRR, inter-rater reliability; PCA, Principal Component Analysis; GCS, Glasgow Coma Scale; R, rater; CI, confidence interval; CCC, Concordance correlation coefficient; IVH, Intraventricular haemorrhage; DCA, Discriminant Component analysis; SAH, Subarachnoid Haemorrhage C1 [Harburg, Leah; McCormack, Erin; Kenney, Kimbra; Moore, Carol; Diaz-Arrastia, Ramon; Bogoslovsky, Tanya] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, 12725 Twinbrook Pkwy, Rockville, MD 20852 USA. [Yang, Kelly] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Vos, Pieter] Slingeland Hosp, Dept Neurol, Doetinchem, Netherlands. [Jacobs, Bram] Univ Med Ctr Groningen, Groningen, Netherlands. [Madden, Christopher J.] Univ Texas Southwestern Med Ctr Dallas, Dept Neurol Surg, Dallas, TX 75390 USA. RP Bogoslovsky, T (reprint author), Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, 12725 Twinbrook Pkwy, Rockville, MD 20852 USA. EM tanya.bogoslovsky.ctr@usuhs.edu NR 39 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0269-9052 EI 1362-301X J9 BRAIN INJURY JI Brain Inj. PY 2017 VL 31 IS 2 BP 174 EP 184 DI 10.1080/02699052.2016.1225989 PG 11 WC Neurosciences; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA EM2RO UT WOS:000395163500004 PM 27936952 ER PT J AU Yang, JD Altekruse, SF Nguyen, MH Gores, GJ Roberts, LR AF Yang, Ju Dong Altekruse, Sean F. Nguyen, Mindie H. Gores, Gregory J. Roberts, Lewis R. TI Impact of Country of Birth on Age at the Time of Diagnosis of Hepatocellular Carcinoma in the United States SO CANCER LA English DT Article DE Africa; age; early onset; liver cancer; Oceania ID HEPATITIS-B-VIRUS; LIVER-CANCER; C-VIRUS; ASSOCIATION; AFLATOXIN; MORTALITY; PATTERNS; AFRICA; RISK AB BACKGROUND: There is global variation in the onset of hepatocellular carcinoma (HCC). The objective of the current study was to investigate the impact of country of birth on age at the time of HCC diagnosis in the United States. METHODS: Incident HCC cases diagnosed between 2000 and 2012 in the Surveillance, Epidemiology, and End Results program 18 registry were included. Factors associated with very early onset (age at diagnosis< 40 years) and early onset (age at diagnosis< 50 years) were identified by logistic regression. RESULTS: A total of 59,907 patients were included. The median age at the time of diagnosis of HCC was 62 years and 76% of the patients were male. Of the 75% of patients for whom information regarding birth country was available, 29% were foreign born. In multivariate logistic regression, birth in West Africa (adjusted odds ratio [AOR], 16.3; 95% confidence interval [95% CI], 9.2-27.9 [P<. 01]), Central/South/other Africa (AOR, 11.0; 95% CI, 4.5-23.7 [P<. 01]), Oceania (AOR, 4.9; 95% CI, 2.9-8.0 [P<. 01]), and East Africa (AOR, 3.5; 95% CI, 1.5-6.8 [P<. 01]) was found to have the strongest association with very early-onset HCC after adjusting for sex and race/ethnicity. Birth in West Africa, Central/South/other Africa, Oceania, or East Africa also was found to be strongly associated with early-onset HCC. CONCLUSIONS: Birth country was found to be independently associated with age at the time of HCC diagnosis in the United States. Birth in Africa (except for North Africa) and Oceania was strongly associated with very early-onset HCC. These findings have implications for the design of comprehensive HCC surveillance programs in the United States. (C) 2016 American Cancer Society. C1 [Yang, Ju Dong; Gores, Gregory J.; Roberts, Lewis R.] Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, 200 First St SW, Rochester, MN 55905 USA. [Altekruse, Sean F.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Nguyen, Mindie H.] Stanford Univ, Stanford Canc Inst, Div Gastroenterol & Hepatol, Palo Alto, CA 94304 USA. [Nguyen, Mindie H.] Stanford Univ, Med Ctr, Ctr Innovat Global Hlth, Palo Alto, CA 94304 USA. RP Roberts, LR (reprint author), Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, 200 First St SW, Rochester, MN 55905 USA. EM Roberts.lewis@mayo.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [T32 DK07198]; National Cancer Institute [CA165076] FX Supported by grant T32 DK07198 from the National Institute of Diabetes and Digestive and Kidney Diseases (to Ju Dong Yang) and grant CA165076 from the National Cancer Institute (to Lewis R. Roberts). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. 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 1 PY 2017 VL 123 IS 1 BP 81 EP 89 DI 10.1002/cncr.30246 PG 9 WC Oncology SC Oncology GA EL6GT UT WOS:000394719100011 PM 27571320 ER PT J AU Brooks, PJ Schuebel, K AF Brooks, P. J. Schuebel, Kornel TI Timeless insights into prevention of acetaldehyde genotoxicity? SO CELL CYCLE LA English DT Editorial Material DE cancer; crosslinks; DNA; protein; DNA repair; Fanconi anemia C1 [Brooks, P. J.; Schuebel, Kornel] Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, Neurogenet Lab, Rockville, MD USA. RP Brooks, PJ (reprint author), Natl Inst Hlth, Natl Ctr Adv Translat Sci NCATS, Div Clin Innovat, 6701 Democracy Blvd,Rm 924, Bethesda, MD 20892 USA. EM pjbrooks@mail.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PY 2017 VL 16 IS 4 BP 308 EP 309 DI 10.1080/15384101.2016.1247570 PG 2 WC Cell Biology SC Cell Biology GA EL4WK UT WOS:000394621400006 PM 27764578 ER PT J AU Mayer-Barber, KD Yan, B AF Mayer-Barber, Katrin D. Yan, Bo TI Clash of the Cytokine Titans: counter-regulation of interleukin-1 and type I interferon-mediated inflammatory responses SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Review DE cytokines; infection; inflammation; interleukin-1; tuberculosis; type-1 interferons ID TUMOR-NECROSIS-FACTOR; MYCOBACTERIUM-TUBERCULOSIS INFECTION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; CHORIOMENINGITIS VIRUS-INFECTION; PATTERN-RECOGNITION RECEPTORS; ENTERICA SEROVAR TYPHIMURIUM; HUMAN-IMMUNODEFICIENCY-VIRUS; TRYPANOSOMA-CRUZI INFECTION; PERSISTENT LCMV INFECTION; INNATE IMMUNE-RESPONSE AB Over the past decades the notion of 'inflammation' has been extended beyond the original hallmarks of rubor (redness), calor (heat), tumor (swelling) and dolor (pain) described by Celsus. We have gained a more detailed understanding of the cellular players and molecular mediators of inflammation which is now being applied and extended to areas of biomedical research such as cancer, obesity, heart disease, metabolism, auto-inflammatory disorders, autoimmunity and infectious diseases. Innate cytokines are often central components of inflammatory responses. Here, we discuss how the type I interferon and interleukin-1 cytokine pathways represent distinct and specialized categories of inflammatory responses and how these key mediators of inflammation counter-regulate each other. C1 [Mayer-Barber, Katrin D.; Yan, Bo] NIAID, Inflammat & Innate Immun Unit, Lab Clin Infect Dis, NIH, Bldg 4,Room 407, Bethesda, MD 20892 USA. RP Mayer-Barber, KD (reprint author), NIAID, Inflammat & Innate Immun Unit, Lab Clin Infect Dis, NIH, Bldg 4,Room 407, Bethesda, MD 20892 USA. EM mayerk@niaid.nih.gov FU Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases FX We thank Drs. Mahtab Moayeri, Dan Barber and Alan Sher for comments and critical reading of the article. This work was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 236 TC 3 Z9 3 U1 2 U2 2 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD JAN PY 2017 VL 14 IS 1 BP 22 EP 35 DI 10.1038/cmi.2016.25 PG 14 WC Immunology SC Immunology GA EL0ZN UT WOS:000394350400004 PM 27264686 ER PT J AU Sher, A Tosh, K Jankovic, D AF Sher, Alan Tosh, Kevin Jankovic, Dragana TI Innate recognition of Toxoplasma gondii in humans involves a mechanism distinct from that utilized by rodents SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Review DE human; innate immunity; mouse; phagocytosis; Toxoplasma gondii ID TOLL-LIKE RECEPTORS; CELL PLASMA-MEMBRANE; DENDRITIC CELLS; OCULAR TOXOPLASMOSIS; INTERFERON-GAMMA; IFN-GAMMA; CLINICAL CHARACTERISTICS; INFLAMMATORY MONOCYTES; CYTOKINE PRODUCTION; ACUTE INFECTION AB Toxoplasma gondii is an intracellular protozoan parasite that infects rodents as part of its natural transmission cycle and induces disease in humans, an end-stage host. As one of the natural hosts of T. gondii, the mouse has been used extensively for elucidating the cellular and molecular basis of immunity to this pathogen while relatively few studies have focused on the response of humans. In our recent work, we identified CD16(+) monocytes and DC1 dendritic cells as the major myeloid cell populations that respond to T. gondii in human peripheral blood. Interestingly, these myeloid subsets represent the opposite counterparts from those triggered by the parasite in mice. Moreover, whereas the innate cytokine response to T. gondii in the mouse involves stimulation of Toll-like receptors by a soluble parasite ligand, the response of human cells instead requires phagocytosis of the live pathogen. We speculate that these marked distinctions in the pathways utilized for innate recognition of toxoplasma in mouse and man reflect the differing roles of the two hosts in the biology of this parasite. C1 [Sher, Alan; Tosh, Kevin; Jankovic, Dragana] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Sher, A; Jankovic, D (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bldg 50,Room 6140, Bethesda, MD 20882 USA. EM asher@niaid.nih.gov; djankovic@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH FX We thank Drs Ricardo Gazzinelli, Lis Antonelli, Carl Feng, Jonathan Howard, Steve Singer and Tom Nutman for helpful discussions. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 48 TC 1 Z9 1 U1 2 U2 2 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD JAN PY 2017 VL 14 IS 1 BP 36 EP 42 DI 10.1038/cmi.2016.12 PG 7 WC Immunology SC Immunology GA EL0ZN UT WOS:000394350400005 PM 27157497 ER PT J AU Li, H Zhang, DL Gao, MN Huang, LM Tang, LG Li, ZJ Chen, XY Zhang, XZ AF Li, Hua Zhang, Deliang Gao, Mengna Huang, Lumei Tang, Longguang Li, Zijing Chen, Xiaoyuan Zhang, Xianzhong TI Highly specific C-C bond cleavage induced FRET fluorescence for in vivo biological nitric oxide imaging SO CHEMICAL SCIENCE LA English DT Article ID REACTIVE OXYGEN; LIVING CELLS; NITROSATIVE STRESS; RATIONAL DESIGN; PROBE; CHEMILUMINESCENCE; CHROMOPHORE; INDICATORS; AGENT; MRI AB A novel Forster resonance energy transfer (FRET) fluorescence "off-on" system based on the highly specific, sensitive and effective C-C bond cleavage of certain dihydropyridine derivatives was reported for real-time quantitative imaging of nitric oxide (NO). 1,4-Dihydropyridine was synthesized as a novel linker which could connect customized fluorophores and their corresponding quenchers. The specific and quantitative response to NO is confirmed using fluorescence spectrometry with the classical example of fluorescein isothiocyanate (FITC) and[4'-(N,N'-dimethylamino) phenylazo] benzoyl (DABCYL). The fluorescence intensity increased linearly with the increase in the amount of NO. Cells incubated with an exogenous NO donor emitted fluorescence as expected. A high fluorescence intensity was detected in macrophages which generate NO when incubated with lipopolysaccharide (LPS). The in vivo imaging shows about an 8-fold contrast between Freund's adjuvant stimulated feet and normal feet in mice after intravenous injection, which was the first example of in vivo semiquantitative fluorescence imaging of NO in mammals. C1 [Li, Hua; Zhang, Deliang; Gao, Mengna; Huang, Lumei; Tang, Longguang; Li, Zijing; Zhang, Xianzhong] 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, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Li, ZJ; Zhang, XZ (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 zijing.li@xmu.edu.cn; zhangxzh@xmu.edu.cn RI Zhang, Xianzhong/A-7754-2012 OI Zhang, Xianzhong/0000-0002-1001-1884 FU National Key Basic Research Program of China [2014CB744503]; National Natural Science Foundation of China [81501534, 21271030, 81471707]; Fundamental Research Funds for the Central Universities [20720150063]; Science Foundation of Fujian Province [2014Y2004] FX This study was financially supported by the National Key Basic Research Program of China (2014CB744503), National Natural Science Foundation of China (81501534, 21271030, 81471707) and partially by the Fundamental Research Funds for the Central Universities (20720150063) and the Science Foundation of Fujian Province (2014Y2004). NR 40 TC 0 Z9 0 U1 2 U2 2 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2041-6520 EI 2041-6539 J9 CHEM SCI JI Chem. Sci. PY 2017 VL 8 IS 3 BP 2199 EP 2203 DI 10.1039/c6sc04071c PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA EN3KH UT WOS:000395906900065 ER PT J AU Simpson, EA Jakobsen, KV Damon, F Suomi, SJ Ferrari, PF Paukner, A AF Simpson, Elizabeth A. Jakobsen, Krisztina V. Damon, Fabrice Suomi, Stephen J. Ferrari, Pier F. Paukner, Annika TI Face Detection and the Development of Own-Species Bias in Infant Macaques SO CHILD DEVELOPMENT LA English DT Article ID COGNITIVE-DEVELOPMENT; NONHUMAN-PRIMATES; SOCIAL ATTENTION; EYE-MOVEMENTS; VISUAL-SEARCH; POP-OUT; PERCEPTION; BIRTH; NEWBORN; AUTISM AB In visually complex environments, numerous items compete for attention. Infants may exhibit attentional efficiency-privileged detection, attention capture, and holding-for face-like stimuli. However, it remains unknown when these biases develop and what role, if any, experience plays in this emerging skill. Here, nursery-reared infant macaques' (Macaca mulatta; n = 10) attention to faces in 10-item arrays of nonfaces was measured using eye tracking. With limited face experience, 3-week-old monkeys were more likely to detect faces and looked longer at faces compared to nonfaces, suggesting a robust face detection system. By 3 months, after peer exposure, infants looked faster to conspecific faces but not heterospecific faces, suggesting an own-species bias in face attention capture, consistent with perceptual attunement. C1 [Simpson, Elizabeth A.] Univ Miami, Coral Gables, FL 33124 USA. [Jakobsen, Krisztina V.] James Madison Univ, Harrisonburg, VA 22807 USA. [Damon, Fabrice] Univ Grenoble Alpes, Grenoble, France. [Suomi, Stephen J.; Paukner, Annika] NIH, Bldg 10, Bethesda, MD 20892 USA. [Ferrari, Pier F.] Univ Parma, Parma, Italy. RP Simpson, EA (reprint author), Univ Miami, Dept Psychol, 5665 Ponce de Leon, Coral Gables, FL 33124 USA. EM simpsone@miami.edu OI Simpson, Elizabeth/0000-0003-2715-2533 FU Division of Intramural Research, NICHD; Alvin V., Jr. and Nancy C. Baird Professorship; NICHD [P01HD064653] FX We thank Scott P. Johnson for constructive feedback on an earlier draft. Supported by the Division of Intramural Research, NICHD, the Alvin V., Jr. and Nancy C. Baird Professorship (KVJ), and NICHD P01HD064653 (PFF). Elizabeth A. Simpson, Krisztina V. Jakobsen, and Annika Paukner developed the study concept and design. Elizabeth A. Simpson, Fabrice Damon, and Annika Paukner collected the data. Elizabeth A. Simpson analyzed and interpreted the data and drafted the manuscript. All authors provided critical revisions and approved the final version of the manuscript for submission. NR 79 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-3920 EI 1467-8624 J9 CHILD DEV JI Child Dev. PD JAN-FEB PY 2017 VL 88 IS 1 BP 103 EP 113 DI 10.1111/cdev.12565 PG 11 WC Psychology, Educational; Psychology, Developmental SC Psychology GA EN4WF UT WOS:000396006900008 PM 27223687 ER PT J AU White, LK Degnan, KA Henderson, HA Perez-Edgar, K Walker, OL Shechner, T Leibenluft, E Bar-Haim, Y Pine, DS Fox, NA AF White, Lauren K. Degnan, Kathryn A. Henderson, Heather A. Perez-Edgar, Koraly Walker, Olga L. Shechner, Tomer Leibenluft, Ellen Bar-Haim, Yair Pine, Daniel S. Fox, Nathan A. TI Developmental Relations Among Behavioral Inhibition, Anxiety, and Attention Biases to Threat and Positive Information SO CHILD DEVELOPMENT LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PROCESSING BIASES; PEDIATRIC ANXIETY; SOCIAL PHOBIA; SELECTIVE ATTENTION; CHILDREN; CHILDHOOD; TEMPERAMENT; DISORDER; WITHDRAWAL AB This study examined relations between behavioral inhibition (BI) assessed in toddlerhood (n = 268) and attention biases (AB) to threat and positive faces and maternal-reported anxiety assessed when children were 5- and 7-year-old. Results revealed that BI predicted anxiety at age 7 in children with AB toward threat, away from positive, or with no bias, at age 7; BI did not predict anxiety for children displaying AB away from threat or toward positive. Five-year AB did not moderate the link between BI and 7-year anxiety. No direct association between AB and BI or anxiety was detected; moreover, children did not show stable AB across development. These findings extend our understanding of the developmental links among BI, AB, and anxiety. C1 [White, Lauren K.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Degnan, Kathryn A.] Catholic Univ, Washington, DC USA. [Henderson, Heather A.] Univ Waterloo, Waterloo, ON, Canada. [Perez-Edgar, Koraly] Penn State Univ, University Pk, PA 16802 USA. [Walker, Olga L.; Fox, Nathan A.] Univ Maryland, College Pk, MD 20742 USA. [Shechner, Tomer] Univ Haifa, Haifa, Israel. [Leibenluft, Ellen; Pine, Daniel S.] NIMH, Bethesda, MD 20892 USA. [Bar-Haim, Yair] Tel Aviv Univ, Tel Aviv, Israel. RP White, LK (reprint author), Childrens Hosp Philadelphia, Dept Child & Adolescent Psychiat & Behav Sci, 3440 Market St,Suite 410, Philadelphia, PA 19104 USA. EM whitelk@email.chop.edu FU National Institutes of Health [MH074454, HD17899] FX This research was supported by grants from the National Institutes of Health (MH074454 and HD17899) to Nathan A. Fox. We would like to thank all the children and parents for their participation in this study. We would also like to acknowledge all the research assistants for their contributions. NR 63 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-3920 EI 1467-8624 J9 CHILD DEV JI Child Dev. PD JAN-FEB PY 2017 VL 88 IS 1 BP 141 EP 155 DI 10.1111/cdev.12696 PG 15 WC Psychology, Educational; Psychology, Developmental SC Psychology GA EN4WF UT WOS:000396006900012 PM 28042902 ER PT J AU Schneider, ML Moore, CF Adkins, M Barr, CS Larson, JA Resch, LM Roberts, A AF Schneider, Mary L. Moore, Colleen F. Adkins, Miriam Barr, Christina S. Larson, Julie A. Resch, Leslie M. Roberts, Andrew TI Sensory Processing in Rhesus Monkeys: Developmental Continuity, Prenatal Treatment, and Genetic Influences SO CHILD DEVELOPMENT LA English DT Article ID LINKED POLYMORPHIC REGION; OVER-RESPONSIVITY; ALCOHOL EXPOSURE; MACACA-MULATTA; FETAL ALCOHOL; TACTILE DEFENSIVENESS; EARLY EXPERIENCE; YOUNG-CHILDREN; 5-HTT GENE; STRESS AB Neonatal sensory processing (tactile and vestibular function) was tested in 78 rhesus macaques from two experiments. At ages 4-5 years, striatal dopamine D-2 receptor binding was examined using positron emission tomography. At ages 5-7 years, adult sensory processing was assessed. Findings were: (a) prenatal stress exposure yielded less optimal neonatal sensory processing; (b) animals carrying the short rh5-HTTLPR allele had less optimal neonatal sensory scores than monkeys homozygous for the long allele; (c) neonatal sensory processing was significantly related to striatal D-2 receptor binding for carriers of the short allele, but not for animals homozygous for the long allele; and (d) there was moderate developmental continuity in sensory processing from the neonatal period to adulthood. C1 [Schneider, Mary L.; Adkins, Miriam; Larson, Julie A.; Resch, Leslie M.] Univ Wisconsin, Dept Kinesiol, Madison, WI 53706 USA. [Schneider, Mary L.; Larson, Julie A.; Resch, Leslie M.] Univ Wisconsin, Harlow Ctr Biol Psychol, Madison, WI 53706 USA. [Schneider, Mary L.; Moore, Colleen F.] Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. [Moore, Colleen F.] Montana State Univ, Dept Psychol, Bozeman, MT 59717 USA. [Barr, Christina S.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Roberts, Andrew] Minnesota State Univ Mankato, Mankato, MN USA. RP Schneider, ML (reprint author), Dept Kinesiol, Psychol 22 North Charter St, Madison, WI 53715 USA.; Schneider, ML (reprint author), Harlow Ctr Biol, Psychol 22 North Charter St, Madison, WI 53715 USA. EM schneider@education.wisc.edu FU National Institute of Alcohol Abuse and Alcoholism [R01 AA12277]; Wallace Research Foundation FX This study was supported by the National Institute of Alcohol Abuse and Alcoholism (R01 AA12277) and the Wallace Research Foundation. NR 63 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-3920 EI 1467-8624 J9 CHILD DEV JI Child Dev. PD JAN-FEB PY 2017 VL 88 IS 1 BP 183 EP 197 DI 10.1111/cdev.12572 PG 15 WC Psychology, Educational; Psychology, Developmental SC Psychology GA EN4WF UT WOS:000396006900015 PM 27338151 ER PT J AU Jensen, K dela Pena-Ponce, MG Piatak, M Shoemaker, R Oswald, K Jacobs, WR Fennelly, G Lucero, C Mollan, KR Hudgens, MG Amedee, A Kozlowski, PA Estes, JD Lifson, JD Van Rompay, KKA Larsen, M De Paris, K AF Jensen, Kara dela Pena-Ponce, Myra Grace Piatak, Michael, Jr. Shoemaker, Rebecca Oswald, Kelli Jacobs, William R., Jr. Fennelly, Glenn Lucero, Carissa Mollan, Katie R. Hudgens, Michael G. Amedee, Angela Kozlowski, Pamela A. Estes, Jacob D. Lifson, Jeffrey D. Van Rompay, Koen K. A. Larsen, Michelle De Paris, Kristina TI Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article DE pediatric HIV/SIV; vaccine; immune activation; myeloid cells ID BACILLUS-CALMETTE-GUERIN; CLASS-I ALLELES; T-LYMPHOCYTE RESPONSES; INDIAN RHESUS MACAQUE; RECOMBINANT BCG; CELL RESPONSES; PULMONARY TUBERCULOSIS; NONSPECIFIC PROTECTION; GENETIC POLYMORPHISMS; SIVMAC239 REPLICATION AB Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M. tuberculosis (AMtb)-simian immunodeficiency virus (SIV) vaccine is immunogenic, and although the vaccine did not prevent oral SIV infection, a subset of vaccinated animals was able to partially control virus replication. However, unexpectedly, vaccinated infants required fewer SIV exposures to become infected compared to naive controls. Considering that the current TB vaccine, Mycobacterium bovis bacillus Calmette-Guerin (BCG), can induce potent innate immune responses and confer pathogen-unspecific trained immunity, we hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in AMtb-SIV-vaccinated infants. To address this question, we used archived samples from unchallenged animals from our previous AMtb-SIV vaccine studies and vaccinated additional infant macaques with BCG or AMtb only. Our results show that vaccinated infants, regardless of vaccine strain or regimen, had enhanced myeloid cell responses. However, CD4(+) T cells were concurrently activated, and the persistence of these activated target cells in oral and/or gastrointestinal tissues may have facilitated oral SIV infection. Immune activation was more pronounced in BCG-vaccinated infant macaques than in AMtb-vaccinated infant macaques, indicating a role for vaccine attenuation. These findings underline the importance of understanding the interplay of vaccine-induced immunity and immune activation and its effect on HIV acquisition risk and outcome in infants. C1 [Jensen, Kara; dela Pena-Ponce, Myra Grace; De Paris, Kristina] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Jensen, Kara; dela Pena-Ponce, Myra Grace; De Paris, Kristina] Univ N Carolina, Ctr AIDS Res, Sch Med, Chapel Hill, NC USA. [Piatak, Michael, Jr.; Shoemaker, Rebecca; Oswald, Kelli; Lucero, Carissa; Estes, Jacob D.; Lifson, Jeffrey D.] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. [Jacobs, William R., Jr.; Larsen, Michelle] Albert Einstein Coll Med, New York, NY USA. [Fennelly, Glenn] Rutgers New Jersey Med Sch, Newark, NJ USA. [Mollan, Katie R.] Univ N Carolina, Lineberger Canc Ctr, Chapel Hill, NC USA. [Mollan, Katie R.; Hudgens, Michael G.] Univ N Carolina, Ctr AIDS Res, Chapel Hill, NC USA. [Hudgens, Michael G.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Amedee, Angela; Kozlowski, Pamela A.] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA USA. [Van Rompay, Koen K. A.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. RP De Paris, K (reprint author), Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. EM abelk@med.unc.edu FU NIH [1R01 DE019064, T32 AI007419, T32 AI007001-36, 5R24RR016038]; Louisiana Vaccine Center - Louisiana Board of Regents; National Cancer Institute, NIH [HHSN261200800001E]; National Center for Research Resources (NCRR); Office of Research Infrastructure Programs/OD [P51 OD011107]; Center for AIDS Research (NIH) [2 P30 AI050410]; UNC Flow Cytometry Core - Department of Microbiology and Immunology; NCI Center Core Support [P30 CA06086] FX These studies were supported by NIH grants 1R01 DE019064 (to K.D.P., M.L., and G.F.), T32 AI007419 (Training in Virology), and T32 AI007001-36 (Training in Sexually Transmitted Diseases and AIDS) (to K.J.), by the Louisiana Vaccine Center funded by the Louisiana Board of Regents (P.A.K.), and in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. The animal studies at the CNPRC were supported by NIH grants RR00169 from the National Center for Research Resources (NCRR; NIH) and the Office of Research Infrastructure Programs/OD P51 OD011107.Studies at UNC Chapel Hill were supported by the Center for AIDS Research (NIH grant 2 P30 AI050410), by the UNC Flow Cytometry Core that receives support from the Department of Microbiology and Immunology and the NCI Center Core Support Grant P30 CA06086 to the UNC Chapel Hill Lineberger Cancer Center. The MHC Genotyping Service is supported by NIH grant 5R24RR016038 awarded to David Watkins at the University of Miami Miller School of Medicine. NR 97 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD JAN PY 2017 VL 24 IS 1 AR UNSP e00360-16 DI 10.1128/CVI.00360-16 PG 27 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EK9DH UT WOS:000394223700005 ER PT J AU de Boer, YS Kosinski, AS Urban, TJ Zhao, Z Long, NY Chalasani, N Kleiner, DE Hoofnagle, JH AF de Boer, Ynto S. Kosinski, Andrzej S. Urban, Thomas J. Zhao, Zhen Long, Nanye Chalasani, Naga Kleiner, David E. Hoofnagle, Jay H. CA Drug-Induced Liver Injury Network TI Features of Autoimmune Hepatitis in Patients With Drug-induced Liver Injury SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE Database Analysis; Toxicity; Hepatotoxicity; Immune Response; Immunoglobulin ID CAUSALITY ASSESSMENT; NETWORK DILIN; OUTCOMES; FAILURE; HEPATOTOXICITY; MINOCYCLINE; METHYLDOPA; DIAGNOSIS; TYPE-1; COHORT AB BACKGROUND & AIMS: Drug-induced liver injury (DILI) has features similar to those of other liver diseases including autoimmune hepatitis (AIH). We aimed to characterize the clinical and autoimmune features of liver injury caused by nitrofurantoin, minocycline, methyldopa, or hydralazine. METHODS: We analyzed data from 88 cases of DILI attributed to nitrofurantoin, minocycline, methyldopa, or hydralazine included in the Drug-Induced Liver Injury Network prospective study from 2004 through 2014. Sera were collected from patients at baseline and follow-up examination and tested for levels of immunoglobulin G (IgG), antibodies to nuclear antigen (ANA), smooth muscle (SMA), and soluble liver antigen (SLA). An autoimmune score was derived on the basis of increases in levels of IgG, ANA, SMA, and SLA (assigned values of 0, 1+, or 2+). AIH- associated HLA-DRB1*03:01 and HLA-DRB1*04:01 allele frequencies were compared with those of the general population (controls). RESULTS: Of the 88 cases, 80 were women (91%), 74% had hepatocellular injury, and 25% had severe injury. At the onset of DILI, 39% of cases had increased levels of IgG, 72% had increased levels of ANA, 60% had increased levels of SMA, and none had increases in SLA. A phenotype of autoimmunity (autoimmune score >= 2) was observed in 82% of cases attributed to nitrofurantoin and 73% of cases attributed to minocycline (73%) but only 55% of cases attributed to methyldopa and 43% of cases attributed to hydralazine (P = .16 for nitrofurantoin and minocycline vs methyldopa and hydralazine). We observed a decrease in numbers of serum samples positive for ANA (P = .01) or SMA (P <.001) and in autoimmune scores (P <.001) between DILI onset and follow-up. Similar percentages of patients with DILI had HLA-DRB1*03: 01 (15%) and HLA-DRB1*04: 01 (9%) as controls (12% and 9%, respectively). CONCLUSIONS: In analysis of data from the DILIN prospective study, we found that most cases of DILI attributed to nitrofurantoin or minocycline and about half of cases that were due to methyldopa and hydralazine have a phenotype of autoimmunity similar to AIH. These features decrease with recovery of the injury and are not associated with the typical HLA alleles found in patients with idiopathic AIH. C1 [de Boer, Ynto S.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [de Boer, Ynto S.] Vrije Univ Amsterdam, Med Ctr, Dept Gastroenterol & Hepatol, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. [Kosinski, Andrzej S.] Duke Clin Res Inst, Durham, NC USA. [Urban, Thomas J.; Long, Nanye] Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Zhao, Zhen] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Chalasani, Naga] Indiana Univ Sch Med, Div Gastroenterol & Hepatol, Indianapolis, IN 46202 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Hoofnagle, Jay H.] NIDDK, Liver Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP de Boer, YS (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Gastroenterol & Hepatol, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands.; Hoofnagle, JH (reprint author), NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, 6707 Democracy Blvd, Bethesda, MD 20852 USA. EM y.deboer@vumc.nl; hoofnaglej@extra.niddk.nih.gov OI de Boer, Ynto/0000-0002-4066-7593 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH) [U01DK065211, U01DK065184, U01DK065201, U01DK083020, U01DK083027, U01DK100928, U01DK065176]; Intramural Division of the National Cancer Institute (NCI), NIH; Foundation for the National Institutes of Health FX The Drug Induced Liver Injury Network (DILIN) is structured as a U01 cooperative agreement supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institutes of Health (NIH) with funds provided by the following grants: U01DK065211 (Indiana University [Purdue]), U01DK065184 (University of Michigan [Ann Arbor]), U01DK065201 (University of North Carolina [Chapel Hill], Asheville, Wake Forest Baptist Medical Center), U01DK083020 (University of Southern California, University of California-Los Angeles [Pfleger Liver Institute]), U01DK083027 (Albert Einstein Medical Center), U01DK100928 (Icahn School of Medicine at Mount Sinai), and U01DK065176 (Duke Clinical Research Institute). Additional support was provided by the Intramural Division of the National Cancer Institute (NCI), NIH. Partial salary support (Y.D.B.) and funding for reagents for autoantibody testing were provided by the Foundation for the National Institutes of Health. A complete listing of participants in DILIN is provided in the Supplementary Material. NR 33 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 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD JAN PY 2017 VL 15 IS 1 BP 103 EP + DI 10.1016/j.cgh.2016.05.043 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EO1XW UT WOS:000396492200025 PM 27311619 ER PT J AU Yang, JD Abdelmalek, MF Guy, CD Gill, RM Lavine, JE Yates, K Klair, J Terrault, NA Clark, JM Unalp-Arida, A Diehl, AM Suzuki, A AF Yang, Ju Dong Abdelmalek, Manal F. Guy, Cynthia D. Gill, Ryan M. Lavine, Joel E. Yates, Katherine Klair, Jagpal Terrault, Norah A. Clark, Jeanne M. Unalp-Arida, Aynur Diehl, Anna Mae Suzuki, Ayako CA Nonalcoholic Steatohepatitis Clini TI Patient Sex, Reproductive Status, and Synthetic Hormone Use Associate With Histologic Severity of Nonalcoholic Steatohepatitis SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE Gender Differences; Fibrosis; Risk Factor Analysis. ID FATTY LIVER-DISEASE; HEPATIC-FIBROSIS; INJURY; PREVALENCE; MENOPAUSE; PATHWAY AB BACKGROUND & AIMS: Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. METHODS: We collected data from 3 large U.S. studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress. RESULTS: Premenopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory-Denk bodies than men and also at an increased risk of lobular inflammation and Mallory-Denk bodies than postmenopausal women (P < .01). Use of oral contraceptives was associated with an increased risk of lobular inflammation and Mallory-Denk bodies in premenopausal women, whereas hormone replacement therapy was associated with an increased risk of lobular inflammation in postmenopausal women (P < .05). CONCLUSIONS: Being a premenopausal woman or a female user of synthetic hormones is associated with increased histologic severity of hepatocyte injury and inflammation among patients with NAFLD at given levels of hepatic metabolic stress. C1 [Yang, Ju Dong] Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, Rochester, MN USA. [Abdelmalek, Manal F.; Diehl, Anna Mae; Suzuki, Ayako] Duke Univ, Gastroenterol & Hepatol, Durham, NC USA. [Guy, Cynthia D.] Duke Univ, Dept Pathol, Durham, NC 27706 USA. [Gill, Ryan M.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Lavine, Joel E.] Columbia Univ, Dept Pediat, New York, NY 10027 USA. [Yates, Katherine] Johns Hopkins Bloomberg Sch Publ Hlth, Nonalcohol Steatohepatitis Clin Res Network, Data Coordinating Ctr, Baltimore, MD USA. [Klair, Jagpal] Univ Iowa Hosp & Clin, Div Gastroenterol & Hepatol, Iowa City, IA 52242 USA. [Terrault, Norah A.] Univ Calif San Francisco, Div Gastroenterol, San Francisco, CA 94143 USA. [Clark, Jeanne M.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Clark, Jeanne M.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Unalp-Arida, Aynur] NIDDK, Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. [Suzuki, Ayako] Cent Arkansas Vet Healthcare Syst, Gastroenterol, Little Rock, AR USA. [Suzuki, Ayako] Univ Arkansas Med Sci, Gastroenterol & Hepatol, Little Rock, AR 72205 USA. RP Suzuki, A (reprint author), Cent Arkansas Vet Healthcare Syst, Div Gastroenterol, 111 HLR, Little Rock, AR 72205 USA. EM ayako.suzuki@va.gov FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713]; National Center for Advancing Translational Sciences (NCATS) [UL1TR000439, UL1TR000077, UL1TR000436, UL1TR000150, UL1TR000424, UL1TR000006, UL1TR000448, UL1TR000040, UL1TR000100, UL1TR000004, UL1TR000423, UL1TR000058, UL1TR000454]; Intramural Research Program of the NIH, National Cancer Institute. FX The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, and U01DK061713). Additional support is received from the National Center for Advancing Translational Sciences (NCATS) (grants UL1TR000439, UL1TR000077, UL1TR000436, UL1TR000150, UL1TR000424, UL1TR000006, UL1TR000448, UL1TR000040, UL1TR000100, UL1TR000004, UL1TR000423, UL1TR000058, and UL1TR000454). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. NR 15 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD JAN PY 2017 VL 15 IS 1 BP 127 EP + DI 10.1016/j.cgh.2016.07.034 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EO1XW UT WOS:000396492200028 PM 27523635 ER PT J AU Pollett, S Boscardin, WJ Azziz-Baumgartner, E Tinoco, YO Soto, G Romero, C Kok, J Biggerstaff, M Viboud, C Rutherford, GW AF Pollett, Simon Boscardin, W. John Azziz-Baumgartner, Eduardo Tinoco, Yeny O. Soto, Giselle Romero, Candice Kok, Jen Biggerstaff, Matthew Viboud, Cecile Rutherford, George W. TI Evaluating Google Flu Trends in Latin America: Important Lessons for the Next Phase of Digital Disease Detection SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Google Flu Trends; Latin America; digital epidemiology ID INFLUENZA; SURVEILLANCE; EPIDEMICS; BURDEN; PERU AB Background. Latin America has a substantial burden of influenza and rising Internet access and could benefit from real-time influenza epidemic prediction web tools such as Google Flu Trends (GFT) to assist in risk communication and resource allocation during epidemics. However, there has never been a published assessment of GFT's accuracy inmost Latin American countries or in any low-to middle-income country. Our aim was to evaluate GFT in Argentina, Bolivia, Brazil, Chile, Mexico, Paraguay, Peru, and Uruguay. Methods. Weekly influenza-test positive proportions for the eight countries were obtained from FluNet for the period January 2011-December 2014. Concurrent weekly Google-predicted influenza activity in the same countries was abstracted from GFT. Pearson correlation coefficients between observed and Google-predicted influenza activity trends were determined for each country. Permutation tests were used to examine background seasonal correlation between FluNet and GFT by country. Results. There were frequent GFT prediction errors, with correlation ranging from r = -0.53 to 0.91. GFT-predicted influenza activity best correlated with FluNet data in Mexico follow by Uruguay, Argentina, Chile, Brazil, Peru, Bolivia and Paraguay. Correlation was generally highest in the more temperate countries with more regular influenza seasonality and lowest in tropical regions. A substantial amount of autocorrelation was noted, suggestive that GFT is not fully specific for influenza virus activity. Conclusions. We note substantial inaccuracies with GFT-predicted influenza activity compared with FluNet throughout Latin America, particularly among tropical countries with irregular influenza seasonality. Our findings offer valuable lessons for future Internet-based biosurveillance tools. C1 [Pollett, Simon; Boscardin, W. John; Rutherford, George W.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Level 2,Mission Hall,3rd St, San Francisco, CA 94143 USA. [Pollett, Simon] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. [Azziz-Baumgartner, Eduardo; Biggerstaff, Matthew] Ctr Dis Control & Prevent, Influenza Div, Atlanta, GA USA. [Tinoco, Yeny O.; Soto, Giselle; Romero, Candice] US Naval Med Res Unit 6, Dept Virol & Emerging Infect Dis, Callao, Peru. [Kok, Jen] Westmead Hosp, Ctr Infect Dis, Level 3, Westmead, NSW, Australia. [Kok, Jen] Westmead Hosp, Microbiol Lab Serv, Inst Clin Pathol & Med Res, Pathol West, Level 3, Westmead, NSW, Australia. [Viboud, Cecile] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Pollett, S (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, Level 2,Mission Hall,3rd St, San Francisco, CA 94143 USA. EM spollett@med.usyd.edu.au FU CDC; US Department of Defense Global Emerging Infections Surveillance [I0082_09_LI] FX The Peruvian community-based surveillance data were originally collected in a study funded by the CDC and the US Department of Defense Global Emerging Infections Surveillance (grant I0082_09_LI). NR 22 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JAN 1 PY 2017 VL 64 IS 1 BP 34 EP 41 DI 10.1093/cid/ciw657 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP1CN UT WOS:000397123100014 PM 27678084 ER PT J AU Chen, DP Davis, BR Simpson, LM Cushman, WC Cutler, JA Dobre, M Ford, CE Louis, GT Muntner, P Oparil, S Piller, LB Pressel, SL Sarnak, MJ Whelton, PK Wright, JT Rahman, M AF Chen, Dhruti P. Davis, Barry R. Simpson, Lara M. Cushman, William C. Cutler, Jeffrey A. Dobre, Mirela Ford, Charles E. Louis, Gail T. Muntner, Paul Oparil, Suzanne Piller, Linda B. Pressel, Sara L. Sarnak, Mark J. Whelton, Paul K. Wright, Jackson T. Rahman, Mahboob CA ALLHAT Collaborative Res Grp TI Association between chronic kidney disease and cancer mortality: A report from the ALLHAT SO CLINICAL NEPHROLOGY LA English DT Article DE chronic kidney disease; cancer; glomerular filtration rate ID LIPID-LOWERING TREATMENT; STAGE RENAL-DISEASE; HEART-ATTACK TRIAL; UNITED-STATES; P-CRESOL; RISK; CKD; POPULATION; COHORT; DEATH AB Background/objectives: Chronic kidney disease (CKD) and cancer are both common in older patients; whether CKD increases risk for cancer is unclear. This study evaluated CKD as a risk factor for cancer mortality in a large cohort of hypertensive patients. Study design: We did post-hoc analyses of in-trial and post-trial data from participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Setting and participants: Participants were = 55 years old with hypertension and one other additional risk factor for coronary heart disease. Predictor: Baseline estimated glomerular filtration rate (eGFR). Outcomes: Cancer mortality was ascertained by cancer-related deaths reported in national databases during and after the trial. Cox proportional hazard models were used to calculate hazard ratios (HRs) adjusted for possible confounders and were stratified by baseline GFR. Results: Participants' mean age was 66.(years. After a mean follow-up of 8.(years, there were 2,338 reported cancer-related deaths. Participants with GFR < 45 mL/min/1.73 m(2) were at increased risk of cancer mortality compared to those with GFR >= 90 mL/min/1.73 m(2) (adjusted HR 1.54 (1.22 -1.94), p-value for trend 0.004). These findings were consistent across subgroups defined by race, gender, and diabetes. Participants with GFR < 45 mL/min/1.73 m(2) were at higher risk for mortality related to colon cancer (p-value for trend 0.048, HR 2.28 (1.12 -4.62)) and urinary tract cancer (p-value for trend 0.001, adjusted HR 2.95 (1.14 -7.65)). Limitations: This is a post hoc analysis of clinical trial data. Conclusions: In a large cohort of hypertensive patients, GFR < 45 mL/min/1.73 m(2) was associated with a higher risk of cancer-related mortality. C1 [Chen, Dhruti P.] Case Western Reserve Univ, Dept Med, Univ Hosp Case Med Ctr, Louis Stokes Cleveland Vet Affairs Med Ctr, Cleveland, OH 44106 USA. [Davis, Barry R.; Simpson, Lara M.; Ford, Charles E.; Muntner, Paul; Piller, Linda B.; Pressel, Sara L.] Univ Texas Houston, Sch Publ Hlth, Div Biostat, Coordinating Ctr Clin Trials, Houston, TX USA. [Cushman, William C.] Memphis Vet Affairs Med Ctr, Prevent Med Sect, Memphis, TN USA. [Cutler, Jeffrey A.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Dobre, Mirela; Wright, Jackson T.; Rahman, Mahboob] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Louis Stokes Cleveland Vet Affairs Med Ctr, Div Nephrol & Hypertens, Cleveland, OH 44106 USA. [Louis, Gail T.; Whelton, Paul K.] Tulane Univ, Hlth Sci Ctr, New Orleans, LA 70118 USA. [Muntner, Paul] UAB, Dept Epidemiol, Birmingham, AL USA. [Oparil, Suzanne] Univ Alabama Birmingham, Dept Med, Birmingham, AL USA. [Sarnak, Mark J.] Tufts Med Ctr, Div Nephrol, Boston, MA USA. RP Rahman, M (reprint author), Case Western Reserve Univ, Div Nephrol & Hypertens, Univ Hosp Case Med Ctr, Louis Stokes Cleveland VA Med Ctr, Cleveland, OH 44106 USA. EM Mahboob.Rahman@UHhospitals.org FU US National Heart, Lung, and Blood Institute [N01-HC-35130, HHSN268201100036C]; Pfizer, Inc. FX This study was supported by contract N01-HC-35130 and HHSN268201100036C from the US National Heart, Lung, and Blood Institute. The Institute's role included involvement in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. The ALLHAT investigators acknowledge contributions of study medications supplied by Pfizer, Inc., (New York, NY, USA) (amlodipine and doxazosin), AstraZeneca (London, UK) (atenolol and lisinopril), and Bristol-Myers Squibb (New York, NY, USA) (pravastatin) and financial support provided by Pfizer, Inc. NR 32 TC 0 Z9 0 U1 1 U2 1 PU DUSTRI-VERLAG DR KARL FEISTLE PI DEISENHOFEN-MUENCHEN PA BAHNHOFSTRASSE 9 POSTFACH 49, D-82032 DEISENHOFEN-MUENCHEN, GERMANY SN 0301-0430 J9 CLIN NEPHROL JI Clin. Nephrol. PD JAN PY 2017 VL 87 IS 1 BP 11 EP 20 DI 10.5414/CN108949 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA EO9TX UT WOS:000397032100002 PM 27900942 ER PT J AU Hourigan, CS AF Hourigan, Christopher S. TI Targets for Immunotherapy in Acute Leukemia SO CURRENT DRUG TARGETS LA English DT Editorial Material ID CANCER C1 [Hourigan, Christopher S.] NHLBI, Myeloid Malignancies Sect, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Hourigan, CS (reprint author), NHLBI, Myeloid Malignancies Sect, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. FU Intramural Research Program of the National Heart, Lung, Blood Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Heart, Lung, Blood Institute of the National Institutes of Health. NR 9 TC 0 Z9 0 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-4501 EI 1873-5592 J9 CURR DRUG TARGETS JI Curr. Drug Targets PY 2017 VL 18 IS 3 BP 256 EP 256 DI 10.2174/1389450117999151116144835 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL1NU UT WOS:000394387900001 PM 28264642 ER PT J AU Shah, NN AF Shah, Nirali N. TI Antibody Based Therapies in Acute Leukemia SO CURRENT DRUG TARGETS LA English DT Review DE Acute leukemia; antibody therapy; blinatumomab; gemtuzumab; inotuzumab; rituximab ID ACUTE-LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; CHILDRENS-ONCOLOGY-GROUP; ACUTE LYMPHOCYTIC-LEUKEMIA; MINIMAL RESIDUAL DISEASE; B-CELL LYMPHOMA; IMMUNOTOXIN MOXETUMOMAB PASUDOTOX; ANTI-CD33 MONOCLONAL-ANTIBODY; SYSTEMIC-LUPUS-ERYTHEMATOSUS; CHILDHOOD-CANCER SURVIVOR AB Despite great progress in the curative treatment of acute leukemia, outcomes for those with relapsed and/or chemotherapy-refractory disease remain poor. Current intensive cytotoxic therapies can be associated with significant morbidity and novel therapies are needed to improve outcomes. Immunotherapy based approaches provide an alternative mechanism of action in the treatment of acute leukemia. Due to cell surface antigen expression, leukemia in particular is amenable to targeted therapies, such as antibody-based therapy. Based on the potential for non-overlapping toxicity, the possibility of synergistic action with standard chemotherapy, and by providing a novel method to overcome chemotherapy resistance, antibody-based therapies have shown potential for benefit. Modifications to standard monoclonal antibodies, including drug conjugation and linkage to T-cells, may further enhance efficacy of antibody-based therapies. Identifying the ideal timing for incorporation of antibody-based therapies, within standard regimens, may lead to improvement in overall outcomes. This article will provide an overview of antibody-based therapies in clinical development for the treatment of acute leukemia in children and adults, with a particular focus on the current strategies and future developments. C1 [Shah, Nirali N.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Shah, NN (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Room 1W-3750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Nirali.Shah@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Warren Grant Magnuson Clinical Center FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and the Warren Grant Magnuson Clinical Center. NR 158 TC 0 Z9 0 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-4501 EI 1873-5592 J9 CURR DRUG TARGETS JI Curr. Drug Targets PY 2017 VL 18 IS 3 BP 257 EP 270 DI 10.2174/1389450117666160905091459 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL1NU UT WOS:000394387900002 PM 27593687 ER PT J AU Goswami, M Hourigan, CS AF Goswami, Meghali Hourigan, Christopher S. TI Novel Antigen Targets for Immunotherapy of Acute Myeloid Leukemia SO CURRENT DRUG TARGETS LA English DT Review DE Acute myeloid leukemia; antigens; immunotherapy ID STEM-CELL TRANSPLANTATION; ACUTE MYELOGENOUS LEUKEMIA; MINIMAL RESIDUAL DISEASE; EXOME ANALYSIS REVEALS; MHC-CLASS-I; T-CELLS; CLONAL HEMATOPOIESIS; MULTIPLE-MYELOMA; CANCER ANTIGENS; NPM1 MUTATION AB Acute myeloid leukemia (AML) was the first malignancy for which immunotherapy, in the form of allogeneic hematopoietic stem cell transplantation (allo-HSCT), was integrated into the standard of care. Allo-HSCT however is an imperfect therapy associated with significant morbidity and mortality while offering only incomplete prevention of AML clinical relapse. These limitations have motivated the search for AML-related antigens that might be used as more specific and effective targets of immunotherapy. While historically such investigations have focused on protein targets expressed uniquely in AML or at significantly higher levels than in normal tissues, this article will review recent discoveries which have identified a novel selection of potential antigen targets for AML immunotherapy, such as non-protein targets including lipids and carbohydrates, neo-antigens created from genetic somatic mutations or altered splicing and post-translational modification of protein targets, together with innovative ways to target overexpressed protein targets presented by cell surface peptide-MHC complexes. These novel antigens represent promising candidates for further development as targets of AML immunotherapy. C1 [Goswami, Meghali; Hourigan, Christopher S.] NHLBI, Myeloid Malignancies Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Goswami, M (reprint author), NHLBI, Myeloid Malignancies Sect, Room 6C-104,10 Ctr Dr, Bethesda, MD 20892 USA. EM meg.goswami@nih.gov FU Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. Meghali Goswami is a predoctoral student in the Institute for Biomedical Sciences at The George Washington University. This work is from a dissertation to be presented to the above program in partial fulfillment of the requirements for the Ph.D. degree. NR 86 TC 1 Z9 1 U1 1 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-4501 EI 1873-5592 J9 CURR DRUG TARGETS JI Curr. Drug Targets PY 2017 VL 18 IS 3 BP 296 EP 303 DI 10.2174/1389450116666150223120005 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL1NU UT WOS:000394387900005 PM 25706110 ER PT J AU Gonzalez, FJ Jiang, CT Xie, C Patterson, AD AF Gonzalez, Frank J. Jiang, Changtao Xie, Cen Patterson, Andrew D. TI Intestinal Farnesoid X Receptor Signaling Modulates Metabolic Disease SO DIGESTIVE DISEASES LA English DT Article; Proceedings Paper CT 24th International Bile Acid Meeting on Bile Acids in Health and Disease CY JUN 17-18, 2016 CL Dusseldorf, GERMANY DE Bile acids; Farnesoid X receptor; Ceramides; Obesity; Diabetes; Non-alcoholic fatty liver disease ID FATTY LIVER-DISEASE; NUCLEAR RECEPTOR; BILE-ACID; OBETICHOLIC ACID; MICE; FXR; HEPATOCARCINOGENESIS; IDENTIFICATION; PHARMACOLOGY; INHIBITION AB Farnesoid X receptor (FXR) regulates the synthesis, transport and enterohepatic circulation of bile acids (BA) by modulating the expression of related genes in the liver and small intestine. The composition of the gut microbiota is correlated with metabolic diseases, notably obesity and non-alcoholic fatty acid disease (NAFLD). Recent studies revealed that bacterial metabolism of BA can modulate FXR signaling in the intestine by altering the composition and concentrations of FXR agonist and antagonist. FXR agonist enhances while FXR antagonist suppresses obesity, NAFLD and insulin resistance. The role of intestinal FXR in metabolic disease was firmly established by the analysis of mice lacking FXR that are metabolic resistant to HFD-induced metabolic disease. This is mediated by FXR modulating in part the expression of genes involved in ceramide synthesis in the small intestine. In ileum of obese mice due to the presence of endogenous FXR agonists produced in the liver, these genes are activated, while in mice with altered levels of specific gut bacteria, levels of an FXR antagonist, tauro-beta-muricholic acid (T-beta-MCA) increase and FXR signaling and ceramide synthesis are repressed. T-beta-MCA, which is metabolized in wild-type mice, led to the discovery of glycine-beta-muricholic acid (Gly-MCA) that is stable in the intestine and a potent inhibitor of FXR signaling. These studies reveal that ceramides produced in the ileum under the control of FXR, influence metabolic disease, and suggest that novel FXR antagonist such as GlyMCA that specifically inhibit intestine FXR, could serve as potential drug for the treatment of metabolic disease. (C) 2017 S. Karger AG, Basel C1 [Gonzalez, Frank J.; Xie, Cen] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Patterson, Andrew D.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Patterson, Andrew D.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Jiang, Changtao] Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing, Peoples R China. [Jiang, Changtao] Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov NR 36 TC 0 Z9 0 U1 3 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0257-2753 EI 1421-9875 J9 DIGEST DIS JI Dig. Dis. PY 2017 VL 35 IS 3 BP 178 EP 184 DI 10.1159/000450908 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EM5MP UT WOS:000395356000005 PM 28249275 ER PT J AU Gonzalez, FJ Xie, C Jiang, C Brocker, C Patterson, AD AF Gonzalez, Frank J. Xie, Cen Jiang, Changtao Brocker, Chad Patterson, Andrew D. TI THE ROLE OF TOXIC LIPIDS METABOLIC DISEASE SO DRUG METABOLISM AND PHARMACOKINETICS LA English DT Meeting Abstract C1 [Gonzalez, Frank J.] Natl Canc Inst, Lab Metab, Bethesda, MD USA. [Xie, Cen; Brocker, Chad] Natl Canc Inst, Bethesda, MD USA. [Jiang, Changtao] Peking Univ, Beijing 100871, Peoples R China. [Patterson, Andrew D.] Penn State Univ, University Pk, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPANESE SOC STUDY XENOBIOTICS PI TOKYO PA INT MED INF CENTER SHINANOMACHI RENGAKAN, 35 SHINANO-MACHI SHINJUKU-KU, TOKYO, 160-0016, JAPAN SN 1347-4367 EI 1880-0920 J9 DRUG METAB PHARMACOK JI Drug Metab. Pharmacokinet. PD JAN PY 2017 VL 32 IS 1 SU S MA S37 BP S11 EP S12 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO9MW UT WOS:000397013800043 ER PT J AU Wang, RP Qi, YP Gu, XQ Lu, F Fan, GR Chai, YF Gonzalez, FJ Gengli, D AF Wang, Renping Qi, Yunpeng Gu, Xueqin Lu, Feng Fan, Guorong Chai, Yifeng Gonzalez, Frank J. Gengli, Duan, Sr. TI METABOLOMICS ILLUSTRATES CELASTROL-MEDIATED SUPPRESSION ON COLITIS SO DRUG METABOLISM AND PHARMACOKINETICS LA English DT Meeting Abstract C1 [Wang, Renping; Qi, Yunpeng; Gu, Xueqin; Lu, Feng; Fan, Guorong; Chai, Yifeng] Second Mil Med Univ, Shanghai, Peoples R China. [Qi, Yunpeng; Gengli, Duan, Sr.] Fudan Univ, Sch Pharm, Dept Pharmaceut Anal, Shanghai, Peoples R China. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU JAPANESE SOC STUDY XENOBIOTICS PI TOKYO PA INT MED INF CENTER SHINANOMACHI RENGAKAN, 35 SHINANO-MACHI SHINJUKU-KU, TOKYO, 160-0016, JAPAN SN 1347-4367 EI 1880-0920 J9 DRUG METAB PHARMACOK JI Drug Metab. Pharmacokinet. PD JAN PY 2017 VL 32 IS 1 SU S MA P121 BP S61 EP S62 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO9MW UT WOS:000397013800204 ER PT J AU Miranda, RA Franco, CCD de Oliveira, JC Barella, LF Tofolo, LP Ribeiro, TA Pavanello, A da Conceicao, EPS Torrezan, R Armitage, J Lisboa, PC de Moura, EG Mathias, PCD Vieira, E AF Miranda, Rosiane Aparecida da Silva Franco, Claudineia Conationi de Oliveira, Julio Cezar Barella, Luiz Felipe Tofolo, Laize Peron Ribeiro, Tatiane Aparecida Pavanello, Audrei Santos da Conceicao, Ellen Paula Torrezan, Rosana Armitage, James Lisboa, Patricia Cristina de Moura, Egberto Gaspar de Freitas Mathias, Paulo Cezar Vieira, Elaine TI Cross-fostering reduces obesity induced by early exposure to monosodium glutamate in male rats SO ENDOCRINE LA English DT Article DE Cross-fostering; Monosodium glutamate; Obesity ID HIGH-FAT DIET; PANCREATIC-ISLETS; MATERNAL OBESITY; OFFSPRING METABOLISM; GLUCOSE-INTOLERANCE; INSULIN-RESISTANCE; LEPTIN RESISTANCE; MILK-COMPOSITION; GENE-EXPRESSION; FEMALE RATS AB Maternal obesity programmes a range of metabolic disturbances for the offspring later in life. Moreover, environmental changes during the suckling period can influence offspring development. Because both periods significantly affect long-term metabolism, we aimed to study whether cross-fostering during the lactation period was sufficient to rescue a programmed obese phenotype in offspring induced by maternal obesity following monosodium L-glutamate (MSG) treatment. Obesity was induced in female Wistar rats by administering subcutaneous MSG (4 mg/g body weight) for the first 5 days of postnatal life. Control and obese female rats were mated in adulthood. The resultant pups were divided into control second generation (F-2) (CTLF2), MSG-treated second generation (F-2) (MSGF(2)), which suckled from their CTL and MSG biological dams, respectively, or CTLF2-CR, control offspring suckled by MSG dams and MSGF(2)-CR, MSG offspring suckled by CTL dams. At 120 days of age, fat tissue accumulation, lipid profile, hypothalamic leptin signalling, glucose tolerance, glucose-induced, and adrenergic inhibition of insulin secretion in isolated pancreatic islets were analysed. Maternal MSG-induced obesity led to an obese phenotype in male offspring, characterized by hyperinsulinaemia, hyperglycaemia, hyperleptinaemia, dyslipidaemia, and impaired leptin signalling, suggesting central leptin resistance, glucose intolerance, impaired glucose-stimulated, and adrenergic inhibition of insulin secretion. Cross-fostering normalized body weight, food intake, leptin signalling, lipid profiles, and insulinaemia, but not glucose homeostasis or insulin secretion from isolated pancreatic islets. Our findings suggest that alterations during the lactation period can mitigate the development of obesity and prevent the programming of adult diseases. C1 [Miranda, Rosiane Aparecida; da Silva Franco, Claudineia Conationi; Tofolo, Laize Peron; Ribeiro, Tatiane Aparecida; Pavanello, Audrei; de Freitas Mathias, Paulo Cezar; Vieira, Elaine] State Univ Maringa UEM, Dept Biotechnol Cell Biol & Genet, Block H67,Room 19,Colombo Ave 5790, Maringa, PR, Brazil. [Miranda, Rosiane Aparecida] Univ Fed Rio de Janeiro, Carlos Chagas Filho Biophys Inst, Rio De Janeiro, RJ, Brazil. [de Oliveira, Julio Cezar] Univ Fed Mato Grosso, Hlth Sci Inst, Sinop, MT, Brazil. [Barella, Luiz Felipe] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Santos da Conceicao, Ellen Paula; Lisboa, Patricia Cristina; de Moura, Egberto Gaspar] Univ Estado Rio De Janeiro, Dept Physiol Sci, Roberto Alcantara Gomes Biol Inst, Rio De Janeiro, RJ, Brazil. [Torrezan, Rosana] Univ Estadual Maringa, Dept Physiol Sci, Maringa, PR, Brazil. [Armitage, James] Deakin Univ, Sch Med Optometr, Geelong, Vic 3216, Australia. RP Miranda, RA (reprint author), State Univ Maringa UEM, Dept Biotechnol Cell Biol & Genet, Block H67,Room 19,Colombo Ave 5790, Maringa, PR, Brazil.; Miranda, RA (reprint author), Univ Fed Rio de Janeiro, Carlos Chagas Filho Biophys Inst, Rio De Janeiro, RJ, Brazil. EM roapmiranda@yahoo.com.br RI Barella, Luiz/C-1181-2014 OI Barella, Luiz/0000-0003-2211-3842 FU Brazilian Federal Foundation; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) FX This work was supported by the Brazilian Federal Foundation, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), and Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES). NR 60 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD JAN PY 2017 VL 55 IS 1 BP 110 EP 121 DI 10.1007/s12020-016-0965-y PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EK9PY UT WOS:000394257600014 PM 27116693 ER PT J AU Mamluk, L O'Doherty, MG Orfanos, P Saitakis, G Woodside, JV Liao, LM Sinha, R Boffetta, P Trichopoulou, A Kee, F AF Mamluk, L. O'Doherty, M. G. Orfanos, P. Saitakis, G. Woodside, J. V. Liao, L. M. Sinha, R. Boffetta, P. Trichopoulou, A. Kee, F. CA CHANCES Consortium TI Fruit and vegetable intake and risk of incident of type 2 diabetes: results from the consortium on health and ageing network of cohorts in Europe and the United States (CHANCES) SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID GREEN LEAFY VEGETABLES; PRIMARY PREVENTION; MAGNESIUM INTAKE; DIETARY NITRATE; MELLITUS; METAANALYSIS; CONSUMPTION; DESIGN; BEETROOT; PROJECT AB BACKGROUND/OBJECTIVES: There is limited information to support definitive recommendations concerning the role of diet in the development of type 2 Diabetes mellitus (T2DM). The results of the latest meta-analyses suggest that an increased consumption of green leafy vegetables may reduce the incidence of diabetes, with either no association or weak associations demonstrated for total fruit and vegetable intake. Few studies have, however, focused on older subjects. SUBJECTS/METHODS: The relationship between T2DM and fruit and vegetable intake was investigated using data from the NIH-AARP study and the EPIC Elderly study. All participants below the age of 50 and/or with a history of cancer, diabetes or coronary heart disease were excluded from the analysis. Multivariate logistic regression analysis was used to calculate the odds ratio of T2DM comparing the highest with the lowest estimated portions of fruit, vegetable, green leafy vegetables and cabbage intake. RESULTS: Comparing people with the highest and lowest estimated portions of fruit, vegetable or green leafy vegetable intake indicated no association with the risk of T2DM. However, although the pooled OR across all studies showed no effect overall, there was significant heterogeneity across cohorts and independent results from the NIH-AARP study showed that fruit and green leafy vegetable intake was associated with a reduced risk of T2DM OR 0.95 (95% CI 0.91,0.99) and OR 0.87 (95% CI 0.87,0.90) respectively. CONCLUSIONS: Fruit and vegetable intake was not shown to be related to incident T2DM in older subjects. Summary analysis also found no associations between green leafy vegetable and cabbage intake and the onset of T2DM. Future dietary pattern studies may shed light on the origin of the heterogeneity across populations. C1 [Mamluk, L.; O'Doherty, M. G.; Woodside, J. V.; Kee, F.] Queens Univ Belfast, UKCRC Ctr Excellence Publ Hlth Northern Ireland, Belfast BT7 1NN, Antrim, North Ireland. [Orfanos, P.; Saitakis, G.; Trichopoulou, A.] Univ Athens, Dept Hyg Epidemiol & Med Stat, Athens, Greece. [Liao, L. M.; Sinha, R.] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Rockville, MD USA. [Boffetta, P.] Mt Sinai Sch Med, Tisch Canc Inst & Inst Translat Epidemiol, New York, NY USA. [Boffetta, P.; Trichopoulou, A.] Hellen Hlth Fdn, Athens, Greece. RP Mamluk, L (reprint author), Univ Bristol, Univ Hosp Bristol NHS Fdn Trust, Sch Social & Community Med, NIHR CLAHRC West,MRC Integrat Epidemiol Unit, Oakfield House,9th Floor, Bristol BS1 2NT, Avon, England. EM l.mamluk@bristol.ac.uk FU European Community [HEALTH -F3-2010-242244]; Intramural Research Program of the NIH, National Cancer Institute FX This work was supported by funding from the European Community's Seventh Framework Programme (FP7/2007-2013) (grant number HEALTH -F3-2010-242244). This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia. Cancer incidence data from California were collected by the California Cancer Registry, California Department of Public Health's Cancer Surveillance and Research Branch, Sacramento, California. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, Lansing, Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (Miami, Florida) under contract with the Florida Department of Health, Tallahassee, Florida. The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Health Sciences Center School of Public Health, New Orleans, Louisiana. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health, Trenton, New Jersey. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry, Raleigh, North Carolina. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services, Phoenix, Arizona. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, Division of Public and Behavioral Health, State of Nevada Department of Health and Human Services, Carson City, NevadaNevada. We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support and analysis. Ethical standard: All of the cohorts obtained ethical approval and written informed consent was obtained from all participants. NR 38 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 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD JAN PY 2017 VL 71 IS 1 BP 83 EP 91 DI 10.1038/ejcn.2016.143 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EK6GU UT WOS:000394023900014 PM 27530474 ER PT J AU Wang, S Meigs, JB Dupuis, J AF Wang, Shuai Meigs, James B. Dupuis, Josee TI Joint association analysis of a binary and a quantitative trait in family samples SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENERALIZED ESTIMATING EQUATIONS; BODY-MASS INDEX; EXTENDED QUASI-LIKELIHOOD; SUSCEPTIBILITY LOCI; GENETIC ASSOCIATION; CLUSTERED DATA; METAANALYSIS; MODELS; RISK AB In recent years, improved genotyping and sequencing technologies have enabled the discovery of new loci associated with various diseases or traits. For instance, by testing the association with each single-nucleotide variant (SNV) separately, genome-wide association studies (GWAS) have achieved tremendous success in identifying SNVs associated with specific traits. However, little is known about the common genetic basis of multiple traits owing to lack of efficient methods. With the use of extended quasi-likelihood, a Wald test has been proposed to perform a bivariate analysis of a continuous and a binary trait in unrelated samples. However, owing to its low computational efficiency, it has not been implemented in real applications to large-scale genetic studies. In this paper, we propose an efficient bivariate robust score test for two traits, one continuous and one binary, based on extended generalized estimating equations. Our approach is applicable to both family-based and unrelated study designs and can be extended to test the association of multiple traits. Our simulation studies demonstrate the type-I error rate of our approach is well controlled in all minor allele frequency (MAF) scenarios, with MAF ranging from 1 to 30%, and the method is more powerful in certain MAF scenarios than univariate testing with correction for multiple testing. Because of the computational advantage of score tests, our approach is readily applicable to GWAS or sequencing studies. Finally, we present a real application to uncover genetic variants associated with body mass index and type-2 diabetes in the Framingham Heart Study. C1 [Wang, Shuai; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, 801 Mass Ave,3rd Floor, Boston, MA 02118 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Med Sch, Dept Med, Boston, MA USA. [Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Wang, S (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, 801 Mass Ave,3rd Floor, Boston, MA 02118 USA. EM tutuwang@bu.edu FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195, HHSN268201500001I]; Affymetrix Inc [N02-HL-6-4278]; National Institute of National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK078616, DK080140]; American Diabetes Association Mentor-Based Postdoctoral Fellowship [7-09-MN-32]; NIDDK [K24 DK080140] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195 & HHSN268201500001I) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278), and by grants from the National Institute of National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616, NIDDK K24 DK080140 and American Diabetes Association Mentor-Based Postdoctoral Fellowship Award # 7-09-MN-32. NR 35 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 JAN PY 2017 VL 25 IS 1 BP 130 EP 136 DI 10.1038/ejhg.2016.134 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EK7OW UT WOS:000394116100020 PM 27782109 ER PT J AU Patton, J Brewer, C Chien, W Johnston, JJ Griffith, AJ Biesecker, LG AF Patton, John Brewer, Carmen Chien, Wade Johnston, Jennifer J. Griffith, Andrew J. Biesecker, Leslie G. TI A genotypic ascertainment approach to refute the association of MYO1A variants with non-syndromic deafness SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HEARING-LOSS; MUTATIONS; GENE; MEDICINE AB Variants in the unconventional myosin gene, MYO1A, have been reported to cause non-syndromic sensorineural hearing loss with a pattern of autosomal dominant inheritance. Others have challenged this association. We used a genotypic ascertainment study design to test the association of MYO1A variants with hearing loss. We evaluated MYO1A variants from a cohort of 951 individuals with exome sequencing who were not ascertained for hearing loss. Five individuals had one of two variants claimed to be associated with sensorineural hearing loss in a prior study and 33 individuals had one of 13 predicted deleterious variants. We obtained audiology evaluations for 12 individuals with these variants of interest. The hearing acuity of the participants was compared with age-and sex-matched controls and published age-and sex-specific reference ranges from a large population of otologically screened adults. None of the participants had bilateral sensorineural hearing loss of moderate or greater severity. These data do not support a causal relationship of variants in MYO1A to sensorineural hearing loss. We suggest that the genotypic ascertainment method is useful to objectively evaluate gene-phenotype associations. C1 [Patton, John; Johnston, Jennifer J.; Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, 50 South Dr Room 5140, Bethesda, MD 20892 USA. [Brewer, Carmen; Chien, Wade; Griffith, Andrew J.] NIDCD, Otolaryngol Branch, NIH, Bethesda, MD USA. [Patton, John] Des Moines Univ, Coll Osteopath Med, Des Moines, IA USA. RP Biesecker, LG (reprint author), NHGRI, Med Genom & Metab Genet Branch, NIH, 50 South Dr Room 5140, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, the National Human Genome Research Institute; Intramural Research Program of the National Institutes of Health, National Institute for Deafness and Communicative Disorders FX The authors are grateful to the ClinSeq participants for their contribution to this work. All authors were supported by the Intramural Research Program of the National Institutes of Health, either the National Human Genome Research Institute (LGB, JP, and JJJ) or the National Institute for Deafness and Communicative Disorders (CB, WC, and AJG). NR 16 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 JAN PY 2017 VL 25 IS 1 BP 147 EP 149 DI 10.1038/ejhg.2016.140 PG 3 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EK7OW UT WOS:000394116100022 PM 27759032 ER PT J AU Vrisekoop, N Artusa, P Monteiro, JP Mandl, JN AF Vrisekoop, Nienke Artusa, Patricio Monteiro, Joao P. Mandl, Judith N. TI Weakly self-reactive T-cell clones can homeostatically expand when present at low numbers SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Lymphopenia-induced proliferation; Regulation of homeostasis; T-cell competition; T-cell diversity; T-cell repertoire ID PRECURSOR FREQUENCY; POSITIVE SELECTION; CUTTING EDGE; NAIVE CD4(+); HOMEOSTASIS; PROLIFERATION; RECEPTOR; COMPETITION; SURVIVAL; MICE AB T-cell division is central to maintaining a stable T-cell pool in adults. It also enables T-cell expansion in neonates, and after depletion by chemotherapy, bone marrow transplantation, or infection. The same signals required for T-cell survival in lymphoreplete settings, IL-7 and T-cell receptor (TCR) interactions with self-peptide MHC (pMHC), induce division when T-cell numbers are low. The strength of reactivity for self-pMHC has been shown to correlate with the capacity of T cells to undergo lymphopenia-induced proliferation (LIP), in that weakly self-reactive T cells are unable to divide, implying that T-cell reconstitution would significantly skew the TCR repertoire toward TCRs with greater self-reactivity and thus compromise T-cell diversity. Here, we show that while CD4(+) T cells with low self-pMHC reactivity experience more intense competition, they are able to divide when present at low enough cell numbers. Thus, at physiological precursor frequencies CD4(+) T cells with low self-pMHC reactivity are able to contribute to the reconstitution of the T-cell pool. C1 [Vrisekoop, Nienke] Univ Med Ctr Utrecht, Lab Translat Immunol, Dept Resp Med, Utrecht, Netherlands. [Artusa, Patricio; Mandl, Judith N.] McGill Univ, Complex Traits Grp, Dept Physiol, Montreal, PQ, Canada. [Monteiro, Joao P.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Vrisekoop, N (reprint author), Univ Med Ctr Utrecht, Lab Translat Immunol, Dept Resp Med, Utrecht, Netherlands.; Mandl, JN (reprint author), McGill Univ, Complex Traits Grp, Dept Physiol, Montreal, PQ, Canada. EM n.vrisekoop@umcutrecht.nl; judith.mandl@mcgill.ca FU Intramural Research Program of NIAID; NIH DHHS; McGill University FX N.V. and J.N.M. performed experiments, analyzed data and wrote the paper, J.P.M. and P.A. performed experiments. This work was supported by the Intramural Research Program of NIAID, NIH DHHS and a startup fund from McGill University (J.N.M.). The authors are grateful to William E. Paul and Ronald N. Germain (N.I.H.), Heather Melichar (U. of Montreal), and Jose A. M. Borghans (UMCU) for discussions and feedback, as well as Julie Edwards in the flow cytometry core at NIH for performing all cell sorts. NR 32 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JAN PY 2017 VL 47 IS 1 BP 68 EP 73 DI 10.1002/eji.201646540 PG 6 WC Immunology SC Immunology GA EL7ZI UT WOS:000394839400011 PM 27792294 ER PT J AU Callahan, R Chestnut, BA Raafat, A AF Callahan, Robert Chestnut, Barry A. Raafat, Ahmed TI Imatinib mesylate (Gleevec) inhibits Notch and c-Myc signaling: Five-day treatment permanently rescues mammary development SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE Mammary gland development; cancer; Notch; c-Myc; Gleevec; ubiquitin; proteasome ID GLYCOGEN-SYNTHASE KINASE-3-BETA; UBIQUITIN-PROTEASOME PATHWAY; TRUNCATED INT3 GENE; LUMINAL CELL-FATE; EPITHELIAL-CELLS; BREAST-CANCER; GLAND DEVELOPMENT; PROGESTERONE-RECEPTOR; INTRACELLULAR DOMAIN; PROTEIN-DEGRADATION AB Wap-Int3 transgenic females expressing the Notch4 intracellular domain (designated Int3) from the whey acidic protein promoter exhibit two phenotypes in the mammary gland: blockage of lobuloalveolar development and lactation, and tumor development with 100% penetrance. Previously, we have shown that treatment of Wap-Int3 tumor bearing mice with Imatinib mesylate (Gleevec) is associated with complete regression of the tumor. In the present study, we show that treatment of Wap-Int3 mice during day 1 through day 6 of pregnancy with Gleevec leads to the restoration of their lobuloalveolar development and ability to lactate in subsequent pregnancies in absence of Gleevec treatment. In addition, these mice do not develop mammary tumors. We investigated the mechanism for Gleevec regulation of Notch signaling and found that Gleevec treatment results in a loss of Int3 protein but not of Int3 mRNA in HC11 mouse mammary epithelial cells expressing Int3. The addition of MG-132, a proteasome inhibitor, shows increased ubiquitination of Int3 in the presence of Gleevec. Thus, Gleevec affects the stability of Int3 by promoting the degradation of Int3 via E3 ubiquitin ligases targeting it for the proteasome degradation. Gleevec is a tyrosine kinase inhibitor that acts on c-Kit and PDGFR. Therefore, we investigated the downstream substrate kinase GSK3 beta to ascertain the possible role that this kinase might play in the stability of Int3. Data show that Gleevec degradation of Int3 is GSK3 beta dependent. We have expanded our study of the effects Gleevec has on tumorigenesis of other oncogenes. We have found that anchorage-independent growth of HC11-c-Myc cells as well as tumor growth in nude mice is inhibited by Gleevec treatment. As with Int3, Gleevec treatment appears to destabilize the c-Myc protein but not mRNA. These results indicate that Gleevec could be a potential therapeutic drug for patients bearing Notch4 and/or c-Myc positive breast carcinomas. C1 [Callahan, Robert; Chestnut, Barry A.; Raafat, Ahmed] NCI, Basic Res Lab, NIH, Bethesda, MD 20814 USA. RP Raafat, A (reprint author), NCI, Basic Res Lab, NIH, Bethesda, MD 20814 USA. EM raafata@mail.nih.gov FU National Cancer Institute's Center for Cancer Research Intramural Research Program (Bethesda, MD) FX The authors thank Dr Gilbert H Smith for his advice and thorough reading of the manuscript, Dr Stefania Santopietro for preliminary data concerning c-Myc and Dr Avinash Bhandoola for his help in completing this project and Dr Lawrence Samelson for his support. The National Cancer Institute's Center for Cancer Research Intramural Research Program (Bethesda, MD) funded this work. NR 80 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1535-3702 EI 1535-3699 J9 EXP BIOL MED JI Exp. Biol. Med. PD JAN PY 2017 VL 242 IS 1 BP 53 EP 67 DI 10.1177/1535370216665175 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK9SA