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 UT WOS:000394263000006 PM 27550925 ER PT J AU Henter, ID de Sousa, RT Gold, PW Brunoni, AR Zarate, CA Machado-Vieira, R AF Henter, Ioline D. de Sousa, Rafael T. Gold, Philip W. Brunoni, Andre R. Zarate, Carlos A., Jr. Machado-Vieira, Rodrigo TI Mood Therapeutics: Novel Pharmacological Approaches for Treating Depression SO EXPERT REVIEW OF CLINICAL PHARMACOLOGY LA English DT Review DE AMPA receptor; bipolar disorder; depression; glutamate; major depressive disorder (MDD); mood; N-methyl-D-aspartate (NMDA); treatment ID PLACEBO-CONTROLLED TRIAL; TREATMENT-RESISTANT DEPRESSION; D-ASPARTATE ANTAGONIST; PROOF-OF-CONCEPT; RANDOMIZED CONTROLLED-TRIAL; ADD-ON TRIAL; PIOGLITAZONE ADJUNCTIVE THERAPY; PSYCHOTIC MAJOR DEPRESSION; RECEIVING HOSPICE CARE; N-ACETYL CYSTEINE AB Introduction: Real-world effectiveness trials suggest that antidepressant efficacy is limited in many patients with mood disorders, underscoring the urgent need for novel therapeutics to treat these disorders. Areas covered: Here, we review the clinical evidence supporting the use of novel modulators for the treatment of mood disorders, including specific glutamate modulators such as: 1) high-trapping glutamatergic modulators; 2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists; 3) NMDA receptor glycine-site partial agonists; and 4) metabotropic glutamate receptor (mGluR) modulators. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the glucocorticoid system, and the inflammation pathway, as well as several additional targets of interest. Clinical evidence is emphasized, and non-pharmacological somatic treatments are not reviewed. In general, this paper only explores agents available in the United States. Expert commentary: Of these novel targets, the most promising - and the ones for whom the most evidence exists - appear to be the ionotropic glutamate receptors. However, moving forward will require us to fully embrace the goal of personalized medicine and will require health professionals to pre-emptively identify potential responders. C1 [Henter, Ioline D.; de Sousa, Rafael T.; Gold, Philip W.; Zarate, Carlos A., Jr.; Machado-Vieira, Rodrigo] NIMH NIH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD USA. [Brunoni, Andre R.] Univ Sao Paulo, Inst Psychiat, Neurosci Lab, LIM 27, Sao Paulo, Brazil. [Brunoni, Andre R.] Univ Sao Paulo, Dept Psychiat, Neurosci Lab, LIM 27, Sao Paulo, Brazil. RP Machado-Vieira, R (reprint author), Expt Therapeut & Pathophysiol Branch, 10 Ctr Dr,Room 7-5341, Bethesda, MD 20892 USA. EM machadovieirar@mail.nih.gov FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [ZIA MH002927]; NARSAD Independent Investigator Award; Brain and Behavior Mood Disorders Research Award FX Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002927), by a NARSAD Independent Investigator Award to CA Zarate, and by a Brain and Behavior Mood Disorders Research Award to CA Zarate. NR 122 TC 0 Z9 0 U1 2 U2 2 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 2 BP 153 EP 166 DI 10.1080/17512433.2017.1253472 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO7DM UT WOS:000396851400003 PM 27781556 ER PT J AU Durdu, M Ilkit, M Tamadon, Y Tolooe, A Rafati, H Seyedmousavi, S AF Durdu, Murat Ilkit, Macit Tamadon, Yalda Tolooe, Ali Rafati, Haleh Seyedmousavi, Seyedmojtaba TI Topical and systemic antifungals in dermatology practice SO EXPERT REVIEW OF CLINICAL PHARMACOLOGY LA English DT Review DE Antifungals; dermatophytosis; Epidermophyton; Microsporum spp; tinea; Trichophyton spp ID IN-VITRO ACTIVITIES; OF-THE-LITERATURE; TRICHOPHYTON-TONSURANS INFECTION; CAPITIS CLINICAL-TRIAL; OCCULT ATHLETES FOOT; TINEA-CAPITIS; MAJOCCHIS GRANULOMA; FUNGAL-INFECTIONS; ORAL TERBINAFINE; STRATUM-CORNEUM AB Introduction: Dermatophytosis is generally defined as an infection of the hair, nails, or glabrous skin. These infections are caused by the keratinophilic fungi Trichophyton spp., Microsporum spp., and Epidermophyton, which have been recovered from both symptomatic and asymptomatic individuals. Although dermatophytosis is generally not a life-threatening condition, these types of infections are among the most common infections worldwide, and their incidence has continued to increase consistently in recent years. Area covered: This article provides an overview of the general characteristics of dermatophytes, including their taxonomy and epidemiology, as well as the different clinical forms and laboratory diagnostics of dermatophytosis. We further classify the topical and systemic antifungal compounds currently used to treat dermatophyte infections. Expert commentary: Antifungal therapy is a central component of patient management for dermatophytosis, and depending on the strategy chosen, topical and/or systemic drugs can be used. However, for effective treatment, it is important to correctly determine the causal agents at the species level, which will enable administration of suitable therapeutics and initiation of appropriate management strategies. C1 [Durdu, Murat] Baskent Univ Adana Hosp, Fac Med, Dept Dermatol, Adana, Turkey. [Ilkit, Macit] Cukurova Univ, Fac Med, Dept Microbiol, Div Mycol, Adana, Turkey. [Tamadon, Yalda] Islamic Azad Univ, Fac Specialized Vet Sci, Dept Small Anim Internal Med, Sci & Res Branch, Tehran, Iran. [Tolooe, Ali] Univ Tehran, Fac Vet Med, Tehran, Iran. [Rafati, Haleh] Erasmus Univ, Med Ctr, Dept Biochem, Rotterdam, Netherlands. [Seyedmousavi, Seyedmojtaba] Radboud Univ Nijmegen Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands. [Seyedmousavi, Seyedmojtaba] Mazandaran Univ Med Sci, Invas Fungi Res Ctr, Sari, Iran. [Seyedmousavi, Seyedmojtaba] NIH, Mol Microbiol Sect, LCID, NIAID, BG 10 RM 11C106,10 Ctr Dr, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Seyedmousavi, S (reprint author), Radboud Univ Nijmegen Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands.; Seyedmousavi, S (reprint author), Mazandaran Univ Med Sci, Invas Fungi Res Ctr, Sari, Iran.; Seyedmousavi, S (reprint author), NIH, Mol Microbiol Sect, LCID, NIAID, BG 10 RM 11C106,10 Ctr Dr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Seyedmousavi@nih.gov NR 120 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 1751-2433 EI 1751-2441 J9 EXPERT REV CLIN PHAR JI Expert Rev. Clin. Pharmacol. PY 2017 VL 10 IS 2 BP 225 EP 237 DI 10.1080/17512433.2017.1263564 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO7DM UT WOS:000396851400009 PM 27868472 ER PT J AU Golden, SA Aleyasin, H Heins, R Flanigan, M Heshmati, M Takahashi, A Russo, SJ Shaham, Y AF Golden, S. A. Aleyasin, H. Heins, R. Flanigan, M. Heshmati, M. Takahashi, A. Russo, S. J. Shaham, Y. TI Persistent conditioned place preference to aggression experience in adult male sexually-experienced CD-1 mice SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Aggression; CD-1; conditioned place preference; D1-Cre; D2-Cre; food self-administration; mice; punishment; reward ID CONTEXT-INDUCED RELAPSE; PUNISHMENT-IMPOSED ABSTINENCE; PAIN-ELICITED AGGRESSION; ALCOHOL SEEKING; POSITIVE REINFORCEMENT; SOCIAL DEFEAT; BEHAVIOR; RAT; HYPOTHALAMUS; REWARD AB We recently developed a conditioned place preference (CPP) procedure, commonly used to study rewarding drug effects, to demonstrate that dominant sexually-experienced CD-1 male mice form CPP to contexts previously associated with defeating subordinate male C57BL/6J mice. Here we further characterized conditioned and unconditioned aggression behavior in CD-1 mice. In Exp. 1 we used CD-1 mice that displayed a variable spectrum of unconditioned aggressive behavior toward younger subordinate C57BL/6J intruder mice. We then trained the CD-1 mice in the CPP procedure where one context was intruder-paired, while a different context was not. We then tested for aggression CPP 1 day after training. In Exp. 2, we tested CD-1 mice for aggression CPP 1 day and 18 days after training. In Exp. 3-4, we trained the CD-1 mice to lever-press for palatable food and tested them for footshock punishment-induced suppression of food-reinforced responding. In Exp. 5, we characterized unconditioned aggression in hybrid CD-1 x C57BL/6J D1-Cre or D2-Cre F1 generation crosses. Persistent aggression CPP was observed in CD-1 mice that either immediately attacked C57BL/6J mice during all screening sessions or mice that gradually developed aggressive behavior during the screening phase. In contrast, CD-1 mice that did not attack the C57BL/6J mice during screening did not develop CPP to contexts previously paired with C57BL/6J mice. The aggressive phenotype did not predict resistance to punishment-induced suppression of food-reinforced responding. CD-1 x D1-Cre or D2-Cre F1 transgenic mice showed strong unconditioned aggression. Our study demonstrates that aggression experience causes persistent CPP and introduces transgenic mice for circuit studies of aggression. C1 [Golden, S. A.; Heins, R.; Shaham, Y.] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Aleyasin, H.; Flanigan, M.; Heshmati, M.; Takahashi, A.; Russo, S. J.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Aleyasin, H.; Flanigan, M.; Heshmati, M.; Takahashi, A.; Russo, S. J.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Takahashi, A.] Univ Tsukuba, Lab Behav Neuroendocrinol, Tsukuba, Ibaraki, Japan. RP Golden, SA (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM sam.golden@nih.gov OI Flanigan, Meghan/0000-0002-3185-7459 FU National Institute on Drug Abuse, Intramural Research Program; PRAT [1FI2GM117583-01]; NIH [R01MH090264] FX Research was supported by the National Institute on Drug Abuse, Intramural Research Program (Y.S.), PRAT 1FI2GM117583-01 (S.A.G.) and NIH grant R01MH090264 (S.J.R). The authors declare that they do not have any conflicts of interest (financial or otherwise) related to the data presented in this manuscript. NR 63 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JAN PY 2017 VL 16 IS 1 BP 44 EP 55 DI 10.1111/gbb.12310 PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA EL1OS UT WOS:000394390300004 PM 27457669 ER PT J AU Dobbs, LK Lemos, JC Alvarez, VA AF Dobbs, L. K. Lemos, J. C. Alvarez, V. A. TI Restructuring of basal ganglia circuitry and associated behaviors triggered by low striatal D2 receptor expression: implications for substance use disorders SO GENES BRAIN AND BEHAVIOR LA English DT Review DE Addiction; basal ganglia; cocaine; D2 receptors; dopamine; G-protein coupled receptors; medium spiny neurons; striatum; substance use disorders; synaptic transmission ID COCAINE-SEEKING BEHAVIOR; MEDIUM SPINY NEURONS; MIDBRAIN DOPAMINE NEURONS; RAT NUCLEUS-ACCUMBENS; ULTRASTRUCTURAL IMMUNOCYTOCHEMICAL LOCALIZATION; PROTEIN-KINASE-C; CHOLINERGIC INTERNEURONS; MICE LACKING; SIGNAL-TRANSDUCTION; RHESUS-MONKEYS AB Dopamine D2 receptors (D2Rs) consistently emerge as a critical substrate for the etiology of some major psychiatric disorders. Indeed, a central theory of substance use disorders (SUDs) postulates that a reduction in D2R levels in the striatum is a determining factor that confers vulnerability to abuse substances. A large number of clinical and preclinical studies strongly support this link between SUDs and D2Rs; however, identifying the mechanism by which low D2Rs facilitate SUDs has been hindered by the complexity of circuit connectivity, the heterogeneity of D2R expression and the multifaceted constellation of phenotypes observed in SUD patient. Animal models are well-suited for understanding the mechanisms because they allow access to the circuitry and the genetic tools that enable a dissection of the D2R heterogeneity. This review discusses recent findings on the functional role of D2Rs and highlights the distinctive contributions of D2Rs expressed on specific neuronal subpopulations to the behavioral responses to stimulant drugs. A circuit-wide restructuring of local and long-range inhibitory connectivity within the basal ganglia is observed in response to manipulation of striatal D2R levels and is accompanied by multiple alterations in dopamine-dependent behaviors. Collectively, these new findings provide compelling evidence for a critical role of striatal D2Rs in shaping basal ganglia connectivity; even among neurons that do not express D2Rs. These findings from animal models have deep clinical implications for SUD patients with low levels D2R availability where a similar restructuring of basal ganglia circuitry is expected to take place. C1 [Dobbs, L. K.; Lemos, J. C.; Alvarez, V. A.] NIAAA, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. RP Alvarez, VA (reprint author), NIAAA, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM alvarezva@mail.nih.gov FU Intramural Research Program of NIAAA at the National Institutes of Health [AA000421]; Intramural Research Program of NINDS at the National Institutes of Health [AA000421]; PRAT Fellowship from NIMGS FX The authors declare no conflict of interest. Funding was provided by the Intramural Research Programs of NIAAA and NINDS at the National Institutes of Health (AA000421) to V.A.A. and PRAT Fellowship from NIMGS to J.C.L. NR 143 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JAN PY 2017 VL 16 IS 1 BP 56 EP 70 DI 10.1111/gbb.12361 PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA EL1OS UT WOS:000394390300005 PM 27860248 ER PT J AU Gremel, CM Lovinger, DM AF Gremel, C. M. Lovinger, D. M. TI Associative and sensorimotor cortico-basal ganglia circuit roles in effects of abused drugs SO GENES BRAIN AND BEHAVIOR LA English DT Review DE Actions; addiction; associative striatum; dopamine; drugs; goal-directed; habits; learning; plasticity; sensorimotor striatum ID CONDITIONED PLACE PREFERENCE; LONG-TERM DEPRESSION; PAVLOVIAN-INSTRUMENTAL TRANSFER; NUCLEUS-ACCUMBENS CORE; CONTEXT-INDUCED REINSTATEMENT; COCAINE-SEEKING BEHAVIOR; CB1 CANNABINOID RECEPTOR; MESSENGER-RNA EXPRESSION; PARS RETICULATA NEURONS; VENTRAL TEGMENTAL AREA AB The mammalian forebrain is characterized by the presence of several parallel cortico-basal ganglia circuits that shape the learning and control of actions. Among these are the associative, limbic and sensorimotor circuits. The function of all of these circuits has now been implicated in responses to drugs of abuse, as well as drug seeking and drug taking. While the limbic circuit has been most widely examined, key roles for the other two circuits in control of goal-directed and habitual instrumental actions related to drugs of abuse have been shown. In this review we describe the three circuits and effects of acute and chronic drug exposure on circuit physiology. Our main emphasis is on drug actions in dorsal striatal components of the associative and sensorimotor circuits. We then review key findings that have implicated these circuits in drug seeking and taking behaviors, as well as drug use disorders. Finally, we consider different models describing how the three cortico-basal ganglia circuits become involved in drug-related behaviors. This topic has implications for drug use disorders and addiction, as treatments that target the balance between the different circuits may be useful for reducing excessive substance use. C1 [Gremel, C. M.] Univ Calif San Diego, Dept Psychol, Neurosci Grad Program, La Jolla, CA 92093 USA. [Lovinger, D. M.] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD USA. RP Gremel, CM (reprint author), Univ Calif San Diego, Dept Psychol, Neurosci Grad Program, La Jolla, CA 92093 USA.; Lovinger, DM (reprint author), NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD USA. EM cgremel@ucsd.edu; lovindav@mail.nih.gov FU NIAAA Division of Intramural Clinical and Biological Research; Pathway to Independence Award [R00 AA021780]; NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation FX This research was supported by the NIAAA Division of Intramural Clinical and Biological Research, and a Pathway to Independence Award R00 AA021780 and NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation to C.M.G. NR 173 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JAN PY 2017 VL 16 IS 1 BP 71 EP 85 DI 10.1111/gbb.12309 PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA EL1OS UT WOS:000394390300006 PM 27457495 ER PT J AU Gebreab, SY Hickson, DA Sims, M Wyatt, SB Davis, SK Correa, A Diez-Rouxf, AV AF Gebreab, Samson Y. Hickson, DeMarc A. Sims, Mario Wyatt, Sharon B. Davis, Sharon K. Correa, Adolfo Diez-Rouxf, Ana V. TI Neighborhood social and physical environments and type 2 diabetes mellitus in African Americans: The Jackson Heart Study SO HEALTH & PLACE LA English DT Article DE African Americans; Type 2 diabetes mellitus; Neighborhood measures; Social environments; Food stores; Physical activity resources; Prevention; Longitudinal analysis ID FAST-FOOD RESTAURANTS; BODY-MASS INDEX; LONGITUDINAL-ASSOCIATIONS; HEALTH DISPARITIES; INSULIN-RESISTANCE; BUILT ENVIRONMENT; ATHEROSCLEROSIS; ADULTS; COHESION; RISK AB Using data from Jackson Heart Study, we investigated the associations of neighborhood social and physical environments with prevalence and incidence of type 2 diabetes mellitus (T2DM) in African Americans (AA). Among non-diabetic participants at baseline (n=3670), 521 (14.2%) developed T2DM during a median followup of 7.3 years. Measures of neighborhood social environments, and food and physical activity resources were derived using survey-and GIS-based methods. Prevalence ratios (PR) and Hazard ratios (HR) were estimated using generalized estimating equations and Cox proportional hazards models. Higher neighborhood social cohesion was associated with a 22% lower incidence of T2DM while higher density of unfavorable food stores was associated with a 34% higher incidence of T2DM after adjusting for individual-level risk factors (HR=0.78 [95% CI:0.62, 0.99] and HR=1.34 [1.12, 1.60], respectively). In addition, neighborhood problems was also associated with prevalence of T2DM (PR=1.12 [1.03, 1.21]) independent of individual-level risk factors. Our findings suggest that efforts to strengthen community ties or to attract healthy food retail outlets might be important strategies to consider for prevention of T2DM in AA. C1 [Gebreab, Samson Y.] NHGRI, Genom Metab Cardiovasc & Inflammatory Branch, Cardiovasc Sect, Social Epidemiol Res Unit, 10 Ctr Dr,Room 7N316,MSC 1644, Bethesda, MD 20892 USA. [Hickson, DeMarc A.] Jackson State Univ, Sch Publ Hlth Initiat, Jackson, MS USA. [Sims, Mario; Correa, Adolfo] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Wyatt, Sharon B.] Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA. [Davis, Sharon K.] NHGRI, Genom Metab Cardiovasc & Inflammatory Branch, Cardiovasc Sect, Social Epidemiol Res Unit, 10 Ctr Dr,Room 7N320,MSC 1644, Bethesda, MD 20892 USA. [Diez-Rouxf, Ana V.] Ctr Integrat Approaches Hlth Dispar, Philadelphia, PA USA. [Diez-Rouxf, Ana V.] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. RP Gebreab, SY (reprint author), NHGRI, Genom Metab Cardiovasc & Inflammatory Branch, Cardiovasc Sect, Social Epidemiol Res Unit, 10 Ctr Dr,Room 7N316,MSC 1644, Bethesda, MD 20892 USA. EM samson.gebreab@nih.gov FU Center for Integrative Approaches to Health Disparities - National Institute on Minority Health and Health Disparities (NIMHD) [2P60MD002249]; Michigan Center for Integrative Approaches to Health Disparities - NIMHD; US Environmental Protection Agency; NIMHD: Environment Supplement [P60 MD002249 05S1]; Multi-ethnic Study of Atherosclerosis Neighborhood Study - National Institutes of Health, National Heart, Lung, and Blood Institute [R01 HL071759]; Intramural Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; NIMHD, Bethesda, MD FX This research is supported by the Center for Integrative Approaches to Health Disparities (2P60MD002249; PI: A. V. Diez-Roux) funded by the National Institute on Minority Health and Health Disparities (NIMHD). The creation of Jackson Heart Study neighborhood environment variables was supported by the Michigan Center for Integrative Approaches to Health Disparities funded by the NIMHD, by US Environmental Protection Agency and NIMHD: Environment Supplement P60 MD002249 05S1 (PI: A. V. Diez-Roux), and by the Multi-ethnic Study of Atherosclerosis Neighborhood Study R01 HL071759 (PI: A. V. Diez-Roux) funded by the National Institutes of Health, National Heart, Lung, and Blood Institute. This research is also supported by the Intramural Program of the National Human Genome Research Institute (PI: S. K. Davis), National Institutes of Health, Bethesda, MD. The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and NIMHD, Bethesda, MD. NR 56 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8292 EI 1873-2054 J9 HEALTH PLACE JI Health Place PD JAN PY 2017 VL 43 BP 128 EP 137 DI 10.1016/j.healthplace.2016.12.001 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EL1SX UT WOS:000394402400016 PM 28033588 ER PT J AU Chua, J Senft, JL Lockett, SJ Brett, PJ Burtnick, MN DeShazer, D Friedlander, AM AF Chua, Jennifer Senft, Jeffrey L. Lockett, Stephen J. Brett, Paul J. Burtnick, Mary N. DeShazer, David Friedlander, Arthur M. TI pH Alkalinization by Chloroquine Suppresses Pathogenic Burkholderia Type 6 Secretion System 1 and Multinucleated Giant Cells SO INFECTION AND IMMUNITY LA English DT Article DE Burkholderia; Madagascar hissing cockroaches; type 3 secretion system; type 6 secretion system; acidification; actin tails; autophagy; chloroquine; multinucleated giant cells; phagosomal escape ID INTRACELLULAR SURVIVAL; VI SECRETION; MURINE MACROPHAGES; IMMUNE-RESPONSE; PSEUDOMALLEI; MALLEI; HOST; THAILANDENSIS; MELIOIDOSIS; FUSION AB Burkholderia mallei and B. pseudomallei cause glanders and melioidosis, respectively, in humans and animals. A hallmark of pathogenesis is the formation of granulomas containing multinucleated giant cells (MNGCs) and cell death. These processes depend on type 6 secretion system 1 (T6SS-1), which is required for virulence in animals. We examined the cell biology of MNGC formation and cell death. We found that chloroquine diphosphate (CLQ), an antimalarial drug, inhibits Burkholderia growth, phagosomal escape, and subsequent MNGC formation. This depends on CLQ's ability to neutralize the acid pH because other alkalinizing compounds similarly inhibit escape and MNGC formation. CLQ inhibits bacterial virulence protein expression because T6SS-1 and some effectors of type 3 secretion system 3 (T3SS-3), which is also required for virulence, are expressed at acid pH. We show that acid pH upregulates the expression of Hcp1 of T6SS-1 and TssM, a protein coregulated with T6SS-1. Finally, we demonstrate that CLQ treatment of Burkholderia-infected Madagascar hissing cockroaches (HCs) increases their survival. This study highlights the multiple mechanisms by which CLQ inhibits growth and virulence and suggests that CLQ be further tested and considered, in conjunction with antibiotic use, for the treatment of diseases caused by Burkholderia. C1 [Chua, Jennifer; Senft, Jeffrey L.; DeShazer, David; Friedlander, Arthur M.] US Army Med Res Inst Infect Dis, Bacteriol Div, Frederick, MD 21702 USA. [Lockett, Stephen J.] Frederick Natl Lab Canc Res, Opt Microscopy & Anal Lab, Leidos Biomed Res Inc, Frederick, MD USA. [Brett, Paul J.; Burtnick, Mary N.] Univ S Alabama, Dept Microbiol & Immunol, Mobile, AL 36688 USA. [Friedlander, Arthur M.] Uniformed Serv Univ Hlth Sci, Dept Med, Room A3060, Bethesda, MD 20814 USA. RP Chua, J; Friedlander, AM (reprint author), US Army Med Res Inst Infect Dis, Bacteriol Div, Frederick, MD 21702 USA.; Friedlander, AM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med, Room A3060, Bethesda, MD 20814 USA. EM Jennifer.Chua.ctr@mail.mil; Arthur.M.Friedlander.civ@mail.mil NR 53 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JAN PY 2017 VL 85 IS 1 AR e00586 DI 10.1128/IAI.00586-16 PG 17 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EL4RD UT WOS:000394607700005 ER PT J AU Rajamanickam, A Munisankar, S Bhootra, Y Dolla, C Nutman, TB Babu, S AF Rajamanickam, Anuradha Munisankar, Saravanan Bhootra, Yukthi Dolla, Chandrakumar Nutman, Thomas B. Babu, Subash TI Microbial Translocation Associated with an Acute-Phase Response and Elevations in MMP-1, HO-1, and Proinflammatory Cytokines in Strongyloides stercoralis Infection SO INFECTION AND IMMUNITY LA English DT Article DE microbial translocation markers; Strongyloides stercoralis; acute-phase proteins; inflammatory markers; proinflammatory cytokines ID C-REACTIVE PROTEIN; HEME OXYGENASE-1; HIV-INFECTION; GASTROINTESTINAL-DISEASES; MATRIX METALLOPROTEINASES; IMMUNE ACTIVATION; ENTERIC NEMATODE; T-CELL; INFLAMMATION; EXPRESSION AB Microbial translocation, characterized by elevated levels of lipopolysaccharide (LPS) and related markers, is a common occurrence in HIV and some parasitic infections. This is usually associated with extensive inflammation and immune activation. To examine the occurrence of microbial translocation and the associated inflammatory response in asymptomatic Strongyloides stercoralis infection, we measured the plasma levels of LPS and other microbial translocation markers, acutephase proteins, inflammatory markers, and proinflammatory cytokines in individuals with (infected [INF]) or without (uninfected [UN]) S. stercoralis infections. Finally, we also measured the levels of all of these markers in INF individuals following treatment of S. stercoralis infection. We show that INF individuals exhibit significantly higher plasma levels of microbial translocation markers (LPS, soluble CD14 [sCD14], intestinal fatty acid-binding protein [iFABP], and endotoxin core IgG antibody [EndoCAb]), acute-phase proteins (alpha-2 macroglobulin [alpha-2M], C-reactive protein [CRP], haptoglobin, and serum amyloid protein A [SAA]), inflammatory markers (matrix metalloproteinase 1 [MMP-1] and heme oxygenase 1 [HO-1]), and proinflammatory cytokines (interleukin-6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1], and IL-1 beta) than do UN individuals. INF individuals exhibit significantly decreased levels of tissue inhibitor of metalloproteinases 4 (TIMP-4). Following treatment of S. stercoralis infection, the elevated levels of microbial translocation markers, acute-phase proteins, and inflammatory markers were all diminished. Our data thus show that S. stercoralis infection is characterized by microbial translocation and accompanying increases in levels of acute-phase proteins and markers of inflammation and provide data to suggest that microbial translocation is a feature of asymptomatic S. stercoralis infection and is associated with an inflammatory response. C1 [Rajamanickam, Anuradha; Munisankar, Saravanan; Bhootra, Yukthi; Babu, Subash] Int Ctr Excellence Res, NIRT, Natl Inst Health, Madras, Tamil Nadu, India. [Dolla, Chandrakumar] Natl Inst Res TB, Madras, Tamil Nadu, India. [Nutman, Thomas B.; Babu, Subash] NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Rajamanickam, A (reprint author), Int Ctr Excellence Res, NIRT, Natl Inst Health, Madras, Tamil Nadu, India. EM anuradha@nirt.res.in FU Division of Intramural Research, NIAID, NIH FX This work was funded by the Division of Intramural Research, NIAID, NIH. NR 49 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 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JAN PY 2017 VL 85 IS 1 AR e00772-16 DI 10.1128/IAI.00772-16 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EL4RD UT WOS:000394607700018 ER PT J AU Sullivan, D AF Sullivan, Debra TI A Guide to Common Skin Disorders while Pregnant SO INTERNATIONAL JOURNAL OF CHILDBIRTH EDUCATION LA English DT Article DE skin disorders; pregnancy; psoriasis; eczema; acne AB Skin conditions during pregnancy and lactation can be a concern for new moms. The childbirth educator would benefit from a brief guide to common disorders and treatment options. A description, symptoms and concerns related to pregnancy, treatment options, and when to seek medical care, are outlined for these more common skin disorders: eczema, psoriasis, acne, and melanoma. C1 [Sullivan, Debra] Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Bethesda, MD USA. [Sullivan, Debra] Natl Inst Hlth, Natl Inst Arthrit & Musculoskeletal & Skin Dis, Bethesda, MD USA. RP Sullivan, D (reprint author), Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Bethesda, MD USA.; Sullivan, D (reprint author), Natl Inst Hlth, Natl Inst Arthrit & Musculoskeletal & Skin Dis, Bethesda, MD USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU INT CHILDBIRTH EDUCATION ASSOC PI RALEIGH PA 1500 SUNDAY DR, STE 102, RALEIGH, NC 27607 USA SN 0887-8625 J9 INT J CHILDBIRTH EDU JI Int. J. Childbirth Educ. PD JAN PY 2017 VL 32 IS 1 BP 16 EP 18 PG 3 WC Nursing SC Nursing GA EO0IG UT WOS:000396380900006 ER PT J AU Stangl, BL Vatsalya, V Zametkin, MR Cooke, ME Plawecki, MH O'Connor, S Ramchandani, VA AF Stangl, Bethany L. Vatsalya, Vatsalya Zametkin, Molly R. Cooke, Megan E. Plawecki, Martin H. O'Connor, Sean Ramchandani, Vijay A. TI Exposure-Response Relationships during Free-Access Intravenous Alcohol Self-Administration in Nondependent Drinkers: Influence of Alcohol Expectancies and Impulsivity SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE alcohol self-administration; i.v.; expectancy; impulsivity; reward ID FAMILY-HISTORY; ELIMINATION RATES; DEHYDROGENASE POLYMORPHISMS; ABSTINENT ALCOHOLICS; ASSOCIATION; VALIDATION; INFUSION; PREDICTS; HUMANS; GENDER AB Background: Self-administration is a hallmark of all addictive drugs, including alcohol. Human laboratory models of alcohol self-administration have characterized alcohol-seeking behavior and served as surrogate measures of the effectiveness of pharmacotherapies for alcohol use disorders. Intravenous alcohol self-administration is a novel method that assesses alcohol exposure driven primarily by the pharmacological response to alcohol and may have utility in characterizing unique behavioral and personality correlates of alcohol-seeking and consumption. Methods: This study examined exposure-response relationships for i.v. alcohol self-administration, and the influence of impulsivity and alcohol expectancy, in healthy, nondependent drinkers (n=112). Participants underwent a 2.5-hour free-access i.v. alcohol self-administration session using the Computerized Alcohol Infusion System. Serial subjective response measures included the Drug Effects Questionnaire and Alcohol Urge Questionnaire. To characterize the motivational aspects of alcohol consumption prior to potential acute adaptation, the number of self-infusions in the first 30 minutes of the free-access session was used to classify participants as low-and high-responders. Results: High-responders showed greater subjective responses during i.v. alcohol self-administration compared with low responders, reflecting robust exposure-driven hedonic responses to alcohol. High-responders also reported heavier drinking patterns and lower scores for negative alcohol expectancies on the Alcohol Effects Questionnaire. High-responders also showed higher measures of impulsivity on a delayed discounting task, supporting previous work associating impulsivity with greater alcohol use and problems. Conclusions: These findings indicate that early-phase measures of free-access i.v. alcohol self-administration are particularly sensitive to the rewarding and motivational properties of alcohol and may provide a unique phenotypic marker of alcohol-seeking behavior. C1 [Stangl, Bethany L.; Vatsalya, Vatsalya; Zametkin, Molly R.; Cooke, Megan E.; Ramchandani, Vijay A.] Natl Inst Alcohol Abuse & Alcoholism, Div Intramural Clin & Biol Res, Sect Human Psychopharmacol, Bethesda, MD USA. [Vatsalya, Vatsalya] Univ Louisville, Robley Rex VA Med Ctr, Louisville, KY USA. [Plawecki, Martin H.; O'Connor, Sean] Indiana Univ Sch Med, Indianapolis, IN USA. [Ramchandani, Vijay A.] Bldg 10,10CRC RM 2 2352, Bethesda, MD 20892 USA. RP Ramchandani, VA (reprint author), Natl Inst Alcohol Abuse & Alcoholism, Div Intramural Clin & Biol Res, Sect Human Psychopharmacol, Bethesda, MD USA.; Ramchandani, VA (reprint author), Bldg 10,10CRC RM 2 2352, Bethesda, MD 20892 USA. EM vijayr@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism Division of Clinical and Biological Research [Z1A AA 000466]; Indiana Alcohol Research Center [P60 AA 07611] FX This work was supported by the National Institute on Alcohol Abuse and Alcoholism Division of Clinical and Biological Research (Z1A AA 000466). The CAIS software was developed with funding from the Indiana Alcohol Research Center (P60 AA 07611). There are no financial interests to disclose. NR 36 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JAN PY 2017 VL 20 IS 1 DI 10.1093/ijnp/pyw090 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EP0TB UT WOS:000397098500004 ER PT J AU Broadney, MM Chahal, N Michels, KA McLain, AC Ghassabian, A Lawrence, DA Yeung, EH AF Broadney, M. M. Chahal, N. Michels, K. A. McLain, A. C. Ghassabian, A. Lawrence, D. A. Yeung, E. H. TI Impact of parental obesity on neonatal markers of inflammation and immune response SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article ID GESTATIONAL WEIGHT-GAIN; BODY-MASS INDEX; CORD BLOOD IGE; MATERNAL OBESITY; NATURAL ANTIBODIES; PLACENTAL BARRIER; EARLY-CHILDHOOD; INFANT-DEATH; RISK-FACTORS; PREGNANCY AB BACKGROUND/OBJECTIVES: Maternal obesity may influence neonatal and childhood morbidities through increased inflammation and/or altered immune response. Less is known about paternal obesity. We hypothesized that excessive parental weight contributes to elevated inflammation and altered immunoglobulin (Ig) profiles in neonates. SUBJECTS/METHODS: In the Upstate KIDS Study maternal pre-pregnancy body mass index (BMI) was obtained from vital records and paternal BMI from maternal report. Biomarkers were measured from newborn dried blood spots (DBS) among neonates whose parents provided consent. Inflammatory scores were calculated by assigning one point for each of five pro-inflammatory biomarkers above the median and one point for an anti-inflammatory cytokine below the median. Linear regression models and generalized estimating equations were used to estimate mean differences (beta) and 95% confidence intervals (CI) in the inflammatory score and Ig levels by parental overweight/obesity status compared with normal weight. RESULTS: Among 2974 pregnancies, 51% were complicated by excessive maternal weight (BMI>5), 73% by excessive paternal weight and 28% by excessive gestational weight gain. Maternal BMI categories of overweight (BMI 25.0-29.9) and obese class II/III (BMI >= 35) were associated with increased neonatal inflammation scores (beta = 0.12, 95% CI: 0.02, 0.21; P = 0.02 and beta = 0.13, CI: - 0.002, 0.26; P = 0.05, respectively) but no increase was observed in the obese class I group (BMI 30-34.9). Mothers with class I and class II/III obesity had newborns with increased IgM levels (beta = 0.11, CI: 0.04, 0.17; P = 0.001 and beta = 0.12, CI: 0.05, 0.19); P < 0.001, respectively). Paternal groups of overweight, obese class I and obese class II/ III had decreased neonatal IgM levels ( beta = - 0.08, CI: - 0.13, - 0.03, P = 0.001; beta = - 0.07, CI: - 0.13, - 0.01, P = 0.029 and beta = - 0.11, CI: - 0.19, - 0.04, P = 0.003, respectively). CONCLUSIONS: Excessive maternal weight was generally associated with increased inflammation and IgM supporting previous observations of maternal obesity and immune dysregulation in offspring. The role of paternal obesity requires further study. C1 [Broadney, M. M.; Chahal, N.; Michels, K. A.; Ghassabian, A.; Yeung, E. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, Bethesda, MD USA. [Broadney, M. M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Bethesda, MD USA. [McLain, A. C.] Univ South Carolina, Dept Epidemiol & Biostat, Columbia, SC USA. [Lawrence, D. A.] New York State Dept Hlth, Ctr Med Sci, Wadsworth Ctr, Immunol Lab, Albany, NY USA. [Lawrence, D. A.] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Albany, NY USA. RP Yeung, EH (reprint author), NICHD, Epidemiol Branch, Div Intramural Populat Hlth Res, 6710B Rockledge Dr,MSC 7004, Bethesda, MD 20817 USA. EM yeungedw@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN275201200005C, HHSN267200700019C] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts #HHSN275201200005C, #HHSN267200700019C). The authors thank all the Upstate KIDS participants and staff for their important contributions. NR 58 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 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD JAN PY 2017 VL 41 IS 1 BP 30 EP 37 DI 10.1038/ijo.2016.187 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA EK7ZG UT WOS:000394143100004 PM 27780976 ER PT J AU Sedaka, NM Olsen, CH Yannai, LE Stutzman, WE Krause, AJ Sherafat-Kazemzadeh, R Condarco, TA Brady, SM Demidowich, AP Reynolds, JC Yanovski, SZ Hubbard, VS Yanovski, JA AF Sedaka, N. M. Olsen, C. H. Yannai, L. E. Stutzman, W. E. Krause, A. J. Sherafat-Kazemzadeh, R. Condarco, T. A. Brady, S. M. Demidowich, A. P. Reynolds, J. C. Yanovski, S. Z. Hubbard, V. S. Yanovski, J. A. TI A longitudinal study of serum insulin and insulin resistance as predictors of weight and body fat gain in African American and Caucasian children SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article ID IMPAIRED FASTING GLUCOSE; OBESE ADOLESCENTS; MASS INDEX; CENTRAL ADIPOSITY; PUBERTAL CHANGES; YOUNG ADULTHOOD; DOUBLE-BLIND; FOOD-INTAKE; LOWER RATES; Z-SCORE AB BACKGROUND: The influence of insulin and insulin resistance (IR) on children's weight and fat gain is unclear. OBJECTIVE: To evaluate insulin and IR as predictors of weight and body fat gain in children at high risk for adult obesity. We hypothesized that baseline IR would be positively associated with follow-up body mass index (BMI) and fat mass. SUBJECTS/METHODS: Two hundred and forty-nine healthy African American and Caucasian children aged 6-12 years at high risk for adult obesity because of early-onset childhood overweight and/or parental overweight were followed for up to 15 years with repeated BMI and fat mass measurements. We examined baseline serum insulin and homeostasis model of assessment-IR (HOMA-IR) as predictors of follow-up BMI Z-score and fat mass by dual-energy X-ray absorptiometry in mixed model longitudinal analyses accounting for baseline body composition, pubertal stage, sociodemographic factors and follow-up interval. RESULTS: At baseline, 39% were obese (BMI >= 95th percentile for age/sex). Data from 1335 annual visits were examined. Children were followed for an average of 7.2 +/- 4.3 years, with a maximum follow-up of 15 years. After accounting for covariates, neither baseline insulin nor HOMA-IR was significantly associated with follow-up BMI (Ps > 0.26), BMIz score (Ps > 0.22), fat mass (Ps > 0.78) or fat mass percentage (Ps > 0.71). In all models, baseline BMI (P < 0.0001), body fat mass (P < 0.0001) and percentage of fat (P < 0.001) were strong positive predictors for change in BMI and fat mass. In models restricted to children without obesity at baseline, some but not all models had significant interaction terms between body adiposity and insulinemia/HOMA-IR that suggested less gain in mass among those with greater insulin or IR. The opposite was found in some models restricted to children with obesity at baseline. CONCLUSIONS: In middle childhood, BMI and fat mass, but not insulin or IR, are strong predictors of children's gains in BMI and fat mass during adolescence. C1 [Sedaka, N. M.; Yannai, L. E.; Stutzman, W. E.; Krause, A. J.; Sherafat-Kazemzadeh, R.; Condarco, T. A.; Brady, S. M.; Demidowich, A. P.; Yanovski, S. Z.; Yanovski, J. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, SGO, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD USA. [Olsen, C. H.] Uniformed Serv Univ Hlth Sci, Biostat Consulting Ctr, Bethesda, MD 20814 USA. [Reynolds, J. C.] NIH, Dept Nucl Med, Hatfield Clin Res Ctr, Bethesda, MD USA. [Yanovski, S. Z.; Hubbard, V. S.] NIDDK, Nutr Sci Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. [Hubbard, V. S.] NIH, Div Nutr Res Coordinat, Bldg 10, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), NICHD, Sect Growth & Obes, Program Dev Endocrinol & Genet, Hatfield Clin Res Ctr, 10 Ctr Dr,Room 1E-3330,MSC 1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov FU Intramural Research Program, NIH; NICHD [1ZIAHD000641]; National Institute for Minority Health and Health Disparities (NIMHD), NIH; Division of Nutrition Research Coordination (DNRC), NIH; Division of Nutrition Research Coordination; National Institute of Diabetes and Digestive and Kidney Diseases FX This study received research support from Intramural Research Program, NIH, grant 1ZIAHD000641 (to JAY) from NICHD with supplemental funding from the National Institute for Minority Health and Health Disparities (NIMHD) and the Division of Nutrition Research Coordination (DNRC), NIH. NMS and AJK were supported by the Division of Nutrition Research Coordination and the National Institute of Diabetes and Digestive and Kidney Diseases. JAY is a Commissioned Officer in the US Public Health Service, Department of Health and Human Services. The funding organizations had no role in the design or conduct of the study; the collection, management, analysis, or interpretation of data; or the preparation of the manuscript. NR 69 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 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD JAN PY 2017 VL 41 IS 1 BP 61 EP 70 DI 10.1038/ijo.2016.145 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA EK7ZG UT WOS:000394143100008 PM 27534840 ER PT J AU Wilson, LE Harlid, S Xu, Z Sandler, DP Taylor, JA AF Wilson, L. E. Harlid, S. Xu, Z. Sandler, D. P. Taylor, J. A. TI An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article ID DIET-INDUCED OBESITY; WAIST CIRCUMFERENCE; LEPTIN SENSITIVITY; INSULIN-RESISTANCE; PERIPHERAL-BLOOD; ADIPOSE-TISSUE; SOCS PROTEINS; BIRTH-WEIGHT; ASSOCIATION; CELLS AB BACKGROUND/OBJECTIVES: The relationship between obesity and chronic disease risk is well-established; the underlying biological mechanisms driving this risk increase may include obesity-related epigenetic modifications. To explore this hypothesis, we conducted a genome-wide analysis of DNA methylation and body mass index (BMI) using data from a subset of women in the Sister Study. SUBJECTS/METHODS: The Sister Study is a cohort of 50 884 US women who had a sister with breast cancer but were free of breast cancer themselves at enrollment. Study participants completed examinations which included measurements of height and weight, and provided blood samples. Blood DNA methylation data generated with the Illumina Infinium HumanMethylation27 BeadChip array covering 27,589 CpG sites was available for 871 women from a prior study of breast cancer and DNA methylation. To identify differentially methylated CpG sites associated with BMI, we analyzed this methylation data using robust linear regression with adjustment for age and case status. For those CpGs passing the false discovery rate significance level, we examined the association in a replication set comprised of a non-overlapping group of 187 women from the Sister Study who had DNA methylation data generated using the Infinium HumanMethylation450 BeadChip array. Analysis of this expanded 450 K array identified additional BMI-associated sites which were investigated with targeted pyrosequencing. RESULTS: Four CpG sites reached genome-wide significance (false discovery rate (FDR) q<0.05) in the discovery set and associations for all four were significant at strict Bonferroni correction in the replication set. An additional 23 sites passed FDR in the replication set and five were replicated by pyrosequencing in the discovery set. Several of the genes identified including ANGPT4, RORC, SOCS3, FSD2, XYLT1, ABCG1, STK39, ASB2 and CRHR2 have been linked to obesity and obesity-related chronic diseases. CONCLUSIONS: Our findings support the hypothesis that obesity-related epigenetic differences are detectable in blood and may be related to risk of chronic disease. C1 [Wilson, L. E.; Harlid, S.; Xu, Z.; Sandler, D. P.; Taylor, J. A.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Harlid, S.] Umea Univ, Oncol, Dept Radiat Sci, Umea, Sweden. RP Taylor, JA (reprint author), NIEHS, Epidemiol Branch, POB 12233 Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM taylor@niehs.nih.gov OI Wilson, Lauren/0000-0002-5953-2293 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES044005, Z01 ES044032, Z01 ES049033] FX We thank Dr Sarah Reese and Dr Yong- Moon Park for their critical review of this manuscript. We would also like to thank the women who volunteered to participate in the Sister Study. We thank the National Institutes of Health (NIH) Center for Inherited Disease Research and the National Institute of Environmental Health Sciences (NIEHS) Molecular Genetics Core and Microarray Core for their technical support. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES044005, Z01 ES044032, and Z01 ES049033) which provided funding for design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review and approval of the manuscript. NR 50 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD JAN PY 2017 VL 41 IS 1 BP 194 EP 199 DI 10.1038/ijo.2016.184 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA EK7ZG UT WOS:000394143100026 PM 27773939 ER PT J AU Eydelman, M Hilmantel, G Tarver, ME Hofmeister, EM May, J Hammel, K Hays, RD Ferris, F AF Eydelman, Malvina Hilmantel, Gene Tarver, Michelle E. Hofmeister, Elizabeth M. May, Jeanine Hammel, Keri Hays, Ron D. Ferris, Frederick, III TI Symptoms and Satisfaction of Patients in the Patient-Reported Outcomes With Laser In Situ Keratomileusis (PROWL) Studies SO JAMA OPHTHALMOLOGY LA English DT Article ID QUALITY-OF-LIFE; SURFACE DISEASE INDEX; WAVE-FRONT ANALYSIS; DRY EYE; REFRACTIVE SURGERY; FOLLOW-UP; FEMTOSECOND LASER; VISUAL SYMPTOMS; RISK-FACTORS; MECHANICAL MICROKERATOME AB IMPORTANCE Patient-reported outcomes should be collected using validated questionnaires prior to and following laser in situ keratomileusis (LASIK) surgery. OBJECTIVE To report the frequency of patient-reported visual symptoms, dry eye symptoms, satisfaction with vision, and satisfaction with LASIK surgery in the Patient-Reported Outcomes With LASIK (PROWL) studies. DESIGN, SETTING, AND PARTICIPANTS The PROWL-1 and PROWL-2 studieswere prospective, observational studies conducted from September 13, 2011, to June 27, 2014. The PROWL-1 study was a single-military center study of 262 active-duty Navy personnel 21 to 52 years of age. The PROWL-2 study was a study of 312 civilians 21 to 57 years of age conducted at 5 private practice and academic centers. The LASIK surgery and the postoperative care were performed based on the usual practice and clinical judgment at the site. Participants completed a self-administered, web-based questionnaire, preoperatively and postoperatively at 1 and 3 months (the PROWL-1 and -2 studies) and at 6 months (the PROWL-2 study). EXPOSURES Participants underwent LASIK surgery formyopia, hyperopia, and/or astigmatism. MAIN OUTCOMES AND MEASURES Visual symptoms (double images, glare, halos, and/or starbursts), dry eye symptoms, participant satisfaction (with vision and LASIK surgery), and clinical measures (visual acuity, refractive error, and slitlamp and posterior segment eye examination findings) were assessed preoperatively and at 1, 3, and 6 months postoperatively. RESULTS A total of 262 participants were enrolled in the PROWL-1 study (mean [SD] age, 29.1 [6.1] years), and a total of 312 participants were enrolled in the PROWL-2 study (mean [SD] age, 31.5 [7.3] years). Visual symptoms and dissatisfaction with vision were common preoperatively. Overall, the prevalence of visual symptoms and dry eye symptoms decreased, although a substantial percentage of participants reported new visual symptoms after surgery (43%[95% CI, 31%-55%] from the PROWL-1 study and 46%[95% CI, 33%-58%] from the PROWL-2 study at 3 months). The percentages of participants in the PROWL-1 study with normal Ocular Surface Disease Index scores were 55%(95% CI, 48%-61%) at baseline, 66%(95% CI, 59%-72%) at 3 months, and 73%(95% CI, 67%-79%) at 6 months. The percentages of participants in the PROWL-2 study with normal Ocular Surface Disease Index scores were 44%(95% CI, 38%-50%) at baseline and 65%(95% CI, 59%-71%) at 3 months. Of those participants who had normal scores at baseline in both the PROWL-1 and -2 studies, about 28%(95% CI, 19%-37%) had mild, moderate, or severe dry eye symptoms at 3 months. While most participants were satisfied, the rates of dissatisfaction with vision ranged from 1% (95% CI, 0%-4%) to 4%(95% CI, 2%-7%), and the rates of dissatisfaction with surgery ranged from 1% (95% CI, 0%-4%) to 2%(95% CI, 1%-5%). CONCLUSIONS AND RELEVANCE The systematic administration of a questionnaire to patients who have undergone LASIK surgery is a new approach to assess symptoms and satisfaction. Our findings support the need for adequate counseling about the possibility of developing new symptoms after LASIK surgery. C1 [Eydelman, Malvina; Hilmantel, Gene; Tarver, Michelle E.] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 66,Room 2410, Silver Spring, MD 20993 USA. [Hofmeister, Elizabeth M.] Navy Med Ctr San Diego, Navy Refract Surg Ctr, Dept Ophthalmol, San Diego, CA USA. [May, Jeanine; Hammel, Keri] Emmes Corp, Rockville, MD USA. [Hays, Ron D.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Ferris, Frederick, III] NEI, Bethesda, MD 20892 USA. RP Eydelman, M (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 66,Room 2410, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 47 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD JAN PY 2017 VL 135 IS 1 DI 10.1001/jamaophthalmol.2016.4587 PG 10 WC Ophthalmology SC Ophthalmology GA EK9PJ UT WOS:000394256100006 PM 27893066 ER PT J AU Hays, RD Tarver, ME Spritzer, KL Reise, S Hilmantel, G Hofmeister, EM Hammel, K May, J Ferris, F Eydelman, M AF Hays, Ron D. Tarver, Michelle E. Spritzer, Karen L. Reise, Steve Hilmantel, Gene Hofmeister, Elizabeth M. Hammel, Keri May, Jeanine Ferris, Frederick, III Eydelman, Malvina TI Assessment of the Psychometric Properties of a Questionnaire Assessing Patient-Reported Outcomes With Laser In Situ Keratomileusis (PROWL) SO JAMA OPHTHALMOLOGY LA English DT Article ID INSTITUTE-REFRACTIVE ERROR; OF-LIFE INSTRUMENT; RELIABILITY; VALIDITY; ANXIETY; SCALE AB IMPORTANCE Patient-reported outcome (PRO) measures for laser in situ keratomileusis (LASIK) are needed. OBJECTIVE To develop PRO measures to assess satisfaction, eye-related symptoms, and their effect on functioning and well-being following LASIK based on patient and expert input. DESIGN, SETTING, AND PARTICIPANTS The Patient-Reported Outcomes With LASIK (PROWL) studies were prospective observational studies of patients undergoing LASIK surgery for myopia, hyperopia, or astigmatism. PROWL-1 was a single-center study of active-duty US Navy personnel and PROWL-2 was a 5-center study of civilians. PROWL-1 enrolled 262 active-duty service personnel and PROWL-2 enrolled 312 civilians 21 years or older who spoke English; 241 individuals in PROWL-1 and 280 in PROWL-2 completed a baseline questionnaire before surgery. The analytic sample included those also completing 1 or more follow-up questionnaires: 240 (99.6%) of those in PROWL-1 and 271 (94.4%) of those in PROWL-2. Questionnaires were self-administered through the internet preoperatively and at 1 and 3 months postoperatively in both studies and at 6 months postoperatively in PROWL-1. PROWL-1 began in August 2011 and was completed May 30, 2014; PROWL-2 began in July 2012 and was completed June 27, 2014. Data were analyzed from June 28, 2014, to October 24, 2016. MAIN OUTCOMES AND MEASURES Scales assessing visual symptoms (double images, glare, halos, and starbursts), dry eye symptoms, satisfaction with vision, and satisfaction with LASIK surgery. Items from the National Eye Institute (NEI) Refractive Error Quality of Life Instrument (NEI-RQL-42), NEI Visual Function Questionnaire (NEI-VFQ), and the Ocular Surface Disease Index (OSDI) were included. All scales are scored on a 0 to 100possible range. Construct validity and responsiveness to change were evaluated (comparing scores before and after surgery). RESULTS The median age of the 240-person PROWL-1 analytic sample was 27 years (range, 21-52 years); 49 were women (20.4%). The median age of the 271-person PROWL-2 analytic sample was 30 years (range, 21-57 years); 147 were women (54.2%). Internal consistency reliabilities for the 4 visual symptom scales ranged from 0.96 to 0.98 in PROWL-1 and from 0.95 to 0.97 in PROWL-2. The median (interquartile range) test-retest intraclass correlation was 0.69 (0.57-0.79) and 0.76 (0.68-0.84) in PROWL-1 and PROWL-2, respectively. Product-moment correlations of satisfaction with surgery with visual symptom scales at follow-up evaluations ranged from r = 0.24 to r = 0.49. Measures improved from baseline to follow-up, with effect sizes of 0.14 to 1.98, but scores on the NEI-RQL-42 glare scale worsened at the 1-month follow-up. Hours of work did not change significantly from baseline to 1-month follow-up, with the mean number (mean [SD] difference) in PROWL-1 of 41.7 vs 40.9 hours (-0.8[18.7]) and in PROWL-2 of 38.8 vs 38.2 hours (-0.6 [17.1]). CONCLUSIONS AND RELEVANCE The results of these studies support the reliability and validity of visual symptom scales to evaluate the effects of LASIK surgery in future studies. C1 [Hays, Ron D.; Spritzer, Karen L.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Hays, Ron D.; Tarver, Michelle E.; Hilmantel, Gene; Eydelman, Malvina] US FDA, Ctr Devices & Radiol Hlth, 10993 New Hampshire Ave,Bldg 66,Room 2410, Silver Spring, MD 20993 USA. [Reise, Steve] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Hofmeister, Elizabeth M.] Naval Med Ctr San Diego, Navy Refract Surg Ctr, Dept Ophthalmol, San Diego, CA USA. [Hammel, Keri; May, Jeanine] Emmes Corp, Rockville, MD USA. [Ferris, Frederick, III] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Eydelman, M (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10993 New Hampshire Ave,Bldg 66,Room 2410, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 25 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD JAN PY 2017 VL 135 IS 1 DI 10.1001/jamaophthalmol.2016.4597 PG 10 WC Ophthalmology SC Ophthalmology GA EK9PJ UT WOS:000394256100005 PM 27893063 ER PT J AU Beachler, DC Engels, EA AF Beachler, Daniel C. Engels, Eric A. TI Chronic Sinusitis and Risk of Head and Neck Cancer in the US Elderly Population SO JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID CHRONIC RHINOSINUSITIS; HUMAN-PAPILLOMAVIRUS; NASOPHARYNGEAL CARCINOMA; UNITED-STATES; MEDICARE DATA; EPIDEMIOLOGY; INDIVIDUALS; ASSOCIATION; PREVALENCE; COHORT AB IMPORTANCE Chronic sinusitis may be involved in the etiology of certain head and neck cancers (HNCs), due to immunodeficiency or inflammation. However, the risk of specific HNCs among people with chronic sinusitis is largely unknown. OBJECTIVE To evaluate the associations of chronic sinusitis with subsequent HNC, including nasopharyngeal cancer (NPC), human papillomavirus-related oropharyngeal cancer (HPV-OPC), and nasal cavity and paranasal sinus cancer (NCPSC), in an elderly US population. DESIGN, SETTING, AND PARTICIPANTS We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to conduct a case-cohort study of US individuals aged 65 years or older during 2004 through 2011. The study included 483 546 Medicare beneficiaries from SEER areas in a 5% random subcohort, and 826 436 from the entire source population who developed cancer (including 21 716 with HNC). MAIN OUTCOMES AND MEASURES Incidence of HNCs including NPC, HPV-OPC, and NCPSC. RESULTS Most individuals were female (57.7%), and the mean (SD) age at entry was 72.6 (8.0) years. Chronic sinusitis was associated with risk of developing HNC (adjusted hazard ratio [aHR], 1.37; 95% CI, 1.27-1.48), particularly NPC (aHR, 3.71; 95% CI, 2.75-5.02), HPV-OPC (aHR, 1.33; 95% CI, 1.13-1.57), and NCPSC (aHR, 5.49; 95% CI, 4.56-6.62). Most of this increased risk was limited to risk within 1 year of the chronic sinusitis diagnosis, as associations were largely attenuated 1 year or more after chronic sinusitis (NPC: aHR, 1.60; 95% CI, 0.96-2.65; HPV-OPC: aHR, 1.07; 95% CI, 0.86-1.32; NCPSC: aHR, 2.47; 95% CI, 1.84-3.31). All 3 HNC subtypes had cumulative incidence of less than 0.07% 8 years after chronic sinusitis diagnosis. CONCLUSIONS AND RELEVANCE Chronic sinusitis is associated with certain HNCs, particularly NPC and NCPSC. These HNCs are rare, and most of the increased HNC risk is limited to within 1 year of chronic sinusitis diagnosis, consistent with surveillance or detection bias. The associations were weaker over longer intervals, suggesting at most a modest role for sinusitis-related inflammation and/or immunodeficiency. C1 [Beachler, Daniel C.; Engels, Eric A.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Beachler, DC (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6-E220, Bethesda, MD 20892 USA. EM daniel.beachler@nih.gov FU Intramural Research Program of the National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. NR 24 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6181 EI 2168-619X J9 JAMA OTOLARYNGOL JI JAMA Otolaryngol-Head Neck Surg. PD JAN PY 2017 VL 143 IS 1 BP 25 EP 31 DI 10.1001/jamaoto.2016.2624 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA EL2HP UT WOS:000394441000004 PM 27606895 ER PT J AU Chen, XL Fann, YC McAuliffe, M Vismer, D Yang, R AF Chen, Xianlai Fann, Yang C. McAuliffe, Matthew Vismer, David Yang, Rong TI Checking Questionable Entry of Personally Identifiable Information Encrypted by One-Way Hash Transformation SO JMIR MEDICAL INFORMATICS LA English DT Article DE data accuracy; personally identifiable information; confidentiality; computer security; quality control; medical record linkage; registries; privacy ID DE-IDENTIFICATION; PRIVACY; ANONYMIZATION AB Background: As one of the several effective solutions for personal privacy protection, a global unique identifier (GUID) is linked with hash codes that are generated from combinations of personally identifiable information (PII) by a one-way hash algorithm. On the GUID server, no PII is permitted to be stored, and only GUID and hash codes are allowed. The quality of PII entry is critical to the GUID system. Objective: The goal of our study was to explore a method of checking questionable entry of PII in this context without using or sending any portion of PII while registering a subject. Methods: According to the principle of GUID system, all possible combination patterns of PII fields were analyzed and used to generate hash codes, which were stored on the GUID server. Based on the matching rules of the GUID system, an error-checking algorithm was developed using set theory to check PII entry errors. We selected 200,000 simulated individuals with randomly-planted errors to evaluate the proposed algorithm. These errors were placed in the required PII fields or optional PII fields. The performance of the proposed algorithm was also tested in the registering system of study subjects. Results: There are 127,700 error-planted subjects, of which 114,464 (89.64%) can still be identified as the previous one and remaining 13,236 (10.36%, 13,236/127,700) are discriminated as new subjects. As expected, 100% of nonidentified subjects had errors within the required PII fields. The possibility that a subject is identified is related to the count and the type of incorrect PII field. For all identified subjects, their errors can be found by the proposed algorithm. The scope of questionable PII fields is also associated with the count and the type of the incorrect PII field. The best situation is to precisely find the exact incorrect PII fields, and the worst situation is to shrink the questionable scope only to a set of 13 PII fields. In the application, the proposed algorithm can give a hint of questionable PII entry and perform as an effective tool. Conclusions: The GUID system has high error tolerance and may correctly identify and associate a subject even with few PII field errors. Correct data entry, especially required PII fields, is critical to avoiding false splits. In the context of one-way hash transformation, the questionable input of PII may be identified by applying set theory operators based on the hash codes. The count and the type of incorrect PII fields play an important role in identifying a subject and locating questionable PII fields. C1 [Chen, Xianlai] Cent S Univ, Inst Informat Secur & Big Data, Changsha, Peoples R China. [Fann, Yang C.] Natl Inst Hlth, Natl Inst Neurol Disorders & Stroke, Div Intramural, Intramural IT & Bioinformat Program, Bethesda, MD USA. [McAuliffe, Matthew] Ctr Informat Technol, Natl Inst Hlth, Div Comp Sci, Bethesda, MD USA. [Vismer, David] Sapient Govt Serv, Arlington, VA USA. [Yang, Rong] Cent S Univ, Xiangya Hosp, 7 Ward,87 Xiangya Rd, Changsha, Peoples R China. RP Yang, R (reprint author), Cent S Univ, Xiangya Hosp, 7 Ward,87 Xiangya Rd, Changsha, Peoples R China. EM cxlyr0576@163.com FU China Scholarship Council; National Social Science Foundation of China [13BTQ052] FX This research is supported by China Scholarship Council, National Social Science Foundation of China (Grant No. 13BTQ052) and a visiting researcher appointment to the NINDS Research Participation Program which is administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the National Institutes of Health. NR 15 TC 0 Z9 0 U1 0 U2 0 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 2291-9694 J9 JMIR MED INF JI JMIR Med. Inf. PD JAN-MAR PY 2017 VL 5 IS 1 AR e2 DI 10.2196/medinform.5054 PG 16 WC Medical Informatics SC Medical Informatics GA EN3FS UT WOS:000395895000002 PM 28213343 ER PT J AU Shukla, V Seo, J Binukumar, BK Amin, ND Reddy, P Grant, P Kuntz, S Kesavapany, S Steiner, J Mishra, SK Tsai, LH Pant, HC AF Shukla, Varsha Seo, Jinsoo Binukumar, B. K. Amin, Niranjana D. Reddy, Preethi Grant, Philip Kuntz, Susan Kesavapany, Sashi Steiner, Joseph Mishra, Santosh K. Tsai, Li-Huei Pant, Harish C. TI TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores Synaptic Function in CK-p25Tg Mice SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Alzheimer's disease; cyclin-dependent kinase 5; hyperphosphorylation; synaptic function; TFP5 ID CYCLIN-DEPENDENT KINASE-5; GLYCOGEN-SYNTHASE KINASE-3-BETA; ALZHEIMERS-DISEASE; ACTIVATOR P25; TAU PHOSPHORYLATION; TRANSGENIC MICE; NEUROFIBRILLARY TANGLES; NEURODEGENERATIVE DISEASES; COGNITIVE FUNCTIONS; AMYLOID-BETA AB It has been reported that cyclin-dependent kinase 5 (cdk5), a critical neuronal kinase, is hyperactivated in Alzheimer's disease (AD) and may be, in part, responsible for the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs). It has been proposed by several laboratories that hyperactive cdk5 results from the overexpression of p25 (a truncated fragment of p35, the normal cdk5 regulator), which, when complexed to cdk5, induces hyperactivity, hyperphosphorylated tau/NFTs, amyloid-beta plaques, and neuronal death. It has previously been shown that intraperitoneal (i.p.) injections of a modified truncated 24-aa peptide (TFP5), derived from the cdk5 activator p35, penetrated the blood-brain barrier and significantly rescued AD-like pathology in 5XFAD model mice. The principal pathology in the 5XFAD mutant, however, is extensive amyloid plaques; hence, as a proof of concept, we believe it is essential to demonstrate the peptide's efficacy in a mouse model expressing high levels of p25, such as the inducible CK-p25Tg model mouse that overexpresses p25 in CamKII positive neurons. Using a modified TFP5 treatment, here we show that peptide i.p. injections in these mice decrease cdk5 hyperactivity, tau, neurofilament-M/H hyperphosphorylation, and restore synaptic function and behavior (i.e., spatial working memory, motor deficit using Rota-rod). It is noteworthy that TFP5 does not inhibit endogenous cdk5/p35 activity, nor other cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive cdk5. C1 [Shukla, Varsha; Binukumar, B. K.; Amin, Niranjana D.; Reddy, Preethi; Grant, Philip; Kuntz, Susan; Steiner, Joseph; Pant, Harish C.] NINDS, NIH, Bethesda, MD 20892 USA. [Seo, Jinsoo; Tsai, Li-Huei] MIT, Picower Inst Learning & Memory, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Kesavapany, Sashi] Natl Univ Singapore, Singapore, Singapore. [Mishra, Santosh K.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MA USA. RP Pant, HC (reprint author), NINDS, NIH, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov FU intramural research program of the DHHS, U.S. National Institutes of Health (NIH), NINDS; NIH RO1 grant [5R01NS051874] FX This work was supported by the intramural research program of the DHHS, U.S. National Institutes of Health (NIH), NINDS and by the NIH RO1 grant (5R01NS051874) to L.-H.T. NR 75 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 56 IS 1 BP 335 EP 349 DI 10.3233/JAD-160916 PG 15 WC Neurosciences SC Neurosciences & Neurology GA EK4GW UT WOS:000393886100028 PM 28085018 ER PT J AU Qin, J Zhang, B Leung, DHY AF Qin, Jing Zhang, Biao Leung, Denis H. Y. TI Efficient Augmented Inverse Probability Weighted Estimation in Missing Data Problems SO JOURNAL OF BUSINESS & ECONOMIC STATISTICS LA English DT Article DE Inverse probability weighting; Missing data; Regression estimate; Semiparametric efficiency ID DOUBLY ROBUST ESTIMATION; SEMIPARAMETRIC EFFICIENCY; REGRESSION-MODELS; PROPENSITY SCORE; INCOMPLETE DATA; GMM AB When analyzing data with missing data, a commonly used method is the inverse probability weighting (IPW) method, which reweights estimating equations with propensity scores. The popularity of the IPW method is due to its simplicity. However, it is often being criticized for being inefficient because most of the information from the incomplete observations is not used. Alternatively, the regression method is known to be efficient but is nonrobust to the misspecification of the regression function. In this article, we propose a novel way of optimally combining the propensity score function and the regression model. The resulting estimating equation enjoys the properties of robustness against misspecification of either the propensity score or the regression function, as well as being locally semiparametric efficient. We demonstrate analytically situations where our method leads to a more efficient estimator than some of its competitors. In a simulation study, we show the new method compares favorably with its competitors in finite samples. Supplementary materials for this article are available online. C1 [Qin, Jing] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Zhang, Biao] Univ Toledo, Dept Math, Toledo, OH 43606 USA. [Leung, Denis H. Y.] Singapore Management Univ, Sch Econ, Singapore 178903, Singapore. RP Qin, J (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jingqin@niaid.nih.gov; bzhang@utnet.utoledo.edu; denisleung@smu.edu.sg FU Research Center at Singapore Management University FX We thank the referees for their perceptive comments and suggestions, that have led to a greatly improved version of this article. Denis Leung's research is partially supported by the Research Center at Singapore Management University. NR 36 TC 0 Z9 0 U1 1 U2 1 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0735-0015 EI 1537-2707 J9 J BUS ECON STAT JI J. Bus. Econ. Stat. PD JAN PY 2017 VL 35 IS 1 BP 86 EP 97 DI 10.1080/07350015.2015.1058266 PG 12 WC Economics; Social Sciences, Mathematical Methods; Statistics & Probability SC Business & Economics; Mathematical Methods In Social Sciences; Mathematics GA EL1VU UT WOS:000394410300007 ER PT J AU Akbeyaz, IH Tirosh, A Robinson, C Broadney, MM Papadakis, GZ Belyavskaya, E Lyssikatos, C Lodish, MB Stratakis, CA AF Akbeyaz, Ismail Hakki Tirosh, Amit Robinson, Cemre Broadney, Miranda M. Papadakis, Georgios Z. Belyavskaya, Elena Lyssikatos, Charalampos Lodish, Maya B. Stratakis, Constantine A. TI Spontaneously Resolving Hyperreninemic Hypertension Caused by Accessory Renal Artery Stenosis in a 13-Year-Old Girl: A Case Report SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Article ID CHILDREN; ADOLESCENTS AB The authors describe the clinical investigation and progress of a 13-year-old girl diagnosed with hypertension 4 years prior to her admission. A thorough history was taken and physical examination performed. Laboratory analysis and relevant radiological evaluation were obtained in order to determine the etiology for suspected secondary hypertension, and later to differentiate between the possible causes of hyperreninemic hypertension. The patient had an accessory left renal artery, presumptively leading to renin secretion by the underperfused kidney. The patient was treated medically with spontaneous resolution of her hypertension and near normalization of plasma renin activity. On repeat imaging, the artery was not demonstrated. The authors concluded that the diagnosis of hyperreninemic hypertension in young ages should prompt investigation for the etiology. However, cautious observation is a valid option that might lead to spontaneous resolution. Published 2016. This article is a U.S. Government work and is in the public domain in the USA C1 [Akbeyaz, Ismail Hakki; Tirosh, Amit; Robinson, Cemre; Broadney, Miranda M.; Belyavskaya, Elena; Lyssikatos, Charalampos; Lodish, Maya B.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. [Akbeyaz, Ismail Hakki] Istanbul Dr Lutfi Kirdar Kartal Egitim & Arastirm, Istanbul, Turkey. [Papadakis, Georgios Z.] NIH, Warren Grant Magnuson Clin Ctr, Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1524-6175 EI 1751-7176 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD JAN PY 2017 VL 19 IS 1 BP 100 EP 102 DI 10.1111/jch.12893 PG 3 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EL3GS UT WOS:000394508200017 PM 27528003 ER PT J AU Mateescu, B Kowal, EJK van Balkom, BWM Bartel, S Bhattacharyya, SN Buzas, EI Buck, AH de Candia, P Chow, FWN Das, S Driedonks, TAP Fernandez-Messina, L Haderk, F Hill, AF Jones, JC Van Keuren-Jensen, KR Lai, CP Lasser, C di Liegro, I Lunavat, TR Lorenowicz, MJ Maas, SLN Mager, I Mittelbrunn, M Momma, S Mukherjee, K Nawaz, M Pegtel, DM Pfaffl, MW Schiffelers, RM Tahara, H Thery, C Tosar, JP Wauben, MHM Witwer, KW Nolte-'T Hoen, ENM AF Mateescu, Bogdan Kowal, Emma J. K. van Balkom, Bas W. M. Bartel, Sabine Bhattacharyya, Suvendra N. Buzas, Edit I. Buck, Amy H. de Candia, Paola Chow, Franklin W. N. Das, Saumya Driedonks, Tom A. P. Fernandez-Messina, Lola Haderk, Franziska Hill, Andrew F. Jones, Jennifer C. Van Keuren-Jensen, Kendall R. Lai, Charles P. Laesser, Cecilia di Liegro, Italia Lunavat, Taral R. Lorenowicz, Magdalena J. Maas, Sybren L. N. Maeger, Imre Mittelbrunn, Maria Momma, Stefan Mukherjee, Kamalika Nawaz, Muhammed Pegtel, D. Michiel Pfaffl, Michael W. Schiffelers, Raymond M. Tahara, Hidetoshi Thery, Clotilde Tosar, Juan Pablo Wauben, Marca H. M. Witwer, Kenneth W. Nolte-'t Hoen, Esther N. M. TI Obstacles and opportunities in the functional analysis of extracellular vesicle RNA - an ISEV position paper SO JOURNAL OF EXTRACELLULAR VESICLES LA English DT Article DE Extracellular vesicles; exosomes; non-coding RNA; mRNA; function; sorting; RNA binding proteins; quantification ID REAL-TIME PCR; EXOSOME-MEDIATED TRANSFER; MESSENGER-RNA; MAMMALIAN-CELLS; ENDOTHELIAL-CELLS; DRUG-DELIVERY; HUMAN PLASMA; IN-VIVO; RT-PCR; INFLAMMATORY RESPONSE AB The release of RNA-containing extracellular vesicles (EV) into the extracellular milieu has been demonstrated in a multitude of different in vitro cell systems and in a variety of body fluids. RNA-containing EV are in the limelight for their capacity to communicate genetically encoded messages to other cells, their suitability as candidate biomarkers for diseases, and their use as therapeutic agents. Although EV-RNA has attracted enormous interest from basic researchers, clinicians, and industry, we currently have limited knowledge on which mechanisms drive and regulate RNA incorporation into EV and on how RNA-encoded messages affect signalling processes in EV-targeted cells. Moreover, EV-RNA research faces various technical challenges, such as standardisation of EV isolation methods, optimisation of methodologies to isolate and characterise minute quantities of RNA found in EV, and development of approaches to demonstrate functional transfer of EV-RNA in vivo. These topics were discussed at the 2015 EV-RNA workshop of the International Society for Extracellular Vesicles. This position paper was written by the participants of the workshop not only to give an overview of the current state of knowledge in the field, but also to clarify that our incomplete knowledge - of the nature of EV(-RNA)s and of how to effectively and reliably study them - currently prohibits the implementation of gold standards in EV-RNA research. In addition, this paper creates awareness of possibilities and limitations of currently used strategies to investigate EV-RNA and calls for caution in interpretation of the obtained data. C1 [Mateescu, Bogdan] ETH, Swiss Fed Inst Technol, Dept Biol, Zurich, Switzerland. [Kowal, Emma J. K.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [van Balkom, Bas W. M.] UMC Utrecht, Dept Hypertens & Nephrol, Utrecht, Netherlands. [Bartel, Sabine] Member German Ctr Lung Res DZL, Airway Res Ctr North ARCN, Leibniz Ctr Med & Biosci, Res Ctr Borstel,Expt Asthma Res,Prior Area Asthma, Borstel, Germany. [Bhattacharyya, Suvendra N.; Mukherjee, Kamalika] CSIR Indian Inst Chem Biol, Kolkata, India. [Buzas, Edit I.] Semmelweis Univ, Dept Genet Cell & Immunobiol, Budapest, Hungary. [Buck, Amy H.; Chow, Franklin W. N.] Univ Edinburgh, Res Ctr Immun Infect & Evolut, Sch Biol Sci, Inst Immunol & Infect, Edinburgh, Midlothian, Scotland. [de Candia, Paola] IRCCS MultiMed, Milan, Italy. [Das, Saumya] Massachusetts Gen Hosp, Cardiovasc Res Inst, Boston, MA 02114 USA. [Driedonks, Tom A. P.; Wauben, Marca H. M.; Nolte-'t Hoen, Esther N. M.] Univ Utrecht, Fac Vet Med, Dept Biochem & Cell Biol, Utrecht, Netherlands. [Fernandez-Messina, Lola] Hosp Princesa, Immunol Serv, Madrid, Spain. [Haderk, Franziska] German Canc Res Ctr, Dept Mol Genet, Heidelberg, Germany. [Haderk, Franziska] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Med, San Francisco, CA 94143 USA. [Hill, Andrew F.] La Trobe Univ, Trobe Inst Mol Sci, Dept Biochem & Genet, Bundoora, Vic, Australia. [Jones, Jennifer C.] NCI, CCR, Vaccine Branch, Mol Immunogenet & Vaccine Res Sect, Bethesda, MD 20892 USA. [Van Keuren-Jensen, Kendall R.] TGen, Neurogen Div, Phoenix, AZ USA. [Lai, Charles P.] Natl Tsing Hua Univ, Inst Biomed Engn, Hsinchu, Taiwan. [Laesser, Cecilia; Lunavat, Taral R.; Maas, Sybren L. N.] Harvard Med Sch, NeuroDiscovery Ctr, Boston, MA 02114 USA. [Laesser, Cecilia; Lunavat, Taral R.; Maas, Sybren L. N.] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Dept Radiol, Boston, MA 02114 USA. [Laesser, Cecilia; Lunavat, Taral R.; Maas, Sybren L. N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Laesser, Cecilia; Lunavat, Taral R.; Maas, Sybren L. N.] Univ Gothenburg, Sahlgrenska Acad, Krefting Res Ctr, Dept Internal Med & Clin Nutr, Gothenburg, Sweden. [di Liegro, Italia] Univ Palermo, Dept Expt Biomed & Clin Neurosci, Palermo, Italy. [Lorenowicz, Magdalena J.] Univ Med Ctr Utrecht & Regenerat Med Ctr, Ctr Mol Med, Utrecht, Netherlands. [Maeger, Imre] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. [Maeger, Imre] Univ Tartu, Inst Technol, Tartu, Estonia. [Mittelbrunn, Maria] Inst Investigac Hosp 12 Octubre, Madrid, Spain. [Momma, Stefan] Goethe Univ Frankfurt, Sch Med, Inst Neurol Edinger Inst, Frankfurt, Germany. [Nawaz, Muhammed] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Pathol & Forens Med, Sao Paulo, Brazil. [Pegtel, D. Michiel] Vrije Univ Amsterdam Med Ctr, Exosomes Res Grp, Dept Pathol, Amsterdam, Netherlands. [Pfaffl, Michael W.] Tech Univ Munich, Sch Life Sci, Anim Physiol & Immunol, Freising Weihenstephan, Germany. [Schiffelers, Raymond M.] Univ Med Ctr Utrecht, Lab Clin Chem & Haematol, Utrecht, Netherlands. [Tahara, Hidetoshi] Hiroshima Univ, Inst Biomed Hlth Sci, Dept Cell & Mol Biol, Hiroshima, Japan. [Thery, Clotilde] PSL Res Univ, Inst Curie, INSERM U932, Paris, France. [Tosar, Juan Pablo] Univ Republica, Fac Sci, Nucl Res Ctr, Funct Genom Unit,Inst Pasteur Montevideo, Montevideo, Uruguay. [Witwer, Kenneth W.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Witwer, Kenneth W.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD USA. RP Nolte-'T Hoen, ENM (reprint author), Univ Utrecht, Fac Vet Med, Dept Biochem & Cell Biol, Utrecht, Netherlands. EM e.n.m.nolte@uu.nl RI Jones, Jennifer/C-8691-2015; thery, clotilde/F-6373-2013; OI Jones, Jennifer/0000-0002-9488-7719; thery, clotilde/0000-0001-8294-6884; Nawaz, Muhammad /0000-0002-0792-8296 FU NIH Common Fund [1U19CA179513-01]; European Research Council under the European Union [337581]; FAPESP (Sao Paulo Research Foundation) [12/24574-3]; CAPES (Coordination for the Improvement of Higher Education Personnel) [BEX 7057/15-6] FX BM is supported by grant 1U19CA179513-01 from the NIH Common Fund. ENMN-TH receives funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement number 337581. MN received funding from FAPESP (Sao Paulo Research Foundation, Proc. No. 12/24574-3) and CAPES (Coordination for the Improvement of Higher Education Personnel, Proc No. BEX 7057/15-6). NR 247 TC 0 Z9 0 U1 5 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 2001-3078 J9 J EXTRACELL VESICLES JI J. Extracell. Vesicles PY 2017 VL 6 AR 1286095 DI 10.1080/20013078.2017.1286095 PG 33 WC Cell Biology SC Cell Biology GA EN7CF UT WOS:000396159000001 PM 28326170 ER PT J AU Kim, H Byun, JS Hallett, M Shin, HW AF Kim, Hyangkyoung Byun, Jun Soo Hallett, Mark Shin, Hae-Won TI Multifocal Myoclonus as a Manifestation of Acute Cerebral Infarction Recovered by Carotid Arterial Stenting SO JOURNAL OF MOVEMENT DISORDERS LA English DT Letter ID EPILEPSIA PARTIALIS CONTINUA; MOVEMENT-DISORDERS; STROKE C1 [Kim, Hyangkyoung] Chung Ang Univ, Coll Med, Dept Surg, Seoul, South Korea. [Byun, Jun Soo] Chung Ang Univ, Coll Med, Dept Radiol, Seoul, South Korea. [Shin, Hae-Won] Chung Ang Univ, Coll Med, Dept Neurol, 102 Heukseok Ro, Seoul 06973, South Korea. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Shin, HW (reprint author), Chung Ang Univ, Coll Med, Dept Neurol, 102 Heukseok Ro, Seoul 06973, South Korea. EM shinhw@cau.ac.kr NR 7 TC 0 Z9 0 U1 0 U2 0 PU KOREAN MOVEMENT DISORDERS SOC PI SEOUL PA 2011 MAPO HANWHA OBELISK, 555, DOHWA-DONG, MAPO-GU, SEOUL, 04167, SOUTH KOREA SN 2005-940X EI 2093-4939 J9 J MOV DISORD JI J. Mov. Disord. PD JAN PY 2017 VL 10 IS 1 BP 64 EP 66 DI 10.14802/jmd.16040 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA EK6OB UT WOS:000394042800010 ER PT J AU Cervetto, C Venturini, A Passalacqua, M Guidolin, D Genedani, S Fuxe, K Borroto-Esquela, DO Cortelli, P Woods, A Maura, G Marcoli, M Agnati, LF AF Cervetto, Chiara Venturini, Arianna Passalacqua, Mario Guidolin, Diego Genedani, Susanna Fuxe, Kjell Borroto-Esquela, Dasiel O. Cortelli, Pietro Woods, Amina Maura, Guido Marcoli, Manuela Agnati, Luigi F. TI A2A-D2 receptor-receptor interaction modulates gliotransmitter release from striatal astrocyte processes SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE astrocyte processes; glutamate; heterodimers; Receptor-receptor interactions ID ADENOSINE A(2A) RECEPTORS; CENTRAL-NERVOUS-SYSTEM; VESICULAR GLUTAMATE RELEASE; HIGHER-ORDER OLIGOMERS; DOPAMINE D2 RECEPTORS; VOLUME TRANSMISSION; BASAL GANGLIA; HETERORECEPTOR COMPLEXES; THERAPEUTIC IMPLICATIONS; ANTIPSYCHOTIC-DRUGS AB Evidence for striatal A2A-D2 heterodimers has led to a new perspective on molecular mechanisms involved in schizophrenia and Parkinson's disease. Despite the increasing recognition of astrocytes' participation in neuropsychiatric disease vulnerability, involvement of striatal astrocytes in A2A and D2 receptor signal transmission has never been explored. Here, we investigated the presence of D2 and A2A receptors in isolated astrocyte processes prepared from adult rat striatum by confocal imaging; the effects of receptor activation were measured on the 4-aminopyridine-evoked release of glutamate from the processes. Confocal analysis showed that A2A and D2 receptors were coexpressed on the same astrocyte processes. Evidence for A2A-D2 receptor-receptor interactions was obtained by measuring the release of the gliotransmitter glutamate: D2 receptors inhibited the glutamate release, while activation of A2A receptors, per se ineffective, abolished the effect of D2 receptor activation. The synthetic D2 peptide VLRRRRKRVN corresponding to the receptor region involved in electrostatic interaction underlying A2A-D2 heteromerization abolished the ability of the A2A receptor to antagonize the D2 receptor-mediated effect. Together, the findings are consistent with heteromerization of native striatal astrocytic A2A-D2 receptors that via allosteric receptor-receptor interactions could play a role in the control of striatal glutamatergic transmission. These new findings suggest possible new pathogenic mechanisms and/or therapeutic approaches to neuropsychiatric disorders. C1 [Cervetto, Chiara; Venturini, Arianna; Maura, Guido; Marcoli, Manuela] Univ Genoa, Sect Pharmacol & Toxicol, Dept Pharm, Genoa, Italy. [Cervetto, Chiara; Maura, Guido; Marcoli, Manuela] Univ Genoa, Ctr Excellence Biomed Res, Viale Benedetto, Genoa, Italy. [Passalacqua, Mario] Univ Genoa, Biochem Sect, Dept Expt Med, Genoa, Italy. [Passalacqua, Mario] Univ Genoa, Italian Inst Biostruct & Biosyst, Genoa, Italy. [Guidolin, Diego] Univ Padua, Dept Neurosci, Padua, Italy. [Genedani, Susanna; Agnati, Luigi F.] Univ Modena & Reggio Emilia, Dept Diagnost Clin Med & Publ Hlth, Via Campi 287, I-41125 Modena, Italy. [Fuxe, Kjell; Borroto-Esquela, Dasiel O.; Agnati, Luigi F.] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. [Cortelli, Pietro] Univ Bologna, Dept Biomed & NeuroMotor Sci DIBINEM, Alma Mater Studiorum, Bologna, Italy. [Cortelli, Pietro] IRCCS Ist Sci Neurol Bologna, Bologna, Italy. [Woods, Amina] NIDA, Struct Biol Unit, NIH, Intramural Res Program, Baltimore, MD USA. RP Agnati, LF (reprint author), Univ Modena & Reggio Emilia, Dept Diagnost Clin Med & Publ Hlth, Via Campi 287, I-41125 Modena, Italy.; Marcoli, M (reprint author), Univ Genoa, Dept Pharm, Viale Cembrano 4, I-16148 Genoa, Italy. EM marcoli@pharmatox.unige.it; luigi.agnati@gmail.com OI Cervetto, Chiara/0000-0001-8290-3008 FU University of Genova, Progetto Ricerca Ateneo [020301002054, D31J1100003005, D31J1100161005]; University of Padova [A.00000.D170.GUIDEX6013] FX The support of University of Genova, Progetto Ricerca Ateneo 2007, 2010 and 2011 [Grant 020301002054 to M.M., Grant D31J1100003005 and D31J1100161005 to C.C.]; and of University of Padova [Grant A.00000.D170.GUIDEX6013 to D.G.] is gratefully acknowledged. All authors have no conflict of interest to declare. NR 84 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD JAN PY 2017 VL 140 IS 2 BP 268 EP 279 DI 10.1111/jnc.13885 PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EL5DD UT WOS:000394640900008 PM 27896809 ER PT J AU Heusinkveld, L Hacker, M Turchan, M Bollig, M Tamargo, C Fisher, W McLaughlin, L Martig, A Charles, D AF Heusinkveld, Lauren Hacker, Mallory Turchan, Maxim Bollig, Madelyn Tamargo, Christina Fisher, William McLaughlin, Lauren Martig, Adria Charles, David TI Patient Perspectives on Deep Brain Stimulation Clinical Research in Early Stage Parkinson's Disease SO JOURNAL OF PARKINSONS DISEASE LA English DT Article DE Parkinson's disease; deep brain stimulation; surveys; patient preference ID DECISION-MAKING; RECRUITMENT; SURGERY; TRIALS AB The FDA has approved a multicenter, double-blind, Phase III, pivotal trial testing deep brain stimulation (DBS) in 280 people with very early stage Parkinson's disease (PD; IDE#G050016). In partnership with The Michael J. Fox Foundation for Parkinson's Research, we conducted a survey to investigate motivating factors, barriers, and gender differences among potentially eligible patients for participation in a trial testing DBS in early PD compared to standard medical treatment. The majority of survey respondents (72%) indicated they would consider learning more about participating. Early PD patients are therefore likely to consider enrolling in trials of invasive therapies that may slow symptom progression and help future patients. C1 [Heusinkveld, Lauren; Hacker, Mallory; Turchan, Maxim; Bollig, Madelyn; Tamargo, Christina; Fisher, William; Charles, David] Vanderbilt Univ Sch Med, Dept Neurol, 1161 21st Ave S,Suite A-1106 MCN, Nashville, TN 37232 USA. [McLaughlin, Lauren] Michael J Fox Fdn Parkinsons Res, New York, NY USA. [Heusinkveld, Lauren] NIAID, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Heusinkveld, L (reprint author), Vanderbilt Univ Sch Med, Dept Neurol, 1161 21st Ave S,Suite A-1106 MCN, Nashville, TN 37232 USA. EM lauren.heusinkveld@gmail.com FU Michael J. Fox Foundation for Parkinson's Research FX This work has been supported by The Michael J. Fox Foundation for Parkinson's Research. NR 19 TC 0 Z9 0 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1877-7171 EI 1877-718X J9 J PARKINSON DIS JI J. Parkinsons Dis. PY 2017 VL 7 IS 1 BP 89 EP 94 DI 10.3233/JPD-161031 PG 6 WC Neurosciences SC Neurosciences & Neurology GA EM9XP UT WOS:000395665200007 PM 27911344 ER PT J AU Suskind, AM Cawthon, PM Nakagawa, S Subak, LL Reinders, I Satterfield, S Cummings, S Cauley, JA Harris, T Huang, AJ AF Suskind, Anne M. Cawthon, Peggy M. Nakagawa, Sanae Subak, Leslee L. Reinders, Ilse Satterfield, Suzanne Cummings, Steve Cauley, Jane A. Harris, Tamara Huang, Alison J. CA Hlth ABC Study TI Urinary Incontinence in Older Women: The Role of Body Composition and Muscle Strength: From the Health, Aging, and Body Composition Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE stress urinary incontinence; urgency urinary incontinence ID CHRONIC BLADDER ISCHEMIA; SELF-RATED HEALTH; MASS INDEX; PHYSICAL PERFORMANCE; OXIDATIVE STRESS; LEAN MASS; MORTALITY; RISK; PEOPLE; ADULTS AB ObjectivesTo evaluate prospective relationships between body composition and muscle strength with predominantly stress urinary incontinence (SUI) and urgency urinary incontinence (UUI) in older women. DesignProspective community-dwelling observational cohort study (Health, Aging, and Body Composition study). ParticipantsWomen initially aged 70 to 79 recruited from Pittsburgh, Pennsylvania, and Memphis, Tennessee (N = 1,475). MeasurementsUrinary incontinence was assessed using structured questionnaires. Body mass index (BMI), grip strength, quadriceps torque, and walking speed were assessed using physical examination and performance testing. Appendicular lean body mass (ALM) and whole-body fat mass were measured using dual-energy X-ray absorptiometry. ResultsAt baseline, 212 (14%) women reported at least monthly predominantly SUI and 233 (16%) at least monthly predominantly UUI. At 3 years, of 1,137 women, 164 (14%) had new or persistent SUI, and 320 (28%) had new or persistent UUI. Women had greater odds of new or persistent SUI if they demonstrated a 5% or greater decrease in grip strength, (adjusted odds ratio (AOR) = 1.60, P = .047) and lower odds of new or persistent SUI if they demonstrated a 5% or greater decrease in BMI (AOR = 0.46, P = .01), a 5% or greater increase in ALM corrected for BMI (AOR = 0.17, P = .004), or a 5% or greater decrease in fat mass (AOR = 0.53, P = .01). Only a 5% or greater increase in walking speed was associated with new or persistent UUI over 3 years (AOR = 1.54, P = .04). ConclusionIn women aged 70 and older, changes in body composition and grip strength were associated with changes in SUI frequency over time. In contrast, changes in these factors did not influence UUI. Findings suggest that optimization of body composition and muscle strength is more likely to modify risk of SUI than of UUI in older women. C1 [Suskind, Anne M.; Subak, Leslee L.] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA. [Cawthon, Peggy M.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Nakagawa, Sanae; Subak, Leslee L.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Subak, Leslee L.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Reinders, Ilse; Harris, Tamara] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Reinders, Ilse] Vrije Univ Amsterdam, Dept Nutr & Dietet Internal Med, Med Ctr, Amsterdam, Netherlands. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Cummings, Steve; Huang, Alison J.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Suskind, AM (reprint author), 400 Parnassus Ave,Box 0738, San Francisco, CA 94143 USA. EM Anne.Suskind@ucsf.edu FU NIDDK [K12 DK83021-07]; K12 Urologic Research Career Development Program; Pepper Center Research Career Development Core Advanced Scholar Award; National Institute on Aging (NIA) [1K23AG038335]; American Federation for Aging Research; Mid-Career Investigator Award in Patient Oriented Research [K24, 2K24DK080775-06]; NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute of Nursing Research Grant [R01-NR012459] FX Dr. Suskind's time was funded by NIDDK K12 DK83021-07; K12 Urologic Research Career Development Program and the Pepper Center Research Career Development Core Advanced Scholar Award. Dr. Huang was supported by a Paul B. Beeson Career Development Award in Aging Research from the National Institute on Aging (NIA) (1K23AG038335) and the American Federation for Aging Research. Dr. Subak was supported by a Mid-Career Investigator Award in Patient Oriented Research (K24; 2K24DK080775-06). This research was supported by NIA Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA Grant R01-AG028050; and National Institute of Nursing Research Grant R01-NR012459. NR 27 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JAN PY 2017 VL 65 IS 1 BP 42 EP 50 DI 10.1111/jgs.14545 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL3WZ UT WOS:000394551300012 PM 27918084 ER PT J AU Howard, G Safford, MM Moy, CS Howard, VJ Kleindorfer, DO Unverzagt, FW Soliman, EZ Flaherty, ML McClure, LA Lackland, DT Wadley, VG Pulley, L Cushman, M AF Howard, George Safford, Monika M. Moy, Claudia S. Howard, Virginia J. Kleindorfer, Dawn O. Unverzagt, Fredrick W. Soliman, Elsayed Z. Flaherty, Matthew L. McClure, Leslie A. Lackland, Daniel T. Wadley, Virginia G. Pulley, LeaVonne Cushman, Mary TI Racial Differences in the Incidence of Cardiovascular Risk Factors in Older Black and White Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE epidemiology; longitudinal cohort study; risk factors; hypertension; diabetes mellitus; lipids and cholesterol; atrial fibrillation ID AMERICAN-HEART-ASSOCIATION; NUTRITION EXAMINATION SURVEY; ATRIAL-FIBRILLATION; BLOOD-PRESSURE; HYPERTENSION INCIDENCE; ATHEROSCLEROSIS RISK; AFRICAN-AMERICANS; NATIONAL-HEALTH; DISEASE; STROKE AB ObjectivesTo describe the incidence of cardiovascular risk factors, or race-related disparities in incidence, across the age spectrum in adults. DesignLongitudinal cohort. SettingNational sample. ParticipantsCommunity-dwelling black and white adults recruited between 2003 and 2007. MeasurementsIncident hypertension, diabetes mellitus, dyslipidemia and atrial fibrillation over 10 years of follow-up in 10,801 adults, stratified according to age (45-54, 55-64, 65-74, 75). ResultsThere was no evidence (P .68) of an age-related difference in the incidence of hypertension for white men (average incidence 38%), black men (48%), or black women (54%), although for white women incidence increased with age (45-54, 27%; 75, 40%). Incidence of diabetes mellitus was lower at older ages for white men (45-54, 15%; 75, 8%), black men (45-54, 29%; 75, 13%), and white women (45-54, 11%; 75, 4%), although there was no evidence (P = .11) of age-related changes for black women (average incidence 21%). For dyslipidemia, incidence for all race-sex groups was approximately 20% for aged 45 to 54 but approximately 30% for aged 54 to 64 and 65 to 74 and approximately 22% for aged 75 and older. Incidence of atrial fibrillation was low at age 45 to 54 (<5%) but for aged 75 and older was approximately 20% for whites and 11% for blacks. The incidence of hypertension, diabetes mellitus, and dyslipidemia was higher in blacks across the age spectrum but lower for atrial fibrillation. ConclusionIncidence of risk factors remains high in older adults. Blacks have a higher incidence of hypertension, diabetes mellitus, and dyslipidemia after age 45, underscoring the ongoing importance of prevention of all three conditions in mid- to later life. C1 [Howard, George] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [Safford, Monika M.] Weill Cornell Med Coll, Div Gen Internal Med, New York, NY USA. [Moy, Claudia S.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Howard, Virginia J.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Kleindorfer, Dawn O.; Flaherty, Matthew L.] Univ Cincinnati, Dept Neurol, Cincinnati, OH USA. [Unverzagt, Fredrick W.] Indiana Univ, Dept Psychol, Indianapolis, IN 46204 USA. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol, Winston Salem, NC USA. [McClure, Leslie A.] Drexel Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Lackland, Daniel T.] Med Univ South Carolina, Dept Neurosci, Charleston, SC USA. [Wadley, Virginia G.] Univ Alabama Birmingham, Sch Med, Dept Gerontol Geriatr & Palliat Care, Birmingham, AL USA. [Pulley, LeaVonne] Univ Arkansas Med Sci, Dept Hlth Behav & Hlth Educ, Little Rock, AR 72205 USA. [Cushman, Mary] Univ Vermont, Sch Med, Dept Med, Burlington, VT 05405 USA. RP Howard, G (reprint author), UAB Sch Publ Hlth, Dept Biostat, 1665 Univ Blvd, Birmingham, AL 35233 USA. EM ghoward@uab.edu FU National Institute of Neurological Disorders and Stroke (NINDS), NIH [U01-NS041588] FX This research project was supported by cooperative agreement U01-NS041588 from the National Institute of Neurological Disorders and Stroke (NINDS), NIH. NR 38 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JAN PY 2017 VL 65 IS 1 BP 83 EP 90 DI 10.1111/jgs.14472 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL3WZ UT WOS:000394551300017 PM 27666895 ER PT J AU Gudmundsson, A Aspelund, T Sigurdsson, G Harris, T Launer, LJ Gudnason, V Jonsson, H AF Gudmundsson, Adalsteinn Aspelund, Thor Sigurdsson, Gunnar Harris, Tamara Launer, Lenore J. Gudnason, Vilmundur Jonsson, Helgi TI Long-Term Hormone Replacement Therapy Is Associated with Low Coronary Artery Calcium Levels in a Cohort of Older Women: The Age, Gene/Environment SusceptibilityReykjavik Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE hormone replacement therapy; coronary artery calcium; older women; epidemiology ID RANDOMIZED CONTROLLED-TRIAL; ESTROGEN PLUS PROGESTIN; HEART-DISEASE; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; PRIMARY PREVENTION; TIMING HYPOTHESIS; VASCULAR ACTIONS; RISK-FACTORS; REYKJAVIK AB ObjectivesTo assess the relationship between hormone replacement therapy (HRT) and coronary artery calcium (CAC). DesignCross-sectional. SettingEstablished population-based cohort in Reykjavik, Iceland. ParticipantsWomen (mean age 76 5) who had completed questionnaires on HRT use (N = 2,867). MeasurementsCoronary artery calcium assessed using computed tomography was the outcome variable and was compared between women with history of HRT and those who had never used HRT and analyzed according to age, length of use, and time after menopause that HRT was initiated. ResultsEight hundred seventy-two (30.4%) participants had used HRT, and 312 (10.9%) were current users. After adjustment for age, other late-life variables, and a propensity score based on midlife data for HRT use as observed in late life, there were significant negative associations between CAC and history and length of HRT use. This association was evident in all age categories. When HRT had been used for longer than 15 years, median CAC level was less than 50% of that observed in never users. The lowest CAC was observed in those who started HRT within 5 years after menopause. The prevalence of coronary events was comparable in both groups. ConclusionA strong association was found between long-term HRT use and low CAC. The negative association between duration of HRT and CAC was evident in all age groups of older women. C1 [Gudmundsson, Adalsteinn; Sigurdsson, Gunnar; Jonsson, Helgi] Landspitali Univ Hosp, Reykjavik, Iceland. [Gudmundsson, Adalsteinn; Aspelund, Thor; Sigurdsson, Gunnar; Gudnason, Vilmundur; Jonsson, Helgi] Univ Iceland, Reykjavik, Iceland. [Aspelund, Thor; Sigurdsson, Gunnar; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Harris, Tamara; Launer, Lenore J.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. RP Gudmundsson, A (reprint author), Landspitali Landakot, Dept Geriatr Med, IS-101 Reykjavik, Iceland. EM adalstg@landspitali.is FU National Institutes of Health (NIH) [N01-AG-12100]; National Institute on Aging; Intramural Research Program, Hjartavernd (The Icelandic Heart Association); Althing (The Icelandic Parliament) FX This work was supported by National Institutes of Health (NIH) Contract N01-AG-12100, the National Institute on Aging, the Intramural Research Program, Hjartavernd (The Icelandic Heart Association), and the Althing (The Icelandic Parliament). NR 39 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JAN PY 2017 VL 65 IS 1 BP 200 EP 206 DI 10.1111/jgs.14461 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL3WZ UT WOS:000394551300033 PM 27861721 ER PT J AU Foster, JC Liu, DP Albert, PS Liu, AY AF Foster, Jared C. Liu, Danping Albert, Paul S. Liu, Aiyi TI Identifying subgroups of enhanced predictive accuracy from longitudinal biomarker data by using tree-based approaches: applications to fetal growth SO JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES A-STATISTICS IN SOCIETY LA English DT Article DE Fetal growth; Personalized medicine; Prediction; Recursive partitioning; Shared random-effects models ID CLINICAL-TRIALS; IDENTIFICATION; SELECTION; MODEL; BART AB Longitudinal monitoring of biomarkers is often helpful for predicting disease or a poor clinical outcome. We consider the prediction of both large and small for gestational age births by using longitudinal ultrasound measurements, and we attempt to identify subgroups of women for whom prediction is more (or less) accurate, should they exist. We propose a tree-based approach to identifying such subgroups, and a pruning algorithm which explicitly incorporates a desired type I error rate, allowing us to control the risk of false discovery of subgroups. The methods proposed are applied to data from the Scandinavian Fetal Growth Study and are evaluated via simulations. C1 [Foster, Jared C.; Liu, Danping; Albert, Paul S.; Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Foster, JC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. EM foster.jared@mayo.edu FU Intramural Research Program of the National Institutes of Health, NICHD FX This research is supported by the Intramural Research Program of the National Institutes of Health, NICHD. For all simulations, we utilized the high performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland (http://biowulf.nih.gov). We thank Professor Xiaogang Su for sharing his recursive partitioning code with us. We also thank the Associate Editor and two reviewers for their helpful comments, which we believe led to a greatly improved version of this paper. NR 21 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0964-1998 EI 1467-985X J9 J R STAT SOC A STAT JI J. R. Stat. Soc. Ser. A-Stat. Soc. PD JAN PY 2017 VL 180 IS 1 BP 247 EP 261 DI 10.1111/rssa.12182 PG 15 WC Social Sciences, Mathematical Methods; Statistics & Probability SC Mathematical Methods In Social Sciences; Mathematics GA EP1AK UT WOS:000397117600012 PM 28239239 ER PT J AU Gonzalez-Freire, M Diaz-Ruiz, A de Cabo, R AF Gonzalez-Freire, Marta Diaz-Ruiz, Alberto de Cabo, Rafael TI 17 alpha-Estradiol: A Novel Therapeutic Intervention to Target Age-related Chronic Inflammation SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material ID LIFE-SPAN; CALORIC RESTRICTION; LONGEVITY; ESTROGEN; HUMANS; BRAIN C1 [Gonzalez-Freire, Marta; Diaz-Ruiz, Alberto; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP de Cabo, R (reprint author), NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov NR 16 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JAN PY 2017 VL 72 IS 1 BP 1 EP 2 DI 10.1093/gerona/glw041 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EO8OF UT WOS:000396948200001 PM 27034507 ER PT J AU Studenski, S AF Studenski, Stephanie TI Utility of Brief Cognitive and Physical Assessments in Clinical Care SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material ID LOWER-EXTREMITY FUNCTION; GAIT SPEED PREDICTS; SUBSEQUENT DISABILITY; OLDER-ADULTS; HOSPITALIZATION; MORTALITY; OUTCOMES C1 [Studenski, Stephanie] NIA, Chief Longitudinal Studies Sect, Intramural Program, 3001 South Hanover St, Baltimore, MD 21225 USA. RP Studenski, S (reprint author), NIA, Chief Longitudinal Studies Sect, Intramural Program, 3001 South Hanover St, Baltimore, MD 21225 USA. EM studenskisa@mail.nih.gov NR 18 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 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JAN PY 2017 VL 72 IS 1 BP 59 EP 60 DI 10.1093/gerona/glw182 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EO8OF UT WOS:000396948200007 PM 27803097 ER PT J AU Patel, VN Pineda, DL Hoffman, MP AF Patel, Vaishali N. Pineda, Dallas L. Hoffman, Matthew P. TI The function of heparan sulfate during branching morphogenesis SO MATRIX BIOLOGY LA English DT Review DE Branching morphogenesis; Extracellular matrix; Heparan sulfate 3-O-sulfotransferase; FGF10; Heparan sulfate; FGFR2b; Growth factors ID FIBROBLAST-GROWTH-FACTOR; N-DEACETYLASE/N-SULFOTRANSFERASE; GOLABI-BEHMEL-SYNDROME; BETA-D-XYLOSIDE; EXTRACELLULAR-MATRIX; SALIVARY-GLANDS; URETERAL BUD; EPITHELIAL MORPHOGENESIS; BASEMENT-MEMBRANES; MICE DEFICIENT AB Branching morphogenesis is a fundamental process in the development of diverse epithelial organs such as the lung, kidney, liver, pancreas, prostate, salivary, lacrimal and mammary glands. A unifying theme during organogenesis is the importance of epithelial cell interactions with the extracellular matrix (ECM) and growth factors (GFs). The diverse developmental mechanisms giving rise to these epithelial organs involve many organ-specific GFs, but a unifying paradigm during organogenesis is the regulation of GF activity by heparan sulfates (HS) on the cell surface and in the ECM. This primarily involves the interactions of GFs with the sulfated side-chains of HS proteoglycans. HS is one of the most diverse biopolymers and modulates GF binding and signaling at the cell surface and in the ECM of all tissues. Here, we review what is known about how HS regulates branching morphogenesis of epithelial organs with emphasis on the developing salivary gland, which is a classic model to investigate epithelial-ECM interactions. We also address the structure, biosynthesis, turnover and function of HS during organogenesis. Understanding the regulatory mechanisms that control HS dynamics may aid in the development of therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine. Published by Elsevier B.V. C1 [Patel, Vaishali N.; Pineda, Dallas L.; Hoffman, Matthew P.] Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Sect, NIH, Bethesda, MD 20892 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 National Institute of Dental and Craniofacial Research at the National Institutes of Health [DE000707-07] FX The authors would like to thank Drs. Jennifer Symonds and Belinda Hauser for comments and critical reading of this manuscript. This work was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research (DE000707-07) at the National Institutes of Health. NR 103 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X EI 1569-1802 J9 MATRIX BIOL JI Matrix Biol. PD JAN PY 2017 VL 57-58 SI SI BP 311 EP 323 DI 10.1016/j.matbio.2016.09.004 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EP0KI UT WOS:000397075800022 PM 27609403 ER PT J AU Boshoff, HI AF Boshoff, Helena I. TI Caught between two proteins: a mycobacterial inhibitor challenges the mold SO MOLECULAR MICROBIOLOGY LA English DT Editorial Material ID TUBERCULOSIS; DRUG; WAG31; IDENTIFICATION; DISCOVERY; TB; INTERACTS; PROTEASE; SCREEN; SQ109 AB Elucidating the target or mechanism of action of potential drugs in the discovery pipeline is an integral component of most programs. For antibacterial compounds, generation of resistant mutants followed by whole genome sequencing has often been successful in uncovering the proteins involved in regulating compound activation, uptake, efflux and importantly, target processes. When this process succeeds, we are quick to declare a target. In a study reported by Sing and Dhar et al. (in press), the combination of resistant mutant generation, whole genome sequencing and recombineering to identify the target of a Mycobacterium tuberculosis growth inhibitor, pointed to a mechanism involving a scaffolding protein, Wag31, involved in polar elongation of mycobacterial cells. Time-lapse microscopy and electron microscopy confirmed the view that this inhibitor resulted in interruption of nascent cell wall biosynthesis. However, co-expression as well as regulated titration of the putative Wag31 target demonstrated that the wild-type allele was dominant and showed no synergy with the inhibitor. The most plausible explanation from their results was that this inhibitor interfered with the interaction of Wag31 with one of its interacting partners in the elongation complex. C1 [Boshoff, Helena I.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Boshoff, HI (reprint author), NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hbosh-off@niaid.nih.gov FU NIAID FX This work was funded by the Intramural Research Program of NIAID. 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 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD JAN PY 2017 VL 103 IS 1 BP 2 EP 6 DI 10.1111/mmi.13570 PG 5 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA EL5VA UT WOS:000394688100002 PM 27802567 ER PT J AU Ni, QQ Teng, ZG Dang, M Tian, Y Zhang, YL Huang, P Su, XD Lu, N Yang, ZL Tian, W Wang, SJ Liu, WF Tang, YX Lu, GM Zhang, LJ AF Ni, Qianqian Teng, Zhaogang Dang, Meng Tian, Ying Zhang, Yunlei Huang, Peng Su, Xiaodan Lu, Nan Yang, Zhenlu Tian, Wei Wang, Shouju Liu, Wenfei Tang, Yuxia Lu, Guangming Zhang, Longjiang TI Gold nanorod embedded large-pore mesoporous organosilica nanospheres for gene and photothermal cooperative therapy of triple negative breast cancer SO NANOSCALE LA English DT Article ID SILICA NANOPARTICLES; SIRNA DELIVERY; INTRACELLULAR TRAFFICKING; TARGETED NANOPARTICLES; CO-DELIVERY; IN-VIVO; CELLS; THERAPEUTICS; DOXORUBICIN; EFFICACY AB To date, clinicians still lack an effective strategy to treat triple negative breast cancer (TNBC). In this work, we design for the first time a gold nanorod embedded large-pore mesoporous organosilica (GNR@LPMO) nanoplatform for gene and photothermal cooperative therapy of TNBC. The synthesized GNR@LPMOs possess a uniform size (175 nm), high surface area (631 m(2) g(-1)), large pore size, excellent photothermal efficiency, and good biocompatibility. Thanks to the large-pore mesoporous organosilica layer, the GNR@LPMO nanoplatforms display much higher loading capacity of siRNA compared with traditional liposome and bare gold nanorods. Thus, functional siRNA can be efficiently delivered into TNBC cells by GNR@LPMOs, causing much higher cell apoptosis through knocking down the PLK1 proteins. By combining the effective gene delivery and photothermal abilities, the GNR@LPMO nanoplatforms are further used for gene and photothermal cooperative therapy of TNBC, which induce a 15 fold higher mice tumor inhibition rate than sole therapy modality, indicating the potential clinical use of this novel nanoplatform in treating TNBC. C1 [Ni, Qianqian; Teng, Zhaogang; Tian, Ying; Zhang, Yunlei; Lu, Nan; Yang, Zhenlu; Tian, Wei; Wang, Shouju; Liu, Wenfei; Tang, Yuxia; Lu, Guangming; Zhang, Longjiang] Nanjing Univ, Jinling Hosp, Dept Med Imaging, Sch Med, 305 Zhongshan East Rd, Nanjing 210002, Jiangsu, Peoples R China. [Ni, Qianqian; Lu, Nan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD USA. [Teng, Zhaogang; Lu, Guangming] Nanjing Univ, Sch Chem & Chem Engn, State Key Lab Analyt Chem Life Sci, Nanjing 210093, Jiangsu, Peoples R China. [Dang, Meng; Su, Xiaodan] Nanjing Univ Posts & Telecommun, Jiangsu Natl Synerget Innovat Ctr Adv Mat SICAM, Key Lab Organ Elect & Informat Displays, Nanjing 210023, Jiangsu, Peoples R China. [Dang, Meng; Su, Xiaodan] Nanjing Univ Posts & Telecommun, Jiangsu Natl Synerget Innovat Ctr Adv Mat SICAM, IAM, Nanjing 210023, Jiangsu, Peoples R China. [Huang, Peng] Shenzhen Univ, Sch Biomed Engn, Guangdong Key Lab Biomed Measurements & Ultrasoud, Shenzhen 518060, Guangdong, Peoples R China. RP Lu, GM; Zhang, LJ (reprint author), Nanjing Univ, Jinling Hosp, Dept Med Imaging, Sch Med, 305 Zhongshan East Rd, Nanjing 210002, Jiangsu, Peoples R China.; Lu, GM (reprint author), Nanjing Univ, Sch Chem & Chem Engn, State Key Lab Analyt Chem Life Sci, Nanjing 210093, Jiangsu, Peoples R China. EM cjr.luguangming@vip.163.com; kevinzhlj@163.com FU National Key Basic Research Program of the PRC [2014CB744501, 2014CB744504]; Major International (Regional) Joint Research Program of China [81120108013]; National Natural Science Foundation of China [81201175, 81530054, 81322020, 81230032, 81601556, 81501538]; Natural Science Foundation of Jiangsu Province [BK20160017, BK20130863] FX We greatly appreciate financial support from the National Key Basic Research Program of the PRC (2014CB744501 and 2014CB744504), the Major International (Regional) Joint Research Program of China (81120108013), the National Natural Science Foundation of China (81201175, 81530054, 81322020, 81230032, 81601556, 81501538), and the Natural Science Foundation of Jiangsu Province (BK20160017 and BK20130863). NR 48 TC 0 Z9 0 U1 10 U2 10 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2017 VL 9 IS 4 BP 1466 EP 1474 DI 10.1039/c6nr07598c PG 9 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EM6KZ UT WOS:000395422800014 PM 28066849 ER PT J AU Vlijm, R Kim, SH De Zwart, PL Dalal, Y Dekker, C AF Vlijm, R. Kim, S. H. De Zwart, P. L. Dalal, Y. Dekker, C. TI The supercoiling state of DNA determines the handedness of both H3 and CENP-A nucleosomes SO NANOSCALE LA English DT Article ID HISTONE (H3-H4)(2) TETRAMER; SINGLE CHROMATIN FIBERS; CORE PARTICLE; CENTROMERIC NUCLEOSOME; ASSEMBLY DYNAMICS; CHIRAL TRANSITION; MAGNETIC TWEEZERS; CRYSTAL-STRUCTURE; CHAPERONE NAP1; IN-VITRO AB Nucleosomes form the unit structure of the genome in eukaryotes, thereby constituting a fundamental tenet of chromatin biology. In canonical nucleosomes, DNA wraps around the histone octamer in a left-handed toroidal ramp. Here, in single-molecule magnetic tweezers studies of chaperone-assisted nucleosome assembly, we show that the handedness of the DNA wrapping around the nucleosome core is intrinsically ambidextrous, and depends on the pre-assembly supercoiling state of the DNA, i.e., it is not uniquely determined by the octameric histone core. Nucleosomes assembled onto negatively supercoiled DNA are found to exhibit a left-handed conformation, whereas assembly onto positively supercoiled DNA results in right-handed nucleosomes. This intrinsic flexibility to adopt both chiralities is observed both for canonical H3 nucleosomes, and for centromere-specific variant CENP-A nucleosomes. These data support recent advances suggesting an intrinsic adaptability of the nucleosome, and provide insights into how nucleosomes-might rapidly re-assemble after cellular processes that generate positive supercoiling in vivo. C1 [Vlijm, R.; Kim, S. H.; De Zwart, P. L.; Dekker, C.] Delft Univ Technol, Dept Bionanosci, Kavli Inst Nanosci Delft, NL-2628 CJ Delft, Netherlands. [Dalal, Y.] NCI, Chromatin Struct & Epigenet Mech Unit, Lab Receptor Biol & Gene Express, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Vlijm, R.] German Canc Res Ctr, Div Opt Nanoscopy, Heidelberg, Germany. RP Dekker, C (reprint author), Delft Univ Technol, Dept Bionanosci, Kavli Inst Nanosci Delft, NL-2628 CJ Delft, Netherlands.; Dalal, Y (reprint author), NCI, Chromatin Struct & Epigenet Mech Unit, Lab Receptor Biol & Gene Express, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM dalaly@mail.nih.gov; C.Dekker@tudelft.nl FU ERC [669598]; Netherlands Organization for Scientific Research (NWO/OCW); Center for Cancer Research, NCI, NIH, USA FX This work was supported by the ERC Advanced Grant SynDiv [grant number 669598 to C. D.]; the Netherlands Organization for Scientific Research (NWO/OCW) [part of the Frontiers of Nanoscience program, to C. D.]; and by the Intramural Research Program of the Center for Cancer Research, NCI, NIH, USA [Y. D.]. NR 65 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 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2017 VL 9 IS 5 BP 1862 EP 1870 DI 10.1039/c6nr06245h PG 9 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EM8XL UT WOS:000395594300013 PM 28094382 ER PT J AU Bhirde, AA Sindiri, S Calco, GN Aronova, MA Beaucage, SL AF Bhirde, Ashwinkumar A. Sindiri, Sivasish Calco, Gina N. Aronova, Maria A. Beaucage, Serge L. TI Algorithm-driven high-throughput screening of colloidal nanoparticles under simulated physiological and therapeutic conditions SO NANOSCALE LA English DT Article ID GOLD NANOPARTICLES; SILVER NANOPARTICLES; PRODUCT QUALITY; DRUG-DELIVERY; CANCER-CELLS; IN-VITRO; NANOMATERIALS; PROTEINS; NANOMEDICINE; CHALLENGES AB Colloidal nanoparticles have shown tremendous potential as cancer drug carriers and as phototherapeutics. However, the stability of nanoparticles under physiological and phototherapeutic conditions is a daunting issue, which needs to be addressed in order to ensure a successful clinical translation. The design, development and implementation of unique algorithms are described herein for high-throughput hydrodynamic size measurements of colloidal nanoparticles. The data obtained from such measurements provide clinically-relevant particle size distribution assessments that are directly related to the stability and aggregation profiles of the nanoparticles under putative physiological and phototherapeutic conditions; those profiles are not only dependent on the size and surface coating of the nanoparticles, but also on their composition. Uncoated nanoparticles showed varying degrees of association with bovine serum albumin, whereas PEGylated nanoparticles did not exhibit significant association with the protein. The algorithm-driven, high-throughput size screening method described in this report provides highly meaningful size measurement patterns stemming from the association of colloidal particles with bovine serum albumin used as a protein model. Noteworthy is that this algorithm-based high-throughput method can accomplish sophisticated hydrodynamic size measurement protocols within days instead of years it would take conventional hydrodynamic size measurement techniques to achieve a similar task. C1 [Bhirde, Ashwinkumar A.; Beaucage, Serge L.] US FDA, Lab Biol Chem, Div Biotechnol Review & Res 4, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Sindiri, Sivasish] NCI, Genet Branch, Oncogen Sect, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Calco, Gina N.; Aronova, Maria A.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. RP Bhirde, AA; Beaucage, SL (reprint author), US FDA, Lab Biol Chem, Div Biotechnol Review & Res 4, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Ashwinkumar.Bhirde@fda.hhs.gov; Serge.Beaucage@fda.hhs.gov FU NCI/FDA IOTF Fellowship FX An NCI/FDA IOTF Fellowship to A. A. B. is gratefully acknowledged. We also thank Mrs Rohini Bhirde for helping with illustrations. NR 50 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 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2017 VL 9 IS 6 BP 2291 EP 2300 DI 10.1039/c6nr08579b PG 10 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EM9JB UT WOS:000395626600024 PM 28127597 ER PT J AU Le, DHT Lee, KL Shukla, S Commandeur, U Steinmetz, NF AF Le, Duc H. T. Lee, Karin L. Shukla, Sourabh Commandeur, Ulrich Steinmetz, Nicole F. TI Potato virus X, a filamentous plant viral nanoparticle for doxorubicin delivery in cancer therapy SO NANOSCALE LA English DT Article ID DRUG-DELIVERY; MOSAIC-VIRUS; IN-VITRO; PROTEIN NANOPARTICLES; CELLS; CHEMOTHERAPY; NANORODS; SHAPE; BIODISTRIBUTION; ENCAPSULATION AB Plant viral nanoparticles (VNPs) are a novel class of nanocarriers with implications for drug delivery in cancer therapy. VNPs are characterized by their highly symmetrical nanoscale structures. Furthermore, plant VNPs are biocompatible, biodegradable, and non-infectious in mammals. VNPs provide a proteinaceous platform technology that can be readily engineered to carry contrast agents and therapies using chemical and genetic modifications. Of particular interest are high aspect ratio, elongated filaments such as the ones formed by potato virus X (PVX, measuring 515 x 13 nm). PVX has demonstrated enhanced tumor homing and penetration properties compared to spherical counterparts. Here, we sought to investigate the potential of PVX as a drug carrier delivering doxorubicin (DOX), a commonly used cancer chemotherapy. We synthesized therapeutic PVX nanoparticles using a simple in-solution mixing protocol; after 5 days of mixing of DOX and PVX and ultra-centrifugal purification, similar to 1000 DOX per PVX were stably associated with the carrier, most likely based on hydrophobic interaction. Efficacy and drug activity of PVX-DOX were confirmed using a panel of cancer cell lines including ovarian cancer, breast cancer, and cervical cancer. Lastly, we demonstrated treatment of athymic mice bearing human MDA-MB-231 breast cancer xenografts: PVX-DOX treatment resulted in reduced tumor growth in this model. Our results open the door for further development of PVX and other high aspect ratio plant VNPs for applications in cancer therapy. C1 [Le, Duc H. T.; Lee, Karin L.; Shukla, Sourabh; Steinmetz, Nicole F.] Case Western Reserve Univ, Dept Biomed Engn, Sch Med, 10900 Euclid Ave, Cleveland, OH 44106 USA. [Le, Duc H. T.; Lee, Karin L.; Shukla, Sourabh; Steinmetz, Nicole F.] Case Western Reserve Univ, Dept Biomed Engn, Sch Engn, 10900 Euclid Ave, Cleveland, OH 44106 USA. [Commandeur, Ulrich] Rhein Westfal TH Aachen, Dept Mol Biotechnol, D-52064 Aachen, Germany. [Steinmetz, Nicole F.] Case Western Reserve Univ, Sch Med, Dept Radiol, 10900 Euclid Ave, Cleveland, OH 44106 USA. [Steinmetz, Nicole F.] Case Western Reserve Univ, Sch Engn, Dept Mat Sci & Engn, 10900 Euclid Ave, Cleveland, OH 44106 USA. [Steinmetz, Nicole F.] Case Western Reserve Univ, Sch Engn, Dept Macromol Sci & Engn, 10900 Euclid Ave, Cleveland, OH 44106 USA. [Steinmetz, Nicole F.] Case Western Reserve Univ, Div Gen Med Sci Oncol, 10900 Euclid Ave, Cleveland, OH 44106 USA. [Lee, Karin L.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Steinmetz, NF (reprint author), Case Western Reserve Univ, Dept Biomed Engn, Sch Med, 10900 Euclid Ave, Cleveland, OH 44106 USA.; Steinmetz, NF (reprint author), Case Western Reserve Univ, Dept Biomed Engn, Sch Engn, 10900 Euclid Ave, Cleveland, OH 44106 USA.; Steinmetz, NF (reprint author), Case Western Reserve Univ, Sch Med, Dept Radiol, 10900 Euclid Ave, Cleveland, OH 44106 USA.; Steinmetz, NF (reprint author), Case Western Reserve Univ, Sch Engn, Dept Mat Sci & Engn, 10900 Euclid Ave, Cleveland, OH 44106 USA.; Steinmetz, NF (reprint author), Case Western Reserve Univ, Sch Engn, Dept Macromol Sci & Engn, 10900 Euclid Ave, Cleveland, OH 44106 USA.; Steinmetz, NF (reprint author), Case Western Reserve Univ, Div Gen Med Sci Oncol, 10900 Euclid Ave, Cleveland, OH 44106 USA. EM nicole.steinmetz@case.edu FU Research Scholar Award from American Cancer Society [128319-RSG-15-144-01-CDD]; National Institutes of Health (NCI) [R25 CA148052]; National Institutes of Health (NIBIB) [T32 EB007509] FX This work was funded by a Research Scholar Award from the American Cancer Society (128319-RSG-15-144-01-CDD to NFS) and National Institutes of Health (NCI R25 CA148052 to KLL, NIBIB T32 EB007509 to KLL). Dr A. M. Wen (CWRU) is thanked for assistance with TEM imaging. NR 58 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 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2017 VL 9 IS 6 BP 2348 EP 2357 DI 10.1039/c6nr09099k PG 10 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EM9JB UT WOS:000395626600031 PM 28144662 ER PT J AU Barber, IS Braae, A Clement, N Patel, T Guetta-Baranes, T Brookes, K Medway, C Chappell, S Guerreiro, R Bras, J Hernandez, D Singleton, A Hardy, J Mann, DM Morgan, K AF Barber, Imelda S. Braae, Anne Clement, Naomi Patel, Tulsi Guetta-Baranes, Tamar Brookes, Keeley Medway, Christopher Chappell, Sally Guerreiro, Rita Bras, Jose Hernandez, Dena Singleton, Andrew Hardy, John Mann, David M. Morgan, Kevin CA ARUK Consortium TI Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; Parkinson's disease; Sporadic; Early-onset; NeuroX; Screening ID PARKINSONS-DISEASE; GENE-MUTATIONS; VARIANTS; FREQUENCY; PINK1; RISK; ASSOCIATION; DYSFUNCTION; DISORDERS; FAMILIES AB We have screened sporadic early-onset Alzheimer's disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals harboring a known causative variant in PARK2 known to cause early-onset Parkinson's disease; p. T240M (n = 1) and p. Q34fs delAG (n = 1). In addition, we identified 3 sEOAD individuals harboring a predicted pathogenic variant in MAPT (p. A469T), which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration. (C) 2016 Elsevier Inc. All rights reserved. C1 [Barber, Imelda S.; Braae, Anne; Clement, Naomi; Patel, Tulsi; Guetta-Baranes, Tamar; Brookes, Keeley; Medway, Christopher; Chappell, Sally; Morgan, Kevin] Univ Nottingham, Queens Med Ctr, Sch Life Sci, Nottingham, England. [Guerreiro, Rita; Bras, Jose; Hardy, John] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Hernandez, Dena; Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Mann, David M.] Univ Manchester, Inst Brain Behav & Mental Hlth, Fac Med & Human Sci, Manchester, Lancs, England. RP Barber, IS (reprint author), Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England. EM imelda.barber@psych.ox.ac.uk FU Alzheimer's Research UK; Big Lottery Fund [ART-BIG2009-1]; Alzheimer's Research UK [ARUK-NCG2012B-1]; School of Life Sciences at The University of Nottingham; Alzheimer's Society FX The University of Nottingham lab is funded by Alzheimer's Research UK and the Big Lottery Fund (ART-BIG2009-1). Imelda S. Barber, PhD studentship is jointly funded by Alzheimer's Research UK (ARUK-NCG2012B-1) and the School of Life Sciences at The University of Nottingham. Jose Bras and Rita Guerreiro's Fellowships are funded by The Alzheimer's Society. NR 40 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JAN PY 2017 VL 49 AR 215.e1 DI 10.1016/j.neurobiolaging.2016.09.008 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA EK5PG UT WOS:000393977700024 ER PT J AU Kun-Rodrigues, C Ross, OA Orme, T Shepherd, C Parkkinen, L Darwent, L Hernandez, D Ansorge, O Clark, LN Honig, LS Marder, K Lemstra, A Scheltens, P van der Flier, W Louwersheimer, E Holstege, H Rogaeva, E St George-Hyslop, P Londos, E Zetterberg, H Barber, I Braae, A Brown, K Morgan, K Maetzler, W Berg, D Troakes, C Al-Sarraj, S Lashley, T Holton, J Compta, Y Van Deerlin, V Trojanowski, JQ Serrano, GE Beach, TG Clarimon, J Lleo, A Morenas-Rodriguez, E Lesage, S Galasko, D Masliah, E Santana, I Diez, M Pastor, P Tienari, PJ Myllykangas, L Oinas, M Revesz, T Lees, A Boeve, BF Petersen, RC Ferman, TJ Escott-Price, V Graff-Radford, N Cairns, NJ Morris, JC Stone, DJ Pickering-Brown, S Mann, D Dickson, DW Halliday, GM Singleton, A Guerreiro, R Bras, J AF Kun-Rodrigues, Celia Ross, Owen A. Orme, Tatiana Shepherd, Claire Parkkinen, Laura Darwent, Lee Hernandez, Dena Ansorge, Olaf Clark, Lorraine N. Honig, Lawrence S. Marder, Karen Lemstra, Afina Scheltens, Philippe van der Flier, Wiesje Louwersheimer, Eva Holstege, Henne Rogaeva, Ekaterina St George-Hyslop, Peter Londos, Elisabet Zetterberg, Henrik Barber, Imelda Braae, Anne Brown, Kristelle Morgan, Kevin Maetzler, Walter Berg, Daniela Troakes, Claire Al-Sarraj, Safa Lashley, Tammaryn Holton, Janice Compta, Yaroslau Van Deerlin, Vivianna Trojanowski, John Q. Serrano, Geidy E. Beach, Thomas G. Clarimon, Jordi Lleo, Alberto Morenas-Rodriguez, Estrella Lesage, Suzanne Galasko, Douglas Masliah, Eliezer Santana, Isabel Diez, Monica Pastor, Pau Tienari, Pentti J. Myllykangas, Liisa Oinas, Minna Revesz, Tamas Lees, Andrew Boeve, Brad F. Petersen, Ronald C. Ferman, Tanis J. Escott-Price, Valentina Graff-Radford, Neill Cairns, Nigel J. Morris, John C. Stone, David J. Pickering-Brown, Stuart Mann, David Dickson, Dennis W. Halliday, Glenda M. Singleton, Andrew Guerreiro, Rita Bras, Jose TI Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies SO NEUROBIOLOGY OF AGING LA English DT Article DE C9orf72; Dementia with Lewy bodies (DLB); Genetic screen AB C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB. (C) 2016 Elsevier Inc. All rights reserved. C1 [Kun-Rodrigues, Celia; Orme, Tatiana; Darwent, Lee; Guerreiro, Rita; Bras, Jose] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Ross, Owen A.; Dickson, Dennis W.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Shepherd, Claire; Halliday, Glenda M.] Neurosci Res Australia, Sydney, NSW, Australia. [Shepherd, Claire; Halliday, Glenda M.] Univ New S Wales, Fac Med, Sch Med Sci, Sydney, NSW, Australia. [Parkkinen, Laura; Ansorge, Olaf] Univ Oxford, Oxford Parkinsons Dis Ctr, Nuffield Dept Clin Neurosci, Oxford, England. [Hernandez, Dena; Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Clark, Lorraine N.; Honig, Lawrence S.; Marder, Karen] Columbia Univ, Taub Inst Alzheimer Dis & Aging Brain, New York, NY 10027 USA. [Clark, Lorraine N.; Honig, Lawrence S.; Marder, Karen] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA. [Lemstra, Afina; Scheltens, Philippe; van der Flier, Wiesje; Louwersheimer, Eva; Holstege, Henne] Vrije Univ Amsterdam Med Ctr, Dept Neurol, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Lemstra, Afina; Scheltens, Philippe; van der Flier, Wiesje; Louwersheimer, Eva; Holstege, Henne] Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Rogaeva, Ekaterina; St George-Hyslop, Peter] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Dept Med, Toronto, ON, Canada. [Londos, Elisabet] Lund Univ, Clin Memory Res Unit, Inst Clin Sci Malmo, Lund, Sweden. [Zetterberg, Henrik] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Zetterberg, Henrik] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Clin Neurochem Lab, Molndal, Sweden. [Barber, Imelda; Braae, Anne; Brown, Kristelle; Morgan, Kevin] Univ Nottingham, Queens Med Ctr, Sch Life Sci, Translat Cell Sci Human Genet, Nottingham, England. [Maetzler, Walter; Berg, Daniela] Univ Tubingen, Ctr Neurol, Dept Neurodegenerat, Hertie Inst Clin Brain Res, Tubingen, Germany. [Maetzler, Walter; Berg, Daniela] Univ Kiel, Dept Neurol, Kiel, Germany. [Troakes, Claire; Al-Sarraj, Safa] Kings Coll London, Dept Basic & Clin Neurosci, London, England. [Troakes, Claire; Al-Sarraj, Safa] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England. [Lashley, Tammaryn; Holton, Janice; Revesz, Tamas; Lees, Andrew] UCL Inst Neurol, Dept Mol Neurosci, Queen Sq Brain Bank, London, England. [Compta, Yaroslau] Univ Barcelona, IDIBAPS, Hosp Clin, Neurol Serv,Clin Neurosci Inst,Movement Disorders, Barcelona, Spain. [Van Deerlin, Vivianna; Trojanowski, John Q.] Univ Penn, Perelman Sch Med, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med, Philadelphia, PA USA. [Serrano, Geidy E.; Beach, Thomas G.] Banner Sun Hlth Res Inst, Sun City, AZ USA. [Clarimon, Jordi; Lleo, Alberto; Morenas-Rodriguez, Estrella] Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, IIB Sant Pau, Dept Neurol, Barcelona, Catalonia, Spain. [Lesage, Suzanne] Univ Paris 06, Sorbonne Univ, INSERM, CNRS,Inst Cerveau & Moelle Epiniere, Paris, France. [Lesage, Suzanne] Hop La Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, Paris, France. [Galasko, Douglas; Masliah, Eliezer] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Galasko, Douglas; Masliah, Eliezer] Vet Affairs San Diego Healthcare Syst, La Jolla, CA 92161 USA. [Santana, Isabel] Ctr Hosp & Univ Coimbra, Coimbra, Portugal. [Diez, Monica; Pastor, Pau] Univ Hosp Mutua Terrassa, Dept Neurol, Memory Unit, Barcelona, Spain. [Diez, Monica; Pastor, Pau] Fdn Mutua Terrassa, Barcelona, Spain. [Diez, Monica; Pastor, Pau] CIBERNED, Madrid, Spain. [Tienari, Pentti J.] Univ Helsinki, Helsinki Univ Hosp, Dept Neurol, Res Programs Unit,Mol Neurol, Helsinki, Finland. [Myllykangas, Liisa] Univ Helsinki, Dept Pathol, Helsinki, Finland. [Oinas, Minna] Helsinki Univ Hosp, Dept Neuropathol & Neurosurg, Helsinki, Finland. [Oinas, Minna] Univ Helsinki, Helsinki, Finland. [Boeve, Brad F.; Petersen, Ronald C.] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Ferman, Tanis J.] Mayo Clin, Dept Psychiat, Jacksonville, FL 32224 USA. [Ferman, Tanis J.] Mayo Clin, Dept Psychol, Jacksonville, FL 32224 USA. [Escott-Price, Valentina] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Graff-Radford, Neill] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Cairns, Nigel J.; Morris, John C.] Washington Univ, Sch Med, Dept Neurol, Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA. [Stone, David J.] Merck Res Labs, Genet & Pharmacogenom, West Point, PA USA. [Pickering-Brown, Stuart; Mann, David] Univ Manchester, Fac Med & Human Sci, Inst Brain Behav & Mental Hlth, Manchester, Lancs, England. [Guerreiro, Rita; Bras, Jose] Univ Aveiro, Dept Med Sci, Aveiro, Portugal. [Guerreiro, Rita; Bras, Jose] Univ Aveiro, Inst Biomed iBiMED, Aveiro, Portugal. RP Bras, J (reprint author), Dept Mol Neurosci, 1 Wakefield St,1st Floor, London WC1N 1PJ, England. RI Revesz, Tamas/A-8732-2010; OI Revesz, Tamas/0000-0003-2501-0259; Mann, Devin/0000-0002-2099-0852 FU National Institutes of Neurological Disease and Stroke; Alzheimer's Society; Lewy Body Society; Neuroscience Research Australia; University of New South Wales; Wellcome Trust; Medical Research Council; Canadian Institutes of Health Research; Ontario Research Fund; ARUK; Big Lottery Fund; Taub Institute; Panasci Fund; Parkinson's Disease Foundation; NIH [NS060113, P50AG008702, P50NS038370, UL1TR000040, AG05131]; Michael J. Fox Foundation for Parkinson's Research, NINDS R01 [NS078086]; Little Family Foundation [NS072187]; Mangurian Foundation Program for Lewy Body Dementia research; Alzheimer Disease Research Center [P50 AG016547]; National Institute on Aging [P50 AG016574, U01 AG006786]; Queen Square Brain Bank at the UCL Institute of Neurology; Brains for Dementia Research project (Alzheimer's Society); Brains for Dementia Research project (ARUK); NIHR UCLH Biomedical Research Centre; Queen Square Dementia Biomedical Research Unit; Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [AG000951-12]; Penn Alzheimer's Disease Core Center [AG10124]; Penn Morris K. Udall Parkinson's Disease Research Center [NS053488]; French program "Investissements d'avenir" [ANR-10-IAIHU-06]; Helsinki University Central Hospital; Folkhalsan Research Foundation; Finnish Academy; Canadian Consortium on Neurodegeneration in Aging (ER); ARUK senior fellowship FX This work was supported in part by the National Institutes of Neurological Disease and Stroke. Jose Bras and Rita Guerreiro are supported by fellowships from the Alzheimer's Society. Tatiana Orme is supported by a scholarship from the Lewy Body Society. For the neuropathologically confirmed samples from Australia, tissues were received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales. This study was also partially funded by the Wellcome Trust, Medical Research Council, Canadian Institutes of Health Research, and Ontario Research Fund. The Nottingham Genetics Group is supported by ARUK and The Big Lottery Fund. The effort from Columbia University was supported by the Taub Institute, the Panasci Fund, the Parkinson's Disease Foundation, and NIH grants NS060113 (Dr Clark), P50AG008702 (P. I. Scott Small), P50NS038370 (P.I.R. Burke), and UL1TR000040 (P.I.H. Ginsberg). Dr Ross is supported by the Michael J. Fox Foundation for Parkinson's Research, NINDS R01# NS078086. The Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 # NS072187) and is supported by The Little Family Foundation and by the Mangurian Foundation Program for Lewy Body Dementia research and the Alzheimer Disease Research Center (P50 AG016547). The work from the Mayo Clinic Rochester is supported by the National Institute on Aging (P50 AG016574 and U01 AG006786). This work has received support from The Queen Square Brain Bank at the UCL Institute of Neurology; where Dr Lashley is funded by an ARUK senior fellowship. Some of the tissue samples studied were provided by the MRC London Neurodegenerative Diseases Brain Bank and the Brains for Dementia Research project (funded by Alzheimer's Society and ARUK). This research was supported in part by both the NIHR UCLH Biomedical Research Centre and the Queen Square Dementia Biomedical Research Unit. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project AG000951-12. The University of Pennsylvania case collection is funded by the Penn Alzheimer's Disease Core Center (AG10124) and the Penn Morris K. Udall Parkinson's Disease Research Center (NS053488). The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac. broadinstitute. org/about. Tissue samples from UCSD are supported by NIH grant AG05131. The authors thank the brain bank GIE NeuroCEB, the French program "Investissements d'avenir" (ANR-10-IAIHU-06). Dr Tienari and Dr Myllykangas are supported by the Helsinki University Central Hospital, the Folkhalsan Research Foundation and the Finnish Academy. This work was in part supported by the Canadian Consortium on Neurodegeneration in Aging (ER). NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JAN PY 2017 VL 49 AR 214.e13 DI 10.1016/j.neurobiolaging.2016.08.023 PG 3 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA EK5PG UT WOS:000393977700022 ER PT J AU Dienel, GA Cruz, NF Sokoloff, L Driscoll, BF AF Dienel, Gerald A. Cruz, Nancy F. Sokoloff, Louis Driscoll, Bernard F. TI Determination of Glucose Utilization Rates in Cultured Astrocytes and Neurons with [C-14]deoxyglucose: Progress, Pitfalls, and Discovery of Intracellular Glucose Compartmentation SO NEUROCHEMICAL RESEARCH LA English DT Article DE Astrocyte; Compartmentation; Deoxyglucose; Glucose; Lumped constant; Neuron ID ENDOPLASMIC-RETICULUM STRESS; SUPPLY-AND-DEMAND; DEOXYGLUCOSE METHOD; LUMPED CONSTANT; SUGAR-TRANSPORT; BLOOD-FLOW; CELL-DEATH; BRAIN; METABOLISM; AUTOPHAGY AB 2-Deoxy-D-[C-14] glucose ([C-14] DG) is commonly used to determine local glucose utilization rates (CMRglc) in living brain and to estimate CMRglc in cultured brain cells as rates of [C-14] DG phosphorylation. Phosphorylation rates of [C-14] DG and its metabolizable fluorescent analog, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxyglucose (2-NBDG), however, do not take into account differences in the kinetics of transport and metabolism of [C-14] DG or 2-NBDG and glucose in neuronal and astrocytic cells in cultures or in single cells in brain tissue, and conclusions drawn from these data may, therefore, not be correct. As a first step toward the goal of quantitative determination of CMRglc in astrocytes and neurons in cultures, the steady-state intracellular-to-extracellular concentration ratios (distribution spaces) for glucose and [C-14] DG were determined in cultured striatal neurons and astrocytes as functions of extracellular glucose concentration. Unexpectedly, the glucose distribution spaces rose during extreme hypoglycemia, exceeding 1.0 in astrocytes, whereas the [C-14] DG distribution space fell at the lowest glucose levels. Calculated CMRglc was greatly overestimated in hypoglycemic and normoglycemic cells because the intracellular glucose concentrations were too high. Determination of the distribution space for [C-14] glucose revealed compartmentation of intracellular glucose in astrocytes, and probably, also in neurons. A smaller metabolic pool is readily accessible to hexokinase and communicates with extracellular glucose, whereas the larger pool is sequestered from hexokinase activity. A new experimental approach using double-labeled assays with DG and glucose is suggested to avoid the limitations imposed by glucose compartmentation on metabolic assays. C1 [Dienel, Gerald A.; Cruz, Nancy F.; Sokoloff, Louis; Driscoll, Bernard F.] NIMH, Cerebral Metab Lab, Bldg 36, Bethesda, MD 20892 USA. [Dienel, Gerald A.] Univ Arkansas Med Sci, Dept Neurol, 4301 W Markham St,Mail Slot 500, Little Rock, AR 72205 USA. RP Dienel, GA (reprint author), NIMH, Cerebral Metab Lab, Bldg 36, Bethesda, MD 20892 USA.; Dienel, GA (reprint author), Univ Arkansas Med Sci, Dept Neurol, 4301 W Markham St,Mail Slot 500, Little Rock, AR 72205 USA. EM gadienel@uams.edu NR 57 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 EI 1573-6903 J9 NEUROCHEM RES JI Neurochem. Res. PD JAN PY 2017 VL 42 IS 1 SI SI BP 50 EP 63 DI 10.1007/s11064-015-1650-x PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EK4TD UT WOS:000393918800006 PM 26141225 ER PT J AU Goulding, DR White, SS McBride, SJ Fenton, SE Harry, GJ AF Goulding, David R. White, Sally S. McBride, Sandra J. Fenton, Suzanne E. Harry, G. Jean TI Gestational exposure to perfluorooctanoic acid (PFOA): Alterations in motor related behaviors SO NEUROTOXICOLOGY LA English DT Article DE Development; Motor activity; Novel environment; Neurotoxicity; Nicotine; Amphetamine ID NATIONAL BIRTH COHORT; BRAIN NICOTINIC RECEPTORS; EVIDENCE-BASED MEDICINE; OPEN-FIELD TEST; PERFLUOROALKYL SUBSTANCES; PRENATAL EXPOSURE; FETAL-GROWTH; PERFLUORINATED CHEMICALS; ADULT MICE; POLYFLUOROALKYL SUBSTANCES AB Perfluoroalkyl and polyfluoroalkyl substances are used in commercial applications and developmental exposure has been implicated in alterations in neurobehavioral functioning. While associations between developmental perfluorooctanoic acid (PFOA) exposure and human outcomes have been inconsistent, studies in experimental animals suggest alterations in motor related behaviors. To examine a dose response pattern of neurobehavioral effects following gestational exposure to PFOA, pregnant CD-1 mice received PFOA (0, 0.1, 0.3,1.0 mg/kg/day) via oral gavage from gestational day 1-17 and the male offspring examined. Motor activity assessments on postnatal day (PND)18, 19, and 20 indicated a shift in the developmental pattern with an elevated activity level observed in the 1.0 mg/kg/day dose group on PND18. In the adult, no alterations were observed in body weights, activity levels, diurnal pattern of running wheel activity, startle response, or pre-pulse startle inhibition. In response to a subcutaneous injection of saline or nicotine (80 mu g/kg), all animals displayed a transient increase in activity likely associated with handling with no differences observed across dose groups. Inhibition of motor activity over 18 days of 400 mu g/kg nicotine injection was not significantly different across dose groups. Hyperactivity induced by 2 mg/kg (+)-methamphetamine hydrochloride intraperitoneal injection was significantly lower in the 1.0 mg/kg/day PFOA dose group as compared to controls. Taken together, these data suggest that the effects on motor-related behaviors with gestational PFOA exposure do not mimic those reported for acute postnatal exposure. Changes were not observed at dose levels under 1.0 mg/kg/ day PFOA. Further examination of pathways associated with methamphetamine-induced activity is warranted. Published by Elsevier B.V. C1 [Goulding, David R.] NIEHS, Comparat Med Branch, Integrated Res Div, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [White, Sally S.; Fenton, Suzanne E.] NIEHS, Reprod Endocrinol Grp, NTPL, DNTP, POB 12233, Res Triangle Pk, NC 27709 USA. [McBride, Sandra J.] Social & Sci Syst Inc, Durham, NC USA. [Harry, G. Jean] NIEHS, Neurotoxicol Grp, NTPL, DNTP, POB 12233, Res Triangle Pk, NC 27709 USA. RP Harry, GJ (reprint author), POB 12233,Mail Drop C1-04, Res Triangle Pk, NC 27709 USA. EM harry@niehs.nih.gov FU Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services [1Z01ES101623, ES021164, ES102785, HHSN273201500077U]; Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services [1Z01ES101623, ES021164, ES102785, HHSN273201500077U] FX This research was supported by the Division of Intramural Research and the Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services #1Z01ES101623; ES021164; ES102785, HHSN273201500077U. The study was initiated by S. White and S. Fenton, who were responsible for dosing and selection of animals; S. White and D. Goulding conducted the behavioral tests; S. McBride performed statistical analysis; and G. Harry was responsible for study design and data interpretation. All authors contributed to writing of the manuscript. NR 72 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X EI 1872-9711 J9 NEUROTOXICOLOGY JI Neurotoxicology PD JAN PY 2017 VL 58 BP 110 EP 119 DI 10.1016/j.neuro.2016.11.008 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA EL1UJ UT WOS:000394406400013 PM 27888120 ER PT J AU Han, B Compton, WM Blanco, C AF Han, Beth Compton, Wilson M. Blanco, Carlos TI Tobacco Use and 12-Month Suicidality Among Adults in the United States SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID NATIONAL EPIDEMIOLOGIC SURVEY; MAJOR DEPRESSIVE DISORDER; CIGARETTE-SMOKING; MENTAL-DISORDERS; REPRESENTATIVE SAMPLE; CLINICAL PREDICTORS; NICOTINE DEPENDENCE; COMORBIDITY-SURVEY; COMPLETED SUICIDE; PREVALENCE AB Introduction: To examine how 12-month prevalences of suicidality vary by tobacco use. Methods: Data were from 325 800 adults who participated in the 2008-2014 National Survey on Drug Use and Health. Descriptive analyses and multivariable multinomial logistic regression models were applied. Results: Among adults aged 18 or older in the United States during 2008-2014, 27.4% (annual average, standard error [SE] = 0.14%) were never tobacco users, 38.8% (SE = 0.17%) were former tobacco users, 5.9% (SE = 0.07%) were past-year users of other types of tobacco (non-cigarette), 20.2% (SE = 0.13%) were past-year cigarette-only users, and 7.7% (SE = 0.07%) were past-year users of cigarettes plus other types of tobacco; 2.6% (SE = 0.04%) had suicidal ideation only, 0.7% (SE = 0.02%) had suicidal ideation and suicide plan only, and 0.5% (SE = 0.02%) attempted suicide. After controlling for covariates, compared with never tobacco users, past-year users of cigarettes plus other types of tobacco were at elevated risk of all examined suicidality outcomes (adjusted relative risks [ARRs] = 1.2-1.7), and past-year cigarette-only users were at higher risk of suicide attempt (ARR = 1.4). Early age of first tobacco use was associated with higher risk of suicidal ideation and suicide plan among former tobacco users, past-year tobacco users, and past-year cigarette users (ARRs = 1.2-1.6). Among past-year tobacco users, frequencies of cigarette and cigar use were associated with suicide attempt (ARRs = 1.4-1.7). Nicotine dependence was associated with suicide attempt among past-year cigarette users (ARR = 1.2). Conclusions: Tobacco use is associated with 12-month suicidality among adults. Patients who use tobacco should be assessed further for mental health status and suicide risk. Implications: Our results revealed that tobacco use is independently associated with the 12-month suicidality outcomes among adults and identified how the prevalences of 12-month suicidality outcomes vary by tobacco use status and use characteristics among adults. These results have important clinical implications. Future research should assess the effectiveness of tobacco use questions as simple screeners for more extensive assessment of mental health status and suicide risk. C1 [Han, Beth] Subst Abuse & Mental Hlth Serv Adm, Ctr Behav Hlth Stat & Qual, Rockville, MD USA. [Compton, Wilson M.; Blanco, Carlos] NIDA, NIH, Bethesda, MD 20892 USA. RP Han, B (reprint author), Subst Abuse & Mental Hlth Serv Adm, 5600 Fishers Lane 15E85C, Rockville, MD 20857 USA. EM beth.han@samhsa.hhs.gov NR 44 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD JAN PY 2017 VL 19 IS 1 BP 39 EP 48 DI 10.1093/ntr/ntw136 PG 10 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA EP0DD UT WOS:000397056100006 PM 27190402 ER PT J AU Pan, P Skaer, CW Wang, HT Kreiser, MA Stirdivant, SM Oshima, K Huang, YW Young, MR Wang, LS AF Pan, Pan Skaer, Chad W. Wang, Hsin-Tzu Kreiser, Michael A. Stirdivant, Steven M. Oshima, Kiyoko Huang, Yi-Wen Young, Matthew R. Wang, Li-Shu TI Systemic Metabolite Changes in Wild-type C57BL/6 Mice Fed Black Raspberries SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; ORAL NUTRITIONAL SUPPLEMENTS; COLORECTAL-CANCER PATIENTS; CELL LUNG-CANCER; MULTIMODALITY TREATMENT; ADENOMA DEVELOPMENT; DOUBLE-BLIND; ANTHOCYANINS; PREVENTION; TRIAL AB Introduction: Freeze-dried black raspberries (BRBs) elicit chemopreventive effects against colorectal cancer in humans and in rodents. The objective of this study was to investigate potential BRB-caused metabolite changes using wild-type (WT) C57BL/6 mice. Methods and results: WT mice were fed either control diet or control diet supplemented with 5% BRBs for 8 wk. A nontargeted metabolomic analysis was conducted on colonic mucosa, liver, and fecal specimens collected from both diet groups. BRBs significantly changed the levels of 41 colonic mucosa metabolites, 40 liver metabolites, and 34 fecal metabolites compared to control diet-fed mice. BRBs reduced 34 lipid metabolites in colonic mucosa and increased levels of amino acids in liver. One metabolite, 3-[3-(sulfooxy) phenyl] propanoic acid, might be a useful biomarker of BRB consumption. In addition, BRB powder was found to contain 30-fold higher levels of linolenate compared to control diets. Consistently, multiple omega-3 polyunsaturated fatty acids (-3 PUFAs), including stearidonate, docosapentaenoate (-3 DPA), eicosapentaenoate (EPA), and docosahexaenoate (DHA), were significantly elevated in livers of BRB-fed mice. Conclusion: The data from the current study suggest that BRBs produce systemic metabolite changes in multiple tissue matrices, supporting our hypothesis that BRBs may serve as both a chemopreventive agent and a beneficial dietary supplement. C1 [Pan, Pan; Skaer, Chad W.; Wang, Hsin-Tzu; Kreiser, Michael A.; Wang, Li-Shu] Med Coll Wisconsin, Dept Med, Div Hematol Oncol, Room C4930,8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Stirdivant, Steven M.] Metabolon Inc, Clin Res & Dev, Durham, NC USA. [Oshima, Kiyoko] Med Coll Wisconsin, Dept Pathol, Milwaukee, WI 53226 USA. [Huang, Yi-Wen] Med Coll Wisconsin, Dept Obstet & Gynecol, Milwaukee, WI 53226 USA. [Young, Matthew R.] NCI, Canc Prevent Div, Rockville, MD USA. RP Wang, LS (reprint author), Med Coll Wisconsin, Dept Med, Div Hematol Oncol, Room C4930,8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM liswang@mcw.edu FU National Institutes of Health [5 R01 CA148818]; American Cancer Society [RSG-13-138-01-CNE] FX The authors thank the National Institutes of Health (grant 5 R01 CA148818) and American Cancer Society (RSG-13-138-01-CNE to L.-S. Wang) for funding this study. NR 36 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 0163-5581 EI 1532-7914 J9 NUTR CANCER JI Nutr. Cancer PY 2017 VL 69 IS 2 BP 299 EP 306 DI 10.1080/01635581.2017.1263748 PG 8 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA EL4TK UT WOS:000394613600014 PM 28094560 ER PT J AU Kambach, DM Halim, AS Cauer, AG Sun, Q Tristan, CA Celiku, O Kesarwala, AH Shankavaram, U Batchelor, E Stommel, JM AF Kambach, Diane M. Halim, Alan S. Cauer, A. Gesine Sun, Qian Tristan, Carlos A. Celiku, Orieta Kesarwala, Aparna H. Shankavaram, Uma Batchelor, Eric Stommel, Jayne M. TI Disabled cell density sensing leads to dysregulated cholesterol synthesis in glioblastoma SO ONCOTARGET LA English DT Article DE cholesterol metabolism; oxygen utilization; glioblastoma; pre-clinical cancer therapies; cell cycle ID TUMOR-CELL; IN-VITRO; PATHWAY; GROWTH; METABOLISM; GLIOMA; AGENTS; ORIGIN; PDGFRA; LINES AB A hallmark of cellular transformation is the evasion of contact-dependent inhibition of growth. To find new therapeutic targets for glioblastoma, we looked for pathways that are inhibited by high cell density in astrocytes but not in glioma cells. Here we report that glioma cells have disabled the normal controls on cholesterol synthesis. At high cell density, astrocytes turn off cholesterol synthesis genes and have low cholesterol levels, but glioma cells keep this pathway on and maintain high cholesterol. Correspondingly, cholesterol pathway upregulation is associated with poor prognosis in glioblastoma patients. Densely-plated glioma cells increase oxygen consumption, aerobic glycolysis, and the pentose phosphate pathway to synthesize cholesterol, resulting in a decrease in reactive oxygen species, TCA cycle intermediates, and ATP. This constitutive cholesterol synthesis is controlled by the cell cycle, as it can be turned off by cyclin-dependent kinase inhibitors and it correlates with disabled cell cycle control though loss of p53 and RB. Finally, glioma cells, but not astrocytes, are sensitive to cholesterol synthesis inhibition downstream of the mevalonate pathway, suggesting that specifically targeting cholesterol synthesis might be an effective treatment for glioblastoma. C1 [Kambach, Diane M.; Halim, Alan S.; Cauer, A. Gesine; Sun, Qian; Tristan, Carlos A.; Celiku, Orieta; Kesarwala, Aparna H.; Shankavaram, Uma; Stommel, Jayne M.] NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Batchelor, Eric] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Stommel, JM (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jayne.stommel@nih.gov FU US National Cancer Institute Center for Cancer Research (NCI-CCR) Intramural Research Program [ZIA BC 011441] FX This work was supported by the US National Cancer Institute Center for Cancer Research (NCI-CCR) Intramural Research Program ZIA BC 011441 (to J.M.S). NR 59 TC 0 Z9 0 U1 0 U2 0 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 PY 2017 VL 8 IS 9 BP 14860 EP 14875 DI 10.18632/oncotarget.14740 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EN4YV UT WOS:000396013700053 ER PT J AU Tsai, FJ Ho, TJ Cheng, CF Shiao, YT Chien, WK Chen, JH Liu, X Tsang, H Lin, TH Liao, CC Huang, SM Li, JP Lin, CW Lin, JG Lan, YC Liu, YH Hung, CH Lin, JC Lin, CC Lai, CH Liang, WM Lin, YJ AF Tsai, Fuu-Jen Ho, Tsung-Jung Cheng, Chi-Fung Shiao, Yi-Tzone Chien, Wen-Kuei Chen, Jin-Hua Liu, Xiang Tsang, Hsinyi Lin, Ting-Hsu Liao, Chiu-Chu Huang, Shao-Mei Li, Ju-Pi Lin, Cheng-Wen Lin, Jaung-Geng Lan, Yu-Ching Liu, Yu-Huei Hung, Chien-Hui Lin, Jung-Chun Lin, Chih-Chien Lai, Chih-Ho Liang, Wen-Miin Lin, Ying-Ju TI Characteristics of Chinese herbal medicine usage in ischemic heart disease patients among type 2 diabetes and their protection against hydrogen peroxide-mediated apoptosis in H9C2 cardiomyoblasts SO ONCOTARGET LA English DT Article DE type 2 diabetes; ischemic heart disease; Chinese herbal medicine; oxidative stress; cardiomyoblasts ID ACUTE MYOCARDIAL-INFARCTION; IMPAIRED GLUCOSE-TOLERANCE; SHAOYAO-GANCAO-DECOCTION; PHARMACOKINETIC COMPARISONS; FERULIC ACID; H2O2-INDUCED APOPTOSIS; DIFFERENT COMBINATIONS; PRESCRIPTION PATTERNS; CARDIOVASCULAR EVENTS; GLYCYRRHETINIC ACID AB Evidence for long-term use of Chinese herbal medicine (CHM) as an adjuvant treatment in patients with type 2 diabetes (T2D) remains limited. This study aimed to assess the frequency of use, utilization patterns, and therapeutic effects of adjuvant CHM for ischemic heart disease (IHD) in patients with T2D in Taiwan. We identified 4620 IHD patients with T2D. After matching for age, gender, and insulin use, 988 subjects each were allocated to a CHM group and a non-CHM group. There were no differences in baseline characteristics except for comorbidities. The CHM group contained more cases with chronic obstructive pulmonary disease, hepatitis, ulcer disease, and hyperlipidemia. The cumulative survival probability was higher in CHM users than in matched non-CHM users aged 60 years or older (P <.0001, log rank test) regardless of gender (P=.0046 for men, P=.0010 for women, log rank test). Among the top 12 CHM combinations, Shu-Jing-Huo-Xue-Tang and Shao-YaoGan- Cao-Tang (13.6%) were the most common. This dual combination improved antiapoptotic activity in H2O2-exposed H9C2 cells by enhancing phosphorylation of glycogen synthase kinase-3 beta and p38 mitogen-activated protein kinase and could increase the survival of myocardial cells. Our study suggests that adjuvant CHM therapy may increase the survival probability and provides a comprehensive list for future investigations of the safety and efficacy of CHM for IHD patients with T2D. C1 [Tsai, Fuu-Jen; Ho, Tsung-Jung; Li, Ju-Pi; Lin, Jaung-Geng; Lin, Ying-Ju] China Med Univ, Sch Chinese Med, Taichung, Taiwan. [Tsai, Fuu-Jen; Lin, Ting-Hsu; Liao, Chiu-Chu; Huang, Shao-Mei; Liu, Yu-Huei; Lin, Ying-Ju] China Med Univ Hosp, Genet Ctr, Dept Med Res, Taichung, Taiwan. [Tsai, Fuu-Jen] Asia Univ, Dept Hlth & Nutr Biotechnol, Taichung, Taiwan. [Ho, Tsung-Jung] China Med Univ, Beigang Hosp, Div Chinese Med, Taiwang, Yunlin, Taiwan. [Ho, Tsung-Jung] China Med Univ, Tainan Municipal An Nan Hosp, Div Chinese Med, Tainan, Taiwan. [Cheng, Chi-Fung; Liang, Wen-Miin] China Med Univ, Sch Publ Hlth, Grad Inst Biostat, Taichung, Taiwan. [Shiao, Yi-Tzone] China Med Univ Hosp, Ctr Heart, Taichung, Taiwan. [Chien, Wen-Kuei; Chen, Jin-Hua] Taipei Med Univ, Coll Management, Ctr Biostat, Taipei, Taiwan. [Chen, Jin-Hua] Taipei Med Univ, Coll Management, Sch Hlth Care Adm, Taipei, Taiwan. [Liu, Xiang; Tsang, Hsinyi] Natl Inst Allergy & Infect Dis, NIH, Bethesda, MD USA. [Li, Ju-Pi] China Med Univ Hosp, Res Ctr, Taichung, Taiwan. [Lin, Cheng-Wen] China Med Univ, Dept Med, Lab Sci & Biotechnol, Taichung, Taiwan. [Lan, Yu-Ching] China Med Univ, Dept Hlth Risk Management, Taichung, Taiwan. [Liu, Yu-Huei] China Med Univ, Grad Inst Integrated Med, Taichung, Taiwan. [Hung, Chien-Hui] Chang Gung Univ, Grad Inst Clin Med Sci, Taipei, Taiwan. [Lin, Jung-Chun] Taipei Med Univ, Coll Med Sci & Technol, Sch Med, Lab Sci & Biotechnol, Taipei, Taiwan. [Lin, Chih-Chien] Providence Univ, Dept Cosmet Sci, Taichung, Taiwan. [Lai, Chih-Ho] Chang Gung Univ, Dept Microbiol & Immunol, Taoyuan, Taiwan. RP Lin, YJ (reprint author), China Med Univ, Sch Chinese Med, Taichung, Taiwan.; Lin, YJ (reprint author), China Med Univ Hosp, Genet Ctr, Dept Med Res, Taichung, Taiwan.; Liang, WM (reprint author), China Med Univ, Sch Publ Hlth, Grad Inst Biostat, Taichung, Taiwan. EM wmliang@mail.cmu.edu.tw; yjlin.kath@gmail.com RI Lan, Yu-Ching/F-2449-2017 OI Lan, Yu-Ching/0000-0003-4781-6405 FU China Medical University [CMU102-PH-01, CMU100-S-01]; China Medical University Hospital [DMR-105-031, DMR-105-098, DMR-106-155]; National Science Council; Ministry of Science and Technology, Taiwan [MOST 103-2320-B-039 -006 -MY3, MOST 105-2314-B-039-037-MY3]; China Medical University under the Aim for Top University Plan of the Ministry of Education, Taiwan FX The authors wish to thank the Division of Chinese Medicine, China Medical University, Beigang Hospital, for administrative assistance and consultation. This study was supported by grants from the China Medical University (CMU102-PH-01 and CMU100-S-01), the China Medical University Hospital (DMR-105-031, DMR-105-098, and DMR-106-155), the National Science Council, the Ministry of Science and Technology, Taiwan (MOST 103-2320-B-039 -006 -MY3 and MOST 105-2314-B-039-037-MY3), and China Medical University under the Aim for Top University Plan of the Ministry of Education, Taiwan. We also thank Dr. Kuan-Teh Jeang and Willy WL Hong for their technical help and suggestions. NR 73 TC 0 Z9 0 U1 1 U2 1 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 PY 2017 VL 8 IS 9 BP 15470 EP 15489 DI 10.18632/oncotarget.14657 PG 20 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EN4YV UT WOS:000396013700103 ER PT J AU Peri, S Caretti, E Tricarico, R Devarajan, K Cheung, M Sementino, E Menges, CW Nicolas, E Vanderveer, LA Howard, S Conrad, P Crowell, JA Campbell, KS Ross, EA Godwin, AK Yeung, AT Clapper, ML Uzzo, RG Henske, EP Ricketts, CJ Vocke, CD Linehan, WM Testa, JR Bellacosa, A Kopelovich, L Knudson, AG AF Peri, Suraj Caretti, Elena Tricarico, Rossella Devarajan, Karthik Cheung, Mitchell Sementino, Eleonora Menges, Craig W. Nicolas, Emmanuelle Vanderveer, Lisa A. Howard, Sharon Conrad, Peggy Crowell, James A. Campbell, Kerry S. Ross, Eric A. Godwin, Andrew K. Yeung, Anthony T. Clapper, Margie L. Uzzo, Robert G. Henske, Elizabeth P. Ricketts, Christopher J. Vocke, Cathy D. Linehan, W. Marston Testa, Joseph R. Bellacosa, Alfonso Kopelovich, Levy Knudson, Alfred G. TI Haploinsufficiency in tumor predisposition syndromes: altered genomic transcription in morphologically normal cells heterozygous for VHL or TSC mutation SO ONCOTARGET LA English DT Article DE VHL; TSC1; TSC2; transcriptomics; primary kidney epithelial cells ID TUBEROUS SCLEROSIS COMPLEX; HIPPEL-LINDAU DISEASE; FAMILIAL ADENOMATOUS POLYPOSIS; CANCER PREVENTION; RENAL-CARCINOMA; SUPPRESSOR GENE; EXPRESSION; HYPOXIA; CARRIERS; PATHWAY AB Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease. Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal " one-hit" cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation. Here, we studied histologically non-transformed renal epithelial cells from patients with inherited disorders that predispose to renal tumors, including von Hippel-Lindau (VHL) disease and Tuberous Sclerosis (TSC). As controls, we studied histologically normal cells from non-cancerous renal epithelium of patients with sporadic clear cell renal cell carcinoma (ccRCC). Gene expression analyses of VHLmut/wt or TSC1/2(mut/wt) versus wild-type (WT) cells revealed transcriptomic alterations previously implicated in the transition to precancerous renal lesions. For example, the gene expression changes in VHLmut/wt cells were consistent with activation of the hypoxia response, associated, in part, with the " Warburg effect". Knockdown of any remaining VHL mRNA using shRNA induced secondary expression changes, such as activation of NF.B and interferon pathways, that are fundamentally important in the development of RCC. We posit that this is a general pattern of hereditary cancer predisposition, wherein haploinsufficiency for VHL or TSC1/2, or potentially other tumor susceptibility genes, is sufficient to promote development of early lesions,while cancer results from inactivation of the remaining normal allele.The gene expression changes identified here are related to the metabolic basis of renal cancer and may constitute suitable targets for early intervention. C1 [Peri, Suraj; Devarajan, Karthik; Ross, Eric A.] Fox Chase Canc Ctr, Dept Biostat & Bioinformat, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Caretti, Elena; Tricarico, Rossella; Bellacosa, Alfonso] Fox Chase Canc Ctr, Canc Epigenet, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Cheung, Mitchell; Sementino, Eleonora; Menges, Craig W.; Nicolas, Emmanuelle; Uzzo, Robert G.; Testa, Joseph R.; Knudson, Alfred G.] Fox Chase Canc Ctr, Canc Biol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Vanderveer, Lisa A.; Yeung, Anthony T.; Clapper, Margie L.] Fox Chase Canc Ctr, Canc Prevent & Control, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Howard, Sharon; Campbell, Kerry S.] Fox Chase Canc Ctr, Blood Cell Dev & Funct, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Conrad, Peggy] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Crowell, James A.] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Rockville, MD USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Uzzo, Robert G.; Testa, Joseph R.] Fox Chase Canc Ctr, Kidney Canc Programs, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Henske, Elizabeth P.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Henske, Elizabeth P.] NCI, Bethesda, MD 20892 USA. [Ricketts, Christopher J.; Vocke, Cathy D.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Kopelovich, Levy] Weill Cornell Med Coll, Dept Med, New York, NY USA. RP Bellacosa, A (reprint author), Fox Chase Canc Ctr, Canc Epigenet, 7701 Burholme Ave, Philadelphia, PA 19111 USA.; Testa, JR (reprint author), Fox Chase Canc Ctr, Canc Biol, 7701 Burholme Ave, Philadelphia, PA 19111 USA.; Testa, JR (reprint author), Fox Chase Canc Ctr, Kidney Canc Programs, 7701 Burholme Ave, Philadelphia, PA 19111 USA.; Kopelovich, L (reprint author), Weill Cornell Med Coll, Dept Med, New York, NY USA. EM joseph.testa@fccc.edu; alfonso.bellacosa@fccc.edu; kopelovichl@gmail.com FU NIH [N01 CN-95037, P30 CA-06927]; FCCC Kidney Keystone Program, an appropriation from the Commonwealth of Pennsylvania; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by NIH contract N01 CN-95037, NIH grant P30 CA-06927, FCCC Kidney Keystone Program, an appropriation from the Commonwealth of Pennsylvania and in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The Cell Culture, Genomics, and Bioinformatics & Biostatistics Facilities of FCCC provided expert assistance in this investigation.; The authors would like to dedicate this article to the memory of Alfred G. Knudson, scientist, mentor and friend, who worked on the manuscript up to his final days and passed away shortly before submission. He will be missed greatly by us and by scientists and clinicians in the fields of oncology and cancer genetics all over the world. NR 48 TC 0 Z9 0 U1 1 U2 1 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 PY 2017 VL 8 IS 11 BP 17628 EP 17642 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EO7NN UT WOS:000396877500020 ER PT J AU Albitar, A Ma, W DeDios, I Estella, J Ahn, I Farooqui, M Wiestner, A Albitar, M AF Albitar, Adam Ma, Wanlong DeDios, Ivan Estella, Jeffrey Ahn, Inhye Farooqui, Mohammed Wiestner, Adrian Albitar, Maher TI Using high-sensitivity sequencing for the detection of mutations in BTK and PLC gamma 2 genes in cellular and cell- free DNA and correlation with progression in patients treated with BTK inhibitors SO ONCOTARGET LA English DT Article DE ibrutinib; CLL; resistance; PLC gamma 2; BTK ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; NUCLEIC-ACID ANALOG; INTRATUMOR HETEROGENEITY; IBRUTINIB; PLASMA; RESISTANCE; EVOLUTION; PATHWAY; CANCER AB Patients with chronic lymphocytic leukemia (CLL) that develop resistance to Bruton tyrosine kinase (BTK) inhibitors are typically positive for mutations in BTK or phospholipase c gamma 2 (PLC gamma 2). We developed a high sensitivity (HS) assay utilizing wild-type blocking polymerase chain reaction achieved via bridged and locked nucleic acids. We used this high sensitivity assay in combination with Sanger sequencing and next generation sequencing (NGS) and tested cellular DNA and cell-free DNA (cfDNA) from patients with CLL treated with the BTK inhibitor, ibrutinib. We also tested ibrutinib-naive patients with CLL. HS testing achieved 100x greater sensitivity than Sanger. HS Sanger sequencing was capable of detecting < 1 mutant allele in background of 1000 wild-type alleles (1:1000). Similar sensitivity was achieved with HS NGS. No BTK or PLC gamma 2 mutations were detected in any of the 44 ibrutinib-naive CLL patients. We demonstrate that without the HS testing 56% of positive samples would have been missed for BTK and 85% of PLC gamma 2 would have been missed. With the use of HS, we were able to detect multiple mutant clones in the same sample in 37.5% of patients; most would have been missed without HS testing. We also demonstrate that with HS sequencing, plasma cfDNA is more reliable than cellular DNA in detecting mutations. Our studies indicate that wild-type blocking and HS sequencing is necessary for proper and early detection of BTK or PLC gamma 2 mutations in monitoring patients treated with BTK inhibitors. Furthermore, cfDNA from plasma is very reliable sample-type for testing. C1 [Albitar, Adam; Ma, Wanlong; DeDios, Ivan; Estella, Jeffrey; Albitar, Maher] NeoGen Labs, Irvine, CA 94043 USA. [Ahn, Inhye] Natl Canc Inst, Med Oncol Serv, Bethesda, MD USA. [Farooqui, Mohammed; Wiestner, Adrian] Natl Heart Lung & Blood Inst, Hematol Branch, Bethesda, MD USA. RP Albitar, M (reprint author), NeoGen Labs, Irvine, CA 94043 USA. EM malbitar@neogenomics.com FU Intramural Research Program of the NHLBI; NCI FX IA, MF, and AW are supported by the Intramural Research Program of the NHLBI and NCI. NR 28 TC 0 Z9 0 U1 1 U2 1 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 PY 2017 VL 8 IS 11 BP 17936 EP 17944 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EO7NN UT WOS:000396877500044 ER PT J AU Fagerholm, R Khan, S Schmidt, MK Garcia-Closas, M Heikkila, P Saarela, J Beesley, J Jamshidi, M Aittomaki, K Liu, JJ Ali, HR Andrulis, IL Beckmann, MW Behrens, S Blows, FM Brenner, H Chang-Claude, J Couch, FJ Czene, K Fasching, PA Figueroa, J Floris, G Glendon, G Guo, Q Hall, P Hallberg, E Hamann, U Holleczek, B Hooning, MJ Hopper, JL Jager, A Kabisch, M Keeman, R Kosma, VM Lambrechts, D Lindblom, A Mannermaa, A Margolin, S Provenzano, E Shah, M Southey, MC Dennis, J Lush, M Michailidou, K Wang, Q Bolla, MK Dunning, AM Easton, DF Pharoah, PDP Chenevix-Trench, G Blomqvist, C Nevanlinna, H AF Fagerholm, Rainer Khan, Sofia Schmidt, Marjanka K. Garcia-Closas, Montserrat Heikkila, Pavi Saarela, Jani Beesley, Jonathan Jamshidi, Maral Aittomaki, Kristiina Liu, Jianjun Ali, H. Raza Andrulis, Irene L. Beckmann, Matthias W. Behrens, Sabine Blows, Fiona M. Brenner, Hermann Chang-Claude, Jenny Couch, Fergus J. Czene, Kamila Fasching, Peter A. Figueroa, Jonine Floris, Giuseppe Glendon, Gord Guo, Qi Hall, Per Hallberg, Emily Hamann, Ute Holleczek, Bernd Hooning, Maartje J. Hopper, John L. Jager, Agnes Kabisch, Maria Keeman, Renske Kosma, Veli-Matti Lambrechts, Diether Lindblom, Annika Mannermaa, Arto Margolin, Sara Provenzano, Elena Shah, Mitul Southey, Melissa C. Dennis, Joe Lush, Michael Michailidou, Kyriaki Wang, Qin Bolla, Manjeet K. Dunning, Alison M. Easton, Douglas F. Pharoah, Paul D. P. Chenevix-Trench, Georgia Blomqvist, Carl Nevanlinna, Heli CA KConFab AOCS Investigators TI TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer SO ONCOTARGET LA English DT Article DE breast cancer; TP53; survival; anthracycline; SNP ID PATHOLOGICAL COMPLETE RESPONSE; NEOADJUVANT CHEMOTHERAPY; CELL-PROLIFERATION; ADJUVANT THERAPY; GENE-MUTATIONS; P53; SUSCEPTIBILITY; DOXORUBICIN; EXPRESSION; LOCI AB TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes. In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p((interaction)) = 3.44 x 10(-5); FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p((interaction)) = 9.57 x 10(-5), FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines. If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer. C1 [Fagerholm, Rainer; Khan, Sofia; Jamshidi, Maral; Nevanlinna, Heli] Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Schmidt, Marjanka K.; Keeman, Renske] Antoni Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Garcia-Closas, Montserrat; Figueroa, Jonine] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Heikkila, Pavi] Univ Helsinki, Helsinki Univ Hosp, Dept Pathol, Helsinki, Finland. [Saarela, Jani] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Beesley, Jonathan; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Aittomaki, Kristiina] Univ Helsinki, Helsinki Univ Hosp, Dept Clin Genet, Helsinki, Finland. [Liu, Jianjun] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Ali, H. Raza] Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England. [Ali, H. Raza] Univ Cambridge, Dept Pathol, Cambridge, England. [Andrulis, Irene L.; Glendon, Gord] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Beckmann, Matthias W.; Fasching, Peter A.; Kosma, Veli-Matti] Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Dept Obstet & Gynaecol, Comprehens Canc Ctr Erlangen EMN, Erlangen, Germany. [Behrens, Sabine] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Blows, Fiona M.; Shah, Mitul; Dunning, Alison M.; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg UCCH, Hamburg, Germany. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Czene, Kamila; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA USA. [Figueroa, Jonine] Univ Edinburgh, Sch Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Floris, Giuseppe] Univ Hosp Leuven, Leuven Canc Inst, KULeuven, Leuven Multidisciplinary Breast Ctr,Dept Oncol, Leuven, Belgium. [Hallberg, Emily] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Hamann, Ute; Kabisch, Maria] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Holleczek, Bernd] Saarland Canc Registry, Saarbrucken, Germany. [Hooning, Maartje J.; Jager, Agnes] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Hopper, John L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [KConFab AOCS Investigators] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Canc Ctr Eastern Finland, Kuopio, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Provenzano, Elena] Univ Cambridge, Addenbrookes Hosp, Dept Oncol, Cambridge, England. [Provenzano, Elena] Univ Cambridge, Hosp NHS Fdn Trust, Addenbrookes Hosp, Dept Histopathol, Cambridge, England. [Provenzano, Elena] Cambridge Expt Canc Med Ctr, Cambridge, England. [Provenzano, Elena] NIHR Cambridge Biomed Res Ctr, Cambridge, England. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Australia. [Dennis, Joe; Lush, Michael; Michailidou, Kyriaki; Wang, Qin; Bolla, Manjeet K.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Michailidou, Kyriaki] Cyprus Inst Neurol & Genet, Dept Elect Microscopy Mol Pathol, Nicosia, Cyprus. [Blomqvist, Carl] Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland. [Blomqvist, Carl] Univ Orebro, Dept Oncol, Orebro, Sweden. RP Nevanlinna, H (reprint author), Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland. EM heli.nevanlinna@hus.fi FU Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute (USA) [UM1 CA164920]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Dutch Cancer Society [NKI 2007-3839, 2009 4363]; ELAN-Fond of the University Hospital of Erlangen; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Helsinki University Central Hospital Research Fund; Academy of Finland [266528]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Stockholm County Council; Karolinska Institutet; Swedish Cancer Society; Gustav V Jubilee foundation; Bert von Kantzows foundation; Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; National Breast Cancer Foundation; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council Victoria; Queensland Cancer Fund; Cancer Council New South Wales; Cancer Council South Australia; Cancer Foundation of Western Australia; Cancer Council Tasmania; National Health and Medical Research Council of Australia (NHMRC) [400413, 400281, 199600]; 'Stichting tegen Kanker' [232-2008, 196-2010]; FWO; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]; Hamburg Cancer Society; German Cancer Research Center (DKFZ); Federal Ministry of Education and Research (BMBF) Germany [01KH0402]; NIH [CA192393, CA116167, CA176785]; NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; DKFZ; [KULPFV/10/016-SymBioSysII] FX The Breast Cancer Association Consortium (BCAC) is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS genotyping infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund.; The Australian Breast Cancer Family Study (ABCFS; John L. Hopper, Melissa C. Southey) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow.; The ABCS study (Marjanka K. Schmidt, Renske Keeman) was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363].; The work of the BBCC (Matthias W. Beckmann, Peter A. Fasching) was partly funded by ELAN-Fond of the University Hospital of Erlangen.; The ESTHER study (Hermann Brenner, Bernd Holleczek) was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe).; The HEBCS (Rainer Fagerholm, Sofia Khan, Paivi Heikkila, Maral Jamshidi, Kristiina Aittomaki, Carl Blomqvist, Heli Nevanlinna) was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union, and the Sigrid Juselius Foundation.; Financial support for KARBAC (Annika Lindblom, Sara Margolin) was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation.; The KBCP (Veli-Matti Kosma, Arto Mannermaa) was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland.; kConFab (Jonathan Beesley, Georgia ChenevixTrench) is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow.; LMBC (Giuseppe Floris, Diether Lambrechts) is supported by the 'Stichting tegen Kanker' (232-2008 and 196-2010). Diether Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII.; The MARIE study (Sabine Behrens, Jenny Chang-Claude) was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402].; The MCBCS (Fergus J. Couch, Emily Hallberg) was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation.; The Ontario Familial Breast Cancer Registry (OFBCR; Irene L. Andrulis, Gord Glendon) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR.; The PBCS (Montserrat Garcia-Closas, Jonine Figueroa) was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA.; The RBCS (Maartje J. Hooning, Agnes Jager) was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318).; The SASBAC (Kamila Czene, Per Hall) study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation.; SEARCH (H. Raza Ali, Fiona M. Blows, Qi Guo, Elena Provenzano, Mitul Shah) is funded by a programme grant from Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge.; SKKDKFZS (Ute Hamann, Maria Kabisch) is supported by the DKFZ. NR 53 TC 0 Z9 0 U1 1 U2 1 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 PY 2017 VL 8 IS 11 BP 18381 EP 18398 DI 10.18632/oncotarget.15110 PG 18 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EO7NN UT WOS:000396877500082 ER PT J AU Xiong, DH Pan, J Zhang, Q Szabo, E Miller, MS Lubet, RA You, M Wang, Y AF Xiong, Donghai Pan, Jing Zhang, Qi Szabo, Eva Miller, Mark Steven Lubet, Ronald A. You, Ming Wang, Yian TI Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents SO ONCOTARGET LA English DT Article DE AUC (area under the curve); GSEA (gene set enrichment analysis); IPA (Ingenuity Pathway Analysis); PPAR (peroxisome proliferator-activated receptor gamma); SCC (squamous cell carcinoma) ID CIRCULATING TUMOR-CELLS; C-KINASE SUBSTRATE; DIAGNOSTIC EVALUATION; BREAST-CANCER; STEM-CELLS; RNA-SEQ; MYC; ADENOCARCINOMA; CARCINOGENESIS; METASTASIS AB Due to exposure to environmental toxicants, a "field cancerization" effect occurs in the lung resulting in the development of a field of initiated but morphologically normal appearing cells in the damaged epithelium of bronchial airways with dysregulated gene expression patterns. Using a mouse model of lung squamous cell carcinoma (SCC), we performed transcriptome sequencing (RNA-Seq) to profile bronchial airway gene expression and found activation of the PI3K and Myc signaling networks in cytologically normal bronchial airway epithelial cells of mice with preneopastic lung SCC lesions, which was reversed by treatment with the PI3K Inhibitor XL-147 and pioglitazone, respectively. Activated MYC signaling was also present in premalignant and tumor tissues from human lung SCC patients. In addition, we identified a key microRNA, mmu-miR-449c-5p, whose suppression significantly up-regulated Myc expression in the normal bronchial airway epithelial cells of mice with early stage SCC lesions. We developed a novel bronchial genomic classifier in mice and validated it in humans. In the classifier, Ppbp (pro-platelet basic protein) was overexpressed 115 fold in the bronchial airways of mice with preneoplastic lung SCC lesions. This is the first report that demonstrates Ppbp as a novel biomarker in the bronchial airway for lung cancer diagnosis. C1 [Xiong, Donghai; Pan, Jing; Zhang, Qi; You, Ming; Wang, Yian] Ctr Canc, Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Xiong, Donghai; Pan, Jing; Zhang, Qi; You, Ming; Wang, Yian] Med Coll Wisconsin, Dept Pharmacol & Toxicol, Milwaukee, WI 53226 USA. [Szabo, Eva; Miller, Mark Steven; Lubet, Ronald A.] Natl Canc Inst, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Rockville, MD 20850 USA. RP You, M; Wang, Y (reprint author), Ctr Canc, Med Coll Wisconsin, Milwaukee, WI 53226 USA.; You, M; Wang, Y (reprint author), Med Coll Wisconsin, Dept Pharmacol & Toxicol, Milwaukee, WI 53226 USA. EM myou@mcw.edu; yiwang@mcw.edu FU National Institutes of Health [N01CN201200015, R01CA134682, R01CA134433, R01CA208648] FX This work was supported in part by National Institutes of Health N01CN201200015, R01CA134682, R01CA134433 & R01CA208648. NR 71 TC 0 Z9 0 U1 0 U2 0 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 PY 2017 VL 8 IS 12 BP 18885 EP 18900 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EO7OE UT WOS:000396879200025 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 Summary of the National Institute of Allergy and Infectious Diseases-sponsored expert panel SO PEDIATRIC DERMATOLOGY LA English DT Article 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, 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, Rochester, NY 14642 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, BC Childrens Hosp, Dept Pediat, Div Allergy & Immunol, Vancouver, BC, Canada. [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, Dept Pediat, San Diego Sch Med, 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, Ann & Robert H Lurie Childrens Hosp Chicago,Div A, Chicago, IL 60611 USA. [Habich, Michele] Cent DuPage Hosp, Northwestern Med, Winfield, IL USA. [Jones, Stacie M.] Univ Arkansas Med Sci, Dept Pediat, Arkansas Childrens Hosp, 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.] Icahn Sch Med Mt Sinai, Dept Pediat, Div Allergy & Immunol, New York, NY 10029 USA. [Schneider, Lynda C.] Boston Childrens Hosp, Div Allergy & Immunol, Boston, MA USA. [Sicherer, Scott H.] Icahn Sch Med Mt Sinai, Div Pediat Allergy & Immunol, New York, NY 10029 USA. [Sidbury, Robert] Univ Washington, Sch Med, Dept Pediat, Div Dermatol,Seattle Childrens Hosp, 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, 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, Div Allergy Immunol & Transplantat, NIH, 5601 Fishers Lane,Room 7C28, Rockville, MD 20892 USA. EM coopersu@niaid.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-8046 EI 1525-1470 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD JAN-FEB PY 2017 VL 34 IS 1 BP 5 EP 12 DI 10.1111/pde.13092 PG 8 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA EK5GT UT WOS:000393955600020 PM 28054718 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 PEDIATRIC DERMATOLOGY LA English DT Article ID HIGH-RISK INFANTS; FOOD ALLERGY; NUTRITIONAL INTERVENTIONS; ANAPHYLACTIC REACTIONS; COMPLEMENTARY FOODS; GRADING QUALITY; BIRTH COHORT; PREVALENCE; LEAP; CONSUMPTION 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 three 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 USA. [Assa'ad, Amal] Univ Cincinnati, Med Ctr, Cincinnati Childrens Hosp, Div Allergy & Immunol, Cincinnati, OH 45267 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, San Rafael, CA USA. [Beck, Lisa A.] Univ Rochester, Med Ctr, Dept Dermatol, San Diego, CA 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, BC Childrens Hosp, Dept Pediat, Div Allergy & Immunol, Vancouver, BC, Canada. [Eichenfield, Lawrence F.] Univ Calif San Diego, San Diego Sch Med, Rady Childrens Hosp, Dept Dermatol, San Diego, CA 92110 USA. [Eichenfield, Lawrence F.] Univ Calif San Diego, San Diego Sch Med, Rady Childrens Hosp, Dept Pediat, San Diego, CA 92110 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, Kentucky Childrens Hosp, Div Gastroenterol Hepatol & Nutr, 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, Chicago, IL 60611 USA. [Gupta, Ruchi S.] Northwestern Univ, Feinberg Sch Med, 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.] Icahn Sch Med Mt Sinai, Dept Pediat, Div Allergy & Immunol, New York, NY 10029 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, Seattle Childrens Hosp, Dept Pediat,Div Dermatol, Seattle, WA 98195 USA. [Spergel, Jonathan] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, 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 USA. [Boyce, Joshua A.] Harvard Med Sch, Dept Pediat, Boston, MA USA. RP Cooper, SF (reprint author), NIH, NIAID, Div Allergy, 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); Aimmune Technologies; National Peanut Board; NIAID; Immune Tolerance Network; HAL Allergy; Epidermolysis Bullosa Research Partnership 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 conflicts of interest. NR 43 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-8046 EI 1525-1470 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD JAN-FEB PY 2017 VL 34 IS 1 BP E1 EP E21 DI 10.1111/pde.13093 PG 21 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA EK5GT UT WOS:000393955600001 PM 28054723 ER PT J AU Bornstein, MH AF Bornstein, Marc H. TI The Specificity Principle in Acculturation Science SO PERSPECTIVES ON PSYCHOLOGICAL SCIENCE LA English DT Article DE acculturation; culture; immigrant; migration; specificity ID CHINESE-AMERICAN ADOLESCENTS; CROSS-CULTURAL-PERSPECTIVE; MOTHER-INFANT INTERACTION; PUERTO-RICAN SEGREGATION; CHILDRENS MENTAL-HEALTH; NON-IMMIGRANT FAMILIES; ETHNIC-MINORITY YOUTH; SEX-ROLE ATTITUDES; SELF-RATED HEALTH; UNITED-STATES AB The specificity principle in acculturation science asserts that specific setting conditions of specific people at specific times moderate specific domains in acculturation by specific processes. Our understanding of acculturation depends critically on what is studied where, in whom, how, and when. This article defines, explains, and illustrates the specificity principle in acculturation science. Research hypotheses about acculturation can be more adequately tested, inconsistencies and discrepancies in the acculturation literature can be satisfactorily resolved, acculturation interventions can be tailored to be more successful, and acculturation policies can be brought to new levels of effectiveness if the specificity principle that governs acculturation science is more widely recognized. C1 [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, NIH, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov FU Intramural Research Program of the National Institutes of Health (NIH) National Institute of Child Health and Human Development (NICHD) FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH) National Institute of Child Health and Human Development (NICHD). NR 398 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1745-6916 EI 1745-6924 J9 PERSPECT PSYCHOL SCI JI Perspect. Psychol. Sci. PD JAN PY 2017 VL 12 IS 1 BP 3 EP 45 DI 10.1177/1745691616655997 PG 43 WC Psychology, Multidisciplinary SC Psychology GA EL0YO UT WOS:000394347900001 PM 28073331 ER PT J AU Umejiego, EN Wang, YH Knepper, MA Chou, CL AF Umejiego, Ezigbobiara N. Wang, Yanhua Knepper, Mark A. Chou, Chung-Lin TI Roflumilast and aquaporin-2 regulation in rat renal inner medullary collecting duct SO PHYSIOLOGICAL REPORTS LA English DT Article DE cAMP phosphodiesterase; kidney; nephrogenic diabetes insipidus; Xchromosome ID NEPHROGENIC DIABETES-INSIPIDUS; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; OBSTRUCTIVE PULMONARY-DISEASE; CAMP-SPECIFIC PHOSPHODIESTERASE; WATER REABSORPTION; URINARY CONCENTRATION; (PRO)RENIN RECEPTOR; SURFACE EXPRESSION; MEMBRANE INSERTION; PROSTAGLANDIN E-2 AB Roflumilast is a cyclic nucleotide phosphodiesterase inhibitor that is FDA-approved for treatment of chronic obstructive pulmonary disease. With a view toward possible use for treatment of patients with X-linked nephrogenic diabetes insipidus (NDI) due to hemizygous mutations in the V2 vasopressin receptor, this study sought to determine the effect of roflumilast on aquaporin-2 (AQP2) phosphorylation, AQP2 trafficking, and water permeability in the rat inner medullary collecting duct (IMCD). In the presence of the vasopressin analog dDAVP (0.1nmol/L), both roflumilast and its active metabolite roflumilast N-oxide (RNO) significantly increased phosphorylation at S256, S264, and S269, and decreased phosphorylation at S261 (immunoblotting) in IMCD suspensions in a dose-dependent manner (3-3000nmol/L). Another commonly used phosphodiesterase inhibitor, IBMX, affected phosphorylation only at the highest concentration in this range. However, neither roflumilast nor RNO had an effect on AQP2 phosphorylation in the absence of vasopressin. Furthermore, roflumilast alone did not increase AQP2 trafficking to the plasma membrane (immunofluorescence) or increase water permeability in freshly microdissected perfused IMCD segments. We conclude that roflumilast can be used to enhance vasopressin's action on AQP2 activity in the renal collecting duct, but has no detectable effect in the absence of vasopressin. These findings suggest that roflumilast may not have a beneficial effect in X-linked NDI, but could find useful application in acquired NDI. C1 [Umejiego, Ezigbobiara N.; Knepper, Mark A.; Chou, Chung-Lin] NHLBI, Epithelial Syst Biol Lab, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wang, Yanhua] Emory Univ, Dept Med, Div Renal, Atlanta, GA 30322 USA. RP Knepper, MA (reprint author), NIH, Bldg 10,Room 6N307,10 Ctr DR,MSC 1603, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov NR 110 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2051-817X J9 PHYSIOL REP JI PHYSIOL. REP. PD JAN PY 2017 VL 5 IS 2 AR e13121 DI 10.14814/phy2.13121 PG 16 WC Physiology SC Physiology GA EK3VE UT WOS:000393855700012 ER PT J AU Zhao, J Nussinov, R Ma, BY AF Zhao, Jun Nussinov, Ruth Ma, Buyong TI Allosteric control of antibody-prion recognition through oxidation of a disulfide bond between the CH and CL chains SO PROTEIN ENGINEERING DESIGN & SELECTION LA English DT Article DE antibody-antigen interaction; bound water molecules; community analysis; disulfide bond; dynamic network; motion correlation ID MOLECULAR-DYNAMICS; CONSTANT-REGION; CONFORMATIONAL-CHANGES; ANTIGEN-BINDING; IMMUNOGLOBULIN CONSTANT; PROTEIN STRUCTURES; ANALYSIS PROGRAM; FLUCTUATIONS; SPECIFICITY; AFFINITY AB Molecular details of the recognition of disordered antigens by their cognate antibodies have not been studied as extensively as folded protein antigens and much is still unknown. To follow the conformational changes in the antibody and cross-talk between its subunits and with antigens, we performed molecular dynamics (MD) simulations of the complex of Fab and prion-associated peptide in the apo and bound forms. We observed that the inter-chain disulfide bond in constant domains restrains the conformational changes of Fab, especially the loops in the CH1 domain, resulting in inhibition of the cross-talk between Fab subdomains that thereby may prevent prion peptide binding. We further identified several negative and positive correlations of motions between the peptide and Fab constant domains, which suggested structural cross-talks between the constant domains and the antigen. The cross-talk was influenced by the inter-chain disulfide bond, which reduced the number of paths between them. Importantly, network analysis of the complex and its bound water molecules observed that those water molecules form an integral part of the Fab/peptide complex network and potential allosteric pathways. On-going work focuses on developing strategies aimed to incorporate these new network communications-including the associated water molecules-toward the grand challenge of antibody design. C1 [Zhao, Jun] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth; Ma, Buyong] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Ma, BY (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. EM mabuyong@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Institutes of Health, National Institute on Deafness and Other Communication Disorders FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health [under contract number HHSN261200800001E]. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. J.Z. was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Deafness and Other Communication Disorders. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 47 TC 0 Z9 0 U1 5 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1741-0126 EI 1741-0134 J9 PROTEIN ENG DES SEL JI Protein Eng. Des. Sel. PD JAN PY 2017 VL 30 IS 1 BP 67 EP 76 DI 10.1093/protein/gzw065 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA EP1EY UT WOS:000397129400009 PM 27899437 ER PT J AU Senese, VP Venuti, P Giordano, F Napolitano, M Esposito, G Bornstein, MH AF Senese, Vincenzo Paolo Venuti, Paola Giordano, Francesca Napolitano, Maria Esposito, Gianluca Bornstein, Marc H. TI Adults' implicit associations to infant positive and negative acoustic cues: Moderation by empathy and gender SO QUARTERLY JOURNAL OF EXPERIMENTAL PSYCHOLOGY LA English DT Article DE Auditory; Implicit affective associations; Infant cry; Infant laugh; Single Category Implicit Association Test ID MATERNAL SENSITIVITY; SOCIAL COGNITION; SEX-DIFFERENCES; CRIES; RESPONSES; MOTHERS; ATTITUDES; DISTRESS; FATHERS; AUTISM AB In this study a novel auditory version of the Single Category Implicit Association Test (SC-IAT-A) was developed to investigate (a) the valence of adults' associations to infant cries and laughs, (b) moderation of implicit associations by gender and empathy, and (c) the robustness of implicit associations controlling for auditory sensitivity. Eighty adults (50% females) were administered two SC-IAT-As, the Empathy Quotient, and the Weinstein Noise Sensitivity Scale. Adults showed positive implicit associations to infant laugh and negative ones to infant cry; only the implicit associations with the infant laugh were negatively related to empathy scores, and no gender differences were observed. Finally, implicit associations to infant cry were affected by noise sensitivity. The SC-IAT-A is useful to evaluate the valence of implicit reactions to infant auditory cues and could provide fresh insights into understanding processes that regulate the quality of adult-infant relationships. C1 [Senese, Vincenzo Paolo; Giordano, Francesca; Napolitano, Maria] Univ Naples 2, Dept Psychol, Psychometr Lab, Viale Ellitt 31, I-81100 Caserta, Italy. [Venuti, Paola] Univ Trento, Dept Cognit Sci & Educ, Trento, Italy. [Esposito, Gianluca] Univ Trento, Dept Cognit Sci & Educ, Affiliat & Social Behav Lab, Trento, Italy. [Esposito, Gianluca] Nanyang Technol Univ, Sch Humanities & Social Sci, Div Psychol, Social & Affiliat Neurosci Lab, Singapore, Singapore. [Bornstein, Marc H.] NICHHD, Eunice Kennedy Shriver, US Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Senese, VP (reprint author), Univ Naples 2, Dept Psychol, Psychometr Lab, Viale Ellitt 31, I-81100 Caserta, Italy. EM vincenzopaolo.senese@unina2.it NR 36 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 1747-0218 EI 1747-0226 J9 Q J EXP PSYCHOL JI Q. J. Exp. Psychol. PY 2017 VL 70 IS 9 BP 1935 EP 1942 DI 10.1080/17470218.2016.1215480 PG 8 WC Psychology, Biological; Physiology; Psychology; Psychology, Experimental SC Psychology; Physiology GA EO6XA UT WOS:000396834600013 PM 27437762 ER PT J AU Munoz, AM Yourik, P Rajagopal, V Nanda, JS Lorsch, JR Walker, SE AF Munoz, Antonio M. Yourik, Paul Rajagopal, Vaishnavi Nanda, Jagpreet S. Lorsch, Jon R. Walker, Sarah E. TI Active yeast ribosome preparation using monolithic anion exchange chromatography SO RNA BIOLOGY LA English DT Article DE Eukaryotic translation; in vitro translation; ribosome; ribosome purification; yeast ID TRANSLATION INITIATION; PURIFICATION; RNAS AB In vitro studies of translation provide critical mechanistic details, yet purification of large amounts of highly active eukaryotic ribosomes remains a challenge for biochemists and structural biologists. Here, we present an optimized method for preparation of highly active yeast ribosomes that could easily be adapted for purification of ribosomes from other species. The use of a nitrogen mill for cell lysis coupled with chromatographic purification of the ribosomes results in 10-fold-increased yield and less variability compared with the traditional approach, which relies on sedimentation through sucrose cushions. We demonstrate that these ribosomes are equivalent to those made using the traditional method in a host of in vitro assays, and that utilization of this new method will consistently produce high yields of active yeast ribosomes. C1 [Munoz, Antonio M.; Yourik, Paul; Nanda, Jagpreet S.; Lorsch, Jon R.; Walker, Sarah E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mech & Regulat Prot Synth, Bethesda, MD USA. [Rajagopal, Vaishnavi] Ra Pharmaceut, Cambridge, MA USA. [Walker, Sarah E.] SUNY Buffalo, Dept Biol Sci, Buffalo, NY USA. RP Walker, SE (reprint author), SUNY Buffalo, Biol Sci, 653 Hochstetter Hall, Buffalo, NY 14260 USA. EM walker47@buffalo.edu FU Intramural Research Program of the National Institutes of Health (NIH) [ZIAHD008940]; NIH [R00GM119173] FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH, ZIAHD008940) and NIH grant R00GM119173 to SEW. NR 21 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 1547-6286 EI 1555-8584 J9 RNA BIOL JI RNA Biol. PY 2017 VL 14 IS 2 BP 188 EP 196 DI 10.1080/15476286.2016.1270004 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EM3HD UT WOS:000395204200007 PM 27981882 ER PT J AU Abdelmohsen, K Panda, AC Munk, R Grammatikakis, I Dudekula, DB De, S Kim, J Noh, JH Kim, KM Martindale, JL Gorospe, M AF Abdelmohsen, Kotb Panda, Amaresh C. Munk, Rachel Grammatikakis, Ioannis Dudekula, Dawood B. De, Supriyo Kim, Jiyoung Noh, Ji Heon Kim, Kyoung Mi Martindale, Jennifer L. Gorospe, Myriam TI Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1 SO RNA BIOLOGY LA English DT Article DE Cell proliferation; circular RNA; circPABPN1; endogenous competing RNA; HuR; PABPN1; RNA-binding Protein; translation ID BINDING PROTEIN HUR; LONG NONCODING RNA; POSTTRANSCRIPTIONAL GENE-REGULATION; MOTIF; ABUNDANT; SPONGES AB HuR influences gene expression programs and hence cellular phenotypes by binding to hundreds of coding and noncoding linear RNAs. However, whether HuR binds to circular RNAs (circRNAs) and impacts on their function is unknown. Here, we have identified en masse circRNAs binding HuR in human cervical carcinoma HeLa cells. One of the most prominent HuR target circRNAs was hsa_circ_0031288, renamed CircPABPN1 as it arises from the PABPN1 pre-mRNA. Further analysis revealed that HuR did not influence CircPABPN1 abundance; interestingly, however, high levels of CircPABPN1 suppressed HuR binding to PABPN1 mRNA. Evaluation of PABPN1 mRNA polysomes indicated that PABPN1 translation was modulated positively by HuR and hence negatively by CircPABPN1. We propose that the extensive binding of CircPABPN1 to HuR prevents HuR binding to PABPN1 mRNA and lowers PABPN1 translation, providing the first example of competition between a circRNA and its cognate mRNA for an RBP that affects translation. C1 [Abdelmohsen, Kotb; Panda, Amaresh C.; Munk, Rachel; Grammatikakis, Ioannis; Dudekula, Dawood B.; De, Supriyo; Kim, Jiyoung; Noh, Ji Heon; Kim, Kyoung Mi; Martindale, Jennifer L.; Gorospe, Myriam] NIA, Lab Genet & Genom, NIH, Baltimore, MD 21224 USA. RP Abdelmohsen, K (reprint author), NIA, Lab Genet & Genom, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM abdelmohsenk@mail.nih.gov NR 34 TC 0 Z9 0 U1 4 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1547-6286 EI 1555-8584 J9 RNA BIOL JI RNA Biol. PY 2017 VL 14 IS 3 BP 361 EP 369 DI 10.1080/15476286.2017.1279788 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO6VN UT WOS:000396830700011 PM 28080204 ER PT J AU Bellatorre, A Choi, K Lewin, D Haynie, D Simons-Morton, B AF Bellatorre, Anna Choi, Kelvin Lewin, Daniel Haynie, Denise Simons-Morton, Bruce TI Relationships Between Smoking and Sleep Problems in Black and White Adolescents SO SLEEP LA English DT Article DE adolescent; smoking; sleep problem; sleep duration; longitudinal ID HIGH-SCHOOL-STUDENTS; UNITED-STATES; SUBSTANCE USE; START TIMES; EARLY-ONSET; DEPRESSION; HEALTH; RISK; PREVALENCE; BEHAVIORS AB Study Objectives: The relationship between sleeping and smoking during adolescence remains unclear and is likely complex. We aim to evaluate the longitudinal reciprocal associations between sleep problems, sleep duration, and smoking among non-Hispanic white (NHW) and non-Hispanic black (NHB) youth. Design: Prospective cohort study Setting: NEXT Generation Health Study Participants: A national sample (N = 1394) of NHB and NHW 10th graders were surveyed annually between 2009 (Wave 1) and 2012 (Wave 3). Interventions: N/A Measurements and Results: Past 30-day smoking, chronic difficulty falling asleep, recent difficulty falling asleep, difficulty staying asleep, and weekday and weekend sleep duration were measured at each wave. Using structural equation models, we observed significant autocorrelations over time for sleep problems and sleep duration. We found significant reciprocal, prospective relationships between smoking and sleep problems. The strengths of the relationships differed by race, with a stronger association between sleep problems and subsequent smoking for NHB than NHW youth. Conversely, a stronger association between smoking and subsequent sleep problems for NHW than NHB youth was observed. These association were independent of demographics, snoring or sleep apnea, body mass index, depressive symptoms, alcohol use, and soda consumption. Conclusions: Reciprocal and prospective relationships exist for youth smoking and sleep problems and duration in both NHW and NHB youth. Further research is needed to unravel the complex relationship between the direct effects of nicotine, lifestyle choices that may link smoking and sleep problems, and racial differences. C1 [Bellatorre, Anna; Choi, Kelvin] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. [Lewin, Daniel] George Washington Univ, Sch Med, Washington, DC USA. [Haynie, Denise; Simons-Morton, Bruce] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Choi, K (reprint author), 9000 Rockville Pike Bldg 3 5W05, Bethesda, MD 20892 USA. EM kelvin.choi@nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 FU Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275201200001I]; National Heart, Lung and Blood Institute (NHLBI); National Institute on Alcohol Abuse and Alcoholism (NIAAA); Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA); National Institute on Drug Abuse (NIDA) FX Bellatorre and Choi's effort is funded by the Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health. The NEXT Generation Health Study is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract # HHSN275201200001I), and the National Heart, Lung and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA), and the National Institute on Drug Abuse (NIDA). NR 45 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 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD JAN 1 PY 2017 VL 40 IS 1 AR PII zsw031 DI 10.1093/sleep/zsw031 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EK7SO UT WOS:000394125700031 ER PT J AU Goldstein, DS AF Goldstein, David S. TI Richard Obituary SO STRESS-THE INTERNATIONAL JOURNAL ON THE BIOLOGY OF STRESS LA English DT Biographical-Item C1 [Goldstein, David S.] Natl Inst Neurol Disorders & Stroke NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. [Goldstein, David S.] NIH, Ctr Clin, Bethesda, MD 20814 USA. RP Goldstein, DS (reprint author), Natl Inst Neurol Disorders & Stroke NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,US Natl Inst Hlth NIH, Bethesda, MD 20892 USA.; Goldstein, DS (reprint author), NIH, Ctr Clin, Bethesda, MD 20814 USA. EM goldsteind@ninds.nih.gov NR 0 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 1025-3890 EI 1607-8888 J9 STRESS JI Stress PY 2017 VL 20 IS 1 BP 1 EP 1 DI 10.1080/10253890.2017.1283090 PG 1 WC Behavioral Sciences; Endocrinology & Metabolism; Neurosciences SC Behavioral Sciences; Endocrinology & Metabolism; Neurosciences & Neurology GA EM3VI UT WOS:000395242300001 PM 28152657 ER PT J AU Kurz, FT Kembro, JM Flesia, AG Armoundas, AA Cortassa, S Aon, MA Lloyd, D AF Kurz, Felix T. Kembro, Jackelyn M. Flesia, Ana G. Armoundas, Antonis A. Cortassa, Sonia Aon, Miguel A. Lloyd, David TI Network dynamics: quantitative analysis of complex behavior in metabolism, organelles, and cells, from experiments to models and back SO WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE LA English DT Review ID DETRENDED FLUCTUATION ANALYSIS; NONSTATIONARY TIME-SERIES; SMALL-WORLD NETWORKS; STOCHASTIC RESONANCE; CIRCADIAN-RHYTHMS; CARDIAC MYOCYTES; SYSTEMS BIOLOGY; MITOCHONDRIAL-FUNCTION; INDIVIDUAL MITOCHONDRIA; REGULATORY NETWORKS AB Advancing from two core traits of biological systems: multilevel network organization and nonlinearity, we review a host of novel and readily available techniques to explore and analyze their complex dynamic behavior within the framework of experimental-computational synergy. In the context of concrete biological examples, analytical methods such as wavelet, power spectra, and metabolomics-fluxomics analyses, are presented, discussed, and their strengths and limitations highlighted. Further shown is how time series from stationary and nonstationary biological variables and signals, such as membrane potential, high-throughput metabolomics, O-2 and CO2 levels, bird locomotion, at the molecular, (sub) cellular, tissue, and whole organ and animal levels, can reveal important information on the properties of the underlying biological networks. Systems biology-inspired computational methods start to pave the way for addressing the integrated functional dynamics of metabolic, organelle and organ networks. As our capacity to unravel the control and regulatory properties of these networks and their dynamics under normal or pathological conditions broadens, so is our ability to address endogenous rhythms and clocks to improve health-span in human aging, and to manage complex metabolic disorders, neurodegeneration, and cancer. (C) 2016 Wiley Periodicals, Inc. C1 [Cortassa, Sonia; Aon, Miguel A.] NIA, NIH, BRC BG Rm 09B119,251 Bayview Blvd, Baltimore, MD 21224 USA. [Kurz, Felix T.; Armoundas, Antonis A.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Kurz, Felix T.] Univ Heidelberg Hosp, Dept Neuroradiol, Heidelberg, Germany. [Kembro, Jackelyn M.] Univ Nacl Cordoba, CONICET, IIByT, Cordoba, Argentina. [Kembro, Jackelyn M.] Univ Nacl Cordoba, Fac Ciencias Exactas Fis & Nat, Inst Ciencia & Tecnol Alimentos, Catedra Quim Biol, Cordoba, Argentina. [Flesia, Ana G.] Univ Nacl Cordoba, CONICET, CIEM, Cordoba, Argentina. [Flesia, Ana G.] Univ Nacl Cordoba, Fac Matemat Astron & Fis FAMAF, Cordoba, Argentina. [Cortassa, Sonia; Aon, Miguel A.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Lloyd, David] Cardiff Univ, Sch Biosci, Cardiff, S Glam, Wales. RP Aon, MA (reprint author), NIA, NIH, BRC BG Rm 09B119,251 Bayview Blvd, Baltimore, MD 21224 USA.; Aon, MA (reprint author), Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. EM maon1@jhu.edu FU Medical Faculty, Heidelberg University; Hoffmann-Klose Foundation (Heidelberg University) FX F.T.K. was supported by a physician-scientist postdoctoral fellowship of the Medical Faculty, Heidelberg University, and by the Hoffmann-Klose Foundation (Heidelberg University). J.M.K. and A.G.F. are career members of the National Research Council (CONICET, Argentina). We would like to thank Prof. Marc R. Roussel (Univ. Lethbridge, Canada) for valuable feedback and permission to reproduce Figure 10. This manuscript, or part of it, has neither been published nor is currently under consideration for publication by any other journal. NR 192 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1939-5094 EI 1939-005X J9 WIRES SYST BIOL MED JI Wiley Interdiscip. Rev.-Syst. Biol PD JAN-FEB PY 2017 VL 9 IS 1 DI 10.1002/wsbm.1352 PG 30 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EL8VP UT WOS:000394898700003 ER PT J AU Narva, AS Romancito, G Faber, T Steele, ME Kempner, KM AF Narva, Andrew S. Romancito, Gayle Faber, Thomas Steele, Michael E. Kempner, Kenneth M. TI Managing CKD by Telemedicine: The Zuni Telenephrology Clinic SO ADVANCES IN CHRONIC KIDNEY DISEASE LA English DT Article DE Telehealth; Telemedicine; Kidney disease; Indian Health Service; Nephrology consultation ID CHRONIC KIDNEY-DISEASE; QUALITY; CARE AB Telemedicine has significant potential to extend nephrology consultation to rural and isolated communities. We describe a telenephrology clinic that has delivered ongoing consultative care from a nephrologist based at the National Institutes of Health in Bethesda, MD, to the Zuni Comprehensive Health Center in western New Mexico. Over the past 9 years, the clinic has conducted 1870 patient visits managing patients using a collaborative approach engaging a nurse case manager, nephrologist, primary clinicians, pharmacists, and community health nurses. A significant proportion of the care provided is directed toward patients with advanced kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m(2)). Although there are unique aspects to the Indian Health Service and to the Zuni community which is served by this clinic, this telemedicine clinic does serve as a demonstration that nephrologic consultative care can be delivered effectively and efficiently to rural high-risk communities using a collaborative and integrated model of care. C1 [Narva, Andrew S.; Romancito, Gayle; Faber, Thomas; Steele, Michael E.; Kempner, Kenneth M.] NIH, Natl Kidney Dis Educ Program, Bethesda, MD USA. [Narva, Andrew S.; Romancito, Gayle; Faber, Thomas; Steele, Michael E.; Kempner, Kenneth M.] Indian Hlth Serv, Zuni Comprehens Community Hlth Ctr, Zuni, Mexico. [Narva, Andrew S.; Romancito, Gayle; Faber, Thomas; Steele, Michael E.; Kempner, Kenneth M.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. NIH, FASN, Natl Kidney Dis Educ Program, NIDDK, 2 Democracy Plaza,Room 6085,6707 Democracy Blvd, Bethesda, MD 20892 USA. RP Narva, AS (reprint author), NIH, FASN, Natl Kidney Dis Educ Program, NIDDK, 2 Democracy Plaza,Room 6085,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM narvaa@niddk.nih.gov FU Intramural NIH HHS [Z99 DK999999] NR 17 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 1548-5595 EI 1548-5609 J9 ADV CHRONIC KIDNEY D JI Adv. Chronic Kidney Dis. PD JAN PY 2017 VL 24 IS 1 BP 6 EP 11 DI 10.1053/j.ackd.2016.11.019 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EN0UI UT WOS:000395725600003 PM 28224944 ER PT J AU Mente, KP O'Donnell, JK Jones, SE Cohen, ML Thompson, NR Bizzi, A Gambetti, P Safar, JG Appleby, BS AF Mente, Karin P. O'Donnell, James K. Jones, Stephen E. Cohen, Mark L. Thompson, Nicolas R. Bizzi, Alberto Gambetti, Pierluigi Safar, Jiri G. Appleby, Brian S. TI Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Correlation of Histopathology and MRI in Prion Disease SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE prion diseases; CJD; positron emission tomography; MRI; neuropathology ID CREUTZFELDT-JAKOB-DISEASE; RAPIDLY PROGRESSIVE DEMENTIA; ALZHEIMERS-DISEASE; DIAGNOSIS; CJD; NEUROINFLAMMATION; CLASSIFICATION; ACTIVATION; MICROGLIA; CSF AB Creutzfeldt-Jakob disease (CJD) and other prion diseases are rapidly progressive spongiform encephalopathies that are invariably fatal. Clinical features and magnetic resonance imaging, electroencephalogram, and cerebrospinal fluid abnormalities may suggest prion disease, but a definitive diagnosis can only be made by means of neuropathologic examination. Fluorodeoxyglucose positron emission tomography (FDG-PET) is not routinely used to evaluate patients with suspected prion disease. This study includes 11 cases of definite prion disease in which FDG-PET scans were obtained. There were 8 sporadic CJD cases, 2 genetic CJD cases, and 1 fatal familial insomnia case. Automated FDG-PET analysis revealed parietal region hypometabolism in all cases. Surprisingly, limbic and mesolimbic hypermetabolism were also present in the majority of cases. When FDG-PET hypometabolism was compared with neuropathologic changes (neuronal loss, astrocytosis, spongiosis), hypometabolism was predictive of neuropathology in 80.6% of cortical regions versus 17.6% of subcortical regions. The odds of neuropathologic changes were 2.1 times higher in cortical regions than subcortical regions (P=0.0265). A similar discordance between cortical and subcortical regions was observed between FDG-PET hypometabolism and magnetic resonance imaging diffusion weighted imaging hyperintensity. This study shows that there may be a relationship between FDG-PET hypometabolism and neuropathology in cortical regions in prion disease but it is unlikely to be helpful for diagnosis. C1 [Mente, Karin P.] Cleveland Clin, Dept Neurol, Cleveland, OH 44106 USA. [Jones, Stephen E.] Cleveland Clin, Dept Diagnost Radiol, Cleveland, OH 44106 USA. [Thompson, Nicolas R.] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. [O'Donnell, James K.] Univ Hosp Case Med Ctr, Dept Radiol, Cleveland, OH USA. [Cohen, Mark L.; Gambetti, Pierluigi; Safar, Jiri G.; Appleby, Brian S.] Univ Hosp Case Med Ctr, Dept Pathol, Cleveland, OH USA. [Safar, Jiri G.; Appleby, Brian S.] Univ Hosp Case Med Ctr, Dept Neurol, Cleveland, OH USA. [Cohen, Mark L.; Gambetti, Pierluigi; Safar, Jiri G.; Appleby, Brian S.] Natl Prion Dis Pathol Surveillance Ctr, Milan, Italy. [Bizzi, Alberto] Humanitas Res Hosp IRCCS, Dept Neuroradiol, Milan, Italy. [Mente, Karin P.] NINDS, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. RP Mente, KP (reprint author), NINDS, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM karinmentemd@gmail.com FU Centers for Disease Control and Prevention [UR8/CCU515004] FX The National Prion Disease Pathology Surveillance Center is supported by the Centers for Disease Control and Prevention (grant UR8/CCU515004 to J.G.S.). NR 31 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 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JAN-MAR PY 2017 VL 31 IS 1 BP 1 EP 7 DI 10.1097/WAD.0000000000000188 PG 7 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA EM8JH UT WOS:000395556900001 PM 28121634 ER PT J AU Sukcharoensin, S AF Sukcharoensin, Sorasart TI A framework for benchmarking the strategic position of bond markets in the competing environment SO BENCHMARKING-AN INTERNATIONAL JOURNAL LA English DT Article DE Benchmarking; Analytic Hierarchy Process (AHP); Bond market; SPACE matrix; Strategic position ID GROWTH AB Purpose - The purpose of this paper is to develop a benchmarking framework for identifying different indicators and their importance in forming the strategic position of Thai bond markets in competitive economies using Strategic Position and Action Evaluation (SPACE) matrix framework. Design/methodology/approach - The Delphi approach is deployed for indicator selection and the framework validation. A questionnaire survey is then used to assess the importance of different factors determining the strategic bond market development and competitiveness using the Analytic Hierarchy Process (AHP) model. Findings - A group of experienced bond market experts assign different levels of importance for each key factor under a given dimension to reach consensus. The results reveal that there are 17 factors affecting the strategic development and competitiveness of the bond market. Among four aspects under the framework, the financial strength dimension is considered by the experts as the most dominant aspect to strategic bond market development, followed by competitive advantage, industry strength, and environment stability, respectively. Practical implications - The benchmarking framework developed in this study is useful for guiding measurement and assessment of the strategic position of bond markets in the competing environment. Originality/value - The author proposes for the first time a conceptual framework based on macro-level data to assess the strategic bond market development and competitiveness using SPACE matrix method. The study employs the Delphi's technique and in-depth interview with bond market experts to build indicators for each dimension under the framework. Second, this paper also applies the AHP to discover the order of relative importance for the indicators identified by the experts through pairwise comparison to reach consensus, which has never been conducted before. C1 [Sukcharoensin, Sorasart] NIDA, Sch Dev Econ, Bangkok, Thailand. RP Sukcharoensin, S (reprint author), NIDA, Sch Dev Econ, Bangkok, Thailand. EM sorasart@nida.ac.th FU National Research Council of Thailand (NCRT) FX This research was supported by National Research Council of Thailand (NCRT). The author would like to show a sincere gratitude to the anonymous bond market experts for sharing their insights and expertise that greatly contributed to the research. The author also thanks the reviewers for their constructive comments and Wanida Jarungkitkul for her research assistances. NR 26 TC 0 Z9 0 U1 0 U2 0 PU EMERALD GROUP PUBLISHING LTD PI BINGLEY PA HOWARD HOUSE, WAGON LANE, BINGLEY BD16 1WA, W YORKSHIRE, ENGLAND SN 1463-5771 EI 1758-4094 J9 BENCHMARKING JI Benchmarking PY 2017 VL 24 IS 2 BP 403 EP 414 DI 10.1108/BIJ-05-2015-0046 PG 12 WC Management SC Business & Economics GA EO5ED UT WOS:000396715000006 ER PT J AU Lowe, JM Nguyen, TA Grimm, SA Gabor, KA Peddada, SD Li, LP Anderson, CW Resnick, MA Menendez, D Fessler, MB AF Lowe, Julie M. Thuy-Ai Nguyen Grimm, Sara A. Gabor, Kristin A. Peddada, Shyamal D. Li, Leping Anderson, Carl W. Resnick, Michael A. Menendez, Daniel Fessler, Michael B. TI The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID LYMPH-NODE METASTASIS; DEATH EFFECTOR DOMAIN; NF-KAPPA-B; CYCLIN D1; MUTANT P53; STRESS-RESPONSE; POOR-PROGNOSIS; CELL; OVEREXPRESSION; GENE AB Tumor necrosis factor-a-induced protein 8 (TNFAIP8) is a stress-response gene that has been associated with cancer, but no studies have differentiated among or defined the regulation or function of any of its several recently described expression variants. We found that TNFAIP8 variant 2 (v2) is overexpressed in multiple human cancers, whereas other variants are commonly downregulated in cancer (v1) or minimally expressed in cancer or normal tissue (v3-v6). Silencing v2 in cancer cells induces p53-independent inhibition of DNA synthesis, widespread binding of p53, and induction of target genes and p53-dependent cell cycle arrest and DNA damage sensitization. Cell cycle arrest induced by v2 silencing requires p53-dependent induction of p21. In response to the chemotherapeutic agent doxorubicin, p53 regulates v2 through binding to an intragenic enhancer, together indicating that p53 and v2 engage in complex reciprocal regulation. We propose that TNFAIP8 v2 promotes human cancer by broadly repressing p53 function, in essence offsetting p53-dependent tumor suppression. C1 [Lowe, Julie M.; Gabor, Kristin A.; Fessler, Michael B.] NIEHS, Immun Inflammat & Dis Lab, NIH, 111 TW Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, NC 27709 USA. [Thuy-Ai Nguyen; Anderson, Carl W.; Resnick, Michael A.; Menendez, Daniel] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Grimm, Sara A.; Peddada, Shyamal D.; Li, Leping] NIEHS, Biostat & Computat Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Lowe, JM; Fessler, MB (reprint author), NIEHS, Immun Inflammat & Dis Lab, NIH, 111 TW Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, NC 27709 USA. EM julie.lowe@nih.gov; fesslerm@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, NIEHS [Z01 ES102005, Z01-ES065079] FX We thank NIEHS core facilities: molecular genomics, viral vector, flow cytometry, microscopy, and the Clinical Research Unit. This research was supported by the Intramural Research Program of the National Institutes of Health, NIEHS (Z01 ES102005, Z01-ES065079). NR 51 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 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JAN PY 2017 VL 24 IS 1 BP 181 EP 191 DI 10.1038/cdd.2016.130 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN1RM UT WOS:000395787600019 PM 27834950 ER PT J AU Deniger, DC Kwong, MLM Pasetto, A Dudley, ME Wunderlich, JR Langhan, MM Lee, CCR Rosenberg, SA AF Deniger, Drew C. Kwong, Mei Li M. Pasetto, Anna Dudley, Mark E. Wunderlich, John R. Langhan, Michelle M. Lee, Chyi-Chia Richard Rosenberg, Steven A. TI A Pilot Trial of the Combination of Vemurafenib with Adoptive Cell Therapy in Patients with Metastatic Melanoma SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; BRAF V600E MUTATION; TARGETED THERAPY; PHASE-II; IMMUNOTHERAPY; INHIBITION; TRAMETINIB; DABRAFENIB; ONCOGENE; SURVIVAL AB Purpose: This pilot feasibility clinical trial evaluated the coad-ministration of vemurafenib, a small-molecule antagonist of BRAFV(600) mutations, and tumor-infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma. Experimental Design: A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration. Vemurafenib was restarted at the time of TIL infusion and was continued for 2 years or until disease progression. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Metastases resected prior to and after 2 weeks of vemurafenib were compared using TCRB deep sequencing, immunohistochemistry, proliferation, and recognition of autologous tumor. Results: The treatment was well tolerated and had a safety profile similar to that of TIL or vemurafenib alone. Seven of 11 patients (64%) experienced an objective clinical response, and 2 patients (18%) had a complete response for 3 years (one response is ongoing at 46 months). Proliferation and viability of infusion bag TILs and peripheral blood T cells were inhibited in vitro by research-grade vemurafenib (PLX4032) when approaching the maximum serum concentration of vemurafenib. TCRB repertoire (clonotypes numbers, clonality, and frequency) did not significantly change between pre-and post-vemurafenib lesions. Recognition of autologous tumor by T cells was similar between TILs grown from pre-and post-vemurafenib metastases. Conclusions: Coadministration of vemurafenib and TILs was safe and feasible and generated objective clinical responses in this small pilot clinical trial. (C) 2016 AACR. C1 [Deniger, Drew C.; Kwong, Mei Li M.; Pasetto, Anna; Wunderlich, John R.; Langhan, Michelle M.; Rosenberg, Steven A.] Ctr Canc Res, Natl Canc Inst, Natl Inst Hlth, Surg Branch, Bldg 10-CRC,Room 3W-3940,10 Ctr Dr MSC 1201, Bethesda, MD 20892 USA. [Dudley, Mark E.] Novartis, Cell & Gene Therapy, Cambridge, MA USA. [Lee, Chyi-Chia Richard] Natl Canc Inst, Natl Inst Hlth, Pathol Lab, Bethesda, MD USA. RP Rosenberg, SA (reprint author), Ctr Canc Res, Natl Canc Inst, Natl Inst Hlth, Surg Branch, Bldg 10-CRC,Room 3W-3940,10 Ctr Dr MSC 1201, Bethesda, MD 20892 USA. EM sar@mail.nih.gov FU Intramural Research Program of the NIH at the NCI FX This research was supported through an award to Steven A. Rosenberg by the Intramural Research Program of the NIH at the NCI. NR 42 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN PY 2017 VL 23 IS 2 BP 351 EP 362 DI 10.1158/1078-0432.CCR-16-0906 PG 12 WC Oncology SC Oncology GA EK4EQ UT WOS:000393880300005 PM 28093487 ER PT J AU Zhu, XG Enomoto, K Zhao, L Zhu, YLJ Willingham, MC Meltzer, P Qi, J Cheng, SY AF Zhu, Xuguang Enomoto, Keisuke Zhao, Li Zhu, Yuelin J. Willingham, Mark C. Meltzer, Paul Qi, Jun Cheng, Sheue-yann TI Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model SO CLINICAL CANCER RESEARCH LA English DT Article ID C-MYC; SELECTIVE-INHIBITION; BET BROMODOMAINS; CANCER; MUTATION; HORMONE; CELLS; TARGETS; FAMILY; MUTANT AB Purpose: New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the Thrb(PV/PV) Kras(G12D) mouse, a model of anaplastic thyroid cancer. Experimental Design: We treated Thrb(PV/PV) Kras(G12D) mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression. Results: JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1-CDK4-Rb-E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation. Conclusions: These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. (C) 2016 AACR. C1 [Zhu, Xuguang; Enomoto, Keisuke; Zhao, Li; Willingham, Mark C.; Cheng, Sheue-yann] NIH, Natl Canc Inst, Mol Biol Lab, Bethesda, MD USA. [Zhu, Yuelin J.; Meltzer, Paul] NIH, Ctr Canc Res, Natl Canc Inst, Lab Genet Branch, Bethesda, MD USA. [Qi, Jun] Dana Farber Canc Inst, Harvard Med Sch, Boston, MA USA. RP Cheng, SY (reprint author), Natl Canc Inst, Mol Biol Lab, 37 Convent Dr,Room 5128, Bethesda, MD USA. EM chengs@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 50 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN PY 2017 VL 23 IS 2 BP 430 EP 440 DI 10.1158/1078-0432.CCR-16-0914 PG 11 WC Oncology SC Oncology GA EK4EQ UT WOS:000393880300013 PM 27440272 ER PT J AU Lok, BH Gardner, EE Schneeberger, VE Ni, A Desmeules, P Rekhtman, N de Stanchina, E Teicher, BA Riaz, N Powell, SN Poirier, JT Rudin, CM AF Lok, Benjamin H. Gardner, Eric E. Schneeberger, Valentina E. Ni, Andy Desmeules, Patrice Rekhtman, Natasha de Stanchina, Elisa Teicher, Beverly A. Riaz, Nadeem Powell, Simon N. Poirier, John T. Rudin, Charles M. TI PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE INHIBITOR; HOMOLOGOUS RECOMBINATION REPAIR; DNA-DAMAGING AGENTS; BREAST-CANCER; PHASE-II; DRUG-SENSITIVITY; BMN 673; INACTIVATION; ABT-888; TUMORS AB Purpose: PARP inhibitors (PARPi) are a novel class of small molecule therapeutics for small cell lung cancer (SCLC). Identification of predictors of response would advance our understanding, and guide clinical application, of this therapeutic strategy. Experimental Design: Efficacy of PARP inhibitors olaparib, rucaparib, and veliparib, as well as etoposide and cisplatin in SCLC cell lines, and gene expression correlates, was analyzed using public datasets. HRD genomic scar scores were calculated from Affymetrix SNP 6.0 arrays. In vitro talazoparib efficacy was measured by cell viability assays. For functional studies, CRISPR/Cas9 and shRNA were used for genomic editing and transcript knockdown, respectively. Protein levels were assessed by immunoblotting and immunohistochemistry (IHC). Quantitative synergy of talazoparib and temozolomide was determined in vitro. In vivo efficacy of talazoparib, temozolomide, and the combination was assessed in patient-derived xenograft (PDX) models. Results: We identified SLFN11, but not HRD genomic scars, as a consistent correlate of response to all three PARPi assessed, with loss of SLFN11 conferring resistance to PARPi. We confirmed these findings in vivo across multiple PDX and defined IHC staining for SLFN11 as a predictor of talazoparib response. As temozolomide has activity in SCLC, we investigated combination therapy with talazoparib and found marked synergy in vitro and efficacy in vivo, which did not solely depend on SLFN11 or MGMT status. Conclusions: SLFN11 is a relevant predictive biomarker of sensitivity to PARP inhibitor monotherapy in SCLC and we identify combinatorial therapy with TMZ as a particularly promising therapeutic strategy that warrants further clinical investigation. Clin Cancer Res; 23(2); 523- 35. (C) 2016 AACR. C1 [Lok, Benjamin H.; Riaz, Nadeem] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA. [Lok, Benjamin H.; Gardner, Eric E.; Schneeberger, Valentina E.; Poirier, John T.; Rudin, Charles M.] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, 1275 York Ave, New York, NY 10021 USA. [Gardner, Eric E.] Johns Hopkins Univ, Dept Pharmacol & Mol Sci, Pharmacol Grad Training Program, Baltimore, MD USA. [Ni, Andy] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Desmeules, Patrice; Rekhtman, Natasha] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [de Stanchina, Elisa] Mem Sloan Kettering Canc Ctr, Antitumor Assessment Core Facil, 1275 York Ave, New York, NY 10021 USA. [Teicher, Beverly A.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Powell, Simon N.] Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 USA. [Poirier, John T.; Rudin, Charles M.] Weill Cornell Med Coll, New York, NY USA. [Poirier, John T.; Rudin, Charles M.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. RP Rudin, CM (reprint author), Mem Sloan Kettering Canc Ctr, 300 East 66th St,Room 1203, New York, NY 10065 USA.; Poirier, JT (reprint author), Mem Sloan Kettering Canc Ctr, 415 E 68th St,Room 1701, New York, NY 10065 USA. EM poirierj@mskcc.org; rudinc@mskcc.org FU BioMarin Pharmaceutical Inc.; National Cancer Institute [P30 CA008748, U54 OD020355-01, R01 CA197936]; LUNGevity; Free to Breathe; Conquer Cancer Foundation of ASCO; Radiological Society of North America [RR1634]; Van Andel Research Institute through the Van Andel Research Institute - Stand Up To Cancer Epigenetics Dream Team Translational Research Grant FX This work was supported by BioMarin Pharmaceutical Inc., the National Cancer Institute (P30 CA008748, U54 OD020355-01, and R01 CA197936, to C.M. Rudin), LUNGevity, and Free to Breathe (J.T. Poirier), Conquer Cancer Foundation of ASCO, and Radiological Society of North America (RR1634, B. H. Lok). Additional research funding provided by the Van Andel Research Institute through the Van Andel Research Institute - Stand Up To Cancer Epigenetics Dream Team Translational Research Grant. Stand Up To Cancer is a program of the Entertainment Industry Foundation, administered by American Association for Cancer Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 50 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN PY 2017 VL 23 IS 2 BP 523 EP 535 DI 10.1158/1078-0432.CCR-16-1040 PG 13 WC Oncology SC Oncology GA EK4EQ UT WOS:000393880300021 PM 27440269 ER PT J AU Wendler, D AF Wendler, David TI The Theory and Practice of Surrogate Decision-Making SO HASTINGS CENTER REPORT LA English DT Article ID CHRONIC CRITICAL ILLNESS; ADVANCE DIRECTIVES; OUTCOMES; CARE C1 [Wendler, David] NIH, Sect Res Eth, Dept Bioeth, Clin Ctr, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Sect Res Eth, Dept Bioeth, Clin Ctr, Bethesda, MD 20892 USA. FU National Institutes of Health FX This work was supported by National Institutes of Health intramural funds. However, the opinions expressed are the author's own. They do not represent the position or policy of the U.S. NIH, the U.S. Public Health Service, or the U.S. Department of Health and Human Services. NR 12 TC 0 Z9 0 U1 3 U2 3 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD JAN-FEB PY 2017 VL 47 IS 1 BP 29 EP 31 DI 10.1002/hast.671 PG 4 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA EO0FX UT WOS:000396374800012 PM 28074586 ER PT J AU Zhao, WL Berger, VW AF Zhao, Wenle Berger, Vance W. TI Better alternatives to permuted block randomization for clinical trials with unequal allocation SO HEMATOLOGY LA English DT Letter ID URN DESIGN; ALGORITHM C1 [Zhao, Wenle] Med Univ South Carolina, Dept Publ Hlth Sci, 135 Cannon St,Suite 305P, Charleston, SC 29425 USA. [Berger, Vance W.] NCI, Biometry Res Grp, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Berger, Vance W.] Univ Maryland Baltimore Cty, Baltimore, MD 20850 USA. RP Zhao, WL (reprint author), Med Univ South Carolina, Dept Publ Hlth Sci, 135 Cannon St,Suite 305P, Charleston, SC 29425 USA. EM zhaow@musc.edu NR 17 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1024-5332 EI 1607-8454 J9 HEMATOLOGY JI Hematology PY 2017 VL 22 IS 1 BP 61 EP 63 DI 10.1080/10245332.2016.1236996 PG 3 WC Hematology SC Hematology GA EN8BI UT WOS:000396225500010 PM 27741936 ER PT J AU Hosek, SG Rudy, B Landovitz, R Kapogiannis, B Siberry, G Rutledge, B Liu, N Brothers, J Mulligan, K Zimet, G Lally, M Mayer, KH Anderson, P Kiser, J Rooney, JF Wilson, CM AF Hosek, Sybil G. Rudy, Bret Landovitz, Raphael Kapogiannis, Bill Siberry, George Rutledge, Brandy Liu, Nancy Brothers, Jennifer Mulligan, Kathleen Zimet, Gregory Lally, Michelle Mayer, Kenneth H. Anderson, Peter Kiser, Jennifer Rooney, James F. Wilson, Craig M. CA Adolescent Trials Network ATN HIV TI An HIV Preexposure Prophylaxis Demonstration Project and Safety Study for Young MSM SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE preexposure prophylaxis; youth; men who have sex with men ID RANDOMIZED CONTROLLED-TRIAL; BONE-MINERAL DENSITY; BLACK-MEN; ANTIRETROVIRAL THERAPY; MEDICATION ADHERENCE; ENCOUNTER FREQUENCY; DIABETES-MELLITUS; BLOOD-PRESSURE; SEX; WOMEN AB Background: Young men who have sex with men (YMSM) are a key population for implementation of preexposure prophylaxis (PrEP) interventions. This open-label study examined adherence to PrEP and assessed sexual behavior among a diverse sample of YMSM in 12 US cities. Methods: Eligible participants were 18- to 22-year-old HIV-uninfected MSM who reported HIV transmission risk behavior in the previous 6 months. Participants were provided daily tenofovir disoproxil fumarate/emtricitabine (Truvada). Study visits occurred at baseline, monthly through week 12, and then quarterly through week 48. Dried blood spots were serially collected for the quantification of tenofovir diphosphate (TFV-DP). Results: Between March and September 2013, 2186 individuals were approached and 400 were found to be preliminarily eligible. Of those 400, 277 were scheduled for an in-person screening visit and 200 were enrolled (mean age = 20.2; 54.5% black, 26.5% Latino). Diagnosis of sexually transmitted infections, including urethral and rectal chlamydial/gonococcal infection and syphilis, at baseline was 22% and remained high across visits. At week 4, 56% of participants had TFV-DP levels consistent with >= 4 pills per week. By week 48, 34% of participants had TFV-DP levels consistent with >= 4 pills per week, with a noticeable drop-off occurring at week 24. Four HIV seroconversions occurred on study (3.29/100 person-years). Condomless sex was reported by.80% of participants, and condomless anal sex with last partner was associated with higher TFV-DP levels. Conclusions: Acceptability of PrEP was high, and most participants achieved protective drug levels during monthly visits. As visit frequency decreased, so did adherence. YMSM in the United States may need PrEP access in youth-friendly settings with tailored adherence support and potentially augmented visit schedules. C1 [Hosek, Sybil G.; Brothers, Jennifer] John H Stroger Jr Hosp Cook Cty, Chicago, IL USA. [Rudy, Bret] NYU, Med Ctr, New York, NY 10016 USA. [Landovitz, Raphael] Univ Calif Los Angeles, Los Angeles, CA USA. [Kapogiannis, Bill; Siberry, George] NICHD, MPIDB, Bethesda, MD USA. [Rutledge, Brandy; Liu, Nancy] Westat Corp, Rockville, MD USA. [Mulligan, Kathleen] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Zimet, Gregory] Indiana Univ, Indianapolis, IN 46204 USA. [Lally, Michelle] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Lally, Michelle] Lifespan Hosp Syst, Providence, RI USA. [Mayer, Kenneth H.] Fenway Hlth, Boston, MA USA. [Anderson, Peter; Kiser, Jennifer] Univ Colorado, Denver, CO 80202 USA. [Rooney, James F.] Gilead Sci, Foster City, CA USA. [Wilson, Craig M.] Univ Alabama Birmingham, Birmingham, AL USA. RP Hosek, SG (reprint author), John H Stroger Jr Hosp Cook Cty, Dept Psychiat, 1900 W Polk St,Room 854, Chicago, IL 60612 USA. EM shosek@cookcountyhhs.org FU National Institutes of Health through the Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD040533, U01 HD040474]; National Institute on Drug Abuse; National Institute of Mental Health; Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) from the National Institutes of Health through the National Institute of Child Health and Human Development [U01 HD 040533, U01 HD 040474]; National Institutes on Drug Abuse; Gilead Sciences; ViiV FX This study was funded under cooperative agreements U01 HD040533 and U01 HD040474 from the National Institutes of Health through the Eunice Kennedy Shriver National Institute of Child Health and Human Development with supplemental funding from the National Institute on Drug Abuse and National Institute of Mental Health. Study drug was donated by Gilead Sciences, Inc., along with supplemental funds for a portion of the dried blood spot testing. Supported by The Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) from the National Institutes of Health (U01 HD 040533 and U01 HD 040474) through the National Institute of Child Health and Human Development (B.K. and S. Lee), with supplemental funding from the National Institutes on Drug Abuse (K. Davenny and S. Kahana) and Mental Health (P. Brouwers, S. Allison). Study drug was donated by Gilead Sciences.; K.M. has received unrestricted research grants from Gilead Sciences and ViiV. P.A. receives donated study drug and contract work from Gilead. J. F.R. is employed by Gilead Sciences, the maker of the study drug. The remaining authors have no funding or conflicts of interest to disclose. The comments and views of the authors do not necessarily represent the views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 37 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JAN 1 PY 2017 VL 74 IS 1 BP 21 EP 29 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EN4RL UT WOS:000395994500009 PM 27632233 ER PT J AU Chaillon, A Smith, DM Vanpouille, C Lisco, A Jordan, P Caballero, G Vargas, M Gianella, S Mehta, SR AF Chaillon, Antoine Smith, Davey M. Vanpouille, Christophe Lisco, Andrea Jordan, Parris Caballero, Gemma Vargas, Milenka Gianella, Sara Mehta, Sanjay R. TI HIV Trafficking Between Blood and Semen During Early Untreated HIV Infection SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE Bayesian inference; phylogeography; compartmentalization; Markov; seminal plasma; PBMC ID HUMAN-IMMUNODEFICIENCY-VIRUS; FEMALE GENITAL-TRACT; ANTIRETROVIRAL THERAPY; SEMINAL PLASMA; CYTOMEGALOVIRUS REPLICATION; CELL-ACTIVATION; GENE FLOW; TYPE-1; COMPARTMENTALIZATION; TRANSMISSION AB Background: Understanding the dynamics of HIV across anatomic compartments is important to design effective eradication strategies. In this study, we evaluated viral trafficking between blood and semen during primary HIV infection in 6 antiretroviral-naive men who have sex with men. Methods: Deep sequencing data of HIV env were generated from longitudinal blood plasma, peripheral blood mononuclear cells, and seminal plasma samples. The presence or absence of viral compartmentalization was assessed using tree-based Slatkin-Maddison and distance-based Fst methods. Phylogeographic analyses were performed using a discrete Bayesian asymmetric approach of diffusion with Markov jump count estimation to evaluate the gene flow between blood and semen during primary HIV infection. Levels of DNA from human herpesviruses and selected inflammatory cytokines were also measured on genital secretions collected at baseline to evaluate potential correlates of increased viral migration between anatomic compartments. Results: We detected varying degrees of compartmentalization in all 6 individuals evaluated. None of them maintained viral compartmentalization between blood and seminal plasma throughout the analyzed time points. Phylogeographic analyses revealed that the HIV population circulating in blood plasma populated the seminal compartment during the earliest stages of infection. In our limited data set, we found no association between local inflammation or herpesvirus shedding at baseline and viral trafficking between semen and blood. Conclusions: The early spread of virus from blood plasma to genital tract and the complex viral interplay between these compartments suggest that viral eradication efforts will require monitoring viral subpopulations in anatomic sites and viral trafficking during the course of infection. C1 [Chaillon, Antoine; Smith, Davey M.; Jordan, Parris; Caballero, Gemma; Vargas, Milenka; Gianella, Sara; Mehta, Sanjay R.] Univ Calif San Diego, Dept Med, 9500 Gilman Dr,Stein Clin Res Bldg 325, La Jolla, CA 92093 USA. [Smith, Davey M.; Mehta, Sanjay R.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Vanpouille, Christophe] NICHHD, NIH, Bethesda, MD 20892 USA. [Lisco, Andrea] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Chaillon, A (reprint author), Univ Calif San Diego, Dept Med, 9500 Gilman Dr,Stein Clin Res Bldg 325, La Jolla, CA 92093 USA. EM achaillon@ucsd.edu FU Department of Veterans Affairs; National Institutes of Health [AI093163, AI036214, AI027763, MH101012, TR000098-04AI100665, MH097520, DA034978, AI068636, MH081482]; AmFAR [108537]; California HIV/AIDS Research Program (CHRP) [F13SD321]; James B. Pendleton Charitable Trust; Bettencourt-Schueller Foundation FX Supported by the Department of Veterans Affairs and Grants from the National Institutes of Health AI093163, AI036214, AI027763, MH101012, TR000098-04AI100665, MH097520, DA034978, AI068636, MH081482, AmFAR Grant 108537, the California HIV/AIDS Research Program (CHRP) Grant F13SD321, the James B. Pendleton Charitable Trust and the Bettencourt-Schueller Foundation. NR 53 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JAN 1 PY 2017 VL 74 IS 1 BP 95 EP 102 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EN4RL UT WOS:000395994500020 PM 27548440 ER PT J AU Eshleman, SH Hudelson, SE Redd, AD Swanstrom, R Ou, SS Zhang, XC Ping, LH Piwowar-Manning, E Porcella, SF Sievers, MF Martens, CA Bruno, D Dukhovlinova, E McCauley, M Gamble, T Fogel, JM Sabin, D Quinn, TC Gunde, L Maliwichi, M Nhando, N Akelo, V Moyo, S Panchia, R Kumarasamy, N Chotirosniramit, N de Melo, MG Pilotto, J Grinsztejn, B Mayer, K Chen, YQ Hughes, JP Cohen, MS AF Eshleman, Susan H. Hudelson, Sarah E. Redd, Andrew D. Swanstrom, Ronald Ou, San-San Zhang, Xinyi Cindy Ping, Li-Hua Piwowar-Manning, Estelle Porcella, Stephen F. Sievers, Matthew F. Martens, Craig A. Bruno, Daniel Dukhovlinova, Elena McCauley, Marybeth Gamble, Theresa Fogel, Jessica M. Sabin, Devin Quinn, Thomas C. Gunde, Laurence Maliwichi, Madalitso Nhando, Nehemiah Akelo, Victor Moyo, Sikhulile Panchia, Ravindre Kumarasamy, Nagalingeswaran Chotirosniramit, Nuntisa de Melo, Marineide Goncalves Pilotto, Jose Grinsztejn, Beatriz Mayer, Kenneth Chen, Ying Q. Hughes, James P. Cohen, Myron S. TI Treatment as Prevention: Characterization of Partner Infections in the HIV Prevention Trials Network 052 Trial SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV-1; serodiscordant couples; partner; transmission; linkage; HPTN 052 ID INTEGRASE INHIBITOR RALTEGRAVIR; ANTIRETROVIRAL THERAPY; TRANSMISSION; RISK AB HIV Prevention Trials Network 052 demonstrated that antiretroviral therapy (ART) prevents HIV transmission in serodiscordant couples. HIV from index-partner pairs was analyzed to determine the genetic linkage status of partner infections. Forty-six infections were classified as linked, indicating that the index was the likely source of the partner's infection. Lack of viral suppression and higher index viral load were associated with linked infection. Eight linked infections were diagnosed after the index started ART: 4 near the time of ART initiation and 4 after ART failure. Linked infections were not observed when the index participant was stably suppressed on ART. C1 [Eshleman, Susan H.; Piwowar-Manning, Estelle; Fogel, Jessica M.; Sabin, Devin] Johns Hopkins Univ, Sch Med, Dept Pathol, 720 Rutland Ave,Ross Bldg,Room 646, Baltimore, MD 21205 USA. [Swanstrom, Ronald] Univ North Carolina Chapel Hill, Dept Biochem & Biophys, Chapel Hill, NC USA. [Ou, San-San; Zhang, Xinyi Cindy] Fred Hutchinson Canc Res Inst, Vaccine & Infect Dis Sci Div, Seattle, WA USA. [Ping, Li-Hua; Dukhovlinova, Elena] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Porcella, Stephen F.; Martens, Craig A.; Bruno, Daniel] NIAID, Genom Unit, Res Technol Sect, Rocky Mt Labs,DIR,NIH, Hamilton, MT USA. [Sievers, Matthew F.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD USA. [McCauley, Marybeth] FHI360, Sci Facilitat Dept, Washington, DC USA. [Gamble, Theresa] FHI360, Sci Facilitat Dept, Durham, NC USA. [Gunde, Laurence] Johns Hopkins Project, Coll Med, Blantyre, Malawi. [Maliwichi, Madalitso] UNC Project, Lilongwe, Malawi. [Nhando, Nehemiah] Univ Zimbabwe, Dept Med, Harare, Zimbabwe. [Akelo, Victor] CDC, Kenya Med Res Inst KEMRI, Ctr Global Hlth, HIV Res Branch, Kisumu, Kenya. [Moyo, Sikhulile] Botswana Harvard AIDS Inst Partnership, BHHRL Clin Trials Unit, Gaborone, Botswana. [Panchia, Ravindre] Chris Hani Baragwanath Hosp, Soweto HPTN CRS, Soweto, South Africa. [Kumarasamy, Nagalingeswaran] YRGCARE Med Ctr, Chennai, Tamil Nadu, India. [Chotirosniramit, Nuntisa] Chiang Mai Univ, Ctr AIDS & STDs, Res Inst Hlth Sci, Chiang Mai 50000, Thailand. [de Melo, Marineide Goncalves] Hosp Nossa Senhora Conceicao, Serv Infectol, Porto Alegre, RS, Brazil. [Pilotto, Jose] Hosp Geral Nova Iguacu, Rio De Janeiro, Brazil. [Pilotto, Jose] Lab AIDS & Imunol Mol IOC Fiocruz, Rio De Janeiro, Brazil. [Grinsztejn, Beatriz] Inst Nacl Infectol Evandro Chagas INI Fiocruz, Rio De Janeiro, Brazil. [Mayer, Kenneth] Fenway Inst, Fenway Hlth & Infect Dis Div, Boston, MA USA. [Mayer, Kenneth] Beth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Boston, MA USA. [Chen, Ying Q.] Fred Hutchinson Canc Res Inst, Vaccine & Infect Dis Div, Seattle, WA USA. [Chen, Ying Q.] Fred Hutchinson Canc Res Inst, Div Publ Hlth Sci, Seattle, WA USA. [Hughes, James P.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Cohen, Myron S.] Univ North Carolina Chapel Hill, Dept Med, Chapel Hill, NC USA. RP Eshleman, SH (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, 720 Rutland Ave,Ross Bldg,Room 646, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu FU HIV Prevention Trials Network (HPTN) - National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Office of AIDS Research, of the National Institutes of Health (NIH), Department of Health and Human Services (DHHS) [UM1AI068613, UM1AI068617, UM1AI068619]; Division of Intramural Research, NIAID, NIH; [R37-AI44667] FX Supported by (1) The HIV Prevention Trials Network (HPTN) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the Office of AIDS Research, of the National Institutes of Health (NIH), Department of Health and Human Services (DHHS) [grant numbers UM1AI068613 (HPTN Network Laboratory-S.H.E., PI), UM1AI068617 (HPTN Statistical and Data Management Center-Deborah Donnell, PI), and UM1AI068619 (HPTN Core and Operations Center-Wafaa El-Sadr, PI)], (2) the Division of Intramural Research, NIAID, NIH, and (3) R37-AI44667 (R.S., PI). NR 18 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JAN 1 PY 2017 VL 74 IS 1 BP 112 EP 116 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EN4RL UT WOS:000395994500022 PM 27532476 ER PT J AU Paganella, MP Cohen, RA Harris, DR Kuchenbecker, RD Sperhacke, RD Kato, SK da Silva, CLO Sturzbecher, FT Oliveira, RHS Pavia-Ruz, N Hazra, R AF Paganella, Machline P. Cohen, Rachel A. Harris, Donald R. Kuchenbecker, Ricardo de Souza Sperhacke, Rosa D. Kato, Sergio K. Oliveira da Silva, Carmem L. Sturzbecher, Fernanda T. Oliveira, Ricardo H. S. Pavia-Ruz, Noris Hazra, Rohan CA NISDI PLACES Protocol TI Association of Dyslipidemia and Glucose Abnormalities With Antiretroviral Treatment in a Cohort of HIV-Infected Latin American Children SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE children; HIV infection; protease inhibitors; dyslipidemia; glucose abnormalities ID HUMAN-IMMUNODEFICIENCY-VIRUS; INSULIN-RESISTANCE; METABOLIC ABNORMALITIES; THERAPY; ADOLESCENTS; MANAGEMENT; ADHERENCE; YOUTH AB Objective: To estimate the incidence of lipid and glucose abnormalities and assess their association with exposure to antire-troviral (ARV) regimens among perinatally HIV-infected Latin American children. Design: Longitudinal cohort study. Methods: Data were analyzed from the Eunice Kennedy Shriver National Institute of Child Health and Human Development International Site Development Initiative Pediatric Latin American Countries Epidemiologic Study. The incidence of dyslipidemia [total cholesterol >200 mg/dL, HDL < 35 mg/dL, LDL > 130 mg/dL, triglycerides > 110 mg/dL (age, 10 years) or > 150 mg/dL (>= 10 years)] and fasting glucose abnormalities [homeostasis model assessment of insulin resistance > 2.5 (Tanner stage 1) or.4.0 (Tanner stage. 1); impaired glucose: 110 to < 126 mg/dL; diabetes: >= 126 mg/dL] was estimated. Proportional hazards regression was used to evaluate the risk of abnormalities associated with ARV regimen, adjusted for covariates. Results: There were 385 children eligible for analysis (mean age 6.6 years). Incident cholesterol abnormalities were reported in 18.1% of participants [95% confidence interval (CI): 14.1% to 22.8%], HDL and LDL cholesterol abnormalities in 19.6% (15.1%-24.7%) and 15.0% (11.3%-19.5%), respectively, and triglyceride abnormalities in 44.2% (37.7%-50.8%). In multivariable analysis, ARV regimen was only associated with triglyceride abnormalities; participants receiving a protease inhibitor (PI)-containing regimen were 3.6 times as likely to experience a triglyceride abnormality as those receiving no ARVs (95% CI: 1.3 to 10.5; P = 0.0167). The cumulative incidence of insulin resistance was 3.8% (1.8%-7.1%); there were no incident cases of diabetes and only 2 of impaired fasting glucose. Conclusions: Children receiving PI-containing regimens were at increased risk of developing triglyceride abnormalities. Continued monitoring of lipid levels in children receiving PI-containing regimens appears warranted. C1 [Paganella, Machline P.; Sperhacke, Rosa D.; Kato, Sergio K.] Univ Caxias Do Sul, Lab Pesquisa HIV AIDS, Caxias Do Sul, RS, Brazil. [Paganella, Machline P.; Kuchenbecker, Ricardo de Souza] Univ Fed Rio Grande do Sul, Postgrad Program Epidemiol, Porto Alegre, RS, Brazil. [Cohen, Rachel A.; Harris, Donald R.] Westat Corp, Rockville, MD USA. [Kato, Sergio K.] UFCSPA, Dept Saude Colet, Porto Alegre, RS, Brazil. [Kato, Sergio K.] Pontificia Univ Catolica Rio Grande Sul PUCRS, Fac Matemat, Dept Estat, Porto Alegre, RS, Brazil. [Oliveira da Silva, Carmem L.] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Sturzbecher, Fernanda T.] Univ Sao Paulo, Hosp Clin, Fac Med Ribeirao Preto, Sao Paulo, Brazil. [Oliveira, Ricardo H. S.] Univ Fed Rio de Janeiro, IPPMG, Rio de Janeiro, Brazil. [Pavia-Ruz, Noris] Hosp Infantil Mexico Dr Federico Gomez, Mexico City, DF, Mexico. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Paganella, MP (reprint author), Univ Caxias Do Sul UCS, CCBS, Lab Pesquisa HIV AIDS LPHA, Rua Francisco Getulio Vargas 1130,Bloco S, BR-95070560 Caxias Do Sul, RS, Brazil. EM mppagane@ucs.br FU NICHD [N01-HD-3-3345, HHSN267200800001C, HHSN275201300003C] FX Supported by NICHD Contracts N01-HD-3-3345 (2002-2007), HHSN267200800001C (2007-2012), and HHSN275201300003C (2012-2017). 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JAN 1 PY 2017 VL 74 IS 1 BP E1 EP E8 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EN4RL UT WOS:000395994500001 PM 27570910 ER PT J AU Ferrari, R Grassi, M Graziano, F Palluzzi, F Archetti, S Bonomi, E Bruni, AC Maletta, RG Bernardi, L Cupidi, C Colao, R Rainero, I Rubino, E Pinessi, L Galimberti, D Scarpini, E Serpente, M Nacmias, B Piaceri, I Bagnoli, S Rossi, G Giaccone, G Tagliavini, F Benussi, L Binetti, G Ghidoni, R Singleton, A Hardy, J Momeni, P Padovani, A Borroni, B AF Ferrari, Raffaele Grassi, Mario Graziano, Francesca Palluzzi, Fernando Archetti, Silvana Bonomi, Elisa Bruni, Amalia C. Maletta, Raffaele G. Bernardi, Livia Cupidi, Chiara Colao, Rosanna Rainero, Innocenzo Rubino, Elisa Pinessi, Lorenzo Galimberti, Daniela Scarpini, Elio Serpente, Maria Nacmias, Benedetta Piaceri, Irene Bagnoli, Silvia Rossi, Giacomina Giaccone, Giorgio Tagliavini, Fabrizio Benussi, Luisa Binetti, Giuliano Ghidoni, Roberta Singleton, Andrew Hardy, John Momeni, Parastoo Padovani, Alessandro Borroni, Barbara TI Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Age at onset; frontotemporal dementia; GWAS; polymorphism ID GENOME-WIDE ASSOCIATION; AUTISM SPECTRUM DISORDER; ALZHEIMER-DISEASE; MUTATION CARRIERS; FTLD; EXPRESSION; IDENTIFICATION; POLYMORPHISM; INDIVIDUALS; FAMILIES AB In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95% CI: -4.64 to -3.07, p< 2x10-(16)) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted. C1 [Ferrari, Raffaele; Hardy, John] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Grassi, Mario; Graziano, Francesca; Palluzzi, Fernando] Univ Pavia, Med & Genom Stat Unit, Dept Brain & Behav Sci, Pavia, Italy. [Archetti, Silvana] Brescia Hosp, Lab Anal 3, Dept Labs, Brescia, Italy. [Bonomi, Elisa; Padovani, Alessandro; Borroni, Barbara] Univ Brescia, Neurol Unit, Dept Clin & Expt Sci, Brescia, Italy. [Bruni, Amalia C.; Maletta, Raffaele G.; Bernardi, Livia; Cupidi, Chiara; Colao, Rosanna] Neurogenet Reg Ctr ASPCZ Lamezia Terme, Lamezia Terme, Italy. [Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo] Univ Torino & Citta Salute & Sci Torino, Dept Neurosci, Neurol 1, Turin, Italy. [Galimberti, Daniela; Scarpini, Elio; Serpente, Maria] Univ Milan, Osped Policlin, Fdn Ca Granda,IRCCS, Dept Pathophysiol & Transplantat,Neurol Unit, Milan, Italy. [Nacmias, Benedetta; Piaceri, Irene; Bagnoli, Silvia] Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy. [Rossi, Giacomina; Giaccone, Giorgio; Tagliavini, Fabrizio] Fdn IRCCS, Ist Neurol Carlo Besta, Div Neurol & Neuropathol 5, Milan, Italy. [Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta] IRCCS, Ist Ctr San Giovanni di Dio Fatebenefratelli, Mol Markers Lab, Brescia, Italy. [Binetti, Giuliano] IRCCS, Ist Ctr San Giovanni di Dio Fatebenefratelli, MAC Memory Ctr, Brescia, Italy. [Singleton, Andrew] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Momeni, Parastoo] Texas Tech Univ, Hlth Sci Ctr, Neurogenet Lab, Dept Internal Med, Lubbock, TX 79430 USA. RP Borroni, B (reprint author), Univ Brescia, Dept Clin & Expt Sci, Ctr Neurodegenerat Disorders, Neurol Unit, Brescia, Italy. EM borroni@inwind.it FU NeTAlz grant; Fondazione Cassa di Risparmio di Pistoia e Pescia [2011.0264 e 2013.0347]; University of Florence; Ricerca Corrente, Italy Ministry of Health; Alzheimer's Society [284] FX This work was supported by NeTAlz grant to A.P., by Fondazione Cassa di Risparmio di Pistoia e Pescia (grants 2011.0264 e 2013.0347), a grant for Research from the University of Florence to B.N., the Ricerca Corrente, Italy Ministry of Health to L.B., R.G., G.B., and Alzheimer's Society (grant number 284) to R.F. NR 36 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 56 IS 4 BP 1271 EP 1278 DI 10.3233/JAD-160949 PG 8 WC Neurosciences SC Neurosciences & Neurology GA EN1FY UT WOS:000395757100007 PM 28128768 ER PT J AU Simmonds, P Becher, P Bukh, J Gould, EA Meyers, G Monath, T Muerhoff, S Pletnev, A Rico-Hesse, R Smith, DB Stapleton, JT AF Simmonds, Peter Becher, Paul Bukh, Jens Gould, Ernest A. Meyers, Gregor Monath, Tom Muerhoff, Scott Pletnev, Alexander Rico-Hesse, Rebecca Smith, Donald B. Stapleton, Jack T. CA ICTV Report Consortium TI ICTV Virus Taxonomy Profile: Flaviviridae SO JOURNAL OF GENERAL VIROLOGY LA English DT Article DE Flaviviridae; taxonomy; ICTV Report AB The Flaviviridae is a family of small enveloped viruses with RNA genomes of 9000-13000 bases. Most infect mammals and birds. Many flaviviruses are host-specific and pathogenic, such as hepatitis C virus in the genus Hepacivirus. The majority of known members in the genus Flavivirus are arthropod borne, and many are important human and veterinary pathogens (e.g. yellow fever virus, dengue virus). This is a summary of the current International Committee on Taxonomy of Viruses (ICTV) report on the taxonomy of the Flaviviridae, which is available at www.ictv.global/report/flaviviridae. C1 [Simmonds, Peter] Univ Oxford, Nuffield Dept Med, Oxford OX1 3SY, England. [Becher, Paul] Univ Vet Med, Inst Virol, D-30559 Hannover, Germany. [Bukh, Jens] Copenhagen Univ Hosp, Copenhagen Hepatitis C Program CO HEP, Hvidovre, Denmark. [Gould, Ernest A.] Fac Med Timone, Unite Virus Emergents, F-13385 Marseille 05, France. [Meyers, Gregor] Friedrich Loeffler Inst, Inst Immunol, Sudufer 10, D-17493 Greifswald, Germany. [Monath, Tom] NewLink Genet Corp, BioProtect Syst, 94 Jackson Rd,Suite 108, Devens, MA 01434 USA. [Muerhoff, Scott] Abbott Labs, 100 Abbott Pk Rd, Abbott Pk, IL 60064 USA. [Pletnev, Alexander] NIAID, NIH, Infect Dis Lab, Bethesda, MD 20892 USA. [Rico-Hesse, Rebecca] Baylor Coll Med, Houston, TX 77030 USA. [Smith, Donald B.] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh EH9 3FL, Midlothian, Scotland. [Stapleton, Jack T.] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Stapleton, Jack T.] Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. RP Simmonds, P (reprint author), Univ Oxford, Nuffield Dept Med, Oxford OX1 3SY, England. EM peter.simmonds@ndm.ox.ac.uk FU Wellcome Trust [WT108418AIA] FX Production of this summary, the online chapter and associated resources was funded by a grant from the Wellcome Trust (WT108418AIA). NR 5 TC 0 Z9 0 U1 3 U2 3 PU MICROBIOLOGY SOC PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER ST, LONDON WC1N 2JU, ERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD JAN PY 2017 VL 98 IS 1 BP 2 EP 3 DI 10.1099/jgv.0.000672 PG 2 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA EN6FA UT WOS:000396098700002 PM 28218572 ER PT J AU Kumar, NP Moideen, K Sivakumar, S Menon, PA Viswanathan, V Kornfeld, H Babu, S AF Kumar, Nathella Pavan Moideen, Kadar Sivakumar, Shanmugam Menon, Pradeep A. Viswanathan, Vijay Kornfeld, Hardy Babu, Subash TI Tuberculosis-diabetes co-morbidity is characterized by heightened systemic levels of circulating angiogenic factors SO JOURNAL OF INFECTION LA English DT Article DE Tuberculosis; Diabetes; Angiogenesis; Biomarkers ID ENDOTHELIAL GROWTH-FACTOR; ACTIVE PULMONARY TUBERCULOSIS; MELLITUS COINCIDENT; LYMPHANGIOGENESIS; HETEROGENEITY; INFLAMMATION; RECEPTORS; GRANULOMA; CYTOKINES; CELLS AB Background: Tuberculosis-diabetes co-morbidity (TB-DM) is characterized by increased inflammation with elevated circulating levels of inflammatory cytokines and other factors. Circulating angiogenic factors are intricately involved in the angiogenesis-inflammation nexus. Methods: To study the association of angiogenic factors with TB-DM, we examined the systemic levels of VEGF-A, VEGF-C, VEGF-D, VEGF-R1, VEGF-R2, VEGF-R3 in individuals with either TB-DM ( n = 44) or TB alone ( n = 44). Results: Circulating levels of VEGF-A, C, D, R1, R2 and R3 were significantly higher in TB-DM compared to TB individuals. Moreover, the levels of VEGF-A, C, R2 and/or R3 were significantly higher in TB-DM with bilateral or cavitary disease or with hemoptysis, suggesting an association with both disease severity and adverse clinical presentation. The levels of these factors also exhibited a significant positive relationship with bacterial burdens and HbA1c levels. In addition, VEGFA, C and R2 levelswere significantly higher (at 2 months of treatment) in culture positive compared to culture negative TB-DM individuals. Finally, the circulating levels of VEGF-A, C, D, R1, R2 and R3 were significantly reduced following successful chemotherapy at 6 months. Conclusion: Our data demonstrate that TB-DM is associated with heightened levels of circulating angiogenic factors, possibly reflecting both dysregulated angiogenesis and exaggerated inflammation. Published by Elsevier Ltd on behalf of The British Infection Association. C1 [Kumar, Nathella Pavan; Moideen, Kadar; Sivakumar, Shanmugam; Menon, Pradeep A.; Babu, Subash] Natl Inst Hlth, NIRT, Int Ctr Excellence Res, Madras, Tamil Nadu, India. [Viswanathan, Vijay] Prof M Viswanathan Diabet Res Ctr, Madras, Tamil Nadu, India. [Kornfeld, Hardy] Univ Massachusetts, Sch Med, Worcester, MA USA. [Babu, Subash] NIAID, LPD, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Babu, S (reprint author), Natl Inst Hlth, NIRT, Int Ctr Excellence Res, Madras, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Indian Department of Biotechnology; Indian Council of Medical Research; National Institute for Allergy and Infectious Diseases, National Institutes of Health; CRDF Global [USB1-31149-XX-13]; Division of Intramural Research, NIAID [100000060]; NIH [100000002] FX We thank the staff of Department of Clinical Research and the Department of Bacteriology, NIRT for valuable assistance in bacterial cultures and radiology and the staff of MVDRC for valuable assistance in recruiting the patients for this study, R. Anuradha, Prabha Chandran and Gokul Raj of the NIH-NIRT-ICER for technical assistance. This work was jointly sponsored by the Indian Department of Biotechnology; the Indian Council of Medical Research; and the National Institute for Allergy and Infectious Diseases, National Institutes of Health, and administered by CRDF Global [grant USB1-31149-XX-13]. This work was also funded in part by the Division of Intramural Research, NIAID (100000060), NIH (100000002). NR 39 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0163-4453 EI 1532-2742 J9 J INFECTION JI J. Infect. PD JAN PY 2017 VL 74 IS 1 BP 10 EP 21 DI 10.1016/j.jinf.2016.08.021 PG 12 WC Infectious Diseases SC Infectious Diseases GA EO0CX UT WOS:000396367000002 PM 27717783 ER PT J AU Singleton, AB Hardy, JA Gasser, T AF Singleton, Andrew B. Hardy, John A. Gasser, Thomas TI The Birth of the Modern Era of Parkinson's Disease Genetics SO JOURNAL OF PARKINSONS DISEASE LA English DT Review ID FAMILIAL ALZHEIMER-DISEASE; PROTEIN-TAU TAU; NEUROFIBRILLARY TANGLES; MUTATIONS; ASSOCIATION; PATHOLOGY; VARIANTS; COMPLEX; GENES; VPS35 C1 [Singleton, Andrew B.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Hardy, John A.] UCL, UCL Inst Neurol, Dept Mol Neurosci, London WC1E 6BT, England. [Gasser, Thomas] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Gasser, Thomas] DZNE, German Ctr Neurodegenerat Dis, Tubingen, Germany. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, Bethesda, MD 20892 USA. EM Singleta@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [ZO1 AG000949] FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project number ZO1 AG000949. NR 30 TC 0 Z9 0 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1877-7171 EI 1877-718X J9 J PARKINSON DIS JI J. Parkinsons Dis. PY 2017 VL 7 SU 1 BP S89 EP S95 DI 10.3233/JPD-179009 PG 7 WC Neurosciences SC Neurosciences & Neurology GA EN8TD UT WOS:000396271800009 PM 28282818 ER PT J AU Al Kasab, S Lynn, MJ Turan, TN Derdeyn, CP Fiorella, D Lane, BF Janis, LS Chimowitz, MI AF Al Kasab, Sami Lynn, Michael J. Turan, Tanya N. Derdeyn, Colin P. Fiorella, David Lane, Bethany F. Janis, L. Scott Chimowitz, Marc I. CA SAMMPRIS Investigators TI Impact of the New American Heart Association/American Stroke Association Definition of Stroke on the Results of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Trial SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Article DE Stroke; TIA; intracranial atherosclerosis; clinical trial ID TRANSIENT ISCHEMIC ATTACK; DIFFUSION; SAMMPRIS; RISK AB Background: An American Heart Association/American Stroke Association (AHA/ASA) writing committee has recently recommended that tissue evidence of cerebral infarction associated with temporary symptoms (CITS) lasting <24 hours should be considered a stroke. We analyzed the impact of considering CITS as equivalent to stroke on the results of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial. Methods: We compared outcomes in the medical (n = 227) and stenting (n = 224) groups in SAMMPRIS using the following primary end point (new components in bold): any stroke, CITS, or death within 30 days after enrollment or within 30 days after a revascularization procedure for the qualifying lesion during follow-up; or ischemic stroke or CITS in the territory of the qualifying artery beyond 30 days. We also compared the use of brain magnetic resonance imaging (MRI) after transient ischemic attacks (TIAs) in both treatment groups. Results: By considering CITS as equivalent to stroke, the number of primary end points increased from 34 to 43 in the medical group and from 52 to 66 in the stenting group of SAMMPRIS. The Kaplan-Meier curves for the primary end points in the 2 groups were significantly different (P = .009). The percentage of patients with reported TIAs who underwent brain MRI was 69% in the medical group and 61% in the stenting group (P = .40). Conclusion: Using the AHA/ASA definition of stroke resulted in a substantially higher primary end point rate in both treatment groups and an even higher benefit from medical therapy over stenting than originally shown in SAMMPRIS. The higher rate of CITS in the stenting group was not due to ascertainment bias. C1 [Al Kasab, Sami; Turan, Tanya N.; Chimowitz, Marc I.] Med Univ South Carolina, Dept Neurol, Charleston, SC 29425 USA. [Lynn, Michael J.; Lane, Bethany F.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Derdeyn, Colin P.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Fiorella, David] SUNY Stony Brook, Dept Neurosurg, Stony Brook, NY USA. [Janis, L. Scott] Natl Inst Hlth, Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP Al Kasab, S (reprint author), Med Univ South Carolina, 96 Jonathan Lucas St,Suite 301 CSB,MSC606, Charleston, SC 29425 USA. EM alkasab@musc.edu FU US Public Health Service National Institute of Neurological Disorders and Stroke (NINDS) [U01 NS058728]; National Institutes of Health [UL1RR029882, UL1RR029889, UL1RR029890, UL1RR024131]; AstraZeneca FX This study was funded by a research grant (U01 NS058728) from the US Public Health Service National Institute of Neurological Disorders and Stroke (NINDS). In addition, the following Clinical and Translational Science Awards, funded by the National Institutes of Health, provided local support for the evaluation of patients in the trial: Medical University of South Carolina (UL1RR029882), University of Florida (UL1RR029889), University of Cincinnati (UL1RR029890), and University of California, San Francisco (UL1RR024131).; Corporate Support: Stryker Neurovascular (formerly Boston Scientific Neurovascular) provided study devices and supplemental funding for third-party device distribution, site monitoring, and study auditing. This research was also supported by the Investigator-Sponsored Study Program of AstraZeneca, which donated rosuvastatin (Crestor) to study patients. NR 15 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 EI 1532-8511 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD JAN PY 2017 VL 26 IS 1 BP 108 EP 115 DI 10.1016/j.jstrokecerebrovasdis.2016.08.038 PG 8 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA EO1AO UT WOS:000396430100026 PM 27765556 ER PT J AU Roederer, MW Kuo, GM Kisor, DF Frye, RF Hoffman, JM Jenkins, J Weitzel, KW AF Roederer, Mary W. Kuo, Grace M. Kisor, David F. Frye, Reginald F. Hoffman, James M. Jenkins, Jean Weitzel, Kristin Wiisanen TI Pharmacogenomics competencies in pharmacy practice: A blueprint for change SO JOURNAL OF THE AMERICAN PHARMACISTS ASSOCIATION LA English DT Editorial Material ID COMMUNITY PHARMACY; ADVANCING PHARMACOGENOMICS; CLINICAL IMPLEMENTATION; PERSONALIZED MEDICINE; EDUCATION; CURRICULUM; PROGRAM; COLLEGES; SCIENCE; SCHOOLS AB The emerging use of genomic data to inform medication therapy populates the medical literature and provides evidence for guidelines in the prescribing information for many medications. Despite the availability of pharmacogenomic studies, few pharmacists feel competent to use these new data in patient care. The first pharmacogenomics competency statement for pharmacists was published in 2002. In 2011, the Pharmacogenomics Special Interest Group of the American Association of Colleges of Pharmacy led a process to update this competency statement with the use of a consensus-based method that incorporated input from multiple key professional pharmacy organizations to reflect growth in genomic science as well as the need for pharmacist application of genomic data. Given the rapidly evolving science, educational needs, and practice models in this area, a standardized competency-based approach to pharmacist education and training in pharmacogenomics is needed to equip pharmacists for leadership roles as essential members of health care teams that implement clinical utilization strategies for genomic data. (C) 2017 American Pharmacists Association((R)). Published by Elsevier Inc. All rights reserved. C1 [Roederer, Mary W.] UNC Eshelman Sch Pharm, Chapel Hill, NC USA. [Kuo, Grace M.] Univ Calif San Diego, Clin Pharm, San Diego, CA 92103 USA. [Kuo, Grace M.] Univ Calif San Diego, Family Med & Publ Hlth, San Diego, CA 92103 USA. [Kisor, David F.] Univ Manchester, Coll Pharm Nat & Hlth Sci, Dept Pharmaceut Sci, Ft Wayne, IN USA. [Frye, Reginald F.; Weitzel, Kristin Wiisanen] Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA. [Hoffman, James M.] St Jude Childrens Res Hosp, Pharmaceut Sci, 332 N Lauderdale St, Memphis, TN 38105 USA. [Hoffman, James M.] Univ Tennessee, Clin Pharm, Hlth Sci Ctr, Memphis, TN USA. [Jenkins, Jean] NHGRI, Genom Healthcare Branch, NIH, Bethesda, MD 20892 USA. RP Roederer, MW (reprint author), 1011 Genet Med Bldg,Mason Farm Rd,CB 7361, Chapel Hill, NC 27599 USA. EM mary.roederer1@gmail.com FU American Lebanese Syrian Associated Charities; National Institutes of Health [CA 21765, R24GM115264-01]; National Institutes of Health/National Center for Advancing Translational Science University of Florida Clinical and Translational Science [UL1 TR000064]; IGNITE Network [U01 HG007269] FX James Hoffman's contributions to this paper were supported by American Lebanese Syrian Associated Charities and National Institutes of Health grants CA 21765 and R24GM115264-01. KristinWeitzel's contributions to this paper were supported by National Institutes of Health/National Center for Advancing Translational Science University of Florida Clinical and Translational Science Awards UL1 TR000064 and IGNITE Network grant U01 HG007269. NR 37 TC 0 Z9 0 U1 0 U2 0 PU AMER PHARMACEUTICAL ASSOC PI WASHINGTON PA 2215 CONSTITUTION AVE NW, WASHINGTON, DC 20037 USA SN 1544-3191 EI 1544-3450 J9 J AM PHARM ASSOC JI J. Am. Pharm. Assoc. PD JAN-FEB PY 2017 VL 57 IS 1 BP 120 EP 125 DI 10.1016/j.japh.2016.08.014 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO0DO UT WOS:000396368700021 PM 27816542 ER PT J AU Weerakoon-Ratnayake, KM O'Neil, CE Uba, FI Soper, SA AF Weerakoon-Ratnayake, Kumuditha M. O'Neil, Colleen E. Uba, Franklin I. Soper, Steven A. TI Thermoplastic nanofluidic devices for biomedical applications SO LAB ON A CHIP LA English DT Review ID MOLECULAR-DYNAMICS SIMULATION; OXYGEN PLASMA TREATMENT; SINGLE DNA NUCLEOTIDES; SURFACE MODIFICATION; ELECTROKINETIC TRANSPORT; MICROFLUIDIC DEVICES; POLYMER NANOCHANNELS; CONCENTRATION POLARIZATION; PHYSIOCHEMICAL PROPERTIES; ELECTROOSMOTIC FLOW AB Microfluidics is now moving into a developmental stage where basic discoveries are being transitioned into the commercial sector so that these discoveries can affect, for example, healthcare. Thus, high production rate microfabrication technologies, such as thermal embossing and/or injection molding, are being used to produce low-cost consumables appropriate for commercial applications. Based on recent reports, it is clear that nanofluidics offers some attractive process capabilities that may provide unique venues for biomolecular analyses that cannot be realized at the microscale. Thus, it would be attractive to consider early in the developmental cycle of nanofluidics production pipelines that can generate devices possessing sub150 nm dimensions in a high production mode and at low-cost to accommodate the commercialization of this exciting technology. Recently, functional sub-150 nm thermoplastic nanofluidic devices have been reported that can provide high process yield rates, which can enable commercial translation of nanofluidics. This review presents an overview of recent advancements in the fabrication, assembly, surface modification and the characterization of thermoplastic nanofluidic devices. Also, several examples in which nanoscale phenomena have been exploited for the analysis of biomolecules are highlighted. Lastly, some general conclusions and future outlooks are presented. C1 [Weerakoon-Ratnayake, Kumuditha M.] Univ N Carolina, Dept Biomed Engn, Chapel Hill, NC 27599 USA. [O'Neil, Colleen E.; Uba, Franklin I.] Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC 27599 USA. [Soper, Steven A.] Univ Kansas, Dept Chem, Lawrence, KS 66045 USA. [Soper, Steven A.] Univ Kansas, Dept Mech Engn, Lawrence, KS 66045 USA. [Soper, Steven A.] Univ Kansas, Med Ctr, NIH, Ctr Canc, Kansas City, KS 66106 USA. [Weerakoon-Ratnayake, Kumuditha M.; O'Neil, Colleen E.; Soper, Steven A.] NIH, Biotechnol Resource Ctr Biomodular Multiscale Sys, Bldg 10, Bethesda, MD 20892 USA. [Soper, Steven A.] Ulsan Natl Inst Sci & Technol, Ulsan, South Korea. RP Soper, SA (reprint author), Univ Kansas, Dept Chem, Lawrence, KS 66045 USA.; Soper, SA (reprint author), Univ Kansas, Dept Mech Engn, Lawrence, KS 66045 USA.; Soper, SA (reprint author), Univ Kansas, Med Ctr, NIH, Ctr Canc, Kansas City, KS 66106 USA.; Soper, SA (reprint author), NIH, Biotechnol Resource Ctr Biomodular Multiscale Sys, Bldg 10, Bethesda, MD 20892 USA.; Soper, SA (reprint author), Ulsan Natl Inst Sci & Technol, Ulsan, South Korea. EM ssoper@ku.edu OI Weerakoon-Ratnayake, Kumuditha/0000-0002-6839-4515 FU National Institutes of Health [R21 HG006278, P41 EB020594]; National Science Foundation [1507577]; Ulsan National Institute of Science and Technology [1.130090.01] FX The authors would like to thank the National Institutes of Health (R21 HG006278; P41 EB020594), the National Science Foundation (1507577) and the Research Fund (1.130090.01) of Ulsan National Institute of Science and Technology for supporting this work. NR 141 TC 0 Z9 0 U1 6 U2 6 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1473-0197 EI 1473-0189 J9 LAB CHIP JI Lab Chip PY 2017 VL 17 IS 3 BP 362 EP 381 DI 10.1039/c6lc01173j PG 20 WC Biochemical Research Methods; Chemistry, Multidisciplinary; Nanoscience & Nanotechnology SC Biochemistry & Molecular Biology; Chemistry; Science & Technology - Other Topics GA EN3CZ UT WOS:000395887900001 PM 28009883 ER PT J AU Cai, BW Wu, J Yu, X Su, XZ Wang, RF AF Cai, Baowei Wu, Jian Yu, Xiao Su, Xin-zhuan Wang, Rong-Fu TI FOSL1 Inhibits Type I Interferon Responses to Malaria and Viral Infections by Blocking TBK1 and TRAF3/TRIF Interactions SO MBIO LA English DT Article ID PERSISTENT LCMV INFECTION; INNATE IMMUNE SENSOR; SIGNALING PATHWAYS; TRANSCRIPTION FACTOR; RIG-I; HOST; FRA-1; GENE; DNA; ACTIVATION AB Innate immune response plays a critical role in controlling invading pathogens, but such an immune response must be tightly regulated. Insufficient or overactivated immune responses may lead to harmful or even fatal consequences. To dissect the complex host-parasite interactions and the molecular mechanisms underlying innate immune responses to infections, here we investigate the role of FOS-like antigen 1 (FOSL1) in regulating the host type I interferon (IFN-I) response to malaria parasite and viral infections. FOSL1 is known as a component of a transcription factor but was recently implicated in regulating the IFN-I response to malaria parasite infection. Here we show that FOSL1 can act as a negative regulator of IFN-I signaling. Upon stimulation with poly(I:C), malaria parasite-infected red blood cells (iRBCs), or vesicular stomatitis virus (VSV), FOSL1 "translocated" from the nucleus to the cytoplasm, where it inhibited the interactions between TNF receptor-associated factor 3 (TRAF3), TIR domain-containing adapter inducing IFN-(TRIF), and Tank-binding kinase 1 (TBK1) via impairing K63-linked polyubiquitination of TRAF3 and TRIF. Importantly, FOSL1 knockout chimeric mice had lower levels of malaria parasitemia or VSV titers in peripheral blood and decreased mortality compared with wild-type (WT) mice. Thus, our findings have identified a new role for FOSL1 in negatively regulating the host IFN-I response to malaria and viral infections and have identified a potential drug target for controlling malaria and other diseases. IMPORTANCE Infections of pathogens can trigger vigorous host immune responses, including activation and production of type I interferon (IFN-I). In this study, we investigated the role of FOSL1, a molecule previously known as a transcription factor, in negatively regulating IFN-I responses to malaria and viral infections. We showed that FOSL1 was upregulated and translocated into the cytoplasm of cells after stimulation for IFN-I production. FOSL1 could affect TRAF3 and TRIF ubiquitination and consequently impaired the association of TRAF3, TRIF, and TBK1, leading to inhibition of IFN-I signaling. In vivo experiments with FOSL1 knockout chimeric mice further validated the negative role of FOSL1 in IFN-I production and antimicrobial responses. This report reveals a new functional role for FOSL1 in IFN-I signaling and dissects the mechanism by which FOSL1 regulates IFN-I responses to malaria and viral infections, which can be explored as a potential drug target for disease control and management. C1 [Cai, Baowei; Su, Xin-zhuan] Xiamen Univ, Innovat Ctr Cell Biol, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen, Fujian, Peoples R China. [Cai, Baowei; Yu, Xiao; Wang, Rong-Fu] Ctr Inflammat & Epigenet, Houston Methodist Res Inst, Houston, TX USA. [Wu, Jian; Su, Xin-zhuan] Lab Malaria & Vector Res, Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Bethesda, MD 20892 USA. [Wang, Rong-Fu] Cornell Univ, Dept Microbiol & Immunol, Dept Weill Cornell Med, Ithaca, NY 14853 USA. [Wang, Rong-Fu] Texas A&M Univ, Coll Med, Inst Biosci & Technol, Houston, TX USA. RP Su, XZ (reprint author), Xiamen Univ, Innovat Ctr Cell Biol, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen, Fujian, Peoples R China.; Su, XZ (reprint author), Lab Malaria & Vector Res, Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Bethesda, MD 20892 USA. EM xsu@niaid.nih.gov; rwang3@tmhs.org FU NCI and NIDA [CA101795, DA030338]; NIH; Cancer Prevention and Research Institute of Texas (CPRIT); Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China [B06016]; Division of Intramural Research; National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported, in part, by grants (CA101795 and DA030338) from NCI and NIDA, NIH, and Cancer Prevention and Research Institute of Texas (CPRIT) ( to R.-F.W.), by Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China (B06016), and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID). NR 38 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JAN-FEB PY 2017 VL 8 IS 1 AR e02161-16 DI 10.1128/mBio.02161-16 PG 14 WC Microbiology SC Microbiology GA EN2JE UT WOS:000395835000006 ER PT J AU Ghequire, MGK Kemland, L Anoz-Carbonell, E Buchanan, SK De Mot, R AF Ghequire, Maarten G. K. Kemland, Lieselore Anoz-Carbonell, Ernesto Buchanan, Susan K. De Mot, Rene TI A Natural Chimeric Pseudomonas Bacteriocin with Novel Pore-Forming Activity Parasitizes the Ferrichrome Transporter SO MBIO LA English DT Article ID COLICIN-M; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; OUTER-MEMBRANE; PYOCINS S2; AERUGINOSA; RECEPTOR; IRON; SIDEROPHORE; MECHANISM AB Modular bacteriocins represent a major group of secreted protein toxins with a narrow spectrum of activity, involved in interference competition between Gram-negative bacteria. These antibacterial proteins include a domain for binding to the target cell and a toxin module at the carboxy terminus. Self-inhibition of producers is provided by coexpression of linked immunity genes that transiently inhibit the toxin's activity through formation of bacteriocin-immunity complexes or by insertion in the inner membrane, depending on the type of toxin module. We demonstrate strain-specific inhibitory activity for PmnH, a Pseudomonas bacteriocin with an unprecedented dual-toxin architecture, hosting both a colicin M domain, potentially interfering with peptidoglycan synthesis, and a novel colicin N-type domain, a pore-forming module distinct from the colicin Ia-type domain in Pseudomonas aeruginosa pyocin S5. A downstream-linked gene product confers PmnH immunity upon susceptible strains. This protein, ImnH, has a transmembrane topology similar to that of Pseudomonas colicin M-like and pore-forming immunity proteins, although homology with either of these is essentially absent. The enhanced killing activity of PmnH under iron-limited growth conditions reflects parasitism of the ferrichrome-type transporter for entry into target cells, a strategy shown here to be used as well by monodomain colicin M-like bacteriocins from pseudomonads. The integration of a second type of toxin module in a bacteriocin gene could offer a competitive advantage against bacteria displaying immunity against only one of both toxic activities. C1 [Ghequire, Maarten G. K.; Kemland, Lieselore; Anoz-Carbonell, Ernesto; De Mot, Rene] Katholieke Univ Leuven, Ctr Microbial & Plant Genet, Heverlee, Belgium. [Ghequire, Maarten G. K.; Buchanan, Susan K.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Mol Biol Lab, Bethesda, MD USA. [Anoz-Carbonell, Ernesto] Univ Zaragoza, Fac Ciencias, Dept Bioqum & Biol Mol Celular, Zaragoza, Spain. RP Ghequire, MGK (reprint author), Katholieke Univ Leuven, Ctr Microbial & Plant Genet, Heverlee, Belgium. EM maarten.ghequire@biw.kuleuven.be FU Fonds voor Weten-schappelijk Onderzoek (FWO) Vlaanderen [12M4615N]; Erasmus + Exchange Program [800019]; Ministry of Education (MECD, Spain); Intramural Research Program of the NIH; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX M.G.K.G. is the recipient of a postdoctoral fellowship from the Fonds voor Weten-schappelijk Onderzoek (FWO) Vlaanderen (12M4615N). E.A.-C. was funded by a scholarship from the Erasmus + Exchange Program (800019), granted by the Ministry of Education (MECD, Spain). S.K.B. was supported by the Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 60 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 2150-7511 J9 MBIO JI mBio PD JAN-FEB PY 2017 VL 8 IS 1 AR e01961-16 DI 10.1128/mBio.01961-16 PG 12 WC Microbiology SC Microbiology GA EN2JE UT WOS:000395835000022 ER PT J AU Keen, EC Bliskovsky, VV Malagon, F Baker, JD Prince, JS Klaus, JS Adhya, SL AF Keen, Eric C. Bliskovsky, Valery V. Malagon, Francisco Baker, James D. Prince, Jeffrey S. Klaus, James S. Adhya, Sankar L. TI Novel "Superspreader" Bacteriophages Promote Horizontal Gene Transfer by Transformation SO MBIO LA English DT Article ID ANTIBIOTIC-RESISTANCE PLASMIDS; ESCHERICHIA-COLI; MARINE-ENVIRONMENT; GENOME; DNA; TRANSDUCTION; SEQUENCE; REPLICATION; DIVERSITY; BACTERIA AB Bacteriophages infect an estimated 10(23) to 10(25) bacterial cells each second, many of which carry physiologically relevant plasmids (e.g., those encoding antibiotic resistance). However, even though phage-plasmid interactions occur on a massive scale and have potentially significant evolutionary, ecological, and biomedical implications, plasmid fate upon phage infection and lysis has not been investigated to date. Here we show that a subset of the natural lytic phage population, which we dub "superspreaders," releases substantial amounts of intact, transformable plasmid DNA upon lysis, thereby promoting horizontal gene transfer by transformation. Two novel Escherichia coli phage superspreaders, SUSP1 and SUSP2, liberated four evolutionarily distinct plasmids with equal efficiency, including two close relatives of prominent antibiotic resistance vectors in natural environments. SUSP2 also mediated the extensive lateral transfer of antibiotic resistance in unbiased communities of soil bacteria from Maryland and Wyoming. Furthermore, the addition of SUSP2 to cocultures of kanamycin-resistant E. coli and kanamycin-sensitive Bacillus sp. bacteria resulted in roughly 1,000-fold more kanamycin-resistant Bacillus sp. bacteria than arose in phage-free controls. Unlike many other lytic phages, neither SUSP1 nor SUSP2 encodes homologs to known hydrolytic endonucleases, suggesting a simple potential mechanism underlying the superspreading phenotype. Consistent with this model, the deletion of endonuclease IV and the nucleoid-disrupting protein ndd from coliphage T4, a phage known to extensively degrade chromosomal DNA, significantly increased its ability to promote plasmid transformation. Taken together, our results suggest that phage superspreaders may play key roles in microbial evolution and ecology but should be avoided in phage therapy and other medical applications. MPORTANCE Bacteriophages (phages), viruses that infect bacteria, are the planet's most numerous biological entities and kill vast numbers of bacteria in natural environments. Many of these bacteria carry plasmids, extrachromosomal DNA elements that frequently encode antibiotic resistance. However, it is largely unknown whether plasmids are destroyed during phage infection or released intact upon phage lysis, whereupon their encoded resistance could be acquired and manifested by other bacteria (transformation). Because phages are being developed to combat antibiotic-resistant bacteria and because transformation is a principal form of horizontal gene transfer, this question has important implications for biomedicine and microbial evolution alike. Here we report the isolation and characterization of two novel Escherichia coli phages, dubbed " superspreaders," that promote extensive plasmid transformation and efficiently disperse antibiotic resistance genes. Our work suggests that phage superspreaders are not suitable for use in medicine but may help drive bacterial evolution in natural environments. C1 [Keen, Eric C.; Baker, James D.; Prince, Jeffrey S.] Univ Miami, Dept Biol, Coral Gables, FL 33124 USA. [Keen, Eric C.; Malagon, Francisco; Adhya, Sankar L.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Bliskovsky, Valery V.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Malagon, Francisco] Henry M Jackson Fdn, Naval Med Res Ctr, Biol Def Res Directorate, Ft Detrick, MD USA. [Klaus, James S.] Univ Miami, Dept Geol Sci, Coral Gables, FL 33124 USA. RP Keen, EC (reprint author), Univ Miami, Dept Biol, Coral Gables, FL 33124 USA.; Keen, EC (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM e.keen@umiami.edu FU Intramural Research Program of the National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. The funders had no role in study design, data collection or interpretation, or the decision to submit the work for publication. NR 45 TC 0 Z9 0 U1 9 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JAN-FEB PY 2017 VL 8 IS 1 AR e02115-16 DI 10.1128/mBio.02115-16 PG 12 WC Microbiology SC Microbiology GA EN2JE UT WOS:000395835000033 ER PT J AU Kelly, PH Bahr, SM Serafim, TD Ajami, NJ Petrosino, JF Meneses, C Kirby, JR Valenzuela, JG Kamhawi, S Wilson, ME AF Kelly, Patrick H. Bahr, Sarah M. Serafim, Tiago D. Ajami, Nadim J. Petrosino, Joseph F. Meneses, Claudio Kirby, John R. Valenzuela, Jesus G. Kamhawi, Shaden Wilson, Mary E. TI The Gut Microbiome of the Vector Lutzomyia longipalpis Is Essential for Survival of Leishmania infantum SO MBIO LA English DT Article ID PHLEBOTOMINE SAND FLIES; VISCERAL LEISHMANIASIS; GENE-EXPRESSION; IRON REDUCTASE; FLY; LIPOPHOSPHOGLYCAN; INFECTION; TSETSE; HOST; METACYCLOGENESIS AB The vector-borne disease leishmaniasis, caused by Leishmania species protozoa, is transmitted to humans by phlebotomine sand flies. Development of Leishmania to infective metacyclic promastigotes in the insect gut, a process termed metacyclogenesis, is an essential prerequisite for transmission. Based on the hypothesis that vector gut microbiota influence the development of virulent parasites, we sequenced midgut microbiomes in the sand fly Lutzomyia longipalpis with or without Leishmania infantum infection. Sucrose-fed sand flies contained a highly diverse, stable midgut microbiome. Blood feeding caused a decrease in microbial richness that eventually recovered. However, bacterial richness progressively decreased in L. infantum-infected sand flies. Acetobacteraceae spp. became dominant and numbers of Pseudomonadaceae spp. diminished coordinately as the parasite underwent metacyclogenesis and parasite numbers increased. Importantly, antibiotic-mediated perturbation of the midgut microbiome rendered sand flies unable to support parasite growth and metacyclogenesis. Together, these data suggest that the sand fly midgut microbiome is a critical factor for Leishmania growth and differentiation to its infective state prior to disease transmission. IMPORTANCE Leishmania infantum, a parasitic protozoan causing fatal visceral leishmaniasis, is transmitted to humans through the bite of the sand fly Lutzomyia longipalpis. Development of the parasite to its virulent metacyclic state occurs in the sand fly gut. In this study, the microbiota within the Lu. longipalpis midgut was delineated by 16S ribosomal DNA (rDNA) sequencing, revealing a highly diverse community composition that lost diversity as parasites developed to their metacyclic state and increased in abundance in infected flies. Perturbing sand fly gut microbiota with an antibiotic cocktail, which alone had no effect on either the parasite or the fly, arrested both the development of virulent parasites and parasite expansion. These findings indicate the importance of bacterial commensals within the insect vector for the development of virulent pathogens, and raise the possibility that impairing the microbial composition within the vector might represent a novel approach to control of vector-borne diseases. C1 [Kelly, Patrick H.; Bahr, Sarah M.; Kirby, John R.; Wilson, Mary E.] Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. [Kelly, Patrick H.; Bahr, Sarah M.; Kirby, John R.; Wilson, Mary E.] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Kelly, Patrick H.; Bahr, Sarah M.; Kirby, John R.; Wilson, Mary E.] Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. [Serafim, Tiago D.; Meneses, Claudio; Valenzuela, Jesus G.; Kamhawi, Shaden] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Ajami, Nadim J.; Petrosino, Joseph F.] Baylor Coll Med, Dept Mol Virol & Microbiol, Alkek Ctr Metagen & Microbiome Res, Houston, TX 77030 USA. [Wilson, Mary E.] Iowa City Vet Affairs Med Ctr, Iowa City, IA 52246 USA. [Bahr, Sarah M.] Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA. RP Wilson, ME (reprint author), Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA.; Wilson, ME (reprint author), Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA.; Wilson, ME (reprint author), Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA.; Wilson, ME (reprint author), Iowa City Vet Affairs Med Ctr, Iowa City, IA 52246 USA. EM mary-wilson@uiowa.edu FU US National Institutes of Health [R01 AI076233, P50 AI-30639, P50 AI-074321]; US Department of Veterans' Affairs [5I01BX001983, 2I01BX000536]; NIH [T32 AI07511]; Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases FX This work was funded in part by grants R01 AI076233 (J.R.K.), P50 AI-30639 (M.E.W.), and P50 AI-074321 (M.E.W.) from the US National Institutes of Health and by grants 5I01BX001983 and 2I01BX000536 from the US Department of Veterans' Affairs (M.E.W.). The work was done in part while P.H.K. was supported by NIH T32 AI07511. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (T.D.S., C.M., J.G.V., and S.K.). NR 50 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 2150-7511 J9 MBIO JI mBio PD JAN-FEB PY 2017 VL 8 IS 1 AR e01121-16 DI 10.1128/mBio.01121-16 PG 12 WC Microbiology SC Microbiology GA EN2JE UT WOS:000395835000035 ER PT J AU Mulye, M Samanta, D Winfree, S Heinzen, RA Gilk, SD AF Mulye, Minal Samanta, Dhritiman Winfree, Seth Heinzen, Robert A. Gilk, Stacey D. TI Elevated Cholesterol in the Coxiella burnetii Intracellular Niche Is Bacteriolytic SO MBIO LA English DT Article ID CHLAMYDIA-TRACHOMATIS; HOST-CELLS; PARASITOPHOROUS VACUOLE; MEMBRANE CHOLESTEROL; PHAGOSOME MATURATION; HUMAN MACROPHAGES; MAMMALIAN-CELLS; GENE-EXPRESSION; LIPID RAFTS; INFECTION AB Coxiella burnetii is an intracellular bacterial pathogen and a significant cause of culture-negative endocarditis in the United States. Upon infection, the nascent Coxiella phagosome fuses with the host endocytic pathway to form a large lysosome-like vacuole called the parasitophorous vacuole (PV). The PV membrane is rich in sterols, and drugs perturbing host cell cholesterol homeostasis inhibit PV formation and bacterial growth. Using cholesterol supplementation of a cholesterol-free cell model system, we found smaller PVs and reduced Coxiella growth as cellular cholesterol concentration increased. Further, we observed in cells with cholesterol a significant number of nonfusogenic PVs that contained degraded bacteria, a phenotype not observed in cholesterol-free cells. Cholesterol had no effect on axenic Coxiella cultures, indicating that only intracellular bacteria are sensitive to cholesterol. Live-cell microscopy revealed that both plasma membrane-derived cholesterol and the exogenous cholesterol carrier protein low-density lipoprotein (LDL) traffic to the PV. To test the possibility that increasing PV cholesterol levels affects bacterial survival, infected cells were treated with U18666A, a drug that traps cholesterol in lysosomes and PVs. U18666A treatment led to PVs containing degraded bacteria and a significant loss in bacterial viability. The PV pH was significantly more acidic in cells with cholesterol or cells treated with U18666A, and the vacuolar ATPase inhibitor bafilomycin blocked cholesterol-induced PV acidification and bacterial death. Additionally, treatment of infected HeLa cells with several FDA-approved cholesterolaltering drugs led to a loss of bacterial viability, a phenotype also rescued by bafilomycin. Collectively, these data suggest that increasing PV cholesterol further acidifies the PV, leading to Coxiella death. IMPORTANCE The intracellular Gram-negative bacterium Coxiella burnetii is a significant cause of culture-negative infectious endocarditis, which can be fatal if untreated. The existing treatment strategy requires prolonged antibiotic treatment, with a 10-year mortality rate of 19% in treated patients. Therefore, new clinical therapies are needed and can be achieved by better understanding C. burnetii pathogenesis. Upon infection of host cells, C. burnetii grows within a specialized replication niche, the parasitophorous vacuole (PV). Recent data have linked cholesterol to intracellular C. burnetii growth and PV formation, leading us to further decipher the role of cholesterol during C. burnetii-host interaction. We observed that increasing PV cholesterol concentration leads to increased acidification of the PV and bacterial death. Further, treatment with FDA-approved drugs that alter host cholesterol homeostasis also killed C. burnetii through PV acidification. Our findings suggest that targeting host cholesterol metabolism might prove clinically efficacious in controlling C. burnetii infection. C1 [Mulye, Minal; Samanta, Dhritiman; Gilk, Stacey D.] Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Winfree, Seth] Indiana Univ, Sch Med, Dept Med, Indiana Ctr Biol Microscopy, Indianapolis, IN USA. [Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Gilk, SD (reprint author), Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. EM sgilk@iupui.edu FU American Heart Association Scientist Development [14SDG18420034]; Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Disease FX This research was supported by an American Heart Association Scientist Development Grant 14SDG18420034 ( S. D. G.) and the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Disease ( R. A. H.). We thank Anna Justis and Tatiana Clemente for critical reading of the manuscript and members of the IU Biology of Intracellular Pathogens Group for helpful suggestions. NR 58 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 2150-7511 J9 MBIO JI mBio PD JAN-FEB PY 2017 VL 8 IS 1 AR e02313- 16 DI 10.1128/mBio.02313-16 PG 18 WC Microbiology SC Microbiology GA EN2JE UT WOS:000395835000046 ER PT J AU Sosnovtsev, SV Sandoval-Jaime, C Parra, GI Tin, CM Jones, RW Soden, J Barnes, D Freeth, J Smith, AW Green, KY AF Sosnovtsev, Stanislav V. Sandoval-Jaime, Carlos Parra, Gabriel I. Tin, Christine M. Jones, Ronald W. Soden, Jo Barnes, Donna Freeth, Jim Smith, Alvin W. Green, Kim Y. TI Identification of Human Junctional Adhesion Molecule 1 as a Functional Receptor for the Hom-1 Calicivirus on Human Cells SO MBIO LA English DT Article ID X-RAY-STRUCTURE; SEA LION VIRUS; FELINE CALICIVIRUS; NONSTRUCTURAL POLYPROTEIN; STRUCTURAL INSIGHTS; NUCLEOTIDE-SEQUENCE; FUSION PROTEINS; CD300 FAMILY; PAN-PANISCUS; EXPRESSION AB The Hom-1 vesivirus was reported in 1998 following the inadvertent transmission of the animal calicivirus San Miguel sea lion virus to a human host in a laboratory. We characterized the Hom-1 strain and investigated the mechanism by which human cells could be infected. An expression library of 3,559 human plasma membrane proteins was screened for reactivity with Hom-1 virus-like particles, and a single interacting protein, human junctional adhesion molecule 1 (hJAM1), was identified. Transient expression of hJAM1 conferred susceptibility to Hom-1 infection on nonpermissive Chinese hamster ovary (CHO) cells. Virus infection was markedly inhibited when CHO cells stably expressing hJAM were pretreated with anti-hJAM1 monoclonal antibodies. Cell lines of human origin were tested for growth of Hom-1, and efficient replication was observed in HepG2, HuH7, and SK-CO15 cells. The three cell lines (of hepatic or intestinal origin) were confirmed to express hJAM1 on their surface, and clustered regularly interspaced short palindromic repeats/Cas9-mediated knockout of the hJAM1 gene in each line abolished Hom-1 propagation. Taken together, our data indicate that entry of the Hom-1 vesivirus into these permissive human cell lines is mediated by the plasma membrane protein hJAM1 as a functional receptor. IMPORTANCE Vesiviruses, such as San Miguel sea lion virus and feline calicivirus, are typically associated with infection in animal hosts. Following the accidental infection of a laboratory worker with San Miguel sea lion virus, a related virus was isolated in cell culture and named Hom-1. In this study, we found that Hom-1 could be propagated in a number of human cell lines, making it the first calicivirus to replicate efficiently in cultured human cells. Screening of a library of human cell surface membrane proteins showed that the virus could utilize human junctional adhesion molecule 1 as a receptor to enter cells and initiate replication. The Hom-1 virus presents a new system for the study of calicivirus biology and species specificity. C1 [Sosnovtsev, Stanislav V.; Sandoval-Jaime, Carlos; Parra, Gabriel I.; Tin, Christine M.; Jones, Ronald W.; Green, Kim Y.] NIAID, Infect Dis Lab, Caliciviruses Sect, NIH, Bethesda, MD 20892 USA. [Smith, Alvin W.] Oregon State Univ, Lab Calicivirus Studies, Corvallis, OR 97331 USA. [Soden, Jo; Barnes, Donna; Freeth, Jim] Retrogenix Ltd, Whaley Bridge, High Peak, England. [Sandoval-Jaime, Carlos] Univ Nacl Autonoma Mexico Cuernavaca, Inst Biotecnol, Cuernavaca, Morelos, Mexico. [Parra, Gabriel I.] US FDA, Div Viral Prod, OVRR, Silver Spring, MD USA. RP Sosnovtsev, SV (reprint author), NIAID, Infect Dis Lab, Caliciviruses Sect, NIH, Bethesda, MD 20892 USA. EM ss216m@nih.gov OI Parra, Gabriel/0000-0002-1102-4740 FU Division of Intramural Research of the NIAID, NIH FX This work was supported by the Division of Intramural Research of the NIAID, NIH. NR 58 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 2150-7511 J9 MBIO JI mBio PD JAN-FEB PY 2017 VL 8 IS 1 AR e00031-17 DI 10.1128/mBio.00031-17 PG 19 WC Microbiology SC Microbiology GA EN2JE UT WOS:000395835000065 ER PT J AU Tripathi, V Zhang, YE AF Tripathi, Veenu Zhang, Ying E. TI Redirecting RNA splicing by SMAD3 turns TGF-beta into a tumor promoter SO MOLECULAR & CELLULAR ONCOLOGY LA English DT Article DE Alternative splicing; EMT; metastasis; PCBP1; SMAD3; TGF-beta ID CANCER AB Transforming growth factor beta (TGF-beta) is a well-known growth inhibitor of normal epithelial cells, but it is also secreted by solid tumors to promote cancer progression. Our recent discovery of SMAD3-PCBP1 complex with direct RNA-binding properties has shed light on how this conversion is implemented by controlling pre-mRNA splicing patterns. C1 [Tripathi, Veenu; Zhang, Ying E.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zhang, YE (reprint author), NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bldg 37,RM 2056B, Bethesda, MD 20892 USA. EM zhangyin@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Research in Y.E. Zhang's lab is supported by intramural program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 10 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 2372-3556 EI 2372-3548 J9 MOL CELL ONCOL JI MOL. CELL ONCOL. PY 2017 VL 4 IS 1 AR UNSP e1265699 DI 10.1080/23723556.2016.1265699 PG 3 WC Oncology SC Oncology GA EO2XA UT WOS:000396558100007 ER PT J AU Nelson, SM Batai, K Ahaghotu, C Agurs-Collins, T Kittles, RA AF Nelson, Shakira M. Batai, Ken Ahaghotu, Chiledum Agurs-Collins, Tanya Kittles, Rick A. TI Association between Serum 25-Hydroxy-Vitamin D and Aggressive Prostate Cancer in African American Men SO NUTRIENTS LA English DT Article DE serum 25-hydroxyvitamin D; rs11568820; calcium; African American men; aggressive prostate cancer; vitamin D receptor small nucleotide polymorphisms ID VITAMIN-D DEFICIENCY; D-RECEPTOR GENE; CALCIUM-SENSING RECEPTOR; 25-HYDROXYVITAMIN D; RISK; HEALTH; POLYMORPHISMS; ABSORPTION; PREVENTION; SUSCEPTIBILITY AB African American men have higher incidence rates of aggressive prostate cancer, where high levels of calcium and serum vitamin D deficient levels play a role in the racial differences in incidence. In this study, we examined associations of serum vitamin D with aggressive prostate cancer to improve our understanding of higher susceptibility of aggressive disease in this racial cohort. From Howard University Hospital, 155 African American men with clinically-identified prostate cancer were identified; 46 aggressive cases, and 58 non-aggressive cases. Serum vitamin D was assessed from fasting blood samples, and total calcium intake was assessed using the Block Food Frequency Questionnaire. Vitamin D receptor polymorphisms from three different loci were genotyped; rs731236, rs1544410, and rs11568820. Multivariate logistic regression models were used to determine odds ratios (OR) and 95% confidence intervals (CI) comparing aggressive to non-aggressive prostate cancer. Vitamin D deficiency (<20 ng/mL) significantly increased risk of aggressive disease (OR: 3.1, 95% CI: 1.03-9.57, p-value = 0.04). Stratification by total calcium showed high calcium levels (>= 800 mg/day) modified this association (OR: 7.3, 95% CI: 2.15-47.68, p-interaction = 0.03). Genetic variant rs11568820 appeared to increase the magnitude of association between deficient serum vitamin D and aggressive prostate cancer (OR: 3.64, 95% CI: 1.12-11.75, p-value = 0.05). These findings suggest that high incidence of aggressive prostate cancer risk in African American men may be due in-part to deficient levels of serum vitamin D. Other factors, including genetics, should be considered for future studies. C1 [Nelson, Shakira M.] NCI, Canc Prevent Div, 9609 Med Ctr Dr,Room 6E402, Bethesda, MD 20892 USA. [Nelson, Shakira M.] NCI, Div Canc Epidemiol & Genet, Metab Epidemiol Branch, 9609 Med Ctr Dr,Room 6E402, Bethesda, MD 20892 USA. [Batai, Ken; Kittles, Rick A.] Univ Arizona, Dept Surg, Div Urol, Tucson, AZ 85721 USA. [Ahaghotu, Chiledum] Carney Hosp Steward Hlth Syst, Dorchester, MA 02124 USA. [Agurs-Collins, Tanya] NCI, Div Canc Control & Populat Studies, Hlth Behav Res Branch, Bethesda, MD 20892 USA. RP Nelson, SM (reprint author), NCI, Canc Prevent Div, 9609 Med Ctr Dr,Room 6E402, Bethesda, MD 20892 USA.; Nelson, SM (reprint author), NCI, Div Canc Epidemiol & Genet, Metab Epidemiol Branch, 9609 Med Ctr Dr,Room 6E402, Bethesda, MD 20892 USA. EM shakira.nelson@nih.gov; kbatai@email.arizona.edu; chiledum.ahaghotu@steward.org; collinsta@mail.nih.gov; rkittles@surgery.arizona.edu FU US National Institutes of Health/National Institute of Minority Health and Health Disparities [5R01MD007105] FX This project was supported by grants through the US National Institutes of Health/National Institute of Minority Health and Health Disparities, grant number 5R01MD007105. NR 45 TC 1 Z9 1 U1 0 U2 0 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD JAN PY 2017 VL 9 IS 1 AR 12 DI 10.3390/nu9010012 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EO1NP UT WOS:000396465500012 ER PT J AU Guitart, X Chern, YJ Ferre, S AF Guitart, Xavier Chern, Yijuang Ferre, Sergi TI Targeting the equilibrative nucleoside transporter ENT1 in Huntington disease SO ONCOTARGET LA English DT Editorial Material DE Huntington disease; adenosine; ENT1; adenosine A(2A) receptor; Neuroscience ID RECEPTORS; ONSET; AGE C1 [Guitart, Xavier] NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Guitart, X (reprint author), NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM guitartx@mail.nih.gov RI Ferre, Sergi/K-6115-2014 OI Ferre, Sergi/0000-0002-1747-1779 NR 6 TC 0 Z9 0 U1 1 U2 1 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 PY 2017 VL 8 IS 8 BP 12550 EP 12551 DI 10.18632/oncotarget.15111 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EN0HX UT WOS:000395692000009 ER PT J AU McClelland, KS Yao, HHC AF McClelland, Kathryn S. Yao, Humphrey H. -C. TI Leveraging Online Resources to Prioritize Candidate Genes for Functional Analyses: Using the Fetal Testis as a Test Case SO SEXUAL DEVELOPMENT LA English DT Review DE Candidate gene; Databases; Data mining; Enrichment; Expression atlas; Gene prioritization; GO terms; Knowledgebases; Ontology; Ovary; Sex determination; Testis; Transcriptomics ID DAVID BIOINFORMATICS RESOURCES; KNOCKOUT MOUSE CONSORTIUM; SEX DETERMINATION REVEALS; EXPRESSION PATTERNS; MENDELIAN INHERITANCE; MUTATION DATABASE; GONAD DEVELOPMENT; LABORATORY MOUSE; GENOME DATABASE; SERTOLI-CELLS AB With each new microarray or RNA-seq experiment, massive quantities of transcriptomic information are generated with the purpose to produce a list of candidate genes for functional analyses. Yet an effective strategy remains elusive to prioritize the genes on these candidate lists. In this review, we outline a priori tizing strategy by taking a step back from the bench and leveraging the rich range of public databases. This in silico approach provides an economical, less biased, and more effective solution. We discuss the publicly available online resources that can be used to answer a range of questions about a gene. Is the gene of interest expressed in the system of interest (using expression databases)? Where else is this gene expressed (using added-value transcriptomic resources)? What pathways and processes is the gene involved in (using enriched gene pathway analysis and mouse knockout databases)? Is this gene correlated with human diseases (using human disease variant databases)? Using mouse fetaltestis as an example, our strategies identified 298 genes annotated as expressed in the fetal testis. We cross-referenced these genes to existing microarray data and narrowed the list down to cell-type-specific candidates (35 for Sertoli cells, 11 for Leydig cells, and 25 for germ cells). Our strategies can be customized so that they allow researchers to effectively and confidently prioritize genes for functional analysis. C1 [McClelland, Kathryn S.; Yao, Humphrey H. -C.] NIEHS, Reprod & Dev Biol Lab, Res Triangle Pk, NC 27709 USA. RP Yao, HHC (reprint author), NIEHS, Reprod & Dev Biol Lab, Res Triangle Pk, NC 27709 USA. EM humphrey.yao@nih.gov FU Intramural Research Program [ES102965]; NIH; National Institute of Environmental Health Sciences FX We thank members of the Yao Lab for helpful discussions on the concepts in this paper. The concept for this review was born out of work done by K.S.M. during her time in the Koopman Lab, University of Queensland, Australia. All work contributing to this review was completed in the Yao Lab, NIEHS/NIH, USA. K.S.M. would like to thank Peter Koopman and Josephine Bowles for their encouragement and support.This research was supported by the Intramural Research Program (ES102965 to H. H.-C. Y.) of the NIH, National Institute of Environmental Health Sciences. The in situ hybridization data in this review is drawn exclusively from the Eurexpress Transcriptome Atlas Database in May 2016. NR 75 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1661-5425 EI 1661-5433 J9 SEX DEV JI Sex. Dev. PY 2017 VL 11 IS 1 BP 1 EP 20 DI 10.1159/000455113 PG 20 WC Developmental Biology SC Developmental Biology GA EN3KK UT WOS:000395907200001 PM 28196369 ER PT J AU Xia, YC Protzer, U AF Xia, Yuchen Protzer, Ulrike TI Control of Hepatitis B Virus by Cytokines SO VIRUSES-BASEL LA English DT Review DE hepatitis B virus (HBV); cytokine; interferon; interferon-induced gene (ISG); cccDNA; therapy ID CHRONIC HCV INFECTION; PLASMA HALF-LIFE; T-CELLS; VIRAL-RNA; POLYETHYLENE-GLYCOL; PROTEIN-SYNTHESIS; GENE-EXPRESSION; TRANSGENIC MICE; CORE PROMOTER; MOUSE MODEL AB Hepatitis B virus (HBV) infection remains a major public health problem worldwide with more than 240 million individuals chronically infected. Current treatments can control HBV replication to a large extent, but cannot eliminate HBV infection. Cytokines have been shown to control HBV replication and contribute to HBV cure in different models. Cytokines play an important role in limiting acute HBV infection in patients and mediate a non-cytolytic clearance of the virus. In this review, we summarize the effects of cytokines and cytokine-induced cellular signaling pathways on different steps of the HBV life cycle, and discuss possible strategies that may contribute to the eradication of HBV through innate immune activation. C1 [Xia, Yuchen] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Protzer, Ulrike] Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Virol, D-81675 Munich, Germany. [Protzer, Ulrike] German Ctr Infect Res DZIF, Munich Partner Site, D-81675 Munich, Germany. RP Protzer, U (reprint author), Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Virol, D-81675 Munich, Germany.; Protzer, U (reprint author), German Ctr Infect Res DZIF, Munich Partner Site, D-81675 Munich, Germany. EM yuchen.xia@nih.gov; protzer@tum.de OI Xia, Yuchen/0000-0001-8460-3893 FU German Research Foundation (DFG) [TRR 36, TRR179]; EU via the HepCar consortium within Horizon; Helmholtz Association via the iMed Initiative; Helmholtz Validation Fund; Helmholtz-Alberta Initiative; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health; ILCA-Bayer fellowship FX Work in the authors' laboratory was funded by the German Research Foundation (DFG) via TRR 36 and TRR179, the EU via the HepCar consortium within Horizon 2020, the Helmholtz Association via the iMed Initiative, the Helmholtz Validation Fund, and the Helmholtz-Alberta Initiative, Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Yuchen Xia is partly sponsored by the ILCA-Bayer fellowship. NR 85 TC 0 Z9 0 U1 1 U2 1 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD JAN PY 2017 VL 9 IS 1 AR 18 DI 10.3390/v9010018 PG 12 WC Virology SC Virology GA EO1RS UT WOS:000396476200017 ER PT J AU Zhu, X Cortes, CR Mathur, K Tomasi, D Momenan, R AF Zhu, Xi Cortes, Carlos R. Mathur, Karan Tomasi, Dardo Momenan, Reza TI Model-free functional connectivity and impulsivity correlates of alcohol dependence: a resting-state study SO ADDICTION BIOLOGY LA English DT Article DE Alcohol dependence; fMRI; functional connectivity; ICA; impulsivity; resting state ID ADDICTION; NETWORK; FMRI; ABSTINENCE; SYNCHRONY; DISORDER; MATTER; SCALE; MRI AB Alcohol dependence is characterized by impulsiveness toward consumption despite negative consequences. Although neuro-imaging studies have implicated some regions underlying this disorder, there is little information regarding its large-scale connectivity pattern. This study investigated the within-and between-network functional connectivity (FC) in alcohol dependence and examined its relationship with clinical impulsivity measures. Using probabilistic independent component analysis on resting-state functionalmagnetic resonance imaging (rs-fMRI) data from 25 alcohol-dependent (AD) and 26 healthy control (HC) participants, we compared the within-and between-network FC between AD and HC. Then, the relationship between FC and impulsiveness as measured by the Barratt Impulsiveness Scale (BIS-11), the UPPS-P Impulsive Scale and the delay discounting task (DDT), was explored. Compared with HC, AD exhibited increased within-network FC in salience (SN), default mode (DMN), orbitofrontal cortex (OFCN), left executive control (LECN) and amygdala-striatum (ASN) networks. Increased between-network FC was found among LECN, ASN and SN. Between-network FC correlations were significantly negative between Negative-Urgency and OFCN pairs with right executive control network (RECN), anterior DMN (a-DMN) and posterior DMN (p-DMN) in AD. DDT was significantly correlated with the between-network FC among the LECN, a-DMN and SN in AD. These findings add evidence to the concept of altered within-network FC and also highlight the role of between-network FC in the pathophysiology of AD. Additionally, this study suggests differential neurobiological bases for different clinical measures of impulsivity that may be used as a systems-level biomarker for alcohol dependence severity and treatment efficacy. C1 [Zhu, Xi; Cortes, Carlos R.; Mathur, Karan; Momenan, Reza] NIAAA, Sect Brain Elect & Imaging, LCTS, NIH, Bethesda, MD USA. [Tomasi, Dardo] NIAAA, Lab Neuroimaging, NIH, Bethesda, MD USA. RP Zhu, X; Momenan, R (reprint author), NIH, CRC, 10 Ctr Dr,MSC1108,Bldg 10,Room 1-5438, Bethesda, MD 20892 USA. EM xi.zhu@nih.gov; rezam@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism intramural funding FX This research was supported by the National Institute on Alcohol Abuse and Alcoholism intramural funding. We thank Michael Kerich for his assistance with image processing. NR 30 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD JAN PY 2017 VL 22 IS 1 BP 206 EP 217 DI 10.1111/adb.12272 PG 12 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA EK4NC UT WOS:000393902700017 PM 26040546 ER PT J AU Witkiewitz, K Hallgren, KA Kranzler, HR Mann, KF Hasin, DS Falk, DE Litten, RZ O'Malley, SS Anton, RF AF Witkiewitz, Katie Hallgren, Kevin A. Kranzler, Henry R. Mann, Karl F. Hasin, Deborah S. Falk, Daniel E. Litten, Raye Z. O'Malley, Stephanie S. Anton, Raymond F. TI Clinical Validation of Reduced Alcohol Consumption After Treatment for Alcohol Dependence Using the World Health Organization Risk Drinking Levels SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE World Health Organization Risk Drinking Levels; Alcohol Dependence; Reduced Alcohol Consumption; Alcohol Treatment Outcomes; Harm Reduction ID HEAVY DRINKING; USE DISORDERS; HARM REDUCTION; PRIMARY-CARE; COSTS; PHARMACOTHERAPIES; INDIVIDUALS; NALMEFENE; TRIAL AB Background: Alcohol use disorder (AUD) is a highly prevalent public health problem associated with considerable individual and societal costs. Abstinence from alcohol is the most widely accepted target of treatment for AUD, but it severely limits treatment options and could deter individuals who prefer to reduce their drinking from seeking treatment. Clinical validation of reduced alcohol consumption as the primary outcome of alcohol clinical trials is critical for expanding treatment options. One potentially useful measure of alcohol treatment outcome is a reduction in the World Health Organization (WHO, International Guide for Monitoring Alcohol Consumption and Related Harm. Geneva, Switzerland, 2000) risk levels of alcohol use (very high risk, high risk, moderate risk, and low risk). For example, a 2-shift reduction in WHO risk levels (e.g., high risk to low risk) has been used by the European Medicines Agency (2010, Guideline on the Development of Medicinal Products for the Treatment of Alcohol Dependence. UK) to evaluate nalmefene as a treatment for alcohol dependence (AD; Mann et al. 2013, Biol Psychiatry 73, 706-13). Methods: The current study was a secondary data analysis of the COMBINE study (n = 1,383; Anton et al., 2006) to examine the association between reductions in WHO risk levels and reductions in alcohol-related consequences and mental health symptoms during and following treatment in patients with AD. Results: Any reduction in WHO risk drinking level during treatment was associated with significantly fewer alcohol-related consequences and improved mental health at the end of treatment and for up to 1 year posttreatment. A greater reduction in WHO risk drinking level predicted a greater reduction in consequences and greater improvements in mental health. Conclusions: Changes in WHO risk levels appear to be a valid end point for alcohol clinical trials. Based on the current findings, reductions in WHO risk drinking levels during treatment reflect meaningful reductions in alcohol-related consequences and improved functioning. C1 [Witkiewitz, Katie] Univ New Mexico, Dept Psychol, MSC 03-2220, Albuquerque, NM 87131 USA. [Hallgren, Kevin A.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA USA. [Kranzler, Henry R.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Mann, Karl F.] Cent Inst Mental Hlth, Dept Addict Behav & Addict Med, Mannheim, Germany. [Hasin, Deborah S.] Columbia Univ, Dept Psychiat, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Falk, Daniel E.; Litten, Raye Z.] NIAAA, NIH, Rockville, MD 20852 USA. [O'Malley, Stephanie S.] Yale Univ, Dept Psychiat, Subst Abuse Treatment Unit, New Haven, CT 06520 USA. [Anton, Raymond F.] Med Univ South Carolina, Charleston, SC USA. RP Witkiewitz, K (reprint author), Univ New Mexico, Dept Psychol, MSC 03-2220, Albuquerque, NM 87131 USA. EM katiew@unm.edu FU U.S. National Institute on Alcohol Abuse and Alcoholism [R01AA022328, T32AA007455] FX This study was funded by the U.S. National Institute on Alcohol Abuse and Alcoholism (R01AA022328, T32AA007455). In addition to the authors, the following individuals are or were members of the Alcohol Clinical Trials Initiative (ACTIVE) Workgroup and provided intellectual input into this manuscript during attendance at Workgroup meetings: Joanne Fertig, PhD, National Institute on Alcohol Abuse and Alcoholism; Keith Isenberg, MD, Anthem Blue Cross Blue Shield; David McCann, PhD, National Institute on Drug Abuse; Didier Meulien, MD, Lundbeck SAS; Roger Meyer, MD, Best Practice Project Management, Inc.; Charles O'Brien, MD, PhD, University of Pennsylvania; Megan Ryan, PhD, National Institute on Alcohol Abuse and Alcoholism; Bernard Silverman, MD, Alkermes, Inc.; Francoise Trinquet, MD, Ethypharm; Benjamin Zakine, MD, Ethypharm. Lindsay Snyder and Sarah Timm (ASCP) provided important administrative support to the ACTIVE workgroup. NR 34 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JAN PY 2017 VL 41 IS 1 BP 179 EP 186 DI 10.1111/acer.13272 PG 8 WC Substance Abuse SC Substance Abuse GA EK4IQ UT WOS:000393890700020 PM 28019652 ER PT J AU LeMaire, SM Raghuram, V Grady, CR Pickering, CM Chou, CL Umejiego, EN Knepper, MA AF LeMaire, Sophia M. Raghuram, Viswanathan Grady, Cameron R. Pickering, Christina M. Chou, Chung-Lin Umejiego, Ezigbobiara N. Knepper, Mark A. TI Serine/threonine phosphatases and aquaporin-2 regulation in renal collecting duct SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE systems biology; collecting duct; kidney; vasopressin; LC-MS/MS ID TANDEM MASS-SPECTRA; MODIFIED PEPTIDES; APICAL MEMBRANE; LC-MS/MS; CELLS; AQP2; VASOPRESSIN; PHOSPHORYLATION; LOCALIZATION; TRAFFICKING AB Phosphorylation of the aquaporin-2 (AQP2) water channel at four COOH-terminal serines plays a central role in the regulation of water permeability of the renal collecting duct. The level of phosphorylation at these sites is determined by a balance between phosphorylation by protein kinases and dephosphorylation by phosphatases. The phosphatases that dephosphorylate AQP2 have not been identified. Here, we use large-scale data integration techniques to identify serine-threonine phosphatases likely to interact with AQP2 in renal collecting duct principal cells. As a first step, we have created a comprehensive list of 38 S/T phosphatase catalytic subunits present in the mammalian genome. Then we used Bayes' theorem to integrate available information from large-scale data sets from proteomic and transcriptomic studies to rank the known S/T phosphatases with regard to the likelihood that they interact with AQP2 in renal collecting duct cells. To broaden the analysis, we have generated new proteomic data (LC-MS/MS) identifying 4538 distinct proteins including 22 S/T phosphatases in cytoplasmic fractions from native inner medullary collecting duct cells from rats. The official gene symbols corresponding to the top-ranked phosphatases (common names in parentheses) were: Ppp1cb (PP1-beta), Ppm1g (PP2C), Ppp1ca (PP1-alpha), Ppp3ca (PP2-B or calcineurin), Ppp2ca (PP2A-alpha), Ppp1cc (PP1-gamma), Ppp2cb (PP2A-beta), Ppp6c (PP6C), and Ppp5c (PP5). This ranking correlates well with results of prior reductionist studies of ion and water channels in renal collecting duct cells. C1 [LeMaire, Sophia M.; Raghuram, Viswanathan; Grady, Cameron R.; Pickering, Christina M.; Chou, Chung-Lin; Umejiego, Ezigbobiara N.; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [LeMaire, Sophia M.] Howard Univ, Coll Med, Washington, DC 20059 USA. RP Knepper, MA (reprint author), NIH, Bldg 10,Rm 6N307,10 Ctr Dr,MSC-1603, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI) [ZO1-HL-001285]; NHLBI Summer Internship Program; National Institute for Biomedical Imaging and Bioengineering; Biomedical Research Training Program for Individuals from Underrepresented Groups of the NHLBI FX The work was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI) (project ZO1-HL-001285, M. A. Knepper). LC-MS/MS studies were performed in the NHLBI Proteomics Core Facility (Director, Marjan Gucek). Sophia LeMaire was supported by the NHLBI Summer Internship Program (Herbert Geller, Director). C. M. Pickering is an undergraduate student from the Department of Chemical Engineering at Auburn University and was a member of the Biomedical Engineering Student Internship Program (BESIP) supported by the National Institute for Biomedical Imaging and Bioengineering (June-August, 2014). E. Umejiego was supported by Biomedical Research Training Program for Individuals from Underrepresented Groups of the NHLBI under the leadership of Dr. Helena Mishoe. NR 35 TC 1 Z9 1 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JAN 1 PY 2017 VL 312 IS 1 BP F84 EP F95 DI 10.1152/ajprenal.00455.2016 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA EK4LG UT WOS:000393897600009 PM 27784696 ER PT J AU Baumer, Y McCurdy, S Alcala, M Mehta, N Lee, BH Ginsberg, MH Boisvert, WA AF Baumer, Yvonne McCurdy, Sara Alcala, Martin Mehta, Nehal Lee, Bog-Hieu Ginsberg, Mark H. Boisvert, William A. TI CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis SO ATHEROSCLEROSIS LA English DT Article DE Vascular smooth muscle cell; CD98; Cell proliferation; Apoptosis; Atherosclerosis ID FIBROUS CAP FORMATION; CLONAL EXPANSION; PLAQUE; APOPTOSIS; MIGRATION; LESIONS AB Background and aims: Vascular smooth muscle cells (VSMC) migrate and proliferate to form a stabilizing fibrous cap that encapsulates atherosclerotic plaques. CD98 is a transmembrane protein made of two subunits, CD98 heavy chain (CD98hc) and one of six light chains, and is known to be involved in cell proliferation and survival. Because the influence of CD98hc on atherosclerosis development is unknown, our aim was to determine if CD98hc expressed on VSMC plays a role in shaping the morphology of atherosclerotic plaques by regulating VSMC function. Methods: In addition to determining the role of CD98hc in VSMC proliferation and apoptosis, we utilized mice with SMC-specific deletion of CD98hc (CD98hc(fl/fl)SM22 alpha Cre(+)) to determine the effects of CD98hc deficiency on VSMC function in atherosclerotic plaque. Results: After culturing for 5 days in vitro, CD98hc(-/-) VSMC displayed dramatically reduced cell counts, reduced proliferation, as well as reduced migration compared to control VSMC. Analysis of aortic VSCM after 8 weeks of HFD showed a reduction in CD98hc(-/-) VSMC proliferation as well as increased apoptosis compared to controls. A long-term atherosclerosis study using SMC-CD98hc(-/-)/ldlr(-/-) mice was performed. Although total plaque area was unchanged, CD98h(-/-) mice showed reduced presence of VSMC within the plaque (2.1 +/- 0.4% vs. 4.3 +/- 0.4% SM22 alpha-positive area per plaque area, p < 0.05), decreased collagen content, as well as increased necrotic core area (25.8 +/- 1.9% vs. 10.9 +/- 1.6%, p < 0.05) compared to control ldlr(-/-) mice. Conclusions: We conclude that CD98hc is required for VSMC proliferation, and that its deficiency leads to significantly reduced presence of VSMC in the neointima. Thus, CD98hc expression in VSMC contributes to the formation of plaques that are morphologically more stable, and thereby protects against atherothrombosis. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Baumer, Yvonne; McCurdy, Sara; Boisvert, William A.] Univ Hawaii, Cardiovasc Res Ctr, John A Burns Sch Med, 651 Ilalo St, Honolulu, HI 96813 USA. [Alcala, Martin] Univ CEU San Pablo, Fac Farm, Dept Chem & Biochem, Madrid, Spain. [Mehta, Nehal] NHLBI, Sect Inflammat & Cardiometab Dis, NIH, Bethesda, MD 20892 USA. [Lee, Bog-Hieu] Chung Ang Univ, Sch Food Sci & Technol, Dept Food & Nutr, Seoul, South Korea. [Ginsberg, Mark H.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Boisvert, William A.] Kazan Fed Univ, Kazan, Russia. RP Boisvert, WA (reprint author), Univ Hawaii, Cardiovasc Res Ctr, John A Burns Sch Med, 651 Ilalo St, Honolulu, HI 96813 USA.; Lee, BH (reprint author), Chung Ang Univ, Sch Food Sci & Technol, Dept Food & Nutr, Seoul, South Korea. EM lbheelb@cau.ac.kr; wab@hawaii.edu OI Boisvert, William/0000-0003-2574-9176; Alcala Diaz-Mor, Martin/0000-0003-4678-8860 FU NIH [R01HL081863, P30GM103341, P20GM103516, P20RR016453, G12RR003061, G12MD007601] FX This project was supported by NIH grant R01HL081863 to WAB. Core facilities were supported by NIH grants P30GM103341, P20GM103516, P20RR016453, G12RR003061, and G12MD007601. NR 25 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 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JAN PY 2017 VL 256 BP 105 EP 114 DI 10.1016/j.atherosclerosis.2016.11.017 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EK4JC UT WOS:000393891900016 PM 28012647 ER PT J AU Turan, TN Smock, A Cotsonis, G Bachman, D Al Kasab, S Lynn, MJ Nizham, A Derdeyn, CP Fiorella, D Janis, S Lane, B Montgomery, J Chimowitz, MI AF Turan, Tanya N. Smock, Alison Cotsonis, Geonge Bachman, David Al Kasab, Sami Lynn, Michael J. Nizham, Azhar Derdeyn, Collin P. Fiorella, David Janis, Scott Lane, Bethany Montgomery, Jean Chimowitz, Marc I. CA SAMMPRIS Investigators TI Is There Benefit from Stenting on Cognitive Function in Intracranial Atherosclerosis? SO CEREBROVASCULAR DISEASES LA English DT Article DE Intracranial stenosis; Stroke; Cognition; Revascularization; Angioplasty and stenting ID AGGRESSIVE MEDICAL-MANAGEMENT; STENOSIS SAMMPRIS; RECURRENT STROKE; TRIAL; PREVENTION; IMPAIRMENT; DESIGN AB Background: Revascularization of stenotic cerebral arteries is hypothesized to improve cognition by increasing cerebral perfusion. Aims: We compared cognition impairment among patients treated with percutaneous angioplasty and stenting (PTAS) and aggressive medical management (AMM) versus AMM alone in the Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) Trial. Methods: In SAMMPRIS, 451 patients with recent transient ischemic attack or stroke attributed to 70-99% intracranial stenosis were randomized to PTAS plus AMM or AMM alone. Patients who had stroke as the qualifying event with National Institutes of Health Stroke Scale indicating aphasia or neglect were excluded from these analyses. Patients with a cerebrovascular event (ischemic stroke, cerebral infarct with temporary signs or intracranial hemorrhage) during followup were excluded from follow-up visit analyses. The Montreal Cognitive Assessment (MoCA) score was used to assess cognition impairment at baseline, 4 months, 12 months and closeout. Cognitive impairment was defined as MoCA < 26. Mean MoCA scores and the percentage of patients with cognitive impairment were compared between treatment groups at each time point using t tests and chi-square tests. Differences in MoCA mean at baseline and follow-up time points were compared using mixed model repeated measures ANOVA and Tukey-Kramer tests. Results: There were no significant differences between the treatment groups for mean MoCA at any time point. Mean MoCA scores improved in both groups. The percentage of patients with cognitive impairment in the AMM versus PTAS groups was not significantly different at any time point. Conclusions: Revascularization with PTAS showed no improvement in cognitive impairment over AMM alone among patients who did not have recurrent cerebrovascular events during follow-up. (C) 2016 S. Karger AG, Basel C1 [Turan, Tanya N.; Smock, Alison; Bachman, David; Al Kasab, Sami; Chimowitz, Marc I.] Med Univ South Carolina, Charleston, SC USA. [Cotsonis, Geonge; Lynn, Michael J.; Nizham, Azhar; Lane, Bethany; Montgomery, Jean] Emory Univ, Atlanta, GA 30322 USA. [Derdeyn, Collin P.] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Fiorella, David] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Janis, Scott] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Turan, TN (reprint author), MUSC Stroke Program, 19 Hagood Ave,Suite 501,Harborview Off Tower, Charleston, SC 29425 USA. EM turan@musc.edu FU National Institute of Neurological Disorders and Stroke (NINDS) [U01 NS058728] FX SAMMPRIS was funded by the National Institute of Neurological Disorders and Stroke (NINDS) U01 NS058728. NR 10 TC 1 Z9 1 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1015-9770 EI 1421-9786 J9 CEREBROVASC DIS JI Cerebrovasc. Dis. PY 2017 VL 43 IS 1-2 BP 31 EP 35 DI 10.1159/000450964 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA EL4IT UT WOS:000394585600006 PM 27820930 ER PT J AU Wilson, EM Rosenthal, ES Kattakuzhy, S Tang, L Kottilil, S AF Wilson, Eleanor M. Rosenthal, Elana S. Kattakuzhy, Sarah Tang, Lydia Kottilil, Shyam TI Clinical Laboratory Testing in the Era of Directly Acting Antiviral Therapies for Hepatitis C SO CLINICAL MICROBIOLOGY REVIEWS LA English DT Review DE directly acting antiviral therapy; hepatitis C virus; viral resistance ID GENOTYPE 1 INFECTION; SUSTAINED VIROLOGICAL RESPONSE; TREATMENT-EXPERIENCED PATIENTS; DACLATASVIR PLUS SOFOSBUVIR; SIMPLE NONINVASIVE INDEX; LABEL PHASE-2 TRIAL; HCV NS5A INHIBITOR; VIRUS-INFECTION; TRANSIENT ELASTOGRAPHY; LIVER FIBROSIS AB Directly acting antiviral (DAA) combination therapies for chronic hepatitis C virus (HCV) infection are highly effective, but treatment decisions remain complex. Laboratory testing is important to evaluate a range of viral, host, and pharmacological factors when considering HCV treatment, and patients must be monitored during and after therapy for safety and to assess the viral response. In this review, we discuss the laboratory tests relevant for the treatment of HCV infection in the era of DAA therapy, grouped according to viral and host factors. C1 [Wilson, Eleanor M.; Kattakuzhy, Sarah; Tang, Lydia; Kottilil, Shyam] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Wilson, Eleanor M.; Rosenthal, Elana S.; Kattakuzhy, Sarah] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Kottilil, Shyam] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA.; Kottilil, S (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM skottilil@ihv.umaryland.edu OI Wilson, Eleanor/0000-0002-4855-514X NR 130 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 0893-8512 EI 1098-6618 J9 CLIN MICROBIOL REV JI Clin. Microbiol. Rev. PD JAN PY 2017 VL 30 IS 1 BP 23 EP 42 DI 10.1128/CMR.00037-16 PG 20 WC Microbiology SC Microbiology GA EO0CR UT WOS:000396366400002 PM 27795306 ER PT J AU Qiu, JM Soderlund-Venermo, M Young, NS AF Qiu, Jianming Soderlund-Venermo, Maria Young, Neal S. TI Human Parvoviruses SO CLINICAL MICROBIOLOGY REVIEWS LA English DT Review DE B19 virus; human bocavirus; parvovirus ID RED-CELL APLASIA; POLYMERASE-CHAIN-REACTION; HUMAN BOCAVIRUS INFECTION; RESPIRATORY-TRACT INFECTIONS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; RENAL-TRANSPLANT RECIPIENTS; ERYTHROID PROGENITOR CELLS; B19 NONSTRUCTURAL PROTEIN; REAL-TIME PCR; NONIMMUNE HYDROPS-FETALIS AB Parvovirus B19 (B19V) and human bocavirus 1 (HBoV1), members of the large Parvoviridae family, are human pathogens responsible for a variety of diseases. For B19V in particular, host features determine disease manifestations. These viruses are prevalent worldwide and are culturable in vitro, and serological and molecular assays are available but require careful interpretation of results. Additional human parvoviruses, including HBoV2 to -4, human parvovirus 4 (PARV4), and human bufavirus (BuV) are also reviewed. The full spectrum of parvovirus disease in humans has yet to be established. Candidate recombinant B19V vaccines have been developed but may not be commercially feasible. We review relevant features of the molecular and cellular biology of these viruses, and the human immune response that they elicit, which have allowed a deep understanding of pathophysiology. C1 [Qiu, Jianming] Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66103 USA. [Soderlund-Venermo, Maria] Univ Helsinki, Dept Virol, Helsinki, Finland. [Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Qiu, JM (reprint author), Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66103 USA. EM jqiu@kumc.edu FU National Institute of Allergy and Infectious Diseases [AI105543, AI112803]; Centers of Biomedical Research Excellence (COBRE) Program of the National Institute of General Medical Sciences, National Institutes of Health [P30 GM103326]; Finnish Medical Foundation; Sigrid Juselius Foundation; Medical Association Liv och Halsa; Helsinki University; Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health FX We acknowledge support from PHS grants AI105543, AI112803, and AI105543 from the National Institute of Allergy and Infectious Diseases; a subaward of P30 GM103326 from the Centers of Biomedical Research Excellence (COBRE) Program of the National Institute of General Medical Sciences, National Institutes of Health (to J.Q.); the Finnish Medical Foundation; the Sigrid Juselius Foundation; the Medical Association Liv och Halsa; the Helsinki University 375-year celebration grant (to M.S.-V.); and the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health (to N.S.Y.). NR 1196 TC 3 Z9 3 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0893-8512 EI 1098-6618 J9 CLIN MICROBIOL REV JI Clin. Microbiol. Rev. PD JAN PY 2017 VL 30 IS 1 BP 43 EP 113 DI 10.1128/CMR.00040-16 PG 71 WC Microbiology SC Microbiology GA EO0CR UT WOS:000396366400003 PM 27806994 ER PT J AU Dzieciol, AM Bachevalier, J Saleem, KS Gadian, DG Saunders, R Chong, WKK Banks, T Mishkin, M Vargha-Khadem, F AF Dzieciol, Anna M. Bachevalier, Jocelyne Saleem, Kadharbatcha S. Gadian, David G. Saunders, Richard Chong, W. K. Kling Banks, Tina Mishkin, Mortimer Vargha-Khadem, Faraneh TI Hippocampal and diencephalic pathology in developmental amnesia SO CORTEX LA English DT Article DE Memory; Hypoxia-ischaemia; Hippocampus; Thalamus; Mammillary bodies ID WERNICKE-KORSAKOFF-SYNDROME; MAMMILLARY BODIES; FDG-PET; TRANSNEURONAL DEGENERATION; TEMPORAL LOBECTOMY; MEMORY IMPAIRMENT; MACAQUE MONKEYS; HEART-FAILURE; BRAIN-DAMAGE; ATROPHY AB Developmental amnesia (DA) is a selective episodic memory disorder associated with hypoxia-induced bilateral hippocampal atrophy of early onset. Despite the systemic impact of hypoxia-ischaemia, the resulting brain damage was previously reported to be largely limited to the hippocampus. However, the thalamus and the mammillary bodies are parts of the hippocampal-diencephalic network and are, therefore also at risk of injury following hypoxic-ischaemic events. Here, we report a neuroimaging investigation of diencephalic damage in a group of 18 patients with DA (age range 11-35 years), and an equal number of controls. Importantly, we uncovered a marked degree of atrophy in the mammillary bodies in two thirds of our patients. In addition, as a group, patients had mildly reduced thalamic volumes. The size of the anterior-mid thalamic (AMT) segment was correlated with patients' visual memory performance. Thus, in addition to the hippocampus, the diencephalic structures also appear to play a role in the patients' memory deficit. (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Dzieciol, Anna M.; Gadian, David G.; Vargha-Khadem, Faraneh] UCL, Great Ormond St Inst Child Hlth, 30 Guilford St, London WC1N 1EH, England. [Bachevalier, Jocelyne] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Saleem, Kadharbatcha S.; Saunders, Richard; Mishkin, Mortimer] NIH, Bldg 10, Bethesda, MD 20892 USA. [Chong, W. K. Kling; Banks, Tina] Great Ormond St Hosp Sick Children, Dept Radiol, London, England. RP Dzieciol, AM (reprint author), UCL, Great Ormond St Inst Child Hlth, 30 Guilford St, London WC1N 1EH, England. EM anna.dzieciol.10@ucl.ac.uk FU Medical Research Council [G03000117/65439, G1002276-E01/1]; Intramural Research Program of the National Institute of Mental Health, National Institutes of Health; National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London FX This work was supported by the Medical Research Council (programme grant numbers G03000117/65439 and G1002276-E01/1), and the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, and supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. NR 68 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD JAN PY 2017 VL 86 BP 33 EP 44 DI 10.1016/j.cortex.2016.09.016 PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA EK4WQ UT WOS:000393929000004 PM 27880886 ER PT J AU Rusiecki, JA Freeman, LEB Bonner, MR Alexander, M Chen, LG Andreotti, G Barry, KH Moore, LE Byun, HM Kamel, F Alavanja, M Hoppin, JA Baccarelli, A AF Rusiecki, Jennifer A. Freeman, Laura E. Beane Bonner, Matthew R. Alexander, Melannie Chen, Ligong Andreotti, Gabriella Barry, Kathryn H. Moore, Lee E. Byun, Hyang-Min Kamel, Freya Alavanja, Michael Hoppin, Jane A. Baccarelli, Andrea TI High pesticide exposure events and DNA methylation among pesticide applicators in the agricultural health study SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE DNA methylation; pesticides; exposure; Agricultural Health Study; epigenetics ID EPIGENETIC TRANSGENERATIONAL ACTIONS; ABERRANT PROMOTER METHYLATION; PERSISTENT ORGANIC POLLUTANTS; INCREASED CANCER BURDEN; ACUTE MYELOID-LEUKEMIA; PROSTATE-CANCER; MULTIPLE GENES; LEUKOCYTE DNA; GSTP1 HYPERMETHYLATION; ENDOCRINE DISRUPTORS AB Pesticide exposure has been associated with acute and chronic adverse health effects. DNA methylation (DNAm) may mediate these effects. We evaluated the association between experiencing unusually high pesticide exposure events (HPEEs) and DNAm among pesticide applicators in the Agricultural Health Study (AHS), a prospective study of applicators from Iowa and North Carolina. DNA was extracted from whole blood from male AHS pesticide applicators (n=695). Questionnaire data were used to ascertain the occurrence of HPEEs over the participant's lifetime. Pyrosequencing was used to quantify DNAm in CDH1, GSTp1, and MGMT promoters, and in the repetitive element, LINE-1. Linear and robust regression analyses evaluated adjusted associations between HPEE and DNAm. Ever having an HPEE (n=142; 24%) was associated with elevated DNAm in the GSTp1 promoter at CpG7 (chr11:67,351,134; P<0.01) and for the mean across the CpGs measured in the GSTp1 promoter (P<0.01). In stratified analyses, elevated GSTP1 promoter DNAm associated with HPEE was more pronounced among applicators >59 years and those with plasma folate levels 16.56 ng/mL (p-interaction <0.01); HPEE was associated with reduced MGMT promoter DNAm at CpG2 (chr10:131,265,803; P=0.03), CpG3 (chr10:131,265,810; P=0.05), and the mean across CpGs measured in the MGMT promoter (P= 0.03) among applicators >59 years and reduced LINE-1 DNAm (P=0.05) among applicators with 16.56 ng/mL plasma folate. Non-specific HPEEs may contribute to increased DNAm in GSTp1, and in some groups, reduced DNAm in MGMT and LINE-1. The impacts of these alterations on disease development are unclear, but elevated GSTp1 promoter DNAm and subsequent gene inactivation has been consistently associated with prostate cancer. Environ. Mol. Mutagen. 58:19-29, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Rusiecki, Jennifer A.; Alexander, Melannie; Chen, Ligong] Uniformed Serv Univ Hlth Sci, Dept Prevent Med, Bethesda, MD 20814 USA. [Freeman, Laura E. Beane; Andreotti, Gabriella; Barry, Kathryn H.; Moore, Lee E.; Alavanja, Michael] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Bonner, Matthew R.] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY USA. [Byun, Hyang-Min] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Kamel, Freya] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Hoppin, Jane A.] North Carolina State Univ, Dept Biol Sci, Ctr Human Hlth & Environm, Raleigh, NC USA. [Baccarelli, Andrea] Harvard Univ, Harvard Sch Publ Hlth, Boston, MA 02115 USA. RP Rusiecki, JA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Prevent Med, Bethesda, MD 20814 USA. EM jennifer.rusiecki@usuhs.edu RI Beane Freeman, Laura/C-4468-2015 OI Beane Freeman, Laura/0000-0003-1294-4124 FU National Institutes of health [R21 CA131934]; National Institutes of Health; National Institute of Environmental Health Sciences [Z01-ES049030, Z01-CP010119] FX Grant sponsor National Institutes of health R21 CA131934.; Grant sponsor: The intramural research program of the National Institutes of Health, the National Institute of Environmental Health Sciences; Grant number: Z01-ES049030.; Grant sponsor: The intramural research program of the National Institutes of health; the National Cancer Institute; Grant number: Z01-CP010119. NR 84 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD JAN PY 2017 VL 58 IS 1 BP 19 EP 29 DI 10.1002/em.22067 PG 11 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA EL5SJ UT WOS:000394680800002 PM 27996157 ER PT J AU Lerro, CC Freeman, LEB Portengen, L Kang, D Lee, K Blair, A Lynch, CF Bakke, B De Roos, AJ Vermeulen, RCH AF Lerro, Catherine C. Freeman, Laura E. Beane Portengen, Lutzen Kang, Daehee Lee, Kyoungho Blair, Aaron Lynch, Charles F. Bakke, Berit De Roos, Anneclaire J. Vermeulen, Roel C. H. TI A longitudinal study of atrazine and 2,4-D exposure and oxidative stress markers among iowa corn farmers SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE agriculture; pesticide; herbicide; oxidative damage ID TANDEM MASS-SPECTROMETRY; LIPID-PEROXIDATION; 2,4-DICHLOROPHENOXYACETIC ACID; DNA-DAMAGE; AGRICULTURAL-WORKERS; URINARY CREATININE; BREAST-CANCER; PESTICIDES; BIOMARKERS; QUANTIFICATION AB Reactive oxygen species, potentially formed through environmental exposures, can overwhelm an organism's antioxidant capabilities resulting in oxidative stress. Long-term oxidative stress is linked with chronic diseases. Pesticide exposures have been shown to cause oxidative stress in vivo. We utilized a longitudinal study of corn farmers and non-farming controls in Iowa to examine the impact of exposure to the widely used herbicides atrazine and 2,4-dichlorophenoxyacetic acid (2,4-D) on markers of oxidative stress. 225 urine samples were collected during five agricultural time periods (pre-planting, planting, growing, harvest, off-season) for 30 farmers who applied pesticides occupationally and 10 controls who did not; all were non-smoking men ages 40-60. Atrazine mercapturate (atrazine metabolite), 2,4-D, and oxidative stress markers (malondialdehyde [MDA], 8-hydroxy-2-deoxyguanosine [8-OHdG], and 8-isoprostaglandin-F-2 [8-isoPGF]) were measured in urine. We calculated estimates and 95% confidence intervals (95%CI) for each pesticide-oxidative stress marker combination using multivariate linear mixed-effect models for repeated measures. Farmers had higher urinary atrazine mercapturate and 2,4-D levels compared with controls. In regression models, after natural log transformation, 2,4-D was associated with elevated levels of 8-OHdG (=0.066, 95%CI=0.008-0.124) and 8-isoPGF (=0.088, 95%CI=0.004-0.172). 2,4-D may be associated with oxidative stress because of modest increases in 8-OHdG, a marker of oxidative DNA damage, and 8-isoPGF, a product of lipoprotein peroxidation, with recent 2,4-D exposure. Future studies should investigate the role of 2,4-D-induced oxidative stress in the pathogenesis of human diseases. Environ. Mol. Mutagen. 58:30-38, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Lerro, Catherine C.; Freeman, Laura E. Beane; Blair, Aaron] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,6E116,MSC 7991, Bethesda, MD 20892 USA. [Portengen, Lutzen; Vermeulen, Roel C. H.] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, NL-3508 Utrecht, Netherlands. [Kang, Daehee] Seoul Natl Univ, Seoul, South Korea. [Lee, Kyoungho] Samsung Elect, Samsung Hlth Res Inst, Yongin 446711, South Korea. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Bakke, Berit] Natl Inst Occupat Hlth, Dept Occupat Hlth Surveillance, Oslo, Norway. [De Roos, Anneclaire J.] Drexel Univ, Dornsife Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [Vermeulen, Roel C. H.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. RP Lerro, CC (reprint author), NCI, Occupat & Environm Epidemiol Branch, 9609 Med Ctr Dr,6E116,MSC 7991, Bethesda, MD 20892 USA. EM lerrocc@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015 OI Beane Freeman, Laura/0000-0003-1294-4124 FU Intramural Research Program of the National institutes of Health; US Environmental Protection Agency FX We would like to thank Dr. Ruth Allen and the University of Iowa field staff including Patricia Gillette, MPH (Special Studies Coordinator), Jeanne De Wall, MA (Field Coordinator), Carol Synder, and Alicia Intlekofer (phlebotomists) for their study contributions, This work was supported by the Intramural Research Program of the National institutes of Health and the US Environmental Protection Agency. NR 52 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD JAN PY 2017 VL 58 IS 1 BP 30 EP 38 DI 10.1002/em.22069 PG 9 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA EL5SJ UT WOS:000394680800003 PM 28116766 ER PT J AU Cohen-Fix, O Askjaer, P AF Cohen-Fix, Orna Askjaer, Peter TI Cell Biology of the Caenorhabditis elegans Nucleus SO GENETICS LA English DT Review DE Caenorhabditis elegans; chromatin; gene expression; lamin; LEM-domain proteins; LINC; P granule; nuclear pore complex; nuclear envelope; nucleocytoplasmic transport; nucleolus; WormBook ID MESSENGER-RNA EXPORT; SUN PROTEIN UNC-84; GILFORD-PROGERIA-SYNDROME; GERMLINE P GRANULES; AFFECT LIFE-SPAN; C.-ELEGANS; PORE COMPLEX; ENVELOPE BREAKDOWN; ENDOPLASMIC-RETICULUM; GENE-EXPRESSION AB Studies on the Caenorhabditis elegans nucleus have provided fascinating insight to the organization and activities of eukaryotic cells. Being the organelle that holds the genetic blueprint of the cell, the nucleus is critical for basically every aspect of cell biology. The stereotypical development of C. elegans from a one cell-stage embryo to a fertile hermaphrodite with 959 somatic nuclei has allowed the identification of mutants with specific alterations in gene expression programs, nuclear morphology, or nuclear positioning. Moreover, the early C. elegans embryo is an excellent model to dissect the mitotic processes of nuclear disassembly and reformation with high spatiotemporal resolution. We review here several features of the C. elegans nucleus, including its composition, structure, and dynamics. We also discuss the spatial organization of chromatin and regulation of gene expression and how this depends on tight control of nucleocytoplasmic transport. Finally, the extensive connections of the nucleus with the cytoskeleton and their implications during development are described. Most processes of the C. elegans nucleus are evolutionarily conserved, highlighting the relevance of this powerful and versatile model organism to human biology. C1 [Cohen-Fix, Orna] NIDDK, Lab Mol & Cellular Biol, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. [Askjaer, Peter] Univ Pablo Olavide, Junta Andalucia, CSIC, Andalusian Ctr Dev Biol, Carretera Utrera Km 1, Seville 41013, Spain. RP Cohen-Fix, O (reprint author), NIDDK, Lab Mol & Cellular Biol, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA.; Askjaer, P (reprint author), Univ Pablo Olavide, Junta Andalucia, CSIC, Andalusian Ctr Dev Biol, Carretera Utrera Km 1, Seville 41013, Spain. EM ornacf@helix.nih.gov; pask@upo.es OI Askjaer, Peter/0000-0003-3192-4428 FU Spanish Ministry of Economy and Competitiveness [BFU2013-42709P]; European Regional Development Fund; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD FX We thank Daniel A. Starr for discussions on LINC function and Thomas Schwartz for identifying potential C. elegans orthologs of NUP88 and GLE1. We also wish to thank Victor Carranco for help with figures. We apologize to our colleagues whose excellent work has not been discussed here owing to space limitation. Work in the O.C.-F. laboratory is funded by an intramural grant from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. Work in the P.A. laboratory is funded by the Spanish Ministry of Economy and Competitiveness (BFU2013-42709P) and the European Regional Development Fund. NR 242 TC 0 Z9 0 U1 0 U2 0 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD JAN PY 2017 VL 205 IS 1 BP 25 EP 59 DI 10.1534/genetics.116.197160 PG 35 WC Genetics & Heredity SC Genetics & Heredity GA EK1HV UT WOS:000393677300003 PM 28049702 ER PT J AU Yang, DH Jung, KW Bang, S Lee, JW Song, MH Floyd-Averette, A Festa, RA Ianiri, G Idnurm, A Thiele, DJ Heitman, J Bahn, YS AF Yang, Dong-Hoon Jung, Kwang-Woo Bang, Soohyun Lee, Jang-Won Song, Min-Hee Floyd-Averette, Anna Festa, Richard A. Ianiri, Giuseppe Idnurm, Alexander Thiele, Dennis J. Heitman, Joseph Bahn, Yong-Sun TI Rewiring of Signaling Networks Modulating Thermotolerance in the Human Pathogen Cryptococcus neoformans SO GENETICS LA English DT Article DE Hsf1; Sch9; transcriptome analysis; high temperature; Cryptococcus neoformans ID HEAT-SHOCK FACTOR; SKN7 RESPONSE REGULATOR; CELL-WALL INTEGRITY; SACCHAROMYCES-CEREVISIAE; TRANSCRIPTION FACTOR; IN-VIVO; TRANSDUCTION PATHWAY; OXIDATIVE STRESS; HIGH-TEMPERATURE; HSP90 CHAPERONE AB Thermotolerance is a crucial virulence attribute for human pathogens, including the fungus Cryptococcus neoformans that causes fatal meningitis in humans. Loss of the protein kinase Sch9 increases C. neoformans thermotolerance, but its regulatory mechanism has remained unknown. Here, we studied the Sch9-dependent and Sch9-independent signaling networks modulating C. neoformans thermotolerance by using genome-wide transcriptome analysis and reverse genetic approaches. During temperature upshift, genes encoding for molecular chaperones and heat shock proteins were upregulated, whereas those for translation, transcription, and sterol biosynthesis were highly suppressed. In this process, Sch9 regulated basal expression levels or induced/repressed expression levels of some temperature-responsive genes, including heat shock transcription factor (HSF1) and heat shock proteins (HSP104 and SSA1). Notably, we found that the HSF1 transcript abundance decreased but the Hsf1 protein became transiently phosphorylated during temperature upshift. Nevertheless, Hsf1 is essential for growth and its overexpression promoted C. neoformans thermotolerance. Transcriptome analysis using an HSF1 overexpressing strain revealed a dual role of Hsf1 in the oxidative stress response and thermotolerance. Chromatin immunoprecipitation demonstrated that Hsf1 binds to the step-type like heat shock element (HSE) of its target genes more efficiently than to the perfect- or gap-type HSE. This study provides insight into the thermotolerance of C. neoformans by elucidating the regulatory mechanisms of Sch9 and Hsf1 through the genome-scale identification of temperature-dependent genes. C1 [Yang, Dong-Hoon; Jung, Kwang-Woo; Bang, Soohyun; Lee, Jang-Won; Song, Min-Hee; Bahn, Yong-Sun] Yonsei Univ, Dept Biotechnol, 50 Yonsei Ro, Seoul 03722, South Korea. [Floyd-Averette, Anna; Festa, Richard A.; Ianiri, Giuseppe; Thiele, Dennis J.; Heitman, Joseph] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. [Floyd-Averette, Anna; Ianiri, Giuseppe; Heitman, Joseph] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Floyd-Averette, Anna; Festa, Richard A.; Ianiri, Giuseppe; Thiele, Dennis J.; Heitman, Joseph] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Idnurm, Alexander] Univ Melbourne, Sch Biosci, Melbourne, Vic 3010, Australia. [Yang, Dong-Hoon] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Festa, Richard A.] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA. RP Bahn, YS (reprint author), Yonsei Univ, Dept Biotechnol, 50 Yonsei Ro, Seoul 03722, South Korea. EM ysbahn@yonsei.ac.kr FU National Research Foundation of Korea from the Ministry of Science, ICT and Future Planning [2015R1A2A1A15055687]; Strategic Initiative for Microbiomes in Agriculture and Food - Ministry of Agriculture, Food and Rural Affairs [9160062]; National Institutes of Health [R21-AI094364, R37-AI39115-19, R01-AI50113-12, R01-GM041840, F32-GM100678] FX This work was supported by National Research Foundation of Korea grants (2015R1A2A1A15055687) from the Ministry of Science, ICT and Future Planning and the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (9160062) (to Y.-S.B.). The work was also supported in part by National Institutes of Health grants R21-AI094364 (to A. I.), R37-AI39115-19 and R01-AI50113-12 (to J.H.), R01-GM041840 (to D.J.T.), and F32-GM100678 (to R.A.F.). NR 60 TC 0 Z9 0 U1 0 U2 0 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD JAN PY 2017 VL 205 IS 1 BP 201 EP + DI 10.1534/genetics.116.190595 PG 43 WC Genetics & Heredity SC Genetics & Heredity GA EK1HV UT WOS:000393677300014 PM 27866167 ER PT J AU Keysar, SB Le, PN Miller, B Jackson, BC Eagles, JR Nieto, C Kim, J Tang, BW Glogowska, MJ Morton, JJ Padilla-Just, N Gomez, K Warnock, E Reisinger, J Arcaroli, JJ Messersmith, WA Wakefield, LM Gao, DX Tan, AC Serracino, H Vasiliou, V Roop, DR Wang, XJ Jimeno, A AF Keysar, Stephen B. Le, Phuong N. Miller, Bettina Jackson, Brian C. Eagles, Justin R. Nieto, Cera Kim, Jihye Tang, Binwu Glogowska, Magdalena J. Morton, J. Jason Padilla-Just, Nuria Gomez, Karina Warnock, Emily Reisinger, Julie Arcaroli, John J. Messersmith, Wells A. Wakefield, Lalage M. Gao, Dexiang Tan, Aik-Choon Serracino, Hilary Vasiliou, Vasilis Roop, Dennis R. Wang, Xiao-Jing Jimeno, Antonio TI Regulation of Head and Neck Squamous Cancer Stem Cells by PI3K and SOX2 SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID TO-MESENCHYMAL TRANSITION; HUMAN-PAPILLOMAVIRUS; SIGNALING PATHWAY; UNITED-STATES; CARCINOMA; METASTASIS; EXPRESSION; RESISTANCE; INHIBITORS; MUTATIONS AB Background: We have an incomplete understanding of the differences between cancer stem cells (CSCs) in human papillomavirus-positive (HPV-positive) and -negative (HPV-negative) head and neck squamous cell cancer (HNSCC). The PI3K pathway has the most frequent activating genetic events in HNSCC (especially HPV-positive driven), but the differential signaling between CSCs and non-CSCs is also unknown. Methods: We addressed these unresolved questions using CSCs identified from 10 HNSCC patient-derived xenografts (PDXs). Sored populations were serially passaged in nude mice to evaluate tumorigenicity and tumor recapitulation. The transcription profile of HNSCC CSCs was characterized by mRNA sequencing, and the susceptibility of CSCs to therapy was investigated using an in vivo model. SOX2 transcriptional activity was used to follow the asymmetric division of PDX-derived CSCs. All statistical tests were two-sided. Results: CSCs were enriched by high aldehyde dehydrogenase (ALDH) activity and CD44 expression and were similar between HPV-positive and HPV-negative cases (percent tumor formation injecting <= 1x10(3) cells: ALDH(+)CD44(high) = 65.8%, ALDH(-)CD44(high) = 33.1%, ALDH(+)CD44(high) = 20.0%; and injecting 1x10(5) cells: ALDH(-)CD44(low) = 4.4%). CSCs were resistant to conventional therapy and had PI3K/mTOR pathway overexpression (GSEA pathway enrichment, P < .001), and PI3K inhibition in vivo decreased their tumorigenicity (40.0%-100.0% across cases). PI3K/mTOR directly regulated SOX2 protein levels, and SOX2 in turn activated ALDH1A1 (P < .001 013C and 067C) expression and ALDH activity (ALDH(+) [%] empty-control vs SOX2, 0.4% +/- 0.4% vs 14.5% +/- 9.8%, P = .03 for 013C and 1.7% +/- 1.3% vs 3.6% +/- 3.4%, P = .04 for 067C) in 013C and 067 cells. SOX2 enhanced sphere and tumor growth (spheres/well, 013C P < .001 and 067C P = .04) and therapy resistance. SOX2 expression prompted mesenchymal-to-epithelial transition (MET) by inducing CDH1 (013C P = .002, 067C P = .01), followed by asymmetric division and proliferation, which contributed to tumor formation. Conclusions: The molecular link between PI3K activation and CSC properties found in this study provides insights into therapeutic strategies for HNSCC. Constitutive expression of SOX2 in HNSCC cells generates a CSC-like population that enables CSC studies. C1 [Keysar, Stephen B.; Le, Phuong N.; Miller, Bettina; Jackson, Brian C.; Eagles, Justin R.; Nieto, Cera; Kim, Jihye; Glogowska, Magdalena J.; Morton, J. Jason; Padilla-Just, Nuria; Gomez, Karina; Warnock, Emily; Reisinger, Julie; Arcaroli, John J.; Messersmith, Wells A.; Tan, Aik-Choon; Jimeno, Antonio] Univ Colorado, Dept Med, Denver Sch Med, Denver, CO USA. [Kim, Jihye; Gao, Dexiang; Tan, Aik-Choon] Univ Colorado, Dept Biostat & Informat, Denver Sch Med, Denver, CO 80202 USA. [Serracino, Hilary; Wang, Xiao-Jing] Univ Colorado, Dept Pathol, Denver Sch Med, Denver, CO 80202 USA. [Roop, Dennis R.] Univ Colorado, Dept Dermatol, Denver Sch Med, Denver, CO 80202 USA. [Roop, Dennis R.; Wang, Xiao-Jing; Jimeno, Antonio] Univ Colorado, Gates Ctr Regenerat Med, Denver Sch Med, Denver, CO 80202 USA. [Tang, Binwu; Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Vasiliou, Vasilis] Yale Sch Med, Yale Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT USA. RP Jimeno, A (reprint author), Univ Colorado, Ctr Canc, Otolaryngol, 12 801 East 17th Ave,Room L18-8101B, Aurora, CO 80045 USA.; Jimeno, A (reprint author), Univ Colorado, Gates Ctr Regenerat Med, Sch Med, 12 801 East 17th Ave,Room L18-8101B, Aurora, CO 80045 USA. EM antonio.jimeno@ucdenver.edu FU National Institutes of Health [R01CA149456, R21DE019712, R01DE024371]; University of Colorado Cancer Center Support Grant [P30-CA046934]; University of Colorado Skin Diseases Research Center Support Grant [P30-AR057212]; Ruth L. Kirschstein National Research Service Award [T32CA17468]; Training in Otolaryngology Research [T32DC012280]; Daniel and Janet Mordecai Foundation; Peter and Rhonda Grant Foundation; [DE020649]; [U01AA021724] FX This work was supported by National Institutes of Health grants R01CA149456 (AJ), R21DE019712 (AJ), and R01DE024371 (XJW and AJ); and P30-CA046934 (University of Colorado Cancer Center Support Grant), P30-AR057212 (University of Colorado Skin Diseases Research Center Support Grant), DE020649 (XJW), U01AA021724 (VV), Ruth L. Kirschstein National Research Service Award T32CA17468 (XJW; PNL trainee), Training in Otolaryngology Research T32DC012280 (CN trainee), the Daniel and Janet Mordecai Foundation (AJ), and the Peter and Rhonda Grant Foundation (AJ). NR 44 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD JAN PY 2017 VL 109 IS 1 AR djw189 DI 10.1093/jnci/djw189 PG 12 WC Oncology SC Oncology GA EK4LX UT WOS:000393899400012 ER PT J AU Spurgeon, SE Till, BG Martin, P Goy, AH Dreyling, MP Gopal, AK LeBlanc, M Leonard, JP Friedberg, JW Baizer, L Little, RF Kahl, BS Smith, MR AF Spurgeon, Stephen E. Till, Brian G. Martin, Peter Goy, Andre H. Dreyling, Martin P. Gopal, Ajay K. LeBlanc, Michael Leonard, John P. Friedberg, Jonathan W. Baizer, Lawrence Little, Richard F. Kahl, Brad S. Smith, Mitchell R. TI Recommendations for Clinical Trial Development in Mantle Cell Lymphoma SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID MINIMAL RESIDUAL DISEASE; PROGRESSION-FREE SURVIVAL; NON-HODGKIN-LYMPHOMA; PHASE-II TRIAL; EMISSION TOMOGRAPHY/COMPUTED TOMOGRAPHY; COOPERATIVE-ONCOLOGY-GROUP; POLYMERASE-CHAIN-REACTION; PARAFFIN-EMBEDDED TISSUE; EUROPEAN-MCL-NETWORK; MAINTENANCE RITUXIMAB AB Mantle cell lymphoma (MCL) comprises around 6% of all non-Hodgkin's lymphoma (NHL) diagnoses. In younger patients, age less than 60 to 65 years, aggressive induction often followed by consolidation with autologous stem cell transplant has suggested improved outcomes in this population. Less intensive therapies in older patients often followed by maintenance have been studied or are under active investigation. However, despite recent advances, MCL remains incurable, with a median overall survival of around five years. Patients with high-risk disease have particularly poor outcomes. Treatment varies widely across institutions, and to date no randomized trials comparing intensive vs less intensive approaches have been reported. Although recent data have highlighted the heterogeneity of MCL outcomes, patient assessment for treatment selection has largely been driven by patient age with little regard to fitness, disease biology, or disease risk. One critical advance is the finding that minimal residual disease status (MRD) after induction correlates with long-term outcomes. As such, its use as a potential end point could inform clinical trial design. In order to more rapidly improve the outcomes of MCL patients, clinical trials are needed that prospectively stratify patients on the basis of MCL biology and disease risk, incorporate novel agents, and use MRD to guide the need for additional therapy. C1 [Spurgeon, Stephen E.] Oregon Hlth & Sci OHSU Univ, Div Hematol & Med Oncol, Knight Canc Inst, Portland, OR USA. [Till, Brian G.; Gopal, Ajay K.] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Clin Res, Dept Med,Div Med Oncol, Seattle, WA 98195 USA. [Martin, Peter; Leonard, John P.] Weill Cornell Med, Dept Med, New York, NY USA. [Goy, Andre H.] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Dreyling, Martin P.] Klinikum Univ Munchen, Dept Med 3, Campus Grosshadern, Munich, Germany. [LeBlanc, Michael] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Friedberg, Jonathan W.] Univ Rochester, Wilmot Canc Ctr, Rochester, NY USA. [Friedberg, Jonathan W.] Univ Rochester, Div Hematol Oncol, Rochester, NY USA. [Baizer, Lawrence] NCI, Coordinating Ctr Clin Trials, NIH, Bethesda, MD 20892 USA. [Little, Richard F.] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Little, Richard F.] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Kahl, Brad S.] Washington Univ, Div Oncol, Dept Med, St Louis, MO USA. [Smith, Mitchell R.] Cleveland Clin, Dept Hematol & Med Oncol, Taussig Canc Inst, Cleveland, OH 44106 USA. RP Spurgeon, SE (reprint author), OHSU Knight Canc Inst, Div Hematol & Med Oncol, 3181 Sam Jackson Pk Rd, Portland, OR 97239 USA. EM spurgeos@ohsu.edu FU Office of the Director, Coordinating Center for Clinical Trials, National Cancer Institute/National Institutes of Health FX Partial support was from the Office of the Director, Coordinating Center for Clinical Trials, National Cancer Institute/National Institutes of Health. NR 96 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD JAN PY 2017 VL 109 IS 1 AR djw263 DI 10.1093/jnci/djw263 PG 10 WC Oncology SC Oncology GA EK4LX UT WOS:000393899400020 ER PT J AU Tian, Y Schwieters, CD Opella, SJ Marassi, FM AF Tian, Ye Schwieters, Charles D. Opella, Stanley J. Marassi, Francesca M. TI High quality NMR structures: a new force field with implicit water and membrane solvation for Xplor-NIH SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Structure calculation; Implicit solvent; Membrane protein; Eefx; Force field ID SOLID-STATE NMR; MACROMOLECULAR STRUCTURE DETERMINATION; MOLECULAR-STRUCTURE DETERMINATION; PROTEIN-STRUCTURE DETERMINATION; ANABAENA SENSORY RHODOPSIN; EFFECTIVE ENERGY FUNCTION; N-TERMINAL DOMAIN; BIOMOLECULAR SIMULATION; STRUCTURE REFINEMENT; STRUCTURE VALIDATION AB Structure determination of proteins by NMR is unique in its ability to measure restraints, very accurately, in environments and under conditions that closely mimic those encountered in vivo. For example, advances in solid-state NMR methods enable structure determination of membrane proteins in detergent-free lipid bilayers, and of large soluble proteins prepared by sedimentation, while parallel advances in solution NMR methods and optimization of detergent-free lipid nanodiscs are rapidly pushing the envelope of the size limit for both soluble and membrane proteins. These experimental advantages, however, are partially squandered during structure calculation, because the commonly used force fields are purely repulsive and neglect solvation, Van der Waals forces and electrostatic energy. Here we describe a new force field, and updated energy functions, for protein structure calculations with EEFx implicit solvation, electrostatics, and Van der Waals Lennard-Jones forces, in the widely used program Xplor-NIH. The new force field is based primarily on CHARMM22, facilitating calculations with a wider range of biomolecules. The new EEFx energy function has been rewritten to enable OpenMP parallelism, and optimized to enhance computation efficiency. It implements solvation, electrostatics, and Van der Waals energy terms together, thus ensuring more consistent and efficient computation of the complete nonbonded energy lists. Updates in the related python module allow detailed analysis of the interaction energies and associated parameters. The new force field and energy function work with both soluble proteins and membrane proteins, including those with cofactors or engineered tags, and are very effective in situations where there are sparse experimental restraints. Results obtained for NMR-restrained calculations with a set of five soluble proteins and five membrane proteins show that structures calculated with EEFx have significant improvements in accuracy, precision, and conformation, and that structure refinement can be obtained by short relaxation with EEFx to obtain improvements in these key metrics. These developments broaden the range of biomolecular structures that can be calculated with high fidelity from NMR restraints. C1 [Tian, Ye; Marassi, Francesca M.] Sanford Burnham Prebys Med Discovery Inst, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Schwieters, Charles D.] NIH, Ctr Informat Technol, Bldg 12A, Bethesda, MD 20892 USA. [Opella, Stanley J.] Univ Calif San Diego, Dept Chem & Biochem, 9500 Gilman Dr, La Jolla, CA 92093 USA. RP Marassi, FM (reprint author), Sanford Burnham Prebys Med Discovery Inst, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM fmarassi@sbmri.org FU National Institutes of Health [GM118186]; Resource for Molecular Imaging of Proteins at UCSD - National Institutes of Health [P41 EB002031]; Intramural Research Program of the Center for Information Technology at the National Institutes of Health FX We thank Vladimir Ladizhansky for helpful discussion. This research was supported by a grant from the National Institutes of Health (GM118186) and by the Resource for Molecular Imaging of Proteins at UCSD supported by the National Institutes of Health (P41 EB002031) and by the Intramural Research Program of the Center for Information Technology at the National Institutes of Health. NR 79 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 EI 1573-5001 J9 J BIOMOL NMR JI J. Biomol. NMR PD JAN PY 2017 VL 67 IS 1 BP 35 EP 49 DI 10.1007/s10858-016-0082-5 PG 15 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA EL1BG UT WOS:000394354900004 PM 28035651 ER PT J AU Goldstein, RB Chou, SP Saha, TD Smith, SM Jung, JS Zhang, HT Pickering, RP Ruan, WJ Huang, BJ Grant, BF AF Goldstein, Rise B. Chou, S. Patricia Saha, Tulshi D. Smith, Sharon M. Jung, Jeesun Zhang, Haitao Pickering, Roger P. Ruan, W. June Huang, Boji Grant, Bridget F. TI The Epidemiology of Antisocial Behavioral Syndromes in Adulthood: Results From the National Epidemiologic Survey on Alcohol and Related Conditions-III SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID 500 PSYCHIATRIC OUTPATIENTS; PERSONALITY-DISORDER; UNITED-STATES; FOLLOW-UP; GENERAL-POPULATION; COMORBIDITY-SURVEY; ANXIETY DISORDERS; SUBSTANCE-ABUSERS; CONDUCT DISORDER; 71 MEN AB Objective: To present current, nationally representative US findings on prevalence, correlates, psychiatric comorbidity, disability, and treatment of DSM-5 antisocial personality disorder (ASPD) and adulthood antisocial behavioral syndrome without conduct disorder before 15 years of age (AABS). Method: Face-to-face interviews were conducted with respondents (N = 36,309) in the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III. DSM-5 alcohol, nicotine, and specific drug use disorders and selected mood, anxiety, trauma-related, eating, and personality disorders were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-5. Results: Prevalences of ASPD and AABS were 4.3% and 20.3%, respectively, and were highest among male, white, Native American, younger, and unmarried respondents, those with high school or less education, lower incomes, and Western residence. Both antisocial syndromes were significantly associated with 12-month and lifetime substance use, dysthymia/persistent depressive, bipolar I, posttraumatic stress, and borderline and schizotypal personality disorders (odds ratios [ORs] = 1.2-7.0). ASPD was additionally associated with 12-month agoraphobia and lifetime generalized anxiety disorder (ORs = 1.3-1.6); AABS, with 12-month and lifetime major depressive and 12-month generalized anxiety disorders (ORs = 1.2-1.3). Both were associated with significant disability (P < .001 to .01). Most antisocial survey respondents were untreated. Conclusions: One in 4 US adults exhibits syndromal antisocial behavior, with similar sociodemographic and psychiatric correlates and disability regardless of whether onset occurred before 15 years of age, illustrating the clinical and public health significance of both ASPD and AABS. In addition to laying groundwork for estimates of social and economic costs, and further etiologic and nosologic research, these findings highlight the urgency of effectively preventing and treating antisocial syndromes, including investigation of whether treatment for comorbidity hastens symptomatic remission and improves quality-of-life outcomes. C1 [Goldstein, Rise B.; Chou, S. Patricia; Saha, Tulshi D.; Smith, Sharon M.; Jung, Jeesun; Zhang, Haitao; Pickering, Roger P.; Ruan, W. June; Huang, Boji; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD USA. RP Goldstein, RB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B13C,MS 7510, Bethesda, MD 20892 USA. EM goldster@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland; National Institutes of Health, NIAAA FX The National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III) is funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) with supplemental support from the National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland. This research was supported in part by the Intramural Program of the National Institutes of Health, NIAAA. NR 70 TC 0 Z9 0 U1 1 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JAN PY 2017 VL 78 IS 1 BP 90 EP 98 DI 10.4088/JCP.15m10358 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EN9OX UT WOS:000396330600013 PM 27035627 ER PT J AU Blanco, C Campbell, AN Wall, MM Olfson, M Wang, S Nunes, EV AF Blanco, Carlos Campbell, Aimee N. Wall, Melanie M. Olfson, Mark Wang, Shuai Nunes, Edward V. TI Toward National Estimates of Effectiveness of Treatment for Substance Use SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID ALCOHOL-USE DISORDER; INTERVIEW SCHEDULE AUDADIS; GENERALIZED ANXIETY DISORDER; PRACTICAL CLINICAL-TRIALS; EPIDEMIOLOGIC-SURVEY; COMMUNITY SAMPLES; DRUG MODULES; CARDIOVASCULAR RESEARCH; TARGET POPULATIONS; INDEPENDENT MOOD AB Objective: To estimate how results would have varied if a substance abuse clinical trial had been conducted with nationally representative adults with substance use and with representative adults receiving substance use treatment. Methods: Results were analyzed from a multisite clinical trial comparing the effectiveness of the Therapeutic Education System to treatment as usual for outpatient addiction treatment (n = 507). Patients were recruited between June 2010 and August 2011. Abstinence was the primary outcome. The general population sample and general population-treated samples were derived from Wave 1 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (n = 43,093). Propensity scores provided a standardized measure of the difference between clinical trial participants and the 2 NESARC samples. The clinical trial was reanalyzed by reweighting the sample with propensity scores derived from the 2 samples to obtain generalizable estimates of treatment effects. Results: Before the clinical trial sample was reweighted, the odds ratio (OR) of response to Therapeutic Education System versus treatment as usual in the trial was 1.62 (95% CI, 1.12-2.35). After the sample was reweighted to be representative of the 2 NESARC groups, ORs were 1.33 (95% CI, 0.34-5.26) for the representative sample with any substance use and 1.64 (95% CI, 0.82-3.27) for the representative treated sample. Conclusions: Applying propensity score weighting to clinical trial results provides a method for estimating the population generalizability of clinical trial findings that relies on effect moderators observed in the study sample and population. Broader confidence intervals in the reweighted samples do not necessarily indicate lack of efficacy of the Therapeutic Education System but rather greater uncertainty concerning effectiveness in general population samples. C1 [Blanco, Carlos] NIDA, Rockville, MD USA. [Campbell, Aimee N.; Wall, Melanie M.; Olfson, Mark; Wang, Shuai; Nunes, Edward V.] Columbia Univ, New York State Psychiat Inst, Dept Psychiat, 1051 Riverside Dr,Unit 24, New York, NY 10032 USA. [Wall, Melanie M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. RP Olfson, M (reprint author), Columbia Univ, New York State Psychiat Inst, Dept Psychiat, 1051 Riverside Dr,Unit 24, New York, NY 10032 USA. EM mo49@cumc.columbia.edu FU National Institute of Health [DA023200, MH0760551, MH082773]; New York State Psychiatric Institute FX Work on this article was supported by National Institute of Health grants DA023200, MH0760551, and MH082773 (Dr Blanco), and the New York State Psychiatric Institute (Drs Blanco, Nunes, Olfson, and Wall). NR 46 TC 0 Z9 0 U1 0 U2 0 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JAN PY 2017 VL 78 IS 1 BP E64 EP E70 DI 10.4088/JCP.15m10333 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EN9OX UT WOS:000396330600007 PM 28129499 ER PT J AU Jensen, JD Yale, RN Krakow, M John, KK King, AJ AF Jensen, Jakob D. Yale, Robert N. Krakow, Melinda John, Kevin K. King, Andy J. TI Theorizing Foreshadowed Death Narratives: Examining the Impact of Character Death on Narrative Processing and Skin Self-Exam Intentions SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID PARALLEL PROCESS MODEL; LOSS-FRAMED MESSAGES; RANDOMIZED CONTROLLED-TRIAL; CANCER SURVIVOR STORIES; AFRICAN-AMERICAN WOMEN; ENTERTAINMENT-EDUCATION; RELATIVE PERSUASIVENESS; HEALTH-PROMOTION; COMMUNICATION; MELANOMA AB Narratives are common in health campaigns and interventions, with many depicting individuals battling a particular illness or disease. Past research has focused primarily on the form and effects of survivor stories, but considerably less attention has been devoted to stories in which 1 or more of the central characters passes away. The goal of the current study was to compare the relative persuasive impact of survivor and death narratives in influencing skin prevention behaviors and to test narrative mediators that might explicate underlying mechanisms of effect. To that end, adults (N=635, M age=32.43 [SD =11.23]) were randdomly assigned to 1 of 6 narrative intervention conditions in an online message experiment. Participants read 1 of 2 stories about a person with melanoma (Rusty or Diane) that was manipulated as a narrative depicting the survival, death, or foreshadowed death of the main character. Foreshaowed death narratives increased intentions to perform a skin self-exam (SSE), a relationship that was mediated by narrative transportation and perceived SSE benefits. The results support the central postulate of narrative transportation theory and the utility of using foreshadowed death narratives in communication-based interventions designed to increase SSE frequency. C1 [Jensen, Jakob D.] Univ Utah, Dept Commun, 2618 LNCO,255 South Cent Campus Dr, Salt Lake City, UT 84112 USA. [Yale, Robert N.] Univ Dallas, Satish & Yasmin Gupta Coll Business, Dallas, TX USA. [Krakow, Melinda] NCI, Bethesda, MD 20892 USA. [John, Kevin K.] Brigham Young Univ, Sch Commun, Provo, UT 84602 USA. [King, Andy J.] Texas Tech Univ, Dept Publ Relat, Lubbock, TX 79409 USA. RP Jensen, JD (reprint author), Univ Utah, Dept Commun, 2618 LNCO,255 South Cent Campus Dr, Salt Lake City, UT 84112 USA. EM jakob.jensen@utah.edu FU National Institutes of Health [1DP2EB022360-01] FX This article was written with support from National Institutes of Health Grant No. 1DP2EB022360-01 (principal investigator: J. Jensen). NR 56 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PY 2017 VL 22 IS 1 BP 84 EP 93 DI 10.1080/10810730.2016.1252816 PG 10 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA EK3XV UT WOS:000393862600010 PM 28060585 ER PT J AU Sanossian, N Fu, KA Liebeskind, DS Starkman, S Hamilton, S Villablanca, JP Burgos, AM Conwit, R Saver, JL AF Sanossian, Nerses Fu, Katherine A. Liebeskind, David S. Starkman, Sidney Hamilton, Scott Villablanca, J. Pablo Burgos, Adrian M. Conwit, Robin Saver, Jeffrey L. TI Utilization of Emergent Neuroimaging for Thrombolysis-Eligible Stroke Patients SO JOURNAL OF NEUROIMAGING LA English DT Article DE Imaging; prehospital; stroke; emergency medical services ID ACUTE ISCHEMIC-STROKE; ANGIOGRAPHY SOURCE IMAGES; COMPUTED-TOMOGRAPHY; FUTILE RECANALIZATION; INFORMED-CONSENT; PERFUSION; MANAGEMENT; ASSOCIATION; METHODOLOGY; ELICITATION AB BACKGROUND: Advances in diagnostic imaging of stroke include multimodal techniques such as noninvasive angiography and perfusion imaging. We aimed to characterize trends in neuroimaging utilization among acute stroke patients. Utilization of multimodal imaging for acute stroke in the community has remained largely uncharacterized despite its increased adoption at academic medical centers. METHODS: We quantified neuroimaging utilization in the emergency department (ED) for 1,700 hyperacute stroke patients presenting < 2 hours after symptom onset who participated in the National Institutes of Health Field Administration of Stroke Therapy-Magnesium (FAST-MAG) study throughout Los Angeles and Orange Counties. FAST-MAG provided no recommendation as to imaging utilization. RESULTS: A total of 1,700 cases were imaged a median (interquartile range [IQR]) of 92 (74-120) minutes after last known well time and 28 (19-41) minutes after ED arrival. The initial scanner used in the ED was computed tomography (CT) in a preponderance of cases (N = 1,612, 95%), with magnetic resonance imaging (MRI) in 88 cases (5%). CT angiography (CTA) was obtained in 192 (11%) and perfusion CT (CTP) in 91 (5.4%) cases. MRI imaging was universally obtained using diffusion-weighted images, 60% with MR angiography and 33% included perfusion imaging. Rates of concomitant CTA or CTP use increased in the later years of the study from 4% in 2005-2006, 2% in 2007-2008, 8% in 2009-2010, and 26% in 2011-2012 (P for trend < .001). CONCLUSIONS: Among acute stroke patients, noncontrast CT was the most common initial imaging strategy in clinical practice in the 2005-2012 time period, though use of concomitant CTA grew to one-quarter of cases, suggestive of an upward trend. C1 [Sanossian, Nerses; Fu, Katherine A.; Burgos, Adrian M.] Univ Southern Calif, Roxanna Todd Hodges Comprehens Stroke Clin, 1540 Alcazar St,Suite 209, Los Angeles, CA 90089 USA. [Sanossian, Nerses; Fu, Katherine A.; Burgos, Adrian M.] Univ Southern Calif, Dept Neurol, 1540 Alcazar St,Suite 209, Los Angeles, CA 90089 USA. [Liebeskind, David S.] Univ Calif Los Angeles, Neurovasc Imaging Res Core, Los Angeles, CA USA. [Liebeskind, David S.; Starkman, Sidney; Villablanca, J. Pablo; Saver, Jeffrey L.] Univ Calif Los Angeles, Stroke Ctr, Los Angeles, CA USA. [Hamilton, Scott] Stanford Univ, Stanford, CA 94305 USA. [Conwit, Robin] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Sanossian, N (reprint author), Univ Southern Calif, Roxanna Todd Hodges Comprehens Stroke Clin, 1540 Alcazar St,Suite 209, Los Angeles, CA 90089 USA.; Sanossian, N (reprint author), Univ Southern Calif, Dept Neurol, 1540 Alcazar St,Suite 209, Los Angeles, CA 90089 USA. EM sanossia@yahoo.com FU NIH-NINDS Award [U01 NS 44364] FX This work was supported by NIH-NINDS Award U01 NS 44364. NR 27 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-2284 EI 1552-6569 J9 J NEUROIMAGING JI J. Neuroimaging PD JAN-FEB PY 2017 VL 27 IS 1 BP 59 EP 64 DI 10.1111/jon.12369 PG 6 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EK4MK UT WOS:000393900700009 PM 27300498 ER PT J AU Mao, X Gu, XL Lu, W AF Mao, Xia Gu, Xinglong Lu, Wei TI GSG1L regulates the strength of AMPA receptor-mediated synaptic transmission but not AMPA receptor kinetics in hippocampal dentate granule neurons SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE AMPA receptor; GSG1L; deactivation; desensitization; synapse; hippocampus; outside-out patch ID TRANSMEMBRANE AUXILIARY SUBUNITS; CALCIUM-PERMEABLE AMPARS; GLUTAMATE RECEPTORS; CORNICHON PROTEINS; TARPS; STARGAZIN; TRAFFICKING; PLASTICITY; EXPRESSION; DESENSITIZATION AB GSG1L is an AMPA receptor (AMPAR) auxiliary subunit that regulates AMPAR trafficking and function in hippocampal CA1 pyramidal neurons. However, its physiological roles in other types of neurons remain to be characterized. Here, we investigated the role of GSG1L in hippocampal dentate granule cells and found that GSG1L is important for the regulation of synaptic strength but is not critical for the modulation of AMPAR deactivation and desensitization kinetics. These data demonstrate a neuronal type-specific role of GSG1L and suggest that physiological function of AMPAR auxiliary subunits may vary in different types of neurons. NEW & NOTEWORTHY GSG1L is a newly identified AMPA receptor (AMPAR) auxiliary subunit and plays a unique role in the regulation of AMPAR trafficking and function in hippocampal CA1 pyramidal neurons. However, its role in the regulation of AMPARs in hippocampal dentate granule cells remains to be characterized. The current work reveals that GSG1L regulates strength of AMPAR-mediated synaptic transmission but not the receptor kinetic properties in hippocampal dentate granule neurons. C1 [Mao, Xia; Gu, Xinglong; Lu, Wei] NINDS, Synapse & Neural Circuit Res Unit, NIH, Bethesda, MD 20892 USA. RP Lu, W (reprint author), 3C-1000 35 Convent Dr, Bethesda, MD 20892 USA. EM luw4@mail.nih.gov FU NINDS Intramural Research Program FX This work was supported by the NINDS Intramural Research Program (W. Lu). NR 41 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JAN 1 PY 2017 VL 117 IS 1 BP 28 EP 35 DI 10.1152/jn.00307.2016 PG 8 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA EK3WZ UT WOS:000393860400004 PM 27707810 ER PT J AU Garcia-Contreras, L Padilla-Carlin, DJ Sung, J VerBerkmoes, J Muttil, P Elbert, K Peloquin, C Edwards, D Hickey, A AF Garcia-Contreras, Lucila Padilla-Carlin, Danielle J. Sung, Jean VerBerkmoes, Jarod Muttil, Pavan Elbert, Katharina Peloquin, Charles Edwards, David Hickey, Anthony TI Pharmacokinetics of Ethionamide Delivered in Spray-Dried Microparticles to the Lungs of Guinea Pigs SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE tuberculosis; ethionamide; porous particles; bioavailability; pharmacokinetics and pulmonary absorption ID LARGE POROUS PARTICLES; PULMONARY DRUG-DELIVERY; RESISTANT TUBERCULOSIS; INHALATION; POWDER; AEROSOL; FORMULATION; PROTHIONAMIDE; CAPREOMYCIN; STRATEGIES AB The use of ethionamide (ETH) in treating multidrug-resistant tuberculosis is limited by severe side effects. ETH disposition after pulmonary administration in spray-dried particles might minimize systemic exposure and side effects. To explore this hypothesis, spray-dried ETH particles were optimized for performance in a dry powder aerosol generator and exposure chamber. ETH particles were administered by the intravenous (IV), oral, or pulmonary routes to guinea pigs. ETH appearance in plasma, bronchoalveolar lavage, and lung tissues was measured and subjected to noncompartmental pharma-cokinetic analysis. Dry powder aerosol generator dispersion of 20% ETH particles gave the highest dose at the exposure chamber ports and fine particle fraction of 72.3%. Pulmonary ETH was absorbed more rapidly and to a greater extent than orally administered drug. At T-max, ETH concentrations were significantly higher in plasma than lungs from IV dosing, whereas insufflation lung concentrations were 5-fold higher than in plasma. AUC((0-t)) (area under the curve) and apparent total body clearance (CL) were similar after IV administration and insufflation. AUC((0-t)) after oral administration was 6- to 7-fold smaller and CL was 6-fold faster. Notably, ETH bioavailability after pulmonary administration was significantly higher (85%) than after oral administration (17%). These results suggest that pulmonary ETH delivery would potentially enhance efficacy for tuberculosis treatment given the high lung concentrations and bioavailability. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Garcia-Contreras, Lucila] Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73104 USA. [Padilla-Carlin, Danielle J.] NIEHS, Ctr Risk & Integrated Sci, Div Extramural Res & Training, RTP, Durham, NC 27709 USA. [Sung, Jean; VerBerkmoes, Jarod; Elbert, Katharina; Edwards, David] Harvard Univ, Biomed Engn, John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Sung, Jean] Pulmatrix, Dept Pharmaceut Dev, Lexington, MA 02421 USA. [Muttil, Pavan] Univ New Mexico, Coll Pharm, Dept Pharmaceut Sci, Albuquerque, NM 87131 USA. [Peloquin, Charles] Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL 32611 USA. [Hickey, Anthony] RTP, RTI Int, Discovery Sci & Technol, Durham, NC 27709 USA. RP Garcia-Contreras, L (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73104 USA. EM lucila-garcia-contreras@ouhsc.edu FU National Institutes of Health/NIAID [5 U01 61336] FX This work was supported by a grant (5 U01 61336) from the National Institutes of Health/NIAID. NR 47 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD JAN PY 2017 VL 106 IS 1 BP 331 EP 337 DI 10.1016/j.xphs.2016.09.033 PG 7 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA EK4TU UT WOS:000393920500036 PM 27842973 ER PT J AU Liu, Y Kuczmarski, MF Miller, ER Nava, MB Zonderman, AB Evans, MK Powe, NR Crews, DC AF Liu, Yang Kuczmarski, Marie Fanelli Miller, Edgar R., III Nava, M. Berenice Zonderman, Alan B. Evans, Michele K. Powe, Neil R. Crews, Deidra C. TI Dietary Habits and Risk of Kidney Function Decline in an Urban Population SO JOURNAL OF RENAL NUTRITION LA English DT Article ID GLOMERULAR-FILTRATION-RATE; ACID LOAD; METABOLIC-ACIDOSIS; SUBGROUP ANALYSIS; SERUM MAGNESIUM; BLOOD-PRESSURE; OLDER-ADULTS; DISEASE; CKD; HYPERTENSION AB Objective: Explore the association between following a Dietary Approaches to Stop Hypertension (DASH)-accordant diet and kidney end points among urban adults. Design: Prospective cohort study. Setting: Healthy Aging in Neighborhoods of Diversity across the Life Span study. Subjects: A total of 1,534 urban dwelling participants of the Healthy Aging in Neighborhoods of Diversity across the Life Span study with a baseline estimated glomerular filtration rate (eGFR) >= 60 mL/minute/1.73 m(2). Intervention: DASH diet accordance determined via a score based on nine target nutrients. Main Outcome Measure: Rapid kidney function decline (eGFR decline >3 mL/minute/1.73 m(2) per year), incident chronic kidney disease (CKD) (follow-up eGFR <60 mL/minute/1.73 m(2)), and eGFR decline >25%. Results: Participants' mean age was 48 years, and 59% were African-American. Median DASH score was 1.5 (range, 0-8). Over a median of 5 years, 13.4% experienced rapid eGFR decline, including 15.2% among participants not following a DASH-accordant diet (score <= 1) and 12.0% with higher accordance (score >1) (P = .08). Outcomes varied by hypertension status. In multinomial logistic regression models, following adjustment for sociodemographic and clinical factors, including total energy intake, low DASH diet accordance was associated with rapid eGFR decline among participants with hypertension (risk ratio, 1.68; 95% confidence interval: 1.17-2.42) but not among those without hypertension (risk ratio, 0.83; 95% confidence interval: 0.56-1.24; P interaction .001). There was no statistically significant association between DASH diet accordance and incident CKD or eGFR decline >25%. Results were similar when DASH diet accordance was analyzed in tertiles. Conclusions: Among urban adults, low accordance to a DASH-type diet was not associated with incident CKD, but was associated with higher risk of rapid eGFR decline among those with hypertension, yet not among those without hypertension. Further study of dietary patterns as a potential target for improving kidney outcomes among high-risk populations is warranted. (C) 2016 by the National Kidney Foundation, Inc. All rights reserved C1 [Liu, Yang; Crews, Deidra C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21205 USA. [Kuczmarski, Marie Fanelli] Univ Delaware, Dept Behav Hlth & Nutr, Newark, DE USA. [Miller, Edgar R., III; Crews, Deidra C.] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [Miller, Edgar R., III] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. [Miller, Edgar R., III] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Nava, M. Berenice] Columbia Univ, Med Ctr, Div Nephrol, New York, NY USA. [Zonderman, Alan B.; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Powe, Neil R.] San Francisco Gen Hosp, Dept Med, San Francisco, CA 94110 USA. [Powe, Neil R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Crews, DC (reprint author), Johns Hopkins Univ, Sch Med, Div Nephrol, 301 Mason F Lord Dr,Suite 2500, Baltimore, MD 21224 USA. EM dcrews1@jhmi.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases, NIH [K23DK097184] FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH). Dr. Crews was supported by grant K23DK097184 from the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. NR 43 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 1051-2276 EI 1532-8503 J9 J RENAL NUTR JI J. Renal Nutr. PD JAN PY 2017 VL 27 IS 1 BP 16 EP 25 DI 10.1053/j.jrn.2016.08.007 PG 10 WC Nutrition & Dietetics; Urology & Nephrology SC Nutrition & Dietetics; Urology & Nephrology GA EK4KP UT WOS:000393895800003 PM 27771303 ER PT J AU Flick, MJ Bugge, TH AF Flick, M. J. Bugge, T. H. TI Plasminogen-receptor (KT): plasminogen activation and beyond SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Editorial Material ID FIBRINOGEN-DEFICIENT MICE; PLG-R-KT; LIGNEOUS CONJUNCTIVITIS; MEDIATED FIBRINOLYSIS; HISTONE H2B; IN-VITRO; KEY ROLE; BINDING; SURFACE; DIFFERENTIATION C1 [Flick, M. J.] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Bugge, T. H.] Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Flick, MJ (reprint author), Cincinnati Childrens Hosp, Canc & Blood Dis Inst, Div Expt Hematol & Canc Biol, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM matthew.flick@cchmc.org FU NHLBI [R01 HL112603]; Intramural Research Program of the NIH, NIDCR FX This research was supported by NHLBI (R01 HL112603) P.I. Matthew J. Flick, and by the Intramural Research Program of the NIH, NIDCR. NR 67 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JAN PY 2017 VL 15 IS 1 BP 150 EP 154 DI 10.1111/jth.13541 PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EK5OI UT WOS:000393975300020 PM 27740735 ER PT J AU Wilkerson, J Abdallah, K Hugh-Jones, C Curt, G Rothenberg, M Simantov, R Murphy, M Morrell, J Beetsch, J Sargent, DJ Scher, HI Lebowitz, P Simon, R Stein, WD Bates, SE Fojo, T AF Wilkerson, Julia Abdallah, Kald Hugh-Jones, Charles Curt, Greg Rothenberg, Mace Simantov, Ronit Murphy, Martin Morrell, Joseph Beetsch, Joel Sargent, Daniel J. Scher, Howard I. Lebowitz, Peter Simon, Richard Stein, Wilfred D. Bates, Susan E. Fojo, Tito TI Estimation of tumour regression and growth rates during treatment in patients with advanced prostate cancer: a retrospective analysis SO LANCET ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; DOCETAXEL PLUS PREDNISONE; PHASE-III TRIAL; OPEN-LABEL; RATE CONSTANTS; DOUBLE-BLIND; SURVIVAL; CHEMOTHERAPY; MITOXANTRONE; PLACEBO AB Background We applied mathematical models to clinical trial data available at Project Data Sphere LLC (Cary, NC, USA), a non-profit universal access data-sharing warehouse. Our aim was to assess the rates of cancer growth and regression using the comparator groups of eight randomised clinical trials that enrolled patients with metastatic castration-resistant prostate cancer. Methods In this retrospective analysis, we used data from eight randomised clinical trials with metastatic castration-resistant prostate cancer to estimate the growth (g) and regression (d) rates of disease burden over time. Rates were obtained by applying mathematical models to prostate-specific antigen levels as the representation of tumour quantity. Rates were compared between study interventions (prednisone, mitoxantrone, and docetaxel) and off-treatment data when on-study treatment had been discontinued to understand disease behaviour during treatment and after discontinuation. Growth (g) was examined for association with a traditional endpoint (overall survival) and for its potential use as an endpoint to reduce sample size in clinical trials. Findings Estimates for g, d, or both were obtained in 2353 (88%) of 2678 patients with data available for analysis; g differentiated docetaxel (a US Food and Drug Administration-approved therapy) from prednisone and mitoxantrone and was predictive of overall survival in a landmark analysis at 8 months. A simulated sample size analysis, in which g was used as the endpoint, compared docetaxel data with mitoxantrone data and showed that small sample sizes were sufficient to achieve 80% power (16, 47, and 25 patients, respectively, in the three docetaxel comparator groups). Similar results were found when the mitoxantrone data were compared with the prednisone data (41, 39, and 41 patients in the three mitoxantrone comparator groups). Finally, after discontinuation of docetaxel therapy, median tumour growth (g) increased by nearly five times. Interpretation The application of mathematical models to existing clinical data allowed estimation of rates of growth and regression that provided new insights in metastatic castration-resistant prostate cancer. The availability of clinical data through initiatives such as Project Data Sphere, when combined with innovative modelling techniques, could greatly enhance our understanding of how cancer responds to treatment, and accelerate the productivity of clinical development programmes. C1 [Wilkerson, Julia] NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD USA. [Abdallah, Kald; Curt, Greg] AstraZeneca, Gaithersburg, MD USA. [Hugh-Jones, Charles] Sanofi US, Bridgewater, NJ USA. [Rothenberg, Mace; Simantov, Ronit] Pfizer Inc, New York, NY USA. [Murphy, Martin; Morrell, Joseph] Project Data Sphere LLC, Cary, NC USA. [Beetsch, Joel] Celgene Corp, Summit, NJ USA. [Sargent, Daniel J.] Mayo Med Ctr, Rochester, MN USA. [Scher, Howard I.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Lebowitz, Peter] Johnson & Johnson, Janssen Pharmaceut Co, New Brunswick, NJ USA. [Simon, Richard] NCI, Biometr Res Program, NIH, Bethesda, MD USA. [Stein, Wilfred D.] Hebrew Univ Jerusalem, Silberman Inst Life Sci, Jerusalem, Israel. [Bates, Susan E.; Fojo, Tito] Columbia Univ, New York Presbyterian Hosp, Dept Med, Div Med Oncol, New York, NY USA. [Bates, Susan E.; Fojo, Tito] James J Peters VA Med Ctr, Bronx, NY USA. RP Fojo, T (reprint author), Univ Colombia, Div Med Oncol, Dept Med, Herbert Irving Pavil,9th Floor, New York, NY 10032 USA. EM atf2116@cumc.columbia.edu NR 35 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD JAN PY 2017 VL 18 IS 1 BP 143 EP 154 DI 10.1016/S1470-2045(16)30633-7 PG 12 WC Oncology SC Oncology GA EN9SX UT WOS:000396341000055 PM 27979599 ER PT J AU Manasanch, EE de Larrea, CF Zingone, A Steinberg, SM Kwok, M Tageja, N Bhutani, M Kazandjian, D Roschewski, M Wu, P Carter, G Zuchlinski, D Mulquin, M Lamping, L Costello, R Burton, D Gil, LA Figg, WD Maric, I Calvo, KR Yuan, C Stetler-Stevenson, M Korde, N Landgren, O AF Manasanch, Elisabet E. de larrea, Carlos Fernandez Zingone, Adriana Steinberg, Seth M. Kwok, Mary Tageja, Nishant Bhutani, Manisha Kazandjian, Dickran Roschewski, Mark Wu, Peter Carter, George Zuchlinski, Diamond Mulquin, Marcia Lamping, Liz Costello, Rene Burton, Deborah Gil, Lindsay A. Figg, William D. Maric, Irina Calvo, Katherine R. Yuan, Constance Stetler-Stevenson, Maryalice Korde, Neha Landgren, Ola TI Enzymatic activities of circulating plasma proteasomes in newly diagnosed multiple myeloma patients treated with carfilzomib, lenalidomide and dexamethasone SO LEUKEMIA & LYMPHOMA LA English DT Article DE Proteasome; myeloma; activity; biomarker ID CELLS; COMBINATION; BORTEZOMIB; LEUKEMIA; DISEASES; MARKERS AB The proteasome inhibitor carfilzomib is highly effective in the treatment of multiple myeloma. It irreversibly binds the chymotrypsin-like active site in the beta 5 subunit of the 20S proteasome. Despite impressive response rates when carfilzomib is used in combination with immunomodulatory agents in newly diagnosed multiple myeloma patients; no biomarker exists to accurately predict response and clinical outcomes. We prospectively assessed the activity in peripheral blood of the chymotrypsin-like (CHYM), caspase-like (CASP) and trypsin-like (TRYP) proteolytic sites in 45 newly diagnosed multiple myeloma patients treated with eight cycles of carfilzomib, lenalidomide and dexamethasone (CRd) (NCT01402284). Samples were collected per protocol and proteasome activity measured through a fluorogenic assay. Median CHYM levels after one dose of carfilzomib decreased by > 70%. CHYM and CASP activity decreased throughout treatment reaching a minimum after eight cycles of treatment. Higher levels of proteasome activity associated with higher disease burden (r > 0.30; p < 0.05) and higher disease stage (0.10 < p < 0.20). No association was found with the probability of achieving a complete response, minimal residual disease negativity or time to best response. Further studies evaluating proteasome activity in malignant plasma cells may help elucidate how proteasome activity can be used as a biomarker in multiple myeloma. C1 [Manasanch, Elisabet E.; de larrea, Carlos Fernandez; Zingone, Adriana; Kwok, Mary; Tageja, Nishant; Bhutani, Manisha; Kazandjian, Dickran; Roschewski, Mark; Wu, Peter; Carter, George; Zuchlinski, Diamond; Mulquin, Marcia; Lamping, Liz; Costello, Rene; Burton, Deborah; Gil, Lindsay A.; Figg, William D.; Korde, Neha; Landgren, Ola] NCI, Multiple Myeloma Sect, NIH, Bethesda, MD 20892 USA. [Manasanch, Elisabet E.] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Div Canc Med, Houston, TX 77030 USA. [de larrea, Carlos Fernandez] Univ Barcelona, IDIBAPS, Hosp Clin Barcelona, Dept Hematol,Amyloidosis & Myeloma Unit, Barcelona, Catalonia, Spain. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Maric, Irina; Calvo, Katherine R.] NIH, Lab Hematol, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Yuan, Constance; Stetler-Stevenson, Maryalice] NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Korde, Neha; Landgren, Ola] Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. RP Landgren, O (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. EM landgrec@mskcc.org NR 21 TC 2 Z9 2 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PY 2017 VL 58 IS 3 BP 639 EP 645 DI 10.1080/10428194.2016.1214953 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA EK4IW UT WOS:000393891300017 PM 27687480 ER PT J AU Shatzer, A Ali, MA Chavez, M Dowdell, K Lee, MJ Tomita, Y El-Hariry, I Trepel, JB Proia, DA Cohen, JI AF Shatzer, Amber Ali, Mir A. Chavez, Mayra Dowdell, Kennichi Lee, Min-Jung Tomita, Yusuke El-Hariry, Iman Trepel, Jane B. Proia, David A. Cohen, Jeffrey I. TI Ganetespib, an HSP90 inhibitor, kills Epstein-Barr virus (EBV)-infected B and T cells and reduces the percentage of EBV-infected cells in the blood SO LEUKEMIA & LYMPHOMA LA English DT Article DE Ganetespib; HSP90; Epstein-Barr virus; Burkitt's lymphoma ID LYMPHOPROLIFERATIVE DISORDERS; BURKITTS-LYMPHOMA; EXPRESSION; CANCER; LINE; ESTABLISHMENT; SUPPRESSES; ACTIVATION; COMPLEX; GROWTH AB HSP90 inhibitors have been shown to kill Epstein-Barr virus (EBV)-infected cells by reducing the level of EBV EBNA-1 and/or LMP1. We treated virus-infected cells with ganetespib, an HSP90 inhibitor currently being evaluated in multiple clinical trials for cancer and found that the drug killed EBV-positive B and T cells and reduced the level of both EBV EBNA-1 and LMP1. Treatment of cells with ganetespib also reduced the level of pAkt. Ganetespib delayed the onset of EBVpositive lymphomas and prolonged survival in SCID mice inoculated with one EBV-transformed B-cell line, but not another B-cell line. The former cell line showed lower levels of EBNA-1 after treatment with ganetespib in vitro. Treatment of a patient with T-cell chronic active EBV with ganetespib reduced the percentage of EBV-positive cells in the peripheral blood. These data indicate that HSP90 inhibitors may have a role in the therapy of certain EBV-associated diseases. C1 [Shatzer, Amber; Ali, Mir A.; Chavez, Mayra; Dowdell, Kennichi; Cohen, Jeffrey I.] NIAID, Lab Infect Dis, NIH, Bethesda, MD 20892 USA. [Lee, Min-Jung; Tomita, Yusuke; Trepel, Jane B.] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [El-Hariry, Iman] Synta Pharmaceut, Lexington, MA USA. RP Cohen, JI (reprint author), NIH, Infect Dis Lab, 50 South Dr, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Cancer Institute FX This work was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases and the National Cancer Institute. We thank Robert Bradley (Synta Pharmaceuticals) for planning and oversight of our clinical study, Jeffery Sample (Pennsylvania State University College of Medicine) for Mutu I, Kem I, and Akata cell lines, Paul Ling (Baylor College of Medicine) and Norio Shimizu (Tokyo Medical and Dental University) for SNT16 cells, Anita Mora (Rocky Mountain Laboratory, NIH) for preparing figures, and Harlan Pietz (Laboratory of Infectious Diseases, NIH) for statistical analyses. NR 30 TC 0 Z9 0 U1 4 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PY 2017 VL 58 IS 4 BP 923 EP 931 DI 10.1080/10428194.2016.1213823 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA EK4JG UT WOS:000393892300023 PM 27686857 ER PT J AU Choung, RS Unalp-Arida, A Ruhl, CE Brantner, TL Everhart, JE Murray, JA AF Choung, Rok Seon Unalp-Arida, Aynur Ruhl, Constance E. Brantner, Tricia L. Everhart, James E. Murray, Joseph A. TI Less Hidden Celiac Disease But Increased Gluten Avoidance Without a Diagnosis in the United States: Findings From the National Health and Nutrition Examination Surveys From 2009 to 2014 SO MAYO CLINIC PROCEEDINGS LA English DT Article ID FREE DIET; DERMATITIS-HERPETIFORMIS; GENERAL-POPULATION; PREVALENCE; CHILDREN; SENSITIVITY; AUSTRALIA; PRODUCTS; FOODS; RISK AB Objective: To investigate the trends in the prevalence of diagnosed celiac disease (CD), undiagnosed CD, and people without celiac disease avoiding gluten (PWAG) in the civilian noninstitutionalized US population from 2009 to 2014. Patients and Methods: We studied the occurrence of CD and PWAG in the 2009 to 2014 National Health and Nutrition Examination Surveys. The serum of all participants aged 6 years or older from the National Health and Nutrition Examination Surveys from 2009 to 2014 was tested for CD serology at Mayo Clinic. Participants were interviewed for a diagnosis of CD and the use of a glutenfree diet (GFD). The design effects of the survey and sample weights were incorporated in all statistical analyses. Results: In the US general population, the prevalence of CD did not change significantly from 0.7% (95% CI, 0.6%-0.8%) in 2009 to 2010 to 0.8% (95% CI, 0.4%-1.2%) in 2011 to 2012 to 0.7% (95% CI, 0.3%-1.0%) in 2013 to 2014. However, the prevalence of undiagnosed CD decreased from 0.6% in 2009 to 2010 to 0.3% in 2013 to 2014. In contrast, the prevalence of PWAG increased significantly from 0.5% (95% CI, 0.2%-0.9%) in 2009 to 2010 to 1.0% (95% CI, 0.6%-1.4%) in 2011 to 2012 to 1.7% (95% CI, 1.1%-2.4%) in 2013 to 2014 (P =.005 for trend). Conclusion: Although the overall prevalence of CD remained stable from 2009 to 2014, the proportion of individuals with CD that is hidden considerably decreased. Moreover, the proportion of individuals without CD but following a GFD increased markedly from 2009 to 2014. Long-term health consequences of a GFD warrant further investigation. (C) 2016 Mayo Foundation for Medical Education and Research C1 [Choung, Rok Seon; Brantner, Tricia L.; Murray, Joseph A.] Mayo Clin, Div Gastroenterol & Hepatol, 200 First St SW, Rochester, MN 55905 USA. [Unalp-Arida, Aynur] Natl Inst Diabet & Digest & Kidney Dis, NIH, Dept Hlth & Human Serv, Rochester, MN USA. [Everhart, James E.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Div Canc Epidemiol & Genet, Rochester, MN USA. RP Murray, JA (reprint author), Mayo Clin, Div Gastroenterol & Hepatol, 200 First St SW, Rochester, MN 55905 USA. EM murray.joseph@mayo.edu FU Centers for Disease Control and Prevention [M26561]; National Institute of Diabetes and Digestive and Kidney Diseases FX This work was partly supported by the Centers for Disease Control and Prevention (contract no. M26561) and the National Institute of Diabetes and Digestive and Kidney Diseases. NR 39 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD JAN PY 2017 VL 92 IS 1 BP 30 EP 38 DI 10.1016/j.mayocp.2016.10.012 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EK4QQ UT WOS:000393912300010 ER PT J AU Barea-Mendoza, JA Cortes-Puch, I Chico-Fernandez, M AF Barea-Mendoza, J. A. Cortes-Puch, I. Chico-Fernandez, M. TI Conflicts of interest in the new consensus based definition of sepsis and septic shock (sepsis-3) SO MEDICINA INTENSIVA LA Spanish DT Letter ID CLINICAL-PRACTICE GUIDELINE C1 [Barea-Mendoza, J. A.; Chico-Fernandez, M.] Hosp 12 Octubre, Serv Med Intens, Madrid, Spain. [Cortes-Puch, I.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Barea-Mendoza, JA (reprint author), Hosp 12 Octubre, Serv Med Intens, Madrid, Spain. EM jbareamendoza@gmail.com NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER DOYMA SL PI BARCELONA PA TRAVESERA DE GARCIA, 17-21, BARCELONA, 08021, SPAIN SN 0210-5691 EI 1578-6749 J9 MED INTENSIVA JI Med. Intensiv. PD JAN-FEB PY 2017 VL 41 IS 1 BP 60 EP 61 DI 10.1016/j.medin.2016.05.001 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA EK3SP UT WOS:000393848000012 PM 27370312 ER PT J AU Varma, VR Varma, S An, Y Hohman, TJ Seddighi, S Casanova, R Beri, A Dammer, EB Seyfried, NT Pletnikova, O Moghekar, A Wilson, MR Lah, JJ O'Brien, RJ Levey, AI Troncoso, JC Albert, MS Thambisetty, M AF Varma, V. R. Varma, S. An, Y. Hohman, T. J. Seddighi, S. Casanova, R. Beri, A. Dammer, E. B. Seyfried, N. T. Pletnikova, O. Moghekar, A. Wilson, M. R. Lah, J. J. O'Brien, R. J. Levey, A. I. Troncoso, J. C. Albert, M. S. Thambisetty, M. CA Predictors Cognitive Decline Norma Alzheimer's Dis Neuroimaging Initi TI Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway SO MOLECULAR PSYCHIATRY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; BLOOD-BRAIN-BARRIER; GENDER-DIFFERENCES; PLASMA BIOMARKERS; CONTROLLED-TRIAL; TRANSGENIC MICE; SYMPTOM ONSET; APOE GENOTYPE; OLDER-ADULTS; FLUID TAU AB Preclinical changes that precede the onset of symptoms and eventual diagnosis of Alzheimer's disease (AD) are a target for potential preventive interventions. A large body of evidence suggests that inflammation is closely associated with AD pathogenesis and may be a promising target pathway for such interventions. However, little is known about the association between systemic inflammation and preclinical AD pathophysiology. We first examined whether the acute-phase protein, alpha-2 macroglobulin (A2M), a major component of the innate immune system, was associated with cerebrospinal fluid (CSF) markers of neuronal injury in preclinical AD and risk of incident AD in the predictors of cognitive decline among normal individuals (BIOCARD) cohort. We find that A2M concentration in blood is significantly associated with CSF concentrations of the neuronal injury markers, tau and phosphorylated tau, and that higher baseline serum A2M concentration is associated with an almost threefold greater risk of progression to clinical symptoms of AD in men. These findings were replicated in the Alzheimer's Disease Neuroimaging (ADNI) study. Then, utilizing a systems level approach combining large multi-tissue gene expression datasets with mass spectrometry-based proteomic analyses of brain tissue, we identified an A2M gene network that includes regulator of calcineurin (RCAN1), an inhibitor of calcineurin, a well-characterized tau phosphatase. A2M gene and protein expression in the brain were significantly associated with gene and protein expression levels of calcineurin. Collectively these novel findings suggest that A2M is associated with preclinical AD, reflects early neuronal injury in the disease course and may be responsive to tau phosphorylation in the brain through the RCAN1-calcineurin pathway. C1 [Varma, V. R.; An, Y.; Seddighi, S.; Thambisetty, M.] NIA, Clin & Translat Neurosci Unit, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Varma, S.] HiThru Analyt, Laurel, MD USA. [Hohman, T. J.] Vanderbilt Univ, Sch Med, Dept Neurol, Nashville, TN 37212 USA. [Casanova, R.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Beri, A.] NIH, Lab Informat Dev BTRIS, Bldg 10, Bethesda, MD 20892 USA. [Dammer, E. B.; Seyfried, N. T.] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. [Pletnikova, O.; Troncoso, J. C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Moghekar, A.; Albert, M. S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Wilson, M. R.] Univ Wollongong, Sch Biol Sci, Wollongong, NSW, Australia. [Lah, J. J.; Levey, A. I.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [O'Brien, R. J.] Duke Univ, Sch Med, Dept Neurol, Durham, NC USA. RP Thambisetty, M (reprint author), NIA, Unit Clin & Translat Neurosci, Lab Behav Neurosci, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM thambisettym@mail.nih.gov FU Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS; NCI/SAIC-Frederick (SAIC-F) [10XS170]; Roswell Park Cancer Institute [10XS171]; Science Care [X10S172]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; Intramural Research Program of the NIH, National Institute on Aging; [HHSN268201000029C]; [10ST1035]; [DA006227]; [DA033684]; [N01MH000028] FX The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI/SAIC-Frederick (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171) and Science Care (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplements to University of Miami Grants DA006227 and DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North CarolinaChapel Hill (MH090936 and MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810) and the University of Pennsylvania (MH101822). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 01/18/2016. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica; Biogen; Bristol-Myers Squibb Company; CereSpir; Cogstate; Eisai; Elan Pharmaceuticals; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche and its affiliated company Genentech; Fujirebio; GE Healthcare; IXICO; Janssen Alzheimer Immunotherapy Research & Development; Johnson & Johnson Pharmaceutical Research & Development; Lumosity; Lundbeck; Merck; Meso Scale Diagnostics; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We are grateful to participants in the Baltimore Longitudinal Study of Aging for their invaluable contribution. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 78 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 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JAN PY 2017 VL 22 IS 1 BP 13 EP 23 DI 10.1038/mp.2016.206 PG 11 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA EK7JD UT WOS:000394101200003 PM 27872486 ER PT J AU Vargish, GA Pelkey, KA Yuan, X Chittajallu, R Collins, D Fang, C McBain, CJ AF Vargish, G. A. Pelkey, K. A. Yuan, X. Chittajallu, R. Collins, D. Fang, C. McBain, C. J. TI Persistent inhibitory circuit defects and disrupted social behaviour following in utero exogenous cannabinoid exposure SO MOLECULAR PSYCHIATRY LA English DT Article ID PRENATAL EXPOSURE; RAT HIPPOCAMPUS; BASKET CELLS; GABAERGIC INTERNEURONS; GLUTAMATERGIC NEURONS; POSTNATAL-DEVELOPMENT; CORTICAL DEVELOPMENT; PERINATAL EXPOSURE; PYRAMIDAL CELLS; GENE-EXPRESSION AB Placental transfer of Delta 9-tetrahydrocannabinol (THC) during pregnancy has the potential to interfere with endogenous cannabinoid (CB) regulation of fetal nervous system development in utero. Here we examined the effect of maternal CB intake on mouse hippocampal interneurons largely focusing on cholecystokinin-expressing interneurons (CCK-INTs), a prominent CB subtype-1 receptor (CB1R) expressing neuronal population throughout development. Maternal treatment with THC or the synthetic CB1R agonist WIN55,212-2 (WIN) produced a significant loss of CCK-INTs in the offspring. Further, residual CCK-INTs in animals prenatally treated with WIN displayed decreased dendritic complexity. Consistent with these anatomical deficits, pups born to CB-treated dams exhibited compromised CCK-INT-mediated feedforward and feedback inhibition. Moreover, pups exposed to WIN in utero lacked constitutive CB1R-mediated suppression of inhibition from residual CCK-INTs and displayed altered social behavior. Our findings add to a growing list of potential cell/circuit underpinnings that may underlie cognitive impairments in offspring of mothers that abuse marijuana during pregnancy. C1 [Vargish, G. A.; Pelkey, K. A.; Yuan, X.; Chittajallu, R.; Collins, D.; Fang, C.; McBain, C. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD 20892 USA. RP McBain, CJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD 20892 USA. EM mcbainc@mail.nih.gov OI Collins, David/0000-0001-8891-1893 FU NICHD intramural award FX We thank Dr George Kunos of NIAAA, NIH, for generously providing THC. G.A.V. is in the Brown University-NIH Neuroscience Partnership Program. This work is supported by an NICHD intramural award to C.J.M. NR 61 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 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JAN PY 2017 VL 22 IS 1 BP 56 EP 67 DI 10.1038/mp.2016.17 PG 12 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA EK7JD UT WOS:000394101200007 PM 26976041 ER PT J AU van de Giessen, E Weinstein, JJ Cassidy, CM Haney, M Dong, Z Ghazzaoui, R Ojeil, N Kegeles, LS Xu, X Vadhan, NP Volkow, ND Slifstein, M Abi-Dargham, A AF van de Giessen, E. Weinstein, J. J. Cassidy, C. M. Haney, M. Dong, Z. Ghazzaoui, R. Ojeil, N. Kegeles, L. S. Xu, X. Vadhan, N. P. Volkow, N. D. Slifstein, M. Abi-Dargham, A. TI Deficits in striatal dopamine release in cannabis dependence SO MOLECULAR PSYCHIATRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; MARIJUANA CRAVING QUESTIONNAIRE; D-2/D-3 RECEPTOR AVAILABILITY; IN-VIVO; VENTRAL STRIATUM; D-2 RECEPTORS; CB1 RECEPTOR; SCHIZOPHRENIA; BRAIN; USERS AB Most drugs of abuse lead to a general blunting of dopamine release in the chronic phase of dependence, which contributes to poor outcome. To test whether cannabis dependence is associated with a similar dopaminergic deficit, we examined striatal and extrastriatal dopamine release in severely cannabis-dependent participants (CD), free of any comorbid conditions, including nicotine use. Eleven CD and 12 healthy controls (HC) completed two positron emission tomography scans with [C-11]-(+)-PHNO, before and after oral administration of d-amphetamine. CD stayed inpatient for 5-7 days prior to the scans to standardize abstinence. Magnetic resonance spectroscopy (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [C-11]-(+)-PHNO-binding potential (Delta BPND) was compared between groups and correlations with MRS glutamate, subclinical psychopathological and neurocognitive parameters were examined. CD had significantly lower Delta BPND in the striatum (P = 0.002, effect size (ES) = 1.48), including the associative striatum (P = 0.003, ES = 1.39), sensorimotor striatum (P = 0.003, ES = 1.41) and the pallidus (P = 0.012, ES = 1.16). Lower dopamine release in the associative striatum correlated with inattention and negative symptoms in CD, and with poorer working memory and probabilistic category learning performance in both CD and HC. No relationships to MRS glutamate and amphetamine-induced subclinical positive symptoms were detected. In conclusion, this study provides evidence that severe cannabis dependence-without the confounds of any comorbidity-is associated with a deficit in striatal dopamine release. This deficit extends to other extrastriatal areas and predicts subclinical psychopathology. C1 [van de Giessen, E.; Weinstein, J. J.; Cassidy, C. M.; Haney, M.; Dong, Z.; Ghazzaoui, R.; Ojeil, N.; Kegeles, L. S.; Xu, X.; Vadhan, N. P.; Slifstein, M.; Abi-Dargham, A.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [van de Giessen, E.; Weinstein, J. J.; Cassidy, C. M.; Haney, M.; Dong, Z.; Ghazzaoui, R.; Ojeil, N.; Kegeles, L. S.; Xu, X.; Vadhan, N. P.; Slifstein, M.; Abi-Dargham, A.] New York State Psychiat Inst & Hosp, 1051 Riverside Dr,Unit 31, New York, NY 10032 USA. [van de Giessen, E.] Acad Med Ctr, Dept Nucl Med, Amsterdam, Netherlands. [Vadhan, N. P.] SUNY Stony Brook, Sch Med, Dept Psychiat, New York, NY USA. [Volkow, N. D.] NIAAA, Bethesda, MD USA. RP van de Giessen, E (reprint author), New York State Psychiat Inst & Hosp, 1051 Riverside Dr,Unit 31, New York, NY 10032 USA. EM e.m.vandegiessen@amc.uva.nl FU National Institute on Drug Abuse [R01 DA022455-01A1]; Rubicon grant from the Netherlands Organisation for Scientific Research [825.12.009] FX Funding for this study was provided by grant R01 DA022455-01A1 from the National Institute on Drug Abuse. Dr van de Giessen was supported by a Rubicon grant from the Netherlands Organisation for Scientific Research (825.12.009). NR 63 TC 1 Z9 1 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JAN PY 2017 VL 22 IS 1 BP 68 EP 75 DI 10.1038/mp.2016.21 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA EK7JD UT WOS:000394101200008 PM 27001613 ER PT J AU Machado-Vieira, R Gold, PW Luckenbaugh, DA Ballard, ED Richards, EM Henter, ID De Sousa, RT Niciu, MJ Yuan, P Zarate, CA AF Machado-Vieira, R. Gold, P. W. Luckenbaugh, D. A. Ballard, E. D. Richards, E. M. Henter, I. D. De Sousa, R. T. Niciu, M. J. Yuan, P. Zarate, C. A., Jr. TI The role of adipokines in the rapid antidepressant effects of ketamine SO MOLECULAR PSYCHIATRY LA English DT Article ID MAJOR DEPRESSIVE DISORDER; INSULIN-RESISTANCE; ADIPONECTIN RECEPTORS; CLINICAL PREDICTORS; CEREBROSPINAL-FLUID; LEPTIN; INFLAMMATION; OBESITY; SYSTEM; ATHEROSCLEROSIS AB We previously found that body mass index (BMI) strongly predicted response to ketamine. Adipokines have a key role in metabolism (including BMI). They directly regulate inflammation and neuroplasticity pathways and also influence insulin sensitivity, bone metabolism and sympathetic outflow; all of these have been implicated in mood disorders. Here, we sought to examine the role of three key adipokines-adiponectin, resistin and leptin-as potential predictors of response to ketamine or as possible transducers of its therapeutic effects. Eighty treatment-resistant subjects who met DSM-IV criteria for either major depressive disorder (MDD) or bipolar disorder I/II and who were currently experiencing a major depressive episode received a single ketamine infusion (0.5 mg kg(-1) for 40 min). Plasma adipokine levels were measured at three time points (pre-infusion baseline, 230 min post infusion and day 1 post infusion). Overall improvement and response were assessed using percent change from baseline on the Montgomery-Asberg Depression Rating Scale and the Hamilton Depression Rating Scale. Lower baseline levels of adiponectin significantly predicted ketamine's antidepressant efficacy, suggesting an adverse metabolic state. Because adiponectin significantly improves insulin sensitivity and has potent anti-inflammatory effects, this finding suggests that specific systemic abnormalities might predict positive response to ketamine. A ketamine-induced decrease in resistin was also observed; because resistin is a potent pro-inflammatory compound, this decrease suggests that ketamine's anti-inflammatory effects may be transduced, in part, by its impact on resistin. Overall, the findings suggest that adipokines may either predict response to ketamine or have a role in its possible therapeutic effects. C1 [Machado-Vieira, R.; Luckenbaugh, D. A.; Ballard, E. D.; Richards, E. M.; Henter, I. D.; De Sousa, R. T.; Niciu, M. J.; Yuan, P.; Zarate, C. A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, 10 Ctr Dr,7SE Unit, Bethesda, MD 20892 USA. [Gold, P. W.] NIMH, Clin Neuroendocrinol Branch, NIH, 10 Ctr Dr,7SE Unit, Bethesda, MD 20892 USA. RP Machado-Vieira, R (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 10 Ctr Dr,7SE Unit, Bethesda, MD 20892 USA. EM machadovieirar@mail.nih.gov OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRPNIMH-NIH) [NCT00088699, ZIA MH002857]; NARSAD Independent Investigator; Brain and Behavior Mood Disorders Research Award FX Funding for this work (NCT00088699) was provided by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRPNIMH-NIH; ZIA MH002857), by a NARSAD Independent Investigator to CAZ and by a Brain and Behavior Mood Disorders Research Award to CAZ. We thank the 7SE research unit and staff for their support. NR 57 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JAN PY 2017 VL 22 IS 1 BP 127 EP 133 DI 10.1038/mp.2016.36 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA EK7JD UT WOS:000394101200015 PM 27046644 ER PT J AU Kubas, A Orain, C De Sancho, D Saujet, L Sensi, M Gauquelin, C Meynial-Salles, I Soucaille, P Bottin, H Baffert, C Fourmond, V Best, RB Blumberger, J Leger, C AF Kubas, Adam Orain, Christophe De Sancho, David Saujet, Laure Sensi, Matteo Gauquelin, Charles Meynial-Salles, Isabelle Soucaille, Philippe Bottin, Herve Baffert, Carole Fourmond, Vincent Best, Robert B. Blumberger, Jochen Leger, Christophe TI Mechanism of O-2 diffusion and reduction in FeFe hydrogenases SO NATURE CHEMISTRY LA English DT Article ID H-CLUSTER; ACTIVE-SITE; MOLECULAR-DYNAMICS; CLOSTRIDIUM-PASTEURIANUM; ACTIVATION BARRIERS; CRYSTAL-STRUCTURE; PROTON TRANSPORT; OXYGEN; INHIBITION; INACTIVATION AB FeFe hydrogenases are the most efficient H-2-producing enzymes. However, inactivation by O-2 remains an obstacle that prevents them being used in many biotechnological devices. Here, we combine electrochemistry, site-directed mutagenesis, molecular dynamics and quantum chemical calculations to uncover the molecular mechanism of O-2 diffusion within the enzyme and its reactions at the active site. We propose that the partial reversibility of the reaction with O-2 results from the four-electron reduction of O-2 to water. The third electron/proton transfer step is the bottleneck for water production, competing with formation of a highly reactive OH radical and hydroxylated cysteine. The rapid delivery of electrons and protons to the active site is therefore crucial to prevent the accumulation of these aggressive species during prolonged O-2 exposure. These findings should provide important clues for the design of hydrogenase mutants with increased resistance to oxidative damage. C1 [Kubas, Adam; Blumberger, Jochen] UCL, Dept Phys & Astron, Gower St, London WC1E 6BT, England. [Kubas, Adam] Polish Acad Sci, Inst Phys Chem, Ul Kasprzaka 44-52, PL-01224 Warsaw, Poland. [Orain, Christophe; Sensi, Matteo; Baffert, Carole; Fourmond, Vincent; Leger, Christophe] Aix Marseille Univ, CNRS, Lab Bioenerget & Ingn Prot, Inst Microbiol Mediterranee, Marseille, France. [De Sancho, David] Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England. [De Sancho, David] CIC NanoGUNE, Tolosa Hiribidea 76, Donostia San Sebastian 20018, Spain. [De Sancho, David] Ikerbasque, Basque Fdn Sci, Maria Diaz de Haro 3, Bilbao 48013, Spain. [Saujet, Laure; Bottin, Herve] Inst Biol & Technol Saclay IBITECS, SB2SM, F-91191 Gif Sur Yvette, France. [Saujet, Laure; Bottin, Herve] Univ Paris Sud, CNRS, CEA, UMR 9198,Inst Biol Integrat Cellule,I2BC, F-91191 Gif Sur Yvette, France. [Gauquelin, Charles; Meynial-Salles, Isabelle; Soucaille, Philippe] Univ Toulouse, INSA, CNRS UMR 5504, UPS,INP,LISBP,INRA UMR792, 135 Ave Rangueil, F-31077 Toulouse 04, France. [Best, Robert B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Blumberger, J (reprint author), UCL, Dept Phys & Astron, Gower St, London WC1E 6BT, England.; Leger, C (reprint author), Aix Marseille Univ, CNRS, Lab Bioenerget & Ingn Prot, Inst Microbiol Mediterranee, Marseille, France. EM j.blumberger@ucl.ac.uk; christophe.leger@imm.cnrs.fr RI Fourmond, Vincent/K-1706-2014; OI Fourmond, Vincent/0000-0001-9837-6214; Leger, Christophe/0000-0002-8871-6059 FU CNRS; INSA; CEA; Agence Nationale de la Recherche [ANR-12-BS08-0014, ANR-14-CE05-0010]; A*MIDEX project [ANR-11-IDEX-0001-02]; "Investissements d'Avenir" French Government program; EPSRC [EP/J016764/1, EP/J015571/1, EP/F067496, EP/L000202]; Ikerbasque Research Fellowship; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; Royal Society for aUniversity Research Fellowship FX The French teams were supported by CNRS, INSA, CEA, Agence Nationale de la Recherche (ANR-12-BS08-0014, ANR-14-CE05-0010) and the A*MIDEX project (no ANR-11-IDEX-0001-02) funded by the "Investissements d'Avenir" French Government program, managed by the French National Research Agency (ANR). The authors thank R. van Lis for constructing the V296F and F290W mutants. D.D.S. acknowledges support from EPSRC grant no. EP/J016764/1 and an Ikerbasque Research Fellowship. A.K. was supported by EPSRC grant no. EP/J015571/1. R.B.B. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. J.B. thanks the Royal Society for aUniversity Research Fellowship. This work was carried out on the HECToR and Archer computing facilities (Edinburgh), access to which was granted through the Materials Chemistry Consortium (EPSRC grants nos EP/F067496 and EP/L000202). The authors acknowledge the use of the UCL Legion High Performance Computing Facility (Legion@UCL) and associated support services in the completion of this work as well as the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). D.D.S. acknowledges PRACE for awarding access to the FERMI resource based in Italy at CINECA. D.D.S. thanks A. Szabo and E. Rosta for discussions. NR 58 TC 2 Z9 2 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1755-4330 EI 1755-4349 J9 NAT CHEM JI Nat. Chem. PD JAN PY 2017 VL 9 IS 1 BP 88 EP 95 DI 10.1038/NCHEM.2592 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA EL3SU UT WOS:000394540400018 PM 27995927 ER PT J AU Takeuchi, M Karasawa, Y Harimoto, K Tanaka, A Shibata, M Sato, T Caspi, RR Ito, M AF Takeuchi, Masaru Karasawa, Yoko Harimoto, Kohzou Tanaka, Atsushi Shibata, Masaki Sato, Tomohito Caspi, Rachel R. Ito, Masataka TI Analysis of Th Cell-related Cytokine Production in Behcet Disease Patients with Uveitis Before and After Infliximab Treatment SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Article DE Behcet disease; infliximab; uveitis ID RETINOID-BINDING PROTEIN; NECROSIS-FACTOR-ALPHA; S-ANTIGEN; THREATENING PANUVEITIS; THERAPY; UVEORETINITIS; AUTOIMMUNITY; POPULATION; EXPRESSION; RESPONSES AB Purpose: To examine antigen-stimulated cytokine production by Behcet disease patients (BD) before and after infliximab infusion. Methods: PBMCs were obtained before and after infliximab infusion in BD patients with or without recurrent uveitis during at least 1 year of infliximab therapy, and from healthy subjects. PBMCs were cultured with IRBP, and Th-related cytokines in cultures were measured. Results: Levels of IL-4, IL-6, IL-10 IL-17A, IL-17F, IL-31, IFN-gamma, and TNF alpha were higher in BD before infliximab infusion than in healthy subjects, and these levels were the highest in BD with recurrent uveitis. After infliximab infusion, these cytokine levels were reduced to a greater extent in BD without recurrent uveitis than in BD with recurrence. Conclusions: Th-related cytokines produced by IRBP-stimulated PBMCs were elevated in BD, and infliximab infusion suppressed these cytokines to a greater extent in BD without recurrent uveitis than in those with recurrence. C1 [Takeuchi, Masaru; Karasawa, Yoko; Harimoto, Kohzou; Tanaka, Atsushi; Shibata, Masaki; Sato, Tomohito] Natl Def Med Coll, Dept Ophthalmol, 3-2 Namiki, Tokorozawa, Saitama 3598513, Japan. [Ito, Masataka] Natl Def Med Coll, Dept Dev Anat & Regenerat Biol, Saitama, Japan. [Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Takeuchi, M (reprint author), Natl Def Med Coll, Dept Ophthalmol, 3-2 Namiki, Tokorozawa, Saitama 3598513, Japan. EM masatake@ndmc.ac.jp FU Japan Society for the Promotion of Science [24592689] FX This work was supported in part by Grant-in-Aid 24592689 for Scientific Research from the Japan Society for the Promotion of Science. NR 43 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0927-3948 EI 1744-5078 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PY 2017 VL 25 IS 1 BP 52 EP 61 DI 10.3109/09273948.2016.1158276 PG 10 WC Ophthalmology SC Ophthalmology GA EK4NY UT WOS:000393905000009 PM 27070371 ER PT J AU Kolyvas, E Rudloff, M Poruchynsky, M Landsman, R Hollevoet, K Venzon, D Alewine, C AF Kolyvas, Emily Rudloff, Michael Poruchynsky, Marianne Landsman, Rebekah Hollevoet, Kevin Venzon, David Alewine, Christine TI Mesothelin-targeted immunotoxin RG7787 has synergistic antitumor activity when combined with taxanes SO ONCOTARGET LA English DT Article DE mesothelin; immunotoxin; paclitaxel; nab-paclitaxel; pancreatic cancer ID THERAPEUTIC ANTIBODY MORAB-009; PANCREATIC-CANCER; ANTIMITOTIC DRUGS; IN-VITRO; PHASE-I; INFUSION; TUMORS; CELLS; TAXOL; SS1P AB Recombinant immunotoxins (RITs) are antibody-based therapeutics that carry a toxin payload. The RG7787 RIT targets the cancer antigen mesothelin to deliver a recombinantly-engineered, reduced immunogenicity variant of Pseudomonas exotoxin A (PE) to the cytosol where it inhibits protein synthesis. Here we demonstrate that maximal doses of RG7787 temporarily halt growth of pancreatic cancer tumor xenografts, similar to the approved drugs gemcitabine and nab-paclitaxel, however, combination of the RIT with nab-paclitaxel produces durable complete regressions in most mice. Synergy between taxane and anti-MSLN RITs has been previously demonstrated in mouse models, but direct interaction of the combination in cell culture was not observed. Here, we show that this favorable interaction occurs in cell culture, is dependent on the dose and duration of RG7787 exposure, requires the catalytically active PE, and still occurs with RIT targeting a non-MSLN surface antigen. Unexpectedly, the combination does not increase RG7787-mediated protein synthesis inhibition nor perturb downstream apoptotic markers of RIT-mediated killing, but does augment levels of acetylated tubulin, a marker of taxane activity. Taken together, these data suggest that PE increases cell sensitivity to taxane-mediated killing by increasing taxane-mediated microtubule stability and priming cells for apoptosis by decreasing levels of the pro-survival factor Mcl-1. C1 [Kolyvas, Emily; Rudloff, Michael; Landsman, Rebekah; Hollevoet, Kevin; Alewine, Christine] NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. [Poruchynsky, Marianne] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Kolyvas, Emily] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Landsman, Rebekah] Stritch Sch Med, Maywood, IL USA. [Hollevoet, Kevin] Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Lab Therapeut & Diagnost Antibodies, Leuven, Belgium. RP Alewine, C (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM alewinecc@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; ASCO Conquer Cancer Foundation Young Investigator Award; National Cancer Institute [2791]; Roche Pharmaceuticals [2791] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, in part by ASCO Conquer Cancer Foundation Young Investigator Award (C.A.) and in part by a Cooperative Research and Development Agreement (#2791) between the National Cancer Institute and Roche Pharmaceuticals. NR 28 TC 0 Z9 0 U1 0 U2 0 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 PY 2017 VL 8 IS 6 BP 9189 EP 9199 DI 10.18632/oncotarget.13984 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EK8NX UT WOS:000394181800026 PM 27999204 ER PT J AU Ogawa, M Tomita, Y Nakamura, Y Lee, MJ Lee, SM Tomita, S Nagaya, T Sato, K Yamauchi, T Iwai, H Kumar, A Haystead, T Shroff, H Choyke, PL Trepel, JB Kobayashi, H AF Ogawa, Mikako Tomita, Yusuke Nakamura, Yuko Lee, Min-Jung Lee, Sunmin Tomita, Saori Nagaya, Tadanobu Sato, Kazuhide Yamauchi, Toyohiko Iwai, Hidenao Kumar, Abhishek Haystead, Timothy Shroff, Hari Choyke, Peter L. Trepel, Jane B. Kobayashi, Hisataka TI Immunogenic cancer cell death selectively induced by near infrared photoimmunotherapy initiates host tumor immunity SO ONCOTARGET LA English DT Article DE near infrared photoimmunotherapy; immunogenic cell death ID PLANE ILLUMINATION MICROSCOPY; THYMIC EPITHELIAL TUMORS; PHASE-2 TRIAL; OPEN-LABEL; CHEMOTHERAPY; APOPTOSIS; EXPRESSION; INDUCTION; THERAPY; SYSTEM AB Immunogenic cell death (ICD) is a form of cell death that activates an adaptive immune response against dead-cell-associated antigens. Cancer cells killed via ICD can elicit antitumor immunity. ICD is efficiently induced by near-infrared photo-immunotherapy (NIR-PIT) that selectively kills target-cells on which antibody-photoabsorber conjugates bind and are activated by NIR light exposure. Advanced live cell microscopies showed that NIR-PIT caused rapid and irreversible damage to the cell membrane function leading to swelling and bursting, releasing intracellular components due to the influx of water into the cell. The process also induces relocation of ICD bio markers including calreticulin, Hsp70 and Hsp90 to the cell surface and the rapid release of immunogenic signals including ATP and HMGB1 followed by maturation of immature dendritic cells. Thus, NIR-PIT is a therapy that kills tumor cells by ICD, eliciting a host immune response against tumor. C1 [Ogawa, Mikako] Hamamatsu Univ Sch Med, Med Photon Res Ctr, Hamamatsu, Shizuoka 4313192, Japan. [Tomita, Yusuke; Lee, Min-Jung; Lee, Sunmin; Tomita, Saori; Trepel, Jane B.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Nakamura, Yuko; Nagaya, Tadanobu; Sato, Kazuhide; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yamauchi, Toyohiko] Hamamatsu Photon KK, Cent Res Lab, Hamamatsu, Shizuoka 4348601, Japan. [Kumar, Abhishek; Shroff, Hari] NIBIB, Sect High Resolut Opt Imaging, NIH, Bethesda, MD 20892 USA. [Haystead, Timothy] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Ogawa, Mikako] Hokkaido Univ, Grad Sch Pharmaceut Sci, Lab Bioanal & Mol Imaging, Sapporo, Hokkaido 0600812, Japan. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; Center for Cancer Research; National Institute of Biomedical Imaging and Bioengineering; PREST, Japan Science and Technology Agency. FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the National Institute of Biomedical Imaging and Bioengineering. This work was also supported by PREST, Japan Science and Technology Agency. We thank A.G. York for introducing A.K. and H.S. to the rest of the team. NR 40 TC 0 Z9 0 U1 1 U2 1 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 PY 2017 VL 8 IS 6 BP 10425 EP 10436 DI 10.18632/oncotarget.14425 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EK8NX UT WOS:000394181800122 PM 28060726 ER PT J AU Avery, RA Katowitz, JA Fisher, MJ Heidary, G Dombi, E Packer, RJ Widemann, BC AF Avery, Robert A. Katowitz, James A. Fisher, Michael J. Heidary, Gena Dombi, Eva Packer, Roger J. Widemann, Brigitte C. CA OPPN Working Grp TI Orbital/Periorbital Plexiform Neurofibromas in Children with Neurofibromatosis Type 1 Multidisciplinary Recommendations for Care SO OPHTHALMOLOGY LA English DT Article ID NERVE SHEATH TUMORS; ORBITO-TEMPORAL NEUROFIBROMATOSIS; REINS INTERNATIONAL COLLABORATION; GROWTH-FACTOR RECEPTOR; CONSORTIUM PHASE-II; CLINICAL-TRIALS; ORBITOTEMPORAL NEUROFIBROMATOSIS; SURGICAL-MANAGEMENT; SCHWANN-CELLS; YOUNG-ADULTS AB Topic: Children and adults with neurofibromatosis type 1 (NF1), a common autosomal dominant condition, manifest a variety of ophthalmologic conditions. Plexiform neurofibromas (PNs) involving the eyelid, orbit, periorbital, and facial structures (orbital-periorbital plexiform neurofibroma [OPPN]) can result in significant visual loss in children. Equally important, OPPNs can cause significant alteration in physical appearance secondary to proptosis, ptosis, and facial disfigurement, leading to social embarrassment and decreased self-esteem. Clinical Relevance: Although NF1 is a relatively common disease in which routine ophthalmologic examinations are required, no formal recommendations for clinical care of children with OPPNs exist. Although medical and surgical interventions have been reported, there are no agreed-on criteria for when OPPNs require therapy and which treatment produces the best outcome. Methods: Because a multidisciplinary team of specialists (oculofacial plastics, pediatric ophthalmology, neuro-ophthalmology, medical genetics, and neuro-oncology) direct management decisions, the absence of a uniform outcome measure that represents visual or aesthetic sequelae complicates the design of evidence-based studies and feasible clinical trials. Results: In September 2013, a multidisciplinary task force, composed of pediatric practitioners from tertiary care centers experienced in caring for children with OPPN, was convened to address the lack of clinical care guidelines for children with OPPN. Conclusions: This consensus statement provides recommendations for ophthalmologic monitoring, outlines treatment indications and forthcoming biologic therapy, and discusses challenges to performing clinical trials in this complicated condition. (C) 2016 by the American Academy of Ophthalmology C1 [Avery, Robert A.; Packer, Roger J.] Childrens Natl Hlth Syst, Gilbert Family Neurofibromatosis Inst, Washington, DC USA. [Avery, Robert A.; Packer, Roger J.] Childrens Natl Hlth Syst, Dept Neurol, Washington, DC USA. [Avery, Robert A.] Childrens Natl Hlth Syst, Dept Ophthalmol, Washington, DC USA. [Packer, Roger J.] Childrens Natl Hlth Syst, Brain Tumor Inst, Washington, DC USA. [Avery, Robert A.; Packer, Roger J.] Childrens Natl Hlth Syst, Ctr Neurosci & Behav, Washington, DC USA. [Avery, Robert A.; Katowitz, James A.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA USA. [Avery, Robert A.; Katowitz, James A.; Fisher, Michael J.] Perelman Sch Med, Philadelphia, PA USA. [Fisher, Michael J.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA USA. [Heidary, Gena] Boston Childrens Hosp, Dept Ophthalmol, Boston, MA USA. [Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Avery, RA (reprint author), Childrens Hosp Philadelphia, Div Ophthalmol, 34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM averyr@email.chop.edu FU CureNFwithJack; Children's Tumor Foundation; National Eye Institute/National Institutes of Health [K23-EY022673]; National Cancer Institute, Center for Cancer Research intramural research program; Gilbert Family Neurofibromatosis Institute FX Supported by "CureNFwithJack" and The Children's Tumor Foundation. None of the study sponsors had a role in the design or content of this article. The authors have received additional support from the following sources: The National Eye Institute/National Institutes of Health Grants K23-EY022673 (to R.A.A.), the National Cancer Institute, Center for Cancer Research intramural research program (to B.C.W.), and the Gilbert Family Neurofibromatosis Institute (to R.A.A., R.J.P.). NR 73 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JAN PY 2017 VL 124 IS 1 BP 123 EP 132 DI 10.1016/j.ophtha.2016.09.020 PG 10 WC Ophthalmology SC Ophthalmology GA EK4KZ UT WOS:000393896900031 PM 27817916 ER PT J AU Annor, F Goodman, M Thyagarajan, B Okosun, I Doumatey, A Gower, BA Il'yasova, D AF Annor, Francis Goodman, Michael Thyagarajan, Bharat Okosun, Ike Doumatey, Ayo Gower, Barbara A. Il'yasova, Dora TI African Ancestry Gradient Is Associated with Lower Systemic F-2-Isoprostane Levels SO OXIDATIVE MEDICINE AND CELLULAR LONGEVITY LA English DT Article ID OXIDATIVE STRESS; WEIGHT-LOSS; URINARY F-2-ISOPROSTANES; MOLECULAR-MECHANISMS; INSULIN SENSITIVITY; ENERGY-EXPENDITURE; RACIAL-DIFFERENCES; SKELETAL-MUSCLE; OXIDANT STRESS; FAT OXIDATION AB Context. Low levels of systemic F-2-isoprostanes (F-2-IsoP) increase the risk of diabetes and weight gain and were found in African Americans. Low F(2)IsoPs could reflect an unfavorable metabolic characteristic, namely, slow mitochondrial metabolism in individuals with African ancestry. Objective. To examine differences in plasma F-2-IsoPs in three groups with a priori different proportion of African ancestry: non-Hispanic Whites (NHWs), US-born African Americans (AAs), and West African immigrants (WAI). Design. Cross-sectional study. Setting. Georgia residents recruited from church communities. Participants. 218 males and females 25-74 years of age, who are self-identified as NHW (n = 83), AA (n = 56), or WAI (n = 79). Main Outcome Measure(s). Plasma F-2-IsoPs quantified by gas chromatography-mass spectrometry. Results. After adjustment for age, gender, obesity, and other comorbidities, WAI had lower levels of plasma F-2-IsoP than AA (beta-coefficient = -9.8, p < 0.001) and AA had lower levels than NHW (beta-coefficient = -30.3, p < 0.001). Similarly, among healthy nonobese participants, F-2-IsoP levels were lowest among WAI, followed by AA, and the highest levels were among NHW. Conclusion. Plasma F-2-IsoPs are inversely associated with African ancestry gradient. Additional studies are required to test whether optimization of systemic F-2-IsoP levels can serve as means to improve race-specific lifestyle and pharmacological intervention targeted to obesity prevention and treatment. C1 [Annor, Francis; Okosun, Ike; Il'yasova, Dora] Georgia State Univ, Sch Publ Hlth, Div Epidemiol & Biostat, One Pk Pl,Suite 630, Atlanta, GA 30303 USA. [Goodman, Michael] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, 1518 Clifton Rd, Atlanta, GA 30322 USA. [Thyagarajan, Bharat] Univ Minnesota, Dept Lab Med & Pathol, 420 Delaware St SE b435, Minneapolis, MN 55455 USA. [Doumatey, Ayo] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bldg 12A,Room 4047,12 South Dr,MSC 5635, Bethesda, MD 20892 USA. [Gower, Barbara A.] Univ Alabama Birmingham, Dept Nutr Sci, 1675 Univ Blvd, Birmingham, AL 35294 USA. RP Il'yasova, D (reprint author), Georgia State Univ, Sch Publ Hlth, Div Epidemiol & Biostat, One Pk Pl,Suite 630, Atlanta, GA 30303 USA. EM dilyasova@gsu.edu NR 46 TC 0 Z9 0 U1 1 U2 1 PU HINDAWI LTD PI LONDON PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, WIT 5HE, ENGLAND SN 1942-0900 EI 1942-0994 J9 OXID MED CELL LONGEV JI Oxidative Med. Cell. Longev. PY 2017 AR 8319176 DI 10.1155/2017/8319176 PG 7 WC Cell Biology SC Cell Biology GA EL9VJ UT WOS:000394967900001 ER PT J AU Chaudhary, U Xia, B Silvoni, S Cohen, LG Birbaumer, N AF Chaudhary, Ujwal Xia, Bin Silvoni, Stefano Cohen, Leonardo G. Birbaumer, Niels TI Brain-Computer Interface-Based Communication in the Completely Locked-In State SO PLOS BIOLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; NEAR-INFRARED SPECTROSCOPY; SLOW CORTICAL POTENTIALS; SELF-REGULATION; EEG ALPHA; PARALYSIS; ALS; OSCILLATIONS; TETRAPLEGIA; PERFORMANCE AB Despite partial success, communication has remained impossible for persons suffering from complete motor paralysis but intact cognitive and emotional processing, a state called complete locked-in state (CLIS). Based on a motor learning theoretical context and on the failure of neuroelectric brain-computer interface (BCI) communication attempts in CLIS, we here report BCI communication using functional near-infrared spectroscopy (fNIRS) and an implicit attentional processing procedure. Four patients suffering from advanced amyotrophic lateral sclerosis (ALS)-two of them in permanent CLIS and two entering the CLIS with-out reliable means of communication - learned to answer personal questions with known answers and open questions all requiring a "yes"or "no" thought using frontocentral oxygenation changes measured with fNIRS. Three patients completed more than 46 sessions spread over several weeks, and one patient (patient W) completed 20 sessions. Online fNIRS classification of personal questions with known answers and open questions using linear support vector machine (SVM) resulted in an above-chance-level correct response rate over 70%. Electroencephalographic oscillations and electrooculographic signals did not exceed the chance-level threshold for correct communication despite occasional differences between the physiological signals representing a "yes" or "no" response. However, electro-encephalogram (EEG) changes in the theta-frequency band correlated with inferior communication performance, probably because of decreased vigilance and attention. If replicated with ALS patients in CLIS, these positive results could indicate the first step towards abolition of complete locked-in states, at least for ALS. C1 [Chaudhary, Ujwal; Birbaumer, Niels] Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany. [Xia, Bin] Shanghai Maritime Univ, Shanghai, Peoples R China. [Silvoni, Stefano] Cent Inst Mental Hlth, Dept Cognit & Clin Neurosci, Mannheim, Germany. [Cohen, Leonardo G.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Birbaumer, Niels] Osped San Camillo, IRCCS, Venice, Italy. [Birbaumer, Niels] Wyss Ctr Bio & Neuroengn, Geneva, Switzerland. RP Chaudhary, U; Birbaumer, N (reprint author), Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany.; Birbaumer, N (reprint author), Osped San Camillo, IRCCS, Venice, Italy.; Birbaumer, N (reprint author), Wyss Ctr Bio & Neuroengn, Geneva, Switzerland. EM chaudharyujwal@gmail.com; niels.birbaumer@uni-tuebingen.de FU Deutsche Forschungsgemeinschaft (DFG) [Bi195]; Stiftung Volkswagenwerk; German Ministry of Education and Research (BMBF grant) [MOTOR-BIC (FKZ 136W0053)]; Baden-Wurttemberg Stiftung, EMOIO from the Federal Ministry of Education and Research [524-4013-16SV7196]; Eva and Horst Kohler-Stiftung; National Natural Science Foundation of China [61550110252]; EU [686764]; San Camillo hospital in Venice, Italy FX The work was funded by grants from the following: Deutsche Forschungsgemeinschaft (DFG, Bi195, Kosellek, http://www.dfg.de/), which supported NB, UC, and BX; Stiftung Volkswagenwerk (VW, https://www.volkswagenstiftung.de/), which supported NB; German Ministry of Education and Research (BMBF grant No.: MOTOR-BIC (FKZ 136W0053, https://www.bmbf.de/), which supported NB; Baden-Wurttemberg Stiftung, EMOIO from the Federal Ministry of Education and Research (524-4013-16SV7196, https://www.bwstiftung.de/startseite/), which supported NB; Eva and Horst Kohler-Stiftung, (Berlin, http://eva-luise-und-horst-koehler-stiftung.de/), which supported NB; National Natural Science Foundation of China (Grant number: 61550110252, http://www.nsfc.gov.cn/publish/portal1/), which supported UC; and EU grant LUMINOUS (Grant number: 686764, https://ec.europa.eu/programmes/horizon202), which supported NB and UC. SS was supported by regular salary from San Camillo hospital in Venice, Italy. LG was supported by the intramural research program of the NINDS, NIH. 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 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD JAN PY 2017 VL 15 IS 1 AR e100593 DI 10.1371/journal.pbio.1002593 PG 25 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA EK2WL UT WOS:000393787500011 PM 28141803 ER PT J AU Nussinov, R Papin, JA Vakser, I AF Nussinov, Ruth Papin, Jason A. Vakser, Ilya TI Computing the Dynamic Supramolecular Structural Proteome SO PLOS COMPUTATIONAL BIOLOGY LA English DT Editorial Material ID DOCKING C1 [Nussinov, Ruth] Natl Canc Inst, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, Tel Aviv, Israel. [Papin, Jason A.] Univ Virginia, Charlottesville, VA USA. [Vakser, Ilya] Univ Kansas, Ctr Computat Biol, Lawrence, KS 66045 USA. RP Nussinov, R (reprint author), Natl Canc Inst, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, Tel Aviv, Israel. EM nussinor@helix.nih.gov NR 14 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JAN PY 2017 VL 13 IS 1 AR e1005290 DI 10.1371/journal.pcbi.1005290 PG 3 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA EK7ZT UT WOS:000394144400020 ER PT J AU Peel, N Iyer, J Naik, A Dougherty, MP Decker, M O'Connell, KF AF Peel, Nina Iyer, Jyoti Naik, Anar Dougherty, Michael P. Decker, Markus O'Connell, Kevin F. TI Protein Phosphatase 1 Down Regulates ZYG-1 Levels to Limit Centriole Duplication SO PLOS GENETICS LA English DT Article ID PLK4-RELATED KINASE ZYG-1; C. ELEGANS EMBRYOS; AURORA-A KINASE; CAENORHABDITIS-ELEGANS; CENTROSOME DUPLICATION; CHROMOSOME SEGREGATION; MOTHER CENTRIOLE; POLO KINASE; HUMAN-CELLS; HISTONE H3 AB In humans perturbations of centriole number are associated with tumorigenesis and microcephaly, therefore appropriate regulation of centriole duplication is critical. The C. elegans homolog of Plk4, ZYG-1, is required for centriole duplication, but our understanding of how ZYG-1 levels are regulated remains incomplete. We have identified the two PP1 orthologs, GSP-1 and GSP-2, and their regulators I-2(SZY-2) and SDS-22 as key regulators of ZYG-1 protein levels. We find that down-regulation of PP1 activity either directly, or by mutation of szy-2 or sds-22 can rescue the loss of centriole duplication associated with a zyg-1 hypomorphic allele. Suppression is achieved through an increase in ZYG-1 levels, and our data indicate that PP1 normally regulates ZYG-1 through a post-translational mechanism. While moderate inhibition of PP1 activity can restore centriole duplication to a zyg-1 mutant, strong inhibition of PP1 in a wild-type background leads to centriole amplification via the production of more than one daughter centriole. Our results thus define a new pathway that limits the number of daughter centrioles produced each cycle. C1 [Peel, Nina; Naik, Anar] Coll New Jersey, Dept Biol, Ewing, NJ 08618 USA. [Iyer, Jyoti; Dougherty, Michael P.; O'Connell, Kevin F.] NIDDK, Lab Biochem & Genet, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. [Decker, Markus] Max Planck Inst Mol Cell Biol & Genet, D-01307 Dresden, Germany. [Decker, Markus] Genentech Inc, Canc Immunol, 1 DNA Way,Mailstop 231A, San Francisco, CA 94080 USA. RP Peel, N (reprint author), Coll New Jersey, Dept Biol, Ewing, NJ 08618 USA.; O'Connell, KF (reprint author), NIDDK, Lab Biochem & Genet, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. EM peeln@tcnj.edu; KevinO@intra.niddk.nih.gov FU National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JAN PY 2017 VL 13 IS 1 AR e1006543 DI 10.1371/journal.pgen.1006543 PG 25 WC Genetics & Heredity SC Genetics & Heredity GA EK8BA UT WOS:000394147700020 ER PT J AU Xiong, B Zhao, YG Beall, S Sadusky, AB Dean, J AF Xiong, Bo Zhao, Yangu Beall, Stephanie Sadusky, Anna Burkart Dean, Jurrien TI A Unique Egg Cortical Granule Localization Motif Is Required for Ovastacin Sequestration to Prevent Premature ZP2 Cleavage and Ensure Female Fertility in Mice SO PLOS GENETICS LA English DT Article ID ZONA-PELLUCIDA PROTEIN; MOUSE EGGS; GAMETE RECOGNITION; MEIOTIC MATURATION; SPERM PENETRATION; OOCYTE MATURATION; HAMSTER EGGS; FETUIN-B; FERTILIZATION; POLYSPERMY AB Monospermic fertilization is mediated by the extracellular zona pellucida composed of ZP1, ZP2 and ZP3. Sperm bind to the N-terminus of ZP2 which is cleaved after fertilization by ovastacin (encoded by Astl) exocytosed from egg cortical granules to prevent sperm binding. Astl Null mice lack the post-fertilization block to sperm binding and the ability to rescue this phenotype with Astl(mCherry) transgenic mice confirms the role of ovastacin in providing a definitive block to polyspermy. During oogenesis, endogenous ovastacin traffics through the endomembrane system prior to storage in peripherally located cortical granules. Deletion mutants of ovastacin(mCherry) expressed in growing oocytes define a unique 7 amino acid motif near its N-terminus that is necessary and sufficient for cortical granule localization. Deletion of the 7 amino acids by CRISPR/Cas9 at the endogenous locus (Astl(Delta)) prevents cortical granule localization of ovastacin. The misdirected enzyme is present within the endomembrane system and ZP2 is prematurely cleaved. Sperm bind poorly to the zona pellucida of Astl(Delta/Delta) mice with partially cleaved ZP2 and female mice are sub-fertile. C1 [Xiong, Bo; Zhao, Yangu; Beall, Stephanie; Sadusky, Anna Burkart; Dean, Jurrien] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Xiong, Bo] Nanjing Agr Univ, Coll Anim Sci & Technol, Nanjing, Peoples R China. RP Xiong, B; Dean, J (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA.; Xiong, B (reprint author), Nanjing Agr Univ, Coll Anim Sci & Technol, Nanjing, Peoples R China. EM xiongbo@njau.edu.cn; jurrien.dean@nih.gov FU Combined Federal Fellowship in Reproductive Endocrinology and Infertility; NIH, NIDDK [DK015603] FX SB was supported by the Combined Federal Fellowship in Reproductive Endocrinology and Infertility and the research was funded by the intramural program of NIH, NIDDK (DK015603). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 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 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JAN PY 2017 VL 13 IS 1 AR e006580 DI 10.1371/journal.pgen.1006580 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA EK8BA UT WOS:000394147700045 PM 28114310 ER PT J AU Mendelson, MM Marioni, RE Joehanes, R Liu, CY Hedman, AK Aslibekyan, S Demerath, EW Guan, WH Zhi, DH Yao, C Huan, TX Willinger, C Chen, B Courchesne, P Multhaup, M Lrvin, MR Cohain, A Schadt, EE Grove, ML Bressler, J North, K Sundstrom, J Gustafsson, S Shah, S Mcrae, AF Harris, SE Gibson, J Redmond, P Coriey, J Murphy, L Starr, JM Kleinbrink, E Lipovich, L Visscher, PM Wray, NR Krauss, RM Fallin, D Feinberg, A Absher, DM Fornage, M Pankow, JS Lind, L Fox, C Ingelsson, E Arnett, DK Boerwinkle, E Liang, L Levy, D Deary, LJ AF Mendelson, Michael M. Marioni, Riccardo E. Joehanes, Roby Liu, Chunyu Hedman, Asa K. Aslibekyan, Stella Demerath, Ellen W. Guan, Weihua Zhi, Degui Yao, Chen Huan, Tianxiao Willinger, Christine Chen, Brian Courchesne, Paul Multhaup, Michael Lrvin, Marguerite R. Cohain, Ariella Schadt, Eric E. Grove, Megan L. Bressler, Jan North, Kari Sundstrom, Johan Gustafsson, Stefan Shah, Sonia McRae, Allan F. Harris, Sarah E. Gibson, Jude Redmond, Paul Coriey, Janie Murphy, Lee Starr, John M. Kleinbrink, Erica Lipovich, Leonard Visscher, Peter M. Wray, Naomi R. Krauss, Ronald M. Fallin, Daniele Feinberg, Andrew Absher, Devin M. Fornage, Myriam Pankow, James S. Lind, Lars Fox, Caroline Ingelsson, Erik Arnett, Donna K. Boerwinkle, Eric Liang, Liming Levy, Daniel Deary, Lan J. TI y Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach SO PLOS MEDICINE LA English DT Article ID EPIGENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; LIPID-LOWERING DRUGS; DIET-INDUCED OBESITY; GENOME-WIDE; ADIPOSE-TISSUE; INSULIN-RESISTANCE; EPIGENETIC ASSOCIATIONS; CARDIOVASCULAR-DISEASE; MILLION PARTICIPANTS AB Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases. C1 [Mendelson, Michael M.; Joehanes, Roby; Liu, Chunyu; Yao, Chen; Huan, Tianxiao; Willinger, Christine; Courchesne, Paul; Fox, Caroline; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Mendelson, Michael M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Mendelson, Michael M.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Mendelson, Michael M.; Joehanes, Roby; Liu, Chunyu; Yao, Chen; Huan, Tianxiao; Willinger, Christine; Chen, Brian; Courchesne, Paul; Fox, Caroline; Levy, Daniel] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA. [Marioni, Riccardo E.; Harris, Sarah E.; Starr, John M.; Visscher, Peter M.; Deary, Lan J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland. [Marioni, Riccardo E.; Harris, Sarah E.] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH8 9YL, Midlothian, Scotland. [Marioni, Riccardo E.; Shah, Sonia; McRae, Allan F.; Visscher, Peter M.; Wray, Naomi R.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Joehanes, Roby] Harvard Med Sch, Hebrew SeniorLife, Boston, MA USA. [Liu, Chunyu] Boston Univ, Dept Biostat, Boston, MA USA. [Hedman, Asa K.; Gustafsson, Stefan; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden. [Aslibekyan, Stella; Lrvin, Marguerite R.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Demerath, Ellen W.; Pankow, James S.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Guan, Weihua] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Zhi, Degui] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [Multhaup, Michael; Fallin, Daniele; Feinberg, Andrew] Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD USA. [Cohain, Ariella; Schadt, Eric E.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Cohain, Ariella; Schadt, Eric E.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Grove, Megan L.; Bressler, Jan; Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [North, Kari] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA. [Sundstrom, Johan; Lind, Lars] Uppsala Univ, Dept Med Sci, Cardiovasc Epidemiol, Uppsala, Sweden. [Shah, Sonia; McRae, Allan F.; Visscher, Peter M.; Wray, Naomi R.] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia. [Gibson, Jude; Murphy, Lee] Univ Edinburgh, Western Gen Hosp, Wellcome Trust Clin Res Facil, Edinburgh EH8 9YL, Midlothian, Scotland. [Redmond, Paul; Coriey, Janie; Deary, Lan J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland. [Kleinbrink, Erica; Lipovich, Leonard] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Kleinbrink, Erica; Lipovich, Leonard] Wayne State Univ, Dept Neurol, Detroit, MI USA. [Krauss, Ronald M.] Childrens Hosp Oakland Res Inst, Oakland, CA USA. [Absher, Devin M.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Ingelsson, Erik] Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Fornage, Myriam] Univ Texas Houston, Brown Fdn Inst Mol Med, Houston, TX USA. [Arnett, Donna K.] Univ Kentucky, Coll Publ Hlth, Lexington, KY USA. RP Levy, D (reprint author), Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.; Levy, D (reprint author), NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA. EM levyd@nih.gov OI Mendelson, Michael/0000-0001-7590-3958 FU National Institutes of Health [N01-HC-25195, HHSN268201500001I]; NIH National Heart, Lung, and Blood Institute [R01 HL 104135-01]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN2682011000010C, HHSN2682011000011C, HHSN2682011000012C]; NIH through the American Recovery and Reinvestment Act of (ARRA) [5RC2HL102419]; Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health; Directors Challenge Award, National Institutes of Health; Division of Intramural Research, National Heart, Lung, and Blood Institute; Center for Information Technology, National Institutes of Health, Bethesda, MD; Tommy Kaplan Fund, Boston Childrens Hospital; NIH [P30 DK46200]; UKs Biotechnology and Biological Sciences Research Council (BBSRC); Royal Society; Chief Scientist Office of the Scottish Government; Age UK (The Disconnected Mind project); Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award); Wellcome Trust Institutional Strategic Support Fund; University of Edinburgh; Age UK; University of Queensland; BBSRC; Economic and Social Research Council (ESRC); Medical Research Council (MRC); University of Edinburgh as part of the cross-council Lifelong Health and Wellbeing initiative [MR/K026992/1]; National Health and Medical Research Council (NHMRC) [613608, APP496667, APP1010374, APP1046880]; NHMRC [613602, 1083656]; Australian Research Council (ARC) [FT0991360] FX The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195 and HHSN268201500001I. The Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) epigenetics study is funded by the NIH National Heart, Lung, and Blood Institute grant R01 HL 104135-01. The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN2682011000010C, HHSN2682011000011C, HHSN2682011000012C). Funding support for Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). 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 Directors Challenge Award, National Institutes of Health (DL, PI). The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. This study utilized the computational resources of the Biowulf system at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). MMM is partly supported by the Tommy Kaplan Fund, Boston Childrens Hospital. LL is partially supported by NIH grant (P30 DK46200). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UKs 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 Age UK (The Disconnected Mind project). Methylation typing was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. REM, SEH, PMV, JMS, and IJD are members of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE). CCACE is supported by funding from the BBSRC, the Economic and Social Research Council (ESRC), the Medical Research Council (MRC), and the University of Edinburgh as part of the cross-council Lifelong Health and Wellbeing initiative (MR/K026992/1). Research reported in this publication was supported by National Health and Medical Research Council (NHMRC) project grants 613608, APP496667, APP1010374 and APP1046880. NHMRC Fellowships to PMV, and NRW (613602) and Australian Research Council (ARC) Future Fellowship to NRW (FT0991360). AFM is supported by the NHMRC fellowship scheme (1083656). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 91 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD JAN PY 2017 VL 14 IS 1 AR e1002215 DI 10.1371/journal.pmed.10022151 PG 30 WC Medicine, General & Internal SC General & Internal Medicine GA EN0SM UT WOS:000395719900011 PM 28095459 ER PT J AU Ferreira-Paim, K Andrade-Silva, L Fonseca, FM Ferreira, TB Mora, DJ Andrade-Silva, J Khan, A Dao, A Reis, EC Almeida, MTG Maltos, A Junior, VR Trilles, L Rickerts, V Chindamporn, A Sykes, JE Cogliati, M Nielsen, K Boekhout, T Fisher, M Kwon-Chung, J Engelthaler, DM Lazera, M Meyer, W Silva-Vergara, ML AF Ferreira-Paim, Kennio Andrade-Silva, Leonardo Fonseca, Fernanda M. Ferreira, Thatiana B. Mora, Delio J. Andrade-Silva, Juliana Khan, Aziza Dao, Aiken Reis, Eduardo C. Almeida, Margarete T. G. Maltos, Andre Junior, Virmondes R. Trilles, Luciana Rickerts, Volker Chindamporn, Ariya Sykes, Jane E. Cogliati, Massimo Nielsen, Kirsten Boekhout, Teun Fisher, Matthew Kwon-Chung, June Engelthaler, David M. Lazera, Marcia Meyer, Wieland Silva-Vergara, Mario L. TI MLST-Based Population Genetic Analysis in a Global Context Reveals Clonality amongst Cryptococcus neoformans var.grubii VNI Isolates from HIV Patients in Southeastern Brazil SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID MULTILOCUS GENOTYPE DATA; SPECIES COMPLEX; MOLECULAR EPIDEMIOLOGY; PHYLOGENETIC INFERENCE; MINAS-GERAIS; GATTII; MENINGITIS; AIDS; DIVERSITY; EVOLUTIONARY AB Cryptococcosis is an important fungal infection in immunocompromised individuals, especially those infected with HIV. In Brazil, despite the free availability of antiretroviral therapy (ART) in the public health system, the mortality rate due to Cryptococcus neoformans meningitis is still high. To obtain a more detailed picture of the population genetic structure of this species in southeast Brazil, we studied 108 clinical isolates from 101 patients and 35 environmental isolates. Among the patients, 59% had a fatal outcome mainly in HIV-positive male patients. All the isolates were found to be C. neoformans var. grubii major molecular type VNI and mating type locus alpha. Twelve were identified as diploid by flow cytometry, being homozygous (A alpha A alpha) for the mating type and by PCR screening of the STE20, GPA1, and PAK1 genes. Using the ISHAM consensus multilocus sequence typing (MLST) scheme, 13 sequence types (ST) were identified, with one being newly described. ST93 was identified from 81 (75%) of the clinical isolates, while ST77 and ST93 were identified from 19 (54%) and 10 (29%) environmental isolates, respectively. The southeastern Brazilian isolates had an overwhelming clonal population structure. When compared with populations from different continents based on data extracted from the ISHAM-MLST database (mlst. mycologylab. org) they showed less genetic variability. Two main clusters within C. neoformans var. grubii VNI were identified that diverged from VNB around 0.58 to 4.8 million years ago. C1 [Ferreira-Paim, Kennio; Khan, Aziza; Dao, Aiken; Meyer, Wieland] Univ Sydney, Ctr Infect Dis & Microbiol, Sydney Med Sch,Westmead Hosp,Mol Mycol Res Lab,We, Marie Bashir Inst Emerging Infect Dis & Biosecur, Sydney, NSW, Australia. [Ferreira-Paim, Kennio; Andrade-Silva, Leonardo; Ferreira, Thatiana B.; Mora, Delio J.; Andrade-Silva, Juliana; Maltos, Andre; Junior, Virmondes R.; Silva-Vergara, Mario L.] Triangulo Mineiro Fed Univ, Dept Infect Dis, Uberaba, Brazil. [Fonseca, Fernanda M.] Fed Univ Piau, Biomed Dept, Parnaiba, Brazil. [Almeida, Margarete T. G.] Fac Med Sao Jose Rio Preto, Dept Infect Dis, Sao Jose Do Rio Preto, Brazil. [Trilles, Luciana; Lazera, Marcia] Fundacao Oswaldo Cruz, Evandro Chagas Natl Inst Infect Dis, Rio De Janeiro, Brazil. [Rickerts, Volker] Robert Koch Inst, Mycol Sect, Berlin, Germany. [Chindamporn, Ariya] Chulalongkorn Univ, Dept Microbiol, Mycol Unit, Fac Med, Bangkok, Thailand. [Sykes, Jane E.] Univ Calif Davis, Dept Med & Epidemiol, Davis, CA 95616 USA. [Cogliati, Massimo] Univ Milan, Dip Sci Biomed Salute, Lab Micol Med, Milan, Italy. [Nielsen, Kirsten] Univ Minnesota, Sch Med, Dept Microbiol & Immunol, Minneapolis, MS USA. [Boekhout, Teun] CBS KNAW Fungal Biodivers Ctr, Dept Yeast & Basidiomycete Res, Utrecht, Netherlands. [Fisher, Matthew] Imperial Coll London, Dept Infect Dis Epidemiol, Norfolk Pl, London, England. [Kwon-Chung, June] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Engelthaler, David M.] Translat Genom Res Inst, Flagstaff, AZ USA. RP Meyer, W (reprint author), Univ Sydney, Ctr Infect Dis & Microbiol, Sydney Med Sch,Westmead Hosp,Mol Mycol Res Lab,We, Marie Bashir Inst Emerging Infect Dis & Biosecur, Sydney, NSW, Australia. EM wieland.meyer@sydney.edu.au FU Minas Gerais Research Foundation (FAPEMIG) [BPD-00507-13]; program science without borders of Coordination for the Improvement of Higher Education Personnel (CAPES), Brazil [098/2012]; National Health and Medical Research Council (NHMRC), Australia [APP1031943]; CAPES Science without Borders visiting fellow from Brazil [9313133]; National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by Minas Gerais Research Foundation (FAPEMIG) - grant # BPD-00507-13 to MLV, and the program science without borders of Coordination for the Improvement of Higher Education Personnel (CAPES), Brazil, grant # 098/2012 to WM and the National Health and Medical Research Council (NH&MRC), Australia, grant # APP1031943 to WM. KFP was supported by a CAPES Science without Borders visiting fellow (No 9313133) from Brazil. JKC was supported by funds from the intramural program of the National Institute of Allergy and Infectious Diseases, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 96 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JAN PY 2017 VL 11 IS 1 DI 10.1371/journal.pntd.0005223 PG 29 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA EK8CR UT WOS:000394152000025 ER PT J AU Hinnebusch, BJ Bland, DM Bosio, CF Jarrett, CO AF Hinnebusch, B. Joseph Bland, David M. Bosio, Christopher F. Jarrett, Clayton O. TI Comparative Ability of Oropsylla montana and Xenopsylla cheopis Fleas to Transmit Yersinia pestis by Two Different Mechanisms SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID EARLY-PHASE TRANSMISSION; PLAGUE EPIZOOTICS; PRAIRIE DOGS; CTENOCEPHALIDES-FELIS; VECTOR COMPETENCE; UNBLOCKED FLEAS; CAT FLEAS; SIPHONAPTERA; CERATOPHYLLIDAE; TEMPERATURE AB Background Transmission of Yersinia pestis by flea bite can occur by two mechanisms. After taking a blood meal from a bacteremic mammal, fleas have the potential to transmit the very next time they feed. This early-phase transmission resembles mechanical transmission in some respects, but the mechanism is unknown. Thereafter, transmission occurs after Yersinia pestis forms a biofilm in the proventricular valve in the flea foregut. The biofilm can impede and sometimes completely block the ingestion of blood, resulting in regurgitative transmission of bacteria into the bite site. In this study, we compared the relative efficiency of the two modes of transmission for Xenopsylla cheopis, a flea known to become completely blocked at a high rate, and Oropsylla montana, a flea that has been considered to rarely develop proventricular blockage. Methodology/Principal findings Fleas that took an infectious blood meal containing Y. pestis were maintained and monitored for four weeks for infection and proventricular blockage. The number of Y. pestis transmitted by groups of fleas by the two modes of transmission was also determined. O. montana readily developed complete proventricular blockage, and large numbers of Y. pestis were transmitted by that mechanism both by it and by X. cheopis, a flea known to block at a high rate. In contrast, few bacteria were transmitted in the early phase by either species. Conclusions A model system incorporating standardized experimental conditions and viability controls was developed to more reliably compare the infection, proventricular blockage and transmission dynamics of different flea vectors, and was used to resolve a long-standing uncertainty concerning the vector competence of O. montana. Both X. cheopis and O. montana are fully capable of transmitting Y. pestis by the proventricular biofilm-dependent mechanism. C1 [Hinnebusch, B. Joseph; Bland, David M.; Bosio, Christopher F.; Jarrett, Clayton O.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Hinnebusch, BJ (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM jhinnebusch@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. http://www.niaid.nih.gov/about/organization/dir/Pages/default.aspx. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JAN PY 2017 VL 11 IS 1 AR e0005276 DI 10.1371/journal.pntd.0005276 PG 15 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA EK8CR UT WOS:000394152000048 ER PT J AU Mlera, L Meade-White, K Saturday, G Scott, D Bloom, ME AF Mlera, Luwanika Meade-White, Kimberly Saturday, Greg Scott, Dana Bloom, Marshall E. TI Modeling Powassan virus infection in Peromyscus leucopus, a natural host SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID TICK-BORNE ENCEPHALITIS; WEST-NILE-VIRUS; NON-VIREMIC TRANSMISSION; NEW-ENGLAND DEER; WILD RODENTS; IXODES-SCAPULARIS; FLAVIVIRUS; NEUROINVASION; VACCINATION; MECHANISM AB The tick-borne flavivirus, Powassan virus (POWV) causes life-threatening encephalitis in humans in North America and Europe. POWV is transmitted by ixodid tick vectors that feed on small to medium-sized mammals, such as Peromyscus leucopus mice, which may serve as either reservoir, bridge or amplification hosts. Intraperitoneal and intracranial inoculation of 4-week old Peromyscus leucopus mice with 10(3) PFU of POWV did not result in overt clinical signs of disease. However, following intracranial inoculation, infected mice seroconverted to POWV and histopathological examinations revealed that the mice uniformly developed mild lymphocytic perivascular cuffing and microgliosis in the brain and spinal cord from 5 to 15 days post infection (dpi), suggesting an early inflammatory response. In contrast, intracranial inoculation of 4-week old C57BL/6 and BALB/c mice was lethal by 5 dpi. Intraperitoneal inoculation was lethal in BALB/c mice, but 40% (2/5) of C57BL/6 mice survived. We concluded that Peromyscus leucopus mice infected i. c. with a lethal dose of POWV support a limited infection, restricted to the central nervous system and mount an antibody response to the virus. However, they fail to develop clinical signs of disease and are able to control the infection. These results suggest the involvement of restriction factors, and the mechanism by which Peromyscus leucopus mice restrict POWV infection remains under study. C1 [Mlera, Luwanika; Bloom, Marshall E.] NIAID, Virol Lab, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. [Meade-White, Kimberly; Saturday, Greg; Scott, Dana] NIAID, Rocky Mt Vet Branch, NIH, Rocky Mt Labs, Hamilton, MT USA. RP Mlera, L; Bloom, ME (reprint author), NIAID, Virol Lab, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. EM Luwanika.Mlera@nih.gov; MBLOOM@niaid.nih.gov FU Division of Intramural Research of the NIAID/NIH FX The study was supported by the Division of Intramural Research of the NIAID/NIH. The funders had no role in in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JAN PY 2017 VL 11 IS 1 AR e0005345 DI 10.1371/journal.pntd.0005346 PG 18 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA EK8CR UT WOS:000394152000085 ER PT J AU Doehl, JSP Sadlova, J Aslan, H Pruzinova, K Metangmo, S Votypka, J Kamhawi, S Volf, P Smith, DF AF Doehl, Johannes S. P. Sadlova, Jovana Aslan, Hamide Pruzinova, Katerina Metangmo, Sonia Votypka, Jan Kamhawi, Shaden Volf, Petr Smith, Deborah F. TI Leishmania HASP and SHERP Genes Are Required for In Vivo Differentiation, Parasite Transmission and Virulence Attenuation in the Host SO PLOS PATHOGENS LA English DT Article ID HIGHER EUKARYOTIC CELLS; REAL-TIME PCR; SAND FLIES; TRYPANOSOMA-BRUCEI; QUANTIFYING LEISHMANIA; PHLEBOTOMUS-PAPATASI; DEVELOPMENTAL-STAGES; MAJOR PROMASTIGOTES; SURFACE-PROTEINS; INFECTIVE STAGE AB Differentiation of extracellular Leishmania promastigotes within their sand fly vector, termed metacyclogenesis, is considered to be essential for parasites to regain mammalian host infectivity. Metacyclogenesis is accompanied by changes in the local parasite environment, including secretion of complex glycoconjugates within the promastigote secretory gel and colonization and degradation of the sand fly stomodeal valve. Deletion of the stage-regulated HASP and SHERP genes on chromosome 23 of Leishmania major is known to stall metacyclogenesis in the sand fly but not in in vitro culture. Here, parasite mutants deficient in specific genes within the HASP/SHERP chromosomal region have been used to investigate their role in metacyclogenesis, parasite transmission and establishment of infection. Metacyclogenesis was stalled in HASP/SHERP mutants in vivo and, although still capable of osmotaxis, these mutants failed to secrete promastigote secretory gel, correlating with a lack of parasite accumulation in the thoracic midgut and failure to colonise the stomodeal valve. These defects prevented parasite transmission to a new mammalian host. Sand fly midgut homogenates modulated parasite behaviour in vitro, suggesting a role for molecular interactions between parasite and vector in Leishmania development within the sand fly. For the first time, stage-regulated expression of the small HASPA proteins in Leishmania (Leishmania) has been demonstrated: HASPA2 is expressed only in extracellular promastigotes and HASPA1 only in intracellular amastigotes. Despite its lack of expression in amastigotes, replacement of HASPA2 into the null locus background delays onset of pathology in BALB/c mice. This HASPA2-dependent effect is reversed by HASPA1 gene addition, suggesting that the HASPAs may have a role in host immunomodulation. C1 [Doehl, Johannes S. P.; Smith, Deborah F.] Univ York, Dept Biol, Ctr Immunol & Infect, York, N Yorkshire, England. [Sadlova, Jovana; Pruzinova, Katerina; Votypka, Jan; Volf, Petr] Charles Univ Prague, Fac Sci, Dept Parasitol, Prague, Czech Republic. [Aslan, Hamide; Metangmo, Sonia; Kamhawi, Shaden] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Smith, DF (reprint author), Univ York, Dept Biol, Ctr Immunol & Infect, York, N Yorkshire, England. EM deborah.smith@york.ac.uk FU Wellcome Trust [077503]; UK Biotechnology and Biological Sciences Research Council; EurNegVec COSTAction [TD1303]; COST-CZ [LD14076]; National Institutes of Allergy and Infectious Diseases, NIH FX This study was supported by the Wellcome Trust (http://www.wellcome.ac.uk; grant no. 077503; DFS), the UK Biotechnology and Biological Sciences Research Council (www.bbsrc.ac.uk/; predoctoral studentship, JSPD), EurNegVec COSTAction TD1303, COST-CZ LD14076 (JS, JV, PV). SK, HA, SM are supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JAN PY 2017 VL 13 IS 1 AR e1006130 DI 10.1371/journal.ppat.1006130 PG 35 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EN1AV UT WOS:000395743500037 ER PT J AU Doria-Rose, NA Altae-Tran, HR Roark, RS Schmidt, SD Sutton, MS Louder, MK Chuang, GY Bailer, RT Cortez, V Kong, R McKee, K O'Dell, S Wang, F Karim, SSA Binley, JM Connors, M Haynes, BF Martin, MA Montefiori, DC Morris, L Overbaugh, J Kwong, PD Mascola, JR Georgiev, IS AF Doria-Rose, Nicole A. Altae-Tran, Han R. Roark, Ryan S. Schmidt, Stephen D. Sutton, Matthew S. Louder, Mark K. Chuang, Gwo-Yu Bailer, Robert T. Cortez, Valerie Kong, Rui McKee, Krisha O'Dell, Sijy Wang, Felicia Karim, Salim S. Abdool Binley, James M. Connors, Mark Haynes, Barton F. Martin, Malcolm A. Montefiori, David C. Morris, Lynn Overbaugh, Julie Kwong, Peter D. Mascola, John R. Georgiev, Ivelin S. TI Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting SO PLOS PATHOGENS LA English DT Article ID B-CELL RESPONSES; MONOCLONAL-ANTIBODIES; HIV-1-INFECTED INDIVIDUALS; HUMANIZED MICE; IN-VIVO; BROAD; PROTECTION; INFECTION; VACCINE; RECOGNITION AB Computational neutralization fingerprinting, NFP, is an efficient and accurate method for predicting the epitope specificities of polyclonal antibody responses to HIV-1 infection. Here, we present next-generation NFP algorithms that substantially improve prediction accuracy for individual donors and enable serologic analysis for entire cohorts. Specifically, we developed algorithms for: (a) selection of optimized virus neutralization panels for NFP analysis, (b) estimation of NFP prediction confidence for each serum sample, and (c) identification of sera with potentially novel epitope specificities. At the individual donor level, the next-generation NFP algorithms particularly improved the ability to detect multiple epitope specificities in a sample, as confirmed both for computationally simulated polyclonal sera and for samples from HIV-infected donors. Specifically, the next-generation NFP algorithms detected multiple specificities in twice as many samples of simulated sera. Further, unlike the first-generation NFP, the new algorithms were able to detect both of the previously confirmed antibody specificities, VRC01-like and PG9-like, in donor CHAVI 0219. At the cohort level, analysis of similar to 150 broadly neutralizing HIV-infected donor samples suggested a potential connection between clade of infection and types of elicited epitope specificities. Most notably, while 10E8-like antibodies were observed in infections from different clades, an enrichment of such antibodies was predicted for clade B samples. Ultimately, such large-scale analyses of antibody responses to HIV-1 infection can help guide the design of epitope- specific vaccines that are tailored to take into account the prevalence of infecting clades within a specific geographic region. Overall, the next-generation NFP technology will be an important tool for the analysis of broadly neutralizing polyclonal antibody responses against HIV-1. C1 [Doria-Rose, Nicole A.; Altae-Tran, Han R.; Roark, Ryan S.; Schmidt, Stephen D.; Sutton, Matthew S.; Louder, Mark K.; Chuang, Gwo-Yu; Bailer, Robert T.; Kong, Rui; McKee, Krisha; O'Dell, Sijy; Kwong, Peter D.; Mascola, John R.; Georgiev, Ivelin S.] NIH, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA. [Cortez, Valerie; Overbaugh, Julie] Fred Hutchinson Canc Res Ctr, Human Biol Div, 1124 Columbia St, Seattle, WA 98104 USA. [Cortez, Valerie] Univ Washington, Program Mol & Cellular Biol, Seattle, WA 98195 USA. [Wang, Felicia; Georgiev, Ivelin S.] Vanderbilt Univ, Vanderbilt Vaccine Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA. [Karim, Salim S. Abdool; Morris, Lynn] Univ KwaZulu Natal, CAPRISA, Durban, South Africa. [Karim, Salim S. Abdool] Columbia Univ, Dept Epidemiol, New York, NY USA. [Binley, James M.] San Diego Biomed Res Inst, San Diego, CA USA. [Connors, Mark] NIH, HIV Specif Immun Sect, Bldg 10, Bethesda, MD 20892 USA. [Haynes, Barton F.; Montefiori, David C.] Duke Univ, Human Vaccine Inst, Durham, NC USA. [Haynes, Barton F.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Dept Immunol, Durham, NC USA. [Haynes, Barton F.] Duke Univ, Ctr HIV AIDS Vaccine Immunology Immunogen Discove, Durham, NC USA. [Martin, Malcolm A.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Montefiori, David C.] Duke Univ, Sch Med, Dept Surg, Durham, NC USA. [Morris, Lynn] Univ Witwatersrand, Johannesburg, South Africa. [Morris, Lynn] Natl Inst Communicable Dis, Ctr HIV & STIs, Johannesburg, South Africa. [Georgiev, Ivelin S.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. [Georgiev, Ivelin S.] Vanderbilt Univ, Dept Elect Engn & Comp Sci, 221 Kirkland Hall, Nashville, TN 37235 USA. RP Georgiev, IS (reprint author), NIH, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA.; Georgiev, IS (reprint author), Vanderbilt Univ, Vanderbilt Vaccine Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA.; Georgiev, IS (reprint author), Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA.; Georgiev, IS (reprint author), Vanderbilt Univ, Dept Elect Engn & Comp Sci, 221 Kirkland Hall, Nashville, TN 37235 USA. EM ivelin.georgiev@vanderbilt.edu FU National Center for Advancing Translational Sciences [KL2TR000446]; NIH [R01 AI38518, R01 AI93278]; Division of Intramural Research and Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH FX Support for this work was provided in part by: (ISG) VUMC Faculty Research Scholars award and CTSA award No. KL2TR000446 from the National Center for Advancing Translational Sciences; (JO) NIH R01 AI38518; (JMB) NIH R01 AI93278; (PDK, JRM) Intramural Research Program of Division of Intramural Research and Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JAN PY 2017 VL 13 IS 1 AR e1006148 DI 10.1371/journal.ppat.1006148 PG 29 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EN1AV UT WOS:000395743500049 ER PT J AU Li, MMH Lau, Z Cheung, P Aguilar, EG Schneider, WM Bozzacco, L Molina, H Buehler, E Takaoka, A Rice, CM Felsenfeld, DP MacDonald, MR AF Li, Melody M. H. Lau, Zerlina Cheung, Pamela Aguilar, Eduardo G. Schneider, William M. Bozzacco, Leonia Molina, Henrik Buehler, Eugen Takaoka, Akinori Rice, Charles M. Felsenfeld, Dan P. MacDonald, Margaret R. TI TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP) SO PLOS PATHOGENS LA English DT Article ID INTERFERON-STIMULATED GENES; VIRAL MESSENGER-RNAS; INFLUENZA-A VIRUS; SINDBIS VIRUS; RIG-I; UBIQUITIN LIGASE; INHIBITION; SCREENS; TARGETS; REPLICATION AB The host factor and interferon (IFN)-stimulated gene (ISG) product, zinc-finger antiviral protein (ZAP), inhibits a number of diverse viruses by usurping and intersecting with multiple cellular pathways. To elucidate its antiviral mechanism, we perform a loss-of-function genome-wide RNAi screen to identify cellular cofactors required for ZAP antiviral activity against the prototype alphavirus, Sindbis virus (SINV). In order to exclude off-target effects, we carry out stringent confirmatory assays to verify the top hits. Important ZAP-liaising partners identified include proteins involved in membrane ion permeability, type I IFN signaling, and post-translational protein modification. The factor contributing most to the antiviral function of ZAP is TRIM25, an E3 ubiquitin and ISG15 ligase. We demonstrate here that TRIM25 interacts with ZAP through the SPRY domain, and TRIM25 mutants lacking the RING or coiled coil domain fail to stimulate ZAP's antiviral activity, suggesting that both TRIM25 ligase activity and its ability to form oligomers are critical for its cofactor function. TRIM25 increases the modification of both the short and long ZAP isoforms by K48-and K63-linked polyubiquitin, although ubiquitination of ZAP does not directly affect its antiviral activity. However, TRIM25 is critical for ZAP's ability to inhibit translation of the incoming SINV genome. Taken together, these data uncover TRIM25 as a bona fide ZAP cofactor that leads to increased ZAP modification enhancing its translational inhibition activity. C1 [Li, Melody M. H.; Aguilar, Eduardo G.; Schneider, William M.; Bozzacco, Leonia; Rice, Charles M.; MacDonald, Margaret R.] Rockefeller Univ, Lab Virol & Infect Dis, 1230 York Ave, New York, NY 10021 USA. [Lau, Zerlina; Cheung, Pamela; Felsenfeld, Dan P.] Icahn Sch Med Mt Sinai, Integrated Screening Core, Expt Therapeut Inst, New York, NY 10029 USA. [Molina, Henrik] Rockefeller Univ, Prote Resource Ctr, 1230 York Ave, New York, NY 10021 USA. [Buehler, Eugen] NIH, Trans NIH RNAi Screening Facil, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Takaoka, Akinori] Hokkaido Univ, Inst Med Genet, Div Signaling Canc & Immunol, Sapporo, Hokkaido, Japan. RP MacDonald, MR (reprint author), Rockefeller Univ, Lab Virol & Infect Dis, 1230 York Ave, New York, NY 10021 USA. EM macdonm@rockefeller.edu FU Women & Science Postdoctoral Fellowship; Starr Foundation; Greenberg Medical Research Institute; National Institutes of Health (NIH) [AI097089, AI114873, AI091707]; National Center for Advancing Translational Sciences (NCATS) [UL1 TR000043]; National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program FX The work was supported in part by the Women & Science Postdoctoral Fellowship, the Starr Foundation, Greenberg Medical Research Institute, National Institutes of Health (NIH) grants AI097089, AI114873, and AI091707, and anonymous donors. The use of the BD LSRII was supported by Grant # UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS) and National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JAN PY 2017 VL 13 IS 1 AR e1006145 DI 10.1371/journal.ppat.1006145 PG 25 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EN1AV UT WOS:000395743500046 ER PT J AU Parra, GI Squires, RB Karangwa, CK Johnson, JA Lepore, CJ Sosnovtsev, SV Green, KY AF Parra, Gabriel I. Squires, R. Burke Karangwa, Consolee K. Johnson, Jordan A. Lepore, Cara J. Sosnovtsev, Stanislav V. Green, Kim Y. TI Static and Evolving Norovirus Genotypes: Implications for Epidemiology and Immunity SO PLOS PATHOGENS LA English DT Article ID INFECTIOUS NONBACTERIAL GASTROENTERITIS; NORWALK-LIKE VIRUSES; RNA VIRUSES; GII.4 NOROVIRUS; SPORADIC GASTROENTERITIS; MOLECULAR EPIDEMIOLOGY; PHYLOGENETIC ANALYSIS; HERD-IMMUNITY; EVOLUTION; CHILDREN AB Noroviruses are major pathogens associated with acute gastroenteritis worldwide. Their RNA genomes are diverse, with two major genogroups (GI and GII) comprised of at least 28 genotypes associated with human disease. To elucidate mechanisms underlying norovirus diversity and evolution, we used a large-scale genomics approach to analyze human norovirus sequences. Comparison of over 2000 nearly full-length ORF2 sequences representing most of the known GI and GII genotypes infecting humans showed a limited number (<= 5) of distinct intra-genotypic variants within each genotype, with the exception of GII. 4. The non-GII. 4 genotypes were comprised of one or more intra-genotypic variants, with each variant containing strains that differed by only a few residues over several decades (remaining "static") and that have co-circulated with no clear epidemiologic pattern. In contrast, the GII. 4 genotype presented the largest number of variants (>10) that have evolved over time with a clear pattern of periodic variant replacement. To expand our understanding of these two patterns of diversification ("static" versus "evolving"), we analyzed using NGS the nearly full-length norovirus genome in healthy individuals infected with GII. 4, GII. 6 or GII. 17 viruses in different outbreak settings. The GII. 4 viruses accumulated mutations rapidly within and between hosts, while the GII. 6 and GII. 17 viruses remained relatively stable, consistent with their diversification patterns. Further analysis of genetic relationships and natural history patterns identified groupings of certain genotypes into larger related clusters designated here as "immunotypes". We propose that "immunotypes" and their evolutionary patterns influence the prevalence of a particular norovirus genotype in the human population. C1 [Parra, Gabriel I.; Karangwa, Consolee K.; Johnson, Jordan A.; Sosnovtsev, Stanislav V.; Green, Kim Y.] NIAID, Caliciviruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Squires, R. Burke] NIAID, Bioinformat & Computat Biosci Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Parra, Gabriel I.; Lepore, Cara J.] US FDA, Div Viral Prod, Silver Spring, MD 20993 USA. RP Parra, GI; Green, KY (reprint author), NIAID, Caliciviruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Parra, GI (reprint author), US FDA, Div Viral Prod, Silver Spring, MD 20993 USA. EM gabriel.parra@fda.hhs.gov; kgreen@niaid.nih.gov OI Green, Lisbeth Kim/0000-0002-8189-7352; Squires, R Burke/0000-0001-9666-6285; Parra, Gabriel/0000-0002-1102-4740 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, DHHS FX This work was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 81 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JAN PY 2017 VL 13 IS 1 AR e1006136 DI 10.1371/journal.ppat.1006136 PG 22 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EN1AV UT WOS:000395743500040 ER PT J AU Viollet, C Davis, DA Tekeste, SS Reczko, M Ziegelbauer, JM Pezzella, F Ragoussis, J Yarchoan, R AF Viollet, Coralie Davis, David A. Tekeste, Shewit S. Reczko, Martin Ziegelbauer, Joseph M. Pezzella, Francesco Ragoussis, Jiannis Yarchoan, Robert TI RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature SO PLOS PATHOGENS LA English DT Article ID ENDOTHELIAL-CELL RESPONSE; PROTEIN-COUPLED RECEPTOR; GROWTH-FACTOR EXPRESSION; INDUCIBLE FACTOR 1-ALPHA; MESSENGER-RNA; DNA-SEQUENCES; SIGNALING PATHWAYS; PANCREATIC-CANCER; IN-VITRO; INDUCTION AB Kaposi sarcoma-associated herpesvirus (KSHV) causes several tumors and hyperproliferative disorders. Hypoxia and hypoxia-inducible factors (HIFs) activate latent and lytic KSHV genes, and several KSHV proteins increase the cellular levels of HIF. Here, we used RNA sequencing, qRT-PCR, Taqman assays, and pathway analysis to explore the miRNA and mRNA response of uninfected and KSHV-infected cells to hypoxia, to compare this with the genetic changes seen in chronic latent KSHV infection, and to explore the degree to which hypoxia and KSHV infection interact in modulating mRNA and miRNA expression. We found that the gene expression signatures for KSHV infection and hypoxia have a 34% overlap. Moreover, there were considerable similarities between the genes up-regulated by hypoxia in uninfected (SLK) and in KSHV-infected (SLKK) cells. hsa-miR-210, a HIF-target known to have pro-angiogenic and anti-apoptotic properties, was significantly up-regulated by both KSHV infection and hypoxia using Taqman assays. Interestingly, expression of KSHV-encoded miRNAs was not affected by hypoxia. These results demonstrate that KSHV harnesses a part of the hypoxic cellular response and that a substantial portion of hypoxia-induced changes in cellular gene expression are induced by KSHV infection. Therefore, targeting hypoxic pathways may be a useful way to develop therapeutic strategies for KSHV-related diseases. C1 [Viollet, Coralie; Davis, David A.; Tekeste, Shewit S.; Ziegelbauer, Joseph M.; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Viollet, Coralie; Ragoussis, Jiannis] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Reczko, Martin; Ragoussis, Jiannis] Alexander Fleming Biomed Sci Res Ctr, Inst Mol Oncol, Vari, Greece. [Pezzella, Francesco] Univ Oxford, Nuffield Div Clin Lab Sci, Oxford, England. [Ragoussis, Jiannis] McGill Univ, Montreal, PQ, Canada. [Ragoussis, Jiannis] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Ragoussis, Jiannis] King Abdulaziz Univ, Dept Biochem, Jeddah, Saudi Arabia. RP Yarchoan, R (reprint author), NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM robert.yarchoan@nih.gov OI Ziegelbauer, Joseph/0000-0001-6464-6941 FU National Institutes of Health, National Cancer Institute; Wellcome Trust [095493] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (https://ccr.cancer.gov/), and by the Wellcome Trust PhD Studentship (http://www.wellcome.ac.uk/Funding/Biomedical-science/index.htm), Award Number 095493. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 117 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JAN PY 2017 VL 13 IS 1 AR e1006143 DI 10.1371/journal.ppat.1006143 PG 31 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EN1AV UT WOS:000395743500045 ER PT J AU Wibmer, CK Gorman, J Ozorowski, G Bhiman, JN Sheward, DJ Elliott, DH Rouelle, J Smira, A Joyce, MG Ndabambi, N Druz, A Asokan, M Burton, DR Connors, M Karim, SSA Mascola, JR Robinson, JE Ward, AB Williamson, C Kwong, PD Morris, L Moore, PL AF Wibmer, Constantinos Kurt Gorman, Jason Ozorowski, Gabriel Bhiman, Jinal N. Sheward, Daniel J. Elliott, Debra H. Rouelle, Julie Smira, Ashley Joyce, M. Gordon Ndabambi, Nonkululeko Druz, Aliaksandr Asokan, Mangai Burton, Dennis R. Connors, Mark Karim, Salim S. Abdool Mascola, John R. Robinson, James E. Ward, Andrew B. Williamson, Carolyn Kwong, Peter D. Morris, Lynn Moore, Penny L. TI Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BROADLY NEUTRALIZING ANTIBODIES; ENVELOPE GLYCOPROTEIN TRIMERS; HUMAN MONOCLONAL-ANTIBODIES; MUCOSAL SHIV CHALLENGE; B-CELL RESPONSES; CONFORMATIONAL EPITOPE; GLYCOSYLATION PROFILES; TYPE-1 INFECTION; VACCINE DESIGN AB A comprehensive understanding of the regions on HIV-1 envelope trimers targeted by broadly neutralizing antibodies may contribute to rational design of an HIV-1 vaccine. We previously identified a participant in the CAPRISA cohort, CAP248, who developed trimer-specific antibodies capable of neutralizing 60% of heterologous viruses at three years post-infection. Here, we report the isolation by B cell culture of monoclonal antibody CAP248-2B, which targets a novel membrane proximal epitope including elements of gp120 and gp41. Despite low maximum inhibition plateaus, often below 50% inhibitory concentrations, the breadth of CAP248-2B significantly correlated with donor plasma. Site-directed mutagene-sis, X-ray crystallography, and negative-stain electron microscopy 3D reconstructions revealed how CAP248-2B recognizes a cleavage-dependent epitope that includes the gp120 C terminus. While this epitope is distinct, it overlapped in parts of gp41 with the epi-topes of broadly neutralizing antibodies PGT151, VRC34, 35O22, 3BC315, and 10E8. CAP248-2B has a conformationally variable paratope with an unusually long 19 amino acid light chain third complementarity determining region. Two phenylalanines at the loop apex were predicted by docking and mutagenesis data to interact with the viral membrane. Neutralization by CAP248-2B is not dependent on any single glycan proximal to its epitope, and low neutralization plateaus could not be completely explained by N-or O-linked glyco-sylation pathway inhibitors, furin co-transfection, or pre-incubation with soluble CD4. Viral escape from CAP248-2B involved a cluster of rare mutations in the gp120-gp41 cleavage sites. Simultaneous introduction of these mutations into heterologous viruses abrogated neutralization by CAP248-2B, but enhanced neutralization sensitivity to 35O22, 4E10, and 10E8 by 10-100-fold. Altogether, this study expands the region of the HIV-1 gp120-gp41 quaternary interface that is a target for broadly neutralizing antibodies and identifies a set of mutations in the gp120 C terminus that exposes the membrane-proximal external region of gp41, with potential utility in HIV vaccine design. C1 [Wibmer, Constantinos Kurt; Bhiman, Jinal N.; Morris, Lynn; Moore, Penny L.] NHLS, NICD, Ctr HIV & STIs, Johannesburg, South Africa. [Wibmer, Constantinos Kurt; Bhiman, Jinal N.; Morris, Lynn; Moore, Penny L.] Univ Witwatersrand, Fac Hlth Sci, Johannesburg, South Africa. [Gorman, Jason; Joyce, M. Gordon; Druz, Aliaksandr; Asokan, Mangai; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ozorowski, Gabriel; Ward, Andrew B.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, CHAVI ID, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Ozorowski, Gabriel; Ward, Andrew B.] Scripps Res Inst, CAVD, La Jolla, CA 92037 USA. [Sheward, Daniel J.; Ndabambi, Nonkululeko; Williamson, Carolyn] Univ Cape Town, Inst Infect Dis & Mol Med IDM, Cape Town, South Africa. [Sheward, Daniel J.; Ndabambi, Nonkululeko; Williamson, Carolyn] Univ Cape Town, Div Med Virol, Cape Town, South Africa. [Sheward, Daniel J.; Ndabambi, Nonkululeko; Williamson, Carolyn] NHLS, Cape Town, South Africa. [Elliott, Debra H.; Rouelle, Julie; Smira, Ashley; Robinson, James E.] Tulane Univ, Med Ctr, Dept Pediat, New Orleans, LA 70118 USA. [Burton, Dennis R.] Scripps Res Inst, CHAVI ID, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp MIT & Harvard, Cambridge, MA USA. [Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Karim, Salim S. Abdool; Williamson, Carolyn; Morris, Lynn; Moore, Penny L.] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa CAPRISA, Durban, South Africa. [Karim, Salim S. Abdool] Columbia Univ, Dept Epidemiol, New York, NY USA. RP Morris, L; Moore, PL (reprint author), NHLS, NICD, Ctr HIV & STIs, Johannesburg, South Africa.; Morris, L; Moore, PL (reprint author), Univ Witwatersrand, Fac Hlth Sci, Johannesburg, South Africa.; Morris, L; Moore, PL (reprint author), Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa CAPRISA, Durban, South Africa. EM lynnm@nicd.ac.za; pennym@nicd.ac.za OI Wibmer, Constantinos Kurt/0000-0003-2329-2280 FU Centre for the AIDS Programme of Research (CAPRISA); South African Medical Research Council (MRC) SHIP program; NIH [A1116086-01]; Vaccine Research Center; National Institute of Allergy and Infectious Diseases (NIAID); HIVRAD NIH grant [AI088610]; South African HIV/AIDS Research and Innovation Platform of the South African Department of Science and Technology; US NIAID; NIH; US Department of Health and Human Services [U19 AI51794]; Columbia University Southern African Fogarty AIDS International Training and Research Program through the Fogarty International Center, NIH [5 D43 TW000231]; Poliomyelitis Research Foundation PhD Bursary; National Research Foundation of South Africa PhD Bursary; Collaboration for AIDS Vaccine Discovery [OPP1115782]; South African Research Chairs Initiative of the Department of Science and Technology; National Research Foundation of South Africa [98341] FX We acknowledge research funding from the Centre for the AIDS Programme of Research (CAPRISA) (SSAK), the South African Medical Research Council (MRC) SHIP program (P.L.M.), the NIH through a U01 grant (A1116086-01) (PLM, LM, JRM and PDK), the intramural research programs of the Vaccine Research Center and the National Institute of Allergy and Infectious Diseases (NIAID) (JRM and PDK) and a HIVRAD NIH grant (JER, CW and LM, AI088610). CAPRISA is funded by the South African HIV/AIDS Research and Innovation Platform of the South African Department of Science and Technology, and was initially supported by the US NIAID, NIH, US Department of Health and Human Services grant U19 AI51794 (SSAK). Funding was received by CKW and JNB from the Columbia University Southern African Fogarty AIDS International Training and Research Program through the Fogarty International Center, NIH grant 5 D43 TW000231 (to Quarraisha Abdool Karim). CKW and JNB are supported by a Poliomyelitis Research Foundation PhD Bursary and a National Research Foundation of South Africa PhD Bursary. Funding for ABW was provided by Collaboration for AIDS Vaccine Discovery grant OPP1115782. PLM is supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No 98341). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 88 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JAN PY 2017 VL 13 IS 1 DI 10.1371/journal.ppat.1006074 PG 30 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EN1AV UT WOS:000395743500012 ER PT J AU Yu, YB Kwon, K Tsitrin, T Bekele, S Sikorski, P Nelson, KE Pieper, R AF Yu, Yanbao Kwon, Keehwan Tsitrin, Tamara Bekele, Shiferaw Sikorski, Patricia Nelson, Karen E. Pieper, Rembert TI Characterization of Early-Phase Neutrophil Extracellular Traps in Urinary Tract Infections SO PLOS PATHOGENS LA English DT Article ID HOST-PATHOGEN INTERACTIONS; STAPHYLOCOCCUS-AUREUS; SAMPLE PREPARATION; PROTEOMIC ANALYSIS; ESCHERICHIA-COLI; CELL-DEATH; PROTEINS; INFLAMMATION; CHROMATIN; STREPTOCOCCUS AB Neutrophils have an important role in the antimicrobial defense and resolution of urinary tract infections (UTIs). Our research suggests that a mechanism known as neutrophil extracellular trap (NET) formation is a defense strategy to combat pathogens that have invaded the urinary tract. A set of human urine specimens with very high neutrophil counts had microscopic evidence of cellular aggregation and lysis. Deoxyribonuclease I (DNase) treatment resulted in disaggregation of such structures, release of DNA fragments and a proteome enriched in histones and azurophilic granule effectors whose quantitative composition was similar to that of previously described in vitro-formed NETs. The effector proteins were further enriched in DNA-protein complexes isolated in native PAGE gels. Immunofluorescence microscopy revealed a flattened morphology of neutrophils associated with decondensed chromatin, remnants of granules in the cell periphery, and myeloperoxidase colocalized with extracellular DNA, features consistent with early-phase NETs. Nuclear staining revealed that a considerable fraction of bacterial cells in these structures were dead. The proteomes of two pathogens, Staphylococcus aureus and Escherichia coli, were indicative of adaptive responses to early-phase NETs, specifically the release of virulence factors and arrest of ribosomal protein synthesis. Finally, we discovered patterns of proteolysis consistent with widespread cleavage of proteins by neutrophil elastase, proteinase 3 and cathepsin G and evidence of citrullination in many nuclear proteins. C1 [Yu, Yanbao; Kwon, Keehwan; Tsitrin, Tamara; Bekele, Shiferaw; Sikorski, Patricia; Nelson, Karen E.; Pieper, Rembert] J Craig Venter Inst, Rockville, MD 20850 USA. [Sikorski, Patricia] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Sikorski, Patricia] Georgetown Univ, Dept Microbiol & Immunol, Washington, DC USA. RP Pieper, R (reprint author), J Craig Venter Inst, Rockville, MD 20850 USA. EM 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; Ruggles Family Foundation FX Generous financial support for this study was provided by the National Institute of General Medical Sciences, National Institutes of Health (grant 5R01GM103598-02), the J. Craig Venter Institute, Dr. J. Craig Venter, and, via a financial contribution to the mass spectrometer, the Ruggles Family Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 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 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JAN PY 2017 VL 13 IS 1 AR e1006151 DI 10.1371/journal.ppat.1006151 PG 25 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EN1AV UT WOS:000395743500051 PM 28129394 ER PT J AU McBride, CM Blocklin, M Lipkus, IM Klein, WMP Brandon, TH AF McBride, Colleen M. Blocklin, Michelle Lipkus, Isaac M. Klein, William M. P. Brandon, Thomas H. TI Patient's lung cancer diagnosis as a cue for relatives' smoking cessation: evaluating the constructs of the teachable moment SO PSYCHO-ONCOLOGY LA English DT Article ID PATIENTS SOCIAL NETWORKS; PHYSICAL-ACTIVITY; POSSIBLE SELVES; NEGATIVE AFFECT; INTERVENTION; BEHAVIOR; SURVIVORSHIP; VALIDATION; INCREASE; OUTCOMES AB Background: To understand whether patient-reported experiences with lung cancer may create teachable moments (TM) for their relatives as evidenced by shifts in their risk perceptions, affective response, and self-image and in turn, motivation to quit smoking. Methods: Patients at a comprehensive cancer center (n = 152) completed a survey within 6 months of lung cancer diagnosis to assess their cancer-related symptoms and openness and enumerated relatives who were smokers. Relative smokers (n = 218) then completed a survey assessing their risk perceptions, affective response, and self-image as a smoker related to the patient's diagnosis (TM mechanisms), and their motivation to quit smoking. Cross-sectional mediation and moderation analyses were conducted to explore the links between patient-reported experiences, and relatives' TM mechanisms, and motivation to quit smoking. Results: Relative-reported affect was a significant mediator of the association between patient-reported symptoms and relative smoker's desire to quit. Relatives' self-image was a significant moderator of the association between patient-reported symptoms and relative smoker's desire to quit, such that patients' reported symptoms were associated with relatives' desire to quit only when the relative smoker reported a generally positive self-image as a smoker. No evidence was found for moderated mediation. However, the link between symptoms and negative affect was moderated by perceptions of risk. Conclusion: Whether smokers experience a family member's lung cancer as a TM is influenced by multiple interrelated cognitive and affective factors that warrant further exploration. Clearer understanding of these factors could inform how to re-invigorate and sustain this motivation to promote concrete actions toward smoking cessation. Copyright (C) 2015 John Wiley & Sons, Ltd. C1 [McBride, Colleen M.] Emory Rollins Sch Publ Hlth, Dept Behav Sci & Hlth Educ, Atlanta, GA USA. [Blocklin, Michelle] Abt Associates Inc, Boston, MA USA. [Lipkus, Isaac M.] Duke Univ, Durham, NC USA. [Klein, William M. P.] NCI, Rockville, MD USA. [Klein, William M. P.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Brandon, Thomas H.] H Lee Moffitt Canc Ctr & Res Inst, Tobacco Res & Intervent Program, Tampa, FL USA. RP McBride, CM (reprint author), Rollins Sch Publ Hlth, 1518 Clifton Rd NE,GCR 564,Mailstop 1518-002-5AA, Atlanta, GA 30322 USA. EM Colleen.marie.mcbride@emory.edu FU National Human Genome Research Institute; National Cancer Institute [5U01-CA-92622] FX This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the National Cancer Institute grant 5U01-CA-92622. The authors have no conflicts of interest to report. NR 39 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD JAN PY 2017 VL 26 IS 1 BP 88 EP 95 DI 10.1002/pon.4011 PG 8 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA EK7VN UT WOS:000394133400013 PM 26514587 ER PT J AU Knudsen, GA Sanders, JM Birnbaum, LS AF Knudsen, Gabriel A. Sanders, J. Michael Birnbaum, Linda S. TI Disposition of the emerging brominated flame retardant, bis(2-ethylhexyl) tetrabromophthalate, in female Sprague Dawley rats: effects of dose, route and repeated administration SO XENOBIOTICA LA English DT Article DE ADME; bioaccumulation; brominated flame retardant; persistent organic pollutant; phthalate ester ID IN-HOUSE DUST; MIXTURE FIREMASTER(R) 550; HUMAN EXPOSURE; INDOOR DUST; TISSUE DISPOSITION; VITRO METABOLISM; DIPHENYL ETHERS; PHASE-OUT; EXCRETION; HEXABROMOCYCLODODECANE AB 1. Bis(2-ethylhexyl)-tetrabromophthalate (BEH-TEBP; CAS No. 26040-51-7; PubChem CID: 117291; MW 706.15 g/mol, elsewhere: TeBrDEPH, TBPH, or BEHTBP) is used as an additive brominated flame retardant in consumer products. 2. Female Sprague Dawley rats eliminated 92-98% of [(14) C]-BEH-TEBP unchanged in feces after oral administration (0.1 or 10 mu mol/kg). A minor amount of each dose (0.8-1%) was found in urine after 72 h. Disposition of orally administered BEH-TEBP in male B6C3F1/Tac mice was similar to female rats. 3. Bioaccumulation of [(14) C]-radioactivity was observed in liver and adrenals following 10 daily oral administrations (0.1 mu mol/kg/day). These tissues contained 5-and 10-fold higher concentrations of [(14) C]-radioactivity, respectively, versus a single dose. 4. IV-administered [(14) C]-BEH-TEBP (0.1 mu mol/kg) was slowly eliminated in feces, with> 15% retained in tissues after 72 h. Bile and fecal extracts from these rats contained the metabolite mono-ethylhexyl tetrabromophthalate (TBMEHP). 5. BEH-TEBP was poorly absorbed, minimally metabolized and eliminated mostly by the fecal route after oral administration. Repeated exposure to BEH-TEBP led to accumulation in some tissues. The toxicological significance of this effect remains to be determined. This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health (Project ZIA BC 011476). C1 [Knudsen, Gabriel A.; Sanders, J. Michael; Birnbaum, Linda S.] NCI, Lab Toxicol & Toxicokinet, 111 TW Alexander Dr,BG 101 Rm C202A, Res Triangle Pk, NC 27709 USA. RP Knudsen, GA (reprint author), NCI, Lab Toxicol & Toxicokinet, 111 TW Alexander Dr,BG 101 Rm C202A, Res Triangle Pk, NC 27709 USA. EM gabriel.knudsen@nih.gov FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health [ZIA BC 011476] FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health (Project ZIA BC 011476). NR 60 TC 2 Z9 2 U1 5 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0049-8254 EI 1366-5928 J9 XENOBIOTICA JI Xenobiotica PY 2017 VL 47 IS 3 BP 245 EP 254 DI 10.1080/00498254.2016.1174793 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EK5FL UT WOS:000393952200008 PM 27098498 ER PT J AU Dias, JP Shardell, MD Carlson, OD Melvin, D Caturegli, G Ferrucci, L Chia, CW Egan, JM Basaria, S AF Dias, J. P. Shardell, M. D. Carlson, O. D. Melvin, D. Caturegli, G. Ferrucci, L. Chia, C. W. Egan, J. M. Basaria, S. TI Testosterone vs. aromatase inhibitor in older men with low testosterone: effects on cardiometabolic parameters SO ANDROLOGY LA English DT Article DE aromatase inhibition; inflammation; insulin sensitivity; lipids; testosterone ID IMPROVES INSULIN SENSITIVITY; RANDOMIZED CONTROLLED-TRIAL; BODY-COMPOSITION; CARDIOVASCULAR EVENTS; REPLACEMENT THERAPY; GLUCOSE-METABOLISM; MALE HYPOGONADISM; HEALTHY-MEN; ELDERLY-MEN; OBESE MEN AB Testosterone (T) replacement is being increasingly offered to older men with age-related decline in testosterone levels. The effects of long-term testosterone replacement and aromatase inhibition (AI) on glucose homeostasis and cardiometabolic markers were determine in older non-diabetic men with low testosterone levels. Men 65years, mean age 71 +/- 3years with serum total T<350ng/dL were randomized in a double-blind, placebo-controlled, parallel-group, proof-of-concept trial evaluating the effects of 5g transdermal testosterone gel (TT) (n=10), 1mg anastrozole (n=10) or placebo (n=9) daily for 12months. Homeostatic Model Assessment of insulin resistance (HOMA(IR)) was the primary outcome. Secondary outcomes included OGIS in response to OGTT, fasting lipids, C-reactive protein (CRP), adipokines, and abdominal and mid-thigh fat by computed tomography. All outcomes were assessed at baseline and 12months. After 12months, absolute changes in HOMA(IR) in both treatment arms (TT group: -0.05 +/- 0.21); (AI group: 0.15 +/- 0.10) were similar to placebo (-0.11 +/- 0.26), as were CRP and fasting lipid levels. Adiponectin levels significantly decreased in the TT group (-1.8 +/- 0.9mg/L, p=0.02) and abdominal subcutaneous fat (-60.34 +/- 3.19cm(2), p=0.003) and leptin levels (-1.5 +/- 1.2ng/mL, p=0.04) were significantly lower with AI. Mid-thigh subcutaneousfat was reduced in both treatment arms (TT group: -4.88 +/- 1.24cm(2), p=0.008); (AI group: -6.05 +/- 0.87cm(2), p=0.0002). In summary, in this proof-of-concept trial, changes in HOMA(IR) AI were similar in all three groups while the effects of intervention on subcutaneous fat distribution and adipokines were variable. Larger efficacy and safety trials are needed before AI pharmacotherapy can be considered as a treatment option for low T levels in older men. C1 [Dias, J. P.; Carlson, O. D.; Melvin, D.; Egan, J. M.] NIA, Lab Clin Invest, Baltimore, MD 21225 USA. [Shardell, M. D.; Caturegli, G.; Ferrucci, L.; Chia, C. W.] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Basaria, S.] Harvard Med Sch, Brigham & Womens Hosp, Sect Mens Hlth Aging & Metab, Boston, MA 02115 USA. RP Egan, JM (reprint author), NIA, Lab Clin Invest, Baltimore, MD 21225 USA.; Basaria, S (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Sect Mens Hlth Aging & Metab, Boston, MA 02115 USA. EM eganj@grc.nia.nih.gov; sbasaria@partners.org FU Intramural Research Program of the NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 43 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 EI 2047-2927 J9 ANDROLOGY-US JI Andrology PD JAN PY 2017 VL 5 IS 1 BP 31 EP 40 DI 10.1111/andr.12284 PG 10 WC Andrology SC Endocrinology & Metabolism GA EK1FS UT WOS:000393671800005 PM 27792869 ER PT J AU Patel, CJ Sundaram, R Louis, GMB AF Patel, C. J. Sundaram, R. Louis, G. M. Buck TI A data-driven search for semen-related phenotypes in conception delay SO ANDROLOGY LA English DT Article DE conception delay; fecundity; semen analysis; sperm quality parameters ID NUTRIENT-WIDE ASSOCIATION; DNA FRAGMENTATION; MALE-INFERTILITY; PREGNANCY; QUALITY; TIME; POPULATION; FERTILITY; MEN; HEALTH AB Sperm count, morphology, and motility have been reported to be predictive of pregnancy, although with equivocal basis prompting some authors to question the prognostic value of semen analysis. To assess the utility of including semen quality data in predicting conception delay or requiring >6 cycles to become pregnant (referred to as conception delay), we utilized novel data-driven analytic techniques in a pre-conception cohort of couples prospectively followed up for time-to-pregnancy. The study cohort comprised 402 (80%) male partners who provided semen samples and had time-to-pregnancy information. Female partners used home pregnancy tests and recorded results in daily journals. Odds ratios (OR), false discovery rates, and 95% confidence intervals (CIs) for conception delay (time-to-pregnancy>6 cycles) were estimated for 40 semen quality phenotypes comprising 35 semen quality endpoints and 5 closely related fecundity determinants (body mass index, time of contraception, lipids, cotinine and seminal white blood cells). Both traditional and strict sperm phenotype measures were associated with lower odds of conception delay. Specifically, for an increase in percent morphologically normal spermatozoa using traditional methods, we observed a 40% decrease in conception delay (OR=0.6, 95% CI=0.50, 0.81; p=0.0003). Similarly, for an increase in strict criteria, we observed a 30% decrease in odds for conception delay (OR=0.7, 95% CI=0.52, 0.83; p=0.001). On the other hand, an increase in percent coiled tail spermatozoa was associated with a 40% increase in the odds for conception delay (OR=1.4, 95% CI=1.12, 1.75; p=0.003). However, our findings suggest that semen phenotypes have little predictive value of conception delay (area under the curve of 73%). In a multivariate model containing significant semen factors and traditional risk factors (i.e. age, body mass index, cotinine and ever having fathered a pregnancy), there was a modest improvement in prediction of conception delay (16% increase in area under the curve, p<0.0002). C1 [Patel, C. J.] Harvard Univ, Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA. [Sundaram, R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Biostat & Bioinformat Branch, NIH, Rockville, MD USA. [Louis, G. M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Off Director, NIH, Rockville, MD USA. RP Patel, CJ (reprint author), Harvard Univ, Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA. EM chirag_patel@hms.harvard.edu OI Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358]; National Institute of Environmental Health Sciences [R00 ES 023504, R21 ES025052] FX This work was supported by Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355; N01-HD-3-3356; N01-HD-3-3358) and a National Institute of Environmental Health Sciences (R00 ES 023504 and R21 ES025052 to CJP). We acknowledge the Reproductive Health Assessment Team, Biomonitoring and Health Assessment Branch, for the analysis of semen samples under a memo of understanding with the NICHD. NR 48 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 EI 2047-2927 J9 ANDROLOGY-US JI Andrology PD JAN PY 2017 VL 5 IS 1 BP 95 EP 102 DI 10.1111/andr.12288 PG 8 WC Andrology SC Endocrinology & Metabolism GA EK1FS UT WOS:000393671800014 PM 27792860 ER PT J AU Michels, KA Kim, K Yeung, EH Plowden, TC Chaljub, EN Lu, YL Mumford, SL AF Michels, K. A. Kim, K. Yeung, E. H. Plowden, T. C. Chaljub, E. N. Lu, Y. -L. Mumford, S. L. TI Adjusting for abstinence time in semen analyses: some considerations SO ANDROLOGY LA English DT Letter ID MEDIATION ANALYSIS; ADJUSTMENT; QUALITY; MODELS; BIAS C1 [Michels, K. A.; Kim, K.; Yeung, E. H.; Plowden, T. C.; Chaljub, E. N.; Mumford, S. L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Plowden, T. C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Lu, Y. -L.] NIH, Div Lib Serv, Off Res Serv, Natl Inst Hlth Lib, Bethesda, MD USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6710B Rockledge Dr,MSC 7004, Bethesda, MD 20892 USA. EM mumfords@mail.nih.gov OI Michels, Kara/0000-0003-2431-2079; Kim, Keewan/0000-0002-1892-6739 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 20 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 EI 2047-2927 J9 ANDROLOGY-US JI Andrology PD JAN PY 2017 VL 5 IS 1 BP 191 EP 193 DI 10.1111/andr.12285 PG 3 WC Andrology SC Endocrinology & Metabolism GA EK1FS UT WOS:000393671800026 PM 27860459 ER PT J AU Van Maldergem, L Besse, A De Paepe, B Blakely, EL Appadurai, V Humble, MM Piard, J Craig, K He, LP Hella, P Debray, FG Martin, JJ Gaussen, M Laloux, P Stevanin, G Van Coster, R Taylor, RW Copeland, WC Mormont, E Bonnen, PE AF Van Maldergem, Lionel Besse, Arnaud De Paepe, Boel Blakely, Emma L. Appadurai, Vivek Humble, Margaret M. Piard, Juliette Craig, Kate He, Langping Hella, Pierre Debray, Francois-Guillaume Martin, Jean-Jacques Gaussen, Marion Laloux, Patrice Stevanin, Giovanni Van Coster, Rudy Taylor, Robert W. Copeland, William C. Mormont, Eric Bonnen, Penelope E. TI POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID MITOCHONDRIAL-DNA DELETIONS; POLYMERASE GAMMA-SUBUNITS; MUTATIONS; DISEASE; OPHTHALMOPLEGIA; MAINTENANCE; VARIANTS; DEMENTIA; PATIENT; TWINKLE AB Objective: Mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative disorders such as ataxia and Parkinson's disease. We describe an extended Belgian pedigree where seven individuals presented with adult-onset cerebellar ataxia, axonal peripheral ataxic neuropathy, and tremor, in variable combination with parkinsonism, seizures, cognitive decline, and ophthalmoplegia. We sought to identify the underlying molecular etiology and characterize the mitochondrial pathophysiology of this neurological syndrome. Methods: Clinical, neurophysiological, and neuroradiological evaluations were conducted. Patient muscle and cultured fibroblasts underwent extensive analyses to assess mitochondrial function. Genetic studies including genome-wide sequencing were conducted. Results: Hallmarks of mitochondrial dysfunction were present in patients' tissues including ultrastructural anomalies of mitochondria, mosaic cytochrome c oxidase deficiency, and multiple mtDNA deletions. We identified a splice acceptor variant in POLG2, c.970-1G>C, segregating with disease in this family and associated with a concomitant decrease in levels of POLG2 protein in patient cells. Interpretation: This work extends the clinical spectrum of POLG2 deficiency to include an overwhelming, adult-onset neurological syndrome that includes cerebellar syndrome, peripheral neuropathy, tremor, and parkinsonism. We therefore suggest to include POLG2 sequencing in the evaluation of ataxia and sensory neuropathy in adults, especially when it is accompanied by tremor or parkinsonism with white matter disease. The demonstration that deletions of mtDNA resulting from autosomal-dominant POLG2 variant lead to a monogenic neurodegenerative multicomponent syndrome provides further evidence for a major role of mitochondrial dysfunction in the pathomechanism of nonsyndromic forms of the component neurodegenerative disorders. C1 [Van Maldergem, Lionel; Piard, Juliette] Univ Franche Comte, Ctr Genet Humaine, Besancon, France. [Van Maldergem, Lionel; Debray, Francois-Guillaume] Univ Hosp, Ctr Human Genet, Metab Unit, Liege, Belgium. [Besse, Arnaud; Appadurai, Vivek; Bonnen, Penelope E.] Baylor Coll Med, Dept Mol & Human Genet, One Baylor Plaza, Houston, TX 77030 USA. [De Paepe, Boel; Van Coster, Rudy] Ghent Univ Hosp, Div Child Neurol & Metab, Dept Pediat, Ghent, Belgium. [Blakely, Emma L.; Craig, Kate; He, Langping; Taylor, Robert W.] Newcastle Univ, Inst Neurosci, Wellcome Trust Ctr Mitochondrial Res, Newcastle Upon Tyne, Tyne & Wear, England. [Humble, Margaret M.; Copeland, William C.] NIEHS, Mitochondrial DNA Replicat Grp, Durham, NC USA. [Hella, Pierre] Sambre & Meuse Reg Hosp, Dept Neurol, Namur, Belgium. [Martin, Jean-Jacques] Univ Antwerp, Born Bunge Fdn, Antwerp, Belgium. [Gaussen, Marion; Stevanin, Giovanni] Sorbonne Univ, UPMC, CNRS, INSERM,U1127,UMR7225, Paris, France. [Gaussen, Marion; Stevanin, Giovanni] Hop La Pitie Salpetriere, Inst Cerveau & Moelle Epiniere, Paris, France. [Gaussen, Marion; Stevanin, Giovanni] PSL Univ, Lab Neurogenet, Ecole Prat Hautes Etud, F-75013 Paris, France. [Laloux, Patrice; Mormont, Eric] Catholic Univ Louvain, CHU UCL Namur, Dept Neurol, B-5530 Yvoir, Belgium. [Mormont, Eric; Bonnen, Penelope E.] UCL Inst Neurosci IoNS, B-1200 Brussels, Belgium. RP Van Maldergem, L (reprint author), Univ Franche Comte, Ctr Genet Humaine, Besancon, France.; Bonnen, PE (reprint author), Baylor Coll Med, Dept Mol & Human Genet, One Baylor Plaza, Houston, TX 77030 USA. EM vmald@hotmail.com; pbonnen@bcm.edu RI De Paepe, Boel/B-7548-2013 OI De Paepe, Boel/0000-0001-9403-4401 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ES065078]; French National Agency for Research (SPATAX-QUEST project); Verum Foundation; European community [E12009DD]; Investissements d'Avenir program [ANR-10-IAIHU-06]; Wellcome Trust Strategic Award [096919Z/11/Z]; Medical Research Council (UK) Centre for Translational Muscle Disease Research [G0601943]; Lily Foundation; UK NHS Highly Specialised "Rare Mitochondrial Disorders of Adults and Children" Service; NIH National Human Genome Research Institute [U54HG006542]; National Institute of Neurological Disorders and Stroke of the National Institutes of Health [R01NS08372] FX This work was financially supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES065078 to M.M.H. and W.C.C.), the French National Agency for Research (SPATAX-QUEST project, to GS), the Verum Foundation (to GS), the European community (7th framework program, Neuromics, E12009DD, to GS), and the Investissements d'Avenir program ANR-10-IAIHU-06 (to ICM institute). RWT is supported by a Wellcome Trust Strategic Award (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Muscle Disease Research (G0601943), The Lily Foundation, and the UK NHS Highly Specialised "Rare Mitochondrial Disorders of Adults and Children" Service. Exome sequencing was performed at Baylor-Hopkins Center for Mendelian Genomics funded by the NIH National Human Genome Research Institute (U54HG006542). Research reported in this publication was supported by National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS08372 to PEB. NR 27 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD JAN PY 2017 VL 4 IS 1 BP 4 EP 14 DI 10.1002/acn3.361 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EK1CY UT WOS:000393664600001 PM 28078310 ER PT J AU Kambouris, M Thevenon, J Soldatos, A Cox, A Stephen, J Ben-Omran, T Al-Sarraj, Y Boulos, H Bone, W Mullikin, JC Masurel-Paulet, A St-Onge, J Dufford, Y Chantegret, C Thauvin-Robinet, C Al-Alami, J Faivre, L Riviere, JB Gahl, WA Bassuk, AG Malicdan, MCV El-Shanti, H AF Kambouris, Marios Thevenon, Julien Soldatos, Ariane Cox, Allison Stephen, Joshi Ben-Omran, Tawfeg Al-Sarraj, Yasser Boulos, Hala Bone, William Mullikin, James C. Masurel-Paulet, Alice St-Onge, Judith Dufford, Yannis Chantegret, Corrine Thauvin-Robinet, Christel Al-Alami, Jamil Faivre, Laurence Riviere, Jean Baptiste Gahl, William A. Bassuk, Alexander G. Malicdan, May Christine V. El-Shanti, Hatem CA NISC Comparative Sequencing TI Biallelic SCN10A mutations in neuromuscular disease and epileptic encephalopathy SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID VOLTAGE-GATED SODIUM; RIB-POLYDACTYLY SYNDROME; ALLEN BRAIN ATLAS; ATRIAL-FIBRILLATION; CHANNELS; GENE; PAIN; NA(V)1.8; ASSOCIATIONS; VARIANTS AB Objectives: Two consanguineous families, one of Sudanese ethnicity presenting progressive neuromuscular disease, severe cognitive impairment, muscle weakness, upper motor neuron lesion, anhydrosis, facial dysmorphism, and recurrent seizures and the other of Egyptian ethnicity presenting with neonatal hypotonia, bradycardia, and recurrent seizures, were evaluated for the causative gene mutation. Methods and Results: Homozygosity mapping and whole exome sequencing (WES) identified damaging homozygous variants in SCN10A, namely c.4514C>T; p.Thr1505Met in the first family and c.4735C>T; p.Arg1579* in the second family. A third family, of Western European descent, included a child with febrile infection-related epilepsy syndrome (FIRES) who also had compound heterozygous missense mutations in SCN10A, namely, c.3482T>C; p.Met1161Thr and c.4709C>A; p.Thr1570Lys. A search for SCN10A variants in three consortia datasets (EuroEPINOMICS, Epi4K/EPGP, Autism/dbGaP) identified an additional five individuals with compound heterozygous variants. A Hispanic male with infantile spasms [c.2842G>C; p.Val948Leu and c.1453C>T; p.Arg485Cys], and a Caucasian female with Lennox-Gastaut syndrome [c.1529C>T; p.Pro510Leu and c.4984G>A; p.Gly1662Ser] in the epilepsy databases and three in the autism databases with [c.4009T>A; p.Ser1337Thr and c.1141A>G; p.Ile381Val], [c.2972C>T; p.Pro991Leu and c.2470C>T; p.His824Tyr], and [c.4009T>A; p.Ser1337Thr and c.2052G>A; p.Met684Ile]. Interpretation: SCN10A is a member of the voltage-gated sodium channel (VGSC) gene family. Sodium channels are responsible for the instigation and proliferation of action potentials in central and peripheral nervous systems. Heterozygous mutations in VGSC genes cause a wide range of epileptic and peripheral nervous system disorders. This report presents autosomal recessive mutations in SCN10A that may be linked to epilepsy-related phenotypes, Lennox-Gastaut syndrome, infantile spasms, and Autism Spectrum Disorder. C1 [Kambouris, Marios] Sidra Med & Res Ctr, Pathol Genet, Doha, Qatar. [Kambouris, Marios; Al-Sarraj, Yasser; El-Shanti, Hatem] Hamad Bin Khalifa Univ, Ctr Med Genet, Qatar Biomed Res Inst, Doha, Qatar. [Kambouris, Marios] Yale Univ, Sch Med, Genet, New Haven, CT USA. [Thevenon, Julien; Masurel-Paulet, Alice; St-Onge, Judith; Dufford, Yannis; Chantegret, Corrine; Thauvin-Robinet, Christel; Faivre, Laurence; Riviere, Jean Baptiste] Hop Enfant, Ctr Genet, Dijon, France. [Soldatos, Ariane; Stephen, Joshi; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Soldatos, Ariane; Bone, William; Gahl, William A.; Malicdan, May Christine V.] NHGRI, Undiagnosed Dis Program, NIH, Bethesda, MD 20892 USA. [Cox, Allison; Bassuk, Alexander G.; El-Shanti, Hatem] Univ Iowa, Pediat, Iowa City, IA USA. [Ben-Omran, Tawfeg] Hamad Med Corp, Pediat, Clin & Metab Genet, Doha, Qatar. [Ben-Omran, Tawfeg] Weill Cornell Med Coll, Doha, Qatar. [Boulos, Hala] Univ Chicago, Human Genet, Chicago, IL 60637 USA. [Mullikin, James C.] Natl Genome Res Inst, Intramural Sequencing Ctr, NIH, Bethesda, MD USA. [Mullikin, James C.; NISC Comparative Sequencing] Natl Genome Res Inst, Comparat Genom Unit, Genome Technol Branch, NIH, Bethesda, MD USA. [Al-Alami, Jamil] Shafallah Med Genet Ctr, Doha, Qatar. [El-Shanti, Hatem] Univ Jordan, Pediat, Amman, Jordan. RP El-Shanti, H (reprint author), Univ Jordan, Dept Pediat, Sch Med, Amman, Jordan. EM h.elshanti@ju.edu.jo OI Al-Sarraj, Yasser/0000-0002-1505-6360 FU Qatar National Research Fund (QNRF) NPRP grant [6-359-3-095, 09-367-3-087]; Shafallah Center Foundation, Doha, Qatar; NIH [1R01 NS064159-01A1, 5R21MH100086-02]; National Human Genome Research Institute Intramural Research Program; Epilepsy Genome/Phenome Project [EPGP-NINDS U01-NS053998]; [R01-MH089208]; [R01-MH089175]; [R01-MH089025]; [R01-MH089004]; [R01-MH089482] FX This publication was made possible in part by Qatar National Research Fund (QNRF) NPRP grant 09-367-3-087 (MK and HE) and NPRP grant 6-359-3-095 (HE and AGB) and by the generous support of the Shafallah Center Foundation, Doha, Qatar. It was also supported by NIH 1R01 NS064159-01A1 (AGB) and 5R21MH100086-02 and the National Human Genome Research Institute Intramural Research Program. The support for the Autism Sequencing Collaborative was provided by grants R01-MH089208 awarded to Mark Daly, R01-MH089175 awarded to Richard Gibbs, R01-MH089025 awarded to Joseph Buxbaum, R01-MH089004 awarded to Gerard Schellenberg and R01-MH089482 awarded to James Sutcliffe. Our appreciation to the Epilepsy Epi4K consortium: Discovery in Epilepsy study (NINDS U01-NS077303) and the Epilepsy Genome/Phenome Project (EPGP-NINDS U01-NS053998). NR 42 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD JAN PY 2017 VL 4 IS 1 BP 26 EP 35 DI 10.1002/acn3.372 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EK1CY UT WOS:000393664600003 PM 28078312 ER PT J AU Foutz, A Appleby, BS Hamlin, C Liu, XQ Yang, S Cohen, Y Chen, W Blevins, J Fausett, C Wang, H Gambetti, P Zhang, SL Hughson, A Tatsuoka, C Schonberger, LB Cohen, ML Caughey, B Safar, JG AF Foutz, Aaron Appleby, Brian S. Hamlin, Clive Liu, Xiaoqin Yang, Sheng Cohen, Yvonne Chen, Wei Blevins, Janis Fausett, Cameron Wang, Han Gambetti, Pierluigi Zhang, Shulin Hughson, Andrew Tatsuoka, Curtis Schonberger, Lawrence B. Cohen, Mark L. Caughey, Byron Safar, Jiri G. TI Diagnostic and prognostic value of human prion detection in cerebrospinal fluid SO ANNALS OF NEUROLOGY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; QUAKING-INDUCED CONVERSION; ALZHEIMERS-DISEASE; MAMMALIAN PRIONS; MOLECULAR-BASIS; 14-3-3 PROTEIN; AMYLOID-BETA; CSF TESTS; SCRAPIE; CLASSIFICATION AB ObjectiveSeveral prion amplification systems have been proposed for detection of prions in cerebrospinal fluid (CSF), most recently, the measurements of prion seeding activity with second-generation real-time quaking-induced conversion (RT-QuIC). The objective of this study was to investigate the diagnostic performance of the RT-QuIC prion test in the broad phenotypic spectrum of prion diseases. MethodsWe performed CSF RT-QuIC testing in 2,141 patients who had rapidly progressive neurological disorders, determined diagnostic sensitivity and specificity in 272 cases that were autopsied, and evaluated the impact of mutations and polymorphisms in the PRNP gene, and type 1 or type 2 human prions on diagnostic performance. ResultsThe 98.5% diagnostic specificity and 92% sensitivity of CSF RT-QuIC in a blinded retrospective analysis matched the 100% specificity and 95% sensitivity of a blind prospective study. The CSF RT-QuIC differentiated 94% of cases of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 from the sCJD MM2 phenotype, and 80% of sCJD VV2 from sCJD VV1. The mixed prion type 1-2 and cases heterozygous for codon 129 generated intermediate CSF RT-QuIC patterns, whereas genetic prion diseases revealed distinct profiles for each PRNP gene mutation. InterpretationThe diagnostic performance of the improved CSF RT-QuIC is superior to surrogate marker tests for prion diseases such as 14-3-3 and tau proteins, and together with PRNP gene sequencing the test allows the major prion subtypes to be differentiated in vivo. This differentiation facilitates prediction of the clinicopathological phenotype and duration of the diseasetwo important considerations for envisioned therapeutic interventions. ANN NEUROL 2017;81:79-92 C1 [Foutz, Aaron; Appleby, Brian S.; Hamlin, Clive; Liu, Xiaoqin; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Gambetti, Pierluigi; Cohen, Mark L.; Safar, Jiri G.] Case Western Reserve Univ, Natl Pr Dis Pathol Surveillance Ctr, Sch Med, Cleveland, OH USA. [Appleby, Brian S.; Hamlin, Clive; Zhang, Shulin; Cohen, Mark L.; Safar, Jiri G.] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA. [Appleby, Brian S.; Yang, Sheng; Fausett, Cameron; Wang, Han; Tatsuoka, Curtis; Safar, Jiri G.] Case Western Reserve Univ, Sch Med, Dept Neurol, Cleveland, OH 44106 USA. [Appleby, Brian S.] Case Western Reserve Univ, Sch Med, Dept Psychiat, Cleveland, OH 44106 USA. [Hughson, Andrew; Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Schonberger, Lawrence B.] Ctr Dis Control & Prevent, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA USA. RP Safar, JG (reprint author), Case Western Reserve Univ, Natl Pr Dis Pathol Surveillance Ctr, 2085 Adlbert Rd, Cleveland, OH 44106 USA. EM jiri.safar@case.edu FU Centers for Disease Control and Prevention [UR8/CCU515004]; NIH, National Institute of Neurological Disorders and Stroke (NINDS) [NS074317]; Charles S. Britton Fund; Alliance Biosecure Foundation; NIH National Institute of Allergy and Infectious Diseases FX This work was supported by the Centers for Disease Control and Prevention (UR8/CCU515004, J.G.S.), NIH, National Institute of Neurological Disorders and Stroke (NINDS) (NS074317, J.G.S.), Charles S. Britton Fund (J.G.S.), Alliance Biosecure Foundation (J.G.S., B.C.), and Intramural Research Program of the NIH National Institute of Allergy and Infectious Diseases (B.C.). NR 54 TC 0 Z9 0 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD JAN PY 2017 VL 81 IS 1 BP 79 EP 92 DI 10.1002/ana.24833 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EJ9QV UT WOS:000393562300008 PM 27893164 ER PT J AU Mesa, R Vannucchi, AM Yacoub, A Zachee, P Garg, M Lyons, R Koschmieder, S Rinaldi, C Byrne, J Hasan, Y Passamonti, F Verstovsek, S Hunter, D Jones, MM Zhen, HL Habr, D Martino, B AF Mesa, Ruben Vannucchi, Alessandro M. Yacoub, Abdulraheem Zachee, Pierre Garg, Mamta Lyons, Roger Koschmieder, Steffen Rinaldi, Ciro Byrne, Jennifer Hasan, Yasmin Passamonti, Francesco Verstovsek, Srdan Hunter, Deborah Jones, Mark M. Zhen, Huiling Habr, Dany Martino, Bruno TI The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF) SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE polycythaemia vera; quality of life; signs and symptoms; Janus kinase; hydroxycarbamide ID QUALITY-OF-LIFE; PLACEBO-CONTROLLED TRIAL; MYELOPROLIFERATIVE NEOPLASMS; ESSENTIAL THROMBOCYTHEMIA; STANDARD THERAPY; MYELOFIBROSIS; HYDROXYUREA; CRITERIA; DISEASE; THROMBOSIS AB The randomized, double-blind, double-dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)-related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV-related symptoms. Patients were randomized 1: 1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, >= 50% improvement from baseline in myeloproliferative neoplasm-symptom assessment form total symptom score cytokine symptom cluster (TSS-C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43.4% vs. 29.6% of ruxolitinib- and hydroxycarbamide-treated patients, respectively (odds ratio, 1.82; 95% confidence interval, 0.82-4.04; P = 0.139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13-16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening-to-baseline TSS-C scores (ratio = 2) receiving ruxolitinib than hydroxycarbamide (47.4% vs. 25.0%; P = 0.0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV-related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement. C1 [Mesa, Ruben] Mayo Clin, Ctr Canc, Scottsdale, AZ USA. [Vannucchi, Alessandro M.] Univ Florence, Ctr Res & Innovat Myeloproliferat Neoplasms, AOU Careggi, Florence, Italy. [Yacoub, Abdulraheem] Univ Kansas, Med Ctr, Westwood, KS USA. [Zachee, Pierre] ZNA Stuivenberg, Antwerp, Belgium. [Garg, Mamta] Leicester Royal Infirm, Leicester, Leics, England. [Lyons, Roger] Texas Oncol, San Antonio, TX USA. [Lyons, Roger] US Oncol Res, San Antonio, TX USA. [Koschmieder, Steffen] Rhein Westfal TH Aachen, Dept Haematol Oncol Haemostaseol & Stem Cell Tran, Fac Med, Aachen, Germany. [Rinaldi, Ciro] Lincoln Univ, Lincoln, England. [Rinaldi, Ciro] United Lincolnshire Hosp Trust, Lincoln, England. [Byrne, Jennifer] Univ Nottingham Hosp, Nottingham, England. [Hasan, Yasmin] Sandwell & West Birmingham Hosp NHS Trust, West Bromwich, England. [Passamonti, Francesco] Univ Insubria, Varese, Italy. [Verstovsek, Srdan] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hunter, Deborah; Jones, Mark M.; Zhen, Huiling] Incyte Corp, Wilmington, DE USA. [Habr, Dany] Novartis Pharmaceut, E Hanover, NJ USA. [Martino, Bruno] Azienda Osped Bianchi Melacrino Morelli, Reggio Di Calabria, Italy. RP Mesa, R (reprint author), Mayo Clin, Ctr Canc, Div Hematol & Med Oncol, NCI Designated Comprehens Canc Ctr, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM mesa.ruben@mayo.edu FU Incyte Corporation FX This study was funded by Incyte Corporation. Writing assistance was provided by Cory Pfeiffenberger, PhD (Complete Healthcare Communications, LLC, an ICON plc company), whose work was funded by Incyte Corporation. NR 27 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JAN PY 2017 VL 176 IS 1 BP 76 EP 85 DI 10.1111/bjh.14382 PG 10 WC Hematology SC Hematology GA EK0JE UT WOS:000393611900009 PM 27858987 ER PT J AU Gil-Krzewska, A Murakami, Y Peruzzi, G O'Brien, KJ Merideth, MA Cullinane, AR Gahl, WA Coligan, JE Gochuico, BR Krzewski, K AF Gil-Krzewska, Aleksandra Murakami, Yousuke Peruzzi, Giovanna O'Brien, Kevin J. Merideth, Melissa A. Cullinane, Andrew R. Gahl, William A. Coligan, John E. Gochuico, Bernadette R. Krzewski, Konrad TI Natural killer cell activity and dysfunction in Hermansky-Pudlak syndrome SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE Hermansky-Pudlak syndrome; NK cell; cytotoxicity; lytic granule exocytosis; immune deficiency ID MICROTUBULE-ORGANIZING CENTER; LYTIC GRANULES; SYNDROME TYPE-2; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; CYTOTOXICITY; POLARIZATION; DEFICIENCY; EXOCYTOSIS; MUTATIONS; CYTOKINE AB Hermansky-Pudlak syndrome (HPS) encompasses disorders with abnormal function of lysosomes and lysosome-related organelles, and some patients who develop immunodeficiency. The basic mechanisms contributing to immune dysfunction in HPS are ill-defined. We analysed natural killer (NK) cells from patients diagnosed with HPS-1, HPS-2, HPS-4, and an unreported HPS subtype. NK cells from an HPS-2 and an unreported HPS subtype share a similar cellular phenotype with defective granule release and cytotoxicity, but differ in cytokine exocytosis. Defining NK cell activity in several types of HPS provides insights into cellular defects of the disorder and understanding of mechanisms contributing to HPS pathogenesis. C1 [Gil-Krzewska, Aleksandra; Murakami, Yousuke; Peruzzi, Giovanna; Coligan, John E.; Krzewski, Konrad] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr,Twinbrook 2,Room 202A, Rockville, MD 20852 USA. [O'Brien, Kevin J.; Gahl, William A.; Gochuico, Bernadette R.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Merideth, Melissa A.; Cullinane, Andrew R.; Gahl, William A.] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Cullinane, Andrew R.; Gahl, William A.] Howard Univ, Coll Med, Dept Anat, Washington, DC USA. [Murakami, Yousuke] Dainippon Sumitomo Pharma, Osaka, Japan. [Peruzzi, Giovanna] Sapienza Univ, Ctr Life Nanosci, Ist Italiano Tecnol, Rome, Italy. RP Krzewski, K (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr,Twinbrook 2,Room 202A, Rockville, MD 20852 USA. EM krzewskikj@niaid.nih.gov OI Peruzzi, Giovanna/0000-0002-6517-9107 FU National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute, National Institutes of Health FX We thank the patients for their contributions to this research. This study was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, and the National Human Genome Research Institute, National Institutes of Health. NR 15 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JAN PY 2017 VL 176 IS 1 BP 118 EP 123 DI 10.1111/bjh.14390 PG 6 WC Hematology SC Hematology GA EK0JE UT WOS:000393611900014 PM 27766632 ER PT J AU Shield, KD Ferlay, J Jemal, A Sankaranarayanan, R Chaturvedi, AK Bray, F Soerjomataram, I AF Shield, Kevin D. Ferlay, Jacques Jemal, Ahmedin Sankaranarayanan, Rengaswamy Chaturvedi, Anil K. Bray, Freddie Soerjomataram, Isabelle TI The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012 SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Article DE incidence; lip; mouth; neoplasms; pharynx ID SQUAMOUS-CELL CARCINOMA; SALIVARY-GLAND CARCINOMA; RISK-FACTORS; NASOPHARYNGEAL CARCINOMA; UNITED-STATES; NECK-CANCER; OROPHARYNGEAL CANCERS; INCREASING INCIDENCE; ALCOHOL-CONSUMPTION; COST-EFFECTIVENESS AB By using data from the International Agency for Research on Cancer publication Cancer Incidence in 5 Continents and GLOBOCAN, this report provides the first consolidated global estimation of the subsite distribution of new cases of lip, oral cavity, and pharyngeal cancers by country, sex, and age for the year 2012. Major geographically based, sex-based, and age-based variations in the incidence of lip, oral cavity, and pharyngeal cancers by subsite were observed. Lip cancers were highly frequent in Australia (associated with solar radiation) and in central and eastern Europe (associated with tobacco smoking). Cancers of the oral cavity and hypopharynx were highly common in south-central Asia, especially in India (associated with smokeless tobacco, bidi, and betel-quid use). Rates of oropharyngeal cancers were elevated in northern America and Europe, notably in Hungary, Slovakia, Germany, and France and were associated with alcohol use, tobacco smoking, and human papillomavirus infection. Nasopharyngeal cancers were most common in northern Africa and eastern/southeast Asia, indicative of genetic susceptibility combined with Epstein-Barr virus infection and early life carcinogenic exposures (nitrosamines and salted foods). The global incidence of lip, oral cavity, and pharyngeal cancers of 529,500, corresponding to 3.8% of all cancer cases, is predicted to rise by 62% to 856,000 cases by 2035 because of changes in demographics. Given the rising incidence of lip, oral cavity, and pharyngeal cancers and the variations in incidence by subsites across world regions and countries, there is a need for local, tailored approaches to prevention, screening, and treatment interventions that will optimally reduce the lip, oral cavity, and pharyngeal cancer burden in future decades. CA Cancer J Clin 2017;67:51-64. (c) 2016 American Cancer Society. C1 [Shield, Kevin D.; Ferlay, Jacques; Bray, Freddie; Soerjomataram, Isabelle] Int Agcy Res Canc, Sect Canc Surveillance, Lyon, France. [Jemal, Ahmedin] Amer Canc Soc, Surveillance & Hlth Serv Res, Atlanta, GA 30329 USA. [Sankaranarayanan, Rengaswamy] Int Agcy Res Canc, Sect Early Detect & Prevent, Screening Grp, Lyon, France. [Chaturvedi, Anil K.] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Rockville, MD USA. RP Shield, KD (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM shieldk@fellows.iarc.fr NR 129 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 EI 1542-4863 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD JAN-FEB PY 2017 VL 67 IS 1 BP 51 EP 64 DI 10.3322/caac.21384 PG 14 WC Oncology SC Oncology GA EK3EA UT WOS:000393807800005 PM 28076666 ER PT J AU Amos, CI Dennis, J Wang, ZM Byun, J Schumacher, FR Gayther, SA Casey, G Hunter, DJ Sellers, TA Gruber, SB Dunning, AM Michailidou, K Fachal, L Doheny, K Spurdle, AB Li, YF Xiao, XJ Romm, J Pugh, E Coetzee, GA Hazelett, DJ Bojesen, SE Caga-Anan, C Haiman, CA Kamal, A Luccarini, C Tessier, D Vincent, D Bacot, F Van den Berg, DJ Nelson, S Demetriades, S Goldgar, DE Couch, FJ Forman, JL Giles, GG Conti, DV Bickeboller, H Risch, A Waldenberger, M Bruske-Hohlfeld, I Hicks, BD Ling, H McGuffog, L Lee, A Kuchenbaecker, K Soucy, P Manz, J Cunningham, JM Butterbach, K Kote-Jarai, Z Kraft, P FitzGerald, L Lindstrom, S Adams, M McKay, JD Phelan, CM Benlloch, S Kelemen, LE Brennan, P Riggan, M O'Mara, TA Shen, HB Shi, YY Thompson, DJ Goodman, MT Nielsen, SF Berchuck, A Laboissiere, S Schmit, SL Shelford, T Edlund, CK Taylor, JA Field, JK Park, SK Offit, K Thomassen, M Schmutzler, R Ottini, L Hung, RJ Marchini, J Al Olama, AA Peters, U Eeles, RA Seldin, MF Gillanders, E Seminara, D Antoniou, AC Pharoah, PDP Chenevix-Trench, G Chanock, SJ Simard, J Easton, DF AF Amos, Christopher I. Dennis, Joe Wang, Zhaoming Byun, Jinyoung Schumacher, Fredrick R. Gayther, Simon A. Casey, Graham Hunter, David J. Sellers, Thomas A. Gruber, Stephen B. Dunning, Alison M. Michailidou, Kyriaki Fachal, Laura Doheny, Kimberly Spurdle, Amanda B. Li, Yafang Xiao, Xiangjun Romm, Jane Pugh, Elizabeth Coetzee, Gerhard A. Hazelett, Dennis J. Bojesen, Stig E. Caga-Anan, Charlisse Haiman, Christopher A. Kamal, Ahsan Luccarini, Craig Tessier, Daniel Vincent, Daniel Bacot, Francois Van den Berg, David J. Nelson, Stefanie Demetriades, Stephen Goldgar, David E. Couch, Fergus J. Forman, Judith L. Giles, Graham G. Conti, David V. Bickeboeller, Heike Risch, Angela Waldenberger, Melanie Brueske-Hohlfeld, Irene Hicks, Belynda D. Ling, Hua McGuffog, Lesley Lee, Andrew Kuchenbaecker, Karoline Soucy, Penny Manz, Judith Cunningham, Julie M. Butterbach, Katja Kote-Jarai, Zsofia Kraft, Peter FitzGerald, Liesel Lindstrom, Sara Adams, Marcia McKay, James D. Phelan, Catherine M. Benlloch, Sara Kelemen, Linda E. Brennan, Paul Riggan, Marjorie O'Mara, Tracy A. Shen, Hongbing Shi, Yongyong Thompson, Deborah J. Goodman, Marc T. Nielsen, Sune F. Berchuck, Andrew Laboissiere, Sylvie Schmit, Stephanie L. Shelford, Tameka Edlund, Christopher K. Taylor, Jack A. Field, John K. Park, Sue K. Offit, Kenneth Thomassen, Mads Schmutzler, Rita Ottini, Laura Hung, Rayjean J. Marchini, Jonathan Al Olama, Ali Amin Peters, Ulrike Eeles, Rosalind A. Seldin, Michael F. Gillanders, Elizabeth Seminara, Daniela Antoniou, Antonis C. Pharoah, Paul D. P. Chenevix-Trench, Georgia Chanock, Stephen J. Simard, Jacques Easton, Douglas F. TI The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; OVARIAN-CANCER; SUSCEPTIBILITY LOCI; PROSTATE-CANCER; ENDOMETRIAL CANCER; LUNG-CANCER; BREAST-CANCER; RISK LOCI; ENVIRONMENT INTERACTIONS; MENDELIAN RANDOMIZATION AB Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits. Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures. Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. (C)2016 AACR. C1 [Amos, Christopher I.; Byun, Jinyoung; Li, Yafang; Xiao, Xiangjun; Kamal, Ahsan; Forman, Judith L.] Geisel Sch Med, Biomed Data Sci, Hanover, NH USA. [Dennis, Joe; Dunning, Alison M.; Michailidou, Kyriaki; Fachal, Laura; Luccarini, Craig; Lee, Andrew; Kuchenbaecker, Karoline; Benlloch, Sara; Thompson, Deborah J.; Al Olama, Ali Amin; Antoniou, Antonis C.; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Cambridge, England. [Wang, Zhaoming] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Schumacher, Fredrick R.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Sch Med, Cleveland, OH 44106 USA. [Gayther, Simon A.; Haiman, Christopher A.] Cedars Sinai Med Ctr, Ctr Bioinformat & Funct Genom, Greater Los Angeles Area, Los Angeles, CA 90048 USA. [Casey, Graham; Gruber, Stephen B.; Van den Berg, David J.; Edlund, Christopher K.] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Hunter, David J.] Harvard Sch Publ Hlth, Program Mol & Genet Epidemiol, Dept Epidemiol, Boston, MA USA. [Sellers, Thomas A.; Phelan, Catherine M.; Schmit, Stephanie L.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Doheny, Kimberly; Romm, Jane; Pugh, Elizabeth; Adams, Marcia] Johns Hopkins Sch Med, Inst Med Genet, Ctr Inherited Dis Res, Baltimore, MD USA. [Spurdle, Amanda B.] QIMR Berghofer Med Res Inst, Mol Canc Epidemiol, Herston, Qld, Australia. [Coetzee, Gerhard A.] Van Andel Res Inst, Grand Rapids, MI USA. [Hazelett, Dennis J.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Bojesen, Stig E.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Caga-Anan, Charlisse; Nelson, Stefanie; Gillanders, Elizabeth; Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Tessier, Daniel; Vincent, Daniel; Bacot, Francois; Laboissiere, Sylvie] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Tessier, Daniel; Vincent, Daniel; Bacot, Francois; Laboissiere, Sylvie] McGill Univ, Montreal, PQ, Canada. [Demetriades, Stephen] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Goldgar, David E.] Huntsman Canc Inst, Salt Lake City, UT USA. [Couch, Fergus J.; Cunningham, Julie M.] Mayo Clin, Rochester, MN USA. [Giles, Graham G.; McGuffog, Lesley; FitzGerald, Liesel] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; McGuffog, Lesley; FitzGerald, Liesel] Menzies Inst Med Res, Canc Genet & Immunol, Hobart, Tas, Australia. [Conti, David V.] Univ Southern Calif, Zilkha Neurogenet Inst, Dept Prevent Med, Div Biostat, Los Angeles, CA USA. [Bickeboeller, Heike] Georg August Univ, Dept Genet Epidemiol, Univ Med Ctr, Gottingen, Germany. [Risch, Angela] Salzburg Univ, Salzburg, Austria. [Risch, Angela] Canc Cluster Salzburg, Salzburg, Austria. [Waldenberger, Melanie; Manz, Judith] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Res Unit Mol Epidemiol, Neuherberg, Germany. [Brueske-Hohlfeld, Irene] Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Hicks, Belynda D.] Frederick Natl Lab Canc Res, Canc Genom Res Lab, Frederick, MD USA. [Soucy, Penny; Simard, Jacques] Univ Quebec, Ctr Genom Lab, Ctr Hosp, Quebec City, PQ, Canada. [Soucy, Penny; Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Butterbach, Katja] German Canc Res Ctr, Canc Epidemiol, Heidelberg, Germany. [Kote-Jarai, Zsofia; Eeles, Rosalind A.] Inst Canc Res, London, England. [Lindstrom, Sara] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [McKay, James D.; Brennan, Paul] World Hlth Org, Int Agcy Res Canc, Lyon, France. [Kelemen, Linda E.] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Riggan, Marjorie; Berchuck, Andrew] Duke Univ, Med Ctr, Dept Gynecol, Durham, NC USA. [O'Mara, Tracy A.; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia. [Shen, Hongbing] Nanjing Med Univ, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Dept Epidemiol & Biostat, Collaborat Innovat Ctr Canc Med,Sch Publ Hlth, Nanjing, Jiangsu, Peoples R China. [Shi, Yongyong] Shanghai Jiao Tong Univ, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Bio X Inst, Shanghai, Peoples R China. [Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Oncol, Copenhagen, Denmark. [Schmit, Stephanie L.] H Lee Moffitt Canc Ctr & Res Inst, Dept Gastrointestinal Oncol, Tampa, FL USA. [Taylor, Jack A.] NIEHS, Mol & Genet Epidemiol Grp, Res Triangle Pk, NC USA. [Field, John K.] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England. [Park, Sue K.] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Offit, Kenneth] Mem Hosp, Clin Genet Serv, New York, NY USA. [Offit, Kenneth] Sloan Kettering Inst, Canc Biol & Genet Program, New York, NY USA. [Offit, Kenneth] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, Odense, Denmark. [Schmutzler, Rita] Univ Klinikum Koln, Zentrum Familiarer Brust & Eierstockkrebs, Cologne, Germany. [Ottini, Laura] Sapienza Univ Rome, Dept Mol Med, Rome, Italy. [Hung, Rayjean J.] Univ Toronto, Mt Sinai Hosp, Lunen Feld Tanenbaum Res Inst, Toronto, ON, Canada. [Marchini, Jonathan] Univ Oxford, Dept Stat, Oxford, England. [Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Seldin, Michael F.] Univ Calif Davis, Dept Biochem & Mol Med, Davis, CA 95616 USA. [Seldin, Michael F.] Univ Calif Davis, Dept Internal Med, Davis, CA 95616 USA. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Risch, Angela] German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany. [Risch, Angela] German Ctr Lung Res, Translat Lung Res Ctr Heidelberg, Heidelberg, Germany. RP Amos, CI (reprint author), Geisel Sch Med Dartmouth, Dept Biomed Data Sci, 1 Med Ctr Dr, Lebanon, NH 03766 USA. EM Christopher.I.Amos@dartmouth.edu RI Risch, Angela/H-2669-2013; OI Risch, Angela/0000-0002-8026-5505; Dunning, Alison Margaret/0000-0001-6651-7166 FU TRICL (Transdisciplinary Research for Cancer of Lung); International Lung Cancer Consortium (ILCCO) by NIH [U19 CA148127-01]; NIH [U19 CA148065, U19 CA148107, R01 CA81488, P30 CA014089, U19-CA148112]; Canadian Cancer Society Research Institute [020214, R01-CA122443, P50-CA116201, CA192393, P50-CA136393, OCAC-CA- 149429, P30-CA15083, R01 CA 136924, R01 CA 190182]; Cancer Research UK [C490/A8339, C1287/A16563, C1287/A10118, C490/A16561, C490/A10119, C490/A10124]; Hospital Clinical Research Program (PHRC); Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; German Cancer Aid [110837]; Government of Canada through Genome Canada; Canadian Institutes of Health Research [MOP-86727]; Ministere de l'Economie, Innovation et Exportation du Quebec through Genome Quebec; Quebec Breast Cancer Foundation; Canadian Breast Cancer Foundation; National Cancer Institute through Breast Cancer Family Registry Cohort [1UM1CA164920-01A1]; European Union [MSCA-IF-2014-EF-656144]; Breast Cancer Research Foundation [P30 CA08748]; Andrew Sabin Foundation; Norris Cotton Cancer Center [P30CA023108]; Quantitative Biology Research Institute [P20GM103534]; Coordinating Center for Screen Detected Lesions [U01CA196386]; [U19 CA148537]; [268201200008I]; [1X01HG007491-01] FX This work was supported by TRICL (Transdisciplinary Research for Cancer of Lung) and International Lung Cancer Consortium (ILCCO) by NIH grant U19 CA148127-01 (to C.I. Amos, J. Byun, Y. Li, X. Xiao, J. L. Forman, A. Risch, H. Bickeboller, M. Waldenberger, I. Bruske, J. Manz, P. Brennan, R. Hung, H. Shen, Y. Shi, A. Kamal, J. K. Field), DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer) by NIH grant U19 CA148065 (to D.J. Hazelett, D.F. Easton, S. Lindstrom, P. Kraft, J. Dennis, A. Dunning, K. Michailidou, L. Fachal, S. Benlloch, J. Cunningham, K. Butterbach, K. Offit, R. Schmutzler, L. Ottini, D. Vincent), CORECT (ColoRectal Transdisciplinary Study) by NIH grants U19 CA148107, R01 CA81488, P30 CA014089 (to S. Gruber, U. Peters, G. Casey), ELLIPSE (ELLIPSE, Elucidating Loci in Prostate Cancer Susceptibility) supported by U19 CA148537 (to F. Schumacher, S.A. Gayther, S.L. Schmit, C.K. Edlund, D.J. Hazelett, G.A. Coetzee, C. Haiman, S. Demetriades, D. Van Den Berg); FOCI (Follow-up of Ovarian Cancer Genetic Association & Interaction Studies) by NIH grant U19-CA148112 (to T.A. Sellers, P. Pharoah, S. Gayther, A. Monteiro, J. Schildkraut, E. Iversen) Canadian Cancer Society Research Institute (grant no. 020214; to R. Hung), R01-CA122443 (to B. Hicks) P50-CA116201, CA192393 (to F. Couch), P50-CA136393 (to J. Cunningham, F. Couch), OCAC-CA- 149429 (to C. Phelan), P30-CA15083 (to B. Hicks), R01 CA 136924 and R01 CA 190182 (to G.A. Coetzee); Cancer Research UK (C490/A8339; to A. Antoniou, P. Pharoah, A. Dunning), (C1287/A16563 and C1287/A10118) to D.F. Easton, C490/A16561 (to P. Pharoah, A. Dunning), C490/A10119 (to A. Dunning, P. Pharoah), C490/A10124 (to A. Dunning, P. Pharoah); ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique, and the Ligue Regionale Contre le Cancer (LRCC; to F. Bacot); DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1; to C.K. Edlund), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). Prostate Lung Colon Ovarian Screening trial: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: to R. Schmutzler, Cologne). The PERSPECTIVE (J. Simard) project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (MOP-86727, to L.E. Kelemen), the Ministere de l'Economie, Innovation et Exportation du Quebec through Genome Quebec, and the Quebec Breast Cancer Foundation, including additional funding from the Canadian Breast Cancer Foundation and the National Cancer Institute through Breast Cancer Family Registry Cohort (#1UM1CA164920-01A1); European Union Framework Programme for Research and Innovation (MSCA-IF-2014-EF-656144; to L. Fachal); The Breast Cancer Research Foundation, P30 CA08748, Andrew Sabin Foundation (to K. Offit). CIDR genotyping for the Oncoarray was conducted under contract 268201200008I (to K. Doheny) and through grant 1X01HG007491-01 (to C.I. Amos).; The Norris Cotton Cancer Center (P30CA023108), The Quantitative Biology Research Institute (P20GM103534), and the Coordinating Center for Screen Detected Lesions (U01CA196386) also supported efforts of C.I. Amos. NR 82 TC 2 Z9 2 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2017 VL 26 IS 1 BP 126 EP 135 DI 10.1158/1055-9965.EPI-16-0106 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EK2JN UT WOS:000393753700018 PM 27697780 ER PT J AU Jankovic, N Geelen, A Winkels, RM Mwungura, B Fedirko, V Jenab, M Illner, AK Brenner, H Ordonez-Mena, JM de Jong, JCK Franco, OH Orfanos, P Trichopoulou, A Boffetta, P Agudo, A Peeters, PH Tjonneland, A Hallmans, G Bueno-De-Mesquita, HB Park, Y Feskens, EJ de Groot, LC Kampman, E AF Jankovic, Nicole Geelen, Anouk Winkels, Renate M. Mwungura, Blaise Fedirko, Veronika Jenab, Mazda Illner, Anne K. Brenner, Hermann Ordonez-Mena, Jose M. de Jong, Jessica C. Kiefte Franco, Oscar H. Orfanos, Philippos Trichopoulou, Antonia Boffetta, Paolo Agudo, Antonio Peeters, Petra H. Tjonneland, Anne Hallmans, Goran Bueno-de-Mesquita, H. Bas Park, Yikyung Feskens, Edith J. de Groot, Lisette C. Kampman, Ellen CA Consortium Hlth Ageing Network Co TI Adherence to the WCRF/AICR Dietary Recommendations for Cancer Prevention and Risk of Cancer in Elderly from Europe and the United States: A Meta-Analysis within the CHANCES Project SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID RESEARCH FUND/AMERICAN INSTITUTE; BREAST-CANCER; RESEARCH GUIDELINES; HEALTH; COHORT; DESIGN; PATTERNS; CONCORDANCE; NUTRITION; MORTALITY AB Background: It is unknown whether dietary recommendations for cancer prevention are applicable to the elderly. We analyzed WCRF/AICR recommendations in cohorts of European and U.S. adults ages 60 years and above. Methods: Individual participant data meta-analysis included 362,114 participants (43% women), from seven prospective cohort studies, free from cancer at enrollment. The WCRF/AICR diet score was based on: (i) energy-dense foods and sugary drinks, (ii) plant foods, (iii) red and processed meat, and (iv) alcoholic drinks. Cox proportional hazards regression was used to examine the association between the diet score and cancer risks. Adjusted, cohort-specific HRs were pooled using random-effects meta-analysis. Risk advancement periods (RAP) were calculated to quantify the time period by which the risk of cancer was postponed among those adhering to the recommendations. Results: After a median follow-up of 11 to 15 years across cohorts, 70,877 cancer cases were identified. Each one-point increase in the WCRF/AICR diet score [range, 0 (no) to 4 (complete adherence)] was significantly associated with a lower risk of total cancer [HR, 0.94; 95% confidence interval (CI), 0.92-0.97], cancers of the colorectum (HR, 0.84; 95% CI, 0.80-0.89) and prostate (HR, 0.94; 95% CI, 0.92-0.97), but not breast or lung. Adherence to an additional component of the WCRF/AICR diet score significantly postponed the incidence of cancer at any site by 1.6 years (RAP, -1.6; 95% CI, -4.09 to -2.16). Conclusions: Adherence to WCRF/AICR dietary recommendations is associated with lower risk of cancer among older adults. Impact: Dietary recommendations for cancer prevention are applicable to the elderly. (C)2016 AACR. C1 [Jankovic, Nicole; Geelen, Anouk; Winkels, Renate M.; Mwungura, Blaise; Feskens, Edith J.; de Groot, Lisette C.; Kampman, Ellen] Wageningen Univ, Div Human Nutr, Dept Agrotechnol & Food Sci, Wageningen, Netherlands. [Jankovic, Nicole] Univ Duisburg Essen, Ctr Clin Epidemiol, Fac Med, Inst Med Informat Biometry & Epidemiol, Hufelandstr 55, D-45147 Essen, Germany. [Fedirko, Veronika] Emory Univ, Winship Canc Ctr, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Jenab, Mazda] Int Agcy Res Canc, Dept Nutr Epidemiol, Lyon, France. [Illner, Anne K.] Inst Polytechn LaSalle Beauvais, Dept Nutr & Hlth Sci, Beauvais, France. [Illner, Anne K.] Int Agcy Res Canc, Dept Dietary Exposure Assessment, Sect Nutr & Metab, Lyon, France. [Brenner, Hermann; Ordonez-Mena, Jose M.] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Canc Prevent Div, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Heidelberg, Germany. [de Jong, Jessica C. Kiefte; Franco, Oscar H.] Univ Med Ctr Rotterdam, Erasmus Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands. [de Jong, Jessica C. Kiefte] Leiden Univ Coll, Global Publ Hlth, The Hague, Netherlands. [Orfanos, Philippos; Trichopoulou, Antonia] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, Athens, Greece. [Orfanos, Philippos; Trichopoulou, Antonia; Boffetta, Paolo] Hellen Hlth Fdn, Athens, Greece. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY USA. [Agudo, Antonio] Catalan Inst Oncol ICO IDIBELL, Canc Epidemiol Res Program, Unit Nutr & Canc, Barcelona, Spain. [Peeters, Petra H.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Tjonneland, Anne] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Bueno-de-Mesquita, H. Bas] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur, Malaysia. [Park, Yikyung] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Park, Yikyung] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. RP Jankovic, N (reprint author), Univ Duisburg Essen, Ctr Clin Epidemiol, Fac Med, Inst Med Informat Biometry & Epidemiol, Hufelandstr 55, D-45147 Essen, Germany. EM Nicole.Jankovic@uk-essen.de OI Ordonez-Mena, Jose Manuel/0000-0002-8965-104X FU FP7 framework programme of the Directorate-General for Research & Innovation in the European Commission [242244]; Regional Government of Andalucia; Regional Government of Asturias; Regional Government of Basque Country; Regional Government of Murcia; Regional Government of Navarra, Spain; Regional Government of Vasterbotten, Sweden; Dutch Ministry of Public Health, Welfare, and Sports; Netherlands Cancer Registry; LK Research Funds; Dutch Prevention Funds; Dutch Zorg Onderzoek Nederland; World Cancer Research Fund; Statistics Netherlands; Danish Cancer Society; Hellenic Health Foundation; Stavros Niarchos Foundation; Intramural Research Program of the NIH; National Cancer Institute; Erasmus Medical Center Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Ministry of Education, Culture, and Science; Ministry of Health, Welfare, and Sports; European Commission; Municipality of Rotterdam FX This work was part of the Consortium on Health and Ageing (CHANCES) project supported by the FP7 framework programme of the Directorate-General for Research & Innovation in the European Commission (grant 242244). All authors received that grant. The CHANCES project is coordinated by the Hellenic Health Foundation, Greece. The included cohorts were financially supported by the Regional Governments of Andalucia, Asturias, Basque Country, Murcia, and Navarra, Spain; the Regional Government of Vasterbotten, Sweden; the Dutch Ministry of Public Health, Welfare, and Sports; the Netherlands Cancer Registry; LK Research Funds; Dutch Prevention Funds; Dutch Zorg Onderzoek Nederland; the World Cancer Research Fund; Statistics Netherlands; the Danish Cancer Society; the Hellenic Health Foundation; the Stavros Niarchos Foundation; the Intramural Research Program of the NIH; the National Cancer Institute; The Rotterdam Elderly Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Ministry of Education, Culture, and Science; the Ministry of Health, Welfare, and Sports; the European Commission; and the Municipality of Rotterdam. NR 32 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2017 VL 26 IS 1 BP 136 EP 144 DI 10.1158/1055-9965.EPI-16-0428 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EK2JN UT WOS:000393753700019 PM 27793797 ER PT J AU Withrow, DR Pole, JD Nishri, ED Tjepkema, M Marrett, LD AF Withrow, Diana R. Pole, Jason D. Nishri, E. Diane Tjepkema, Michael Marrett, Loraine D. TI Cancer Survival Disparities Between First Nation and Non-Aboriginal Adults in Canada: Follow-up of the 1991 Census Mortality Cohort SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NEW-ZEALAND; ETHNIC INEQUALITIES; AMERICAN-INDIANS; CERVICAL-CANCER; BREAST-CANCER; SOCIOECONOMIC INEQUALITIES; INDIGENOUS AUSTRALIANS; PROSTATE CARCINOMA; COLORECTAL-CANCER; MATCHED COHORT AB Background: The burden of cancer among indigenous people in Canada has been understudied due to a lack of ethnic identifiers in cancer registries. We compared cancer survival among First Nations to that among non-Aboriginal adults in Canada in the first national study of its kind to date. Methods: A population-based cohort of approximately 2 million respondents to the 1991 Canadian Long Form Census was followed for cancer diagnoses and deaths using probabilistic linkage to cancer and death registries until 2009. Excess mortality rate ratios (EMRR) and 5-year age-standardized relative survival rates were calculated for 15 cancers using age, sex, ethnicity, and calendar-time-specific life tables derived from the cohort at large. Results: First Nations diagnosed with cancers of the colon and rectum, lung and bronchus, breast, prostate, oral cavity and pharynx, cervix, ovary, or with non-Hodgkin lymphoma and leukemia all had significantly poorer 5-year survival than their non-Aboriginal peers. For colorectal cancer, a significant disparity was only present between 2001 and 2009 (EMRR: 1.52; 95% CI, 1.28-1.80). For prostate cancer, a significant disparity was only present between 1992 and 2000 (EMRR: 2.76; 95% CI, 1.81-4.21). Adjusting for income and rurality had little impact on the EMRRs. Conclusions: Compared with non-Aboriginals, First Nations people had poorer survival for 14 of 15 of the most common cancers, and disparities could not be explained by income and rurality. Impact: The results of this study can serve as a benchmark for monitoring progress toward narrowing the gap in survival. (C)2016 AACR. C1 [Withrow, Diana R.; Nishri, E. Diane; Marrett, Loraine D.] Canc Care Ontario, Prevent & Canc Control, Toronto, ON, Canada. [Withrow, Diana R.; Pole, Jason D.; Marrett, Loraine D.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Pole, Jason D.] Pediat Oncol Grp Ontario, Toronto, ON, Canada. [Tjepkema, Michael] STAT Canada, Hlth Anal Div, Ottawa, ON, Canada. RP Withrow, DR (reprint author), NCI, Radiat Epidemiol Branch, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM diana.withrow@nih.gov FU Canadian Institutes for Health Research Open Operating entitled "Cancer incidence and survival in First Nations and Metis adults in Canada: follow-up of the census cohort" FX The work was supported by a Canadian Institutes for Health Research Open Operating Grant entitled "Cancer incidence and survival in First Nations and Metis adults in Canada: follow-up of the 1991 census cohort". NR 65 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2017 VL 26 IS 1 BP 145 EP 151 DI 10.1158/1055-9965.EPI-16-0706 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EK2JN UT WOS:000393753700020 PM 27965294 ER PT J AU Lance, P Alberts, DS Thompson, PA Fales, L Wang, F Jose, JS Jacobs, ET Goodman, PJ Darke, AK Yee, M Minasian, L Thompson, IM Roe, DJ AF Lance, Peter Alberts, David S. Thompson, Patricia A. Fales, Liane Wang, Fang Jose, Jerilyn San Jacobs, Elizabeth T. Goodman, Phyllis J. Darke, Amy K. Yee, Monica Minasian, Lori Thompson, Ian M. Roe, Denise J. TI Colorectal Adenomas in Participants of the SELECT Randomized Trial of Selenium and Vitamin E for Prostate Cancer Prevention SO CANCER PREVENTION RESEARCH LA English DT Article ID BASE-LINE CHARACTERISTICS; ALPHA-TOCOPHEROL; SUBGROUP ANALYSES; CLINICAL-TRIAL; COLON-CANCER; RISK; SUPPLEMENTATION; STATISTICS AB Selenium and vitamin E micronutrients have been advocated for the prevention of colorectal cancer. Colorectal adenoma occurrence was used as a surrogate for colorectal cancer in an ancillary study to the Selenium and Vitamin E Cancer Prevention Trial (SELECT) for prostate cancer prevention. The primary objective was to measure the effect of selenium (as selenomethionine) on colorectal adenomas occurrence, with the effect of vitamin E (as alpha-tocopherol) supplementation on colorectal adenoma occurrence considered as a secondary objective. Participants who underwent lower endoscopy while in SELECT were identified from a subgroup of the 35,533 men randomized in the trial. Adenoma occurrence was ascertained from the endoscopy and pathology reports for these procedures. Relative Risk (RR) estimates and 95% confidence intervals (CI) of adenoma occurrence were generated comparing those randomized to selenium versus placebo and to vitamin E versus placebo based on the full factorial design. Evaluable endoscopy information was obtained for 6,546 participants, of whom 2,286 had 1+ adenomas. Apart from 21 flexible sigmoidoscopies, all the procedures yielding adenomas were colonoscopies. Adenomas occurred in 34.2% and 35.7%, respectively, of participants whose intervention included or did not include selenium. Compared with placebo, the RR for adenoma occurrence in participants randomized to selenium was 0.96 (95% CI, 0.90-1.02; P = 0.194). Vitamin E did not affect adenoma occurrence compared with placebo (RR = 1.03; 95% CI, 0.96-1.10; P = 0.38). Neither selenium nor vitamin E supplementation can be recommended for colorectal adenoma prevention. (C) 2016 AACR. C1 [Lance, Peter; Alberts, David S.; Thompson, Patricia A.; Fales, Liane; Wang, Fang; Jose, Jerilyn San; Jacobs, Elizabeth T.; Roe, Denise J.] Univ Arizona, Ctr Canc, 1515 N Campbell Ave, Tucson, AZ 85724 USA. [Goodman, Phyllis J.; Darke, Amy K.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Yee, Monica] SWOG Stat Ctr Canc Res & Biostat, Seattle, WA USA. [Minasian, Lori] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Thompson, Patricia A.; Wang, Fang] SUNY Stony Brook, Stony Brook, NY 11794 USA. RP Lance, P (reprint author), Univ Arizona, Ctr Canc, 1515 N Campbell Ave, Tucson, AZ 85724 USA. EM plance@uacc.arizona.edu FU [R01 CA124862]; [U10 CA37429]; [UM1 CA182883] FX This work was funded in part by Public Health Services grants R01 CA124862 (to P. Lance), U10 CA37429 (to C.D. Blanke), and UM1 CA182883(to I.M. Thompson/C.M. Tangen). NR 25 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD JAN PY 2017 VL 10 IS 1 BP 45 EP 54 DI 10.1158/1940-6207.CAPR-16-0104 PG 10 WC Oncology SC Oncology GA EK1OF UT WOS:000393694500004 PM 27777235 ER PT J AU Song, KH Woo, SR Chung, JY Lee, HJ Oh, SJ Hong, SO Shim, J Kim, YN Rho, SB Hong, SM Cho, H Hibi, M Bae, DJ Kim, SY Kim, MG Kim, TW Bae, YK AF Song, Kwon-Ho Woo, Seon Rang Chung, Joon-Yong Lee, Hyo-Jung Oh, Se Jin Hong, Soon-Oh Shim, Jaegal Kim, Yong Nyun Rho, Seung Bae Hong, Seung-Mo Cho, Hanbyoul Hibi, Masahiko Bae, Dong-Jun Kim, Sang-Yeob Kim, Min Gyu Kim, Tae Woo Bae, Young-Ki TI REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival SO CELL DEATH & DISEASE LA English DT Article ID FOXO TRANSCRIPTION FACTORS; RAB GERANYLGERANYL TRANSFERASE; CHOROIDEREMIA GENE-PRODUCT; ZEBRAFISH MODEL; FAMILY-MEMBERS; GROWTH-CONTROL; DEGENERATION; PROTEINS; HOMEOSTASIS; EXPRESSION AB Rab escort protein 1 (REP1) is a component of Rab geranyl-geranyl transferase 2 complex. Mutations in REP1 cause a disease called choroideremia (CHM), which is an X-linked eye disease. Although it is postulated that REP1 has functions in cell survival or death of various tissues in addition to the eye, how REP1 functions in normal and cancer cells remains to be elucidated. Here, we demonstrated that REP1 is required for the survival of intestinal cells in addition to eyes or a variety of cells in zebrafish, and also has important roles in tumorigenesis. Notably, REP1 is highly expressed in colon cancer tissues and cell lines, and silencing of REP1 sensitizes colon cancer cells to serum starvation-and 5-FU-induced apoptosis. In an effort to elucidate the molecular mechanisms underlying REP1-mediated cell survival under those stress conditions, we identified FOXO3 as a binding partner of REP1 using a yeast two-hybrid (Y2H) assay system, and we demonstrated that REP1 blocked the nuclear trans-localization of FOXO3 through physically interacting with FOXO3, thereby suppressing FOXO3-mediated apoptosis. Importantly, the inhibition of REP1 combined with 5-FU treatment could lead to significant retarded tumor growth in a xenograft tumor model of human cancer cells. Thus, our results suggest that REP1 could be a new therapeutic target in combination treatment for colon cancer patients. C1 [Song, Kwon-Ho; Woo, Seon Rang; Lee, Hyo-Jung; Oh, Se Jin; Hong, Soon-Oh; Kim, Tae Woo] Korea Univ, Grad Sch Med, Dept Biomed Sci, Lab Tumor Immunol, Room 319,Moonsook Med Hall,73 Inchon Ro, Seoul 02841, South Korea. [Song, Kwon-Ho; Woo, Seon Rang; Lee, Hyo-Jung; Oh, Se Jin; Hong, Soon-Oh; Kim, Tae Woo] Korea Univ, Coll Med, Dept Biochem, Seoul, South Korea. [Song, Kwon-Ho; Lee, Hyo-Jung; Oh, Se Jin; Hong, Soon-Oh; Kim, Tae Woo] Korea Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Woo, Seon Rang; Kim, Tae Woo] Korea Univ, Coll Med, Translat Res Inst Incurable Dis, Seoul, South Korea. [Chung, Joon-Yong; Cho, Hanbyoul] NCI, Expt Pathol Lab, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Shim, Jaegal; Kim, Yong Nyun; Bae, Young-Ki] Natl Canc Ctr, Res Inst, Comparat Biomed Res Branch, 323 Ilsan Ro, Gyeonggi Do 10408, Goyang, South Korea. [Rho, Seung Bae] Natl Canc Ctr, Res Inst, Gynecol Canc Branch, Goyang, South Korea. [Hong, Seung-Mo] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 05505, South Korea. [Cho, Hanbyoul] Yonsei Univ, Coll Med, Gangnam Severance Hosp, Dept Obstet & Gynecol, Seoul, South Korea. [Hibi, Masahiko] Nagoya Univ, Biosci & Biotechnol Ctr, Nagoya, Aichi, Japan. [Bae, Dong-Jun; Kim, Sang-Yeob] ASAN Med Ctr, ASAN Inst Life Sci, Seoul, South Korea. [Kim, Sang-Yeob] Univ Ulsan, Coll Med, Dept Convergence Med, Seoul, South Korea. [Kim, Min Gyu] Catholic Univ Korea, Sch Med, Seoul, South Korea. RP Kim, TW (reprint author), Korea Univ, Grad Sch Med, Dept Biomed Sci, Lab Tumor Immunol, Room 319,Moonsook Med Hall,73 Inchon Ro, Seoul 02841, South Korea.; Bae, YK (reprint author), Natl Canc Ctr, Res Inst, Comparat Biomed Res Branch, 323 Ilsan Ro, Gyeonggi Do 10408, Goyang, South Korea. EM twkim0421@korea.ac.kr; zebra@ncc.re.kr OI Chung, Joon-Yong/0000-0001-5041-5982 FU National Research Foundation of Korea [NRF-2014R1A2A1A10054205, NRF-2013M3A9D3045881]; National Cancer Center, Korea [NCC-1310420, NCC-1610380] FX This work was funded by the National Research Foundation of Korea (NRF-2014R1A2A1A10054205 and NRF-2013M3A9D3045881), and National Cancer Center, Korea (NCC-1310420 and NCC-1610380). pCS4+ vectors (3xFlag, and EGFP) were provided by Chang-Yeol Yeo. NR 54 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD JAN PY 2017 VL 8 AR e2536 DI 10.1038/cddis.2016.462 PG 13 WC Cell Biology SC Cell Biology GA EK1IM UT WOS:000393679000027 PM 28055019 ER PT J AU Sharma, K Janik, JE O'Mahony, D Stewart, D Pittaluga, S Stetler-Stevenson, M Jaffe, ES Raffeld, M Fleisher, TA Lee, CC Steinberg, SM Waldmann, TA Morris, JC AF Sharma, Kamal Janik, John E. O'Mahony, Deirdre Stewart, Donn Pittaluga, Stefania Stetler-Stevenson, Maryalice Jaffe, Elaine S. Raffeld, Mark Fleisher, Thomas A. Lee, Cathryn C. Steinberg, Seth M. Waldmann, Thomas A. Morris, John C. TI Phase II Study of Alemtuzumab (CAMPATH-1) in Patients with HTLV-1-Associated Adult T-cell Leukemia/lymphoma SO CLINICAL CANCER RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ANTI-CD52 MONOCLONAL-ANTIBODY; NON-HODGKINS-LYMPHOMAS; HUMAN CD52 ANTIBODY; MURINE MODEL; EFFECTIVE THERAPY; PROLYMPHOCYTIC LEUKEMIA; PERIPHERAL-BLOOD; INTERFERON-ALPHA; SEZARY-SYNDROME AB Purpose: Therapeutic regimens for adult T-cell leukemia/lymphoma (ATL) are limited with unsatisfactory results, thereby warranting development of novel therapies. This study investigated antitumor activity and toxicity of alemtuzumab with regard to response, duration of response, progression-free survival, and overall survival in patients with human T-cell lymphotropic virus-1 (HTLV-1)-associated ATL. Experimental Design: Twenty-nine patients with chronic, acute, and lymphomatous types of ATL were enrolled in a single-institution, nonrandomized, open-label phase II trial wherein patients received intravenous alemtuzumab 30 mg three times weekly for a maximum of 12 weeks. Results: Twenty-nine patients were evaluable for response and toxicity. The overall objective response was 15 of 29 patients [95% confidence interval (CI), 32.5%-70.6%]. The 15 patients who responded manifested a median time to response of 1.1 months. Median response duration was 1.4 months for the whole group and 14.5 months among responders. Median progression-free survival was 2.0 months. Median overall survival was 5.9 months. The most common adverse events were 2 with vasovagal episodes (7%) and 3 with hypotensive episodes (10%), leukopenia (41%) grade 3 and (17%) grade 4, lymphocytopenia (59%) grade 3, neutropenia (31%) grade 3, anemia (24%), and thrombocytopenia (10%). All patients developed cytomegalovirus antigenemia (CMV). Three were symptomatic and all responded to antiviral therapy. Grade 3 or 4 infections were reported in 4 (14%) of patients. Conclusions: Alemtuzumab induced responses in patients with acute HTLV-1-associated ATL with acceptable toxicity, but with short duration of responses. These studies support inclusion of alemtuzumab in novel multidrug therapies for ATL. (C) 2016 AACR. C1 [Sharma, Kamal; Janik, John E.; O'Mahony, Deirdre; Stewart, Donn; Lee, Cathryn C.; Waldmann, Thomas A.; Morris, John C.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pittaluga, Stefania; Stetler-Stevenson, Maryalice; Jaffe, Elaine S.; Raffeld, Mark] NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Fleisher, Thomas A.] NIH, Dept Clin Pathol, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH,Clin Ctr, Bldg 10,Room 4N115, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU Intramural NIH HHS [Z01 SC004002-38] NR 50 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN PY 2017 VL 23 IS 1 BP 35 EP 42 DI 10.1158/1078-0432.CCR-16-1022 PG 8 WC Oncology SC Oncology GA EK4DC UT WOS:000393876300007 PM 27486175 ER PT J AU Zhao, SS Geybels, MS Leonardson, A Rubicz, R Kolb, S Yan, QX Klotzle, B Bibikova, M Hurtado-Coll, A Troyer, D Lance, R Lin, DW Wright, JL Ostrander, EA Fan, JB Feng, ZD Stanford, JL AF Zhao, Shanshan Geybels, Milan S. Leonardson, Amy Rubicz, Rohina Kolb, Suzanne Yan, Qingxiang Klotzle, Brandy Bibikova, Marina Hurtado-Coll, Antonio Troyer, Dean Lance, Raymond Lin, Daniel W. Wright, Jonathan L. Ostrander, Elaine A. Fan, Jian-Bing Feng, Ziding Stanford, Janet L. TI Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID BIOCHEMICAL RECURRENCE; RADICAL PROSTATECTOMY; PROMOTER HYPERMETHYLATION; GLEASON SCORE; RISK; GENE; MORTALITY; BIOPSY; ASSOCIATION; SURVIVAL AB Purpose: Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Experimental Design: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum. Results: Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P < 0.05) AUC (range, 0.66-0.75) or pAUC (range, 0.007-0.009). The biomarkers that improved discrimination of patients with metastatic-lethal prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sumalone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86-0.89; all P < 0.05). Conclusions: Eight differentially methylated CpGs that distinguish patientswithmetastatic-lethal from nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. (C) 2016 AACR. C1 [Zhao, Shanshan] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Geybels, Milan S.; Leonardson, Amy; Rubicz, Rohina; Kolb, Suzanne; Lin, Daniel W.; Wright, Jonathan L.; Stanford, Janet L.] Fred Hutchison Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA USA. [Geybels, Milan S.] Maastricht Univ, GROW Sch Oncol & Dev Biol, Dept Epidemiol, Maastricht, Netherlands. [Yan, Qingxiang; Feng, Ziding] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Klotzle, Brandy; Bibikova, Marina; Fan, Jian-Bing] Illumina Inc, San Diego, CA USA. [Hurtado-Coll, Antonio] Univ British Columbia, Dept Urol Sci, Vancouver, BC, Canada. [Hurtado-Coll, Antonio] Vancouver Gen Hosp, Prostate Ctr, Vancouver, BC, Canada. [Troyer, Dean] Eastern Virginia Med Sch, Dept Pathol, Norfolk, VA 23501 USA. [Troyer, Dean] Eastern Virginia Med Sch, Dept Microbiol, Norfolk, VA 23501 USA. [Troyer, Dean] Eastern Virginia Med Sch, Dept Mol Cell Biol, Norfolk, VA 23501 USA. [Lance, Raymond] Eastern Virginia Med Sch, Dept Urol, Norfolk, VA 23501 USA. [Lin, Daniel W.; Wright, Jonathan L.] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Ostrander, Elaine A.] NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Stanford, JL (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,M4-B874, Seattle, WA 98109 USA. EM jstanfor@fredhutch.org OI Ostrander, Elaine/0000-0001-6075-9738 FU NCI [R01 CA056678, R01 CA092579, K05 CA175147, P50 CA097186]; Fred Hutchinson Cancer Research Center; National Human Genome Research Institute; National Institute of Environmental Health Sciences; Prostate Cancer Foundation; Dutch Cancer Society [BUIT 2014-6645] FX This work was supported by grants from the NCI (R01 CA056678, R01 CA092579, K05 CA175147, and P50 CA097186), with additional support provided by the Fred Hutchinson Cancer Research Center, the Intramural Program of the National Human Genome Research Institute, the National Institute of Environmental Health Sciences, and the Prostate Cancer Foundation. Illumina, Inc. provided and performed the methylation arrays. M.S. Geybels is the recipient of a Dutch Cancer Society Fellowship (BUIT 2014-6645). NR 46 TC 2 Z9 2 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN PY 2017 VL 23 IS 1 BP 311 EP 319 DI 10.1158/1078-0432.CCR-16-0549 PG 9 WC Oncology SC Oncology GA EK4DC UT WOS:000393876300034 PM 27358489 ER PT J AU Balderston, NL Vytal, KE O'Connell, K Torrisi, S Letkiewicz, A Ernst, M Grillon, C AF Balderston, Nicholas L. Vytal, Katherine E. O'Connell, Katherine Torrisi, Salvatore Letkiewicz, Allison Ernst, Monique Grillon, Christian TI Anxiety Patients Show Reduced Working Memory Related dlPFC Activation During Safety and Threat SO DEPRESSION AND ANXIETY LA English DT Article DE anxiety; anxiety disorders; functional MRI; cognition; GAD; generalized anxiety disorder; stress ID POSTTRAUMATIC-STRESS-DISORDER; VENTROMEDIAL PREFRONTAL CORTEX; FEAR-POTENTIATED STARTLE; CEREBRAL-BLOOD-FLOW; SUSTAINED ANXIETY; TRAIT ANXIETY; ATTENTION; TASK; METAANALYSIS; EXTINCTION AB BackgroundAnxiety patients exhibit deficits in cognitive tasks that require prefrontal control of attention, including those that tap working memory (WM). However, it is unclear whether these deficits reflect threat-related processes or symptoms of the disorder. Here, we distinguish between these hypotheses by determining the effect of shock threat versus safety on the neural substrates of WM performance in anxiety patients and healthy controls. MethodsPatients, diagnosed with generalized and/or social anxiety disorder, and controls performed blocks of an N-back WM task during periods of safety and threat of shock. We recorded blood-oxygen-level dependent (BOLD) activity during the task, and investigated the effect of clinical anxiety (patients vs. controls) and threat on WM load-related BOLD activation. ResultsBehaviorally, patients showed an overall impairment in both accuracy and reaction time compared to controls, independent of threat. At the neural level, patients showed less WM load-related activation in the dorsolateral prefrontal cortex, a region critical for cognitive control. In addition, patients showed less WM load-related deactivation in the ventromedial prefrontal cortex and posterior cingulate cortex, which are regions of the default mode network. Most importantly, these effects were not modulated by threat. ConclusionsThis work suggests that the cognitive deficits seen in anxiety patients may represent a key component of clinical anxiety, rather than a consequence of threat. C1 [Balderston, Nicholas L.; Vytal, Katherine E.; O'Connell, Katherine; Torrisi, Salvatore; Letkiewicz, Allison; Ernst, Monique; Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, NIH, 15k North Dr, Bethesda, MD 20892 USA. RP Balderston, NL (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, NIH, 15k North Dr, Bethesda, MD 20892 USA. EM Nicholas.balderston@mail.nih.gov FU National Institute of Mental Health [ZIAMH002798] FX Contract grant sponsor: National Institute of Mental Health; Contract grant number: ZIAMH002798 NR 78 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JAN PY 2017 VL 34 IS 1 BP 25 EP 36 DI 10.1002/da.22518 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA EK2RI UT WOS:000393774000003 PM 27110997 ER PT J AU Scheidweiler, KB Andersson, M Swortwood, MJ Sempio, C Huestis, MA AF Scheidweiler, Karl B. Andersson, Maria Swortwood, Madeleine J. Sempio, Cristina Huestis, Marilyn A. TI Long-term stability of cannabinoids in oral fluid after controlled cannabis administration SO DRUG TESTING AND ANALYSIS LA English DT Article DE oral fluid; cannabinoid; stability; liquid chromatography-mass spectrometry ID CONTROLLED SMOKED CANNABIS; TANDEM MASS-SPECTROMETRY; COLLECTION DEVICE; CHRONIC FREQUENT; WHOLE-BLOOD; SMOKING AB Cannabinoid stability in oral fluid (OF) is important for assuring accurate results since OF has become a valid alternative matrix of choice for drug testing. We previously published OF cannabinoid stability studies using Quantisal, Oral-Eze (R), and StatSure devices stored at room temperature for 1week, 4 degrees C for up to 4weeks, and at -20 degrees C up to 24weeks. Extending refrigerated stability up to 3months would be helpful for clinical and forensic testing, for re-analysis of OF samples and for batching research analyses. Individual authentic OF pools were prepared after controlled smoking of a 6.9% (9)-tetrahydracannabinol cannabis cigarette; the Quantisal device was utilized for OF collection. Fifteen healthy volunteers participated in the Institutional Review Board-approved study. Stability for THC, 11-nor-9-carboxy-THC (THCCOOH), (9)-tetrahydrocannabivarin (THCV), cannabidiol (CBD), and cannabigerol (CBG) were determined after storage at 4 degrees C for 1, 2, and 3months. Results within +/- 20% of baseline concentrations were considered stable. All analytes were stable for up to 2months at 4 degrees C for all participants with positive baseline concentrations. Baseline concentrations were highly variable. In total, THC, THCCOOH, THCV, CBD, and CBG were stable for 3months at 4 degrees C for pooled positive specimens from 14 of 15, 8 of 9, 7 of 8, 8 of 9, and 9 of 10 participants, respectively. In conclusion, Quantisal-collected OF specimens should be stored at 4 degrees C for no more than two months to assure accurate THC, THCCOOH, THCV, CBD, and CBG quantitative results; only one participant's OF was unstable at three months. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Scheidweiler, Karl B.; Andersson, Maria; Swortwood, Madeleine J.; Sempio, Cristina; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program,NIH, 251 Bayview Blvd,Suite 200 Room 05A721, Baltimore, MD 21224 USA. [Huestis, Marilyn A.] Univ Maryland, Sch Med, 655 West Baltimore St, Baltimore, MD 21224 USA. RP Scheidweiler, KB (reprint author), NIDA, Chem & Drug Metab, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program,NIH, 251 Bayview Blvd,Suite 200 Room 05A721, Baltimore, MD 21224 USA. EM kbscheid@gmail.com FU Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health FX The research was supported by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health. A Material Transfer Agreement with Immunalysis Inc., provided the Quantisal (TM) collection devices for the study, but Immunalysis Inc., had no role in study design, data analysis, or presentation of results. NR 20 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD JAN PY 2017 VL 9 IS 1 BP 143 EP 147 DI 10.1002/dta.2056 PG 5 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA EK4BV UT WOS:000393873000014 PM 27539096 ER PT J AU Goldenholz, DM Kuhn, A Austermuehle, A Bachler, M Mayer, C Wassertheurer, S Inati, SK Theodore, WH AF Goldenholz, Daniel M. Kuhn, Amanda Austermuehle, Alison Bachler, Martin Mayer, Christopher Wassertheurer, Siegfried Inati, Sara K. Theodore, William H. TI Long-term monitoring of cardiorespiratory patterns in drug-resistant epilepsy SO EPILEPSIA LA English DT Article DE Cardiac; EEG; Epilepsy monitoring; All epilepsy; seizures; Autonomic diseases ID SUDDEN UNEXPECTED DEATH; GENERALIZED EEG SUPPRESSION; OBSTRUCTIVE SLEEP-APNEA; RESPIRATORY DYSFUNCTION; POSTICTAL IMMOBILITY; ICTAL HYPOXEMIA; RISK-FACTORS; HEART-RATE; SEIZURES; SEVERITY AB ObjectiveSudden unexplained death in epilepsy (SUDEP) during inpatient electroencephalography (EEG) monitoring has been a rare but potentially preventable event, with associated cardiopulmonary markers. To date, no systematic evaluation of alarm settings for a continuous pulse oximeter (SpO(2)) has been performed. In addition, evaluation of the interrelationship between the ictal and interictal states for cardiopulmonary measures has not been reported. MethodsPatients with epilepsy were monitored using video-EEG, SpO(2), and electrocardiography (ECG). Alarm thresholds were tested systematically, balancing the number of false alarms with true seizure detections. Additional cardiopulmonary patterns were explored using automated ECG analysis software. ResultsOne hundred ninety-three seizures (32 generalized) were evaluated from 45 patients (7,104 h recorded). Alarm thresholds of 80-86% SpO(2) detected 63-73% of all generalized convulsions and 20-28% of all focal seizures (81-94% of generalized and 25-36% of focal seizures when considering only evaluable data). These same thresholds resulted in 25-146 min between false alarms. The sequential probability of ictal SpO(2) revealed a potential common seizure termination pathway of desaturation. A statistical model of corrected QT intervals (QTc), heart rate (HR), and SpO(2) revealed close cardiopulmonary coupling ictally. Joint probability maps of QTc and SpO(2) demonstrated that many patients had baseline dysfunction in either cardiac, pulmonary, or both domains, and that ictally there was dissociationsome patients exhibited further dysfunction in one or both domains. SignificanceOptimal selection of continuous pulse oximetry thresholds involves a tradeoff between seizure detection accuracy and false alarm frequency. Alarming at 86% for patients that tend to have fewer false alarms and at 80% for those who have more, would likely result in a reasonable tradeoff. The cardiopulmonary findings may lead to SUDEP biomarkers and early seizure termination therapies. C1 [Goldenholz, Daniel M.; Kuhn, Amanda; Austermuehle, Alison; Inati, Sara K.; Theodore, William H.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bachler, Martin; Mayer, Christopher; Wassertheurer, Siegfried] Austrian Inst Technol, Vienna, Austria. RP Goldenholz, DM (reprint author), NINDS, Clin Epilepsy Sect, CNP, DIR,NIH, 10 Ctr Dr,10 CRC,Room 5S-207,MSC 1408, Bethesda, MD 20892 USA. EM daniel.goldenholz@nih.gov OI Goldenholz, Daniel/0000-0002-8370-2758; Inati, Sara/0000-0002-7587-5085 FU National Institute of Neurological Disorders and Stroke Division of Intramural Research; Government of Lower Austria; Europaischer Fonds fur Regionale Entwicklung (EFRE) [WST3-T-81/015-2008] FX This study was supported by the National Institute of Neurological Disorders and Stroke Division of Intramural Research. The development and evaluation of the ECG algorithms used in this work were partly supported by a grant of the Government of Lower Austria and Europaischer Fonds fur Regionale Entwicklung (EFRE), contract number WST3-T-81/015-2008. NR 35 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD JAN PY 2017 VL 58 IS 1 BP 77 EP 84 DI 10.1111/epi.13606 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EK1JX UT WOS:000393682700011 PM 27864903 ER PT J AU Hwang, YS Daar, IO AF Hwang, Yoo-Seok Daar, Ira O. TI A frog's view of EphrinB signaling SO GENESIS LA English DT Review DE Xenopus; Eph; development ID XENOPUS-TROPICALIS; TISSUE SEPARATION; CYTOPLASMIC DOMAIN; UBIQUITIN LIGASES; CELL-CELL; EYE FIELD; RECEPTOR; ADHESION; EMBRYOS; LIGAND AB Cell-cell and cell-substrate adhesion are essential to the proper formation and maintenance of tissue patterns during development, and deregulation of these processes can lead to invasion and metastasis of cancer cells. Cell surface adhesion and signaling molecules are key players in both normal development and cancer progression. One set of cell surface proteins, the Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, are significant regulators of these processes. During embryonic development, the Eph/ephrin signaling system is involved in cell-cell contact events that result in cell sorting and boundary formation between receptor and ligand bearing cells. When migrating cells that display the membrane bound ligands or receptors come in contact with cells bearing the cognate partner, the response may be adhesion or repulsion, ultimately leading to the proper positioning of these cells. During cancer progression, the signaling between these receptor/ligand pairs is often deregulated, leading to increased invasion and metastasis. To gain mechanistic insight into the pathways that mediate Eph receptor and ephrin signaling we have relied upon a very tractable system, the frog Xenopus. This model system has proven to be extremely versatile, and represents a relatively quick and manipulable system to explore signaling events and the in vivo processes affected by these signals. C1 [Hwang, Yoo-Seok; Daar, Ira O.] NCI, Canc & Dev Biol Lab, Bldg 560,Room 22-90D, Frederick, MD 21702 USA. RP Daar, IO (reprint author), NCI, Canc & Dev Biol Lab, Bldg 560,Room 22-90D, Frederick, MD 21702 USA. EM daari@mail.nih.gov FU Research Program of the National Institutes of Health, National Cancer Institute FX Research Program of the National Institutes of Health, National Cancer Institute NR 40 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-954X EI 1526-968X J9 GENESIS JI Genesis PD JAN PY 2017 VL 55 IS 1-2 DI 10.1002/dvg.23002 PG 9 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA EK5HV UT WOS:000393958400010 ER PT J AU Haynes, BF Mascola, JR AF Haynes, Barton F. Mascola, John R. TI The quest for an antibody-based HIV vaccine SO IMMUNOLOGICAL REVIEWS LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; IG KNOCKIN MICE; NEUTRALIZING ANTIBODIES; EFFICACY TRIAL; DOUBLE-BLIND; IMMUNOGEN DESIGN; INFECTION; IMMUNIZATION; RESPONSES; THAILAND C1 [Haynes, Barton F.] Duke Univ, Sch Med, Dept Med, Duke Human Vaccine Inst, Durham, NC 27706 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Dept Immunol, Duke Human Vaccine Inst, Durham, NC 27708 USA. [Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Haynes, BF (reprint author), Duke Univ, Sch Med, Dept Med, Duke Human Vaccine Inst, Durham, NC 27706 USA.; Haynes, BF (reprint author), Duke Univ, Sch Med, Dept Immunol, Duke Human Vaccine Inst, Durham, NC 27708 USA.; Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM barton.haynes@duke.edu; jmascola@nih.gov FU NIH, NIAID Division of AIDS [AI100645]; NIH Intramural Funds FX NIH, NIAID Division of AIDS, Grant/Award Number: AI100645; NIH Intramural Funds NR 62 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD JAN PY 2017 VL 275 IS 1 BP 5 EP 10 DI 10.1111/imr.12517 PG 6 WC Immunology SC Immunology GA EK5LX UT WOS:000393969000001 PM 28133795 ER PT J AU Moir, S Fauci, AS AF Moir, Susan Fauci, Anthony S. TI B-cell responses to HIV infection SO IMMUNOLOGICAL REVIEWS LA English DT Review DE B cells; HIV; HIV-specific humoral immunity; pathogenesis; persisting viremia ID T FOLLICULAR HELPER; IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; BROADLY NEUTRALIZING ANTIBODIES; HUMAN MONOCLONAL-ANTIBODIES; MEMORY B; PLASMA-CELLS; DISEASE PROGRESSION; IMMUNE-RESPONSE; BONE-MARROW AB The induction of neutralizing antibodies directed against the human immunodeficiency virus (HIV) has received considerable attention in recent years, in part driven by renewed interest and opportunities for antibody-based strategies for prevention such as passive transfer of antibodies and the development of preventive vaccines, as well as immune-based therapeutic interventions. Advances in the ability to screen, isolate, and characterize HIV-specific antibodies have led to the identification of a new generation of potent broadly neutralizing antibodies (bNAbs). The majority of these antibodies have been isolated from B cells of chronically HIV-infected individuals with detectable viremia. In this review, we provide insight into the phenotypic and functional attributes of human B cells, with a focus on HIV-specific memory B cells and plasmablasts/cells that are responsible for sustaining humoral immune responses against HIV. We discuss the abnormalities in B cells that occur in HIV infection both in the peripheral blood and lymphoid tissues, especially in the setting of persisting viremia. Finally, we consider the opportunities and drawbacks of intensively interrogating antibodies isolated from HIV-infected individuals to guide strategies aimed at developing effective antibody-based vaccine and therapeutic interventions for HIV. C1 [Moir, Susan; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Moir, S (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov FU Intramural Research Program of NIAID, NIH FX Intramural Research Program of NIAID, NIH. NR 173 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD JAN PY 2017 VL 275 IS 1 BP 33 EP 48 DI 10.1111/imr.12502 PG 16 WC Immunology SC Immunology GA EK5LX UT WOS:000393969000004 PM 28133792 ER PT J AU Kwong, PD Chuang, GY DeKosky, BJ Gindin, T Georgiev, IS Lemmin, T Schramm, CA Sheng, ZZ Soto, C Yang, AS Mascola, JR Shapiro, L AF Kwong, Peter D. Chuang, Gwo-Yu DeKosky, Brandon J. Gindin, Tatyana Georgiev, Ivelin S. Lemmin, Thomas Schramm, Chaim A. Sheng, Zizhang Soto, Cinque Yang, An-Suei Mascola, John R. Shapiro, Lawrence TI Antibodyomics: bioinformatics technologies for understanding B-cell immunity to HIV-1 SO IMMUNOLOGICAL REVIEWS LA English DT Review DE bioinformatics; B-cell ontogeny; broadly neutralizing antibodies; HIV vaccine; information technology; massively parallel sequencing ID BROADLY NEUTRALIZING ANTIBODIES; HIGH-THROUGHPUT EXPERIMENTS; INFLUENZA-A VIRUSES; MOLECULAR-DYNAMICS; HIV-1-NEUTRALIZING ANTIBODIES; REPLICA EXCHANGE; VACCINE DESIGN; CRYOELECTRON MICROSCOPY; MONOCLONAL-ANTIBODIES; ENVELOPE GLYCOPROTEIN AB Numerous antibodies have been identified from HIV-1-infected donors that neutralize diverse strains of HIV-1. These antibodies may provide the basis for a B cell-mediated HIV-1 vaccine. However, it has been unclear how to elicit similar antibodies by vaccination. To address this issue, we have undertaken an informatics-based approach to understand the genetic and immunologic processes controlling the development of HIV-1-neutralizing antibodies. As DNA sequencing comprises the fastest growing database of biological information, we focused on incorporating next-generation sequencing of B-cell transcripts to determine the origin, maturation pathway, and prevalence of broadly neutralizing antibody lineages (Antibodyomics1, 2, 4, and 6). We also incorporated large-scale robotic analyses of serum neutralization to identify and quantify neutralizing antibodies in donor cohorts (Antibodyomics3). Statistical analyses furnish another layer of insight (Antibodyomics5), with physical characteristics of antibodies and their targets through molecular dynamics simulations (Antibodyomics7) and free energy perturbation analyses (Antibodyomics8) providing information-rich output. Functional interrogation of individual antibodies (Antibodyomics9) and synthetic antibody libraries (Antibodyomics10) also yields multi-dimensional data by which to understand and improve antibodies. Antibodyomics, described here, thus comprise resolution-enhancing tools, which collectively embody an information-driven discovery engine aimed toward the development of effective B cell-based vaccines. C1 [Kwong, Peter D.; Chuang, Gwo-Yu; DeKosky, Brandon J.; Schramm, Chaim A.; Soto, Cinque; Mascola, John R.; Shapiro, Lawrence] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kwong, Peter D.; Gindin, Tatyana; Schramm, Chaim A.; Sheng, Zizhang; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA. [Georgiev, Ivelin S.] Vanderbilt Univ, Med Ctr, Vanderbilt Vaccine Ctr, Nashville, TN USA. [Georgiev, Ivelin S.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA. [Lemmin, Thomas] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA. [Schramm, Chaim A.; Sheng, Zizhang; Shapiro, Lawrence] Columbia Univ, Dept Syst Biol, New York, NY USA. [Yang, An-Suei] Acad Sinica, Genom Res Ctr, Taipei, Taiwan. RP Shapiro, L (reprint author), Columbia Univ, New York, NY 10027 USA. EM shapiro@convex.hhmi.columbia.edu FU Swiss National Foundation of Science Fellowship [164691]; NIH [P01-AI104722]; Academia Sinica [MOST104-0210-01-09-02]; Taiwan Protein Project [MOST105-0210-01-12-01]; Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) FX We thank G. Georgiou and A. Ellington for developing the paired sequencing methodology used in Antibodyomics4 and R. Friesner for developing the FEP methodology used in Antibodyomics8. We thank T. Bylund, S. Patel, C.-H. Shen, and Z. Zhang for crucial input to development and applications, B. Honig for bioinformatics guidance, J. Stuckey for assistance with figures, and members of the Structural Biology Section and Structural Bioinformatics Core Section of the Vaccine Research Center for helpful comments. Support for this work was provided by a Swiss National Foundation of Science Fellowship (164691) to T. L., by NIH grant P01-AI104722 to L. S., by Academia Sinica grant MOST104-0210-01-09-02 and Taiwan Protein Project grant MOST105-0210-01-12-01 to A. S. Y., and by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). NR 128 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD JAN PY 2017 VL 275 IS 1 BP 108 EP 128 DI 10.1111/imr.12480 PG 21 WC Immunology SC Immunology GA EK5LX UT WOS:000393969000009 PM 28133812 ER PT J AU Moore, PL Gorman, J Doria-Rose, NA Morris, L AF Moore, Penny L. Gorman, Jason Doria-Rose, Nicole A. Morris, Lynn TI Ontogeny-based immunogens for the induction of V2-directed HIV broadly neutralizing antibodies SO IMMUNOLOGICAL REVIEWS LA English DT Review DE broadly neutralizing antibodies; HIV; long CDR H3; ontogeny; trimeric immunogens; V2-apex ID IMMUNODEFICIENCY-VIRUS TYPE-1; GP120 ENVELOPE GLYCOPROTEIN; VACCINE DESIGN; B-CELLS; DISEASE PROGRESSION; CRYSTAL-STRUCTURE; EFFICACY TRIAL; C INFECTION; ENV; RESPONSES AB The development of a preventative HIV vaccine able to elicit broadly neutralizing antibodies (bNAbs) remains a major challenge. Antibodies that recognize the V2 region at the apex of the HIV envelope trimer are among the most common bNAb specificities during chronic infection and many exhibit remarkable breadth and potency. Understanding the developmental pathway of these antibodies has provided insights into their precursors, and the viral strains that engage them, as well as defined how such antibodies mature to acquire breadth. V2-apex bNAbs are derived from rare precursors with long anionic CDR H3s that are often deleted in the B cell repertoire. However, longitudinal studies suggest that once engaged, these precursors contain many of the structural elements required for neutralization, and can rapidly acquire breadth through moderate levels of somatic hypermutation in response to emerging viral variants. These commonalities in the precursors and mechanism of neutralization have enabled the identification of viral strains that show enhanced reactivity for V2 precursors from multiple donors, and may form the basis of germline targeting approaches. In parallel, new structural insights into the HIV trimer, the target of these quaternary antibodies, has created invaluable new opportunities for ontogeny-based immunogens designed to select for rare V2-bNAb precursors, and drive them toward breadth. C1 [Moore, Penny L.; Morris, Lynn] Natl Hlth Lab Serv, Ctr HIV & STIs, Natl Inst Communicable Dis, Johannesburg, South Africa. [Moore, Penny L.; Morris, Lynn] Univ Witwatersrand, Fac Hlth Sci, Johannesburg, South Africa. [Moore, Penny L.; Morris, Lynn] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa CAPRISA, Durban, South Africa. [Gorman, Jason; Doria-Rose, Nicole A.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Moore, PL (reprint author), Univ Witwatersrand, Johannesburg, South Africa.; Moore, PL (reprint author), Natl Inst Communicable Dis, Johannesburg, South Africa. EM pennym@nicd.ac.za FU South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA); South African Medical Research Council; Intramural Research Program of the Vaccine Research Center, US National Institute of Allergy and Infectious Diseases (NIAID); Division of AIDS, NIAID, NIH [AI116086-01, AI104387-01A1] FX South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA); South African Medical Research Council; Intramural Research Program of the Vaccine Research Center, US National Institute of Allergy and Infectious Diseases (NIAID); Division of AIDS, NIAID, NIH, Grant/Award Number: AI116086-01 and AI104387-01A1 NR 90 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD JAN PY 2017 VL 275 IS 1 BP 217 EP 229 DI 10.1111/imr.12501 PG 13 WC Immunology SC Immunology GA EK5LX UT WOS:000393969000015 PM 28133797 ER PT J AU Pegu, A Hessell, AJ Mascola, JR Haigwood, NL AF Pegu, Amarendra Hessell, Ann J. Mascola, John R. Haigwood, Nancy L. TI Use of broadly neutralizing antibodies for HIV-1 prevention SO IMMUNOLOGICAL REVIEWS LA English DT Review DE Fc-effector functions; HIV-1 antibodies; Neutralizing antibodies; pre-exposure prophylaxis; SHIV protection ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODY; MUCOSAL SHIV CHALLENGE; CELL-MEDIATED CYTOTOXICITY; INFECTED RHESUS-MONKEYS; IN-VIVO ACTIVITY; PBL-SCID MICE; PASSIVE-IMMUNIZATION; HUMANIZED MICE; FC-RECEPTOR AB Antibodies have a long history in antiviral therapy, but until recently, they have not been actively pursued for HIV-1 due to modest potency and breadth of early human monoclonal antibodies (MAbs) and perceived insurmountable technical, financial, and logistical hurdles. Recent advances in the identification and characterization of MAbs with the ability to potently neutralize diverse HIV-1 isolates have reinvigorated discussion and testing of these products in humans, since new broadly neutralizing MAbs (bnMAbs) are more likely to be effective against worldwide strains of HIV-1. In animal models, there is abundant evidence that bnMAbs can block infection in a dose-dependent manner, and the more potent bnMAbs will allow clinical testing at infusion doses that are practically achievable. Moreover, recent advances in antibody engineering are providing further improvements in MAb potency, breadth, and half-life. This review summarizes the current state of the field of bnMAb protection in animal models as well as a review of variables that are critical for antiviral activity. Several bnMAbs are currently in clinical testing, and we offer perspectives on their use as pre-exposure prophylaxis (PrEP), potential benefits beyond sterilizing immunity, and a discussion of future approaches to engineer novel molecules. C1 [Pegu, Amarendra; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hessell, Ann J.; Haigwood, Nancy L.] Oregon Hlth & Sci Univ, Oregon Natl Primate Ctr, Beaverton, OR USA. RP Haigwood, NL (reprint author), Oregon Hlth & Sci Univ, Oregon Natl Primate Ctr, Pathobiol & Immunol, Beaverton, OR 97006 USA. EM haigwoon@ohsu.edu FU Vaccine Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; PHS [P51-OD011092] FX Vaccine Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; PHS, Grant/Award Number: P51-OD011092 NR 165 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD JAN PY 2017 VL 275 IS 1 BP 296 EP 312 DI 10.1111/imr.12511 PG 17 WC Immunology SC Immunology GA EK5LX UT WOS:000393969000021 PM 28133803 ER PT J AU Margolis, DM Koup, RA Ferrari, G AF Margolis, David M. Koup, Richard A. Ferrari, Guido TI HIV antibodies for treatment of HIV infection SO IMMUNOLOGICAL REVIEWS LA English DT Review DE ADCC; cure; entry inhibition; HIV; monoclonal antibodies ID HUMAN-IMMUNODEFICIENCY-VIRUS; DEPENDENT CELLULAR CYTOTOXICITY; BROADLY NEUTRALIZING ANTIBODIES; SUPPRESSIVE ANTIRETROVIRAL THERAPY; CD4-SPECIFIC MONOCLONAL-ANTIBODY; LOW-LEVEL VIREMIA; CD4(+) T-CELLS; IN-VIVO; RHESUS-MONKEYS; RALTEGRAVIR INTENSIFICATION AB The bar is high to improve on current combination antiretroviral therapy (ART), now highly effective, safe, and simple. However, antibodies that bind the HIV envelope are able to uniquely target the virus as it seeks to enter new target cells, or as it is expressed from previously infected cells. Furthermore, the use of antibodies against HIV as a therapeutic may offer advantages. Antibodies can have long half-lives, and are being considered as partners for long-acting antiretrovirals for use in therapy or prevention of HIV infection. Early studies in animal models and in clinical trials suggest that such antibodies can have antiviral activity but, as with small-molecule antiretrovirals, the issues of viral escape and resistance will have to be addressed. Most promising, however, are the unique properties of anti-HIV antibodies: the potential ability to opsonize viral particles, to direct antibody-dependent cellular cytotoxicity (ADCC) against actively infected cells, and ultimately the ability to direct the clearance of HIV-infected cells by effector cells of the immune system. These distinctive activities suggest that HIV antibodies and their derivatives may play an important role in the next frontier of HIV therapeutics, the effort to develop treatments that could lead to an HIV cure. C1 [Margolis, David M.] Univ North Carolina Chapel Hill, UNC HIV Cure Ctr, Dept Med, Chapel Hill, NC USA. [Margolis, David M.] Univ North Carolina Chapel Hill, UNC HIV Cure Ctr, Dept Microbiol, Chapel Hill, NC USA. [Margolis, David M.] Univ North Carolina Chapel Hill, UNC HIV Cure Ctr, Dept Immunol, Chapel Hill, NC USA. [Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Ferrari, Guido] Duke Univ, Duke Human Vaccine Inst, Durham, NC USA. [Ferrari, Guido] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Koup, RA (reprint author), Vaccine Res Ctr, Bethesda, MD USA. EM rkoup@mail.nih.gov OI Margolis, David/0000-0001-5714-0002 FU NIAID [UM1-AI100645-01]; NIAID, NIDA, NIMH, NINDS [UM1 AI126619]; UNC CFAR, NIAID [P30-AI50410]; Bill and Melinda Gates Foundation [OPP1032325] FX NIAID, Grant/Award Number: UM1-AI100645-01; NIAID, NIDA, NIMH, NINDS, Grant/Award Number: UM1 AI126619; UNC CFAR, NIAID, Grant/Award Number: P30-AI50410; Bill and Melinda Gates Foundation, Grant/Award Number: OPP1032325. NR 113 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD JAN PY 2017 VL 275 IS 1 BP 313 EP 323 DI 10.1111/imr.12506 PG 11 WC Immunology SC Immunology GA EK5LX UT WOS:000393969000022 PM 28133794 ER PT J AU Sechi, S Polli, M Marelli, S Talenti, A Crepaldi, P Fiore, F Spissu, N Dreger, DL Zedda, M Dimauro, C Ostrander, EA Di Cerbo, A Cocco, R AF Sechi, Sara Polli, Michele Marelli, Stefano Talenti, Andrea Crepaldi, Paola Fiore, Filippo Spissu, Nicoletta Dreger, Dayna L. Zedda, Marco Dimauro, Corrado Ostrander, Elaine A. Di Cerbo, Alessandro Cocco, Raffaella TI Fonni's dog: morphological and genetic characteristics for a breed standard definition SO ITALIAN JOURNAL OF ANIMAL SCIENCE LA English DT Article DE Cane fonnese; Sardinia; Fonni's dog; ENCI ID GENOME-WIDE SNP; HETEROZYGOSITY; MARKERS AB Italy is home to several populations of native dogs that reside only in certain demographic regions. Such dog populations have not been under tight selection by humans and, as such, have never been officially recognised as breeds. One such population is the 'Cane Fonnese' or Fonni's Dog, which features uniform morphologic and behavioural traits that reproduce across generations, thus qualifying Fonni's Dog as a true breed eligible for recognition by national or international breed registries. The Fonni's Dog population examined in the present work is native to Sardinia, where they are used as property or livestock guardian dogs. As such, they are greatly appreciated by the local populace. We have carried out morphological evaluations on 200 Fonni's Dogs with the aim of developing a standard breed definition upon which the foundation of the Fonni's Dog breed can be based. We have also reported genetic data of the Fonni's Dog compared to four other established breeds sampled from the same geographic area. C1 [Sechi, Sara; Fiore, Filippo; Spissu, Nicoletta] Univ Sassari, Dipartimento Med Vet & Clin Med Vet, Sassari, Italy. [Polli, Michele; Marelli, Stefano; Talenti, Andrea; Crepaldi, Paola] Univ Milan, DIVET, Milan, Italy. [Dreger, Dayna L.; Ostrander, Elaine A.; Cocco, Raffaella] NHGRI, NIH, Bethesda, MD 20892 USA. [Zedda, Marco] Univ Sassari, Dipartimento Med Vet, Sassari, Italy. [Dimauro, Corrado] Univ Sassari, Dipartimento Agr, Sez Sci Zootecn, Sassari, Italy. [Di Cerbo, Alessandro] Univ G dAnnunzio, Scuola Specializzaz Biochim Clin, Chieti, Italy. RP Di Cerbo, A (reprint author), Univ G dAnnunzio, Scuola Specializzaz Biochim Clin, Chieti, Italy. EM alessandro811@hotmail.it OI Ostrander, Elaine/0000-0001-6075-9738 FU Intramural Programme of the National Human Genome Research Institute; P. O. R. Sardegna (Fondi FESR) FX This study is part of a research project titled 'Detection of morphological, genetic and behavioural characteristics of Fonni's Dog, aimed at selection and official recognition of this breed by ENCI'. It is co-financed through P. O. R. Sardegna 2006-2008 (Fondi FESR). EAO and DLD thank the Intramural Programme of the National Human Genome Research Institute for the support. NR 28 TC 0 Z9 0 U1 2 U2 2 PU PAGEPRESS PUBL PI PAVIA PA MEDITGROUP, VIA G BELLI, 4, PAVIA, 27100, ITALY SN 1594-4077 EI 1828-051X J9 ITAL J ANIM SCI JI Ital. J. Anim. Sci. PY 2017 VL 16 IS 1 BP 22 EP 30 DI 10.1080/1828051X.2016.1248867 PG 9 WC Agriculture, Dairy & Animal Science; Agriculture, Multidisciplinary; Veterinary Sciences SC Agriculture; Veterinary Sciences GA EL8WG UT WOS:000394900400004 ER PT J AU Arthur, KC Doyle, C Chio, A Traynor, BJ AF Arthur, Karissa C. Doyle, Carly Chio, Adriano Traynor, Bryan J. TI Use of Genetic Testing in Amyotrophic Lateral Sclerosis by Neurologists SO JAMA NEUROLOGY LA English DT Letter C1 [Arthur, Karissa C.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Doyle, Carly] Northeast ALS Consortium, Boston, MA USA. [Chio, Adriano] Univ Turin, Rita Levi Montalcini Dept Neurosci, Turin, Italy. RP Traynor, BJ (reprint author), NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM traynorb@mail.nih.gov FU Intramural Research Program of the US National Institutes of Health (NIH), National Institute on Aging [Z01-AG000949-02]; European Community's Health Seventh Framework Programme (FP7) [259867]; Joint Programme-Neurodegenerative Disease Research (Italian Ministry of Education and University) (Strength Project); Vialli and Mauro Foundation; NIH FX This work was supported in part by the Intramural Research Program of the US National Institutes of Health (NIH), National Institute on Aging (grant Z01-AG000949-02). This research was made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and 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, aswell as other private donors. For a complete list, please visit the Foundation website at http://fnih.org/about/financials. This work was supported in part by the European Community's Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867), the Joint Programme-Neurodegenerative Disease Research (Italian Ministry of Education and University) (Strength Project), and the Vialli and Mauro Foundation for ALS (grant No. 4). NR 3 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 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD JAN 1 PY 2017 VL 74 IS 1 BP 125 EP 126 DI 10.1001/jamaneurol.2016.4540 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA EK1IK UT WOS:000393678800023 PM 27893008 ER PT J AU Polancich, S AF Polancich, Shea TI Developing an Organizational Model for Improvement: From Translation to Practice SO JOURNAL FOR HEALTHCARE QUALITY LA English DT Article DE improvement; organizational model; evidence-informed; translation ID QUALITY IMPROVEMENT; SUSTAIN AB This department column highlights translation of research into healthcare quality practice. Achieving the highest quality in healthcare is a goal that requires focused attention and accountability. Standardization in practice through translation and application of evidence-informed practice promotes excellence in outcomes. To meet the goal of achieving the highest quality of care through evidence-informed translation and application in practice, organizations should outline a plan for developing, organizing, implementing, and evaluating evidence-informed improvement interventions. The purpose of this article is to provide an example for developing an organizational model for improvement from concept to application. C1 [Polancich, Shea] Univ Alabama Birmingham UAB, Sch Nursing, Birmingham, AL 35294 USA. [Polancich, Shea] UAB, Med Ctr, Birmingham, AL 35294 USA. [Polancich, Shea] Vanderbilt Univ, Med Ctr, Nashville, TN 37235 USA. [Polancich, Shea] NINR Res, NIH, Texas Hlth Resources, Bethesda, MD 20892 USA. [Polancich, Shea] George Mason Univ, Fairfax, VA 22030 USA. RP Polancich, S (reprint author), Univ Alabama Birmingham UAB, Sch Nursing, Birmingham, AL 35294 USA.; Polancich, S (reprint author), UAB, Med Ctr, Birmingham, AL 35294 USA.; Polancich, S (reprint author), Vanderbilt Univ, Med Ctr, Nashville, TN 37235 USA.; Polancich, S (reprint author), NINR Res, NIH, Texas Hlth Resources, Bethesda, MD 20892 USA.; Polancich, S (reprint author), George Mason Univ, Fairfax, VA 22030 USA. EM polancs@uab.edu NR 15 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 1062-2551 EI 1945-1474 J9 J HEALTHC QUAL JI J. Healthc. Qual. PD JAN-FEB PY 2017 VL 39 IS 1 BP 28 EP 33 DI 10.1097/JHQ.0000000000000076 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EK2ZB UT WOS:000393794600006 PM 28045765 ER PT J AU Fink, AK Yanik, EL Marshall, BC Wilschanski, M Lynch, CF Austin, AA Copeland, G Safaeian, M Engels, EA AF Fink, Aliza K. Yanik, Elizabeth L. Marshall, Bruce C. Wilschanski, Michael Lynch, Charles F. Austin, April A. Copeland, Glenn Safaeian, Mahboobeh Engels, Eric A. TI Cancer risk among lung transplant recipients with cystic fibrosis SO JOURNAL OF CYSTIC FIBROSIS LA English DT Article DE Cancer; Transplant ID SOLID-ORGAN TRANSPLANTATION; CUMULATIVE INCIDENCE; ADULT PATIENTS; UNITED-STATES; ADENOCARCINOMA; CARCINOMA; PATIENT AB Background: Previous studies demonstrated increased digestive tract cancers among individuals with cystic fibrosis (CF), particularly among lung transplant recipients. We describe cancer incidence among CF and non-CF lung recipients. Methods: We used data from the US transplant registry and 16 cancer registries. Standardized incidence ratios (SIRs) compared cancer incidence to the general population, and Competing risk methods were used for the cumulative incidence of colorectal cancer. Results: We evaluated 10,179 lung recipients (1681 with CF). Risk was more strongly increased in CF recipients than non-CF recipients for overall cancer (SIR 9.9 vs. 2.7) and multiple cancers including colorectal cancer (24.2 vs. 1.7), esophageal cancer (56.3 vs. 1.3), and non-Hodgkin lymphoma (61.8 vs. 9.4). At five years post-transplant, colorectal cancer was diagnosed in 0.3% of CF recipients aged <50 at transplant and 6.4% aged 50. Conclusions: CF recipients have increased risk for colorectal cancer, suggesting a need for enhanced screening. (C) 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. C1 [Fink, Aliza K.; Marshall, Bruce C.] Cyst Fibrosis Fdn, 6931 Arlington Rd, Bethesda, MD 20814 USA. [Yanik, Elizabeth L.; Safaeian, Mahboobeh; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Wilschanski, Michael] Hadassah Hebrew Univ, Med Ctr, Dept Pediat Gastroenterol, Jerusalem, Israel. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Austin, April A.] New York State Dept Hlth, New York State Canc Registry, New York, NY USA. [Copeland, Glenn] Michigan Dept Hlth & Human Serv, Michigan Canc Surveillance Program, Lansing, MI USA. RP Fink, AK (reprint author), Cyst Fibrosis Fdn, 6931 Arlington Rd, Bethesda, MD 20814 USA. EM afink@cff.org OI Yanik, Elizabeth/0000-0002-5835-0201 FU Intramural Research Program of the National Cancer Institute; Health Resources and Services Administration [HHSH250201500009C]; SEER Program of the National Cancer Institute: California [HHSN261201000036C, HHSN261201000035C, HHSN261201000034C]; SEER Program of the National Cancer Institute: Connecticut [HHSN261201000024C]; SEER Program of the National Cancer Institute: Hawaii [HHSN261201000037C, N01-PC-35137, N01-PC-35139]; SEER Program of the National Cancer Institute: Iowa [HSN261201000032C, N01-PC-35143]; SEER Program of the National Cancer Institute: New Jersey [HHSN261201300021I, N01-PC-2013-00021]; SEER Program of the National Cancer Institute: Seattle-Puget Sound [N01-PC-35142]; SEER Program of the National Cancer Institute: Utah [HHSN2612013000171]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: California [1U58 DP000807-01]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Colorado [U58 DP000848-04]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Georgia [5U58DP003875-01]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Illinois [5U58DP003883-03]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Maryland [U58DP12-1205 3919-03]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Michigan [5U58DP003921-03]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: New Jersey [5U58/DP003931-02]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: New York [U58DP003879]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: North Carolina [U58DP000832]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Texas [5U58DP000824-04]; state of California; state of Colorado; state of Connecticut; state of Illinois; state of Iowa; state of Massachusetts (Massachusetts Cancer Prevention and Control Cooperative Agreement) [5458DP003920]; state of New Jersey; state of New York (Cancer Surveillance Improvement Initiative); state of Texas; state of Utah; state of Washington; University of Utah; Fred Hutchinson Cancer Research Center in Seattle, WA; state of California (Tina Clarke); state of Colorado (Jack Finch); state of Connecticut (Lou Gonsalves); state of Georgia (Rana Bayakly); state of Hawaii (Brenda Hernandez); state of Illinois (Lori Koch); state of Kentucky (Jaclyn Nee); state of Michigan; state of New Jersey (Xiaoling Niu); state of New York (Amy Kahn); state of North Carolina (Chandrika Rao); state of Texas (Leticia Nogueria); state of Utah (Janna Harrell); state of Seattle-Puget Sound area of Washington (Margaret Madeleine); [HHSH250201000018C]; [HHSH234200537009C] FX This research was supported in part by the Intramural Research Program of the National Cancer Institute. The authors gratefully acknowledge the support and assistance provided by individuals at the Health Resources and Services Administration (Monica Lin), the SRTR (Ajay Israni, Bertram Kasiske, Paul Newkirk, Jon Snyder), and the following cancer registries: the states of California (Tina Clarke), Colorado (Jack Finch), Connecticut (Lou Gonsalves), Georgia (Rana Bayakly), Hawaii (Brenda Hernandez), Iowa, Illinois (Lori Koch), Kentucky (Jaclyn Nee), Michigan, New Jersey (Xiaoling Niu), New York (Amy Kahn), North Carolina (Chandrika Rao), Texas (Leticia Nogueria), and Utah (Janna Harrell), and the Seattle-Puget Sound area of Washington (Margaret Madeleine). We also thank analysts at Information Management Services for programming support (David Castenson, Matthew Chaloux, Michael Curry, Ruth Parsons).; The SRTR is currently operated under contract number HHSH250201500009C (Health Resources and Services Administration) by the Minneapolis Medical Research Foundation, Minneapolis, MN. Previously the SRTR was managed under contracts HHSH250201000018C and HHSH234200537009C. The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C, and HHSN261201000034C), Connecticut (HHSN261201000024C), Hawaii (HHSN261201000037C, N01-PC-35137, and N01-PC-35139), Iowa (HSN261201000032C and N01-PC-35143), New Jersey (HHSN261201300021I, N01-PC-2013-00021), Seattle-Puget Sound (N01-PC-35142), and Utah (HHSN2612013000171). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP003875-01), Illinois (5U58DP003883-03), Maryland (U58DP12-1205 3919-03), Michigan (5U58DP003921-03), New Jersey (5U58/DP003931-02), New York (U58DP003879), North Carolina (U58DP000832) and Texas (5U58DP000824-04). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, Massachusetts (Massachusetts Cancer Prevention and Control Cooperative Agreement 5458DP003920), New Jersey, New York (including the Cancer Surveillance Improvement Initiative), Texas, Utah, and Washington, as well as the University of Utah and Fred Hutchinson Cancer Research Center in Seattle, WA. NR 23 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-1993 EI 1873-5010 J9 J CYST FIBROS JI J. Cyst. Fibros PD JAN PY 2017 VL 16 IS 1 BP 91 EP 97 DI 10.1016/j.jcf.2016.07.011 PG 7 WC Respiratory System SC Respiratory System GA EK0PS UT WOS:000393629700018 PM 27539828 ER PT J AU Agarwal, HK Mertan, FV Sankineni, S Bernardo, M Senegas, J Keupp, J Daar, D Merino, M Wood, BJ Pinto, PA Choyke, PL Turkbey, B AF Agarwal, Harsh K. Mertan, Francesca V. Sankineni, Sandeep Bernardo, Marcelino Senegas, Julien Keupp, Jochen Daar, Dagane Merino, Maria Wood, Bradford J. Pinto, Peter A. Choyke, Peter L. Turkbey, Baris TI Optimal High b-Value for Diffusion Weighted MRI in Diagnosing High Risk Prostate Cancers in the Peripheral Zone SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article ID RADICAL PROSTATECTOMY; CLINICAL UTILITY; TUMOR-DETECTION; 3 T; LOCALIZATION; FUSION; AGGRESSIVENESS; RECURRENCE; CONTRAST; CURVES AB Purpose: To retrospectively determine the optimal b-value(s) of diffusion-weighted imaging (DWI) associated with intermediate-high risk cancer in the peripheral zone (PZ) of the prostate. Materials and Methods: Forty-two consecutive patients underwent multi b-value (16 evenly spaced b-values between 0 and 2000 s/mm(2)) DWI along with multi-parametric MRI (MP-MRI) of the prostate at 3 Tesla followed by trans-rectal ultrasound/MRI fusion guided targeted biopsy of suspicious lesions detected at MP-MRI. Computed DWI images up to a simulated b-value of 4000 s/mm(2) were also obtained using a pair of b-values (b = 133 and 400 or 667 or 933 s/mm(2)) from the multi b-value DWI. The contrast ratio of average intensity of the targeted lesions and the background PZ was determined. Receiver operator characteristic curves and the area under the curve (AUCs) were obtained for separating patients eligible for active surveillance with low risk prostate cancers from intermediate-high risk prostate cancers as per the cancer of the prostate risk assessment (CAPRA) scoring system. Results: The AUC first increased then decreased with the increase in b-values reaching maximum at b = 1600 s/mm(2) (0.74) with no statistically significant different AUC of DWI with b-values 1067-2000 s/mm(2). The AUC of computed DWI increased then decreased with the increase in b-values reaching a maximum of 0.75 around b = 2000 s/mm(2). There was no statistically significant difference between the AUC of optimal acquired DWI and either of optimal computed DWI. Conclusion: The optimal b-value for acquired DWI in differentiating intermediate-high from low risk prostate cancers in the PZ is b = 1600 s/mm(2). The computed DWI has similar performance as that of acquired DWI with the optimal performance around b = 2000 s/mm(2). C1 [Agarwal, Harsh K.; Mertan, Francesca V.; Sankineni, Sandeep; Bernardo, Marcelino; Daar, Dagane; Choyke, Peter L.; Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Agarwal, Harsh K.] Philips Res North Amer, Cambridge, MA USA. [Bernardo, Marcelino; Daar, Dagane] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Frederick, MD USA. [Senegas, Julien; Keupp, Jochen] Philips Res Labs, Hamburg, Germany. [Merino, Maria] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, 10 Ctr Dr,MSC 1182,Bldg 10,Room B3B85, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov NR 35 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD JAN PY 2017 VL 45 IS 1 BP 125 EP 131 DI 10.1002/jmri.25353 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EK0YR UT WOS:000393653500013 PM 27383502 ER PT J AU Greer, MD Brown, AM Shih, JH Summers, RM Marko, J Law, YM Sankineni, S George, AK Merino, MJ Pinto, PA Choyke, PL Turkbey, B AF Greer, Matthew D. Brown, Anna M. Shih, Joanna H. Summers, Ronald M. Marko, Jamie Law, Yan Mee Sankineni, Sandeep George, Arvin K. Merino, Maria J. Pinto, Peter A. Choyke, Peter L. Turkbey, Baris TI Accuracy and Agreement of PIRADSv2 for Prostate Cancer mpMRI: A Multireader Study SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article ID TRANSRECTAL ULTRASOUND BIOPSY; FUSION-GUIDED BIOPSY; RADS VERSION 2; PI-RADS; DATA SYSTEM; INTEROBSERVER AGREEMENT; LOW KAPPA; PARADOXES; DIAGNOSIS; V2 AB Purpose: Multiparametric MRI (mpMRI) improves the detection of clinically significant prostate cancer, but is limited by interobserver variation. The second version of theProstate Imaging Reporting and Data System (PIRADSv2) was recently proposed as a standard for interpreting mpMRI. To assess the performance and interobserver agreement of PIRADSv2 we performed a multi-reader study with five radiologists of varying experience. Materials and Methods: Five radiologists (n=2 prostate dedicated, n=3 general body) blinded to clinicopathologic results detected and scored lesions on prostate mpMRI using PIRADSv2. The endorectal coil 3 Tesla MRI included T2W, diffusion-weighted imaging (apparent diffusion coefficient, b2000), and dynamic contrast enhancement. Thirty-four consecutive patients were included. Results were correlated with radical prostatectomy whole-mount histopathology produced with patient-specific three-dimensional molds. An index lesion was defined on pathology as the lesion with highest Gleason score or largest volume if equivalent grades. Average sensitivity and positive predictive values (PPVs) for all lesions and index lesions were determined using generalized estimating equations. Interobserver agreement was evaluated using index of specific agreement. Results: Average sensitivity was 91% for detecting index lesions and 63% for all lesions across all readers. PPV was 85% for PIRADS >= 3 and 90% for PIRADS >= 4. Specialists performed better only for PIRADS >= 4 with sensitivity 90% versus 79% (P=0.01) for index lesions. Index of specific agreement among readers was 93% for the detection of index lesions, 74% for the detection of all lesions, and 85% for scoring index lesions, and 58% for scoring all lesions. Conclusion: By using PIRADSv2, general body radiologists and prostate specialists can detect high-grade index prostate cancer lesions with high sensitivity and agreement. C1 [Greer, Matthew D.; Brown, Anna M.; Sankineni, Sandeep; Choyke, Peter L.; Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Greer, Matthew D.] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Brown, Anna M.] Duke Univ, Sch Med, Durham, NC USA. [Shih, Joanna H.] NCI, Biometr Res Program, NIH, Bethesda, MD 20892 USA. [Summers, Ronald M.] Natl Inst Hlth Clin Ctr, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci, Bethesda, MD USA. [Marko, Jamie] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Law, Yan Mee] Singapore Gen Hosp, Singapore, Singapore. [George, Arvin K.; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), 10 Ctr Dr,Room B3B85, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov OI Greer, Matthew/0000-0003-4409-4398 FU Intramural Research Program, National Institutes of Health, National Cancer Institute and Clinical Center; NIH FX This research was funded in part by the Intramural Research Program, National Institutes of Health, National Cancer Institute and Clinical Center. This 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 generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Newport Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. Authors have no conflicts of interest to disclose. NR 25 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD JAN PY 2017 VL 45 IS 2 BP 579 EP 585 DI 10.1002/jmri.25372 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EK0ZB UT WOS:000393654500025 PM 27391860 ER PT J AU Salami, SS Ben-Levi, E Yaskiv, O Turkbey, B Villani, R Rastinehad, AR AF Salami, Simpa S. Ben-Levi, Eran Yaskiv, Oksana Turkbey, Baris Villani, Robert Rastinehad, Ardeshir R. TI Risk Stratification of Prostate Cancer Utilizing Apparent Diffusion Coefficient Value and Lesion Volume on Multiparametric MRI SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article ID ACTIVE SURVEILLANCE; TARGETED BIOPSY; HISTOPATHOLOGY; TESLA; MEN AB Purpose: To evaluate the performance of apparent diffusion coefficient (ADC) and lesion volume in potentially risk-stratifying patients with prostate cancer (PCa). Materials and Methods: Men with elevated prostate-specific antigen or abnormal digital rectal exam underwent a 3T multiparametric magnetic resonance imaging (mpMRI) with endorectal coil. ADC maps were calculated using b values of 0, 500, 1000, and 1500; additional images were obtained with b value of 2000. We prospectively enrolled 312 men with lesions suspicious for cancer (suspicion score 2-5) on mpMRI. MRI/ultrasound fusion-guided prostate biopsies were performed. Mean ADC of suspicious lesions were correlated against lesion volume, Gleason and D'Amico risk. Results: The cancer detection rate of fusion biopsy per lesion was 45.6% (206/452). Cancerous lesions were larger (median volume: 0.40 vs. 0.30cm(3); P=0.016). The median ADC (x10(-6) mm(2)/sec) for lesions negative and positive for PCa were 984.5 and 666.5, respectively (P < 0.0001). The AUC of ADC in predicting PCa was 0.79. Larger lesions were associated with higher risk PCa (Gleason and D'Amico) and lower ADC (all P < 0.0001). Conclusion: The mean ADC of suspicious lesions on mpMRI was inversely correlated, while lesion volume had a direct correlation with PCa detection. Future follow-up studies are needed to assess longitudinal cancer risks of suspicious mpMRI lesions. C1 [Salami, Simpa S.] Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI USA. [Ben-Levi, Eran; Villani, Robert] Hofstra North Shore LIJ Sch Med, Dept Radiol, New Hyde Pk, NY USA. [Yaskiv, Oksana] Hofstra North Shore LIJ Sch Med, Dept Pathol, New Hyde Pk, NY USA. [Turkbey, Baris] Natl Inst Hlth, Mol Imaging Program, Bethesda, MD USA. [Rastinehad, Ardeshir R.] Icahn Sch Med Mt Sinai, Dept Urol, New York, NY 10029 USA. RP Rastinehad, AR (reprint author), Icahn Sch Med Mt Sinai, One Gustav Levy Pl,POB 1272, New York, NY 10029 USA. EM Art.rastinehad@mountsinai.org NR 32 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD JAN PY 2017 VL 45 IS 2 BP 610 EP 616 DI 10.1002/jmri.25363 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EK0ZB UT WOS:000393654500028 PM 27405584 ER PT J AU Shen, Y Ning, J Qin, J AF Shen, Yu Ning, Jing Qin, Jing TI Nonparametric and semiparametric regression estimation for length-biased survival data SO LIFETIME DATA ANALYSIS LA English DT Article DE Length-biased sampling; Estimating equation; Left truncation; Likelihood; Nonparametric estimator; Semiparametric models ID RIGHT-CENSORED DATA; PREVALENT COHORT DATA; FAILURE TIME MODEL; TRANSFORMATION MODELS; SAMPLING DATA; HAZARDS REGRESSION; PARTIAL LIKELIHOOD; RANDOM TRUNCATION; COX MODEL; INFERENCE AB For the past several decades, nonparametric and semiparametric modeling for conventional right-censored survival data has been investigated intensively under a noninformative censoring mechanism. However, these methods may not be applicable for analyzing right-censored survival data that arise from prevalent cohorts when the failure times are subject to length-biased sampling. This review article is intended to provide a summary of some newly developed methods as well as established methods for analyzing length-biased data. C1 [Shen, Yu; Ning, Jing] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Qin, Jing] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Shen, Y (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. EM yshen@mdanderson.org; jning@mdanderson.org; jingqin@niaid.nih.gov FU U.S. NIH [CA079466, CA016672]; Seniors' Independence Research Program, through the National Health Research and Development Program (NHRDP) of Health Canada [6606-3954-MC(S)]; Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program; NHRDP Project [6603-1417-302(R)]; Bayer Incorporated; British Columbia Health Research Foundation [38 (93-2), 34 (96-1)] FX The work was supported in part by the U.S. NIH Grants CA079466 and CA016672. The authors thank Professor Asgharian and the investigators from the Canadian Study of Health and Aging for generously sharing the dementia data. The data reported in this article were collected as part of the Canadian Study of Health and Aging. The core study was funded by the Seniors' Independence Research Program, through the National Health Research and Development Program (NHRDP) of Health Canada Project 6606-3954-MC(S). Additional funding was provided by Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program, NHRDP Project 6603-1417-302(R), Bayer Incorporated, and the British Columbia Health Research Foundation Projects 38 (93-2) and 34 (96-1). The study was coordinated through the University of Ottawa and the Division of Aging and Seniors, Health Canada. NR 63 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1380-7870 EI 1572-9249 J9 LIFETIME DATA ANAL JI Lifetime Data Anal. PD JAN PY 2017 VL 23 IS 1 SI SI BP 3 EP 24 DI 10.1007/s10985-016-9367-y PG 22 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA EK2IS UT WOS:000393751600002 PM 27086362 ER PT J AU Guan, Z Qin, J AF Guan, Zhong Qin, Jing TI Empirical likelihood method for non-ignorable missing data problems SO LIFETIME DATA ANALYSIS LA English DT Article DE Constrained estimation; Empirical likelihood; Non-ignorable missing data; Survey sampling ID SEMIPARAMETRIC ESTIMATION; AUXILIARY INFORMATION; ESTIMATING EQUATIONS; ROBUST ESTIMATION; REGRESSION; INFERENCE; NONRESPONSE; MODELS; BIAS; IMPUTATION AB Missing response problem is ubiquitous in survey sampling, medical, social science and epidemiology studies. It is well known that non-ignorable missing is the most difficult missing data problem where the missing of a response depends on its own value. In statistical literature, unlike the ignorable missing data problem, not many papers on non-ignorable missing data are available except for the full parametric model based approach. In this paper we study a semiparametric model for non-ignorable missing data in which the missing probability is known up to some parameters, but the underlying distributions are not specified. By employing Owen (1988)'s empirical likelihood method we can obtain the constrained maximum empirical likelihood estimators of the parameters in the missing probability and the mean response which are shown to be asymptotically normal. Moreover the likelihood ratio statistic can be used to test whether the missing of the responses is non-ignorable or completely at random. The theoretical results are confirmed by a simulation study. As an illustration, the analysis of a real AIDS trial data shows that the missing of CD4 counts around two years are non-ignorable and the sample mean based on observed data only is biased. C1 [Guan, Zhong] Indiana Univ, Dept Math Sci, South Bend, IN 46634 USA. [Qin, Jing] NIAID, Biostat Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Guan, Z (reprint author), Indiana Univ, Dept Math Sci, South Bend, IN 46634 USA. EM zguan@iusb.edu NR 37 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1380-7870 EI 1572-9249 J9 LIFETIME DATA ANAL JI Lifetime Data Anal. PD JAN PY 2017 VL 23 IS 1 SI SI BP 113 EP 135 DI 10.1007/s10985-016-9381-0 PG 23 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA EK2IS UT WOS:000393751600007 PM 27647436 ER PT J AU Desnick, RJ Barton, NW Furbish, S Grabowski, GA Karlsson, S Kolodny, EH Medin, JA Murray, GJ Mistry, PK Patterson, MC Schiffmann, R Weinreb, NJ AF Desnick, Robert J. Barton, Norman W. Furbish, Scott Grabowski, Gregory A. Karlsson, Stefan Kolodny, Edwin H. Medin, Jeffrey A. Murray, Gary J. Mistry, Pramod K. Patterson, Marc C. Schiffmann, Raphael Weinreb, Neal J. TI Roscoe Owen Brady, MD: Remembrances of co-investigators and colleagues SO MOLECULAR GENETICS AND METABOLISM LA English DT Article AB To celebrate the research visions and accomplishments of the late Roscoe O. Brady (1923-2016), remembrance commentaries were requested from several of his postdoctoral research fellows and colleagues. These commentaries not only reflect on the accomplishments of Dr. Brady, but they also share some of the backstories and experiences working in the Brady laboratory. They provide insights and perspectives on Brady's research activities, and especially on his efforts to develop an effective treatment for patients with Type 1 Gaucher disease. These remembrances illuminate Brady's efforts to implement the latest scientific advances with an outstanding team of young co-investigators to develop and demonstrate the safety and effectiveness of the first enzyme replacement therapy for a lysosomal storage disease. Brady's pursuit and persistence in accomplishing his research objectives provide insights into this remarkably successful physician scientist who paved the way for the development of treatments for patients with other lysosomal storage diseases. (C) 2016 Elsevier Inc. All rights reserved. C1 [Desnick, Robert J.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Barton, Norman W.] Shire, Neurosci Therapeut Area, Lexington, MA 02421 USA. [Grabowski, Gregory A.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45267 USA. [Karlsson, Stefan] Lund Univ, Dept Mol Med & Gene Therapy, Lund, Sweden. [Kolodny, Edwin H.] NYU, Sch Med, Dept Neurol, 550 1St Ave, New York, NY 10012 USA. [Medin, Jeffrey A.] Med Coll Wisconsin, Dept Pediat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Medin, Jeffrey A.] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA. [Murray, Gary J.] NIAAA, Div Metab & Hlth Effects, Bethesda, MD 20892 USA. [Mistry, Pramod K.] Yale Univ, Dept Med, Sch Med, New Haven, CT 06520 USA. [Mistry, Pramod K.] Yale Univ, Dept Pediat, Sch Med, New Haven, CT 06520 USA. [Mistry, Pramod K.] Yale Univ, Dept Cellular & Mol Physiol, Sch Med, New Haven, CT 06520 USA. [Patterson, Marc C.] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Patterson, Marc C.] Mayo Clin, Dept Pediat, Rochester, MN 55905 USA. [Patterson, Marc C.] Mayo Clin, Dept Med Genet, Rochester, MN 55905 USA. [Schiffmann, Raphael] Baylor Res Inst, Inst Metab Dis, Dallas, TX 75087 USA. [Weinreb, Neal J.] Univ Miami, Miller Sch Med, Dept Human Genet & Med, Miami, FL 33136 USA. RP Desnick, RJ (reprint author), Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. EM Robert.desnick@mssm.edu NR 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN-FEB PY 2017 VL 120 IS 1-2 BP 1 EP 7 DI 10.1016/j.ymgme.2016.10.010 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EK2CC UT WOS:000393734000379 PM 27866832 ER PT J AU Mistry, PK Lopez, G Schiffmann, R Barton, NW Weinreb, NJ Sidransky, E AF Mistry, Pramod K. Lopez, Grisel Schiffmann, Raphael Barton, Norman W. Weinreb, Neal J. Sidransky, Ellen TI Gaucher disease: Progress and ongoing challenges SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Gaucher disease; Glucocerebrosidase; Lysosomal storage disorder; Enzyme replacement therapy; Dr. Roscoe Brady; Parkinsonism ID ENZYME REPLACEMENT THERAPY; MACROPHAGE-TARGETED GLUCOCEREBROSIDASE; SUBSTRATE REDUCTION THERAPY; PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; BETA-GLUCOCEREBROSIDASE; OPEN-LABEL; PHARMACOLOGICAL CHAPERONES; MONOCLONAL GAMMOPATHY; ELIGLUSTAT TARTRATE AB Over the past decades, tremendous progress has been made in the field of Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators. Published by Elsevier Inc. C1 [Mistry, Pramod K.] Yale Univ, Sch Med, Dept Internal Med, 333 Cedar St,LMP 1080,POB 208019, New Haven, CT 06520 USA. [Lopez, Grisel; Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bldg 35A Room 1E623,35 Convent Dr, Bethesda, MD 20892 USA. [Schiffmann, Raphael] Baylor Res Inst, Inst Metab Dis, Dallas, TX 75226 USA. [Barton, Norman W.] Shire Plc, Therapeut Area Head Neurosci, 300 Shire Way, Lexington, MA 02421 USA. [Weinreb, Neal J.] Univ Miami, Miller Sch Med, Dept Human Genet & Med Hematol, UHlth Sylvester Coral Springs, 8170 Royal Palm Blvd, Coral Springs, FL 33065 USA. RP Sidransky, E (reprint author), NHGRI, Med Genet Branch, NIH, Bldg 35A Room 1E623,35 Convent Dr, Bethesda, MD 20892 USA. EM Pramod.mistry@yale.edu; glopez@mail.nih.gov; Raphael.Schiffmann@BSWHealth.org; nbarton@shire.com; boneal@winning.com; sidranse@mail.nih.gov FU National Human Genome Research Institute; National Institute of Health; Merck; National Institutes of Arthritis, Musculoskeletal and Skin Diseases [AR 65932]; Center of Excellence Grant in Clinical Translational Research from Genzyme, a Sanofi Company; Genzyme; Shire; Protalix Biotherapeutics; Amicus Therapeutics; Genzyme-Sanofi; Shire HGT FX The work of GL and ES was supported by the intramural program of the National Human Genome Research Institute and the National Institute of Health. The Sidransky laboratory received research support under a Cooperative Research and Development Agreement with Merck.; PKM is supported by a grant from the National Institutes of Arthritis, Musculoskeletal and Skin Diseases AR 65932 and Center of Excellence Grant in Clinical Translational Research from Genzyme, a Sanofi Company. He has received research support, honoraria and consulting fees from Genzyme.; RS has received research support from Shire, Protalix Biotherapeutics and Amicus Therapeutics.; NJW serves on Medical or Scientific Advisory Boards for Genzyme-Sanofi, Shire HGT and Pfizer for which he has received honoraria. He has consulted for Genzyme-Sanofi and for Pfizer and has received research support from Genzyme-Sanofi and from Shire HGT. NR 165 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN-FEB PY 2017 VL 120 IS 1-2 BP 8 EP 21 DI 10.1016/j.ymgme.2016.11.006 PG 14 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EK2CC UT WOS:000393734000380 PM 27916601 ER PT J AU Choi, EY Kaler, SG AF Choi, Eun-Young Kaler, Stephen G. TI Dose-ranging comparison of choroid plexus-directed versus pan-neuronal-directed recombinant AAV gene therapy in a murine model of alpha-mannosidosis SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 13th Annual Research Meeting on We're Organizing Research for Lysosomal Diseases (WORLD) CY FEB 13-17, 2017 CL San Diego, CA C1 [Choi, Eun-Young; Kaler, Stephen G.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN-FEB PY 2017 VL 120 IS 1-2 MA 57 BP S36 EP S36 DI 10.1016/j.ymgme.2016.11.066 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EK2CC UT WOS:000393734000059 ER PT J AU Grey, R Trivdei, N Johnson, KR Gonzalez, A Berhe, B Elkahloun, AG Sidransky, E Tayebi, N AF Grey, Richard Trivdei, Niraj Johnson, Kory R. Gonzalez, Ashley Berhe, Bahafta Elkahloun, Abdel G. Sidransky, Ellen Tayebi, Nahid TI Looking for diamonds in the rough: identifying differentially expressed modifier genes in mouse models for type 2 Gaucher disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 13th Annual Research Meeting on We're Organizing Research for Lysosomal Diseases (WORLD) CY FEB 13-17, 2017 CL San Diego, CA C1 [Grey, Richard; Trivdei, Niraj; Gonzalez, Ashley; Berhe, Bahafta; Elkahloun, Abdel G.; Sidransky, Ellen; Tayebi, Nahid] NHGRI, NIH, Bethesda, MD 20892 USA. [Johnson, Kory R.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN-FEB PY 2017 VL 120 IS 1-2 MA 120 BP S58 EP S58 DI 10.1016/j.ymgme.2016.11.129 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EK2CC UT WOS:000393734000122 ER PT J AU Hassan, S Grey, R Donovan, F Biegstraaten, M Hollak, C Sidransky, E Tayebi, N AF Hassan, Shahzeb Grey, Richard Donovan, Frank Biegstraaten, Marieke Hollak, Carla Sidransky, Ellen Tayebi, Nahid TI Looking beyond the realm of traditional genetics: DNA methylation differences in discordant Gaucher disease twins SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 13th Annual Research Meeting on We're Organizing Research for Lysosomal Diseases (WORLD) CY FEB 13-17, 2017 CL San Diego, CA C1 [Hassan, Shahzeb; Grey, Richard; Donovan, Frank; Sidransky, Ellen; Tayebi, Nahid] NHGRI, NIH, Bethesda, MD 20892 USA. [Biegstraaten, Marieke; Hollak, Carla] Acad Med Ctr, Amsterdam, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN-FEB PY 2017 VL 120 IS 1-2 MA 136 BP S63 EP S63 DI 10.1016/j.ymgme.2016.11.145 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EK2CC UT WOS:000393734000138 ER PT J AU Jung, O Patnaik, S Westbroek, W Stachel, S Breslin, M Cramer, P Titus, S Vos, T Marugan, J Sidransky, E AF Jung, Olive Patnaik, Samarjit Westbroek, Wendy Stachel, Shawn Breslin, Michael Cramer, Paige Titus, Steve Vos, Ty Marugan, Juan Sidransky, Ellen TI Novel molecular tools to advance the evaluation of Gaucher disease therapeutics in live cells SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 13th Annual Research Meeting on We're Organizing Research for Lysosomal Diseases (WORLD) CY FEB 13-17, 2017 CL San Diego, CA C1 [Jung, Olive] NHGRI, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Patnaik, Samarjit; Titus, Steve; Vos, Ty; Marugan, Juan] Natl Ctr Adv Translat Sci, Rockville, MD USA. [Westbroek, Wendy; Sidransky, Ellen] Natl Human Genome Res Inst, Bethesda, MD USA. [Stachel, Shawn; Breslin, Michael; Cramer, Paige] Merck Res Labs, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN-FEB PY 2017 VL 120 IS 1-2 MA 161 BP S72 EP S72 DI 10.1016/j.ymgme.2016.11.170 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EK2CC UT WOS:000393734000163 ER PT J AU Lal, TRR Weiss, K Monestime, G Tayebi, N Lopez, G Sidransky, E AF Lal, Tamanna R. Roshan Weiss, Karin Monestime, Ginanina Tayebi, Nahid Lopez, Grisel Sidransky, Ellen TI Type 2 Gaucher disease: Where do we go from here? SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 13th Annual Research Meeting on We're Organizing Research for Lysosomal Diseases (WORLD) CY FEB 13-17, 2017 CL San Diego, CA C1 [Lal, Tamanna R. Roshan] Johns Hopkins Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Weiss, Karin; Monestime, Ginanina; Tayebi, Nahid; Lopez, Grisel; Sidransky, Ellen] NHGRI, Mol Genet Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN-FEB PY 2017 VL 120 IS 1-2 MA 291 BP S116 EP S117 DI 10.1016/j.ymgme.2016.11.300 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EK2CC UT WOS:000393734000292 ER PT J AU Lim, JA Raben, N AF Lim, Jeong-A Raben, Nina TI Modulation of mTOR signaling as a therapeutic approach for Pompe disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 13th Annual Research Meeting on We're Organizing Research for Lysosomal Diseases (WORLD) CY FEB 13-17, 2017 CL San Diego, CA C1 [Lim, Jeong-A; Raben, Nina] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN-FEB PY 2017 VL 120 IS 1-2 MA 194 BP S84 EP S84 DI 10.1016/j.ymgme.2016.11.203 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EK2CC UT WOS:000393734000196 ER PT J AU Machielse, BN Porter, FD Yergey, AL Berry-Kravis, EM Darling, A Rao, R AF Machielse, Bernardus N. Porter, Forbes D. Yergey, Alfred L. Berry-Kravis, Elizabeth M. Darling, Allan Rao, Ravi TI VTS-270 for the treatment of Niemann-Pick disease type C SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 13th Annual Research Meeting on We're Organizing Research for Lysosomal Diseases (WORLD) CY FEB 13-17, 2017 CL San Diego, CA C1 [Machielse, Bernardus N.; Darling, Allan; Rao, Ravi] Vtesse Inc, Bethesda, MD USA. [Porter, Forbes D.] NICHD, NIH, Bethesda, MD USA. [Yergey, Alfred L.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Berry-Kravis, Elizabeth M.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. FU Vtesse, Inc. FX Sponsored by Vtesse, Inc. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN-FEB PY 2017 VL 120 IS 1-2 MA 210 BP S89 EP S90 DI 10.1016/j.ymgme.2016.11.219 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EK2CC UT WOS:000393734000212 ER PT J AU McMahon, B Aflaki, E Borger, D Grey, R Kirby, M Anderson, S Lopez, G Sidransky, E AF McMahon, Benjamin Aflaki, Elma Borger, Daniel Grey, Richard Kirby, Martha Anderson, Stacie Lopez, Grisel Sidransky, Ellen TI Impaired phagosome maturation in Gaucher macrophages provides a new target for therapeutic intervention target SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 13th Annual Research Meeting on We're Organizing Research for Lysosomal Diseases (WORLD) CY FEB 13-17, 2017 CL San Diego, CA C1 [McMahon, Benjamin; Aflaki, Elma; Borger, Daniel; Grey, Richard; Kirby, Martha; Anderson, Stacie; Lopez, Grisel; Sidransky, Ellen] NHGRI, NIH, Washington, DC USA. FU NHGRI; NIH FX This work was funded by the Intramural Research Program of the NHGRI and NIH. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN-FEB PY 2017 VL 120 IS 1-2 MA 223 BP S94 EP S94 DI 10.1016/j.ymgme.2016.11.232 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EK2CC UT WOS:000393734000225 ER PT J AU Steward, AM Monestime, G Groden, C Wiggs, E Tayebi, N Lal, TR Lopez, G Sidransky, E AF Steward, Alta M. Monestime, Gianina Groden, Catherine Wiggs, Edythe Tayebi, Nahid Lal, Tamanna Roshan Lopez, Grisel Sidransky, Ellen TI Sibling pairs with Gaucher disease discordant for Parkinsonism SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 13th Annual Research Meeting on We're Organizing Research for Lysosomal Diseases (WORLD) CY FEB 13-17, 2017 CL San Diego, CA C1 [Steward, Alta M.; Monestime, Gianina; Groden, Catherine; Wiggs, Edythe; Tayebi, Nahid; Lal, Tamanna Roshan; Lopez, Grisel; Sidransky, Ellen] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN-FEB PY 2017 VL 120 IS 1-2 MA 325 BP S127 EP S128 DI 10.1016/j.ymgme.2016.11.334 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EK2CC UT WOS:000393734000326 ER PT J AU Reich, DS AF Reich, Daniel S. TI Visualization of cortical MS lesions with MRI need not be further improved - Commentary SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article C1 [Reich, Daniel S.] NINDS, Translat Neuroradiol Sect, Div Neuroimmunol & Neurovirol, NIH, Bethesda, MD 20892 USA. RP Reich, DS (reprint author), NINDS, Translat Neuroradiol Sect, Div Neuroimmunol & Neurovirol, NIH, Bethesda, MD 20892 USA. EM reichds@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke FX The author thanks Martina Absinta and Irene Cortese for helpful comments and acknowledges support from the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD JAN PY 2017 VL 23 IS 1 BP 19 EP 20 DI 10.1177/1352458516666188 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EK4OH UT WOS:000393906000006 PM 27566451 ER PT J AU Sloan, DH BrintzenhofeSzoc, K Kichline, T Baker, K Pinzon, JP Tafe, C Li, LS Cheng, MJ Berger, A AF Sloan, Danetta Hendricks BrintzenhofeSzoc, Karlynn Kichline, Tiffany Baker, Karen Pinzon, Jean-Paul Tafe, Christina Li, Lingsheng Cheng, M. Jennifer Berger, Ann TI An assessment of meaning in life-threatening illness: development of the Healing Experience in All Life Stressors (HEALS) SO PATIENT-RELATED OUTCOME MEASURES LA English DT Article DE palliative care; psycho-social spiritual assessment; validation; instrumentation ID POSTTRAUMATIC GROWTH; CANCER; INSTRUMENT; OUTCOMES; CARE AB Context: Patients with life-threatening or chronic illness report an experience of increased positive psychological, social, and/or spiritual change during diagnosis and/or treatment of their illness, even in the face of unfavorable prognosis. This transformation begins through the ability to make their life meaningful by forming meaningful connections that emerge through self-introspection and relationships with a divine entity, nature, and other people. The Healing Experience in All Life Stressors (HEALS) assessment provides a way to identify distress-causing changes that may interfere with the development of meaning and psycho-social-spiritual homeostasis. Objective: Preliminary examination of responses to items on the HEALS and examination of the factor structure. Method: The 48-item HEALS questionnaire was developed using a multistep process: literature review for concept development, item generation from qualitative data, and face and content validity by expert panel. In the current study, HEALS was completed by 100 patients diagnosed with life-limiting disease and seen by the palliative care team at a large research institution in the US. Exploratory factor analysis techniques were used to determine scale structure of the instrument. Results: Outcome testing of sample adequacy using Kaiser-Meyer-Olkin statistic was 0.75, which exceeds the recommended value of 0.60. The HEALS show very good internal consistency with a Cronbach's alpha of 0.94. Overall results of the exploratory factor analysis established a four-factor questionnaire: 1) religion; 2) spirituality, demonstrated by a) interaction with a religious community and b) belief in higher power; 3) intrapersonal; and 4) interpersonal relationships expressed through psychological changes resulting in enhanced outlook and improvement in relationships with family and friends. Conclusion: This study involved the initial step to commence the process of scale validation, with promising outcomes identifying subscales as an effective way to assess the construct of healing. These findings support further examination using cognitive appraisal and confirmatory factor analysis. C1 [Sloan, Danetta Hendricks; Kichline, Tiffany; Baker, Karen; Pinzon, Jean-Paul; Tafe, Christina; Li, Lingsheng; Cheng, M. Jennifer; Berger, Ann] NIH, Pain & Palliat Care, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [BrintzenhofeSzoc, Karlynn] Univ Cincinnati, Sch Social Work, Coll Allied Hlth Sci, Cincinnati, OH USA. RP Sloan, DH (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Bldg 10-CRC MSC 1517, Bethesda, MD 20892 USA. EM dhendr49@gmail.com FU Intramural Research Program of the NIH, Clinical Center FX The Intramural Research Program of the NIH, Clinical Center supported this research. The authors gratefully acknowledge Erin Mistretta, NIH Summer Intern 2016, for her contribution to this project. NR 29 TC 0 Z9 0 U1 0 U2 0 PU DOVE MEDICAL PRESS LTD PI ALBANY PA PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND SN 1179-271X J9 PATIENT-RELAT OUTCOM JI PATIENT-RELAT. OUTCOME MEAS. PY 2017 VL 8 DI 10.2147/PROM.S118696 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EL4RO UT WOS:000394608800001 ER PT J AU Shetty, A Hawkins, JV Gupta, A AF Shetty, A. Hawkins, J. V. Gupta, A. TI Peritoneal Dialysis Using Soluble Ferric Pyrophosphate as an Iron Supplement in Rabbits SO PERITONEAL DIALYSIS INTERNATIONAL LA English DT Letter C1 [Shetty, A.] Dallas Nephrol Associates, Dallas, TX USA. [Hawkins, J. V.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gupta, A.] Univ Calif Irvine, Div Nephrol, Irvine, CA 92717 USA. [Gupta, A.] Rockwell Med Inc, Wixom, MI 48393 USA. RP Gupta, A (reprint author), Univ Calif Irvine, Div Nephrol, Irvine, CA 92717 USA.; Gupta, A (reprint author), Rockwell Med Inc, Wixom, MI 48393 USA. EM ajayg1@uci.edu FU National Kidney Foundation of Michigan, Ann Arbor, MI, USA FX Financial support was provided by the National Kidney Foundation of Michigan, Ann Arbor, MI, USA, which had no role in the conduct of the research or in the preparation of the manuscript. The authors thank Gerard Zasuwa, MS, Division of Nephrology, and George W. Divine, PhD, Department of Biostatistics, Henry Ford Hospital, Detroit, MI, USA, for data management and analysis, and Mahul B. Amin, MD, Department of Pathology, Henry Ford Hospital, Detroit MI, USA, for examining the pathology specimens. Editorial assistance was provided by Lillian L. Neff (Innovative Analytics, Inc, Kalamazoo, MI, USA). NR 4 TC 1 Z9 1 U1 0 U2 0 PU MULTIMED INC PI TORONTO PA 66 MARTIN ST, TORONTO, ON L9T 2R2, CANADA SN 0896-8608 J9 PERITON DIALYSIS INT JI Perit. Dial. Int. PD JAN-FEB PY 2017 VL 37 IS 1 BP 121 EP U179 DI 10.3747/pdi.2016.00045 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EK1ID UT WOS:000393678100022 PM 28153971 ER PT J AU Meylan, F Siegel, RM AF Meylan, Francoise Siegel, Richard M. TI TNF superfamily cytokines in the promotion of Th9 differentiation and immunopathology SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE TNF superfamily cytokines; Th9; Lung inflammation; Tumor immunology ID NECROSIS-FACTOR RECEPTOR; NF-KAPPA-B; T-CELL RESPONSES; SIGNAL-TRANSDUCTION PATHWAYS; ALLERGIC LUNG INFLAMMATION; INNATE LYMPHOID-CELLS; AIRWAY INFLAMMATION; ANTITUMOR IMMUNITY; T-HELPER-2 CELLS; TUMOR-REGRESSION AB The tumor necrosis factor (TNF) receptors and their corresponding cytokine ligands have been implicated in many aspects of the biology of immune functions. TNF receptors have key roles during various stages of T cell homeostasis. Many of them can co-stimulate lymphocyte proliferation and cytokine production. Additionally, several TNF cytokines can regulate T cell differentiation, including promoting Th1, Th2, Th17, and more recently the newly described Th9 subset. Four TNF family cytokines have been identified as regulators for IL-9 production by T cells. OX40L, TL1A, and GITRL can promote Th9 formation but can also divert iTreg into Th9, while 4-1BBL seems to inhibit IL-9 production from iTreg and has not been studied for its ability to promote Th9 generation. Regulation of IL-9 production by TNF family cytokines has repercussions in vivo, including enhancement of anti-tumor immunity and immunopathology in allergic lung and ocular inflammation. Regulating T cell production of IL-9 through blockade or agonism of TNF family cytokine receptors may be a therapeutic strategy for autoimmune and allergic diseases and in tumor. C1 [Meylan, Francoise; Siegel, Richard M.] NIAMS, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Meylan, F (reprint author), NIAMS, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. EM meylanf@mail.nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the U.S. National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the U.S. National Institutes of Health. NR 69 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 EI 1863-2300 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD JAN PY 2017 VL 39 IS 1 BP 21 EP 28 DI 10.1007/s00281-016-0612-y PG 8 WC Immunology; Pathology SC Immunology; Pathology GA EK0SO UT WOS:000393637600004 PM 27896636 ER PT J AU Willoughby, AS Chiu, SJ Silverman, RK Farsiu, S Bailey, C Wiley, HE Ferris, FL Jaffe, GJ AF Willoughby, Alex S. Chiu, Stephanie J. Silverman, Rachel K. Farsiu, Sina Bailey, Clare Wiley, Henry E. Ferris, Frederick L., III Jaffe, Glenn J. TI Platform-Independent Cirrus and Spectralis Thickness Measurements in Eyes with Diabetic Macular Edema Using Fully Automated Software SO TRANSLATIONAL VISION SCIENCE & TECHNOLOGY LA English DT Article DE optical coherence tomography; diabetic macular edema; diabetic retinopathy ID OPTICAL COHERENCE TOMOGRAPHY; RETINAL THICKNESS; INTRAVITREAL BEVACIZUMAB; IMAGES; REPRODUCIBILITY; SEGMENTATION; DEGENERATION; INSTRUMENTS; THERAPY; DRUSEN AB Purpose: We determine whether the automated segmentation software, Duke Optical Coherence Tomography Retinal Analysis Program (DOCTRAP), can measure, in a platform-independent manner, retinal thickness on Cirrus and Spectralis spectral domain optical coherence tomography (SD-OCT) images in eyes with diabetic macular edema (DME) under treatment in a clinical trial. Methods: Automatic segmentation software was used to segment the internal limiting membrane (ILM), inner retinal pigment epithelium (RPE), and Bruch's membrane (BM) in SD-OCT images acquired by Cirrus and Spectralis commercial systems, from the same eye, on the same day during a clinical interventional DME trial. Mean retinal thickness differences were compared across commercial and DOCTRAP platforms using intraclass correlation (ICC) and Bland-Altman plots. Results: The mean 1 mm central subfield thickness difference (standard error [SE]) comparing segmentation of Spectralis images with DOCTRAP versus HEYEX was 0.7 (0.3) mu m (0.2 pixels). The corresponding values comparing segmentation of Cirrus images with DOCTRAP versus Cirrus software was 2.2 (0.7)mu m. The mean 1 mm central subfield thickness difference (SE) comparing segmentation of Cirrus and Spectralis scan pairs with DOCTRAP using BM as the outer retinal boundary was -2.3 (0.9)mu m compared to 2.8 (0.9) mu m with inner RPE as the outer boundary. Conclusions: DOCTRAP segmentation of Cirrus and Spectralis images produces validated thickness measurements that are very similar to each other, and very similar to the values generated by the corresponding commercial software in eyes with treated DME. Translational Relevance: This software enables automatic total retinal thickness measurements across two OCT platforms, a process that is impractical to perform manually. C1 [Willoughby, Alex S.; Chiu, Stephanie J.; Farsiu, Sina; Jaffe, Glenn J.] Duke Univ, Dept Ophthalmol, Durham, NC USA. [Bailey, Clare] Univ Hosp Bristol Natl Hlth Serv Fdn Trust, Bristol, Avon, England. [Wiley, Henry E.; Ferris, Frederick L., III] NEI, NIH, Bethesda, MD 20892 USA. RP Jaffe, GJ (reprint author), Duke Eye Ctr, Box 3802, Durham, NC 27710 USA. EM glenn.jaffe@dm.duke.edu FU National Eye Institute, NIH, Department of Health and Human Services [HHSN263201200001C, NIH R01 EY022691]; National Institute for Health Research's Clinical Research Network West of England; Moorfields Biomedical Research Center as part of the Universities and National Institutes Transatlantic Eye (UNITE) consortium FX Supported by the National Eye Institute, NIH, Department of Health and Human Services under Contract No. HHSN263201200001C and NIH R01 EY022691; by the National Institute for Health Research's Clinical Research Network West of England; and Moorfields Biomedical Research Center as part of the Universities and National Institutes Transatlantic Eye (UNITE) consortium. NR 31 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 2164-2591 J9 TRANSL VIS SCI TECHN JI Transl. Vis. Sci. Technol. PD JAN PY 2017 VL 6 IS 1 AR 9 DI 10.1167/tvst.6.1.9 PG 13 WC Ophthalmology SC Ophthalmology GA EK1GW UT WOS:000393674800008 PM 28180033 ER PT J AU Mukherjee, K Chio, TI Gu, H Banerjee, A Sorrentino, AM Sackett, DL Bane, SL AF Mukherjee, Kamalika Chio, Tak Ian Gu, Han Banerjee, Abhijit Sorrentino, Anthony M. Sackett, Dan L. Bane, Susan L. TI Benzocoumarin Hydrazine: A Large Stokes Shift Fluorogenic Sensor for Detecting Carbonyls in Isolated Biomolecules and in Live Cells SO ACS SENSORS LA English DT Article DE fluorophore; hydrazone; coumarin; bioconjugation; carbonylation; oxidative stress; live cells; microscopy ID OXIDATIVE STRESS; HYDROGEN-PEROXIDE; INTRACELLULAR ACIDIFICATION; PROTEIN CARBONYLATION; PYRUVATE; DYES; AGGREGATION; MECHANISM; PROBES; STATE AB Detection and quantification of biomolecule carbonylation, a critical manifestation of oxidative stress, allows better understanding of associated disease states. Existing approaches for such analyses require further processing of cells and tissues, which leads to loss of both spatial and temporal information about carbonylated biomolecules in cells. Live cell detection of these species requires sensors that are nontoxic, sufficiently reactive with the biocarbonyl in the intracellular milieu, and detectable with commonly available instrumentation. Presented here is a new fluorescent sensor for biomolecule carbonyl detection: a hydrazine derivative of a benzocoumarin, 7-hydrazinyl-4-methyl-2H-benzo[h]chromen-2-one (BzCH), which meets these requirements. This probe is especially well suited for live cell studies. It can be excited by a laser line common to many fluorescence microscopes. The emission maximum of BzCH undergoes a substantial red shift upon hydrazone formation (from similar to 430 to similar to 550 nm), which is the result of fluorophore disaggregation. Additionally, the hydrazone exhibits an exceptionally large Stokes shift (similar to 195 nm). The latter properties eliminate self-quenching of the probe and the need to remove unreacted fluorophore for reliable carbonyl detection. Thus, biomolecule carbonylation can be detected and quantified in cells and in cell extracts in a one-step procedure using this probe. C1 [Mukherjee, Kamalika; Chio, Tak Ian; Gu, Han; Banerjee, Abhijit; Sorrentino, Anthony M.; Bane, Susan L.] SUNY Binghamton, Dept Chem, Binghamton, NY 13902 USA. [Sackett, Dan L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Mukherjee, Kamalika] Harvard Med Sch, Massachusetts Gen Hosp, 149 13th St, Charlestown, MA 02129 USA. [Banerjee, Abhijit] Thermax Ltd, Chem Div, 97-E,Gen Block, Pune 411026, Maharashtra, India. RP Bane, SL (reprint author), SUNY Binghamton, Dept Chem, Binghamton, NY 13902 USA. EM sbane@binghamton.edu FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH [R15 GM-102867]; NSF [CHE-0922815] FX This work was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by NIH Grant R15 GM-102867. The Regional NMR Facility (600 MHz instrument) at Binghamton University is supported by NSF(CHE-0922815). The authors thank Mr. David Tuttle for photographing the gels and for expert assistance with image processing, Professor Rebecca Kissling for scientific discussion and assistance with organic synthesis, and Professor Ming An for the generous gift of A549 cells. NR 26 TC 0 Z9 0 U1 11 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2379-3694 J9 ACS SENSORS JI ACS Sens. PD JAN PY 2017 VL 2 IS 1 BP 128 EP 134 DI 10.1021/acssensors.6b00616 PG 7 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology SC Chemistry; Science & Technology - Other Topics GA EJ3CF UT WOS:000393088300017 ER PT J AU Zhu, BP Fei, CL Wang, C Zhu, YH Yang, XF Zheng, HR Zhou, QF Shung, KK AF Zhu, Benpeng Fei, Chunlong Wang, Chen Zhu, Yuhang Yang, Xiaofei Zheng, Hairong Zhou, Qifa Shung, K. Kirk TI Self-Focused AIScN Film Ultrasound Transducer for Individual Cell Manipulation SO ACS SENSORS LA English DT Article DE self-focused AIScN film; ultrahigh frequency; ultrasound transducer; cell manipulation; acoustic radiation force ID HIGH-FREQUENCY; TWEEZERS; FORCES AB Precise cell positioning is indispensable in the fields of biophysics and cellular biology. Acoustic microbeam produced by a highly focused ultrasound transducer has recently been investigated for a particle or cell manipulation. By virtue of the relatively good piezoelectric property, Sc doped AIN film was introduced for a highly focused ultrasound transducer application. Using a sputtering approach, a self focused AIScN film based device has been designed, fabricated, and characterized at a frequency of' similar to 230 MHz. It had a narrow lateral beam width (similar to 8.2 mu m). The AIScN ultrasound transducer was not only shown to be capable of remote controlling a single 10 mu m polystyrene microsphere in distilled water, but also demonstrated to possess the capability to manipulate without contact individual 10 mu m epidermoid carcinoma cell in two dimensions within a range of hundreds of micrometers in phosphate buffered saline. Most importantly, the cell manipulation was realized in continuous mode and no switch-on and -off operation was needed. These results suggest that self-focused AIScN film ultrasound transducer is a promising candidate for biomedical and molecular biology applications. C1 [Zhu, Benpeng; Zhu, Yuhang; Yang, Xiaofei] Huazhong Univ Sci & Technol, Sch Opt & Elect Informat, Wuhan 430074, Peoples R China. [Zhu, Benpeng; Zhou, Qifa; Shung, K. Kirk] Univ Southern Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Zhu, Benpeng; Zhou, Qifa; Shung, K. Kirk] Univ Southern Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Fei, Chunlong] Xidian Univ, Sch Microelect, Xian 710071, Peoples R China. [Wang, Chen; Zheng, Hairong] Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen 518055, Peoples R China. RP Zhu, BP (reprint author), Huazhong Univ Sci & Technol, Sch Opt & Elect Informat, Wuhan 430074, Peoples R China.; Zhu, BP (reprint author), Univ Southern Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA.; Zhu, BP (reprint author), Univ Southern Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM benpengzhu@hust.edu.cn FU Natural Science Foundation of China [61371016, 11574096, 11604251]; National Key Scientific Instrument and Equipment Development Projects of China [2013YQ160551]; Science and Technology Support Project of Hubei Province [2015BHE012]; Fundamental Research Funds for the Central Universities [2016YXZD038]; NIH [R01-EB12058, P41-EB002182] FX This work was supported by the Natural Science Foundation of China (Grant no. 61371016, 11574096,11604251), National Key Scientific Instrument and Equipment Development Projects of China under contract 2013YQ160551, The Science and Technology Support Project of Hubei Province (2015BHE012), the Fundamental Research Funds for the Central Universities(2016YXZD038), and it also partially supported from NIH Grant no. R01-EB12058 and P41-EB002182. We thank Mr. Xiangli Liu and Mr. Baiqian Yan for their assistance in discussion and we also thank the Analytical and Testing Center of Huazhong University of Science & Technology. NR 24 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2379-3694 J9 ACS SENSORS JI ACS Sens. PD JAN PY 2017 VL 2 IS 1 BP 172 EP 177 DI 10.1021/acssensors.6b00713 PG 6 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology SC Chemistry; Science & Technology - Other Topics GA EJ3CF UT WOS:000393088300023 ER PT J AU Kim, YY Je, IG Kim, MJ Kang, BC Choi, YA Baek, MC Lee, B Choi, JK Park, HR Shin, TY Lee, S Yoon, SB Lee, SR Khang, D Kim, SH AF Kim, Yeon-Yong Je, In-Gyu Kim, Min Jong Kang, Byeong-Cheol Choi, Young-Ae Baek, Moon-Chang Lee, Byungheon Choi, Jin Kyeong Park, Hae Ran Shin, Tae-Yong Lee, Soyoung Yoon, Seung-Bin Lee, Sang-Rae Khang, Dongwoo Kim, Sang-Hyun TI 2-Hydroxy-3-methoxybenzoic acid attenuates mast cell-mediated allergic reaction in mice via modulation of the Fc epsilon RI signaling pathway SO ACTA PHARMACOLOGICA SINICA LA English DT Article DE type I hypersensitivity; allergic inflammation; o-vanillic acid; histamine; pro-inflammatory cytokine; high affinity IgE receptor; RBL-2H3 cells; rat peritoneal mast cells ID NF-KAPPA-B; VANILLIC ACID; ATOPIC-DERMATITIS; INFLAMMATION; SUPPRESSION; HISTAMINE; ACTIVATION; MECHANISMS; OVALBUMIN; COMPOUND AB Mast cells are important effector cells in immunoglobulin (Ig) E-mediated allergic reactions such as asthma, atopic dermatitis and rhinitis. Vanillic acid, a natural product, has shown anti-oxidant and anti-inflammatory activities. In the present study, we investigated the anti-allergic inflammatory effects of ortho-vanillic acid (2-hydroxy-3-methoxybenzoic acid, o-VA) that was a derivative of vanillic acid isolated from Amomum xanthioides. In mouse anaphylaxis models, oral administration of o-VA (2, 10, 50 mg/kg) dose-dependently attenuated ovalbumin-induced active systemic anaphylaxis and IgE-mediated cutaneous allergic reactions such as hypothermia, histamine release, IgE production and vasodilation; administration of o-VA also suppressed the mast cell degranulator compound 48/80-induced anaphylaxis. In cultured mast cell line RBL-2H3 and isolated rat peritoneal mast cells in vitro, pretreatment with o-VA (1-100 mu mol/L) dose-dependently inhibited DNP-HSA-induced degranulation of mast cells by decreasing the intracellular free calcium level, and suppressed the expression of pro-inflammatory cytokines TNF-alpha and IL-4. Pretreatment of RBL-2H3 cells with o-VA suppressed DNP-HSA-induced phosphorylation of Lyn, Syk, Akt, and the nuclear translocation of nuclear factor-kappa B. In conclusion, o-VA suppresses the mast cell-mediated allergic inflammatory response by blocking the signaling pathways downstream of high affinity IgE receptor (Fc epsilon RI) on the surface of mast cells. C1 [Kim, Yeon-Yong; Je, In-Gyu; Kim, Min Jong; Kang, Byeong-Cheol; Choi, Young-Ae; Choi, Jin Kyeong; Kim, Sang-Hyun] Kyungpook Natl Univ, Sch Med, Dept Pharmacol, CMRI, Daegu 700422, South Korea. [Baek, Moon-Chang] Kyungpook Natl Univ, Sch Med, Dept Mol Med, Daegu 700422, South Korea. [Lee, Byungheon] Kyungpook Natl Univ, Sch Med, Dept Biochem & Cell Biol, Daegu 700422, South Korea. [Je, In-Gyu] ILDONG Pharmaceut Co Ltd, Res Labs, Hwaseong 18449, South Korea. [Choi, Jin Kyeong] NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Park, Hae Ran; Shin, Tae-Yong] Woosuk Univ, Coll Pharm, Jeonju 565701, South Korea. [Lee, Soyoung] Korea Res Inst Biosci & Biotechnol, Nat Prod Res Ctr, Jeongeup 580185, South Korea. [Yoon, Seung-Bin; Lee, Sang-Rae] Korea Res Inst Biosci & Biotechnol, Natl Primate Res Ctr, Ochang 28116, South Korea. [Khang, Dongwoo] Gachon Univ, Sch Med, Dept Mol Med, Incheon 406840, South Korea. RP Kim, SH (reprint author), Kyungpook Natl Univ, Sch Med, Dept Pharmacol, CMRI, Daegu 700422, South Korea.; Khang, D (reprint author), Gachon Univ, Sch Med, Dept Mol Med, Incheon 406840, South Korea. EM dkhang@gachon.ac.kr; shkim72@knu.ac.kr FU National Research Foundation of Korea Grant - Korean Government [2014R1A5A2009242, 2012M3A9B6055416, 2016R1A2-B4008513]; KRIBB Research Initiative Program [KGM-4611613]; High Value-added Food Technology Development Program, Ministry of Agriculture, Food and Rural Affairs FX This work was supported by a National Research Foundation of Korea Grant funded by the Korean Government (2014R1A5A2009242, 2012M3A9B6055416, and 2016R1A2-B4008513), the KRIBB Research Initiative Program (KGM-4611613), and the High Value-added Food Technology Development Program, Ministry of Agriculture, Food and Rural Affairs. NR 40 TC 1 Z9 1 U1 1 U2 1 PU ACTA PHARMACOLOGICA SINICA PI SHANGHAI PA 294 TAI-YUAN RD, SHANGHAI, 200031, PEOPLES R CHINA SN 1671-4083 EI 1745-7254 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JAN PY 2017 VL 38 IS 1 BP 90 EP 99 DI 10.1038/aps.2016.112 PG 10 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EJ9IX UT WOS:000393540900008 PM 27890918 ER PT J AU Brosh, RM AF Brosh, Robert M., Jr. TI Special Issue Monogenic Accelerated Aging Disorders with Perturbations to Normal DNA and Chromosome Function SO AGEING RESEARCH REVIEWS LA English DT Editorial Material C1 [Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov NR 9 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 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD JAN PY 2017 VL 33 SI SI BP 1 EP 2 DI 10.1016/j.arr.2016.09.009 PG 2 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA EJ9DX UT WOS:000393527900001 PM 27693620 ER PT J AU Karikkineth, AC Scheibye-Knudsen, M Fivenson, E Croteau, DL Bohr, VA AF Karikkineth, Ajoy C. Scheibye-Knudsen, Morten Fivenson, Elayne Croteau, Deborah L. Bohr, Vilhelm A. TI Cockayne syndrome: Clinical features, model systems and pathways SO AGEING RESEARCH REVIEWS LA English DT Review DE Cockayne syndrome; Progeria; Neurodegeneration; Mitochondria; Transcription; Parylation ID SYNDROME GROUP-B; NUCLEOTIDE EXCISION-REPAIR; TRANSCRIPTION-COUPLED REPAIR; MITOCHONDRIAL-DNA DAMAGE; HIGH-FAT DIET; CAENORHABDITIS-ELEGANS; XERODERMA-PIGMENTOSUM; GROUP-A; INTRACRANIAL CALCIFICATION; OXIDATIVE STRESS AB Cockayne syndrome (CS) is a disorder characterized by a variety of clinical features including cachectic dwarfism, severe neurological manifestations including microcephaly and cognitive deficits, pigmentary retinopathy, cataracts, sensorineural deafness, and ambulatory and feeding difficulties, leading to death by 12 years of age on average. It is an autosomal recessive disorder, with a prevalence of approximately 2.5 per million. There are several phenotypes (1-3) and two complementation groups (CSA and CSB), and CS overlaps with xeroderma pigmentosum (XP). It has been considered a progeria, and many of the clinical features resemble accelerated aging. As such, the study of CS affords an opportunity to better understand the underlying mechanisms of aging. The molecular basis of CS has traditionally been ascribed to defects in transcription and transcription-coupled nucleotide excision repair (TC-NER). However, recent work suggests that defects in base excision DNA repair and mitochondrial functions may also play key roles. This opens up the possibility for molecular interventions in CS, and by extrapolation, possibly in aging. Published by Elsevier B.V. C1 [Karikkineth, Ajoy C.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Scheibye-Knudsen, Morten; Fivenson, Elayne; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. [Scheibye-Knudsen, Morten] Univ Copenhagen, Dept Cellular & Mol Med, DK-1168 Copenhagen, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. EM vbohr@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. We would like to thank Dr. Nazir Okur and Tyler Golato for critically reading the manuscript. NR 149 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD JAN PY 2017 VL 33 SI SI BP 3 EP 17 DI 10.1016/j.arr.2016.08.002 PG 15 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA EJ9DX UT WOS:000393527900002 PM 27507608 ER PT J AU Brosh, RM Bellani, M Liu, Y Seidman, MM AF Brosh, Robert M., Jr. Bellani, Marina Liu, Yie Seidman, Michael M. TI Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging SO AGEING RESEARCH REVIEWS LA English DT Review DE Fanconi Anemia; Aging; DNA repair; Bone marrow failure; Hematopoietic stem cells; Inflammatory response; Oxidative stress; Epigenetic; Telomere ID TUMOR-NECROSIS-FACTOR; BONE-MARROW FAILURE; VIVO PROOXIDANT STATE; IN-VIVO; OXIDATIVE STRESS; FACTOR-ALPHA; TNF-ALPHA; REPLICATION STRESS; ELEVATED LEVELS; SELF-RENEWAL AB Fanconi Anemia (FA) is a rare autosomal genetic disorder characterized by progressive bone marrow failure (BMF), endocrine dysfunction, cancer, and other clinical features commonly associated with normal aging. The anemia stems directly from an accelerated decline of the hematopoietic stem cell compartment. Although FA is a complex heterogeneous disease linked to mutations in 19 currently identified genes, there has been much progress in understanding the molecular pathology involved. FA is broadly considered a DNA repair disorder and the FA gene products, together with other DNA repair factors, have been implicated in interstrand cross-link (ICL) repair. However, in addition to the defective DNA damage response, altered epigenetic regulation, and telomere defects, FA is also marked by elevated levels of inflammatory mediators in circulation, a hallmark of faster decline in not only other hereditary aging disorders but also normal aging. In this review, we offer a perspective of FA as a monogenic accelerated aging disorder, citing the latest evidence for its multi-factorial deficiencies underlying its unique clinical and cellular features. Published by Elsevier B.V. C1 [Brosh, Robert M., Jr.; Bellani, Marina; Liu, Yie; Seidman, Michael M.] NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr Bldg,251 Bayview Blvd, Baltimore, MD 21224 USA. RP Brosh, RM; Seidman, MM (reprint author), NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr Bldg,251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov; seidmanm@mail.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging [Z01AG000752-08, Z01AG000746-08]; Fanconi Anemia Research Fund FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (Z01AG000752-08; Z01AG000746-08) and the Fanconi Anemia Research Fund (RMB, MMS). NR 115 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD JAN PY 2017 VL 33 SI SI BP 67 EP 75 DI 10.1016/j.arr.2016.05.005 PG 9 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA EJ9DX UT WOS:000393527900007 PM 27223997 ER PT J AU DeBalsi, KL Hoff, KE Copeland, WC AF DeBalsi, Karen L. Hoff, Kirsten E. Copeland, William C. TI Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases SO AGEING RESEARCH REVIEWS LA English DT Review DE Mitochondrial DNA mutations; MtDNA replication; DNA polymerase gamma; POLG; Aging; Age-related diseases ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; TRANSCRIPTION-FACTOR-A; HUMAN SKELETAL-MUSCLE; STRUCTURE-FUNCTION DEFECTS; SOMATIC MTDNA MUTATIONS; HYDROGEN-PEROXIDE RELEASE; SUBSTANTIA-NIGRA NEURONS; POLYMERASE GAMMA-GENE; CULTURED HUMAN-CELLS; PARKINSONS-DISEASE AB As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age related diseases. Mitochondria( DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase gamma (Pol gamma) and several other associated proteins, which compose the mtDNA replication machinery. Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations. Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration. We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases. Additionally, interventions to improve mitochondrial function and attenuate the symptoms of aging are examined. Published by Elsevier B.V. C1 [DeBalsi, Karen L.; Hoff, Kirsten E.; Copeland, William C.] NIEHS, Genome Integr & Struct Biol Lab, NIH, 111 TW Alexander Dr,Bldg 101,Rm E316, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, 111 TW Alexander Dr,Bldg 101,Rm E316, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ES 065078] FX This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES 065078). NR 271 TC 2 Z9 2 U1 4 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD JAN PY 2017 VL 33 SI SI BP 89 EP 104 DI 10.1016/j.arr.2016.04.006 PG 16 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA EJ9DX UT WOS:000393527900009 PM 27143693 ER PT J AU Chen, SC Wasserman, DT AF Chen, Stephanie C. Wasserman, David T. TI A Framework for Unrestricted Prenatal Whole-Genome Sequencing: Respecting and Enhancing the Autonomy of Prospective Parents SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE children and families; clinical genetics; decision making; disability; informed consent; reproductive technologies ID IN-VITRO FERTILIZATION; DOWN-SYNDROME; MICROARRAY ANALYSIS; GENERAL-POPULATION; PREGNANT-WOMEN; DIAGNOSIS; ATTITUDES; CARE; CHOICE; HEALTH AB Noninvasive, prenatal whole genome sequencing (NIPW) may be a technological reality in the near future, making available a vast array of genetic information early in pregnancy at no risk to the fetus or mother. Many worry that the timing, safety, and ease of the test will lead to informational overload and reproductive consumerism. The prevailing response among commentators has been to restrict conditions eligible for testing based on medical severity, which imposes disputed value judgments and devalues those living with eligible conditions. To avoid these difficulties, we propose an unrestricted testing policy, under which prospective parents could obtain information on any variant of known significance after a careful informed consent process that uses an interactive decision aid to deliver a mandatory presentation on the purposes, techniques, and limitations of genomic testing, as well as optional resources for reflection and consultation. This process would encourage thoughtful, informed deliberation by prospective parents before deciding whether or how to use NIPW. C1 [Chen, Stephanie C.; Wasserman, David T.] NIH, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. RP Wasserman, DT (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. EM david.wasserman@nih.gov FU Intramural Research Program at the National Institutes of Health (NIH) FX Supported by the Intramural Research Program at the National Institutes of Health (NIH). NR 111 TC 13 Z9 13 U1 3 U2 3 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 1 BP 3 EP 18 DI 10.1080/15265161.2016.1251632 PG 16 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EI9GH UT WOS:000392815400006 PM 27996923 ER PT J AU Berkman, BE Bayefsky, M AF Berkman, Benjamin E. Bayefsky, Michelle TI Prenatal Whole Genome Sequencing: An Argument for Professional Self-Regulation SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID FUTURE C1 [Berkman, Benjamin E.] NIH, Bldg 10,Room 1C118,10 Ctr Dr,MSC 1156, Bethesda, MD 20892 USA. [Bayefsky, Michelle] Harvard Med Sch, Boston, MA USA. RP Berkman, BE (reprint author), NIH, Dept Bioeth, Bldg 10,Room 1C118,10 Ctr Dr,MSC 1156, Bethesda, MD 20892 USA. EM berkmanbe@mail.nih.gov NR 10 TC 2 Z9 2 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 1 BP 26 EP 28 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EI9GH UT WOS:000392815400010 PM 27996921 ER PT J AU Chen, SC Wasserman, DT AF Chen, Stephanie C. Wasserman, David T. TI Response to Open Peer Commentaries on "A Framework for Unrestricted Prenatal Whole-Genome Sequencing: Respecting and Enhancing the Autonomy of Prospective Parents" SO AMERICAN JOURNAL OF BIOETHICS LA English DT Letter C1 [Chen, Stephanie C.; Wasserman, David T.] NIH, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. RP Wasserman, DT (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. EM david.wasserman@nih.gov NR 13 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 1 BP W1 EP W3 DI 10.1080/15265161.2016.1260784 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EI9GH UT WOS:000392815400001 PM 27996911 ER PT J AU Prescott, J Feldmann, H Safronetz, D AF Prescott, Joseph Feldmann, Heinz Safronetz, David TI Amending Koch's postulates for viral disease: When "growth in pure culture" leads to a loss of virulence SO ANTIVIRAL RESEARCH LA English DT Article DE Virus; Viral pathogens; Cell culture; Attenuation; Adaptation; Disease modeling ID MEASLES-VIRUS; HEMORRHAGIC-FEVER; CELL-CULTURE; HANTAVIRUS INFECTION; CYNOMOLGUS MACAQUES; PUUMALA HANTAVIRUS; DENDRITIC CELLS; GUINEA-PIGS; ADAPTATION; MODEL AB It is a common laboratory practice to propagate viruses in cell culture. While convenient, these methodologies often result in unintentional genetic alterations, which have led to adaptation and even attenuation in animal models of disease. An example is the attenuation of hantaviruses (family: Bunyaviridae, genus: Hantavirus) when cultured in vitro. In this case, viruses propagated in the natural reservoir species cause disease in nonhuman primates that closely mimics the human disease, but passaging in cell culture attenuates these viruses to the extent that do not cause any measurable disease in nonhuman primates. As efforts to develop animal models progress, it will be important to take into account the influences that culture in vitro may have on the virulence of viruses. In this review we discuss this phenomenon in the context of past and recent examples in the published literature. (C) 2016 Elsevier B.V. All rights reserved. C1 [Prescott, Joseph; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, 903 South 4th St, Hamilton, MT 59840 USA. [Safronetz, David] Publ Hlth Agcy Canada, Natl Microbiol Lab, Zoonot Dis & Special Pathogens, 1015 Arlington St, Winnipeg, MB R3E 3R2, Canada. [Feldmann, Heinz; Safronetz, David] Univ Manitoba, Dept Med Microbiol, 745 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada. RP Prescott, J (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, 903 South 4th St, Hamilton, MT 59840 USA.; Safronetz, D (reprint author), Publ Hlth Agcy Canada, Natl Microbiol Lab, Zoonot Dis & Special Pathogens, 1015 Arlington St, Winnipeg, MB R3E 3R2, Canada. EM prescottjb@niaid.nih.gov; david.safronetz@phac-aspc.gc.ca FU Intramural NIH HHS [Z99 AI999999] NR 35 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD JAN PY 2017 VL 137 BP 1 EP 5 DI 10.1016/j.antiviral.2016.11.002 PG 5 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA EJ1YA UT WOS:000393005300001 PM 27832942 ER PT J AU Willems, L Hasegawa, H Accolla, R Bangham, C Bazarbachi, A Bertazzoni, U Carneiro-Proietti, ABDF Cheng, H Chieco-Bianchi, L Ciminale, V Coelho-dos-Reis, J Esparza, J Gallo, RC Gessain, A Gotuzzo, E Hall, W Harford, J Hermine, O Jacobson, S Macchi, B Macpherson, C Mahieux, R Matsuoka, M Murphy, E Peloponese, JM Simon, V Tagaya, Y Taylor, GP Watanabe, T Yamano, Y AF Willems, Luc Hasegawa, Hideki Accolla, Roberto Bangham, Charles Bazarbachi, Ali Bertazzoni, Umberto de Freitas Carneiro-Proietti, Anna Barbara Cheng, Hua Chieco-Bianchi, Luigi Ciminale, Vincenzo Coelho-dos-Reis, Jordana Esparza, Jose Gallo, Robert C. Gessain, Antoine Gotuzzo, Eduardo Hall, William Harford, Joseph Hermine, Olivier Jacobson, Steven Macchi, Beatrice Macpherson, Calum Mahieux, Renaud Matsuoka, Masao Murphy, Edward Peloponese, Jean-Marie Simon, Viviana Tagaya, Yutaka Taylor, Graham P. Watanabe, Toshiki Yamano, Yoshihisa TI Reducing the global burden of HTLV-1 infection: An agenda for research and action SO ANTIVIRAL RESEARCH LA English DT Review DE HTLV-1; Vaccine; Oncogene; Retrovirus; Leukemia ID T-CELL LEUKEMIA; INTERFERON-ALPHA; VIRUS; LEUKEMIA/LYMPHOMA; ZIDOVUDINE; LYMPHOMA; DISEASES; SAFETY; TAX AB Even though an estimated 10-20 million people worldwide are infected with the oncogenic retrovirus, human T-Iymphotropic virus type 1 (HTLV-1), its epidemiology is poorly understood, and little effort has been made to reduce its prevalence. In response to this situation, the Global Virus Network launched a taskforce in 2014 to develop new methods of prevention and treatment of HTLV-1 infection and promote basic research. HTLV-1 is the etiological agent of two life-threatening diseases, adult T-cell leukemia and HTLV-associated myelopathy/tropical spastic paraparesis, for which no effective therapy is currently available. Although the modes of transmission of HTLV-1 resemble those of the more familiar HIV-1, routine diagnostic methods are generally unavailable to support the prevention of new infections. In the present article, the Taskforce proposes a series of actions to expand epidemiological studies; increase research on mechanisms of HTLV-1 persistence, replication and pathogenesis; discover effective treatments; and develop prophylactic and therapeutic vaccines. (C) 2016 Elsevier B.V. All rights reserved. C1 [Willems, Luc] Univ Liege, B-4000 Liege, Belgium. [Hasegawa, Hideki] Natl Inst Infect Dis, Tokyo, Japan. [Accolla, Roberto] Univ Insubria, Varese, Italy. [Bangham, Charles; Taylor, Graham P.] Imperial Coll, London, England. [Bazarbachi, Ali] Amer Univ Beirut, Beirut, Lebanon. [Bertazzoni, Umberto] Univ Verona, Verona, Italy. [de Freitas Carneiro-Proietti, Anna Barbara] Fundacao Hemominas, Belo Horizonte, MG, Brazil. [Cheng, Hua; Esparza, Jose; Gallo, Robert C.; Tagaya, Yutaka] Inst Human Virol, Baltimore, MD USA. [Chieco-Bianchi, Luigi; Ciminale, Vincenzo] Univ Padua, Padua, Italy. [Coelho-dos-Reis, Jordana] Fiocruz MS, Rene Rachou Res Ctr, Belo Brazil Horizonte, Brazil. [Gessain, Antoine] Inst Pasteur, Paris, France. [Gotuzzo, Eduardo] Trop Med Inst Alexander Von Humboldt, Lima, Peru. [Hall, William] Ctr Res Infect Dis, Dublin, Ireland. [Harford, Joseph] Natl Canc Inst, NIH, Bethesda, MD USA. [Hermine, Olivier] Hop Necker Enfants Malad, Paris, France. [Jacobson, Steven] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Macchi, Beatrice] Univ Roma Tor Vergata, Rome, Italy. [Macpherson, Calum] St Georges Univ, True Blue, Grenada. [Mahieux, Renaud] Ecole Normale Super Lyon, Lyon, France. [Matsuoka, Masao] Kyoto Univ, Kyoto, Japan. [Murphy, Edward] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Peloponese, Jean-Marie] Univ Montpellier, Montpellier, France. [Simon, Viviana] Icahn Sch Med, Mt Sinai, NY USA. [Watanabe, Toshiki] Univ Tokyo, Tokyo, Japan. [Yamano, Yoshihisa] St Marianna Univ, Sch Med, Kanagawa, Japan. [Willems, Luc; Hasegawa, Hideki] Chairs HTLV Taskforce Global Virus Network, Bethesda, MD 20894 USA. RP Willems, L (reprint author), Univ Liege, B-4000 Liege, Belgium.; Willems, L (reprint author), Chairs HTLV Taskforce Global Virus Network, Bethesda, MD 20894 USA. EM luc.willems@ulg.ac.be OI Bertazzoni, Umberto/0000-0002-2445-4213; Peloponese, Jean-Marie/0000-0002-9677-9703; Bangham, Charles/0000-0003-2624-3599 FU "Fonds National de la Recherche Scientifique" (FNRS); Televie; Interuniversity Attraction Poles (IAP) Program "Virus-host interplay at the early phases of infection" BELVIR; Belgian Science Policy Office; Belgian Foundation against Cancer (FBC); "Centre anticancereux pres ULg" (CAC); "Fonds Leon Fredericq" (FLF); "AgricultureIsLife" project of Gembloux Agrobiotech (GxABT); ULg Fonds Speciaux pour la Recherche; "Plan Cancer" of the "Service Public Federal" FX We thank Natalia Mercer for manuscript preparation. This work received financial support of the "Fonds National de la Recherche Scientifique" (FNRS), the Televie, the Interuniversity Attraction Poles (IAP) Program "Virus-host interplay at the early phases of infection" BELVIR initiated by the Belgian Science Policy Office, the Belgian Foundation against Cancer (FBC), the "Centre anticancereux pres ULg" (CAC) and the "Fonds Leon Fredericq" (FLF), the "AgricultureIsLife" project of Gembloux Agrobiotech (GxABT), the "ULg Fonds Speciaux pour la Recherche" and the "Plan Cancer" of the "Service Public Federal". NR 30 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD JAN PY 2017 VL 137 BP 41 EP 48 DI 10.1016/j.antiviral.2016.10.015 PG 8 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA EJ1YA UT WOS:000393005300005 PM 27840202 ER PT J AU Sun, W He, SH Martinez-Romero, C Kouznetsova, J Tawa, G Xu, M Shinn, P Fisher, EG Long, Y Motabar, O Yang, S Sanderson, PE Williamson, PR Garcia-Sastre, A Qiu, XG Zheng, W AF Sun, Wei He, Shihua Martinez-Romero, Caries Kouznetsova, Jennifer Tawa, Gregory Xu, Miao Shinn, Paul Fisher, Ethan G. Long, Yan Motabar, Omid Yang, Shu Sanderson, Philip E. Williamson, Peter R. Garcia-Sastre, Adolfo Qiu, Xiangguo Zheng, Wei TI Synergistic drug combination effectively blocks Ebola virus infection SO ANTIVIRAL RESEARCH LA English DT Article DE Ebola treatment; Ebola prevention; Drug combination; Drug repurposing; Polypharmacology ID NIEMANN-PICK C1; ENTRY; PHARMACOKINETICS; POSACONAZOLE; CLARITHROMYCIN; IDENTIFICATION; GLYCOPROTEIN; MEFLOQUINE; RESISTANCE; REQUIRES AB Although a group of FDA-approved drugs were previously identified with activity against Ebola virus (EBOV), most of them are not clinically useful because their human blood concentrations are not high enough to inhibit EBOV infection. We screened 795 unique three-drug combinations in an EBOV entry assay. Two sets of three-drug combinations, toremifene-mefloquine-posaconazole and toremifeneclarithromycin-posaconazole, were identified that effectively blocked EBOV entry and were further validated for inhibition of live EBOV infection. The individual drug concentrations in the combinations were reduced to clinically relevant levels. We identified mechanisms of action of these drugs: functional inhibitions of Niemann Pick Cl, acid sphingomyelinase, and lysosomal calcium release. Our findings identify the drug combinations with potential to treat EBOV infection. Published by Elsevier B.V. C1 [Sun, Wei; Kouznetsova, Jennifer; Tawa, Gregory; Xu, Miao; Shinn, Paul; Fisher, Ethan G.; Long, Yan; Motabar, Omid; Yang, Shu; Sanderson, Philip E.; Zheng, Wei] Natl Inst Hlth, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. [He, Shihua; Qiu, Xiangguo] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, 1015 Arlington St, Winnipeg, MB R3E 3R2, Canada. [He, Shihua; Qiu, Xiangguo] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0J9, Canada. [Martinez-Romero, Caries; Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Dept Microbiol, 1468 Madison Ave, New York, NY 10029 USA. [Martinez-Romero, Caries; Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, New York, NY 10029 USA. [Williamson, Peter R.] Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Dept Med, Div Infect Dis, New York, NY 10029 USA. RP Zheng, W (reprint author), Natl Inst Hlth, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Bethesda, MD 20892 USA.; Qiu, XG (reprint author), Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, 1015 Arlington St, Winnipeg, MB R3E 3R2, Canada.; Garcia-Sastre, A (reprint author), Icahn Sch Med Mt Sinai, Dept Microbiol, 1468 Madison Ave, New York, NY 10029 USA. EM Adolfo.Garcia-Sastre@mssm.edu; xiangguo.qiu@phac-aspc.gc.ca; wzheng@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU National Center for Advancing Translational Sciences; National Institute of Allergy and Infectious Diseases, National Institutes of Health; Public Health Agency of Canada (Canadian Safety and Security Program grant); NIH [R01AI079110, R01AI089539] FX This work was supported by the Intramural Research Programs of National Center for Advancing Translational Sciences and National Institute of Allergy and Infectious Diseases, National Institutes of Health. Antiviral assays in Xiangguo Qiu's lab was supported by the Public Health Agency of Canada (Canadian Safety and Security Program grant). Antiviral screen assays in Adolfo Garcia-Sastre's lab was supported by NIH grants R01AI079110 and R01AI089539. NR 32 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD JAN PY 2017 VL 137 BP 165 EP 172 DI 10.1016/j.antiviral.2016.11.017 PG 8 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA EJ1YA UT WOS:000393005300020 PM 27890675 ER PT J AU Elagha, A Fuisz, A AF Elagha, Abdalla Fuisz, Anthon TI Fatty Left Ventricular Cardiomyopathy: An Under-Diagnosed Disease SO ARQUIVOS BRASILEIROS DE CARDIOLOGIA LA English DT Editorial Material DE Cardiomyopathy; Dilated; Tomography; X Ray-Computed/methods; Ventricular Dysfunction; Left; Lipoma C1 [Elagha, Abdalla] Cairo Univ Hosp, Cairo, Egypt. [Elagha, Abdalla] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Fuisz, Anthon] Westchester Med Ctr, New York, NY USA. RP Elagha, A (reprint author), 1 Saraya St,Third Floor, Cairo 11211, Egypt. EM abdallaaa@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU ARQUIVOS BRASILEIROS CARDIOLOGIA PI RIO DE JANEIRO PA AVENIDA MARECHAL CAMARA 160-330 CENTRO, RIO DE JANEIRO, RJ 20 020-907, BRAZIL SN 0066-782X J9 ARQ BRAS CARDIOL JI Arq. Bras. Cardiol. PD JAN PY 2017 VL 108 IS 1 BP 91 EP 92 DI 10.5935/abc.20160199 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EK7ZD UT WOS:000394142800015 PM 28146209 ER PT J AU Justis, AV Hansen, B Beare, PA King, KB Heinzen, RA Gilk, SD AF Justis, Anna V. Hansen, Bryan Beare, Paul A. King, Kourtney B. Heinzen, Robert A. Gilk, Stacey D. TI Interactions between the Coxiella burnetii parasitophorous vacuole and the endoplasmic reticulum involve the host protein ORP1L SO CELLULAR MICROBIOLOGY LA English DT Article ID CHOLESTEROL SENSOR ORP1L; MEMBRANE CONTACT SITES; CHLAMYDIA-TRACHOMATIS; MATURATION; EFFECTOR; RAB7; RAB7-RILP-P150(GLUED); LOCALIZATION; TRAFFICKING; METABOLISM AB Coxiella burnetii is a gram-negative intracellular bacterium that forms a large, lysosome-like parasitophorous vacuole (PV) essential for bacterial replication. Host membrane lipids are critical for the formation and maintenance of this intracellular niche, yet the mechanisms by which Coxiella manipulates host cell lipid metabolism, trafficking and signalling are unknown. Oxysterol-binding protein-related protein 1 long (ORP1L) is a mammalian lipid-binding protein that plays a dual role in cholesterol-dependent endocytic trafficking as well as interactions between endosomes and the endoplasmic reticulum (ER). We found that ORP1L localized to the Coxiella PV within 12 h of infection through a process requiring the Coxiella Dot/Icm Type 4B secretion system, which secretes effector proteins into the host cell cytoplasm where they manipulate trafficking and signalling pathways. The ORP1L N-terminal ankyrin repeats were necessary and sufficient for PV localization, indicating that ORP1L binds a PV membrane protein. Strikingly, ORP1L simultaneously co-localized with the PV and ER, and electron microscopy revealed membrane contact sites between the PV and ER membranes. In ORP1L-depleted cells, PVs were significantly smaller than PVs from control cells. These data suggest that ORP1L is specifically recruited by the bacteria to the Coxiella PV, where it influences PV membrane dynamics and interactions with the ER. C1 [Justis, Anna V.; King, Kourtney B.; Gilk, Stacey D.] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Hansen, Bryan] NIH, Res Technol Branch, Hamilton, MT USA. [Heinzen, Robert A.] NIAID, Lab Bacteriol, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Gilk, SD (reprint author), Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. EM sgilk@iupui.edu FU Showalter Trust Fund; NIH NRSA Immunology and Infectious Disease Training Program [T32AI060519]; Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Disease FX This research was supported by the Showalter Trust Fund (S.D.G), NIH NRSA Immunology and Infectious Disease Training Program T32AI060519 (A.V.J.) and the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Disease (R.A.H.). We thank Seth Winfree, Minal Mulye and Dhritiman Samanta for critical reading of the manuscript and members of the IU Biology of Intracellular Pathogens Group for helpful suggestions. The authors have no conflict of interest to declare. NR 51 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-5814 EI 1462-5822 J9 CELL MICROBIOL JI Cell Microbiol. PD JAN PY 2017 VL 19 IS 1 AR UNSP e12637 DI 10.1111/cmi.12637 PG 13 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA EJ6DN UT WOS:000393308900008 ER PT J AU Chatterjee, NA Shah, RV Murthy, VL Praestgaard, A Shah, SJ Ventetuolo, CE Barr, RG Kronmal, R Lima, JAC Bluemke, DA Jerosch-Herold, M Alonso, A Kawut, SM AF Chatterjee, Neal A. Shah, Ravi V. Murthy, Venkatesh L. Praestgaard, Amy Shah, Sanjiv J. Ventetuolo, Corey E. Barr, R. Graham Kronmal, Richard Lima, Joao A. C. Bluemke, David A. Jerosch-Herold, Michael Alonso, Alvaro Kawut, Steven M. TI Right Ventricular Structure and Function Are Associated With Incident Atrial Fibrillation MESA-RV Study (Multi-Ethnic Study of Atherosclerosis-Right Ventricle) SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE atrial fibrillation; heart failure; heart ventricles; magnetic resonance imaging ID PULMONARY ARTERIAL-HYPERTENSION; SUCCESSFUL CATHETER ABLATION; PRESERVED EJECTION FRACTION; C-REACTIVE PROTEIN; HEART-FAILURE; SYSTOLIC FUNCTION; SEX-HORMONES; RISK-FACTORS; SLEEP-APNEA; PREVALENCE AB Background-Right ventricular (RV) morphology has been associated with drivers of atrial fibrillation (AF) risk, including left ventricular and pulmonary pathology, systemic inflammation, and neurohormonal activation. The aim of this study was to investigate the association between RV morphology and risk of incident AF. Methods and Results-We interpreted cardiac magnetic resonance imaging in 4204 participants free of clinical cardiovascular disease in the MESA (Multi-Ethnic Study of Atherosclerosis). Incident AF was determined using hospital discharge records, study electrocardiograms, and Medicare claims data. The study sample (n=3819) was 61 +/- 10 years old and 47% male with 47.2% current/former smokers. After adjustment for demographics and clinical factors, including incident heart failure, higher RV ejection fraction (hazard ratio, 1.16 per SD; 95% confidence interval, 1.03-1.32; P=0.02) and greater RV mass (hazard ratio, 1.25 per SD; 95% confidence interval, 1.08-1.44; P=0.002) were significantly associated with incident AF. After additional adjustment for the respective left ventricular parameter, higher RV ejection fraction remained significantly associated with incident AF (hazard ratio, 1.15 per SD; 95% confidence interval, 1.01-1.32; P=0.04), whereas the association was attenuated for RV mass (hazard ratio, 1.16 per SD; 95% confidence interval, 0.99-1.35; P=0.07). In a subset of patients with available spirometry (n=2540), higher RV ejection fraction and mass remained significantly associated with incident AF after additional adjustment for lung function (P=0.02 for both). Conclusions-Higher RV ejection fraction and greater RV mass were associated with an increased risk of AF in a multiethnic population free of clinical cardiovascular disease at baseline. C1 [Jerosch-Herold, Michael] Brigham & Womens Hosp, Div Radiol, 75 Francis St, Boston, MA 02115 USA. [Chatterjee, Neal A.; Shah, Ravi V.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Radiol, Div Nucl Med & Mol Imaging, Ann Arbor, MI 48109 USA. [Praestgaard, Amy; Kawut, Steven M.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Perelman Sch Med, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Perelman Sch Med, Pulm Allergy & Crit Care Div, Dept Med, Philadelphia, PA 19104 USA. [Shah, Sanjiv J.] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Cardiol, Chicago, IL 60611 USA. [Ventetuolo, Corey E.] Brown Univ, Alpert Med Sch, Dept Med & Hlth Serv Policy & Practice, Providence, RI 02912 USA. [Barr, R. Graham] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA. [Kronmal, Richard] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Radiol & Imaging Sci, NIH, Ctr Clin, Bethesda, MD USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. [Alonso, Alvaro] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. RP Kawut, SM (reprint author), Univ Penn, Pulm Vasc Dis Program, Perelman Sch Med, 718 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM kawut@upenn.edu FU National Heart, Lung, and Blood Institute [T-32 HL-007575]; National Institutes of Health [R01-HL086719, R01-HL077612, K24-HL103844, N01-HC95159, N01-HC95160, N01-HC95161, N01-HC95162, N01-HC95163, N01-HC95164, N01-HC95165, N01-HC95166, N01-HC95167, N01-HC95168, N01-HC95169] FX Dr Chatterjee was supported by National Heart, Lung, and Blood Institute T-32 HL-007575 which does not represent a relevant disclosure but does support time for writing. This study was funded by National Institutes of Health R01-HL086719, R01-HL077612, K24-HL103844, and N01-HC95159 through N01-HC95169. NR 49 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3149 EI 1941-3084 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD JAN PY 2017 VL 10 IS 1 AR e004738 DI 10.1161/CIRCEP.116.004738 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ4IF UT WOS:000393179400010 ER PT J AU Stratakis, C AF Stratakis, Constantine TI An update on the genetics of adrenal diseases SO CLINICAL ENDOCRINOLOGY LA English DT Meeting Abstract C1 [Stratakis, Constantine] NICHHD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD JAN PY 2017 VL 86 SU S1 MA 118 BP 16 EP 16 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EJ8DB UT WOS:000393453600044 ER PT J AU Karunasena, N Han, TS Mallappa, A Elman, M Merke, DP Ross, RJM Daniel, E AF Karunasena, Nayananjani Han, Thang S. Mallappa, Ashwini Elman, Meredith Merke, Deborah P. Ross, Richard J. M. Daniel, Eleni TI Androgens correlate with increased erythropoiesis in women with congenital adrenal hyperplasia SO CLINICAL ENDOCRINOLOGY LA English DT Article ID OLDER MEN; ERYTHROID PROGENITORS; SHEEHANS-SYNDROME; HORMONE-THERAPY; TESTOSTERONE; ANEMIA; DISEASE; GLUCOCORTICOIDS; POLYCYTHEMIA; DEFICIENCY AB Objective Hyperandrogenism in congenital adrenal hyperplasia (CAH) provides an in vivo model for exploring the effect of androgens on erythropoiesis in women. We investigated the association of androgens with haemoglobin (Hb) and haematocrit (Hct) in women with CAH. Design Cross-validation study. Patients Women with CAH from Sheffield Teaching Hospitals, UK (cohort 1, the training set: n = 23) and National Institutes of Health, USA (cohort 2, the validation set: n = 53). Measurements Androgens, full blood count and basic biochemistry, all measured on the same day. Demographic and anthropometric data. Results Significant age-adjusted correlations (P < 0.001) were observed for Ln testosterone with Hb and Hct in cohorts 1 and 2 (Hb r = 0.712 & 0.524 and Hct r = 0.705 & 0.466), which remained significant after adjustments for CAH status, glucocorticoid treatment dose and serum creatinine. In the combined cohorts, Hb correlated with androstenedione (P = 0.002) and 17-hydroxyprogesterone (P = 0.008). Hb and Hct were significantly higher in cohort 1 than those in cohort 2, while there were no group differences in androgen levels, glucocorticoid treatment dose or body mass index. In both cohorts, women with Hb and Hct in the highest tertile had significantly higher testosterone levels than women with Hb and Hct in the lowest tertile. Conclusions In women with CAH, erythropoiesis may be driven by androgens and could be considered a biomarker for disease control. C1 [Karunasena, Nayananjani; Ross, Richard J. M.; Daniel, Eleni] Univ Sheffield, Dept Oncol & Metab, Sheffield, S Yorkshire, England. [Han, Thang S.] Royal Holloway Univ London ICR2UL, Inst Cardiovasc Res, Surrey, England. [Han, Thang S.] Ashford & St Peters NHS Fdn Trust, Surrey, England. [Mallappa, Ashwini; Elman, Meredith; Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Ctr Clin, Bethesda, MD USA. RP Daniel, E (reprint author), Univ Sheffield, Sch Med, Dept Oncol & Metab, Beech Hill Rd,E Floor Room EU10, Sheffield S10 2RX, S Yorkshire, England. EM e.daniel@sheffield.ac.uk FU Intramural Research Program of the National Institutes of Health; Sri Lankan Government; European Commission under a Framework 7 Grant [281654 - TAIN] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health. NK was funded by a scholarship from the Sri Lankan Government. ED was funded by the European Commission under a Framework 7 Grant (No: 281654 - TAIN) www.tain-project.org. NR 35 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD JAN PY 2017 VL 86 IS 1 BP 19 EP 25 DI 10.1111/cen.13148 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EJ8CZ UT WOS:000393453400004 PM 27344964 ER PT J AU Nilubol, N Merkel, R Yang, LL Patel, D Reynolds, JC Sadowski, SM Neychev, V Kebebew, E AF Nilubol, Naris Merkel, Roxanne Yang, Lily Patel, Dhaval Reynolds, James C. Sadowski, Samira M. Neychev, Vladimir Kebebew, Electron TI A phase II trial of valproic acid in patients with advanced, radioiodine-resistant thyroid cancers of follicular cell origin SO CLINICAL ENDOCRINOLOGY LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; GENE-EXPRESSION; RETINOIC ACID; IODINE UPTAKE; SOLID TUMORS; THERAPY; CARCINOMA; THYROGLOBULIN; SENSITIVITY; APOPTOSIS AB Objective Valproic acid (VA) is a histone deacetylase (HDAC) inhibitor that has antiproliferative effects on several types of cancer, including thyroid cancer. In addition, VA has been reported to upregulate the sodium-iodine symporter in thyroid cancer cells and increases radioiodine uptake in preclinical studies. The aim of this study was to assess the antiproliferative effects of VA and to evaluate if VA can increase the radioiodine uptake in patients with advanced, radioiodine-negative thyroid cancer. Design An open-label Simon two-stage phase II trial. Patients and Measurements Valproic acid was administered orally, and doses were adjusted to maintain serum trough levels between 50 and 100 mg/l for 10 weeks, followed by injections of recombinant human thyroid-stimulating hormone and a radioiodine uptake scan. Anatomical imaging studies were performed at week 16 to assess tumour response and radioiodine therapy in patients with increased radioiodine uptake. Results Thirteen patients with a median age of 66 years (50-78 years) were enrolled and evaluated. Seven patients had papillary thyroid cancer (PTC), two had follicular variant PTC, two had follicular thyroid cancer, and two had Hurthle cell carcinoma. None of the 10 patients who completed the 10-week treatment had increased radioiodine uptake at their tumour sites. Three patients were taken off the study prior to the 10-week radioiodine uptake scan: one with grade-3 hepatic toxicity, one with disease progression and one for noncompliance. Four of 13 patients had decreased stimulated serum thyroglobulin with VA treatment. None of the patients had complete or partial responses based on Response Evaluation Criteria in Solid Tumors (RECIST), and six patients had disease progression. Conclusions Valproic acid does not increase radioiodine uptake and does not have anticancer activity in patients with advanced, radioiodine-negative thyroid cancer of follicular cell origin. C1 [Nilubol, Naris; Merkel, Roxanne; Yang, Lily; Patel, Dhaval; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Reynolds, James C.] NIH, Dept Nucl Med, Clin Res Ctr, Bethesda, MD USA. [Sadowski, Samira M.] Univ Hosp Geneva, Thorac & Endocrine Surg, Geneva, Switzerland. [Neychev, Vladimir] Alexandrovska Med Univ, Univ Multiprofile Hosp Act Treatment, Dept Surg, Sofia, Bulgaria. RP Nilubol, N (reprint author), NCI, Endocrine Oncol Branch, NIH, Clin Res Ctr, Bldg 10 CRC,Room 4-5932, Bethesda, MD 20892 USA. EM naris.nilubol@nih.gov OI Patel, Dhaval/0000-0002-5744-568X FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX The research activities performed in this manuscript were supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 33 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD JAN PY 2017 VL 86 IS 1 BP 128 EP 133 DI 10.1111/cen.13154 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EJ8CZ UT WOS:000393453400017 PM 27392538 ER PT J AU Stratman, AN Pezoa, SA Farrelly, OM Castranova, D Dye, LE Butler, MG Sidik, H Talbot, WS Weinstein, BM AF Stratman, Amber N. Pezoa, Sofia A. Farrelly, Olivia M. Castranova, Daniel Dye, Louis E., III Butler, Matthew G. Sidik, Harwin Talbot, William S. Weinstein, Brant M. TI Interactions between mural cells and endothelial cells stabilize the developing zebrafish dorsal aorta SO DEVELOPMENT LA English DT Article DE Vascular smooth muscle; Pericyte; Zebrafish; PDGFR signaling; Vascular basement membrane ID SMOOTH-MUSCLE-CELLS; BLOOD-BRAIN-BARRIER; BASEMENT-MEMBRANE FORMATION; GROWTH-FACTOR; PDGF-B; VASCULAR DEVELOPMENT; EXPRESSION PATTERNS; SCLEROTOMAL ORIGIN; VESSEL FORMATION; GENE-EXPRESSION AB Mural cells (vascular smooth muscle cells and pericytes) play an essential role in the development of the vasculature, promoting vascular quiescence and long-term vessel stabilization through their interactions with endothelial cells. However, the mechanistic details of how mural cells stabilize vessels are not fully understood. We have examined the emergence and functional role of mural cells investing the dorsal aorta during early development using the zebrafish. Consistent with previous literature, our data suggest that cells ensheathing the dorsal aorta emerge from a sub-population of cells in the adjacent sclerotome. Inhibition of mural cell recruitment to the dorsal aorta through disruption of pdgfr signaling leads to a reduced vascular basement membrane, which in turn results in enhanced dorsal aorta vessel elasticity and failure to restrict aortic diameter. Our results provide direct in vivo evidence for a functional role for mural cells in patterning and stabilization of the early vasculature through production and maintenance of the vascular basement membrane to prevent abnormal aortic expansion and elasticity. C1 [Stratman, Amber N.; Pezoa, Sofia A.; Farrelly, Olivia M.; Castranova, Daniel; Butler, Matthew G.; Weinstein, Brant M.] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Dye, Louis E., III] NICHHD, Microscopy & Imaging Core, NIH, Bethesda, MD 20892 USA. [Sidik, Harwin; Talbot, William S.] Stanford Univ, Dept Dev Biol, Sch Med, Stanford, CA 94305 USA. RP Weinstein, BM (reprint author), NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM flyingfish2@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [ZIA-HD001011, ZIA-HD008915]; National Institutes of Health [R01NS050223]; Agency for Science, Technology and Research (A*STAR) fellowship; National Heart, Lung, and Blood Institute/NIH K99 Pathway to Independence Award FX This work was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIA-HD001011 and ZIA-HD008915 to B.M.W.), the National Institutes of Health (R01NS050223 to W.S.T.), an Agency for Science, Technology and Research (A*STAR) fellowship (to H.S.) and a National Heart, Lung, and Blood Institute/NIH K99 Pathway to Independence Award (to A.N.S.). Deposited in PMC for release after 12 months. NR 71 TC 0 Z9 0 U1 1 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD JAN 1 PY 2017 VL 144 IS 1 BP 115 EP 127 DI 10.1242/dev.143131 PG 13 WC Developmental Biology SC Developmental Biology GA EJ8DK UT WOS:000393454900015 PM 27913637 ER PT J AU Sandfort, V Bluemke, DA AF Sandfort, V. Bluemke, D. A. TI CT calcium scoring. History, current status and outlook SO DIAGNOSTIC AND INTERVENTIONAL IMAGING LA English DT Review DE CT; Cardiac imaging; Coronary calcium ID CORONARY-ARTERY CALCIUM; TRADITIONAL RISK-FACTORS; HEINZ NIXDORF RECALL; COMPUTED-TOMOGRAPHY; ASYMPTOMATIC INDIVIDUALS; CARDIOVASCULAR EVENTS; ATHEROSCLEROSIS MESA; HEART-ASSOCIATION; AMERICAN-COLLEGE; CALCIFICATION AB Cardiovascular risk assessment has assumed a prominent role in the course of preventive care of all adults. Traditionally cardiovascular risk assessment has been performed using risk factors including gender, age, smoking history, lipid status, diabetes status, and family history. Increasingly, imaging has been deployed to directly detect coronary atherosclerotic disease. Quantification of coronary calcium (e.g., Agatston method, calcium mass and volume) is readily detected using helical CT scanners. Large multicenter cohort studies have enabled a better understanding of the relevance of coronary calcium detection. The purpose of this review is to review the methods for quantification of coronary artery calcium, as well as to present current and future perspectives on calcium scoring for cardiovascular risk stratification. Published by Elsevier Masson SAS on behalf of Editions francaises de radiologie. C1 [Sandfort, V.; Bluemke, D. A.] NIH, Radiol & Imaging Sci, Ctr Clin, 9000 Rockville Pike,10 Ctr Dr,Bld 10,Room 1C356, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, 9000 Rockville Pike,10 Ctr Dr,Bld 10,Room 1C356, Bethesda, MD 20892 USA. EM david.bluemke@nih.gov FU National Institutes of Health Intramural research program FX Funding provided by the National Institutes of Health Intramural research program. NR 32 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 2211-5684 J9 DIAGN INTERV IMAG JI Diagn. Interv. Imaging PD JAN PY 2017 VL 98 IS 1 BP 3 EP 10 DI 10.1016/j.diii.2016.06.007 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ4RG UT WOS:000393203900002 PM 27423708 ER PT J AU Thompson, KA Kelly, NR Schvey, NA Brady, SM Courville, AB Tanofsky-Kraff, M Yanovski, SZ Yanovski, JA Shomaker, LB AF Thompson, Katherine A. Kelly, Nichole R. Schvey, Natasha A. Brady, Sheila M. Courville, Amber B. Tanofsky-Kraff, Marian Yanovski, Susan Z. Yanovski, Jack A. Shomaker, Lauren B. TI Internalization of appearance ideals mediates the relationship between appearance-related pressures from peers and emotional eating among adolescent boys and girls SO EATING BEHAVIORS LA English DT Article DE Emotional eating; Pressure to be thin; Pressure to be muscular; Internalization of appearance ideals; Adolescents ID TRIPARTITE INFLUENCE MODEL; DUAL-PATHWAY MODEL; BODY-IMAGE; INTERPERSONAL INFLUENCES; SOCIOCULTURAL ATTITUDES; GENDER-DIFFERENCES; PUBERTAL CHANGES; CHILDREN; DISTURBANCE; VALIDATION AB Appearance-related pressures have been associated with binge eating in previous studies. Yet, it is unclear if these pressures are associated with emotional eating or if specific sources of pressure are differentially associated with emotional eating. We studied the associations between multiple sources of appearance-related pressures, including pressure to be thin and pressure to increase muscularity, and emotional eating in 300 adolescents (M-age = 153, SD = 1.4, 60% female). Controlling for age, race, puberty, body mass index (BMI) z-score, and sex, both pressure to be thin and pressure to be more muscular from same-sex peers were positively associated with emotional eating in response to feeling angry/frustrated and unsettled (ps < 0.05). Pressure from same-sex peers to be more muscular also was associated with eating when depressed (p < 0.05), and muscularity pressure from opposite-sex peers related to eating in response to anger/frustration (p < 0.05). All associations were fully mediated by internalization of appearance ideals according to Western cultural standards (ps < 0.001). Associations of pressures from mothers and fathers with emotional eating were non-significant. Results considering sex as a moderator of the associations between appearance-related pressures and emotional eating were non-significant. Findings illustrate that both pressure to be thin and muscular from peers are related to more frequent emotional eating among both boys and girls, and these associations are explained through internalization of appearance-related ideals. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Thompson, Katherine A.; Kelly, Nichole R.; Schvey, Natasha A.; Brady, Sheila M.; Tanofsky-Kraff, Marian; Yanovski, Jack A.; Shomaker, Lauren B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,US Dept HHS, 10 Ctr Dr, Bethesda, MD 20892 USA. [Kelly, Nichole R.] Coll Educ, Dept Counseling Psychol & Human Serv, 5207 Univ Oregon, Eugene, OR 97403 USA. [Schvey, Natasha A.; Tanofsky-Kraff, Marian] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Courville, Amber B.] NIH, Dept Nutr, Hatfield Clin Res Ctr, 10 Ctr Dr, Bethesda, MD 20892 USA. [Yanovski, Susan Z.] NIDDK, Div Digest Dis & Nutr, NIH, DHHS, 6707 Democracy Blvd, Bethesda, MD 20892 USA. [Shomaker, Lauren B.] Colorado State Univ, Colorado Sch Publ Hlth, Dept Human Dev & Family Studies, Ft Collins, CO 80523 USA. RP Shomaker, LB (reprint author), 1570 Campus Delivery, Ft Collins, CO 80523 USA. EM lauren.shomaker@colostate.edu FU Intramural NIH HHS [ZIA HD000641-21, Z01 HD000641-13, Z99 HD999999]; NICHD NIH HHS [F32 HD056762, R00 HD069516, K99 HD069516] NR 43 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1471-0153 EI 1873-7358 J9 EAT BEHAV JI Eat. Behav. PD JAN PY 2017 VL 24 BP 66 EP 73 DI 10.1016/j.eatbeh.2016.12.008 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ5GM UT WOS:000393245800012 PM 28038437 ER PT J AU Mereu, M Chun, LE Prisinzano, TE Newman, AH Katz, JL Tanda, G AF Mereu, Maddalena Chun, Lauren E. Prisinzano, Thomas E. Newman, Amy H. Katz, Jonathan L. Tanda, Gianluigi TI The unique psychostimulant profile of (+/-)-modafinil: investigation of behavioral and neurochemical effects in mice SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE ADHD; cocaine abuse and addiction; dopamine microdialysis; methylphenidate; modafinil; nucleus accumbens shell ID DOPAMINE UPTAKE INHIBITORS; PROMOTING DRUG MODAFINIL; PLACEBO-CONTROLLED TRIAL; RATS DISCRIMINATING COCAINE; MEDIAL PREOPTIC AREA; SPRAGUE-DAWLEY RATS; NUCLEUS-ACCUMBENS; DOUBLE-BLIND; LOCOMOTOR SENSITIZATION; POSTERIOR HYPOTHALAMUS AB Blockade of dopamine (DA) reuptake via the dopamine transporter (DAT) is a primary mechanism identified as underlying the therapeutic actions of (+/-)-modafinil (modafinil) and its R-enantiomer, armodafinil. Herein, we explored the neurochemical and behavioral actions of modafinil to better characterize its psychostimulant profile. Swiss-Webster mice were implanted with micro-dialysis probes in the nucleus accumbens shell (NAS) or core (NAC) to evaluate changes in DA levels related to acute reinforcing actions of drugs of abuse. Additionally, subjective effects were studied in mice trained to discriminate 10 mg/kg cocaine (i.p.) from saline. Modafinil (17-300 mg/kg, i.p.) significantly increased NAS and NAC DA levels that at the highest doses reached similar to 300% at 1 h, and lasted > 6 h in duration. These elevated DA levels did not show statistically significant regional differences between the NAS and NAC. Modafinil produced cocaine-like subjective effects at 56-100 mg/kg when administered at 5 and 60 min before the start of the session, and enhanced cocaine effects when the two were administered in combination. Despite sharing subjective effects with cocaine, modafinil's psychostimulant profile was unique compared to that of cocaine and like compounds. Modafinil had lower potency and efficacy than cocaine in stimulating NAS DA. In addition, the cocaine-like subjective effects of modafinil were obtained at lower doses and earlier onset times than expected based on its dopaminergic effects. These studies suggest that although inhibition of DA reuptake may be a primary mechanism underlying modafinil's therapeutic actions, non DA-dependent actions may be playing a role in its psychostimulant profile. C1 [Mereu, Maddalena; Chun, Lauren E.; Newman, Amy H.; Tanda, Gianluigi] NIDA, Medicat Dev Program, Mol Targets & Medicat Discovery Branch, Dept Hlth & Human Serv,Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. [Prisinzano, Thomas E.] Univ Kansas, Dept Med Chem, Lawrence, KS USA. [Newman, Amy H.] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Dept Hlth & Human Serv,Intramural Res Program,NIH, Baltimore, MD USA. [Katz, Jonathan L.] NIDA, Psychobiol Sect, Mol Neuropsychiat Res Branch, Dept Hlth & Human Serv,Intramural Res Program,NIH, Baltimore, MD USA. RP Tanda, G (reprint author), NIDA, Medicat Dev Program, Mol Targets & Medicat Discovery Branch, Dept Hlth & Human Serv,Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM gtanda@mail.nih.gov FU Medication Development Program, NIDA-IRP, NIH/DHHS FX The present manuscript has been funded by the Medication Development Program, NIDA-IRP, NIH/DHHS. NR 61 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JAN PY 2017 VL 45 IS 1 BP 167 EP 174 DI 10.1111/ejn.13376 PG 8 WC Neurosciences SC Neurosciences & Neurology GA EJ4II UT WOS:000393179800016 ER PT J AU Chun, DS Berse, B Venne, VL DuVall, SL Filipski, KK Kelley, MJ Meyer, LJ Icardi, MS Lynch, JA AF Chun, Danielle S. Berse, Brygida Venne, Vickie L. DuVall, Scott L. Filipski, Kelly K. Kelley, Michael J. Meyer, Laurence J. Icardi, Michael S. Lynch, Julie A. TI BRCA testing within the Department of Veterans Affairs: concordance with clinical practice guidelines SO FAMILIAL CANCER LA English DT Article DE Genetic testing; Breast cancer; BRCA; Clinical guidelines ID BREAST-CANCER; AMERICAN SOCIETY; SUSCEPTIBILITY; WOMEN AB Guideline-concordant cancer care is a priority within the Department of Veterans Affairs (VA). In 2009, the VA expanded its capacity to treat breast cancer patients within VA medical centers (VAMCs). We sought to determine whether male and female Veterans diagnosed with breast cancer received BRCA testing as recommended by the National Comprehensive Cancer Network (NCCN) guidelines on Genetic/Familial High-Risk Assessment in Breast and Ovarian Cancer (v. 1.2010-1.2012). Using the 2011-2012 VA Central Cancer Registry and BRCA test orders from Myriad Genetics, we conducted a retrospective study. The outcome variable was a recommendation for genetic counseling or BRCA testing, determined by chart review. Independent variables expected to predict testing included region, site of care, and patient characteristics. We performed descriptive analysis of all patients and conducted multivariable logistic regression on patients who sought care at VAMCs that offered BRCA testing. Of the 462 Veterans who met NCCN testing criteria, 126 (27 %) received guideline-concordant care, either a referral for counseling or actual testing. No BRCA testing was recommended in 49 (50 %) VAMCs that provide cancer treatment. Surprisingly, patients with second primary breast cancer were less likely to be referred/tested (OR 0.39; CI 0.17, 0.89; p = 0.025). For patients under age 51, a yearly increase in age decreased likelihood of referral or testing (OR 0.85; CI 0.76, 0.94; p < 0.001). There were no differences in testing by race. In conclusion, there was significant underutilization and lack of access to BRCA testing for Veterans diagnosed with breast cancer. Our research suggests the need for clinical decision support tools to facilitate delivery of guideline-concordant cancer care and improve Veteran access to BRCA testing. C1 [Chun, Danielle S.; Venne, Vickie L.; DuVall, Scott L.; Meyer, Laurence J.] VA Salt Lake City Hlth Care Syst, 500 Foothill Dr, Salt Lake City, UT 84148 USA. [Chun, Danielle S.; DuVall, Scott L.; Meyer, Laurence J.; Lynch, Julie A.] Univ Utah, Sch Med, 500 Foothill Dr, Salt Lake City, UT 84148 USA. [Berse, Brygida] Vet Hlth Adm, 200 Springs Rd, Bedford, MA 01730 USA. [Berse, Brygida] Boston Univ, Sch Med, 72 E Concord St, Boston, MA 02118 USA. [Berse, Brygida; Lynch, Julie A.] RTI Int, 307 Waverley Oaks Rd, Waltham, MA 02452 USA. [Filipski, Kelly K.] NCI, 9609 Med Ctr Dr,Rm 4E228,MSC 9763, Bethesda, MD 20892 USA. [Kelley, Michael J.] Durham VA Med Ctr, 508 Fulton St, Durham, NC 27705 USA. [Kelley, Michael J.] Duke Univ, 508 Fulton St,Hem Onc 111G, Durham, NC 27705 USA. [Icardi, Michael S.] Vet Hlth Adm, 601 Highway 6 West, Iowa City, IA 52246 USA. [Icardi, Michael S.] Univ Iowa, 601 Highway 6 West, Iowa City, IA 52246 USA. [Lynch, Julie A.] VA Salt Lake City Hlth Care Syst, 200 Springs Rd, Bedford, MA 01730 USA. RP Lynch, JA (reprint author), Univ Utah, Sch Med, 500 Foothill Dr, Salt Lake City, UT 84148 USA.; Lynch, JA (reprint author), RTI Int, 307 Waverley Oaks Rd, Waltham, MA 02452 USA.; Lynch, JA (reprint author), VA Salt Lake City Hlth Care Syst, 200 Springs Rd, Bedford, MA 01730 USA. EM Julie.Lynch@va.gov FU Department of Veterans Affairs Informatics and Computing Infrastructure (VINCI), VA HSR RES [13-457]; National Cancer Institute [IAA 14001-0000-01001] FX This research was supported using resources and facilities at the VA Salt Lake City Health Care System with funding from the Department of Veterans Affairs Informatics and Computing Infrastructure (VINCI), VA HSR RES 13-457 (to S. L. DuVall). B. Berse and J. A. Lynch are funded by the National Cancer Institute through an Interagency Agreement. IAA 14001-0000-01001. NR 23 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 EI 1573-7292 J9 FAM CANCER JI Fam. Cancer PD JAN PY 2017 VL 16 IS 1 BP 41 EP 49 DI 10.1007/s10689-016-9921-5 PG 9 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA EJ0ZU UT WOS:000392940700005 PM 27589855 ER PT J AU Von Tungeln, LS Walker, NJ Olson, GR Maria, CBMD Felton, RP Thorn, BT Marques, MM Pogribny, IP Doerge, DR Beland, FA AF Von Tungeln, Linda S. Walker, Nigel J. Olson, Greg R. Mendoza, Maria C. B. Felton, Robert P. Thorn, Brett T. Matilde Marques, M. Pogribny, Igor P. Doerge, Daniel R. Beland, Frederick A. TI Low dose assessment of the carcinogenicity of furan in male F344/N Nctr rats in a 2-year gavage study SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Furan; Tumorigenicity; Cholangiocarcinoma; Cholangiofibrosis; Rats; Bioassay ID GAS CHROMATOGRAPHY/MASS SPECTROMETRY; BIG BLUE RATS; FISCHER-344 RATS; REACTIVE METABOLITE; CELL-PROLIFERATION; GENE-EXPRESSION; DRINKING-WATER; IN-VIVO; ACRYLAMIDE; EXPOSURE AB Furan is a volatile organic chemical that is a contaminant in many common foods. Furan is hepatocarcinogenic in mice and rats; however, the risk to humans from dietary exposure to furan cannot be estimated accurately because the lowest tested dose of furan in a 2-year bioassay in rats gave nearly a 100% incidence of cholangiocarcinoma. To provide bioassay data that can be used in preparing risk assessments, the carcinogenicity of furan was determined in male F344/N Nctr rats administered 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92, and 2 mg furan/kg body weight (BW) by gavage 5 days/week for 2 years. Exposure to furan was associated with the development of malignant mesothelioma on membranes surrounding the epididymis and on the testicular tunics, with the increase being significant at 2 mg furan/kg BW. There was also a dose-related increase in the incidence of mononuclear cell leukemia, with the increase in incidence being significant at 0.092, 0.2, 0.92, and 2 mg furan/kg BW. Dose-related nonneoplastic liver lesions included cholangiofibrosis, mixed cell foci, basophilic foci, biliary tract hyperplasia, oval cell hyperplasia, regenerative hyperplasia, and cytoplasmic vacuolization. The most sensitive non-neoplastic lesion was cholangiofibrosis, the frequency of which increased significantly at 0.2 mg furan/kg BW. Published by Elsevier Ltd. C1 [Von Tungeln, Linda S.; Pogribny, Igor P.; Doerge, Daniel R.; Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, HFT 110,3900 NCTR Rd, Jefferson, AR 72079 USA. [Walker, Nigel J.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Olson, Greg R.] Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Mendoza, Maria C. B.; Felton, Robert P.; Thorn, Brett T.] Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Matilde Marques, M.] Univ Lisbon, Ctr Quim Estrutural, Inst Super Tecn, P-1049001 Lisbon, Portugal. RP Beland, FA (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, HFT 110,3900 NCTR Rd, Jefferson, AR 72079 USA. EM frederick.beland@fda.hhs.gov OI Marques, M. Matilde/0000-0002-7526-4962 FU Intramural Research Program of the NIH/National Institute of Environmental Health Sciences (NIEHS) [224-12-0003, AES12013]; Fundacao para a Ciencia e a Tecnologia, Portugal [RECI/QEQ-MED/0330/2012, UID/QUI/00100/2013] FX We thank F. Michelle McLellen and Matthew S. Bryant for conducting the chemical analyses and Andy Matson and James Carson for preparing dosing solutions and providing animal care. This study was supported by the Intramural Research Program of the NIH/National Institute of Environmental Health Sciences (NIEHS) via an Interagency Agreement between the NTP/NIEHS and the NCTR/FDA (NCTR/FDA IAG #224-12-0003; NIH/NTP IAG #AES12013). Financial support was also provided by Fundacao para a Ciencia e a Tecnologia, Portugal (Grants RECI/QEQ-MED/0330/2012 and UID/QUI/00100/2013). The opinions expressed in this paper do not necessarily represent those of the U.S. Food and Drug Administration. NR 63 TC 0 Z9 0 U1 4 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD JAN PY 2017 VL 99 BP 170 EP 181 DI 10.1016/j.fct.2016.11.015 PG 12 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA EI8WV UT WOS:000392789800016 PM 27871980 ER PT J AU Tosar, JP Cayota, A Eitan, E Halushka, MK Witwer, KW AF Tosar, Juan Pablo Cayota, Alfonso Eitan, Erez Halushka, Marc K. Witwer, Kenneth W. TI Ribonucleic artefacts: are some extracellular RNA discoveries driven by cell culture medium components? SO JOURNAL OF EXTRACELLULAR VESICLES LA English DT Review DE RNA; extracellular vesicles; exosomes; microvesicles; ultracentrifugation; serum; cell culture; microRNA; contamination; artefact ID CIRCULATING MICRORNAS; EXPRESSION PROFILE; MIRNA EXPRESSION; FETAL BOVINE; EXOSOMES; MICROVESICLES; VESICLES; ORIGIN; CONTAMINATION; BIOMARKER AB In a recently published study, Anna Krichevsky and colleagues raise the important question of whether results of in vitro extracellular RNA (exRNA) studies, including extracellular vesicle (EV) investigations, are confounded by the presence of RNA in cell culture medium components such as foetal bovine serum (FBS). The answer, according to their data, is a resounding "yes". Even after lengthy ultracentrifugation to remove bovine EVs from FBS, the majority of exRNA in FBS remained. Although technical factors may affect the degree of depletion, residual EVs and exRNA in FBS could influence the conclusions of in vitro studies: certainly, for secreted RNA, and possibly also for cell-associated RNA. In this commentary, we critically examine some of the literature in this field, including a recent study from some of the authors of this piece, in light of the Wei et al. study and explore how cell culture-derived RNAs may affect what we think we know about EV RNAs. These findings hold particular consequence as the field moves towards a deeper understanding of EV-RNA associations and potential functions. C1 [Tosar, Juan Pablo; Cayota, Alfonso] Inst Pasteur Montevideo, Funct Genom Unit, Montevideo, Uruguay. [Tosar, Juan Pablo] Univ Republica, Nucl Res Ctr, Fac Sci, Montevideo, Uruguay. [Cayota, Alfonso] Univ Republica, Dept Med, Fac Med, Montevideo, Uruguay. [Eitan, Erez] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Halushka, Marc K.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Witwer, Kenneth W.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, 733 N Broadway,MRB 829, Baltimore, MD 21205 USA. [Witwer, Kenneth W.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Witwer, KW (reprint author), Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, 733 N Broadway,MRB 829, Baltimore, MD 21205 USA. EM kwitwer1@jhmi.edu FU US National Institute on Drug Abuse, National Institutes of Health [R01 DA040385] FX This work was supported in part by the US National Institute on Drug Abuse, National Institutes of Health [grant number R01 DA040385] (to KWW). NR 51 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 2001-3078 J9 J EXTRACELL VESICLES JI J. Extracell. Vesicles PY 2017 VL 6 AR 1272832 DI 10.1080/20013078.2016.1272832 PG 10 WC Cell Biology SC Cell Biology GA EK4UI UT WOS:000393922100001 PM 28326168 ER PT J AU Ma, M Rice, TA Percopo, CM Rosenberg, HF AF Ma, Michelle Rice, Tyler A. Percopo, Caroline M. Rosenberg, Helene F. TI Silkworm larvae plasma (SLP) assay for detection of bacteria: False positives secondary to inflammation in vivo SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE Lactobacillus; Inflammation; Pattern recognition receptors ID LETHAL PNEUMOVIRUS INFECTION; RESPIRATORY VIRUS-INFECTION; PEPTIDOGLYCAN; PROTECTION; CLEARANCE; IMMUNITY; SYSTEM; TRACT; NOD2 AB The silkworm larvae plasma (SLP) assay has been developed as a means to detect bacterial peptidoglycan as a surrogate for live bacteria. Here, we present results that indicate that generation of melanin by this assay is not fully reliable as a surrogate marker for bacterial count. Published by Elsevier B.V. C1 [Ma, Michelle; Rice, Tyler A.; Percopo, Caroline M.; Rosenberg, Helene F.] NIAID, Inflammat Immunobiol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Rice, Tyler A.] Yale Univ, Grad Dept Immunobiol, New Haven, CT USA. RP Rosenberg, HF (reprint author), IIS LAD NIAID, Bldg 50,Room 6241, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU Division of Intramural Research of the NIAID [A1000943] FX This work is supported by the Division of Intramural Research of the NIAID (A1000943 to HFR). NR 24 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 EI 1872-8359 J9 J MICROBIOL METH JI J. Microbiol. Methods PD JAN PY 2017 VL 132 BP 9 EP 13 DI 10.1016/j.mimet.2016.11.009 PG 5 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA EJ2CI UT WOS:000393017100003 PM 27840194 ER PT J AU Hockman, D Dong, M Zheng, H Kumar, S Huff, MD Grigorenko, E Beanan, M Duncan, R AF Hockman, Donna Dong, Ming Zheng, Hong Kumar, Sanjai Huff, Matthew D. Grigorenko, Elena Beanan, Maureen Duncan, Robert TI Comparison of multiplex PCR hybridization-based and singleplex real-time PCR-based assays for detection of low prevalence pathogens in spiked samples SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE Spiked specimens; Blood-borne pathogens; Real-time PCR; Target Enriched Multiplex PCR ID POLYMERASE-CHAIN-REACTION; FRANCISELLA-TULARENSIS; BLOOD AB Molecular diagnostic devices are increasingly finding utility in clinical laboratories. Demonstration of the effectiveness of these devices is dependent upon comparing results from clinical samples tested with the new device to an alternative testing method. The preparation of mock clinical specimens will be necessary for the validation of molecular diagnostic devices when a sufficient number of clinical specimens is unobtainable. Examples include rare pathogens, some of which are pathogens posing a biological weapon threat. Here we describe standardized steps for developers to follow for the culture and quantification of three organisms used to spike human whole blood to create mock specimens. The three organisms chosen for this study were the Live Vaccine Strain (LVS) of Francisella tularensis, surrogate for a potential biothreat pathogen, Escherichia coil, a representative Gram-negative bacterium and Babesia microti (Franca) Reichenow Peabody strain, representing a protozoan parasite. Mock specimens were prepared with blood from both healthy donors and donors with nonspecific symptoms including fever, malaise, and flu-like symptoms. There was no significant difference in detection results between the two groups for any pathogen. Testing of the mock samples was compared on two platforms, Target Enriched Multiplex-PCR (TEM-PCRTm) and singleplex real-time PCR (RT-PCR). Results were reproducible on both platforms. The reproducibility demonstrated by obtaining the same results between two testing methods and between healthy and symptomatic mock specimens, indicates the standardized methods described for creating the mock specimens are valid and effective for evaluating diagnostic devices. Published by Elsevier B.V. C1 [Hockman, Donna; Huff, Matthew D.; Grigorenko, Elena] Diatherix Labs LLC, Huntsville, AL USA. [Dong, Ming; Zheng, Hong; Kumar, Sanjai; Duncan, Robert] US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Beanan, Maureen] NIAID, Off Biodef Res Resources & Translat Res, Div Microbiol & Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Duncan, R (reprint author), US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD USA. EM robert.duncan@fda.hhs.gov RI Hockman, Donna/D-7237-2017 OI Hockman, Donna/0000-0002-1790-0895 FU NIAID [AAI13005-002] FX The Francisella tularensis culture was initiated from a colony gratefully obtained from Dr. Karen Elkin's laboratory (FDA/CBER). We wish to acknowledge that this work was supported by NIAID through an Interagency Agreement AAI13005-002 awarded to CBER/FDA. Thanks to Karen Elkins, PhD and Rene Reese, PhD for reading and commenting on the manuscript. NR 20 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 EI 1872-8359 J9 J MICROBIOL METH JI J. Microbiol. Methods PD JAN PY 2017 VL 132 BP 76 EP 82 DI 10.1016/j.mimet.2016.11.005 PG 7 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA EJ2CI UT WOS:000393017100013 PM 27838540 ER PT J AU Suzuki, Y Saito, Y Goto, M Newman, DJ O'Keefe, BR Lee, KH Nakagawa-Goto, K AF Suzuki, Yuki Saito, Yohei Goto, Masuo Newman, David J. O'Keefe, Barry R. Lee, Kuo-Hsiung Nakagawa-Goto, Kyoko TI (-)-Neocaryachine, an Antiproliferative Pavine Alkaloid from Cryptocarya laevigata, Induces DNA Double-Strand Breaks SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID INHIBITORY-ACTIVITY; PLANT DIVERSITY; CHINENSIS HEMSL; N-OXIDE; BARK; LAURACEAE; FLAVONOIDS; LEAVES; PHENANTHROINDOLIZIDINE; CONCINNA AB Twelve benzylisoquinoline alkaloids, including pavine and phenanthroindolizidine types, were isolated from a MeOH/CH2Cl2 extract of Cryptocarya laevigata (stem bark) through bioactivity-guided fractionation for antitumor effects. Selected compounds were evaluated for antiproliferative activity against five human tumor cell lines, including a multidrug-resistant subline. Since more common 2,3,8,9-tetrasubstituted pavine alkaloids, such as crychine (3), exhibit very mild or no cytotoxicity, this compound type has not been well investigated for antitumor activity. Thus, this report is the first discovery of a 7-hydroxylated pavine alkaloid, (-)-neocaryachine (1), to demonstrate strong antiproliferative activity, with IC50 values of 0.06 to 0.41 mu M against five tested tumor cell lines, including an MDR subline. Further mechanism of action studies revealed that 1 impacts the cellular S-phase by inducing DNA double-strand breaks. C1 [Suzuki, Yuki; Saito, Yohei; Nakagawa-Goto, Kyoko] Kanazawa Univ, Sch Pharmaceut Sci, Coll Med Pharmaceut & Hlth Sci, Kanazawa, Ishikawa 9201192, Japan. [Goto, Masuo; Lee, Kuo-Hsiung; Nakagawa-Goto, Kyoko] Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA. [O'Keefe, Barry R.] NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. [O'Keefe, Barry R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Lee, Kuo-Hsiung] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Lee, Kuo-Hsiung] China Med Univ & Hosp, Chinese Med Res & Dev Ctr, 2 Yuh Der Rd, Taichung 40447, Taiwan. RP Nakagawa-Goto, K (reprint author), Kanazawa Univ, Sch Pharmaceut Sci, Coll Med Pharmaceut & Hlth Sci, Kanazawa, Ishikawa 9201192, Japan.; Goto, M; Nakagawa-Goto, K (reprint author), Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA. EM goto@med.unc.edu; kngoto@p.kanazawa-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology (JSPS KAKENHI, Japan) [25293024, 25670054]; University Research Council (UNC); Eshelman Institute for Innovation, Chapel Hill, North Carolina; NIH from the National Cancer Institute [CA177584] FX We appreciate critical comments, suggestions, and editing of the manuscript by Dr. S. L. Morris-Natschke (UNC-CH). We wish to thank the Microscopy Service Laboratory (UNC-CH) for confocal microscopy. This study was supported by a Grant in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (JSPS KAKENHI, Japan) awarded to K.N.G. (Grant Numbers 25293024 and 25670054) and by a grant from the University Research Council (UNC) as well as the Eshelman Institute for Innovation, Chapel Hill, North Carolina, awarded to M.G. This work was also supported by NIH grant CA177584 from the National Cancer Institute, awarded to K.H.L. We also thank the Biological Testing Branch, DTP, DCTD, NCI, for performing the NCI 60-cell cytotoxicity assay and the Natural Products Support Group, Leidos Biomedical Inc., for plant extraction. NR 41 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD JAN PY 2017 VL 80 IS 1 BP 220 EP 224 DI 10.1021/acs.jnatprod.6b01153 PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA EJ3CS UT WOS:000393089600031 PM 28099003 ER PT J AU Marshall, KE Hughson, A Vascellari, S Priola, SA Sakudo, A Onodera, T Baron, GS AF Marshall, Karen E. Hughson, Andrew Vascellari, Sarah Priola, Suzette A. Sakudo, Akikazu Onodera, Takashi Baron, Gerald S. TI PrP Knockout Cells Expressing Transmembrane PrP Resist Prion Infection SO JOURNAL OF VIROLOGY LA English DT Article DE GPI; NpL2; PrP; neuron; prion; raft; transmembrane; transmissible spongiform encephalopathy ID GPI-ANCHORED PROTEINS; SCRAPIE-ASSOCIATED FORM; IN-VITRO GENERATION; NEUROBLASTOMA-CELLS; LIPID RAFTS; HEPARAN-SULFATE; LIVING CELLS; SIALIC-ACID; CONVERSION; PROTEASE AB Glycosylphosphatidylinositol (GPI) anchoring of the prion protein (PrPC) influences PrPC misfolding into the disease-associated isoform, PrPres, as well as prion propagation and infectivity. GPI proteins are found in cholesterol-and sphingolipid-rich membrane regions called rafts. Exchanging the GPI anchor for a nonraft transmembrane sequence redirects PrPC away from rafts. Previous studies showed that nonraft transmembrane PrPC variants resist conversion to PrPres when transfected into scrapie-infected N2a neuroblastoma cells, likely due to segregation of transmembrane PrPC and GPI-anchored PrPres in distinct membrane environments. Thus, it remained unclear whether transmembrane PrPC might convert to PrPres if seeded by an exogenous source of PrPres not associated with host cell rafts and without the potential influence of endogenous expression of GPI-anchored PrPC. To further explore these questions, constructs containing either a C-terminal wild-type GPI anchor signal sequence or a nonraft transmembrane sequence containing a flexible linker were expressed in a cell line derived from PrP knockout hippocampal neurons, NpL2. NpL2 cells have physiological similarities to primary neurons, representing a novel and advantageous model for studying transmissible spongiform encephalopathy (TSE) infection. Cells were infected with inocula from multiple prion strains and in different biochemical states (i.e., membrane bound as in brain microsomes from wild-type mice or purified GPI-anchorless amyloid fibrils). Only GPI-anchored PrPC supported persistent PrPres propagation. Our data provide strong evidence that in cell culture GPI anchor-directed membrane association of PrPC is required for persistent PrPres propagation, implicating raft microdomains as a location for conversion. IMPORTANCE Mechanisms of prion propagation, and what makes them transmissible, are poorly understood. Glycosylphosphatidylinositol (GPI) membrane anchoring of the prion protein (PrPC) directs it to specific regions of cell membranes called rafts. In order to test the importance of the raft environment on prion propagation, we developed a novel model for prion infection where cells expressing either GPI-anchored PrPC or transmembrane-anchored PrPC, which partitions it to a different location, were treated with infectious, misfolded forms of the prion protein, PrPres. We show that only GPI-anchored PrPC was able to convert to PrPres and able to serially propagate. The results strongly suggest that GPI anchoring and the localization of PrPC to rafts are crucial to the ability of PrPC to propagate as a prion. C1 [Marshall, Karen E.; Hughson, Andrew; Vascellari, Sarah; Priola, Suzette A.; Baron, Gerald S.] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. [Sakudo, Akikazu; Onodera, Takashi] Univ Tokyo, Sch Agr & Life Sci, Res Ctr Food Safety, Tokyo, Japan. [Marshall, Karen E.] Univ Sussex, Sch Life Sci, Brighton, E Sussex, England. [Vascellari, Sarah] Univ Cagliari, Dept Biomed Sci, Monserrato, Italy. [Sakudo, Akikazu] Univ Ryukyus, Sch Hlth Sci, Lab Biometab Chem, Nishihara, Okinawa, Japan. RP Baron, GS (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. EM geraldsbaron@gmail.com FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI000982-06, AI000982-07, AI000982-08] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (project numbers AI000982-06, AI000982-07, and AI000982-08). NR 132 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 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2017 VL 91 IS 2 AR UNSP e01686 DI 10.1128/JVI.01686-16 PG 20 WC Virology SC Virology GA EJ4MX UT WOS:000393192500016 ER PT J AU Wirblich, C Coleman, CM Kurup, D Abraham, TS Bernbaum, JG Jahrling, PB Hensley, LE Johnson, RF Frieman, MB Schnell, MJ AF Wirblich, Christoph Coleman, Christopher M. Kurup, Drishya Abraham, Tara S. Bernbaum, John G. Jahrling, Peter B. Hensley, Lisa E. Johnson, Reed F. Frieman, Matthew B. Schnell, Matthias J. TI One-Health: a Safe, Efficient, Dual-Use Vaccine for Humans and Animals against Middle East Respiratory Syndrome Coronavirus and Rabies Virus SO JOURNAL OF VIROLOGY LA English DT Article DE MERS-CoV; coronavirus; immunization; rabies; rhabdovirus ID TO-HUMAN TRANSMISSION; RECEPTOR-BINDING DOMAIN; MERS-COV; SPIKE PROTEIN; NEUTRALIZING ANTIBODIES; CANDIDATE VACCINE; RHESUS MACAQUES; SAUDI-ARABIA; MOUSE MODEL; S-PROTEIN AB Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 and is a highly pathogenic respiratory virus. There are no treatment options against MERS-CoV for humans or animals, and there are no large-scale clinical trials for therapies against MERS-CoV. To address this need, we developed an inactivated rabies virus (RABV) that contains the MERS-CoV spike (S) protein expressed on its surface. Our initial recombinant vaccine, BNSP333-S, expresses a full-length wild-type MERS-CoV S protein; however, it showed significantly reduced viral titers compared to those of the parental RABV strain and only low-level incorporation of full-length MERS-CoV S into RABV particles. Therefore, we developed a RABV-MERS vector that contained the MERS-CoV S1 domain of the MERS-CoV S protein fused to the RABV G protein C terminus (BNSP333-S1). BNSP333-S1 grew to titers similar to those of the parental vaccine vector BNSP333, and the RABV G-MERS-CoV S1 fusion protein was efficiently expressed and incorporated into RABV particles. When we vaccinated mice, chemically inactivated BNSP333-S1 induced high-titer neutralizing antibodies. Next, we challenged both vaccinated mice and control mice with MERS-CoV after adenovirus transduction of the human dipeptidyl peptidase 4 (hDPP4) receptor and then analyzed the ability of mice to control MERS-CoV infection. Our results demonstrated that vaccinated mice were fully protected from the MERS-CoV challenge, as indicated by the significantly lower MERS-CoV titers and MERS-CoV and mRNA levels in challenged mice than those in unvaccinated controls. These data establish that an inactivated RABV-MERS S-based vaccine may be effective for use in animals and humans in areas where MERS-CoV is endemic. IMPORTANCE Rabies virus-based vectors have been proven to be efficient dual vaccines against rabies and emergent infectious diseases such as Ebola virus. Here we show that inactivated rabies virus particles containing the MERS-CoV S1 protein induce potent immune responses against MERS-CoV and RABV. This novel vaccine is easy to produce and may be useful to protect target animals, such as camels, as well as humans from deadly MERS-CoV and RABV infections. Our results indicate that this vaccine approach can prevent disease, and the RABV-based vaccine platform may be a valuable tool for timely vaccine development against emerging infectious diseases. C1 [Wirblich, Christoph; Kurup, Drishya; Abraham, Tara S.; Schnell, Matthias J.] Thomas Jefferson Univ, Dept Microbiol & Immunol, Sydney Kimmel Med Coll, Philadelphia, PA 19107 USA. [Coleman, Christopher M.; Frieman, Matthew B.] Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Bernbaum, John G.; Jahrling, Peter B.; Hensley, Lisa E.] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD USA. [Jahrling, Peter B.; Johnson, Reed F.] NIAID, Emerging Viral Pathogens Sect, NIH, Ft Detrick, MD USA. [Schnell, Matthias J.] Thomas Jefferson Univ, Jefferson Vaccine Ctr, Philadelphia, PA 19107 USA. RP Schnell, MJ (reprint author), Thomas Jefferson Univ, Dept Microbiol & Immunol, Sydney Kimmel Med Coll, Philadelphia, PA 19107 USA.; Schnell, MJ (reprint author), Thomas Jefferson Univ, Jefferson Vaccine Ctr, Philadelphia, PA 19107 USA. EM Matthias.Schnell@jefferson.edu FU U.S. National Institute of Allergy and Infectious Diseases (NIAID) Division of Intramural Research; NIAID Division of Clinical Research; NIAID [R01AI105204, R01AI 5R01AI095569, HHSN272200700016I]; Jefferson Vaccine Center; Battelle Memorial Institute's prime contract FX This work was supported in part by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) Division of Intramural Research, the NIAID Division of Clinical Research, NIAID grant R01AI105204 to M.J.S., NIAID grant R01AI 5R01AI095569 to M.B.F., and the Jefferson Vaccine Center. This work was funded in part through Battelle Memorial Institute's prime contract with the NIAID under contract no. HHSN272200700016I. A subcontractor to Battelle Memorial Institute who performed this work is J.G.B., an employee of Tunnell Government Services, Inc. This work utilized the Bioimaging Shared Resource of the Sidney Kimmel Cancer Center (NCI 5 P30 CA-56036). NR 66 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 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2017 VL 91 IS 2 AR UNSP e02040-16 DI 10.1128/JVI.02040-16 PG 15 WC Virology SC Virology GA EJ4MX UT WOS:000393192500033 ER PT J AU Bradley, CJ Yabroff, KR Warren, JL Zeruto, C Chawla, N Lamont, EB AF Bradley, Cathy J. Yabroff, K. Robin Warren, Joan L. Zeruto, Christopher Chawla, Neetu Lamont, Elizabeth B. TI Use of High-cost Systemic Treatments in Elderly mCRC Patients In Reply SO MEDICAL CARE LA English DT Letter ID MEDICARE MANAGED CARE; TRADITIONAL MEDICARE; CANCER C1 [Bradley, Cathy J.] Univ Colorado, Colorado Comprehens Canc Ctr, Dept Hlth Syst Management & Policy, Aurora, CO 80045 USA. [Yabroff, K. Robin; Warren, Joan L.; Chawla, Neetu] NCI, Hlth Serv & Econ Branch, Bethesda, MD 20892 USA. [Zeruto, Christopher] Informat Management Serv Inc, Rockville, MD USA. [Lamont, Elizabeth B.] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Boston, MA 02114 USA. [Lamont, Elizabeth B.] Massachusetts Gen Hosp, Ctr Canc, Dept Hlth Care Policy, Boston, MA USA. [Lamont, Elizabeth B.] Harvard Med Sch, Boston, MA USA. RP Bradley, CJ (reprint author), Univ Colorado, Colorado Comprehens Canc Ctr, Dept Hlth Syst Management & Policy, Aurora, CO 80045 USA. FU National Cancer Institute FX The authors declare no conflict of interest. Bradley's work for the original manuscript was partially supported by a contract from the National Cancer Institute. NR 8 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD JAN PY 2017 VL 55 IS 1 BP 86 EP 87 PG 3 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EJ0RO UT WOS:000392918200015 PM 27547951 ER PT J AU Holderfield, M Morrison, DK AF Holderfield, Matthew Morrison, Deborah K. TI RAS SIGNALING Divide and conquer SO NATURE CHEMICAL BIOLOGY LA English DT News Item ID FORMS DIMERS; SURFACES C1 [Holderfield, Matthew] NCI, NCI RAS Initiat, Frederick Natl Lab Canc Res, Leidos Biomed Res, Frederick, MD 21701 USA. [Morrison, Deborah K.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21701 USA. RP Morrison, DK (reprint author), NCI, Lab Cell & Dev Signaling, Frederick, MD 21701 USA. EM morrisod@mail.nih.gov NR 10 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD JAN PY 2017 VL 13 IS 1 BP 7 EP 8 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EJ5OI UT WOS:000393267200004 ER PT J AU Choyke, PL Loeb, S AF Choyke, Peter L. Loeb, Stacy TI Active Surveillance of Prostate Cancer SO ONCOLOGY-NEW YORK LA English DT Article ID SYSTEM C1 [Choyke, Peter L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Loeb, Stacy] NYU, Dept Urol, New York, NY USA. [Loeb, Stacy] NYU, Dept Populat Hlth, New York, NY USA. RP Choyke, PL (reprint author), NCI, Mol Imaging Program, Bethesda, MD 20892 USA. FU Louis Feil Charitable Lead Trust; National Cancer Institute at the National Institutes of Health [K07CA178258] FX Dr. Loeb is supported by the Louis Feil Charitable Lead Trust and the National Cancer Institute at the National Institutes of Health (Award Number K07CA178258). NR 12 TC 0 Z9 0 U1 1 U2 1 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JAN PY 2017 VL 31 IS 1 BP 67 EP 70 PG 4 WC Oncology SC Oncology GA EJ6XE UT WOS:000393363300010 ER PT J AU Ashktorab, H Mokarram, P Azimi, H Olumi, H Varma, S Nickerson, ML Brim, H AF Ashktorab, Hassan Mokarram, Pooneh Azimi, Hamed Olumi, Hasti Varma, Sudhir Nickerson, Michael L. Brim, Hassan TI Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer SO ONCOTARGET LA English DT Article DE targeted exome sequencing; colon; Iranian; Shirazi; Caucasian ID DNA MISMATCH REPAIR; FREQUENTLY MUTATED GENE; MICROSATELLITE INSTABILITY; CLINICOPATHOLOGICAL FEATURES; AFRICAN-AMERICANS; BRAF MUTATION; PROTEIN; CELLS; COLON; MSH3 AB PURPOSE: Next Generation Sequencing (NGS) is currently used to establish mutational profiles in many multigene diseases such as colorectal cancer (CRC), which is on the rise in many parts of the developing World including, Iran. Little is known about its genetic hallmarks in these populations. AIM: To identify variants in 15 CRC-associated genes in patients of Iranian descent. RESULTS: There were 51 validated variants distributed on 12 genes: 22% MSH3 (n = 11/51), 10% MSH6 (n = 5/51), 8% AMER1 (n = 4/51), 20% APC (n = 10/51), 2% BRAF (n = 1/51), 2% KRAS (n = 1/51), 12% PIK3CA (n = 6/51), 8% TGF beta R2A (n = 4/51), 2% SMAD4 (n = 1/51), 4% SOX9 (n = 2/51), 6% TCF7L2 (n = 3/51), and 6% TP53 (n = 3/51). Most known and distinct variants were in mismatch repair genes (MMR, 32%) and APC (20%). Among oncogenes, PIK3CA was the top target (12%). MATERIALS AND METHODS: CRC specimens from 63 Shirazi patients were used to establish the variant' profile on an Ion Torrent platform by targeted exome sequencing. To rule-out technical artifacts, the variants were validated in 13 of these samples using an Illumina NGS platform. Validated variants were annotated and compared to variants from publically available databases. An in-silico functional analysis was performed. MSI status of the analyzed samples was established. CONCLUSION: These results illustrate for the first time CRC mutational profile in Iranian patients. MSH3, MSH6, APC and PIK3CA genes seem to play a bigger role in the path to cancer in this population. These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies. C1 [Ashktorab, Hassan; Azimi, Hamed; Olumi, Hasti] Howard Univ, Coll Med, Dept Med, Washington, DC USA. [Ashktorab, Hassan; Azimi, Hamed; Olumi, Hasti] Howard Univ, Ctr Canc, Coll Med, Washington, DC 20059 USA. [Brim, Hassan] Howard Univ, Coll Med, Dept Pathol, Washington, DC 20059 USA. [Varma, Sudhir] Hithru LLC, Silver Spring, MD USA. [Nickerson, Michael L.] NCI, Lab Translat Gen, Bethesda, MD 20892 USA. [Mokarram, Pooneh] Shiraz Univ Med Sci, Dept Biochem, Shiraz, Iran. RP Ashktorab, H (reprint author), Howard Univ, Coll Med, Dept Med, Washington, DC USA.; Ashktorab, H (reprint author), Howard Univ, Ctr Canc, Coll Med, Washington, DC 20059 USA.; Nickerson, ML (reprint author), NCI, Lab Translat Gen, Bethesda, MD 20892 USA. EM hashktorab@howard.edu; nickersonml@od.nih.gov FU National Institute on Minority Health and Health Disparities of the National Institutes of Health [G12MD007597] FX This project was supported (in part) by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Number G12MD007597. NR 62 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 PY 2017 VL 8 IS 5 BP 7852 EP 7866 DI 10.18632/oncotarget.13977 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EJ5YP UT WOS:000393295500058 PM 28002797 ER PT J AU Nagaya, T Nakamura, Y Sato, K Harada, T Choyke, PL Hodge, JW Schlom, J Kobayashi, H AF Nagaya, Tadanobu Nakamura, Yuko Sato, Kazuhide Harada, Toshiko Choyke, Peter L. Hodge, James W. Schlom, Jeffrey Kobayashi, Hisataka TI Near infrared photoimmunotherapy with avelumab, an antiprogrammed death-ligand 1 (PD-L1) antibody SO ONCOTARGET LA English DT Article DE near infrared photoimmunotherapy; PD-L1; lung cancer ID ANTI-PD-L1 ANTIBODY; ENHANCED PERMEABILITY; INTERFERON-GAMMA; LUNG-CANCER; TUMOR-CELLS; MELANOMA; METASTASIS; EXPRESSION; SAFETY; MODEL AB Near Infrared-Photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). Programmed cell death protein-1 ligand (PD-L1) is emerging as a molecular target. Here, we describe the efficacy of NIR-PIT, using fully human IgG1 anti-PD-L1 monoclonal antibody (mAb), avelumab, conjugated to the photo-absorber, IR700DX, in a PD-L1 expressing H441 cell line, papillary adenocarcinoma of lung. Avelumab-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR in vitro. In the in vivo study, avelumab-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 mu g of avelumab-IR700 i.v.; (3) NIR light exposure only, NIR light was administered; (4) 100 mu g of avelumab-IR700 i.v., NIR light was administered. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups (p < 0.001), and significantly prolonged survival was achieved (p < 0.01 vs other groups). In conclusion, the anti-PD-L1 antibody, avelumab, is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with avelumab-IR700 is a promising candidate of the treatment of PD-L1-expressing tumors that could be readily translated to humans. C1 [Nagaya, Tadanobu; Nakamura, Yuko; Sato, Kazuhide; Harada, Toshiko; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hodge, James W.; Schlom, Jeffrey] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 41 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 1949-2553 J9 ONCOTARGET JI Oncotarget PY 2017 VL 8 IS 5 BP 8807 EP 8817 DI 10.18632/oncotarget.12410 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EJ5YP UT WOS:000393295500137 PM 27716622 ER PT J AU Kelley, EE Paes, AMD Yadav, H Quijano, C Cassina, A Trostchansky, A AF Kelley, Eric E. Paes, Antonio Marcus de Andrade Yadav, Hariom Quijano, Celia Cassina, Adriana Trostchansky, Andres TI Interplay between Oxidative Stress and Metabolism in Signalling and Disease 2016 SO OXIDATIVE MEDICINE AND CELLULAR LONGEVITY LA English DT Editorial Material C1 [Kelley, Eric E.] West Virginia Univ, Dept Physiol & Pharmacol, Morgantown, WV 26506 USA. [Paes, Antonio Marcus de Andrade] Univ Fed Maranhao, Dept Physiol Sci, Lab Expt Physiol, Sao Luis, MA, Brazil. [Yadav, Hariom] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Quijano, Celia; Cassina, Adriana; Trostchansky, Andres] Univ Republica, Fac Med, Dept Bioquim, Montevideo, Uruguay. [Quijano, Celia; Cassina, Adriana; Trostchansky, Andres] Univ Republica, Fac Med, Ctr Free Rad & Biomed Res, Montevideo, Uruguay. RP Trostchansky, A (reprint author), Univ Republica, Fac Med, Dept Bioquim, Montevideo, Uruguay.; Trostchansky, A (reprint author), Univ Republica, Fac Med, Ctr Free Rad & Biomed Res, Montevideo, Uruguay. EM trocha@fmed.edu.uy OI Paes, Antonio Marcus de Andrade/0000-0002-3803-9803; Trostchansky, Andres/0000-0002-9721-7577; Yadav, Hariom/0000-0003-4504-1597 NR 0 TC 0 Z9 0 U1 0 U2 0 PU HINDAWI LTD PI LONDON PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, WIT 5HE, ENGLAND SN 1942-0900 EI 1942-0994 J9 OXID MED CELL LONGEV JI Oxidative Med. Cell. Longev. PY 2017 AR 7013972 DI 10.1155/2017/7013972 PG 2 WC Cell Biology SC Cell Biology GA EK7RH UT WOS:000394122400001 ER PT J AU Dahiya, N Sarachana, T Kulkarni, S Wood, WH Zhang, YQ Becker, KG Wang, BD Atreya, CD AF Dahiya, Neetu Sarachana, Tewarit Kulkarni, Sandhya Wood, William H., III Zhang, Yongqing Becker, Kevin G. Wang, Bi-Dar Atreya, Chintamani D. TI miR-570 interacts with mitochondrial ATPase subunit g (ATP5L) encoding mRNA in stored platelets SO PLATELETS LA English DT Article DE ATP5L; microarray; microRNA; platelets; storage lesion ID STORAGE; MICRORNAS; DYSFUNCTION; CORRELATE AB Loss of platelet quality during ex vivo storage is a major concern in the transfusion medicine field and it has been known that platelet mitochondrial dysfunction is associated with storage time. In the last decade, small noncoding RNAs also known as microRNAs (miRNAs) have been reported to regulate key cellular processes through their target sequence interactions with selected mRNAs. In this study, we focused on understanding the mechanisms of platelet mitochondrial dysfunction during storage through miRNA regulation of mRNAs. RNA was isolated from day 0, day 5, and day 9 of stored human leukocyte-depleted platelets and subjected to differential miRNA and mRNA profiling. The miRNA profiling identified several miRNAs at low levels including a set of 12 different miR-548 family members (miR-548a-3p, miR-548aa, miR-548x, miR-548ac, miR-548c-3p, miR-603, miR-548aj, miR-548ae, miR-548z, miR-548u, miR-548al, and miR-570-3p). The mRNA profiling identified, among many, the mitochondria] ATP synthase subunit g (ATP5L) mRNA at high levels during storage. Target Scan algorithm for potential targets of miR-570-3p also identified ATP5L as one of its targets. We further identified two target sites for miR-570-3p in the 3' untranslated region (3'UTR) of ATP5L mRNA. While ATP5L is a subunit of F(0)ATPase complex, its function is not established yet. Overexpression of miR-570-3p in platelets resulted in reduced levels of ATP5L mRNA and concomitant ATP loss. These experimental results provide first-time insights into the miRNA mRNA interactions underlying mitochondrial dysfunction in ex vivo stored platelets and warrants further investigation. C1 [Dahiya, Neetu; Sarachana, Tewarit; Kulkarni, Sandhya; Atreya, Chintamani D.] US FDA, Sect Cell Biol, Lab Cellular Hematol, Div Hematol,Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Sarachana, Tewarit] Chulalongkorn Univ, Fac Allied Hlth Sci, Dept Clin Chem, Bangkok, Thailand. [Wood, William H., III; Zhang, Yongqing; Becker, Kevin G.] NIA, Lab Genet, Baltimore, MD 21224 USA. [Wang, Bi-Dar] George Washington Sch Med & Hlth Sci, Dept Pharmacol & Physiol, Washington, DC USA. RP Atreya, CD (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 71,Room 4236, Silver Spring, MD 20993 USA. EM chintamani.atreya@fda.hhs.gov FU Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration; Center for Biologics Evaluation and Research FX Chintamani D. Atreya received funding for this study from the Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration. Neetu Dahiya and Tewarit Sarachana are recipients of a postdoctoral fellowship at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The collaborative work performed by the coauthors Kevin G. Becker, William H. Wood, and Yongqing Zhang at the National Institute on Aging, NIH, was supported by their Intramural Research Program. NR 21 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 0953-7104 EI 1369-1635 J9 PLATELETS JI Platelets PD JAN PY 2017 VL 28 IS 1 BP 74 EP 81 DI 10.1080/09537104.2016.1203405 PG 8 WC Cell Biology; Hematology SC Cell Biology; Hematology GA EJ5OZ UT WOS:000393268900013 PM 27561077 ER PT J AU Kushwaha, D Xu, P Kovac, P AF Kushwaha, Divya Xu, Peng Kovac, Pavol TI Carbohydrates as potentially versatile core subcarriers for multivalent immunogens SO RSC ADVANCES LA English DT Article ID OLIGOSACCHARIDE MIMETICS; PSEUDOMONAS-AERUGINOSA; CENTERED GLYCOCLUSTERS; REDUCTIVE DIMERIZATION; SECONDARY-AMINES; PROTEIN CARRIER; CLICK CHEMISTRY; LECTIN; AZIDES; RECOGNITION AB Synthetic multivalent glycoclusters that carry carbohydrate antigen epitopes have been recognized as promising candidates for the development of carbohydrate based vaccines. Here we describe a convergent strategy for the synthesis of conjugation-ready multivalent glycoclusters using sugars as versatile core subcarriers. D-Glucose and gentiobiose were converted into poly-alkyne functionalized cores which were then decorated with an azide bearing model ligand D-glucose using click chemistry, to form structurally well-defined tetra-and heptavalent glycoclusters. Each cluster was conjugated to a model protein bovine serum albumin (BSA) by squaric acid chemistry. Carbohydrate clusters can be prepared in a variety of sizes and spatial arrangements by altering the structure and configuration of the core, depending on the mono-, or oligosaccharides used for their assembly. It is suggested that the use of carbohydrate as core subcarriers provides an opportunity to tailor the size and topology of antigens and modify multivalent presentation of immunogens in a way to optimize cluster effect for stronger immunoreactivity. C1 [Kushwaha, Divya; Xu, Peng; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIDDK, LBC, NIH, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH) and National Institute of Diabetes and Digestive and Kidney Diseases. NR 47 TC 0 Z9 0 U1 1 U2 1 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2046-2069 J9 RSC ADV JI RSC Adv. PY 2017 VL 7 IS 13 BP 7591 EP 7603 DI 10.1039/c6ra27181b PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA EK2KV UT WOS:000393757100019 ER PT J AU Beerman, I AF Beerman, Isabel TI Accumulation of DNA damage in the aged hematopoietic stem cell compartment SO SEMINARS IN HEMATOLOGY LA English DT Article DE DNA damage; HSC; Hematopoietic stem cells; Aging ID ACUTE MYELOID-LEUKEMIA; DETECTABLE CLONAL MOSAICISM; SELF-RENEWAL; BONE-MARROW; PROGENITOR CELLS; GENE-EXPRESSION; LIFE-SPAN; REPOPULATING ABILITY; TELOMERASE ACTIVITY; OXIDATIVE STRESS AB Aging is associated with loss of functional potential of multiple tissue systems, and there has been significant interest in understanding how tissue-specific cells contribute to this decline. DNA damage accumulation has been widely associated with aging in differentiated cell types. However, tissue-specific stem cells were once thought to be a geno-protected population, as damage accrued in a stem cell population has the potential to be inherited by differentiated progeny, as well as propagated within the stem cell compartment through self-renewal divisions. This review will discuss the evidence for DNA damage accumulation in the aged HSC compartment, potential drivers, and finally the consequences of the acquired damage. Published by Elsevier Inc. C1 [Beerman, Isabel] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Beerman, I (reprint author), 251 Bayview Blvd,Suite 100-10C220, Baltimore, MD 21224 USA. EM isabel.beerman@nih.gov FU Intramural Research Program of the NIH, National Institute on Aging; [K01 AG050813-01A1] FX Supported in part by K01 AG050813-01A1 and by the Intramural Research Program of the NIH, National Institute on Aging. NR 118 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD JAN PY 2017 VL 54 IS 1 BP 12 EP 18 DI 10.1053/j.seminhematol.2016.11.001 PG 7 WC Hematology SC Hematology GA EJ8AY UT WOS:000393445800003 PM 28088982 ER PT J AU Ribeiro, JMC Slovak, M Francischetti, IMB AF Ribeiro, Jose M. C. Slovak, Mirko Francischetti, Ivo M. B. TI An insight into the sialome of Hyalomma excavatum SO TICKS AND TICK-BORNE DISEASES LA English DT Article DE Tick; Salivary gland; Saliva; Transcriptome; Sialome ID RHIPICEPHALUS BOOPHILUS MICROPLUS; SALIVARY-GLAND; TICK SALIVA; HAEMAPHYSALIS-LONGICORNIS; SEQUENCE ALIGNMENT; MOLECULAR-CLONING; BINDING-PROTEINS; PREDICTION; METALLOPROTEASE; SANGUINEUS AB Tick saliva contains hundreds or thousands of proteins that help blood feeding by impairing their hosts' hemostasis, inflammation and immunity. Salivary gland transcriptomes allow the disclosure of this pharmacologically active potion that consists of several multi-gene families, many of which are tick-specific. We here report the "de novo" assembly of similar to 138 million reads deriving from a cDNA library from salivary glands of adult male and female Hyalomma excavatum leading to the public deposition of 5337 coding sequences to GenBank. Among the deducted putative secreted proteins, metalloproteases, glycine rich proteins, mucins, anticoagulants of the madanin family and lipocalins were the most expressed. Novel protein families were identified. These sequences will permit proteomic studies aiming at identification of target antigens, epidemiological markers or salivary pharmaceuticals of interest, and contribute to our understanding of the fast evolution of the tick sialome. Published by Elsevier GmbH. C1 [Ribeiro, Jose M. C.; Francischetti, Ivo M. B.] NIAID, Lab Malaria & Vector Res, Bethesda, MD 20852 USA. [Slovak, Mirko] Slovak Acad Sci, Inst Zool, Dubravska Cesta 9, Bratislava 84506, Slovakia. RP Ribeiro, JMC (reprint author), NIAID, Lab Malaria & Vector Res, Bethesda, MD 20852 USA. EM jribeiro@nih.gov; slovak.mirko@gmail.com; ifrancischetti@niaid.nih.gov OI Ribeiro, Jose/0000-0002-9107-0818 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; Slovak Research and Development Agency [APVV-0737-12]; Slovak VEGA grant [2/0089/13] FX JMCR and IMBF were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. MS was partially supported by the Slovak Research and Development Agency (APVV-0737-12) and by Slovak VEGA grant 2/0089/13. Because JMCR and IMBF are government employees and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U.S. subject to a government use license. NR 41 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1877-959X EI 1877-9603 J9 TICKS TICK-BORNE DIS JI Ticks Tick-Borne Dis. PY 2017 VL 8 IS 2 BP 201 EP 207 DI 10.1016/j.ttbdis.2016.08.011 PG 7 WC Infectious Diseases; Microbiology; Parasitology SC Infectious Diseases; Microbiology; Parasitology GA EJ5KK UT WOS:000393256700001 PM 28049606 ER PT J AU Kuo, HC Ferre, CL Carmel, JB Gowatsky, JL Stanford, AD Rowny, SB Lisanby, SH Gordon, AM Friel, KM AF Kuo, Hsing-Ching Ferre, Claudio L. Carmel, Jason B. Gowatsky, Jaimie L. Stanford, Arielle D. Rowny, Stefan B. Lisanby, Sarah H. Gordon, Andrew M. Friel, Kathleen M. TI Using diffusion tensor imaging to identify corticospinal tract projection patterns in children with unilateral spastic cerebral palsy SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Article ID INDUCED MOVEMENT THERAPY; CONGENITAL HEMIPLEGIA; RANDOMIZED-TRIAL; MOTOR; PLASTICITY; INJURY; TRACTOGRAPHY; HEMIPARESIS; DYSGENESIS; DEFICITS AB AIM To determine whether diffusion tensor imaging (DTI) can be an independent assessment for identifying the corticospinal tract (CST) projecting from the more-affected motor cortex in children with unilateral spastic cerebral palsy (CP). METHOD Twenty children with unilateral spastic CP participated in this study (16 males, four females; mean age 9y 2 mo [standard deviation (SD) 3y 2mo], Manual Ability Classification System [MACS] level I-III). We used DTI tractography to reconstruct the CST projecting from the more-affected motor cortex. We mapped the motor representation of the more-affected hand by stimulating the more-and the less-affected motor cortex measured with single-pulse transcranial magnetic stimulation (TMS). We then verified the presence or absence of the contralateral CST by comparing the TMS map and DTI tractography. Fisher's exact test was used to determine the association between findings of TMS and DTI. RESULTS DTI tractography successfully identified the CST controlling the more-affected hand (sensitivity=82%, specificity=78%). INTERPRETATION Contralateral CST projecting from the lesioned motor cortex assessed by DTI is consistent with findings of TMS mapping. Since CST connectivity may be predictive of response to certain upper extremity treatments, DTI-identified CST connectivity may potentially be valuable for determining such connectivity where TMS is unavailable or inadvisable for children with seizures. C1 [Kuo, Hsing-Ching; Gordon, Andrew M.] Columbia Univ, Coll Teachers, Dept Biobehav Sci, New York, NY 10027 USA. [Ferre, Claudio L.; Carmel, Jason B.; Friel, Kathleen M.] Burke Cornell Med Res Inst, 785 Mamaroneck Ave, White Plains, NY 10605 USA. [Carmel, Jason B.; Friel, Kathleen M.] Weill Cornell Med Coll, Brain Mind Res Inst, New York, NY USA. [Carmel, Jason B.; Friel, Kathleen M.] Weill Cornell Med Coll, Dept Neurol, New York, NY USA. [Carmel, Jason B.] Weill Cornell Med Coll, Dept Pediat, New York, NY USA. [Gowatsky, Jaimie L.; Rowny, Stefan B.] Columbia Univ, New York State Psychiat Inst, New York, NY USA. [Stanford, Arielle D.] Alkermes Inc, Clin Sci, Waltham, MA USA. [Lisanby, Sarah H.] NIH, Div Translat Res, Rockville, MD USA. RP Friel, KM (reprint author), Burke Cornell Med Res Inst, 785 Mamaroneck Ave, White Plains, NY 10605 USA. EM kaf3001@med.cornell.edu FU National Institutes of Health [R01HD076436A1, K01NS062116, KL2 RR024157, UL1 RR024156, TL1 RR024158, K08 NS073796] FX We thank families and volunteers participating in this study. We also thank those individuals involved: Bruce Bassi, David Murphy, Bruce Luber, Marina Brandao, Jason Fuller, Stephen Dashnaw, Greg Westin, Charles Schroeder, Dan Javitt, Karen Chin. Grant support: KF (R01HD076436A1, K01NS062116, KL2 RR024157, UL1 RR024156, TL1 RR024158). JBC (K08 NS073796). The National Institutes of Health provided funding that paid for researchers' time and MRI fees. The funder was not involved in study design, data analysis, manuscript preparation, or publication decisions. The authors have stated that they had no interests which might be perceived as posing a conflict or bias. NR 26 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1622 EI 1469-8749 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD JAN PY 2017 VL 59 IS 1 BP 65 EP 71 DI 10.1111/dmcn.13192 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA EI9LP UT WOS:000392829900019 PM 27465858 ER PT J AU Kerridge, BT Pickering, RP Saha, TD Ruan, WJ Chou, SP Zhang, HT Jung, J Hasin, DS AF Kerridge, Bradley T. Pickering, Roger P. Saha, Tulshi D. Ruan, W. June Chou, S. Patricia Zhang, Haitao Jung, Jeesun Hasin, Deborah S. TI Prevalence, sociodemographic correlates and DSM-5 substance use disorders and other psychiatric disorders among sexual minorities in the United States SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Sexual minorities; Substance use disorders; Psychiatric disorders; Gay/lesbian; Bisexual; Disparities ID NATIONAL EPIDEMIOLOGIC SURVEY; ALCOHOL-USE DISORDER; GENERAL-POPULATION SAMPLE; DRUG-USE DISORDERS; MENTAL-HEALTH; REPRESENTATIVE SAMPLE; BISEXUAL POPULATIONS; PROCEDURAL VALIDITY; GAY MEN; ORIENTATION AB Purpose: The purpose of this study was to present current nationally representative data on the prevalences, sociodemographic correlates and risk of DSM-5 substance use disorders and other psychiatric disorders among sexual minorities (SMs) relative to heterosexuals, and among SMs by gender. Methods: Data were derived from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III. Results: In the general noninstitutionalized population, 1.5%, 1.3% and 0.5% of individuals self-identified as gay/lesbian, bisexual and not sure sexual orientations. Men were more likely to report gay/lesbian orientation than women (1.8% vs. 1.2%). Women were more likely than men to report bisexual (1.8% vs. 0.8%) and not sure (0.6% vs. 0.4%) sexual orientations. Sociodemographic characteristics varied across sexual orientation and gender. Relative to heterosexuals, disparities in substance use and psychiatric disorders were found across sexual orientations, especially among bisexual women. Greater rates of specific psychiatric disorders were also demonstrated by women reporting bisexual and not sure orientations relative to lesbian women, with fewer differences in rates of psychopathology among SM men. Conclusions: Despite growing acceptance of SMs and SM rights over the past decade, substantial mental health disparities exist among these subgroups of the U.S. noninstitutionalized population, especially among bisexual women. More research is needed to understand these mental health disparities, while considering nuances of multiple intersecting minority identities and unique contextual factors. Findings: underscore the importance of advancing future population-based research that includes detailed information on the health and well-being of SMs in the United States. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Kerridge, Bradley T.; Hasin, Deborah S.] New York State Psychiat Inst & Hosp, 1051 Riverside Dr Unit 123, New York, NY 10032 USA. [Pickering, Roger P.; Saha, Tulshi D.; Ruan, W. June; Chou, S. Patricia; Zhang, Haitao; Jung, Jeesun] NIAAA, Epidemiol & Biometry Branch, NIH, 5635 Fishers Lane, Rockville, MD 20852 USA. [Hasin, Deborah S.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10027 USA. RP Kerridge, BT (reprint author), New York State Psychiat Inst & Hosp, 1051 Riverside Dr Unit 123, New York, NY 10032 USA. EM bradleykerridge@gmail.com FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Drug Abuse (NIDA); NIDA [F32DA036431]; [R01 DA034244] FX The NESARC-III was sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), with supplemental support from the National Institute on Drug Abuse (NIDA). Support is also acknowledged from F32DA036431, NIDA, for Dr. Kerridge and from R01 DA034244, for Dr. Hasin. The sponsor had no role in the study design; collection, analysis and interpretation of the data: in the writing of the report and in the decision to submit the article for publication. NR 57 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JAN 1 PY 2017 VL 170 BP 82 EP 92 DI 10.1016/j.drugalcdep.2016.10.038 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EI8TT UT WOS:000392781700012 PM 27883948 ER PT J AU Oronsky, B Paulmurugan, R Foygel, K Scicinski, J Knox, SJ Peehl, D Zhao, HJ Ning, SC Cabrales, P Summers, TA Reid, TR Fitch, WL Kim, MM Trepel, JB Lee, MJ Kesari, S Abrouk, ND Day, RM Oronsky, A Ray, CM Carterg, CA AF Oronsky, Bryan Paulmurugan, Ramasamy Foygel, Kira Scicinski, Jan Knox, Susan J. Peehl, Donna Zhao, Hongjuan Ning, Shoucheng Cabrales, Pedro Summers, Thomas A., Jr. Reid, Tony R. Fitch, William L. Kim, Michelle M. Trepel, Jane B. Lee, Min-Jung Kesari, Santosh Abrouk, Nacer D. Day, Regina M. Oronsky, Arnold Ray, Carolyn M. Carterg, Corey A. TI RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Article DE Tumor associated macrophages; cancer therapy; RRx-001; cancer stem cells ID EPIGENETIC AGENT; ANTICANCER AGENT; ENDOTHELIAL-CELLS; DRUG-RESISTANCE; CANCER; METABOLISM; RECEPTOR AB Introduction: According to Hanahan and Weinberg, cancer manifests as six essential physiologic hallmarks: (1) self-sufficiency in growth signals, (2) insensitivity to growth-inhibitory signals, (3) evasion of programmed cell death, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) invasion and metastasis. As a facilitator of these traits as well as immunosuppression and chemoresistance, the presence of tumor-associated macrophages (TAMs) may serve as the seventh hallmark of cancer. Anticancer agents that successfully reprogram TAMs to target rather than support tumor cells may hold the key to better therapeutic outcomes. Areas covered: This article summarizes the characteristics of the macrophage-stimulating agent RRx-001, a molecular iconoclast, sourced from the aerospace industry, with a particular emphasis on the cell-to-cell transfer mechanism of action (RBCs to TAMs) underlying its antitumor activity as well as its chemo and radioprotective properties, consolidated from various preclinical and clinical studies. Expert opinion: RRx-001 is macrophage-stimulating agent with the potential to synergize with chemotherapy, radiotherapy and immunotherapy while simultaneously protecting normal tissues from their cytotoxic effects. Given the promising indications of activity in multiple tumor types and these normal tissue protective properties, RRx-001 may be used to treat a broad spectrum of malignancies, if it is approved in the future. C1 [Oronsky, Bryan; Scicinski, Jan] EpicentRx No Dept, Palo Alto, CA USA. [Paulmurugan, Ramasamy; Foygel, Kira] Stanford Univ, Dept Radiol, Palo Alto, CA 94304 USA. [Knox, Susan J.; Ning, Shoucheng] Stanford Univ, Dept Radiat Oncol, Palo Alto, CA 94304 USA. [Peehl, Donna; Zhao, Hongjuan] Stanford Univ, Dept Urol, Palo Alto, CA 94304 USA. [Fitch, William L.] Stanford Univ, Dept Anesthesia, Palo Alto, CA 94304 USA. [Cabrales, Pedro] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Summers, Thomas A., Jr.; Carterg, Corey A.] Walter Reed Natl Mil Med Ctr, Murtha Canc Ctr, Bethesda, MD USA. [Reid, Tony R.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Trepel, Jane B.; Lee, Min-Jung] NCI, NIH, Bethesda, MD 20892 USA. [Kesari, Santosh] Providence St Johns Hlth Ctr, John Wayne Canc Inst, Santa Monica, CA USA. [Kim, Michelle M.; Abrouk, Nacer D.] Innovexe, Bethesda, MD USA. [Day, Regina M.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD USA. [Oronsky, Arnold] InterWest Partners, Hartford, CT USA. [Ray, Carolyn M.] St Francis Hosp & Med Ctr, Ctr Canc, Hartford, CT USA. RP Paulmurugan, R (reprint author), Stanford Univ, Sch Med, Dept Radiol, 3155 Porter Dr, Palo Alto, CA 94304 USA. EM paulmur8@stanford.edu NR 35 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1354-3784 EI 1744-7658 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PY 2017 VL 26 IS 1 BP 109 EP 119 DI 10.1080/13543784.2017.1268600 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI9PM UT WOS:000392840700012 PM 27935336 ER EF