FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Ford, AQ Touchette, N Hall, BF Hwang, A Hombach, J AF Ford, Andrew Q. Touchette, Nancy Hall, B. Fenton Hwang, Angela Hombach, Joachim TI Global Vaccine and Immunization Research Forum: Opportunities and challenges in vaccine discovery, development, and delivery SO VACCINE LA English DT Article DE GVIRF; GVAP ID RTS,S/AS01 MALARIA VACCINE; AFRICAN INFANTS; PHASE-3 TRIAL AB The World Health Organization, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Bill & Melinda Gates Foundation convened the first Global Vaccine and Immunization Research Forum (GVIRF) in March 2014. This first GVIRF aimed to track recent progress of the Global Vaccine Action Plan research and development agenda, identify opportunities and challenges, promote partnerships in vaccine research, and facilitate the inclusion of all stakeholders in vaccine research and development. Leading scientists, vaccine developers, and public health officials from around the world discussed scientific and technical challenges in vaccine development, research to improve the impact of immunization, and regulatory issues. This report summarizes the discussions and conclusions from the forum participants. C1 [Ford, Andrew Q.; Hall, B. Fenton] NIAID, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Touchette, Nancy] NIAID, Off Global Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hwang, Angela] Bill & Melinda Gates Fdn, Seattle, WA USA. [Hombach, Joachim] WHO, Dept Immunizat Vaccines & Biol, CH-1211 Geneva, Switzerland. RP Ford, AQ (reprint author), NIAID, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM andrew.ford@nih.gov FU NIAID [U01AI108543]; Bill & Melinda Gates Foundation [1041765] FX We thank the members of the scientific organizing committee for their dedication and contribution to the development of the meeting agenda: Dr. Norman Baylor, Dr. M.L. (Raj) Bhan, Professor John Clemens, Dr. Tumani Corrah, Professor David Durrheim, Dr. Thomas Evans, Professor Ingileif Jonsdottir, Professor Rosanna Lagos, Dr. Odile Leroy, Dr. Kathleen Neuzil, Dr. Alexander Precioso, Professor Helen Rees, Dr. Yiming Shao, and Dr. Anita Zaidi. Additionally, we thank the session chairs, panelists, and discussants for their valuable slides, presentations, and comments; and the meeting participants for their thorough and insightful discussions. This forum was supported in part by NIAID cooperative agreement number U01AI108543 and a grant from the Bill & Melinda Gates Foundation (1041765). NR 21 TC 0 Z9 0 U1 0 U2 3 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 MAR 18 PY 2016 VL 34 IS 13 BP 1489 EP 1495 DI 10.1016/j.vaccine.2015.11.038 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DH4NS UT WOS:000372763300001 PM 26626210 ER PT J AU Menazza, S Murphy, E AF Menazza, Sara Murphy, Elizabeth TI The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System SO CIRCULATION RESEARCH LA English DT Review DE estrogens; MAP kinase signaling pathways; PI3 kinases; receptors; G-protein-coupled; signal transduction ID NITRIC-OXIDE SYNTHASE; VASCULAR SMOOTH-MUSCLE; ISCHEMIA-REPERFUSION INJURY; HUMAN ENDOTHELIAL-CELLS; SPONTANEOUSLY HYPERTENSIVE-RATS; PULMONARY-ARTERY ENDOTHELIUM; INHIBITS CARDIAC-HYPERTROPHY; EPIDERMAL-GROWTH-FACTOR; HEAT-SHOCK-PROTEIN; 17 BETA-ESTRADIOL AB Estrogen has important effects on cardiovascular function including regulation of vascular function, blood pressure, endothelial relaxation, and the development of hypertrophy and cardioprotection. However, the mechanisms by which estrogen mediates these effects are still poorly understood. As detailed in this review, estrogen can regulate transcription by binding to 2 nuclear receptors, ER and ER, which differentially regulate gene transcription. ER and ER regulation of gene transcription is further modulated by tissue-specific coactivators and corepressors. Estrogen can bind to ER and ER localized at the plasma membrane as well as G-protein-coupled estrogen receptor to initiate membrane delimited signaling, which enhances kinase signaling pathways that can have acute and long-term effects. The kinase signaling pathways can also mediate transcriptional changes and can synergize with the ER to regulate cell function. This review will summarize the beneficial effects of estrogen in protecting the cardiovascular system through ER-dependent mechanisms with an emphasis on the role of the recently described ER membrane signaling mechanisms. C1 [Menazza, Sara; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bldg 10,Rm 8N202,10 Ctr Dr, Bethesda, MD 20892 USA. RP Menazza, S (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10,Rm 8N202,10 Ctr Dr, Bethesda, MD 20892 USA. EM sara.menazza@nih.gov FU National Heart, Lung, and Blood Institute Intramural funds FX This work was supported by National Heart, Lung, and Blood Institute Intramural funds. NR 167 TC 4 Z9 4 U1 8 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAR 18 PY 2016 VL 118 IS 6 BP 994 EP 1007 DI 10.1161/CIRCRESAHA.115.305376 PG 14 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DG5WQ UT WOS:000372150600012 PM 26838792 ER PT J AU Chaiworapongsa, T Romero, R Korzeniewski, SJ Chaemsaithong, P Hernandez-Andrade, E Segars, JH DeCherney, AH McCoy, MC Kim, CJ Yeo, L Hassan, SS AF Chaiworapongsa, Tinnakorn Romero, Roberto Korzeniewski, Steven J. Chaemsaithong, Piya Hernandez-Andrade, Edgar Segars, James H. DeCherney, Alan H. McCoy, M. Cathleen Kim, Chong Jai Yeo, Lami Hassan, Sonia S. TI Pravastatin to prevent recurrent fetal death in massive perivillous fibrin deposition of the placenta (MPFD) SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Angiogenic factors; maternal floor infarction; placental growth factor; preeclampsia; proton pump inhibitor; soluble endoglin; soluble vascular endothelial growth factor receptor-1 ID MATERNAL FLOOR INFARCTION; ANTI-ANGIOGENIC FACTORS; FACTOR RECEPTOR-1 CONCENTRATION; FOR-GESTATIONAL-AGE; GROWTH-FACTOR; INTRAVENOUS IMMUNOGLOBULIN; ANTIFETAL REJECTION; SOLUBLE ENDOGLIN; EARLY-PREGNANCY; MURINE MODEL AB Massive perivillous fibrin deposition of the placenta (MPFD) or maternal floor infarction (MFI) is a serious condition associated with recurrent complications including fetal death and severe fetal growth restriction. There is no method to evaluate the risk of adverse outcome in subsequent pregnancies, or effective prevention. Recent observations suggest that MFI is characterized by an imbalance in angiogenic/anti-angiogenic factors in early pregnancy; therefore, determination of these biomarkers may identify the patient at risk for recurrence. We report the case of a pregnant woman with a history of four consecutive pregnancy losses, the last of which was affected by MFI. Abnormalities of the anti-angiogenic factor, sVEGFR-1, and soluble endoglin (sEng) were detected early in the index pregnancy, and treatment with pravastatin corrected the abnormalities. Treatment resulted in a live birth infant at 34 weeks of gestation who had normal biometric parameters and developmental milestones at the age of 2. This is the first reported successful use of pravastatin to reverse an angiogenic/anti-angiogenic imbalance and prevent fetal death. C1 [Chaiworapongsa, Tinnakorn; Romero, Roberto; Korzeniewski, Steven J.; Chaemsaithong, Piya; Hernandez-Andrade, Edgar; Kim, Chong Jai; Yeo, Lami; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Chaiworapongsa, Tinnakorn; Korzeniewski, Steven J.; Chaemsaithong, Piya; Hernandez-Andrade, Edgar; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto; Korzeniewski, Steven J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Dept Mol Obstet & Genet, Detroit, MI 48201 USA. [Segars, James H.; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [McCoy, M. Cathleen] Winchester Med Ctr, Perinatal Unit, Winchester Obstet & Gynecol, Winchester, VA USA. [Kim, Chong Jai] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NIH, NICHD,Hutzel Womens Hos,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM tchaiwor@med.wayne.edu; rromero@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX The authors report no conflicts of interest. 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, DHHS. NR 101 TC 6 Z9 6 U1 1 U2 13 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD MAR 18 PY 2016 VL 29 IS 6 BP 855 EP 862 DI 10.3109/14767058.2015.1022864 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CY3PQ UT WOS:000366322400001 PM 25893545 ER PT J AU Meffre, E Louie, A Bannock, J Kim, LJY Ho, J Frear, CC Kardava, L Wang, W Buckner, CM Wang, YM Fankuchen, OR Gittens, KR Chun, TW Li, YX Fauci, AS Moir, S AF Meffre, Eric Louie, Aaron Bannock, Jason Kim, Leo J. Y. Ho, Jason Frear, Cody C. Kardava, Lela Wang, Wei Buckner, Clarisa M. Wang, Yimeng Fankuchen, Olivia R. Gittens, Kathleen R. Chun, Tae-Wook Li, Yuxing Fauci, Anthony S. Moir, Susan TI Maturational characteristics of HIV-specific antibodies in viremic individuals SO JCI INSIGHT LA English DT Article ID MEMORY B-CELLS; WISKOTT-ALDRICH SYNDROME; VIRUS TYPE-1 INFECTION; V-H GENES; NEUTRALIZING ANTIBODIES; PERIPHERAL-BLOOD; IMMUNE DYSREGULATION; SITE ANTIBODIES; GERMINAL CENTER; CD4 BINDING AB Despite the rare appearance of potent HIV-neutralizing mAbs in infected individuals requiring prolonged affinity maturation, little is known regarding this process in the majority of viremic individuals. HIV-infected individuals with chronic HIV viremia have elevated numbers of nonconventional tissue-like memory (TLM) B cells that predominate in blood over conventional resting memory (RM) B cells. Accordingly, we investigated affinity maturation in these 2 memory B cell populations. Analysis of IgG-expressing TLM B cells revealed a higher number of cell divisions compared with RM B cells; however, TLM B cells paradoxically displayed significantly lower frequencies of somatic hypermutation (SHM). To assess Ab reactivity in TLM and RM B cells, single-cell cloning was performed on HIV envelope CD4-binding site-sorted (CD4bs-sorted) B cells from 3 individuals with chronic HIV viremia. Several clonal families were present among the 127 cloned recombinant mAbs, with evidence of crosstalk between TLM and RM B cell populations that was largely restricted to non-VH4 families. Despite evidence of common origins, SHM frequencies were significantly decreased in TLM-derived mAbs compared with SHM frequencies in RM-derived mAbs. However, both cell populations had lower frequencies of SHMs than did broadly neutralizing CD4bs-specific mAbs. There was a significant correlation between SHM frequencies and the HIV-neutralizing capacities of the mAbs. Furthermore, HIV neutralization was significantly higher in the RM-derived mAbs compared with that seen in the TLM-derived mAbs, and both SHM frequencies and neutralizing capacity were lowest in TLM-derived mAbs with high polyreactivity. Thus, deficiencies in memory B cells that arise during chronic HIV viremia provide insight into the inadequacy of the Ab response in viremic individuals. C1 [Meffre, Eric; Bannock, Jason] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [Louie, Aaron; Kim, Leo J. Y.; Ho, Jason; Frear, Cody C.; Kardava, Lela; Wang, Wei; Buckner, Clarisa M.; Fankuchen, Olivia R.; Chun, Tae-Wook; Fauci, Anthony S.; Moir, Susan] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wang, Yimeng; Li, Yuxing] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD USA. [Gittens, Kathleen R.] NIAID, Crit Care Med Dept, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Li, Yuxing] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kim, Leo J. Y.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Ho, Jason] Boehringer Ingelheim GmbH & Co KG, Ridgefield, CT USA. [Frear, Cody C.] Arizona State Univ, Tempe, AZ USA. RP Meffre, E (reprint author), Yale Univ, Sch Med, 300 George St,Room 353F, New Haven, CT 06511 USA.; Moir, S (reprint author), NIH, 9000 Rockville Pike,Bldg 10,Room 6A02, Bethesda, MD 20892 USA. EM Eric.meffre@yale.edu; smoir@niaid.nih.gov NR 74 TC 2 Z9 2 U1 2 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD MAR 17 PY 2016 VL 1 IS 3 AR e84610 DI 10.1172/jci.insight.84610 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1IR UT WOS:000387104000003 ER PT J AU Kulkarni, A Ertekin, D Lee, CH Hummel, T AF Kulkarni, Abhishek Ertekin, Deniz Lee, Chi-Hon Hummel, Thomas TI Birth order dependent growth cone segregation determines synaptic layer identity in the Drosophila visual system SO ELIFE LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; REGULATES TARGET SPECIFICITY; REPRESSIBLE CELL MARKER; N-CADHERIN; AXON-AXON; PHOTORECEPTOR NEURONS; TRANSMEMBRANE PROTEIN; SPECTRAL PREFERENCE; NEURAL DEVELOPMENT; CIRCUIT FORMATION AB The precise recognition of appropriate synaptic partner neurons is a critical step during neural circuit assembly. However, little is known about the developmental context in which recognition specificity is important to establish synaptic contacts. We show that in the Drosophila visual system, sequential segregation of photoreceptor afferents, reflecting their birth order, lead to differential positioning of their growth cones in the early target region. By combining loss-and gain-of-function analyses we demonstrate that relative differences in the expression of the transcription factor Sequoia regulate R cell growth cone segregation. This initial growth cone positioning is consolidated via cell-adhesion molecule Capricious in R8 axons. Further, we show that the initial growth cone positioning determines synaptic layer selection through proximity-based axon-target interactions. Taken together, we demonstrate that birth order dependent pre-patterning of afferent growth cones is an essential pre-requisite for the identification of synaptic partner neurons during visual map formation in Drosophila. C1 [Kulkarni, Abhishek; Ertekin, Deniz; Hummel, Thomas] Univ Vienna, Dept Neurobiol, Vienna, Austria. [Lee, Chi-Hon] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, Sect Neuronal Connect, Bethesda, MD USA. RP Hummel, T (reprint author), Univ Vienna, Dept Neurobiol, Vienna, Austria. EM thomas.hummel@univie.ac.at OI Ertekin, Deniz/0000-0001-9480-8622 FU Deutsche Forschungsgemeinschaft [Hu992/1-2]; Schram Foundation [BCA01] FX Deutsche Forschungsgemeinschaft Hu992/1-2 Thomas Hummelr Schram Foundation BCA01 Thomas Hummelr The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 94 TC 1 Z9 1 U1 1 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 17 PY 2016 VL 5 AR e13715 DI 10.7554/eLife.13715 PG 22 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DV2GT UT WOS:000382739500001 PM 26987017 ER PT J AU Draizen, EJ Shaytan, AK Marino-Ramirez, L Talbert, PB Landsman, D Panchenko, AR AF Draizen, Eli J. Shaytan, Alexey K. Marino-Ramirez, Leonardo Talbert, Paul B. Landsman, David Panchenko, Anna R. TI HistoneDB 2.0: a histone database with variants-an integrated resource to explore histones and their variants SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID CHROMATIN-STRUCTURE; NUCLEOSOME; SEQUENCE; DNA; MECHANISMS; INSIGHTS; BINDING; YEAST; H1 AB Compaction of DNA into chromatin is a characteristic feature of eukaryotic organisms. The core (H2A, H2B, H3, H4) and linker (H1) histone proteins are responsible for this compaction through the formation of nucleosomes and higher order chromatin aggregates. Moreover, histones are intricately involved in chromatin functioning and provide a means for genome dynamic regulation through specific histone variants and histone post-translational modifications. 'HistoneDB 2.0 - with variants' is a comprehensive database of histone protein sequences, classified by histone types and variants. All entries in the database are supplemented by rich sequence and structural annotations with many interactive tools to explore and compare sequences of different variants from various organisms. The core of the database is a manually curated set of histone sequences grouped into 30 different variant subsets with variant-specific annotations. The curated set is supplemented by an automatically extracted set of histone sequences from the non-redundant protein database using algorithms trained on the curated set. The interactive web site supports various searching strategies in both datasets: browsing of phylogenetic trees; on-demand generation of multiple sequence alignments with feature annotations; classification of histone-like sequences and browsing of the taxonomic diversity for every histone variant. HistoneDB 2.0 is a resource for the interactive comparative analysis of histone protein sequences and their implications for chromatin function. C1 [Draizen, Eli J.; Shaytan, Alexey K.; Marino-Ramirez, Leonardo; Landsman, David; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. [Talbert, Paul B.] Fred Hutchinson Canc Res Ctr, Howard Hughes Med Inst, Div Basic Sci, Seattle, WA 98109 USA. RP Landsman, D; Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM landsman@ncbi.nlm.nih.gov; panch@ncbi.nlm.nih.gov RI Shaytan, Alexey/D-7306-2012; OI Shaytan, Alexey/0000-0003-0312-938X; Marino-Ramirez, Leonardo/0000-0002-5716-8512; Landsman, David/0000-0002-9819-6675 FU National Library of Medicine, NIH; US-Russia Collaboration in the Biomedical Sciences NIH visiting fellows program FX This work was supported by the Intramural Research Program of the National Library of Medicine, NIH. A.S. was supported in part by the US-Russia Collaboration in the Biomedical Sciences NIH visiting fellows program. NR 40 TC 1 Z9 1 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD MAR 17 PY 2016 AR baw014 DI 10.1093/database/baw014 PG 10 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DJ3FJ UT WOS:000374089900001 ER PT J AU Morena, D Maestro, N Bersani, F Forni, PE Lingua, MF Foglizzo, V Scepanovic, P Miretti, S Morotti, A Shern, JF Khan, J Ala, U Provero, P Sala, V Crepaldi, T Gasparini, P Casanova, M Ferrari, A Sozzi, G Chiarle, R Ponzetto, C Taulli, R AF Morena, Deborah Maestro, Nicola Bersani, Francesca Forni, Paolo Emanuele Lingua, Marcello Francesco Foglizzo, Valentina Scepanovic, Peter Miretti, Silvia Morotti, Alessandro Shern, Jack F. Khan, Javed Ala, Ugo Provero, Paolo Sala, Valentian Crepaldi, Tiziana Gasparini, Patrizia Casanova, Michela Ferrari, Andrea Sozzi, Gabriella Chiarle, Roberto Ponzetto, Carola Taulli, Riccardo TI Hepatocyte Growth Factor-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes SO ELIFE LA English DT Article ID SOFT-TISSUE SARCOMAS; UNDIFFERENTIATED PLEOMORPHIC SARCOMA; CHILDRENS ONCOLOGY GROUP; ADULT SKELETAL-MUSCLE; EMBRYONAL RHABDOMYOSARCOMA; ALVEOLAR RHABDOMYOSARCOMA; INTRATUMOR HETEROGENEITY; FIBROUS HISTIOCYTOMA; LARGE SERIES; STEM-CELLS AB Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes. Here we investigate the relevance of the satellite cell (SC) niche in sarcoma development by using Hepatocyte Growth Factor (HGF) to perturb the niche microenvironment. In a Pax7 wild type background, HGF stimulation mainly causes ERMS that originate from satellite cells following a process of multistep progression. Conversely, in a Pax7 null genotype ERMS incidence drops, while UPS becomes the most frequent subtype. Murine EfRMS display genetic heterogeneity similar to their human counterpart. Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation. Finally, our results provide a rationale for the use of combination therapy, tailored on specific amplifications and activated signaling pathways, to minimize resistance emerging from sarcomas heterogeneity. C1 [Morena, Deborah; Maestro, Nicola; Bersani, Francesca; Forni, Paolo Emanuele; Lingua, Marcello Francesco; Foglizzo, Valentina; Scepanovic, Peter; Sala, Valentian; Crepaldi, Tiziana; Ponzetto, Carola; Taulli, Riccardo] Univ Turin, Dept Oncol, Turin, Italy. [Morena, Deborah; Maestro, Nicola; Bersani, Francesca; Forni, Paolo Emanuele; Lingua, Marcello Francesco; Foglizzo, Valentina; Scepanovic, Peter; Chiarle, Roberto; Ponzetto, Carola; Taulli, Riccardo] Ctr Expt Res & Med Studies, CeRMS, Turin, Italy. [Miretti, Silvia] Univ Turin, Dept Vet Sci, Grugliasco, Italy. [Morotti, Alessandro] Univ Turin, Dept Clin & Biol Sci, Orbassano, Italy. [Shern, Jack F.; Khan, Javed] NIH, Pediat Oncol Branch, Oncogen Sect, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Ala, Ugo; Provero, Paolo; Chiarle, Roberto] Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy. [Gasparini, Patrizia; Casanova, Michela; Ferrari, Andrea; Sozzi, Gabriella] Fdn IRCCS Ist Nazl Tumori, Dept Expt Oncol, Milan, Italy. [Chiarle, Roberto] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Chiarle, Roberto] Harvard Univ, Sch Med, Boston, MA USA. [Maestro, Nicola] UCL, Samantha Dickson Canc Unit, Canc Inst, London, England. [Bersani, Francesca] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Canc Ctr, Charlestown, MA USA. [Forni, Paolo Emanuele] SUNY Albany, Dept Biol Sci, Albany, NY 12222 USA. [Forni, Paolo Emanuele] SUNY Albany, Ctr Neurosci Res, Albany, NY 12222 USA. [Foglizzo, Valentina] Francis Crick Inst, Mill Hill Lab, London, England. [Scepanovic, Peter] Ecole Polytech Fed Lausanne, Sch Life Sci, CH-1015 Lausanne, Switzerland. [Scepanovic, Peter] Swiss Inst Bioinformat, Lausanne, Switzerland. RP Taulli, R (reprint author), Univ Turin, Dept Oncol, Turin, Italy.; Taulli, R (reprint author), Ctr Expt Res & Med Studies, CeRMS, Turin, Italy. EM riccardo.taulli@unito.it RI Ala, Ugo/K-2029-2016; sozzi, gabriella/G-8259-2011; Casanova, Michela/K-8436-2016; Khan, Javed/P-9157-2014; Gasparini, Patrizia/Q-7626-2016; OI Ala, Ugo/0000-0001-5408-6397; sozzi, gabriella/0000-0001-9360-6914; Casanova, Michela/0000-0003-0368-7883; Khan, Javed/0000-0002-5858-0488; Gasparini, Patrizia/0000-0002-9548-3724; Morotti, Alessandro/0000-0002-8407-2903; Ferrari, Andrea/0000-0002-4724-0517 FU Italian Association for Cancer Research [IG12089, 15405]; Regione Piemonte; Associazione Bianca Garavaglia [A/15/01N] FX Italian Association for Cancer Research AIRC Project number, IG12089 Carola Ponzetto; Regione Piemonte IMMONC Project Carola Ponzetto; Italian Association for Cancer Research AIRC Start-Up, Project number 15405 Riccardo Taulli; Associazione Bianca Garavaglia A/15/01N Gabriella Sozzi NR 68 TC 1 Z9 1 U1 1 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 17 PY 2016 VL 5 AR e12116 DI 10.7554/eLife.12116 PG 24 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ0ML UT WOS:000373897900001 ER PT J AU Machlus, KR Wu, SK Stumpo, DJ Soussou, TS Paul, DS Campbell, RA Kalwa, H Michel, T Bergmeier, W Weyrich, AS Blackshear, PJ Hartwig, JH Italiano, JE AF Machlus, Kellie R. Wu, Stephen K. Stumpo, Deborah J. Soussou, Thomas S. Paul, David S. Campbell, Robert A. Kalwa, Hermann Michel, Thomas Bergmeier, Wolfgang Weyrich, Andrew S. Blackshear, Perry J. Hartwig, John H. Italiano, Joseph E., Jr. TI Synthesis and dephosphorylation of MARCKS in the late stages of megakaryocyte maturation drive proplatelet formation SO BLOOD LA English DT Article ID C-KINASE SUBSTRATE; DEMARCATION MEMBRANE SYSTEM; PLATELET PRODUCTION; IN-VITRO; EFFECTOR DOMAIN; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; RAT MEGAKARYOCYTES; AROMATIC RESIDUES; SH-SY5Y CELLS; PROTEIN AB Platelets are essential for hemostasis, and thrombocytopenia is a major clinical problem. Megakaryocytes (MKs) generate platelets by extending long processes, proplatelets, into sinusoidal blood vessels. However, very little is known about what regulates proplatelet formation. To uncover which proteins were dynamically changing during this process, we compared the proteome and transcriptome of round vs proplatelet-producing MKs by 2D difference gel electrophoresis (DIGE) and polysome profiling, respectively. Our data revealed a significant increase in a poorly-characterized MK protein, myristoylated alanine-rich C-kinase substrate (MARCKS), which was upregulated 3.4- and 5.7 -fold in proplatelet-producing MKs in 2D DIGE and polysome profiling analyses, respectively. MARCKS is a protein kinase C (PKC) substrate that binds PIP2. In MKs, it localized to both the plasma and demarcation membranes. MARCKS inhibition by peptide significantly decreased proplatelet formation 53%. To examine the role of MARCKS in the PKC pathway, we treated MKs with polymethacrylate (PMA), which markedly increased MARCKS phosphorylation while significantly inhibiting proplatelet formation 84%, suggesting that MARCKS phosphorylation reduces proplatelet formation. We hypothesized that MARCKS phosphorylation promotes Arp2/3 phosphorylation, which subsequently downregulates proplatelet formation; both MARCKS and Arp2 were dephosphorylated in MKs making proplatelets, and Arp2 inhibition enhanced proplatelet formation. Finally, we used MARCKS knockout (KO) mice to probe the direct role of MARCKS in proplatelet formation; MARCKS KO MKs displayed significantly decreased proplatelet levels. MARCKS expression and signaling in primary MKs is a novel finding. We propose that MARCKS acts as a "molecular switch," binding to and regulating PIP2 signaling to regulate processes like proplatelet extension (microtubule-driven) vs proplatelet branching (Arp2/3 and actin polymerization-driven). C1 [Machlus, Kellie R.; Wu, Stephen K.; Soussou, Thomas S.; Hartwig, John H.; Italiano, Joseph E., Jr.] Brigham & Womens Hosp, Dept Med, Div Hematol, 75 Francis St, Boston, MA 02115 USA. [Machlus, Kellie R.; Italiano, Joseph E., Jr.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Stumpo, Deborah J.; Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC USA. [Paul, David S.; Bergmeier, Wolfgang] Univ N Carolina, McAllister Heart Inst, Dept Biochem & Biophys, Chapel Hill, NC USA. [Campbell, Robert A.; Weyrich, Andrew S.] Univ Utah, Sch Med, Program Mol Med, Salt Lake City, UT USA. [Campbell, Robert A.; Weyrich, Andrew S.] Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT USA. [Kalwa, Hermann; Michel, Thomas] Harvard Univ, Sch Med, Brigham & Womens Hosp, Cardiovasc Med Div,Dept Med, Boston, MA 02115 USA. [Italiano, Joseph E., Jr.] Childrens Hosp, Dept Surg, Vasc Biol Program, 300 Longwood Ave, Boston, MA 02115 USA. RP Italiano, JE (reprint author), Brigham & Womens Hosp, 1 Blackfan Circle,Karp 5, Boston, MA 02115 USA. EM jitaliano@partners.org FU National Institutes of Health National Heart, Lung, and Blood Institute [R01H168130, 5F32HL118865-02, PO1 HL48743, P01 HL120846, R01 HL126547, U54 HL112311]; American Heart Association FX This work was supported in part by grants from the National Institutes of Health National Heart, Lung, and Blood Institute R01H168130 (J.E.I.), 5F32HL118865-02 (K.R.M.), PO1 HL48743 (T.M.), P01 HL120846 (W.B.), and R01 HL126547 and U54 HL112311 (A.S.W.); and an American Heart Association Postdoctoral Fellowship (H.K.). J.E.I. is an American Society of Hematology Junior Faculty Scholar. NR 58 TC 1 Z9 1 U1 2 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 MAR 17 PY 2016 VL 127 IS 11 BP 1468 EP 1480 DI 10.1182/blood-2015-08663146 PG 13 WC Hematology SC Hematology GA DI4XW UT WOS:000373503700017 PM 26744461 ER PT J AU Burvenich, IJG Lee, FT O'Keefe, GJ Makris, D Cao, D Gong, S Rigopoulos, A Allan, LC Brechbiel, MW Liu, ZQ Ramsland, PA Scott, AM AF Burvenich, Ingrid J. G. Lee, Fook-Thean O'Keefe, Graeme J. Makris, Dahna Cao, Diana Gong, Sylvia Rigopoulos, Angela Allan, Laura C. Brechbiel, Martin W. Liu, Zhanqi Ramsland, Paul A. Scott, Andrew M. TI Engineering anti-Lewis-Y hu3S193 antibodies with improved therapeutic ratio for radioimmunotherapy of epithelial cancers SO EJNMMI RESEARCH LA English DT Article DE Therapeutic ratio; Payload delivery; Antibody engineering; Small animal imaging; Lewis-Y ID MONOCLONAL-ANTIBODY; ENHANCED EFFICACY; SOLID TUMORS; FC-RECEPTOR; BIODISTRIBUTION; IGG; FRAGMENTS; PHARMACOKINETICS; CATABOLISM; BINDING AB Background: The aim of the study was to explore Fc mutations of a humanised anti-Lewis-Y antibody (IgG1) hu3S193 as a strategy to improve therapeutic ratios for therapeutic payload delivery. Methods: Four hu3S193 variants (I253A, H310A, H435A and I253A/H310A) were generated via site-directed mutagenesis and radiolabelled with diagnostic isotopes iodine-125 or indium-111. Biodistribution studies in Lewis-Y-positive tumour-bearing mice were used to calculate the dose in tumours and organs for therapeutic isotopes (iodine-131, yttrium-90 and lutetium-177). Results: In-111-labelled I253A and H435A showed similar slow kinetics (t(1/2 beta), 63.2 and 62.2 h, respectively) and a maximum tumour uptake of 33.11 +/- 4.05 and 33.69 +/- 3.77 percentage injected dose per gramme (%ID/g), respectively. 111In-labelled I253A/H310A cleared fastest (t(1/2 beta), 9.1 h) with the lowest maximum tumour uptake (23.72 +/- 0.85 % ID/g). The highest increase in tumour-to-blood area under the curve (AUC) ratio was observed with the metal-labelled mutants (Y-90 and Lu-177). Lu-177-CHX-A" DTPA-hu3S193 I253A/H310A (6:1) showed the highest tumour-to-blood AUC ratio compared to wild type (3:1) and other variants and doubling of calculated dose to tumour based on red marrow dose constraints. Conclusions: These results suggest that hu3S193 Fc can be engineered with improved therapeutic ratios for Y-90- and Lu-177-based therapy, with the best candidate being hu3S193 I253A/H310A for Lu-177-based therapy. C1 [Burvenich, Ingrid J. G.; Lee, Fook-Thean; Makris, Dahna; Cao, Diana; Rigopoulos, Angela; Allan, Laura C.; Liu, Zhanqi; Scott, Andrew M.] Ludwig Inst Canc Res, Tumour Targeting Lab, Melbourne, Vic 3050, Australia. [Burvenich, Ingrid J. G.; Lee, Fook-Thean; Makris, Dahna; Cao, Diana; Rigopoulos, Angela; Allan, Laura C.; Liu, Zhanqi; Scott, Andrew M.] Olivia Newton John Canc Res Inst, Melbourne, Vic, Australia. [Burvenich, Ingrid J. G.; O'Keefe, Graeme J.; Scott, Andrew M.] La Trobe Univ, Sch Canc Med, Melbourne, Vic, Australia. [O'Keefe, Graeme J.; Gong, Sylvia; Scott, Andrew M.] Austin Hlth, Dept Mol Imaging & Therapy, Melbourne, Vic, Australia. [Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Ramsland, Paul A.] RMIT Univ, Sch Sci, Bundoora, Vic, Australia. [Ramsland, Paul A.] Burnet Inst, Ctr Biomed Res, Melbourne, Vic, Australia. [Ramsland, Paul A.] Monash Univ, Dept Immunol, Melbourne, Vic 3004, Australia. [Ramsland, Paul A.] Univ Melbourne, Austin Hlth, Dept Surg, Heidelberg, Vic, Australia. [Scott, Andrew M.] Univ Melbourne, Fac Med, Melbourne, Vic, Australia. [Scott, Andrew M.] Olivia Newton John Canc Res Inst, 145-163 Studley Rd, Heidelberg, Vic 3084, Australia. RP Scott, AM (reprint author), Ludwig Inst Canc Res, Tumour Targeting Lab, Melbourne, Vic 3050, Australia.; Scott, AM (reprint author), Olivia Newton John Canc Res Inst, Melbourne, Vic, Australia.; Scott, AM (reprint author), La Trobe Univ, Sch Canc Med, Melbourne, Vic, Australia.; Scott, AM (reprint author), Austin Hlth, Dept Mol Imaging & Therapy, Melbourne, Vic, Australia.; Scott, AM (reprint author), Univ Melbourne, Fac Med, Melbourne, Vic, Australia.; Scott, AM (reprint author), Olivia Newton John Canc Res Inst, 145-163 Studley Rd, Heidelberg, Vic 3084, Australia. EM andrew.scott@onjcri.org.au FU National Health and Medical Research Council [542512, 1030469, 487922]; Ludwig Cancer Research; Operational Infrastructure Support Program by the Victorian Government; Intramural Research Program of the NIH, National Cancer Institute, Centre for Cancer Research FX This research was supported by National Health and Medical Research Council Project Grants 542512, 1030469, National Health and Medical Research Council Program grant 487922, National Health and Medical Research Council Practitioner Fellowship (A.M.S.), and in part by Ludwig Cancer Research, by funds from the Operational Infrastructure Support Program provided by the Victorian Government, and the Intramural Research Program of the NIH, National Cancer Institute, Centre for Cancer Research. NR 42 TC 0 Z9 0 U1 12 U2 29 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2191-219X J9 EJNMMI RES JI EJNMMI Res. PD MAR 17 PY 2016 VL 6 AR 26 DI 10.1186/s13550-016-0180-0 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DI3UX UT WOS:000373425100001 PM 26983636 ER PT J AU Yen, YF Jen, I Chen, M Chuang, PH Liu, YL Sharp, GB Chen, YMA AF Yen, Yung-Feng Jen, Ian Chen, Marcelo Chuang, Pei-Hung Liu, Yen-Ling Sharp, Gerald B. Chen, Yi-Ming Arthur TI Association of Cytomegalovirus End-Organ Disease with Stroke in People Living with HIV/AIDS: A Nationwide Population-Based Cohort Study SO PLOS ONE LA English DT Article ID HIV-INFECTED PATIENTS; SMOOTH-MUSCLE-CELLS; RISK; TAIWAN; VIRUS; EXPRESSION; INFARCTION; EVENTS; BURDEN AB Objectives Cytomegalovirus (CMV) infection might increase the risk of cardiovascular event. However, data on the link between incident stroke and co-infections of CMV and human immunodeficiency virus (HIV) are limited and inconsistent. This nationwide population-based cohort study analyzed the association of CMV end-organ disease and stroke among people living with HIV/AIDS (PLWHA). Methods From January 1, 1998, this study identified adult HIV individuals with and without CMV endorgan disease in the Taiwan National Health Insurance Research Database. All patients were observed for incident stroke and were followed until December 31, 2012. Time-dependent analysis was used to evaluate associations of CMV end-organ disease with stroke. Results Of the 22,581 PLWHA identified (439 with CMV end-organ disease and 22,142 without CMV end-organ disease), 228 (1.01%) had all-cause stroke during a mean follow-up period of 4.85 years, including 169 (0.75%) with ischemic stroke and 59 (0.26%) with hemorrhagic stroke. After adjusting for age, sex, comorbidities, opportunistic infections after HIV diagnosis, and antiretroviral treatment, CMV end-organ disease was found to be an independent risk factor for incident all-cause stroke (adjusted hazard ratio [AHR], 3.07; 95% confidence interval [CI], 1.70 to 5.55). When stroke type was considered, CMV end-organ disease was significantly positively associated with the risk of ischemic stroke (AHR, 3.14; 95% CI, 1.49 to 6.62) but not hemorrhagic stroke (AHR, 2.52; 95% CI, 0.64 to 9.91). Conclusions This study suggested that CMV end-organ disease was an independent predictor of ischemic stroke among PLWHA. C1 [Yen, Yung-Feng] Taipei City Hosp, Taipei City Govt, Infect Dis Sect, Taipei, Taiwan. [Yen, Yung-Feng] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. [Yen, Yung-Feng; Jen, Ian; Chuang, Pei-Hung; Liu, Yen-Ling; Chen, Yi-Ming Arthur] Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung, Taiwan. [Jen, Ian] Natl Yang Ming Univ, Dept & Inst Publ Hlth, Taipei 112, Taiwan. [Chen, Marcelo] Mackay Mem Hosp, Dept Urol, Taipei, Taiwan. [Chen, Marcelo] Mackay Jr Coll Med Nursing & Management, Dept Cosmet Applicat & Management, Taipei, Taiwan. [Chuang, Pei-Hung] Taipei Vet Gen Hosp, Ctr Prevent & Treatment Occupat Injury & Dis, Taipei, Taiwan. [Chuang, Pei-Hung] Taipei Vet Gen Hosp, Dept Med, Div Clin Toxicol & Occupat Med, Taipei, Taiwan. [Sharp, Gerald B.] NIAID, Epidemiol Branch, Basic Sci Program, Div AIDS,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Chen, Yi-Ming Arthur] Kaohsiung Med Univ, Dept Microbiol, Kaohsiung, Taiwan. [Chen, Yi-Ming Arthur] Kaohsiung Med Univ, Inst Med Res, Kaohsiung, Taiwan. RP Chen, YMA (reprint author), Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung, Taiwan.; Chen, YMA (reprint author), Kaohsiung Med Univ, Dept Microbiol, Kaohsiung, Taiwan.; Chen, YMA (reprint author), Kaohsiung Med Univ, Inst Med Res, Kaohsiung, Taiwan. EM arthur@kmu.edu.tw FU amfAR (The Foundation for AIDS Research); U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute, International Epidemiologic Databases to Evaluate AIDS (IeDEA) [U01AI069907]; Kaohsiung Medical University "Aim for the Top Universities Grant" grant [KMU-TP103E01] FX This research was supported by a grant from amfAR (The Foundation for AIDS Research), with support from the U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Cancer Institute, as part of the International Epidemiologic Databases to Evaluate AIDS (IeDEA; U01AI069907). This study was also supported by Kaohsiung Medical University "Aim for the Top Universities Grant" grant No. KMU-TP103E01. The interpretation and conclusions contained herein are solely the responsibility of the authors and do not represent any of the above-mentioned institutions. NR 27 TC 1 Z9 1 U1 3 U2 6 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 MAR 17 PY 2016 VL 11 IS 3 AR e0151684 DI 10.1371/journal.pone.0151684 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH1YG UT WOS:000372580300112 PM 26986005 ER PT J AU Zheng, WW de Sancho, D Best, RB AF Zheng, Wenwei de Sancho, David Best, Robert B. TI Modulation of Folding Internal Friction by Local and Global Barrier Heights SO JOURNAL OF PHYSICAL CHEMISTRY LETTERS LA English DT Article ID SOLVENT VISCOSITY; CHEMICAL-REACTIONS; CHAIN DYNAMICS; RATE CONSTANTS; PROTEIN; DEPENDENCE; DIFFUSION; MODEL; RATES; COEFFICIENTS AB Recent experiments have revealed an unexpected deviation from a first power dependence of protein relaxation times on solvent viscosity, an effect that has been attributed to "internal friction". One clear source of internal friction in protein dynamics is the isomerization of dihedral angles. A key outstanding question is whether the global folding barrier height influences the measured internal friction, based on the observation that the folding rates of fast-folding proteins, with smaller folding free energy barriers, tend to exhibit larger internal friction. Here, by studying two alanine-based peptides, we find that systematic variation of global folding barrier heights has little effect on the internal friction for folding rates. On the other hand, increasing local torsion angle barriers leads to increased internal friction, which is consistent with solvent memory effects being the origin of the viscosity dependence. Thus, it appears that local torsion transitions determine the viscosity dependence of the diffusion coefficient on the global coordinate and, in turn, internal friction effects on the folding rate. C1 [Zheng, Wenwei; Best, Robert B.] NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. [de Sancho, David] CIC NanoGUNE, Donostia San Sebastian 20018, Spain. [de Sancho, David] Ikerbasque, Basque Fdn Sci, Maria Diaz de Haro 3, Bilbao 48013, Spain. RP Best, RB (reprint author), NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. EM robertbe@helix.nih.gov RI De Sancho, David/C-4995-2009; Best, Robert/H-7588-2016; nanoGUNE, CIC/A-2623-2015 OI De Sancho, David/0000-0002-8985-2685; Best, Robert/0000-0002-7893-3543; FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; Ikerbasque Research Fellowship FX W.Z. and R.B.B. were supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. D.d.S. is supported by an Ikerbasque Research Fellowship. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 44 TC 1 Z9 1 U1 6 U2 12 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 MAR 17 PY 2016 VL 7 IS 6 BP 1028 EP 1034 DI 10.1021/acs.jpclett.6b00329 PG 7 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Atomic, Molecular & Chemical SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DH1RF UT WOS:000372561900014 PM 26947615 ER PT J AU Ghitza, UE AF Ghitza, Udi E. TI Commentary: rewriting the Valuation and Salience of alcohol-related Stimuli via memory reconsolidation SO FRONTIERS IN PSYCHIATRY LA English DT Editorial Material DE alcohol drinking; memory retrieval; alcohol use disorder; drug use disorder; substance use disorder; addiction; alcohol abuse; drug abuse ID NEURONAL ENSEMBLES; PREFRONTAL CORTEX; ADDICTION; RELAPSE C1 [Ghitza, Udi E.] NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. RP Ghitza, UE (reprint author), NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. EM ghitzau@nida.nih.gov NR 14 TC 0 Z9 0 U1 1 U2 2 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 MAR 17 PY 2016 VL 7 AR 41 DI 10.3389/fpsyt.2016.00041 PG 3 WC Psychiatry SC Psychiatry GA DG5WL UT WOS:000372150000001 PM 27014104 ER PT J AU Li, H Zhao, X Yan, X Jessen, WJ Kim, MO Dombi, E Liu, PP Huang, G Wu, J AF Li, H. Zhao, X. Yan, X. Jessen, W. J. Kim, M-O Dombi, E. Liu, P. P. Huang, G. Wu, J. TI Runx1 contributes to neurofibromatosis type 1 neurofibroma formation SO ONCOGENE LA English DT Article ID DERMAL NEUROFIBROMAS; SCHWANN-CELLS; NF1; DIFFERENTIATION; PROLIFERATION; GENE; MICROENVIRONMENT; HEMATOPOIESIS; EXPRESSION; MATURATION AB Neurofibromatosis type 1 (NF1) patients are predisposed to neurofibromas but the driver(s) that contribute to neurofibroma formation are not fully understood. By cross comparison of microarray gene lists on human neurofibroma-initiating cells and developed neurofibroma Schwann cells (SCs) we identified RUNX1 overexpression in human neurofibroma initiation cells, suggesting RUNX1 might relate to neurofibroma formation. Immunostaining confirmed RUNX1 protein overexpression in human plexiform neurofibromas. Runx1 overexpression was confirmed in mouse Schwann cell progenitors (SCPs) and mouse neurofibromas at the messenger RNA and protein levels. Genetic inhibition of Runx1 expression by small hairpin RNA or pharmacological inhibition of Runx1 function by a Runx1/Cbf beta interaction inhibitor, Ro5-3335, decreased mouse neurofibroma sphere number in vitro. Targeted genetic deletion of Runx1 in SCs and SCPs delayed mouse neurofibroma formation in vivo. Mechanistically, loss of Nf1 increased embryonic day 12.5 Runx1(+)/Blbp(+) progenitors that enable tumor formation. These results suggest that Runx1 has an important role in Nf1 neurofibroma initiation, and inhibition of RUNX1 function might provide a novel potential therapeutic treatment strategy for neurofibroma patients. C1 [Li, H.; Zhao, X.; Yan, X.; Jessen, W. J.; Huang, G.; Wu, J.] Univ Cincinnati, Cincinnati Childrens Hosp, Cincinnati Childrens Hosp Res Fdn, Div Expt Hematol & Canc Biol,Canc & Blood Dis Ins, Cincinnati, OH 45229 USA. [Kim, M-O] Univ Cincinnati, Cincinnati Childrens Hosp, Cincinnati Childrens Hosp Res Fdn, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA. [Dombi, E.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Liu, P. P.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Wu, J (reprint author), Univ Cincinnati, Cincinnati Childrens Hosp, Cincinnati Childrens Hosp Res Fdn, Div Expt Hematol & Canc Biol,Canc & Blood Dis Ins, Cincinnati, OH 45229 USA. EM Jianqiang.wu@cchmc.org OI Jessen, Walter/0000-0003-3840-4337 FU Cincinnati Children's Hospital Trustee Grant; [NS28840] FX We thank Dr Nancy Ratner for providing the microarray data (supported by NS28840 to NR) and critical review and helpful discussions of the manuscript. This work was supported by a Cincinnati Children's Hospital Trustee Grant to JW. NR 30 TC 3 Z9 3 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 MAR 17 PY 2016 VL 35 IS 11 BP 1468 EP 1474 DI 10.1038/onc.2015.207 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DG6LQ UT WOS:000372196400013 PM 26073082 ER PT J AU Ma, XY Jiao, XD Ma, ZW Hejtmancik, JF AF Ma, Xiaoyin Jiao, Xiaodong Ma, Zhiwei Hejtmancik, J. Fielding TI Polymorphism rs7278468 is associated with Age-related cataract through decreasing transcriptional activity of the CRYAA promoter SO SCIENTIFIC REPORTS LA English DT Article ID ALPHA-A-CRYSTALLIN; NORMAL LENS NUCLEI; TGF-BETA; GENETIC-HETEROGENEITY; ITALIAN POPULATION; MOLECULAR-BASIS; CELLS; EXPRESSION; MUTATIONS; CHROMATIN AB CRYAA plays critical functional roles in lens transparency and opacity, and polymorphisms near CRYAA have been associated with age-related cataract (ARC). This study examines polymorphisms in the CRYAA promoter region for association with ARC and elucidates the mechanisms of this association. Three SNPs nominally associated with ARC were identified in the promoter region of CRYAA: rs3761382 (P = 0.06, OR (Odds ratio) = 1.5), rs13053109 (P = 0.04, OR = 1.6), rs7278468 (P = 0.007, OR = 0.6). The C-G-T haplotype increased the risk for ARC overall (P = 0.005, OR = 1.8), and both alleles and haplotypes show a stronger association with cortical cataract (rs3761382, P = 0.002, OR = 2.1; rs13053109, P = 0.002, OR = 2.1; rs7278468, P = 0.0007, OR = 0.5; C-G-T haplotype, P = 0.0003, OR = 2.2). The C-G-T risk haplotype decreased transcriptional activity through rs7278468, which lies in a consensus binding site for the transcription repressor KLF10. KLF10 binding inhibited CRYAA transcription, and both binding and inhibition were greater with the T rs7278468 allele. Knockdown of KLF10 in HLE cells partially rescued the transcriptional activity of CRYAA with rs7278468 T allele, but did not affect activity with the G allele. Thus, our data suggest that the T allele of rs7278468 in the CRYAA promoter is associated with ARC through increasing binding of KLF-10 and thus decreasing CRYAA transcription. C1 [Ma, Xiaoyin] Wenzhou Med Univ, Lab Dev Cell Biol & Dis, Sch Ophthalmol & Optometry, Wenzhou 325003, Peoples R China. [Ma, Xiaoyin] Wenzhou Med Univ, Hosp Eye, Wenzhou 325003, Peoples R China. [Ma, Xiaoyin; Jiao, Xiaodong; Ma, Zhiwei; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Hejtmancik, JF (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. EM f3h@helix.nih.gov NR 39 TC 0 Z9 0 U1 0 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 MAR 17 PY 2016 VL 6 AR 23206 DI 10.1038/srep23206 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG5VD UT WOS:000372146400002 PM 26984531 ER PT J AU Satomura, A Miura, N Kuroda, K Ueda, M AF Satomura, Atsushi Miura, Natsuko Kuroda, Kouichi Ueda, Mitsuyoshi TI Reconstruction of thermotolerant yeast by one-point mutation identified through whole-genome analyses of adaptively-evolved strains SO SCIENTIFIC REPORTS LA English DT Article ID DEPENDENT PROTEIN-KINASE; SACCHAROMYCES-CEREVISIAE; TRANSCRIPTION FACTORS; NUCLEAR-LOCALIZATION; ADENYLATE-CYCLASE; OXIDATIVE STRESS; GENE-EXPRESSION; DIAUXIC SHIFT; CYCLIC-AMP; A ACTIVITY AB Saccharomyces cerevisiae is used as a host strain in bioproduction, because of its rapid growth, ease of genetic manipulation, and high reducing capacity. However, the heat produced during the fermentation processes inhibits the biological activities and growth of the yeast cells. We performed whole-genome sequencing of 19 intermediate strains previously obtained during adaptation experiments under heat stress; 49 mutations were found in the adaptation steps. Phylogenetic tree revealed at least five events in which these strains had acquired mutations in the CDC25 gene. Reconstructed CDC25 point mutants based on a parental strain had acquired thermotolerance without any growth defects. These mutations led to the downregulation of the cAMP-dependent protein kinase (PKA) signaling pathway, which controls a variety of processes such as cell-cycle progression and stress tolerance. The one-point mutations in CDC25 were involved in the global transcriptional regulation through the cAMP/PKA pathway. Additionally, the mutations enabled efficient ethanol fermentation at 39 degrees C, suggesting that the one-point mutations in CDC25 may contribute to bioproduction. C1 [Satomura, Atsushi; Miura, Natsuko; Kuroda, Kouichi; Ueda, Mitsuyoshi] Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Sakyo Ku, Kyoto, Japan. [Satomura, Atsushi] Japan Soc Promot Sci, Sakyo Ku, Kyoto, Japan. [Miura, Natsuko] NCI, Radiat Oncol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. RP Ueda, M (reprint author), Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Sakyo Ku, Kyoto, Japan. EM miueda@kais.kyoto-u.ac.jp FU Japan Society for the Promotion of Science [26-1413]; Ministry of Economy, Trade and Industry (METI), Japan; JST-CREST FX This work was supported by a Grant-in-Aid for JSPS Fellows (No. 26-1413) from Japan Society for the Promotion of Science, the commission for Development of Artificial Genes Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI), Japan, and, JST-CREST. We thank Dr. Hiroki Takahashi from Graduate School of Pharmaceutical Sciences, Chiba University for the advice about the analysis of whole genome sequencing. NR 51 TC 0 Z9 0 U1 7 U2 13 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 MAR 17 PY 2016 VL 6 AR 23157 DI 10.1038/srep23157 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG5VC UT WOS:000372146300001 PM 26984760 ER PT J AU Liang, TJ AF Liang, T. Jake TI VIROLOGY The X-Files of hepatitis B SO NATURE LA English DT Editorial Material ID IN-VIVO; INFECTION; PROTEIN; CCCDNA; DNA C1 [Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM jliang@nih.gov NR 13 TC 0 Z9 0 U1 3 U2 8 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 MAR 17 PY 2016 VL 531 IS 7594 BP 313 EP 314 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG4TA UT WOS:000372064300040 PM 26983537 ER PT J AU Kuehn, HS Boisson, B Cunningham-Rundles, C Reichenbach, J Stray-Pedersen, A Gelfand, EW Maffucci, P Pierce, KR Abbott, JK Voelkerding, KV South, ST Augustine, NH Bush, JS Dolen, WK Wray, BB Itan, Y Cobat, A Sorte, HS Ganesan, S Prader, S Martins, TB Lawrence, MG Orange, JS Calvo, KR Niemela, JE Casanova, JL Fleisher, TA Hill, HR Kumanovics, A Conley, ME Rosenzweig, SD AF Kuehn, H. S. Boisson, B. Cunningham-Rundles, C. Reichenbach, J. Stray-Pedersen, A. Gelfand, E. W. Maffucci, P. Pierce, K. R. Abbott, J. K. Voelkerding, K. V. South, S. T. Augustine, N. H. Bush, J. S. Dolen, W. K. Wray, B. B. Itan, Y. Cobat, A. Sorte, H. S. Ganesan, S. Prader, S. Martins, T. B. Lawrence, M. G. Orange, J. S. Calvo, K. R. Niemela, J. E. Casanova, J. -L. Fleisher, T. A. Hill, H. R. Kumanovics, A. Conley, M. E. Rosenzweig, S. D. TI Loss of B Cells in Patients with Heterozygous Mutations in IKAROS SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COMMON VARIABLE IMMUNODEFICIENCY; ACUTE LYMPHOBLASTIC-LEUKEMIA; TRANSCRIPTION FACTOR; GERMLINE MUTATIONS; GENE; DIFFERENTIATION; HAPLOINSUFFICIENCY; AGAMMAGLOBULINEMIA; IMMUNITY; HETEROCHROMATIN AB BACKGROUND Common variable immunodeficiency (CVID) is characterized by late-onset hypo-gammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. C1 [Boisson, B.; Itan, Y.; Cobat, A.; Casanova, J. -L.; Conley, M. E.] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, 1230 York Ave,Box 163, New York, NY 10065 USA. [Kuehn, H. S.; Calvo, K. R.; Niemela, J. E.; Fleisher, T. A.; Rosenzweig, S. D.] NIAID, Dept Lab Med, NIH, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Rosenzweig, S. D.] NIAID, Primary Immunodeficiency Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ganesan, S.] NIAID, Biol Imaging Sect, Res Technol Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Casanova, J. -L.] Howard Hughes Med Inst, New York, NY USA. [Cunningham-Rundles, C.; Maffucci, P.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Cunningham-Rundles, C.; Maffucci, P.] Icahn Sch Med Mt Sinai, Inst Immunol, New York, NY 10029 USA. [Cobat, A.; Casanova, J. -L.] INSERM, U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France. [Cobat, A.; Casanova, J. -L.] Paris Descartes Univ, Imagine Inst, Paris, France. [Reichenbach, J.; Prader, S.] Univ Childrens Hosp Zurich, Div Immunol, Zurich, Switzerland. [Reichenbach, J.; Prader, S.] Childrens Res Ctr, Zurich, Switzerland. [Reichenbach, J.] Univ Zurich, Zurich, Switzerland. [Stray-Pedersen, A.; Orange, J. S.] Texas Childrens Hosp, Ctr Human Immunobiol, Houston, TX 77030 USA. [Stray-Pedersen, A.; Orange, J. S.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Stray-Pedersen, A.] Baylor Coll Med, Baylor Hopkins Ctr Mendelian Genom, Dept Mol & Human Genet, Houston, TX 77030 USA. [Stray-Pedersen, A.] Oslo Univ Hosp, Norwegian Unit Natl Newborn Screening, Oslo, Norway. [Sorte, H. S.] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway. [Pierce, K. R.] Univ Tennessee, Coll Med, Memphis, TN USA. [Gelfand, E. W.; Abbott, J. K.] Natl Jewish Hlth, Dept Pediat, Div Allergy & Immunol, Denver, CO USA. [Voelkerding, K. V.; South, S. T.; Augustine, N. H.; Martins, T. B.; Hill, H. R.; Kumanovics, A.] Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT USA. [Hill, H. R.] Univ Utah, Sch Med, Dept Pediat & Med, Salt Lake City, UT USA. [Martins, T. B.] ARUP Labs, ARUP Associated Reg & Univ Pathologists Inst Clin, Salt Lake City, UT USA. [Bush, J. S.; Dolen, W. K.; Wray, B. B.] Augusta Univ, Med Coll Georgia, Dept Pediat, Div Allergy Immunol & Pediat Rheumatol, Augusta, GA USA. [Lawrence, M. G.] Univ Virginia, Dept Med, Div Asthma Allergy & Immunol, Charlottesville, VA USA. RP Conley, ME (reprint author), Rockefeller Univ, St Giles Lab Human Genet Infect Dis, 1230 York Ave,Box 163, New York, NY 10065 USA. EM mconley@rockefeller.edu RI Abbott, Jordan/P-2509-2016 OI Abbott, Jordan/0000-0001-6334-5266 FU National Institutes of Health and others FX Funded by the National Institutes of Health and others. NR 41 TC 11 Z9 11 U1 2 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 17 PY 2016 VL 374 IS 11 BP 1032 EP 1043 DI 10.1056/NEJMoa1512234 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DG4TR UT WOS:000372066100007 PM 26981933 ER PT J AU Poleg-Polsky, A Diamond, JS AF Poleg-Polsky, Alon Diamond, Jeffrey S. TI NMDA Receptors Multiplicatively Scale Visual Signals and Enhance Directional Motion Discrimination in Retinal Ganglion Cells SO NEURON LA English DT Article ID LATERAL GENICULATE-NUCLEUS; STARBURST AMACRINE CELLS; NEURONS IN-VIVO; RABBIT RETINA; DENDRITIC INTEGRATION; SYNAPTIC INTEGRATION; STIMULUS SELECTIVITY; SHUNTING INHIBITION; PYRAMIDAL NEURONS; CORTICAL-NEURONS AB Postsynaptic responses in many CNS neurons are typically small and variable, often making it difficult to distinguish physiologically relevant signals from background noise. To extract salient information, neurons are thought to integrate multiple synaptic inputs and/or selectively amplify specific synaptic activation patterns. Here, we present evidence for a third strategy: directionally selective ganglion cells (DSGCs) in the mouse retina multiplicatively scale visual signals via a mechanism that requires both nonlinear NMDA receptor (NMDAR) conductances in DSGC dendrites and directionally tuned inhibition provided by the upstream retinal circuitry. Postsynaptic multiplication enables DSGCs to discriminate visual motion more accurately in noisy visual conditions without compromising directional tuning. These findings demonstrate a novel role for NMDARs in synaptic processing and provide new insights into how synaptic and network features interact to accomplish physiologically relevant neural computations. C1 [Poleg-Polsky, Alon; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, NIH, 35 Convent Dr,Bldg 35A,Room 3E-621, Bethesda, MD 20892 USA. RP Poleg-Polsky, A (reprint author), NINDS, Synapt Physiol Sect, NIH, 35 Convent Dr,Bldg 35A,Room 3E-621, Bethesda, MD 20892 USA. EM polegpolskya@mail.nih.gov RI Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 FU NINDS Intramural Research Program [NS003145] FX We thank Ms. Hua Tian for mouse husbandry and genotyping support; Drs. Nelson Spruston, Mark Stopfer, Nitin Gupta, Nicholas Oesch, and Rowland Taylor and his lab members for discussions; and Drs. Kevin Briggman, Wei Li, and Nicholas Oesch for comments on the manuscript. This work was supported by the NINDS Intramural Research Program (NS003145). NR 62 TC 3 Z9 4 U1 4 U2 5 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 MAR 16 PY 2016 VL 89 IS 6 BP 1277 EP 1290 DI 10.1016/neuron.2016.02.013 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DI5UI UT WOS:000373565600016 PM 26948896 ER PT J AU Sanders, AM Magnanelli, TJ Bragg, AE Tovar, JD AF Sanders, Allix M. Magnanelli, Timothy J. Bragg, Arthur E. Tovar, John D. TI Photoinduced Electron Transfer within Supramolecular Donor-Acceptor Peptide Nanostructures under Aqueous Conditions SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PORPHYRIN-FULLERENE TRIAD; CHARGE SEPARATION; CONDUCTING-POLYMER; ENERGY-TRANSFER; STRUCTURAL RELAXATION; NEURITE OUTGROWTH; DYADS; LIGHT; NANOMATERIALS; RECOMBINATION AB We report the synthesis, self-assembly, and electron transfer capabilities of peptide-based electron donor acceptor molecules and supramolecular nanostructures. These modified peptides contain pi-conjugated oligothiophene electron donor cores that are peripherally substituted with naphthalene diimide electron acceptors installed via imidation of site-specific lysine residues. These molecules self-assemble into one-dimensional nanostructures in aqueous media, as shown through steady-state absorption, photoluminescence, and circular dichroism spectra, as well as transmission electron microscopy. Excitation of the oligothiophene donor moieties results in electron transfer to the acceptor units, ultimately creating polar, charge-separated states that persist for over a nanosecond as observed with transient absorption spectroscopy. This study demonstrates how transient electric fields can be engineered into aqueous nanomaterials of biomedical relevance through external, temporally controlled photonic inputs. C1 [Sanders, Allix M.; Magnanelli, Timothy J.; Bragg, Arthur E.; Tovar, John D.] Johns Hopkins Univ, Dept Chem, Krieger Sch Arts & Sci, 3400 North Charles St, Baltimore, MD 21218 USA. [Tovar, John D.] Johns Hopkins Univ, Dept Mat Sci & Engn, Whiting Sch Engn, 3400 North Charles St, Baltimore, MD 21218 USA. [Tovar, John D.] Johns Hopkins Univ, Inst NanoBioTechnol, 3400 North Charles St, Baltimore, MD 21218 USA. [Sanders, Allix M.] NCI, Frederick, MD 21702 USA. RP Tovar, JD (reprint author), Johns Hopkins Univ, Dept Chem, Krieger Sch Arts & Sci, 3400 North Charles St, Baltimore, MD 21218 USA.; Tovar, JD (reprint author), Johns Hopkins Univ, Dept Mat Sci & Engn, Whiting Sch Engn, 3400 North Charles St, Baltimore, MD 21218 USA.; Tovar, JD (reprint author), Johns Hopkins Univ, Inst NanoBioTechnol, 3400 North Charles St, Baltimore, MD 21218 USA. EM tovar@jhu.edu FU Johns Hopkins University; U.S. Department of Energy, Office of Basic Energy Sciences [DE-SC0004857]; National Science Foundation [DMR-1407493]; Harry and Cleio Greer Fellowship FX We thank Johns Hopkins University, the U.S. Department of Energy, Office of Basic Energy Sciences (DE-SC0004857 to J.D.T. for synthesis of peptide nanomaterials), and the National Science Foundation (DMR-1407493 to J.D.T. for electric field creation in biomaterials) for generous support. A.M.S. was the recipient of a Harry and Cleio Greer Fellowship. NR 54 TC 5 Z9 5 U1 18 U2 95 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAR 16 PY 2016 VL 138 IS 10 BP 3362 EP 3370 DI 10.1021/jacs.5b12001 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA DH0MG UT WOS:000372477700019 PM 26900714 ER PT J AU Schmid, T Blees, JS Bajer, MM Wild, J Pescatori, L Crucitti, GC Scipione, L Costi, R Henrich, CJ Brune, B Colburn, NH Di Santo, R AF Schmid, Tobias Blees, Johanna S. Bajer, Magdalena M. Wild, Janine Pescatori, Luca Crucitti, Giuliana Cuzzucoli Scipione, Luigi Costi, Roberta Henrich, Curtis J. Bruene, Bernhard Colburn, Nancy H. Di Santo, Roberto TI Diaryl Disulfides as Novel Stabilizers of Tumor Suppressor Pdcd4 SO PLOS ONE LA English DT Article ID PROGRAMMED CELL-DEATH; TRANSLATION INHIBITOR; CELL-DEATH-4; DEGRADATION; EXPRESSION; PROTEIN; TRANSCRIPTION; INFLAMMATION; APOPTOSIS; OXIDATION AB The translation inhibitor and tumor suppressor Pdcd4 was reported to be lost in various tumors and put forward as prognostic marker in tumorigenesis. Decreased Pdcd4 protein stability due to PI3K-mTOR-p70(S6K1) dependent phosphorylation of Pdcd4 followed by beta-TrCP1-mediated ubiquitination, and proteasomal destruction of the protein was characterized as a major mechanism contributing to the loss of Pdcd4 expression in tumors. In an attempt to identify stabilizers of Pdcd4, we used a luciferase-based high-throughput compatible cellular assay to monitor phosphorylation-dependent proteasomal degradation of Pdcd4 in response to mitogen stimulation. Following a screen of approximately 2000 compounds, we identified 1,2-bis(4-chlorophenyl)disulfide as a novel Pdcd4 stabilizer. To determine an initial structure-activity relationship, we used 3 additional compounds, synthesized according to previous reports, and 2 commercially available compounds for further testing, in which either the linker between the aryls was modified (compounds 2-4) or the chlorine residues were replaced by groups with different electronic properties (compounds 5 and 6). We observed that those compounds with alterations in the sulfide linker completely lost the Pdcd4 stabilizing potential. In contrast, modifications in the chlorine residues showed only minor effects on the Pdcd4 stabilizing activity. A reporter with a mutated phospho-degron verified the specificity of the compounds for stabilizing the Pdcd4 reporter. Interestingly, the active diaryl disulfides inhibited proliferation and viability at concentrations where they stabilized Pdcd4, suggesting that Pdcd4 stabilization might contribute to the anti-proliferative properties. Finally, computational modelling indicated that the flexibility of the disulfide linker might be necessary to exert the biological functions of the compounds, as the inactive compound appeared to be energetically more restricted. C1 [Schmid, Tobias; Blees, Johanna S.; Bajer, Magdalena M.; Wild, Janine; Bruene, Bernhard] Goethe Univ Frankfurt, Fac Med, Inst Biochem 1, D-60590 Frankfurt, Germany. [Pescatori, Luca; Crucitti, Giuliana Cuzzucoli; Scipione, Luigi; Costi, Roberta; Di Santo, Roberto] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur, Fdn Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Rome, Italy. [Henrich, Curtis J.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Henrich, Curtis J.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Colburn, Nancy H.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. RP Schmid, T (reprint author), Goethe Univ Frankfurt, Fac Med, Inst Biochem 1, D-60590 Frankfurt, Germany. EM T.Schmid@biochem.uni-frankfurt.de RI Pescatori, Luca/H-5917-2016; OI Pescatori, Luca/0000-0003-4734-7856; scipione, luigi/0000-0002-2006-7005 FU DFG [GRK1172, SCHM2663/3]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Leidos Biomedical Research, Inc. FX This work was supported by the DFG (GRK1172 (MMB) and SCHM2663/3 (TS)). This research was further supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project was also funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Furthermore, Leidos Biomedical Research, Inc., a contractor to the National Cancer Institute, provided support in the form of salaries for one author [CJH]. The specific roles of this author are articulated in the 'author contributions' section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 16 PY 2016 VL 11 IS 3 AR e0151643 DI 10.1371/journal.pone.0151643 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH1WF UT WOS:000372574900108 PM 26982744 ER PT J AU Cole, AA Chen, XB Reese, TS AF Cole, Andy A. Chen, Xiaobing Reese, Thomas S. TI A Network of Three Types of Filaments Organizes Synaptic Vesicles for Storage, Mobilization, and Docking SO JOURNAL OF NEUROSCIENCE LA English DT Article DE docking; presynaptic; storage; synaptic vesicles; tomography; vesicle mobilization ID ACTIVE ZONE; CRYOELECTRON MICROSCOPY; NEUROMUSCULAR-JUNCTION; POSTSYNAPTIC DENSITY; HIPPOCAMPAL SYNAPSES; ELECTRON TOMOGRAPHY; ARCHITECTURE; RELEASE; TRANSMISSION; CYTOMATRIX AB Synaptic transmission between neurons requires precise management of synaptic vesicles. While individual molecular components of the presynaptic terminal are well known, exactly how the molecules are organized into a molecular machine serving the storage and mobilization of synaptic vesicles to the active zone remains unclear. Here we report three filament types associated with synaptic vesicles in glutamatergic synapses revealed by electron microscope tomography in unstimulated, dissociated rat hippocampal neurons. One filament type, likely corresponding to the SNAREpin complex, extends from the active zone membrane and surrounds docked vesicles. A second filament type contacts all vesicles throughout the active zone and pairs vesicles together. On the third filament type, vesicles attach to side branches extending from the long filament core and form vesicle clusters that are distributed throughout the vesicle cloud and along the active zone membrane. Detailed analysis of presynaptic structure reveals how each of the three filament types interacts with synaptic vesicles, providing a means to traffic reserved and recycled vesicles from the cloud of vesicles into the docking position at the active zone. C1 [Cole, Andy A.; Chen, Xiaobing; Reese, Thomas S.] NINDS, Neurobiol Lab, NIH, 49 Convent Dr,Room 3A68, Bethesda, MD 20892 USA. [Cole, Andy A.] Northwestern Univ, Feinberg Sch Med, Dept Cellular & Mol Biol, Chicago, IL 60611 USA. RP Cole, AA (reprint author), NINDS, Neurobiol Lab, NIH, 49 Convent Dr,Room 3A68, Bethesda, MD 20892 USA. EM cole.andy.a@gmail.com OI Cole, Andy/0000-0002-3271-0774 FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke. We thank Dr. Richard Leapman, National Institute of Biomedical Imaging and Bioengineering, NIH, for the use of his FEI Tecnai 300 kV electron microscope and his support in the acquisition of tomographic data; Rita Azzam and Virginia Crocker for preparing the sections for tomography; and Christine Winters for preparing hippocampal cultures, as well as performing high-pressure freezing and freeze-substitution for tomography. NR 41 TC 4 Z9 4 U1 2 U2 6 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 MAR 16 PY 2016 VL 36 IS 11 BP 3222 EP 3230 DI 10.1523/JNEUROSCI.2939-15.2016 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DG4YC UT WOS:000372078100011 PM 26985032 ER PT J AU Marchant, NJ Campbell, EJ Whitaker, LR Harvey, BK Kaganovsky, K Adhikary, S Hope, BT Heins, RC Prisinzano, TE Vardy, E Bonci, A Bossert, JM Shaham, Y AF Marchant, Nathan J. Campbell, Erin J. Whitaker, Leslie R. Harvey, Brandon K. Kaganovsky, Konstantin Adhikary, Sweta Hope, Bruce T. Heins, Robert C. Prisinzano, Thomas E. Vardy, Eyal Bonci, Antonello Bossert, Jennifer M. Shaham, Yavin TI Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence SO JOURNAL OF NEUROSCIENCE LA English DT Article DE alcohol; chemogenetics; nucleus accumbens; punishment; relapse; ventral subiculum ID EXTINGUISHED REWARD SEEKING; NUCLEUS-ACCUMBENS DOPAMINE; INDUCED REINSTATEMENT; COCAINE-SEEKING; BASOLATERAL AMYGDALA; DRUG-SEEKING; HEROIN SEEKING; LATERAL HYPOTHALAMUS; GLUTAMATE RECEPTORS; DORSAL HIPPOCAMPUS AB In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking. We recently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub -> NAc shell projection. Next, we reversibly inactivated the vSub with GABA receptor agonists (muscimol + baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory kappa opioid-receptor based DREADD (KORD) in vSub -> NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub -> NAc projection in this relapse. C1 [Marchant, Nathan J.; Whitaker, Leslie R.; Kaganovsky, Konstantin; Adhikary, Sweta; Hope, Bruce T.; Heins, Robert C.; Bossert, Jennifer M.; Shaham, Yavin] NIDA, Behav Neurosci Branch, IRP, NIH, Baltimore, MD 21224 USA. [Harvey, Brandon K.] NIDA, Optogenet & Transgen Technol Core, IRP, NIH, Baltimore, MD 21224 USA. [Bonci, Antonello] NIDA, Cellular Neurobiol Res Branch, IRP, NIH, Baltimore, MD 21224 USA. [Marchant, Nathan J.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne, Vic 2337, Australia. [Prisinzano, Thomas E.] Univ Kansas, Sch Pharm, Dept Med Chem, Lawrence, KS 66045 USA. [Vardy, Eyal] Merck Pharmaceut, Kenilworth, NJ 07033 USA. [Campbell, Erin J.] Univ Newcastle, Sch Biomed Sci & Pharm, Neurobiol Addict Lab, Prior Res Ctr Translat Neurosci & Mental Hlth, Newcastle, NSW 2308, Australia. [Campbell, Erin J.] Hunter Med Res Inst, Newcastle, NSW 2308, Australia. RP Marchant, NJ; Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, IRP, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM nathan.marchant@nih.gov; yavin.shaham@nih.gov RI Hope, Bruce/A-9223-2010; OI Hope, Bruce/0000-0001-5804-7061; Kaganovsky, Konstantin/0000-0002-1577-109X FU National Institute on Drug Abuse, Intramural Research Program; National Health and Medical Research Council Early Career Fellowship [1053308] FX This work was supported by the National Institute on Drug Abuse, Intramural Research Program. N.J.M. was supported by National Health and Medical Research Council Early Career Fellowship 1053308. We thank Dr. Bryan Roth for providing the KORD virus. NR 71 TC 4 Z9 4 U1 3 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 16 PY 2016 VL 36 IS 11 BP 3281 EP 3294 DI 10.1523/JNEUROSCI.4299-15.2016 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DG4YC UT WOS:000372078100016 PM 26985037 ER PT J AU Kirkpatrick, BD Whitehead, SS Pierce, KK Tibery, CM Grier, PL Hynes, NA Larsson, CJ Sabundayo, BP Talaat, KR Janiak, A Carmolli, MP Luke, CJ Diehl, SA Durbin, AP AF Kirkpatrick, Beth D. Whitehead, Stephen S. Pierce, Kristen K. Tibery, Cecilia M. Grier, Palmtama L. Hynes, Noreen A. Larsson, Catherine J. Sabundayo, Beulah P. Talaat, Kawsar R. Janiak, Anna Carmolli, Marya P. Luke, Catherine J. Diehl, Sean A. Durbin, Anna P. TI The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID FLAVIVIRUS-NAIVE ADULTS; VIRUS-INFECTIONS; HEALTHY; SAFE; RESPONSES; IMMUNOGENICITY; ENHANCEMENT; VOLUNTEERS; ANTIBODIES; CANDIDATE AB A dengue human challenge model can be an important tool to identify candidate dengue vaccines that should be further evaluated in large efficacy trials in endemic areas. Dengue is responsible for about 390 million infections annually. Protective efficacy results for the most advanced dengue vaccine candidate (CYD) were disappointing despite its ability to induce neutralizing antibodies against all four dengue virus (DENV) serotypes. TV003 is a live attenuated tetravalent DENV vaccine currently in phase 2 evaluation. To better assess the protective efficacy of TV003, a randomized double-blind, placebo-controlled trial in which recipients of TV003 or placebo were challenged 6 months later with a DENV-2 strain, rDEN2 Delta 30, was conducted. The primary endpoint of the trial was protection against dengue infection, defined as rDEN2 Delta 30 viremia. Secondary endpoints were protection against rash and neutropenia. All 21 recipients of TV003 who were challenged with rDEN2 Delta 30 were protected from infection with rDEN2 Delta 30. None developed viremia, rash, or neutropenia after challenge. In contrast, 100% of the 20 placebo recipients who were challenged with rDEN2 Delta 30 developed viremia, 80% developed rash, and 20% developed neutropenia. TV003 induced complete protection against challenge with rDEN2 Delta 30 administered 6 months after vaccination. TV003 will be further evaluated in dengue-endemic areas. The controlled dengue human challenge model can accelerate vaccine development by evaluating the protection afforded by the vaccine, thereby eliminating poor candidates from further consideration before the initiation of large efficacy trials. C1 [Kirkpatrick, Beth D.; Pierce, Kristen K.; Larsson, Catherine J.; Carmolli, Marya P.; Diehl, Sean A.] Univ Vermont, Coll Med, Vaccine Testing Ctr, Dept Med, Burlington, VT 05401 USA. [Whitehead, Stephen S.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Tibery, Cecilia M.; Grier, Palmtama L.; Sabundayo, Beulah P.; Talaat, Kawsar R.; Janiak, Anna; Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Baltimore, MD 21205 USA. [Hynes, Noreen A.; Luke, Catherine J.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. RP Durbin, AP (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Baltimore, MD 21205 USA. EM adurbin1@jhu.edu FU National Institutes of Allergy and Infectious Diseases Intramural Research Program, NIH [HHSN272200900010C] FX This work was supported by the National Institutes of Allergy and Infectious Diseases Intramural Research Program, NIH (contract no. HHSN272200900010C). NR 35 TC 16 Z9 17 U1 7 U2 12 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 MAR 16 PY 2016 VL 8 IS 330 AR 330ra36 DI 10.1126/scitranslmed.aaf1517 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DG4YS UT WOS:000372079700004 PM 27089205 ER PT J AU Wilkinson, MD Dumontier, M Aalbersberg, IJ Appleton, G Axton, M Baak, A Blomberg, N Boiten, JW Santos, LBD Bourne, PE Bouwman, J Brookes, AJ Clark, T Crosas, M Dillo, I Dumon, O Edmunds, S Evelo, CT Finkers, R Gonzalez-Beltran, A Gray, AJG Groth, P Goble, C Grethe, JS Heringa, J 't Hoen, PAC Hooft, R Kuhn, T Kok, R Kok, J Lusher, SJ Martone, ME Mons, A Packer, AL Persson, B Rocca-Serra, P Roos, M van Schaik, R Sansone, SA Schultes, E Sengstag, T Slater, T Strawn, G Swertz, MA Thompson, M van der Lei, J van Mulligen, E Velterop, J Waagmeester, A Wittenburg, P Wolstencroft, K Zhao, J Mons, B AF Wilkinson, Mark D. Dumontier, Michel Aalbersberg, IJsbrand Jan Appleton, Gabrielle Axton, Myles Baak, Arie Blomberg, Niklas Boiten, Jan-Willem Santos, Luiz Bonino da Silva Bourne, Philip E. Bouwman, Jildau Brookes, Anthony J. Clark, Tim Crosas, Merce Dillo, Ingrid Dumon, Olivier Edmunds, Scott Evelo, Chris T. Finkers, Richard Gonzalez-Beltran, Alejandra Gray, Alasdair J. G. Groth, Paul Goble, Carole Grethe, Jeffrey S. Heringa, Jaap 't Hoen, Peter A. C. Hooft, Rob Kuhn, Tobias Kok, Ruben Kok, Joost Lusher, Scott J. Martone, Maryann E. Mons, Albert Packer, Abel L. Persson, Bengt Rocca-Serra, Philippe Roos, Marco van Schaik, Rene Sansone, Susanna-Assunta Schultes, Erik Sengstag, Thierry Slater, Ted Strawn, George Swertz, Morris A. Thompson, Mark van der Lei, Johan van Mulligen, Erik Velterop, Jan Waagmeester, Andra Wittenburg, Peter Wolstencroft, Katherine Zhao, Jun Mons, Barend TI Comment: The FAIR Guiding Principles for scientific data management and stewardship SO SCIENTIFIC DATA LA English DT Article ID PROTEIN DATA-BANK; BIOLOGY AB There is an urgent need to improve the infrastructure supporting the reuse of scholarly data. A diverse set of stakeholders-representing academia, industry, funding agencies, and scholarly publishers-have come together to design and jointly endorse a concise and measureable set of principles that we refer to as the FAIR Data Principles. The intent is that these may act as a guideline for those wishing to enhance the reusability of their data holdings. Distinct from peer initiatives that focus on the human scholar, the FAIR Principles put specific emphasis on enhancing the ability of machines to automatically find and use the data, in addition to supporting its reuse by individuals. This Comment is the first formal publication of the FAIR Principles, and includes the rationale behind them, and some exemplar implementations in the community. C1 [Wilkinson, Mark D.] Univ Politecn Madrid, Ctr Plant Biotechnol & Genom, Madrid 28223, Spain. [Dumontier, Michel] Stanford Univ, Stanford, CA 94305 USA. [Aalbersberg, IJsbrand Jan; Appleton, Gabrielle; Dumon, Olivier; Groth, Paul] Elsevier, NL-1043 NX Amsterdam, Netherlands. [Axton, Myles] Nat Genet, Beijing 100044, Peoples R China. [Baak, Arie] Euretos & Phortos Consultants, NL-2741 CA Rotterdam, Netherlands. [Blomberg, Niklas] ELIXIR, Wellcome Genome Campus, Hinxton CB10 1SA, England. [Boiten, Jan-Willem] Lygature, NL-5656 AG Eindhoven, Netherlands. [Santos, Luiz Bonino da Silva] Vrije Univ Amsterdam, Dutch Techctr Life Sci, NL-1081 HV Amsterdam, Netherlands. [Bourne, Philip E.] NIH, Off Director, Bethesda, MD 20892 USA. [Bouwman, Jildau] TNO, NL-3700 AJ Zeist, Netherlands. [Brookes, Anthony J.] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. [Clark, Tim] Harvard Med Sch, Boston, MA 02115 USA. [Crosas, Merce] Harvard Univ, Cambridge, MA 02138 USA. [Dillo, Ingrid] DANS, NL-2593 HW The Hague, Netherlands. [Edmunds, Scott] Beijing Genom Inst, GigaSci, Shenzhen 518083, Peoples R China. [Evelo, Chris T.] Maastricht Univ, Dept Bioinformat, NL-6200 MD Maastricht, Netherlands. [Finkers, Richard] Wageningen UR Plant Breeding, NL-6708 PB Wageningen, Netherlands. [Gonzalez-Beltran, Alejandra; Rocca-Serra, Philippe; Sansone, Susanna-Assunta] Univ Oxford, Oxford E Res Ctr, Oxford OX1 3QG, England. [Gray, Alasdair J. G.] Heriot Watt Univ, Edinburgh EH14 4AS, Midlothian, Scotland. [Goble, Carole] Univ Manchester, Sch Comp Sci, Manchester M13 9PL, Lancs, England. [Grethe, Jeffrey S.] Univ Calif San Diego, Sch Med, Ctr Res Biol Syst, La Jolla, CA 92093 USA. [Heringa, Jaap; Kok, Ruben] Dutch Techctr Life Sci, NL-3501 DE Utrecht, Netherlands. ['t Hoen, Peter A. C.; Kok, Joost] Leiden Univ, Med Ctr, Dept Human Genet, Dutch Techctr Life Sci, NL-2300 RC Leiden, Netherlands. [Hooft, Rob] Dutch TechCtr Life Sci, NL-3501 DE Utrecht, Netherlands. [Hooft, Rob] ELIXIR NL, NL-3501 DE Utrecht, Netherlands. [Kuhn, Tobias] Vrije Univ Amsterdam, NL-1081 HV Amsterdam, Netherlands. [Kok, Joost] Leiden Univ, Leiden Ctr Data Sci, NL-2300 RA Leiden, Netherlands. [Lusher, Scott J.] Netherlands eSci Ctr, NL-1098 XG Amsterdam, Netherlands. [Martone, Maryann E.] Univ Calif San Diego, Natl Ctr Microscopy & Imaging Res, San Diego, CA 92103 USA. [Mons, Albert] Phortos Consultants, San Diego, CA 92011 USA. [Mons, Albert] UNIFESP Fdn, SciELO FAPESP Program, BR-05468901 Sao Paulo, Brazil. [Persson, Bengt] Uppsala Univ, Bioinformat Infrastruct Life Sci BILS, Sci Life Lab, Dept Cell & Mol Biol, S-75124 Uppsala, Sweden. [Roos, Marco; Thompson, Mark] Leiden Univ, Med Ctr, NL-2333 ZA Leiden, Netherlands. [van Schaik, Rene] Bayer CropSci, B-1831 Gent Area, Belgium. [Schultes, Erik] Leiden Univ, Med Ctr, Leiden Inst Adv Comp Sci, NL-2300 RA Leiden, Netherlands. [Sengstag, Thierry] Swiss Inst Bioinformat, CH-4056 Basel, Switzerland. [Sengstag, Thierry] Univ Basel, CH-4056 Basel, Switzerland. [Slater, Ted] Cray Inc, Seattle, WA 98164 USA. [Swertz, Morris A.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 GZ Groningen, Netherlands. [van der Lei, Johan; van Mulligen, Erik] Erasmus MC, NL-3015 CE Rotterdam, Netherlands. [Waagmeester, Andra] Micelio, B-2180 Antwerp, Belgium. [Wittenburg, Peter] Max Planck Compute & Data Facil, MPS, D-85748 Garching, Germany. [Wolstencroft, Katherine] Leiden Univ, Leiden Inst Adv Comp Sci, NL-2333 CA Leiden, Netherlands. [Zhao, Jun] Univ Oxford, Dept Comp Sci, Oxford OX1 3QD, England. [Mons, Barend] Leiden Univ, Med Ctr, Leiden & Dutch TechCtr Life Sci, NL-2333 ZA Utrecht, Netherlands. [Mons, Barend] Netherlands eSci Ctr, NL-1098 XG Amsterdam, Netherlands. [Mons, Barend] Erasmus MC, NL-3015 CE Rotterdam, Netherlands. RP Mons, B (reprint author), Leiden Univ, Med Ctr, Leiden & Dutch TechCtr Life Sci, NL-2333 ZA Utrecht, Netherlands.; Mons, B (reprint author), Netherlands eSci Ctr, NL-1098 XG Amsterdam, Netherlands.; Mons, B (reprint author), Erasmus MC, NL-3015 CE Rotterdam, Netherlands. EM barend.mons@dtls.nl OI Grethe, Jeffrey/0000-0001-5212-7052; Appleton, Gaby/0000-0003-0179-7384; Wilkinson, Mark/0000-0001-6960-357X FU Lorentz center; Dutch Techcenter for the Life Sciences; Netherlands eScience Center FX The original Lorentz Workshop 'Jointly Designing a Data FAIRport' was organized by Barend Mons in collaboration with and co-sponsored by the Lorentz center, The Dutch Techcenter for the Life Sciences and the Netherlands eScience Center. The principles and themes described in this manuscript represent the significant voluntary contributions and participation of the authors at, and/or subsequent to, this workshop and from the wider Force11, BD2K and ELIXIR communities. We also acknowledge and thank the organizers and backers of the NBDC/DBCLS BioHackathon 2015, where several of the authors made significant revisions to the FAIR Principles. NR 30 TC 34 Z9 34 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2052-4463 J9 SCI DATA JI Sci. Data PD MAR 15 PY 2016 VL 3 AR UNSP 160018 DI 10.1038/sdata.2016.18 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF3GX UT WOS:000390213900001 ER PT J AU Lee, J Jamal, M Yan, WS Young, D Song, YJ Chen, YM Katta, S Ravindranath, L Srinivasan, A Cullen, J Kagan, J Srivastava, S Dobi, A Rosner, IL McLeod, DG Sesterhenn, IA Srivastava, S Petrovics, G AF Lee, Jocelyn Jamal, Muhammad Yan, Wusheng Young, Denise Song, Yingjie Chen, Yongmei Katta, Shilpa Ravindranath, Lakshmi Srinivasan, Alagarsamy Cullen, Jennifer Kagan, Jacob Srivastava, Sudhir Dobi, Albert Rosner, Inger L. McLeod, David G. Sesterhenn, Isabell A. Srivastava, Shiv Petrovics, Gyorgy TI Increased expression of PCGEM1 IncRNA in prostate cancer of African American men SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Noncoding RNAs and Cancer - Mechanisms to Medicines CY DEC 04-07, 2015 CL Boston, MA SP Amer Assoc Canc Res C1 [Lee, Jocelyn; Jamal, Muhammad; Yan, Wusheng; Young, Denise; Song, Yingjie; Chen, Yongmei; Katta, Shilpa; Ravindranath, Lakshmi; Srinivasan, Alagarsamy; Cullen, Jennifer; Dobi, Albert; Srivastava, Shiv; Petrovics, Gyorgy] USUHS, Dept Surg, Ctr Prostate Dis Res, Rockville, MD USA. [Kagan, Jacob; Srivastava, Sudhir] NCI, Canc Prevent Div, Rockville, MD USA. [Rosner, Inger L.; McLeod, David G.] Walter Reed Natl Mil Med Ctr, Urol Serv, Bethesda, MD USA. [Sesterhenn, Isabell A.] Joint Pathol Ctr, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2016 VL 76 SU 6 MA A35 DI 10.1158/1538-7445.NONRNA15-A35 PG 2 WC Oncology SC Oncology GA DM0VD UT WOS:000376063000081 ER PT J AU Sharma, V Khurana, S Kubben, N Abdelmohsen, K Oberdoerffer, P Gorospe, M Misteli, T AF Sharma, Vivek Khurana, Simran Kubben, Nard Abdelmohsen, Kotb Oberdoerffer, Philipp Gorospe, Myriam Misteli, Tom TI A IncRNA regulates DNA repair by homologous recombination SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Noncoding RNAs and Cancer - Mechanisms to Medicines CY DEC 04-07, 2015 CL Boston, MA SP Amer Assoc Canc Res C1 [Sharma, Vivek; Khurana, Simran; Kubben, Nard; Oberdoerffer, Philipp; Misteli, Tom] NCI, Bethesda, MD 20892 USA. [Abdelmohsen, Kotb; Gorospe, Myriam] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 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 MAR 15 PY 2016 VL 76 SU 6 MA PR03 DI 10.1158/1538-7445.NONRNA15-PRO3 PG 2 WC Oncology SC Oncology GA DM0VD UT WOS:000376063000062 ER PT J AU Ho, WS Feldman, MJ Maric, D Amable, L Hall, MD Feldman, GM Ray-Chaudhury, A Lizak, MJ Vera, JC Robison, RA Zhuang, ZP Heiss, JD AF Ho, Winson S. Feldman, Michael J. Maric, Dragan Amable, Lauren Hall, Matthew D. Feldman, Gerald M. Ray-Chaudhury, Abhik Lizak, Martin J. Vera, Juan-Carlos Robison, R. Aaron Zhuang, Zhengping Heiss, John D. TI PP2A inhibition with LB100 enhances cisplatin cytotoxicity and overcomes cisplatin resistance in medulloblastoma cells SO ONCOTARGET LA English DT Article DE medulloblastoma; PP2A; LB100; STAT3; cisplatin ID PROTEIN PHOSPHATASE 2A; MITOTIC CATASTROPHE; GROWTH ARREST; BRAIN-TUMORS; STAT3; CANCER; PHOSPHORYLATION; TARGET; CHEMOTHERAPY; CARBOPLATIN AB The protein phosphatase 2A (PP2A) inhibitor, LB100, has been shown in pre-clinical studies to be an effective chemo- and radio-sensitizer for treatment of various cancers. We investigated effects associated with LB100 treatment alone and in combination with cisplatin for medulloblastoma (MB) in vitro and in vivo in an intracranial xenograft model. We demonstrated that LB100 had a potent effect on MB cells. By itself, LB100 inhibited proliferation and induced significant apoptosis in a range of pediatric MB cell lines. It also attenuated MB cell migration, a pre-requirement for invasion. When used in combination, LB100 enhanced cisplatin-mediated cytotoxic effects. Cell viability in the presence of 1 uM cisplatin alone was 61% (DAOY), 100% (D341), and 58% (D283), but decreased with the addition of 2 mu M of LB100 to 26% (DAOY), 67% (D341), and 27% (D283), (p < 0.005). LB100 suppressed phosphorylation of the STAT3 protein and several STAT3 downstream targets. Also, LB100 directly increased cisplatin uptake and overcame cisplatin-resistance in vitro. Finally, LB100 exhibited potent in vivo anti-neoplastic activity in combination with cisplatin in an intracranial xenograft model. C1 [Ho, Winson S.; Feldman, Michael J.; Ray-Chaudhury, Abhik; Zhuang, Zhengping; Heiss, John D.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, NINDS Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. [Amable, Lauren] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD 20892 USA. [Hall, Matthew D.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Feldman, Gerald M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Lizak, Martin J.] NINDS, In Vivo NMR Ctr, NIH, Bethesda, MD 20892 USA. [Vera, Juan-Carlos] Tulane Univ, Sch Med, New Orleans, LA 70112 USA. [Robison, R. Aaron] Univ So Calif, Childrens Hosp Los Angeles, Div Neurosurg, Los Angeles, CA 90027 USA. RP Zhuang, ZP; Heiss, JD (reprint author), NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM zhuangp@ninds.nih.gov; HeissJ@ninds.nih.gov OI Robison, Richard Aaron/0000-0001-8014-9451 FU NINDS of the National Institutes of Health; NIMHD of the National Institutes of Health; NCATS of the National Institutes of Health FX This research was supported by the Intramural Research Programs of NINDS, NIMHD and NCATS of the National Institutes of Health. NR 41 TC 1 Z9 1 U1 5 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 15 PY 2016 VL 7 IS 11 BP 12447 EP 12463 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LW UT WOS:000375679600054 PM 26799670 ER PT J AU Itkonen, HM Gorad, SS Duveau, DY Martin, SES Barkovskaya, A Bathen, TF Moestue, SA Mills, IG AF Itkonen, Harri M. Gorad, Saurabh S. Duveau, Damien Y. Martin, Sara E. S. Barkovskaya, Anna Bathen, Tone F. Moestue, Siver A. Mills, Ian G. TI Inhibition of O-GlcNAc transferase activity reprograms prostate cancer cell metabolism SO ONCOTARGET LA English DT Article DE androgen receptor; prostate cancer; metabolism; glycosylation; O-GlcNAc transferase ID IN-VIVO; C-MYC; PHOSPHORYLATION; FOXM1; GLCNACYLATION; BIOSYNTHESIS; SPECTROSCOPY; MECHANISMS; EXPRESSION; NETWORK AB Metabolic networks are highly connected and complex, but a single enzyme, O-GlcNAc transferase (OGT) can sense the availability of metabolites and also modify target proteins. We show that inhibition of OGT activity inhibits the proliferation of prostate cancer cells, leads to sustained loss of c-MYC and suppresses the expression of CDK1, elevated expression of which predicts prostate cancer recurrence (p= 0.00179). Metabolic profiling revealed decreased glucose consumption and lactate production after OGT inhibition. This decreased glycolytic activity specifically sensitized prostate cancer cells, but not cells representing normal prostate epithelium, to inhibitors of oxidative phosphorylation (rotenone and metformin). Intra-cellular alanine was depleted upon OGT inhibitor treatment. OGT inhibitor increased the expression and activity of alanine aminotransferase (GPT2), an enzyme that can be targeted with a clinically approved drug, cycloserine. Simultaneous inhibition of OGT and GPT2 inhibited cell viability and growth rate, and additionally activated a cell death response. These combinatorial effects were predominantly seen in prostate cancer cells, but not in a cell-line derived from normal prostate epithelium. Combinatorial treatments were confirmed with two inhibitors against both OGT and GPT2. Taken together, here we report the reprogramming of energy metabolism upon inhibition of OGT activity, and identify synergistically lethal combinations that are prostate cancer cell specific. C1 [Itkonen, Harri M.; Mills, Ian G.] Univ Oslo, Ctr Mol Med Norway, Prostate Canc Res Grp, Oslo, Norway. [Itkonen, Harri M.; Mills, Ian G.] Oslo Univ Hosp, Oslo, Norway. [Gorad, Saurabh S.; Barkovskaya, Anna; Bathen, Tone F.; Moestue, Siver A.] NTNU, Dept Circulat & Med Imaging, Trondheim, Norway. [Gorad, Saurabh S.; Moestue, Siver A.] St Olavs Univ Hosp, Trondheim, Norway. [Duveau, Damien Y.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Martin, Sara E. S.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Harvard Inst Med, Boston, MA USA. [Mills, Ian G.] Oslo Univ Hosp, Dept Mol Oncol, Oslo, Norway. [Barkovskaya, Anna] Oslo Univ Hosp, Radium Hosp, Inst Canc Res, Dept Tumor Biol, Oslo, Norway. [Mills, Ian G.] Queens Univ Belfast, CCRCB, PCUK Movember Ctr Excellence Prostate Canc Res, Belfast, Antrim, North Ireland. RP Itkonen, HM; Mills, IG (reprint author), Univ Oslo, Ctr Mol Med Norway, Prostate Canc Res Grp, Oslo, Norway.; Itkonen, HM; Mills, IG (reprint author), Oslo Univ Hosp, Oslo, Norway.; Mills, IG (reprint author), Oslo Univ Hosp, Dept Mol Oncol, Oslo, Norway.; Mills, IG (reprint author), Queens Univ Belfast, CCRCB, PCUK Movember Ctr Excellence Prostate Canc Res, Belfast, Antrim, North Ireland. EM harri.itkonen@ncmm.uio.no; ian.mills@ncmm.uio.no FU Norwegian Cancer Society; Norwegian Research Council; Helse Sor-Ost; University of Oslo through the Centre for Molecular Medicine (Norway) part of the Nordic EMBL (European Molecular Biology Laboratory); Cambridge University through the Department of Oncology; Belfast-Manchester Movember Centre of Excellence in Belfast [CE013_2004]; Prostate Cancer UK; Faculty of Medicine at NTNU; Central Norway Regional Health Authority; National Institutes of Health [R01 GM094263] FX HMI is funded by the Norwegian Cancer Society. IGM is supported in Oslo by funding from the Norwegian Research Council, Helse Sor-Ost and the University of Oslo through the Centre for Molecular Medicine (Norway), which is a part of the Nordic EMBL (European Molecular Biology Laboratory) partnership. IGM holds a visiting scientist position with Cancer Research UK through the Cambridge Research Institute and a Senior Honorary Visiting Research Fellowship with Cambridge University through the Department of Oncology. IGM is supported in Belfast by the Belfast-Manchester Movember Centre of Excellence (CE013_2004), funded in partnership with Prostate Cancer UK. The NMR spectroscopy was performed at the MR Core Facility, Norwegian University of Science and Technology (NTNU). The MR core facility is funded by the Faculty of Medicine at NTNU and Central Norway Regional Health Authority. SESM is supported through National Institutes of Health R01 GM094263 granted to Suzanne Walker. NR 46 TC 4 Z9 4 U1 4 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 15 PY 2016 VL 7 IS 11 BP 12464 EP 12476 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LW UT WOS:000375679600055 PM 26824323 ER PT J AU Marien, E Meister, M Muley, T del Pulgar, TG Derua, R Spraggins, JM Van de Plas, R Vanderhoydonc, F Machiels, J Binda, MM Dehairs, J Willette-Brown, J Hu, YL Dienemann, H Thomas, M Schnabel, PA Caprioli, RM Lacal, JC Waelkens, E Swinnen, JV AF Marien, Eyra Meister, Michael Muley, Thomas Gomez del Pulgar, Teresa Derua, Rita Spraggins, Jeffrey M. Van de Plas, Raf Vanderhoydonc, Frank Machiels, Jelle Binda, Maria Mercedes Dehairs, Jonas Willette-Brown, Jami Hu, Yinling Dienemann, Hendrik Thomas, Michael Schnabel, Philipp A. Caprioli, Richard M. Carlos Lacal, Juan Waelkens, Etienne Swinnen, Johannes V. TI Phospholipid profiling identifies acyl chain elongation as a ubiquitous trait and potential target for the treatment of lung squamous cell carcinoma SO ONCOTARGET LA English DT Article DE lipidomics; phospholipids; cancer; ELOVL; lung SCC ID FATTY-ACID ELONGATION; IKK-ALPHA; NONALCOHOLIC STEATOHEPATITIS; HEPATOCELLULAR-CARCINOMA; MEMBRANE-PROTEINS; LIPID-METABOLISM; CANCER; ELOVL6; DIFFERENTIATION; ADENOCARCINOMA AB Lung cancer is the leading cause of cancer death. Beyond first line treatment, few therapeutic options are available, particularly for squamous cell carcinoma (SCC). Here, we have explored the phospholipidomes of 30 human SCCs and found that they almost invariably (in 96.7% of cases) contain phospholipids with longer acyl chains compared to matched normal tissues. This trait was confirmed using in situ 2D-imaging MS on tissue sections and by phospholipidomics of tumor and normal lung tissue of the L-Ikka(KA/KA) mouse model of lung SCC. In both human and mouse, the increase in acyl chain length in cancer tissue was accompanied by significant changes in the expression of acyl chain elongases (ELOVLs). Functional screening of differentially expressed ELOVLs by selective gene knockdown in SCC cell lines followed by phospholipidomics revealed ELOVL6 as the main elongation enzyme responsible for acyl chain elongation in cancer cells. Interestingly, inhibition of ELOVL6 drastically reduced colony formation of multiple SCC cell lines in vitro and significantly attenuated their growth as xenografts in vivo in mouse models. These findings identify acyl chain elongation as one of the most common traits of lung SCC discovered so far and pinpoint ELOVL6 as a novel potential target for cancer intervention. C1 [Marien, Eyra; Vanderhoydonc, Frank; Machiels, Jelle; Dehairs, Jonas; Swinnen, Johannes V.] Univ Leuven, KU Leuven, Lab Lipid Metab & Canc, LKI,Leuven Canc Inst,Dept Oncol, Leuven, Belgium. [Meister, Michael; Muley, Thomas] Univ Heidelberg Hosp, Thoraxklin, Translat Res Unit, Heidelberg, Germany. [Meister, Michael; Muley, Thomas; Dienemann, Hendrik; Thomas, Michael; Schnabel, Philipp A.] Translat Lung Res Ctr Heidelberg, TLRC H, Heidelberg, Germany. [Gomez del Pulgar, Teresa; Carlos Lacal, Juan] Fdn Jimenez Diaz, Div Translat Oncol, E-28040 Madrid, Spain. [Derua, Rita; Waelkens, Etienne] Univ Leuven, KU Leuven, Lab Prot Phosphorylat & Prote, Dept Cellular & Mol Med, Leuven, Belgium. [Spraggins, Jeffrey M.; Van de Plas, Raf; Caprioli, Richard M.] Vanderbilt Univ, Dept Biochem, Med Ctr, Nashville, TN 37232 USA. [Spraggins, Jeffrey M.; Van de Plas, Raf; Caprioli, Richard M.] Mass Spectrometry Res Ctr, Nashville, TN USA. [Van de Plas, Raf] Delft Univ Technol, Delft Ctr Syst & Control, Delft, Netherlands. [Binda, Maria Mercedes] Univ Leuven, KU Leuven, Dept Oncol, LKI,Leuven Canc Inst,Abdominal Surg Oncol, Leuven, Belgium. [Willette-Brown, Jami; Hu, Yinling] NCI, Ctr Canc Res, Canc & Inflammat Program, Frederick, MD 21701 USA. [Dienemann, Hendrik] Univ Heidelberg Hosp, Thoraxklin, Dept Surg, Heidelberg, Germany. [Thomas, Michael] Univ Heidelberg Hosp, Thoraxklin, Dept Thorac Oncol, Heidelberg, Germany. [Schnabel, Philipp A.] Univ Saarland, Inst Allgemeine & Spezielle Pathol, Homburg, Germany. RP Swinnen, JV (reprint author), Univ Leuven, KU Leuven, Lab Lipid Metab & Canc, LKI,Leuven Canc Inst,Dept Oncol, Leuven, Belgium. EM johan.swinnen@med.kuleuven.be RI Lacal, Juan Carlos/N-9064-2015 OI Lacal, Juan Carlos/0000-0002-1908-2777 FU EU [Canceralia EU-259737]; Research Foundation-Flanders (FWO) [G.0691.12]; KU Leuven [GOA/11/2009, GOA/12/016]; Foundation Fournier Majoie (FFM); Stichting tegen Kanker [F/2014/324]; Belgian Science Policy [IAP 7/13]; Agency for Innovation by Science and Technology IWT-Flanders; Flemish League against Cancer (VLK); National Institutes of Health [NIH/NIGMS R01 GM058008-16, NIH/NIGMS P41 GM103391-05]; NIH [1S10OD012359-01]; Comunidad de Madrid [S2010/BMD-2326] FX This research was supported by EU FP7 grant Canceralia EU-259737 (to J.Sw., M.M., T.M. and M.T.), grant G.0691.12 from the Research Foundation-Flanders (FWO) (to J.Sw.), GOA/11/2009 (to J.Sw.) and GOA/12/016 (to E.W.) grants of the KU Leuven, a grant from the Foundation Fournier Majoie (FFM) (to J.Sw.), grant F/2014/324 from the Stichting tegen Kanker (to J.Sw.) and a grant from the Belgian Science Policy (IAP 7/13) (to E.W.). E.M. and J.D. are recipients of a fellowship of the Agency for Innovation by Science and Technology IWT-Flanders. The work of E.M. was also supported by the Flemish League against Cancer (VLK). The work by J.Sp., R.V. and R.M.C. is supported by National Institutes of Health grants NIH/NIGMS R01 GM058008-16 and NIH/NIGMS P41 GM103391-05 and the NIH Shared instrumentation Grant Program 1S10OD012359-01. The work by J.C.L. was supported by a grant from Comunidad de Madrid (S2010/BMD-2326). NR 50 TC 3 Z9 3 U1 3 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 15 PY 2016 VL 7 IS 11 BP 12582 EP 12597 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LW UT WOS:000375679600063 PM 26862848 ER PT J AU de Bruin, LO Yang, W Capuder, K Lee, YN Antolini, M Meyers, R Gellert, M Musunuru, K Manis, J Notarangelo, L AF de Bruin, Lisa Ott Yang, Wei Capuder, Kelly Lee, Yu Nee Antolini, Maddalena Meyers, Robin Gellert, Martin Musunuru, Kiran Manis, John Notarangelo, Luigi TI Rapid generation of novel models of RAG1 deficiency by CRISPR/Cas9-induced mutagenesis in murine zygotes SO ONCOTARGET LA English DT Article DE recombination activation gene 1; RAG1; genome editing; immunodeficiency; CRISPR/Cas9 ID ONE-STEP GENERATION; OMENN-SYNDROME; V(D)J RECOMBINATION; T-CELLS; GRANULOMATOUS-DISEASE; MODIFIED MICE; MUTATIONS; IMMUNODEFICIENCY; LYMPHOCYTES; GENES AB Mutations in the Recombination Activating Gene 1 (RAG1) can cause a wide variety of clinical and immunological phenotypes in humans, ranging from absence of T and B lymphocytes to occurrence of autoimmune manifestations associated with expansion of oligoclonal T cells and production of autoantibodies. Although the mechanisms underlying this phenotypic heterogeneity remain poorly understood, some genotype-phenotype correlations can be made. Currently, mouse models of Rag deficiency are restricted to RAG1(-/-) mice and to knock-in models carrying severe missense mutations. The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 system is a novel and powerful gene-editing strategy that permits targeted introduction of DNA double strand breaks with high efficiency through simultaneous delivery of the Cas9 endonuclease and a guide RNA (gRNA). Here, we report on CRISPR-based, single-step generation and characterization of mutant mouse models in which gene editing was attempted around residue 838 of RAG1, a region whose functional role had not been studied previously. C1 [de Bruin, Lisa Ott; Capuder, Kelly; Lee, Yu Nee; Antolini, Maddalena; Notarangelo, Luigi] Harvard Univ, Sch Med, Div Immunol, Boston Childrens Hosp, Boston, MA USA. [de Bruin, Lisa Ott] Wilhelmina Childrens Hosp, Utrecht Univ Med Ctr, Pediat Immunol, Utrecht, Netherlands. [Yang, Wei; Gellert, Martin] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Meyers, Robin] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Musunuru, Kiran] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Musunuru, Kiran; Notarangelo, Luigi] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Manis, John] Harvard Univ, Div Transfus Med, Dept Lab Med, Boston Childrens Hosp,Med Sch, Boston, MA USA. RP Notarangelo, L (reprint author), Harvard Univ, Sch Med, Div Immunol, Boston Childrens Hosp, Boston, MA USA.; Notarangelo, L (reprint author), Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM Luigi.Notarangelo@childrens.harvard.edu FU National Institute of Health, National Institute of Allergy and Infectious Diseases [R01AI100887, R21A1088510]; March of Dimes grant [MOD - 6FY10-282]; T32 fellowship grant [5T32AI007512]; intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX This work was supported by grant R01AI100887 from the National Institute of Health, National Institute of Allergy and Infectious Diseases (to LN) and March of Dimes grant MOD - 6FY10-282 (to). LO is supported by T32 fellowship grant 5T32AI007512. The research of WY and MG is supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. JM is supported by grant R21A1088510 from the National Institute of Health, National Institute of Allergy and Infectious Diseases. NR 34 TC 1 Z9 1 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 15 PY 2016 VL 7 IS 11 BP 12962 EP 12974 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LW UT WOS:000375679600092 ER PT J AU Booth, L Shuch, B Albers, T Roberts, JL Tavallai, M Proniuk, S Zukiwski, A Wang, DS Chen, CS Bottaro, D Ecroyd, H Lebedyeva, IO Dent, P AF Booth, Laurence Shuch, Brian Albers, Thomas Roberts, Jane L. Tavallai, Mehrad Proniuk, Stefan Zukiwski, Alexander Wang, Dasheng Chen, Ching-Shih Bottaro, Don Ecroyd, Heath Lebedyeva, Iryna O. Dent, Paul TI Multi-kinase inhibitors can associate with heat shock proteins through their NH2-termini by which they suppress chaperone function SO ONCOTARGET LA English DT Article DE OSU-03012; sorafenib; pazopanib; chaperones; ATPase ID GENERAL FORCE-FIELD; IMPLICIT SOLVENT CALCULATIONS; MOLECULAR-DYNAMICS; DEPENDENT INCREASES; THERAPEUTIC TARGET; TRANSFORMED-CELLS; HSP27 HSPB1; OSU-03012; PHOSPHORYLATION; ACTIVATION AB We performed proteomic studies using the GRP78 chaperone-inhibitor drug AR-12 (OSU-03012) as bait. Multiple additional chaperone and chaperone-associated proteins were shown to interact with AR-12, including: GRP75, HSP75, BAG2; HSP27; ULK-1; and thioredoxin. AR-12 down-regulated in situ immuno-fluorescence detection of ATP binding chaperones using antibodies directed against the NH2-termini of the proteins but only weakly reduced detection using antibodies directed against the central and COOH portions of the proteins. Traditional SDS-PAGE and western blotting assessment methods did not exhibit any alterations in chaperone detection. AR-12 altered the sub-cellular distribution of chaperone proteins, abolishing their punctate speckled patterning concomitant with changes in protein co-localization. AR-12 inhibited chaperone ATPase activity, which was enhanced by sildenafil; inhibited chaperone - chaperone and chaperone - client interactions; and docked in silico with the ATPase domains of HSP90 and of HSP70. AR-12 combined with sildenafil in a GRP78 plus HSP27 - dependent fashion to profoundly activate an eIF2a/ATF4/CHOP/Beclin1 pathway in parallel with inactivating mTOR and increasing ATG13 phosphorylation, collectively resulting in formation of punctate toxic autophagosomes. Over-expression of [GRP78 and HSP27] prevented: AR-12-induced activation of ER stress signaling and maintained mTOR activity; AR-12-mediated down-regulation of thioredoxin, MCL-1 and c-FLIP-s; and preserved tumor cell viability. Thus the inhibition of chaperone protein functions by AR-12 and by multi-kinase inhibitors very likely explains why these agents have anti-tumor effects in multiple genetically diverse tumor cell types. C1 [Booth, Laurence; Roberts, Jane L.; Tavallai, Mehrad; Dent, Paul] Virginia Commonwealth Univ, Dept Biochem & Mol Biophys, Richmond, VA 23298 USA. [Shuch, Brian] Yale Univ, Sch Med, Urol & Diagnost Radiol, 333 Cedar St, New Haven, CT 06520 USA. [Shuch, Brian; Bottaro, Don] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Wang, Dasheng; Chen, Ching-Shih] Ohio State Univ, US Med Chem & Pharmacognosy, Sch Pharm, Mol & Translat Sci, Columbus, OH 43210 USA. [Proniuk, Stefan; Zukiwski, Alexander] Arno Therapeut, Flemington, NJ 08822 USA. [Ecroyd, Heath] Univ Wollongong, Sch Biol Sci, Wollongong, NSW 2522, Australia. [Ecroyd, Heath] Univ Wollongong, Illawarra Hlth, Wollongong, NSW 2522, Australia. [Ecroyd, Heath] Univ Wollongong, Med Res Inst, Wollongong, NSW 2522, Australia. [Albers, Thomas; Lebedyeva, Iryna O.] Augusta Univ, Dept Chem & Phys, Augusta, GA 30912 USA. RP Dent, P (reprint author), Virginia Commonwealth Univ, Dept Biochem & Mol Biophys, Richmond, VA 23298 USA. EM pdent@vcu.edu OI Ecroyd, Heath/0000-0001-7574-0044 FU Betts family fund FX Thanks to Dr. H.F. Young (Neurosurgery, VCU) and the Betts family fund for support in the purchase of the Hermes Wiscan instrument. PD wishes to thank Mr. Daniel Leon (VCU personnel, Dent laboratory) for assistance during these studies. NR 51 TC 6 Z9 6 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 15 PY 2016 VL 7 IS 11 BP 12975 EP 12996 PG 22 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LW UT WOS:000375679600093 PM 26887051 ER PT J AU Giles, AJ Reid, CM Evans, JD Murgai, M Vicioso, Y Highfill, SL Kasai, M Vahdat, L Mackall, CL Lyden, D Wexler, L Kaplan, RN AF Giles, Amber Jin Reid, Caitlin Marie Evans, Justin DeWayne Murgai, Meera Vicioso, Yorleny Highfill, Steven Lorenz Kasai, Miki Vahdat, Linda Mackall, Crystal Lee Lyden, David Wexler, Leonard Kaplan, Rosandra Natasha TI Activation of Hematopoietic Stem/Progenitor Cells Promotes Immunosuppression Within the Pre-metastatic Niche SO CANCER RESEARCH LA English DT Article ID MYELOID CELLS; PREMETASTATIC NICHE; BREAST-CANCER; SELF-RENEWAL; STEM-CELLS; SUPPRESSOR-CELLS; CXCR4 ANTAGONIST; PROGENITOR CELLS; STROMAL CELLS; MOBILIZATION AB Metastatic tumors have been shown to establish microenvironments in distant tissues that are permissive to disseminated tumor cells. Hematopoietic cells contribute to this microenvironment, yet the precise initiating events responsible for establishing the pre-metastatic niche remain unclear. Here, we tracked the developmental fate of hematopoietic stem and progenitor cells (HSPC) in tumor-bearing mice. We show that a distant primary tumor drives the expansion of HSPCs within the bone marrow and their mobilization to the bloodstream. Treatment of purified HSPCs cultured ex vivo with tumor-conditioned media induced their proliferation as well as their differentiation into immunosuppressive myeloid cells. We furthered tracked purified HSPCs in vivo and found they differentiated into myeloid-derived suppressor cells in early metastatic sites of tumor-bearing mice. The number of CD11b(+)Ly6g(+) cells in metastatic sites was significantly increased by HSPC mobilization and decreased if tumor-mediated mobilization was inhibited. Moreover, pharmacologic mobilization of HSPCs increased metastasis, whereas depletion of Gr1(+) cells abrogated the metastasis-promoting effects of HSPC mobilization. Finally, we detected elevated levels of HSPCs in the circulation of newly diagnosed cancer patients, which correlated with increased risk for metastatic progression. Taken together, our results highlight bone marrow activation as one of the earliest steps of the metastatic process and identify circulating HSPCs as potential clinical indicators of metastatic niche formation. (C) 2015 AACR. C1 [Giles, Amber Jin; Reid, Caitlin Marie; Evans, Justin DeWayne; Murgai, Meera; Vicioso, Yorleny; Highfill, Steven Lorenz; Kasai, Miki; Mackall, Crystal Lee; Kaplan, Rosandra Natasha] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Vahdat, Linda] Weill Cornell Med Coll, Div Hematol & Oncol, Dept Med, New York, NY USA. [Lyden, David] Weill Cornell Med Coll, Childrens Canc & Blood Fdn Labs, Dept Pediat, New York, NY USA. [Lyden, David] Weill Cornell Med Coll, Childrens Canc & Blood Fdn Labs, Dept Cell Biol, New York, NY USA. [Lyden, David] Weill Cornell Med Coll, Childrens Canc & Blood Fdn Labs, Dept Dev Biol, New York, NY USA. [Wexler, Leonard] Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 USA. RP Kaplan, RN (reprint author), NCI, Ctr Canc Res, NIH, 10 Ctr Dr MSC 1100, Bethesda, MD 20892 USA. EM kaplanrn@mail.nih.gov FU Intramural NIH HHS [ZIA BC011332-02, ZIA BC011332-01, Z99 CA999999]; NCI NIH HHS [P30 CA008748] NR 43 TC 8 Z9 8 U1 1 U2 2 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 MAR 15 PY 2016 VL 76 IS 6 BP 1335 EP 1347 DI 10.1158/0008-5472.CAN-15-0204 PG 13 WC Oncology SC Oncology GA DL7WR UT WOS:000375851600006 PM 26719537 ER PT J AU Ali-Rahmani, F FitzGerald, DJ Martin, S Patel, P Prunotto, M Ormanoglu, P Thomas, C Pastan, I AF Ali-Rahmani, Fatima FitzGerald, David J. Martin, Scott Patel, Paresma Prunotto, Marco Ormanoglu, Pinar Thomas, Craig Pastan, Ira TI Anticancer Effects of Mesothelin-Targeted Immunotoxin Therapy Are Regulated by Tyrosine Kinase DDR1 SO CANCER RESEARCH LA English DT Article ID TRIPLE-NEGATIVE BREAST; DOMAIN RECEPTOR 1; PANCREATIC-CANCER; PSEUDOMONAS EXOTOXIN; INHIBITORS; COLLAGEN; OVARIAN; IDENTIFICATION; ACTIVATION; EXPRESSION AB Recombinant immunotoxins (RIT) have been highly successful in cancer therapy due, in part, to the high cancer-specific expression of cell surface antigens such as mesothelin, which is over-expressed in mesothelioma, ovarian, lung, breast, and pancreatic cancers, but is limited in normal cells. RG7787 is a clinically optimized RIT consisting of a humanized anti-mesothelin Fab fused to domain III of Pseudomonas exotoxin A, in which immunogenic B-cell epitopes are silenced. To enhance the therapeutic efficacy of RITs, we conducted a kinome RNAi sensitization screen, which identified discoidin domain receptor 1 (DDR1), a collagen-activated tyrosine kinase, as a potential target. The collagen/DDR1 axis is implicated in tumor-stromal interactions and potentially affects tumor response to therapy. Therefore, we investigated the effects of DDR1 on RIT. Knockdown of DDR1 by siRNA or treatment with inhibitor, 7rh, greatly enhanced the cytotoxic activity of RG7787 in several cancer cell lines. Investigation into the mechanism of action showed DDR1 silencing was associated with decreased expression of several ribosomal proteins and enhanced inhibition of protein synthesis. Conversely, induction of DDR1 expression or collagen-stimulated DDR1 activity protected cancer cells from RG7787 killing. Moreover, the combination of RG7787 and DDR1 inhibitor caused greater shrinkage of tumor xenografts than either agent alone. These data demonstrate that DDR1 is a key modulator of RIT activity and represents a novel therapeutic strategy to improve targeting of mesothelin-expressing cancers. (C) 2015 AACR. C1 [Ali-Rahmani, Fatima; FitzGerald, David J.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Martin, Scott; Patel, Paresma; Ormanoglu, Pinar; Thomas, Craig] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Prunotto, Marco] F Hoffmann La Roche Ltd, Roche Innovat Ctr Basel, Discovery Technol, Basel, Switzerland. [Martin, Scott] Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU Intramural NIH HHS [ZIA BC008753-33] NR 34 TC 4 Z9 4 U1 0 U2 3 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 MAR 15 PY 2016 VL 76 IS 6 BP 1560 EP 1568 DI 10.1158/0008-5472.CAN-15-2401 PG 9 WC Oncology SC Oncology GA DL7WR UT WOS:000375851600026 PM 26719540 ER PT J AU Cook, JA Chandramouli, GVR Anver, MR Sowers, AL Thetford, A Krausz, KW Gonzalez, FJ Mitchell, JB Patterson, AD AF Cook, John A. Chandramouli, Gadisetti V. R. Anver, Miriam R. Sowers, Anastasia L. Thetford, Angela Krausz, Kristopher W. Gonzalez, Frank J. Mitchell, James B. Patterson, Andrew D. TI Mass Spectrometry-Based Metabolomics Identifies Longitudinal Urinary Metabolite Profiles Predictive of Radiation-Induced Cancer SO CANCER RESEARCH LA English DT Article ID GAMMA-IRRADIATED RATS; BIOMARKER DISCOVERY; RANDOM FORESTS; MICE; STRESS; COUNTERMEASURES; EXPOSURE; COLD; ACID; LIFE AB Nonlethal exposure to ionizing radiation (IR) is a public concern due to its known carcinogenic effects. Although latency periods for IR-induced neoplasms are relatively long, the ability to detect cancer as early as possible is highly advantageous for effective therapeutic intervention. Therefore, we hypothesized that metabolites in the urine from mice exposed to total body radiation (TBI) would predict for the presence of cancer before a palpable mass was detected. In this study, we exposed mice to 0 or 5.4 Gy TBI, collected urine samples periodically over 1 year, and assayed urine metabolites by using mass spectrometry. Longitudinal data analysis within the first year post-TBI revealed that cancers, including hematopoietic, solid, and benign neoplasms, could be distinguished by unique urinary signatures as early as 3 months post-TBI. Furthermore, a distinction among different types of malignancies could be clearly delineated as early as 3 months post-TBI for hematopoietic neoplasms, 6 months for solid neoplasms, and by 1 year for benign neoplasms. Moreover, the feature profile for radiation-exposed mice 6 months post-TBI was found to be similar to nonirradiated control mice at 18 months, suggesting that TBI accelerates aging. These results demonstrate that urine feature profiles following TBI can identify cancers in mice prior to macroscopic detection, with important implications for the early diagnosis and treatment. (C) 2016 AACR. C1 [Cook, John A.; Chandramouli, Gadisetti V. R.; Sowers, Anastasia L.; Thetford, Angela; Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Anver, Miriam R.] Leidos Biomed Res Inc, Pathol Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Krausz, Kristopher W.; Gonzalez, Frank J.] 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. RP Mitchell, JB (reprint author), NCI, Radiat Biol Branch, Bldg 10,Room B3-B69,9000 Rockville Pike, Bethesda, MD 20892 USA. EM james.mitchell3@nih.gov RI Patterson, Andrew/G-3852-2012 OI Patterson, Andrew/0000-0003-2073-0070 FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS [ZIA BC010946-08]; NCI NIH HHS [HHSN261200800001E] NR 29 TC 2 Z9 2 U1 1 U2 10 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 MAR 15 PY 2016 VL 76 IS 6 BP 1569 EP 1577 DI 10.1158/0008-5472.CAN-15-2416 PG 9 WC Oncology SC Oncology GA DL7WR UT WOS:000375851600027 PM 26880804 ER PT J AU Anderson, TMR Ma, SH Raj, GV Cidlowski, JA Helle, TM Knutson, TP Krutilina, RI Seagroves, TN Lange, CA AF Anderson, Tarah M. Regan Ma, Shi Hong Raj, Ganesh V. Cidlowski, John A. Helle, Taylor M. Knutson, Todd P. Krutilina, Raisa I. Seagroves, Tiffany N. Lange, Carol A. TI Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer SO CANCER RESEARCH LA English DT Article ID ESTROGEN-RECEPTOR; TYROSINE KINASE; PROGNOSTIC-SIGNIFICANCE; MOLECULAR-MECHANISMS; MAMMARY-GLAND; GLUTAMIC-ACID; SOLID TUMORS; CELLS; EXPRESSION; PELP1 AB Cancer cells use stress response pathways to sustain their pathogenic behavior. In breast cancer, stress response-associated phenotypes are mediated by the breast tumor kinase, Brk (PTK6), via the hypoxia-inducible factors HIF-1 alpha and HIF-2 alpha. Given that glucocorticoid receptor (GR) is highly expressed in triple-negative breast cancer (TNBC), we investigated cross-talk between stress hormone-driven GR signaling and HIF-regulated physiologic stress. Primary TNBC tumor explants or cell lines treated with the GR ligand dexamethasone exhibited robust induction of Brk mRNA and protein that was HIF1/2-dependent. HIF and GR coassembled on the BRK promoter in response to either hypoxia or dexamethasone, indicating that Brk is a direct GR/HIF target. Notably, HIF-2 alpha, not HIF-1 alpha, expression was induced by GR signaling, and the important steroid receptor coactivator PELP1 was also found to be induced in a HIF-dependent manner. Mechanistic investigations showed how PELP1 interacted with GR to activate Brk expression and demonstrated that physiologic cell stress, including hypoxia, promoted phosphorylation of GR serine 134, initiating a feed-forward signaling loop that contributed significantly to Brk upregulation. Collectively, our findings linked cellular stress (HIF) and stress hormone (cortisol) signaling in TNBC, identifying the phospho-GR/HIF/PELP1 complex as a potential therapeutic target to limit Brk-driven progression and metastasis in TNBC patients. (C) 2016 AACR. C1 [Anderson, Tarah M. Regan; Helle, Taylor M.; Knutson, Todd P.; Lange, Carol A.] Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. [Anderson, Tarah M. Regan; Helle, Taylor M.; Knutson, Todd P.; Lange, Carol A.] Univ Minnesota, Dept Pharmacol, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. [Anderson, Tarah M. Regan; Helle, Taylor M.; Knutson, Todd P.; Lange, Carol A.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Ma, Shi Hong; Raj, Ganesh V.] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. [Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Krutilina, Raisa I.; Seagroves, Tiffany N.] Univ Tennessee HSC, Dept Pathol & Lab Med, Memphis, TN USA. [Krutilina, Raisa I.; Seagroves, Tiffany N.] Univ Tennessee HSC, Ctr Canc Res, Memphis, TN USA. RP Lange, CA (reprint author), Univ Minnesota, 2231 6th ST SE,Canc Cardiol Res Bldg, Minneapolis, MN 55455 USA. EM lange047@umn.edu NR 50 TC 4 Z9 4 U1 3 U2 3 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 MAR 15 PY 2016 VL 76 IS 6 BP 1653 EP 1663 DI 10.1158/0008-5472.CAN-15-2510 PG 11 WC Oncology SC Oncology GA DL7WR UT WOS:000375851600035 ER PT J AU Kurihara, T Westenskow, PD Gantner, ML Usui, Y Schultz, A Bravo, S Aguilar, E Wittgrove, C Friedlander, MSH Paris, LP Chew, E Siuzdak, G Friedlander, M AF Kurihara, Toshihide Westenskow, Peter D. Gantner, Marin L. Usui, Yoshihiko Schultz, Andrew Bravo, Stephen Aguilar, Edith Wittgrove, Carli Friedlander, Mollie S. H. Paris, Liliana P. Chew, Emily Siuzdak, Gary Friedlander, Martin TI Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration SO ELIFE LA English DT Article ID AGE-RELATED MACULOPATHY; CHOROIDAL NEOVASCULAR MEMBRANES; MACULAR DEGENERATION; BRUCHS MEMBRANE; LIPOFUSCIN FLUOROPHORE; MORPHOMETRIC-ANALYSIS; GEOGRAPHIC ATROPHY; BLOOD-FLOW; FUNDUS AUTOFLUORESCENCE; HYDRAULIC CONDUCTIVITY AB Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies. C1 [Kurihara, Toshihide; Westenskow, Peter D.; Usui, Yoshihiko; Bravo, Stephen; Aguilar, Edith; Wittgrove, Carli; Friedlander, Mollie S. H.; Paris, Liliana P.; Friedlander, Martin] Scripps Res Inst, Dept Cell & Mol Biol, La Jolla, CA USA. [Westenskow, Peter D.; Gantner, Marin L.] Lowy Med Res Inst, La Jolla, CA USA. [Schultz, Andrew; Siuzdak, Gary] Scripps Res Inst, Ctr Metabol, La Jolla, CA USA. [Chew, Emily] NEI, NIH, Bethesda, MD 20892 USA. [Kurihara, Toshihide] Keio Univ, Sch Med, Dept Ophthalmol, Tokyo, Japan. [Usui, Yoshihiko] Tokyo Med Univ Hosp, Dept Ophthalmol, Shinjuku Ku, Tokyo, Japan. RP Friedlander, M (reprint author), Scripps Res Inst, Dept Cell & Mol Biol, La Jolla, CA USA. EM friedlan@scripps.edu OI Westenskow, Peter/0000-0001-9841-6220 FU National Eye Institute [EY11254]; Lowy Medical Research Institute MacTel Project; Manpei Suzuki Diabetes Foundation; Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad; National Eye Institute FX National Eye Institute EY11254 Martin Friedlander; The Lowy Medical Research Institute MacTel Project Martin Friedlander; Manpei Suzuki Diabetes Foundation Postdoctoral support Toshihide Kurihara; Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad Postdoctoral support Toshihide Kurihara; National Eye Institute Postdoctoral support Peter D Westenskow; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 101 TC 7 Z9 7 U1 2 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 MAR 15 PY 2016 VL 5 AR e14319 DI 10.7554/eLife.14319 PG 22 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DK9DG UT WOS:000375230100001 ER PT J AU Ying, TL Li, W Dimitrov, DS AF Ying, Tianlei Li, Wei Dimitrov, Dimiter S. TI Discovery of T-Cell Infection and Apoptosis by Middle East Respiratory Syndrome Coronavirus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material DE MERS-CoV; immunopathology; IFN; cytokine/chemokine; T cell; DPP4; apoptosis ID DENDRITIC CELLS; 4A; PATHOGENESIS; REPLICATION; ACTIVATION; PROTEIN C1 [Ying, Tianlei] Fudan Univ, Shanghai Med Coll, MOE MOH, Key Lab Med Mol Virol, Shanghai, Peoples R China. [Li, Wei; Dimitrov, Dimiter S.] NCI, Prot Interact Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21701 USA. RP Ying, TL (reprint author), 131 Dong An Rd, Shanghai 200032, Peoples R China. EM tlying@fudan.edu.cn FU Intramural NIH HHS NR 18 TC 1 Z9 2 U1 2 U2 6 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 MAR 15 PY 2016 VL 213 IS 6 BP 877 EP 879 DI 10.1093/infdis/jiv381 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DJ4ON UT WOS:000374186000001 PM 26203059 ER PT J AU Sobhanie, M Matsuoka, Y Jegaskanda, S Fitzgerald, T Mallory, R Chen, ZY Luke, C Treanor, J Subbarao, K AF Sobhanie, Mahdee Matsuoka, Yumiko Jegaskanda, Sinthujan Fitzgerald, Theresa Mallory, Raburn Chen, Zhongying Luke, Catherine Treanor, John Subbarao, Kanta TI Evaluation of the Safety and Immunogenicity of a Candidate Pandemic Live Attenuated Influenza Vaccine (pLAIV) Against Influenza A(H7N9) SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE pandemic influenza; live vaccine; immune memory ID PHASE-I TRIAL; VIRUS VACCINE; HEALTHY-ADULTS; ANTIBODY-RESPONSE; YOUNG-CHILDREN; H7N9; H5N1; HEMAGGLUTININ; PROTECTION; INFECTION AB Background. We evaluated a candidate A/Anhui/2013(H7N9) pandemic live attenuated influenza vaccine (pLAIV) in healthy adults, and assessed the ability of 1 or 2 doses to induce immune memory. Methods. Healthy subjects in 2 age groups (18-49 years and 50-70 years) with undetectable hemagglutination-inhibiting (HAI) antibody to H7N9 were enrolled. Younger subjects received either 1 or 2 intranasal doses of 10(7.0) fluorescent focus units of A/Anhui/1/2013 pLAIV, while older subjects received a single dose. All subjects received a single 30-mu g dose of unadjuvanted, antigenically matched A/Shanghai2/2013(H7N9) pandemic inactivated influenza vaccine (pIIV) 12 weeks after their first dose of pLAIV. Results. Both vaccines were well tolerated. Serum HAI antibody responses were detected in 0 of 32 younger subjects and 1 of 17 older subjects after 1 dose of pLAIV and in 2 of 16 younger subjects after a second dose. Strong serum antibody responses were detected after a single subsequent dose of pIIV that was broadly reactive against H7 influenza viruses. Conclusions. An A(H7N9) pLAIV candidate was safe in both age groups. Priming with pLAIV resulted in responses to subsequent pIIV that exceeded those seen in naive subjects in previous reports. The A(H7N9) pLAIV induces strong immune memory that can be demonstrated by exposure to subsequent antigenic challenge. C1 [Sobhanie, Mahdee; Fitzgerald, Theresa; Treanor, John] Univ Rochester, Med Ctr, Dept Med, New York, NY USA. [Matsuoka, Yumiko; Jegaskanda, Sinthujan; Luke, Catherine; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Mallory, Raburn; Chen, Zhongying] Medimmune, Gaithersburg, MD USA. [Jegaskanda, Sinthujan] Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Melbourne, Vic, Australia. RP Treanor, J (reprint author), Univ Rochester, Med Ctr, Dept Med, Div Infect Dis, 601 Elmwood Ave,Rm 3-6208, Rochester, NY 14642 USA. EM john_treanor@urmc.rochester.edu FU Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); MedImmune [AI-0155]; Division of Intramural Research, NIAID, NIH; Biomedical Advanced Research and Development Authority, Department of Health and Human Services [HHSN272200900026C]; National Health and Medical Research Council, Australia [APP1072127] FX This work was supported by the Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and MedImmune (cooperative research and development agreement AI-0155); the Division of Intramural Research, NIAID, NIH; the Biomedical Advanced Research and Development Authority, Department of Health and Human Services (contract HHSN272200900026C); and the National Health and Medical Research Council, Australia (early career fellowship APP1072127 to S. J.). NR 26 TC 5 Z9 5 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2016 VL 213 IS 6 BP 922 EP 929 DI 10.1093/infdis/jiv526 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DJ4ON UT WOS:000374186000008 PM 26655841 ER PT J AU Harari, A Chen, ZG Rodriguez, AC Hildesheim, A Porras, C Herrero, R Wacholder, S Panagiotou, OA Befano, B Burk, RD Schiffman, M AF Harari, Ariana Chen, Zigui Cecilia Rodriguez, Ana Hildesheim, Allan Porras, Carolina Herrero, Rolando Wacholder, Sholom Panagiotou, Orestis A. Befano, Brian Burk, Robert D. Schiffman, Mark CA Costa Rica HPV Vaccine Trial Grp TI Cross-protection of the Bivalent Human Papillomavirus (HPV) Vaccine Against Variants of Genetically Related High-Risk HPV Infections SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HPV vaccine; cross-protection; HPV variants ID MAJOR CAPSID PROTEIN; NEUTRALIZING CONFORMATIONAL EPITOPES; CERVICAL INTRAEPITHELIAL NEOPLASIA; RANDOMIZED CONTROLLED-TRIAL; VIRUS-LIKE PARTICLES; COSTA-RICA; DOUBLE-BLIND; YOUNG-WOMEN; QUADRIVALENT VACCINE; TYPE-18 VARIANTS AB Background. Results from the Costa Rica Vaccine Trial (CVT) demonstrated partial cross-protection by the bivalent human papillomavirus (HPV) vaccine, which targets HPV-16 and HPV-18, against HPV-31, -33, and -45 infection and an increased incidence of HPV-51 infection. Methods. A study nested within the CVT intention-to-treat cohort was designed to assess high-risk HPV variant lineage-specific vaccine efficacy (VE). The 2 main end points were (1) long-term incident infections persisting for >= 2 years and/or progression to high-grade squamous intraepithelial lesions (ie, cervical intraepithelial neoplasia grade 2/3 [CIN 2/3]) and (2) incident transient infections lasting for <2 years. For efficiency, incident infections due to HPV-16, -18, -31, -33, -35, -45, and -51 resulting in persistent infection and/or CIN 2/3 were matched (ratio, 1: 2) to the more-frequent transient viral infections, by HPV type. Variant lineages were determined by sequencing the upstream regulatory region and/or E6 region. Results. VEs against persistent or transient infections with HPV-16, -18, -33, -35, -45, and -51 did not differ significantly by variant lineage. As the possible exception, VEs against persistent infection and/or CIN 2/3 due to HPV-31 A/B and HPV-31C variants were -7.1% (95% confidence interval [CI], -33.9% to 0%) and 86.4% (95% CI, 65.1%-97.1%), respectively (P = .02 for test of equal VE). No difference in VE was observed by variant among transient HPV-31 infections (P = .68). Conclusions. Overall, sequence variation at the variant level does not appear to explain partial cross-protection by the bivalent HPV vaccine. C1 [Harari, Ariana; Burk, Robert D.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. [Chen, Zigui; Burk, Robert D.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10461 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10461 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Hildesheim, Allan; Wacholder, Sholom; Panagiotou, Orestis A.; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Befano, Brian] Informat Management Serv Inc, Silver Spring, MD USA. [Cecilia Rodriguez, Ana; Porras, Carolina; Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Herrero, Rolando] WHO, Int Agcy Res Canc, Lyon, France. RP Burk, RD (reprint author), Albert Einstein Coll Med, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM robert.burk@einstein.yu.edu RI Chen, Zigui/E-8490-2017 FU National Cancer Institute, National Institutes of Health (NIH) [CA78527, P30 CA13330, N01-CP-11005]; NIH Office of Research on Women's Health; GlaxoSmithKline Biologicals [FDA BB-IND 7920] FX This work was supported by the National Cancer Institute, National Institutes of Health (NIH; awards CA78527, P30 CA13330, and N01-CP-11005); the NIH Office of Research on Women's Health; and GlaxoSmithKline Biologicals (clinical trials agreement FDA BB-IND 7920). NR 47 TC 1 Z9 1 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2016 VL 213 IS 6 BP 939 EP 947 DI 10.1093/infdis/jiv519 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DJ4ON UT WOS:000374186000011 PM 26518044 ER PT J AU Grabowski, MK Kong, XR Gray, RH Serwadda, D Kigozi, G Gravitt, PE Nalugoda, F Reynolds, SJ Wawer, MJ Redd, AD Watya, S Quinn, TC Tobian, AAR AF Grabowski, Mary K. Kong, Xiangrong Gray, Ronald H. Serwadda, David Kigozi, Godfrey Gravitt, Patti E. Nalugoda, Fred Reynolds, Steven J. Wawer, Maria J. Redd, Andrew D. Watya, Stephen Quinn, Thomas C. Tobian, Aaron A. R. TI Partner Human Papillomavirus Viral Load and Incident Human Papillomavirus Detection in Heterosexual Couples SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE human papillomavirus; viral load; transmission; male circumcision; HIV; Africa; Uganda; penile cancer; cervical cancer; sexually transmitted infections ID RISK HUMAN-PAPILLOMAVIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; GENITAL HUMAN-PAPILLOMAVIRUS; RANDOMIZED CONTROLLED-TRIAL; MALE CIRCUMCISION; NATURAL-HISTORY; FEMALE PARTNERS; THERAPEUTIC VACCINES; HIV ACQUISITION; INFECTION AB Background. The association between partner human papillomavirus (HPV) viral load and incident HPV detection in heterosexual couples is unknown. Methods. HPV genotypes were detected in 632 human immunodeficiency virus (HIV)-negative couples followed for 2 years in a male circumcision trial in Rakai, Uganda, using the Roche HPV Linear Array. This assay detects 37 genotypes and provides a semi-quantitative measure of viral load based on the intensity (graded 1-4) of the genotype-specific band; a band intensity of 1 indicates a low genotype-specific HPV load, whereas an intensity of 4 indicates a high load. Using Poisson regression with generalized estimating equations, we measured the association between partner's genotype-specific viral load and detection of that genotype in the HPV-discordant partner 1 year later. Results. Incident detection of HPV genotypes was 10.6% among men (54 of 508 genotype-specific visit intervals) and 9.0% among women (55 of 611 genotype-specific visit intervals). Use of male partners with a baseline genotype-specific band intensity of 1 as a reference yielded adjusted relative risks (aRRs) of 1.14 (95% confidence interval [CI], .58-2.27]) for incident detection of that genotype among women whose male partner had a baseline band intensity of 2, 1.75 (95% CI, .97-3.17) among those whose partner had an intensity of 3, and 2.52 (95% CI, 1.40-4.54) among those whose partner had an intensity of 4. Use of female partners with a baseline genotype-specific band intensity of 1 as a reference yielded an aRR of 2.83 (95% CI, 1.50-5.33) for incident detection of that genotype among men whose female partner had a baseline band intensity of 4. These associations were similar for high-risk and low-risk genotypes. Male circumcision also was associated with significant reductions in incident HPV detection in men (aRR, 0.53 [95% CI, .30-.95]) and women (aRR, 0.42 [95% CI, .23-.76]). Conclusions. In heterosexual couples, the genotype-specific HPV load in one partner is associated with the risk of new detection of that genotype in the other partner. Interventions that reduce the HPV load may reduce the incidence of HPV transmission. C1 [Grabowski, Mary K.; Kong, Xiangrong; Gray, Ronald H.; Gravitt, Patti E.; Reynolds, Steven J.; Wawer, Maria J.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Nalugoda, Fred; Reynolds, Steven J.; Redd, Andrew D.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Reynolds, Steven J.; Redd, Andrew D.; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gravitt, Patti E.] Univ New Mexico, Sch Med, Dept Pathol, Albuquerque, NM 87131 USA. [Gray, Ronald H.; Serwadda, David; Kigozi, Godfrey; Reynolds, Steven J.; Wawer, Maria J.; Quinn, Thomas C.; Tobian, Aaron A. R.] Rakai Hlth Sci Program, Entebbe, Uganda. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Watya, Stephen] Makerere Univ, Dept Urol, Kampala, Uganda. RP Grabowski, MK (reprint author), Johns Hopkins Univ, Dept Epidemiol, 627 N Washington St, Baltimore, MD 21205 USA. EM mgrabow2@jhu.edu FU National Institutes of Health (NIH) [U1AI51171, 1K23AI093152-01A1, T32AI102]; Bill and Melinda Gates Foundation [22006.02]; National Institute of Allergy and Infectious Diseases (NIAID), NIH [1K23AI093152-01A1, U01-AI-068613, 3U01-AI075115-03S1]; Division of Intramural Research, NIAID, NIH; Doris Duke Charitable Foundation [22006.02] FX This work was supported by the National Institutes of Health (NIH; grants U1AI51171, 1K23AI093152-01A1 [to A. A. R. T.], and T32AI102 [to M. K. G.]); the Bill and Melinda Gates Foundation (grant 22006.02); the National Institute of Allergy and Infectious Diseases (NIAID), NIH (grants 1K23AI093152-01A1, U01-AI-068613, and 3U01-AI075115-03S1); the Division of Intramural Research, NIAID, NIH; and the Doris Duke Charitable Foundation (clinician scientist development awards to A. A. R. T. [no. 22006.02] and M. K. G.). NR 50 TC 1 Z9 2 U1 0 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 MAR 15 PY 2016 VL 213 IS 6 BP 948 EP 956 DI 10.1093/infdis/jiv541 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DJ4ON UT WOS:000374186000012 PM 26597261 ER PT J AU Sanna, PP Kawamura, T Chen, J Koob, GF Roberts, AJ Vendruscolo, LF Repunte-Canonigo, V AF Sanna, P. P. Kawamura, T. Chen, J. Koob, G. F. Roberts, A. J. Vendruscolo, L. F. Repunte-Canonigo, V. TI 11 beta-hydroxysteroid dehydrogenase inhibition as a new potential therapeutic target for alcohol abuse SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID ALDOSTERONE-SENSITIVE NEURONS; CORTICOTROPIN-RELEASING-FACTOR; PRE-RECEPTOR REGULATION; PITUITARY-ADRENAL AXIS; PEPTIC-ULCER DISEASE; ETHANOL DRINKING; SOCIAL-ISOLATION; STRESS HORMONES; DEPENDENT RATS; SOLITARY TRACT AB The identification of new and more effective treatments for alcohol abuse remains a priority. Alcohol intake activates glucocorticoids, which have a key role in alcohol's reinforcing properties. Glucocorticoid effects are modulated in part by the activity of 11 beta-hydroxysteroid dehydrogenases (11 beta-HSD) acting as pre-receptors. Here, we tested the effects on alcohol intake of the 11 beta-HSD inhibitor carbenoxolone (CBX, 18 beta-glycyrrhetinic acid 3 beta-O-hemisuccinate), which has been extensively used in the clinic for the treatment of gastritis and peptic ulcer and is active on both 11 beta-HSD1 and 11 beta-HSD2 isoforms. We observed that CBX reduces both baseline and excessive drinking in rats and mice. The CBX diastereomer 18 alpha-glycyrrhetinic acid 3 beta-O-hemisuccinate (alpha CBX), which we found to be selective for 11 beta-HSD2, was also effective in reducing alcohol drinking in mice. Thus, 11 beta-HSD inhibitors may be a promising new class of candidate alcohol abuse medications, and existing 11 beta-HSD inhibitor drugs may be potentially re-purposed for alcohol abuse treatment. C1 [Sanna, P. P.; Kawamura, T.; Chen, J.; Roberts, A. J.; Repunte-Canonigo, V.] Scripps Res Inst, Dept Mol & Cellular Neurosci, 10550 North Torrey Pines Rd, La Jolla, CA 90237 USA. [Koob, G. F.] NIAAA, Rockville, MD 20852 USA. [Vendruscolo, L. F.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. RP Sanna, PP (reprint author), Scripps Res Inst, Dept Mol & Cellular Neurosci, 10550 North Torrey Pines Rd, La Jolla, CA 90237 USA. EM psanna@scripps.edu RI koob, george/P-8791-2016 FU NIH [AA020960, AA021667, AA017371, AA020893]; National Institute on Drug Abuse Intramural Research Program FX This work was supported by NIH grants AA020960, AA021667, AA017371 and AA020893 and by the National Institute on Drug Abuse Intramural Research Program (LFV). NR 72 TC 1 Z9 1 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD MAR 15 PY 2016 VL 6 AR e760 DI 10.1038/tp.2016.13 PG 7 WC Psychiatry SC Psychiatry GA DJ0OX UT WOS:000373904900006 PM 26978742 ER PT J AU Merchant, MS Wright, M Baird, K Wexler, LH Rodriguez-Galindo, C Bernstein, D Delbrook, C Lodish, M Bishop, R Wolchok, JD Streicher, H Mackall, CL AF Merchant, Melinda S. Wright, Matthew Baird, Kristin Wexler, Leonard H. Rodriguez-Galindo, Carlos Bernstein, Donna Delbrook, Cindy Lodish, Maya Bishop, Rachel Wolchok, Jedd D. Streicher, Howard Mackall, Crystal L. TI Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC MELANOMA; CTLA-4 BLOCKADE; CANCER-IMMUNOTHERAPY; ADVERSE EVENTS; ANTIBODY; EFFICACY; INTERLEUKIN-2; NEUROBLASTOMA; ADOLESCENTS; CHILDREN AB Purpose: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase I protocol. Experimental Design: This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects <= 21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. Results: Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory solid tumors (n = 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T-cell populations. Six subjects had confirmed stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma). Conclusions: Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance. (C) 2015 AACR. C1 [Merchant, Melinda S.; Wright, Matthew; Baird, Kristin; Bernstein, Donna; Delbrook, Cindy; Mackall, Crystal L.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wexler, Leonard H.] Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 USA. [Wexler, Leonard H.; Wolchok, Jedd D.] Weill Cornell Med Coll, New York, NY USA. [Rodriguez-Galindo, Carlos] Dana Farber Canc Inst, Pediat Oncol, Boston, MA 02115 USA. [Lodish, Maya] NICHHD, NIH, Bethesda, MD 20892 USA. [Bishop, Rachel] NEI, NIH, Bethesda, MD 20892 USA. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Streicher, Howard] NCI, Invest Drug Branch, NIH, Bethesda, MD 20892 USA. RP Mackall, CL (reprint author), NCI, 10 Ctr Dr,Bldg 10 CRC,Room 1W-3750, Bethesda, MD 20892 USA. EM mackallc@mail.nih.gov FU NIH, NCI FX This research was supported in part by the Intramural Research Program of the NIH, NCI. NR 32 TC 8 Z9 9 U1 2 U2 6 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 MAR 15 PY 2016 VL 22 IS 6 BP 1364 EP 1370 DI 10.1158/1078-0432.CCR-15-0491 PG 7 WC Oncology SC Oncology GA DI2WD UT WOS:000373358900011 PM 26534966 ER PT J AU Haas, DM Ehrenthal, DB Koch, MA Catov, JM Barnes, SE Facco, F Parker, CB Mercer, BM Bairey-Merz, CN Silver, RM Wapner, RJ Simhan, HN Hoffman, MK Grobman, WA Greenland, P Wing, DA Saade, GR Parry, S Zee, PC Reddy, UM Pemberton, VL Burwen, DR AF Haas, David M. Ehrenthal, Deborah B. Koch, Matthew A. Catov, Janet M. Barnes, Shannon E. Facco, Francesca Parker, Corette B. Mercer, Brian M. Bairey-Merz, C. Noel Silver, Robert M. Wapner, Ronald J. Simhan, Hyagriv N. Hoffman, Matthew K. Grobman, William A. Greenland, Philip Wing, Deborah A. Saade, George R. Parry, Samuel Zee, Phyllis C. Reddy, Uma M. Pemberton, Victoria L. Burwen, Dale R. TI Pregnancy as a Window to Future Cardiovascular Health: Design and Implementation of the nuMoM2b Heart Health Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cardiovascular disease; cohort study; heart health; methods; pregnancy; women's health ID 3-FACTOR EATING QUESTIONNAIRE; POSTNATAL DEPRESSION SCALE; OBSTRUCTIVE SLEEP-APNEA; PERCEIVED STRESS; RISK-FACTORS; WOMENS HEALTH; DISEASE RISK; POSTPARTUM DEPRESSION; ENDOTHELIAL FUNCTION; PHYSICAL-ACTIVITY AB The National Institute of Child Health and Human Development's Nulliparous Pregnancy Outcomes Study-Monitoring Mothers-to-Be (nuMoM2b) Heart Health Study (HHS) was designed to investigate the relationships between adverse pregnancy outcomes and modifiable risk factors for cardiovascular disease. The ongoing nuMoM2b-HHS, which started in 2013, is a prospective follow-up of the nuMoM2b cohort, which included 10,038 women recruited between 2010 and 2013 from 8 centers across the United States who were initially observed over the course of their first pregnancies. In this report, we detail the design and study procedures of the nuMoM2b-HHS. Women in the pregnancy cohort who consented to be contacted for participation in future studies were approached at 6-month intervals to ascertain health information and to maintain ongoing contact. Two to 5 years after completion of the pregnancy documented in the nuMoM2b, women in the nuMoM2b-HHS were invited to an in-person study visit. During this visit, they completed psychosocial and medical history questionnaires and had clinical measurements and biological specimens obtained. A subcohort of participants who had objective assessments of sleep-disordered breathing during pregnancy were asked to repeat this investigation. This unique prospective observational study includes a large, geographically and ethnically diverse cohort, rich depth of phenotypic information about adverse pregnancy outcomes, and clinical data and biospecimens from early in the index pregnancy onward. Data obtained from this cohort will provide mechanistic and clinical insights into how data on a first pregnancy can provide information about the potential development of subsequent risk factors for cardiovascular disease. C1 [Haas, David M.; Barnes, Shannon E.] Indiana Univ, Sch Med, Dept Obstet & Gynecol, Indianapolis, IN 46202 USA. [Ehrenthal, Deborah B.] Univ Wisconsin, Dept Med, Madison, WI USA. [Koch, Matthew A.; Parker, Corette B.] RTI Int, Res Triangle Pk, NC USA. [Catov, Janet M.; Facco, Francesca; Simhan, Hyagriv N.] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Mercer, Brian M.] Case Western Reserve Univ, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. [Bairey-Merz, C. Noel] Cedars Sinai Med Ctr, Dept Med, Div Cardiol, Los Angeles, CA 90048 USA. [Silver, Robert M.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Silver, Robert M.] Intermt Healthcare, Salt Lake City, UT USA. [Wapner, Ronald J.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Hoffman, Matthew K.] Christiana Care, Dept Obstet & Gynecol, Wilmington, DE USA. [Grobman, William A.] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL USA. [Greenland, Philip] Northwestern Univ, Dept Med, Div Cardiol, Chicago, IL 60611 USA. [Wing, Deborah A.] Univ Calif Irvine, Dept Obstet & Gynecol, Irvine, CA 92717 USA. [Saade, George R.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Parry, Samuel] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Zee, Phyllis C.] Northwestern Univ, Dept Neurol, Chicago, IL USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Pemberton, Victoria L.; Burwen, Dale R.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Haas, DM (reprint author), Indiana Univ Sch Med, Dept Obstet & Gynecol, 550 N Univ Blvd,UH 2440, Indianapolis, IN 46202 USA. EM dahaas@iupui.edu FU National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10-HL119991, U10-HL119989, U10-HL120034, U10-HL119990, U10-HL120006, U10-HL119992, U10-HL120019, U10-HL119993, U10-HL120018]; National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health [UL1TR001108]; University of California, Irvine [UL1TR000153] FX This study is supported by cooperative agreement funding from the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development: grant U10-HL119991 to RTI International; grant U10-HL119989 to Case Western Reserve University; grant U10-HL120034 to Columbia University; grant U10-HL119990 to Indiana University; grant U10-HL120006 to the University of Pittsburgh; grant U10-HL119992 to Northwestern University; grant U10-HL120019 to the University of California, Irvine; grant U10-HL119993 to University of Pennsylvania; and grant U10-HL120018 to the University of Utah. In addition, support was provided by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health to Clinical and Translational Science Institutes at Indiana University (grant UL1TR001108) and University of California, Irvine (grant UL1TR000153). NR 114 TC 1 Z9 1 U1 5 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 15 PY 2016 VL 183 IS 6 BP 519 EP 530 DI 10.1093/aje/kwv309 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DH1XY UT WOS:000372579500002 PM 26825925 ER PT J AU Wynn, TA Vannella, KM AF Wynn, Thomas A. Vannella, Kevin M. TI Macrophages in Tissue Repair, Regeneration, and Fibrosis SO IMMUNITY LA English DT Review ID SKELETAL-MUSCLE REGENERATION; MESENCHYMAL STEM-CELLS; MURINE LIVER FIBROSIS; INJURED SPINAL-CORD; REGULATORY T-CELLS; GROWTH-FACTOR; RESIDENT MACROPHAGES; INNATE IMMUNITY; M2 MACROPHAGES; RENAL INJURY AB Inflammatory monocytes and tissue-resident macrophages are key regulators of tissue repair, regeneration, and fibrosis. After tissue injury, monocytes and macrophages undergo marked phenotypic and functional changes to play critical roles during the initiation, maintenance, and resolution phases of tissue repair. Disturbances in macrophage function can lead to aberrant repair, such that uncontrolled production of inflammatory mediators and growth factors, deficient generation of anti-inflammatory macrophages, or failed communication between macrophages and epithelial cells, endothelial cells, fibroblasts, and stem or tissue progenitor cells all contribute to a state of persistent injury, and this could lead to the development of pathological fibrosis. In this review, we discuss the mechanisms that instruct macrophages to adopt pro-inflammatory, pro-wound-healing, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-resolving, and tissue-regenerating phenotypes after injury, and we highlight how some of these mechanisms and macrophage activation states could be exploited therapeutically. C1 [Wynn, Thomas A.; Vannella, Kevin M.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wynn, TA (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov FU NIAID of the NIH FX T.A.W. and K.M.V. are supported by the intramural research program at the NIAID of the NIH. We would like to sincerely thank Ethan Tyler and Alan Hoofring of the NIH Medical Arts for help with figures. Both authors would also like to acknowledge the following colleagues at the NIH and abroad for many fruitful discussions on this topic: Peter Murray, John Pesce, Mark Wilson, Satish Madala, Rafael Prado, Trey Gieseck, David Cantu, Kayla Knilans, Robert Thompson, Lee Borthwick, Luke Barron, Kevin Hart, and Thiru Ramalingam. NR 127 TC 36 Z9 38 U1 30 U2 60 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAR 15 PY 2016 VL 44 IS 3 BP 450 EP 462 DI 10.1016/j.immuni.2016.02.015 PG 13 WC Immunology SC Immunology GA DH4VR UT WOS:000372784200002 PM 26982353 ER PT J AU Sen, R AF Sen, Ranjan TI A Pioneer's Tail SO IMMUNITY LA English DT Editorial Material ID ESTABLISHMENT; REPRESSION; COMMITMENT; CHROMATIN AB In this issue of Immunity, Boller et al. (2016) show that a C-terminal domain of EBF1 is required for chromatin binding and induction of DNase I hypersensitive sites. These properties mark EBF1 as a pioneer factor in B cell development and demonstrate a role for non-DNA binding domains in this process. C1 [Sen, Ranjan] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. RP Sen, R (reprint author), NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. EM senra@mail.nih.gov NR 9 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAR 15 PY 2016 VL 44 IS 3 BP 516 EP 518 DI 10.1016/j.immuni.2016.03.005 PG 3 WC Immunology SC Immunology GA DH4VR UT WOS:000372784200007 PM 26982358 ER PT J AU Riteau, N Sher, A AF Riteau, Nicolas Sher, Alan TI Chitosan: An Adjuvant with an Unanticipated STING SO IMMUNITY LA English DT Editorial Material ID INTERFERON AB Adjuvants promote adaptive immunity through the triggering of innate signals that are largely poorly understood. In this issue of Immunity, Lavelle and colleagues describe an unexpected role for the DNA sensing cGAS-STING pathway in the mechanism of action of the Th1 cell-promoting polysaccharide adjuvant chitosan. C1 [Riteau, Nicolas; Sher, Alan] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Sher, A (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM asher@niaid.nih.gov FU Intramural NIH HHS NR 10 TC 2 Z9 2 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAR 15 PY 2016 VL 44 IS 3 BP 522 EP 524 DI 10.1016/j.immuni.2016.03.002 PG 4 WC Immunology SC Immunology GA DH4VR UT WOS:000372784200010 PM 26982361 ER PT J AU Robb, MA McInnes, PM Califf, RM AF Robb, Melissa A. McInnes, Pamela M. Califf, Robert M. TI Biomarkers and Surrogate Endpoints Developing Common Terminology and Definitions SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Robb, Melissa A.] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak,Bldg 51,Rm 6360, Silver Spring, MD 20993 USA. [McInnes, Pamela M.] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Califf, Robert M.] US FDA, Silver Spring, MD USA. RP Robb, MA (reprint author), US FDA, Off Med Policy, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak,Bldg 51,Rm 6360, Silver Spring, MD 20993 USA. EM melissa.robb@fda.hhs.gov NR 6 TC 5 Z9 5 U1 0 U2 6 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 MAR 15 PY 2016 VL 315 IS 11 BP 1107 EP 1108 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DG5ZB UT WOS:000372159800011 PM 26978201 ER PT J AU Hosseinzadeh, P Mirts, EN Pfister, TD Gao, YG Mayne, C Robinson, H Tajkhorshid, E Lu, Y AF Hosseinzadeh, Parisa Mirts, Evan N. Pfister, Thomas D. Gao, Yi-Gui Mayne, Christopher Robinson, Howard Tajkhorshid, Emad Lu, Yi TI Enhancing Mn(II)-Binding and Manganese Peroxidase Activity in a Designed Cytochrome c Peroxidase through Fine-Tuning Secondary-Sphere Interactions SO BIOCHEMISTRY LA English DT Article ID PHANEROCHAETE-CHRYSOSPORIUM; CRYSTAL-STRUCTURE; LIGNIN BIOSYNTHESIS; HEME PEROXIDASE; MN-PEROXIDASE; BINDING-SITE; AMINO-ACIDS; OXIDATION; SUBSTRATE; REDUCTION AB Noncovalent second-shell interactions are important in controlling metal-binding affinity and activity in metalloenzymes, but fine-tuning these interactions in designed metalloenzymes has not been fully explored. As a result, most,designed metalloenzymes have low metal-binding affinity and activity. Here we identified three mutations in the second coordination shell of an engineered Mn(II)-binding site in cytochrome c peroxidase (called MnCcP.1, containing Glu45, Glu37, and Glu181 ligands) that mimics the native manganese peroxidase (MnP), and explored their effects on both Mn(II)-binding affinity and MnP activity. First, removing a hydrogen bond to Glu45 through Tyr36Phe mutation enhanced Mn(II)-binding affinity, as evidenced by a 2.8-fold decrease in the K-M of Mn(II) oxidation. Second, introducing a salt bridge through Lys179Arg mutation improved Glu35 and Glu181 coordination to Mn(II), decreasing Km 2.6-fold. Third, eliminating a steric clash that prevented Glu37 from orienting toward Mn(II) resulted in an 8.6-fold increase in k(cat)/K-M, arising primarily from a 3.6-fold decrease in K-M, with a K-M value comparable to that of the native enzyme (0.28 mM vs 0.19 mM for Pleurotus eryngii MnP PS3). We further demonstrated that while the effects of Tyr36Phe and Lys179Arg mutations are additive, because involved in secondary-shell interactions to different ligands, other combinations of mutations were antagonistic because they act on, different aspects of the Mn(II) coordination at the same residues. Finally, we showed that these MnCcP variants are functional models of MnP that mimic its activity in both Mn(II) oxidation and degradation of a phenolic lignin model compound and kraft lignin. In addition to achieving KM in a designed protein that is similar to the that of native enzyme, our results offer molecular insight into the role of noncovalent interactions around metal-binding sites for improving metal binding and overall activity; such insight can be applied to rationally enhance these properties in other metalloenzyrnes and their models. C1 [Hosseinzadeh, Parisa; Pfister, Thomas D.; Tajkhorshid, Emad; Lu, Yi] Univ Illinois, Dept Biochem, Urbana, IL 61801 USA. [Gao, Yi-Gui; Lu, Yi] Univ Illinois, Dept Chem, Urbana, IL 61801 USA. [Mirts, Evan N.; Tajkhorshid, Emad; Lu, Yi] Univ Illinois, Ctr Biophys & Quantitat Biol, Urbana, IL 61801 USA. [Mayne, Christopher; Tajkhorshid, Emad] Univ Illinois, Beckman Inst Adv Sci & Technol, Urbana, IL 61801 USA. [Robinson, Howard] Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. [Pfister, Thomas D.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Human Toxicol & Pharmacol, Appl Dev Directorate, Frederick, MD 21702 USA. RP Lu, Y (reprint author), Univ Illinois, Dept Biochem, Urbana, IL 61801 USA.; Lu, Y (reprint author), Univ Illinois, Dept Chem, Urbana, IL 61801 USA.; Lu, Y (reprint author), Univ Illinois, Ctr Biophys & Quantitat Biol, Urbana, IL 61801 USA. EM yi-lu@illinois.edu RI Lu, Yi/B-5461-2010 OI Lu, Yi/0000-0003-1221-6709 FU National Institutes of Health [R01GM062211, P41-GM104601] FX This material is based on work supported by the National Institutes of Health via Grant R01GM062211 (to Y.L.) and Grant P41-GM104601 (E.T. and C.M.). NR 70 TC 3 Z9 3 U1 7 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 15 PY 2016 VL 55 IS 10 BP 1494 EP 1502 DI 10.1021/acs.biochem.5b01299 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DG9GY UT WOS:000372392000008 PM 26885726 ER PT J AU Nohata, N Uchida, Y Stratman, AN Adams, RH Zheng, Y Weinstein, BM Mukouyama, YS Gutkind, JS AF Nohata, Nijiro Uchida, Yutaka Stratman, Amber N. Adams, Ralf H. Zheng, Yi Weinstein, Brant M. Mukouyama, Yoh-Suke Gutkind, J. Silvio TI Temporal-specific roles of Rac1 during vascular development and retinal angiogenesis SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Rac1; Angiogenesis; Conditional gene knockout mouse; In vitro three dimensional collagen matrix model ID ENDOTHELIAL-CELLS; MOUSE RETINA; VE-CADHERIN; RHO-GTPASES; CARDIOVASCULAR DEVELOPMENT; SPHINGOSINE KINASE-1; IN-VITRO; PROTEIN; PERMEABILITY; SPHINGOSINE-1-PHOSPHATE AB Angiogenesis, the formation of new blood vessels by remodeling and growth of pre-existing vessels, is a highly orchestrated process that requires a tight balance between pro-angiogenic and anti-angiogenic factors and the integration of their corresponding signaling networks. The family of Rho GTPases, including RhoA, Rac1, and Cdc42, play a central role in many cell biological processes that involve cytoskeletal changes and cell movement. Specifically for Rac1, we have shown that excision of Rac1 using a Tie2-Cre animal line results in embryonic lethality in midgestation (embryonic day (E) 9.5), with multiple vascular defects. However, Tie2-Cre can be also expressed during vasculogenesis, prior to angiogenesis, and is active in some hematopoietic precursors that can affect vessel formation. To circumvent these limitations, we have now conditionally deleted Rac1 in a temporally controlled and endothelial-restricted fashion using Cdh5(PAC)-iCreERT2 transgenic mice. In this highly controlled experimental in vivo system, we now show that Rac1 is required for embryonic vascular integrity and angiogenesis, and for the formation of superficial and deep vascular networks in the post-natal developing retina, the latter involving a novel specific function for Rac1 in vertical blood vessel sprouting. Aligned with these findings, we show that RAC1 is spatially involved in endothelial cell migration, invasion, and radial sprouting activities in 3D collagen matrix in vitro models. Hence, Rac1 and its downstream molecules may represent potential antiangiogeneic therapeutic targets for the treatment of many human diseases that involve aberrant neovascularization and blood vessel overgrowth. (C) 2016 Published by Elsevier Inc. C1 [Nohata, Nijiro; Gutkind, J. Silvio] Univ Calif San Diego, Moores Canc Ctr, 3855 Hlth Sci Dr 0803, La Jolla, CA 92093 USA. [Uchida, Yutaka; Mukouyama, Yoh-Suke] NHLBI, Lab Stem Cell & Neurovascular Biol, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20814 USA. [Stratman, Amber N.; Weinstein, Brant M.] NICHHD, Sect Vertebrate Dev, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Adams, Ralf H.] Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, D-48149 Munster, Germany. [Adams, Ralf H.] Univ Munster, Fac Med, D-48149 Munster, Germany. [Zheng, Yi] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp, Canc & Blood Dis Inst, Cincinnati, OH 45229 USA. [Gutkind, J. Silvio] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. RP Gutkind, JS (reprint author), Univ Calif San Diego, Moores Canc Ctr, 3855 Hlth Sci Dr 0803, La Jolla, CA 92093 USA. EM sgutkind@ucsd.edu FU Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research [Z01DE000558]; UC San Diego Moores Cancer Center and Office of the Dean, Medical School, UC San Diego FX This work was partially supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research (Project Z01DE000558), and by funds provided by the UC San Diego Moores Cancer Center and Office of the Dean, Medical School, UC San Diego. NR 58 TC 2 Z9 2 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD MAR 15 PY 2016 VL 411 IS 2 BP 183 EP 194 DI 10.1016/j.ydbio.2016.02.005 PG 12 WC Developmental Biology SC Developmental Biology GA DG9DR UT WOS:000372383500003 PM 26872874 ER PT J AU Kaltcheva, MM Anderson, MJ Harfe, BD Lewandoski, M AF Kaltcheva, Maria M. Anderson, Matthew J. Harfe, Brian D. Lewandoski, Mark TI BMPs are direct triggers of interdigital programmed cell death SO DEVELOPMENTAL BIOLOGY LA English DT Article DE BMP; FGF; Limb development; Programmed cell death; Reactive oxygen species; Syndactyly ID RETINOIC ACID; MOUSE LIMB; IN-VIVO; DIGIT IDENTITY; APOPTOSIS; EXPRESSION; DIFFERENTIATION; OUTGROWTH; GENERATION; MICE AB (PCD), except in species with webbed limbs. Although bone morphogenetic proteins (BMPs) have long been known to be players in this process, it is unclear if they play a direct role in the interdigital mesenchyme or if they only act indirectly, by affecting fibroblast growth factor (FGF) signaling. A series of genetic studies have shown that BMPs act indirectly by regulating the withdrawal of FGF activity from the apical ectodermal ridge (AER); this FGF activity acts as a cell survival factor for the underlying mesenchyme. Other studies using exogenous factors to inhibit BMP activity in explanted mouse limbs suggest that BMPs do not act directly in the mesenchyme. To address the question of whether BMPs act directly, we used an interdigit-specific Cre line to inactivate several genes that encode components of the BMP signaling pathway, without perturbing the normal downregulation of AER-FGF activity. Of three Bmps expressed in the interdigital mesenchyme, Bmp7 is necessary for PCD, but Bmp2 and Bmp4 both have redundant roles, with Bmp2 being the more prominent player. Removing BMP signals to the interdigit by deleting the receptor gene, Bmpr1a, causes a loss of PCD and syndactyly, thereby unequivocally proving that BMPs are direct triggers of PCD in this tissue. We present a model in which two events must occur for normal interdigital PCD: the presence of a BMP death trigger and the absence of an FGF survival activity. We demonstrate that neither event is required for formation of the interdigital vasculature, which is necessary for PCD. However, both events converge on the production of reactive oxygen species that activate PCD. (C) 2016 Published by Elsevier Inc. C1 [Kaltcheva, Maria M.; Anderson, Matthew J.; Lewandoski, Mark] NCI, Genet Vertebrate Dev Sect, Canc & Dev Biol Lab, NIH, Frederick, MD 21702 USA. [Harfe, Brian D.] Univ Florida, Genet Inst, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. RP Lewandoski, M (reprint author), NCI, Genet Vertebrate Dev Sect, Canc & Dev Biol Lab, NIH, Frederick, MD 21702 USA. EM Lewandom@mail.nih.gov FU Center for Cancer Research of the Intramural Research Program of the National Institutes of Health through the National Cancer Institute FX We thank Cindy Elder and Erika Truffer for excellent technical assistance. We are grateful to Stephen Lockett (Optical Microscopy and Analysis Laboratory) for assistance with confocal microscopy, Joseph Kalen and the Small Animal Imaging Program for assistance with planar X-ray acquisition, and to Elazar Zelzer and Sharon Krief for technical advice and helpful discussion. Thanks to Naiche Adler, Alan Perantoni, and Jianjian Zhu for insightful comments on the manuscript. We thank Chuxia Deng for the Smad4flox mice and Gregg Duester for the Rar beta plasmid. We greatly appreciate Chen-Ming Fan, Susan Mackem, and Yingzi Yang for helpful discussion. This work was supported by the Center for Cancer Research of the Intramural Research Program of the National Institutes of Health through the National Cancer Institute. NR 74 TC 3 Z9 3 U1 3 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD MAR 15 PY 2016 VL 411 IS 2 BP 266 EP 276 DI 10.1016/j.ydbio.2015.12.016 PG 11 WC Developmental Biology SC Developmental Biology GA DG9DR UT WOS:000372383500010 PM 26826495 ER PT J AU Bally, APR Austin, JW Boss, JM AF Bally, Alexander P. R. Austin, James W. Boss, Jeremy M. TI Genetic and Epigenetic Regulation of PD-1 Expression SO JOURNAL OF IMMUNOLOGY LA English DT Review ID CD8(+) T-CELLS; CHRONIC VIRAL-INFECTION; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; INHIBITORY RECEPTOR PD-1; PROGRAMMED DEATH 1; TRANSCRIPTION FACTOR; EFFECTOR FUNCTION; UP-REGULATION; ANTITUMOR IMMUNITY; DNA METHYLATION AB The inhibitory immune receptor programmed cell death-1 (PD-1) is intricately regulated. In T cells, PD-1 is expressed in response to most immune challenges, but it is rapidly downregulated in acute settings, allowing for normal immune responses. On chronically stimulated Ag-specific T cells, PD-1 expression remains high, leading to an impaired response to stimuli. Ab blockade of PD-1 interactions during chronic Ag settings partially restores immune function and is now used clinically to treat a variety of devastating cancers. Understanding the regulation of PD-1 expression may be useful for developing novel immune-based therapies. In this review, the molecular mechanisms that drive dynamic PD-1 expression during acute and chronic antigenic stimuli are discussed. An array of cis-DNA elements, transcription factors, and epigenetic components, including DNA methylation and histone modifications, control PD-1 expression. The interplay between these regulators fine-tunes PD-1 expression in different inflammatory environments and across numerous cell types to modulate immune responses. C1 Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Austin, James W.] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Boss, JM (reprint author), Emory Univ, Dept Microbiol & Immunol, 1510 Clifton Rd NE,Room 3001, Atlanta, GA 30322 USA. EM jmboss@emory.edu OI Boss, Jeremy/0000-0002-2432-1840 FU National Institutes of Health Grant [R01 AI113021, T32AI007610-12] FX This work was supported by National Institutes of Health Grant R01 AI113021 (to J.M.B.). A.P.R.B. was supported in part by National Institutes of Health Grant T32AI007610-12. NR 98 TC 5 Z9 5 U1 1 U2 19 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2016 VL 196 IS 6 BP 2431 EP 2437 DI 10.4049/jimmunol.1502643 PG 7 WC Immunology SC Immunology GA DG8MK UT WOS:000372338100001 PM 26945088 ER PT J AU Xu, Y Romero, R Miller, D Kadam, L Mial, TN Plazyo, O Garcia-Flores, V Hassan, SS Xu, ZH Tarca, AL Drewlo, S Gomez-Lopez, N AF Xu, Yi Romero, Roberto Miller, Derek Kadam, Leena Mial, Tara N. Plazyo, Olesya Garcia-Flores, Valeria Hassan, Sonia S. Xu, Zhonghui Tarca, Adi L. Drewlo, Sascha Gomez-Lopez, Nardhy TI An M1-like Macrophage Polarization in Decidual Tissue during Spontaneous Preterm Labor That Is Attenuated by Rosiglitazone Treatment SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACTIVATED-RECEPTOR-GAMMA; HUMAN GESTATIONAL TISSUES; COLONY-STIMULATING FACTOR; JEG3 CHORIOCARCINOMA CELLS; NECROSIS-FACTOR PRODUCTION; FETAL-MATERNAL INTERFACE; HUMAN TERM PARTURITION; GROWTH-FACTOR-BETA; PPAR-GAMMA; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2) AB Decidual macrophages are implicated in the local inflammatory response that accompanies spontaneous pretermlabor/birth; however, their role is poorly understood. We hypothesized that decidual macrophages undergo a proinflammatory (M1) polarization during spontaneous preterm labor and that PPAR gamma activation via rosiglitazone (RSG) would attenuate the macrophage-mediated inflammatory response, preventing preterm birth. In this study, we show that: 1) decidual macrophages undergo an M1-like polarization during spontaneous term and preterm labor; 2) anti-inflammatory (M2)-like macrophages are more abundant than M1-like macrophages in decidual tissue; 3) decidual M2-like macrophages are reduced in preterm pregnancies compared with term pregnancies, regardless of the presence of labor; 4) decidual macrophages express high levels of TNF and IL-12 but low levels of peroxisome proliferator-activated receptor gamma (PPARg) during spontaneous preterm labor; 5) decidual macrophages from women who underwent spontaneous preterm labor display plasticity by M1 <-> M2 polarization in vitro; 6) incubation with RSG reduces the expression of TNF and IL-12 in decidual macrophages from women who underwent spontaneous preterm labor; and 7) treatment with RSG reduces the rate of LPS-induced preterm birth and improves neonatal outcomes by reducing the systemic proinflammatory response and downregulating mRNA and protein expression of NF-kappa B, TNF, and IL-10 in decidual and myometrial macrophages in C57BL/6J mice. In summary, we demonstrated that decidual M1-like macrophages are associated with spontaneous preterm labor and that PPARg activation via RSG can attenuate the macrophage-mediated proinflammatory response, preventing preterm birth and improving neonatal outcomes. These findings suggest that the PPAR gamma pathway is a new molecular target for future preventative strategies for spontaneous preterm labor/birth. C1 [Xu, Yi; Romero, Roberto; Miller, Derek; Mial, Tara N.; Plazyo, Olesya; Garcia-Flores, Valeria; Hassan, Sonia S.; Xu, Zhonghui; Tarca, Adi L.; Gomez-Lopez, Nardhy] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Xu, Yi; Romero, Roberto; Miller, Derek; Mial, Tara N.; Plazyo, Olesya; Garcia-Flores, Valeria; Hassan, Sonia S.; Xu, Zhonghui; Tarca, Adi L.; Gomez-Lopez, Nardhy] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,US Dept Hlth & Human Serv, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48825 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Kadam, Leena; Mial, Tara N.; Garcia-Flores, Valeria; Hassan, Sonia S.; Xu, Zhonghui; Tarca, Adi L.; Drewlo, Sascha; Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. RP Gomez-Lopez, N (reprint author), Wayne State Univ, Sch Med, Dept Obstet & Gynecol, CS Mott Ctr Human Growth & Dev, 275 East Hancock St, Detroit, MI 48201 USA. EM nardhy.gomez-lopez@wayne.edu RI Gomez-Lopez, Nardhy/R-7664-2016; OI Gomez-Lopez, Nardhy/0000-0002-3406-5262; Miller, Derek/0000-0002-5812-7771 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services; Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health FX This research was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services and the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health. NR 157 TC 2 Z9 3 U1 2 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2016 VL 196 IS 6 BP 2476 EP 2491 DI 10.4049/jimmunol.1502055 PG 16 WC Immunology SC Immunology GA DG8MK UT WOS:000372338100007 PM 26889045 ER PT J AU Zeng, M Smith, AJ Shang, L Wietgrefe, SW Voss, JE Carlis, JV Li, QS Piatak, M Lifson, JD Johnson, RP Haase, AT AF Zeng, Ming Smith, Anthony J. Shang, Liang Wietgrefe, Stephen W. Voss, James E. Carlis, John V. Li, Qingsheng Piatak, Michael, Jr. Lifson, Jeffrey D. Johnson, R. Paul Haase, Ashley T. TI Mucosal Humoral Immune Response to SIVmac239 Delta nef Vaccination and Vaginal Challenge SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CLASS SWITCH RECOMBINATION; ATTENUATED SIV VACCINES; CELL MATURATION ANTIGEN; NECROSIS-FACTOR FAMILY; MEMORY B-CELLS; T-CELLS; ACTIVATING FACTOR; FC-RECEPTOR; TNF FAMILY AB Live attenuated vaccines such as SIV with a deleted nef gene have provided the most robust protection against subsequent vaginal challenge with wild-type (WT) SIV in the SIV-rhesus macaque model of HIV-1 transmission to women. Hence, identifying correlates of this protection could enable design of an effective HIV-1 vaccine. One such prechallenge correlate of protection from vaginal challenge has recently been identified as a system with three components: 1) IgG Abs reacting with the viral envelope glycoprotein trimeric gp41; 2) produced by plasma cells in the submucosa and ectopic tertiary lymphoid follicles in the ectocervix and vagina; and 3) concentrated on the path of virus entry by the neonatal FcR in the overlying epithelium. We now examine the mucosal production of the Ab component of this system after vaginal challenge. We show that vaginal challenge immediately elicits striking increases in plasma cells not only in the female reproductive tract but also at other mucosal sites, and that these increases correlate with low but persistent replication at mucosal sites. We describe vaginal ectopic follicles that are structurally and functionally organized similar to follicles in secondary lymphoid organs, and we provide inferential evidence for a key role of the female reproductive tract epithelium in facilitating Ab production, affinity maturation, and class switch recombination. Vaccination thus accesses an epithelial-immune system axis in the female reproductive tract to respond to exposure to mucosal pathogens. Designing strategies to mimic this system could advance development of an effective HIV-1 vaccine. C1 [Zeng, Ming; Smith, Anthony J.; Shang, Liang; Wietgrefe, Stephen W.; Li, Qingsheng; Haase, Ashley T.] Univ Minnesota, Sch Med, Dept Microbiol & Immunol, 690 23rd Ave SE, Minneapolis, MN 55455 USA. [Voss, James E.] Scripps Res Inst, Dept Immunol & Microbial Sci, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, Ctr HIV AIDS Vaccine Immunol & Immunogen Design, La Jolla, CA 92037 USA. [Voss, James E.] Univ Minnesota, Dept Comp Sci & Engn, Coll Sci & Engn, Minneapolis, MN 55455 USA. [Piatak, Michael, Jr.; Lifson, Jeffrey D.] NCI, AIDS & Canc Virus Program, Sci Applicat Int Corp, Frederick Inc, Frederick, MD 21702 USA. [Johnson, R. Paul] Harvard Univ, Sch Med, New England Primate Res Ctr, Southborough, MA 01772 USA. [Johnson, R. Paul] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Zeng, Ming] Univ Texas SW Med Ctr Dallas, Ctr Genet Host Def, Dallas, TX 75390 USA. [Smith, Anthony J.] Amer Univ Antigua, Bridge To MD Program, New York, NY USA. [Li, Qingsheng] Univ Nebraska, Sch Biol Sci, Nebraska Ctr Virol, Lincoln, NE USA. [Johnson, R. Paul] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. RP Haase, AT (reprint author), Univ Minnesota, Sch Med, Dept Microbiol & Immunol, 690 23rd Ave SE, Minneapolis, MN 55455 USA. EM haase001@umn.edu FU International AIDS Vaccine Initiative, National Institutes of Health [AI071306, U19 AI095985, OD01110]; National Cancer Institute/National Institutes of Health [HHSN261200800001E] FX This work was supported by the International AIDS Vaccine Initiative, National Institutes of Health Grants AI071306, U19 AI095985, and OD01110, and in part by federal funds from National Cancer Institute/National Institutes of Health Contract HHSN261200800001E. NR 39 TC 3 Z9 3 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2016 VL 196 IS 6 BP 2809 EP 2818 DI 10.4049/jimmunol.1500156 PG 10 WC Immunology SC Immunology GA DG8MK UT WOS:000372338100037 PM 26864031 ER PT J AU Reid, WC Ibrahim, WG Kim, SJ Denaro, F Casas, R Lee, DE Maric, D Hammoud, DA AF Reid, William C. Ibrahim, Wael G. Kim, Saejeong J. Denaro, Frank Casas, Rafael Lee, Dianne E. Maric, Dragan Hammoud, Dima A. TI Characterization of neuropathology in the HIV-1 transgenic rat at different ages SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Neuro-HIV; HIV-1 transgenic rat; Viral proteins; Neuropathology; Astrocytic loss; Neurotoxicity ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; VITAMIN-A-DEFICIENCY; HUMANIZED MICE; GENE-EXPRESSION; NEUROCOGNITIVE DISORDERS; ANTIRETROVIRAL THERAPY; COGNITIVE DEFICITS; NEW-GENERATION; INFECTION AB The transgenic HIV-1 rat (Tg) is a commonly used neuroHlV model with documented neurologic/behavioral deficits. Using immunofluorescent staining of the Tg brain, we found astrocytic dysfunction/damage, as well as dopaminergic neuronal loss/dysfunction, both of which worsening significantly in the striatum with age. We saw mild microglial activation in young Tg brains, but this decreased with age. There were no differences in neurogenesis potential suggesting a neurodegenerative rather than a neurodevelopmental process. Gp120 CSF levels exceeded serum gp120 levels in some animals, suggesting local viral protein production in the brain. Further probing of the pathophysiology underlying astrocytic injury in this model is warranted. Published by Elsevier B.V. C1 [Reid, William C.; Ibrahim, Wael G.; Casas, Rafael; Lee, Dianne E.; Hammoud, Dima A.] NIH, CIDI, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Kim, Saejeong J.] NIH, Frank Lab, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Denaro, Frank] Morgan State Univ, Dept Biol, Baltimore, MD 21239 USA. [Maric, Dragan] NINDS, DIR, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Hammoud, DA (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Room 1C368, Bethesda, MD 20814 USA. EM hammoudd@cc.nih.gov FU Center for Infectious Disease Imaging (CIDI), National Institutes of Health FX Sources of funding: This work was supported by the Center for Infectious Disease Imaging (CIDI), National Institutes of Health (Intramural Program). NR 73 TC 3 Z9 3 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 EI 1872-8421 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD MAR 15 PY 2016 VL 292 BP 116 EP 125 DI 10.1016/j.jneuroim.2016.01.022 PG 10 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DH1RC UT WOS:000372561600018 PM 26943969 ER PT J AU Son, A Park, S Shin, DM Muallem, S AF Son, Aran Park, Seonghee Shin, Dong Min Muallem, Shmuel TI Orai1 and STIM1 in ER/PM junctions: roles in pancreatic cell function and dysfunction SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE signaling; PM; ER; junctions; pancreas ID MEMBRANE CONTACT SITES; INTERACTION MOLECULE-1 STIM1; PAROTID ACINAR-CELLS; FAST CA2+-DEPENDENT INACTIVATION; OXYSTEROL-BINDING PROTEINS; CANONICAL TRPC CHANNELS; OPERATED CALCIUM-ENTRY; SALIVARY-GLAND CELLS; ER-PM JUNCTIONS; PLASMA-MEMBRANE AB Membrane contact sites (MCS) are critical junctions that form between the endoplasmic reticulum (ER) and membranes of various organelles, including the plasma membrane (PM). Signaling complexes, including mediators of Ca2+ signaling, are assembled within MCS, such as the ER/PM junction. This is most evident in polarized epithelial cells, such as pancreatic cells. Core Ca2+ signaling proteins cluster at the apical pole, the site of inositol 1,4,5-trisphosphate-mediated Ca2+ release and Orai1/transient receptor potential canonical-mediated store-dependent Ca2+ entry. Recent advances have characterized the proteins that tether the membranes at MCS and the role of these proteins in modulating physiological and pathological intracellular signaling. This review discusses recent advances in the characterization of Ca2+ signaling at ER/PM junctions and the relation of these junctions to physiological and pathological Ca2+ signaling in pancreatic acini. C1 [Son, Aran; Muallem, Shmuel] Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bldg 10,Rm 1N-112, Bethesda, MD 20892 USA. [Park, Seonghee] Ewha Womans Univ, Sch Med, Dept Physiol, Seoul, South Korea. [Shin, Dong Min] Yonsei Univ, Coll Dent, Dept Oral Biol, BK PLUS Project 21, Seoul 120749, South Korea. RP Muallem, S (reprint author), Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bldg 10,Rm 1N-112, Bethesda, MD 20892 USA. EM shmuel.muallem@nih.gov FU National Institutes of Health/National Institute of Dental and Craniofacial Research intramural grant [DE-000735]; National Foundation of Korea Grant - Korean Government [NRF-2013S1A2A2035370, 2015R1A2A1A15054157] FX This work was supported by National Institutes of Health/National Institute of Dental and Craniofacial Research intramural grant DE-000735 and by the National Foundation of Korea Grant funded by the Korean Government (NRF-2013S1A2A2035370, 2015R1A2A1A15054157). NR 128 TC 2 Z9 2 U1 0 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 EI 1522-1563 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD MAR 15 PY 2016 VL 310 IS 6 BP C414 EP C422 DI 10.1152/ajpcell.00349.2015 PG 9 WC Cell Biology; Physiology SC Cell Biology; Physiology GA DG5CV UT WOS:000372091500003 PM 26739495 ER PT J AU Ahuja, S Knudsen, L Chillappagari, S Henneke, I Ruppert, C Korfei, M Gochuico, BR Bellusci, S Seeger, W Ochs, M Guenther, A Mahavadi, P AF Ahuja, Saket Knudsen, Lars Chillappagari, Shashi Henneke, Ingrid Ruppert, Clemens Korfei, Martina Gochuico, Bernadette R. Bellusci, Saverio Seeger, Werner Ochs, Matthias Guenther, Andreas Mahavadi, Poornima TI MAP1LC3B overexpression protects against Hermansky-Pudlak syndrome type-1-induced defective autophagy in vitro SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE autophagy; Hermansky-Pudlak syndrome; alveolar epithelial cells; Hermansky-Pudlak syndrome-associated interstitial pneumonia; apoptosis; lung fibrosis ID LYSOSOME-RELATED ORGANELLES; IDIOPATHIC PULMONARY-FIBROSIS; INTERSTITIAL PNEUMONIA; STORAGE DISORDERS; QUALITY-CONTROL; MOUSE MODEL; LIFE-SPAN; DISEASE; MICE; ACCUMULATION AB Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder, and some patients with HPS develop pulmonary fibrosis, known as HPS-associated interstitial pneumonia (HPSIP). We have previously reported that HPSIP is associated with severe surfactant accumulation, lysosomal stress, and alveolar epithelial cell type II (AECII) apoptosis. Here, we hypothesized that defective autophagy might result in excessive lysosomal stress in HPSIP. Key autophagy proteins, including LC3B lipidation and p62, were increased in HPS1/2 mice lungs. Electron microscopy demonstrated a preferable binding of LC3B to the interior of lamellar bodies in the AECII of HPS1/2 mice, whereas in wild-type mice it was present on the limiting membrane in addition to the interior of the lamellar bodies. Similar observations were noted in human HPS1 lung sections. In vitro knockdown of HPS1 revealed increased LC3B lipidation and p62 accumulation, associated with an increase in proapoptotic caspases. Overexpression of LC3B decreased the HPS1 knock-down-induced p62 accumulation, whereas rapamycin treatment did not show the same effect. We conclude that loss of HPS1 protein results in impaired autophagy that is restored by exogenous LC3B and that defective autophagy might therefore play a critical role in the development and progression of HPSIP. C1 [Ahuja, Saket; Chillappagari, Shashi; Henneke, Ingrid; Ruppert, Clemens; Korfei, Martina; Bellusci, Saverio; Seeger, Werner; Guenther, Andreas; Mahavadi, Poornima] Univ Giessen, Dept Internal Med, Giessen, Germany. [Ahuja, Saket; Chillappagari, Shashi; Henneke, Ingrid; Ruppert, Clemens; Korfei, Martina; Bellusci, Saverio; Seeger, Werner; Guenther, Andreas; Mahavadi, Poornima] Univ Giessen & Marburg Lung Ctr, D-35390 Giessen, Germany. [Knudsen, Lars; Ochs, Matthias] Hannover Med Sch, Inst Funct & Appl Anat, Hannover, Germany. [Knudsen, Lars; Ochs, Matthias] Biomed Res End Stage & Obstruct Lung Dis Hannov B, Hannover, Germany. [Knudsen, Lars; Ochs, Matthias] REBIRTH Cluster Excellence, Hannover, Germany. [Chillappagari, Shashi] Univ Giessen, Dept Pediat, D-35390 Giessen, Germany. [Ruppert, Clemens; Bellusci, Saverio; Seeger, Werner; Guenther, Andreas] Excellence Cluster Cardiopulm Syst, Giessen, Germany. [Gochuico, Bernadette R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Seeger, Werner; Guenther, Andreas] Lung Clin Waldhof Elgershausen, Greifenstein, Germany. RP Guenther, A (reprint author), Klin Str 36, D-35392 Giessen, Germany. EM Andreas.Guenther@innere.med.uni-giessen.de RI Knudsen, Lars/G-3146-2013 FU Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This work was funded in part by the Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany and in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 58 TC 3 Z9 3 U1 4 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD MAR 15 PY 2016 VL 310 IS 6 BP L519 EP L531 DI 10.1152/ajplung.00213.2015 PG 13 WC Physiology; Respiratory System SC Physiology; Respiratory System GA DG5AE UT WOS:000372083700004 PM 26719147 ER PT J AU Motohashi, T Watanabe, N Nishioka, M Nakatake, Y Yulan, P Mochizuki, H Kawamura, Y Ko, MSH Goshima, N Kunisada, T AF Motohashi, Tsutomu Watanabe, Natsuki Nishioka, Masahiro Nakatake, Yuhki Yulan, Piao Mochizuki, Hiromi Kawamura, Yoshifumi Ko, Minoru S. H. Goshima, Naoki Kunisada, Takahiro TI Gene array analysis of neural crest cells identifies transcription factors necessary for direct conversion of embryonic fibroblasts into neural crest cells SO BIOLOGY OPEN LA English DT Article DE Neural crest; Mouse embryonic fibroblasts; Sox10; Direct conversion ID KRUPPEL-LIKE FACTOR-4; STEM-CELLS; DEFINED FACTORS; C-MYC; REGULATORY NETWORK; NERVOUS-SYSTEM; FACTOR SOX10; ADULT SKIN; MOUSE; DIFFERENTIATION AB Neural crest cells (NC cells) are multipotent cells that emerge from the edge of the neural folds and migrate throughout the developing embryo. Although the gene regulatory network for generation of NC cells has been elucidated in detail, it has not been revealed which of the factors in the network are pivotal to directing NC identity. In this study we analyzed the gene expression profile of a pure NC subpopulation isolated from Sox10-IRES-Venus mice and investigated whether these genes played a key role in the direct conversion of Sox10-IRES-Venus mouse embryonic fibroblasts (MEFs) into NC cells. The comparative molecular profiles of NC cells and neural tube cells in 9.5-day embryos revealed genes including transcription factors selectively expressed in developing trunk NC cells. Among 25 NC cell-specific transcription factor genes tested, SOX10 and SOX9 were capable of converting MEFs into SOX10-positive (SOX10+) cells. The SOX10+ cells were then shown to differentiate into neurons, glial cells, smooth muscle cells, adipocytes and osteoblasts. These SOX10+ cells also showed limited self-renewal ability, suggesting that SOX10 and SOX9 directly converted MEFs into NC cells. Conversely, the remaining transcription factors, including well-known NC cell specifiers, were unable to convert MEFs into SOX10+ NC cells. These results suggest that SOX10 and SOX9 are the key factors necessary for the direct conversion of MEFs into NC cells. C1 [Motohashi, Tsutomu; Watanabe, Natsuki; Nishioka, Masahiro; Kunisada, Takahiro] Gifu Univ, Grad Sch Med, Dept Tissue & Organ Dev Regenerat & Adv Med Sci, Gifu 5011194, Japan. [Motohashi, Tsutomu; Kunisada, Takahiro] Japan Sci & Technol Agcy JST, Core Res Evolut Sci & Technol CREST, Tokyo 1020076, Japan. [Nakatake, Yuhki; Yulan, Piao; Ko, Minoru S. H.] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Nakatake, Yuhki; Ko, Minoru S. H.] Keio Univ, Sch Med, Sakaguchi Lab, Dept Syst Med, Tokyo 1608582, Japan. [Mochizuki, Hiromi; Kawamura, Yoshifumi] Japan Biol Informat Consortium JBiC, Tokyo 1358073, Japan. [Goshima, Naoki] Natl Inst Adv Ind Sci & Technol, Mol Profiling Res Ctr Drug Discovery, Tokyo 1350064, Japan. RP Motohashi, T (reprint author), Gifu Univ, Grad Sch Med, Dept Tissue & Organ Dev Regenerat & Adv Med Sci, Gifu 5011194, Japan.; Motohashi, T (reprint author), Japan Sci & Technol Agcy JST, Core Res Evolut Sci & Technol CREST, Tokyo 1020076, Japan. EM tmotohas@gifu-u.ac.jp FU Gifu University Graduate School of Medicine Research Grant Program; Japan Science and Technology Agency CREST; Japan Society for Promotion for Science [26460273]; Intramural Research Program of the National Institutes of Health, National Institute on Aging, USA FX This study was supported by the Gifu University Graduate School of Medicine Research Grant Program, by a research grant from Japan Science and Technology Agency CREST, and by a grant from the program Grants-in-Aid for Scientific Research (C) from the Japan Society for Promotion for Science [26460273]. A part of the work was also supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, USA. NR 76 TC 0 Z9 0 U1 1 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 2046-6390 J9 BIOL OPEN JI Biol. Open PD MAR 15 PY 2016 VL 5 IS 3 BP 311 EP 322 DI 10.1242/bio.015735 PG 12 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DG8AJ UT WOS:000372304500013 PM 26873953 ER PT J AU Alvarez, C Aravena, A Tapia, T Rozenblum, E Solis, L Corvalan, A Camus, M Alvarez, M Munroe, D Maass, A Carvallo, P AF Alvarez, Carolina Aravena, Andres Tapia, Teresa Rozenblum, Ester Solis, Luisa Corvalan, Alejandro Camus, Mauricio Alvarez, Manuel Munroe, David Maass, Alejandro Carvallo, Pilar TI Different Array CGH profiles within hereditary breast cancer tumors associated to BRCA1 expression and overall survival SO BMC CANCER LA English DT Article DE Breast cancer; BRCAX; Array CGH; Tumor suppressor; Oncogenes; Genomic losses; Genomic gains ID COMPARATIVE GENOMIC HYBRIDIZATION; TO-MESENCHYMAL TRANSITION; PROMOTER HYPERMETHYLATION; SUPPRESSOR GENES; DOWN-REGULATION; POOR-PROGNOSIS; OVARIAN-CANCER; PROTEIN; GROWTH; CELLS AB Background: Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. Moreover, specific genomic alterations may contribute to the identification of potential therapeutic targets and offer a more personalized treatment to breast cancer patients. Methods: Forty seven tumors from hereditary breast cancer cases, previously analyzed for BRCA1 expression, and screened for germline BRCA1 and 2 mutations, were analyzed by Array based Comparative Genomic Hybridization (aCGH) using Agilent 4x44K arrays. Overall survival was established for tumors in different clusters using Log-rank (Mantel-Cox) Test. Gene lists obtained from aCGH analysis were analyzed for Gene Ontology enrichment using GOrilla and DAVID tools. Results: Genomic profiling of the tumors showed specific alterations associated to BRCA1 or 2 mutation status, and BRCA1 expression in the tumors, affecting relevant cellular processes. Similar cellular functions were found affected in BRCA1 not expressing and BRCA1 or 2 mutated tumors. Hierarchical clustering classified hereditary breast tumors in four major, groups according to the type and amount of genomic alterations, showing one group with a significantly poor overall survival (p = 0.0221). Within this cluster, deletion of PLEKHO1, GDF11, DARC, DAG1 and CD63 may be associated to the worse outcome of the patients. Conclusions: These results support the fact that BRCA1 lack of expression in tumors should be used as a marker for BRCAness and to select these patients for synthetic lethality approaches such as treatment with PARP inhibitors. In addition, the identification of specific alterations in breast tumors associated with poor survival, immune response or with a BRCAness phenotype will allow the use of a more personalized treatment in these patients. C1 [Alvarez, Carolina; Tapia, Teresa; Carvallo, Pilar] Pontificia Univ Catolica Chile, Fac Biol Sci, Dept Cellular & Mol Biol, Alameda 340, Santiago, Chile. [Aravena, Andres; Maass, Alejandro] Univ Chile, CNRS, UMI 2807, Mathom,Ctr Math Modeling, Santiago, Chile. [Aravena, Andres; Maass, Alejandro] Univ Chile, Ctr Genome Regulat Fondap 15090007, Santiago, Chile. [Rozenblum, Ester; Munroe, David] NCI, Lab Mol Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Solis, Luisa; Corvalan, Alejandro] Pontificia Univ Catolica Chile, Fac Med, Dept Anatomopathol, Alameda 340, Santiago, Chile. [Camus, Mauricio] Pontificia Univ Catolica Chile, Fac Med, Canc Ctr, Alameda 340, Santiago, Chile. [Alvarez, Manuel] Clin Las Condes, Santiago, Chile. [Maass, Alejandro] Univ Chile, Dept Math Engn, Santiago, Chile. [Aravena, Andres] Istanbul Univ, Dept Mol Biol & Genet, Fac Sci, TR-34134 Istanbul, Turkey. RP Carvallo, P (reprint author), Pontificia Univ Catolica Chile, Fac Biol Sci, Dept Cellular & Mol Biol, Alameda 340, Santiago, Chile. EM pcarvallo@bio.puc.cl RI Maass, Alejandro/D-5848-2012; OI Maass, Alejandro/0000-0002-7038-4527; Aravena, Andres/0000-0003-3754-9235 FU FONDECYT [1040779, 1120200]; CONICYT; Fulbright Foundation; National Cancer Institute, National Institutes of Health [N01-CO-12400] FX We thank FONDECYT grants 1040779 and 1120200, CONICYT and Fulbright Foundation for C. Alvarez fellowships. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 63 TC 0 Z9 1 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAR 15 PY 2016 VL 16 AR 219 DI 10.1186/s12885-016-2261-x PG 14 WC Oncology SC Oncology GA DG5BV UT WOS:000372088500002 PM 26979459 ER PT J AU Yang, J Diaz, N Adelsberger, J Zhou, XY Stevens, R Rupert, A Metcalf, JA Baseler, M Barbon, C Imamichi, T Lempicki, R Cosentino, LM AF Yang, Jun Diaz, Norma Adelsberger, Joseph Zhou, Xueyuan Stevens, Randy Rupert, Adam Metcalf, Julia A. Baseler, Mike Barbon, Christine Imamichi, Tomozumi Lempicki, Richard Cosentino, Louis M. TI The effects of storage temperature on PBMC gene expression SO BMC IMMUNOLOGY LA English DT Article DE Cryopreservation; Peripheral blood mononuclear cells; Gene expression ID BLOOD MONONUCLEAR-CELLS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; HISTONE H2AX PHOSPHORYLATION; DNA-DAMAGE; INTERFERON-GAMMA; FLOW-CYTOMETRY; WHOLE-BLOOD; CRYOPRESERVATION; APOPTOSIS; RESPONSES AB Background: Cryopreservation of peripheral blood mononuclear cells (PBMCs) is a common and essential practice in conducting research. There are different reports in the literature as to whether cryopreserved PBMCs need to only be stored <=- 150 degrees C or can be stored for a specified time at -80 degrees C. Therefore, we performed gene expression analysis on cryopreserved PBMCs stored at both temperatures for 14 months and PBMCs that underwent temperature cycling 104 times between these 2 storage temperatures. Real-time RT-PCR was performed to confirm the involvement of specific genes associated with identified cellular pathways. All cryopreserved/stored samples were compared to freshly isolated PBMCs and between storage conditions. Results: We identified a total of 1,367 genes whose expression after 14 months of storage was affected >3 fold in PBMCs following isolation, cryopreservation and thawing as compared to freshly isolated PBMC aliquots that did not undergo cryopreservation. Sixty-six of these genes were shared among two or more major stress-related cellular pathways (stress responses, immune activation and cell death). Thirteen genes involved in these pathways were tested by real-time RT-PCR and the results agreed with the corresponding microarray data. There was no significant change on the gene expression if the PBMCs experienced brief but repetitive temperature cycling as compared to those that were constantly kept <= -150 degrees C. However, there were 18 genes identified to be different when PBMCs were stored at -80 degrees C but did not change when stored < -150 degrees C. A correlation was also found between the expressions of 2'-5'-oligoadenylate synthetase (OAS2), a known interferon stimulated gene (IFSG), and poor PBMC recovery post-thaw. PBMC recovery and viability were better when the cells were stored <= -150 degrees C as compared to -80 degrees C. Conclusions: Not only is the viability and recovery of PBMCs affected during cryopreservation but also their gene expression pattern, as compared to freshly isolated PBMCs. Different storage temperature of PBMCs can activate or suppress different genes, but the cycling between -80 degrees C and -150 degrees C did not produce significant alterations in gene expression when compared to PBMCs stored <= -150 degrees C. Further analysis by gene expression of various PBMC processing and cryopreservation procedures is currently underway, as is identifying possible molecular mechanisms. C1 [Barbon, Christine; Cosentino, Louis M.] Biogen, 125 Broadway, Cambridge, MA 02142 USA. [Yang, Jun; Diaz, Norma; Adelsberger, Joseph; Zhou, Xueyuan; Stevens, Randy; Rupert, Adam; Baseler, Mike; Imamichi, Tomozumi; Lempicki, Richard] Leidos Biomed Res Inc, Frederick, MD 21702 USA. [Metcalf, Julia A.] NIAID, Div Clin Res, NIH, Rockville, MD 20852 USA. RP Cosentino, LM (reprint author), Biogen, 125 Broadway, Cambridge, MA 02142 USA. EM louis.cosentino@biogen.com FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Disease FX This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.; This research was supported in part by the National Institute of Allergy and Infectious Disease. NR 61 TC 2 Z9 2 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD MAR 15 PY 2016 VL 17 AR 6 DI 10.1186/s12865-016-0144-1 PG 15 WC Immunology SC Immunology GA DG3JD UT WOS:000371964500001 PM 26979060 ER PT J AU Vytal, KE Arkin, NE Overstreet, C Lieberman, L Grillon, C AF Vytal, Katherine E. Arkin, Nicole E. Overstreet, Cassie Lieberman, Lynne Grillon, Christian TI Induced-anxiety differentially disrupts working memory in generalized anxiety disorder SO BMC PSYCHIATRY LA English DT Article DE Generalized anxiety disorder; Working memory; Anxiety; Startle reflex; Threat of shock ID ATTENTIONAL CONTROL-THEORY; TRAIT ANXIETY; YOUNG-ADULTS; PERFORMANCE; THREAT; COGNITION; EMOTION; WORRY AB Background: Anxiety is characterized by a bias towards threatening information, anxious apprehension, and disrupted concentration. Previous research in healthy subjects suggests that working memory (WM) is disrupted by induced anxiety, but that increased task-demand reduces anxiety and WM is preserved. However, it is unknown if patients with generalized anxiety disorder (GAD) can similarly normalize their performance on difficult WM tasks while reducing their anxiety. Increased threat-related bias and impoverished top-down control in trait anxiety suggests that patients may not reap the same cognitive and emotional benefits from demanding tasks that those low in anxiety. Here we examine this possibility using a WM task of varying difficulty. Methods: GAD patients (N = 30) and healthy controls (N = 30) performed an n-back task (no-load, 1-back, 2-back, and 3-back) while at risk for shock (threat) or safe from shock (safe). Anxiety was measured via startle reflex and self-report. Results: As predicted, healthy controls' performance was impaired under threat during low-load tasks and facilitated during high-load tasks. In contrast, GAD patients' performance was impaired under threat regardless of WM load. Anxiety was reduced as cognitive load increased in both groups. Conclusions: The divergence of emotion regulation (reduction) and performance (persistent impairment) in the patient but not the control group, suggests that different top-down mechanisms may be operating to reduce anxiety. Continued WM disruption in patients indicates that attentional resources are allocated to emotion regulation instead of goal-directed behavior. Implications for our understanding of cognitive disruption in patients, and related therapeutic interventions are discussed. C1 [Vytal, Katherine E.; Arkin, Nicole E.; Overstreet, Cassie; Lieberman, Lynne; Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. RP Vytal, KE (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM katye.vytal@mail.nih.gov FU National Institute of Mental Health intramural research program FX We would like to thank Marilla Geraci and Daniel Pine for their clinical supervision in this study. Funding was provided by the National Institute of Mental Health intramural research program. NR 35 TC 0 Z9 0 U1 12 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-244X J9 BMC PSYCHIATRY JI BMC Psychiatry PD MAR 15 PY 2016 VL 16 AR 62 DI 10.1186/s12888-016-0748-2 PG 9 WC Psychiatry SC Psychiatry GA DG3IC UT WOS:000371961700002 PM 26976146 ER PT J AU Chen, FJ Zhang, YQ Senbabaoglu, Y Ciriello, G Yang, LX Reznik, E Shuch, B Micevic, G De Velasco, G Shinbrot, E Noble, MS Lu, YL Covington, KR Xi, L Drummond, JA Muzny, D Kang, H Lee, J Tamboli, P Reuter, V Shelley, CS Kaipparettu, BA Bottaro, DP Godwin, AK Gibbs, RA Getz, G Kucherlapati, R Park, PJ Sander, C Henske, EP Zhou, JH Kwiatkowski, DJ Ho, TH Choueiri, TK Hsieh, JJ Akbani, R Mills, GB Hakimi, AA Wheeler, DA Creighton, CJ AF Chen, Fengju Zhang, Yiqun Senbabaoglu, Yasin Ciriello, Giovanni Yang, Lixing Reznik, Ed Shuch, Brian Micevic, Goran De Velasco, Guillermo Shinbrot, Eve Noble, Michael S. Lu, Yiling Covington, Kyle R. Xi, Liu Drummond, Jennifer A. Muzny, Donna Kang, Hyojin Lee, Junehawk Tamboli, Pheroze Reuter, Victor Shelley, Carl Simon Kaipparettu, Benny A. Bottaro, Donald P. Godwin, Andrew K. Gibbs, Richard A. Getz, Gad Kucherlapati, Raju Park, Peter J. Sander, Chris Henske, Elizabeth P. Zhou, Jane H. Kwiatkowski, David J. Ho, Thai H. Choueiri, Toni K. Hsieh, James J. Akbani, Rehan Mills, Gordon B. Hakimi, A. Ari Wheeler, David A. Creighton, Chad J. TI Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma SO CELL REPORTS LA English DT Article ID CANCER; EXPRESSION; EVEROLIMUS; MUTATIONS; LANDSCAPE; DISCOVERY; SURVIVAL; BAP1 AB On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset. C1 [Chen, Fengju; Zhang, Yiqun; Kaipparettu, Benny A.; Creighton, Chad J.] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA. [Senbabaoglu, Yasin; Reznik, Ed; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10065 USA. [Ciriello, Giovanni] Univ Lausanne, Dept Computat Biol, CH-1015 Lausanne, Switzerland. [Yang, Lixing; Park, Peter J.] Harvard Univ, Sch Med, Dept Biomed Informat, Boston, MA 02115 USA. [Shuch, Brian] Yale Univ, Sch Med, Dept Urol, New Haven, CT 06520 USA. [Micevic, Goran] Yale Univ, Dept Dermatol, New Haven, CT 06510 USA. [Micevic, Goran] Yale Univ, Dept Pathol, New Haven, CT 06510 USA. [De Velasco, Guillermo; Choueiri, Toni K.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Shinbrot, Eve; Covington, Kyle R.; Xi, Liu; Drummond, Jennifer A.; Muzny, Donna; Gibbs, Richard A.; Wheeler, David A.; Creighton, Chad J.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Noble, Michael S.; Getz, Gad; Henske, Elizabeth P.; Kwiatkowski, David J.] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Noble, Michael S.; Getz, Gad; Henske, Elizabeth P.; Kwiatkowski, David J.] Harvard Univ, Cambridge, MA 02142 USA. [Lu, Yiling; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77054 USA. [Kang, Hyojin; Lee, Junehawk] Korea Inst Sci & Technol Informat KAIST, Dept Convergence Technol Res, Daejeon 305806, South Korea. [Lee, Junehawk] Korea Adv Inst Sci & Technol, Dept Bio & Brain Engn, Daejeon 305806, South Korea. [Tamboli, Pheroze] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Reuter, Victor] Mem Sloan Kettering Canc, Dept Pathol, New York, NY 10065 USA. [Shelley, Carl Simon] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53726 USA. [Kaipparettu, Benny A.; Gibbs, Richard A.; Wheeler, David A.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Bottaro, Donald P.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66160 USA. [Getz, Gad] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Kucherlapati, Raju; Henske, Elizabeth P.; Kwiatkowski, David J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kucherlapati, Raju; Henske, Elizabeth P.; Kwiatkowski, David J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Zhou, Jane H.] Tufts Univ, Sch Med, Tufts Med Ctr, Dept Pathol & Lab Med, Boston, MA 02111 USA. [Ho, Thai H.] Mayo Clin, Div Hematol & Med Oncol, Scottsdale, AZ 85054 USA. [Hsieh, James J.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Akbani, Rehan; Creighton, Chad J.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Hakimi, A. Ari] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, New York, NY 10065 USA. [Creighton, Chad J.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. RP Creighton, CJ (reprint author), Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.; Creighton, CJ (reprint author), Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.; Creighton, CJ (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA.; Creighton, CJ (reprint author), Baylor Coll Med, Dept Med, Houston, TX 77030 USA. EM creighto@bcm.edu OI Micevic, Goran/0000-0003-0329-1053 FU NIH grant [CA125123]; Cancer Prevention and Research Institute of Texas grant [RP120713] FX This work was supported in part by NIH grant CA125123 and Cancer Prevention and Research Institute of Texas grant RP120713. A full listing of supporting grants is included in Supplemental Experimental Procedures. NR 35 TC 18 Z9 18 U1 4 U2 10 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 MAR 15 PY 2016 VL 14 IS 10 BP 2476 EP 2489 DI 10.1016/j.celrep.2016.02.024 PG 14 WC Cell Biology SC Cell Biology GA DG3VN UT WOS:000371998700018 PM 26947078 ER PT J AU Polizzotto, MN Uldrick, TS Wyvill, KM Aleman, K Marshall, V Wang, V Whitby, D Pittaluga, S Jaffe, ES Millo, C Tosato, G Little, RF Steinberg, SM Sereti, I Yarchoan, R AF Polizzotto, Mark N. Uldrick, Thomas S. Wyvill, Kathleen M. Aleman, Karen Marshall, Vickie Wang, Victoria Whitby, Denise Pittaluga, Stefania Jaffe, Elaine S. Millo, Corina Tosato, Giovanna Little, Richard F. Steinberg, Seth M. Sereti, Irini Yarchoan, Robert TI Clinical Features and Outcomes of Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV)-associated Inflammation: Prospective Characterization of KSHV Inflammatory Cytokine Syndrome (KICS) SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV; Kaposi sarcoma herpesvirus (KSHV); Human Herpesvirus 8 (HHV-8); IL-6; IL-10 ID MULTICENTRIC CASTLEMAN-DISEASE; HIV-INFECTED PATIENTS; DNA-SEQUENCES; VIRAL INTERLEUKIN-6; AIDS; HUMAN-HERPESVIRUS-8; VIRUS; TRIAL; LYMPHOMAS; NAIVE AB Background. Kaposi sarcoma herpesvirus (KSHV) is the cause of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and a form of Castleman disease (KSHV-MCD). Recently a KSHV-associated inflammatory cytokine syndrome (KICS) distinct from KSHV-MCD was reported. Methods. We prospectively characterized the clinical, laboratory, virologic and immunologic features of KICS by evaluating symptomatic adults with KSHV using a prespecified definition. These features and overall survival were compared with controls from 2 prospectively characterized human immunodeficiency virus (HIV)-infected cohorts, including 1 with KSHV coinfection. Results. All 10 KICS subjects were HIV infected males; 5 had HIV viral load (VL) suppressed <50 copies mL (median 72, range <50-74 375); all had KS and 2 also had PEL. All had multiple severe symptoms attributable to KICS: median number of symptoms 8 (6-11), median grade of worst symptom 3 (2-4). These included gastrointestinal disturbance (present in 9); edema (9); respiratory (6); and effusions (5). Laboratory abnormalities included anemia (all); hypoalbuminemia (all) and thrombocytopenia (6). None developed KSHV-MCD; 6 died with median survival from KICS diagnosis 13.6 months. KICS subjects compared with controls had more severe symptoms; lower hemoglobin and albumin; higher C-reactive protein; higher KSHV VL; elevated interleukin (IL)-6 and IL-10; and an increased risk of death (all P <.05). Anemia and hypoalbuminemia at presentation were independently associated with early death. Conclusions. KICS subjects demonstrated diverse severe symptoms, a high rate of KSHV-associated tumors, high mortality, and a distinct IL-6/IL-10 signature. KICS may be an important unrecognized cause of morbidity and mortality, including symptoms previously ascribed to HIV. Exploration of KSHV-directed therapy is warranted. C1 [Polizzotto, Mark N.; Uldrick, Thomas S.; Wyvill, Kathleen M.; Aleman, Karen; Wang, Victoria; Little, Richard F.; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, Bldg 10,Rm 6N106, Bethesda, MD 20892 USA. [Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Marshall, Vickie; Whitby, Denise] NIAID, Viral Oncol Sect, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Millo, Corina] NIAID, Positron Emiss Tomog Dept, Ctr Clin, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sereti, Irini] NIAID, HIV Pathogenesis Sect, Immunoregulat Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Polizzotto, Mark N.] UNSW Australia, Kirby Inst Infect & Immun Soc, Sydney, NSW, Australia. RP Yarchoan, R (reprint author), NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, Bldg 10,Rm 6N106, Bethesda, MD 20892 USA. EM robert.yarchoan@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute; National Cancer Institute, NIH [HHSN261200800001E] FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute. This work has also been funded in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. NR 30 TC 7 Z9 8 U1 1 U2 4 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 MAR 15 PY 2016 VL 62 IS 6 BP 730 EP 738 DI 10.1093/cid/civ996 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DF9XU UT WOS:000371716700008 PM 26658701 ER PT J AU Gupta, A Mathad, JS Abdel-Rahman, SM Albano, JD Botgros, R Brown, V Browning, RS Dawson, L Dooley, KE Gnanashanmugam, D Grinsztejn, B Hernandez-Diaz, S Jean-Philippe, P Kim, P Lyerly, AD Mirochnick, M Mofenson, LM Montepiedra, G Piper, J Sahin, L Savic, R Smith, B Spiegel, H Swaminathan, S Watts, DH White, A AF Gupta, Amita Mathad, Jyoti S. Abdel-Rahman, Susan M. Albano, Jessica D. Botgros, Radu Brown, Vikki Browning, Renee S. Dawson, Liza Dooley, Kelly E. Gnanashanmugam, Devasena Grinsztejn, Beatriz Hernandez-Diaz, Sonia Jean-Philippe, Patrick Kim, Peter Lyerly, Anne D. Mirochnick, Mark Mofenson, Lynne M. Montepiedra, Grace Piper, Jeanna Sahin, Leyla Savic, Radojka Smith, Betsy Spiegel, Hans Swaminathan, Soumya Watts, D. Heather White, Amina TI Toward Earlier Inclusion of Pregnant and Postpartum Women in Tuberculosis Drug Trials: Consensus Statements From an International Expert Panel SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE tuberculosis; MDR tuberculosis; latent tuberculosis infection; pregnancy; clinical trials ID CLINICAL-RESEARCH; SOUTH-AFRICA; MATERNAL MORTALITY; GLOBAL BURDEN; INFECTION; HIV-1; PHARMACOKINETICS; TRANSMISSION; COINFECTION; COUNTRIES AB Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15-44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population. C1 [Gupta, Amita] Johns Hopkins Univ, Div Infect Dis, Baltimore, MD USA. [Gupta, Amita] Johns Hopkins Univ, Dept Int Hlth, 600 N Wolfe St,Phipps 540B, Baltimore, MD 21287 USA. [Dooley, Kelly E.] Johns Hopkins Univ, Sch Med, Div Clin Pharmacol, Baltimore, MD USA. [Dooley, Kelly E.] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. [Browning, Renee S.; Dawson, Liza; Gnanashanmugam, Devasena; Kim, Peter; Piper, Jeanna; Smith, Betsy] NIAID, Div Aids, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Jean-Philippe, Patrick; Spiegel, Hans] HJF DAIDS, Dept Hlth & Human Serv, Bethesda, MD USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [White, Amina] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Sahin, Leyla] FDA Off New Drugs, Div Pediat & Maternal Hlth, Silver Spring, MD USA. [Mathad, Jyoti S.] Weill Cornell Med Coll, Ctr Global Hlth, Div Infect Dis, New York, NY USA. [Abdel-Rahman, Susan M.] Childrens Mercy Hosp, Div Clin Pharmacol, Kansas City, MO 64108 USA. [Albano, Jessica D.] Post Approval & Strateg Serv, Raleigh, NC USA. [Brown, Vikki] INC Res, Womens Hlth & Med Affairs, Raleigh, NC USA. [Lyerly, Anne D.] Univ N Carolina, Ctr Bioeth, Chapel Hill, NC USA. [Lyerly, Anne D.] Univ N Carolina, Dept Social Med, Chapel Hill, NC USA. [Hernandez-Diaz, Sonia] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA. [Montepiedra, Grace] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Ctr Biostat AIDS Res, Cambridge, MA 02138 USA. [Mirochnick, Mark] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02215 USA. [Savic, Radojka] Univ Calif San Francisco, Sch Pharm, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Savic, Radojka] Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. [Watts, D. Heather] US Dept State, Off Global AIDS Coordinator, Washington, DC 20520 USA. [Botgros, Radu] European Med Agcy, London, England. [Grinsztejn, Beatriz] Inst Pesquisa Clin Evandro Chagas Fiocruz, Rio De Janeiro, Brazil. [Swaminathan, Soumya] Natl Inst Res TB, Chennai, Tamil Nadu, India. RP Gupta, A (reprint author), Johns Hopkins Univ, Dept Int Hlth, 600 N Wolfe St,Phipps 540B, Baltimore, MD 21287 USA.; Gupta, A (reprint author), Johns Hopkins Univ, Div Infect Dis, Ctr Clin Global Hlth Educ, 600 N Wolfe St,Phipps 540B, Baltimore, MD 21287 USA. EM agupta25@jhmi.edu OI Lyerly, Anne/0000-0003-2211-6920 FU NIAID NIH HHS [HHSN272200800014C, T32 AI007613, UM1 AI068616, UM1 AI068632, UM1 AI069476]; NIGMS NIH HHS [T32 GM066691]; PHS HHS [HHSN272200800014C] NR 61 TC 3 Z9 3 U1 0 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 MAR 15 PY 2016 VL 62 IS 6 BP 761 EP 769 DI 10.1093/cid/civ991 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DF9XU UT WOS:000371716700013 PM 26658057 ER PT J AU Xie, YL Rosen, LB Sereti, I Barber, DL Chen, RY Hsu, DC Qasba, SS Zerbe, CS Holland, SM Browne, SK AF Xie, Yingda L. Rosen, Lindsey B. Sereti, Irini Barber, Daniel L. Chen, Ray Y. Hsu, Denise C. Qasba, S. Sonia Zerbe, Christa S. Holland, Steven M. Browne, Sarah K. TI Severe Paradoxical Reaction During Treatment of Disseminated Tuberculosis in a Patient With Neutralizing Anti-IFN gamma Autoantibodies SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE paradoxical reaction; autoantibodies; interferon-gamma; disseminated tuberculosis; IRIS ID RECONSTITUTION INFLAMMATORY SYNDROME; CD4(+) T-CELLS; INTERFERON-GAMMA; MYCOBACTERIAL INFECTION; PULMONARY TUBERCULOSIS; THERAPY; DISEASE; SUSCEPTIBILITY; RESPONSES AB Interferon-gamma (IFN gamma) neutralizing autoantibodies are associated with disseminated nontuberculous mycobacterial infections. We report a previously healthy Thai woman with disseminated tuberculosis and high-titer IFN gamma-neutralizing autoantibodies, who developed a severe inflammatory reaction during anti-tuberculosis treatment. IFN gamma contributes to host control of tuberculosis but appears inessential for tuberculosis paradoxical reactions. C1 [Xie, Yingda L.; Rosen, Lindsey B.; Chen, Ray Y.; Zerbe, Christa S.; Holland, Steven M.; Browne, Sarah K.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sereti, Irini; Hsu, Denise C.] NIAID, Lab Immunoregulat, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Barber, Daniel L.] NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Qasba, S. Sonia] Montgomery Cty Hlth Dept, Silver Spring, MD USA. [Browne, Sarah K.] FDA, Ctr Biol Evaluat & Res, Div Vaccines & Related Prod Applicat, Silver Spring, MD USA. RP Holland, SM (reprint author), Bldg 10-CRC,Rm B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health [ZO1-AI00647-06] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (ZO1-AI00647-06). S. K. B. is currently in the FDA/CBER (Food and Drug Administration/Center for Biologics Evaluation and Research). NR 22 TC 3 Z9 3 U1 2 U2 3 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 MAR 15 PY 2016 VL 62 IS 6 BP 770 EP 773 DI 10.1093/cid/civ995 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DF9XU UT WOS:000371716700014 PM 26646678 ER PT J AU Evans, S Follmann, D Schoenfeld, D Fowler, VG Chambers, HF AF Evans, Scott Follmann, Dean Schoenfeld, David Fowler, Vance G., Jr. Chambers, Henry F. TI DOOR/RADAR: A Gateway Into the Unknown? Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Evans, Scott] Harvard Univ, Boston, MA 02115 USA. [Follmann, Dean] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Schoenfeld, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fowler, Vance G., Jr.] Duke Univ, Durham, NC USA. [Chambers, Henry F.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Evans, S (reprint author), Harvard Univ, Sch Publ Hlth, CBAR Biostat, FXB 513,651 Huntington Ave, Boston, MA 02115 USA. EM evans@sdac.harvard.edu FU NIAID NIH HHS [UM1 AI104681, K24 AI093969, K24-AI093969, UM1-AI104681] NR 2 TC 0 Z9 0 U1 0 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 MAR 15 PY 2016 VL 62 IS 6 BP 815 EP 816 DI 10.1093/cid/civ1003 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DF9XU UT WOS:000371716700029 PM 26658301 ER PT J AU Henriksen, S Pang, R Wronkiewicz, M AF Henriksen, Sid Pang, Rich Wronkiewicz, Mark TI A simple generative model of the mouse mesoscale connectome SO ELIFE LA English DT Article ID SMALL-WORLD NETWORKS; CAENORHABDITIS-ELEGANS; NEUROTROPHIC FACTOR; CEREBRAL-CORTEX; BRAIN NETWORKS; INTEGRATION; SEGREGATION; SIMULATION; SYSTEM AB Recent technological advances now allow for the collection of vast data sets detailing the intricate neural connectivity patterns of various organisms. Oh et al. (2014) recently published the most complete description of the mouse mesoscale connectome acquired to date. Here we give an in-depth characterization of this connectome and propose a generative network model which utilizes two elemental organizational principles: proximal attachment - outgoing connections are more likely to attach to nearby nodes than to distant ones, and source growth - nodes with many outgoing connections are likely to form new outgoing connections. We show that this model captures essential principles governing network organization at the mesoscale level in the mouse brain and is consistent with biologically plausible developmental processes. C1 [Henriksen, Sid] NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Henriksen, Sid] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Pang, Rich; Wronkiewicz, Mark] Univ Washington, Grad Program Neurosci, Seattle, WA 98195 USA. RP Henriksen, S (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA.; Henriksen, S (reprint author), Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England.; Pang, R; Wronkiewicz, M (reprint author), Univ Washington, Grad Program Neurosci, Seattle, WA 98195 USA. EM henriksen@gmail.com; rpang@uw.edu; wronk@uw.edu OI Pang, Rich/0000-0002-2644-6110; Wronkiewicz, Mark/0000-0002-6521-3256 FU Allen Institute for Brain Science FX We thank the Allen Institute for Brain Science for generously providing the dataset used in this analysis and for funding the Summer Workshop on the Dynamic Brain - the course in which this project was conceived. We also thank the directors of this course, Christof Koch and Adrienne Fairhall. Additionally, we are grateful to Marcus Kaiser, Martha Bosma, and the reviewers for helpful comments and suggestions. NR 41 TC 3 Z9 3 U1 2 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 15 PY 2016 VL 5 AR e12366 DI 10.7554/eLife.12366 PG 19 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DG3LM UT WOS:000371970900001 PM 26978793 ER PT J AU Thongthip, S Bellani, M Gregg, SQ Sridhar, S Conti, BA Chen, YL Seidman, MM Smogorzewska, A AF Thongthip, Supawat Bellani, Marina Gregg, Siobhan Q. Sridhar, Sunandini Conti, Brooke A. Chen, Yanglu Seidman, Michael M. Smogorzewska, Agata TI Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction SO GENES & DEVELOPMENT LA English DT Article DE DNA damage; interstrand cross-link repair; karyomegalic interstitial nephritis; Fanconi anemia; FAN1; SNM1A ID ANEMIA-ASSOCIATED NUCLEASE; FANCONI-ANEMIA; INTERSTITIAL NEPHRITIS; GENOMIC INSTABILITY; HUMAN SNM1A; FANCD2; PROTEIN; CANCER; MICE; KIAA1018/FAN1 AB Deficiency of FANCD2/FANCI-associated nuclease 1 (FAN1) in humans leads to karyomegalic interstitial nephritis (KIN), a rare hereditary kidney disease characterized by chronic renal fibrosis, tubular degeneration, and characteristic polyploid nuclei in multiple tissues. The mechanism of how FAN1 protects cells is largely unknown but is thought to involve FAN1's function in DNA interstrand cross-link (ICL) repair. Here, we describe a Fan1-deficient mouse and show that FAN1 is required for cellular and organismal resistance to ICLs. We show that the ubiquitin-binding zinc finger (UBZ) domain of FAN1, which is needed for interaction with FANCD2, is not required for the initial rapid recruitment of FAN1 to ICLs or for its role in DNA ICL resistance. Epistasis analyses reveal that FAN1 has cross-link repair activities that are independent of the Fanconi anemia proteins and that this activity is redundant with the 5'-3' exonuclease SNM1A. Karyomegaly becomes prominent in kidneys and livers of Fan1-deficient mice with age, and mice develop liver dysfunction. Treatment of Fan1-deficient mice with ICL-inducing agents results in pronounced thymic and bone marrow hypocellularity and the disappearance of c-kit(+) cells. Our results provide insight into the mechanism of FAN1 in ICL repair and demonstrate that the Fan1 mouse model effectively recapitulates the pathological features of human FAN1 deficiency. C1 [Thongthip, Supawat; Gregg, Siobhan Q.; Sridhar, Sunandini; Conti, Brooke A.; Chen, Yanglu; Smogorzewska, Agata] Rockefeller Univ, Lab Genome Maintenance, New York, NY 10065 USA. [Bellani, Marina; Seidman, Michael M.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Smogorzewska, A (reprint author), Rockefeller Univ, Lab Genome Maintenance, New York, NY 10065 USA. EM asmogorzewska@rockefeller.edu OI Addie, Siobhan/0000-0001-5509-0726 FU National Institutes of Health Cancer Center [P30 CA008748]; Intramural Research Program of the National Institutes of Health, the National Institute on Aging; Rita Allen Foundation Scholars Program; National Institutes of Health [RO1 HL120922] FX We thank the members of the Smogorzewska laboratory for comments on the manuscript, and Johannes Walter for comments on the manuscript and sharing unpublished results. We thank Manish Ponda for helpful discussion, Markus Grompe for sharing Fancd2- and Fanca-deficient mice, and Paula Cohen for sharing Slx4- and Mus81-deficient mice. We thank Charlotte Cockram for the cloning of Snm1a CRISPR guide RNA plasmid. We are grateful to Chingwen Yang and members of the Gene Targeting Center, the Transgenic Services Center, the Comparative Bioscience Center, the Genomics Center, and the Flow Cytometry Resource Center at The Rockefeller University, and Michelle Lepherd and members of the Center for Comparative Medicine and Pathology at Memorial Sloan Kettering Cancer Center (MSKCC). FISH analysis was performed at the MSKCC Molecular Cytogenetics Core supported by National Institutes of Health Cancer Center support grant P30 CA008748. We thank John Rouse for antibodies against mouse FAN1. We thank John Rouse and Friedhelm Hildebrandt for sharing unpublished data. The mouse Fan1 targeting vector was generated by the trans-National Institutes of Health KOMP and obtained from the KOMP Repository (http://www.komp.org). This research was supported in part by the Intramural Research Program of the National Institutes of Health, the National Institute on Aging (M.S.), and grants from the Rita Allen Foundation Scholars Program (A.S.) and the National Institutes of Health (RO1 HL120922 to A.S.). NR 60 TC 0 Z9 0 U1 1 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD MAR 15 PY 2016 VL 30 IS 6 BP 645 EP 659 DI 10.1101/gad.276261.115 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DG3MU UT WOS:000371974500004 PM 26980189 ER PT J AU Xue, XY Papusha, A Choi, KY Bonner, JN Kumar, S Niu, HY Kaur, H Zheng, XF Donnianni, RA Lu, L Lichten, M Zhao, XL Ira, G Sung, P AF Xue, Xiaoyu Papusha, Alma Choi, Koyi Bonner, Jaclyn N. Kumar, Sandeep Niu, Hengyao Kaur, Hardeep Zheng, Xiao-Feng Donnianni, Roberto A. Lu, Lucy Lichten, Michael Zhao, Xiaolan Ira, Grzegorz Sung, Patrick TI Differential regulation of the anti-crossover and replication fork regression activities of Mph1 by Mte1 SO GENES & DEVELOPMENT LA English DT Article DE Mph1; Mte1; MHF; homologous recombination; genome replication; crossover formation ID COMPLEMENTATION GROUP-M; RECOMBINATION INTERMEDIATE METABOLISM; FANCONI-ANEMIA PATHWAY; HISTONE-FOLD COMPLEX; STRAND BREAK REPAIR; SACCHAROMYCES-CEREVISIAE; LINK REPAIR; HOMOLOGOUS RECOMBINATION; BRANCH MIGRATION; CANCER GENOMICS AB We identified Mte1 (Mph1-associated telomere maintenance protein 1) as a multifunctional regulator of Saccharomyces cerevisiae Mph1, a member of the FANCM family of DNA motor proteins important for DNA replication fork repair and crossover suppression during homologous recombination. We show that Mte1 interacts with Mph1 and DNA species that resemble a DNA replication fork and the Dloop formed during recombination. Biochemically, Mte1 stimulates Mph1-mediated DNA replication fork regression and branch migration in a model substrate. Consistent with this activity, genetic analysis reveals that Mte1 functions with Mph1 and the associated MHF complex in replication fork repair. Surprisingly, Mte1 antagonizes the D-loop-dissociative activity of Mph1-MHF and exerts a procrossover role in mitotic recombination. We further show that the influence of Mte1 on Mph1 activities requires its binding to Mph1 and DNA. Thus, Mte1 differentially regulates Mph1 activities to achieve distinct outcomes in recombination and replication fork repair. C1 [Xue, Xiaoyu; Niu, Hengyao; Zheng, Xiao-Feng; Lu, Lucy; Sung, Patrick] Yale Univ, Dept Mol Biophys & Biochem, Sch Med, New Haven, CT 06520 USA. [Papusha, Alma; Kumar, Sandeep; Ira, Grzegorz] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Choi, Koyi; Bonner, Jaclyn N.; Zhao, Xiaolan] Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10065 USA. [Kaur, Hardeep; Lichten, Michael] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. [Donnianni, Roberto A.] Columbia Univ, Dept Microbiol & Immunol, Med Ctr, New York, NY 10032 USA. [Niu, Hengyao] Indiana Univ, Dept Mol & Cellular Biochem, Bloomington, IN 47405 USA. [Zheng, Xiao-Feng] Harvard Univ, Dept Radiat Oncol, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Sung, P (reprint author), Yale Univ, Dept Mol Biophys & Biochem, Sch Med, New Haven, CT 06520 USA.; Ira, G (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.; Zhao, XL (reprint author), Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10065 USA. EM zhaox1@mkscc.org; gira@bcm.edu; patrick.sung@yale.edu RI Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 FU US National Institutes of Health [ES007061, ES015252, ES015632, GM057814, GM080600, GM080670]; Intramural Research Program of the National Institutes of Health through the Center for Cancer Research at the National Cancer Institute FX We acknowledge Dr. Kazuishi Kubota and Dr. Steven Gygi (Harvard Medical School) for their help in mass spectrometry. This study was supported by US National Institutes of Health grants ES007061, ES015252, ES015632, GM057814, GM080600, and GM080670 and the Intramural Research Program of the National Institutes of Health through the Center for Cancer Research at the National Cancer Institute. NR 51 TC 2 Z9 2 U1 1 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD MAR 15 PY 2016 VL 30 IS 6 BP 687 EP 699 DI 10.1101/gad.276139.115 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DG3MU UT WOS:000371974500007 PM 26966246 ER PT J AU Figueroa, JD Middlebrooks, CD Banday, AR Ye, YQ Garcia-Closas, M Chatterjee, N Koutros, S Kiemeney, LA Rafnar, T Bishop, T Furberg, H Matullo, G Golka, K Gago-Dominguez, M Taylor, JA Fletcher, T Siddiq, A Cortessis, VK Kooperberg, C Cussenot, O Benhamou, S Prescott, J Porru, S Dinney, CP Malats, N Baris, D Purdue, MP Jacobs, EJ Albanes, D Wang, ZM Chung, CC Vermeulen, SH Aben, KK Galesloot, TE Thorleifsson, G Sulem, P Stefansson, K Kiltie, AE Harland, M Teo, M Offit, K Vijai, J Bajorin, D Kopp, R Fiorito, G Guarrera, S Sacerdote, C Selinski, S Hengstler, JG Gerullis, H Ovsiannikov, D Blaszkewicz, M Castelao, JE Calaza, M Martinez, ME Cordeiro, P Xu, ZL Panduri, V Kumar, R Gurzau, E Koppova, K Bueno-De-Mesquita, HB Ljungberg, B Clavel-Chapelon, F Weiderpass, E Krogh, V Dorronsoro, M Travis, RC Tjonneland, A Brennan, P Chang-Claude, J Riboli, E Conti, D Stern, MC Pike, MC Van den Berg, D Yuan, JM Hohensee, C Jeppson, RP Cancel-Tassin, G Roupret, M Comperat, E Turman, C De Vivo, I Giovannucci, E Hunter, DJ Kraft, P Lindstrom, S Carta, A Pavanello, S Arici, C Mastrangelo, G Kamat, AM Zhang, LR Gong, Yl Pu, X Hutchinson, A Burdett, L Wheeler, WA Karagas, MR Johnson, A Schned, A Hosain, GMM Schwenn, M Kogevinas, M Tardon, A Serra, C Carrato, A Garcia-Closas, R Lloreta, J Andriole, G Grubb, R Black, A Diver, WR Gapstur, SM Weinstein, S Virtamo, J Haiman, CA Landi, MT Caporaso, NE Fraumeni, JF Vineis, P Wu, XF Chanock, SJ Silverman, DT Prokunina-Olsson, L Rothman, N AF Figueroa, Jonine D. Middlebrooks, Candace D. Banday, A. Rouf Ye, Yuanqing Garcia-Closas, Montserrat Chatterjee, Nilanjan Koutros, Stella Kiemeney, Lambertus A. Rafnar, Thorunn Bishop, Timothy Furberg, Helena Matullo, Giuseppe Golka, Klaus Gago-Dominguez, Manuela Taylor, Jack A. Fletcher, Tony Siddiq, Afshan Cortessis, Victoria K. Kooperberg, Charles Cussenot, Olivier Benhamou, Simone Prescott, Jennifer Porru, Stefano Dinney, Colin P. Malats, Nuria Baris, Dalsu Purdue, Mark P. Jacobs, Eric J. Albanes, Demetrius Wang, Zhaoming Chung, Charles C. Vermeulen, Sita H. Aben, Katja K. Galesloot, Tessel E. Thorleifsson, Gudmar Sulem, Patrick Stefansson, Kari Kiltie, Anne E. Harland, Mark Teo, Mark Offit, Kenneth Vijai, Joseph Bajorin, Dean Kopp, Ryan Fiorito, Giovanni Guarrera, Simonetta Sacerdote, Carlotta Selinski, Silvia Hengstler, Jan G. Gerullis, Holger Ovsiannikov, Daniel Blaszkewicz, Meinolf Esteban Castelao, Jose Calaza, Manuel Martinez, Maria Elena Cordeiro, Patricia Xu, Zongli Panduri, Vijayalakshmi Kumar, Rajiv Gurzau, Eugene Koppova, Kvetoslava Bueno-De-Mesquita, H. Bas Ljungberg, Borje Clavel-Chapelon, Francoise Weiderpass, Elisabete Krogh, Vittorio Dorronsoro, Miren Travis, Ruth C. Tjonneland, Anne Brennan, Paul Chang-Claude, Jenny Riboli, Elio Conti, David Stern, Marianna C. Pike, Malcolm C. Van den Berg, David Yuan, Jian-Min Hohensee, Chancellor Jeppson, Rebecca P. Cancel-Tassin, Geraldine Roupret, Morgan Comperat, Eva Turman, Constance De Vivo, Immaculata Giovannucci, Edward Hunter, David J. Kraft, Peter Lindstrom, Sara Carta, Angela Pavanello, Sofia Arici, Cecilia Mastrangelo, Giuseppe Kamat, Ashish M. Zhang, Liren Gong, Yilei Pu, Xia Hutchinson, Amy Burdett, Laurie Wheeler, William A. Karagas, Margaret R. Johnson, Alison Schned, Alan Hosain, G. M. Monawar Schwenn, Molly Kogevinas, Manolis Tardon, Adonina Serra, Consol Carrato, Alfredo Garcia-Closas, Reina Lloreta, Josep Andriole, Gerald, Jr. Grubb, Robert, III Black, Amanda Diver, W. Ryan Gapstur, Susan M. Weinstein, Stephanie Virtamo, Jarmo Haiman, Christopher A. Landi, Maria Teresa Caporaso, Neil E. Fraumeni, Joseph F., Jr. Vineis, Paolo Wu, Xifeng Chanock, Stephen J. Silverman, Debra T. Prokunina-Olsson, Ludmila Rothman, Nathaniel TI Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; NUCLEOTIDE EXCHANGE FACTOR; NAT2 SLOW ACETYLATION; CONFERS SUSCEPTIBILITY; RECOMBINATION HOTSPOTS; GENETIC-VARIATION; SEQUENCE VARIANT; GSTM1 NULL; SMOKING; METAANALYSIS AB Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1x 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 x 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 x 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P <= 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer. C1 [Figueroa, Jonine D.; Middlebrooks, Candace D.; Banday, A. Rouf; Garcia-Closas, Montserrat; Chatterjee, Nilanjan; Koutros, Stella; Baris, Dalsu; Purdue, Mark P.; Albanes, Demetrius; Chung, Charles C.; Black, Amanda; Weinstein, Stephanie; Landi, Maria Teresa; Caporaso, Neil E.; Fraumeni, Joseph F., Jr.; Chanock, Stephen J.; Silverman, Debra T.; Prokunina-Olsson, Ludmila; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Figueroa, Jonine D.] Univ Edinburgh, Inst Genet & Mol Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Ye, Yuanqing; Zhang, Liren; Gong, Yilei; Pu, Xia; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Dinney, Colin P.; Chung, Charles C.; Kamat, Ashish M.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Kiemeney, Lambertus A.; Vermeulen, Sita H.; Aben, Katja K.; Galesloot, Tessel E.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 ED Nijmegen, Netherlands. [Rafnar, Thorunn; Thorleifsson, Gudmar; Sulem, Patrick; Stefansson, Kari] Amgen Inc, deCODE Genet, Reykjavik, Iceland. [Bishop, Timothy; Harland, Mark; Pike, Malcolm C.] Univ Leeds, Epidemiol & Biostat Sect, Leeds LS9 7TF, W Yorkshire, England. [Teo, Mark] Univ Leeds, Leeds Inst Canc & Pathol, Radiotherapy Res Grp, Leeds LS9 7TF, W Yorkshire, England. [Furberg, Helena] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA. [Offit, Kenneth; Vijai, Joseph] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Bajorin, Dean] Mem Sloan Kettering Canc Ctr, Dept Med, Div Solid Tumor Oncol, Genitourinary Oncol Serv, 1275 York Ave, New York, NY 10021 USA. [Kopp, Ryan] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, 1275 York Ave, New York, NY 10021 USA. [Matullo, Giuseppe; Fiorito, Giovanni; Guarrera, Simonetta] Univ Turin, Dept Med Sci, Turin, Italy. [Matullo, Giuseppe; Fiorito, Giovanni; Guarrera, Simonetta; Vineis, Paolo] Human Genet Fdn, Turin, Italy. [Golka, Klaus; Selinski, Silvia; Hengstler, Jan G.; Blaszkewicz, Meinolf] Leibniz Res Ctr Working Environm & Human Factor, Dortmund, Germany. [Gago-Dominguez, Manuela; Calaza, Manuel] Inst Invest Sanit Santiago IDIS, Serv Galego Saude SERGAS, Galician Fdn Genom Med, Genom Med Grp, Santiago De Compostela, Spain. [Taylor, Jack A.; Xu, Zongli; Panduri, Vijayalakshmi] NIEHS, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Taylor, Jack A.; Panduri, Vijayalakshmi] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Fletcher, Tony] London Sch Hyg & Trop Med, London WC1, England. [Siddiq, Afshan; Bueno-De-Mesquita, H. Bas; Riboli, Elio; Conti, David; Stern, Marianna C.; Van den Berg, David] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC, PHE Ctr Environm & Hlth, London, England. [Cortessis, Victoria K.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cortessis, Victoria K.; Conti, David; Stern, Marianna C.; Van den Berg, David; Haiman, Christopher A.] Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. [Cortessis, Victoria K.; De Vivo, Immaculata] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Kooperberg, Charles; Hohensee, Chancellor; Jeppson, Rebecca P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Cussenot, Olivier] Tenon, Dept Urol, Paris, France. [Roupret, Morgan] Pitie Salpetriere, Dept Urol, Paris, France. [Comperat, Eva] Pitie Salpetriere, AP HP, Dept Pathol, Paris, France. [Cussenot, Olivier; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva] Ctr Rech Pathol Prostat, Paris, France. [Cussenot, Olivier; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva] Univ Paris 06, ONCOTYPE URO, GRC 5, Paris, France. [Benhamou, Simone] Fdn Jean Dausset Ctr Etud Polymorphisme Humain CE, INSERM, U946, Paris, France. [Benhamou, Simone] Inst Gustave Roussy, UMR8200, Ctr Natl Rech Sci, Villejuif, France. [Prescott, Jennifer; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Prescott, Jennifer; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Prescott, Jennifer; Turman, Constance; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA. [Giovannucci, Edward; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, 665 Huntington Ave, Boston, MA 02115 USA. [Porru, Stefano; Carta, Angela; Arici, Cecilia] Univ Brescia, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth, Brescia, Italy. [Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain. [Jacobs, Eric J.; Diver, W. Ryan; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Wang, Zhaoming; Hutchinson, Amy; Burdett, Laurie] Natl Canc Inst, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD USA. [Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Stefansson, Kari] Univ Oxford, Dept Oncol, CRUK MRC Oxford Inst Radiat Oncol, Old Rd Campus,Res Bldg,Roosevelt Dr, Oxford OX3 7DQ, England. [Sacerdote, Carlotta] CPO Piemonte, Canc Epidemiol, Turin, Italy. [Gerullis, Holger] Carl von Ossietzky Univ Oldenburg, Sch Med & Hlth Sci, Klinikum Oldenburg, Univ Hosp Urol, D-26111 Oldenburg, Germany. [Gerullis, Holger] Lukasklin Neuss, Dept Urol, Neuss, Germany. [Ovsiannikov, Daniel] St Josefs Hosp, Dept Urol, Dortmund, Germany. [Esteban Castelao, Jose] Xerencia Xest Integrada Vigo SERGAS, Inst Invest Biomed IBI Orense Pontevedra Vigo, Oncol & Genet Unit, Complejo Hosp, Vigo, Spain. [Calaza, Manuel] Univ Santiago de Compostela, Ctr Res Mol Med & Chron Dis CIMUS, Galicia, Spain. [Martinez, Maria Elena] Univ Calif San Diego, Dept Family Med & Publ Hlth, Moores Canc Ctr, San Diego, CA 92103 USA. [Cordeiro, Patricia] Univ Santiago de Compostela, Serv Galego Saude SERGAS, Dept Urol, Complejo Hosp, Santiago De Compostela, Spain. [Kumar, Rajiv; Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Baden Wurttembe, Germany. [Kumar, Rajiv; Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany. [Gurzau, Eugene] Ctr Environm Hlth, Cluj Napoca, Romania. [Koppova, Kvetoslava] State Hlth Inst, Banska Bystrica, Slovakia. [Bueno-De-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, Bilthoven, Netherlands. [Bueno-De-Mesquita, H. Bas] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur, Malaysia. [Ljungberg, Borje] Umea Univ, Dept Surg & Perioperat Sci, Urol & Androl, Umea, Sweden. [Clavel-Chapelon, Francoise] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, U1018, Nutr Hormones & Womens Hlth Team, F-94805 Villejuif, France. [Clavel-Chapelon, Francoise; Weiderpass, Elisabete] Univ Paris Sud, UMRS 1018, F-94805 Villejuif, France. [Clavel-Chapelon, Francoise] Inst Gustave Roussy, Rue Camille Desmoulins, F-94805 Villejuif, France. [Weiderpass, Elisabete] Arctic Univ Norway, Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Canc Registry Norway, Inst Population Based Canc Res, Oslo, Norway. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland. [Krogh, Vittorio] Ist Nazl Tumori, Fdn IRCCS, Epidemiol & Prevent Unit, Via Venezian 1, I-20133 Milan, Italy. [Dorronsoro, Miren] BioDonostia Res Inst, Dept Hlth, Basque, Basque Region, Spain. [Dorronsoro, Miren; Kogevinas, Manolis; Tardon, Adonina; Serra, Consol; Lloreta, Josep] CIBERESP, Madrid, Spain. [Travis, Ruth C.] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Tjonneland, Anne] Danish Canc Soc, Res Ctr, Copenhagen, Denmark. [Brennan, Paul] IARC, Lyon, France. [Yuan, Jian-Min] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Hunter, David J.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Pavanello, Sofia; Mastrangelo, Giuseppe] Univ Padua, Dept Cardiac Thorac & Vasc Sci, Padua, Italy. [Wheeler, William A.] Informat Management Serv Inc, Silver Spring, MD USA. [Karagas, Margaret R.; Schned, Alan] Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Hosain, G. M. Monawar] New Hampshire State Canc Registry, Concord, NH USA. [Schwenn, Molly] Maine Canc Registry, Augusta, GA USA. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Kogevinas, Manolis; Serra, Consol] Hosp del Mar, Municipal Inst Med Res, IMIM, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. [Tardon, Adonina] Univ Oviedo, Inst Univ Oncol, Oviedo, Spain. [Serra, Consol] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Carrato, Alfredo] Ramon y Cajal Univ Hosp, IRYCIS, Madrid, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna, Spain. [Andriole, Gerald, Jr.; Grubb, Robert, III] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Figueroa, JD (reprint author), Univ Edinburgh, Sch Med, Usher Inst Populat Hlth Sci & Informat, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland. EM jonine.figueroa@ed.ac.uk RI Galesloot, Tessel/P-6667-2015; Aben, Katja/G-9686-2016; Benhamou, Simone/K-6554-2015; Krogh, Vittorio/K-2628-2016; Matullo, Giuseppe/K-6383-2016; Vermeulen, H.H.M./L-4716-2015; Weiderpass, Elisabete/M-4029-2016; Kogevinas, Manolis/C-3918-2017; OI Malats, Nuria/0000-0003-2538-3784; Cancel-Tassin, Geraldine/0000-0002-9583-6382; Aben, Katja/0000-0002-0214-2147; Krogh, Vittorio/0000-0003-0122-8624; Weiderpass, Elisabete/0000-0003-2237-0128; Kiltie, Anne/0000-0001-7208-2912; Sacerdote, Carlotta/0000-0002-8008-5096; xu, zongli/0000-0002-9034-8902; taylor, jack/0000-0001-5303-6398 FU MSK Cancer Center Support Grant/Core Grant [P30 CA008748] FX For a list of all the investigators who have contributed to WHI science, please visit: https://cleo.whi.org/researchers/SitePages/Write%20a%20Paper.aspx. The Memorial Sloan Kettering investigators gratefully acknowledge the MSK Cancer Center Support Grant/Core Grant (P30 CA008748). NR 42 TC 2 Z9 2 U1 3 U2 29 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 MAR 15 PY 2016 VL 25 IS 6 BP 1203 EP 1214 DI 10.1093/hmg/ddv492 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DG5XD UT WOS:000372152900013 PM 26732427 ER PT J AU Burns, JM Miura, K Sullivan, J Long, CA Barnwell, JW AF Burns, James M., Jr. Miura, Kazutoyo Sullivan, JoAnn Long, Carole A. Barnwell, John W. TI Immunogenicity of a chimeric Plasmodium falciparum merozoite surface protein vaccine in Aotus monkeys SO MALARIA JOURNAL LA English DT Article DE Blood-stage malaria vaccine; Aotus monkeys; Vaccine carrier protein ID BLOOD-STAGE MALARIA; WHOLE PARASITE; PHASE-3 TRIAL; PROTECTION; IMMUNIZATION; RESPONSES; CHILDREN; ANTIBODY; SPOROZOITES; CHALLENGE AB Background: The production of properly folded, recombinant sub-unit Plasmodium falciparum malaria vaccine candidates in sufficient quantities is often a challenge. Success in vaccine immunogenicity studies in small animal models does not always predict immunogenicity in non-human primates and/or human subjects. The aim of this study was to assess the immunogenicity of a chimeric blood-stage malaria vaccine in Aotus monkeys. This vaccine candidate includes the neutralizing B cell epitopes of P. falciparum merozoite surface protein 1 (rPfMSP1(19)) genetically linked to a highly immunogenic, well-conserved P. falciparum merozoite surface protein 8 (rPfMSP8 (Delta Asn/Asp)) partner. Methods: Aotus nancymaae monkeys were immunized with purified rPfMSP1/8 or rPfMSP8 (Delta Asn/Asp) formulated with Montanide ISA 720 as adjuvant, or with adjuvant alone. Antibody responses to MSP1(19) and MSP8 domains were measured by ELISA following primary, secondary and tertiary immunizations. The functionality of vaccine-induced antibodies was assessed in a standard P. falciparum blood-stage in vitro growth inhibition assay. Non-parametric tests with corrections for multiple comparisons when appropriate were used to determine the significance of differences in antigen-specific IgG titres and in parasite growth inhibition. Results: The chimeric rPfMSP1/8 vaccine was shown to be well tolerated and highly immunogenic with boost-able antibody responses elicited to both PfMSP8 and PfMSP1(19) domains. Elicited antibodies were highly cross-reactive between FVO and 3D7 alleles of PfMSP1(19) and potently inhibited the in vitro growth of P. falciparum blood-stage parasites. Conclusions: Similar to previous results with inbred and outbred mice and with rabbits, the PfMSP1/8 vaccine was shown to be highly effective in eliciting P. falciparum growth inhibitory antibodies upon immunization of non-human primates. The data support the further assessment of PfMSP1/8 as a component of a multivalent vaccine for use in human subjects. As important, the data indicate that rPfMSP8 (Delta Asn/Asp) can be used as a malaria specific carrier protein to: (1) drive production of antibody responses to neutralizing B cell epitopes of heterologous vaccine candidates and (2) facilitate production of properly folded, recombinant P. falciparum subunit vaccines in high yield. C1 [Burns, James M., Jr.; Long, Carole A.] Drexel Univ, Coll Med, Ctr Mol Parasitol, Dept Microbiol & Immunol, 2900 Queen Lane, Philadelphia, PA 19129 USA. [Miura, Kazutoyo; Long, Carole A.] NIAID, Malaria Immunol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Sullivan, JoAnn; Barnwell, John W.] Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Atlanta, GA 30329 USA. RP Burns, JM (reprint author), Drexel Univ, Coll Med, Ctr Mol Parasitol, Dept Microbiol & Immunol, 2900 Queen Lane, Philadelphia, PA 19129 USA. EM jburns@drexelmed.edu FU NIH-NIAID [AI035661, AI114292]; Department of Microbiology and Immunology, Drexel University College of Medicine; Intramural Program of NIH-NIAID; PATH Malaria Vaccine Initiative FX This work was supported by NIH-NIAID Grants AI035661 (JMB) and AI114292 (JMB), the Department of Microbiology and Immunology, Drexel University College of Medicine (JMB) and the Intramural Program of NIH-NIAID (CAL). The GIA Reference Center where the GIA assay was performed was supported by the PATH Malaria Vaccine Initiative. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 35 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 1475-2875 J9 MALARIA J JI Malar. J. PD MAR 15 PY 2016 VL 15 AR 159 DI 10.1186/s12936-016-1226-5 PG 7 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DG3JT UT WOS:000371966200001 PM 26975721 ER PT J AU White, LR Edland, SD Hemmy, LS Montine, KS Zarow, C Sonnen, JA Uyehara-Lock, JH Gelber, RP Ross, GW Petrovitch, H Masaki, KH Lim, KO Launer, LJ Montine, TJ AF White, Lon R. Edland, Steven D. Hemmy, Laura S. Montine, Kathleen S. Zarow, Chris Sonnen, Joshua A. Uyehara-Lock, Jane H. Gelber, Rebecca P. Ross, G. Webster Petrovitch, Helen Masaki, Kamal H. Lim, Kelvin O. Launer, Lenore J. Montine, Thomas J. TI Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies SO NEUROLOGY LA English DT Article ID ALZHEIMER-DISEASE PATHOLOGY; HIPPOCAMPAL SCLEROSIS; OLDER PERSONS; ADULT CHANGES; HUMAN BRAIN; DEMENTIA; COMMON; MICROINFARCTS; CONSORTIUM; AUTOPSY AB Objective:To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels.Methods:The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined.Results:Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no cognitive impairment despite Braak stage V) was strongly associated with minimal or no comorbid abnormalities, with fewer neocortical AD lesions, and weakly with longer interval between final testing and autopsy.Conclusions:Total burden of comorbid neuropathologic abnormalities, rather than any single lesion type, was the most relevant determinant of cognitive impairment in both cohorts, often despite clinical diagnosis of only AD. These findings emphasize challenges to dementia pathogenesis and intervention research and to accurate diagnoses during life. C1 [White, Lon R.; Gelber, Rebecca P.; Ross, G. Webster; Petrovitch, Helen] Univ Hawaii, John A Burns Sch Med, Pacific Hlth Res & Educ Inst, Honolulu, HI 96822 USA. [White, Lon R.; Petrovitch, Helen; Masaki, Kamal H.] Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. [Uyehara-Lock, Jane H.] Univ Hawaii, John A Burns Sch Med, Dept Pathol, Honolulu, HI 96822 USA. [Ross, G. Webster; Petrovitch, Helen] Univ Hawaii, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. [White, Lon R.; Launer, Lenore J.] NIH, Natl Inst Aging, Lab Epidemiol & Populat Sci, Intramural Res Program, Bldg 10, Bethesda, MD 20892 USA. [Edland, Steven D.] Univ Calif San Diego, Dept Family Prevent Med, La Jolla, CA 92093 USA. [Edland, Steven D.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Hemmy, Laura S.; Lim, Kelvin O.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [White, Lon R.; Hemmy, Laura S.; Lim, Kelvin O.] VA Med Ctr, Geriatr Res Educ & Clin Ctr, Minneapolis, MN USA. [Montine, Kathleen S.; Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Zarow, Chris] Univ So Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA 90033 USA. [Sonnen, Joshua A.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Gelber, Rebecca P.; Ross, G. Webster; Petrovitch, Helen] VA Pacific Islands Hlth Care Syst, Honolulu, HI USA. [Masaki, Kamal H.] Kuakini Med Ctr, Honolulu, HI USA. RP White, LR (reprint author), Univ Hawaii, John A Burns Sch Med, Pacific Hlth Res & Educ Inst, Honolulu, HI 96822 USA.; White, LR (reprint author), Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA.; White, LR (reprint author), NIH, Natl Inst Aging, Lab Epidemiol & Populat Sci, Intramural Res Program, Bldg 10, Bethesda, MD 20892 USA.; White, LR (reprint author), VA Med Ctr, Geriatr Res Educ & Clin Ctr, Minneapolis, MN USA. EM lon@hawaii.edu FU NIH [U01 AG046871, R03 AG046614]; Intramural Research Program of the NIH, National Institute on Aging, ALZ Assn [ZEN-12-239028]; Chia-Ling Chang Fund of the Hawaii Community Foundation; Office of Research and Development, Department of Veterans Affairs Pacific Islands Health Care System; Nancy and Buster Alvord Endowment FX Supported by NIH grants U01 AG046871 and R03 AG046614; the Intramural Research Program of the NIH, National Institute on Aging, ALZ Assn ZEN-12-239028; the Chia-Ling Chang Fund of the Hawaii Community Foundation; the Office of Research and Development, Department of Veterans Affairs Pacific Islands Health Care System; and the Nancy and Buster Alvord Endowment. NR 35 TC 7 Z9 7 U1 4 U2 11 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 MAR 15 PY 2016 VL 86 IS 11 BP 1000 EP 1008 DI 10.1212/WNL.0000000000002480 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DG2HF UT WOS:000371887200005 PM 26888993 ER PT J AU Espigol-Frigole, G Planas-Rigol, E Ohnuki, H Salvucci, O Kwak, H Ravichandran, S Luke, B Cid, MC Tosato, G AF Espigol-Frigole, Georgina Planas-Rigol, Ester Ohnuki, Hidetaka Salvucci, Ombretta Kwak, Hyeongil Ravichandran, Sarangan Luke, Brian Cid, Maria C. Tosato, Giovanna TI Identification of IL-23p19 as an endothelial proinflammatory peptide that promotes gp130-STAT3 signaling SO SCIENCE SIGNALING LA English DT Article ID GIANT-CELL ARTERITIS; SARCOMA-ASSOCIATED HERPESVIRUS; VIRAL INTERLEUKIN-6; RECEPTOR; GP130; CYTOKINE; IL-6; INFLAMMATION; EXPRESSION; TISSUE AB Interleukin-23 (IL-23), a heterodimeric cytokine composed of the unique p19 peptide (IL-23p19) and a peptide called IL-12p40, which is shared with IL-12, is implicated in Crohn's disease, rheumatoid arthritis, psoriasis, and other immune-mediated inflammatory diseases. Endothelial cells produce the IL-23p19 peptide in the absence of the IL-12p40 chain and thus do not make heterodimeric IL-23. We found that intracellular IL-23p19 increased the cell surface abundances of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells, which enhanced the attachment of leukocytes and increased their transendothelial migration. Intracellular p19 associated with the cytokine receptor subunit gp130 and stimulated the gp130-dependent activation of signal transducer and activator of transcription 3 (STAT3) signaling. Proinflammatory factors promoted the generation of IL-23p19 in endothelial cells. The adventitial capillaries of inflamed temporal arteries in patients with giant-cell arteritis (GCA) had endothelial p19 protein associated with gp130, but did not contain the IL-12p40 chain. Because adventitial capillaries are essential for the entry of inflammatory cells into arterial walls, these data suggest that p19 may contribute to GCA disease and could represent a therapeutic target. Our results provide evidence that IL-23p19 is a previously unrecognized endothelial proinflammatory peptide that promotes leukocyte transendothelial migration, advancing our current understanding of the complexities of inflammatory responses. C1 [Espigol-Frigole, Georgina; Planas-Rigol, Ester; Ohnuki, Hidetaka; Salvucci, Ombretta; Kwak, Hyeongil; Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Espigol-Frigole, Georgina; Planas-Rigol, Ester; Cid, Maria C.] Univ Barcelona, IDIBAPS CRB CELLEX, Dept Syst Autoimmune Dis, Clin Inst Med & Dermatol,Hosp Clin, E-08036 Barcelona, Spain. [Ravichandran, Sarangan; Luke, Brian] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. RP Espigol-Frigole, G; Tosato, G (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Espigol-Frigole, G (reprint author), Univ Barcelona, IDIBAPS CRB CELLEX, Dept Syst Autoimmune Dis, Clin Inst Med & Dermatol,Hosp Clin, E-08036 Barcelona, Spain. EM georginaespigol@gmail.com; Tosatog@mail.nih.gov RI Ohnuki, Hidetaka/E-1877-2012; OI Ohnuki, Hidetaka/0000-0001-8951-3264; Cid Xutgla, Maria Cinta/0000-0002-4730-0938 FU Center for Cancer Research/National Cancer Institute (NCI)/NIH; Federal funds from the NCI, NIH [HHSN261200800001E]; Ministerio de Economia y Competitividad [SAF 2014 57708-R11/30073]; Instituto de Salud Carlos III [PIE13/00033, PI15/00092] FX This work was supported by the intramural research program of Center for Cancer Research/National Cancer Institute (NCI)/NIH. The computational analysis in this project was funded with Federal funds from the NCI, NIH, under contract no. HHSN261200800001E, and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. M.C.C. was funded by the Ministerio de Economia y Competitividad (SAF 2014 57708-R11/30073). E.P.-R. and G.E.-F. were partially funded by the Instituto de Salud Carlos III (PIE13/00033 and PI15/00092, respectively). NR 33 TC 3 Z9 3 U1 0 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAR 15 PY 2016 VL 9 IS 419 AR ra28 DI 10.1126/scisignal.aad2357 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG4ZT UT WOS:000372082400001 PM 26980441 ER PT J AU Lozoya, OA Gilchrist, CL Guilak, F AF Lozoya, Oswaldo A. Gilchrist, Christopher L. Guilak, Farshid TI Universally Conserved Relationships between Nuclear Shape and Cytoplasmic Mechanical Properties in Human Stem Cells SO SCIENTIFIC REPORTS LA English DT Article ID PARTICLE-TRACKING MICRORHEOLOGY; BRANCHING MORPHOGENESIS; ACTIN POLYMERIZATION; EMBRYONIC-TISSUES; CYTOSKELETAL; MIGRATION; DYNAMICS; MATRIX; MECHANOTRANSDUCTION; DIFFERENTIATION AB The ability of cells to proliferate, differentiate, transduce extracellular signals and assemble tissues involves structural connections between nucleus and cytoskeleton. Yet, how the mechanics of these connections vary inside stem cells is not fully understood. To address those questions, we combined two-dimensional particle-tracking microrheology and morphological measures using variable reduction techniques to measure whether cytoplasmic mechanics allow for discrimination between different human adherent stem cell types and across different culture conditions. Here we show that nuclear shape is a quantifiable discriminant of mechanical properties in the perinuclear cytoskeleton (pnCSK) of various stem cell types. Also, we find the pnCSK is a region with different mechanical properties than elsewhere in the cytoskeleton, with heterogeneously distributed locations exhibiting subdiffusive features, and which obeys physical relations conserved among various stem cell types. Finally, we offer a prospective basis to discriminate between stem cell types by coupling perinuclear mechanical properties to nuclear shape. C1 [Lozoya, Oswaldo A.] NIEHS, Epigenet & Stem Cell Biol Lab, Res Triangle Pk, NC 27709 USA. [Gilchrist, Christopher L.; Guilak, Farshid] Duke Univ, Dept Biomed Engn, Durham, NC 27708 USA. [Guilak, Farshid] Washington Univ, Dept Orthopaed Surg, St Louis, MO 63110 USA. [Guilak, Farshid] Washington Univ, Dept Biomed Engn, St Louis, MO 63110 USA. [Guilak, Farshid] Washington Univ, Dept Dev Biol, St Louis, MO 63110 USA. [Guilak, Farshid] Shriners Hosp Children St Louis, St Louis, MO 63110 USA. RP Guilak, F (reprint author), Washington Univ, Dept Orthopaed Surg, St Louis, MO 63110 USA.; Guilak, F (reprint author), Washington Univ, Dept Biomed Engn, St Louis, MO 63110 USA.; Guilak, F (reprint author), Washington Univ, Dept Dev Biol, St Louis, MO 63110 USA.; Guilak, F (reprint author), Shriners Hosp Children St Louis, St Louis, MO 63110 USA. EM guilak@wustl.edu OI Guilak, Farshid/0000-0001-7380-0330 FU NIH [AR050245, AR048182, AG015768, AG046927, AR065888, GM069331, AI007217] FX We thank Drs. Richard Superfine and E. Timothy O'Brien at the Center for Computer Integrated Systems for Microscopy and Manipulation (CISMM) in the University of North Carolina at Chapel Hill for discussions on experimental designs and access to microrheology equipment. We also thank Peter Lawson and Daniel O'Keefe for their contributions in the implementation of microrheology technologies at Duke University's Orthopaedic Research Laboratories (ORL). Microphotopatterning was performed in the Shared Materials Instrumentation Facility at Duke University. We are also immensely grateful to both Dr. Brenton D. Hoffman at Duke University and Dr. Sharon R. Lubkin at North Carolina State University for discussions on microrheology data analysis, postprocessing, and multivariate techniques, as well as their comments on earlier versions of this manuscript. Funding support for O.A.L. in stipends and training-related expenses were provided by NIH institutional training grants to Duke University (GM069331, AI007217). This research was supported in part by NIH grants to F.G.(AR050245, AR048182, AG015768, AG046927) and C.L.G. (AR065888). NR 64 TC 2 Z9 2 U1 2 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 MAR 15 PY 2016 VL 6 AR 23047 DI 10.1038/srep23047 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG5OB UT WOS:000372126600001 PM 26976044 ER PT J AU Vijay, V Moland, CL Han, T Fuscoe, JC Lee, T Herman, EH Jenkins, GR Lewis, SM Cummings, CA Gao, Y Cao, ZJ Yu, LR Desai, VG AF Vijay, Vikrant Moland, Carrie L. Han, Tao Fuscoe, James C. Lee, Taewon Herman, Eugene H. Jenkins, G. Ronald Lewis, Sherry M. Cummings, Connie A. Gao, Yuan Cao, Zhijun Yu, Li-Rong Desai, Varsha G. TI Early transcriptional changes in cardiac mitochondria during chronic doxorubicin exposure and mitigation by dexrazoxane in mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Doxorubicin; Dexrazoxane; Mitochondria; Biomarkers; Cardiotoxicity ID ANTHRACYCLINE-INDUCED CARDIOTOXICITY; ADRIAMYCIN-INDUCED CARDIOMYOPATHY; ACUTE LYMPHOBLASTIC-LEUKEMIA; INDUCED MYOCARDIAL DAMAGE; FATTY-ACID-METABOLISM; GENE-EXPRESSION; MOUSE MODEL; NADH DEHYDROGENASE; ENERGY-METABOLISM; SKELETAL-MUSCLE AB Identification of early biomarkers of cardiotoxicity could help initiate means to ameliorate the cardiotoxic actions of clinically useful drugs such as doxorubicin (DOX). Since DOX has been shown to target mitochondria, transcriptional levels of mitochondria-related genes were evaluated to identify early candidate biomarkers in hearts of male B6C3F(1) mice given a weekly intravenous dose of 3 mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8 weeks (6, 9, 12, 18, or 24 mg/kg cumulative DOX doses, respectively). Also, a group of mice was pretreated (intraperitoneally) with the cardio-protectant, dexrazoxane (DXZ; 60 mg/kg) 30 min before each weekly dose of DOX or SAL. At necropsy a week after the last dose, increased plasma concentrations of cardiac troponin T (cTnT) were detected at 18 and 24 mg/kg cumulative DOX doses, whereas myocardial alterations were observed only at the 24 mg/kg dose. Of 1019 genes interrogated, 185, 109, 140, 184, and 451 genes were differentially expressed at 6, 9, 12, 18, and 24 mg/kg cumulative DOX doses, respectively, compared to concurrent SAL-treated controls. Of these, expression of 61 genes associated with energy metabolism and apoptosis was significantly altered before and after occurrence of myocardial injury, suggesting these as early genomics markers of cardiotoxicity. Much of these DOX-induced transcriptional changes were attenuated by pretreatment of mice with DXZ. Also, DXZ treatment significantly reduced plasma cTnT concentration and completely ameliorated cardiac alterations induced by 24 mg/kg cumulative DOX. This information on early transcriptional changes during DOX treatment may be useful in designing cardioprotective strategies targeting mitochondria. Published by Elsevier Inc. C1 [Vijay, Vikrant; Moland, Carrie L.; Han, Tao; Fuscoe, James C.; Jenkins, G. Ronald; Desai, Varsha G.] US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Lee, Taewon] Korea Univ, Dept Math, Sejong, South Korea. [Herman, Eugene H.] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Lewis, Sherry M.] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Cummings, Connie A.] UltraPath Imaging, 2228 Page Rd, Durham, NC 27703 USA. [Gao, Yuan; Cao, Zhijun; Yu, Li-Rong] US FDA, Biomarkers & Alternat Models Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Desai, VG (reprint author), US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM varsha.desai@fda.hhs.gov RI Vijay, Vikrant/E-7651-2010 OI Vijay, Vikrant/0000-0001-8425-1285 NR 88 TC 3 Z9 3 U1 2 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAR 15 PY 2016 VL 295 BP 68 EP 84 DI 10.1016/j.taap.2016.02.003 PG 17 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DG3DT UT WOS:000371950400007 PM 26873546 ER PT J AU Wang, HS Coligan, JE Morse, HC AF Wang, Hongsheng Coligan, John E. Morse, Herbert C., III TI Emerging Functions of Natural IgM and Its Fc Receptor FCMR in Immune Homeostasis SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE natural IgM; FCMR; autoimmunity; homeostasis; inflammation ID EPSTEIN-BARR VIRUS; B-CELL REPERTOIRE; MU-R; REPERFUSION INJURY; ALPHA/MU-RECEPTOR; BONE-MARROW; T-CELLS; MONOCLONAL AUTOANTIBODIES; AUTOIMMUNE-DISEASE; ANTIBODY-RESPONSES AB Most natural IgM antibodies are encoded by germline Ig sequences and are produced in large quantities by both mice and humans in the absence of intentional immunization. Natural IgM are reactive with many conserved epitopes, including those shared by microorganisms and autoantigens. As a result, these antibodies play important roles in clearing intruding pathogens, as well as apoptotic/necrotic cells and otherwise damaged tissues. While natural IgM binds to target structures with low affinity due to a lack of significant selection by somatic hypermutation, its pentameric structure with 10 antigen-binding sites enables these antibodies to bind multivalent target antigens with high avidity. Opsonization of antigen complexed with IgM is mediated by cell surface Fc receptors. While the existence of Fc alpha/mu receptor has been known for some time, only recently has the Fc receptor specific for IgM (FCMR) been identified. In this review, we focus on our current understandings of how natural IgM and FCMR regulate the immune system and maintain homeostasis under physiological and pathological conditions. C1 [Wang, Hongsheng; Morse, Herbert C., III] NIAID, Immunogenet Lab, Virol & Cellular Immunol Sect, NIH, Rockville, MD 20852 USA. [Coligan, John E.] NIAID, Immunogenet Lab, Receptor Cell Biol Sect, NIH, Rockville, MD 20852 USA. RP Wang, HS; Morse, HC (reprint author), NIAID, Immunogenet Lab, Virol & Cellular Immunol Sect, NIH, Rockville, MD 20852 USA. EM wanghongs@niaid.nih.gov; hmorse@niaid.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by the Intramural Research Programs of the NIH, National Institute of Allergy and Infectious Diseases (NIAID) (HW, JC, and HM). NR 64 TC 3 Z9 3 U1 3 U2 10 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD MAR 15 PY 2016 VL 7 AR 99 DI 10.3389/fimmu.2016.00099 PG 7 WC Immunology SC Immunology GA DG3KT UT WOS:000371968900001 PM 27014278 ER PT J AU Inskip, PD Sigurdson, AJ Veiga, L Bhatti, P Ronckers, C Rajaraman, P Boukheris, H Stovall, M Smith, S Hammond, S Henderson, TO Watt, TC Mertens, AC Leisenring, W Stratton, K Whitton, J Donaldson, SS Armstrong, GT Robison, LL Neglia, JP AF Inskip, Peter D. Sigurdson, Alice J. Veiga, Lene Bhatti, Parveen Ronckers, Cecile Rajaraman, Preetha Boukheris, Houda Stovall, Marilyn Smith, Susan Hammond, Sue Henderson, Tara O. Watt, Tanya C. Mertens, Ann C. Leisenring, Wendy Stratton, Kayla Whitton, John Donaldson, Sarah S. Armstrong, Gregory T. Robison, Leslie L. Neglia, Joseph P. TI Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID PRIMARY THYROID-CANCER; BREAST-CANCER; IONIZING-RADIATION; 5-YEAR SURVIVORS; NERVOUS-SYSTEM; RISK; CHEMOTHERAPY; TUMORS; RADIOTHERAPY; NEOPLASMS AB Objectives: The majority of childhood cancer patients now achieve long-term survival, but the treatments that cured their malignancy often put them at risk of adverse health outcomes years later. New cancers are among the most serious of these late effects. The aims of this review are to compare and contrast radiation dose-response relationships for new solid cancers in a large cohort of childhood cancer survivors and to discuss interactions among treatment and host factors. Methods: This review is based on previously published site-specific analyses for subsequent primary cancers of the brain, breast, thyroid gland, bone and soft tissue, salivary glands, and skin among 12,268 5-year childhood cancer survivors in the Childhood Cancer Survivor Study. Analyses included tumor site-specific, individual radiation dose reconstruction based on radiation therapy records. Radiation-related second cancer risks were estimated using conditional logistic or Poisson regression models for excess relative risk (ERR). Results: Linear dose-response relationships over a wide range of radiation dose (050 Gy) were seen for all cancer sites except the thyroid gland. The steepest slopes occurred for sarcoma, meningioma, and nonmelanoma skin cancer (ERR/Gy > 1.00), with glioma and cancers of the breast and salivary glands forming a second group (ERR/Gy = 0.27-0.36). The relative risk for thyroid cancer increased up to 15-20 Gy and then decreased with increasing dose. The risk of thyroid cancer also was positively associated with chemotherapy, but the chemotherapy effect was not seen among those who also received very high doses of radiation to the thyroid. The excess risk of radiation-related breast cancer was sharply reduced among women who received 5 Gy or more to the ovaries. Conclusions: The results suggest that the effect of high-dose irradiation is consistent with a linear dose-response for most organs, but they also reveal important organ-specific and host-specific differences in susceptibility and interactions between different aspects of treatment. Published by Elsevier Inc. C1 [Inskip, Peter D.; Sigurdson, Alice J.; Veiga, Lene; Bhatti, Parveen; Ronckers, Cecile; Rajaraman, Preetha; Boukheris, Houda] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Bhatti, Parveen; Leisenring, Wendy; Stratton, Kayla; Whitton, John] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Ronckers, Cecile] Emma Childrens Hosp, Acad Med Ctr, Dept Pediat Oncol, Amsterdam, Netherlands. [Boukheris, Houda] Univ Oran, Sch Med, Oran, Algeria. [Stovall, Marilyn; Smith, Susan] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Hammond, Sue] Childrens Hosp, Dept Lab Med & Pathol, 700 Childrens Dr, Columbus, OH 43205 USA. [Hammond, Sue] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Henderson, Tara O.] Univ Chicago, Dept Pediat, Sect Hematol Oncol & Stem Cell Transplantat, Chicago, IL 60637 USA. [Watt, Tanya C.] Univ Texas SW Med Ctr Dallas, Dept Pediat Oncol, Dallas, TX 75390 USA. [Mertens, Ann C.] Emory Univ, Childrens Healthcare Atlanta, Aflac Canc Ctr, Atlanta, GA 30322 USA. [Mertens, Ann C.] Emory Univ, Childrens Healthcare Atlanta, Blood Disorders Serv, Atlanta, GA 30322 USA. [Donaldson, Sarah S.] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Armstrong, Gregory T.; Robison, Leslie L.] St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, 332 N Lauderdale St, Memphis, TN 38105 USA. [Neglia, Joseph P.] Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55455 USA. RP Inskip, PD (reprint author), 5421 Marlin St, Rockville, MD 20837 USA. EM inskippeter@gmail.com FU Intramural NIH HHS; NCI NIH HHS [CA55727, U24 CA055727] NR 43 TC 4 Z9 4 U1 3 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 BP 800 EP 807 DI 10.1016/j.ijrobp.2015.11.046 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900021 PM 26972653 ER PT J AU Blackstone, C Belmont, LD AF Blackstone, Craig Belmont, Lisa D. TI Cell biology and the "real world" SO MOLECULAR BIOLOGY OF THE CELL LA English DT Editorial Material C1 [Blackstone, Craig] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Belmont, Lisa D.] Genentech Inc, Discovery Oncol, San Francisco, CA 94080 USA. RP Blackstone, C (reprint author), NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA.; Belmont, LD (reprint author), Genentech Inc, Discovery Oncol, San Francisco, CA 94080 USA. EM blackstc@ninds.nih.gov; belmont.lisa@gene.com NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAR 15 PY 2016 VL 27 IS 6 BP 878 EP 879 DI 10.1091/mbc.E15-11-0764 PG 2 WC Cell Biology SC Cell Biology GA DG2HA UT WOS:000371886600004 PM 26976931 ER PT J AU Vecchiarelli, AG Li, M Mizuuchi, M Hwang, LC Seol, Y Neuman, KC Mizuuchi, K AF Vecchiarelli, Anthony G. Li, Min Mizuuchi, Michiyo Hwang, Ling Chin Seol, Yeonee Neuman, Keir C. Mizuuchi, Kiyoshi TI Membrane-bound MinDE complex acts as a toggle switch that drives Min oscillation coupled to cytoplasmic depletion of MinD SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell division; subcellular organization; pattern formation; self-organization; intracellular positioning ID DIVISION REGULATOR MINE; TO-POLE OSCILLATIONS; ESCHERICHIA-COLI; CELL-DIVISION; TOPOLOGICAL REGULATION; PATTERN-FORMATION; PROTEIN-PATTERNS; INHIBITOR MINC; RAPID POLE; IN-VITRO AB The Escherichia coli Min system self-organizes into a cell-pole to cell-pole oscillator on the membrane to prevent divisions at the cell poles. Reconstituting the Min system on a lipid bilayer has contributed to elucidating the oscillatory mechanism. However, previous in vitro patterns were attained with protein densities on the bilayer far in excess of those in vivo and failed to recapitulate the standing wave oscillations observed in vivo. Here we studied Min protein patterning at limiting MinD concentrations reflecting the in vivo conditions. We identified "burst" patterns-radially expanding and imploding binding zones of MinD, accompanied by a peripheral ring of MinE. Bursts share several features with the in vivo dynamics of the Min system including standing wave oscillations. Our data support a patterning mechanism whereby the MinD-to-MinE ratio on the membrane acts as a toggle switch: recruiting and stabilizing MinD on the membrane when the ratio is high and releasing MinD from the membrane when the ratio is low. Coupling this toggle switch behavior with MinD depletion from the cytoplasm drives a self-organized standing wave oscillator. C1 [Vecchiarelli, Anthony G.; Li, Min; Mizuuchi, Michiyo; Hwang, Ling Chin; Mizuuchi, Kiyoshi] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Seol, Yeonee; Neuman, Keir C.] NHLBI, Lab Single Mol Biophys, NIH, Bethesda, MD 20892 USA. [Hwang, Ling Chin] Univ Sheffield, Dept Mol Biol & Biotechnol, Western Bank, Sheffield S10 2TN, S Yorkshire, England. RP Mizuuchi, K (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM kiyoshimi@helix.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institutes of Health; Department of Health and Human Services; Nancy Nossal Fellowship FX This work was supported by the intramural research fund for National Institute of Diabetes and Digestive and Kidney Diseases (K.M.); the National Heart, Lung, and Blood Institute (K.C.N.); National Institutes of Health; Department of Health and Human Services; and the Nancy Nossal Fellowship (A.G.V. and L.C.H.). NR 41 TC 3 Z9 3 U1 2 U2 8 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 MAR 15 PY 2016 VL 113 IS 11 BP E1479 EP E1488 DI 10.1073/pnas.1600644113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG4BF UT WOS:000372014200012 PM 26884160 ER PT J AU Wilson, DJ Orsel, K Waddington, J Rajeev, M Sweeny, AR Joseph, T Grigg, ME Raverty, SA AF Wilson, Devon J. Orsel, Karin Waddington, Josh Rajeev, Malavika Sweeny, Amy R. Joseph, Tomy Grigg, Michael E. Raverty, Stephen A. TI Neospora caninum is the leading cause of bovine fetal loss in British Columbia, Canada SO VETERINARY PARASITOLOGY LA English DT Article DE Neospora caninum; Bovine neosporosis; Abortion; Fetal loss; British Columbia ID DAIRY-CATTLE; DIAGNOSIS; ABORTIONS; INFECTION; HERDS; TRANSMISSION; NETHERLANDS; SEROLOGY; ANIMALS; LESIONS AB The protozoan pathogen Neospora caninum is recognized as a leading cause of infectious abortions in cattle worldwide. To evaluate the impact of neosporosis on dairy and beef herd production, a retrospective, longitudinal study was performed to identify the impact of neosporosis alongside other causes of fetal abortion in British Columbia, Canada. Retrospective analysis of pathology records of bovine fetal submissions submitted to the Animal Health Centre, Abbotsford, British Columbia, a provincial veterinary diagnostic laboratory, from January 2007 to July 2013 identified 182 abortion cases (passive surveillance). From July 2013 to May 2014, an active surveillance program identified a further 54 abortion cases from dairy farmers in the Upper Fraser Valley, British Columbia. Of the total 236 fetal submissions analyzed, N. caninum was diagnosed in 18.2% of cases, making it the most commonly identified infectious agent associated with fetal loss. During active surveillance, N. caninum was associated with 41% of fetuses submitted compared to 13.3% during passive surveillance (p < 0.001). Breed of dam was significantly associated with N. caninum diagnosis, with a higher prevalence in dairy versus beef breeds, and fetuses of 3-6 months gestational age had the highest prevalence of N. caninum. There was no significant association with dam parity. N. caninum was diagnosed in every year except 2009 and cases were geographically widespread throughout the province. Furthermore, the active surveillance program demonstrates that N. caninum is highly prevalent in the Upper Fraser Valley and is a major causal agent of production losses in this dairy intensive region. (C) 2016 Elsevier B.V. All rights reserved. C1 [Wilson, Devon J.] Univ Saskatchewan, Western Coll Vet Med, Saskatoon, SK S7N 5B4, Canada. [Wilson, Devon J.; Joseph, Tomy; Raverty, Stephen A.] BC Minist Agr, Ctr Anim Hlth, 1767 Angus Campbell Rd, Abbotsford, BC V3G 2M3, Canada. [Orsel, Karin] Univ Calgary, Fac Vet Med, Dept Prod Anim Hlth, Calgary, AB T2N 4N1, Canada. [Waddington, Josh] Greenbelt Vet Serv Ltd, 8451 Harvard Pl, Chilliwack, BC V2P 7Z5, Canada. [Rajeev, Malavika; Sweeny, Amy R.; Grigg, Michael E.] NIAID, Mol Parasitol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Raverty, SA (reprint author), BC Minist Agr, Ctr Anim Hlth, 1767 Angus Campbell Rd, Abbotsford, BC V3G 2M3, Canada.; Grigg, ME (reprint author), NIAID, Mol Parasitol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM griggm@niaid.nih.gov; Stephen.Raverty@gov.bc.ca FU Canadian Institute for Advanced Research (CIFAR) program FX The data in this paper were collected with the support of the Agriculture and Agri-food Canada's Growing Forward-2 initiative and the Intramural Research Program of the NIH and NIAID (MEG). MEG is a scholar of the Canadian Institute for Advanced Research (CIFAR) program for Integrated Microbial Diversity. The authors acknowledge the professional and technical staff from the AHC, BC and NIH, MD, along with the veterinarians and staff of Greenbelt Veterinary Services, and the Fraser Valley Dairy producers for their dedicated contributions to the project. NR 30 TC 1 Z9 2 U1 3 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4017 EI 1873-2550 J9 VET PARASITOL JI Vet. Parasitol. PD MAR 15 PY 2016 VL 218 BP 46 EP 51 DI 10.1016/j.vetpar.2016.01.006 PG 6 WC Parasitology; Veterinary Sciences SC Parasitology; Veterinary Sciences GA DF2QF UT WOS:000371188200008 PM 26872927 ER PT J AU Teijido, O Ganesan, YT Llanos, R Peton, A Urtecho, JB Soprani, A Villamayor, A Antonsson, B Manon, S Dejean, L AF Teijido, Oscar Ganesan, Yogesh Tengarai Llanos, Raul Peton, Ashley Urtecho, Jean -Baptiste Soprani, Adauri Villamayor, Aimee Antonsson, Bruno Manon, Stephen Dejean, Laurent TI A sandwich ELISA for the conformation-specific quantification of the activated form of human Bax SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE ELISA; Bax Conformation specificity; Apoptosis; Mitochondria ID APOPTOSIS-INDUCED CHANNEL; BCL-2 FAMILY PROTEINS; MITOCHONDRIAL APOPTOSIS; CYTOCHROME-C; MEMBRANE PERMEABILIZATION; CELL-DEATH; MAC; EXPRESSION; MEMBERS AB Bcl-2 family proteins are critical regulators of mitochondrial outer membrane permeabilization (MOMP), which represents the point of no return of apoptotic cell death. The exposure of the Bax N-terminus at the mitochondria reflects Bax activation; and this activated configuration of the Bax protein is associated with MOMP. N-terminal exposure can be detected using specific monoclonal and/or polyclonal antibodies, and the onset of activated Bax has extensively been used as an early marker of apoptosis. The protocols of immunoprecipitation and/or immunocytochemistry commonly used to detect activated Bax are long and tedious, and allow semiquantification of the antigen at best. The sandwich ELISA protocol we developed has a 5 ng/mL detection limit and is highly specific for the activated conformation of Bax. This ELISA allows a rapid quantification of activated human Bax in whole cells and isolated mitochondria protein extracts. These properties grant this assay the potential to further clarify the prognostic and diagnostic value of activated Bax in disorders associated with deregulated apoptotic pathways such as degenerative diseases or cancer. (C) 2016 Elsevier Inc. All rights reserved. C1 [Teijido, Oscar] Eunice Kennedy Shriver Natl Inst Child Care & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Ganesan, Yogesh Tengarai] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Llanos, Raul; Peton, Ashley; Urtecho, Jean -Baptiste; Dejean, Laurent] Calif State Univ Fresno, Dept Chem, Fresno, CA 93740 USA. [Soprani, Adauri; Villamayor, Aimee] NYU, Dept Basic Sci, Coll Dent, New York, NY 10010 USA. [Antonsson, Bruno] Merck Serono SA, Geneva Res Ctr, Geneva, Switzerland. [Manon, Stephen] Univ Bordeaux, CNRS, UMR5095, 1 Rue Camille St Saens, F-33077 Bordeaux, France. RP Dejean, L (reprint author), Calif State Univ Fresno, Dept Chem, Fresno, CA 93740 USA. EM ldejean@csufresno.edu RI Manon, Stephen/C-7088-2017 FU NYU Research Challenge Funds; CSU Fresno startup funds FX We are grateful to Kathleen Kinnally, Pablo Peixoto, and Shin Young Ryu (NYU CD) for helpful discussions. This study has been supported by NYU Research Challenge Funds and CSU Fresno startup funds to LD. NR 26 TC 1 Z9 1 U1 3 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAR 15 PY 2016 VL 497 BP 90 EP 94 DI 10.1016/j.ab.2015.12.016 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DE8TP UT WOS:000370909900014 PM 26748144 ER PT J AU Armstrong, MM Freedman, CJ Jung, JE Zheng, Y Kalyanaraman, C Jacobson, MP Simeonov, A Maloney, DJ van Leyen, K Jadhav, A Holman, TR AF Armstrong, Michelle M. Freedman, Cody J. Jung, Joo Eun Zheng, Yi Kalyanaraman, Chakrapani Jacobson, Matthew P. Simeonov, Anton Maloney, David J. van Leyen, Klaus Jadhav, Ajit Holman, Theodore R. TI A potent and selective inhibitor targeting human and murine 12/15-LOX SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Inhibitor; Selective; High-throughput; Lipoxygenase; Human; Murine ID 15-LIPOXYGENASE INHIBITORS; 5-LIPOXYGENASE INHIBITORS; LIPOXYGENASE; STROKE; 12/15-LIPOXYGENASE; DERIVATIVES; PATHWAYS AB Human reticulocyte 12/15-lipoxygenase (h12/15-LOX) is a lipid-oxidizing enzyme that can directly oxidize lipid membranes in the absence of a phospholipase, leading to a direct attack on organelles, such as the mitochondria. This cytotoxic activity of h12/15-LOX is up-regulated in neurons and endothelial cells after a stroke and thought to contribute to both neuronal cell death and blood-brain barrier leakage. The discovery of inhibitors that selectively target recombinant h12/15-LOX in vitro, as well as possessing activity against the murine ortholog ex vivo, could potentially support a novel therapeutic strategy for the treatment of stroke. Herein, we report a new family of inhibitors discovered in a High Throughput Screen ( HTS) that are selective and potent against recombinant h12/15-LOX and cellular mouse 12/15-LOX ( m12/15-LOX). MLS000099089 ( compound 99089), the parent molecule, exhibits an IC50 potency of 3.4 +/- 0.5 mu M against h12/15-LOX in vitro and an ex vivo IC50 potency of approximately 10 mu M in a mouse neuronal cell line, HT-22. Compound 99089 displays greater than 30-fold selectivity versus h5-LOX and COX-2, 15-fold versus h15-LOX-2 and 10-fold versus h12-LOX, when tested at 20 mu M inhibitor concentration. Steady-state inhibition kinetics reveals that the mode of inhibition of 99089 against h12/15-LOX is that of a mixed inhibitor with a K-ic of 1.0 +/- 0.08 lM and a K-iu of 6.0 +/- 3.3 mu M. These data indicate that 99089 and related derivatives may serve as a starting point for the development of anti-stroke therapeutics due to their ability to selectively target h12/15-LOX in vitro and m12/15-LOX ex vivo. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Armstrong, Michelle M.; Freedman, Cody J.; Holman, Theodore R.] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95060 USA. [Jung, Joo Eun; Zheng, Yi; van Leyen, Klaus] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroprotect Res Lab,Dept Radiol, Charlestown, MA 02129 USA. [Kalyanaraman, Chakrapani; Jacobson, Matthew P.] Univ Calif San Francisco, Sch Pharm, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. [Simeonov, Anton; Maloney, David J.; Jadhav, Ajit] Natl Inst Hlth, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. RP Holman, TR (reprint author), Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95060 USA. EM holman@ucsc.edu FU NIH - United States [NS081180] FX This work was supported by the NIH - United States NS081180. NR 33 TC 1 Z9 1 U1 3 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAR 15 PY 2016 VL 24 IS 6 BP 1183 EP 1190 DI 10.1016/j.bmc.2016.01.042 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DE7MZ UT WOS:000370822700003 PM 26899595 ER PT J AU Ann, J Ki, Y Yoon, S Kim, MS Lee, JU Kim, C Lee, S Jung, A Baek, J Hong, S Choi, S Pearce, LV Esch, TE Turcios, NA Lewin, NE Ogunjirin, AE Herold, BKA McCall, AK Blumberg, PM Lee, J AF Ann, Jihyae Ki, Yooran Yoon, Suyoung Kim, Myeong Seop Lee, Jung-Un Kim, Changhoon Lee, Sunho Jung, Aeran Baek, Jisoo Hong, Sunhye Choi, Sun Pearce, Larry V. Esch, Timothy E. Turcios, Noe A. Lewin, Nancy E. Ogunjirin, Adebowale E. Herold, Brienna K. A. McCall, Anna K. Blumberg, Peter M. Lee, Jeewoo TI 2-Sulfonamidopyridine C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Vanilloid receptor 1; TRPV1 antagonists; Analgesic ID VANILLOID CAPSAICIN RECEPTORS; ANALGESIC AGENTS; AGONIST ACTIVITY; FORMALIN TEST; 2-(3-FLUORO-4-METHYLSULFONYLAMINOPHENYL)PROPANAMIDES; ACTIVATION; MECHANISMS; DOCKING AB A series of 2-sulfonamidopyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide were investigated as hTRPV1 ligands. Systematic modification on the 2-sulfonamido group provided highly potent TRPV1 antagonists. The N-benzyl phenylsulfonamide derivatives 12 and 23 in particular showed higher affinities than that of lead compound 1. Compound 12 exhibited strong analgesic activity in the formalin pain model. Docking analysis of its chiral S-form 12S in our hTRPV1 homology model indicated that its high affinity might arise from additional hydrophobic interactions not present in lead compound 1S. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Ann, Jihyae; Ki, Yooran; Yoon, Suyoung; Kim, Myeong Seop; Lee, Jung-Un; Kim, Changhoon; Lee, Sunho; Jung, Aeran; Baek, Jisoo; Lee, Jeewoo] Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea. [Hong, Sunhye; Choi, Sun] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Coll Pharm, Natl Leading Res Lab Mol Modeling & Drug Design, Seoul 120750, South Korea. [Pearce, Larry V.; Esch, Timothy E.; Turcios, Noe A.; Lewin, Nancy E.; Ogunjirin, Adebowale E.; Herold, Brienna K. A.; McCall, Anna K.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU Korea Science and Engineering Foundation (KOSEF) [NRF-2007-0056817]; National Leading Research Lab (NLRL) program in South Korea [2011-0028885]; Intramural Research Program of the NIH, Center for Cancer Research, NCI in the USA [Z1A BC 005270] FX This research was supported by research grants from the Korea Science and Engineering Foundation (KOSEF) (NRF-2007-0056817) and the National Leading Research Lab (NLRL) program (2011-0028885) in South Korea, and in part by the Intramural Research Program of the NIH, Center for Cancer Research, NCI (Project Z1A BC 005270) in the USA. NR 34 TC 0 Z9 0 U1 2 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAR 15 PY 2016 VL 24 IS 6 BP 1231 EP 1240 DI 10.1016/j.bmc.2016.01.051 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DE7MZ UT WOS:000370822700009 PM 26860926 ER PT J AU Allard, JS Perez, EJ Fukui, K Carpenter, P Ingram, DK de Cabo, R AF Allard, Joanne S. Perez, Evelyn J. Fukui, Koji Carpenter, Priscilla Ingram, Donald K. de Cabo, Rafael TI Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Metformin; BDNF; Water maze; Nrf2; NGF; Neurotrophin 3 ID ACTIVATED PROTEIN-KINASE; DEPENDENT DIABETIC-PATIENTS; FATTY-ACID OXIDATION; ALZHEIMERS-DISEASE; INSULIN SENSITIVITY; CEREBRAL-ISCHEMIA; ANTIDIABETIC DRUG; SKELETAL-MUSCLE; POTENTIAL ROLE; MOUSE MODEL AB Long-term use of anti-diabetic agents has become commonplace as rates of obesity, metabolic syndrome and diabetes continue to escalate. Metformin, a commonly used anti-diabetic drug, has been shown to have many beneficial effects outside of its therapeutic regulation of glucose metabolism and insulin sensitivity. Studies on metformin's effects on the central nervous system are limited and predominantly consist of in vitro studies and a few in vivo studies with short-term treatment in relatively young animals; some provide support for metformin as a neuroprotective agent while others show evidence that metformin may be deleterious to neuronal survival. In this study, we examined the effect of long-term metformin treatment on brain neurotrophins and cognition in aged male C57Bl/6 mice. Mice were fed control (C), high-fat (HF) or a high-fat diet supplemented with metformin (HFM) for 6 months. Metformin decreased body fat composition and attenuated declines in motor function induced by a HF diet. Performance in the Morris water maze test of hippocampal based memory function, showed that metformin prevented impairment of spatial reference memory associated with the HF diet. Quantitative RT-PCR on brain homogenates revealed decreased transcription of BDNF, NGF and NTF3; however protein levels were not altered. Metformin treatment also decreased expression of the antioxidant pathway regulator, Nrf2. The decrease in transcription of neurotrophic factors and Nrf2 with chronic metformin intake, cautions of the possibility that extended metformin use may alter brain biochemistry in a manner that creates a vulnerable brain environment and warrants further investigation. (C) 2015 Elsevier B.V. All rights reserved. C1 [Allard, Joanne S.; Carpenter, Priscilla] Howard Univ, Coll Med, Dept Physiol & Biophys, 520 W St NW, Washington, DC 20059 USA. [Perez, Evelyn J.] NIA, Neurocognit Aging Sect, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Fukui, Koji] Shibaura Inst Technol, Physiol Chem Lab, Dept Biosci & Engn, Minuma Ku, Fukasaku 307, Saitama 3378570, Japan. [Allard, Joanne S.; Fukui, Koji; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Ingram, Donald K.] Louisiana State Univ Syst, Nutr Neurosci & Aging Lab, Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. RP Allard, JS (reprint author), Howard Univ, Coll Med, Dept Physiol & Biophys, Room 2408B,520 W St NW, Washington, DC 20059 USA.; de Cabo, R (reprint author), NIA, Expt Gerontol Sect, TGB, NIH, 251 Bayview Blvd Suite 100 Room 9C218, Baltimore, MD 21224 USA. EM joanne.allard@howard.edu; decabora@grc.nia.nih.gov RI de Cabo, Rafael/J-5230-2016 OI de Cabo, Rafael/0000-0002-3354-2442 FU Intramural Research Program of the National Institute on Aging (NIA), National Institutes of Health [1R25AG047843-01] FX We are grateful to Dawn Nines, Dawn Phillips-Boyer and Justine Lucas for their exemplary animal care service. We thank Federico Butelman from Farmhispania S.A., a FDA-approved cGMP company, for providing the metformin used in this study. This research was supported by the Intramural Research Program of the National Institute on Aging (NIA), National Institutes of Health and also by NIA extramural Grant# 1R25AG047843-01. NR 64 TC 6 Z9 8 U1 2 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 15 PY 2016 VL 301 BP 1 EP 9 DI 10.1016/j.bbr.2015.12.012 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DD7MM UT WOS:000370108600001 PM 26698400 ER PT J AU Zhou, CK Check, DP Lortet-Tieulent, J Laversanne, M Jemal, A Ferlay, J Bray, F Cook, MB Devesa, SS AF Zhou, Cindy Ke Check, David P. Lortet-Tieulent, Joannie Laversanne, Mathieu Jemal, Ahmedin Ferlay, Jacques Bray, Freddie Cook, Michael B. Devesa, Susan S. TI Prostate cancer incidence in 43 populations worldwide: An analysis of time trends overall and by age group SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE prostatic neoplasms; incidence; age-specific; trends; international ID UNITED-STATES; INTERPRETING TRENDS; SOCIETY GUIDELINES; GENERAL-PRACTICE; MEN; MORTALITY; RATES; DIAGNOSIS; COUNTRIES; PATTERNS AB Prostate cancer is a significant public health burden and a major cause of morbidity and mortality among men worldwide. Analyzing geographic patterns and temporal trends may help identify high-risk populations, suggest the degree of PSA testing, and provide clues to etiology. We used incidence data available from the International Agency for Research on Cancer (IARC) and certain cancer registries for 43 populations across five continents during a median period of 24 years. Trends in overall prostate cancer rates showed five distinct patterns ranging from generally monotonic increases to peaking of rates followed by declines, which coincide somewhat with changes in the prevalence of PSA testing. Trends in age-specific rates generally mirrored those in the overall rates, with several notable exceptions. For populations where overall rates increased rapidly and then peaked, exemplified in North America and Oceania, the highest incidence tended to be most pronounced and occurred during earlier calendar years among older men compared with younger ones. For populations with almost continual increases in overall rates, exemplified in Eastern Europe and Asia, peaks were evident among men aged >= 75 years in many instances. Rates for ages 45-54 years did not clearly stabilize or decline in the majority of studied populations. Global geographic variation remained substantial for both overall and age-specific incidence rates regardless of levels of PSA testing, with the lowest rates consistently in Asia. Explanations for the persistent geographic differences and the continuing increases of especially early-onset prostate cancer remain unclear. C1 [Zhou, Cindy Ke; Check, David P.; Cook, Michael B.; Devesa, Susan S.] NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Rm 7-E210,MSC 9774, Bethesda, MD 20892 USA. [Lortet-Tieulent, Joannie; Jemal, Ahmedin] Amer Canc Soc, Surveillance & Hlth Serv Res, Intramural Res Dept, Atlanta, GA 30329 USA. [Laversanne, Mathieu; Ferlay, Jacques; Bray, Freddie] Int Agcy Res Canc, Sect Canc Surveillance, 150 Cours Albert Thomas, F-69372 Lyon, France. RP Zhou, CK (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Rm 7-E210,MSC 9774, Bethesda, MD 20892 USA.; Zhou, CK (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 7-E210,MSC 9774, Bethesda, MD 20892 USA. EM ke.zhou@nih.gov RI Cook, Michael/A-5641-2009; Zhou, Cindy /H-2165-2015 OI Cook, Michael/0000-0002-0533-7302; Zhou, Cindy /0000-0003-4814-4305 FU Intramural Program of Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX Grant sponsors: Intramural Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health NR 50 TC 16 Z9 18 U1 7 U2 17 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 MAR 15 PY 2016 VL 138 IS 6 BP 1388 EP 1400 DI 10.1002/ijc.29894 PG 13 WC Oncology SC Oncology GA DD7CI UT WOS:000370080900009 PM 26488767 ER PT J AU Bacak, BJ Kim, T Smith, JC Rubin, JE Rybak, IA AF Bacak, Bartholomew J. Kim, Taegyo Smith, Jeffrey C. Rubin, Jonathan E. Rybak, Ilya A. TI Mixed-mode oscillations and population bursting in the pre-Botzinger complex SO ELIFE LA English DT Article ID RESPIRATORY RHYTHM GENERATION; LOCOMOTOR PATTERN GENERATION; DEPENDENT POTASSIUM CHANNELS; NONSPECIFIC CATION CURRENT; MAMMALIAN BRAIN-STEM; PREBOTZINGER COMPLEX; PACEMAKER NEURONS; NEURAL-NETWORK; NEONATAL MICE; IN-VITRO AB This study focuses on computational and theoretical investigations of neuronal activity arising in the pre-Botzinger complex (pre-BetC), a medullary region generating the inspiratory phase of breathing in mammals. A progressive increase of neuronal excitability in medullary slices containing the pre-BotC produces mixed-mode oscillations (MMOs) characterized by large amplitude population bursts alternating with a series of small amplitude bursts. Using two different computational models, we demonstrate that MMOs emerge within a heterogeneous excitatory neural network because of progressive neuronal recruitment and synchronization. The MMO pattern depends on the distributed neuronal excitability, the density and weights of network interconnections, and the cellular properties underlying endogenous bursting. Critically, the latter should provide a reduction of spiking frequency within neuronal bursts with increasing burst frequency and a dependence of the after-burst recovery period on burst amplitude. Our study highlights a novel mechanism by which heterogeneity naturally leads to complex dynamics in rhythmic neuronal populations. C1 [Bacak, Bartholomew J.; Kim, Taegyo; Rybak, Ilya A.] Drexel Univ, Dept Neurobiol & Anat, Coll Med, Philadelphia, PA 19104 USA. [Smith, Jeffrey C.] NINDS, Cellular & Syst Neurobiol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Rubin, Jonathan E.] Univ Pittsburgh, Dept Math, Pittsburgh, PA USA. RP Bacak, BJ (reprint author), Drexel Univ, Dept Neurobiol & Anat, Coll Med, Philadelphia, PA 19104 USA. EM BartBacak@gmail.com OI Bacak, Bartholomew/0000-0003-0727-3928; Rubin, Jonathan/0000-0002-1513-1551; Rybak, Ilya/0000-0003-3461-349X FU National Institute of Neurological Disorders and Stroke [NS069220]; National Science Foundation [DMS-1312508] FX National Institute of Neurological Disorders and Stroke NS069220 Bartholomew J Bacak Taegyo Kim Jeffrey C Smith Ilya A Rybak; National Science Foundation DMS-1312508 Jonathan E Rubin; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 61 TC 0 Z9 0 U1 4 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 14 PY 2016 VL 5 AR e13403 DI 10.7554/eLife.13403 PG 26 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EB5WR UT WOS:000387451900001 PM 26974345 ER PT J AU Theis, D Ivanic, J Windus, TL Ruedenberg, K AF Theis, Daniel Ivanic, Joseph Windus, Theresa L. Ruedenberg, Klaus TI The transition from the open minimum to the ring minimum on the ground state and on the lowest excited state of like symmetry in ozone: A configuration interaction study SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID CORRELATION-ENERGY EXTRAPOLATION; LYING ELECTRONIC STATES; CONSISTENT-FIELD METHOD; MULTIPLE ACTIVE SPACES; DISSOCIATION THRESHOLD; VARIABLE OCCUPATIONS; CONICAL INTERSECTION; THEORETICAL EVIDENCE; MOLECULAR-DYNAMICS; ATMOSPHERIC OZONE AB The metastable ring structure of the ozone 1(1)A(1) ground state, which theoretical calculations have shown to exist, has so far eluded experimental detection. An accurate prediction for the energy difference between this isomer and the lower open structure is therefore of interest, as is a prediction for the isomerization barrier between them, which results from interactions between the lowest two (1)A(1) states. In the present work, valence correlated energies of the 1(1)A(1) state and the 2(1)A(1) state were calculated at the 1(1)A(1) open minimum, the 1(1)A(1) ring minimum, the transition state between these two minima, the minimum of the 2(1)A(1) state, and the conical intersection between the two states. The geometries were determined at the full-valence multi-configuration self-consistent-field level. Configuration interaction (CI) expansions up to quadruple excitations were calculated with triple-zeta atomic basis sets. The CI expansions based on eight different reference configuration spaces were explored. To obtain some of the quadruple excitation energies, the method of Correlation Energy Extrapolation by Intrinsic Scaling was generalized to the simultaneous extrapolation for two states. This extrapolation method was shown to be very accurate. On the other hand, none of the CI expansions were found to have converged to millihartree (mh) accuracy at the quadruple excitation level. The data suggest that convergence to mh accuracy is probably attained at the sextuple excitation level. On the 1(1)A(1) state, the present calculations yield the estimates of (ring minimum-open minimum) similar to 45-50 mh and (transition state-open minimum) similar to 85-90 mh. For the (2(1)A(1)-(1)A(1)) excitation energy, the estimate of similar to 130-170 mh is found at the open minimum and 270-310 mh at the ring minimum. At the transition state, the difference (2(1)A(1)-(1)A(1)) is found to be between 1 and 10 mh. The geometry of the transition state on the 1(1)A(1) surface and that of the minimum on the 2(1)A(1) surface nearly coincide. More accurate predictions of the energy differences also require CI expansions to at least sextuple excitations with respect to the valence space. For every wave function considered, the omission of the correlations of the 2s oxygen orbitals, which is a widely used approximation, was found to cause errors of about +/-10 mh with respect to the energy differences. (C) 2016 AIP Publishing LLC. C1 [Theis, Daniel; Windus, Theresa L.; Ruedenberg, Klaus] Iowa State Univ, Dept Chem, Ames, IA 50011 USA. [Theis, Daniel; Windus, Theresa L.; Ruedenberg, Klaus] Iowa State Univ, Ames Lab USDOE, Ames, IA 50011 USA. [Ivanic, Joseph] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, DSITP, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Theis, D (reprint author), Iowa State Univ, Dept Chem, Ames, IA 50011 USA.; Theis, D (reprint author), Iowa State Univ, Ames Lab USDOE, Ames, IA 50011 USA. FU US Department of Energy, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences & Biosciences through Ames Laboratory at Iowa State University [DE-AC02-07CH11358]; National Cancer Institute, National Institutes of Health [HHSN 261200800001E] FX This work was supported by the US Department of Energy, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences & Biosciences through the Ames Laboratory at Iowa State University under Contract No. DE-AC02-07CH11358. In part (for J.I.), the work was also supported with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN 261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services. NR 78 TC 2 Z9 2 U1 4 U2 15 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD MAR 14 PY 2016 VL 144 IS 10 AR 104304 DI 10.1063/1.4942019 PG 18 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DH7LE UT WOS:000372974600018 PM 26979690 ER PT J AU Motzek, A Knezevic, J Switzeny, OJ Cooper, A Baric, I Beluzic, R Strauss, KA Puffenberger, EG Mudd, SH Vugrek, O Zechner, U AF Motzek, Antje Knezevic, Jelena Switzeny, Olivier J. Cooper, Alexis Baric, Ivo Beluzic, Robert Strauss, Kevin A. Puffenberger, Erik G. Mudd, S. Harvey Vugrek, Oliver Zechner, Ulrich TI Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency SO PLOS ONE LA English DT Article ID HUTCHINSON-GILFORD PROGERIA; DNA METHYLTRANSFERASE GENE; CYCLIN-A GENE; IMMUNODEFICIENCY SYNDROME; L-HOMOCYSTEINE; GERM-LINE; METHYLATION; HYPOMETHYLATION; HYPERHOMOCYSTEINEMIA; MICE AB S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal recessive disorder in methionine metabolism caused by mutations in the AHCY gene. Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, mostly associated with hypermethioninaemia, elevated serum creatine kinase levels and increased genome wide DNA methylation. The prime function of AHCY is to hydrolyse and efficiently remove S-adenosylhomocysteine, the by-product of transmethylation reactions and one of the most potent methyltransferase inhibitors. In this study, we set out to more specifically characterize DNA methylation changes in blood samples from patients with AHCY deficiency. Global DNA methylation was increased in two of three analysed patients. In addition, we analysed the DNA methylation levels at differentially methylated regions (DMRs) of six imprinted genes (MEST, SNRPN, LIT1, H19, GTL2 and PEG3) as well as Alu and LINE1 repetitive elements in seven patients. Three patients showed a hypermethylation in up to five imprinted gene DMRs. Abnormal methylation in Alu and LINE1 repetitive elements was not observed. We conclude that DNA hypermethylation seems to be a frequent but not a constant feature associated with AHCY deficiency that affects different genomic regions to different degrees. Thus AHCY deficiency may represent an ideal model disease for studying the molecular origins and biological consequences of DNA hypermethylation due to impaired cellular methylation status. C1 [Motzek, Antje; Cooper, Alexis; Zechner, Ulrich] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Human Genet, D-55122 Mainz, Germany. [Knezevic, Jelena; Beluzic, Robert; Vugrek, Oliver] Rudjer Boskovic Inst, Div Mol Med, Zagreb, Croatia. [Switzeny, Olivier J.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Toxicol, D-55122 Mainz, Germany. [Baric, Ivo] Univ Hosp Ctr Zagreb, Dept Pediat, Zagreb, Croatia. [Baric, Ivo] Univ Zagreb, Sch Med, Zagreb 41001, Croatia. [Strauss, Kevin A.; Puffenberger, Erik G.] Clin Special Children, Strasburg, PA USA. [Strauss, Kevin A.; Puffenberger, Erik G.] Franklin & Marshall Coll, Lancaster, PA 17604 USA. [Mudd, S. Harvey] NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Zechner, U (reprint author), Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Human Genet, D-55122 Mainz, Germany.; Vugrek, O (reprint author), Rudjer Boskovic Inst, Div Mol Med, Zagreb, Croatia. EM ovugrek@irb.hr; ulrich.zechner@unimedizin-mainz.de FU European Union [316289 - InnoMol, FP7-REGPOT-2012-2013-1]; German Academic Exchange Service; Ministry of Science, Education and Sport of the Republic of Croatia [54392779] FX Our work was supported by funds received from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement No 316289 - InnoMol, FP7-REGPOT-2012-2013-1, as well as from the German Academic Exchange Service and the Ministry of Science, Education and Sport of the Republic of Croatia (project reference number 54392779). NR 59 TC 0 Z9 0 U1 4 U2 7 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 MAR 14 PY 2016 VL 11 IS 3 AR e0151261 DI 10.1371/journal.pone.0151261 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH1UO UT WOS:000372570600060 PM 26974671 ER PT J AU Tong, YX Chen, Q Nichols, TE Rasetti, R Callicott, JH Berman, KF Weinberger, DR Mattay, VS AF Tong, Yunxia Chen, Qiang Nichols, Thomas E. Rasetti, Roberta Callicott, Joseph H. Berman, Karen F. Weinberger, Daniel R. Mattay, Venkata S. TI Seeking Optimal Region-Of-Interest (ROI) Single-Value Summary Measures for fMRI Studies in Imaging Genetics SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; DORSOLATERAL PREFRONTAL CORTEX; ALZHEIMERS-DISEASE; QUANTITATIVE TRAIT; BRAIN; SCHIZOPHRENIA; ACTIVATION; DYSFUNCTION; PHENOTYPES; SEARCH AB A data-driven hypothesis-free genome-wide association (GWA) approach in imaging genetics studies allows screening the entire genome to discover novel genes that modulate brain structure, chemistry, and function. However, a whole brain voxel-wise analysis approach in such genome-wide based imaging genetic studies can be computationally intense and also likely has low statistical power since a stringent multiple comparisons correction is needed for searching over the entire genome and brain. In imaging genetics with functional magnetic resonance imaging (fMRI) phenotypes, since many experimental paradigms activate focal regions that can be pre-specified based on a priori knowledge, reducing the voxel-wise search to single-value summary measures within a priori ROIs could prove efficient and promising. The goal of this investigation is to evaluate the sensitivity and reliability of different single-value ROI summary measures and provide guidance in future work. Four different fMRI databases were tested and comparisons across different groups (patients with schizophrenia, their siblings, vs. normal control subjects; across genotype groups) were conducted. Our results show that four of these measures, particularly those that represent values from the top most-activated voxels within an ROI are more powerful at reliably detecting group differences and generating greater effect sizes than the others. C1 [Tong, Yunxia; Callicott, Joseph H.; Berman, Karen F.] NIMH, Clin & Translat Neurosci Branch, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Chen, Qiang; Weinberger, Daniel R.; Mattay, Venkata S.] Lieber Inst Brain Dev, Johns Hopkins Med Campus, Baltimore, MD USA. [Nichols, Thomas E.] Univ Warwick, Dept Stat, Warwick, England. [Rasetti, Roberta] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weinberger, Daniel R.; Mattay, Venkata S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Mattay, Venkata S.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. RP Tong, YX (reprint author), NIMH, Clin & Translat Neurosci Branch, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. EM yunxia@mail.nih.gov FU National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America [NCT: 00001486, 95-M-0150]; National Institute of Mental Health, NIH, Bethesda, MD, USA [NCT: 00001486, 95-M-0150] FX This research was supported by the Intramural Research Program (NCT: 00001486; Protocol ID: 95-M-0150) of the National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, United States of America.; This research was supported by the Intramural Research Program (NCT: 00001486; Protocol ID: 95-M-0150) of the National Institute of Mental Health, NIH, Bethesda, MD 20892, USA. NR 38 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 14 PY 2016 VL 11 IS 3 AR e0151391 DI 10.1371/journal.pone.0151391 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH1UO UT WOS:000372570600074 PM 26974435 ER PT J AU Zhang, TH Casanova, R Resnick, SM Manson, JE Baker, LD Padual, CB Kuller, LH Bryan, RN Espeland, MA Davatzikos, C AF Zhang, Tianhao Casanova, Ramon Resnick, Susan M. Manson, Joann E. Baker, Laura D. Padual, Claudia B. Kuller, Lewis H. Bryan, R. Nick Espeland, Mark A. Davatzikos, Christos TI Effects of Hormone Therapy on Brain Volumes Changes of Postmenopausal Women Revealed by Optimally-Discriminative Voxel-Based Morphometry SO PLOS ONE LA English DT Article ID ANTERIOR CINGULATE CORTEX; HEALTH INITIATIVE MEMORY; SUBCLINICAL CEREBROVASCULAR-DISEASE; CONJUGATED EQUINE ESTROGENS; MILD COGNITIVE IMPAIRMENT; WHIMS-MRI; MAGNETIC-RESONANCE; FRONTOTEMPORAL DEMENTIA; ALZHEIMERS-DISEASE; PREFRONTAL CORTEX AB Backgrounds The Women's Health Initiative Memory Study Magnetic Resonance Imaging (WHIMS-MRI) provides an opportunity to evaluate how menopausal hormone therapy (HT) affects the structure of older women's brains. Our earlier work based on region of interest (ROI) analysis demonstrated potential structural changes underlying adverse effects of HT on cognition. However, the ROI-based analysis is limited in statistical power and precision, and cannot provide fine-grained mapping of whole-brain changes. Methods We aimed to identify local structural differences between HT and placebo groups from WHIMS-MRI in a whole-brain refined level, by using a novel method, named Optimally-Discriminative Voxel-Based Analysis (ODVBA). ODVBA is a recently proposed imaging pattern analysis approach for group comparisons utilizing a spatially adaptive analysis scheme to accurately locate areas of group differences, thereby providing superior sensitivity and specificity to detect the structural brain changes over conventional methods. Results Women assigned to HT treatments had significant Gray Matter (GM) losses compared to the placebo groups in the anterior cingulate and the adjacent medial frontal gyrus, and the orbitofrontal cortex, which persisted after multiple comparison corrections. There were no regions where HT was significantly associated with larger volumes compared to placebo, although a trend of marginal significance was found in the posterior cingulate cortical area. The CEE-Alone and CEE+MPA groups, although compared with different placebo controls, demonstrated similar effects according to the spatial patterns of structural changes. Conclusions HT had adverse effects on GM volumes and risk for cognitive impairment and dementia in older women. These findings advanced our understanding of the neurobiological underpinnings of HT effects. C1 [Zhang, Tianhao; Bryan, R. Nick; Davatzikos, Christos] Univ Penn, Dept Radiol, Ctr Biomed Image Comp & Analyt, Philadelphia, PA 19104 USA. [Casanova, Ramon; Espeland, Mark A.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Manson, Joann E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Manson, Joann E.] Harvard Univ, Sch Med, Boston, MA USA. [Manson, Joann E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Baker, Laura D.] Wake Forest Sch Med, Dept Internal Med & Epidemiol, Winston Salem, NC USA. [Padual, Claudia B.] VA Palo Alto Hlth Care Syst, Sierra Pacific Mental Illness Res Educ & Clin Ctr, Palo Alto, CA USA. [Padual, Claudia B.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Kuller, Lewis H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. RP Zhang, TH (reprint author), Univ Penn, Dept Radiol, Ctr Biomed Image Comp & Analyt, Philadelphia, PA 19104 USA. EM tianhao.zhang@uphs.upenn.edu FU National Heart, Lung, and Blood Institute; National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; NIH [R01AG14971] FX The WHI program is funded by the National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov/), National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. TZ and CD were supported by NIH grant R01AG14971. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 4 Z9 4 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 14 PY 2016 VL 11 IS 3 AR e0150834 DI 10.1371/journal.pone.0150834 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH1UO UT WOS:000372570600034 PM 26974440 ER PT J AU Pei, YX Liu, KW Wang, J Garancher, A Tao, R Esparza, LA Maier, DL Udaka, YT Murad, N Morrissy, S Seker-Cin, H Brabetz, S Qi, L Kogiso, M Schubert, S Olson, JM Cho, YJ Li, XN Crawford, JR Levy, ML Kool, M Pfister, SM Taylor, MD Wechsler-Reya, RJ AF Pei, Yanxin Liu, Kun-Wei Wang, Jun Garancher, Alexandra Tao, Ran Esparza, Lourdes A. Maier, Donna L. Udaka, Yoko T. Murad, Najiba Morrissy, Sorana Seker-Cin, Huriye Brabetz, Sebastian Qi, Lin Kogiso, Mari Schubert, Simone Olson, James M. Cho, Yoon-Jae Li, Xiao-Nan Crawford, John R. Levy, Michael L. Kool, Marcel Pfister, Stefan M. Taylor, Michael D. Wechsler-Reya, Robert J. TI HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma SO CANCER CELL LA English DT Article ID GENE-EXPRESSION; PHASE-I; DOSE-ESCALATION; MOUSE MODELS; SOLID TUMORS; CHILDREN; FOXO; COMBINATION; VORINOSTAT; LYMPHOMA AB Medulloblastoma (MB) is a highly malignant pediatric brain tumor. Despite aggressive therapy, many patients succumb to the disease, and survivors experience severe side effects from treatment. MYC-driven MB has a particularly poor prognosis and would greatly benefit from more effective therapies. We used an animal model of MYC-driven MB to screen for drugs that decrease viability of tumor cells. Among the most effective compounds were histone deacetylase inhibitors (HDACIs). HDACIs potently inhibit survival of MYC-driven MB cells in vitro, in part by inducing expression of the FOXO1 tumor suppressor gene. HDACIs also synergize with phosphatidylinositol 3-kinase inhibitors to inhibit tumor growth in vivo. These studies identify an effective combination therapy for the most aggressive form of MB. C1 [Pei, Yanxin; Liu, Kun-Wei; Wang, Jun; Garancher, Alexandra; Esparza, Lourdes A.; Maier, Donna L.; Wechsler-Reya, Robert J.] NCI, Tumor Initiat & Maintenance Program, Designated Canc Ctr, Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA 92037 USA. [Pei, Yanxin; Tao, Ran; Murad, Najiba] Childrens Natl Med Ctr, Canc & Immunol Dept, Brain Tumor Inst, Washington, DC 20010 USA. [Udaka, Yoko T.; Crawford, John R.] Univ Calif San Diego, Dept Pediat, Rady Childrens Hosp, San Diego, CA 92123 USA. [Morrissy, Sorana; Taylor, Michael D.] Hosp Sick Children, Program Dev & Stem Cell Biol, Div Neurosurg, Toronto, ON M5G 0A4, Canada. [Seker-Cin, Huriye; Brabetz, Sebastian; Kool, Marcel; Pfister, Stefan M.] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany. [Seker-Cin, Huriye; Brabetz, Sebastian; Kool, Marcel; Pfister, Stefan M.] German Canc Consortium, Core Ctr, D-69120 Heidelberg, Germany. [Qi, Lin; Kogiso, Mari; Li, Xiao-Nan] Baylor Coll Med, Texas Childrens Canc Ctr, Dept Pediat, Brain Tumor Program, Houston, TX 77030 USA. [Schubert, Simone; Cho, Yoon-Jae] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Olson, James M.] Seattle Childrens Hosp, Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Crawford, John R.] Univ Calif San Diego, Rady Childrens Hosp, Dept Neurosci, San Diego, CA 92123 USA. [Levy, Michael L.] Univ Calif San Diego, Rady Childrens Hosp, Dept Neurosurg, San Diego, CA 92123 USA. [Taylor, Michael D.] Hosp Sick Children, Div Neurosurg, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. RP Wechsler-Reya, RJ (reprint author), NCI, Tumor Initiat & Maintenance Program, Designated Canc Ctr, Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA 92037 USA. EM rwreya@sbpdiscovery.org FU NCI [CA122759, CA030199, CA159859]; Alex's Lemonade Stand Foundation; CureSearch for Children's Cancer; California Institute for Regenerative Medicine [LA1-01747] FX We thank Adriana Charbono and the SBP Animal Facility for assistance with colony maintenance; Amy Cortez and Yoav Altman of the Flow Cytometry Shared Resource and Karl Marquez and Eric O'Connor of the Stem Cell Core at UCSD for help with FACS sorting; Eduard Sergienko, Fu-Yue Zeng, and Thomas Chung of the Conrad Prebys Center for Chemical Genomics for help with assay development and high-throughput screening, and Giovanni Paternostro for help with synergy analysis; Subu Govindarajan of the Analytical Genomics Shared Resource for help with microarray analysis; Feng Qi and Jian-Liang (Jason) Li of the Bioinformatics Shared Resource for help with analysis of microarray data; and Christian Smith for assistance with artwork. This work was supported by NCI grant numbers CA122759 and CA030199 (R.W.R.) and CA159859 (R.W.R. and M.D.T.), by grants from Alex's Lemonade Stand Foundation (R.W.R.) and CureSearch for Children's Cancer (R.W.R. and M.D.T.) and by a Leadership Award (LA1-01747) from the California Institute for Regenerative Medicine (R.W.R.). NR 44 TC 6 Z9 6 U1 3 U2 10 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 MAR 14 PY 2016 VL 29 IS 3 BP 311 EP 323 DI 10.1016/j.ccell.2016.02.011 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DG8JB UT WOS:000372329000010 PM 26977882 ER PT J AU Chun, HJE Lim, EL Heravi-Moussavi, A Saberi, S Mungall, KL Bilenky, M Carles, A Tse, K Shlafman, I Zhu, K Qian, JQ Palmquist, DL He, A Long, W Goya, R Ng, M LeBlanc, VG Pleasance, E Thiessen, N Wong, T Chuah, E Zhao, YJ Schein, JE Gerhard, DS Taylor, MD Mungall, AJ Moore, RA Ma, Y Jones, SJM Perlman, EJ Hirst, M Marra, MA AF Chun, Hye-Jung E. Lim, Emilia L. Heravi-Moussavi, Alireza Saberi, Saeed Mungall, Karen L. Bilenky, Mikhail Carles, Annaick Tse, Kane Shlafman, Inna Zhu, Kelsey Qian, Jenny Q. Palmquist, Diana L. He, An Long, William Goya, Rodrigo Ng, Michelle LeBlanc, Veronique G. Pleasance, Erin Thiessen, Nina Wong, Tina Chuah, Eric Zhao, Yong-Jun Schein, Jacquie E. Gerhard, Daniela S. Taylor, Michael D. Mungall, Andrew J. Moore, Richard A. Ma, Yussanne Jones, Steven J. M. Perlman, Elizabeth J. Hirst, Martin Marra, Marco A. TI Genome-Wide Profiles of Extra-cranial Malignant Rhabdoid Tumors Reveal Heterogeneity and Dysregulated Developmental Pathways SO CANCER CELL LA English DT Article ID LONG-TERM SURVIVAL; ATYPICAL TERATOID/RHABDOID TUMORS; MICRORNA EXPRESSION PROFILES; PROMOTER CPG METHYLATION; SUPPRESSOR SNF5 LEADS; NATIONAL-WILMS-TUMOR; LARGE GENE LISTS; EPIGENETIC INACTIVATION; INTEGRATIVE ANALYSIS; CELL-CYCLE AB Malignant rhabdoid tumors (MRTs) are rare lethal tumors of childhood that most commonly occur in the kidney and brain. MRTs are driven by SMARCB1 loss, but the molecular consequences of SMARCB1 loss in extra-cranial tumors have not been comprehensively described and genomic resources for analyses of extra-cranial MRT are limited. To provide such data, we used whole-genome sequencing, whole-genome bisulfite sequencing, whole transcriptome (RNA-seq) and microRNA sequencing (miRNA-seq), and histone modification profiling to characterize extra-cranial MRTs. Our analyses revealed gene expression and methylation subgroups and focused on dysregulated pathways, including those involved in neural crest development. C1 [Chun, Hye-Jung E.; Lim, Emilia L.; Heravi-Moussavi, Alireza; Mungall, Karen L.; Bilenky, Mikhail; Tse, Kane; Shlafman, Inna; Zhu, Kelsey; Qian, Jenny Q.; Palmquist, Diana L.; He, An; Long, William; Goya, Rodrigo; Ng, Michelle; LeBlanc, Veronique G.; Pleasance, Erin; Thiessen, Nina; Wong, Tina; Chuah, Eric; Zhao, Yong-Jun; Mungall, Andrew J.; Moore, Richard A.; Ma, Yussanne; Jones, Steven J. M.; Hirst, Martin; Marra, Marco A.] British Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada. [Saberi, Saeed; Carles, Annaick; Hirst, Martin] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V6T 1Z4, Canada. [Gerhard, Daniela S.] NCI, Off Canc Genom, NIH, Bethesda, MD 20892 USA. [Taylor, Michael D.] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G IX8, Canada. [Jones, Steven J. M.] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada. [Perlman, Elizabeth J.] Northwestern Univ, Feinberg Sch Med, Lurie Childrens Hosp, Dept Pathol & Lab Med, Chicago, IL 60611 USA. [Perlman, Elizabeth J.] Northwestern Univ, Robert H Lurie Canc Ctr, Chicago, IL 60611 USA. [Jones, Steven J. M.; Marra, Marco A.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada. RP Marra, MA (reprint author), British Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada.; Marra, MA (reprint author), Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada. EM mmarra@bcgsc.ca RI Hirst, Martin/B-7684-2016; Marra, Marco/B-5987-2008 FU National Cancer Institute, NIH [NO1-CO-12400, HHSN261200800001E] FX We thank the Library Construction, Biospecimen, Sequencing, and Bioinformatics teams at Canada's Michael Smith Genome Sciences Centre for technical assistance, Dr. Karen Novik for project management, and Dr. Robert Camfield for reviewing the manuscript. M.A.M. acknowledges the BC Cancer Agency, the BC Cancer Foundation, the Canada Foundation for Innovation, the Canada Research Chairs program, Genome British Columbia, and the Canadian Institutes of Health Research (CIHR-262119 and FDN-143288). This project has been funded in whole or in part with Federal Funds from the National Cancer Institute, NIH, under contract nos. NO1-CO-12400 and HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 86 TC 6 Z9 6 U1 4 U2 9 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 MAR 14 PY 2016 VL 29 IS 3 BP 394 EP 406 DI 10.1016/j.ccell.2016.02.009 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DG8JB UT WOS:000372329000016 PM 26977886 ER PT J AU Waldstein, SR Moody, DLB McNeely, JM Allen, AJ Sprung, MR Shah, MT Al'Najjar, E Evans, MK Zonderman, AB AF Waldstein, Shari R. Moody, Danielle L. Beatty McNeely, Jessica M. Allen, Allyssa J. Sprung, Mollie R. Shah, Mauli T. Al'Najjar, Elias Evans, Michele K. Zonderman, Alan B. TI Cross-sectional relations of race and poverty status to cardiovascular risk factors in the Healthy Aging in Neighborhoods of Diversity across the Lifespan (HANDLS) study SO BMC PUBLIC HEALTH LA English DT Article DE Race; Socioeconomic status; Poverty; Cardiovascular risk factors; Blood pressure; Lipids; Body composition; Glucose; C-reactive protein ID SOCIOECONOMIC-STATUS; RACIAL DISPARITIES; ETHNIC DISPARITIES; UNITED-STATES; DISEASE RISK; ATHEROSCLEROSIS; WOMEN; ASSOCIATION; EDUCATION; STRESS AB Background: Examine interactive relations of race and poverty status with cardiovascular disease (CVD) risk factors in a socioeconomically diverse sample of urban-dwelling African American (AA) and White adults. Methods: Participants were 2,270 AAs and Whites (57 % AA; 57 % female; ages 30-64 years) who completed the first wave of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. CVD risk factors assessed included body mass index (BMI), waist circumference (WC), total cholesterol (TC), high-and low-density lipoprotein cholesterol (HDL-C, LDL-C), triglycerides (TG), glycated hemoglobin (HbA1c), high-sensitivity C-reactive protein (CRP), and systolic, diastolic, and pulse pressure (SBP, DBP, PP). Interactive and independent relations of race, poverty status, and sex were examined for each outcome via ordinary least squares regression adjusted for age, education, literacy, substance use, depressive symptoms, perceived health care barriers, medical co-morbidities, and medications. Results: Significant interactions of race and poverty status (p's < .05) indicated that AAs living in poverty had lower BMI and WC and higher HDL-C than non-poverty AAs, whereas Whites living in poverty had higher BMI and WC and lower HDL-C than non-poverty Whites. Main effects of race revealed that AAs had higher levels of HbA1c, SBP, and PP, and Whites had higher levels of TC, LDL-C and TG (p's <.05). Conclusion: Poverty status moderated race differences for BMI, WC, and HDL-C, conveying increased risk among Whites living in poverty, but reduced risk in their AA counterparts. Race differences for six additional risk factors withstood extensive statistical adjustments including SES indicators. C1 [Waldstein, Shari R.; Moody, Danielle L. Beatty; McNeely, Jessica M.; Allen, Allyssa J.; Sprung, Mollie R.; Shah, Mauli T.] Univ Maryland Baltimore Cty, Dept Psychol, 1000 Hilltop Circle, Baltimore, MD 21250 USA. [McNeely, Jessica M.; Shah, Mauli T.; Evans, Michele K.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA. [Al'Najjar, Elias] Univ Maryland Baltimore Cty, Dept Math & Stat, Baltimore, MD 21250 USA. RP Waldstein, SR (reprint author), Univ Maryland Baltimore Cty, Dept Psychol, 1000 Hilltop Circle, Baltimore, MD 21250 USA. EM waldstei@umbc.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging's Intramural Research Program [Z01-AG000194, RO1 AG034161] FX This work was supported by the National Institute on Aging's Intramural Research Program (Z01-AG000194), and RO1 AG034161. NR 36 TC 0 Z9 0 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD MAR 14 PY 2016 VL 16 AR 258 DI 10.1186/s12889-016-2945-9 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG2FB UT WOS:000371880800001 PM 26975845 ER PT J AU Olnes, MJ Kotliarov, Y Biancotto, A Cheung, F Chen, JG Shi, RY Zhou, HZ Wang, E Tsang, JS Nussenblatt, R AF Olnes, Matthew J. Kotliarov, Yuri Biancotto, Angelique Cheung, Foo Chen, Jinguo Shi, Rongye Zhou, Huizhi Wang, Ena Tsang, John S. Nussenblatt, Robert CA CHI Consortium TI Effects of Systemically Administered Hydrocortisone on the Human Immunome SO SCIENTIFIC REPORTS LA English DT Article ID NATURAL-KILLER-CELLS; REGULATORY T-CELLS; TH17 CELLS; HUMAN LYMPHOCYTES; SYSTEMS BIOLOGY; DENDRITIC CELLS; HUMAN MONOCYTES; FLOW-CYTOMETRY; HUMAN-DISEASE; SEX-HORMONES AB Corticosteroids have been used for decades to modulate inflammation therapeutically, yet there is a paucity of data on their effects in humans. We examined the changes in cellular and molecular immune system parameters, or "immunome", in healthy humans after systemic corticosteroid administration. We used multiplexed techniques to query the immunome in 20 volunteers at baseline, and after intravenous hydrocortisone (HC) administered at moderate (250 mg) and low (50 mg) doses, to provide insight into how corticosteroids exert their effects. We performed comprehensive phenotyping of 120 lymphocyte subsets by high dimensional flow cytometry, and observed a decline in circulating specific B and T cell subsets, which reached their nadir 4-8 hours after administration of HC. However, B and T cells rebounded above baseline 24 hours after HC infusion, while NK cell numbers remained stable. Whole transcriptome profiling revealed down regulation of NF-kappa B signaling, apoptosis, and cell death signaling transcripts that preceded lymphocyte population changes, with activation of NK cell and glucocorticoid receptor signaling transcripts. Our study is the first to systematically characterize the effects of corticosteroids on the human immunome, and we demonstrate that HC exerts differential effects on B and T lymphocytes and natural killer cells in humans. C1 [Olnes, Matthew J.; Kotliarov, Yuri; Biancotto, Angelique; Cheung, Foo; Chen, Jinguo; Shi, Rongye; Zhou, Huizhi; Wang, Ena; Tsang, John S.; Nussenblatt, Robert] NIH, Trans NIH Ctr Human Immunol Autoimmun & Inflammat, Bldg 10, Bethesda, MD 20892 USA. [Olnes, Matthew J.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Tsang, John S.] NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Nussenblatt, Robert] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Olnes, Matthew J.] Alaska Native Tribal Hlth Consortium, Dept Hematol, Anchorage, AK 99508 USA. [Wang, Ena] Sidra Med & Res Ctr, Doha, Qatar. RP Olnes, MJ (reprint author), NIH, Trans NIH Ctr Human Immunol Autoimmun & Inflammat, Bldg 10, Bethesda, MD 20892 USA.; Olnes, MJ (reprint author), NHLBI, Hematol Branch, Bethesda, MD 20892 USA.; Olnes, MJ (reprint author), Alaska Native Tribal Hlth Consortium, Dept Hematol, Anchorage, AK 99508 USA. EM mjolnes@anthc.org RI Kotliarov, Yuri/B-6938-2017 FU National Institutes of Health; National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute of Arthritis, Musculoskeletal and Skin Diseases; National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; National Institute of Environmental Health Sciences; National Eye Institute; National Human Genome Research Institute FX We would like to thank the NIH Clinical Center Staff for excellent clinical support; and Jennifer Stoddard, Kimberly Lemberg, Shakuntala Gurprasad, and Dr. Sergio Rosenzweig from the NIH Clinical Center for laboratory support. This work was funded by the Intramural Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Heart, Lung, and Blood Institute, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institute of Child Health and Human Development, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Eye Institute, and National Human Genome Research Institute. NR 49 TC 4 Z9 4 U1 0 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 MAR 14 PY 2016 VL 6 AR 23002 DI 10.1038/srep23002 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG1ZC UT WOS:000371865000001 PM 26972611 ER PT J AU Song, MA Marian, C Brasky, TM Reisinger, S Djordjevic, M Shields, PG AF Song, Min-Ae Marian, Catalin Brasky, Theodore M. Reisinger, Sarah Djordjevic, Mirjana Shields, Peter G. TI Chemical and toxicological characteristics of conventional and low-TSNA moist snuff tobacco products SO TOXICOLOGY LETTERS LA English DT Article DE Cancer risk; Carcinogens; Smokeless tobacco; Moist snuff; TSNAs ID RISK-ASSESSMENT PRINCIPLES; SMOKELESS TOBACCO; N-NITROSAMINES; MASS SPECTROMETRY; CIGARETTE-SMOKE; UNITED-STATES; ORAL-CANCER; NICOTINE; CARCINOGEN; ALCOHOL AB Use of smokeless tobacco products (STPs) is associated with oral cavity cancer and other health risks. Comprehensive analysis for chemical composition and toxicity is needed to compare conventional and newer STPs with lower tobacco-specific nitrosamines (TSNAs) yields. Seven conventional and 12 low-TSNA moist snuff products purchased in the U.S., Sweden, and South Africa were analyzed for 18 chemical constituents (International Agency for Research on Cancer classified carcinogens), pH, nicotine, and free nicotine. Chemicals were compared in each product using Wilcoxon rank-sum test and principle component analysis (PCA). Conventional compared to low-TSNA moist snuff products had higher ammonia, benzo[a] pyrene, cadmium, nickel, nicotine, nitrate, and TSNAs and had lower arsenic in dry weight content and per mg nicotine. Lead and chromium were significantly higher in low-TSNA moist snuff products. PCA showed a clear difference for constituents between conventional and low-TSNA moist snuff products. Differences among products were reduced when considered on a per mg nicotine basis. As one way to contextualize differences in constituent levels, probabilistic lifetime cancer risk was estimated for chemicals included in The University of California's carcinogenic potency database (CPDB). Estimated probabilistic cancer risks were 3.77-fold or 3-fold higher in conventional compared to low-TSNA moist snuff products under dry weight or under per mg nicotine content, respectively. In vitro testing for the STPs indicated low level toxicity and no substantial differences. The comprehensive chemical characterization of both conventional and low-TSNA moist snuff products from this study provides a broader assessment of understanding differences in carcinogenic potential of the products. In addition, the high levels and probabilistic cancer risk estimates for certain chemical constituents of smokeless tobacco products will further inform regulatory decision makers and aid them in their efforts to reduce carcinogen exposure in smokeless tobacco products. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Song, Min-Ae] Ohio State Univ, Div Epidemiol, Coll Publ Hlth, Columbus, OH 43210 USA. [Song, Min-Ae; Marian, Catalin; Brasky, Theodore M.; Reisinger, Sarah; Shields, Peter G.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Song, Min-Ae; Marian, Catalin; Brasky, Theodore M.; Reisinger, Sarah; Shields, Peter G.] James Canc Hosp, Columbus, OH USA. [Marian, Catalin] Victor Babes Univ Med & Pharm, Biochem & Pharmacol Dept, Timisoara 300041, Romania. [Djordjevic, Mirjana] NCI, Tobacco Control Res Branch, Rockville, MD USA. RP Shields, PG (reprint author), Ohio State Univ, Dept Med, James Comprehens Canc Ctr, 460 W 10th Ave,9th Floor,Suite D920, Columbus, OH 43210 USA. EM peter.shields@osumc.edu OI Reisinger, Sarah/0000-0002-3076-5405 FU National Cancer Institute of the National Institutes of Health (NIH) [P50CA180908]; Food and Drug Administration (FDA) Center for Tobacco Products; National Cancer Institute and the National Institute on Drug Abuse [P50 84718]; National Cancer Institute under contract, Laboratory Assessment of Tobacco Use Behavior and Exposure to Toxins [NCI N01-PC-64402] FX Research reported in this publication was supported by grant number P50CA180908 from the National Cancer Institute of the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) Center for Tobacco Products. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the FDA. Transdisciplinary Tobacco Use Research Center grants P50 84718 from the National Cancer Institute and the National Institute on Drug Abuse, and NCI N01-PC-64402 by the National Cancer Institute under contract, Laboratory Assessment of Tobacco Use Behavior and Exposure to Toxins. The authors are grateful to Drs. Cecilia Magnusson and Lekan Ayo-Yusuf for purchasing the moist snuff products from Sweden and South Africa. We also would like to acknowledge Drs. Richard Higby and William Rickert for contribution to the chemical analysis and the in vitrotoxicity assays, respectively. NR 43 TC 0 Z9 0 U1 2 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 EI 1879-3169 J9 TOXICOL LETT JI Toxicol. Lett. PD MAR 14 PY 2016 VL 245 BP 68 EP 77 DI 10.1016/j.toxlet.2016.01.012 PG 10 WC Toxicology SC Toxicology GA DD5CU UT WOS:000369941000009 PM 26802282 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI The meaning of biological information SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES LA English DT Editorial Material DE information; meaning; evolution; selfish elements ID INTERGENIC NONCODING RNAS; DE-NOVO GENES; GENOME EVOLUTION; PERVASIVE TRANSCRIPTION; EUKARYOTIC GENOME; CELLULAR GENES; JUNK DNA; COMPLEXITY; ELEMENTS; HEDGEHOG AB Biological information encoded in genomes is fundamentally different from and effectively orthogonal to Shannon entropy. The biologically relevant concept of information has to do with 'meaning', i.e. encoding various biological functions with various degree of evolutionary conservation. Apart from direct experimentation, the meaning, or biological information content, can be extracted and quantified from alignments of homologous nucleotide or amino acid sequences but generally not from a single sequence, using appropriately modified information theoretical formulae. For short, information encoded in genomes is defined vertically but not horizontally. Informally but substantially, biological information density seems to be equivalent to 'meaning' of genomic sequences that spans the entire range from sharply defined, universal meaning to effective meaninglessness. Large fractions of genomes, up to 90% in some plants, belong within the domain of fuzzy meaning. The sequences with fuzzy meaning can be recruited for various functions, with the meaning subsequently fixed, and also could perform generic functional roles that do not require sequence conservation. Biological meaning is continuously transferred between the genomes of selfish elements and hosts in the process of their coevolution. Thus, in order to adequately describe genome function and evolution, the concepts of information theory have to be adapted to incorporate the notion of meaning that is central to biology. C1 [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov NR 71 TC 8 Z9 9 U1 5 U2 21 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1364-503X EI 1471-2962 J9 PHILOS T R SOC A JI Philos. Trans. R. Soc. A-Math. Phys. Eng. Sci. PD MAR 13 PY 2016 VL 374 IS 2063 AR 20150065 DI 10.1098/rsta.2015.0065 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD1OE UT WOS:000369690200005 ER PT J AU Hou, LP Heilbronner, U Degenhardt, F Adli, M Akiyama, K Akula, N Ardau, R Arias, B Backlund, L Banzato, CEM Benabarre, A Bengesser, S Bhattacharjee, AK Biernacka, JM Birner, A Brichant-Petitjean, C Bui, ET Cervantes, P Chen, GB Chen, HC Chillotti, C Cichon, S Clark, SR Colom, F Cousins, DA Cruceanu, C Czerski, PM Dantas, CR Dayer, A Eacute;tain, B Falkai, P Forstner, AJ Frisen, L Fullerton, JM Gard, S Garnham, JS Goes, FS Grof, P Gruber, O Hashimoto, R Hauser, J Herms, S Hoffmann, P Hofmann, A Jamain, S Jimenez, E Kahn, JP Kassem, L Kittel-Schneider, S Kliwicki, S Konig, B Kusumi, I Lackner, N Laje, G Landen, M Lavebratt, C Leboyer, M Leckband, SG Jaramillo, CAL MacQueen, G Manchia, M Martinsson, L Mattheisen, M McCarthy, MJ McElroy, SL Mitjans, M Mondimore, FM Monteleone, P Nievergelt, CM Nothen, MM Ouml;sby, U Ozaki, N Perlis, RH Pfennig, A Reich-Erkelenz, D Rouleau, GA Schofield, PR Schubert, KO Schweizer, BW Seemuller, F Severino, G Shekhtman, T Shilling, PD Shimoda, K Simhandl, C Slaney, CM Smoller, JW Squassina, A Stamm, T Stopkova, P Tighe, SK Tortorella, A Turecki, G Volkert, J Witt, S Wright, A Young, LT Zandi, PP Potash, JB DePaulo, JR Bauer, M Reininghaus, EZ Novak, T Aubry, JM Maj, M Baune, BT Mitchell, PB Vieta, E Frye, MA Rybakowski, JK Kuo, PH Kato, T Grigoroiu-Serbanescu, M Reif, A Del Zompo, M Bellivier, F Schalling, M Wray, NR Kelsoe, JR Alda, M Rietschel, M McMahon, FJ Schulze, TG AF Hou, Liping Heilbronner, Urs Degenhardt, Franziska Adli, Mazda Akiyama, Kazufumi Akula, Nirmala Ardau, Raffaella Arias, Barbara Backlund, Lena Banzato, Claudio E. M. Benabarre, Antoni Bengesser, Susanne Bhattacharjee, Abesh Kumar Biernacka, Joanna M. Birner, Armin Brichant-Petitjean, Clara Bui, Elise T. Cervantes, Pablo Chen, Guo-Bo Chen, Hsi-Chung Chillotti, Caterina Cichon, Sven Clark, Scott R. Colom, Francesc Cousins, David A. Cruceanu, Cristiana Czerski, Piotr M. Dantas, Clarissa R. Dayer, Alexandre Etain, Bruno Falkai, Peter Forstner, Andreas J. Frisen, Louise Fullerton, Janice M. Gard, Sebastien Garnham, Julie S. Goes, Fernando S. Grof, Paul Gruber, Oliver Hashimoto, Ryota Hauser, Joanna Herms, Stefan Hoffmann, Per Hofmann, Andrea Jamain, Stephane Jimenez, Esther Kahn, Jean-Pierre Kassem, Layla Kittel-Schneider, Sarah Kliwicki, Sebastian Koenig, Barbara Kusumi, Ichiro Lackner, Nina Laje, Gonzalo Landen, Mikael Lavebratt, Catharina Leboyer, Marion Leckband, Susan G. Lopez Jaramillo, Carlos A. MacQueen, Glenda Manchia, Mirko Martinsson, Lina Mattheisen, Manuel McCarthy, Michael J. McElroy, Susan L. Mitjans, Marina Mondimore, Francis M. Monteleone, Palmiero Nievergelt, Caroline M. Noethen, Markus M. Oesby, Urban Ozaki, Norio Perlis, Roy H. Pfennig, Andrea Reich-Erkelenz, Daniela Rouleau, Guy A. Schofield, Peter R. Schubert, K. Oliver Schweizer, Barbara W. Seemueller, Florian Severino, Giovanni Shekhtman, Tatyana Shilling, Paul D. Shimoda, Kazutaka Simhandl, Christian Slaney, Claire M. Smoller, Jordan W. Squassina, Alessio Stamm, Thomas Stopkova, Pavla Tighe, Sarah K. Tortorella, Alfonso Turecki, Gustavo Volkert, Julia Witt, Stephanie Wright, Adam Young, L. Trevor Zandi, Peter P. Potash, James B. DePaulo, J. Raymond Bauer, Michael Reininghaus, Eva Z. Novak, Tomas Aubry, Jean-Michel Maj, Mario Baune, Bernhard T. Mitchell, Philip B. Vieta, Eduard Frye, Mark A. Rybakowski, Janusz K. Kuo, Po-Hsiu Kato, Tadafumi Grigoroiu-Serbanescu, Maria Reif, Andreas Del Zompo, Maria Bellivier, Frank Schalling, Martin Wray, Naomi R. Kelsoe, John R. Alda, Martin Rietschel, Marcella McMahon, Francis J. Schulze, Thomas G. TI Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study SO LANCET LA English DT Article ID PROPHYLACTIC LITHIUM; GENOTYPE IMPUTATION; I DISORDER; THERAPY; PHARMACOGENETICS; GADL1 AB Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p= 1.37 x 10(-8); rs78015114, p= 1.31 x 10(-8); rs74795342, p= 3.31 x 10(-9); and rs75222709, p= 3.50 x 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p= 0.03268, hazard ratio 3.8, 95% CI 1.1-13.0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. C1 [Hou, Liping; Akula, Nirmala; Bui, Elise T.; Kassem, Layla; Laje, Gonzalo; McMahon, Francis J.; Schulze, Thomas G.] NIMH, Intramural Res Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Heilbronner, Urs; Reich-Erkelenz, Daniela; Schulze, Thomas G.] Univ Munich, Inst Psychiat Phen & Genom, Munich, Germany. [Falkai, Peter; Seemueller, Florian] Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany. [Heilbronner, Urs; Gruber, Oliver; Schulze, Thomas G.] Univ Gottingen, Univ Med Ctr UMG, Dept Psychiat & Psychotherapy, D-37073 Gottingen, Germany. [Degenhardt, Franziska; Cichon, Sven; Forstner, Andreas J.; Herms, Stefan; Hoffmann, Per; Hofmann, Andrea; Noethen, Markus M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Degenhardt, Franziska; Cichon, Sven; Forstner, Andreas J.; Herms, Stefan; Hoffmann, Per; Hofmann, Andrea; Noethen, Markus M.] Life & Brain Ctr, Dept Genom, Bonn, Germany. [Adli, Mazda; Stamm, Thomas] Charite, Dept Psychiat & Psychotherapy, Campus Charite Mitte, D-13353 Berlin, Germany. [Adli, Mazda] Fliedner Klin Berlin, Ctr Psychiat Psychotherapy & Psychosomat Med, Berlin, Germany. [Akiyama, Kazufumi] Dokkyo Med Univ, Dept Biol Psychiat & Neurosci, Sch Med, Mibu, Tochigi, Japan. [Ardau, Raffaella; Chillotti, Caterina; Del Zompo, Maria] Hosp Univ Agcy Cagliari, Clin Pharmacol Unit, Cagliari, Italy. [Arias, Barbara; Mitjans, Marina] Univ Barcelona, CIBERSAM, Fac Biol, Dept Biol Anim,Unitat Antropol Dp Biol Anim, Barcelona, Catalonia, Spain. [Arias, Barbara; Mitjans, Marina] Univ Barcelona, CIBERSAM, Inst Biomed IBUB, Barcelona, Catalonia, Spain. [Backlund, Lena; Frisen, Louise; Lavebratt, Catharina; Leckband, Susan G.; Schalling, Martin] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Frisen, Louise] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Oesby, Urban] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden. [Frisen, Louise] Child & Adolescent Psychiat Res Ctr, Stockholm, Sweden. [Banzato, Claudio E. M.; Dantas, Clarissa R.] Univ Campinas Unicamp, Dept Psychiat, Campinas, SP, Brazil. [Benabarre, Antoni; Colom, Francesc; Jimenez, Esther; Vieta, Eduard] Univ Barcelona, IDIBAPS, CIBERSAM, Bipolar Disorder Program,Inst Neurosci,Hosp Clin, Barcelona, Catalonia, Spain. [Bengesser, Susanne; Birner, Armin; Lackner, Nina; Reininghaus, Eva Z.] Med Univ Graz, Dept Psychiat, Neurobiol Background & Anthropometr Bipolar Affec, Graz, Austria. [Shekhtman, Tatyana; Kelsoe, John R.] San Diego Healthcare Syst, Vet Adm, San Diego, CA USA. [Bhattacharjee, Abesh Kumar; Nievergelt, Caroline M.; Shekhtman, Tatyana; Shilling, Paul D.; Kelsoe, John R.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Biernacka, Joanna M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Biernacka, Joanna M.; Frye, Mark A.] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA. [Brichant-Petitjean, Clara; Bellivier, Frank] Univ Paris Diderot Pole Psychiat, INSERM, UMR S 1144, Grp Hosp Lariboisiere F Widal,AP HP, Paris, France. [Cervantes, Pablo] McGill Univ, Ctr Hlth, Neuromodulat Unit, Montreal, PQ, Canada. [Chen, Guo-Bo; Wray, Naomi R.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Chen, Hsi-Chung] Natl Taiwan Univ Hosp, Dept Psychiat, Taipei, Taiwan. [Chen, Hsi-Chung] Natl Taiwan Univ Hosp, Ctr Sleep Disorders, Taipei, Taiwan. [Kuo, Po-Hsiu] Natl Taiwan Univ, Inst Epidemiol & Prevent Med, Taipei 10764, Taiwan. [Cichon, Sven; Herms, Stefan; Hoffmann, Per] Univ Basel Hosp, Human Genom Res Grp, Dept Biomed, CH-4031 Basel, Switzerland. [Clark, Scott R.; Schubert, K. Oliver; Baune, Bernhard T.] Univ Adelaide, Discipline Psychiat, Adelaide, SA, Australia. [Cousins, David A.] Newcastle Univ, Campus Ageing & Vital, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Cruceanu, Cristiana; Turecki, Gustavo] McGill Univ, Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada. [Czerski, Piotr M.; Hauser, Joanna] Poznan Univ Med Sci, Psychiat Genet Unit, Poznan, Poland. [Dayer, Alexandre; Aubry, Jean-Michel] Univ Hosp Geneva, Dept Mental Hlth & Psychiat, Mood Disorders Unit, Geneva, Switzerland. [Etain, Bruno; Jamain, Stephane] Hop Henri Mondor, INSERM, U955, Psychiat Translat, F-94010 Creteil, France. [Fullerton, Janice M.; Schofield, Peter R.] Neurosci Res Australia, Mental Illness Res Theme, Sydney, NSW, Australia. [Fullerton, Janice M.; Schofield, Peter R.] Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia. [Gard, Sebastien] Ctr Hosp Charles Perrens, Pole Psychiat Gen Univ, Bordeaux, France. [Garnham, Julie S.; Slaney, Claire M.; Alda, Martin] Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada. [Goes, Fernando S.; Mondimore, Francis M.; Schweizer, Barbara W.; DePaulo, J. Raymond; Schulze, Thomas G.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Grof, Paul] Mood Disorders Ctr Ottawa, Ottawa, ON, Canada. [Hashimoto, Ryota] Osaka Univ, Mol Res Ctr Childrens Mental Dev, United Grad Sch Child Dev, Osaka, Japan. [Kahn, Jean-Pierre] Univ Lorraine, Ctr Psychotherap Nancy Laxou, Serv Psychiat & Psychol Clin, Nancy, France. [Kittel-Schneider, Sarah; Volkert, Julia; Reif, Andreas] Univ Hosp Frankfurt, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany. [Kliwicki, Sebastian; Rybakowski, Janusz K.] Poznan Univ Med Sci, Dept Adult Psychiat, Poznan, Poland. [Koenig, Barbara] Landesklinikum Neunkirchen, Dept Psychiat & Psychotherapeut Med, Neunkirchen, Austria. [Kusumi, Ichiro] Hokkaido Univ, Grad Sch Med, Dept Psychiat, Sapporo, Hokkaido, Japan. [Landen, Mikael] Gothenburg Univ, Inst Neurosci & Physiol, Sahlgrenska Acad, Gothenburg, Sweden. [Landen, Mikael] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Martinsson, Lina] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Leboyer, Marion] Hop Albert Chenevier Henri Mondor, Assistance Publ Hop Paris, Pole Psychiat, Creteil, France. [Leckband, Susan G.] San Diego Healthcare Syst, Dept Pharm, San Diego, CA USA. [McCarthy, Michael J.] San Diego Healthcare Syst, Dept Psychiat, San Diego, CA USA. [Lopez Jaramillo, Carlos A.] Univ Antioquia, Dept Psychiat, Medellin, Colombia. [MacQueen, Glenda] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Manchia, Mirko; Severino, Giovanni; Squassina, Alessio; Del Zompo, Maria] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy. [Manchia, Mirko] Dalhousie Univ, Dept Pharmacol, Halifax, NS B3H 4H7, Canada. [Mattheisen, Manuel] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [McElroy, Susan L.] Univ Cincinnati, Lindner Ctr Hope, Dept Psychiat, Mason, OH USA. [Monteleone, Palmiero] Univ Salerno, Dept Med & Surg, Neurosci Sect, I-84100 Salerno, Italy. [Monteleone, Palmiero; Tortorella, Alfonso; Maj, Mario] Univ Naples SUN, Dept Psychiat, Naples, Italy. [Ozaki, Norio] Nagoya Univ, Grad Sch Med, Dept Psychiat, Nagoya, Aichi 4648601, Japan. [Perlis, Roy H.; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Perlis, Roy H.; Smoller, Jordan W.] Harvard Univ, Sch Med, Boston, MA USA. [Pfennig, Andrea; Bauer, Michael] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Psychiat & Psychotherapy, Fac Med, D-01062 Dresden, Germany. [Rouleau, Guy A.] McGill Univ, Montreal Neurol Inst & Hosp, Montreal, PQ, Canada. [Shimoda, Kazutaka] Dokkyo Med Univ, Sch Med, Dept Psychiat, Mibu, Tochigi, Japan. [Simhandl, Christian] Bipolar Ctr Wiener Neustadt, Wiener Neustadt, Austria. [Stopkova, Pavla; Novak, Tomas; Alda, Martin] Natl Inst Mental Hlth, Klecany, Czech Republic. [Tighe, Sarah K.; Potash, James B.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Tighe, Sarah K.] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Tighe, Sarah K.] Univ Iowa, Coll Publ Hlth, VA Qual Scholars Program, Iowa City VA Hosp, Iowa City, IA USA. [Witt, Stephanie; Rietschel, Marcella; Schulze, Thomas G.] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany. [Wright, Adam; Mitchell, Philip B.] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Wright, Adam; Mitchell, Philip B.] Black Dog Inst, Sydney, NSW, Australia. [Young, L. Trevor] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Zandi, Peter P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Kato, Tadafumi] RIKEN, Brain Sci Inst, Lab Mol Dynam Mental Disorders, Saitama, Japan. [Grigoroiu-Serbanescu, Maria] Alexandru Obregia Psychiat Hosp, Biometr Psychiat Genet Res Unit, Bucharest, Romania. RP Schulze, TG (reprint author), Univ Munich, Med Ctr, IPPG, Munich, Germany.; McMahon, FJ (reprint author), NIMH, Human Genet Branch, Intramural Res Program, Bethesda, MD 20892 USA.; McMahon, FJ (reprint author), NIMH, Genet Basis Mood & Anxiety Disorders Sect, Intramural Res Program, Bethesda, MD 20892 USA. EM mcmahonf@mail.nih.gov; thomas.schulze@med.uni-muenchen.de RI Banzato, Claudio/B-2517-2008; Hou, Liping/G-1648-2011; BELLIVIER, FRANK/H-5197-2012; Novak, Tomas/B-8008-2017; Chen, Hsi-Chung/E-9949-2017; OI Mitjans, Marina/0000-0001-5543-7320; Colom, Francesc/0000-0002-9516-9030; Kato, Tadafumi/0000-0001-7856-3952; Squassina, Alessio/0000-0001-7415-7607; Etain, Bruno/0000-0002-5377-1488; Dayer, Alexandre/0000-0002-4490-9780; Grigoroiu-Serbanescu, Maria/0000-0002-1304-6687; Chen, Guo-Bo/0000-0001-5475-8237; Mitchell, Philip/0000-0002-7954-5235; Banzato, Claudio/0000-0002-8556-3982; Manchia, Mirko/0000-0003-4175-6413; Kittel-Schneider, Sarah/0000-0003-3057-6150; Hou, Liping/0000-0003-3972-245X; Novak, Tomas/0000-0001-9156-9654; Chen, Hsi-Chung/0000-0003-3191-0093; Nievergelt, Caroline/0000-0001-5766-8923; Reininghaus, Eva/0000-0001-5964-4087; McMahon, Francis/0000-0002-9469-305X; Nothen, Markus/0000-0002-8770-2464 FU Deutsche Forschungsgemeinschaft; National Institute of Mental Health Intramural Research Program; Deutsche Forschungsgemeinschaft (DFG) [RI 908/7-1, FOR2107, RI 908/11-1, NO 246/10-1]; National Institute of Mental Health [ZIA-MH00284311, NCT00001174]; German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under e:Med Programme; German Federal Ministry of Education and Research (BMBF); Alfried Krupp von Bohlen und Halbach-Stiftung; BONFOR Programme of the University of Bonn, Germany; Land Steiermark; Swedish Research Council; Swedish Brain Foundation; Karolinska Institutet; Karolinska University Hospital; NIH from National Cancer Institute [P50CA89392]; NIH from National Institute of Drug Abuse [5K02DA021237]; Canadian Institutes of Health Research [64410]; Australian NHMRC Program Grant [1037196]; Centro de Investigacion en Red de Salud Mental (CIBERSAM) IDIBAPS [PI080247, PI1200906, PI12/00018]; Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement [2014SGR1636, 2014SGR398]; Swiss National Science Foundation [32003B_125469]; Swiss National Science Foundation (NCCR Synapsy); Medical Research Council Clinician Scientist Fellowship Award [MR/L006642/1]; Swedish Research Council [523-2011-3807]; UEFISCDI, Romania [89/2012]; Taiwan Ministry of Science and Technology [MST 99-2314-B-002-140-MY3, 102-2314-B-002-117-MY3]; University of Antioquia; Ministry of Health of the Czech Republic [IGA NT13891]; Reuben Stoltzfus Bipolar Research Fund; James Wah Fund; Project MATCH; Dr-Lisa-Oehler-Foundation (Kassel, Germany); Sardinia Regional Government POR Sardegna FSE Operational Program of the Autonomous Region of Sardinia, European Social Fund; Australian NHMRC Fellowships [613602, 1078901]; Stanley Center for Psychiatric Research at the Broad Institute FX Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.; We are greatly indebted to all the study participants without whom this research would not have been possible. We thank the members of our Scientific Advisory Board for critical input over the course of the project. This work was in part funded by the Deutsche Forschungsgemeinschaft (DFG; grant no RI 908/7-1; grant FOR2107, RI 908/11-1 to Marcella Rietschel, Michael Bauer, and Thomas G Schulze, NO 246/10-1 to MMN) and the Intramural Research Program of the National Institute of Mental Health (ZIA-MH00284311; NCT00001174). The genotyping was in part funded by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grants awarded to TGS, MR, and MMN). OG, AP, TSt, MB, AR, and TGS received support from the German Federal Ministry of Education and Research (BMBF) within the framework of the BipolLife network. MMN received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. Franziska Degenhardt received support from the BONFOR Programme of the University of Bonn, Germany. EZR received funding from the Land Steiermark as principal investigator. MS received funds from the Swedish Research Council, Swedish Brain Foundation and funds from Karolinska Institutet and Karolinska University Hospital. Some data and biomaterials were collected as part of eleven projects (Study 40) that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 2003-07, the principal investigators and co-investigators were: Indiana University, Indianapolis, IN, R01 MH59545 (John Nurnberger, Marvin J Miller, Elizabeth S Bowman, N Leela Rau, P Ryan Moe, Nalini Samavedy, Rif El-Mallakh [University of Louisville], Husseini Manji [Johnson and Johnson], Debra A Glitz [Wayne State University], Eric T Meyer [Oxford University, UK], Carrie Smiley, Tatiana Foroud, Leah Flury, Danielle M Dick [Virginia Commonwealth University], Howard Edenberg); Washington University, St Louis, MO, R01 MH059534 (John Rice, Theodore Reich, Allison Goate, Laura Bierut [K02 DA21237]); Johns Hopkins University, Baltimore, R01 MH59533 (Melvin McInnis, J Raymond DePaulo Jr, Dean F MacKinnon, Francis M Mondimore, James B Potash, Peter P Zandi, Dimitrios Avramopoulos, Jennifer Payne); University of Pennsylvania, PA, R01 MH59553 (Wade Berrettini); University of California at San Francisco, CA, R01 MH60068 (William Byerley, Sophia Vinogradov); University of Iowa, IA, R01 MH059548 (William Coryell, Raymond Crowe); University of Chicago, IL, R01 MH59535 (Elliot Gershon, Judith Badner, Francis McMahon, Chunyu Liu, Alan Sanders, Maria Caserta, Steven Dinwiddie, Tu Nguyen, Donna Harakal); University of California at San Diego, CA, R01 MH59567 (John Kelsoe, Rebecca McKinney); Rush University, IL, R01 MH059556 (William Scheftner, Howard M Kravitz, Diana Marta, Annette Vaughn-Brown, Laurie Bederow); and NIMH Intramural Research Program, Bethesda, 1Z01MH002810-01 (Francis J McMahon, Layla Kassem, PsyD, Sevilla Detera-Wadleigh, Lisa Austin, Dennis L Murphy [Howard University], William B Lawson, Evarista Nwulia, Maria Hipolito). This work was supported by the NIH grants P50CA89392 from the National Cancer Institute and 5K02DA021237 from the National Institute of Drug Abuse. The Canadian part of the study was supported by a grant #64410 from the Canadian Institutes of Health Research to MAl. We wish to thank Joanne Petite and Giselle Kraus for assistance with data collection.; Collection and phenotyping of the Australian UNSW sample, by PBM, PRS, JMF, and AW, was funded by an Australian NHMRC Program Grant (No. 1037196). The collection of the Barcelona sample was supported by the Centro de Investigacion en Red de Salud Mental (CIBERSAM) IDIBAPS (grant numbers PI080247, PI1200906, PI12/00018), and Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (2014SGR1636 and 2014SGR398). J-MA and AD were supported by the Swiss National Science Foundation (grant number 32003B_125469 and NCCR Synapsy). DC was supported by a Medical Research Council Clinician Scientist Fellowship Award (MR/L006642/1). LF was supported by the Swedish Research Council (grant no 523-2011-3807). MG-S was supported by UEFISCDI, Romania, grant no 89/2012. P-HK was funded by the Taiwan Ministry of Science and Technology (grant no MST 99-2314-B-002-140-MY3 and 102-2314-B-002-117-MY3). CALJ was funded by the "Estrategia de Sostenibilidad 2014-2015" program of the University of Antioquia. TN was supported by the Ministry of Health of the Czech Republic (grant no IGA NT13891). JBP was supported by the Reuben Stoltzfus Bipolar Research Fund and with SKT received funding from the James Wah Fund and Project MATCH. TGS and UH received support from the Dr-Lisa-Oehler-Foundation (Kassel, Germany). AS has a postdoctoral fellowship funded by the Sardinia Regional Government POR Sardegna FSE Operational Program of the Autonomous Region of Sardinia, European Social Fund 2007-2013-Axis IV Human Resources, Objective l.3, Line of Activity l.3.1. NRW was funded by Australian NHMRC Fellowships 613602 and 1078901. MMan is now a resident in the psychiatry training program at the Section of Psychiatry, Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. Genotyping for part of the Swedish sample was funded by the Stanley Center for Psychiatric Research at the Broad Institute. NR 33 TC 23 Z9 25 U1 12 U2 33 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 MAR 12 PY 2016 VL 387 IS 10023 BP 1085 EP 1093 DI 10.1016/S0140-6736(16)00143-4 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DG0SD UT WOS:000371775000028 PM 26806518 ER PT J AU Vuorenpaa, A Jorgensen, TN Newman, AH Madsen, KL Scheinin, M Gether, U AF Vuorenpaeaa, Anne Jorgensen, Trine N. Newman, Amy H. Madsen, Kenneth L. Scheinin, Mika Gether, Ulrik TI Differential Internalization Rates and Postendocytic Sorting of the Norepinephrine and Dopamine Transporters Are Controlled by Structural Elements in the N Termini SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE dopamine transporter; monoamine transporter; neurotransmitter transport; protein chimera; trafficking; internalization; norepinephrine transporter; recycling; transporter regulation ID PROTEIN-KINASE-C; ENDOCYTIC RECYCLING SIGNAL; GAMMA-AMINOBUTYRIC-ACID; TRANS-GOLGI NETWORK; SURFACE EXPRESSION; CELL-LINES; SUBCELLULAR-LOCALIZATION; MEDIATED INTERNALIZATION; ORTHOSTATIC INTOLERANCE; LYSOSOMAL DEGRADATION AB The norepinephrine transporter (NET) mediates reuptake of synaptically released norepinephrine in central and peripheral noradrenergic neurons. The molecular processes governing availability of NET in the plasma membrane are poorly understood. Here we use the fluorescent cocaine analogue JHC 1-64, as well as several other approaches, to investigate the trafficking itinerary of NET in live noradrenergic neurons. Confocal imaging revealed extensive constitutive internalization of JHC 1-64-labeled NET in the neuronal somata, proximal extensions and presynaptic boutons. Phorbol 12-myristate 13-acetate increased intracellular accumulation of JHC 1-64-labeled NET and caused a parallel reduction in uptake capacity. Internalized NET strongly colocalized with the long loop recycling marker Rab11, whereas less overlap was seen with the short loop recycling marker Rab4 and the late endosomal marker Rab7. Moreover, mitigating Rab11 function by overexpression of dominant negative Rab11 impaired NET function. Sorting of NET to the Rab11 recycling compartment was further supported by confocal imaging and reversible biotinylation experiments in transfected differentiated CATH.a cells. In contrast to NET, the dopamine transporter displayed markedly less constitutive internalization and limited sorting to the Rab11 recycling compartment in the differentiated CATH.a cells. Exchange of domains between the two homologous transporters revealed that this difference was determined by non-conserved structural elements in the intracellular N terminus. We conclude that NET displays a distinct trafficking itinerary characterized by continuous shuffling between the plasma membrane and the Rab11 recycling compartment and that the functional integrity of the Rab11 compartment is critical for maintaining proper presynaptic NET function. C1 [Vuorenpaeaa, Anne; Jorgensen, Trine N.; Madsen, Kenneth L.; Gether, Ulrik] Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, Mol Neuropharmacol & Genet Lab,Panum Inst 18 6, DK-2200 Copenhagen N, Denmark. [Vuorenpaeaa, Anne; Scheinin, Mika] Univ Turku, Dept Pharmacol Drug Dev & Therapeut, FI-20014 Turku, Finland. [Vuorenpaeaa, Anne; Scheinin, Mika] Turku Univ Hosp, Clin Pharmacol Unit, FI-20520 Turku, Finland. [Newman, Amy H.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gether, U (reprint author), Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, Mol Neuropharmacol & Genet Lab,Panum Inst 18 6, DK-2200 Copenhagen N, Denmark. EM gether@sund.ku.dk RI Madsen, Kenneth/C-7778-2012; OI Madsen, Kenneth/0000-0001-9274-6691; Gether, Ulrik/0000-0002-0020-3807 FU FinPharma Doctoral program; National Institutes of Health [P01 DA 12408]; Danish Council for Independent Research-Medical Sciences; Lundbeck Foundation Center for Biomembranes in Nanomedicine; Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health FX This work was supported by the FinPharma Doctoral program (to A. V.), National Institutes of Health Grant P01 DA 12408 (to U. G.), the Danish Council for Independent Research-Medical Sciences (to U. G.), the Lundbeck Foundation Center for Biomembranes in Nanomedicine (to U. G.), and the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health (to A. H. N.). 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 78 TC 1 Z9 1 U1 2 U2 5 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 MAR 11 PY 2016 VL 291 IS 11 BP 5634 EP 5651 DI 10.1074/jbc.M115.702050 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DH1NN UT WOS:000372551800016 PM 26786096 ER PT J AU Kim, J Lee, KJ Kim, JS Rho, JG Shin, JJ Song, WK Lee, EK Egan, JM Kim, W AF Kim, Jihye Lee, Kyung Jin Kim, Jung Seok Rho, Jun Gi Shin, Jung Jae Song, Woo Keun Lee, Eun Kyung Egan, Josephine M. Kim, Wook TI Cannabinoids Regulate Bcl-2 and Cyclin D2 Expression in Pancreatic beta Cells SO PLOS ONE LA English DT Article ID INSULIN-RESISTANCE; PROSTATE-CANCER; DEATH; RECEPTOR; PHOSPHORYLATION; SURVIVAL; P27(KIP1); KNOCKOUT; BINDING; MICE AB Recent reports have shown that cannabinoid 1 receptors (CB1Rs) are expressed in pancreatic beta cells, where they induce cell death and cell cycle arrest by directly inhibiting insulin receptor activation. Here, we report that CB1Rs regulate the expression of the anti-apoptotic protein Bcl-2 and cell cycle regulator cyclin D2 in pancreatic beta cells. Treatment of MIN6 and beta TC6 cells with a synthetic CB1R agonist, WIN55,212-2, led to a decrease in the expression of Bcl-2 and cyclin D2, in turn inducing cell cycle arrest in G0/G1 phase and caspase-3-dependent apoptosis. Additionally, genetic deletion and pharmacological blockade of CB1Rs after injury in mice led to increased levels of Bcl-2 and cyclin D2 in pancreatic beta cells. These findings provide evidence for the involvement of Bcl-2 and cyclin D2 mediated by CB1Rs in the regulation of beta-cell survival and growth, and will serve as a basis for developing new therapeutic interventions to enhance beta-cell function and growth in diabetes. C1 [Kim, Jihye; Kim, Jung Seok; Rho, Jun Gi; Shin, Jung Jae; Kim, Wook] Ajou Univ, Dept Mol Sci & Technol, Suwon 16499, South Korea. [Lee, Kyung Jin] Univ Ulsan, Coll Med, Asan Inst Life Sci, Dept Convergence Med,Asan Med Ctr, Seoul 05505, South Korea. [Song, Woo Keun] Gwangju Inst Sci & Technol, Dept Life Sci, Bio Imaging & Cell Dynam Res Ctr, Kwangju 61005, South Korea. [Lee, Eun Kyung] Catholic Univ Korea, Dept Biochem, Coll Med, Seoul 06591, South Korea. [Egan, Josephine M.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. RP Kim, W (reprint author), Ajou Univ, Dept Mol Sci & Technol, Suwon 16499, South Korea.; Egan, JM (reprint author), NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. EM eganj@grc.nia.nih.gov; wookkim21@ajou.ac.kr FU Ministry of Education [NRF-2015R1A2A1A15054227, NRF-2009-0093826, NRF-2014R1A2A1A11053431]; Intramural Research Program of the NIH/NIA; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT Future FX This work was supported by a Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future and the Ministry of Education (NRF-2015R1A2A1A15054227 and NRF-2009-0093826 for WK and NRF-2014R1A2A1A11053431 for EKL). JME was supported by the Intramural Research Program of the NIH/NIA. NR 26 TC 0 Z9 0 U1 0 U2 7 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 MAR 11 PY 2016 VL 11 IS 3 AR e0150981 DI 10.1371/journal.pone.0150981 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3SC UT WOS:000371989200025 PM 26967640 ER PT J AU Troche, JR Mayne, ST Freedman, ND Shebl, FM Guertin, KA Cross, AJ Abnet, CC AF Troche, Jose Ramon Mayne, Susan T. Freedman, Neal D. Shebl, Fatma M. Guertin, Kristin A. Cross, Amanda J. Abnet, Christian C. TI Alcohol Consumption-Related Metabolites in Relation to Colorectal Cancer and Adenoma: Two Case-Control Studies Using Serum Biomarkers SO PLOS ONE LA English DT Article ID DOSE-RESPONSE METAANALYSIS; CIGARETTE-SMOKING; UNITED-STATES; RISK; EPIDEMIOLOGY; COHORT; METABOLOMICS; MORTALITY; MIGRANTS; TOBACCO AB Alcohol is a known carcinogen that may be associated with colorectal cancer. However, most epidemiologic studies assess alcoholic beverage consumption using self-reported data, leading to potential exposure misclassification. Biomarkers of alcohol consumption may provide an alternative, complementary approach that reduces misclassification and incorporates individual differences in alcohol metabolism. Therefore, we evaluated the relationship between previously identified alcohol consumption-related metabolites and colorectal cancer and adenoma using serum metabolomics data from two studies. Data on colorectal cancer were obtained from a nested case-control study of 502 US adults (252 cases, 250 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Data on colorectal adenoma were obtained from a case-control study of 197 US adults (120 cases, 77 controls) from the Navy Colon Adenoma Study. Unconditional multivariable logistic regression models were fit to calculate odds ratios (OR) and 95% confidence intervals (CI) for eight alcohol consumption-related metabolites identified in a previous analysis: ethyl glucuronide; 4-androstene-3beta, 17beta-diol disulfate 1; 5-alpha-androstan-3beta, 17beta-diol disulfate; 16-hydroxypalmitate; bilirubin (E, Z or Z, E); cyclo (-leu-pro); dihomo-linoleate (20: 2n6); and palmitoleate (16: 1n7). We found no clear association between these alcohol consumption-related metabolites and either endpoint. However, we did observe an inverse association between cyclo (-leu-pro) and colorectal adenoma that was only observed in the highest metabolite quantile (OR4th vs. 1st Quantile = 0.30, 95% CI: 0.12-0.78; P-trend = 0.047), but no association for colorectal cancer. In conclusion, there were no adverse associations between alcohol consumption-related metabolites and colorectal cancer or adenoma. C1 [Troche, Jose Ramon; Mayne, Susan T.; Shebl, Fatma M.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Troche, Jose Ramon; Freedman, Neal D.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Mayne, Susan T.; Shebl, Fatma M.] Yale Canc Ctr, New Haven, CT USA. [Guertin, Kristin A.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Cross, Amanda J.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Epidemiol & Biostat, Sch Publ Hlth, St Marys Campus,Norfolk Pl, London, England. [Mayne, Susan T.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Troche, JR (reprint author), Yale Univ, Sch Publ Hlth, New Haven, CT USA.; Troche, JR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. EM joseramon.troche@yale.edu RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health; National Institutes of Health [T32 CA105666] FX This work was partially supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health (http://www.cancer.gov/research/nci-role/intramural) and the National Institutes of Health (http://www.nih.gov/), grant T32 CA105666. NR 47 TC 0 Z9 0 U1 7 U2 12 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 MAR 11 PY 2016 VL 11 IS 3 AR e0150962 DI 10.1371/journal.pone.0150962 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3SC UT WOS:000371989200024 PM 26967509 ER PT J AU Brunk, E Mih, N Monk, J Zhang, Z O'Brien, EJ Bliven, SE Chen, K Chang, RL Bourne, PE Palsson, BO AF Brunk, Elizabeth Mih, Nathan Monk, Jonathan Zhang, Zhen O'Brien, Edward J. Bliven, Spencer E. Chen, Ke Chang, Roger L. Bourne, Philip E. Palsson, Bernhard O. TI Systems biology of the structural proteome SO BMC SYSTEMS BIOLOGY LA English DT Article ID COMPLETE GENOME SEQUENCE; LATERAL GENE-TRANSFER; ESCHERICHIA-COLI; THERMOTOGA-MARITIMA; FAMILIES DATABASE; I-TASSER; STRUCTURE PREDICTION; METABOLIC NETWORK; PROTEINS; EVOLUTION AB Background: The success of genome-scale models (GEMs) can be attributed to the high-quality, bottom-up reconstructions of metabolic, protein synthesis, and transcriptional regulatory networks on an organism-specific basis. Such reconstructions are biochemically, genetically, and genomically structured knowledge bases that can be converted into a mathematical format to enable a myriad of computational biological studies. In recent years, genome-scale reconstructions have been extended to include protein structural information, which has opened up new vistas in systems biology research and empowered applications in structural systems biology and systems pharmacology. Results: Here, we present the generation, application, and dissemination of genome-scale models with protein structures (GEM-PRO) for Escherichia coli and Thermotoga maritima. We show the utility of integrating molecular scale analyses with systems biology approaches by discussing several comparative analyses on the temperature dependence of growth, the distribution of protein fold families, substrate specificity, and characteristic features of whole cell proteomes. Finally, to aid in the grand challenge of big data to knowledge, we provide several explicit tutorials of how protein-related information can be linked to genome-scale models in a public GitHub repository (https://github.com/SBRG/GEMPro/tree/master/GEMPro_recon/). Conclusions: Translating genome-scale, protein-related information to structured data in the format of a GEM provides a direct mapping of gene to gene-product to protein structure to biochemical reaction to network states to phenotypic function. Integration of molecular-level details of individual proteins, such as their physical, chemical, and structural properties, further expands the description of biochemical network-level properties, and can ultimately influence how to model and predict whole cell phenotypes as well as perform comparative systems biology approaches to study differences between organisms. GEM-PRO offers insight into the physical embodiment of an organism's genotype, and its use in this comparative framework enables exploration of adaptive strategies for these organisms, opening the door to many new lines of research. With these provided tools, tutorials, and background, the reader will be in a position to run GEM-PRO for their own purposes. C1 [Brunk, Elizabeth; Monk, Jonathan; Zhang, Zhen; O'Brien, Edward J.; Chen, Ke; Palsson, Bernhard O.] Univ Calif La Jolla, Dept Bioengn, San Diego, CA 92093 USA. [Brunk, Elizabeth] Joint BioEnergy Inst, Emeryville, CA 94608 USA. [Mih, Nathan; O'Brien, Edward J.] Univ Calif La Jolla, Bioinformat & Syst Biol Program, San Diego, CA 92093 USA. [O'Brien, Edward J.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Chang, Roger L.] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02115 USA. [Bourne, Philip E.] NIH, Off Director, Bethesda, MD 20894 USA. RP Palsson, BO (reprint author), Univ Calif La Jolla, Dept Bioengn, San Diego, CA 92093 USA. EM palsson@eng.ucsd.edu OI Bliven, Spencer/0000-0002-1200-1698 FU Swiss National Science Foundation [p2elp2_148961]; Gordon and Betty Moore Foundation [GBMF 2550.04]; National Institutes of Health [GM057089]; Intramural Research Program of the National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health FX The authors acknowledge support from the Swiss National Science Foundation (grant p2elp2_148961 to E.C.B), the Gordon and Betty Moore Foundation GBMF 2550.04 Life Sciences Research Foundation postdoctoral fellowship (to R.L.C.). We also acknowledge funding from the National Institutes of Health (grant GM057089). This research was supported in part by the Intramural Research Program of the National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health (support to S.B. and P.B.). The authors also gratefully acknowledge NERSC supercomputer facilities and Ali Ebrahim for technical support. NR 114 TC 7 Z9 7 U1 3 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD MAR 11 PY 2016 VL 10 AR 26 DI 10.1186/s12918-016-0271-6 PG 16 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DG0TU UT WOS:000371779400001 PM 26969117 ER PT J AU Zhao, F Zhou, J Li, R Dudley, EA Ye, XQ AF Zhao, Fei Zhou, Jun Li, Rong Dudley, Elizabeth A. Ye, Xiaoqin TI Novel function of LHFPL2 in female and male distal reproductive tract development SO SCIENTIFIC REPORTS LA English DT Article ID VAS-DEFERENS; EARLY-PREGNANCY; POSTWEANING EXPOSURE; DIETARY ZEARALENONE; GENISTEIN EXPOSURE; VAGINAL ATRESIA; HEARING-LOSS; HAIR-CELLS; MICE; GENE AB Congenital reproductive tract anomalies could impair fertility. Female and male reproductive tracts are developed from Mullerian ducts and Wolffian ducts, respectively, involving initiation, elongation and differentiation. Genetic basis solely for distal reproductive tract development is largely unknown. Lhfpl2 (lipoma HMGIC fusion partner-like 2) encodes a tetra-transmembrane protein with unknown functions. It is expressed in follicle cells of ovary and epithelial cells of reproductive tracts. A spontaneous point mutation of Lhfpl2 (LHFPL2(G102E)) leads to infertility in 100% female mice, which have normal ovarian development, ovulation, uterine development, and uterine response to exogenous estrogen stimulation, but abnormal upper longitudinal vaginal septum and lower vaginal agenesis. Infertility is also observed in similar to 70% mutant males, which have normal mating behavior and sperm counts, but abnormal distal vas deferens convolution resulting in complete and incomplete blockage of reproductive tract in infertile and fertile males, respectively. On embryonic day 15.5, mutant Mullerian ducts and Wolffian ducts have elongated but their duct tips are enlarged and fail to merge with the urogenital sinus. These findings provide a novel function of LHFPL2 and a novel genetic basis for distal reproductive tract development; they also emphasize the importance of an additional merging phase for proper reproductive tract development. C1 [Zhao, Fei; Zhou, Jun; Li, Rong; Dudley, Elizabeth A.; Ye, Xiaoqin] Univ Georgia, Coll Vet Med, Dept Physiol & Pharmacol, Athens, GA 30602 USA. [Zhao, Fei; Zhou, Jun; Li, Rong; Dudley, Elizabeth A.; Ye, Xiaoqin] Univ Georgia, Interdisciplinary Toxicol Program, Athens, GA 30602 USA. [Zhao, Fei] NIEHS, Reprod Dev Biol Grp, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. RP Ye, XQ (reprint author), Univ Georgia, Coll Vet Med, Dept Physiol & Pharmacol, Athens, GA 30602 USA.; Ye, XQ (reprint author), Univ Georgia, Interdisciplinary Toxicol Program, Athens, GA 30602 USA. EM ye@uga.edu FU Office of the Vice President for Research, Interdisciplinary Toxicology Program; National Institutes of Health [NIH R15HD066301, NIH R01HD065939]; ORWH; NICHD; Department of Physiology and Pharmacology at the University of Georgia FX The authors thank the Department of Pathology in the College of Veterinary Medicine, University of Georgia for access to the imaging system; Office of the Vice President for Research, Interdisciplinary Toxicology Program, and Department of Physiology and Pharmacology at the University of Georgia, the National Institutes of Health (NIH R15HD066301 and NIH R01HD065939 (co-funded by ORWH and NICHD) to XY) for financial support. NR 62 TC 0 Z9 0 U1 2 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 MAR 11 PY 2016 VL 6 AR 23037 DI 10.1038/srep23037 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG1WJ UT WOS:000371857900001 PM 26964900 ER PT J AU Hoppe, T Petrone, A AF Hoppe, Travis Petrone, Anna TI Integer sequence discovery from small graphs SO DISCRETE APPLIED MATHEMATICS LA English DT Article DE Graph; Integer sequence; Database; Invariant; Generator ID DATABASE; GENERATION AB We have exhaustively enumerated all simple, connected graphs of a finite order and have computed a selection of invariants over this set. Integer sequences were constructed from these invariants and checked against the Online Encyclopedia of Integer Sequences (OEIS). 141 new sequences were added and six sequences were extended. From the graph database, we were able to programmatically suggest relationships among the invariants. It will be shown that we can readily visualize any sequence of graphs with a given criteria. The code has been released as an open-source framework for further analysis and the database was constructed to be extensible to invariants not considered in this work. Published by Elsevier B.V. C1 [Hoppe, Travis] NIDDK, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Petrone, Anna] Univ Maryland, Dept Civil Engn, Bethesda, MD USA. RP Hoppe, T (reprint author), NIDDK, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hoppeta@mail.nih.gov OI Hoppe, Travis/0000-0002-4694-3050; Petrone, Anna/0000-0002-1226-7525 FU Intramural NIH HHS [Z99 DK999999] NR 35 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-218X EI 1872-6771 J9 DISCRETE APPL MATH JI Discret Appl. Math. PD MAR 11 PY 2016 VL 201 BP 172 EP 181 DI 10.1016/j.dam.2015.07.017 PG 10 WC Mathematics, Applied SC Mathematics GA DE0KF UT WOS:000370313100014 PM 27034526 ER PT J AU Ramsden, CE Ringel, A Majchrzak-Hong, SF Yang, J Blanchard, H Zamora, D Loewke, JD Rapoport, SI Hibbeln, JR Davis, JM Hammock, BD Taha, AY AF Ramsden, Christopher E. Ringel, Amit Majchrzak-Hong, Sharon F. Yang, Jun Blanchard, Helene Zamora, Daisy Loewke, James D. Rapoport, Stanley I. Hibbeln, Joseph R. Davis, John M. Hammock, Bruce D. Taha, Ameer Y. TI Dietary linoleic acid-induced alterations in pro- and anti-nociceptive lipid autacoids: Implications for idiopathic pain syndromes? SO MOLECULAR PAIN LA English DT Article DE Oxylipin; linoleic acid; omega-6; omega-3; idiopathic; pain ID POLYUNSATURATED FATTY-ACIDS; PSORIATIC SKIN; INFLAMMATORY HYPERALGESIA; ARACHIDONIC-ACID; RANDOMIZED-TRIAL; RAT-BRAIN; TRPV1; N-3; METABOLITES; MIGRAINE AB Background: Chronic idiopathic pain syndromes are major causes of personal suffering, disability, and societal expense. Dietary n-6 linoleic acid has increased markedly in modern industrialized populations over the past century. These high amounts of linoleic acid could hypothetically predispose to physical pain by increasing the production of pro-nociceptive linoleic acid-derived lipid autacoids and by interfering with the production of anti-nociceptive lipid autacoids derived from n-3 fatty acids. Here, we used a rat model to determine the effect of increasing dietary linoleic acid as a controlled variable for 15 weeks on nociceptive lipid autacoids and their precursor n-6 and n-3 fatty acids in tissues associated with idiopathic pain syndromes. Results: Increasing dietary linoleic acid markedly increased the abundance of linoleic acid and its pro-nociceptive derivatives and reduced the abundance of n-3 eicosapentaenoic acid and docosahexaenoic acid and their anti-nociceptive monoepoxide derivatives. Diet-induced changes occurred in a tissue-specific manner, with marked alterations of nociceptive lipid autacoids in both peripheral and central tissues, and the most pronounced changes in their fatty acid precursors in peripheral tissues. Conclusions: The present findings provide biochemical support for the hypothesis that the high linoleic acid content of modern industrialized diets may create a biochemical susceptibility to develop chronic pain. Dietary linoleic acid lowering should be further investigated as part of an integrative strategy for the prevention and management of idiopathic pain syndromes. C1 [Ramsden, Christopher E.; Ringel, Amit; Majchrzak-Hong, Sharon F.; Loewke, James D.; Hibbeln, Joseph R.] NIAAA, Lab Membrane Biochem, NIH, Bethesda, MD USA. [Ramsden, Christopher E.] Univ N Carolina, Dept Phys Med & Rehabil, Chapel Hill, NC USA. [Yang, Jun; Hammock, Bruce D.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Yang, Jun; Rapoport, Stanley I.; Hammock, Bruce D.] Univ Calif Davis, UCD Comprehens Canc Ctr, Sacramento, CA 95817 USA. [Blanchard, Helene; Taha, Ameer Y.] NIA, Bethesda, MD 20892 USA. [Zamora, Daisy; Davis, John M.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Davis, John M.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Taha, Ameer Y.] Univ Calif Davis, Coll Agr & Environm Sci, Dept Food Sci & Technol, Davis, CA 95616 USA. RP Ramsden, CE (reprint author), NIAAA, NIH, 31 Ctr Dr,Bldg 31,Room 1B54C, Rockville, MD 20852 USA. EM chris.ramsden@nih.gov FU Mayday Fund; NIEHS [RO1ES002710]; NINDS [U54NS079202]; NIDDK [U24097154]; National Institute on Aging; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Partial support was provided by the Mayday Fund, NIEHS RO1ES002710, NINDS U54NS079202, and NIDDK U24097154, and the Intramural Programs of the National Institute on Aging and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 53 TC 1 Z9 1 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD MAR 10 PY 2016 VL 12 DI 10.1177/1744806916636386 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DM9XT UT WOS:000376719700001 ER PT J AU Shah, MA Renfro, LA Allegra, CJ Andre, T de Gramont, A Schmoll, HJ Haller, DG Alberts, SR Yothers, G Sargent, DJ AF Shah, Manish A. Renfro, Lindsay A. Allegra, Carmen J. Andre, Thierry de Gramont, Aimery Schmoll, Hans-Joachim Haller, Daniel G. Alberts, Steven R. Yothers, Greg Sargent, Daniel J. TI Impact of Patient Factors on Recurrence Risk and Time Dependency of Oxaliplatin Benefit in Patients With Colon Cancer: Analysis From Modern-Era Adjuvant Studies in the Adjuvant Colon Cancer End Points (ACCENT) Database SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID FOLLOW-UP; STAGES II; STAGE-II; FLUOROURACIL; LEUCOVORIN; SURVIVAL; TRIAL; PROTOCOL AB Purpose Fluorouracil plus leucovorin (FU + LV) adjuvant chemotherapy reduced the risk of recurrence and death across all time points in a pooled analysis of 20,898 patients with colon cancer from 18 randomized studies. The impact of oxaliplatin added to FU + LV on the time course of recurrence and survival remains unknown. Patients and Methods A total of 12,233 patients enrolled to the randomized trials C-07, C-08, N0147, MOSAIC (Adjuvant Treatment of Colon Cancer), and XELOXA (Adjuvant XELOX) were pooled to examine the impact of oxaliplatin and tumor-specific factors on the time course of recurrence and death. For each end point, continuous-time risk was modeled over 6 years post treatment in all oxaliplatin-treated patients and patients concurrently randomized to FU + LV with or without oxaliplatin; the latter analyses supported time-dependent treatment comparisons. Results Addition of oxaliplatin significantly reduced the risk of recurrence within the first 14 months post treatment for patients with stage II disease and within the first 4 years for patients with stage III disease. Oxaliplatin also significantly reduced risk of death from 2 to 6 years post treatment for patients with stage III disease, with no differences in timing of outcomes between treatment groups (ie, oxaliplatin did not simply postpone recurrence or death compared with FU + LV alone). Patients with stage II disease receiving oxaliplatin did not exhibit a significant reduction in risk of death in the first 6 years post treatment. Recurrence risk peaked near 14 months for both treatments, and risk of recurrence and death increased with increased tumor and nodal burden. Conclusions These analyses support the addition of oxaliplatin to fluoropyrimidine-based adjuvant therapy in patients with stage III disease and underscore the need for adequate surveillance of patients with colon cancer during the first 3 years after adjuvant therapy. (C) 2016 by American Society of Clinical Oncology C1 [Shah, Manish A.] New York Presbyterian Hosp, Weill Cornell Med Coll, New York, NY USA. [Renfro, Lindsay A.; Alberts, Steven R.; Sargent, Daniel J.] Mayo Clin, Rochester, MN USA. [Allegra, Carmen J.] Univ Florida, Gainesville, FL USA. [Andre, Thierry] Hop St Antoine, F-75571 Paris, France. [de Gramont, Aimery] Franco British Inst, Levallois Perret, France. [Schmoll, Hans-Joachim] Univ Clin Halle Saale, Halle, Germany. [Haller, Daniel G.] Univ Penn, Philadelphia, PA 19104 USA. [Yothers, Greg] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. RP Shah, MA (reprint author), Cornell Univ, New York Presbyterian Hosp, Med, New York, NY 10021 USA.; Shah, MA (reprint author), Cornell Univ, New York Presbyterian Hosp, Weill Med Coll, Ctr Adv Digest Care, New York, NY 10021 USA. EM mas9313@med.cornell.edu OI Yothers, Greg/0000-0002-7965-7333 FU National Cancer Institute [CA25224] FX Supported by Grant No. CA25224 from the National Cancer Institute. NR 19 TC 5 Z9 5 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2016 VL 34 IS 8 BP 843 EP + DI 10.1200/JCO.2015.63.0558 PG 14 WC Oncology SC Oncology GA DJ6OV UT WOS:000374333700016 PM 26811529 ER PT J AU Jacoby, E Yang, YM Qin, HY Chien, CD Kochenderfer, JN Fry, TJ AF Jacoby, Elad Yang, Yinmeng Qin, Haiying Chien, Christopher D. Kochenderfer, James N. Fry, Terry J. TI Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; VERSUS-HOST-DISEASE; CHIMERIC ANTIGEN RECEPTOR; DONOR LEUKOCYTE INFUSIONS; MALIGNANCY; APOPTOSIS; CANCER; MODEL; RECONSTITUTION AB Acute lymphoblastic leukemia (ALL) persisting or relapsing following bone marrow transplantation (BMT) has a dismal prognosis. Success with chimeric antigen receptor (CAR) T cells offers an opportunity to treat these patients with leukemia-redirected donor-derived T cells, which may be more functional than T cells derived from patients with leukemia but have the potential to mediate graft-versus-host disease (GVHD). We, together with others, have previously demonstrated tumor-specific T-cell dysfunction in the allogeneic environment. Here, we studied CAR T-cell function following BMT using an immunocompetent murine model of minor mismatched allogeneic transplantation followed by donor-derived CD19-CAR T cells. Allogeneic donor-derived CD19-CAR T cells eliminated residual ALL with equal potency to those administered after syngeneic BMT. Surprisingly, allogeneic CAR T cells mediated lethal acute GVHD with early mortality, which is atypical for this minor mismatch model. We demonstrated that both allogeneic and syngeneic CAR T cells show initial expansion as effector T cells, with a higher peak but rapid deletion of allogeneic CAR T cells. Interestingly, CAR-mediated acute GVHD was only seen in the presence of leukemia, suggesting CAR-target interactions induced GVHD. Indeed, serum interleukin (IL)-6 was elevated only in the presence of both leukemia and CAR T cells, and IL-6 neutralization ameliorated the severity of GVHD in a delayed donor lymphocyte infusion model. Finally, allogeneic CD4(+) CAR T cells were responsible for GVHD, which correlated with their ability to produce IL-6 upon CAR stimulation. Altogether, we demonstrate that donor-derived allogeneic CAR T cells are active but have the capacity to drive GVHD. C1 [Jacoby, Elad; Yang, Yinmeng; Qin, Haiying; Chien, Christopher D.; Fry, Terry J.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 1-3750,10 Ctr Dr, Bethesda, MD 20892 USA. [Kochenderfer, James N.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Fry, TJ (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 1-3750,10 Ctr Dr, Bethesda, MD 20892 USA. EM fryt@mail.nih.gov NR 45 TC 12 Z9 12 U1 2 U2 7 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 MAR 10 PY 2016 VL 127 IS 10 BP 1361 EP 1370 DI 10.1182/blood-2015-08-664250 PG 10 WC Hematology SC Hematology GA DI4XC UT WOS:000373501700021 PM 26660684 ER PT J AU Fischbach, MA Segre, JA AF Fischbach, Michael A. Segre, Julia A. TI Signaling in Host-Associated Microbial Communities SO CELL LA English DT Review ID INVASIVE ESCHERICHIA-COLI; HUMAN GUT MICROBIOME; FUNGUS-GROWING ANTS; REGULATORY T-CELLS; CROHNS-DISEASE; CLOSTRIDIUM-DIFFICILE; FOOD-INTAKE; COMMENSAL; DIET; BACTERIA AB Human-associated microbiota form and stabilize communities based on interspecies interactions. We review how these microbe-microbe and microbe-host interactions are communicated to shape communities over a human's lifes pan,including periods of health and disease. Modeling and dissecting signaling in host-associated communities is crucial to understand their function and will open the door to therapies that prevent or correct microbial community dysfunction to promote health and treat disease. C1 [Fischbach, Michael A.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Fischbach, Michael A.] Univ Calif San Francisco, Calif Inst Quantitat Biosci, San Francisco, CA 94143 USA. [Segre, Julia A.] Natl Human Genome Res Inst, Microbial Genom Sect, Translat & Funct Genom Branch, Bethesda, MD 20892 USA. RP Fischbach, MA (reprint author), Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA.; Fischbach, MA (reprint author), Univ Calif San Francisco, Calif Inst Quantitat Biosci, San Francisco, CA 94143 USA.; Segre, JA (reprint author), Natl Human Genome Res Inst, Microbial Genom Sect, Translat & Funct Genom Branch, Bethesda, MD 20892 USA. EM fischbach@fischbachgroup.org; jsegre@nhgri.nih.gov FU NIH [R01 DK101674, R01 AI101018]; Pfizer; David and Lucile Packard Foundation; Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease Award; Byers Award in Basic Science from the Program for Breakthrough Biomedical Research; NIH NHGRI Intramural Research Program FX M.A.F. is supported by NIH R01 DK101674, NIH R01 AI101018, a research award from Pfizer, a Fellowship for Science and Engineering from the David and Lucile Packard Foundation, a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease Award, and the Byers Award in Basic Science from the Program for Breakthrough Biomedical Research. J.A.S. is supported by NIH NHGRI Intramural Research Program. M.A.F. is on the scientific advisory board of NGM Biopharmaceuticals, a co-founder of Revolution Medicines, and a director of Achaogen. NR 99 TC 6 Z9 7 U1 23 U2 55 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 MAR 10 PY 2016 VL 164 IS 6 BP 1288 EP 1300 DI 10.1016/j.cell.2016.02.037 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DH4VY UT WOS:000372784900025 PM 26967294 ER PT J AU Farrell, MS McCorvy, JD Huang, XP Urban, DJ White, KL Giguere, PM Doak, AK Bernstein, AI Stout, KA Park, SM Rodriguiz, RM Gray, BW Hyatt, WS Norwood, AP Webster, KA Gannon, BM Miller, GW Porter, JH Shoichet, BK Fantegrossi, WE Wetsel, WC Roth, BL AF Farrell, Martilias S. McCorvy, John D. Huang, Xi-Ping Urban, Daniel J. White, Kate L. Giguere, Patrick M. Doak, Allison K. Bernstein, Alison I. Stout, Kristen A. Park, Su Mi Rodriguiz, Ramona M. Gray, Bradley W. Hyatt, William S. Norwood, Andrew P. Webster, Kevin A. Gannon, Brenda M. Miller, Gary W. Porter, Joseph H. Shoichet, Brian K. Fantegrossi, William E. Wetsel, William C. Roth, Bryan L. TI In Vitro and In Vivo Characterization of the Alkaloid Nuciferine SO PLOS ONE LA English DT Article ID DISCRIMINATIVE STIMULUS PROPERTIES; ATYPICAL ANTIPSYCHOTIC-DRUG; PROTEIN-COUPLED RECEPTORS; HIGH-THROUGHPUT SCREEN; COLLOIDAL AGGREGATION; C57BL/6 MICE; SEROTONIN RECEPTORS; CLOZAPINE; AGONIST; RATS AB Rationale The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays. Methods Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms. Results Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D-2, D-5 and 5-HT6, an agonist at 5-HT1A and D-4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy. Conclusions The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions. C1 [Farrell, Martilias S.; McCorvy, John D.; Huang, Xi-Ping; Urban, Daniel J.; White, Kate L.; Giguere, Patrick M.; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Program Neurosci, Chapel Hill, NC USA. [Roth, Bryan L.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Carolina Inst Dev Disabil, Chapel Hill, NC USA. [Roth, Bryan L.] Univ N Carolina, Sch Pharm, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Chapel Hill, NC USA. [Gray, Bradley W.; Hyatt, William S.; Norwood, Andrew P.; Gannon, Brenda M.; Fantegrossi, William E.] Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA. [Webster, Kevin A.; Porter, Joseph H.] Virginia Commonwealth Univ, Dept Psychol, Box 2018, Richmond, VA 23284 USA. [Doak, Allison K.; Shoichet, Brian K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA. [Bernstein, Alison I.; Stout, Kristen A.; Miller, Gary W.] Emory Univ, Dept Environm Hlth, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Bernstein, Alison I.; Stout, Kristen A.] Emory Univ, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA. [Park, Su Mi; Rodriguiz, Ramona M.; Wetsel, William C.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Mouse Behav & Neuroendocrine Anal Core Facil, Durham, NC USA. [Park, Su Mi; Rodriguiz, Ramona M.; Wetsel, William C.] Duke Univ, Med Ctr, Dept Cell Biol, Mouse Behav & Neuroendocrine Anal Core Facil, Durham, NC 27710 USA. [Park, Su Mi; Rodriguiz, Ramona M.; Wetsel, William C.] Duke Univ, Med Ctr, Dept Neurobiol, Mouse Behav & Neuroendocrine Anal Core Facil, Durham, NC 27710 USA. RP Farrell, MS (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. EM martilias_farrell@med.unc.edu FU National Institutes of Health [1F31MH091921]; National Institutes of Mental Health Psychoactive Drug Screening Program [RO1MH61887, U19MH82441]; Michael Hooker Chair in Pharmacology [P30 ES 019776, T32 ES 012870]; AIB; NIH [GM71630, GM71896] FX This work was funded by National Institutes of Health Grants #1F31MH091921 to MSF and RO1MH61887, U19MH82441, the National Institutes of Mental Health Psychoactive Drug Screening Program and the Michael Hooker Chair in Pharmacology to BLR; P30 ES 019776 and T32 ES 012870 to GWM and AIB, and and NIH GM71630 and GM71896 to BKS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 2 Z9 2 U1 6 U2 10 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 MAR 10 PY 2016 VL 11 IS 3 AR e0150602 DI 10.1371/journal.pone.0150602 PG 27 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3TL UT WOS:000371993000044 PM 26963248 ER PT J AU Sorber, R Teper, Y Abisoye-Ogunniyan, A Waterfall, JJ Davis, S Killian, JK Pineda, M Ray, S McCord, MR Pflicke, H Burkett, SS Meltzer, PS Rudloff, U AF Sorber, Rebecca Teper, Yaroslav Abisoye-Ogunniyan, Abisola Waterfall, Joshua J. Davis, Sean Killian, J. Keith Pineda, Marbin Ray, Satyajit McCord, Matt R. Pflicke, Holger Burkett, Sandra Sczerba Meltzer, Paul S. Rudloff, Udo TI Whole Genome Sequencing of Newly Established Pancreatic Cancer Lines Identifies Novel Somatic Mutation (c.2587G>A) in Axon Guidance Receptor Plexin A1 as Enhancer of Proliferation and Invasion SO PLOS ONE LA English DT Article ID DRUG-SENSITIVITY; PLUS GEMCITABINE; CLINICAL-TRIALS; ADENOCARCINOMA; PATHWAYS; CELLS; METASTASIS; MELANOMA; TARGETS; GENES AB The genetic profile of human pancreatic cancers harbors considerable heterogeneity, which suggests a possible explanation for the pronounced inefficacy of single therapies in this disease. This observation has led to a belief that custom therapies based on individual tumor profiles are necessary to more effectively treat pancreatic cancer. It has recently been discovered that axon guidance genes are affected by somatic structural variants in up to 25% of human pancreatic cancers. Thus far, however, some of these mutations have only been correlated to survival probability and no function has been assigned to these observed axon guidance gene mutations in pancreatic cancer. In this study we established three novel pancreatic cancer cell lines and performed whole genome sequencing to discover novel mutations in axon guidance genes that may contribute to the cancer phenotype of these cells. We discovered, among other novel somatic variants in axon guidance pathway genes, a novel mutation in the PLXNA1 receptor (c.2587G>A) in newly established cell line SB.06 that mediates oncogenic cues of increased invasion and proliferation in SB.06 cells and increased invasion in 293T cells upon stimulation with the receptor's natural ligand semaphorin 3A compared to wild type PLXNA1 cells. Mutant PLXNA1 signaling was associated with increased Rho-GTPase and p42/p44 MAPK signaling activity and cytoskeletal expansion, but not changes in E-cadherin, vimentin, or metalloproteinase 9 expression levels. Pharmacologic inhibition of the Rho-GTPase family member CDC42 selectively abrogated PLXNA1 c.2587G>A-mediated increased invasion. These findings provide in-vitro confirmation that somatic mutations in axon guidance genes can provide oncogenic gain-of-function signals and may contribute to pancreatic cancer progression. C1 [Sorber, Rebecca; Teper, Yaroslav; Abisoye-Ogunniyan, Abisola; McCord, Matt R.; Pflicke, Holger; Rudloff, Udo] NCI, Thorac & GI Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Waterfall, Joshua J.; Davis, Sean; Killian, J. Keith; Pineda, Marbin; Meltzer, Paul S.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Ray, Satyajit] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Burkett, Sandra Sczerba] NCI, Mol Cytogenet Sect, MCGP, Ctr Canc Res,NIH, Frederick, MD 20892 USA. [Abisoye-Ogunniyan, Abisola] Tuskegee Univ, Dept Biol, Tuskegee, AL 36088 USA. [Abisoye-Ogunniyan, Abisola] Tuskegee Univ, Ctr Canc Res, Tuskegee, AL 36088 USA. RP Rudloff, U (reprint author), NCI, Thorac & GI Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM rudloffu@mail.nih.gov FU NIH; Pfizer Inc; Doris Duke Charitable Foundation; Newport Foundation; American Association for Dental Research; Howard Hughes Medical Institute; Colgate-Palmolive Company FX This research was made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, The Doris Duke Charitable Foundation, The Newport Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. NR 42 TC 2 Z9 2 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 10 PY 2016 VL 11 IS 3 AR e0149833 DI 10.1371/journal.pone.0149833 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3TL UT WOS:000371993000020 PM 26962861 ER PT J AU Yu, SQ Cai, YY Lyons, C Johnson, RF Postnikova, E Mazur, S Johnson, JC Radoshitzky, SR Bailey, AL Lauck, M Goldberg, TL O'Connor, DH Jahrling, PB Friedrich, TC Kuhn, JH AF Yu, Shuiqing Cai, Yingyun Lyons, Cassandra Johnson, Reed F. Postnikova, Elena Mazur, Steven Johnson, Joshua C. Radoshitzky, Sheli R. Bailey, Adam L. Lauck, Michael Goldberg, Tony L. O'Connor, David H. Jahrling, Peter B. Friedrich, Thomas C. Kuhn, Jens H. TI Specific Detection of Two Divergent Simian Arteriviruses Using RNAscope In Situ Hybridization SO PLOS ONE LA English DT Article ID RESPIRATORY-SYNDROME-VIRUS; HEMORRHAGIC-FEVER; MACAQUES; DISEASE; TISSUES; RNA; CIRCOVIRUS; INFECTION AB Simian hemorrhagic fever (SHF) is an often lethal disease of Asian macaques. Simian hemorrhagic fever virus (SHFV) is one of at least three distinct simian arteriviruses that can cause SHF, but pathogenesis studies using modern methods have been scarce. Even seemingly straightforward studies, such as examining viral tissue and cell tropism in vivo, have been difficult to conduct due to the absence of standardized SHFV-specific reagents. Here we report the establishment of an in situ hybridization assay for the detection of SHFV and distantly related Kibale red colobus virus 1 (KRCV-1) RNA in cell culture. In addition, we detected SHFV RNA in formalin-fixed, paraffin-embedded tissues from an infected rhesus monkey (Macaca mulatta). The assay is easily performed and can clearly distinguish between SHFV and KRCV-1. Thus, if further developed, this assay may be useful during future studies evaluating the mechanisms by which a simian arterivirus with a restricted cell tropism can cause a lethal nonhuman primate disease similar in clinical presentation to human viral hemorrhagic fevers. C1 [Yu, Shuiqing; Cai, Yingyun; Lyons, Cassandra; Postnikova, Elena; Mazur, Steven; Johnson, Joshua C.; Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [Johnson, Reed F.; Jahrling, Peter B.] NIAID, Emerging Infect Pathogens Sect, NIH, Frederick, MD USA. [Radoshitzky, Sheli R.] US Army Med Res Inst Infect Dis, Frederick, MD USA. [Bailey, Adam L.; Lauck, Michael; Goldberg, Tony L.; O'Connor, David H.; Friedrich, Thomas C.] Univ Wisconsin, Madison, WI USA. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. EM kuhnjens@mail.nih.gov OI Friedrich, Thomas/0000-0001-9831-6895 FU Battelle Memorial Institute's prime contract the US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I]; Battelle Memorial Institute; Tunnell Government Services; MRIGlobal; NIAID Division of Intramural Research; National Institutes of Health (NIH) [TW009237, R01 AI077376]; Office of Research Infrastructure Programs (ORIP) [P51OD011106] FX The content of this publication does not necessarily reflect the views or policies of the US Department of Defense, the US Department of Health and Human Services, the US Department of the Army, or the institutions and companies affiliated with the authors. This work was funded in part through Battelle Memorial Institute's prime contract the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016I (S.Y., Y.C., C.L., E.P., S.M., J.C.J., P.B.J., J.H.K.). S.Y. and J.C.J. performed this work as employees of Battelle Memorial Institute. Subcontractors to Battelle Memorial Institute who performed this work are: Y.C., C.L., E.P., and J.H.K, employees of Tunnell Government Services, Inc.; and S.M., an employee of MRIGlobal. Battelle Memorial Institute, Tunnell Government Services, and MRIGlobal provided support in the form of salaries, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. All work under contract HHSN272200700016I is performed under the agreement/understanding that it will belong to the client and will be affiliated directly to the NIH/NIAID Integrated Research Facility at Fort Detrick. The specific roles of these authors are articulated in the 'author contributions' section. This work was also supported, in part, by the NIAID Division of Intramural Research (R.F.J., P.B.J.), by National Institutes of Health (NIH) grant TW009237 as part of the joint NIH-NSF Ecology of Infectious Disease program, grant R01 AI077376, and by the Office of Research Infrastructure Programs (ORIP) grant P51OD011106 (A.L.B., M.L., T.L.G., D.H.O'C., T.C.F.). These funders did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 0 Z9 0 U1 0 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 MAR 10 PY 2016 VL 11 IS 3 AR e0151313 DI 10.1371/journal.pone.0151313 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3TL UT WOS:000371993000136 PM 26963736 ER PT J AU Gramlich, PA Westbroek, W Feldman, RA Awad, O Mello, N Remington, MP Sun, Y Zhang, WJ Sidransky, E Betenbaugh, MJ Fishman, PS AF Gramlich, Paul A. Westbroek, Wendy Feldman, Ricardo A. Awad, Ola Mello, Nicholas Remington, Mary P. Sun, Ying Zhang, Wujuan Sidransky, Ellen Betenbaugh, Michael J. Fishman, Paul S. TI A peptide-linked recombinant glucocerebrosidase for targeted neuronal delivery: Design, production, and assessment SO JOURNAL OF BIOTECHNOLOGY LA English DT Article DE Gaucher's disease (GD); Glucocerebrosidase; Enzyme-replacement therapy; Linker design; Rabies-derived peptide ID PROTEIN TRANSDUCTION DOMAIN; CELL-PENETRATING PEPTIDES; ACID BETA-GLUCOSIDASE; TOXIN FRAGMENT-C; ENZYME REPLACEMENT THERAPY; CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; GAUCHER-DISEASE; TETANUS TOXIN; FUSION PROTEIN AB Although recombinant glucocerebrosidase (GCase) is the standard therapy for the inherited lysosomal storage disease Gaucher's disease (GD), enzyme replacement is not effective when the central nervous system is affected. We created a series of recombinant genes/proteins where GCase was linked to different membrane binding peptides including the Tat peptide, the rabies glycoprotein derived peptide (RDP), the binding domain from tetanus toxin (TTC), and a tetanus like peptide (Tet1). The majority of these proteins were well-expressed in a mammalian producer cell line (HEK 293F). Purified recombinant Tat-GCase and RDP-GCase showed similar GCase protein delivery to a neuronal cell line that genetically lacks the functional enzyme, and greater delivery than control GCase, Cerezyme (Genzyme). This initial result was unexpected based on observations of superior protein delivery to neurons with RDP as a vector. A recombinant protein where a fragment of the flexible hinge region from IgA (IgAh) was introduced between RDP and GCase showed substantially enhanced GCase neuronal delivery (2.5 times over Tat-GCase), suggesting that the original construct resulted in interference with the capacity of RDP to bind neuronal membranes. Extended treatment of these knockout neuronal cells with either Tat-GCase or RDP-IgAh-GCase resulted in an >90% reduction in the lipid substrate glucosylsphingosine, approaching normal levels. Further in vivo studies of RDP-IgAh-GCase as well as Tat-GCase are warranted to assess their potential as treatments for neuronopathic forms of GD. These peptide vectors are especially attractive as they have the potential to carry a protein across the blood-brain barrier, avoiding invasive direct brain delivery. (C) 2016 Elsevier B.V. All rights reserved. C1 [Gramlich, Paul A.; Betenbaugh, Michael J.] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21201 USA. [Gramlich, Paul A.; Mello, Nicholas; Remington, Mary P.; Fishman, Paul S.] Vet Affairs Maryland Hlth Care Serv, Res Serv, Baltimore, MD USA. [Westbroek, Wendy; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Feldman, Ricardo A.; Awad, Ola] Univ Maryland, Sch Med, Dept Microbiol & Immunol, College Pk, MD USA. [Mello, Nicholas] Univ Maryland, Sch Med, Dept Mol Med, College Pk, MD USA. [Sun, Ying] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Sun, Ying] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. [Zhang, Wujuan] Cincinnati Childrens Hosp Med Ctr, Div Pathol & Lab Med, Cincinnati, OH 45229 USA. [Fishman, Paul S.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. RP Gramlich, PA (reprint author), Johns Hopkins Univ, 3400 N Charles St Maryland Hall 221, Baltimore, MD 21201 USA. EM pgramli1@jhu.edu FU Department of Veteran's Administration REAP fellowship FX The authors would like to thank the Department of Veteran's Administration REAP fellowship for generous funding of this research. NR 68 TC 4 Z9 4 U1 4 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1656 EI 1873-4863 J9 J BIOTECHNOL JI J. Biotechnol. PD MAR 10 PY 2016 VL 221 BP 1 EP 12 DI 10.1016/j.jbiotec.2016.01.015 PG 12 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DF6IO UT WOS:000371459300001 PM 26795355 ER PT J AU Ma, C Kesarwala, AH Eggert, T Medina-Echeverz, J Kleiner, DE Jin, P Stroncek, DF Terabe, M Kapoor, V ElGindi, M Han, MJ Thornton, AM Zhang, HB Egger, M Luo, J Felsher, DW McVicar, DW Weber, A Eikenwalder, MH Greten, TF AF Ma, Chi Kesarwala, Aparna H. Eggert, Tobias Medina-Echeverz, Jose Kleiner, David E. Jin, Ping Stroncek, David F. Terabe, Masaki Kapoor, Veena ElGindi, Mei Han, Miaojun Thornton, Angela M. Zhang, Haibo Egger, Michele Luo, Ji Felsher, Dean W. McVicar, Daniel W. Weber, Achim Eikenwalder, Mathias H. Greten, Tim F. TI NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis SO NATURE LA English DT Article ID FATTY LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; HEPATOCELLULAR-CARCINOMA; SUPPRESSOR-CELLS; LIPID-METABOLISM; MICE; CANCER; OBESITY; HEPATOCYTES; INFLAMMATION AB Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer(1-5). However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4+ but not CD8+ T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4+ T lymphocytes have greater mitochondrial mass than CD8+ T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4+ T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4+ T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance. C1 [Ma, Chi; Eggert, Tobias; Medina-Echeverz, Jose; ElGindi, Mei; Han, Miaojun; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Kesarwala, Aparna H.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Stroncek, David F.] NCI, Lab Pathol, NIH, Bethesda, MD 20892 USA. [Jin, Ping; Stroncek, David F.] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Terabe, Masaki] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Kapoor, Veena] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Thornton, Angela M.] NIAID, Lab Immunol, NIH, Bethesda, MD 20892 USA. [Zhang, Haibo; Luo, Ji] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Egger, Michele; Weber, Achim] Univ Zurich, Inst Surg Pathol, CH-8091 Zurich, Switzerland. [Egger, Michele; Weber, Achim] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Felsher, Dean W.] Stanford Univ, Dept Pathol & Med, Div Oncol, Stanford, CA 94305 USA. [McVicar, Daniel W.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Eikenwalder, Mathias H.] Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Virol, D-81675 Munich, Germany. [Eikenwalder, Mathias H.] German Canc Res Ctr, Div Chron Inflammat & Canc, D-69120 Heidelberg, Germany. RP Greten, TF (reprint author), NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM tim.greten@nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases; Intramural Program Grant, NIH, National Cancer Institute (NCI) [ZIABC011303]; European Research Council; Stiftung Experimentelle Biomedizin (Hofschneider Stiftung); Pre-clinical Comprehensive Center (PCCC); Helmholtz foundation; Krebsliga Schweiz (Oncosuisse); Promedica Stiftung, Switzerland; Intramural Research Program of the NIH, NCI FX We would like to thank J. Berzofsky, W. Stoffel, E. M. Shevach and S. Thorgeirsson for helpful discussion. A.M.T. was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases. J.L. was supported by the Intramural Program Grant ZIABC011303, NIH, National Cancer Institute (NCI). M.H. was supported by a European Research Council starting grant (LiverCancerMechanism), the Stiftung Experimentelle Biomedizin (Hofschneider Stiftung), the Pre-clinical Comprehensive Center (PCCC) and the Helmholtz foundation. A. W. was supported by grants from the Krebsliga Schweiz (Oncosuisse) and the Promedica Stiftung, Switzerland. D.E.K., A.H.K., D.W.M. and T.F.G. were supported by the Intramural Research Program of the NIH, NCI. NR 41 TC 25 Z9 25 U1 21 U2 41 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 MAR 10 PY 2016 VL 531 IS 7593 BP 253 EP + DI 10.1038/nature16969 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF9EZ UT WOS:000371665100046 PM 26934227 ER PT J AU Bruinsma, RF Comas-Garcia, M Garmann, RF Grosberg, AY AF Bruinsma, R. F. Comas-Garcia, M. Garmann, R. F. Grosberg, A. Y. TI Equilibrium self-assembly of small RNA viruses SO PHYSICAL REVIEW E LA English DT Article ID TOBACCO-MOSAIC-VIRUS; VIRAL CAPSID PROTEIN; SINGLE-STRANDED RNA; SPHERICAL PLANT-VIRUS; ELECTROSTATIC INTERACTIONS; PHASE-DIAGRAM; COAT PROTEIN; POLYELECTROLYTES; MOLECULES; PARTICLES AB We propose a description for the quasiequilibrium self-assembly of small, single-stranded (ss) RNA viruses whose capsid proteins (CPs) have flexible, positively charged, disordered tails that associate with the negatively charged RNA genome molecules. We describe the assembly of such viruses as the interplay between two coupled phase-transition-like events: the formation of the protein shell (the capsid) by CPs and the condensation of a large ss viral RNA molecule. Electrostatic repulsion between the CPs competes with attractive hydrophobic interactions and attractive interaction between neutralized RNA segments mediated by the tail groups. An assembly diagram is derived in terms of the strength of attractive interactions between CPs and between CPs and the RNA molecules. It is compared with the results of recent studies of viral assembly. We demonstrate that the conventional theory of self-assembly, which does describe the assembly of empty capsids, is in general not applicable to the self-assembly of RNA-encapsidating virions. C1 [Bruinsma, R. F.] Univ Calif Los Angeles, Dept Phys & Astron, Los Angeles, CA 90095 USA. [Bruinsma, R. F.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Comas-Garcia, M.] NCI, HIV Dynam & Replicat Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Garmann, R. F.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Grosberg, A. Y.] NYU, Dept Phys, 4 Washington Pl, New York, NY 10003 USA. [Grosberg, A. Y.] NYU, Ctr Soft Matter Res, 4 Washington Pl, New York, NY 10003 USA. RP Bruinsma, RF (reprint author), Univ Calif Los Angeles, Dept Phys & Astron, Los Angeles, CA 90095 USA.; Bruinsma, RF (reprint author), Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. OI Comas-Garcia, Mauricio/0000-0002-7733-5138 FU National Science Foundation (USA) [DMR-1309423, PHY-1066293] FX We wish to thank Chuck Knobler for numerous suggestions, discussions, and readings of the manuscript. We also wish to thank Vinny Manoharan for a critical reading of the draft. We are grateful to Jack Johnson for providing the image used for Fig. 1. We would like to thank as well Michael Hagan and Boris Shklovskii for discussions and comments. R.B. thanks the National Science Foundation (USA) for support under Grant No. DMR-1309423. The work of AYG on this project was supported in part by the National Science Foundation (USA) under Grant No. PHY-1066293. Both A.Y.G. and R.B. wish to thank the Aspen Center for Physics for its hospitality and for hosting a workshop on the physics of viral assembly where some of the work was done. NR 55 TC 5 Z9 5 U1 8 U2 16 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2470-0045 EI 2470-0053 J9 PHYS REV E JI Phys. Rev. E PD MAR 9 PY 2016 VL 93 IS 3 AR 032405 DI 10.1103/PhysRevE.93.032405 PG 14 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA DG0HL UT WOS:000371745800005 PM 27078388 ER PT J AU Sette, P O'Connor, SK Yerramilli, VS Dussupt, V Nagashima, K Chutiraka, K Lingappa, J Scarlata, S Bouamr, F AF Sette, Paola O'Connor, Sarah K. Yerramilli, V. Siddartha Dussupt, Vincent Nagashima, Kunio Chutiraka, Kasana Lingappa, Jaisri Scarlata, Suzanne Bouamr, Fadila TI HIV-1 Nucleocapsid Mimics the Membrane Adaptor Syntenin PDZ to Gain Access to ESCRTs and Promote Virus Budding SO CELL HOST & MICROBE LA English DT Article ID MURINE LEUKEMIA-VIRUS; PLASMA-MEMBRANE; LIPID RAFTS; BRO1 DOMAIN; TYPE-1 GAG; T-CELLS; PARTICLE RELEASE; STRUCTURAL BASIS; BASIC REGION; PROTEIN AB HIV-1 recruits cellular endosomal sorting complexes required for transport (ESCRTs) to bud virions from the membrane. Disruption of the viral nucleocapsid (NC) domain integrity affects HIV-1 budding. However, the molecular mechanisms of NC's involvement in HIV budding remain unclear. We find that NC mimics the PDZ domains of syntenin, a membrane-binding adaptor involved in cell-to-cell contact/communication, to capture the Bro1 domain of ALIX, which is an ESCRTs recruiting cellular adaptor. NC binds membranes via basic residues in either the distal or proximal zinc fingers, and NC-membrane binding is essential for Bro1 capture and HIV-1 budding. Removal of RNA enhances NC membrane binding, suggesting a dynamic competition between membrane lipids and RNA for the same binding sites in NC. Remarkably, syntenin PDZ can substitute for NC function in HIV-1 budding. Thus, NC mimics syntenin PDZs to function as a membrane-binding adaptor critical for HIV-1 budding at specific micro-domains of the membrane. C1 [Sette, Paola; O'Connor, Sarah K.; Dussupt, Vincent; Bouamr, Fadila] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20894 USA. [Chutiraka, Kasana; Lingappa, Jaisri] Univ Washington, Dept Global Hlth, Seattle, WA 98102 USA. [Yerramilli, V. Siddartha; Scarlata, Suzanne] SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY 11794 USA. [Nagashima, Kunio] Frederick Natl Lab Canc Res, Electron Microscope Lab, Frederick, MD 21701 USA. [Scarlata, Suzanne] Worcester Polytech Inst, Dept Chem & Biochem, Worcester, MA 01609 USA. RP Bouamr, F (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20894 USA. EM bouamrf@mail.nih.gov FU Intramural AIDS Targeted Antiviral Program (IATAP); Intramural AIDS Research Fellowship (IARF); NIAID Division of Intramural Research; Public Health Service [AI-106397] FX We thank the AIDS Research and Reference Reagent Program in the Division of AIDS at NIAID for providing the HIV-1 Gag p24 hybridoma (183-H12-5C) obtained from B. Chesebro. We thank B. Schneider, S. MacFarlane, and S. Knecht at the Fred Hutchinson Cancer Research Center Electron Microscopy Shared Resources for assistance with transmission EM imaging, and Ron Montelaro for the anti-EIAV serum. This work was supported by the Intramural AIDS Targeted Antiviral Program (IATAP) grant to F.B., by the Intramural AIDS Research Fellowship (IARF) to P.S., by the NIAID Division of Intramural Research (F.B.), and by Public Health Service grant AI-106397 to J.L. NR 66 TC 1 Z9 1 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAR 9 PY 2016 VL 19 IS 3 BP 336 EP 348 DI 10.1016/j.chom.2016.02.004 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DH0FI UT WOS:000372457500011 PM 26962944 ER PT J AU Henderson, BJ Wall, TR Henley, BM Kim, CH Nichols, WA Moaddel, R Xiao, C Lester, HA AF Henderson, Brandon J. Wall, Teagan R. Henley, Beverley M. Kim, Charlene H. Nichols, Weston A. Moaddel, Ruin Xiao, Cheng Lester, Henry A. TI Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward SO JOURNAL OF NEUROSCIENCE LA English DT Article DE neuron; electrophysiology; menthol; nicotine; nicotinic receptor; reward ID ALPHA-4-BETA-2-ASTERISK-NICOTINIC ACETYLCHOLINE-RECEPTORS; SUBUNIT STOICHIOMETRY; SMOKING-BEHAVIOR; PHARMACOLOGICAL CHAPERONE; ENDOPLASMIC-RETICULUM; CIGARETTE SMOKERS; IN-VITRO; EXPRESSION; ACTIVATION; TRAFFICKING AB Upregulation of beta 2 subunit-containing (beta 2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate beta 2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of alpha 4 and alpha 6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of alpha 4* nAChRs, complementing that of chronic nicotine alone, which upregulates alpha 4 subunit-containing (alpha 4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nM menthol alone also increased nAChR number and favored the formation of (alpha 4)(3)(beta 2) 2 nAChRs; this contrasts with the action of nicotine itself, which favors (alpha 4)(2)(beta 2) 3 nAChRs. Menthol alone also increases the number of alpha 6 beta 2 receptors that exclude the beta 3 subunit. Thus, menthol stabilizes lower-sensitivity alpha 4* and alpha 6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway. C1 [Henderson, Brandon J.; Wall, Teagan R.; Henley, Beverley M.; Kim, Charlene H.; Nichols, Weston A.; Xiao, Cheng; Lester, Henry A.] CALTECH, Div Biol & Biol Engn, 1200 E Calif Blvd,MC 156-29, Pasadena, CA 91125 USA. [Moaddel, Ruin] NIA, Baltimore, MD 21224 USA. RP Lester, HA (reprint author), CALTECH, Div Biol & Biol Engn, 1200 E Calif Blvd,MC 156-29, Pasadena, CA 91125 USA. EM Lester@Caltech.edu FU National Institutes of Health (NIH) [DA017279, DA019375, DA033721, DA036061, DA037161, DA037743]; National Institute on Aging (NIH) Intramural Research Program; California Tobacco-Related Disease Research Program [17RT0127] FX This work was supported by the National Institutes of Health (NIH; DA017279, DA019375, DA033721, DA036061, DA037161, and DA037743), the National Institute on Aging (NIH) Intramural Research Program, and the California Tobacco-Related Disease Research Program (17RT0127). We thank Michael Marks, Sharon Grady, and Ying Xie for menthol assays. We thank Heather Gold for help with bioinformatics. NR 66 TC 2 Z9 2 U1 1 U2 4 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 MAR 9 PY 2016 VL 36 IS 10 BP 2957 EP 2974 DI 10.1523/JNEUROSCI.4194-15.2016 PG 18 WC Neurosciences SC Neurosciences & Neurology GA DG4XR UT WOS:000372077000010 PM 26961950 ER PT J AU Barbano, MF Wang, HL Morales, M Wise, RA AF Barbano, M. Flavia Wang, Hui-Ling Morales, Marisela Wise, Roy A. TI Feeding and Reward Are Differentially Induced by Activating GABAergic Lateral Hypothalamic Projections to VTA SO JOURNAL OF NEUROSCIENCE LA English DT Article DE feeding; GABA; lateral hypothalamus; optogenetics; reward; ventral tegmental area ID VENTRAL TEGMENTAL AREA; BRAIN-STIMULATION REWARD; SELF-STIMULATION; ELECTRICAL-STIMULATION; NEURONS; NEUROTENSIN; DOPAMINE; RATS; BEHAVIOR; NEUROTRANSMITTERS AB Electrical stimulation of the lateral hypothalamus (LH) has two motivational effects: long trains of stimulation induce drive-like effects such as eating, and short trains are rewarding. It has not been clear whether a single set of activated fibers subserves the two effects. Previous optogenetic stimulation studies have confirmed that reinforcement and induction of feeding can each be induced by selective stimulation of GABAergic fibers originating in the bed nucleus of the LH and projecting to the ventral tegmental area (VTA). In the present study we determined the optimal stimulation parameters for each of the two optogenetically induced effects in food-sated mice. Stimulation-induced eating was strongest with 5 Hz and progressively weaker with 10 and 20 Hz. Stimulation-induced reward was strongest with 40 Hz and progressively weaker with lower or higher frequencies. Mean preferred duration for continuous 40 Hz stimulation was 61.6 s in a "real-time" place preference task; mean preferred duration for 5Hz stimulation was 45.6 s. The differential effects of high-and low-frequency stimulation of this pathway seem most likely to be due to differential effects on downstream targets. C1 [Barbano, M. Flavia; Wang, Hui-Ling; Morales, Marisela; Wise, Roy A.] NIDA, Integrat Neurosci Res Branch, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Barbano, M. Flavia] Johns Hopkins Univ, Dept Psychol & Brain Sci, 3400 North Charles St, Baltimore, MD 21218 USA. RP Wise, RA (reprint author), NIDA, Integrat Neurosci Res Branch, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM rwise@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse. We thank the NIDA Optogenetic and Transgenic Technology Core for providing the viral vectors used in this study. NR 41 TC 8 Z9 8 U1 4 U2 12 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 MAR 9 PY 2016 VL 36 IS 10 BP 2975 EP 2985 DI 10.1523/JNEUROSCI.3799-15.2016 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DG4XR UT WOS:000372077000011 PM 26961951 ER PT J AU Song, H Abnet, CC Andren-Sandberg, A Chaturvedi, AK Ye, WM AF Song, Huan Abnet, Christian C. Andren-Sandberg, Ake Chaturvedi, Anil K. Ye, Weimin TI Risk of Gastrointestinal Cancers among Patients with Appendectomy: A Large-Scale Swedish Register-Based Cohort Study during 1970-2009 SO PLOS ONE LA English DT Article ID ACUTE APPENDICITIS; HELICOBACTER-PYLORI; INCIDENTAL APPENDECTOMY; NEGATIVE APPENDECTOMY; UNITED-STATES; EPIDEMIOLOGY; CHILDHOOD; SWEDEN; CHILDREN; SMOKING AB Background Removal of the appendix might induce physiological changes in the gastrointestinal tract, and subsequently play a role in carcinogenesis. Therefore, we conducted a nationwide register-based cohort study in Sweden to investigate whether appendectomy is associated with altered risks of gastrointestinal cancers. Methods A population-based cohort study was conducted using the Swedish national registries, including 480,382 eligible patients followed during the period of 1970-2009 for the occurrence of site-specific gastrointestinal cancer (esophageal/gastric/colon/rectal cancer). Outcome and censoring information was collected by linkage to health and demography registers. We examined the incidence of appendectomy in Sweden using data from 1987-2009. We also calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) to estimate the relative gastrointestinal cancer risk through comparison to the general population. Results We noted an overall decrease in the age-standardized incidence of appendectomy among the entire Swedish population from 189.3 to 105.6 per 100,000 individuals between 1987 and 2009. Grouped by different discharge diagnosis, acute appendicitis, incidental appendectomy, and entirely negative appendectomy continuously decreased over the study period, while the perforation ratio (18%-23%) stayed relatively constant. Compared to the general population, no excess cancer risk was observed for gastrointestinal cancers under study with the exception of a marginally elevated risk for esophageal adenocarcinoma (SIR 1.32, 95% CI 1.09-1.58). Conclusions In Sweden, the incidence of appendectomy and acute appendicitis has decreased during 1987-2009. No excess gastrointestinal cancer risks were observed among these appendectomized patients, with the possible exception of esophageal adenocarcinoma. C1 [Song, Huan; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Abnet, Christian C.; Chaturvedi, Anil K.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Andren-Sandberg, Ake] Karolinska Univ Hosp, Dept Digest Dis, Stockholm, Sweden. RP Song, H; Ye, WM (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. EM huan.song@ki.se; weimin.ye@ki.se RI Abnet, Christian/C-4111-2015; OI Abnet, Christian/0000-0002-3008-7843; Song, Huan/0000-0003-3845-8079 FU Swedish Research Council (SIMSAM Grant) [80748301]; Intramural Research Program of the National Cancer Institute, NIH; China Scholarship Council FX This work was supported by grants from Swedish Research Council (SIMSAM Grant, grant number: 80748301) and Intramural Research Program of the National Cancer Institute, NIH; H.S. was also partly supported by a scholarship from China Scholarship Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 0 Z9 0 U1 2 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 MAR 9 PY 2016 VL 11 IS 3 AR e0151262 DI 10.1371/journal.pone.0151262 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3TF UT WOS:000371992300114 PM 26959234 ER PT J AU Zheng, JD Huo, XX Huai, Y Xiao, L Jiang, H Klena, J Greene, CM Xing, XS Huang, JG Liu, SL Peng, YX Yang, H Luo, J Peng, ZB Liu, LL Chen, MY Chen, H Zhang, YZ Huang, DQ Guan, XH Feng, LZ Zhan, FX Hu, DJ Varma, JK Yu, HJ AF Zheng, Jiandong Huo, Xixiang Huai, Yang Xiao, Lin Jiang, Hui Klena, John Greene, Carolyn M. Xing, Xuesen Huang, Jigui Liu, Shali Peng, Youxing Yang, Hui Luo, Jun Peng, Zhibin Liu, Linlin Chen, Maoyi Chen, Hui Zhang, Yuzhi Huang, Danqin Guan, Xuhua Feng, Luzhao Zhan, Faxian Hu, Dale J. Varma, Jay K. Yu, Hongjie TI Epidemiology, Seasonality and Treatment of Hospitalized Adults and Adolescents with Influenza in Jingzhou, China, 2010-2012 SO PLOS ONE LA English DT Article ID COMMUNITY-ACQUIRED PNEUMONIA; RESPIRATORY SYNCYTIAL VIRUS; NEURAMINIDASE INHIBITORS; PRIMARY-CARE; RISK-FACTORS; INFECTION; MORTALITY; CORTICOSTEROIDS; METAANALYSIS; VACCINATION AB Background After the 2009 influenza A (H1 N1) pandemic, we conducted hospital-based severe acute respiratory infection (SARI) surveillance in one central Chinese city to assess disease burden attributable to influenza among adults and adolescents. Methods We defined an adult SARI case as a hospitalized patient aged >= 15 years with temperature >= 38.0 degrees C and at least one of the following: cough, sore throat, tachypnea, difficulty breathing, abnormal breath sounds on auscultation, sputum production, hemoptysis, chest pain, or chest radiograph consistent with pneumonia. For each enrolled SARI case-patient, we completed a standardized case report form, and collected a nasopharyngeal swab within 24 hours of admission. Specimens were tested for influenza viruses by real-time reverse transcription polymerase chain reaction (rRT-PCR). We analyzed data from adult SARI cases in four hospitals in Jingzhou, China from April 2010 to April 2012. Results Of 1,790 adult SARI patients enrolled, 40% were aged >= 65 years old. The median duration of hospitalization was 9 days. Nearly all were prescribed antibiotics during theirhospitalization, less than 1% were prescribed oseltamivir, and 28% were prescribed corticosteroids. Only 0.1% reported receiving influenza vaccination in the past year. Of 1,704 samples tested, 16% were positive for influenza. Influenza activity in all age groups showed winter-spring and summer peaks. Influenza-positive patients had a longer duration from illness onset to hospitalization and a shorter duration from hospital admission to discharge or death compared to influenza negative SARI patients. Conclusions There is substantial burden of influenza-associated SARI hospitalizations in Jingzhou, China, especially among older adults. More effective promotion of annual seasonal influenza vaccination and timely oseltamivir treatment among high risk groups may improve influenza prevention and control in China. C1 [Zheng, Jiandong; Jiang, Hui; Peng, Zhibin; Feng, Luzhao; Yu, Hongjie] Chinese Ctr Dis Control & Prevent, Key Lab Surveillance & Early Warning Infect Dis, Div Infect Dis, Beijing, Peoples R China. [Huo, Xixiang; Xing, Xuesen; Liu, Linlin; Chen, Hui; Huang, Danqin; Guan, Xuhua; Zhan, Faxian] Hubei Prov Ctr Dis Control & Prevent, Wuhan, Peoples R China. [Huai, Yang; Klena, John; Greene, Carolyn M.; Zhang, Yuzhi; Hu, Dale J.; Varma, Jay K.] Ctr Dis Control & Prevent, Ctr Global Hlth, China US Collaborat Program Emerging & Reemerging, Beijing, Peoples R China. [Xiao, Lin; Huang, Jigui; Chen, Maoyi] Jingzhou Ctr Dis Control & Prevent, Jingzhou, Peoples R China. [Klena, John; Hu, Dale J.; Varma, Jay K.] Ctr Dis Control & Prevent, Global Dis Detect Branch, Div Global Hlth Protect, Ctr Global Hlth, Atlanta, GA USA. [Greene, Carolyn M.] Ctr Dis Control & Prevent, Influenza Div, Atlanta, GA USA. [Liu, Shali] Jingzhou Cent Hosp, Jingzhou, Peoples R China. [Peng, Youxing] Jingzhou First Peoples Hosp, Jingzhou, Peoples R China. [Yang, Hui] Jingzhou Second Peoples Hosp, Jingzhou, Peoples R China. [Luo, Jun] Jingzhou Maternal & Childrens Hosp, Jingzhou, Peoples R China. [Hu, Dale J.] NIAID, Vaccine Res Program, Div Aids, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Yu, HJ (reprint author), Chinese Ctr Dis Control & Prevent, Key Lab Surveillance & Early Warning Infect Dis, Div Infect Dis, Beijing, Peoples R China. EM yuhj@chinacdc.cn FU Cooperative Agreement Number [5U2GGH000018]; Centers for Disease Control and Prevention FX This study was supported by the Cooperative Agreement Number, 5U2GGH000018, funded by the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the Department of Health and Human Services. NR 38 TC 0 Z9 0 U1 1 U2 6 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 MAR 9 PY 2016 VL 11 IS 3 AR e0150713 DI 10.1371/journal.pone.0150713 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3TF UT WOS:000371992300068 PM 26958855 ER PT J AU Liao, XH Meena, NP Southall, N Liu, LH Swaroop, M Zhang, AL Xiang, JJ Parent, CA Zheng, W Kimmel, AR AF Liao, Xin-Hua Meena, Netra Pal Southall, Noel Liu, Lunhua Swaroop, Manju Zhang, Arina Li Xiang, Jan Jian Parent, Carole A. Zheng, Wei Kimmel, Alan R. TI A High-Throughput, Multi-Cell Phenotype Assay for the Identification of Novel Inhibitors of Chemotaxis/Migration SO SCIENTIFIC REPORTS LA English DT Article ID CELL-MIGRATION ASSAY; DICTYOSTELIUM-DISCOIDEUM; IN-VITRO; NEUTROPHIL CHEMOTAXIS; ACTIN POLYMERIZATION; CHEMOKINE RECEPTORS; LATRUNCULIN-A; CANCER-CELLS; KINASE; RESPONSES AB Chemotaxis and cell migration are fundamental, universal eukaryotic processes essential for biological functions such as embryogenesis, immunity, cell renewal, and wound healing, as well as for pathogenesis of many diseases including cancer metastasis and chronic inflammation. To identify novel chemotaxis inhibitors as probes for mechanistic studies and leads for development of new therapeutics, we developed a unique, unbiased phenotypic chemotaxis-dependent Dictyostelium aggregation assay for high-throughput screening using rapid, laser-scanning cytometry. Under defined conditions, individual Dictyostelium secrete chemoattractants, migrate, and aggregate. Chemotaxis is quantified by laser-scanning cytometry with a GFP marker expressed only in cells after chemotaxis/multi-cell aggregation. We applied the assay to screen 1,280 known compounds in a 1536-well plate format and identified two chemotaxis inhibitors. The chemotaxis inhibitory activities of both compounds were confirmed in both Dictyostelium and in human neutrophils in a directed EZ-TAXIscan chemotaxis assay. The compounds were also shown to inhibit migration of two human cancer cell lines in monolayer scratch assays. This test screen demonstrated that the miniaturized assay is extremely suited for highthroughput screening of very large libraries of small molecules to identify novel classes of chemotaxis/migratory inhibitors for drug development and research tools for targeting chemotactic pathways universal to humans and other systems. C1 [Liao, Xin-Hua; Zhang, Arina Li; Xiang, Jan Jian] Fujian Med Univ, Sch Basic Med Sci, Inst Translat Med, Fuzhou 350108, Fujian, Peoples R China. [Liao, Xin-Hua; Meena, Netra Pal; Kimmel, Alan R.] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Southall, Noel; Swaroop, Manju; Zheng, Wei] Natl Ctr Adv Translat Sci, Therapeut Rare & Neglected Dis, NIH, Bethesda, MD 20892 USA. [Liu, Lunhua; Parent, Carole A.] NCI, Cellular & Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Liao, XH (reprint author), Fujian Med Univ, Sch Basic Med Sci, Inst Translat Med, Fuzhou 350108, Fujian, Peoples R China.; Liao, XH; Kimmel, AR (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM xinhualiao@foxmail.com; alank@helix.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Intramural Research Programs of The National Institutes of Health; National Cancer Institute; National Center for Advancing Translational Sciences; National Institute of Diabetes and Digestive and Kidney Diseases; Molecular Libraries Initiative of the NIH Roadmap for Medical Research FX This research was supported by the Intramural Research Programs of The National Institutes of Health, The National Cancer Institute, The National Center for Advancing Translational Sciences, The National Institute of Diabetes and Digestive and Kidney Diseases, and The Molecular Libraries Initiative of the NIH Roadmap for Medical Research. The authors thank Amy Melpolder and the National Institutes of Health Blood Bank for providing human blood from healthy volunteers. The authors also thank the compound management group in NCATS/NIH for providing the compounds used in this study. Finally, we wish to thank Dr. Pundrik Jaiswal for comments, interest, and assistance and Dr. Aleksandra Nita-Lazar and colleagues for access to EZ-TAXIScan. NR 53 TC 3 Z9 3 U1 4 U2 11 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 MAR 9 PY 2016 VL 6 AR 22273 DI 10.1038/srep22273 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF8HC UT WOS:000371597300001 PM 26956526 ER PT J AU Rutledge, SD Douglas, TA Nicholson, JM Vila-Casadesus, M Kantzler, CL Wangsa, D Barroso-Vilares, M Kale, SD Logarinho, E Cimini, D AF Rutledge, Samuel D. Douglas, Temple A. Nicholson, Joshua M. Vila-Casadesus, Maria Kantzler, Courtney L. Wangsa, Darawalee Barroso-Vilares, Monika Kale, Shiv D. Logarinho, Elsa Cimini, Daniela TI Selective advantage of trisomic human cells cultured in non-standard conditions SO SCIENTIFIC REPORTS LA English DT Article ID PHA-STIMULATED LYMPHOCYTES; CHROMOSOMAL INSTABILITY; CANCER-CELLS; ANEUPLOIDY UNDERLIES; MULTIDRUG-RESISTANCE; GENETIC INSTABILITY; SPORADIC ANEUPLOIDY; COLORECTAL-CANCER; MITOTIC ERRORS; TRANSCRIPTOME AB An abnormal chromosome number, a condition known as aneuploidy, is a ubiquitous feature of cancer cells. A number of studies have shown that aneuploidy impairs cellular fitness. However, there is also evidence that aneuploidy can arise in response to specific challenges and can confer a selective advantage under certain environmental stresses. Cancer cells are likely exposed to a number of challenging conditions arising within the tumor microenvironment. To investigate whether aneuploidy may confer a selective advantage to cancer cells, we employed a controlled experimental system. We used the diploid, colorectal cancer cell line DLD1 and two DLD1-derived cell lines carrying single-chromosome aneuploidies to assess a number of cancer cell properties. Such properties, which included rates of proliferation and apoptosis, anchorage-independent growth, and invasiveness, were assessed both under standard culture conditions and under conditions of stress (i.e., serum starvation, drug treatment, hypoxia). Similar experiments were performed in diploid vs. aneuploid non-transformed human primary cells. Overall, our data show that aneuploidy can confer selective advantage to human cells cultured under non-standard conditions. These findings indicate that aneuploidy can increase the adaptability of cells, even those, such as cancer cells, that are already characterized by increased proliferative capacity and aggressive tumorigenic phenotypes. C1 [Rutledge, Samuel D.; Nicholson, Joshua M.; Kantzler, Courtney L.; Cimini, Daniela] Dept Biol Sci, Blacksburg, VA 24061 USA. [Rutledge, Samuel D.; Douglas, Temple A.; Nicholson, Joshua M.; Kantzler, Courtney L.; Kale, Shiv D.; Cimini, Daniela] Virginia Tech, Biocomplex Inst, 1015 Life Sci Circle, Blacksburg, VA 24061 USA. [Douglas, Temple A.] Virginia Tech, Biomed Engn, Blacksburg, VA 24061 USA. [Vila-Casadesus, Maria] CIBERehd, Bioinformat Platform, Barcelona, Spain. [Wangsa, Darawalee] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Barroso-Vilares, Monika; Logarinho, Elsa] Univ Porto, Inst Invest & Inovacao Saude i3S, Aging & Aneuploidy Lab, Inst Biol Mol & Celular, Rua Alfredo Allen 208, P-4200135 Oporto, Portugal. [Logarinho, Elsa] Univ Porto, Fac Med, Dept Expt Biol, Cell Div Unit, Alameda Prof Hernani Monteiro, P-4200319 Oporto, Portugal. RP Cimini, D (reprint author), Dept Biol Sci, Blacksburg, VA 24061 USA.; Cimini, D (reprint author), Virginia Tech, Biocomplex Inst, 1015 Life Sci Circle, Blacksburg, VA 24061 USA. EM cimini@vt.edu RI Cimini, Daniela/A-3039-2016; Vila Casadesus, Maria/J-8207-2016; OI Cimini, Daniela/0000-0002-4082-4894; Vila Casadesus, Maria/0000-0001-6597-7953; Vilares, Monika/0000-0002-4012-3895; Logarinho, Elsa/0000-0002-8741-0744 FU NSF [MCB-0842551, MCB-1517506]; HFSP grant [RGY0069/2010]; Virginia Tech University Libraries; Dept. of Biological Sciences (Virginia Tech) FX We would like to acknowledge Thomas Ried (National Cancer Institute, NIH) for providing the aneuploid CRC cell lines. We also thank Silke Hauf and Rich Walker for providing important feedback throughout the execution of this project. Finally, we thank all the members of the Hauf and Cimini labs for helpful comments and discussions. SDR was partly supported through Graduate Teaching Assistantships provided by the Dept. of Biological Sciences (Virginia Tech). Work in the Cimini lab partly funded by NSF grants MCB-0842551 and MCB-1517506 and HFSP grant RGY0069/2010. We further acknowledge the Virginia Tech University Libraries for covering the publication fees through the Open Access Subvention Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 4 Z9 4 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 9 PY 2016 VL 6 AR 22828 DI 10.1038/srep22828 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF8SD UT WOS:000371627800001 PM 26956415 ER PT J AU Zhang, TF Tang, XG Liu, QX Jiang, YP Huang, XX Zhou, QF AF Zhang, T. F. Tang, X. G. Liu, Q. X. Jiang, Y. P. Huang, X. X. Zhou, Q. F. TI Energy-storage properties and high-temperature dielectric relaxation behaviors of relaxor ferroelectric Pb(Mg1/3Nb2/3)O-3-PbTiO3 ceramics SO JOURNAL OF PHYSICS D-APPLIED PHYSICS LA English DT Article DE PMN-PT ceramic; relaxor behavior; dielectric relaxation; energy-storage ID ELECTRICAL-PROPERTIES; SINGLE-CRYSTALS; PERFORMANCE; BI-SRTIO3; FILMS AB (1 - x)Pb(Mg1/3Nb2/3)O-3-xPbTiO(3) (x = 0, 5, and 10 mol%) ceramics were prepared using a conventional mixed oxide solid state reaction method. The low-temperature relaxor behavior of (1 - x)Pb(Mg1/3Nb2/3)O-3-xPbTiO(3) ceramics were examined in the temperature range from 120 to 523 K. A broad dielectric maximum that shifted to higher temperatures with increasing frequency, signified the relaxor-type behavior of these ceramics. The value of the relaxation parameter gamma = 1.61-1.94 estimated from the linear fit of the modified Curie-Weiss law indicated the relaxor nature. High-temperature dielectric relaxation phenomena were found in the temperature region 600-850 K. Energy-storage properties were also analyzed, and the energy-storage density calculated from hysteresis loops reached about 0.47 J cm(-3) at room temperature. C1 [Zhang, T. F.; Tang, X. G.; Liu, Q. X.; Jiang, Y. P.; Huang, X. X.] Guangdong Univ Technol, Guangzhou Higher Educ Mega Ctr, Sch Phys & Optoelect Engn, Guangzhou 510006, Guangdong, Peoples R China. [Zhou, Q. F.] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Zhou, Q. F.] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. RP Tang, XG (reprint author), Guangdong Univ Technol, Guangzhou Higher Educ Mega Ctr, Sch Phys & Optoelect Engn, Guangzhou 510006, Guangdong, Peoples R China. EM xgtang@gdut.edu.cn FU National Natural Science Foundation of China [11202054, 11574057] FX This work was supported by the National Natural Science Foundation of China (Grant Nos. 11202054 and 11574057). NR 43 TC 8 Z9 8 U1 21 U2 62 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0022-3727 EI 1361-6463 J9 J PHYS D APPL PHYS JI J. Phys. D-Appl. Phys. PD MAR 9 PY 2016 VL 49 IS 9 AR 095302 DI 10.1088/0022-3727/49/9/095302 PG 8 WC Physics, Applied SC Physics GA DC8UX UT WOS:000369496300023 ER PT J AU Yamaguchi, K Iglesias-Bartolome, R Wang, ZY Callejas-Valera, JL Amornphimoltham, P Molinolo, AA Cohen, EE Califano, JA Lippman, SM Luo, J Gutkind, JS AF Yamaguchi, Kosuke Iglesias-Bartolome, Ramiro Wang, Zhiyong Callejas-Valera, Juan Luis Amornphimoltham, Panomwat Molinolo, Alfredo A. Cohen, Ezra E. Califano, Joseph A. Lippman, Scott M. Luo, Ji Gutkind, J. Silvio TI A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA(+) oral cancers SO ONCOTARGET LA English DT Article DE synthetic lethality screen; shRNA library; rapamycin; trametinib; co-targeting therapy ID SQUAMOUS-CELL CARCINOMAS; CULTURED HUMAN-CELLS; NECK-CANCER; MAMMALIAN TARGET; MOLECULAR TARGET; SHRNA LIBRARIES; HEAD; RAPAMYCIN; GROWTH; COMBINATION AB mTOR inhibition has emerged as a promising strategy for head and neck squamous cell carcinomas (HNSCC) treatment. However, most targeted therapies ultimately develop resistance due to the activation of adaptive survival signaling mechanisms limiting the activity of targeted agents. Thus, co-targeting key adaptive mechanisms may enable more effective cancer cell killing. Here, we performed a synthetic lethality screen using shRNA libraries to identify druggable candidates for combinatorial signal inhibition. We found that the ERK pathway was the most highly represented. Combination of rapamycin with trametinib, a MEK1/2 inhibitor, demonstrated strong synergism in HNSCC-derived cells in vitro and in vivo, including HNSCC cells expressing the HRAS and PIK3CA oncogenes. Interestingly, cleaved caspase-3 was potently induced by the combination therapy in PIK3CA(+) cells in vitro and tumor xenografts. Moreover, ectopic expression of PIK3CA mutations into PIK3CA(-) HNSCC cells sensitized them to the pro-apoptotic activity of the combination therapy. These findings indicate that co-targeting the mTOR/ERK pathways may provide a suitable precision strategy for HNSCC treatment. Moreover, PIK3CA(+) HNSCC are particularly prone to undergo apoptosis after mTOR and ERK inhibition, thereby providing a potential biomarker of predictive value for the selection of patients that may benefit from this combination therapy. C1 [Yamaguchi, Kosuke; Wang, Zhiyong; Callejas-Valera, Juan Luis; Amornphimoltham, Panomwat; Molinolo, Alfredo A.; Cohen, Ezra E.; Califano, Joseph A.; Lippman, Scott M.; Gutkind, J. Silvio] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA. [Iglesias-Bartolome, Ramiro] NIAMSD, Skin Biol Lab, NIH, Bethesda, MD USA. [Luo, Ji] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Gutkind, JS (reprint author), Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA.; Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. EM sgutkind@ucsd.edu NR 39 TC 1 Z9 1 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 8 PY 2016 VL 7 IS 10 BP 10696 EP 10709 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LK UT WOS:000375678300002 PM 26882569 ER PT J AU Kim, S Song, JH Kim, S Qu, P Martin, BK Sehareen, WS Haines, DC Lin, PNC Sharan, SK Chang, S AF Kim, Sinae Song, Jin Hoi Kim, Seokho Qu, Peng Martin, Betty K. Sehareen, Waheed S. Haines, Diana C. Lin, Pengnian C. Sharan, Shyam K. Chang, Suhwan TI Loss of oncogenic miR-155 in tumor cells promotes tumor growth by enhancing C/EBP-beta-mediated MDSC infiltration SO ONCOTARGET LA English DT Article DE miR-155; MDSC; C/EBP-beta; cytokine; breast cancer ID CCAAT/ENHANCER-BINDING PROTEIN; NF-KAPPA-B; BREAST-CANCER; SUPPRESSOR-CELLS; IMMUNE FUNCTION; MAMMARY-TUMORS; MICRORNA-155; BRCA1; GENE; RNA AB The oncogenic role of microRNA-155 (miR-155) in leukemia is well established but its role in other cancers, especially breast cancer, is gradually emerging. In this study we examined the effect of mir-155 loss in a well-characterized spontaneous breast cancer mouse model where Brca1 and Trp53 are deleted by K14-Cre. miR-155 is known to be up-regulated in BRCA1-deficient tumors. Surprisingly, complete loss of miR-155 (miR-155(ko/ko)) did not alter the tumor free survival of the mutant mice. However, we found increased infiltration of myeloid derived suppressor cells (MDSCs) in miR-155 deficient tumors. In addition, cytokine/chemokine array analysis revealed altered level of cytokines that are implicated in the recruitment of MDSCs. Mechanistically, we identified C/EBP-beta, a known miR-155 target, to regulate the expression of these cytokines in the miR-155-deficient cells. Furthermore, using an allograft model, we showed that inhibition of miR-155 in cancer cells suppressed in vivo growth, which was restored by the loss of miR-155 in the microenvironment. Taken together, we have uncovered a novel tumor suppressive function of miR-155 in the tumor microenvironment, which is also dependent on miR-155 expression in the tumor cells. Because of the oncogenic as well as tumor suppressive roles of miR-155, our findings warrant caution against a systemic inhibition of miR-155 for anticancer therapy. C1 [Kim, Sinae; Chang, Suhwan] Univ Ulsan, Sch Med, Dept Physiol, Dept Biomed Sci, Seoul, South Korea. [Song, Jin Hoi; Kim, Seokho] Korea Res Inst Biosci & Biotechnol, Aging Res Ctr, Taejeon, South Korea. [Haines, Diana C.] Frederick Natl Lab Canc, Leidos Inc, Pathol Histotechnol Lab, Frederick, MD USA. [Qu, Peng; Martin, Betty K.; Sehareen, Waheed S.; Lin, Pengnian C.; Sharan, Shyam K.] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Chang, S (reprint author), Univ Ulsan, Sch Med, Dept Physiol, Dept Biomed Sci, Seoul, South Korea.; Sharan, SK (reprint author), NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. EM sharans@mail.nih.gov; suhwan.chang@amc.seoul.kr FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health; Korean Health Technology R&D Project, Ministry if Health & Welfare, Republic of Korea [HI14C2640]; Asan Institute for Life Sciences [2015-571] FX We thank Drs. Peter Johnson and Jonathan Keller and for helpful discussions and critical review of the manuscript. This study was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health (S.K.S) and grants to S.C. from the Korean Health Technology R&D Project, Ministry if Health & Welfare, Republic of Korea (Grant No. HI14C2640) and Asan Institute for Life Sciences (Grant No. 2015-571) NR 37 TC 2 Z9 2 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 8 PY 2016 VL 7 IS 10 BP 11094 EP 11112 PG 19 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LK UT WOS:000375678300030 PM 26848978 ER PT J AU Wiers, CE Shumay, E Cabrera, E Shokri-Kojori, E Gladwin, TE Skarda, E Cunningham, SI Kim, SW Wong, TC Tomasi, D Wang, GJ Volkow, ND AF Wiers, C. E. Shumay, E. Cabrera, E. Shokri-Kojori, E. Gladwin, T. E. Skarda, E. Cunningham, S. I. Kim, S. W. Wong, T. C. Tomasi, D. Wang, G-J Volkow, N. D. TI Reduced sleep duration mediates decreases in striatal D2/D3 receptor availability in cocaine abusers SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; DOPAMINE D2 RECEPTORS; HUMAN BRAIN; GRAPHICAL ANALYSIS; NUCLEUS-ACCUMBENS; ADDICTION; DEPENDENCE; PET; IMPULSIVITY; MARIJUANA AB Neuroimaging studies have documented reduced striatal dopamine D2/D3 receptor (D2/D3R) availability in cocaine abusers, which has been associated with impaired prefrontal activity and vulnerability for relapse. However, the mechanism(s) underlying the decreases in D2/D3R remain poorly understood. Recent studies have shown that sleep deprivation is associated with a downregulation of striatal D2/D3R in healthy volunteers. As cocaine abusers have disrupted sleep patterns, here we investigated whether reduced sleep duration mediates the relationship between cocaine abuse and low striatal D2/D3R availability. We used positron emission tomography with [C-11] raclopride to measure striatal D2/D3R availability in 24 active cocaine abusers and 21 matched healthy controls, and interviewed them about their daily sleep patterns. Compared with controls, cocaine abusers had shorter sleep duration, went to bed later and reported longer periods of sleep disturbances. In addition, cocaine abusers had reduced striatal D2/D3R availability. Sleep duration predicted striatal D2/D3R availability and statistically mediated the relationship between cocaine abuse and striatal D2/D3R availability. These findings suggest that impaired sleep patterns contribute to the low striatal D2/D3R availability in cocaine abusers. As sleep impairments are similarly observed in other types of substance abusers (for example, alcohol and methamphetamine), this mechanism may also underlie reductions in D2/D3R availability in these groups. The current findings have clinical implications suggesting that interventions to improve sleep patterns in cocaine abusers undergoing detoxification might be beneficial in improving their clinical outcomes. C1 [Wiers, C. E.; Shumay, E.; Cabrera, E.; Shokri-Kojori, E.; Skarda, E.; Cunningham, S. I.; Kim, S. W.; Wong, T. C.; Tomasi, D.; Wang, G-J; Volkow, N. D.] NIAAA, Lab Neuroimaging, NIH, 10 Ctr Dr,Room B2L124, Bethesda, MD 20892 USA. [Gladwin, T. E.] Univ Amsterdam, Dept Psychol, Addict Dev & Psychopathol Lab, Amsterdam, Netherlands. [Gladwin, T. E.] Minist Def, Res Ctr Mil Mental Hlth, Utrecht, Netherlands. [Volkow, N. D.] NIDA, NIH, Bethesda, MD 20892 USA. RP Wiers, CE (reprint author), NIAAA, Lab Neuroimaging, NIH, 10 Ctr Dr,Room B2L124, Bethesda, MD 20892 USA. EM corinde.wiers@nih.gov FU National Institutes of Health Intramural Research Program [Y1AA-3009]; German Research Foundation FX The work was supported by the National Institutes of Health Intramural Research Program and grant number Y1AA-3009 to NDV. CEW received funding from the German Research Foundation. NR 60 TC 2 Z9 2 U1 2 U2 6 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 MAR 8 PY 2016 VL 6 AR e752 DI 10.1038/tp.2016.14 PG 8 WC Psychiatry SC Psychiatry GA DJ0OA UT WOS:000373902600001 PM 26954979 ER PT J AU Ramakrishnan, SK Zhang, HB Takahashi, S Centofanti, B Periyasamy, S Weisz, K Chen, Z Uhler, MD Rui, LY Gonzalez, FJ Shah, YM AF Ramakrishnan, Sadeesh K. Zhang, Huabing Takahashi, Shogo Centofanti, Brook Periyasamy, Sarvesh Weisz, Kevin Chen, Zheng Uhler, Michael D. Rui, Liangyou Gonzalez, Frank J. Shah, Yatrik M. TI HIF2 alpha Is an Essential Molecular Brake for Postprandial Hepatic Glucagon Response Independent of Insulin Signaling SO CELL METABOLISM LA English DT Article ID RECEPTOR KNOCKOUT MICE; CHUVASH POLYCYTHEMIA; GLUCOSE-METABOLISM; COACTIVATOR TORC2; BLOOD-GLUCOSE; IN-VIVO; HYPOXIA; GLUCONEOGENESIS; HYPERGLUCAGONEMIA; HYPERGLYCEMIA AB Glucagon drives hepatic gluconeogenesis and maintains blood glucose levels during fasting. The mechanism that attenuates glucagon action following refeeding is not understood. The present study demonstrates an increase in perivenous liver hypoxia immediately after feeding, which stabilizes hypoxia-inducible factor 2 alpha (HIF2 alpha) in liver. The transient postprandial increase in hepatic HIF2 alpha attenuates glucagon signaling. Hepatocyte-specific disruption of HIF2 alpha increases postprandial blood glucose and potentiates the glucagon response. Independent of insulin/AKT signaling, activation of hepatic HIF2 alpha resulted in lower blood glucose, improved glucose tolerance, and decreased gluconeogenesis due to blunted hepatic glucagon action. Mechanistically, HIF2 alpha abrogated glucagon-PKA signaling by activating cAMP-phosphodiesterases in a MEK/ERK-dependent manner. Repression of glucagon signaling by HIF2 alpha ameliorated hyperglycemia in streptozotocin-induced diabetes and acute insulin-resistant animal models. This study reveals that HIF2 alpha is essential for the acute postprandial regulation of hepatic glucagon signaling and suggests HIF2 alpha as a potential therapeutic target in the treatment of diabetes. C1 [Ramakrishnan, Sadeesh K.; Zhang, Huabing; Centofanti, Brook; Periyasamy, Sarvesh; Weisz, Kevin; Chen, Zheng; Rui, Liangyou; Shah, Yatrik M.] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Uhler, Michael D.] Univ Michigan, Sch Med, Dept Biol Chem, Ann Arbor, MI 48109 USA. [Shah, Yatrik M.] Univ Michigan, Sch Med, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Takahashi, Shogo; Gonzalez, Frank J.] NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Shah, YM (reprint author), Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA.; Shah, YM (reprint author), Univ Michigan, Sch Med, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. EM shahy@umich.edu FU NIH [CA148828, DK095201]; University of Michigan Gastrointestinal Peptide Center Gastrointestinal Peptide Research Center [P30 DK034933]; Diabetes Research and Training Center [P30 DK20572]; NCI; AHA-James and Donna Dickenson-Sublett award [15POST22650034] FX This work was supported by NIH grants (CA148828 and DK095201 to Y.M.S.), The University of Michigan Gastrointestinal Peptide Center Gastrointestinal Peptide Research Center (P30 DK034933), and the Diabetes Research and Training Center (P30 DK20572). The NCI Intramural Research Program supported F.J.G., and S.K.R. was supported by a postdoctoral fellowship from AHA-James and Donna Dickenson-Sublett award (15POST22650034). NR 42 TC 1 Z9 1 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD MAR 8 PY 2016 VL 23 IS 3 BP 505 EP 516 DI 10.1016/j.cmet.2016.01.004 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DI6MU UT WOS:000373614100017 PM 26853750 ER PT J AU Davidson, SM Papagiannakopoulos, T Olenchock, BA Heyman, JE Keibler, MA Luengo, A Bauer, MR Jha, AK O'Brien, JP Pierce, KA Gui, DY Sullivan, LB Wasylenko, TM Subbaraj, L Chin, CR Stephanopolous, G Mott, BT Jacks, T Clish, CB Heiden, MGV AF Davidson, Shawn M. Papagiannakopoulos, Thales Olenchock, Benjamin A. Heyman, Julia E. Keibler, Mark A. Luengo, Alba Bauer, Matthew R. Jha, Abhishek K. O'Brien, James P. Pierce, Kerry A. Gui, Dan Y. Sullivan, Lucas B. Wasylenko, Thomas M. Subbaraj, Lakshmipriya Chin, Christopher R. Stephanopolous, Gregory Mott, Bryan T. Jacks, Tyler Clish, Clary B. Heiden, Matthew G. Vander TI Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer SO CELL METABOLISM LA English DT Article ID TUMOR-CELLS; IN-VIVO; MITOCHONDRIAL METABOLISM; PYRUVATE-CARBOXYLASE; BREAST-CANCER; K-RAS; GLUTAMINE; GROWTH; MICE; PROLIFERATION AB Cultured cells convert glucose to lactate, and glutamine is the major source of tricarboxylic acid (TCA)-cycle carbon, but whether the same metabolic phenotype is found in tumors is less studied. We infused mice with lung cancers with isotope-labeled glucose or glutamine and compared the fate of these nutrients in tumor and normal tissue. As expected, lung tumors exhibit increased lactate production from glucose. However, glutamine utilization by both lung tumors and normal lung was minimal, with lung tumors showing increased glucose contribution to the TCA cycle relative to normal lung tissue. Deletion of enzymes involved in glucose oxidation demonstrates that glucose carbon contribution to the TCA cycle is required for tumor formation. These data suggest that understanding nutrient utilization by tumors can predict metabolic dependencies of cancers in vivo. Furthermore, these data argue that the in vivo environment is an important determinant of the metabolic phenotype of cancer cells. C1 [Davidson, Shawn M.; Papagiannakopoulos, Thales; Olenchock, Benjamin A.; Heyman, Julia E.; Luengo, Alba; Bauer, Matthew R.; O'Brien, James P.; Gui, Dan Y.; Sullivan, Lucas B.; Subbaraj, Lakshmipriya; Chin, Christopher R.; Jacks, Tyler; Heiden, Matthew G. Vander] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Davidson, Shawn M.; Olenchock, Benjamin A.; Luengo, Alba; Pierce, Kerry A.; Jacks, Tyler; Heiden, Matthew G. Vander] Broad Inst IT, Cambridge, MA 02142 USA. [Davidson, Shawn M.; Olenchock, Benjamin A.; Pierce, Kerry A.; Clish, Clary B.; Heiden, Matthew G. Vander] Harvard Univ, Cambridge, MA 02142 USA. [Olenchock, Benjamin A.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Keibler, Mark A.; Stephanopolous, Gregory] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Jha, Abhishek K.] Elucidata Corp, Dept Chem Engn, Cambridge, MA 02139 USA. [Mott, Bryan T.] Natl Ctr Adv Translat Sci, NIH, Bethesda, MD 20892 USA. [Heiden, Matthew G. Vander] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Heiden, MGV (reprint author), MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA.; Heiden, MGV (reprint author), Broad Inst IT, Cambridge, MA 02142 USA.; Heiden, MGV (reprint author), Harvard Univ, Cambridge, MA 02142 USA.; Heiden, MGV (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM mvh@mit.edu FU NSF; Hope Funds for Cancer Research Fellowship; Gilead Sciences Research Scholars Program; Broad Institute SPARC program; Ludwig Center at MIT; Burroughs Wellcome Fund; NIH [P30CA1405141, R01CA168653]; [T32GM007287]; [K08HL119355]; [T32GM007753] FX We thank Natalia Drosu for reagents and advice, the Swanson Biotechnology Center for mouse tissue processing, and the M.G.V.H. lab for thoughtful discussions. S.M.D. and A.L. were supported by an NSF Graduate Research Fellowship and T32GM007287. T.P. received support from Hope Funds for Cancer Research Fellowship. B.A.O. received support from K08HL119355 and Gilead Sciences Research Scholars Program. D.Y.G. received support from T32GM007753. M.G.V.H acknowledges support from the Broad Institute SPARC program, the Ludwig Center at MIT, the Burroughs Wellcome Fund, and the NIH (P30CA1405141, R01CA168653). M.G.V.H. is a consultant and scientific advisory board member, and A.K.J. is a consultant, for Agios Pharmaceuticals. NR 47 TC 47 Z9 47 U1 11 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD MAR 8 PY 2016 VL 23 IS 3 BP 517 EP 528 DI 10.1016/j.cmet.2016.01.007 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DI6MU UT WOS:000373614100018 PM 26853747 ER PT J AU Alvarez, VA AF Alvarez, Veronica A. TI Clues on the coding of reward cues by the nucleus accumbens SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID NEURONS C1 [Alvarez, Veronica A.] Natl Inst Alcohol Abuse & Alcoholism, Intramural Res Program, Bethesda, MD 20892 USA. RP Alvarez, VA (reprint author), Natl Inst Alcohol Abuse & Alcoholism, Intramural Res Program, Bethesda, MD 20892 USA. EM alvarezva@mail.nih.gov RI Alvarez, Veronica /E-9745-2015 OI Alvarez, Veronica /0000-0003-2611-8675 FU Intramural NIH HHS; NIAAA NIH HHS [AA000421] NR 7 TC 0 Z9 0 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 8 PY 2016 VL 113 IS 10 BP 2560 EP 2562 DI 10.1073/pnas.1601162113 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG4AW UT WOS:000372013300019 PM 26917689 ER PT J AU Mesquita, RD Vionette-Amaral, RJ Lowenberger, C Rivera-Pomar, R Monteiro, FA Minx, P Spieth, J Carvalho, AB Panzera, F Lawson, D Torres, AQ Ribeiro, JMC Sorgine, MHF Waterhouse, RM Montague, MJ Abad-Franch, F Alves-Bezerra, M Amaral, LR Araujo, H Araujo, RN Aravind, L Atella, GC Azambuja, P Berni, M Bittencourt-Cunha, PR Braz, GRC Calderon-Fernandez, G Carareto, CMA Christensen, MB Costa, IR Costa, SG Dansa, M Daumas, CRO De-Paula, IF Dias, FA Dimopoulos, G Emrich, SJ Esponda-Behrens, N Fampa, P Fernandez-Medina, RD da Fonseca, RN Fontenele, M Fronick, C Fulton, LA Gandara, AC Garcia, ES Genta, FA Giraldo-Calderon, GI Gomes, B Gondim, KC Granzotto, A Guarneri, AA Guigo, R Harry, M Hughes, DST Jablonka, W Jacquin-Joly, E Juarez, MP Koerich, LB Lange, AB Latorre-Estivalis, JM Lavore, A Lawrence, GG Lazoski, C Lazzari, CR Lopes, RR Lorenzo, MG Lugon, MD Majerowicz, D Marcet, PL Mariotti, M Masuda, H Megy, K Melo, ACA Missirlis, F Mota, T Noriega, FG Nouzova, M Nunes, RD Oliveir, RLL Oliveira-Silveira, G Ons, S Orchard, I Pagola, L Paiva-Silva, GO Pascual, A Pavan, MG Pedrini, N Peixoto, AA Pereira, MH Pike, A Polycarpo, C Prosdocimi, F Ribeiro-Rodrigues, R Robertson, HM Salerno, AP Salmon, D Santesmasses, D Schama, R Seabra-Junior, ES Silva-Cardoso, L Silva-Neto, MAC Souza-Gomes, M Sterkel, M Taracena, ML Tojo, M Tu, ZJ Tubio, JMC Ursic-Bedoya, R Venancio, TM Walter-Nuno, AB Wilson, D Warren, WC Wilson, RK Huebner, E Dotson, EM Oliveira, PL AF Mesquita, Rafael D. Vionette-Amaral, Raquel J. Lowenberger, Carl Rivera-Pomar, Rolando Monteiro, Fernando A. Minx, Patrick Spieth, John Carvalho, A. Bernardo Panzera, Francisco Lawson, Daniel Torres, Andre Q. Ribeiro, Jose M. C. Sorgine, Marcos H. F. Waterhouse, Robert M. Montague, Michael J. Abad-Franch, Fernando Alves-Bezerra, Michele Amaral, Laurence R. Araujo, HelenaM. Araujo, Ricardo N. Aravind, L. Atella, Georgia C. Azambuja, Patricia Berni, Mateus Bittencourt-Cunha, Paula R. Braz, Gloria R. C. Calderon-Fernandez, Gustavo Carareto, Claudia M. A. Christensen, Mikkel B. Costa, Igor R. Costa, Samara G. Dansa, Marilvia Daumas-Filho, Carlos R. O. De-Paula, Iron F. Dias, Felipe A. Dimopoulos, George Emrich, Scott J. Esponda-Behrens, Natalia Fampa, Patricia Fernandez-Medina, Rita D. da Fonseca, Rodrigo N. Fontenele, Marcio Fronick, Catrina Fulton, Lucinda A. Gandara, Ana Caroline Garcia, Eloi S. Genta, Fernando A. Giraldo-Calderon, Gloria I. Gomes, Bruno Gondim, Katia C. Granzotto, Adriana Guarneri, Alessandra A. Guigo, Roderic Harry, Myriam Hughes, Daniel S. T. Jablonka, Willy Jacquin-Joly, Emmanuelle Juarez, M. Patricia Koerich, Leonardo B. Lange, Angela B. Latorre-Estivalis, Jose Manuel Lavore, Andres Lawrence, Gena G. Lazoski, Cristiano Lazzari, Claudio R. Lopes, Raphael R. Lorenzo, Marcelo G. Lugon, Magda D. Majerowicz, David Marcet, Paula L. Mariotti, Marco Masuda, Hatisaburo Megy, Karine Melo, Ana C. A. Missirlis, Fanis Mota, Theo Noriega, Fernando G. Nouzova, Marcela Nunes, Rodrigo D. Oliveir, Raquel L. L. Oliveira-Silveira, Gilbert Ons, Sheila Orchard, Ian Pagola, Lucia Paiva-Silva, Gabriela O. Pascual, Agustina Pavan, Marcio G. Pedrini, Nicolas Peixoto, Alexandre A. Pereira, Marcos H. Pike, Andrew Polycarpo, Carla Prosdocimi, Francisco Ribeiro-Rodrigues, Rodrigo Robertson, Hugh M. Salerno, Ana Paula Salmon, Didier Santesmasses, Didac Schama, Renata Seabra-Junior, Eloy S. Silva-Cardoso, Livia Silva-Neto, Mario A. C. Souza-Gomes, Matheus Sterkel, Marcos Taracena, Mabel L. Tojo, Marta Tu, Zhijian Jake Tubio, Jose M. C. Ursic-Bedoya, Raul Venancio, Thiago M. Walter-Nuno, Ana Beatriz Wilson, Derek Warren, Wesley C. Wilson, Richard K. Huebner, Erwin Dotson, Ellen M. Oliveira, Pedro L. TI Genome of Rhodnius prolixus, an insect vector of Chagas disease, reveals unique adaptations to hematophagy and parasite infection (vol 112, pg 14936, 2015) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Correction C1 [Mesquita, Rafael D.; Torres, Andre Q.; Braz, Gloria R. C.; Melo, Ana C. A.] Univ Fed Rio de Janeiro, Inst Quim, Dept Bioquim, BR-21941909 Rio De Janeiro, Brazil. [Mesquita, Rafael D.; Monteiro, Fernando A.; Sorgine, Marcos H. F.; Araujo, HelenaM.; Araujo, Ricardo N.; Atella, Georgia C.; Azambuja, Patricia; Braz, Gloria R. C.; Dias, Felipe A.; da Fonseca, Rodrigo N.; Fontenele, Marcio; Gandara, Ana Caroline; Garcia, Eloi S.; Genta, Fernando A.; Gomes, Bruno; Gondim, Katia C.; Guarneri, Alessandra A.; Koerich, Leonardo B.; Latorre-Estivalis, Jose Manuel; Lazoski, Cristiano; Lorenzo, Marcelo G.; Masuda, Hatisaburo; Melo, Ana C. A.; Nunes, Rodrigo D.; Paiva-Silva, Gabriela O.; Peixoto, Alexandre A.; Pereira, Marcos H.; Polycarpo, Carla; Schama, Renata; Silva-Neto, Mario A. C.; Venancio, Thiago M.; Oliveira, Pedro L.] Inst Nacl Ciencia & Tecnol Entomol Mol, BR-21941591 Rio De Janeiro, Brazil. [Vionette-Amaral, Raquel J.; Sorgine, Marcos H. F.; Alves-Bezerra, Michele; Atella, Georgia C.; Bittencourt-Cunha, Paula R.; Costa, Igor R.; Daumas-Filho, Carlos R. O.; De-Paula, Iron F.; Dias, Felipe A.; Fontenele, Marcio; Gandara, Ana Caroline; Gondim, Katia C.; Jablonka, Willy; Lopes, Raphael R.; Majerowicz, David; Masuda, Hatisaburo; Nunes, Rodrigo D.; Oliveira-Silveira, Gilbert; Paiva-Silva, Gabriela O.; Polycarpo, Carla; Prosdocimi, Francisco; Salmon, Didier; Silva-Cardoso, Livia; Silva-Neto, Mario A. C.; Sterkel, Marcos; Taracena, Mabel L.; Walter-Nuno, Ana Beatriz; Oliveira, Pedro L.] Univ Fed Rio de Janeiro, Inst Bioquim Med Leopoldo Meis, Programa Biol Mol & Biotecnol, BR-21941591 Rio De Janeiro, Brazil. [Lowenberger, Carl] Simon Fraser Univ, Biol Sci, Burnaby, BC V5A 1S6, Canada. [Rivera-Pomar, Rolando; Esponda-Behrens, Natalia; Lavore, Andres; Ons, Sheila; Pagola, Lucia; Pascual, Agustina] Univ Nacl La Plata, Ctr Reg Estudios Genom, RA-1900 La Plata, Argentina. [Rivera-Pomar, Rolando] Univ Nacl Noroeste Buenos Aires, Ctr Bioinvest, RA-2700 Pergamino, Argentina. [Monteiro, Fernando A.; Torres, Andre Q.; Azambuja, Patricia; Costa, Samara G.; Garcia, Eloi S.; Genta, Fernando A.; Gomes, Bruno; Pavan, Marcio G.; Peixoto, Alexandre A.; Schama, Renata] Fundacao Oswaldo Cruz, Inst Oswaldo Cruz, BR-21040900 Rio De Janeiro, Brazil. [Minx, Patrick; Spieth, John; Montague, Michael J.; Fronick, Catrina; Fulton, Lucinda A.; Warren, Wesley C.; Wilson, Richard K.] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO 63108 USA. [Carvalho, A. Bernardo; Koerich, Leonardo B.; Lazoski, Cristiano] Univ Fed Rio de Janeiro, Inst Biol, Dept Genet, BR-21941590 Rio De Janeiro, Brazil. [Panzera, Francisco] Univ Republica, Fac Ciencias, Secc Genet Evolut, Montevideo 11400, Uruguay. [Lawson, Daniel; Christensen, Mikkel B.; Hughes, Daniel S. T.; Megy, Karine; Wilson, Derek] European Bioinformat Inst, European Mol Biol Lab, Welcome Trust Genome Campus, Cambridge CB10 1SD, England. [Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, NIH, Rockville, MD 20852 USA. [Waterhouse, Robert M.] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland. [Waterhouse, Robert M.] Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland. [Waterhouse, Robert M.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Waterhouse, Robert M.] MIT & Harvard, Broad Inst, Cambridge, MA 02142 USA. [Abad-Franch, Fernando] Fundacao Oswaldo Cruz, Inst Leonidas & Maria Deane, Grp Pesquisa Ecol Doencas Transmissiveis Amazonia, BR-69057070 Amazonas, Brazil. [Amaral, Laurence R.; Souza-Gomes, Matheus] Univ Fed Uberlandia, Fac Computacao, Inst Genet & Bioquim, Lab Bioinformat & Anal Mol, BR-38700002 Uberlandia, MG, Brazil. [Araujo, HelenaM.; Berni, Mateus] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, BR-21941591 Rio De Janeiro, Brazil. [Araujo, Ricardo N.; Pereira, Marcos H.] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Parasitol, BR-31270901 Belo Horizonte, MG, Brazil. [Aravind, L.] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Rockville, MD 20894 USA. [Calderon-Fernandez, Gustavo; Juarez, M. Patricia; Pedrini, Nicolas] Univ Nacl La Plata, CONICET, Fac Ciencias Med, Inst Invest Bioquim La Plata, RA-1900 La Plata, Argentina. [Carareto, Claudia M. A.; Granzotto, Adriana] Univ Estadual Paulista, Dept Biol, BR-15054000 Sao Paulo, Brazil. [Dansa, Marilvia; Lugon, Magda D.; Venancio, Thiago M.] Univ Estadual Norte Fluminense, Ctr Biociencias & Biotecnol, Lab Quim & Funcao Proteinas & Peptideos, BR-28013602 Rio De Janeiro, Brazil. [Dimopoulos, George; Pike, Andrew] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Emrich, Scott J.] Univ Notre Dame, Dept Comp Sci & Engn, Notre Dame, IN 46556 USA. [Fampa, Patricia; Oliveir, Raquel L. L.] Univ Fed Rural Rio de Janeiro, Inst Ciencias Biol & Saude, Dept Biol Anim, BR-23897000 Rio De Janeiro, Brazil. [Fernandez-Medina, Rita D.] Fdn Oswaldo Cruz Rio de Janeiro, Escola Nacl Saude Publ, BR-21040360 Rio De Janeiro, Brazil. [da Fonseca, Rodrigo N.] Univ Fed Rio de Janeiro, Nucleo Pesquisas Ecol Macae, BR-27910970 Rio De Janeiro, Brazil. [Giraldo-Calderon, Gloria I.] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. [Guarneri, Alessandra A.; Latorre-Estivalis, Jose Manuel; Lorenzo, Marcelo G.] Fundacao Oswaldo Cruz, Ctr Pesquisas Rene Rachou, BR-30190002 Belo Horizonte, MG, Brazil. [Guigo, Roderic; Mariotti, Marco; Santesmasses, Didac] Barcelona Inst Sci & Technol, Ctr Genom Regulat, Barcelona 08003, Catalonia, Spain. [Guigo, Roderic; Mariotti, Marco; Santesmasses, Didac] Univ Pompeu Fabra, Barcelona 08003, Catalonia, Spain. [Harry, Myriam] CNRS, Inst Rech Dev, Lab Evolut Genome & Speciat, UPR9034 UR 072, F-91198 Gif Sur Yvette, France. [Harry, Myriam] Univ Paris 11, F-91400 Orsay, France. [Jacquin-Joly, Emmanuelle] French Natl Inst Agr Res, Inst Ecol & Environm Sci Paris, F-78000 Versailles, France. [Lange, Angela B.; Orchard, Ian] Univ Toronto, Dept Biol, Mississauga, ON L5L 1C6, Canada. [Lawrence, Gena G.; Marcet, Paula L.; Dotson, Ellen M.] Ctr Dis Control & Prevent, Entomol Branch, Div Parasit Dis & Malaria, Atlanta, GA 30329 USA. [Lazzari, Claudio R.] Univ Tours, CNRS, Inst Rech Biol Insecte, UMR7261, F-37200 Tours, France. [Majerowicz, David] Univ Fed Rio de Janeiro, Fac Farm, Dept Biotecnol Farmaceut, BR-21941902 Rio De Janeiro, Brazil. [Missirlis, Fanis] Inst Politecn Nacl Zacatenco, Ctr Invest & Estudios Avanzados, Dept Physiol Biophys & Neurosci, Mexico City 03760, DF, Mexico. [Mota, Theo] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Fisiol & Biofis, BR-31270901 Belo Horizonte, MG, Brazil. [Noriega, Fernando G.; Nouzova, Marcela] Florida Int Univ, Dept Biol Sci, Miami, FL 33199 USA. [Ribeiro-Rodrigues, Rodrigo] Univ Fed Espirito Santo, Nucleo Doencas Infecciosas, BR-29043900 Espirito Santo, Brazil. [Robertson, Hugh M.] Univ Illinois, Dept Entomol, Urbana, IL 61801 USA. [Salerno, Ana Paula; Seabra-Junior, Eloy S.] Inst Fed Educ Ciencia & Tecnol Rio de Janeiro, BR-20270021 Rio De Janeiro, Brazil. [Tojo, Marta] Univ Santiago de Compostela, Inst Invest Sanit, Ctr Resesarch Mol Med & Chron Dis, Dept Physiol,Sch Med, Santiago De Compostela 15782, Spain. [Tu, Zhijian Jake] Virginia Polytech Inst & State Univ, Dept Biochem, Blacksburg, VA 24061 USA. [Tubio, Jose M. C.] Univ Cambridge, Dept Vet Med, Cambridge CB3 0ES, England. [Huebner, Erwin] Univ Manitoba, Dept Biol Sci, Winnipeg, MB R3T 2N2, Canada. RP Mesquita, RD (reprint author), Univ Fed Rio de Janeiro, Inst Quim, Dept Bioquim, BR-21941909 Rio De Janeiro, Brazil.; Mesquita, RD (reprint author), Inst Nacl Ciencia & Tecnol Entomol Mol, BR-21941591 Rio De Janeiro, Brazil. RI Pereira, Marcos/A-3774-2012; Prosdocimi, Francisco/F-6847-2012; Venancio, Thiago/B-5003-2011; Guigo, Roderic/D-1303-2010; Carareto, Claudia/D-2814-2012 OI Prosdocimi, Francisco/0000-0002-6761-3069; Guigo, Roderic/0000-0002-5738-4477; NR 1 TC 2 Z9 2 U1 5 U2 14 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 MAR 8 PY 2016 VL 113 IS 10 BP E1415 EP E1416 DI 10.1073/pnas.1600205113 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG4AW UT WOS:000372013300016 ER PT J AU Jha, A Muallem, S AF Jha, Archana Muallem, Shmuel TI The CAR that drives Ca2+ to Orai1 SO SCIENCE SIGNALING LA English DT Article ID CHANNEL; MICRODOMAINS; PERMEATION; ACTIVATION; DEPLETION AB How Ca2+ permeates the Orai1 channel and the mechanism by which the channel achieves high Ca2+ selectivity remain critical questions in understanding store-operated Ca2+ influx. In research published in Science Signaling, Frischauf et al. identified a Ca2+-accumulating region (CAR) in the extracellular opening of Orai1, which explains how concentrating Ca2+ at the mouth of Orai1 facilitates channel permeation and contributes to selectivity. C1 [Jha, Archana; Muallem, Shmuel] Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Muallem, S (reprint author), Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM shmuel.muallem@nih.gov NR 10 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAR 8 PY 2016 VL 9 IS 418 AR fs5 DI 10.1126/scisignal.aaf1941 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG4YW UT WOS:000372080100004 PM 26956483 ER PT J AU Erlandson, KJ Bisht, H Weisberg, AS Hyun, SI Hansen, BT Fischer, ER Hinshaw, JE Moss, B AF Erlandson, Karl J. Bisht, Himani Weisberg, Andrea S. Hyun, Seong-In Hansen, Bryan T. Fischer, Elizabeth R. Hinshaw, Jenny E. Moss, Bernard TI Poxviruses Encode a Reticulon-Like Protein that Promotes Membrane Curvature SO CELL REPORTS LA English DT Article ID TUBULAR ENDOPLASMIC-RETICULUM; VACCINIA VIRUS MORPHOGENESIS; A17L ENVELOPE PROTEIN; INTERMEDIATE COMPARTMENT; IMMATURE VIRIONS; RNA-POLYMERASE; TOPOLOGY; RECOMBINANT; BIOGENESIS; EXPRESSION AB Poxviruses are enveloped DNA viruses that replicate within the cytoplasm. The first viral structures are crescents and spherical particles, with a lipoprotein membrane bilayer, that are thought to be derived from the ER. We determined that A17, a conserved viral transmembrane protein essential for crescent formation, forms homo-oligomers and shares topological features with cellular reticulon-like proteins. The latter cell proteins promote membrane curvature and contribute to the tubular structure of the ER. When the purified A17 protein was incorporated into liposomes, 25 nm diameter vesicles and tubules formed at low and high A17 concentrations, respectively. In addition, intracellular expression of A17 in the absence of other viral structural proteins transformed the ER into aggregated three-dimensional (3D) tubular networks. We suggest that A17 is a viral reticulon-like protein that contributes to curvature during biogenesis of the poxvirus membrane. C1 [Erlandson, Karl J.; Bisht, Himani; Weisberg, Andrea S.; Hyun, Seong-In; Moss, Bernard] NIAID, Lab Viral Dis, NIH, Bethesda, MD 20892 USA. [Hansen, Bryan T.; Fischer, Elizabeth R.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Hinshaw, Jenny E.] NIDDK, Struct Cell Biol Sect, NIH, Bethesda, MD 20892 USA. [Bisht, Himani] US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. RP Moss, B (reprint author), NIAID, Lab Viral Dis, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID; NIGMS PRAT fellowship FX Support was from the Division of Intramural Research, NIAID. K.J.E. received support from an NIGMS PRAT fellowship. NR 27 TC 1 Z9 1 U1 3 U2 7 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 MAR 8 PY 2016 VL 14 IS 9 BP 2084 EP 2091 DI 10.1016/j.celrep.2016.01.075 PG 8 WC Cell Biology SC Cell Biology GA DF6LJ UT WOS:000371466900006 PM 26923595 ER PT J AU Vandenberg, LN Gerona, RR Kannan, K Taylor, JA van Breemen, RB Dickenson, CA Liao, CY Yuan, Y Newbold, RR Padmanabhan, V vom Saal, FS Woodruff, TJ AF Vandenberg, Laura N. Gerona, Roy R. Kannan, Kurunthachalam Taylor, Julia A. van Breemen, Richard B. Dickenson, Carrie A. Liao, Chunyang Yuan, Yang Newbold, Retha R. Padmanabhan, Vasantha vom Saal, Frederick S. Woodruff, Tracey J. TI A round robin approach to the analysis of bisphenol a (BPA) in human blood samples (vol 13, 25, 2014) SO ENVIRONMENTAL HEALTH LA English DT Correction C1 [Vandenberg, Laura N.] Univ Massachusetts, Sch Publ Hlth, Div Environm Hlth Sci, Amherst, MA 01003 USA. [Gerona, Roy R.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Kannan, Kurunthachalam] SUNY Albany, New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12222 USA. [Taylor, Julia A.; vom Saal, Frederick S.] Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. [van Breemen, Richard B.; Yuan, Yang] Univ Illinois, Coll Pharm, Chicago, IL USA. [Dickenson, Carrie A.; Woodruff, Tracey J.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, Program Reprod Hlth & Environm, San Francisco, CA 94143 USA. [Liao, Chunyang] NY State Dept Publ Hlth, Wadsworth Ctr, Albany, NY USA. [Newbold, Retha R.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Padmanabhan, Vasantha] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Padmanabhan, Vasantha] Univ Michigan, Reprod Sci Program, Ann Arbor, MI 48109 USA. RP Woodruff, TJ (reprint author), Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, Program Reprod Hlth & Environm, San Francisco, CA 94143 USA. EM woodrufft@obgyn.ucsf.edu FU NICHD NIH HHS [R01 HD021341]; NIDDK NIH HHS [P30 DK020572]; NIEHS NIH HHS [R01 ES017005, R21 ES017763, P01 ES022841, P20 ES018135, R01 ES013527] NR 1 TC 0 Z9 0 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD MAR 8 PY 2016 VL 15 AR 43 DI 10.1186/s12940-016-0126-z PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DF6JT UT WOS:000371462500001 PM 26956378 ER PT J AU Nixon-Abell, J Berwick, DC Granno, S Spain, VA Blackstone, C Harvey, K AF Nixon-Abell, Jonathon Berwick, Daniel C. Granno, Simone Spain, Victoria A. Blackstone, Craig Harvey, Kirsten TI Protective LRRK2 R1398H Variant Enhances GTPase and Wnt Signaling Activity SO FRONTIERS IN MOLECULAR NEUROSCIENCE LA English DT Article DE GTPase activity; LRRK2; Parkinson's disease; protective genetic variant; Wnt signaling ID REPEAT KINASE 2; DISEASE-ASSOCIATED MUTATIONS; FAMILIAL PARKINSONS-DISEASE; NERVOUS-SYSTEM; ROC DOMAIN; PROTEINS; BINDING; GENE; PHOSPHORYLATION; SUSCEPTIBILITY AB Mutations in LRRK2 are a common cause of familial and idiopathic Parkinson's disease (PD). Recently, the LRRK2 GTPase domain R1398H variant was suggested in genetic studies to confer protection against PD but mechanistic data supporting this is lacking. Here, we present evidence that R1398H affects GTPase function, axon outgrowth, and Wnt signaling in a manner opposite to pathogenic LRRK2 mutations. LRRK2 R1398H GTPase domain dimerization and GTP hydrolysis were increased whereas GTP binding was reduced, leading to a decrease in active GTP-bound LRRK2. This protective variant also increased axon length of primary cortical neurones in comparison to wild-type LRRK2, whereas the R1441G LRRK2 pathogenic mutant decreased axon outgrowth. Importantly, R1398H enhanced the stimulatory effect of LRRK2 on canonical Wnt signaling whereas the G2385R risk variant, in accordance with all previously tested pathogenic LRRK2 mutants, had the opposite effect. Molecular modeling placed R1398H in close proximity to PD-causing mutations suggesting that this protective LRRK2 variant, like familial mutations, affects intramolecular RocCOR domain interactions. Thus, our data suggest that R1398H LRRK2 is a bona fide protective variant. The opposite effects of protective versus PD associated LRRK2 variants on GTPase function and canonical Wnt signaling activity also suggests that regulation of these two basic signaling mechanisms is important for neuronal function. We conclude that LRRK2 mediated Wnt signaling and GTPase function are fundamental in conferring disease susceptibility and have clear implications for therapeutic target identification. C1 [Nixon-Abell, Jonathon; Berwick, Daniel C.; Granno, Simone; Spain, Victoria A.; Harvey, Kirsten] UCL, UCL Sch Pharm, Dept Pharmacol, London, England. [Nixon-Abell, Jonathon; Blackstone, Craig] NINDS, Neurogenet Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Berwick, Daniel C.] Open Univ, Dept Life Hlth & Chem Sci, Milton Keynes MK7 6AA, Bucks, England. RP Harvey, K (reprint author), UCL, UCL Sch Pharm, Dept Pharmacol, London, England. EM kirsten.harvey@ucl.ac.uk RI Berwick, Dan/J-2378-2012; OI Berwick, Dan/0000-0002-7144-7841; Nixon-Abell, Jonathon/0000-0003-4169-0012 FU Wellcome Trust [WT088145AIA, WT095010MA]; Medical Research Council [MR/IVI00676X/1]; Vera Down British Medical Association Research Grant; Intramural Research Program of the NINDS, National Institutes of Health FX This work was supported by The Wellcome Trust [WT088145AIA, WT095010MA to KH], the Medical Research Council [MR/IVI00676X/1 to KH] and a Vera Down British Medical Association Research Grant [to KH]. CB and IN-A were also supported by the Intramural Research Program of the NINDS, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 5 Z9 5 U1 3 U2 10 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5099 J9 FRONT MOL NEUROSCI JI Front. Molec. Neurosci. PD MAR 8 PY 2016 VL 9 AR 18 DI 10.3389/fnmol.2016.00018 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DF8FY UT WOS:000371594000001 PM 27013965 ER PT J AU Sadacca, BF Jones, JL Schoenbaum, G AF Sadacca, Brian F. Jones, Joshua L. Schoenbaum, Geoffrey TI Midbrain dopamine neurons compute inferred and cached value prediction errors in a common framework SO ELIFE LA English DT Article ID VENTRAL TEGMENTAL AREA; ORBITOFRONTAL CORTEX; NUCLEUS-ACCUMBENS; DECISION-MAKING; REWARD; SIGNALS; MODEL; RESPONSES; BEHAVIOR; STIMULUS AB Midbrain dopamine neurons have been proposed to signal reward prediction errors as defined in temporal difference (TD) learning algorithms. While these models have been extremely powerful in interpreting dopamine activity, they typically do not use value derived through inference in computing errors. This is important because much real world behavior - and thus many opportunities for error-driven learning - is based on such predictions. Here, we show that error-signaling rat dopamine neurons respond to the inferred, model-based value of cues that have not been paired with reward and do so in the same framework as they track the putative cached value of cues previously paired with reward. This suggests that dopamine neurons access a wider variety of information than contemplated by standard TD models and that, while their firing conforms to predictions of TD models in some cases, they may not be restricted to signaling errors from TD predictions. C1 [Sadacca, Brian F.; Jones, Joshua L.; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD USA. RP Schoenbaum, G (reprint author), NIDA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM brian.sadacca@nih.gov; geoffrey.schoenbaum@nih.gov OI Sadacca, Brian/0000-0003-1425-6077 FU National Institute on Drug Abuse FX National Institute on Drug Abuse IRP Geoffrey Schoenbaum NR 57 TC 9 Z9 9 U1 3 U2 11 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 7 PY 2016 VL 5 AR e13665 DI 10.7554/eLife.13665 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ0KV UT WOS:000373893000001 ER PT J AU Pokatayev, V Hasin, N Chon, H Cerritelli, SM Sakhuja, K Ward, JM Morris, HD Yan, N Crouch, RJ AF Pokatayev, Vladislav Hasin, Naushaba Chon, Hyongi Cerritelli, Susana M. Sakhuja, Kiran Ward, Jerrold M. Morris, H. Douglas Yan, Nan Crouch, Robert J. TI RNase H2 catalytic core Aicardi-Goutieres syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID AUTOIMMUNE-DISEASE; GENOME INTEGRITY; RIBONUCLEASE H2; TREX1; DNA; MUTATIONS; ACTIVATION; SUBUNITS; REMOVAL; GENES AB The neuroinflammatory autoimmune disease Aicardi-Goutieres syndrome (AGS) develops from mutations in genes encoding several nucleotide-processing proteins, including RNase H2. Defective RNase H2 may induce accumulation of self-nucleic acid species that trigger chronic type I interferon and inflammatory responses, leading to AGS pathology. We created a knock-in mouse model with an RNase H2 AGS mutation in a highly conserved residue of the catalytic subunit, Rnaseh2a(G37S/G37S) (G37S), to understand disease pathology. G37S homozygotes are perinatal lethal, in contrast to the early embryonic lethality previously reported for Rnaseh2b- or Rnaseh2c-null mice. Importantly, we found that the G37S mutation led to increased expression of interferon-stimulated genes dependent on the cGAS-STING signaling pathway. Ablation of STING in the G37S mice results in partial rescue of the perinatal lethality, with viable mice exhibiting white spotting on their ventral surface. We believe that the G37S knock-in mouse provides an excellent animal model for studying RNA SEH2-associated autoimmune diseases. C1 [Pokatayev, Vladislav; Yan, Nan] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Pokatayev, Vladislav; Yan, Nan] Univ Texas SW Med Ctr Dallas, Dept Microbiol, Dallas, TX 75390 USA. [Hasin, Naushaba; Chon, Hyongi; Cerritelli, Susana M.; Sakhuja, Kiran; Crouch, Robert J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, Bethesda, MD 20892 USA. [Ward, Jerrold M.] NIAID, Immunogenet Lab, Bethesda, MD 20892 USA. [Morris, H. Douglas] NINDS, NIH Mouse Imaging Facil, NIH, Bethesda, MD 21042 USA. RP Crouch, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, Bethesda, MD 20892 USA. EM crouchr@helix.nih.gov FU National Institutes of Health [AI098569, AR067135]; Alliance for Lupus Research [329774]; UT Southwestern Immunology graduate program training grant [2T32AI005284]; Intramural Research Program of the National Institutes of Health FX This work is supported by grants from the National Institutes of Health (AI098569 and AR067135 to N. Yan), Alliance for Lupus Research (329774 N. Yan), UT Southwestern Immunology graduate program training grant (2T32AI005284 to V. Pokatayev), and in part by the Intramural Research Program of the National Institutes of Health. NR 32 TC 10 Z9 10 U1 2 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD MAR 7 PY 2016 VL 213 IS 3 BP 329 EP 336 DI 10.1084/jem.20151464 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DI3HS UT WOS:000373390300004 PM 26880576 ER PT J AU Waksman, R Rogers, T AF Waksman, Ron Rogers, Toby TI Transcatheter aortic valve replacement The American perspective on transcatheter aortic valve replacement SO EUROPEAN HEART JOURNAL LA English DT Editorial Material C1 [Waksman, Ron] MedStar Heart & Vasc Inst, MedStar Cardiovasc Res Network & Adv Educ, Washington, DC 20010 USA. [Rogers, Toby] MedStar Heart & Vasc Inst, Washington, DC USA. [Rogers, Toby] Natl Inst Hlth, Bethesda, MD USA. RP Waksman, R (reprint author), MedStar Heart & Vasc Inst, MedStar Cardiovasc Res Network & Adv Educ, Washington, DC 20010 USA. EM ron.waksman@medstar.net OI Rogers, Toby/0000-0002-6043-3137 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD MAR 7 PY 2016 VL 37 IS 10 BP 797 EP 799 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DG9JZ UT WOS:000372400000003 PM 27458634 ER PT J AU Chen, XY Fei, CL Chen, ZY Chen, RM Yu, P Chen, ZP Shung, KK Zhou, QF AF Chen, Xiaoyang Fei, Chunlong Chen, Zeyu Chen, Ruimin Yu, Ping Chen, Zhongping Shung, K. Kirk Zhou, Qifa TI Simulation and fabrication of 0-3 composite PZT films for ultrahigh frequency (100-300 MHz) ultrasonic transducers SO JOURNAL OF APPLIED PHYSICS LA English DT Article ID PIEZOELECTRIC PROPERTIES; THICK-FILMS; CONNECTIVITY; TWEEZERS AB This paper presents simulation, fabrication, and characterization of single-element ultrahigh frequency (100-300-MHz) needle ultrasonic transducers based on 0-3 composite Pb(Zr0.52Ti0.48)O-3 (PZT) films prepared by using composite ceramic sol-gel film and sol-infiltration technique. The center frequency of the developed transducer at 300-MHz was the highest frequency of PbTiO3 ceramic-based ultrasonic transducers ever reported. Furthermore, a brief description of the composite model was followed by the development of a new expression for predicting the longitudinal velocity, the clamped dielectric constant, and the complex electromechanical coupling coefficient k(t) of these films, which is very important in ultrasonic transducer design. Moreover, these parameters are difficult to obtain by measuring the frequency dependence of impedance and phase angle because of the weak signal of the previous 0-3 composite films transducer (> 100 MHz). The modeling results show that the Cubes model with a geometric factor n = 0.05 fits well with the measured data. This model will be helpful for developing the 0-3 composite systems for ultrahigh frequency ultrasonic transducer design. (C) 2016 AIP Publishing LLC. C1 [Chen, Xiaoyang; Chen, Zhongping] Univ Calif Irvine, Beckman Laser Inst & Med Clin, Irvine, CA 92612 USA. [Chen, Xiaoyang; Chen, Zhongping] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92612 USA. [Chen, Xiaoyang; Yu, Ping] Sichuan Univ, Coll Mat Sci & Engn, Chengdu 610064, Peoples R China. [Fei, Chunlong; Chen, Zeyu; Chen, Ruimin; Shung, K. Kirk; Zhou, Qifa] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Fei, Chunlong; Chen, Zeyu; Chen, Ruimin; Shung, K. Kirk; Zhou, Qifa] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP Chen, XY (reprint author), Univ Calif Irvine, Beckman Laser Inst & Med Clin, Irvine, CA 92612 USA. FU National Institutes of Health [P41-EB002182]; China Scholarship Council (CSC) FX This work was supported by the National Institutes of Health (Grant No. P41-EB002182) and the China Scholarship Council (CSC). NR 25 TC 2 Z9 2 U1 9 U2 19 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-8979 EI 1089-7550 J9 J APPL PHYS JI J. Appl. Phys. PD MAR 7 PY 2016 VL 119 IS 9 AR 094103 DI 10.1063/1.4942857 PG 9 WC Physics, Applied SC Physics GA DG8RS UT WOS:000372351900021 ER PT J AU Mo, A Luo, CY Davis, FP Mukamel, EA Henry, GL Nery, JR Urich, MA Picard, S Lister, R Eddy, SR Beer, MA Ecker, JR Nathans, J AF Mo, Alisa Luo, Chongyuan Davis, Fred P. Mukamel, Eran A. Henry, Gilbert L. Nery, Joseph R. Urich, Mark A. Picard, Serge Lister, Ryan Eddy, Sean R. Beer, Michael A. Ecker, Joseph R. Nathans, Jeremy TI Epigenomic landscapes of retinal rods and cones SO ELIFE LA English DT Article ID DNA METHYLATION; CHIP-SEQ; PHOTORECEPTOR DEVELOPMENT; REGULATORY REGIONS; MOUSE GENOME; RNA-SEQ; RETINITIS-PIGMENTOSA; HIERARCHICAL MODEL; CRE RECOMBINASE; TRANSGENIC MICE AB Rod and cone photoreceptors are highly similar in many respects but they have important functional and molecular differences. Here, we investigate genome-wide patterns of DNA methylation and chromatin accessibility in mouse rods and cones and correlate differences in these features with gene expression, histone marks, transcription factor binding, and DNA sequence motifs. Loss of NR2E3 in rods shifts their epigenomes to a more cone -like state. The data further reveal wide differences in DNA methylation between retinal photoreceptors and brain neurons. Surprisingly, we also find a substantial fraction of DNA hypo -methylated regions in adult rods that are not in active chromatin. Many of these regions exhibit hallmarks of regulatory regions that were active earlier in neuronal development, suggesting that these regions could remain undermethylated due to the highly compact chromatin in mature rods. This work defines the epigenomic landscapes of rods and cones, revealing features relevant to photoreceptor development and function. C1 [Mo, Alisa; Nathans, Jeremy] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Mo, Alisa; Nathans, Jeremy] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Luo, Chongyuan; Nery, Joseph R.; Urich, Mark A.; Lister, Ryan; Ecker, Joseph R.] Salk Inst Biol Studies, Genom Anal Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Luo, Chongyuan; Ecker, Joseph R.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. [Davis, Fred P.; Henry, Gilbert L.; Picard, Serge; Eddy, Sean R.] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA. [Mukamel, Eran A.] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA. [Lister, Ryan] Univ Western Australia, ARC Ctr Excellence Plant Energy Biol, Crawley, WA, Australia. [Beer, Michael A.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Beer, Michael A.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Nathans, Jeremy] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Nathans, Jeremy] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. [Davis, Fred P.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Eddy, Sean R.] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Eddy, Sean R.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Eddy, Sean R.] Harvard Univ, John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA. RP Nathans, J (reprint author), Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA.; Nathans, J (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA.; Nathans, J (reprint author), Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA.; Nathans, J (reprint author), Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. EM jnathans@jhmi.edu RI Ecker, Joseph/B-9144-2008; OI Ecker, Joseph/0000-0001-5799-5895; Lister, Ryan/0000-0001-6637-7239; Eddy, Sean/0000-0001-6676-4706 FU National Institute of General Medical Sciences [T32]; National Institutes of Health; Howard Hughes Medical Institute; National Institute of Neurological Disorders and Stroke [R00NS080911]; National Institutes of Health [R01HG0007348, 1-U01-MH105985]; Gordon and Betty Moore Foundation [GBMF3034] FX National Institute of General Medical Sciences Medical Scientist Training Program (T32) Alisa Mo; National Institutes of Health Visual Neuroscience Training Program Alisa Mo; Howard Hughes Medical Institute Chongyuan Luo Sean R Eddy Joseph R Ecker Jeremy Nathans Fred P Davis Gilbert L Henry Serge Picard; National Institute of Neurological Disorders and Stroke R00NS080911 Eran A Mukamel; National Institutes of Health R01HG0007348 Michael A Beer; National Institute of Mental Health 1-U01-MH105985 Joseph R Ecker; Gordon and Betty Moore Foundation GBMF3034 Joseph R Ecker NR 81 TC 9 Z9 9 U1 3 U2 13 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 7 PY 2016 VL 5 AR e11613 DI 10.7554/eLife.11613 PG 29 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DG2IW UT WOS:000371891600001 PM 26949250 ER PT J AU Dehghan, A Bis, JC White, CC Smith, AV Morrison, AC Cupples, LA Trompet, S Chasman, DI Lumley, T Volker, U Buckley, BM Ding, JZ Jensen, MK Folsom, AR Kritchevsky, SB Girman, CJ Ford, I Dorr, M Salomaa, V Uitterlinden, AG Eiriksdottir, G Vasan, RS Franceschini, N Carty, CL Virtamo, J Demissie, S Amouyel, P Arveiler, D Heckbert, SR Ferrieres, J Ducimetiere, P Smith, NL Wang, YA Siscovick, DS Rice, KM Wiklund, PG Taylor, KD Evans, A Kee, F Rotter, JI Karvanen, J Kuulasmaa, K Heiss, G Kraft, P Launer, LJ Hofman, A Markus, MRP Rose, LM Silander, K Wagner, P Benjamin, EJ Lohman, K Stott, DJ Rivadeneira, F Harris, TB Levy, D Liu, YM Rimm, EB Jukema, JW Volzke, H Ridker, PM Blankenberg, S Franco, OH Gudnason, V Psaty, BM Boerwinkle, E O'Donnell, CJ AF Dehghan, Abbas Bis, Joshua C. White, Charles C. Smith, Albert Vernon Morrison, Alanna C. Cupples, L. Adrienne Trompet, Stella Chasman, Daniel I. Lumley, Thomas Voelker, Uwe Buckley, Brendan M. Ding, Jingzhong Jensen, Majken K. Folsom, Aaron R. Kritchevsky, Stephen B. Girman, Cynthia J. Ford, Ian Doerr, Marcus Salomaa, Veikko Uitterlinden, Andre G. Eiriksdottir, Gudny Vasan, Ramachandran S. Franceschini, Nora Carty, Cara L. Virtamo, Jarmo Demissie, Serkalem Amouyel, Philippe Arveiler, Dominique Heckbert, Susan R. Ferrieres, Jean Ducimetiere, Pierre Smith, Nicholas L. Wang, Ying A. Siscovick, David S. Rice, Kenneth M. Wiklund, Per-Gunnar Taylor, Kent D. Evans, Alun Kee, Frank Rotter, Jerome I. Karvanen, Juha Kuulasmaa, Kari Heiss, Gerardo Kraft, Peter Launer, Lenore J. Hofman, Albert Markus, Marcello R. P. Rose, Lynda M. Silander, Kaisa Wagner, Peter Benjamin, Emelia J. Lohman, Kurt Stott, David J. Rivadeneira, Fernando Harris, Tamara B. Levy, Daniel Liu, Yongmei Rimm, Eric B. Jukema, J. Wouter Voelzke, Henry Ridker, Paul M. Blankenberg, Stefan Franco, Oscar H. Gudnason, Vilmundur Psaty, Bruce M. Boerwinkle, Eric O'Donnell, Christopher J. TI Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium SO PLOS ONE LA English DT Article ID CARDIOVASCULAR-DISEASE; CHROMOSOME 9P21; RISK; DESIGN; METAANALYSIS; SUSCEPTIBILITY; PREDICTION; ROTTERDAM AB Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5x10(-6) in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5x10(-6); 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8x10(-3)) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2x10(-9)). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2x10(-3)). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders. C1 [Dehghan, Abbas; Uitterlinden, Andre G.; Hofman, Albert; Rivadeneira, Fernando; Franco, Oscar H.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Bis, Joshua C.; Heckbert, Susan R.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [White, Charles C.; Cupples, L. Adrienne; Demissie, Serkalem; Wang, Ying A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Smith, Albert Vernon; Eiriksdottir, Gudny; Gudnason, Vilmundur] Icelandic Heart Assoc, Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Morrison, Alanna C.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Morrison, Alanna C.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Cupples, L. Adrienne; Vasan, Ramachandran S.; Benjamin, Emelia J.; Levy, Daniel; O'Donnell, Christopher J.] Boston Univ, Framingham, MA USA. [Cupples, L. Adrienne; Vasan, Ramachandran S.; Benjamin, Emelia J.; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Chasman, Daniel I.; Rose, Lynda M.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Chasman, Daniel I.; Rose, Lynda M.; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA USA. [Lumley, Thomas; Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Voelker, Uwe; Doerr, Marcus; Markus, Marcello R. P.; Voelzke, Henry] DZHK German Ctr Cardiovasc Res, Partner Site, Greifswald, Germany. [Buckley, Brendan M.] Univ Coll, Dept Pharmacol & Therapeut, Cork, Ireland. [Ding, Jingzhong] Wake Forest Univ, Dept Internal Med, Div Geriatr, Winston Salem, NC 27109 USA. [Jensen, Majken K.; Rimm, Eric B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Jensen, Majken K.; Rimm, Eric B.] Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA USA. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Girman, Cynthia J.; Franceschini, Nora; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Girman, Cynthia J.] Merck Sharp & Dohme Corp, Dept Epidemiol, Merck Res Labs, Whitehouse Stn, NJ USA. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Doerr, Marcus] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany. [Salomaa, Veikko; Virtamo, Jarmo; Karvanen, Juha; Kuulasmaa, Kari; Silander, Kaisa; Wagner, Peter] Natl Inst Hlth & Welf, Helsinki, Finland. [Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Carty, Cara L.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Amouyel, Philippe] Inst Pasteur, Dept Epidemiol & Publ Hlth, F-59019 Lille, France. [Arveiler, Dominique] Univ Strasbourg, Dept Epidemiol & Publ Hlth, EA 3430, Strasbourg, France. [Heckbert, Susan R.; Smith, Nicholas L.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan R.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Ferrieres, Jean] Toulouse Univ Hosp, Dept Cardiol, Toulouse, France. [Ferrieres, Jean] Toulouse Univ Hosp, Dept Epidemiol, Toulouse, France. [Ducimetiere, Pierre] Natl Inst Hlth & Med Res, U258, Paris, France. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs, Off Res & Dev, Seattle, WA USA. [Wang, Ying A.] Novartis Inst Biomed Res, 250 Massachusetts Ave, Cambridge, MA USA. [Siscovick, David S.] New York Acad Med, New York, NY USA. [Wiklund, Per-Gunnar] Umea Univ Hosp, Dept Med, S-90185 Umea, Sweden. [Taylor, Kent D.; Rotter, Jerome I.] Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA USA. [Taylor, Kent D.; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Evans, Alun; Kee, Frank] Queens Univ Belfast, UKCRC Ctr Excellence Publ Hlth Res Northern Irela, Belfast, Antrim, North Ireland. [Karvanen, Juha] Univ Jyvaskyla, Dept Math & Stat, Jyvaskyla, Finland. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Markus, Marcello R. P.; Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Silander, Kaisa; Wagner, Peter] Univ Helsinki, Inst Mol Med FIMM, Helsinki, Finland. [Lohman, Kurt; Liu, Yongmei] Wake Forest Sch Med, Dept Epidemiol & Prevent, Publ Hlth Sci, Winston Salem, NC 27157 USA. [Stott, David J.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Rivadeneira, Fernando] Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, Leiden, Netherlands. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Blankenberg, Stefan] Univ Heart Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Boerwinkle, Eric] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Boston Vet Adm Healthcare, Cardiol Sect, Dept Med, Boston, MA USA. RP Dehghan, A (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands.; O'Donnell, CJ (reprint author), Boston Univ, Framingham, MA USA.; O'Donnell, CJ (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA.; O'Donnell, CJ (reprint author), NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA.; O'Donnell, CJ (reprint author), Boston Vet Adm Healthcare, Cardiol Sect, Dept Med, Boston, MA USA. EM a.dehghan@erasmusmc.nl; odonnellc@nhlbi.nih.gov RI Smith, Albert Vernon/K-5150-2015; OI Smith, Albert Vernon/0000-0003-1942-5845; Kuulasmaa, Kari/0000-0003-2165-1411; Markus, Marcello Ricardo Paulista/0000-0002-6234-4955; Ramachandran, Vasan/0000-0001-7357-5970; Dehghan, Abbas/0000-0001-6403-016X FU Merck Sharp Dohme Corp.; Novartis Institutes for Biomedical Research FX There were no current funding sources for this study. Merck Sharp & Dohme Corp. provided support in the form of salary for author Cynthia J. Girman, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the 'author contributions' section. Novartis Institutes for Biomedical Research provided support in the form of salary for author Ying A. Wang, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the 'author contributions' section. NR 28 TC 6 Z9 6 U1 4 U2 6 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 MAR 7 PY 2016 VL 11 IS 3 AR e0144997 DI 10.1371/journal.pone.0144997 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3SL UT WOS:000371990100004 PM 26950853 ER PT J AU Jones, DS Rowe, CG Chen, B Reiter, K Rausch, KM Narum, DL Wu, YM Duffy, PE AF Jones, David S. Rowe, Christopher G. Chen, Beth Reiter, Karine Rausch, Kelly M. Narum, David L. Wu, Yimin Duffy, Patrick E. TI A Method for Producing Protein Nanoparticles with Applications in Vaccines SO PLOS ONE LA English DT Article ID MALARIA VACCINE; CONJUGATE VACCINES; IN-VITRO; ANTIBODY; PEPTIDE; CARRIER; IMMUNOGENICITY; EXPRESSION; PROTECTION; CANDIDATE AB A practical method is described for synthesizing conjugated protein nanoparticles using thioether (thiol-maleimide) cross-linking chemistry. This method fills the need for a reliable and reproducible synthesis of protein conjugate vaccines for preclinical studies, which can be adapted to produce comparable material for clinical studies. The described method appears to be generally applicable to the production of nanoparticles from a variety of soluble proteins having different structural features. Examples presented include single-component particles of the malarial antigens AMA1, CSP and Pfs25, and two component particles comprised of those antigens covalently cross-linked with the immunogenic carrier protein EPA (a detoxified form of exotoxin A from Pseudomonas aeruginosa). The average molar masses (Mw) of particles in the different preparations ranged from 487 kDa to 3,420 kDa, with hydrodynamic radii (Rh) ranging from 12.1 nm to 38.3 nm. The antigenic properties and secondary structures of the proteins within the particles appear to be largely intact, with no significant changes seen in their far UV circular dichroism spectra, or in their ability to bind conformation-dependent monoclonal antibodies. Mice vaccinated with mixed particles of Pfs25 or CSP and EPA generated significantly greater antigen-specific antibody levels compared with mice vaccinated with the respective unmodified monomeric antigens, validating the potential of antigen-EPA nanoparticles as vaccines. C1 [Jones, David S.; Rowe, Christopher G.; Chen, Beth; Reiter, Karine; Rausch, Kelly M.; Narum, David L.; Wu, Yimin; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. RP Jones, DS (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. EM dsj123@aol.com FU Division of Intramural Research (DIR) of NIAID, NIH; Malaria Vaccine Initiative (MVI) FX This work was supported by the Division of Intramural Research (DIR) of NIAID, NIH. A portion was funded by the Malaria Vaccine Initiative (MVI). NR 29 TC 1 Z9 1 U1 7 U2 11 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 MAR 7 PY 2016 VL 11 IS 3 AR e0138761 DI 10.1371/journal.pone.0138761 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3SL UT WOS:000371990100001 PM 26950441 ER PT J AU Michaud, M Gros, V Tardif, M Brugiere, S Ferro, M Prinz, WA Toulmay, A Mathur, J Wozny, M Falconet, D Marechal, E Block, MA Jouhet, J AF Michaud, Morgane Gros, Valerie Tardif, Marianne Brugiere, Sabine Ferro, Myriam Prinz, William A. Toulmay, Alexandre Mathur, Jaideep Wozny, Michael Falconet, Denis Marechal, Eric Block, Maryse A. Jouhet, Juliette TI AtMic60 Is Involved in Plant Mitochondria Lipid Trafficking and Is Part of a Large Complex SO CURRENT BIOLOGY LA English DT Article ID CRISTAE ORGANIZING SYSTEM; CONTACT SITE; PHOSPHATE DEPRIVATION; MEMBRANE ARCHITECTURE; PROTEIN BIOGENESIS; PLASMA-MEMBRANE; MITOFILIN; ARABIDOPSIS; CHLOROPLAST; PHOSPHATIDYLCHOLINE AB The mitochondrion is an organelle originating from an endosymbiotic event and playing a role in several fundamental processes such as energy production, metabolite syntheses, and programmed cell death. This organelle is delineated by two membranes whose synthesis requires an extensive exchange of phospholipids with other cellular organelles such as endoplasmic reticulum (ER) and vacuolar membranes in yeast. These transfers of phospholipids are thought to occur by a non-vesicular pathway at contact sites between two closely apposed membranes. In plants, little is known about the biogenesis of mitochondrial membranes. Contact sites between ER and mitochondria are suspected to play a similar role in phospholipid trafficking as in yeast, but this has never been demonstrated. In contrast, it has been shown that plastids are able to transfer lipids to mitochondria during phosphate starvation. However, the proteins involved in such transfer are still unknown. Here, we identified in Arabidopsis thaliana a large lipid-enriched complex called the mitochondrial transmembrane lipoprotein (MTL) complex. The MTL complex contains proteins located in the two mitochondrial membranes and conserved in all eukaryotic cells, such as the TOM complex and AtMic60, a component of the MICOS complex. We demonstrate that AtMic60 contributes to the export of phosphatidylethanolamine from mitochondria and the import of galactoglycerolipids from plastids during phosphate starvation. Furthermore, AtMic60 promotes lipid desorption from membranes, likely as an initial step for lipid transfer, and binds to Tom40, suggesting that AtMic60 could regulate the tethering between the inner and outer membranes of mitochondria. C1 [Michaud, Morgane; Gros, Valerie; Falconet, Denis; Marechal, Eric; Block, Maryse A.; Jouhet, Juliette] Univ Grenoble Alpes, CNRS, CEA, Lab Physiol Cellulaire & Vegetale,INRA,UMR 5168, F-38000 Grenoble, France. [Tardif, Marianne; Brugiere, Sabine; Ferro, Myriam] Univ Grenoble Alpes, INSERM, CEA U1038, Lab Biol Grande Echelle, F-38000 Grenoble, France. [Prinz, William A.; Toulmay, Alexandre] NIDDKD, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Mathur, Jaideep; Wozny, Michael] Univ Guelph, Dept Mol & Cellular Biol, Guelph, ON N1G 2W1, Canada. RP Michaud, M; Jouhet, J (reprint author), Univ Grenoble Alpes, CNRS, CEA, Lab Physiol Cellulaire & Vegetale,INRA,UMR 5168, F-38000 Grenoble, France. EM morganemichaud71@gmail.com; juliette.jouhet@cea.fr FU French National Research Agency [ANR-12-JSV2-001 Chloromitolipid, ANR-10-INBS-08 ProFI, ANR-10-LABEX-04 GRAL Labex]; EMBO [ASTF-638-2014] FX This work was supported by the French National Research Agency (ANR-12-JSV2-001 Chloromitolipid; ANR-10-INBS-08 ProFI, Proteomics French Infrastructure; and ANR-10-LABEX-04 GRAL Labex, Grenoble Alliance for Integrated Structural Cell Biology) and EMBO (ASTF-638-2014). We thank Olivier Clerc and Gregoire Denay for assistance in MS and GC data processing, Anne-Marie Hesse and Thomas Burger for assistance in proteomic MS data processing, and Claude Alban for advice on protein production and purification. NR 37 TC 5 Z9 5 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD MAR 7 PY 2016 VL 26 IS 5 BP 627 EP 639 DI 10.1016/j.cub.2016.01.011 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DF5OK UT WOS:000371401200021 PM 26898467 ER PT J AU Comrie, WA Burkhardt, JK AF Comrie, William A. Burkhardt, Janis K. TI Action and Traction: Cytoskeletal Control of Receptor Triggering at the Immunological Synapse SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE immunological synapse; actin; cytoskeleton; mechanotransduction; integrin; T cell receptor; adhesion; costimulation ID T-CELL-RECEPTOR; ALDRICH-SYNDROME PROTEIN; SUPRAMOLECULAR ACTIVATION CLUSTER; TYROSINE-PHOSPHATASE INHIBITOR; PLASMA-MEMBRANE MICRODOMAINS; LEUKOCYTE INTEGRIN LFA-1; MATURE DENDRITIC CELLS; KINASE-C-THETA; ANTIGEN-RECEPTOR; CYTOPLASMIC DOMAIN AB It is well known that F-actin dynamics drive the micron-scale cell shape changes required for migration and immunological synapse (IS) formation. In addition, recent evidence points to a more intimate role for the actin cytoskeleton in promoting T cell activation. Mechanotransduction, the conversion of mechanical input into intracellular biochemical changes, is thought to play a critical role in several aspects of immunoreceptor triggering and downstream signal transduction. Multiple molecules associated with signaling events at the IS have been shown to respond to physical force, including the TCR, costimulatory molecules, adhesion molecules, and several downstream adapters. In at least some cases, it is clear that the relevant forces are exerted by dynamics of the T cell actomyosin cytoskeleton. Interestingly, there is evidence that the cytoskeleton of the antigen-presenting cell also plays an active role in T cell activation, by countering the molecular forces exerted by the T cell at the IS. Since actin polymerization is itself driven by TCR and costimulatory signaling pathways, a complex relationship exists between actin dynamics and receptor activation. This review will focus on recent advances in our understanding of the mechanosensitive aspects of T cell activation, paying specific attention to how F-actin-directed forces applied from both sides of the IS fit into current models of receptor triggering and activation. C1 [Comrie, William A.; Burkhardt, Janis K.] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Comrie, William A.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Burkhardt, JK (reprint author), Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM jburkhar@mail.med.upenn.edu FU NIH [R01A1065644, R01 HL128551, R01GM104867] FX This work was supported by NIH grants R01A1065644, R01 HL128551, and R01GM104867. NR 267 TC 6 Z9 6 U1 10 U2 23 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD MAR 7 PY 2016 VL 7 BP 1 EP 25 AR 68 DI 10.3389/fimmu.2016.00068 PG 25 WC Immunology SC Immunology GA DF4MX UT WOS:000371324000001 PM 27014258 ER PT J AU Kasumba, IN Bestor, A Tilly, K Rosa, PA AF Kasumba, Irene N. Bestor, Aaron Tilly, Kit Rosa, Patricia A. TI Virulence of the Lyme disease spirochete before and after the tick bloodmeal: a quantitative assessment SO PARASITES & VECTORS LA English DT Article DE Borrelia burgdorferi; Ixodes ticks; Conditional priming; Lyme disease spirochete ID OUTER-SURFACE PROTEIN; BORRELIA-BURGDORFERI TRANSMISSION; RPOS REGULATORY PATHWAY; WHITE-FOOTED MICE; IXODES-SCAPULARIS; MAMMALIAN INFECTION; RESPONSE REGULATOR; SALIVARY-GLANDS; LIFE-CYCLE; EXPRESSION AB Background: Borrelia burgdorferi, the tick-transmitted agent of Lyme disease, adapts to different environments as it cycles between an arthropod vector and vertebrate host. Signals encountered during nymphal tick feeding prior to transmission activate a regulon that is controlled by the alternative sigma factors RpoN and RpoS, which are required for mammalian infection. The ingested bloodmeal also provides nutrients that stimulate spirochete replication. Although the influence of tick feeding on spirochete growth and gene expression is well documented, a quantitative assessment of spirochete virulence before and after tick feeding has not been made. Methods: Homogenates were prepared from unfed and fed infected Ixodes scapularis nymphs that had acquired B. burgdorferi as larvae. Serially diluted tick homogenates were needle-inoculated into mice to determine the infectious dose of tick-derived spirochetes before and after the bloodmeal. Mouse infection was assessed by sero-reactivity with B. burgdorferi whole cell lysates on immunoblots and attempted isolation of spirochetes from mouse tissues. Viable spirochetes in tick-derived inocula were quantified by colony formation in solid media. Results: We found that an inoculum containing as many as 104 B. burgdorferi from unfed ticks is largely non-infectious, while the calculated ID50 for spirochetes from fed ticks is similar to 30 organisms. Engineered constitutive production of the essential virulence factor OspC by spirochetes within unfed ticks did not confer an infectious phenotype. Conclusion: Conditional priming of B. burgdorferi during tick feeding induces changes in addition to OspC that are required for infection of the mammalian host. C1 [Kasumba, Irene N.; Bestor, Aaron; Tilly, Kit; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Kasumba, Irene N.] Univ Maryland, Sch Med, Dept Geog Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. RP Rosa, PA (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM prosa@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Martha Thayer, David Bland, Crystal Richards, Frank Gherardini, Tom Schwan and Phil Stewart for critical review of the manuscript. We are grateful to Vinod Nair and Anita Mora for assistance with graphics. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 58 TC 1 Z9 1 U1 6 U2 15 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 MAR 7 PY 2016 VL 9 AR 129 DI 10.1186/s13071-016-1380-1 PG 8 WC Parasitology SC Parasitology GA DF6IB UT WOS:000371458000001 PM 26951688 ER PT J AU O'Dea, EB Snelson, H Bansal, S AF O'Dea, Eamon B. Snelson, Harry Bansal, Shweta TI Using heterogeneity in the population structure of US swine farms to compare transmission models for porcine epidemic diarrhoea SO SCIENTIFIC REPORTS LA English DT Article ID BOVINE TUBERCULOSIS; VIRUS-INFECTION; UNITED-STATES; GREAT-BRITAIN; SPREAD; MOVEMENTS; SELECTION; DISEASES; CATTLE; TIME AB In 2013, U.S. swine producers were confronted with the disruptive emergence of porcine epidemic diarrhoea (PED). Movement of animals among farms is hypothesised to have played a role in the spread of PED among farms. Via this or other mechanisms, the rate of spread may also depend on the geographic density of farms and climate. To evaluate such effects on a large scale, we analyse state-level counts of outbreaks with variables describing the distribution of farm sizes and types, aggregate flows of animals among farms, and an index of climate. Our first main finding is that it is possible for a correlation analysis to be sensitive to transmission model parameters. This finding is based on a global sensitivity analysis of correlations on simulated data that included a biased and noisy observation model based on the available PED data. Our second main finding is that flows are significantly associated with the reports of PED outbreaks. This finding is based on correlations of pairwise relationships and regression modeling of total and weekly outbreak counts. These findings illustrate how variation in population structure may be employed along with observational data to improve understanding of disease spread. C1 [O'Dea, Eamon B.; Bansal, Shweta] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Snelson, Harry] Amer Assoc Swine Veterinarians, Perry, IA 50220 USA. [Bansal, Shweta] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [O'Dea, Eamon B.] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. RP Bansal, S (reprint author), Georgetown Univ, Dept Biol, Washington, DC 20057 USA.; Bansal, S (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM shweta.bansal@georgetown.edu OI Bansal, Shweta/0000-0002-1740-5421; O'Dea, Eamon/0000-0003-4748-683X FU Fogarty International Center, National Institutes of Health; Department of Homeland Security Science & Technology Directorate Foreign Animal Disease Modeling Program [HSHQDC-12-C-0014]; RAPIDD Program of the Science & Technology Directorate, Department of Homeland Security FX This work was supported by the RAPIDD Program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health; as well as the Department of Homeland Security Science & Technology Directorate Foreign Animal Disease Modeling Program through contract # HSHQDC-12-C-0014. We thank John Korslund for useful feedback on veterinary subject matter. We thank John Drake and Chris Dibble for comments that improved the clarity of the writing. NR 43 TC 0 Z9 0 U1 1 U2 9 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 MAR 7 PY 2016 VL 6 AR 22248 DI 10.1038/srep22248 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF5PO UT WOS:000371404400001 PM 26947420 ER PT J AU Pourmorteza, A Dang, H Siewerdsen, JH Stayman, JW AF Pourmorteza, A. Dang, H. Siewerdsen, J. H. Stayman, J. W. TI Reconstruction of difference in sequential CT studies using penalized likelihood estimation SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE computed tomography; cone-beam CT; model-based image reconstruction; statistical image reconstruction; prior image-based reconstruction; penalized likelihood estimation; image-guided radiotherapy ID CONE-BEAM CT; GUIDED RADIATION-THERAPY; COMPUTED-TOMOGRAPHY; CLINICAL-APPLICATIONS; IMAGE-RECONSTRUCTION; REGISTRATION; PROJECTION; FRAMEWORK AB Characterization of anatomical change and other differences is important in sequential computed tomography (CT) imaging, where a high-fidelity patient-specific prior image is typically present, but is not used, in the reconstruction of subsequent anatomical states. Here, we introduce a penalized likelihood (PL) method called reconstruction of difference (RoD) to directly reconstruct a difference image volume using both the current projection data and the (unregistered) prior image integrated into the forward model for the measurement data. The algorithm utilizes an alternating minimization to find both the registration and reconstruction estimates. This formulation allows direct control over the image properties of the difference image, permitting regularization strategies that inhibit noise and structural differences due to inconsistencies between the prior image and the current data. Additionally, if the change is known to be local, RoD allows local acquisition and reconstruction, as opposed to traditional model-based approaches that require a full support field of view (or other modifications). We compared the performance of RoD to a standard PL algorithm, in simulation studies and using test-bench cone-beam CT data. The performances of local and global RoD approaches were similar, with local RoD providing a significant computational speedup. In comparison across a range of data with differing fidelity, the local RoD approach consistently showed lower error (with respect to a truth image) than PL in both noisy data and sparsely sampled projection scenarios. In a study of the prior image registration performance of RoD, a clinically reasonable capture ranges were demonstrated. Lastly, the registration algorithm had a broad capture range and the error for reconstruction of CT data was 35% and 20% less than filtered back-projection for RoD and PL, respectively. The RoD has potential for delivering high-quality difference images in a range of sequential clinical scenarios including image-guided surgeries and treatments where accurate and quantitative assessments of anatomical change is desired. C1 [Pourmorteza, A.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20814 USA. [Dang, H.; Siewerdsen, J. H.; Stayman, J. W.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. RP Stayman, JW (reprint author), Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. EM web.stayman@jhu.edu FU academic-industry partnership with Elekta (Stockholm, Sweden); National Institutes of Health [R01EB017226] FX This work supported in part by an academic-industry partnership with Elekta (Stockholm, Sweden) and the National Institutes of Health grant R01EB017226. The authors thank Drs Junghoon Lee and John Wong (Department of Radiation Oncology, Johns Hopkins University) for collaboration and valuable conversations. NR 36 TC 0 Z9 0 U1 0 U2 4 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 MAR 7 PY 2016 VL 61 IS 5 BP 1986 EP 2002 DI 10.1088/0031-9155/61/5/1986 PG 17 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DE2JF UT WOS:000370452900009 PM 26894795 ER PT J AU Afasizheva, A Devine, A Tillman, H Fung, KL Vieira, WD Blehm, BH Kotobuki, Y Busby, B Chen, EI Tanner, K AF Afasizheva, Anna Devine, Alexus Tillman, Heather Fung, King Leung Vieira, Wilfred D. Blehm, Benjamin H. Kotobuki, Yorihisa Busby, Ben Chen, Emily I. Tanner, Kandice TI Mitogen-activated protein kinase signaling causes malignant melanoma cells to differentially alter extracellular matrix biosynthesis to promote cell survival SO BMC CANCER LA English DT Article DE Melanoma; Fibronectin; Extracellular matrix; MAPK; Integrin; Tenascin-C; Vemurafenib; Dabrafenib ID MEDIATED DRUG-RESISTANCE; METASTATIC MELANOMA; BREAST-CANCER; 3-DIMENSIONAL CULTURE; MULTIDRUG-RESISTANCE; OVARIAN-CANCER; OPEN-LABEL; IN-VIVO; FIBRONECTIN; BRAF AB Background: Intrinsic and acquired resistance to drug therapies remains a challenge for malignant melanoma patients. Intratumoral heterogeneities within the tumor microenvironment contribute additional complexity to the determinants of drug efficacy and acquired resistance. Methods: We use 3D biomimetic platforms to understand dynamics in extracellular matrix (ECM) biogenesis following pharmaceutical intervention against mitogen-activated protein kinases (MAPK) signaling. We further determined temporal evolution of secreted ECM components by isogenic melanoma cell clones. Results: We found that the cell clones differentially secrete and assemble a myriad of ECM molecules into dense fibrillar and globular networks. We show that cells can modulate their ECM biosynthesis in response to external insults. Fibronectin (FN) is one of the key architectural components, modulating the efficacy of a broad spectrum of drug therapies. Stable cell lines engineered to secrete minimal levels of FN showed a concomitant increase in secretion of Tenascin-C and became sensitive to BRAF(V600E) and ERK inhibition as clonally-derived 3D tumor aggregates. These cells failed to assemble exogenous FN despite maintaining the integrin machinery to facilitate cell-ECM cross-talk. We determined that only clones that increased FN production via p38 MAPK and beta 1 integrin survived drug treatment. Conclusions: These data suggest that tumor cells engineer drug resistance by altering their ECM biosynthesis. Therefore, drug treatment may induce ECM biosynthesis, contributing to de novo resistance. C1 [Afasizheva, Anna; Devine, Alexus; Fung, King Leung; Vieira, Wilfred D.; Blehm, Benjamin H.; Kotobuki, Yorihisa; Tanner, Kandice] NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. [Tillman, Heather] NCI, Lab Genitourinary Canc Pathogenesis, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. [Busby, Ben] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Chen, Emily I.] Columbia Univ, Med Ctr, Prote Shared Resource Herbert Irving Comprehens C, New York, NY 10032 USA. [Chen, Emily I.] Columbia Univ, Med Ctr, Dept Pharmacol, New York, NY 10032 USA. RP Tanner, K (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM kandice.tanner@nih.gov OI fung, king leung/0000-0002-8549-1384 FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 58 TC 1 Z9 1 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAR 5 PY 2016 VL 16 AR 186 DI 10.1186/s12885-016-2211-7 PG 15 WC Oncology SC Oncology GA DF9GO UT WOS:000371669200002 PM 26944546 ER PT J AU Gonzalez-Mariscal, I Krzysik-Walker, SM Kim, W Rouse, M Egan, JM AF Gonzalez-Mariscal, Isabel Krzysik-Walker, Susan M. Kim, Wook Rouse, Michael Egan, Josephine M. TI Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Adenylyl cyclase; cAMP; CB1; GLP-1; Incretin; Insulin secretion ID GLUCAGON-LIKE PEPTIDE-1; PANCREATIC BETA-CELL; HIGH-FAT DIET; ENDOCANNABINOID DYSREGULATION; REDUCES OBESITY; ENERGY-BALANCE; CB1 RECEPTORS; BODY-WEIGHT; FOOD-INTAKE; RIMONABANT AB The cannabinoid 1 receptor (CBI) is an important regulator of energy metabolism. Reports of in vivo and in vitro studies give conflicting results regarding its role in insulin secretion, possibly due to circulatory factors, such as incretins. We hypothesized that this receptor may be a regulator of the entero-insular axis. We found that despite lower food consumption and lower body weight postprandial GLP-1 plasma concentrations were increased in CB1(-/-) mice compared to CB1(+/+) mice administered a standard diet or high fat/sugar diet. Upon exogenous GLP-1 treatment, CB1(-/-) mice had increased glucose stimulated insulin secretion. In mouse insulinoma cells, cannabinoids reduced GLP-1R-mediated intracellular CAMP accumulation and subsequent insulin secretion. Importantly, such effects were also evident in human islets, and were prevented by pharmacologic blockade of CB1. Collectively, these findings suggest a novel mechanism in which endocannabinoids are negative modulators of incretin-mediated insulin secretion. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Gonzalez-Mariscal, Isabel; Krzysik-Walker, Susan M.; Kim, Wook; Rouse, Michael; Egan, Josephine M.] NIA, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Kim, Wook] Ajou Univ, Dept Mol Sci & Technol, Suwon 443749, South Korea. RP Kim, W (reprint author), Ajou Univ, 206 World Cup Ro, Suwon 443749, South Korea. EM wookkim21@ajou.ac.kr OI Gonzalez Mariscal, Isabel/0000-0003-1186-1212 FU Intramural Research Program of National Institute on Aging within the National Institutes of Health; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT Future [NRF-2012R1A1A1041352, NRF-2015R1A2A1A15054227]; Ministry of Education [NRF-2009-0093826] FX This work was supported by the Intramural Research Program of National Institute on Aging within the National Institutes of Health. WK was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future (NRF-2012R1A1A1041352 and NRF-2015R1A2A1A15054227) and the Ministry of Education (NRF-2009-0093826). NR 49 TC 3 Z9 3 U1 1 U2 5 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 MAR 5 PY 2016 VL 423 IS C BP 1 EP 10 DI 10.1016/j.mce.2015.12.015 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DF9BC UT WOS:000371654200001 PM 26724516 ER PT J AU Sinka, ME Golding, N Massey, NC Wiebe, A Huang, Z Hay, SI Moyes, CL AF Sinka, Marianne E. Golding, Nick Massey, N. Claire Wiebe, Antoinette Huang, Zhi Hay, Simon I. Moyes, Catherine L. TI Modelling the relative abundance of the primary African vectors of malaria before and after the implementation of indoor, insecticide-based vector control SO MALARIA JOURNAL LA English DT Article DE Relative abundance; Vector; Mosquito; Anopheles; Africa; Insecticide control; Malaria ID ANOPHELES-GAMBIAE COMPLEX; PLASMODIUM-FALCIPARUM; WESTERN KENYA; AN.-GAMBIAE; ARABIENSIS; TRANSMISSION; CULICIDAE; MOSQUITOS; FUNESTUS; DIPTERA AB Background: Malaria remains a heavy burden across sub-Saharan Africa where transmission is maintained by some of the world's most efficient vectors. Indoor insecticide-based control measures have significantly reduced transmission, yet elimination remains a distant target. Knowing the relative abundance of the primary vector species can provide transmission models with much needed information to guide targeted control measures. Moreover, understanding how existing interventions are impacting on these relative abundances highlights where alternative control (e.g., larval source management) is needed. Methods: Using the habitat suitability probabilities generated by predictive species distribution models combined with data collated from the literature, a multinomial generalized additive model was applied to produce relative abundance estimates for Anopheles arabiensis, Anopheles funestus and Anopheles gambiae/Anopheles coluzzii. Using pre-and post-intervention abundance data, estimates of the effect of indoor insecticide-based interventions on these relative abundances were made and are illustrated in post-intervention maps. Results: Conditional effect plots and relative abundance maps illustrate the individual species' predicted habitat suitability and how they interact when in sympatry. Anopheles arabiensis and An. funestus show an affinity in habitat preference at the expense of An. gambiae/An. coluzzii, whereas increasing habitat suitability for An. gambiae/An. coluzzii is conversely less suitable for An. arabiensis but has little effect on An. funestus. Indoor insecticide-based interventions had a negative impact on the relative abundance of An. funestus, and a lesser effect on An. arabiensis. Indoor residual spraying had the greatest impact on the relative abundance of An. funestus, and a lesser effect on An. gambiae/An. coluzzii. Insecticide-treated bed nets reduced the relative abundance of both species equally. These results do not indicate changes in the absolute abundance of these species, which may be reduced for all species overall. Conclusions: The maps presented here highlight the interactions between the primary vector species in sub-Saharan Africa and demonstrate that An. funestus is more susceptible to certain indoor-based insecticide interventions than An. gambiae/An. coluzzii, which in turn, is more susceptible than An. arabiensis. This may provide An. arabiensis with a competitive advantage where it is found in sympatry with other more endophilic vectors, and potentially increase the need for outdoor-based vector interventions to deal with any residual transmission barring the way to malaria elimination. C1 [Sinka, Marianne E.; Massey, N. Claire; Huang, Zhi] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Golding, Nick; Wiebe, Antoinette; Hay, Simon I.; Moyes, Catherine L.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Hay, Simon I.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. [Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Sinka, ME (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. EM marianne.sinka@zoo.ox.ac.uk OI Hay, Simon/0000-0002-0611-7272; Golding, Nick/0000-0001-8916-5570; Moyes, Catherine/0000-0002-8028-4079 FU Bill and Melinda Gates Foundation through the Vector-borne Disease Network (VecNet); Bill and Melinda Gates Foundation [OPP1053338, OPP1119467, OPP1106023, OPP1093011]; Wellcome Trust [095066]; RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX MES, NCM, AW, ZH, and CLM were funded by the Bill and Melinda Gates Foundation through the Vector-borne Disease Network (VecNet) (http://vecnet.org). NG is funded by a grant from the Bill and Melinda Gates Foundation (#OPP1053338). SIH is funded by a Senior Research Fellowship from the Wellcome Trust (#095066), and grants from the Bill and Melinda Gates Foundation (OPP1119467, OPP1106023 and OPP1093011). SIH would also like to acknowledge funding support the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 39 TC 5 Z9 5 U1 6 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD MAR 5 PY 2016 VL 15 AR 42 DI 10.1186/s12936-016-1187-8 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DF6KL UT WOS:000371464400002 PM 26945997 ER PT J AU Burge, CA Friedman, CS Getchell, R House, M Lafferty, KD Mydlarz, LD Prager, KC Sutherland, KP Renault, T Kiryu, I Vega-Thurber, R AF Burge, Colleen A. Friedman, Carolyn S. Getchell, Rodman House, Marcia Lafferty, Kevin D. Mydlarz, Laura D. Prager, Katherine C. Sutherland, Kathryn P. Renault, Tristan Kiryu, Ikunari Vega-Thurber, Rebecca TI Complementary approaches to diagnosing marine diseases: a union of the modern and the classic SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE marine disease; aetiology; diagnostics; marine epizootics ID CANDIDATUS XENOHALIOTIS CALIFORNIENSIS; WHITE POX DISEASE; RICKETTSIALES-LIKE PROKARYOTE; HEMORRHAGIC SEPTICEMIA VIRUS; LIONS ZALOPHUS-CALIFORNIANUS; ABALONE HALIOTIS-CRACHERODII; OYSTER CRASSOSTREA-GIGAS; CARIBBEAN ELKHORN CORAL; IN-SITU HYBRIDIZATION; PRINCE-WILLIAM-SOUND AB Linking marine epizootics to a specific aetiology is notoriously difficult. Recent diagnostic successes show that marine disease diagnosis requires both modern, cutting-edge technology (e.g. metagenomics, quantitative real-time PCR) and more classic methods (e.g. transect surveys, histopathology and cell culture). Here, we discuss how this combination of traditional and modern approaches is necessary for rapid and accurate identification of marine diseases, and emphasize how sole reliance on any one technology or technique may lead disease investigations astray. We present diagnostic approaches at different scales, from the macro (environment, community, population and organismal scales) to the micro (tissue, organ, cell and genomic scales). We use disease case studies from a broad range of taxa to illustrate diagnostic successes from combining traditional and modern diagnostic methods. Finally, we recognize the need for increased capacity of centralized databases, networks, data repositories and contingency plans for diagnosis and management of marine disease. C1 [Burge, Colleen A.] Univ Maryland Baltimore Cty, Inst Marine & Environm Technol, 701 E Pratt St, Baltimore, MD 21202 USA. [Friedman, Carolyn S.] Univ Washington, Sch Aquat & Fishery Sci, Box 355020, Seattle, WA 98195 USA. [Getchell, Rodman] Cornell Univ, Coll Vet Med, Dept Microbiol & Immunol, Vet Med Ctr C4 177, 930 Campus Rd, Ithaca, NY 14853 USA. [House, Marcia] Northwest Indian Fisheries Commiss, 6730 Martin Way East, Olympia, WA 98516 USA. [Lafferty, Kevin D.] Univ Calif Santa Barbara, Inst Marine Sci, Western Ecol Res Ctr, US Geol Survey, Santa Barbara, CA 93106 USA. [Mydlarz, Laura D.] Univ Texas Arlington, Dept Biol, 501 South Nedderman, Arlington, TX 76019 USA. [Prager, Katherine C.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Prager, Katherine C.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Sutherland, Kathryn P.] Rollins Coll, Dept Biol, Winter Pk, FL 32789 USA. [Renault, Tristan] IFREMER, Dept Ressources Biol & Environm, Rue Ile Yeu, F-44311 Nantes 03, France. [Kiryu, Ikunari] Fisheries Res Agcy, Natl Res Inst Aquaculture, Tsu, Mie 5160193, Japan. [Vega-Thurber, Rebecca] Oregon State Univ, 454 Nash Hall, Corvallis, OR 97330 USA. RP Burge, CA (reprint author), Univ Maryland Baltimore Cty, Inst Marine & Environm Technol, 701 E Pratt St, Baltimore, MD 21202 USA. EM colleenb@umbc.edu FU National Science Foundation (NSF) Ecology and Evolution of Infectious Diseases [OCE-1215977]; NSF-NIH Ecology of Infectious Disease program [EF1015032]; NSF [OCE-1335657]; NSF grant IOS [1017458]; California Sea Grant [NA10OAR4170060] FX This work was conducted as part of the Ecology of Infectious Marine Disease Research Coordination Network (EIMD-RCN) (http://www.eeb.cornell.edu/ecologymarinedisease/Home/Home.html) funded by National Science Foundation (NSF) Ecology and Evolution of Infectious Diseases grant OCE-1215977. K.P.S. acknowledges funding provided by NSF-NIH Ecology of Infectious Disease program grant EF1015032. K.C.P. was supported by the NSF (OCE-1335657). NSF grant IOS no. 1017458 to L.D.M. C.A.B. and C.S.F. acknowledge support from California Sea Grant (NA10OAR4170060). NR 118 TC 9 Z9 9 U1 6 U2 32 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAR 5 PY 2016 VL 371 IS 1689 AR 20150207 DI 10.1098/rstb.2015.0207 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DF2CU UT WOS:000371148300005 ER PT J AU Branduardi, D Marinelli, F Faraldo-Gomez, JD AF Branduardi, Davide Marinelli, Fabrizio Faraldo-Gomez, Jose D. TI Atomic-Resolution Dissection of the Energetics and Mechanism of Isomerization of Hydrated ATP-Mg2+ Through the SOMA String Method SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE molecular dynamics simulations; string method-metadynamics; replica-exchange; free-energy calculations ID MOLECULAR SIMULATION; ENERGY; EFFICIENT; DYNAMICS; METADYNAMICS; BIOMOLECULES; SYSTEMS; BIAS AB The atomic mechanisms of isomerization of ATP-Mg2+ in solution are characterized using the recently developed String Method with Optimal Molecular Alignment (SOMA) and molecular-dynamics simulations. Bias-Exchange Metadynamics simulations are first performed to identify the primary conformers of the ATP-Mg2+ complex and their connectivity. SOMA is then used to elucidate the minimum free-energy path (MFEP) for each transition, in a 48-dimensional space. Analysis of the per-atom contributions to the global free-energy profiles reveals that the mechanism of these transitions is controlled by the Mg2+ ion and its coordinating oxygen atoms in the triphosphate moiety, as well as by the ion-hydration shell. Metadynamics simulations in path collective variables based on the MFEP demonstrate these isomerizations proceed across a narrow channel of configurational space, thus validating the premise underlying SOMA. This study provides a roadmap for the examination of conformational changes in biomolecules, based on complementary enhanced-sampling techniques with different strengths. (C) 2015 Wiley Periodicals, Inc. C1 [Branduardi, Davide; Faraldo-Gomez, Jose D.] Max Planck Inst Biophys, Theoret Mol Biophys Grp, Max von Laue Str 3, DE-60438 Frankfurt, Germany. [Marinelli, Fabrizio; Faraldo-Gomez, Jose D.] NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 5635FL,Suite T-800, Bethesda, MD 20892 USA. RP Branduardi, D; Faraldo-Gomez, JD (reprint author), Max Planck Inst Biophys, Theoret Mol Biophys Grp, Max von Laue Str 3, DE-60438 Frankfurt, Germany.; Faraldo-Gomez, JD (reprint author), NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 5635FL,Suite T-800, Bethesda, MD 20892 USA. EM davide.branduardi@gmail.com; jose.faraldo@nih.gov RI Faraldo-Gomez, Jose/H-7127-2016 FU Max Planck Institute of Biophysics in Frankfurt am Main, Germany; Division of Intramural Research of the National Heart, Lung and Blood Institute at the National Institutes of Health in Bethesda, MD FX Contract grant sponsor: Max Planck Institute of Biophysics, in Frankfurt am Main, Germany; Contract grant sponsor: Division of Intramural Research of the National Heart, Lung and Blood Institute at the National Institutes of Health in Bethesda, MD NR 42 TC 1 Z9 1 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 EI 1096-987X J9 J COMPUT CHEM JI J. Comput. Chem. PD MAR 5 PY 2016 VL 37 IS 6 SI SI BP 575 EP 586 DI 10.1002/jcc.23991 PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA DD9OF UT WOS:000370254600005 PM 26149527 ER PT J AU Wu, XW Brooks, BR Vanden-Eijnden, E AF Wu, Xiongwu Brooks, Bernard R. Vanden-Eijnden, Eric TI Self-Guided Langevin Dynamics via Generalized Langevin Equation SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE self-guided Langevin dynamics; generalized Langevin equation; molecular simulation; conformational sampling; canonical ensemble AB Self-guided Langevin dynamics (SGLD) is a molecular simulation method that enhances conformational search and sampling via acceleration of the low frequency motions of the system. This acceleration is produced via introduction of a guiding force which breaks down the detailed-balance property of the dynamics, implying that some reweighting is necessary to perform equilibrium sampling. Here, we eliminate the need of reweighing and show that the NVT and NPT ensembles are sampled exactly by a new version of self-guided motion involving a generalized Langevin equation (GLE) in which the random force is modified so as to restore detailed-balance. Through the examples of alanine dipeptide and argon liquid, we show that this SGLD-GLE method has enhanced conformational sampling capabilities compared with regular Langevin dynamics (LD) while being of comparable computational complexity. In particular, SGLD-GLE is fully size extensive and can be used in arbitrarily large systems, making it an appealing alternative to LD. (C) 2015 Wiley Periodicals, Inc. C1 [Wu, Xiongwu; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Vanden-Eijnden, Eric] NYU, Courant Inst Math Sci, 251 Mercer St, New York, NY 10012 USA. RP Wu, XW (reprint author), NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM wuxw@nhlbi.nih.gov FU Intramural Research Program of the NIH, NHLBI; NIH [N00014-11-1-0345]; NSF [1207432] FX Contract grant sponsor: Intramural Research Program of the NIH, NHLBI, and NIH; Contract NSF Grant 1207432 and NIH Grant N00014-11-1-0345 NR 13 TC 4 Z9 4 U1 6 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 EI 1096-987X J9 J COMPUT CHEM JI J. Comput. Chem. PD MAR 5 PY 2016 VL 37 IS 6 SI SI BP 595 EP 601 DI 10.1002/jcc.24015 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA DD9OF UT WOS:000370254600007 PM 26183423 ER PT J AU Amato, R Miotto, O Woodrow, CJ Almagro-Garcia, J Sinha, I Campino, S Mead, D Drury, E Kekre, M Sanders, M Amambua-Ngwa, A Amaratunga, C Amenga-Etego, L Andrianaranjaka, V Apinjoh, T Ashley, E Auburn, S Awandare, GA Baraka, V Barry, A Boni, MF Borrmann, S Bousema, T Branch, O Bull, PC Chotivanich, K Conway, DJ Craig, A Day, NP Djimde, A Dolecek, C Dondorp, AM Drakeley, C Duffy, P Echeverry, DF Egwang, TG Fairhurst, RM Faiz, MA Fanello, CI Hien, TT Hodgson, A Imwong, M Ishengoma, D Lim, P Lon, C Marfurt, J Marsh, K Mayxay, M Michon, P Mobegi, V Mokuolu, OA Montgomery, J Mueller, I Kyaw, MP Newton, PN Nosten, F Noviyanti, R Nzila, A Ocholla, H Oduro, A Onyamboko, M Ouedraogo, JB Phyo, APP Plowe, C Price, RN Pukrittayakamee, S Randrianarivelojosia, M Ringwald, P Ruiz, L Saunders, D Shayo, A Siba, P Takala-Harrison, S Thanh, TNN Thathy, V Verra, F Wendler, J White, NJ Ye, H Cornelius, VJ Giacomantonio, R Muddyman, D Henrichs, C Malangone, C Jyothi, D Pearson, RD Rayner, JC McVean, G Rockett, KA Miles, A Vauterin, P Jeffery, B Manske, M Stalker, J Maclnnis, B Kwiatkowski, DP AF Amato, Roberto Miotto, Olivo Woodrow, Charles J. Almagro-Garcia, Jacob Sinha, Ipsita Campino, Susana Mead, Daniel Drury, Eleanor Kekre, Mihir Sanders, Mandy Amambua-Ngwa, Alfred Amaratunga, Chanaki Amenga-Etego, Lucas Andrianaranjaka, Voahangy Apinjoh, Tobias Ashley, Elizabeth Auburn, Sarah Awandare, Gordon A. Baraka, Vito Barry, Alyssa Boni, Maciej F. Borrmann, Steffen Bousema, Teun Branch, Oralee Bull, Peter C. Chotivanich, Kesinee Conway, David J. Craig, Alister Day, Nicholas P. Djimde, Abdoulaye Dolecek, Christiane Dondorp, Arjen M. Drakeley, Chris Duffy, Patrick Echeverry, Diego F. Egwang, Thomas G. Fairhurst, Rick M. Faiz, Md. Abul Fanello, Caterina I. Tran Tinh Hien Hodgson, Abraham Imwong, Mallika Ishengoma, Deus Lim, Pharath Lon, Chanthap Marfurt, Jutta Marsh, Kevin Mayxay, Mayfong Michon, Pascal Mobegi, Victor Mokuolu, Olugbenga A. Montgomery, Jacqui Mueller, Ivo Kyaw, Myat Phone Newton, Paul N. Nosten, Francois Noviyanti, Rintis Nzila, Alexis Ocholla, Harold Oduro, Abraham Onyamboko, Marie Ouedraogo, Jean-Bosco Phyo, Aung Pyae P. Plowe, Christopher Price, Ric N. Pukrittayakamee, Sasithon Randrianarivelojosia, Milijaona Ringwald, Pascal Ruiz, Lastenia Saunders, David Shayo, Alex Siba, Peter Takala-Harrison, Shannon Thanh, Thuy-Nhien N. Thathy, Vandana Verra, Federica Wendler, Jason White, Nicholas J. Ye, Htut Cornelius, Victoria J. Giacomantonio, Rachel Muddyman, Dawn Henrichs, Christa Malangone, Cinzia Jyothi, Dushyanth Pearson, Richard D. Rayner, Julian C. McVean, Gilean Rockett, Kirk A. Miles, Alistair Vauterin, Paul Jeffery, Ben Manske, Magnus Stalker, Jim Maclnnis, Bronwyn Kwiatkowski, Dominic P. CA MalariaGEN Plasmodium Falciparum C TI Genomic epidemiology of artemisinin resistant malaria SO ELIFE LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; MOLECULAR POPULATION-GENETICS; SOFT SELECTIVE SWEEPS; SUB-SAHARAN AFRICA; SUBSTITUTION MATRICES; DRUG-RESISTANCE; ADAPTATION; MUTATIONS; EVOLUTION; CAMBODIA AB The current epidemic of artemisinin resistant Plasmodium falciparum in Southeast Asia is the result of a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelchl3 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of variations that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelchl3 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions. C1 [Amato, Roberto; Miotto, Olivo; Almagro-Garcia, Jacob; Campino, Susana; Mead, Daniel; Drury, Eleanor; Kekre, Mihir; Sanders, Mandy; Giacomantonio, Rachel; Muddyman, Dawn; Malangone, Cinzia; Jyothi, Dushyanth; Pearson, Richard D.; Rayner, Julian C.; Rockett, Kirk A.; Miles, Alistair; Manske, Magnus; Stalker, Jim; Maclnnis, Bronwyn; Kwiatkowski, Dominic P.] Wellcome Trust Sanger Inst, Cambridge, England. [Amato, Roberto; Miotto, Olivo; Almagro-Garcia, Jacob; Wendler, Jason; Cornelius, Victoria J.; Giacomantonio, Rachel; Henrichs, Christa; Pearson, Richard D.; McVean, Gilean; Rockett, Kirk A.; Miles, Alistair; Vauterin, Paul; Jeffery, Ben; Kwiatkowski, Dominic P.] Wellcome Trust Ctr Human Genet, Ctr Genom & Global Hlth, Oxford, England. [Miotto, Olivo; Woodrow, Charles J.; Sinha, Ipsita; Ashley, Elizabeth; Day, Nicholas P.; Dondorp, Arjen M.; Fanello, Caterina I.; Imwong, Mallika; White, Nicholas J.] Mahidol Univ, Mahidol Oxford Trop Med Res Unit, Bangkok 10700, Thailand. [Woodrow, Charles J.; Boni, Maciej F.; Bull, Peter C.; Day, Nicholas P.; Dolecek, Christiane; Dondorp, Arjen M.; Tran Tinh Hien; Price, Ric N.; Thanh, Thuy-Nhien N.; White, Nicholas J.] Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England. [Amambua-Ngwa, Alfred; Conway, David J.; Mobegi, Victor] MRC Unit, Banjul, Gambia. [Amaratunga, Chanaki; Duffy, Patrick; Fairhurst, Rick M.; Lim, Pharath] NIAID, NIH, Rockville, MD USA. [Amenga-Etego, Lucas; Tran Tinh Hien; Oduro, Abraham] Navrongo Hlth Res Ctr, Navrongo, Ghana. [Andrianaranjaka, Voahangy; Randrianarivelojosia, Milijaona] Inst Pasteur Madagascar, Malaria Res Unit, Antananarivo, Madagascar. [Apinjoh, Tobias] Univ Buea, Buea, Cameroon. [Auburn, Sarah; Marfurt, Jutta; Price, Ric N.] Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia. [Auburn, Sarah; Marfurt, Jutta; Price, Ric N.] Charles Darwin Univ, Darwin, NT 0909, Australia. [Awandare, Gordon A.] Univ Ghana, Coll Basic & Appl Sci, West African Ctr Cell Biol Infect Pathogens, Legon, Ghana. [Baraka, Vito; Ishengoma, Deus] Natl Inst Med Res, Tanga Ctr, Tanga, Tanzania. [Baraka, Vito] Univ Antwerp, Dept Epidemiol, Int Hlth Unit, B-2020 Antwerp, Belgium. [Barry, Alyssa] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Div Populat Hlth & Immun, Parkville, Vic 3050, Australia. [Barry, Alyssa; Mueller, Ivo] Univ Melbourne, Dept Med Biol, Carlton, Vic 3053, Australia. [Boni, Maciej F.] Univ Oxford, Ho Chi Minh City, Vietnam. [Borrmann, Steffen; Bull, Peter C.; Marsh, Kevin; Thathy, Vandana] Wellcome Trust Collaborat Res Program, Kenya Med Res Inst, Kilifi, Kenya. [Borrmann, Steffen] Univ Tubingen, Inst Trop Med, Tubingen, Germany. [Bousema, Teun; Conway, David J.; Drakeley, Chris; Mobegi, Victor; Verra, Federica] London Sch Hyg & Trop Med, London WC1, England. [Branch, Oralee] NYU, Sch Med, New York, NY USA. [Chotivanich, Kesinee; Pukrittayakamee, Sasithon] Mahidol Univ, Fac Trop Med, Bangkok, Thailand. [Craig, Alister] Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. [Djimde, Abdoulaye] Univ Bamako, Fac Med, Malaria Res & Training Ctr, Bamako, Mali. [Dolecek, Christiane; Tran Tinh Hien; Thanh, Thuy-Nhien N.] Univ Oxford, Clin Res Unit, Ho Chi Minh City, Vietnam. [Echeverry, Diego F.] Purdue Univ, Dept Entomol, W Lafayette, IN 47907 USA. [Echeverry, Diego F.] CIDEIM, Int Ctr Med Res & Training, Cali, Colombia. [Egwang, Thomas G.] Med Biotech Labs, Kampala, Uganda. [Faiz, Md. Abul] Malaria Res Grp, Dhaka, Bangladesh. [Faiz, Md. Abul] Dev Care Fdn, Dhaka, Bangladesh. [Lim, Pharath] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. [Lon, Chanthap; Saunders, David] Armed Forces Res Inst Med Sci, US Army Med Component, Dept Immunol & Med, Bangkok 10400, Thailand. [Mayxay, Mayfong; Newton, Paul N.] Lao Oxford Mahosot Hosp Wellcome Trust Res Unit, Vientiane, Lao PDR, England. [Mayxay, Mayfong] Univ Hlth Sci, Fac Postgrad Studies, Vientiane, Lao PDR, England. [Michon, Pascal] Divine Word Univ, Fac Med & Hlth Sci, Madang, Papua N Guinea. [Mokuolu, Olugbenga A.] Univ Ilorin, Dept Paediat & Child Hlth, Ilorin, Nigeria. [Montgomery, Jacqui] Penn State Univ, Dept Biol & Entomol, University Pk, PA 16802 USA. [Kyaw, Myat Phone; Ye, Htut] Minist Hlth, Dept Med Res Lower Myanmar, Yangon, Myanmar. [Nosten, Francois] Mahidol Univ, Mahido Oxford Trop Med Res Unit, Mae Sot, Thailand. [Nosten, Francois; Phyo, Aung Pyae P.] Shoklo Malaria Res Unit, Mae Sot, Thailand. [Noviyanti, Rintis] Eijkman Inst Mol Biol, Jakarta, Indonesia. [Nzila, Alexis] King Fahd Univ Petr & Minerals, Dept Biol, Dhahran, Saudi Arabia. [Ocholla, Harold] Malawi Liverpool Wellcome Trust Clin Res Programm, Lilongwe, Malawi. [Onyamboko, Marie] Univ Kinshasa, Kinshasa, Zaire. [Ouedraogo, Jean-Bosco] Direct Regionale Ouest, Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso. [Phyo, Aung Pyae P.] Shoklo Malaria Res Unit, Bangkok, Thailand. [Plowe, Christopher; Takala-Harrison, Shannon] Univ Maryland, Sch Med, Inst Global Hlth, Baltimore, MD 21201 USA. [Ringwald, Pascal] WHO, Global Malaria Programme, CH-1211 Geneva, Switzerland. [Ruiz, Lastenia] Univ Nacl Amazonia Peruana, Iquitos, Peru. [Shayo, Alex] Univ Dodoma, Dept Biotechnol & Bioinformat, Dodoma, Tanzania. [Siba, Peter] Papua New Guinea Inst Med Res, Madang, Papua N Guinea. RP Amato, R; Miotto, O; Kwiatkowski, DP (reprint author), Wellcome Trust Sanger Inst, Cambridge, England.; Amato, R; Miotto, O; Kwiatkowski, DP (reprint author), Wellcome Trust Ctr Human Genet, Ctr Genom & Global Hlth, Oxford, England.; Miotto, O (reprint author), Mahidol Univ, Mahidol Oxford Trop Med Res Unit, Bangkok 10700, Thailand. EM ra4@sanger.ac.uk; olivo@tropmedres.ac; dominic@sanger.ac.uk RI Bousema, Teun/N-3574-2014; OI Awandare, Gordon/0000-0002-8793-3641; Miotto, Olivo/0000-0001-8060-6771; Baraka, Vito /0000-0001-9694-9293; Conway, David/0000-0002-8711-3037; Craig, Alister/0000-0003-0914-6164; Jyothi, Dushyanth/0000-0002-0448-5303; Auburn, Sarah/0000-0002-4638-536X; Rayner, Julian/0000-0002-9835-1014; Kwiatkowski, Dominic/0000-0002-5023-0176; Pyae Phyo, Aung/0000-0002-0383-9624; Mead, Daniel/0000-0001-7717-4330; Manske, Magnus/0000-0001-5916-0947; Price, Richard/0000-0003-2000-2874 FU Wellcome Trust [98051, 090532/Z/09/Z, 90770, 0892375/H/09/Z]; Medical Research Council [G0600718]; Bill and Melinda Gates Foundation [OPP1040463]; National Institute of Allergy and Infectious Diseases FX Wellcome Trust WT Sanger Institute Core Funding, 98051 Roberto Amato Susana Campino Daniel Mead Eleanor Drury Mihir Kekre Mandy Sanders Victoria J Cornelius Rachel Giacomantonio Dawn Muddyman Cinzia Malangone Dushyanth Jyothi Richard D Pearson Julian C Rayner Kirk A Rockett Alistair Miles Heinrich M Manske Jim Stalker Bronwyn MacInnis Dominic P Kwiatkowski; Wellcome Trust WT Centre for Human Genetics Core Funding, 090532/Z/09/Z Roberto Amato Jacob Almagro-Garcia Victoria J Cornelius Rachel Giacomantonio Christa Henrichs Richard D Pearson Gilean McVean Kirk A Rockett Alistair Miles Paul Vauterin Ben Jeffery Dominic P Kwiatkowski; Wellcome Trust WT Stategic Award, 90770 Roberto Amato Olivo Miotto Jacob Almagro-Garcia Susana Campino Daniel Mead Eleanor Drury Mihir Kekre Lucas Amenga-Etego Tobias Apinjoh Abdoulaye Djimde Deus Ishengoma Milijaona Randrianarivelojosia Victoria J Cornelius Rachel Giacomantonio Dawn Muddyman Christa Henrichs Cinzia Malangone Dushyanth Jyothi Richard D Pearson Kirk A Rockett Alistair Miles Paul Vauterin Ben Jeffery Heinrich M Manske Jim Stalker Bronwyn MacInnis Dominic P Kwiatkowski; Medical Research Council Centre for Genomics and Global Health, G0600718 Roberto Amato Olivo Miotto Jacob Almagro-Garcia Lucas Amenga-Etego Tobias Apinjoh Abdoulaye Djimde Deus Ishengoma Victoria J Cornelius Rachel Giacomantonio Dawn Muddyman Gilean McVean Kirk A Rockett Alistair Miles Paul Vauterin Ben Jeffery Heinrich M Manske Jim Stalker Bronwyn MacInnis Dominic P Kwiatkowski; Bill and Melinda Gates Foundation Grant OPP1040463 Roberto Amato Olivo Miotto Charles J Woodrow Ipsita Sinha Elizabeth Ashley Nicholas P Day Arjen M Dondorp Mallika Imwong Nicholas J White Dominic P Kwiatkowski; Wellcome Trust WT Mahidol University Oxford Tropical Medicine Research Programme, 0892375/H/09/Z Olivo Miotto Charles J Woodrow Ipsita Sinha Elizabeth Ashley Nicholas P Day Arjen M Dondorp Caterina I Fanello Mayfong Mayxay Paul N Newton Francois Nosten Nicholas J White; National Institute of Allergy and Infectious Diseases Intramural Research Program Chanaki Amaratunga Rick M Fairhurst Pharath Lim NR 53 TC 2 Z9 3 U1 7 U2 19 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 4 PY 2016 VL 5 AR e08714 DI 10.7554/eLife.08714 PG 29 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DG2IH UT WOS:000371890100001 ER PT J AU Eroglu, A Gentleman, S Poliakov, E Redmond, TM AF Eroglu, Abdulkerim Gentleman, Susan Poliakov, Eugenia Redmond, T. Michael TI Inhibition of RPE65 Retinol Isomerase Activity by Inhibitors of Lipid Metabolism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE enzyme inhibitor; liposome; retinal metabolism; retinoid; vision; RPE65; triacsin C; visual cycle; fatty acyl:CoA ligase ID ACYL-COA SYNTHETASE; VISUAL CYCLE; TRIACSIN-C; ISOMEROHYDROLASE ACTIVITY; ARACHIDONIC-ACID; ISOMERIZATION; VASODILATORS; DEGENERATION; WS-1228-A; MECHANISM AB RPE65 is the isomerase catalyzing conversion of all-trans-retinyl ester (atRE) into 11-cis-retinol in the retinal visual cycle. Crystal structures of RPE65 and site-directed mutagenesis reveal aspects of its catalytic mechanism, especially retinyl moiety isomerization, but other aspects remain to be determined. To investigate potential interactions between RPE65 and lipid metabolism enzymes, HEK293-F cells were transfected with expression vectors for visual cycle proteins and co-transfected with either fatty acyl:CoA ligases (ACSLs) 1, 3, or 6 or the SLC27A family fatty acyl-CoA synthase FATP2/SLCA27A2 to test their effect on isomerase activity. These experiments showed that RPE65 activity was reduced by co-expression of ACSLs or FATP2. Surprisingly, however, in attempting to relieve the ACSL-mediated inhibition, we discovered that triacsin C, an inhibitor of ACSLs, also potently inhibited RPE65 isomerase activity in cellulo. We found triacsin C to be a competitive inhibitor of RPE65 (IC50 = 500 nm). We confirmed that triacsin C competes directly with atRE by incubating membranes prepared from chicken RPE65-transfected cells with liposomes containing 0-1 m atRE. Other inhibitors of ACSLs had modest inhibitory effects compared with triascin C. In conclusion, we have identified an inhibitor of ACSLs as a potent inhibitor of RPE65 that competes with the atRE substrate of RPE65 for binding. Triacsin C, with an alkenyl chain resembling but not identical to either acyl or retinyl chains, may compete with binding of the acyl moiety of atRE via the alkenyl moiety. Its inhibitory effect, however, may reside in its nitrosohydrazone/triazene moiety. C1 [Eroglu, Abdulkerim; Gentleman, Susan; Poliakov, Eugenia; Redmond, T. Michael] NEI, Lab Retinal Cell & Mol Biol, Natl Inst Hlth, Bldg 6,Rm 117A,6 Ctr Dr,MSC 0608, Bethesda, MD 20892 USA. RP Redmond, TM (reprint author), NEI, Lab Retinal Cell & Mol Biol, Natl Inst Hlth, Bldg 6,Rm 117A,6 Ctr Dr,MSC 0608, Bethesda, MD 20892 USA. EM redmondd@helix.nih.gov OI Redmond, T. Michael/0000-0002-1813-5291 FU Intramural Research Program of National Eye Institute, National Institutes of Health (U.S. Department of Health and Human Services) FX This work was supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health (U.S. Department of Health and Human Services). 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 33 TC 1 Z9 1 U1 0 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 MAR 4 PY 2016 VL 291 IS 10 BP 4966 EP 4973 DI 10.1074/jbc.M115.685651 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF8WF UT WOS:000371640600012 PM 26719343 ER PT J AU Belcher, AM Yen, CCC Notardonato, L Ross, TJ Volkow, ND Yang, YH Stein, EA Silva, AC Tomasi, D AF Belcher, Annabelle M. Yen, Cecil Chern-Chyi Notardonato, Lucia Ross, Thomas J. Volkow, Nora D. Yang, Yihong Stein, Elliot A. Silva, Afonso C. Tomasi, Dardo TI Functional Connectivity Hubs and Networks in the Awake Marmoset Brain SO FRONTIERS IN INTEGRATIVE NEUROSCIENCE LA English DT Article DE resting-state fMRI; functional connectivity; hubs; resting-state networks ID DEFAULT-MODE NETWORK; MAGNETIC-RESONANCE; STRUCTURAL CONNECTIVITY; MONKEYS; ORGANIZATION; CORTEX; CONNECTOME; DYNAMICS; LESSONS; ANATOMY AB In combination with advances in analytical methods, resting-state fMRI is allowing unprecedented access to a better understanding of the network organization of the brain. Increasing evidence suggests that this architecture may incorporate highly functionally connected nodes, or "hubs", and we have recently proposed local functional connectivity density (/FCD) mapping to identify highly-connected nodes in the human brain. Here, we imaged awake nonhuman primates to test whether, like the human brain, the marmoset brain contains FC hubs. Ten adult common marmosets (Callithrix jacchus) were acclimated to mild, comfortable restraint using individualized helmets. Following restraint training, resting BOLD data were acquired during eight consecutive 10 min scans for each subject. /FCD revealed prominent cortical and subcortical hubs of connectivity across the marmoset brain; specifically, in primary and secondary visual cortices (V1/V2), higher-order visual association areas (A19M/V6[DM]), posterior parietal and posterior cingulate areas (PGM and A23b/A31), thalamus, dorsal and ventral striatal areas (caudate, putamen, lateral septal nucleus, and anterior cingulate cortex (A24a). /FCD hubs were highly connected to widespread areas of the brain, and further revealed significant network-network interactions. These data provide a baseline platform for future investigations in a nonhuman primate model of the brain's network topology. C1 [Belcher, Annabelle M.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Belcher, Annabelle M.; Ross, Thomas J.; Yang, Yihong; Stein, Elliot A.] NIDA, NIH, Baltimore, MD USA. [Yen, Cecil Chern-Chyi; Notardonato, Lucia; Silva, Afonso C.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Volkow, Nora D.] NIDA, NIH, Rockville, MD USA. [Volkow, Nora D.; Tomasi, Dardo] NIAAA, NIH, Bethesda, MD USA. RP Tomasi, D (reprint author), NIAAA, NIH, Bethesda, MD USA. EM dardo.tomasi@nih.gov RI Yen, Cecil/C-2212-2009 OI Yen, Cecil/0000-0002-1519-9791 NR 55 TC 3 Z9 3 U1 4 U2 5 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 MAR 4 PY 2016 VL 10 AR 9 DI 10.3389/fnint.2016.00009 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DF5HB UT WOS:000371381300001 PM 26973476 ER PT J AU Zhao, X Smith, DL Tatem, AJ AF Zhao, Xia Smith, David L. Tatem, Andrew J. TI Exploring the spatiotemporal drivers of malaria elimination in Europe SO MALARIA JOURNAL LA English DT Article DE Malaria elimination; Europe; GIS; Malaria risk mapping ID PLASMODIUM-VIVAX MALARIA; CLIMATE-CHANGE; ERADICATION; URBANIZATION; TRANSMISSION; AFRICA; BURDEN; VECTOR; METAANALYSIS; FEASIBILITY AB Background: Europe once had widespread malaria, but today it is free from endemic transmission. Changing land use, agricultural practices, housing quality, urbanization, climate change, and improved healthcare are among the many factors thought to have played a role in the declines of malaria seen, but their effects and relative contributions have rarely been quantified. Methods: Spatial datasets on changes in climate, wealth, life expectancy, urbanization, and land use trends over the past century were combined with datasets depicting the reduction in malaria transmission across 31 European countries, and the relationships were explored. Moreover, the conditions in current malaria-eliminating countries were compared with those in Europe at the time of declining transmission and elimination to assess similarities. Results/conclusions: Indicators relating to socio-economic improvements such as wealth, life expectancy and urbanization were strongly correlated with the decline of malaria in Europe, whereas those describing climatic and land use changes showed weaker relationships. Present-day malaria-elimination countries have now arrived at similar socio-economic indicator levels as European countries at the time malaria elimination was achieved, offering hope for achievement of sustainable elimination. C1 [Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden. [Zhao, Xia; Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, WorldPop Project, Southampton, Hants, England. [Smith, David L.; Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Smith, David L.] Univ Oxford, Dept Zool, Oxford, England. RP Tatem, AJ (reprint author), Flowminder Fdn, Stockholm, Sweden.; Tatem, AJ (reprint author), Univ Southampton, Dept Geog & Environm, WorldPop Project, Southampton, Hants, England.; Tatem, AJ (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM Andy.Tatem@gmail.com FU NIH/NIAID [U19AI089674]; Bill and Melinda Gates Foundation [OPP1106427, 1032350]; Wellcome Trust Sustaining Health Grant [106866/Z/15/Z]; Fogarty International Center, National Institutes of Health; Clinton Health Access Initiative; RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security FX AJT is supported by funding from NIH/NIAID (U19AI089674), the Bill and Melinda Gates Foundation (OPP1106427, 1032350), a Wellcome Trust Sustaining Health Grant (106866/Z/15/Z), the Clinton Health Access Initiative and the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. This work forms part of the WorldPop Project (http://www.worldpop.org) and the Flowminder Foundation (http://www.flowminder.org). NR 50 TC 0 Z9 0 U1 3 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD MAR 4 PY 2016 VL 15 AR 122 DI 10.1186/s12936-016-1175-z PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DF6KN UT WOS:000371464600001 PM 26944257 ER PT J AU Wang, JB Fan, JH Dawsey, SM Sinha, R Freedman, ND Taylor, PR Qiao, YL Abnet, CC AF Wang, Jian-Bing Fan, Jin-Hu Dawsey, Sanford M. Sinha, Rashmi Freedman, Neal D. Taylor, Philip R. Qiao, You-Lin Abnet, Christian C. TI Dietary components and risk of total, cancer and cardiovascular disease mortality in the Linxian Nutrition Intervention Trials cohort in China SO SCIENTIFIC REPORTS LA English DT Article ID CORONARY-HEART-DISEASE; FOLLOW-UP; VEGETABLE CONSUMPTION; NUT CONSUMPTION; WHOLE-GRAIN; ALL-CAUSE; FRUIT; WOMEN; HEALTH; VEGETARIANS AB Although previous studies have shown that dietary consumption of certain food groups is associated with a lower risk of cancer, heart disease and stroke mortality in western populations, limited prospective data are available from China. We prospectively examined the association between dietary intake of different food groups at baseline and risk of total, cancer, heart disease and stroke mortality outcomes in the Linxian Nutrition Intervention Trials(NIT) cohort. In 1984-1991, 2445 subjects aged 40-69 years from the Linxian NIT cohort completed a food frequency questionnaire. Deaths from esophageal and gastric cancer, heart disease and stroke were identified through up to 26 years of follow-up. We used Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals for associations between intake of groups of food items and these mortality endpoints. We concluded that higher intake of certain food groups was associated with lower risk of gastric cancer, heart disease and stroke mortality in a prospective cohort in rural China. Our findings provide additional evidence that increasing intake of grains, vegetables, beans, fruits and nuts may help reduce mortality from these diseases. C1 [Wang, Jian-Bing; Fan, Jin-Hu; Qiao, You-Lin] Chinese Acad Med Sci, Canc Inst Hosp, Dept Canc Epidemiol, Beijing 100021, Peoples R China. [Wang, Jian-Bing; Fan, Jin-Hu; Qiao, You-Lin] Peking Union Med Coll, Beijing 100021, Peoples R China. [Wang, Jian-Bing; Dawsey, Sanford M.; Sinha, Rashmi; Freedman, Neal D.; Abnet, Christian C.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Wang, Jian-Bing] Zhejiang Univ, Sch Publ Hlth, Dept Epidemiol & Hlth Stat, Hangzhou 310058, Zhejiang, Peoples R China. [Taylor, Philip R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. RP Qiao, YL (reprint author), Chinese Acad Med Sci, Canc Inst Hosp, Dept Canc Epidemiol, Beijing 100021, Peoples R China.; Qiao, YL (reprint author), Peking Union Med Coll, Beijing 100021, Peoples R China.; Abnet, CC (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. EM qiaoy@cicams.ac.cn; abnetc@mail.nih.gov RI Abnet, Christian/C-4111-2015; Qiao, You-Lin/B-4139-2012 OI Abnet, Christian/0000-0002-3008-7843; Qiao, You-Lin/0000-0001-6380-0871 FU National Cancer Institute [N01-SC-91030, N01-RC-47701]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Cancer Institute, Chinese Academy of Medical Sciences FX This work was supported in part by National Cancer Institute contracts (N01-SC-91030 and N01-RC-47701 to the Cancer Institute, Chinese Academy of Medical Sciences); in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; and in part by Cancer Institute, Chinese Academy of Medical Sciences. The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, decision to publish or preparation of the manuscript. NR 35 TC 5 Z9 6 U1 6 U2 10 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 MAR 4 PY 2016 VL 6 AR 22619 DI 10.1038/srep22619 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF5VQ UT WOS:000371421100002 PM 26939909 ER PT J AU Motley, MP Madsen, DH Jurgensen, HJ Spencer, DE Szabo, R Holmbeck, K Flick, MJ Lawrence, DA Castellino, FJ Weigert, R Bugge, TH AF Motley, Michael P. Madsen, Daniel H. Jurgensen, Henrik J. Spencer, David E. Szabo, Roman Holmbeck, Kenn Flick, Matthew J. Lawrence, Daniel A. Castellino, Francis J. Weigert, Roberto Bugge, Thomas H. TI A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo SO BLOOD LA English DT Article ID TISSUE-PLASMINOGEN-ACTIVATOR; INTRAVITAL 2-PHOTON MICROSCOPY; RECEPTOR-INDEPENDENT ROLE; LIGNEOUS CONJUNCTIVITIS; DEFICIENT MICE; UROKINASE RECEPTOR; MANNOSE RECEPTOR; HUMAN MONOCYTES; CRESCENTIC GLOMERULONEPHRITIS; MATRIX-METALLOPROTEINASE AB Extravascular fibrin deposition accompanies many human diseases and causes chronic inflammation and organ damage, unless removed in a timely manner. Here, we used intravital microscopy to investigate how fibrin is removed from extravascular space. Fibrin placed into the dermis of mice underwent cellular endocytosis and lysosomal targeting, revealing a novel intracellular pathway for extravascular fibrin degradation. A C-C chemokine receptor type 2 (CCR2)-positive macrophage subpopulation constituted the majority of fibrin-uptaking cells. Consequently, cellular fibrin uptake was diminished by elimination of CCR2-expressing cells. The CCR2-positive macrophage subtype was different from collagen-internalizing M2-like macrophages. Cellular fibrin uptake was strictly dependent on plasminogen and plasminogen activator. Surprisingly, however, fibrin endocytosis was unimpeded by the absence of the fibrin(ogen) receptors, aMb2 and ICAM-1, the myeloid cell integrin-binding site on fibrin or the endocytic collagen receptor, the mannose receptor. The study identifies a novel fibrin endocytic pathway engaged in extravascular fibrin clearance and shows that interstitial fibrin and collagen are cleared by different subsets of macrophages employing distinct molecular pathways. C1 [Motley, Michael P.; Madsen, Daniel H.; Jurgensen, Henrik J.; Spencer, David E.; Szabo, Roman; Weigert, Roberto; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Madsen, Daniel H.] Herlev Univ Hosp, Ctr Canc Immune Therapy, Dept Haematol, DK-2730 Herlev, Denmark. [Madsen, Daniel H.; Jurgensen, Henrik J.] Univ Copenhagen, Rigshosp, Finsen Lab, Biotech Res & Innovat Ctr, DK-2100 Copenhagen, Denmark. [Holmbeck, Kenn] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Flick, Matthew J.] Cincinnati Childrens Hosp, Div Expt Hematol & Canc Biol, Cincinnati, OH USA. [Lawrence, Daniel A.] Univ Michigan, Sch Med, Div Cardiovasc Med, Internal Med, Ann Arbor, MI USA. [Castellino, Francis J.] Univ Notre Dame, WM Keck Ctr Transgene Res, Notre Dame, IN 46556 USA. [Castellino, Francis J.] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. RP Bugge, TH (reprint author), Natl Inst Dent & Craniofacial Res, NIH, 30 Convent Dr,Room 320, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov OI Madsen, Daniel Hargboel/0000-0002-3183-6201 FU Intramural Research Program of the National Institutes of Health; National Institute of Dental and Craniofacial Research; National Heart, Lung, and Blood Institute [R01 HL55374, HL013423]; National Institute of Neurological Disorders and Stroke [R01 NS079639]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR056990]; Danish Cancer Society FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research, by the National Heart, Lung, and Blood Institute (R01 HL55374) and National Institute of Neurological Disorders and Stroke (R01 NS079639) (D.A.L.), National Heart, Lung, and Blood Institute (HL013423) (F.J.C.), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR056990) (M.J.F.). H.J.J. was supported by a Fellowship from the Danish Cancer Society. NR 88 TC 1 Z9 1 U1 2 U2 4 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 MAR 3 PY 2016 VL 127 IS 9 BP 1085 EP 1096 DI 10.1182/blood-2015-05-644260 PG 12 WC Hematology SC Hematology GA DI3MB UT WOS:000373401700008 PM 26647393 ER PT J AU Lee, YU Son, M Kim, J Shim, YH Kawasaki, I AF Lee, Yong-Uk Son, Miseol Kim, Jiyoung Shim, Yhong-Hee Kawasaki, Ichiro TI CDC-25.2, a C. elegans ortholog of cdc25, is essential for the progression of intestinal divisions SO CELL CYCLE LA English DT Article DE cell-cycle regulation; endoreduplication; cdc-25.2; lin-35; intestinal division; Binucleation; C. elegans; nuclear division; lin-23; cdc-25.1 ID NEMATODE CAENORHABDITIS-ELEGANS; CELL-CYCLE CONTROL; FISSION YEAST; NEGATIVE REGULATION; HOMOLOG; GENE; DROSOPHILA; EMBRYO; PHOSPHATASE; GERMLINE AB Intestinal divisions in Caenorhabditis elegans take place in 3 stages: (1) cell divisions during embryogenesis, (2) binucleations at the L1 stage, and (3) endoreduplications at the end of each larval stage. Here, we report that CDC-25.2, a C. elegans ortholog of Cdc25, is required for these specialized division cycles between the 16E cell stage and the onset of endoreduplication. Results of our genetic analyses suggest that CDC-25.2 regulates intestinal cell divisions and binucleations by counteracting WEE-1.3 and by activating the CDK-1/CYB-1 complex. CDC-25.2 activity is then repressed by LIN-23 E3 ubiquitin ligase before the onset of intestinal endoreduplication, and this repression is maintained by LIN-35, the C. elegans ortholog of Retinoblastoma (Rb). These findings indicate that timely regulation of CDC-25.2 activity is essential for the progression of specialized division cycles and development of the C. elegans intestine. C1 [Lee, Yong-Uk; Son, Miseol; Kim, Jiyoung; Shim, Yhong-Hee; Kawasaki, Ichiro] Konkuk Univ, Dept Biosci & Biotechnol, 120 Neungdong Ro, Seoul 143701, South Korea. [Kim, Jiyoung] NIA, Genet Lab, BRC, NIH, Baltimore, MD 21224 USA. [Kawasaki, Ichiro] Konkuk Univ, Inst KU Biotechnol, Seoul, South Korea. RP Shim, YH; Kawasaki, I (reprint author), Konkuk Univ, Dept Biosci & Biotechnol, 120 Neungdong Ro, Seoul 143701, South Korea. EM yshim@konkuk.ac.kr; ikawasak@mac.com RI Kawasaki, Ichiro/D-6864-2011; OI Kawasaki, Ichiro/0000-0003-1722-0993 FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Republic of Korea [2010-0011182, NRF-2013R1A1A2009090, 2010-0009509, NRF-2013R1A1A2009820]; KU Brain Pool Program of Konkuk University; Hi Seoul Science Fellowship from the Seoul Scholarship Foundation; CureBio FX This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Republic of Korea [grant numbers 2010-0011182 and NRF-2013R1A1A2009090 to Y.-H.S., 2010-0009509 and NRF-2013R1A1A2009820 to I.K.]. This research was also supported by the 2014 KU Brain Pool Program of Konkuk University to I.K. and by the Hi Seoul Science Fellowship from the Seoul Scholarship Foundation to Y.-U.L. We also thank CureBio for supporting this project. NR 54 TC 3 Z9 3 U1 3 U2 5 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 PD MAR 3 PY 2016 VL 15 IS 5 BP 654 EP 666 DI 10.1080/15384101.2016.1146839 PG 13 WC Cell Biology SC Cell Biology GA DI8BV UT WOS:000373726800012 PM 27104746 ER PT J AU Knickelbein, JE Chew, EY Sen, HN AF Knickelbein, Jared E. Chew, Emily Y. Sen, H. Nida TI Intraocular Inflammation Following Intravitreal Injection of Anti-VEGF Medications for Neovascular Age-Related Macular Degeneration SO OPHTHALMIC EPIDEMIOLOGY LA English DT Editorial Material ID ENDOPHTHALMITIS C1 [Knickelbein, Jared E.; Chew, Emily Y.; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. RP Knickelbein, JE (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM knickelbeinje@nei.nih.gov NR 7 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 0928-6586 EI 1744-5086 J9 OPHTHAL EPIDEMIOL JI Ophthalmic Epidemiol. PD MAR 3 PY 2016 VL 23 IS 2 BP 69 EP 70 DI 10.3109/09286586.2015.1122067 PG 2 WC Ophthalmology SC Ophthalmology GA DH4FU UT WOS:000372741700001 PM 26996429 ER PT J AU Ostrander, E AF Ostrander, Elaine TI 2015 Curt Stern Award Introduction: Leonid Kruglyak SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Editorial Material C1 [Ostrander, Elaine] NHGRI, NIH, Bethesda, MD 20892 USA. RP Ostrander, E (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 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 MAR 3 PY 2016 VL 98 IS 3 BP 427 EP 427 DI 10.1016/j.ajhg.2015.11.007 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA DG9DN UT WOS:000372383100004 PM 26942279 ER PT J AU Darnell, AJ Austin, H Bluemke, DA Cannon, RO Fischbeck, K Gahl, W Goldman, D Grady, C Greene, MH Holland, SM Hull, SC Porter, FD Resnik, D Rubinstein, WS Biesecker, LG AF Darnell, Andrew J. Austin, Howard Bluemke, David A. Cannon, Richard O., III Fischbeck, Kenneth Gahl, William Goldman, David Grady, Christine Greene, Mark H. Holland, Steven M. Hull, Sara Chandros Porter, Forbes D. Resnik, David Rubinstein, Wendy S. Biesecker, Leslie G. TI A Clinical Service to Support the Return of Secondary Genomic Findings in Human Research SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MANAGING INCIDENTAL FINDINGS; GENETIC RESEARCH; EXOME; RECOMMENDATIONS; PROFESSIONALS; PERSPECTIVES; PARTICIPANTS; DUTY AB Human genome and exome sequencing are powerful research tools that can generate secondary findings beyond the scope of the research. Most secondary genomic findings are of low importance, but some (for a current estimate of 1%-3% of individuals) confer high risk of a serious disease that could be mitigated by timely medical intervention. The impact and scope of secondary findings in genome and exome sequencing will only increase in the future. There is considerable agreement that high-impact findings should be returned to participants, but many researchers performing genomic research studies do not have the background, skills, or resources to identify, verify, interpret, and return such variants. Here, we introduce a proposal for the formation of a secondary-genomic-findings service (SGFS) that would support researchers by enabling the return of clinically actionable sequencing results to research participants in a standardized manner. We describe a proposed structure for such a centralized service and evaluate the advantages and challenges of the approach. We suggest that such a service would be of greater benefit to all parties involved than present practice, which is highly variable. We encourage research centers to consider the adoption of a centralized SGFS. C1 [Darnell, Andrew J.] Duke Univ, Program Sci & Soc, Durham, NC 27710 USA. [Austin, Howard] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. [Bluemke, David A.] NIH Clin Ctr, Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Cannon, Richard O., III] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Fischbeck, Kenneth] NINCDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Gahl, William] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Goldman, David] NIAAA, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Grady, Christine; Hull, Sara Chandros] NIH, Clin Res Ctr, Dept Bioeth, Bethesda, MD 20892 USA. [Greene, Mark H.] NCI, Clin Genet Branch, NIH, Bethesda, MD 20892 USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Hull, Sara Chandros] NHGRI, Bioeth Core, NIH, Bethesda, MD 20892 USA. [Porter, Forbes D.] NICHHD, Sect Mol Dysmorphol, NIH, Bethesda, MD 20892 USA. [Resnik, David] Natl Inst Environm Hlth Sci, Off Director, NIH, Bethesda, MD 20892 USA. [Rubinstein, Wendy S.] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Informat Engn Branch, Bethesda, MD 20892 USA. [Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Bluemke, David/0000-0002-8323-8086 FU Intramural NIH HHS NR 30 TC 3 Z9 3 U1 1 U2 3 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 MAR 3 PY 2016 VL 98 IS 3 BP 435 EP 441 DI 10.1016/j.ajhg.2016.01.010 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA DG9DN UT WOS:000372383100008 PM 26942283 ER PT J AU Hua, X Hyland, PL Huang, J Song, L Zhu, B Caporaso, NE Landi, MT Chatterjee, N Shi, JX AF Hua, Xing Hyland, Paula L. Huang, Jing Song, Lei Zhu, Bin Caporaso, Neil E. Landi, Maria Teresa Chatterjee, Nilanjan Shi, Jianxin TI MEGSA: A Powerful and Flexible Framework for Analyzing Mutual Exclusivity of Tumor Mutations SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MUTATED DRIVER PATHWAYS; ACUTE MYELOID-LEUKEMIA; HUMAN P53 GENE; LUNG-CANCER; CELL-LINES; EXPRESSION; DISCOVERY; HETEROGENEITY; REQUIREMENT; MODULES AB The central challenges in tumor sequencing studies is to identify driver genes and pathways, investigate their functional relationships, and nominate drug targets. The efficiency of these analyses, particularly for infrequently mutated genes, is compromised when subjects carry different combinations of driver mutations. Mutual exclusivity analysis helps address these challenges. To identify mutually exclusive gene sets (MEGS), we developed a powerful and flexible analytic framework based on a likelihood ratio test and a model selection procedure. Extensive simulations demonstrated that our method outperformed existing methods for both statistical power and the capability of identifying the exact MEGS, particularly for highly imbalanced MEGS. Our method can be used for de novo discovery, for pathway-guided searches, or for expanding established small MEGS. We applied out Method to the whole-exome sequencing data for 13 cancer types from The Cancer Genome Atlas (TCGA). We identified multiple previously unreported non-pairwise MEGS in multiple cancer types. For acute myeloid leukemia, we identified a MEGS with five genes (FLT3, IDH2, NRAS, KIT, and TP53) and a MEGS (NPM1, TP53, and RUNX1) whose mutation status was strongly associated with survival (p = 6.7 x 10(-4)). For breast cancer, we identified a significant MEGS consisting of TP53 and four infrequently mutated genes (ARID1A, AKT1, MED23, and TBL1XR1), providing support for their role as cancer drivers. C1 [Hua, Xing; Hyland, Paula L.; Song, Lei; Zhu, Bin; Caporaso, Neil E.; Landi, Maria Teresa; Chatterjee, Nilanjan; Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Huang, Jing] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Shi, JX (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM jianxin.shi@nih.gov FU National Cancer Institute Intramural Research Program FX This study utilized the computational resources of the NIH HPC Biowulf cluster. The authors are supported by the National Cancer Institute Intramural Research Program. NR 47 TC 4 Z9 4 U1 1 U2 4 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 MAR 3 PY 2016 VL 98 IS 3 BP 442 EP 455 DI 10.1016/j.ajhg.2015.12.021 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DG9DN UT WOS:000372383100009 PM 26899600 ER PT J AU Lesage, S Drouet, V Majounie, E Deramecourt, V Jacoupy, M Nicolas, A Cormier-Dequaire, F Hassoun, SM Pujol, C Ciura, S Erpapazoglou, Z Usenko, T Maurage, CA Sahbatou, M Liebau, S Ding, JH Bilgic, B Emre, M Erginel-Unaltuna, N Guven, G Tison, F Tranchant, C Vidailhet, M Corvol, JC Krack, P Leutenegger, AL Nalls, MA Hernandez, DG Heutink, P Gibbs, JR Hardy, J Wood, NW Gasser, T Durr, A Deleuze, JF Tazir, M Destee, A Lohmann, E Kabashi, E Singleton, A Corti, O Brice, A AF Lesage, Suzanne Drouet, Valerie Majounie, Elisa Deramecourt, Vincent Jacoupy, Maxime Nicolas, Aude Cormier-Dequaire, Florence Hassoun, Sidi Mohamed Pujol, Claire Ciura, Sorana Erpapazoglou, Zoi Usenko, Tatiana Maurage, Claude-Alain Sahbatou, Mourad Liebau, Stefan Ding, Jinhui Bilgic, Basar Emre, Murat Erginel-Unaltuna, Nihan Guven, Gamze Tison, Francois Tranchant, Christine Vidailhet, Marie Corvol, Jean-Christophe Krack, Paul Leutenegger, Anne-Louise Nalls, Michael A. Hernandez, Dena G. Heutink, Peter Gibbs, J. Raphael Hardy, John Wood, Nicholas W. Gasser, Thomas Durr, Alexandra Deleuze, Jean-Francois Tazir, Meriem Destee, Alain Lohmann, Ebba Kabashi, Edor Singleton, Andrew Corti, Olga Brice, Alexis CA French Parkinson's Dis Genetics St IPDGC TI Loss of VPS1 3C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SEQUENCING DATA; NITRIC-OXIDE; DISEASE; PROTEIN; MUTATIONS; PINK1; GENE; INTERACT; ASSOCIATION; CLEARANCE AB Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are, associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent initophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression. C1 [Lesage, Suzanne; Drouet, Valerie; Jacoupy, Maxime; Nicolas, Aude; Cormier-Dequaire, Florence; Hassoun, Sidi Mohamed; Pujol, Claire; Ciura, Sorana; Erpapazoglou, Zoi; Usenko, Tatiana; Vidailhet, Marie; Corvol, Jean-Christophe; Durr, Alexandra; Kabashi, Edor; Corti, Olga; Brice, Alexis] Univ Paris 06, Sorbonne Univ, UMR S 1127, F-75013 Paris, France. [Lesage, Suzanne; Drouet, Valerie; Jacoupy, Maxime; Nicolas, Aude; Cormier-Dequaire, Florence; Hassoun, Sidi Mohamed; Pujol, Claire; Ciura, Sorana; Erpapazoglou, Zoi; Usenko, Tatiana; Vidailhet, Marie; Corvol, Jean-Christophe; Durr, Alexandra; Kabashi, Edor; Corti, Olga; Brice, Alexis] Inserm U 1127, F-75013 Paris, France. [Lesage, Suzanne; Drouet, Valerie; Jacoupy, Maxime; Nicolas, Aude; Cormier-Dequaire, Florence; Hassoun, Sidi Mohamed; Pujol, Claire; Ciura, Sorana; Erpapazoglou, Zoi; Usenko, Tatiana; Vidailhet, Marie; Corvol, Jean-Christophe; Durr, Alexandra; Kabashi, Edor; Corti, Olga; Brice, Alexis] CNRS UMR 7225, F-75013 Paris, France. [Lesage, Suzanne; Drouet, Valerie; Jacoupy, Maxime; Nicolas, Aude; Cormier-Dequaire, Florence; Hassoun, Sidi Mohamed; Pujol, Claire; Ciura, Sorana; Erpapazoglou, Zoi; Usenko, Tatiana; Vidailhet, Marie; Corvol, Jean-Christophe; Durr, Alexandra; Kabashi, Edor; Corti, Olga; Brice, Alexis] ICM, Inst Cerveau & Moelle Epiniere, F-75013 Paris, France. [Majounie, Elisa; Ding, Jinhui; Nalls, Michael A.; Hernandez, Dena G.; Gibbs, J. Raphael] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Deramecourt, Vincent; Maurage, Claude-Alain] Univ Lille Nord France, Lille Univ Hosp, Dept Histol & Pathol, F-59000 Lille, France. [Corvol, Jean-Christophe] Ctr Invest Clin Pitie Neurosci CIC 1422, F-75013 Paris, France. [Sahbatou, Mourad] Fdn Jean Dausset, CEPH, F-75010 Paris, France. [Liebau, Stefan] Univ Tubingen, Inst Neuroanat, D-72074 Tubingen, Germany. [Bilgic, Basar; Emre, Murat; Lohmann, Ebba] Istanbul Univ, Istanbul Fac Med, Dept Neurol, Behav Neurol & Movement Disorders Unit, TR-34390 Istanbul, Turkey. [Erginel-Unaltuna, Nihan; Guven, Gamze] Istanbul Univ, Inst Expt Med, Dept Genet, TR-34390 Istanbul, Turkey. [Tison, Francois] Univ Bordeaux, Inst Malad Neurodegenerat, F-33000 Bordeaux, France. [Tison, Francois] CHU Bordeaux, F-33000 Bordeaux, France. [Tranchant, Christine] Hop Univ, Serv Neurol, Pole Tete Cou CETD, F-67000 Strasbourg, France. [Vidailhet, Marie] Hop La Pitie Salpetriere, Federat Neurol, Pole Malad Syst Nerveux, F-75013 Paris, France. [Krack, Paul] Univ Grenoble 1, CHU Grenoble, Dept Neurol, F-38000 Grenoble, France. [Krack, Paul] INSERM U836, F-38000 Grenoble, France. [Leutenegger, Anne-Louise] Inserm U946, F-75010 Paris, France. [Leutenegger, Anne-Louise] Univ Paris Diderot, Inst Univ Hernatol, UMR946, F-75010 Paris, France. [Heutink, Peter; Gasser, Thomas] Univ Tubingen, Hertie Inst Clin Brain Res, D-72074 Tubingen, Germany. [Heutink, Peter; Gasser, Thomas; Lohmann, Ebba] German Ctr Neurodegenerat Dis, DZNE, D-72074 Tubingen, Germany. [Hardy, John; Wood, Nicholas W.] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Durr, Alexandra; Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, F-75013 Paris, France. [Deleuze, Jean-Francois] Ctr Natl Genotypage, Inst Genom, CEA, F-91000 Evry, France. [Tazir, Meriem] CHU Mustapha, Serv Neurol, Algiers 16000, Algeria. [Destee, Alain] Univ Lille, Lille Univ Hosp, Inserm U837, Movement Disorders Unit, F-59000 Lille, France. [Lohmann, Ebba] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, D-72076 Tubingen, Germany. RP Corti, O; Brice, A (reprint author), Univ Paris 06, Sorbonne Univ, UMR S 1127, F-75013 Paris, France.; Corti, O; Brice, A (reprint author), Inserm U 1127, F-75013 Paris, France.; Corti, O; Brice, A (reprint author), CNRS UMR 7225, F-75013 Paris, France.; Corti, O; Brice, A (reprint author), ICM, Inst Cerveau & Moelle Epiniere, F-75013 Paris, France. EM olga.corti@upmc.fr; alexis.brice@upmc.fr RI van de Warrenburg, Bart/D-1935-2010; Revesz, Tamas/A-8732-2010; Kabashi, Edor/C-5408-2014; Hardy, John/C-2451-2009; Lubbe, Steven/L-8261-2013; Singleton, Andrew/C-3010-2009; Corti, Olga/I-4981-2016; Morris, Huw/B-8527-2008; Wood, Nicholas/C-2505-2009; Leutenegger, Anne-Louise/B-5597-2009; Deloukas, Panos/B-2922-2013; bilgic, basar/E-4821-2012; Scheffer, Hans/E-4644-2012; corvol, jean-christophe/I-6387-2012 OI Revesz, Tamas/0000-0003-2501-0259; Kabashi, Edor/0000-0003-4118-251X; Corti, Olga/0000-0003-2093-7389; Morris, Huw/0000-0002-5473-3774; Wood, Nicholas/0000-0002-9500-3348; Leutenegger, Anne-Louise/0000-0002-1302-4357; Deloukas, Panos/0000-0001-9251-070X; Scheffer, Hans/0000-0002-2986-0915; corvol, jean-christophe/0000-0001-7325-0199 FU National Research Funding Agency [ANR-08-NEUR-004-01]; ERA-NET NEURON; France-Parkinson Association; Roger de Spoelberch Foundation [R12123DD]; French Academy of Sciences; French program "Investissements d'avenir" [ANR-10-IAIHU-06]; European Joint Programme - Neurodegenerative Disease Research (JPND-COURAGE-PD) project; National Institute on Aging; National Institutes of Neurological Disorders and Stroke, NIH; Department of Health and Human Services [Z01 AG000958]; Department of Health and Human Services (MRC) [G1100643/1]; European Social Fund; Ministry of Science, Research, and the Arts, Baden-Wurttemberg; Department of Defense [10064005/11348001]; French Health Ministry (PHRC); France Parkinson Association; Lille University Hospital; Atip/Avenir from the National Institute of Health and Medical Research (INSERM); ANR; ERA-NET E-rare program; France Alzheimer Association; Marie Curie Actions; Cognacq-Jay Foundation; EMBO; AFM-Telethon FX The authors are grateful to the families for their participation in this study. We thank Merle Ruberg for critical reading of the manuscript, the DNA and Cell Bank of ICM, the Plate-Forme d'Imagerie Cellulaire de la Pitie-Salpetriere (PICPS), and Ebru Ozer and Meltem Pak for sample preparation. We are grateful to the Lille brain bank for the gift of a brain ("Lille Neurobank," BB-0033-00030). This study was supported by the National Research Funding Agency (ANR-08-NEUR-004-01) in association with ERA-NET NEURON, the France-Parkinson Association, the Roger de Spoelberch Foundation (R12123DD), the French Academy of Sciences, the French program "Investissements d'avenir" (ANR-10-IAIHU-06), and the European Joint Programme - Neurodegenerative Disease Research (JPND-COURAGE-PD) project. This study was also supported by the Intramural Research Program of the National Institute on Aging and the National Institutes of Neurological Disorders and Stroke, NIH, Department of Health and Human Services (project Z01 AG000958 and by MRC Grant G1100643/1), by the European Social Fund, and by the Ministry of Science, Research, and the Arts, Baden-Wurttemberg. This work was also supported by the Department of Defense, including grant 10064005/11348001, the French Health Ministry (PHRC), France Parkinson Association, Lille University Hospital (A. Destee), the Atip/Avenir from the National Institute of Health and Medical Research (INSERM), the ANR in association with the ERA-NET E-rare program, the France Alzheimer Association, and a Career Integration Grant from Marie Curie Actions (E.K.). C.P. received a postdoctoral fellowship from the Cognacq-Jay Foundation. S.C. received postdoctoral fellowships from EMBO and AFM-Telethon. NR 43 TC 24 Z9 24 U1 12 U2 32 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 MAR 3 PY 2016 VL 98 IS 3 BP 500 EP 513 DI 10.1016/j.ajhg.2016.01.014 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DG9DN UT WOS:000372383100013 PM 26942284 ER PT J AU Bennett, JT Tan, TY Alcantara, D Tetrault, M Timms, AE Jensen, D Collins, S Nowaczyk, MJM Lindhurst, MJ Christensen, KM Braddock, SR Brandling-Bennett, H Hennekam, RCM Chung, B Lehman, A Su, J Ng, S Amor, DJ Majewski, J Biesecker, LG Boycott, KM Dobyns, WB O'Driscoll, M Moog, U McDonell, LM AF Bennett, James T. Tan, Tiong Yang Alcantara, Diana Tetrault, Martine Timms, Andrew E. Jensen, Dana Collins, Sarah Nowaczyk, Malgorzata J. M. Lindhurst, Marjorie J. Christensen, Katherine M. Braddock, Stephen R. Brandling-Bennett, Heather Hennekam, Raoul C. M. Chung, Brian Lehman, Anna Su, John Ng, SuYuen Amor, David J. Majewski, Jacek Biesecker, Les G. Boycott, Kym M. Dobyns, William B. O'Driscoll, Mark Moog, Ute McDonell, Laura M. CA Univ Washington Ctr Mendelian Geno Care4Rare Canada Consortium TI Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID RECEPTOR TYROSINE KINASES; GROWTH-FACTOR RECEPTOR-3; LOW-GRADE GLIOMAS; CROUZON-SYNDROME; OCULOECTODERMAL SYNDROME; THANATOPHORIC DYSPLASIA; PILOCYTIC ASTROCYTOMA; GENE; CRANIOSYNOSTOSIS; CANCER AB Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (plys656G1u) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis. C1 [Bennett, James T.; Dobyns, William B.] Univ Washington, Dept Pediat Genet, Seattle, WA 98195 USA. [Bennett, James T.; Jensen, Dana; Collins, Sarah; Dobyns, William B.] Seattle Childrens Res Inst, Ctr Integrat Brain Res, Seattle, WA 98101 USA. [Tan, Tiong Yang; Amor, David J.] Univ Melbourne, Dept Paediat, Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Melbourne, Vic 3052, Australia. [Alcantara, Diana; O'Driscoll, Mark] Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England. [Tetrault, Martine; Majewski, Jacek] McGill Univ, Dept Human Genet, Montreal, PQ H3A 0G4, Canada. [Timms, Andrew E.] Seattle Childrens Res Inst, Ctr Dev Biol & Regenerat Med, Seattle, WA 98101 USA. [Nowaczyk, Malgorzata J. M.] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON L8S 4J9, Canada. [Lindhurst, Marjorie J.; Biesecker, Les G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Christensen, Katherine M.; Braddock, Stephen R.] Cardinal Glennon Childrens Med Ctr, Dept Pediat, St Louis, MO 63104 USA. [Brandling-Bennett, Heather] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Brandling-Bennett, Heather] Univ Washington, Dept Med Dermatol, Seattle, WA 98195 USA. [Hennekam, Raoul C. M.] Univ Amsterdam, Acad Med Ctr, Dept Pediat, NL-1105 AZ Amsterdam, Netherlands. [Chung, Brian] Univ Hong Kong, Queen Mary Hosp, Dept Paediat & Adolescent Med, 21 Sassoon Rd, Hong Kong, Hong Kong, Peoples R China. [Lehman, Anna] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada. [Su, John; Ng, SuYuen] Monash Univ, Eastern Hlth, Dept Dermatol, Box Hill, Vic 3128, Australia. [Boycott, Kym M.; McDonell, Laura M.] Univ Ottawa, Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON K1H 5B2, Canada. [Dobyns, William B.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Moog, Ute] Heidelberg Univ, Inst Human Genet, D-69120 Heidelberg, Germany. RP O'Driscoll, M (reprint author), Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England.; Moog, U (reprint author), Heidelberg Univ, Inst Human Genet, D-69120 Heidelberg, Germany. EM m.o-driscoll@sussex.ac.uk; ute.moog@med.uni-heidelberg.de RI Su, John/E-6040-2017; OI Su, John/0000-0002-4021-5423; Lehman, Anna/0000-0003-0636-123X; Dobyns, William/0000-0002-7681-2844 FU Care4Rare Canada Consortium - Genome Canada; Canadian Institutes of Health Research; Ontario Genomics Institute; Ontario Research Fund; Genome Quebec; Children's Hospital of Eastern Ontario Foundation; National Institute of Neurological Disorders and Stroke (NINDS) [1R01NS092772]; National Human Genome Research Institute of the National Institutes of Health; National Human Genome Research Institute; National Heart, Lung and Blood Institute [U54HG006493]; Reseau de Medecine Genique Appliquee; CIHR; Consortium National de Formation en Sante; Australian National Health and Medical Research Council Postdoctoral Overseas Training Scholarship [607431]; Cancer Research UK FX We are grateful to the individuals and families who participated in this study. Research reported in this publication was supported by the Care4Rare Canada Consortium (Enhanced Care for Rare Genetic Diseases in Canada) funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and Children's Hospital of Eastern Ontario Foundation; and by the National Institute of Neurological Disorders and Stroke (NINDS) under award numbers 1R01NS092772 (W.B.D.) and the National Human Genome Research Institute of the National Institutes of Health. Some sequencing in this study was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grant U54HG006493 to Drs. Debbie Nickerson, Jay Shendure, and Michael Bamshad. M.J.L. and L.G.B. are supported by the Intramural Research Program of the National Human Genome Research Institute. We also acknowledge the contributions of the high-throughput sequencing platform of the McGill University and Genome Quebec Innovation Centre, Montreal, Canada. M.T. received a post-doctoral fellowship from the Reseau de Medecine Genique Appliquee. L.M.M. is supported by a scholarship from the (CIHR) and Consortium National de Formation en Sante. T.Y.T. was supported by an Australian National Health and Medical Research Council Postdoctoral Overseas Training Scholarship (#607431). D.A. and M.O'D. are supported by Cancer Research UK. None of the authors have any conflicts of interest to declare. NR 60 TC 2 Z9 2 U1 0 U2 4 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 MAR 3 PY 2016 VL 98 IS 3 BP 579 EP 587 DI 10.1016/j.ajhg.2016.02.006 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DG9DN UT WOS:000372383100020 PM 26942290 ER PT J AU Sun, C Wiestner, A AF Sun, Clare Wiestner, Adrian TI Under the microscope: CCL3 and T cells in the microenvironment of chronic lymphocytic leukemia SO LEUKEMIA & LYMPHOMA LA English DT Editorial Material ID CHEMOKINES; ADHESION C1 [Sun, Clare; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 4E-5140, Bethesda, MD 20892 USA. RP Sun, C (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 4E-5140, Bethesda, MD 20892 USA. EM clare.sun@nih.gov FU Intramural NIH HHS NR 11 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAR 3 PY 2016 VL 57 IS 3 BP 501 EP 502 DI 10.3109/10428194.2015.1085979 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA DH0UO UT WOS:000372499800001 PM 26695886 ER PT J AU Kendrick, S Tus, K Wright, G Jaffe, ES Rosenwald, A Campo, E Chan, WC Connors, JM Braziel, RM Ott, G Delabie, J Cook, JR Weisenburger, DD Greiner, TC Fu, K Staudt, LM Gascoyne, RD Scott, DW Rimsza, LM AF Kendrick, Samantha Tus, Katalin Wright, George Jaffe, Elaine S. Rosenwald, Andreas Campo, Elias Chan, Wing Chung Connors, Joseph M. Braziel, Rita M. Ott, German Delabie, Jan Cook, James R. Weisenburger, Dennis D. Greiner, Timothy C. Fu, Kai Staudt, Louis M. Gascoyne, Randy D. Scott, David W. Rimsza, Lisa M. TI Diffuse large B-cell lymphoma cell-of-origin classification using the Lymph2Cx assay in the context of BCL2 and MYC expression status SO LEUKEMIA & LYMPHOMA LA English DT Letter ID RITUXIMAB PLUS CYCLOPHOSPHAMIDE; GENE-EXPRESSION; PROTEIN EXPRESSION; VINCRISTINE; DOXORUBICIN; PREDNISONE; SIGNATURES; SURVIVAL C1 [Kendrick, Samantha; Tus, Katalin; Rimsza, Lisa M.] Univ Arizona, Dept Pathol, 1501 N Campbell Ave,Room 5208, Tucson, AZ 85724 USA. [Wright, George] NCI, Bethesda, MD 20892 USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. [Rosenwald, Andreas] Univ Wurzburg, Inst Pathol, Josef Schneider Str 2, Wurzburg, Germany. [Rosenwald, Andreas] Comprehens Canc Ctr Mainfranken, Wurzburg, Germany. [Campo, Elias] Hosp Clin Barcelona, Dept Pathol, Barcelona, Spain. [Chan, Wing Chung; Weisenburger, Dennis D.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Connors, Joseph M.; Gascoyne, Randy D.; Scott, David W.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Dept Clin Pathol, Portland, OR 97201 USA. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany. [Delabie, Jan] Oslo Univ Hosp, Radiumhosp, Dept Pathol, Oslo, Norway. [Cook, James R.] Cleveland Clin, Dept Mol Pathol & Lab Med, Cleveland, OH 44106 USA. [Greiner, Timothy C.; Fu, Kai] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. RP Rimsza, LM (reprint author), Univ Arizona, Dept Pathol, 1501 N Campbell Ave,Room 5208, Tucson, AZ 85724 USA. EM lrimsza@pathology.arizona.edu RI Campo, elias/O-7192-2016 OI Campo, elias/0000-0001-9850-9793 FU NCI NIH HHS [U01 CA157581, 1U01CA157581-01] NR 14 TC 1 Z9 1 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAR 3 PY 2016 VL 57 IS 3 BP 717 EP 720 DI 10.3109/10428194.2015.1072767 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA DH0UO UT WOS:000372499800032 PM 26437080 ER PT J AU Sun, N Youle, RJ Finkel, T AF Sun, Nuo Youle, Richard J. Finkel, Toren TI The Mitochondrial Basis of Aging SO MOLECULAR CELL LA English DT Review ID EXTENDS LIFE-SPAN; PYRUVATE-DEHYDROGENASE COMPLEX; ONCOGENE-INDUCED SENESCENCE; PARKIN-MEDIATED MITOPHAGY; HEMATOPOIETIC STEM-CELLS; SKELETAL-MUSCLE; CAENORHABDITIS-ELEGANS; QUALITY-CONTROL; OXIDATIVE STRESS; DNA MUTATIONS AB A decline inmitochondrial quality and activity has been associated with normal aging and correlated with the development of a wide range of age-related diseases. Here, we review the evidence that a decline in mitochondria function contributes to aging. In particular, we discuss how mitochondria contribute to specific aspects of the aging process, including cellular senescence, chronic inflammation, and the age-dependent decline in stem cell activity. Signaling pathways regulating the mitochondrial unfolded protein response and mitophagy are also reviewed, with particular emphasis placed on how these pathways might, in turn, regulate longevity. Taken together, these observations suggest that mitochondria influence or regulate a number of key aspects of aging and suggest that strategies directed at improving mitochondrial quality and function might have far-reaching beneficial effects. C1 [Sun, Nuo; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. [Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA.; Youle, RJ (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM richard.youle@nih.guy; finkelt@nih.gov FU NIH Intramural Funds; Leducq Foundation Transatlantic Network Award FX We are grateful to members of the T.F. and R.J.Y. labs for helpful comments and to Ilsa Rovira for help with the preparation of the manuscript. This work was supported by NIH Intramural Funds and a Leducq Foundation Transatlantic Network Award. NR 137 TC 28 Z9 28 U1 16 U2 47 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD MAR 3 PY 2016 VL 61 IS 5 BP 654 EP 666 DI 10.1016/j.molcel.2016.01.028 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG8IJ UT WOS:000372326800006 PM 26942670 ER PT J AU Pan, JA Sun, Y Jiang, YP Bott, AJ Jaber, N Dou, ZX Yang, B Chen, JS Catanzaro, JM Du, CY Ding, WX Diaz-Meco, MT Moscat, J Ozato, K Lin, RZ Zong, WX AF Pan, Ji-An Sun, Yu Jiang, Ya-Ping Bott, Alex J. Jaber, Nadia Dou, Zhixun Yang, Bin Chen, Juei-Suei Catanzaro, Joseph M. Du, Chunying Ding, Wen-Xing Diaz-Meco, Maria T. Moscat, Jorge Ozato, Keiko Lin, Richard Z. Zong, Wei-Xing TI TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis SO MOLECULAR CELL LA English DT Article ID TRANSCRIPTION FACTOR NRF2; CHAIN BINDING-PROTEIN; CELL-DEATH; RETROVIRAL RESTRICTION; SELECTIVE AUTOPHAGY; SEQUESTOSOME 1/P62; OXIDATIVE STRESS; UBIQUITIN LIGASE; POOR-PROGNOSIS; LEUKEMIA-CELLS AB TRIM21 is a RING finger domain-containing ubiquitin E3 ligase whose expression is elevated in autoimmune disease. While TRIM21 plays an important role in immune activation during pathogen infection, little is known about its inherent cellular function. Here we show that TRIM21 plays an essential role in redox regulation by directly interacting with SQSTM1/p62 and ubiquitylating p62 at lysine 7 (K7) via K63-linkage. As p62 oligomerizes and sequesters client proteins in inclusions, the TRIM21-mediated p62 ubiquitylation abrogates p62 oligomerization and sequestration of proteins including Keap1, a negative regulator of antioxidant response. TRIM21-deficient cells display an enhanced antioxidant response and reduced cell death in response to oxidative stress. Genetic ablation of TRIM21 in mice confers protection from oxidative damages caused by arsenic-induced liver insult and pressure overload heart injury. Therefore, TRIM21 plays an essential role in p62-regulated redox homeostasis and may be a viable target for treating pathological conditions resulting from oxidative damage. C1 [Pan, Ji-An; Sun, Yu; Bott, Alex J.; Zong, Wei-Xing] Rutgers State Univ, Ernest Mario Sch Pharm, Dept Biol Chem, 164 Frelinghuysen Rd, Piscataway, NJ 08854 USA. [Pan, Ji-An; Sun, Yu; Bott, Alex J.; Zong, Wei-Xing] Rutgers Canc Inst New Jersey, 195 Little Albany St, New Brunswick, NJ 08903 USA. [Pan, Ji-An; Sun, Yu; Bott, Alex J.; Jaber, Nadia; Dou, Zhixun; Chen, Juei-Suei; Catanzaro, Joseph M.; Zong, Wei-Xing] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. [Jiang, Ya-Ping; Lin, Richard Z.] SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY 11794 USA. [Yang, Bin] Tianjin Third Cent Hosp, Key Lab Artificial Cells, Tianjin 300170, Peoples R China. [Du, Chunying] Univ Cincinnati, Dept Canc Biol, Cincinnati, OH 45267 USA. [Ding, Wen-Xing] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. [Diaz-Meco, Maria T.; Moscat, Jorge] Sanford Burnham Prebys Med Discovery Inst, Canc Metab & Signaling Networks Program, La Jolla, CA 92037 USA. [Ozato, Keiko] NICHD, Div Dev Biol, NIH, Bethesda, MD 20892 USA. [Lin, Richard Z.] Dept Vet Affairs Med Ctr, Northport, NY 11768 USA. RP Pan, JA; Zong, WX (reprint author), Rutgers State Univ, Ernest Mario Sch Pharm, Dept Biol Chem, 164 Frelinghuysen Rd, Piscataway, NJ 08854 USA.; Pan, JA; Zong, WX (reprint author), Rutgers Canc Inst New Jersey, 195 Little Albany St, New Brunswick, NJ 08903 USA.; Pan, JA; Zong, WX (reprint author), SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. EM jian.pan@pharmacy.rutgers.edu; weixing.zong@pharmacy.rutgers.edu OI Bott, Alex/0000-0003-2273-8922 FU NIH [R01CA129536, R01GM97355, R01CA172025, R01DK108743, R01CA192642, 5P30CA030199]; Department of Veterans Affairs Merit Review Program; Municipal Healthy Bureau of Tianjin, China [12KG107] FX We thank Drs. Michael Frohman (Stony Brook University), Terje Johanson (University of Tromso, Norway), Huikuan Lin (M.D. Anderson Cancer Center), Noboru Mizushima (University of Tokyo), and Zhenyu Yue (Mt Sinai School of Medicine) for reagents. We thank Drs. Yanxiang Zhao (Hong Kong Polytechnic University) and David Goldfarb (University of Rochester) for insightful comments. This work was supported by grants from NIH (R01CA129536 and R01GM97355 to W.-X.Z., R01CA172025 and R01DK108743 to J.M., R01CA192642 to M.T.D.-M., 5P30CA030199 to M.T.D.-M., and J.M.), Department of Veterans Affairs Merit Review Program (to R.Z.L.), and a key project (12KG107) from the Municipal Healthy Bureau of Tianjin, China (to B.Y.). NR 49 TC 5 Z9 5 U1 3 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD MAR 3 PY 2016 VL 61 IS 5 BP 720 EP 733 DI 10.1016/j.molcel.2016.02.007 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG8IJ UT WOS:000372326800012 PM 26942676 ER PT J AU Sugiyama, T Thillainadesan, G Chalamcharla, VR Meng, ZJ Balachandran, V Dhakshnamoorthy, J Zhou, M Grewal, SIS AF Sugiyama, Tomoyasu Thillainadesan, Gobi Chalamcharla, Venkata R. Meng, Zhaojing Balachandran, Vanivilasini Dhakshnamoorthy, Jothy Zhou, Ming Grewal, Shiv I. S. TI Enhancer of Rudimentary Cooperates with Conserved RNA-Processing Factors to Promote Meiotic mRNA Decay and Facultative Heterochromatin Assembly SO MOLECULAR CELL LA English DT Article ID FISSION YEAST; SELECTIVE ELIMINATION; SCHIZOSACCHAROMYCES-POMBE; CCR4-NOT COMPLEX; MEIOSIS; GENES; EXPRESSION; EXOSOME; PROTEIN; CANCER AB Erh1, the fission yeast homolog of Enhancer of rudimentary, is implicated in meiotic mRNA elimination during vegetative growth, but its function is poorly understood. We show that Erh1 and the RNA-binding protein Mmi1 form a stoichiometric complex, called the Erh1-Mmi1 complex (EMC), to promote meiotic mRNA decay and facultative heterochromatin assembly. To perform these functions, EMC associates with two distinct complexes, Mtl1-Red1 core (MTREC) and CCR4-NOT. Whereas MTREC facilitates assembly of heterochromatin islands coating meiotic genes silenced by the nuclear exosome, CCR4-NOT promotes RNAi-dependent heterochromatin domain (HOOD) formation at EMC-target loci. CCR4-NOT also assembles HOODs at retrotransposons and regulated genes containing cryptic introns. We find that CCR4-NOT facilitates HOOD assembly through its association with the conserved Pir2/ARS2 protein, and also maintains rDNA integrity and silencing by promoting heterochromatin formation. Our results reveal connections among Erh1, CCR4-NOT, Pir2/ARS2, and RNAi, which target heterochromatin to regulate gene expression and protect genome integrity. C1 [Sugiyama, Tomoyasu; Thillainadesan, Gobi; Chalamcharla, Venkata R.; Balachandran, Vanivilasini; Dhakshnamoorthy, Jothy; Grewal, Shiv I. S.] NCI, Biochem & Mol Biol Lab, Bethesda, MD 20892 USA. [Meng, Zhaojing; Zhou, Ming] Frederick Natl Lab Canc Res, Lab Prote & Analyt Technol, Frederick, MD 21702 USA. RP Grewal, SIS (reprint author), NCI, Biochem & Mol Biol Lab, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov OI Sugiyama, Tomoyasu/0000-0001-5704-6606 FU NIH; National Cancer Institute FX We thank J. Cooper, A. Kelly, K. Sawin, K. Tatebayashi, Y. Watanabe, M. Yamamoto, A. Yamashita, and the National Bio Resource Project (NBRP) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, for S. pombe strains and materials; H.P. Cam, H.D. Folco, S. Yamanaka, and M. Zofall for technical advice; J. Barrowman for her valuable help in editing the manuscript; and members of the S.I.S.G. lab for helpful discussions. T.S. thanks R. Sugioka-Sugiyama for her support. This research was supported by the Intramural Research Program of the NIH and by the National Cancer Institute. NR 49 TC 3 Z9 3 U1 5 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD MAR 3 PY 2016 VL 61 IS 5 BP 747 EP 759 DI 10.1016/j.molcel.2016.01.029 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG8IJ UT WOS:000372326800014 PM 26942678 ER PT J AU Non, AL Roman, JC Gross, CL Gilman, SE Loucks, EB Buka, SL Kubzansky, LD AF Non, Amy L. Roman, Jorge Carlos Gross, Christopher L. Gilman, Stephen E. Loucks, Eric B. Buka, Stephen L. Kubzansky, Laura D. TI Early childhood social disadvantage is associated with poor health behaviours in adulthood SO ANNALS OF HUMAN BIOLOGY LA English DT Article DE Alcohol; body mass index; early life adversity; childhood socioeconomic status; smoking ID CORONARY-HEART-DISEASE; SOCIOECONOMIC-STATUS; CUMULATIVE RISK; LIFE-COURSE; ALCOHOL-CONSUMPTION; CIGARETTE-SMOKING; WOMENS HEALTH; OBESITY; ADOLESCENCE; EXPERIENCES AB Background: Individual health behaviours are considered important risk factors for cardiometabolic diseases. These behaviours may be socially patterned by early exposure to social disadvantage, but few studies have prospectively tested this hypothesis empirically. Aim: This study investigated whether childhood social disadvantage was associated with likelihood of engaging in less healthy behaviours 40 years later. Subjects and methods: Prospective data were analysed from the New England Family Study, a 2005-2007 adult follow-up of a cohort initiated in 1959-1966 (n = 565). Childhood social environment (age 7 years) was assessed using a cumulative index of socioeconomic and family stability factors. Logistic regression models evaluated associations between social disadvantage and each health-related behaviour and obesity in adulthood. Results: Relative to low disadvantage, higher disadvantage was associated with 3.6-fold greater odds of smoking (95% CI = 1.9-7.0), 4.8-fold greater odds (in women only) of excess alcohol consumption (95% CI = 1.6-14.2) and 2.7-fold greater odds of obesity (95% CI = 1.3-5.5), but was not associated with unhealthy diet or physical inactivity. Conclusion: These findings suggest childhood social disadvantage may contribute to adult cardiometabolic disease by predisposing children to adopt certain unhealthy behaviours. If replicated, such findings may support intervention strategies that target social environmental factors and behavioural pathways that are established early in life. C1 [Non, Amy L.] Univ Calif San Diego, Dept Anthropol, 9500 Gilman Dr 0532, La Jolla, CA 92093 USA. [Roman, Jorge Carlos] San Diego State Univ, Dept Math & Stat, San Diego, CA 92182 USA. [Gross, Christopher L.] Vanderbilt Univ, Dept Med Hlth & Soc, 221 Kirkland Hall, Nashville, TN 37235 USA. [Gilman, Stephen E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Gilman, Stephen E.; Kubzansky, Laura D.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Loucks, Eric B.; Buka, Stephen L.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. RP Non, AL (reprint author), Univ Calif San Diego, Dept Anthropol, 9500 Gilman Dr 0532, La Jolla, CA 92093 USA. EM alnon@ucsd.edu OI Gilman, Stephen/0000-0002-8331-6419 FU National Institutes of Health Transdisciplinary Tobacco Use Research Center of National Cancer Institute [P50 CA98029, CA084719]; National Institute on Drug Abuse; National Institute of Aging [AG023397]; Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development; Robert Wood Johnson Health and Society Scholars Program FX The authors thank all study participants and attendees of the Society for the Study of Human Biology symposium on Biology of Poverty for helpful feedback on the project. This work was supported by the National Institutes of Health Transdisciplinary Tobacco Use Research Center (awards P50 CA98029 and CA084719) of the National Cancer Institute and the National Institute on Drug Abuse; the National Institute of Aging (grant AG023397); the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; and the Robert Wood Johnson Health and Society Scholars Program (to ALN). NR 48 TC 2 Z9 2 U1 5 U2 12 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0301-4460 EI 1464-5033 J9 ANN HUM BIOL JI Ann. Hum. Biol. PD MAR 3 PY 2016 VL 43 IS 2 SI SI BP 144 EP 153 DI 10.3109/03014460.2015.1136357 PG 10 WC Anthropology; Biology; Public, Environmental & Occupational Health SC Anthropology; Life Sciences & Biomedicine - Other Topics; Public, Environmental & Occupational Health GA DG6RQ UT WOS:000372214200007 PM 26727037 ER PT J AU Torres-Salazar, D Gonzalez-Suarez, ADM Amara, SG AF Torres-Salazar, Delany Gonzalez-Suarez, Aneysis D. M. Amara, Susan G. TI Transport and channel functions in EAATs: the missing link SO CHANNELS LA English DT Editorial Material DE transporters; ion channels; anion conductance; glutamate; coupled transport ID ANION CONDUCTANCE; GLUTAMATE; SUBSTRATE C1 [Torres-Salazar, Delany; Gonzalez-Suarez, Aneysis D. M.; Amara, Susan G.] NIMH, NIH, Bethesda, ME USA. RP Torres-Salazar, D (reprint author), NIMH, NIH, 35 Convent Dr,Room 3A-207, Bethesda, MD 20892 USA. EM delany.torressalazar@nih.gov NR 8 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1933-6950 EI 1933-6969 J9 CHANNELS JI Channels PD MAR 3 PY 2016 VL 10 IS 2 BP 86 EP 87 DI 10.1080/19336950.2015.1119631 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DG5IV UT WOS:000372112100007 PM 26683197 ER PT J AU Fins, JJ Kodish, E Cohn, F Danis, M Derse, AR Dubler, NN Goulden, B Kuczewski, M Mercer, MB Pearlman, RA Smith, ML Tarzian, A Youngner, SJ AF Fins, Joseph J. Kodish, Eric Cohn, Felicia Danis, Marion Derse, Arthur R. Dubler, Nancy Neveloff Goulden, Barbara Kuczewski, Mark Mercer, Mary Beth Pearlman, Robert A. Smith, Martin L. Tarzian, Anita Youngner, Stuart J. TI A Pilot Evaluation of Portfolios for Quality Attestation of Clinical Ethics Consultants SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE quality assessment; portfolio evaluation; ethics consultants; clinical ethics consultation AB Although clinical ethics consultation is a high-stakes endeavor with an increasing prominence in health care systems, progress in developing standards for quality is challenging. In this article, we describe the results of a pilot project utilizing portfolios as an evaluation tool. We found that this approach is feasible and resulted in a reasonably wide distribution of scores among the 23 submitted portfolios that we evaluated. We discuss limitations and implications of these results, and suggest that this is a significant step on the pathway to an eventual certification process for clinical ethics consultants. C1 [Fins, Joseph J.] New York Presbyterian Hosp, Weill Cornell Ctr, New York, NY 10021 USA. [Kodish, Eric] Cleveland Clin, Cleveland, OH USA. [Cohn, Felicia] Kaiser Permanente Orange Cty, New York, NY USA. [Cohn, Felicia] Amer Soc Bioeth & Humanities, Chicago, IL USA. [Danis, Marion] NIH, Bethesda, MD USA. [Derse, Arthur R.] Med Coll Wisconsin, Madison, WI USA. [Dubler, Nancy Neveloff] New York City Hlth & Hosp Corp, New York, NY USA. [Dubler, Nancy Neveloff] NYU, Langone Med Ctr, New York, NY 10003 USA. [Goulden, Barbara; Mercer, Mary Beth; Smith, Martin L.] Cleveland Clin, Cleveland, OH USA. [Kuczewski, Mark] Loyola Univ Chicago, Chicago, IL USA. [Pearlman, Robert A.] Natl Ctr Eth Hlth Care, Dept Vet Affairs, Chicago, IL USA. [Tarzian, Anita] Univ Maryland, Sch Nursing, Bethesda, MD USA. [Tarzian, Anita] Univ Maryland, Sch Law, Bethesda, MD USA. [Youngner, Stuart J.] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Fins, JJ (reprint author), New York Presbyterian Hosp, Div Med Eth, Weill Cornell Ctr, 435 East 70th St Suite 4-J, New York, NY 10021 USA. EM jjfins@med.cornell.edu FU Greenwall Foundation; Josiah Macy Jr. Foundation FX We are grateful to the Greenwall Foundation and the Josiah Macy Jr. Foundation for funding this effort, and to the Cleveland Clinic for administrative support. We appreciate the wise counsel and guidance of Drs. George Thibault and Bernard Lo and the Board of Directors of ASBH for their support and helpful comments on this article. We also thank the VA team that was responsible for developing and providing the draft version of the Ethics Consultation Quality Assessment Tool for use in this project. We are grateful to the three anonymous peer reviewers and AJOB editors for their helpful suggestions to improve the article. Finally, we thank all those who submitted letters of intent, and especially the 23 individuals who compiled and submitted pilot portfolios. NR 7 TC 14 Z9 14 U1 1 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD MAR 3 PY 2016 VL 16 IS 3 BP 15 EP 24 DI 10.1080/15265161.2015.1134705 PG 10 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DF7NJ UT WOS:000371544100003 PM 26913652 ER PT J AU Glaser, R York, A Dimitrakakis, C AF Glaser, R. York, A. Dimitrakakis, C. TI Effect of testosterone therapy on the female voice SO CLIMACTERIC LA English DT Article DE menopause; aging; voice; implant; Testosterone; fundamental frequency; women ID CAPE-V; WOMEN; ENDOMETRIOSIS; FREQUENCY; LARYNX; IMPACT; MEN AB Objectives This prospective study was designed to investigate the effect of testosterone, delivered by subcutaneous implants, on the female voice. Methods Ten women who had opted for testosterone therapy were recruited for voice analysis. Voices were recorded prior to treatment and at 3 months, 6 months, and 12 months while on testosterone therapy. Acoustic samples were collected with subjects reading a sentence, reading a paragraph, and participating in a conversation. Significant changes in the voice over time were investigated using a repeated-measures analysis of variance with the fundamental frequency (F-0) as a response variable. Demographic variables associated with characteristics of the voice were assessed. Results There were no significant differences in average F-0 related to smoking history, menopausal status, weight, or body mass index. There was no difference in average fundamental speaking frequency (sentence, paragraph, conversation) between the pre-treatment group and any post-treatment group at 3 and 12 months. There was an increase in sentence speech F-0 at 6 months. Two of three patients with lower than expected F-0 at baseline improved on testosterone therapy. Conclusion Therapeutic levels of testosterone, delivered by subcutaneous implant, had no adverse affect on the female voice including lowering or deepening of the voice. C1 [Glaser, R.] Dayton & Wright State Univ, Dept Surg, Millennium Wellness Ctr, Boonshoft Sch Med, Dayton, OH USA. [York, A.] York Data Anal, Seattle, WA USA. [Dimitrakakis, C.] Univ Athens, Sch Med, Dept Ob Gyn 1, GR-11527 Athens, Greece. [Dimitrakakis, C.] NICHD, NIH, Bethesda, MD USA. RP Glaser, R (reprint author), Dayton & Wright State Univ, Dept Surg, Millennium Wellness Ctr, Boonshoft Sch Med, Dayton, OH USA. EM rglaser@woh.rr.com NR 28 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1369-7137 EI 1473-0804 J9 CLIMACTERIC JI Climacteric PD MAR 3 PY 2016 VL 19 IS 2 BP 198 EP 203 DI 10.3109/13697137.2015.1136925 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DF7ML UT WOS:000371541700008 PM 26857354 ER PT J AU Tan, ML Tran, KN Pickard, FC Simmonett, AC Brooks, BR Ichiye, T AF Tan, Ming-Liang Tran, Kelly N. Pickard, Frank C. Simmonett, Andrew C. Brooks, Bernard R. Ichiye, Toshiko TI Molecular Multipole Potential Energy Functions for Water SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID LIQUID WATER; COMPUTER-SIMULATIONS; AB-INITIO; DYNAMICS; MODEL; POLARIZATION; TEMPERATURE; DEPENDENCE; DIFFUSION; EXPANSION AB Water is the most common liquid on this planet, with many unique properties that make it essential for life as we know it. These properties must arise from features in the charge distribution of a water molecule, so it is essential to capture these features in potential energy functions for water to reproduce its liquid state properties in computer simulations. Recently, models that utilize a multipole expansion located on a single site in the water molecule, or "molecular multipole models", have been shown to rival and even surpass site models with up to five sites in reproducing both the electrostatic potential around a molecule and a variety of liquid state properties in simulations. However, despite decades of work using multipoles, confusion still remains about how to truncate the multipole expansions efficiently and accurately. This is particularly important when using molecular multipole expansions to describe water molecules in the liquid state, where the short-range interactions must be accurate, because the higher order multipoles of a water molecule are large. Here, truncation schemes designed for a recent efficient algorithm for multipoles in molecular dynamics simulations are assessed for how well they reproduce results for a simple three-site model of water when the multipole moments and Lennard-Jones parameters of that model are used. In addition, the multipole analysis indicates that site models that do not account for out-of-plane electron denSity overestimate the stability of a non-hydrogen-bonded conformation, leading to serious consequences for the simulated liquid. C1 [Tan, Ming-Liang; Tran, Kelly N.; Ichiye, Toshiko] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. [Tan, Ming-Liang; Pickard, Frank C.; Simmonett, Andrew C.; Brooks, Bernard R.; Ichiye, Toshiko] NHLBI, Lab Computat Biol, NIH, Rockville, MD 20892 USA. RP Ichiye, T (reprint author), Georgetown Univ, Dept Chem, Washington, DC 20057 USA.; Ichiye, T (reprint author), NHLBI, Lab Computat Biol, NIH, Rockville, MD 20892 USA. EM ti9@georgetown.edu FU National Science Foundation [CHE-1464766, OCI-1053575]; McGowan Foundation; Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute FX The authors are grateful for support from the National Science Foundation through Grant No. CHE-1464766 and from the McGowan Foundation. This research was also supported in part by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute. This work used computer time on the Extreme Science and Engineering Discovery Environment (XSEDE) granted via MCB990010, which is supported by National Science Foundation Grant No. OCI-1053575; the Medusa cluster, which is maintained by University Information Services at Georgetown University; and the LoBoS cluster at the Laboratory for Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health. NR 51 TC 3 Z9 3 U1 6 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAR 3 PY 2016 VL 120 IS 8 BP 1833 EP 1842 DI 10.1021/acs.jpcb.5b09565 PG 10 WC Chemistry, Physical SC Chemistry GA DF7UI UT WOS:000371562700048 PM 26562223 ER PT J AU Taber, JM Howell, JL Emanuel, AS Klein, WMP Ferrer, RA Harris, PR AF Taber, Jennifer M. Howell, Jennifer L. Emanuel, Amber S. Klein, William M. P. Ferrer, Rebecca A. Harris, Peter R. TI Associations of spontaneous self-affirmation with health care experiences and health information seeking in a national survey of US adults SO PSYCHOLOGY & HEALTH LA English DT Article DE Health Information National Trends Survey; self-affirmation; information seeking; patient-provider relationship ID SOCIAL-PSYCHOLOGICAL INTERVENTION; STEREOTYPE THREAT; DISTINGUISHING OPTIMISM; ACHIEVEMENT GAP; AVOIDANCE; COMMUNICATION; DISPARITIES; BEHAVIOR; VALUES; RACE AB Objective: Self-affirming - such as by reflecting on one's strengths and values - reduces defensiveness to threatening information, reduces negative effects of stereotype threat and promotes prosociality. These outcomes may promote physical health, highlighting a need to examine the role of self-affirmation in medical and health contexts.Design: Data were collected as part of the nationally representative, cross-sectional, 2013 Health Information National Trends Survey. Items were completed by 2731 respondents.Main Outcome Measures: Respondents answered questions about spontaneous self-affirmation tendencies, perceptions of providers and health care, involvement in medical appointments, health information seeking and engagement in medical research.Results: Spontaneous self-affirmation was associated with more positive perceptions of communication with one's provider, better perceived quality of care, greater likelihood of asking questions in a medical appointment, greater information seeking for oneself and multiple indices of surrogate information seeking (i.e. seeking information for others). Four of eight significant associations remained significant when controlling for optimism. The associations of self-affirmation with aspects of the patient-provider relationship were not modified by factors likely to be associated with stereotype threat (e.g. race or BMI).Conclusion: Spontaneous self-affirmation was related to positive outcomes in health contexts. Experimental research is needed to further explore the causal nature of these associations. C1 [Taber, Jennifer M.; Klein, William M. P.; Ferrer, Rebecca A.] NCI, NIH, Bethesda, MD 20892 USA. [Howell, Jennifer L.] Univ Florida, Dept Psychol, Gainesville, FL 32611 USA. [Emanuel, Amber S.] Univ Florida, Dept Community Dent & Behav Sci, Southeast Ctr Res Reduce Dispar Oral Hlth, Gainseville, FL USA. [Harris, Peter R.] Univ Sussex, Dept Psychol, Brighton, E Sussex, England. [Howell, Jennifer L.] Ohio Univ, Dept Psychol, Athens, OH 45701 USA. RP Taber, JM (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM Jennifer.taber@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 67 TC 2 Z9 2 U1 6 U2 15 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0887-0446 EI 1476-8321 J9 PSYCHOL HEALTH JI Psychol. Health PD MAR 3 PY 2016 VL 31 IS 3 BP 292 EP 309 DI 10.1080/08870446.2015.1085986 PG 18 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary SC Public, Environmental & Occupational Health; Psychology GA DG1EM UT WOS:000371808400003 PM 26315683 ER PT J AU Beekman, JB Ferrer, RA Klein, WMP Persky, S AF Beekman, Janine B. Ferrer, Rebecca A. Klein, William M. P. Persky, Susan TI Effects of perceived weight discrimination on willingness to adopt unhealthy behaviours: influence of genomic information SO PSYCHOLOGY & HEALTH LA English DT Article DE genomic information; obesity; weight discrimination; weight and weight loss; doctor-patient interaction; personalised medicine ID AMERICAN YOUNG-ADULTS; RACIAL-DISCRIMINATION; BODY-WEIGHT; FOOD-INTAKE; DECISION-MAKING; HEALTH BEHAVIOR; RISK COGNITIONS; SUBSTANCE USE; HIV-RISK; OBESITY AB Objective: Weight-based discrimination negatively influences health, potentially via increased willingness to engage in unhealthful behaviours. This study examines whether the provision of genomic obesity information in a clinical context can lead to less willingness to engage in unhealthy eating and alcohol consumption through a mediated process including reduced perceptions of blame and discrimination.Design: A total of 201 overweight or obese women aged 20-50 interacted with a virtual physician in a simulated clinical primary care environment, which included physician-delivered information that emphasised either genomic or behavioural underpinnings of weight and weight loss.Main Outcome Measures: Perceived blame and weight discrimination from the doctor, and willingness to eat unhealthy foods and consume alcohol.Results: Controlling for BMI and race, participants who received genomic information perceived less blame from the doctor than participants who received behavioural information. In a serial multiple mediation model, reduced perceived blame was associated with less perceived discrimination, and in turn, lower willingness to eat unhealthy foods and drink alcohol.Conclusion: Providing patients with genomic information about weight and weight loss may positively influence interpersonal dynamics between patients and providers by reducing perceived blame and perceived discrimination. These improved dynamics, in turn, positively influence health cognitions. C1 [Beekman, Janine B.] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Ferrer, Rebecca A.; Klein, William M. P.] NCI, Behav Res Program, Rockville, MD USA. [Persky, Susan] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. RP Beekman, JB (reprint author), George Washington Univ, Dept Psychol, Washington, DC 20052 USA. EM janine1@gwmail.gwu.edu FU National Human Genome Research Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 65 TC 0 Z9 0 U1 5 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0887-0446 EI 1476-8321 J9 PSYCHOL HEALTH JI Psychol. Health PD MAR 3 PY 2016 VL 31 IS 3 BP 334 EP 348 DI 10.1080/08870446.2015.1099654 PG 15 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary SC Public, Environmental & Occupational Health; Psychology GA DG1EM UT WOS:000371808400007 PM 26406164 ER PT J AU Madan, RA Gulley, JL AF Madan, Ravi A. Gulley, James L. TI Prospects for the future of prostate cancer vaccines SO EXPERT REVIEW OF VACCINES LA English DT Editorial Material DE combination therapy; therapeutic cancer vaccines; Vaccines; immune combinations; prostate cancer ID DOSE-ESCALATION TRIAL; CASTRATION; IMMUNOTHERAPY; ABIRATERONE; ANTAGONIST; IPILIMUMAB; THERAPY; ANTIGEN; CELLS; MEN AB Cancer therapy is undergoing a revolution fueled by clinical data demonstrating that the immune system has significant anti-tumor capability. Although the main focus of this revolution currently rests upon immune checkpoint inhibitors in diseases such as melanoma, lung and bladder cancer, it was actually a therapeutic cancer vaccine in prostate cancer that provided the first data demonstrating that a modern immunotherapy, beyond cytokines, could enhance clinical outcomes. As immunotherapy is poised to take center stage among cancer therapies, the role of cancer vaccines remains somewhat undefined in prostate cancer, though emerging data suggest that vaccines could play a crucial therapeutic role. C1 [Madan, Ravi A.; Gulley, James L.] NCI, Genitourinary Malignancies Branch, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Genitourinary Malignancies Branch, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 20 TC 1 Z9 1 U1 0 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-0584 EI 1744-8395 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD MAR 3 PY 2016 VL 15 IS 3 BP 271 EP 274 DI 10.1586/14760584.2015.1118348 PG 4 WC Immunology SC Immunology GA DE6EV UT WOS:000370727400001 PM 26560494 ER PT J AU Elmunzer, BJ Serrano, J Chak, A Edmundowicz, SA Papachristou, GI Scheiman, JM Singh, VK Varadurajulu, S Vargo, JJ Willingham, FF Barons, TH Cote, GA Romagnuolo, J Wood-Williams, A Depue, EK Spitzer, RL Spino, C Foster, LD Durkalski, V AF Elmunzer, B. Joseph Serrano, Jose Chak, Amitabh Edmundowicz, Steven A. Papachristou, Georgios I. Scheiman, James M. Singh, Vikesh K. Varadurajulu, Shyam Vargo, John J. Willingham, Field F. Barons, Todd H. Cote, Gregory A. Romagnuolo, Joseph Wood-Williams, April Depue, Emily K. Spitzer, Rebecca L. Spino, Cathie Foster, Lydia D. Durkalski, Valerie CA SVI Study Grp US Cooperative Outcomes Res Endosc TI Rectal indomethacin alone versus indomethacin and prophylactic pancreatic stent placement for preventing pancreatitis after ERCP: study protocol for a randomized controlled trial SO TRIALS LA English DT Article ID ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY; DUCT STENTS; METAANALYSIS; SPHINCTEROTOMY; SUPERIOR; RISK AB Background: The combination of prophylactic pancreatic stent placement (PSP) - a temporary plastic stent placed in the pancreatic duct - and rectal non-steroidal anti-inflammatory drugs (NSAIDs) is recommended for preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk cases. Preliminary data, however, suggest that PSP may be unnecessary if rectal NSAIDs are administered. Given the costs and potential risks of PSP, we aim to determine whether rectal indomethacin obviates the need for pancreatic stent placement in patients undergoing high-risk ERCP. Methods/Design: The SVI (Stent vs. Indomethacin) trial is a comparative effectiveness, multicenter, randomized, double-blind, non-inferiority study of rectal indomethacin alone versus the combination of rectal indomethacin and PSP for preventing PEP in high-risk cases. One thousand four hundred and thirty subjects undergoing high-risk ERCP, in whom PSP is planned solely for PEP prevention, will be randomized to indomethacin alone or combination therapy. Those who are aware of study group assignment, including the endoscopist, will not be involved in the post-procedure care of the patient for at least 48 hours. Subjects will be assessed for PEP and its severity by a panel of independent and blinded adjudicators. Indomethacin alone will be declared non-inferior to combination therapy if the two-sided 95 % upper confidence bound of the treatment difference is less than 5 % between the two groups. Biological specimens will be obtained from trial participants and centrally banked. Discussion: The SVI trial is designed to determine whether PSP remains necessary in the era of NSAIDs pharmacoprevention. The associated bio-repository will establish the groundwork for important scientific breakthrough. C1 [Elmunzer, B. Joseph; Cote, Gregory A.; Wood-Williams, April; Depue, Emily K.; Spitzer, Rebecca L.] Med Univ S Carolina, Div Gastroenterol & Hepatol, MSC 702,114 Doughty St,Suite 249, Charleston, SC 29425 USA. [Serrano, Jose] NIH, Inst Diabet & Digest & Kidney Dis, Bldg 10, Bethesda, MD 20892 USA. [Chak, Amitabh] Univ Hosp Cleveland, Case Med Ctr, Cleveland, OH 44106 USA. [Edmundowicz, Steven A.] Washington Univ, Sch Med, Div Gastroenterol, St Louis, MO 63110 USA. [Papachristou, Georgios I.] Univ Pittsburgh, Med Ctr, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. [Scheiman, James M.] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. [Singh, Vikesh K.] Johns Hopkins Med Inst, Div Gastroenterol, Baltimore, MD 21205 USA. [Varadurajulu, Shyam] Florida Hosp, Ctr Intervent Endoscopy, Orlando, FL USA. [Vargo, John J.] Cleveland Clin Fdn, Dept Gastroenterol & Hepatol, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Willingham, Field F.] Emory Univ, Sch Med, Div Digest Dis, Atlanta, GA USA. [Barons, Todd H.] Univ N Carolina, Sch Med, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. [Romagnuolo, Joseph] Tidelands Hlth, Murrels Inlet, SC USA. [Spino, Cathie] Univ Michigan, Sch Med, Dept Publ Hlth, Ann Arbor, MI USA. [Foster, Lydia D.; Durkalski, Valerie] Med Univ S Carolina, Dept Publ Hlth Sci, Data Coordinat Unit, Charleston, SC 29425 USA. RP Elmunzer, BJ (reprint author), Med Univ S Carolina, Div Gastroenterol & Hepatol, MSC 702,114 Doughty St,Suite 249, Charleston, SC 29425 USA. EM elmurzer@musc.edu FU National Institutes of Diabetes and Digestive and Kidney Diseases [U34DK099845, U01DK104833] FX This study is funded by grants U34DK099845 and U01DK104833 from the National Institutes of Diabetes and Digestive and Kidney Diseases. This organization has contributed scientifically and operationally to the design and conduct of this trial. NR 22 TC 3 Z9 3 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD MAR 3 PY 2016 VL 17 AR 120 DI 10.1186/s13063-016-1251-2 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DF6LO UT WOS:000371467400003 PM 26941086 ER PT J AU Lauer, M Valantine, H Collins, FS AF Lauer, Michael Valantine, Hannah Collins, Francis S. TI NIH push to stop sexual harassment SO NATURE LA English DT Letter C1 [Lauer, Michael; Valantine, Hannah; Collins, Francis S.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Lauer, M (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM michael.lauer@nih.gov NR 0 TC 1 Z9 1 U1 0 U2 2 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 MAR 3 PY 2016 VL 531 IS 7592 BP 35 EP 35 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF2YW UT WOS:000371211900027 PM 26935689 ER PT J AU Kirchdoerfer, RN Cottrell, CA Wang, NS Pallesen, J Yassine, HM Turner, HL Corbett, KS Graham, BS McLellan, JS Ward, AB AF Kirchdoerfer, Robert N. Cottrell, Christopher A. Wang, Nianshuang Pallesen, Jesper Yassine, Hadi M. Turner, Hannah L. Corbett, Kizzmekia S. Graham, Barney S. McLellan, Jason S. Ward, Andrew B. TI Pre-fusion structure of a human coronavirus spike protein SO NATURE LA English DT Article ID ACUTE RESPIRATORY SYNDROME; RECEPTOR-BINDING DOMAIN; CRYO-EM STRUCTURE; EBOLA-VIRUS GLYCOPROTEIN; HIV-1 ENVELOPE TRIMER; ELECTRON-MICROSCOPY; CRYSTAL-STRUCTURE; SARS CORONAVIRUS; NEUTRALIZING ANTIBODIES; CRYOELECTRON MICROSCOPY AB HKU1 is a human betacoronavirus that causes mild yet prevalent respiratory disease1, and is related to the zoonotic SARS(2) and MERS3 betacoronaviruses, which have high fatality rates and pandemic potential. Cell tropism and host range is determined in part by the coronavirus spike (S) protein(4), which binds cellular receptors and mediates membrane fusion. As the largest known class I fusion protein, its size and extensive glycosylation have hindered structural studies of the full ectodomain, thus preventing a molecular understanding of its function and limiting development of effective interventions. Here we present the 4.0 resolution structure of the trimeric HKU1 S protein determined using singleparticle cryo-electron microscopy. In the pre-fusion conformation, the receptor-binding subunits, S1, rest above the fusion-mediating subunits, S2, preventing their conformational rearrangement. Surprisingly, the S1 C-terminal domains are interdigitated and form extensive quaternary interactions that occlude surfaces known in other coronaviruses to bind protein receptors. These features, along with the location of the two protease sites known to be important for coronavirus entry, provide a structural basis to support a model of membrane fusion mediated by progressive S protein destabilization through receptor binding and proteolytic cleavage. These studies should also serve as a foundation for the structure-based design of betacoronavirus vaccine immunogens. C1 [Kirchdoerfer, Robert N.; Cottrell, Christopher A.; Pallesen, Jesper; Turner, Hannah L.; Ward, Andrew B.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Wang, Nianshuang; McLellan, Jason S.] Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH 03755 USA. [Yassine, Hadi M.; Corbett, Kizzmekia S.; Graham, Barney S.] NIAID, Viral Pathogenesis Lab, Bldg 40,Room 2502,40 Convent Dr, Bethesda, MD 20892 USA. [Yassine, Hadi M.] Qatar Univ, Biomed Res Ctr, QU NRC, Zone 5,Room D130, Doha, Qatar. RP Ward, AB (reprint author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.; McLellan, JS (reprint author), Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH 03755 USA. EM Jason.S.McLellan@Dartmouth.edu; ABWard@Scripps.edu RI Ward, Andrew/F-9203-2014 OI Ward, Andrew/0000-0001-7153-3769 FU Scripps Research Institute; Geisel School of Medicine at Dartmouth; intramural NIAID; NIH [R56 AI118016] FX We thank colleagues and members of our laboratories for critical reading of the manuscript. This work was supported by start-up funds to A.B.W. from the Scripps Research Institute and to J.S.M from the Geisel School of Medicine at Dartmouth, and funding from intramural NIAID to B.S.G. Partial salary support for R.N.K. was provided by NIH grant R56 AI118016. This is manuscript 29286 from TSRI. NR 57 TC 20 Z9 21 U1 7 U2 30 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 MAR 3 PY 2016 VL 531 IS 7592 BP 118 EP + DI 10.1038/nature17200 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF2YW UT WOS:000371211900052 PM 26935699 ER PT J AU Pecoraro, A Pacciolla, A O'Cleirigh, C Mimiaga, M Kwiatek, P Blokhina, E Verbitskaya, E Krupitsky, E Woody, GE AF Pecoraro, Anna Pacciolla, Aureliano O'Cleirigh, Conall Mimiaga, Matthew Kwiatek, Piotr Blokhina, Elena Verbitskaya, Elena Krupitsky, Evgeny Woody, George E. TI Proactive coping and spirituality among patients who left or remained in antiretroviral treatment in St Petersburg, Russian Federation SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE AIDS; retention; Russian Federation; HIV; attrition; positive psychology; spirituality ID POSITIVE PSYCHOLOGY; HIV; MEDICATIONS; ADHERENCE; THERAPY AB Positive Psychology, the study of "positive" factors or strengths and evidence-based interventions to increase them, is a rapidly developing field that is beginning to be applied to HIV care. Proactive coping and spirituality are two positive characteristics that have been examined in multiple chronic serious health conditions. In the present study, lost-to-care (LTCs; did not attend treatment for >= 12 months; n = 120) and engaged-in-care HIV clinic patients (EICs; attended treatment for >= 12 months and adherent with antiretrovirals; n = 120) in Leningrad Oblast, Russian Federation were compared on the Proactive Coping Inventory and View of God Scale. EICs had higher scores in proactive coping [t(229) = 3.69; p = .001] and instrumental [t(232) = 2.17; p = .03] and emotional [t(233) = 2.33; p = .02] support, indicating that they engage in autonomous goal setting and self-regulate their thoughts and behaviors; obtain advice and support from their social network; and cope with emotional distress by turning to others. LTCs had higher scores in avoidance coping [t(236) = -2.31; p = .02]. More EICs were spiritual, religious, or both [ chi(2)(1, N = 239) = 7.49, p = .006]. EICs were more likely to believe in God/Higher Power [chi(2)(1, N = 239 = 8.89, p = .002] and an afterlife [ chi(2)(1, N = 236) = 5.11, p = .024]; have a relationship with God/Higher Power [ chi(2)(1, N = 237) = 12.76, p = .000]; and call on God/Higher Power for help, healing, or protection [ chi(2)(1, N = 239) = 9.61]. EICs had more positive [t(238) = 2.78; p = .006] and less negative [t(236) = -2.38; p = .002] views of God. Similar proportions, but slightly more EICs than LTCs were members of a faith community; members of a12-step group; or attended religious or spiritual services, meetings, or activities. More EICs than LTCs engaged in private spiritual or religious activities, such as prayer or meditation [ chi(2)(1, N = 239) = 9.226, p = .002]. C1 [Pecoraro, Anna; Woody, George E.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Pecoraro, Anna; Woody, George E.] NIDA Clin Trials Network, Delaware Valley Node, Philadelphia, PA USA. [Pacciolla, Aureliano] LUMSA, Dipartimento Sci Umane, Rome, Italy. [O'Cleirigh, Conall; Mimiaga, Matthew] Harvard Univ, Sch Med, Boston, MA USA. [O'Cleirigh, Conall] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mimiaga, Matthew] Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Kwiatek, Piotr] Pontifical Salesian Univ, Univ Pontificia Salesiana, Dipartimento Psicol, Rome, Italy. [Blokhina, Elena; Verbitskaya, Elena; Krupitsky, Evgeny] First Pavlov State Med Sch, Valdman Inst Pharmacol, St Petersburg, Russia. [Krupitsky, Evgeny] Bekhterev Res Psychoneurol Inst, St Petersburg, Russia. RP Pecoraro, A (reprint author), Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA.; Pecoraro, A (reprint author), NIDA Clin Trials Network, Delaware Valley Node, Philadelphia, PA USA. EM annp@mail.med.upenn.edu OI Verbitskaya, Elena/0000-0003-3770-993X FU Office of the US Global AIDS Coordinator through the PEPFAR program [PEPFAR] [R01-DA026336] FX This study was supported by funding from the Office of the US Global AIDS Coordinator through the PEPFAR program [PEPFAR Supplement to R01-DA026336]. NR 22 TC 0 Z9 0 U1 1 U2 6 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD MAR 3 PY 2016 VL 28 IS 3 BP 334 EP 338 DI 10.1080/09540121.2015.1096895 PG 5 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 DE5PD UT WOS:000370682600010 PM 26461806 ER PT J AU Lee, J Romero, R Kim, SM Chaemsaithong, P Park, CW Park, JS Jun, JK Yoon, BH AF Lee, JoonHo Romero, Roberto Kim, Sun Min Chaemsaithong, Piya Park, Chan-Wook Park, Joong Shin Jun, Jong Kwan Yoon, Bo Hyun TI A new anti-microbial combination prolongs the latency period, reduces acute histologic chorioamnionitis as well as funisitis, and improves neonatal outcomes in preterm PROM SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Ceftriaxone; cerebral palsy; clarithromycin; intra-amniotic infection; intra-amniotic inflammation; intra-ventricular hemorrhage; metronidazole; preterm birth ID FLUID MATRIX METALLOPROTEINASE-8; URINARY-TRACT-INFECTIONS; PLACEBO-CONTROLLED TRIAL; BLOOD-CELL COUNT; INTRAPARTUM ANTIBIOTIC-PROPHYLAXIS; RESISTANT PSEUDOMONAS-AERUGINOSA; ADVERSE PREGNANCY OUTCOMES; RANDOMIZED CLINICAL-TRIAL; POLYMERASE-CHAIN-REACTION; C-REACTIVE PROTEIN AB Objective: Antibiotic administration is a standard practice in preterm premature rupture of membranes (PROM). Specific anti-microbial agents often include ampicillin and/or erythromycin. Anaerobes and genital mycoplasmas are frequently involved in preterm PROM, but are not adequately covered by antibiotics routinely used in clinical practice. Our objective was to compare outcomes of PROM treated with standard antibiotic administration versus a new combination more effective against these bacteria.Study design: A retrospective study compared perinatal outcomes in 314 patients with PROM <34 weeks receiving anti-microbial regimen 1 (ampicillin and/or cephalosporins; n=195, 1993-2003) versus regimen 2 (ceftriaxone, clarithromycin and metronidazole; n=119, 2003-2012). Intra-amniotic infection/inflammation was assessed by positive amniotic fluid culture and/or an elevated amniotic fluid MMP-8 concentration (>23ng/mL).Results: (1) Patients treated with regimen 2 had a longer median antibiotic-to-delivery interval than those with regimen 1 [median (interquartile range) 23d (10-51d) versus 12d (5-52d), p<0.01]; (2) patients who received regimen 2 had lower rates of acute histologic chorioamnionitis (50.5% versus 66.7%, p<0.05) and funisitis (13.9% versus 42.9%, p<0.001) than those who had received regimen 1; (3) the rates of intra-ventricular hemorrhage (IVH) and cerebral palsy (CP) were significantly lower in patients allocated to regimen 2 than regimen 1 (IVH: 2.1% versus 19.0%, p<0.001 and CP: 0% versus 5.7%, p<0.05); and (4) subgroup analysis showed that regimen 2 improved perinatal outcomes in pregnancies with intra-amniotic infection/inflammation, but not in those without intra-amniotic infection/inflammation (after adjusting for gestational age and antenatal corticosteroid administration).Conclusion: A new antibiotic combination consisting of ceftriaxone, clarithromycin, and metronidazole prolonged the latency period, reduced acute histologic chorioamnionitis/funisitis, and improved neonatal outcomes in patients with preterm PROM. These findings suggest that the combination of anti-microbial agents (ceftriaxone, clarithromycin, and metronidazole) may improve perinatal outcome in preterm PROM. C1 [Lee, JoonHo; Kim, Sun Min; Park, Chan-Wook; Park, Joong Shin; Jun, Jong Kwan; Yoon, Bo Hyun] Seoul Natl Univ, Dept Obstet & Gynecol, Coll Med, Seoul 110744, South Korea. [Romero, Roberto; Chaemsaithong, Piya] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Romero, Roberto; Chaemsaithong, Piya] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, 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. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Chaemsaithong, Piya] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Yoon, BH (reprint author), Seoul Natl Univ, Dept Obstet & Gynecol, Coll Med, Seoul 110744, South Korea. EM romeror@mail.nih.gov; yoonbh@snu.ac.kr FU Korean Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI12C0768]; Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH/DHHS), U.S.A. FX The authors report no conflicts of interest. This research was supported by a grant of the Korean Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI12C0768). This research was also supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH/DHHS), U.S.A. NR 242 TC 2 Z9 2 U1 2 U2 17 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD MAR 3 PY 2016 VL 29 IS 5 BP 707 EP 720 DI 10.3109/14767058.2015.1020293 PG 14 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CY3PX UT WOS:000366323100005 PM 26373262 ER PT J AU Mueller, E AF Mueller, Elisabetta TI Browning and Graying: Novel Transcriptional Regulators of Brown and Beige Fat Tissues and Aging SO FRONTIERS IN ENDOCRINOLOGY LA English DT Review DE age-associated metabolic dysfunction; brown fat thermogenesis; transcription factors; HSF1; FoxA3 ID ADIPOSE-TISSUE; ADAPTIVE THERMOGENESIS; ADIPOCYTE DIFFERENTIATION; METABOLIC DYSFUNCTION; INSULIN-RESISTANCE; ADULT HUMANS; PGC-1-ALPHA; PRDM16; COACTIVATOR; OBESITY AB Obesity represents a major risk factor for the development of a number of metabolic disorders, including cardiovascular disease and type 2 diabetes. Since the discovery that brown and beige fat cells exist in adult humans and contribute to energy expenditure, increasing interest has been devoted to the understanding of the molecular switches turning on calorie utilization. It has been reported that the ability of thermogenic tissues to burn energy declines during aging, possibly contributing to the development of metabolic dysfunction late in life. This review will focus on the recently identified transcriptional modulators of brown and beige cells and will discuss the potential impact of some of these thermogenic factors on age-associated metabolic disorders. C1 [Mueller, Elisabetta] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Mueller, E (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. EM elisabettam@niddk.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases FX I am thankful to Pasha Sarraf, Xinran Ma, and Lingyan Xu for helpful discussions and to Camilla Sarraf-Mueller for support during the preparation of this manuscript. The work performed in my laboratory cited in this review was funded by the Intramural Research Program of the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases. NR 48 TC 2 Z9 2 U1 4 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PD MAR 2 PY 2016 VL 7 AR 19 DI 10.3389/fendo.2016.00019 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP4ZW UT WOS:000378506800001 PM 26973598 ER PT J AU Vargish, GA McBain, CJ AF Vargish, Geoffrey A. McBain, Chris J. TI The Hyperpolarization-Activated Cation Current I-h: The Missing Link Connecting Cannabinoids to Cognition SO NEURON LA English DT Editorial Material ID RECEPTORS; CELLS AB In this issue of Neuron, Maroso et al. (2016) describe a novel link between cannabinoids and cognition. They show that CB1Rs bidirectionally modulate HCN-mediated Ih in a subset of CA1 pyramidal neurons to influence both short- and long-term circuit dynamics and alter spatial working memory in behaving mice. C1 [Vargish, Geoffrey A.; McBain, Chris 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 NR 13 TC 0 Z9 0 U1 8 U2 8 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 MAR 2 PY 2016 VL 89 IS 5 BP 889 EP 891 DI 10.1016/j.neuron.2016.02.027 PG 3 WC Neurosciences SC Neurosciences & Neurology GA DI5UG UT WOS:000373565400004 PM 26938438 ER PT J AU Kilicoglu, H Demner-Fushman, D AF Kilicoglu, Halil Demner-Fushman, Dina TI Bio-SCoRes: A Smorgasbord Architecture for Coreference Resolution in Biomedical Text SO PLOS ONE LA English DT Article ID DISCOURSE; FRAMEWORK; RECORDS; DOMAIN AB Coreference resolution is one of the fundamental and challenging tasks in natural language processing. Resolving coreference successfully can have a significant positive effect on downstream natural language processing tasks, such as information extraction and question answering. The importance of coreference resolution for biomedical text analysis applications has increasingly been acknowledged. One of the difficulties in coreference resolution stems from the fact that distinct types of coreference (e.g., anaphora, appositive) are expressed with a variety of lexical and syntactic means (e.g., personal pronouns, definite noun phrases), and that resolution of each combination often requires a different approach. In the biomedical domain, it is common for coreference annotation and resolution efforts to focus on specific subcategories of coreference deemed important for the downstream task. In the current work, we aim to address some of these concerns regarding coreference resolution in biomedical text. We propose a general, modular framework underpinned by a smorgasbord architecture (Bio-SCoRes), which incorporates a variety of coreference types, their mentions and allows fine-grained specification of resolution strategies to resolve coreference of distinct coreference type-mention pairs. For development and evaluation, we used a corpus of structured drug labels annotated with fine-grained coreference information. In addition, we evaluated our approach on two other corpora (i2b2/VA discharge summaries and protein coreference dataset) to investigate its generality and ease of adaptation to other biomedical text types. Our results demonstrate the usefulness of our novel smorgasbord architecture. The specific pipelines based on the architecture perform successfully in linking coreferential mention pairs, while we find that recognition of full mention clusters is more challenging. The corpus of structured drug labels (SPL) as well as the components of Bio-SCoRes and some of the pipelines based on it are publicly available at https://github.com/kilicogluh/Bio-SCoRes. We believe that Bio-SCoRes can serve as a strong and extensible baseline system for coreference resolution of biomedical text. C1 [Kilicoglu, Halil; Demner-Fushman, Dina] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RP Kilicoglu, H (reprint author), NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM kilicogluh@mail.nih.gov FU intramural research program at the U.S. National Library of Medicine, National Institutes of Health FX This work was supported by the intramural research program at the U.S. National Library of Medicine, National Institutes of Health.; We thank Sonya Shooshan and Laritza Rodriguez for their contributions to the annotation study. This work was supported by the intramural research program at the U.S. National Library of Medicine, National Institutes of Health. NR 64 TC 0 Z9 0 U1 4 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 MAR 2 PY 2016 VL 11 IS 3 AR e0148538 DI 10.1371/journal.pone.0148538 PG 38 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG0AN UT WOS:000371724200010 PM 26934708 ER PT J AU Zhang, CL Bao, W Tobias, DK Chavarro, JE Hu, FB AF Zhang, Cuilin Bao, Wei Tobias, Deirdre K. Chavarro, Jorge E. Hu, Frank B. TI Authors' reply to Gachi, Mullie and colleagues, and Weatherburn SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Letter ID GESTATIONAL DIABETES-MELLITUS; DIETARY FIBER INTAKE; GLYCEMIC INDEX; QUESTIONNAIRE; FOODS; RISK; LOAD C1 [Zhang, Cuilin; Bao, Wei] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Tobias, Deirdre K.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Tobias, Deirdre K.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Tobias, Deirdre K.; Chavarro, Jorge E.; Hu, Frank B.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chavarro, Jorge E.; Hu, Frank B.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chavarro, Jorge E.; Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Chavarro, Jorge E.; Hu, Frank B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. EM zhangcu@mail.nih.gov OI Bao, Wei/0000-0002-7301-5786 NR 15 TC 0 Z9 0 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD MAR 2 PY 2016 VL 352 AR i1191 DI 10.1136/bmj.i1191 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DG0LN UT WOS:000371756500016 PM 26936855 ER PT J AU Berman, JW Carvallo, L Buckner, CM Luers, A Prevedel, L Bennett, MV Eugenin, EA AF Berman, Joan W. Carvallo, Loreto Buckner, Clarisa M. Luers, Aimee Prevedel, Lisa Bennett, Michael V. Eugenin, Eliseo A. TI HIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Gap junctions; AIDS; Dementia; Glia; Connexin ID IMMUNODEFICIENCY-VIRUS TYPE-1; CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; DEPENDENT MECHANISM; GENE-EXPRESSION; GAP-JUNCTIONS; NEUROCOGNITIVE DISORDERS; PROTEIN; APOPTOSIS; TRANSCRIPTION AB Background: HIV-associated neurocognitive disorders (HAND) are a major complication in at least half of the infected population despite effective antiretroviral treatment and immune reconstitution. HIV-associated CNS damage is not correlated with active viral replication but instead is associated with mechanisms that regulate inflammation and neuronal compromise. Our data indicate that one of these mechanisms is mediated by gap junction channels and/or hemichannels. Normally, gap junction channels shutdown under inflammatory conditions, including viral diseases. However, HIV infection upregulates Connexin43 (Cx43) expression and maintains gap junctional communication by unknown mechanism(s). Methods: Human primary astrocytes were exposed to several HIV proteins as well as to HIV, and expression and function of Connexin43- and Connexin30-containing channels were determined by western blot, immunofluorescence, microinjection of a fluorescent tracer and chromatin immunoprecipitation (ChIP). Results: Here, we demonstrate that HIV infection increases Cx43 expression in vivo. HIV-tat, the transactivator of the virus, and no other HIV proteins tested, increases Cx43 expression and maintains functional gap junctional communication in human astrocytes. Cx43 upregulation is mediated by binding of the HIV-tat protein to the Cx43 promoter, but not to the Cx30 promoter, resulting in increased Cx43 messenger RNA (mRNA) and protein as well as gap junctional communication. Conclusions: We propose that HIV-tat contributes to the spread of intracellular toxic signals generated in a few HIV-infected cells into surrounding uninfected cells by upregulating gap junctional communication. In the current antiretroviral era, where HIV replication is often completely suppressed, viral factors such as HIV-tat are still produced and released from infected cells. Thus, blocking the effects of HIV-tat could result in new strategies to reduce the damaging consequences of HIV infection of the CNS. C1 [Berman, Joan W.; Carvallo, Loreto; Buckner, Clarisa M.; Luers, Aimee] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10467 USA. [Berman, Joan W.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Bennett, Michael V.] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10467 USA. [Prevedel, Lisa; Eugenin, Eliseo A.] PHRI, 225 Warren St, Newark, NJ 07103 USA. [Prevedel, Lisa; Eugenin, Eliseo A.] Rutgers State Univ, Dept Microbiol & Mol Genet, 225 Warren St, Newark, NJ 07103 USA. [Buckner, Clarisa M.] NIAID, Immunoregulat Lab, Bldg 10, Bethesda, MD 20892 USA. RP Eugenin, EA (reprint author), PHRI, 225 Warren St, Newark, NJ 07103 USA.; Eugenin, EA (reprint author), Rutgers State Univ, Dept Microbiol & Mol Genet, 225 Warren St, Newark, NJ 07103 USA. EM eliseo.eugenin@rutgers.edu FU National Institutes of Health [MH075679, MH102113, MH090958, MH096625] FX We thank the Fetal Tissue Repository at the Albert Einstein College of Medicine and the National NeuroAIDS Tissue Consortium (NNTC). This work was supported by the National Institutes of Health grants MH075679, MH102113, MH090958 (to J.W.B. and L.C.), and MH096625 (to E.A.E.). NR 51 TC 1 Z9 1 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAR 2 PY 2016 VL 13 AR 54 DI 10.1186/s12974-016-0510-1 PG 11 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DF2XV UT WOS:000371208700001 PM 26934876 ER PT J AU MacNevin, CJ Toutchkine, A Marston, DJ Hsu, CW Tsygankov, D Li, L Liu, B Qi, T Nguyen, DV Hahn, KM AF MacNevin, Christopher J. Toutchkine, Alexei Marston, Daniel J. Hsu, Chia-Wen Tsygankov, Denis Li, Li Liu, Bei Qi, Timothy Dan-Vinh Nguyen Hahn, Klaus M. TI Ratiometric Imaging Using a Single Dye Enables Simultaneous Visualization of Rac1 and Cdc42 Activation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ALDRICH-SYNDROME PROTEIN; MEROCYANINE DYES; LIVING CELLS; LIVE-CELL; DYNAMICS; SOLVATOCHROMISM; PROTRUSION; BIOSENSOR; CYANINE; BINDING AB Biosensors that report endogenous protein activity in vivo can be based on environment-sensing fluorescent dyes. The dyes can be attached to reagents that bind selectively to a specific conformation of the targeted protein, such that binding leads to a fluorescence change. Dyes that are sufficiently bright for use at low, nonperturbing intracellular concentrations typically undergo changes in intensity rather than the shifts in excitation or emission maxima that would enable precise quantitation through ratiometric imaging. We report here mero199, an environment-sensing dye that undergoes a 33 nm solvent-dependent shift in excitation. The dye was used to generate a ratiometric biosensor of Cdc42 (CRIB199) without the need for additional fluorophores. CRIB199 was used in the same cell with a FRET sensor of Rac1 activation to simultaneously observe Cdc42 and Rac1 activity in cellular protrusions, indicating that Rac1 but not Cdc42 activity was reduced during tail retraction, and specific protrusions had reduced Cdc42 activity. A novel program (EdgeProps) used to correlate localized activation with cell edge dynamics indicated that Rac1 was specifically reduced during retraction. C1 [MacNevin, Christopher J.; Toutchkine, Alexei; Marston, Daniel J.; Hsu, Chia-Wen; Tsygankov, Denis; Li, Li; Liu, Bei; Qi, Timothy; Dan-Vinh Nguyen; Hahn, Klaus M.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Toutchkine, Alexei] Sigma Aldrich Co, Natick, MA 01760 USA. [Hsu, Chia-Wen] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Tsygankov, Denis] Georgia Inst Technol, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. [Tsygankov, Denis] Emory Univ, Bethesda, MD 20892 USA. [Li, Li] Med Univ S Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA. [Li, Li] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Li, Li] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. RP Hahn, KM (reprint author), Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. EM khahn@med.unc.edu OI Tsygankov, Denis/0000-0002-1180-3584 FU American Cancer Society [119169-PF-10-183-01-TBE]; National Institutes of Health [P01-GM103723, P41-EB002025] FX This work was supported by funding from the American Cancer Society (CJM 119169-PF-10-183-01-TBE) and the National Institutes of Health (P01-GM103723 and P41-EB002025). NR 36 TC 2 Z9 2 U1 10 U2 43 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAR 2 PY 2016 VL 138 IS 8 BP 2571 EP 2575 DI 10.1021/jacs.5b09764 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA DF6GK UT WOS:000371453700027 PM 26863024 ER PT J AU Li, YJ Chow, CC Courville, AB Sumner, AE Periwal, V AF Li, Yanjun Chow, Carson C. Courville, Amber B. Sumner, Anne E. Periwal, Vipul TI Modeling glucose and free fatty acid kinetics in glucose and meal tolerance test SO THEORETICAL BIOLOGY AND MEDICAL MODELLING LA English DT Article DE Glucose tolerance test; Lipolysis; Appearance rate ID VISCERAL ADIPOSE-TISSUE; AFRICAN-AMERICAN WOMEN; MINIMAL-MODEL; INSULIN SENSITIVITY; METABOLISM; OBESITY; RESISTANCE; TRANSPORT; TRIGLYCERIDE; ABSORPTION AB Background: Quantitative evaluation of insulin regulation on plasma glucose and free fatty acid (FFA) in response to external glucose challenge is clinically important to assess the development of insulin resistance (World J Diabetes 1:36-47, 2010). Mathematical minimal models (MMs) based on insulin modified frequently-sampled intravenous glucose tolerance tests (IM-FSIGT) are widely applied to ascertain an insulin sensitivity index (IEEE Rev Biomed Eng 2:54-96, 2009). Furthermore, it is important to investigate insulin regulation on glucose and FFA in postprandial state as a normal physiological condition. A simple way to calculate the appearance rate (Ra) of glucose and FFA would be especially helpful to evaluate glucose and FFA kinetics for clinical applications. Methods: A new MM is developed to simulate the insulin modulation of plasma glucose and FFA, combining IM-FSIGT with a mixed meal tolerance test (MT). A novel simple functional form for the appearance rate (Ra) of glucose or FFA in the MT is developed. Model results are compared with two other models for data obtained from 28 non-diabetic women (13 African American, 15 white). Results: The new functional form for Ra of glucose is an acceptable empirical approximation to the experimental Ra for a subset of individuals. When both glucose and FFA are included in FSIGT and MT, the new model is preferred using the Bayes Information Criterion (BIC). Conclusions: Model simulations show that the new MM allows consistent application to both IM-FSIGT and MT data, balancing model complexity and data fitting. While the appearance of glucose in the circulation has an important effect on FFA kinetics in MT, the rate of appearance of FFA can be neglected for the time-period modeled. C1 [Li, Yanjun; Chow, Carson C.; Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, LBM, MSC 5621, Bethesda, MD 20892 USA. [Courville, Amber B.] NIDDK, Dept Nutr, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Sumner, Anne E.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Periwal, V (reprint author), NIDDK, Lab Biol Modeling, NIH, LBM, MSC 5621, Bethesda, MD 20892 USA. EM vipulp@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, NIDDK; Clinical Center of the NIH FX Li, Chow, Sumner and Periwal were supported by the Intramural Research Program of the National Institutes of Health, NIDDK and Courville was supported by the Clinical Center of the NIH. NR 43 TC 0 Z9 0 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4682 J9 THEOR BIOL MED MODEL JI Theor. Biol. Med. Model. PD MAR 2 PY 2016 VL 13 AR 8 DI 10.1186/s12976-016-0036-3 PG 20 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DF4FB UT WOS:000371302200001 PM 26934990 ER PT J AU Hyatt, JPK Nguyen, L Hall, AE Huber, AM Kocan, JC Mattison, JA de Cabo, R LaRocque, JR Talmadge, RJ AF Hyatt, Jon-Philippe K. Nguyen, Lisa Hall, Allison E. Huber, Ashley M. Kocan, Jessica C. Mattison, Julie A. de Cabo, Rafael LaRocque, Jeannine R. Talmadge, Robert J. TI Muscle-Specific Myosin Heavy Chain Shifts in Response to a Long-Term High Fat/High Sugar Diet and Resveratrol Treatment in Nonhuman Primates SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE skeletal muscle; MHC; rhesus macaque; PGC-1 alpha; GLUT4 ID HUMAN SKELETAL-MUSCLE; INTERNAL REFERENCE GENES; LIFE-SPAN; ELECTRICAL-STIMULATION; INFLAMMATORY RESPONSE; FIBER CHARACTERISTICS; PROTEIN EXPRESSION; ADIPOSE-TISSUE; RHESUS-MONKEYS; HIGH-FAT AB Shifts in myosin heavy chain (MHC) expression within skeletal muscle can be induced by a host of stimuli including, but not limited to, physical activity, alterations in neural activity, aging, and diet or obesity. Here, we hypothesized that both age and a long-term (2 year) high fat/high sugar diet (HFS) would induce a slow to fast MHC shift within the plantaris, soleus, and extensor digitorum longus (EDL) muscles from rhesus monkeys. Furthermore, we tested whether supplementation with resveratrol, a naturally occurring compound that has been attributed with augmenting aerobic potential through mitochondria' proliferation, would counteract any diet-induced MHC changes by promoting a fast to slow isoform switch. In general, we found that MHC isoforms were not altered by aging during mid-life. The HFS diet had the largest impact within the soleus muscle where the greatest slow to fast isoform shifts were observed in both mRNA and protein indicators. As expected, long-term resveratrol treatment counteracted, or blunted, these diet-induced shifts within the soleus muscle. The plantaris muscle also demonstrated a fast-to-slow phenotypic response to resveratrol treatment. In conclusion, diet or resveratrol treatment impacts skeletal muscle phenotype in a muscle-specific manner and resveratrol supplementation may be one approach for promoting the fatigue-resistant MHC (type I) isoform especially if its expression is blunted as a result of a long-term high fat/sugar diet. C1 [Hyatt, Jon-Philippe K.; Hall, Allison E.; Huber, Ashley M.; Kocan, Jessica C.; LaRocque, Jeannine R.] Georgetown Univ, Dept Human Sci, Washington, DC USA. [Nguyen, Lisa; Talmadge, Robert J.] Calif State Polytech Univ Pomona, Dept Biol Sci, Pomona, CA 91768 USA. [Mattison, Julie A.; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Hyatt, JPK (reprint author), Georgetown Univ, Dept Human Sci, Washington, DC USA. EM jkh22@ceorgetown.edu RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU National Institute on Aging Intramural Research Program, NIH; Sigma Xi Society FX The authors would like to thank Fadia Haddad for helpful insight on myosin heavy chain primers construction and Elisa Jayne Bienenstock for statistical work and consultation. Myosin heavy chain antibodies were generously supplied by S. Schiaflino (University of Padova, Padova, Italy). This study was supported in part by the National Institute on Aging Intramural Research Program, NIH, and the Sigma Xi Society Grants-in-Aid Research Program for undergraduate student researchers. NR 62 TC 0 Z9 0 U1 3 U2 9 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD MAR 2 PY 2016 VL 7 AR 77 DI 10.3389/fphys.2016.00077 PG 11 WC Physiology SC Physiology GA DF1SX UT WOS:000371120600001 PM 26973542 ER PT J AU Wester, JC McBain, CJ AF Wester, Jason C. McBain, Chris J. TI Interneurons Differentially Contribute to Spontaneous Network Activity in the Developing Hippocampus Dependent on Their Embryonic Lineage SO JOURNAL OF NEUROSCIENCE LA English DT Article DE giant depolarizing potential; hippocampus; interneurons ID GIANT DEPOLARIZING POTENTIALS; DUAL INTRACELLULAR-RECORDINGS; RAT HIPPOCAMPUS; PYRAMIDAL NEURONS; GLUTAMATERGIC SYNAPSES; CORTICAL INTERNEURONS; POSTNATAL-DEVELOPMENT; NEONATAL HIPPOCAMPUS; SYNAPTIC POTENTIALS; TRANSMITTER RELEASE AB Spontaneously generated network activity is a hallmark of developing neural circuits, and plays an important role in the formation of synaptic connections. In the rodent hippocampus, this activity is observed in vitro as giant depolarizing potentials (GDPs) during the first postnatal week. Interneurons importantly contribute to GDPs, due to the depolarizing actions of GABA early in development. While they are highly diverse, cortical interneurons can be segregated into two distinct groups based on their embryonic lineage from either the medial or caudal ganglionic eminences (MGE and CGE). There is evidence suggesting CGE-derived interneurons are important for GDP generation; however, their contribution relative to those from the MGE has never been directly tested. Here, we optogenetically inhibited either MGE-or CGE-derived interneurons in a region-specific manner in mouse neonatal hippocampus in vitro. In CA1, where interneurons are the primary source of recurrent excitation, we found that those from the MGE strongly and preferentially contributed to GDP generation. Furthermore, in dual whole-cell patch recordings in neonatal CA1, MGE interneurons formed synaptic connections to and from neighboring pyramidal cells at a much higher rate than those from the CGE. These MGE interneurons were commonly perisomatic targeting, in contrast to those from the CGE, which were dendrite targeting. Finally, inhibiting MGE interneurons in CA1 suppressed GDPs in CA3 and vice versa; conversely, they could also trigger GDPs in CA1 that propagated to CA3 and vice versa. Our data demonstrate a key role for MGE-derived interneurons in both generating and coordinating GDPs across the hippocampus. C1 [Wester, Jason C.; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD 20892 USA. RP McBain, CJ (reprint author), NICHD, Program Dev Neurobiol, NIH, Bethesda, MD 20892 USA. EM mcbainc@mail.nih.gov FU NICHD Intramural Award; National Institute of Neurological Disorders and Stroke Competitive Fellowship Award FX This work was supported by a NICHD Intramural Award to C.J.M. and a National Institute of Neurological Disorders and Stroke Competitive Fellowship Award to J.C.W. NR 62 TC 1 Z9 1 U1 2 U2 7 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 MAR 2 PY 2016 VL 36 IS 9 BP 2646 EP 2662 DI 10.1523/JNEUROSCI.4000-15.2016 PG 17 WC Neurosciences SC Neurosciences & Neurology GA DF2BV UT WOS:000371145400011 PM 26937006 ER PT J AU Wang, X Zhao, L Zhang, J Fariss, RN Ma, WX Kretschmer, F Wang, MH Qian, HH Badea, TC Diamond, JS Gan, WB Roger, JE Wong, WT AF Wang, Xu Zhao, Lian Zhang, Jun Fariss, Robert N. Ma, Wenxin Kretschmer, Friedrich Wang, Minhua Qian, Hao Hua Badea, Tudor C. Diamond, Jeffrey S. Gan, Wen-Biao Roger, Jerome E. Wong, Wai T. TI Requirement for Microglia for the Maintenance of Synaptic Function and Integrity in the Mature Retina SO JOURNAL OF NEUROSCIENCE LA English DT Article DE degeneration; electroretinogram; glia; microglia; retina; synapse ID IN-VIVO; RNA-SEQ; NEURAL CIRCUITS; MYELOID CELLS; MOUSE RETINA; ADULT BRAIN; MICE; ACTIVATION; EXPRESSION; ABLATION AB Microglia, the principal resident immune cell of the CNS, exert significant influence on neurons during development and in pathological situations. However, if and how microglia contribute to normal neuronal function in the mature uninjured CNS is not well understood. We used the model of the adult mouse retina, a part of the CNS amenable to structural and functional analysis, to investigate the constitutive role of microglia by depleting microglia from the retina in a sustained manner using genetic methods. We discovered that microglia are not acutely required for the maintenance of adult retinal architecture, the survival of retinal neurons, or the laminar organization of their dendritic and axonal compartments. However, sustained microglial depletion results in the degeneration of photoreceptor synapses in the outer plexiform layer, leading to a progressive functional deterioration in retinal light responses. Our results demonstrate that microglia are constitutively required for the maintenance of synaptic structure in the adult retina and for synaptic transmission underlying normal visual function. Our findings on constitutive microglial function are relevant in understanding microglial contributions to pathology and in the consideration of therapeutic interventions that reduce or perturb constitutive microglial function. C1 [Wang, Xu; Zhao, Lian; Ma, Wenxin; Wang, Minhua; Wong, Wai T.] NINDS, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. [Fariss, Robert N.] NINDS, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. [Kretschmer, Friedrich; Badea, Tudor C.] NINDS, Retinal Circuit Dev & Genet Unit, NIH, Bethesda, MD 20892 USA. [Qian, Hao Hua] NINDS, Visual Funct Core, NEI, NIH, Bethesda, MD 20892 USA. [Zhang, Jun; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, NIH, Bethesda, MD 20892 USA. [Gan, Wen-Biao] NYU, Sch Med, Dept Neurosci & Physiol, Skirball Inst, New York, NY 10016 USA. [Roger, Jerome E.] Ctr Etud & Rech Therapeut Ophtalmol Retina France, Orsay, France. [Roger, Jerome E.] Univ Paris Saclay, Univ Paris 11, Paris Saclay Inst Neurosci, CNRS, F-91405 Orsay, France. RP Wong, WT (reprint author), 6 Ctr Dr 6-217, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Diamond, Jeffrey/C-1835-2015; Wong, Wai/B-6118-2017; OI Diamond, Jeffrey/0000-0002-1770-2629; Wong, Wai/0000-0003-0681-4016; Roger, Jerome/0000-0002-5061-230X FU National Eye Institute Intramural Research Program; National Institute of Neurological Disorders and Stroke; US National Institutes of Health [1R01NS087198] FX This work was supported by funds from the National Eye Institute Intramural Research Program (W.T.W., R.N.F., H.h.Q., T.C.B.), the National Institute of Neurological Disorders and Stroke (J.S.D.) and by the US National Institutes of Health Grants 1R01NS087198 (W.-B.G.). We thank Jan Singaravelu for assistance in image analysis. NR 60 TC 5 Z9 5 U1 2 U2 14 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 MAR 2 PY 2016 VL 36 IS 9 BP 2827 EP 2842 DI 10.1523/JNEUROSCI.3575-15.2016 PG 16 WC Neurosciences SC Neurosciences & Neurology GA DF2BV UT WOS:000371145400024 PM 26937019 ER PT J AU Yeh, CH Bai, XT Moles, R Ratner, L Waldmann, TA Watanabe, T Nicot, C AF Yeh, Chien-Hung Bai, Xue Tao Moles, Ramona Ratner, Lee Waldmann, Thomas A. Watanabe, Toshiki Nicot, Christophe TI Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia (vol 15, 15, 2016) SO MOLECULAR CANCER LA English DT Correction C1 [Yeh, Chien-Hung; Bai, Xue Tao; Moles, Ramona; Nicot, Christophe] Univ Kansas, Med Ctr, Ctr Viral Oncol, Dept Pathol, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. [Ratner, Lee] Washington Univ, Sch Med, Dept Med, Div Mol Oncol, St Louis, MO 63110 USA. [Waldmann, Thomas A.] NIH, Lymphoid Malignancies Branch, Ctr Canc Res, Bldg 10,Room 4 N-115,10 Ctr Dr, Bethesda, MD 20892 USA. [Watanabe, Toshiki] Univ Tokyo, Dept Med Genome Sci, Tokyo, Japan. RP Nicot, C (reprint author), Univ Kansas, Med Ctr, Ctr Viral Oncol, Dept Pathol, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM cnicot@kumc.edu NR 1 TC 0 Z9 0 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD MAR 2 PY 2016 VL 15 AR 20 DI 10.1186/s12943-016-0504-8 PG 1 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA DF2BK UT WOS:000371144100001 PM 26936184 ER PT J AU Marchenko, V Koizumi, H Mosher, B Koshiya, N Tariq, MF Bezdudnaya, TG Zhang, RL Molkov, YI Rybak, IA Smith, JC AF Marchenko, Vitaliy Koizumi, Hidehiko Mosher, Bryan Koshiya, Naohiro Tariq, Mohammad F. Bezdudnaya, Tatiana G. Zhang, Ruli Molkov, Yaroslav I. Rybak, Ilya A. Smith, Jeffrey C. TI Perturbations of Respiratory Rhythm and Pattern by Disrupting Synaptic Inhibition within Pre-Botzinger and Botzinger Complexes SO ENEURO LA English DT Article DE Botzinger complex; brainstem; central pattern generation; pre-Botzinger complex; respiration; synaptic inhibition ID ROSTRAL VENTROLATERAL MEDULLA; MAMMALIAN BRAIN-STEM; EXPIRATORY NEURONS; PREBOTZINGER COMPLEX; FUNCTIONAL ARCHITECTURE; GLYCINERGIC INHIBITION; INSPIRATORY ACTIVITY; DECEREBRATE RAT; IN-VIVO; GENERATION AB The pre-Botzinger (pre-BotC) and Botzinger (BotC) complexes are the brainstem compartments containing interneurons considered to be critically involved in generating respiratory rhythm and motor pattern in mammals. Current models postulate that both generation of the rhythm and coordination of the inspiratory-expiratory pattern involve inhibitory synaptic interactions within and between these regions. Both regions contain glycinergic and GABAergic neurons, and rhythmically active neurons in these regions receive appropriately coordinated phasic inhibition necessary for generation of the normal three-phase respiratory pattern. However, recent experiments attempting to disrupt glycinergic and GABAergic postsynaptic inhibition in the pre-BotC and BotC in adult rats in vivo have questioned the critical role of synaptic inhibition in these regions, as well as the importance of the BotC, which contradicts previous physiological and pharmacological studies. To further evaluate the roles of synaptic inhibition and the BotC, we bilaterally microinjected the GABA(A) receptor antagonist gabazine and glycinergic receptor antagonist strychnine into the pre-BotC or BotC in anesthetized adult rats in vivo and in perfused in situ brainstem-spinal cord preparations from juvenile rats. Muscimol was microinjected to suppress neuronal activity in the pre-BotC or BotC. In both preparations, disrupting inhibition within pre-BotC or BotC caused major site-specific perturbations of the rhythm and disrupted the three-phase motor pattern, in some experiments terminating rhythmic motor output. Suppressing BotC activity also potently disturbed the rhythm and motor pattern. We conclude that inhibitory circuit interactions within and between the pre-BotC and BotC critically regulate rhythmogenesis and are required for normal respiratory motor pattern generation. C1 [Marchenko, Vitaliy; Bezdudnaya, Tatiana G.; Rybak, Ilya A.] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19129 USA. [Koizumi, Hidehiko; Mosher, Bryan; Koshiya, Naohiro; Tariq, Mohammad F.; Zhang, Ruli; Smith, Jeffrey C.] NINDS, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Molkov, Yaroslav I.] Georgia State Univ, Dept Math & Stat, Atlanta, GA 30302 USA. RP Smith, JC (reprint author), NINDS, NIH, 49 Convent Dr,Room 2A10, Bethesda, MD 20892 USA. EM smithj2@helix.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke; NIH [R01 NS069220, R01 AT008632] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke, and NIH Grants R01 NS069220 and R01 AT008632 NR 51 TC 2 Z9 2 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD MAR-APR PY 2016 VL 3 IS 2 AR UNSP e0011-16.2016 DI 10.1523/ENEURO.0011-16.2016 PG 23 WC Neurosciences SC Neurosciences & Neurology GA EH7AY UT WOS:000391926400006 ER PT J AU Martinez-Monedero, R Liu, C Weisz, C Vyas, P Fuchs, PA Glowatzki, E AF Martinez-Monedero, Rodrigo Liu, Chang Weisz, Catherine Vyas, Pankhuri Fuchs, Paul Albert Glowatzki, Elisabeth TI GluA2-Containing AMPA Receptors Distinguish Ribbon-Associated from Ribbonless Afferent Contacts on Rat Cochlear Hair Cells SO ENEURO LA English DT Article DE AMPA receptors; cochlear afferents; outer hair cells; postsynaptic densities ID GUINEA-PIG COCHLEA; SPIRAL GANGLION NEURONS; METABOTROPIC GLUTAMATE RECEPTORS; KAINATE RECEPTORS; SYNAPTIC RIBBONS; EXCITATORY SYNAPSES; RECIPROCAL SYNAPSES; AUDITORY NEURONS; SILENT SYNAPSES; ADULT CATS AB Mechanosensory hair cells release glutamate at ribbon synapses to excite postsynaptic afferent neurons, via AMPA-type ionotropic glutamate receptors (AMPARs). However, type II afferent neurons contacting outer hair cells in the mammalian cochlea were thought to differ in this respect, failing to show GluA immunolabeling and with many "ribbonless" afferent contacts. Here it is shown that antibodies to the AMPAR subunit GluA2 labeled afferent contacts below inner and outer hair cells in the rat cochlea, and that synaptic currents in type II afferents had AMPAR-specific pharmacology. Only half the postsynaptic densities of type II afferents that labeled for PSD-95, Shank, or Homer were associated with GluA2 immunopuncta or presynaptic ribbons, the "empty slots" corresponding to ribbonless contacts described previously. These results extend the universality of AMPAergic transmission by hair cells, and support the existence of silent afferent contacts. C1 [Martinez-Monedero, Rodrigo; Vyas, Pankhuri; Fuchs, Paul Albert; Glowatzki, Elisabeth] Johns Hopkins Univ, Sch Med, Ctr Hearing & Balance, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. [Liu, Chang; Weisz, Catherine] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Fuchs, Paul Albert; Glowatzki, Elisabeth] Johns Hopkins Univ, Sch Med, Ctr Sensory Biol, Inst Basic Biomed Sci, Baltimore, MD 21205 USA. [Martinez-Monedero, Rodrigo] Univ Southern Calif, USC Tina & Rick Caruso Dept Otolaryngol Head & Ne, Keck Sch Med USC, Los Angeles, CA 90033 USA. [Martinez-Monedero, Rodrigo] Univ Southern Calif, Dept Stem Cell Biol & Regenerat Med, Keck Sch Med USC, Los Angeles, CA 90033 USA. [Weisz, Catherine] Natl Inst Deafness & Other Commun Disorders, Sect Neuronal Circuitry, NIH, Bethesda, MD 20892 USA. RP Fuchs, PA; Glowatzki, E (reprint author), Johns Hopkins Univ, Sch Med, Ctr Hearing & Balance, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA.; Fuchs, PA; Glowatzki, E (reprint author), Johns Hopkins Univ, Sch Med, Ctr Sensory Biol, Inst Basic Biomed Sci, Baltimore, MD 21205 USA. EM pfuchs1@jhmi.edu; eglowat1@jhmi.edu FU National Institute on Deafness and Other Communication Disorders (NIDCD) [R01-DC-006476, R01-DC-011741, P30-DC-005211, T32-DC-000023, F31-DC-010948]; Multiphoton Imaging Core grant [NS050274]; John Mitchell, Jr. Trust; David M. Rubenstein Fund for Hearing Research; Intramural Research Program of the National Institutes of Health, NIDCD FX This research was supported by National Institute on Deafness and Other Communication Disorders (NIDCD) Grants R01-DC-006476 (to E.G.), R01-DC-011741 (to P.F.), P30-DC-005211 (to the Center for Hearing and Balance), T32-DC-000023 (to C.W.), and F31-DC-010948 (to C.W.); Grant NS050274, a Multiphoton Imaging Core grant (to Hopkins Neuroscience); the John Mitchell, Jr. Trust; and the David M. Rubenstein Fund for Hearing Research (to Department of Otolaryngology-Head and Neck Surgery). This research also was supported in part by the Intramural Research Program of the National Institutes of Health, NIDCD (to C.W.). NR 107 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 2373-2822 J9 ENEURO JI eNeuro PD MAR-APR PY 2016 VL 3 IS 2 AR UNSP e0078-16.2016 DI 10.1523/ENEURO.0078-16.2016 PG 17 WC Neurosciences SC Neurosciences & Neurology GA EH7AY UT WOS:000391926400023 ER PT J AU Sare, RM Levine, M Smith, CB AF Sare, R. Michelle Levine, Merlin Smith, Carolyn Beebe TI Behavioral Phenotype of Fmr1 Knock-Out Mice during Active Phase in an Altered Light/Dark Cycle SO ENEURO LA English DT Article DE activity; anxiety; circadian phase; fragile X; learning and memory; social behavior ID FRAGILE-X-SYNDROME; ELEVATED PLUS-MAZE; MOUSE MODEL; MENTAL-RETARDATION; CIRCADIAN PHASE; AUTISM; RATS; DISCRIMINATION; ILLUMINATION; METABOLISM AB Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability and is a disorder that is also highly associated with autism. FXS occurs as a result of an expanded CGG repeat sequence leading to transcriptional silencing. In an animal model of FXS in which Fmr1 is knocked out (Fmr1 KO), many physical, physiological, and behavioral characteristics of the human disease are recapitulated. Prior characterization of the mouse model was conducted during the day, the inactive phase of the circadian cycle. Circadian rhythms are an important contributor to behavior and may play a role in the study of disease phenotype. Moreover, changes in the parameters of circadian rhythm are known to occur in FXS animal models. We conducted an investigation of key behavioral phenotypes in Fmr1 KO mice during their active phase. We report that phase did not alter the Fmr1 KO phenotype in open field activity, anxiety, and learning and memory. There was a slight effect of phase on social behavior as measured by time in chamber, but not by time spent sniffing. Our data strengthen the existing data characterizing the phenotype of Fmr1 KO mice, indicating that it is independent of circadian phase. C1 [Sare, R. Michelle; Levine, Merlin; Smith, Carolyn Beebe] NIMH, Sect Neuroadaptat & Prot Metab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Smith, CB (reprint author), 10 Ctr Dr,Room 2D56, Bethesda, MD 20892 USA. EM beebe@mail.nih.gov FU Intramural Research Program of the National Institutes of Mental Health; Autism Speaks awarded [8679] FX This work was funded by the Intramural Research Program of the National Institutes of Mental Health, and by a postdoctoral fellowship (#8679) from Autism Speaks awarded to R.M.S. NR 31 TC 0 Z9 0 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD MAR-APR PY 2016 VL 3 IS 2 AR UNSP e0035-16.2016 DI 10.1523/ENEURO.0035-16.2016 PG 8 WC Neurosciences SC Neurosciences & Neurology GA EH7AY UT WOS:000391926400013 ER PT J AU Soumier, A Carter, RM Schoenfeld, TJ Cameron, HA AF Soumier, Amelie Carter, Rayna M. Schoenfeld, Timothy J. Cameron, Heather A. TI New Hippocampal Neurons Mature Rapidly in Response to Ketamine But Are Not Required for Its Acute Antidepressant Effects on Neophagia in Rats SO ENEURO LA English DT Article DE antidepressive agents; cell proliferation; dentate gyrus; mood disorders; neurogenesis; neuronal maturation ID GENERATED GRANULE CELLS; NMDA RECEPTOR BLOCKADE; FORCED SWIMMING TEST; DENTATE GYRUS; ANIMAL-MODELS; SYNAPTIC PLASTICITY; ADULT NEUROGENESIS; NEUROPSYCHIATRIC DISORDERS; ACTING ANTIDEPRESSANTS; DEPRESSION AB Virtually all antidepressant agents increase the birth of granule neurons in the adult dentate gyrus in rodents, providing a key basis for the neurogenesis hypothesis of antidepressant action. The novel antidepressant ketamine, however, shows antidepressant activity in humans within hours, far too rapid for a mechanism involving neuronal birth. Ketamine could potentially act more rapidly by enhancing maturation of new neurons born weeks earlier. To test this possibility, we assessed the effects of S-ketamine (S-(+)-ketamine hydrochloride) injection on maturation, as well as birth and survival, of new dentate gyrus granule neurons in rats, using the immediate-early gene zif268, proliferating cell nuclear antigen, and BrdU, respectively. We show that S-ketamine has rapid effects on new neurons, increasing the proportion of functionally mature young granule neurons within 2 h. A single injection of S-ketamine also increased cell proliferation and functional maturation, and decreased depressive-like behavior, for at least 4 weeks in rats treated with long-term corticosterone administration (a depression model) and controls. However, the behavioral effects of S-ketamine on neophagia were unaffected by elimination of adult neurogenesis. Together, these results indicate that ketamine has surprisingly rapid and long-lasting effects on the recruitment of young neurons into hippocampal networks, but that ketamine has antidepressant-like effects that are independent of adult neurogenesis. C1 [Soumier, Amelie; Carter, Rayna M.; Schoenfeld, Timothy J.; Cameron, Heather A.] NIMH, Sect Neuroplast, NIH, Bethesda, MD 20892 USA. RP Cameron, HA (reprint author), NIH, 35 Lincoln Dr,MSC 3718, Bethesda, MD 20892 USA. EM heathercameron@mail.nih.gov FU Intramural Program of the National Institutes of Health, National Institute of Mental Health [ZIAMH002784] FX This work was supported by the Intramural Program of the National Institutes of Health, National Institute of Mental Health (Grant ZIAMH002784 to H.A.C). NR 62 TC 1 Z9 1 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD MAR-APR PY 2016 VL 3 IS 2 AR UNSP e0116-15.2016 DI 10.1523/ENEURO.0116-15.2016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EH7AY UT WOS:000391926400028 ER PT J AU Galiatsatos, P Melia, MT Silhan, LL AF Galiatsatos, Panagis Melia, Michael T. Silhan, Leann L. TI Human Immunodeficiency Virus and Allergic Bronchopulmonary Aspergillosis: Case Report and Review of Literature SO OPEN FORUM INFECTIOUS DISEASES LA English DT Review DE allergic bronchopulmonary aspergillosis; bronchiectasis; HIV infection ID HIV-1 INFECTION; IMMUNITY AB Allergic bronchopulmonary aspergillosis (ABPA) results from a hypersensitivity response to airways colonization with Aspergillus fumigatus, and it occurs most often in individuals with asthma or cystic fibrosis. Allergic bronchopulmonary aspergillosis is an indolent, but potentially progressive, disease in patients. In patients infected with human immunodeficiency virus (HIV), ABPA is rare, and its description in the literature is limited to case reports. We describe the occurrence of ABPA in a 37-year-old woman with well controlled HIV infection. This represents the first documented case of ABPA in an HIV-infected patient whose only pulmonary comorbidity included the ramifications of prior acute respiratory distress syndrome due to Pneumocystis jirovecii pneumonia. We also review prior case reports of ABPA in HIV-infected patients and consider risk factors for its development. C1 [Galiatsatos, Panagis] NIH, Crit Care Med, Bldg 10, Bethesda, MD 20892 USA. [Melia, Michael T.] Johns Hopkins Med, Div Infect Dis, Baltimore, MD USA. [Silhan, Leann L.] Johns Hopkins Med, Div Pulm & Crit Care Med, Baltimore, MD USA. RP Galiatsatos, P (reprint author), NIH, Dept Crit Care Med, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM panagis.galiatsatos@nih.gov NR 15 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 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SPR PY 2016 VL 3 IS 2 DI 10.1093/ofid/ofw116 PG 3 WC Infectious Diseases SC Infectious Diseases GA EC3IR UT WOS:000388020200065 ER PT J AU Nason, MC Patel, EU Kirkpatrick, AR Prodger, JL Shahabi, K Tobian, AAR Gianella, S Kalibbala, S Ssebbowa, P Kaul, R Gray, RH Quinn, TC Serwadda, D Reynolds, SJ Redd, AD AF Nason, Martha C. Patel, Eshan U. Kirkpatrick, Allison R. Prodger, Jessica L. Shahabi, Kamnoosh Tobian, Aaron A. R. Gianella, Sara Kalibbala, Sarah Ssebbowa, Paschal Kaul, Rupert Gray, Ronald H. Quinn, Thomas C. Serwadda, David Reynolds, Steven J. Redd, Andrew D. TI Immunological Signaling During Herpes Simplex Virus-2 and Cytomegalovirus Vaginal Shedding After Initiation of Antiretroviral Treatment SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE HIV; HSV-2; CMV; Cytokine; viral shedding ID RECONSTITUTION INFLAMMATORY SYNDROME; IMMUNE RESTORATION DISEASE; HIV-INFECTED PATIENTS; DAILY ACYCLOVIR; SYNDROME IRIS; THERAPY; TYPE-2; UGANDA; RAKAI AB Vaginal proinflammatory cytokine expression during herpes virus reactivation was examined in human immunodeficiency virus-infected women before and after initiation of antiretroviral therapy (ART). Vaginal swabs were screened for levels of cytokines interleukin (IL)-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor (TNF)-alpha, and interferon-gamma. The relative risk (RR) of herpes simplex virus-2 or cytomegalovirus (CMV) shedding being associated with cytokine levels above the median were estimated. Herpes simplex virus-2 shedding was significantly associated with higher levels of IL-6 (RR=1.4, P=.003) and TNF-alpha(RR=1.3, P=.010), whereas CMV shedding was associated with higher IL-6 (RR=1.3, P=.006) and IL-2 (RR=1.4, P=.01). The association of viral shedding with higher IL-6 levels suggests that herpes virus reactivation may be playing a role in immune activation after ART initiation. C1 [Nason, Martha C.] NIAID, Biostat Res Branch, NIH, Baltimore, MD USA. [Patel, Eshan U.; Kirkpatrick, Allison R.; Prodger, Jessica L.; Quinn, Thomas C.; Reynolds, Steven J.; Redd, Andrew D.] NIAID, Lab Immunoregulat, NIH, Baltimore, MD USA. [Shahabi, Kamnoosh; Kaul, Rupert] Univ Toronto, Dept Infect Dis, Toronto, ON M5S 1A1, Canada. [Tobian, Aaron A. R.] Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD USA. [Tobian, Aaron A. R.; Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Quinn, Thomas C.; Reynolds, Steven J.; Redd, Andrew D.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Gianella, Sara] Univ Calif San Diego, Dept Infect Dis, San Diego, CA 92103 USA. [Ssebbowa, Paschal; Gray, Ronald H.; Serwadda, David; Reynolds, Steven J.] Rakai Hlth Sci Program, Entebbe, Uganda. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. RP Redd, AD (reprint author), Rangos Bldg Room 527,851 N Wolfe St, Baltimore, MD 21205 USA. EM aredd2@jhmi.edu NR 18 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SPR PY 2016 VL 3 IS 2 DI 10.1093/ofid/ofw073 PG 5 WC Infectious Diseases SC Infectious Diseases GA EC3IR UT WOS:000388020200029 ER PT J AU Wright, PF Hoen, AG Ilyushina, NA Brown, EP Ackerman, ME Wieland-Alter, W Connor, RI Jegaskanda, S Rosenberg-Hasson, Y Haynes, BC Luke, CJ Subbarao, K Treanor, JJ AF Wright, Peter F. Hoen, Anne G. Ilyushina, Natalia A. Brown, Eric P. Ackerman, Margaret E. Wieland-Alter, Wendy Connor, Ruth I. Jegaskanda, Sinthujan Rosenberg-Hasson, Yael Haynes, Brenda C. Luke, Catherine J. Subbarao, Kanta Treanor, John J. TI Correlates of Immunity to Influenza as Determined by Challenge of Children with Live, Attenuated Influenza Vaccine SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE humoral immunity; influenza vaccine; mucosal immunity; vaccine ID WILD-TYPE VIRUS; YOUNG-CHILDREN; IMMUNIZATION PRACTICES; ADVISORY-COMMITTEE; UNITED-STATES; COLD; RESISTANCE; RECOMMENDATIONS; PREVENTION; ANTIBODIES AB Background. The efficacy of live, attenuated live attenuated influenza vaccine(LAIV) and inactivated influenza vaccine(IIV) is poorly explained by either single or composite immune responses to vaccination. Protective biomarkers were therefore studied in response to LAIV or IIV followed by LAIV challenge in children. Methods. Serum and mucosal responses to LAIV or IIV were analyzed using immunologic assays to assess both quantitative and functional responses. Cytokines and chemokines were measured in nasal washes collected before vaccination, on days 2, 4, and 7 after initial LAIV, and again after LAIV challenge using a 63-multiplex Luminex panel. Results. Patterns of immunity induced by LAIV and IIV were significantly different. Serum responses induced by IIV, including hemagglutination inhibition, did not correlate with detection or quantitation of LAIV on subsequent challenge. Modalities that induced sterilizing immunity seen after LAIV challenge could not be defined by any measurements of mucosal or serum antibodies induced by the initial LAIV immunization. No single cytokine or chemokine was predictive of protection. Conclusions. The mechanism of protective immunity observed after LAIV could not be defined, and traditional measurements of immunity to IIV did not correlate with protection against an LAIV challenge. C1 [Wright, Peter F.; Ilyushina, Natalia A.] Geisel Sch Med Dartmouth, Dept Pediat, Lebanon, NH USA. [Hoen, Anne G.] Geisel Sch Med Dartmouth, Dept Epidemiol, Lebanon, NH USA. [Wieland-Alter, Wendy; Haynes, Brenda C.] Geisel Sch Med Dartmouth, Dept Med, Lebanon, NH USA. [Connor, Ruth I.] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Lebanon, NH USA. [Brown, Eric P.; Ackerman, Margaret E.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Jegaskanda, Sinthujan; Luke, Catherine J.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Rosenberg-Hasson, Yael] Stanford Univ, Inst Immun Transplantat & Infect, Human Immune Monitoring Ctr, Palo Alto, CA 94304 USA. [Treanor, John J.] Univ Rochester, Dept Med, New York, NY USA. [Ilyushina, Natalia A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Wright, PF (reprint author), Geisel Sch Med Dartmouth, Div Infect Dis & Int Med, One Med Ctr Dr, Lebanon, NH 03756 USA. EM peter.f.wright@dartmouth.edu NR 25 TC 4 Z9 4 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SPR PY 2016 VL 3 IS 2 DI 10.1093/ofid/ofw108 PG 8 WC Infectious Diseases SC Infectious Diseases GA EC3IR UT WOS:000388020200061 ER PT J AU Zwiebel, J AF Zwiebel, James TI The Effect on Drug Development of the National Cancer Institute's Cancer Therapy Evaluation Program SO CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY LA English DT Editorial Material C1 [Zwiebel, James] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Rockville, MD 20850 USA. RP Zwiebel, J (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Rockville, MD 20850 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU MILLENNIUM MEDICAL PUBLISHING, INC PI NEW YORK PA 611 BROADWAY, STE 310, NEW YORK, NY 10012 USA SN 1543-0790 J9 CLIN ADV HEMATOL ONC JI Clin. Adv. Hematol. Oncol. PD MAR PY 2016 VL 14 IS 3 BP 157 EP 159 PG 3 WC Oncology SC Oncology GA EB4HD UT WOS:000387330500004 PM 27058027 ER PT J AU Lipinski, MJ Albelda, MT Frias, JC Anderson, SA Luger, D Westman, PC Escarcega, RO Hellinga, DG Waksman, R Arai, AE Epstein, SE AF Lipinski, Michael J. Albelda, M. Teresa Frias, Juan C. Anderson, Stasia A. Luger, Dror Westman, Peter C. Escarcega, Ricardo O. Hellinga, David G. Waksman, Ron Arai, Andrew E. Epstein, Stephen E. TI Multimodality imaging demonstrates trafficking of liposomes preferentially to ischemic myocardium SO CARDIOVASCULAR REVASCULARIZATION MEDICINE LA English DT Article DE Myocardial infarction; Imaging; Nanoparticle; Liposome ID INJURY; REPERFUSION; NANOPARTICLES; INFARCTION; HEART AB Introduction: Nanoparticles may serve as a promising means to deliver novel therapeutics to the myocardium following myocardial infarction. We sought to determine whether lipid-based liposomal nanoparticles can be shown through different imaging modalities to specifically target injured myocardium following intravenous injection in an ischemia-reperfusion murine myocardial infarction model. Methods: Mice underwent ischemia-reperfusion surgery and then either received tail-vein injection with gadolinium-and fluorescent-labeled liposomes or no injection (control). The hearts were harvested 24 h later and underwent T1 and T2-weighted ex vivo imaging using a 7 Tesla Bruker magnet. The hearts were then sectioned for immunohistochemistry and optical fluorescent imaging. Results: Themean size of the liposomes was 100 nm. T1-weighted signal intensity was significantly increased in the ischemic vs. the non-ischemic myocardium for mice that received liposomes compared with control. Optical imaging demonstrated significant fluorescence within the infarct area for the liposome group compared with control (163+/-31% vs. 13+/-14%, p=0.001) and fluorescent microscopy confirmed the presence of liposomes within the ischemic myocardium. Conclusions: Liposomes traffic to the heart and preferentially home to regions of myocardial injury, enabling improved diagnosis of myocardial injury and could serve as a vehicle for drug delivery. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lipinski, Michael J.; Luger, Dror; Westman, Peter C.; Escarcega, Ricardo O.; Hellinga, David G.; Waksman, Ron; Epstein, Stephen E.] MedStar Washington Hosp Ctr, MedStar Heart & Vasc Inst, 111 Irving St NW,Suite 4B, Washington, DC 20010 USA. [Albelda, M. Teresa] IIS La Fe, Grp Invest Biomed Imagen, GIBI230, Valencia, Spain. [Frias, Juan C.] Univ CEU Cardenal Herrera, Dept Ciencias Biomed, Valencia, Spain. [Anderson, Stasia A.; Arai, Andrew E.] NHLBI, Adv Cardiovasc Imaging Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Lipinski, MJ (reprint author), MedStar Washington Hosp Ctr, MedStar Heart & Vasc Inst, 111 Irving St NW,Suite 4B, Washington, DC 20010 USA. EM mjlipinski12@gmail.com RI Frias, Juan/F-9778-2016; Albelda Gimeno, Maria Teresa/J-5929-2012; OI Frias, Juan/0000-0002-2948-5086; Albelda Gimeno, M. Teresa/0000-0002-9572-8912 FU Intramural NIH HHS [ZIC HL005909-08] NR 15 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1553-8389 EI 1878-0938 J9 CARDIOVASC REVASCULA JI Cardiovasc. Revascularization Med. PD MAR PY 2016 VL 17 IS 2 BP 106 EP 112 DI 10.1016/j.carrev.2016.01.003 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA9KG UT WOS:000386961900007 PM 26874740 ER PT J AU Mazumder, R Choi, S Clymer, BD White, RD Kolipaka, A AF Mazumder, Ria Choi, Seongjin Clymer, Bradley D. White, Richard D. Kolipaka, Arunark TI Diffusion Tensor Imaging of Healthy and Infarcted Porcine Hearts: Study on the Impact of Formalin Fixation SO JOURNAL OF MEDICAL IMAGING AND RADIATION SCIENCES LA English DT Article DE Myocardial infarction; diffusion tensor imaging; formalin fixation; remodeling ID ACUTE MYOCARDIAL-INFARCTION; CARDIOVASCULAR MAGNETIC-RESONANCE; DELAYED CONTRAST ENHANCEMENT; LEFT-VENTRICULAR FUNCTION; IN-VIVO; HISTOLOGICAL VALIDATION; FIBER ARCHITECTURE; POSTMYOCARDIAL INFARCTION; WATER RELAXATION; NERVOUS-TISSUE AB Background: Because of the complexities with in-vivo cardiac diffusion tensor imaging (DTI), ex-vivo formalin-fixed specimens are used to investigate cardiac remodeling in diseases, and reported results have shown conflicting trends. This study investigates the impact of formalin fixation on diffusion properties and optimizes tracking parameters based on controls to understand remodeling in myocardial infarction (MI). Methods: DTI was performed on four healthy (controls) and four MI-induced, formalin-fixed (PoMI) ex-vivo porcine hearts. Controls were scanned before fixation (PrCtrl) and rescanned (PoCtrl) after formalin fixation. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were estimated in all hearts. Tracking parameters (FA, tract termination angle [ TTA], and fiber length) were optimized in controls and then used to investigate structural remodeling in PoMI hearts. Results: Fixation increased ADC and decreased FA. PoMI showed increased ADC but decreased FA in the infarcted region compared to the remote region. TTA showed a sharp increase in slope from 5 degrees to 10 degrees, which flattened after 25 degrees in all groups. Mean fiber length for different tracking length ranges showed that PoCtrl had shorter fibers compared with PrCtrl. Fibers around the infarction were shorter in length and disarrayed compared to the PoCtrl group. Conclusion: Formalin fixation affects diffusion properties; hence, DTI parametric trends observed in pathology may be influenced by the fixation process, which can cause contradictory findings. C1 [Mazumder, Ria; Clymer, Bradley D.] Ohio State Univ, Dept Elect & Comp Engn, Columbus, OH 43210 USA. [Choi, Seongjin; White, Richard D.; Kolipaka, Arunark] Ohio State Univ, Dept Radiol, Columbus, OH 43210 USA. [White, Richard D.; Kolipaka, Arunark] Ohio State Univ, Dept Internal Med, Div Cardiovasc Med, Davis Heart & Lung Res Inst 244, Columbus, OH 43210 USA. [Choi, Seongjin] NIA, NIH, Intramural Res Program, Harbor Hosp NM 534, 3001 S Hanover St, Baltimore, MD 21225 USA. RP Kolipaka, A (reprint author), Ohio State Univ, Wexner Med Ctr, 395 West 12th Ave,4th Floor, Columbus, OH 43210 USA. EM Arunark.Kolipaka@osumc.edu OI Choi, Seongjin/0000-0002-4549-7335 FU NCATS NIH HHS [UL1 TR000090, UL1 TR001070]; NHLBI NIH HHS [R01 HL124096]; None [AHA_13SDG14690027] NR 57 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1939-8654 J9 J MED IMAGING RADIAT JI J. Med. Imaging Radiat. Sci. PD MAR PY 2016 VL 47 IS 1 BP 74 EP 85 DI 10.1016/j.jmir.2015.10.007 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EB0NX UT WOS:000387041800012 PM 26989451 ER PT J AU Dimitrova, D Ross, L AF Dimitrova, Dimana Ross, Lawrence TI Coccidioidomycosis: Experience From a Children's Hospital in an Area of Endemicity SO JOURNAL OF THE PEDIATRIC INFECTIOUS DISEASES SOCIETY LA English DT Article DE disseminated coccidioidomycosis; pulmonary coccidioidomycosis ID UNITED-STATES; CALIFORNIA AB The incidence of coccidioidomycosis is increasing, and published pediatric experience is limited. This study further characterizes pediatric coccidioidomycosis by describing experience with 64 patients cared for at Children's Hospital of Los Angeles over 20 years, with focus on sites of involvement and severity, as well as serologic profiles of affected children. C1 [Dimitrova, Dimana] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ross, Lawrence] Childrens Hosp Los Angeles, Div Infect Dis, Los Angeles, CA 90027 USA. [Ross, Lawrence] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. RP Ross, L (reprint author), 4650 W Sunset Blvd, Los Angeles, CA 90027 USA. EM lross@chla.usc.edu NR 14 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2048-7193 EI 2048-7207 J9 J PEDIATR INFECT DIS JI J. Pediatr. Infect. Dis. Soc. PD MAR PY 2016 VL 5 IS 1 BP 89 EP 92 DI 10.1093/jpids/piu091 PG 4 WC Infectious Diseases SC Infectious Diseases GA DZ8PS UT WOS:000386133900017 PM 26908496 ER PT J AU Fadel, TR Farrell, DF Friedersdorf, LE Griep, MH Hoover, MD Meador, MA Meyyappan, M AF Fadel, Tarek R. Farrell, Dorothy F. Friedersdorf, Lisa E. Griep, Mark H. Hoover, Mark D. Meador, Michael A. Meyyappan, M. TI Toward the Responsible Development and Commercialization of Sensor Nanotechnologies SO ACS SENSORS LA English DT Article DE nanosensors; engineered nanomaterials; commercialization; data quality; life cycle ID CARBON NANOTUBES; NANOPORE SENSORS; DNA; NANOPARTICLES; GRAPHENE; NANOMATERIALS; NANOSENSORS; TRANSISTOR; MOLECULES; SYSTEM AB Nanotechnology-enabled sensors (or nano sensors) will play an important role in enabling the progression toward ubiquitous information systems as the Internet of Things (IoT) emerges. Nanosensors offer new, miniaturized solutions in physiochemical and biological sensing that enable increased sensitivity, specificity, and multiplexing capability, all with the compelling economic drivers of low cost and high-energy efficiency. In the United States, Federal agencies participating in the National Nano technology Initiative (NNI) "Nanotechnology for Sensors and Sensors for Nanotechnology: Improving and Protecting Health, Safety, and the Environment" Nanotechnology Signature Initiative (the Sensors NSI), address both the opportunity of using nanotechnology to advance sensor development and the challenges of developing sensors to keep pace with the increasingly widespread use of engineered nanomaterials. This perspective article will introduce and provide background on the NNI signature initiative on sensors. Recent efforts by the Sensors NSI aimed at promoting the successful development and commercialization of nanosensors will be reviewed and examples of sensor nanotechnologies will be highlighted. Future directions and critical challenges for sensor development will also be discussed. C1 [Fadel, Tarek R.; Friedersdorf, Lisa E.; Meador, Michael A.] Natl Nanotechnol Coordinat Off, 4201 Wilson Blvd,Suite 405, Arlington, VA 22230 USA. [Farrell, Dorothy F.] NCI, NIH, 31 Ctr Dr,10A52, Bethesda, MD 20892 USA. [Griep, Mark H.] US Army, Res Lab, Aberdeen, MD 21005 USA. [Hoover, Mark D.] NIOSH, 1095 Willowdale Rd, Morgantown, WV 26505 USA. [Meyyappan, M.] NASA, Ames Res Ctr, Ctr Nanotechnol, Moffett Field, CA 94035 USA. RP Fadel, TR (reprint author), Natl Nanotechnol Coordinat Off, 4201 Wilson Blvd,Suite 405, Arlington, VA 22230 USA. EM TFadel@nnco.nano.gov NR 76 TC 1 Z9 1 U1 7 U2 7 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 MAR PY 2016 VL 1 IS 3 BP 207 EP 216 DI 10.1021/acssensors.5b00279 PG 10 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology SC Chemistry; Science & Technology - Other Topics GA DY9OT UT WOS:000385464400002 PM 28261665 ER PT J AU Short, KR Kasper, J van der Aa, S Andeweg, AC Zaaraoui-Boutahar, F Goeijenbier, M Richard, M Herold, S Becker, C Scott, DP Limpens, RWAL Koster, AJ Barcena, M Fouchier, RAM Kirkpatrick, CJ Kuiken, T AF Short, Kirsty R. Kasper, Jennifer van der Aa, Stijn Andeweg, Arno C. Zaaraoui-Boutahar, Fatiha Goeijenbier, Marco Richard, Mathilde Herold, Susanne Becker, Christin Scott, Dana P. Limpens, Ronald W. A. L. Koster, Abraham J. Barcena, Montserrat Fouchier, Ron A. M. Kirkpatrick, Charles James Kuiken, Thijs TI Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article ID MICROVASCULAR ENDOTHELIAL-CELLS; A-VIRUS; H5N1 VIRUS; PROINFLAMMATORY CYTOKINES; INFECTION; PATHOGENESIS; APOPTOSIS; COAGULATION; ACTIVATION; PATHOLOGY AB A major cause of respiratory failure during influenza A virus (IAV) infection is damage to the epithelial-endothelial barrier of the pulmonary alveolus. Damage to this barrier results in flooding of the alveolar lumen with proteinaceous oedema fluid, erythrocytes and inflammatory cells. To date, the exact roles of pulmonary epithelial and endothelial cells in this process remain unclear. Here, we used an in vitro co-culture model to understand how IAV damages the pulmonary epithelial-endothelial barrier. Human epithelial cells were seeded on the upper half of a transwell membrane while human endothelial cells were seeded on the lower half. These cells were then grown in co-culture and IAV was added to the upper chamber. We showed that the addition of IAV (H1N1 and H5N1 subtypes) resulted in significant barrier damage. Interestingly, we found that, while endothelial cells mounted a pro-inflammatory/pro-coagulant response to a viral infection in the adjacent epithelial cells, damage to the alveolar epithelial-endothelial barrier occurred independently of endothelial cells. Rather, barrier damage was associated with disruption of tight junctions amongst epithelial cells, and specifically with loss of tight junction protein claudin-4. Taken together, these data suggest that maintaining epithelial cell integrity is key in reducing pulmonary oedema during IAV infection. C1 [Short, Kirsty R.; van der Aa, Stijn; Andeweg, Arno C.; Zaaraoui-Boutahar, Fatiha; Goeijenbier, Marco; Richard, Mathilde; Fouchier, Ron A. M.; Kuiken, Thijs] Erasmus MC, Dept Virosci, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. [Short, Kirsty R.] Univ Queensland, Sch Biomed Sci, Brisbane, Qld, Australia. [Kasper, Jennifer; Kirkpatrick, Charles James] Johannes Gutenberg Univ Mainz, Inst Pathol, Univ Med Ctr, Mainz, Germany. [Herold, Susanne; Becker, Christin] Univ Giessen, UGMLC, Giessen, Germany. [Herold, Susanne; Becker, Christin] German Ctr Lung Res DZL, Giessen, Germany. [Scott, Dana P.] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH, Hamilton, MT USA. [Limpens, Ronald W. A. L.; Koster, Abraham J.; Barcena, Montserrat] Leiden Univ, Sect Electron Microscopy, Dept Mol Cell Biol, Med Ctr, Leiden, Netherlands. RP Kuiken, T (reprint author), Erasmus MC, Dept Virosci, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. EM t.kuiken@erasmusmc.nl RI Barcena, Montserrat/B-5823-2012; Fouchier, Ron/A-1911-2014; Richard, Mathilde/F-5461-2017 OI Barcena, Montserrat/0000-0002-7719-4443; Fouchier, Ron/0000-0001-8095-2869; Richard, Mathilde/0000-0003-0240-9312 FU National Health and Medical Research Council (Canberra, Australia) [1054081]; European Union [278976]; VIRGO consortium - Netherlands Genomics Initiative; Dutch Government [FES0908]; German Research Foundation [SFB TR84, SFB 1021]; German Center for Lung Research (DZL); Netherlands Organisation for Scientific Research (NWO) [MEERVOUD-836.10.003] FX K.R. Short is supported by a National Health and Medical Research Council (Canberra, Australia) C.J. Martin post-doctoral fellowship (1054081). This study was funded in part by the European Union Seventh Framework Programme project ANTIGONE (grant agreement number 278976), and by the VIRGO consortium, which is funded by the Netherlands Genomics Initiative and by the Dutch Government (project number FES0908). S. Herold is funded by the German Research Foundation (SFB TR84 B2 and SFB 1021 C5) and the German Center for Lung Research (DZL). M. Barcena is supported by a Netherlands Organisation for Scientific Research (NWO) MEERVOUD-836.10.003 grant. Funding information for this article has been deposited with FundRef. NR 41 TC 5 Z9 5 U1 3 U2 7 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 MAR PY 2016 VL 47 IS 3 BP 954 EP 966 DI 10.1183/13993003.01282-2015 PG 13 WC Respiratory System SC Respiratory System GA DZ6DB UT WOS:000385950700032 PM 26743480 ER PT J AU Elmariah, S Farrell, LA Daher, M Shi, X Keyes, MJ Cain, CH Pomerantsev, E Vlahakes, GJ Inglessis, I Passeri, JJ Palacios, IF Fox, CS Rhee, EP Gerszten, RE AF Elmariah, Sammy Farrell, Laurie A. Daher, Maureen Shi, Xu Keyes, Michelle J. Cain, Carolyn H. Pomerantsev, Eugene Vlahakes, Gus J. Inglessis, Ignacio Passeri, Jonathan J. Palacios, Igor F. Fox, Caroline S. Rhee, Eugene P. Gerszten, Robert E. TI Metabolite Profiles Predict Acute Kidney Injury and Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE aortic stenosis; kidney; metabolomics; mortality; transcatheter aortic valve implantation ID CARDIAC-SURGERY; S-ADENOSYLHOMOCYSTEINE; IMPLANTATION INCIDENCE; SERUM CREATININE; RENAL-FUNCTION; RISK; DISEASE; ATHEROSCLEROSIS; BIOMARKER; STENOSIS AB Background-Acute kidney injury (AKI) occurs commonly after transcatheter aortic valve replacement (TAVR) and is associated with markedly increased postoperative mortality. We previously identified plasma metabolites predictive of incident chronic kidney disease, but whether metabolite profiles can identify those at risk of AKI is unknown. Methods and Results-We performed liquid chromatography-mass spectrometry-based metabolite profiling on plasma from patients undergoing TAVR and subjects from the community-based Framingham Heart Study (N=2164). AKI was defined by using the Valve Academic Research Consortium-2 criteria. Of 44 patients (mean age 82 +/- 9 years, 52% female) undergoing TAVR, 22 (50%) had chronic kidney disease and 9 (20%) developed AKI. Of 85 metabolites profiled, we detected markedly concordant cross-sectional metabolic changes associated with chronic kidney disease in the hospital-based TAVR and Framingham Heart Study cohorts. Baseline levels of 5-adenosylhomocysteine predicted AKI after TAVR, despite adjustment for baseline glomerular filtration rate (odds ratio per 1-SD increase 5.97, 95% CI 1.62-22.0; P=0.007). Of the patients who had AKI, 6 (66.7%) subsequently died, compared with 3 (8.6%) deaths among those patients who did not develop AKI (P=0.0008) over a median follow-up of 7.8 months. 5-adenosylhomocysteine was predictive of all-cause mortality after TAVR (hazard ratio per 1-SD increase 2.96, 95% CI 1.33-6.58; P=0.008), independent of baseline glomerular filtration rate. Conclusions-In an elderly population with severe aortic stenosis undergoing TAVR, metabolite profiling improves the prediction of AKI. Given the multifactorial nature of AKI after TAVR, metabolite profiles may identify those patients with reduced renal reserve. C1 [Elmariah, Sammy; Farrell, Laurie A.; Daher, Maureen; Shi, Xu; Keyes, Michelle J.; Cain, Carolyn H.; Pomerantsev, Eugene; Inglessis, Ignacio; Passeri, Jonathan J.; Palacios, Igor F.; Gerszten, Robert E.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Elmariah, Sammy; Farrell, Laurie A.; Shi, Xu; Keyes, Michelle J.; Rhee, Eugene P.; Gerszten, Robert E.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA USA. [Vlahakes, Gus J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Cardiac Surg, Boston, MA USA. [Rhee, Eugene P.] Harvard Med Sch, Massachusetts Gen Hosp, Div Nephrol, Boston, MA USA. [Elmariah, Sammy] Harvard Clin Res Inst, Boston, MA USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Boston Univ, Sch Med, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. RP Gerszten, RE (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Simches Res Bldg,185 Cambridge St,3208, Boston, MA 02114 USA. EM gerszten.robert@mgh.harvard.edu FU American Heart Association [14 FTF20440012]; National Institutes of Health [R01DK081572, R01HL098280, N01HC25195]; MGH Heart Center Hassenfeld Cardiovascular Research Scholar Program FX We are appreciative of support from the American Heart Association (14 FTF20440012 to Elmariah), the National Institutes of Health (R01DK081572 and R01HL098280 to Gerszten and N01HC25195 to the Framingham Heart Study), and the MGH Heart Center Hassenfeld Cardiovascular Research Scholar Program (to Elmariah). NR 33 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAR PY 2016 VL 5 IS 3 AR e002712 DI 10.1161/JAHA.115.002712 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY7MA UT WOS:000385312200018 PM 27068627 ER PT J AU Lee, JJ Pedley, A Hoffmann, U Massaro, JM Keaney, JF Vasan, RS Fox, CS AF Lee, Jane J. Pedley, Alison Hoffmann, Udo Massaro, Joseph M. Keaney, John F., Jr. Vasan, Ramachandran S. Fox, Caroline S. TI Cross-Sectional Associations of Computed Tomography (CT)-Derived Adipose Tissue Density and Adipokines: The Framingham Heart Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE adipokine; adipose tissue; computed tomography; epidemiology ID METABOLIC RISK-FACTORS; BODY-FAT DISTRIBUTION; II DIABETES-MELLITUS; INSULIN-RESISTANCE; ADIPOCYTE SIZE; CELL-SIZE; CARDIOMETABOLIC RISK; ABDOMINAL OBESITY; ECTOPIC FAT; ADIPONECTIN AB Background-Excess accumulation of abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) is associated with adverse levels of adipokines and cardiovascular disease risk. Whether fat quality is associated with adipokines has not been firmly established. This study examined the association between abdominal SAT and VAT density, an indirect measure of fat quality, with a panel of metabolic regulatory biomarkers secreted by adipose tissue or the liver independently of absolute fat volumes. Methods and Results-We evaluated 1829 Framingham Heart Study participants (44.9% women). Abdominal SAT and VAT density was estimated indirectly by adipose tissue attenuation using computed tomography. Adipokines included adiponectin, leptin receptor, leptin, fatty acid-binding protein 4 (FABP-4), retinol-binding protein 4 (RBP-4), and fetuin-A. Fat density was associated with all the biomarkers evaluated, except fetuin-A. Lower fat density (ie, more-negative fat attenuation) was associated with lower adiponectin and leptin receptor, but higher leptin and FABP-4 levels (all P<0.0001). SAT density was inversely associated with RPB-4 in both sexes, whereas the association between VAT density and RPB-4 was only observed in men (P<0.0001). In women, after additional adjustment for respective fat volume, SAT density retained the significant associations with adiponectin, leptin, FABP-4, and RBP-4; and VAT density with adiponectin only (all P<0.0001). In men, significant associations were maintained upon additional adjustment for respective fat volume (P<0.005). Conclusions-Lower abdominal fat density was associated with a profile of biomarkers suggestive of greater cardiometabolic risk. These observations support that fat density may be a valid biomarker of cardiometabolic risk. C1 [Lee, Jane J.; Pedley, Alison; Vasan, Ramachandran S.; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham Heart Study, Framingham, MA USA. [Lee, Jane J.; Pedley, Alison; Vasan, Ramachandran S.; Fox, Caroline S.] NHLBI, Populat Studies Branch, Framingham, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Keaney, John F., Jr.] Univ Massachusetts, Sch Med, Div Cardiovasc Med, Worcester, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Dept Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Med Sch, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU National Heart, Lung and Blood Institute [N01-HC-25195, R01DK080739] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195) and by R01DK080739 (Vasan). NR 52 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAR PY 2016 VL 5 IS 3 AR e002545 DI 10.1161/JAHA.115.002545 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY7MA UT WOS:000385312200009 PM 26927600 ER PT J AU McDermott, MM Guralnik, JM Tian, L Kibbe, MR Ferrucci, L Zhao, LH Liu, K Liao, YH Gao, Y Criqui, MH AF McDermott, Mary M. Guralnik, Jack M. Tian, Lu Kibbe, Melina R. Ferrucci, Luigi Zhao, Lihui Liu, Kiang Liao, Yihua Gao, Ying Criqui, Michael H. TI Incidence and Prognostic Significance of Depressive Symptoms in Peripheral Artery Disease SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE atherosclerosis; cardiovascular disease; peripheral vascular disease ID ANKLE-BRACHIAL INDEX; AMERICAN-HEART-ASSOCIATION; LEG SYMPTOMS; FUNCTIONAL DECLINE; RISK-FACTORS; FOLLOW-UP; MYOCARDIAL-INFARCTION; IMMUNE-SYSTEM; MORTALITY; WOMEN AB Background-We compared the incidence of depression, defined by a Geriatric Depression Score (GDS) >= 6, between people with versus without peripheral artery disease (PAD). We determined whether depressive symptoms were associated with increased mortality in people with and without PAD. Methods and Results-Nine hundred and fifty-one PAD patients and 478 non-PAD patients were recruited from Chicago medical centers and followed prospectively. At baseline and annually, participants completed the GDS (0-15 scale, score >= 6=depression) and 6-minute walk. Cause of death was confirmed with death certificates. The prevalence of a GDS >= 6 at baseline was 186/951 (19.6%) among PAD versus 63/478 (13.2%) among non-PAD participants (P= 0.003). During a mean follow-up of 2.7 +/- 1.2 years, 122/712 (17.1%) of participants with PAD versus 51/403 (12.7%) without PAD developed a GDS >= 6 (P= 0.047). Adjusting for age, sex, race, comorbidities, and other confounders, PAD participants had an increased rate of developing a GDS >= 6 compared to non-PAD participants (hazard ratio=1.54 (95% CI=1.05-2.25, P=0.026). This association was not statistically significant after adjusting for 6-minute walk (P= 0.258). Among PAD participants, a baseline GDS >= 6 was associated with increased all-cause mortality, adjusting for confounders (hazard ratio=1.57, 95% CI=1.12-2.21, P=0.009). This association was not significant after adjusting for 6-minute walk (P=0.224). Conclusions-People with PAD have a higher incidence of depressive symptoms than people without PAD. In PAD, depressive symptoms are associated with increased all-cause and cardiovascular mortality. These associations are explained in part by poorer 6-minute walk among people with PAD and among depressed people with PAD, respectively. C1 [McDermott, Mary M.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [McDermott, Mary M.; Zhao, Lihui; Liu, Kiang; Liao, Yihua; Gao, Ying] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Kibbe, Melina R.] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Tian, Lu] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Kibbe, Melina R.] Jesse Brown Vet Affairs Med Ctr, Chicago, IL USA. [Ferrucci, Luigi] NIA, Bethesda, MD 20892 USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. RP McDermott, MM (reprint author), 750 North Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU National Heart Lung and Blood Institute (NHLBI) [R01-HL083064, R01-HL64739, R01-HL58099, R01-HL076298, R01-HL71223, R01-HL109244] FX Funded by the National Heart Lung and Blood Institute (NHLBI); R01-HL083064, R01-HL64739, R01-HL58099, R01-HL076298, R01-HL71223, and R01-HL109244. NR 40 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAR PY 2016 VL 5 IS 3 AR e002959 DI 10.1161/JAHA.115.002959 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY7MA UT WOS:000385312200042 PM 26994131 ER PT J AU Redmond, N Booth, JN Tanner, RM Diaz, KM Abdalla, M Sims, M Muntner, P Shimbo, D AF Redmond, Nicole Booth, John N., III Tanner, Rikki M. Diaz, Keith M. Abdalla, Marwah Sims, Mario Muntner, Paul Shimbo, Daichi TI Prevalence of Masked Hypertension and Its Association With Subclinical Cardiovascular Disease in African Americans: Results From the Jackson Heart Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE blood pressure; cardiovascular diseases; epidemiology; hypertension ID AMBULATORY BLOOD-PRESSURE; EUROPEAN-SOCIETY; POPULATION; PREHYPERTENSION; DETERMINANTS; COMMITTEE; POSITION; RISK; HOME AB Background-Studies consisting mostly of whites have shown that the prevalence of masked hypertension differs by prehypertension status. Using data from the Jackson Heart Study, an exclusively African American population-based cohort, we evaluated the association of masked hypertension and prehypertension with left ventricular mass index and common carotid intima media thickness. Methods and Results-At the baseline visit, clinic blood pressure (CBP) measurement and 24-hour ambulatory blood pressure monitoring were performed. Masked hypertension was defined as mean systolic/diastolic CBP <140/90 mm Hg and mean daytime systolic/diastolic ambulatory blood pressure >= 135/85 mm Hg. Clinic hypertension was defined as mean systolic/diastolic CBP >= 140/90 mm Hg. Normal CBP was defined as mean systolic/diastolic CBP <120/80 mm Hg and prehypertension as mean systolic/diastolic CBP 120 to 139/80 to 89 mm Hg. The analytic sample included 909 participants. Among participants with systolic/diastolic CBP <140/90 mm Hg, the prevalence of masked hypertension and prehypertension was 27.5% and 62.4%, respectively. The prevalence of masked hypertension among those with normal CBP and prehypertension was 12.9% and 36.3%, respectively. In a fully adjusted model, which included prehypertension status and antihypertensive medication use as covariates, left ventricular mass index was 7.94 g/m(2) lower among those without masked hypertension compared to participants with masked hypertension (P<0.001). Left ventricular mass index was also 4.77 g/m(2) lower among those with clinic hypertension, but this difference was not statistically significant (P=0.068). There were no significant differences in left ventricular mass index between participants with and without masked hypertension, or clinic hypertension. Conclusions-Masked hypertension was common among African Americans with prehypertension and also normal CBP, and was associated with subclinical cardiovascular disease. C1 [Redmond, Nicole] NHLBI, Clin Applicat & Prevent Branch, Bldg 10, Bethesda, MD 20892 USA. [Booth, John N., III; Tanner, Rikki M.; Muntner, Paul] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Diaz, Keith M.; Abdalla, Marwah; Shimbo, Daichi] Columbia Univ, Dept Med, Med Ctr, New York, NY USA. [Sims, Mario] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. RP Redmond, N (reprint author), NHLBI, Clin Applicat & Prevent Branch, Rockledge Ctr 2, RKL2 BG RM 10106,Suite 10218,6701 Rockledge Dr, Bethesda, MD 20817 USA. EM nredmond@uab.edu FU Jackson State University [N01-HC-95170]; University of Mississippi Medical Center [N01-HC-95171]; Touglaoo College [N01-HC-95172]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300046C, HHSN26820 1300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities (NIMHD) at the National Institute of Health (NIH); NHLBI/NIH [R01-HL117323, K24-HL125704, P01-HL047540-19S1, R01-HL116470-02S1, R01-HL117323-02S2]; Agency for Healthcare Research and Quality (AHRQ) [K12-HS023009]; NIMHD [P60MD002249, U54MD008176] FX The manuscript for this study has been reviewed by the Jackson Heart Study for scientific content and consistency of data interpretation with previous JHS publications. The JHS is supported and conducted in collaboration with Jackson State University (N01-HC-95170); University of Mississippi Medical Center (N01-HC-95171); and Touglaoo College (N01-HC-95172) and contracts HHSN268201300046C, HHSN26820 1300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities (NIMHD) at the National Institute of Health (NIH). This work was also supported by grants R01-HL117323 (Drs Muntner and Shimbo), K24-HL125704 (Dr Shimbo), Diversity Supplements P01-HL047540-19S1 and R01-HL116470-02S1 (Dr Diaz) and R01-HL117323-02S2 (Dr Abdalla), all from NHLBI/NIH. Dr Redmond was supported by career development award K12-HS023009 from the Agency for Healthcare Research and Quality (AHRQ). Dr Sims is supported by the grants P60MD002249 and U54MD008176 from the NIMHD. NR 33 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAR PY 2016 VL 5 IS 3 AR e002284 DI 10.1161/JAHA.115.002284 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY7MA UT WOS:000385312200003 PM 27025968 ER PT J AU Santhanakrishnan, R Wang, N Larson, MG Magnani, JM Vasan, RS Wang, TJ Yap, J Feng, L Yap, KB Ong, HY Ng, TP Richards, AM Lam, CSP Ho, JE AF Santhanakrishnan, Rajalakshmi Wang, Na Larson, Martin G. Magnani, Jared M. Vasan, Ramachandran S. Wang, Thomas J. Yap, Jonathan Feng, Liang Yap, Keng B. Ong, Hean Y. Ng, Tze P. Richards, Arthur Mark Lam, Carolyn S. P. Ho, Jennifer E. TI Racial Differences in Electrocardiographic Characteristics and Prognostic Significance in Whites Versus Asians SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE electrocardiography; epidemiology; left ventricular hypertrophy; mortality; race ID LEFT-VENTRICULAR HYPERTROPHY; AMERICAN-HEART-ASSOCIATION; QT INTERVAL; MYOCARDIAL-INFARCTION; CHINESE SUBJECTS; NORMAL LIMITS; POPULATION; AGE; COMMITTEE; CRITERIA AB Background-Racial differences in electrocardiographic (ECG) characteristics and prognostic significance among Whites and Asians are not well described. Methods and Results-We studied 2677 White Framingham Heart Study participants (57% women) and 2972 Asian (64% women) Singapore Longitudinal Aging Study participants (mean age 66 years in both) free of myocardial infarction or heart failure. Racial differences in ECG characteristics and effect on mortality were assessed. In linear regression models, PR interval was longer in Asians compared with Whites (multivariable-adjusted beta +/- SE 5.0 +/- 1.4 ms in men and 6.6 +/- 0.9 ms in women, both P<0.0006). QT interval was shorter in Asian men (beta +/- SE -6.2 +/- 1.2 ms, P<0.0001) and longer in Asian women (beta +/- SE 3.6 +/- 0.9 ms, P=0.02) compared to White men and women, respectively. Asians had greater odds of having ECG left ventricular hypertrophy (LVH) compared with Whites (odds ratio [OR] 3.56, 95% confidence interval [CI] 1.36-9.35 for men, OR 1.93, 95% CI 1.35-2.76 for women, both P<0.02). Over a mean follow-up of 11 +/- 3 years in Framingham and 8 +/- 3 years in Singapore, mortality rates were 24.5 and 13.4 per 1000 person-years among Whites and Asians, respectively. In Cox models, the presence of LVH had a greater effect on all-cause mortality in Asians compared with Whites (hazard ratio [HR] 2.66, 95% CI 1.83-3.88 vs HR 1.30, 95% CI 0.90-1.89, P for interaction=0.02). Conclusion-Our findings from two large community-based cohorts show prominent race differences in ECG characteristics between Whites and Asians, and also suggest a differential association with mortality. These differences may carry implications for race-specific ECG reference ranges and cardiovascular risk. C1 [Santhanakrishnan, Rajalakshmi; Magnani, Jared M.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med & Epidemiol, Boston, MA 02118 USA. [Wang, Na] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.; Magnani, Jared M.; Vasan, Ramachandran S.; Ho, Jennifer E.] NHLBI, Framingham, MA USA. [Larson, Martin G.; Magnani, Jared M.; Vasan, Ramachandran S.; Ho, Jennifer E.] Boston Univ Framingham Heart Study, Framingham, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Dept Med, Div Cardiovasc Med, Nashville, TN USA. [Yap, Jonathan; Lam, Carolyn S. P.] Natl Heart Ctr Singapore, Dept Cardiol, Singapore, Singapore. [Feng, Liang; Lam, Carolyn S. P.] Duke NUS Grad Med Sch, Singapore, Singapore. [Yap, Keng B.] Ng Teng Fong Hosp, Geriatr Med, Singapore, Singapore. [Ong, Hean Y.] Khoo Teck Puat Hosp, Dept Cardiol, Singapore, Singapore. [Ng, Tze P.] Yong Loo Lin Sch Med, Singapore, Singapore. [Richards, Arthur Mark] Natl Univ Hlth Syst, Cardiovasc Res Inst, Singapore, Singapore. [Richards, Arthur Mark] Univ Otago, Christchurch Heart Inst, Christchurch, New Zealand. [Ho, Jennifer E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ho, Jennifer E.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Ho, JE (reprint author), Massachusetts Gen Hosp, CPZN 185 Cambridge St,3224, Boston, MA 02114 USA. EM jho1@partners.org FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, HHSN268201500001I]; National Institutes of Health [K23-HL116780]; Boston University School of Medicine, Department of Medicine Career Investment award (Boston, MA) FX This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195 and HHSN268201500001I). This work was supported by the National Institutes of Health-K23-HL116780 (Dr Ho). Dr Ho is supported by a Boston University School of Medicine, Department of Medicine Career Investment award (Boston, MA). 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 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAR PY 2016 VL 5 IS 3 AR e002956 DI 10.1161/JAHA.115.002956 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY7MA UT WOS:000385312200040 PM 27016575 ER PT J AU Truong, QA Schulman-Marcus, J Zakroysky, P Chou, ET Nagurney, JT Fleg, JL Schoenfeld, DA Udelson, JE Hoffmann, U Woodard, PK AF Truong, Quynh A. Schulman-Marcus, Joshua Zakroysky, Pearl Chou, Eric T. Nagurney, John T. Fleg, Jerome L. Schoenfeld, David A. Udelson, James E. Hoffmann, Udo Woodard, Pamela K. TI Coronary CT Angiography Versus Standard Emergency Department Evaluation for Acute Chest Pain and Diabetic Patients: Is There Benefit With Early Coronary CT Angiography? SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE acute coronary syndrome; cardiac computed tomography; chest pain diagnosis; diabetes mellitus; emergency department ID COMPUTED TOMOGRAPHIC ANGIOGRAPHY; ACUTE CARDIAC ISCHEMIA; MYOCARDIAL-INFARCTION; ASSISTED TOMOGRAPHY; ARTERY-DISEASE; RISK-FACTORS; TRIAL; MULTICENTER; MELLITUS; ACQUISITION AB Background-Cardiac computed tomography angiography (CCTA) reduces emergency department length of stay compared with standard evaluation in patients with low-and intermediate-risk acute chest pain. Whether diabetic patients have similar benefits is unknown. Methods and Results-In this prespecified analysis of the Rule Out Myocardial Ischemia/Infarction by Computer Assisted Tomography (ROMICAT II) multicenter trial, we randomized 1000 patients (17% diabetic) with symptoms suggestive of acute coronary syndrome to CCTA or standard evaluation. The rate of acute coronary syndrome was 8% in both diabetic and nondiabetic patients (P=1.0). Length of stay was unaffected by the CCTA strategy for diabetic patients (23.9 versus 27.2 hours, P=0.86) but was reduced for nondiabetic patients compared with standard evaluation (8.4 versus 26.5 hours, P<0.0001; P interaction=0.004). CCTA resulted in 3-fold more direct emergency department discharge in both groups (each P=0.0001, P interaction=0.27). No difference in hospital admissions was seen between the 2 strategies in diabetic and nondiabetic patients (P interaction=0.09). Both groups had more downstream testing and higher radiation doses with CCTA, but these were highest in diabetic patients (all P interaction=0.04). Diabetic patients had fewer normal CCTAs than nondiabetic patients (32% versus 50%, P=0.003) and similar normalcy rates with standard evaluation (P=0.70). Notably, 66% of diabetic patients had no or mild stenosis by CCTA with short length of stay comparable to that of nondiabetic patients (P=0.34), whereas those with > 50% stenosis had a high prevalence of acute coronary syndrome, invasive coronary angiography, and revascularization. Conclusions-Knowledge of coronary anatomy with CCTA is beneficial for diabetic patients and can discriminate between lower risk patients with no or little coronary artery disease who can be discharged immediately and higher risk patients with moderate to severe disease who warrant further workup. C1 [Truong, Quynh A.; Schulman-Marcus, Joshua] New York Presbyterian Hosp, Dalio Inst Cardiovasc Imaging, New York, NY USA. [Truong, Quynh A.; Schulman-Marcus, Joshua] Weill Cornell Med Coll, New York, NY USA. [Nagurney, John T.] Massachusetts Gen Hosp, Emergency Dept, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, Boston, MA 02114 USA. [Zakroysky, Pearl; Schoenfeld, David A.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Biostat, Boston, MA USA. [Chou, Eric T.] Kaiser Permanente, Fontana Med Ctr, Fontana, CA USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA USA. [Woodard, Pamela K.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. RP Woodard, PK (reprint author), 510 South Kingshighway Blvd 8131, St Louis, MO 63110 USA. EM woodardp@mir.wustl.edu FU NIH/NHLBI [U01HL092040, U01HL092022]; NIH [K23HL098370, L30HL093896] FX The study was supported by the NIH/NHLBI (U01HL092040 and U01HL092022). Dr Truong was supported by the NIH (K23HL098370 and L30HL093896). NR 19 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAR PY 2016 VL 5 IS 3 AR e003137 DI 10.1161/JAHA.115.003137 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY7MA UT WOS:000385312200053 PM 27006119 ER PT J AU Hu, LS Zhang, HB Bergholz, J Sun, SN Xiao, ZXJ AF Hu, Linshan Zhang, Haibo Bergholz, Johann Sun, Shengnan Xiao, Zhi-Xiong Jim TI MDM2/MDMX: Master negative regulators for p53 and RB SO MOLECULAR & CELLULAR ONCOLOGY LA English DT Editorial Material DE MDM2; MDMX; p53; RB ID RETINOBLASTOMA PROTEIN; MDM2; INACTIVATION; SUPPRESSION; PATHWAY AB MDM2 (mouse double minute 2 homolog) and MDMX (double minute X human homolog, also known as MDM4) are critical negative regulators of tumor protein p53. Our recent work shows that MDMX binds to and promotes degradation of retinoblastoma protein (RB) in an MDM2-dependent manner. In a xenograft tumor growth mouse model, silencing of MDMX results in inhibition of p53-deficient tumor growth, which can be effectively reversed by concomitant RB silencing. Thus, MDMX exerts its oncogenic activity via suppression of RB. C1 [Hu, Linshan; Zhang, Haibo; Bergholz, Johann; Sun, Shengnan; Xiao, Zhi-Xiong Jim] Sichuan Univ, Coll Life Sci, Ctr Growth Metab & Aging, Key Lab Bioresource & Ecoenvironm,Minist Educ, Chengdu, Peoples R China. [Zhang, Haibo] NCI, LCBG, Bethesda, MD 20892 USA. [Bergholz, Johann] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Xiao, ZXJ (reprint author), Sichuan Univ, Coll Life Sci, Ctr Growth Metab & Aging, Key Lab Bioresource & Ecoenvironm,Minist Educ, Chengdu, Peoples R China. EM jimzx@scu.edu.cn NR 10 TC 1 Z9 1 U1 2 U2 2 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. PD MAR PY 2016 VL 3 IS 2 AR UNSP e1106635 DI 10.1080/23723556.2015.1106635 PG 3 WC Oncology SC Oncology GA DY6OR UT WOS:000385247100052 PM 27308631 ER PT J AU Chmelar, J Kotal, J Karim, S Kopacek, P Francischetti, IMB Pedra, JHF Kotsyfakis, M AF Chmelar, Jindrich Kotal, Jan Karim, Shahid Kopacek, Petr Francischetti, Ivo M. B. Pedra, Joao H. F. Kotsyfakis, Michail TI Sialomes and Mialomes: A Systems-Biology View of Tick Tissues and Tick-Host Interactions SO TRENDS IN PARASITOLOGY LA English DT Review ID RHIPICEPHALUS BOOPHILUS MICROPLUS; SALIVARY-GLAND TRANSCRIPTOME; VARIABILIS ACARI IXODIDAE; AMERICAN DOG TICK; IXODES-RICINUS; HARD TICK; CATTLE TICK; AMBLYOMMA-AMERICANUM; BABESIA-BOVIS; PATHOGEN TRANSMISSION AB Tick saliva facilitates tick feeding and infection of the host. Gene expression analysis of tick salivary glands and other tissues involved in host-pathogen interactions has revealed a wide range of bioactive tick proteins. Transcriptomic analysis has been a milestone in the field and has recently been enhanced by next-generation sequencing (NGS). Furthermore, the application of quantitative proteomics to ticks with unknown genomes has provided deeper insights into the molecular mechanisms underlying tick hematophagy, pathogen transmission, and tick-host-pathogen interactions. We review current knowledge on the transcriptomics and proteomics of tick tissues from a systems-biology perspective and discuss future challenges in the field. C1 [Chmelar, Jindrich; Kotal, Jan] Univ South Bohemia Ceske Budejovice, Fac Sci, Budweis, Czech Republic. [Chmelar, Jindrich] Tech Univ Dresden, Dept Clin Pathobiochem, Dresden, Germany. [Kotal, Jan; Kopacek, Petr; Kotsyfakis, Michail] Acad Sci Czech Republic, Ctr Biol, Inst Parasitol, Budweis, Czech Republic. [Karim, Shahid] Univ Southern Mississippi, Dept Biol Sci, Hattiesburg, MS 39406 USA. [Francischetti, Ivo M. B.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Pedra, Joao H. F.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Kotsyfakis, M (reprint author), Acad Sci Czech Republic, Ctr Biol, Inst Parasitol, Budweis, Czech Republic. EM mich_kotsyfakis@yahoo.com RI Kopacek, Petr/G-8414-2014; Kotsyfakis, Michail/G-9525-2014; OI Kotsyfakis, Michail/0000-0002-7526-1876; Pedra, Joao/0000-0001-8740-2667 FU Grant Agency of the Czech Republic (GACR) [P502/12/2409, 13-11043S]; Czech Academy of Sciences [RVO60077344]; 7th Framework Program of the European Commission (FP7) [PIRG07-GA-2010-268177]; National Institutes of Health [R01 AI093653]; University of Maryland-Baltimore, School of Medicine; Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH; USA); Czech Academy of Sciences (Jan Evangelista Purkyne Fellowship) FX We thank Nextgenediting (nextgenediting.com) for providing editorial assistance. This work was supported by the Grant Agency of the Czech Republic (GACR grant P502/12/2409 to M.K. and grant 13-11043S to P.K.), the Czech Academy of Sciences (grant RVO60077344 to the Biology Center, Institute of Parasitology), and the 7th Framework Program of the European Commission (FP7; Marie Curie Reintegration grant PIRG07-GA-2010-268177 to M.K.). This publication reflects only the view of the authors; the European Commission is not liable for any use that may be made of the information contained herein. M.K. and J.H.F.P. were supported by the National Institutes of Health (R01 AI093653) and J.H.F.P. was supported by start-up funds provided by the University of Maryland-Baltimore, School of Medicine. I.M.B.F. was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH; USA). M.K. received support from the Czech Academy of Sciences (Jan Evangelista Purkyne Fellowship). Because I.M.B.F. is a government employee and this is a government work, the work is in the public domain in the USA. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and be use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. Rights can be established outside the USA subject to a government use license. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 87 TC 11 Z9 11 U1 9 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 EI 1471-5007 J9 TRENDS PARASITOL JI Trends Parasitol. PD MAR PY 2016 VL 32 IS 3 BP 242 EP 254 DI 10.1016/j.pt.2015.10.002 PG 13 WC Parasitology SC Parasitology GA DZ5HJ UT WOS:000385892300010 PM 26520005 ER PT J AU Dessalvi, S Boccardo, F Molinari, L Spinaci, S Campisi, CC Ferrari, GM Campisi, C AF Dessalvi, S. Boccardo, F. Molinari, L. Spinaci, S. Campisi, C. C. Ferrari, G. M. Campisi, C. TI CHYLOPERITONEUM: DIAGNOSTIC AND THERAPEUTIC OPTIONS SO LYMPHOLOGY LA English DT Article DE chyloperitoneum; chylous ascites; chylous reflux; chylous vessels; imaging; lymphangio-MR; CT-lymphangiography; treatment; chylo-venous anastomosis ID LYMPH-NODE DISSECTION; CHYLOUS ASCITES; RISK-FACTORS; GYNECOLOGIC MALIGNANCIES; LIVER-TRANSPLANTATION; MANAGEMENT; SURGERY; LYMPHANGIOGRAPHY AB Chyloperitoneum is not rare and is often associated with other chylous disorders particularly in more complex clinical conditions. An accurate diagnostic study is indispensable to plan the correct therapeutic approach, and we examined the long-term outcomes of our experience in the management of primary and secondary chyloperitoneum in fifty-eight patients (50 adults and 8 children; 34 primary and 24 secondary forms). Diagnostic assessment consisted of paracentesis, whole body lymphoscintigraphy, lymphangio-MR, and lymphangio-CT (LAG-CT). The management of chyloperitoneum consisted initially of non-operative procedures (MCT diet, TPN, octreotide). Surgical treatment was performed in patients not responsive to conservative methods and involved different options using surgical and microsurgical approaches. Microsurgical techniques included chylous venous shunts connecting chyliferous vessels and mesenteric veins. Fibrin glue or platelet gel injection at the site of the chylous leakage was also used to treat one case of refractory secondary chyloperitoneum. Patients were followed clinically and instrumentally (echography and labs tests) for 6 months to over 5 years. We found that LAG-CT was the primary diagnostic modality to provide precise topographic information concerning the site, cause, and extension of chylous pathology, all of which allowed proper planning of therapeutic procedures. Thirty-four patients did not have a relapse of the chyloperitoneum and 22 patients had a persistence of a small quantity of ascites with no protein imbalance. We observed early relapse of chylous ascites in 2 cases that required a peritoneal-jugular shunt leading to good outcomes. An accurate diagnostic study (above all LAG-CT) and a microsurgical approach proved to represent an effective management of chyloperitoneum refractory to non-operative treatment. C1 [Dessalvi, S.; Boccardo, F.; Molinari, L.; Spinaci, S.; Campisi, C. C.; Campisi, C.] Univ Genoa, Dept Surg, Unit Lymphat Surg, Natl Canc Inst,IRCCS S Martino IST, I-16126 Genoa, Italy. [Ferrari, G. M.] Univ Genoa, Transfus Ctr, IRCCS S Martino IST, Natl Canc Inst, I-16126 Genoa, Italy. RP Dessalvi, S (reprint author), Univ Genoa, IRCCS S Martino Hosp, Canc Inst IST, Largo R Benzi 10, I-16132 Genoa, Italy. EM saradessalvi@hotmail.it FU ISL Presidential Young Investigator Award FX S. Dessalvi was awarded an ISL Presidential Young Investigator Award for her presentation of this work at the 25th World Congress of Lymphology in San Francisco in September 2015. NR 20 TC 0 Z9 0 U1 2 U2 2 PU LYMPHOLOGY PI TUCSON PA C/O C L WITTE MD 1501 N CAMPBELL AVE DEPT SURGERY, TUCSON, AZ 85724 USA SN 0024-7766 J9 LYMPHOLOGY JI Lymphology PD MAR PY 2016 VL 49 IS 1 BP 1 EP 7 PG 7 WC Immunology; Physiology SC Immunology; Physiology GA DY1OD UT WOS:000384863400001 ER PT J AU Konradt, C Ueno, N Christian, DA Delong, JH Pritchard, GH Herz, J Bzik, DJ Koshy, AA McGavern, DB Lodoen, MB Hunter, CA AF Konradt, Christoph Ueno, Norikiyo Christian, David A. Delong, Jonathan H. Pritchard, Gretchen Harms Herz, Jasmin Bzik, David J. Koshy, Anita A. McGavern, Dorian B. Lodoen, Melissa B. Hunter, Christopher A. TI Endothelial cells are a replicative niche for entry of Toxoplasma gondii to the central nervous system SO NATURE MICROBIOLOGY LA English DT Article ID BLOOD-BRAIN-BARRIER; IN-VIVO; PARASITE DISSEMINATION; PATHOGEN INTERACTIONS; SHEAR-STRESS; MOUSE-BRAIN; T-CELLS; INFECTION; MIGRATION; DYNAMICS AB An important function of the blood-brain barrier is to exclude pathogens from the central nervous system, but some microorganisms benefit from the ability to enter this site. It has been proposed that Toxoplasma gondii can cross biological barriers as a motile extracellular form that uses transcellular or paracellular migration, or by infecting a host cell that then crosses the blood-brain barrier. Unexpectedly, analysis of acutely infected mice revealed significant numbers of free parasites in the blood and the presence of infected endothelial cells in the brain vasculature. The use of diverse transgenic parasites combined with reporter mice and intravital imaging demonstrated that replication in and lysis of endothelial cells precedes invasion of the central nervous system, and highlight a novel mechanism for parasite entry to the central nervous system. C1 [Konradt, Christoph; Christian, David A.; Delong, Jonathan H.; Pritchard, Gretchen Harms; Hunter, Christopher A.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Ueno, Norikiyo; Lodoen, Melissa B.] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. [Ueno, Norikiyo; Lodoen, Melissa B.] Univ Calif Irvine, Inst Immunol, Irvine, CA 92697 USA. [Herz, Jasmin; McGavern, Dorian B.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bzik, David J.] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Lebanon, NH 03756 USA. [Koshy, Anita A.] Univ Arizona, Dept Neurol, Tucson, AZ 85724 USA. RP Hunter, CA (reprint author), Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. EM chunter@vet.upenn.edu FU German Research Foundation (DFG) [KO 4609-1/1]; National Institutes of Health [NIH AI 41158, NIH NS065116, NIH AI041930]; American Heart Association [14BGIA20380675, 15POST25550021]; University of Arizona; BIO5 Institute; NIH [S10RR027128]; School of Veterinary Medicine; University of Pennsylvania; Commonwealth of Pennsylvania FX C.K. was supported by research grant KO 4609-1/1 from the German Research Foundation (DFG). This work was supported by grants from the National Institutes of Health (NIH AI 41158 to C.A.H., NIH NS065116 to A.A.K., NIH AI041930 to D.J.B.), the American Heart Association (14BGIA20380675 to M.B.L. and 15POST25550021 to N.U.) and the University of Arizona and the BIO5 Institute (A.A.K.). Imaging experiments were performed in the PennVet Imaging Core Facility on instrumentation supported by NIH S10RR027128, the School of Veterinary Medicine, the University of Pennsylvania, and the Commonwealth of Pennsylvania. sIgM-ko mice were provided by G. Debes (University of Pennsylvania). C.A.H is the Mindy Halikman Heyer President's Distinguished Chair. NR 44 TC 8 Z9 8 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND EI 2058-5276 J9 NAT MICROBIOL JI NAT. MICROBIOL PD MAR PY 2016 VL 1 IS 3 AR 16001 DI 10.1038/NMICROBIOL.2016.1 PG 8 WC Microbiology SC Microbiology GA DW4HU UT WOS:000383604600007 PM 27572166 ER PT J AU Sprecher, A Feldmann, H Hensley, LE Kobinger, G Nichol, ST Strong, J Van Herp, M AF Sprecher, Armand Feldmann, Heinz Hensley, Lisa E. Kobinger, Gary Nichol, Stuart T. Strong, Jim Van Herp, Michel TI Ebola virus is unlikely to become endemic in West Africa SO NATURE MICROBIOLOGY LA English DT Editorial Material ID BATS; INFECTION AB Concern over Ebola becoming endemic in West Africa has appeared in the medical and lay media. Routes of transmission, rates of viral evolution, suitability of humans as hosts and rarity of spillover events make this very unlikely. Without evidence that endemic Ebola is likely, ending epidemics should remain the focus. C1 [Sprecher, Armand; Van Herp, Michel] Med Sans Frontieres, Rue Arbre Benit 46, B-1050 Brussels, Belgium. [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, 903 S 4th St, Hamilton, MT 59840 USA. [Hensley, Lisa E.] Integrated Res Facil, Frederick, MD USA. [Hensley, Lisa E.] NIAID, 8200 Res Plaza Way, Frederick, MD 21702 USA. [Kobinger, Gary; Strong, Jim] Natl Microbiol Lab, 1015 Arlington St, Winnipeg, MB, Canada. [Nichol, Stuart T.] Ctr Dis Control & Prevent, Viral Special Pathogens Branch, Div High Consequence Pathogens & Pathol, 1600 Clifton Rd NE, Atlanta, GA 30333 USA. RP Sprecher, A (reprint author), Med Sans Frontieres, Rue Arbre Benit 46, B-1050 Brussels, Belgium. EM armand.sprecher@brussels.msf.org NR 16 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND EI 2058-5276 J9 NAT MICROBIOL JI NAT. MICROBIOL PD MAR PY 2016 VL 1 IS 3 AR 16007 DI 10.1038/NMICROBIOL.2016.7 PG 2 WC Microbiology SC Microbiology GA DW4HU UT WOS:000383604600019 PM 27572170 ER PT J AU Wang, H Li, LL Wu, TX Hou, B Wu, S Qiu, YH Feng, F Cui, LY AF Wang, Han Li, Linling Wu, Tianxia Hou, Bo Wu, Shuang Qiu, Yunhai Feng, Feng Cui, Liying TI Increased cerebellar activation after repetitive transcranial magnetic stimulation over the primary motor cortex in patients with multiple system atrophy SO ANNALS OF TRANSLATIONAL MEDICINE LA English DT Article DE Multiple system atrophy (MSA); repetitive transcranial magnetic stimulation (rTMS); functional magnetic resonance imaging (fMRI); unified multiple system atrophy rating scale (UMSARS); cerebellum ID PARKINSONS-DISEASE; NATURAL-HISTORY; RATING-SCALE; RTMS; METAANALYSIS; PERFORMANCE; DISORDERS AB Background: Previous review reported that the high-frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor area (M1) of Parkinson's disease (PD) patients could alleviate their symptoms. This study aimed to investigate the effect of rTMS over the left M1 of patients with multiple system atrophy (MSA). Methods: Fifteen MSA patients were randomly assigned to receive a 10-session real (EP: group of experimental patients; n = 7) or sham (CP: group of control patients; n = 8) rTMS stimulation over two weeks. The overall experimental procedure consisted of two functional magnetic resonance imaging (fMRI) sessions, before and after a 10-session rTMS treatment. A complex self-paced sequential tapping task was performed during fMRI scanning. In addition, 18 age and gender matched healthy controls (HC) were enrolled. Subjects from the HC group did not receive any rTMS treatment and they underwent fMRI examination only once. The primary end point was the motor score change of the Unified Multiple System Atrophy Rating Scale (UMSARS-II) measured before and after the 5th and 10th session. Task-related activation was also compared among groups. Results: After active rTMS treatment, only patients of EP group significant improvement in UMSARS-II score. Compared to HC, MSA patients showed significant activation over similar brain areas except for the cerebellum. Increased activation was obtained in the bilateral cerebellum after rTMS treatment in the EP group. On the contrary, no increased activation was identified in the CP group. Conclusions: Our results highlight rTMS over M1 induced motor improvement in MSA patients that may be associated with increased activation in the cerebellum. C1 [Wang, Han; Wu, Shuang; Cui, Liying] Beijing Union Med Coll Hosp, Dept Neurol, Beijing 100730, Peoples R China. [Li, Linling; Qiu, Yunhai] Chinese Acad Sci, Shenzhen Inst Adv Technol, Inst Biomed & Hlth Engn, Res Ctr Neural Engn, Shenzhen 518055, Peoples R China. [Wu, Tianxia] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Hou, Bo; Feng, Feng] Beijing Union Med Coll Hosp, Dept Radiol, Beijing 100730, Peoples R China. [Cui, Liying] Chinese Acad Med Sci Neurosci, Ctr Neurosci, Beijing 100730, Peoples R China. RP Wang, H (reprint author), Beijing Union Med Coll Hosp, Dept Neurol, Beijing 100730, Peoples R China.; Qiu, YH (reprint author), Chinese Acad Sci, Shenzhen Inst Adv Technol, Inst Biomed & Hlth Engn, Res Ctr Neural Engn, Shenzhen 518055, Peoples R China. EM wanghanpumch@163.com; yh.qiu@siat.ac.cn FU National Natural Science Foundation [30800352]; Science Technology and Innovation Committee of Shenzhen [JC201005270293A, JC201104220257A]; Hundred Talents Program of Chinese Academy of Sciences Grant [Y14408] FX This work was supported by the National Natural Science Foundation (30800352 to H Wang); the Science Technology and Innovation Committee of Shenzhen (JC201005270293A and JC201104220257A to Y Qiu); and the Hundred Talents Program of Chinese Academy of Sciences Grant (Y14408 to Y Qiu). NR 34 TC 0 Z9 0 U1 1 U2 1 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2305-5839 EI 2305-5847 J9 ANN TRANSL MED JI ANN. TRANSL. MED. PD MAR PY 2016 VL 4 IS 6 AR 103 DI 10.21037/atm.2016.03.24 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DY0MZ UT WOS:000384792200001 PM 27127756 ER PT J AU Hong, CW Chow, L Turkbey, EB Lencioni, R Libutti, SK Wood, BJ AF Hong, Cheng William Chow, Lucy Turkbey, Evrim B. Lencioni, Riccardo Libutti, Steven K. Wood, Bradford J. TI Imaging Features of Radiofrequency Ablation with Heat-Deployed Liposomal Doxorubicin in Hepatic Tumors SO CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article DE Interventional oncology; Radiofrequency ablation; Hepatocellular carcinoma (HCC); Tumor/tumour/neoplasm ID SMALL HEPATOCELLULAR-CARCINOMA; MULTIPHASE HELICAL CT; COLORECTAL-CANCER; THERMAL ABLATION; METASTASES; RESECTION; SURVIVAL; LIVER; RECURRENCE AB Introduction The imaging features of unresectable hepatic malignancies in patients who underwent radiofrequency ablation (RFA) in combination with lyso-thermosensitive liposomal doxorubicin (LTLD) were determined. Materials and Methods A phase I dose escalation study combining RFA with LTLD was performed with peri-and post-procedural CT and MRI. Imaging features were analyzed and measured in terms of ablative zone size and surrounding penumbra size. The dynamic imaging appearance was described qualitatively immediately following the procedure and at 1-month follow-up. The control group receiving liver RFA without LTLD was compared to the study group in terms of imaging features and post-ablative zone size dynamics at follow-up. Results Post-treatment scans of hepatic lesions treated with RFA and LTLD have distinctive imaging characteristics when compared to those treated with RFA alone. The addition of LTLD resulted in a regular or smooth enhancing rim on T1W MRI which often correlated with increased attenuation on CT. The LTLD-treated ablation zones were stable or enlarged at follow-up four weeks later in 69 % of study subjects as opposed to conventional RFA where the ablation zone underwent involution compared to imaging acquired immediately after the procedure. Conclusion The imaging features following RFA with LTLD were different from those after standard RFA and can mimic residual or recurrent tumor. Knowledge of the subtle findings between the two groups can help avoid misinterpretation and proper identification of treatment failure in this setting. Increased size of the LTLD-treated ablation zone after RFA suggests the ongoing drug-induced biological effects. C1 [Hong, Cheng William; Chow, Lucy; Wood, Bradford J.] NIH, Ctr Intervent Oncol, Ctr Clin, 10 Ctr Dr MSC 1182, Bethesda, MD 20892 USA. [Hong, Cheng William; Chow, Lucy; Turkbey, Evrim B.; Wood, Bradford J.] NIH, Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr MSC 1074, Bethesda, MD 20892 USA. [Lencioni, Riccardo] Pisa Univ Hosp, Div Diagnost Imaging & Intervent, Dept Hepatol & Liver Transplantat, Via Paradisa 2,Bldg 29, I-56124 Pisa, Italy. [Libutti, Steven K.] Albert Einstein Coll Med, Dept Surg, Montefiore Einstein Ctr Canc Care, 111 East 210th St, Bronx, NY 10467 USA. [Libutti, Steven K.; Wood, Bradford J.] NCI, NIH, 9609 Med Ctr Dr,GB 9609 MSC 9760, Bethesda, MD 20892 USA. RP Hong, CW (reprint author), NIH, Ctr Intervent Oncol, Ctr Clin, 10 Ctr Dr MSC 1182, Bethesda, MD 20892 USA.; Hong, CW (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr MSC 1074, Bethesda, MD 20892 USA. EM williamhongcheng@gmail.com; lucychow282@gmail.com; evrimbengi@yahoo.com; riccardo.lencioni@med.unipi.it; slibutti@montefiore.org; bwood@nih.gov FU Center for Interventional Oncology; National Cancer Institute; Intramural Research Program of the National Institutes of Health (NIH); NIH; Pfizer Inc; Leona M. and Harry B. Helmsley Charitable Trust; Howard Hughes Medical Institute FX This work was supported by the Center for Interventional Oncology, the National Cancer Institute, and the Intramural Research Program of the National Institutes of Health (NIH). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, The Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at http://www.fnih.org/work/programs-development/medical-research-scholars- program). NR 23 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0174-1551 EI 1432-086X J9 CARDIOVASC INTER RAD JI Cardiovasc. Interv. Radiol. PD MAR PY 2016 VL 39 IS 3 BP 409 EP 416 DI 10.1007/s00270-015-1186-0 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DX9OK UT WOS:000384724800011 PM 26228246 ER PT J AU Ang, SY Uebersohn, A Spencer, CI Huang, Y Lee, JE Ge, K Bruneau, BG AF Ang, Siang-Yun Uebersohn, Alec Spencer, C. Ian Huang, Yu Lee, Ji-Eun Ge, Kai Bruneau, Benoit G. TI KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation SO DEVELOPMENT LA English DT Article DE KMT2D; MLL2; MLL4; ALR; Kabuki syndrome; H3K4 methylation; Heart development; Mouse ID CHANNEL-BLOCKING ACTIVITY; KABUKI-SYNDROME; GENE-EXPRESSION; CARDIAC-ARRHYTHMIA; COMPASS FAMILY; HYPOXIA; DEFECTS; TRANSCRIPTION; ACTIVATION; LINEAGE AB KMT2D, which encodes a histone H3K4 methyltransferase, has been implicated in human congenital heart disease in the context of Kabuki syndrome. However, its role in heart development is not understood. Here, we demonstrate a requirement for KMT2D in cardiac precursors and cardiomyocytes during cardiogenesis in mice. Gene expression analysis revealed downregulation of ion transport and cell cycle genes, leading to altered calcium handling and cell cycle defects. We further determined that myocardial Kmt2d deletion led to decreased H3K4me1 and H3K4me2 at enhancers and promoters. Finally, we identified KMT2D-bound regions in cardiomyocytes, of which a subset was associated with decreased gene expression and decreased H3K4me2 in mutant hearts. This subset included genes related to ion transport, hypoxia-reoxygenation and cell cycle regulation, suggesting that KMT2D is important for these processes. Our findings indicate that KMT2D is essential for regulating cardiac gene expression during heart development primarily via H3K4 di-methylation. C1 [Ang, Siang-Yun; Uebersohn, Alec; Spencer, C. Ian; Huang, Yu; Bruneau, Benoit G.] Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA. [Ang, Siang-Yun; Uebersohn, Alec; Spencer, C. Ian; Huang, Yu; Bruneau, Benoit G.] Roddenberry Ctr Stem Cell Biol & Med Gladstone, San Francisco, CA 94158 USA. [Ang, Siang-Yun; Bruneau, Benoit G.] Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94158 USA. [Lee, Ji-Eun; Ge, Kai] NIDDK, NIH, Bethesda, MD 20892 USA. [Bruneau, Benoit G.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Bruneau, Benoit G.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. RP Bruneau, BG (reprint author), Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA.; Bruneau, BG (reprint author), Roddenberry Ctr Stem Cell Biol & Med Gladstone, San Francisco, CA 94158 USA.; Bruneau, BG (reprint author), Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94158 USA.; Bruneau, BG (reprint author), Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA.; Bruneau, BG (reprint author), Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. EM benoit.bruneau@gladstone.ucsf.edu OI Ge, Kai/0000-0002-7442-5138; Uebersohn, Alec/0000-0003-2052-8358 FU Agency of Science, Technology and Research Singapore (A*STAR); Intramural Research Program of the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); NIH/National Heart, Lung, and Blood Institute (NHLBI) [NHLBI Bench to Bassinet Program] [U01HL098179/UM1HL098179]; Lawrence J. and Florence A. DeGeorge Charitable Trust/American Heart Association Established Investigator Award, an NIH/National Center for Research Resources (NCRR) grant [C06 RR018928] FX S.-Y.A. was supported by a graduate fellowship from Agency of Science, Technology and Research Singapore (A*STAR). Work in the K.G. laboratory was supported by the Intramural Research Program of the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). B.G.B. was supported by a grant from NIH/National Heart, Lung, and Blood Institute (NHLBI) [NHLBI Bench to Bassinet Program, U01HL098179/UM1HL098179], by the Lawrence J. and Florence A. DeGeorge Charitable Trust/American Heart Association Established Investigator Award, an NIH/National Center for Research Resources (NCRR) grant [C06 RR018928] to the J. David Gladstone Institutes, and by William H. Younger, Jr. Deposited in PMC for immediate release. NR 63 TC 4 Z9 4 U1 3 U2 3 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 MAR 1 PY 2016 VL 143 IS 5 BP 810 EP 821 DI 10.1242/dev.132688 PG 12 WC Developmental Biology SC Developmental Biology GA DX9XD UT WOS:000384749400009 PM 26932671 ER PT J AU Demner-Fushman, D Kohli, MD Rosenman, MB Shooshan, SE Rodriguez, L Antani, S Thoma, GR McDonald, CJ AF Demner-Fushman, Dina Kohli, Marc D. Rosenman, Marc B. Shooshan, Sonya E. Rodriguez, Laritza Antani, Sameer Thoma, George R. McDonald, Clement J. TI Preparing a collection of radiology examinations for distribution and retrieval SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE information storage and retrieval; abstracting and indexing; radiography; medical records; biometric identification ID NEGATION AB Objective Clinical documents made available for secondary use play an increasingly important role in discovery of clinical knowledge, development of research methods, and education. An important step in facilitating secondary use of clinical document collections is easy access to descriptions and samples that represent the content of the collections. This paper presents an approach to developing a collection of radiology examinations, including both the images and radiologist narrative reports, and making them publicly available in a searchable database. Materials and Methods The authors collected 3996 radiology reports from the Indiana Network for Patient Care and 8121 associated images from the hospitals' picture archiving systems. The images and reports were de-identified automatically and then the automatic de-identification was manually verified. The authors coded the key findings of the reports and empirically assessed the benefits of manual coding on retrieval. Results The automatic de-identification of the narrative was aggressive and achieved 100% precision at the cost of rendering a few findings uninterpretable. Automatic de-identification of images was not quite as perfect. Images for two of 3996 patients (0.05%) showed protected health information. Manual encoding of findings improved retrieval precision. Conclusion Stringent de-identification methods can remove all identifiers from text radiology reports. DICOM de-identification of images does not remove all identifying information and needs special attention to images scanned from film. Adding manual coding to the radiologist narrative reports significantly improved relevancy of the retrieved clinical documents. The de-identified Indiana chest X-ray collection is available for searching and downloading from the National Library of Medicine (http://openi.nlm.nih.gov/). C1 [Demner-Fushman, Dina; Shooshan, Sonya E.; Rodriguez, Laritza; McDonald, Clement J.] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bldg 38A,Room 10S-1022,Rockville Pike MSC 3824, Bethesda, MD 20894 USA. [Kohli, Marc D.] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Informat, Indianapolis, IN 46202 USA. [Rosenman, Marc B.] Indiana Univ Sch Med, Dept Pediat, Childrens Hlth Serv Res, Indianapolis, IN 46202 USA. [Antani, Sameer; Thoma, George R.] NIH, Commun Engn Branch, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bldg 38A,Room 10S-1022,Rockville Pike MSC 3824, Bethesda, MD 20894 USA. RP Demner-Fushman, D (reprint author), NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bldg 38A,Room 10S-1022,Rockville Pike MSC 3824, Bethesda, MD 20894 USA. EM ddemner@mail.nih.gov FU Intramural Research Program of the National Library of Medicine, National Institutes of Health FX This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. This work was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. NR 19 TC 1 Z9 1 U1 3 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAR PY 2016 VL 23 IS 2 BP 304 EP 310 DI 10.1093/jamia/ocv080 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DW6SN UT WOS:000383781600010 PM 26133894 ER PT J AU Gonzales, FA Shariff-Marco, S Langer, MM Reeve, BB Nuru-Jeter, AM Dwyer, LA Gomez, SL AF Gonzales, Felisa A. Shariff-Marco, Salma Langer, Michelle M. Reeve, Bryce B. Nuru-Jeter, Amani M. Dwyer, Laura A. Gomez, Scarlett Lin TI Validation of a new medical discrimination scale among a diverse population of breast cancer survivors SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Gonzales, Felisa A.; Dwyer, Laura A.] NCI, Rockville, MD USA. [Shariff-Marco, Salma; Gomez, Scarlett Lin] Canc Prevent Inst Calif, Fremont, CA USA. [Langer, Michelle M.; Reeve, Bryce B.] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Nuru-Jeter, Amani M.] Univ Calif Berkeley, Berkeley, CA 94720 USA. NR 0 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 MAR PY 2016 VL 25 IS 3 SU S MA C16 DI 10.1158/1538-7755.DISP15-C16 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300090 ER PT J AU Kim, S Hu, FJ DeRoo, L Meier, H Parks, C Sandler, D AF Kim, Sangmi Hu, Fengjiao DeRoo, Lisa Meier, Helen Parks, Christine Sandler, Dale TI Optimism and breast cancer risk: Results from a prospective cohort study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Kim, Sangmi; Hu, Fengjiao] Georgia Regents Univ, Augusta, GA USA. [DeRoo, Lisa; Meier, Helen; Parks, Christine; Sandler, Dale] NIEHS, Durham, NC 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA C39 DI 10.1158/1538-7755.DISP15-C39 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300079 ER PT J AU Layne, TM Weinstein, S Ma, XM Graubard, BI Mayne, ST Albanes, D AF Layne, Tracy M. Weinstein, Stephanie Ma, Xiaomei Graubard, Barry I. Mayne, Susan T. Albanes, Demetrius TI Serum vitamin D and risk of prostate cancer among black men in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Layne, Tracy M.] NCI, Yale Sch Publ Hlth, NIH, Bethesda, MD 20892 USA. [Weinstein, Stephanie; Graubard, Barry I.; Albanes, Demetrius] NCI, NIH, Bethesda, MD 20892 USA. [Ma, Xiaomei; Mayne, Susan T.] Yale Sch Publ Hlth, New Haven, CT 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA C41 DI 10.1158/1538-7755.DISP15-C41 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300080 ER PT J AU Bloomfield, GS Narayan, KMV Sampson, UKA Narula, J AF Bloomfield, Gerald S. Narayan, K. M. Venkat Sampson, Uchechukwu K. A. Narula, Jagat TI What Defines a Valuable Investment in Global Health Research? SO GLOBAL HEART LA English DT Editorial Material ID DISEASE; MORTALITY; AFRICA; HEART C1 [Bloomfield, Gerald S.] Duke Univ, Med Ctr, Duke Clin Res Inst, Dept Med, Durham, NC USA. [Bloomfield, Gerald S.] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Narayan, K. M. Venkat] Emory Univ, Rollins Sch Publ Hlth, Emory Global Diabet Res Ctr, Atlanta, GA 30322 USA. [Sampson, Uchechukwu K. A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bethesda, MD 20892 USA. [Narula, Jagat] Mt Sinai Hosp, Dept Med, New York, NY 10029 USA. RP Narula, J (reprint author), Mt Sinai Hosp, Dept Med, New York, NY 10029 USA. EM jagat.narula@mountsinai.org NR 24 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2211-8160 EI 2211-8179 J9 GLOB HEART JI Glob. Heart PD MAR PY 2016 VL 11 IS 1 BP 1 EP 3 DI 10.1016/j.gheart.2015.12.007 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV1II UT WOS:000382674100001 PM 27102017 ER PT J AU Engelgau, MM Sampson, UK Rabadan-Diehl, C Smith, R Miranda, J Bloomfield, GS Belis, D Narayan, KMV AF Engelgau, Michael M. Sampson, Uchechukwu K. Rabadan-Diehl, Cristina Smith, Richard Miranda, Jaime Bloomfield, Gerald S. Belis, Deshiree Narayan, K. M. Venkat CA Natl Hlth Lung & Blood Inst-United TI Tackling NCD in LMIC Achievements and Lessons Learned From the NHLBI-UnitedHealth Global Health Centers of Excellence Program SO GLOBAL HEART LA English DT Review ID NONCOMMUNICABLE DISEASES; EPIDEMIOLOGY; SCIENCE; AFRICA; BURDEN; GOALS; MODEL; TRIAL; KENYA; RISK AB Effectively tackling the growing noncommunicable disease (NCD) burden in low- and middle-income countries (LMIC) is a major challenge. To address research needs in this setting for NCDs, in 2009, National Heart, Lung, and Blood Institute (NHLBI) and UnitedHealth Group (UHG) engaged in a public-private partnership that supported a network of 11 LMIC-based research centers and created the NHLBI-UnitedHealth Global Health Centers of Excellence (COE) Program. The Program's overall goal was to contribute to reducing the cardiovascular and lung disease burdens by catalyzing in-country research institutions to develop a global network of biomedical research centers. Key elements of the Program included team science and collaborative approaches, developing research and training platforms for future investigators, and creating a data commons. This Program embraced a strategic approach for tackling NCDs in LMICs and will provide capacity for locally driven research efforts that can identify and address priority health issues in specific countries' settings. C1 [Engelgau, Michael M.; Sampson, Uchechukwu K.; Rabadan-Diehl, Cristina; Smith, Richard; Miranda, Jaime; Bloomfield, Gerald S.; Belis, Deshiree; Narayan, K. M. Venkat; Natl Hlth Lung & Blood Inst-United] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bethesda, MD 20892 USA. RP Engelgau, MM (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bethesda, MD 20892 USA. EM michael.engelgau@nih.gov OI Prabhakaran, Dorairaj/0000-0002-3172-834X; Reddy, K Srinath/0000-0003-3416-3548 FU Intramural NIH HHS [Z99 HL999999]; Medical Research Council [MR/M007405/1]; Wellcome Trust [091077] NR 40 TC 12 Z9 12 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2211-8160 EI 2211-8179 J9 GLOB HEART JI Glob. Heart PD MAR PY 2016 VL 11 IS 1 BP 5 EP 15 DI 10.1016/j.gheart.2015.12.016 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV1II UT WOS:000382674100002 PM 27102018 ER PT J AU Bloomfield, GS Xavier, D Belis, D Alam, D Davis, P Prabhakaran, D Ghannem, H Gilman, RH Kamath, D Kimaiyo, S Levit, N Martinez, H Mejicano, G Miranda, JJ Koehlmoos, TP Rabadan-Diehl, C Ramirez-Zea, M Rubinstein, A Sacksteder, KA Steyn, K Tandon, N Vedanthan, R Wolbach, T Wu, YF Yan, LJL AF Bloomfield, Gerald S. Xavier, Denis Belis, Deshiree Alam, Dewan Davis, Patricia Prabhakaran, Dorairaj Ghannem, Hassen Gilman, Robert H. Kamath, Deepak Kimaiyo, Sylvester Levit, Naomi Martinez, Homero Mejicano, Gabriela Jaime Miranda, J. Koehlmoos, Tracey Perez Rabadan-Diehl, Cristina Ramirez-Zea, Manuel Rubinstein, Adolfo Sacksteder, Katherine A. Steyn, Krisela Tandon, Nikhil Vedanthan, Rajesh Wolbach, Tracy Wu, Yangfeng Yan, Lijing L. TI Training and Capacity Building in LMIC for Research in Heart and Lung Diseases The NHLBI-UnitedHealth Global Health Centers of Excellence Program SO GLOBAL HEART LA English DT Review ID CARDIOVASCULAR RESEARCH; MYOCARDIAL-INFARCTION; COUNTRIES; OPPORTUNITIES; PREVENTION; INTERHEART; COMMUNITY; AFRICA; BURDEN AB Stemming the tide of noncommunicable diseases (NCDs) worldwide requires a multipronged approach. Although much attention has been paid to disease control measures, there is relatively little consideration of the importance of training the next generation of health-related researchers to play their important role in this global epidemic. The lack of support for early stage investigators in low-and middle-income countries interested in the global NCD field has resulted in inadequate funding opportunities for research, insufficient training in advanced research methodology and data analysis, lack of mentorship in manuscript and grant writing, and meager institutional support for developing, submitting, and administering research applications and awards. To address this unmet need, The National Heart, Lung, and Blood Institute-UnitedHealth Collaborating Centers of Excellence initiative created a Training Subcommittee that coordinated and developed an intensive, mentored health-related research experience for a number of early stage investigators from the 11 Centers of Excellence around the world. We describe the challenges faced by early stage investigators in low-and middle-income countries, the organization and scope of the Training Subcommittee, training activities, early outcomes of the early stage investigators (foreign and domestic) and training materials that have been developed by this program that are available to the public. By investing in the careers of individuals in a supportive global NCD network, we demonstrate the impact that an investment in training individuals from low-and middle-income countries can have on the preferred future of or current efforts to combat NCDs. C1 [Bloomfield, Gerald S.] Duke Univ, Dept Med, Duke Clin Res Inst, Durham, NC USA. [Bloomfield, Gerald S.] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Xavier, Denis] St Johns Med Coll & Res Inst, Dept Pharmacol, Bangalore, Karnataka, India. [Xavier, Denis] St Johns Med Coll & Res Inst, Div Clin Res & Training, Bangalore, Karnataka, India. [Belis, Deshiree; Kamath, Deepak] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Alam, Dewan] Li Ka Shing Knowledge Inst, Ctr Global Hlth Res, Toronto, ON, Canada. [Davis, Patricia; Wolbach, Tracy] Westat Corp, Rockville, MD USA. [Prabhakaran, Dorairaj] PHFI, New Delhi, India. [Prabhakaran, Dorairaj] CCDC, New Delhi, India. [Ghannem, Hassen] Univ Hosp Farhat Hached, Chron Dis Prevent Res Ctr, Dept Epidemiol, Sousse, Tunisia. [Gilman, Robert H.; Sacksteder, Katherine A.] Johns Hopkins Univ, Dept Int Hlth, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kimaiyo, Sylvester] Moi Univ, AMPATH, Sch Med, Coll Hlth Sci, Eldoret, Kenya. [Kimaiyo, Sylvester] Moi Teaching & Referral Hosp, Eldoret, Kenya. [Levit, Naomi; Steyn, Krisela] Univ Cape Town, CDIA, Dept Med, Fac Hlth Sci, Cape Town, South Africa. [Levit, Naomi; Steyn, Krisela] Univ Cape Town, Div Diabet Med & Endocrinol, Dept Med, Fac Hlth Sci, Cape Town, South Africa. [Martinez, Homero] RAND Corp, Santa Monica, CA USA. [Mejicano, Gabriela; Ramirez-Zea, Manuel] Inst Nutr Cent Amer & Panama, INCAP Res Ctr Prevent Chron Dis CIIPEC, Guatemala City, Guatemala. [Jaime Miranda, J.] Univ Peruana Cayetano Heredia, CRONICAS Ctr Excellence Chron Dis, Lima, Peru. [Jaime Miranda, J.] Univ Peruana Cayetano Heredia, Dept Med, Sch Med, Lima, Peru. [Koehlmoos, Tracey Perez] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Rabadan-Diehl, Cristina] US Dept HHS, Off Global Affairs, Washington, DC 20201 USA. [Rubinstein, Adolfo] Inst Clin Effectiveness & Hlth Policy IECS, South Amer Ctr Excellence Cardiovasc Hlth CESCAS, Buenos Aires, DF, Argentina. [Tandon, Nikhil] All India Inst Med Sci, New Delhi, India. [Vedanthan, Rajesh] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Wu, Yangfeng; Yan, Lijing L.] Peking Univ, Hlth Sci Ctr, George Inst Global Hlth, Beijing, Peoples R China. [Wu, Yangfeng] Peking Univ, Clin Res Inst, Dept Epidemiol & Biostat, Sch Publ Hlth, Beijing, Peoples R China. [Yan, Lijing L.] Duke Kunshan Univ, Duke Global Hlth Inst, Kunshan, Peoples R China. [Yan, Lijing L.] Duke Kunshan Univ, Global Hlth Res Ctr, Kunshan, Peoples R China. RP Belis, D (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. EM deshiree.belis@nih.gov OI Prabhakaran, Dorairaj/0000-0002-3172-834X FU FIC NIH HHS [K01 TW 009218-05, K01 TW008407, K01 TW009218, K01TW008407]; Intramural NIH HHS [Z99 HL999999]; NHLBI NIH HHS [HHSN268200900025C, HHSN268200900026C, HHSN268200900027C, HHSN268200900028C, HHSN268200900029C, HHSN268200900030C, HHSN268200900031C, HHSN268200900033C, HHSN268200900032C] NR 27 TC 5 Z9 5 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2211-8160 EI 2211-8179 J9 GLOB HEART JI Glob. Heart PD MAR PY 2016 VL 11 IS 1 BP 17 EP 25 DI 10.1016/j.gheart.2016.01.004 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV1II UT WOS:000382674100014 PM 27102019 ER PT J AU Sampson, UKA Chambers, D Riley, W Glass, RI Engelgau, MM Mensah, GA AF Sampson, Uchechukwu K. A. Chambers, David Riley, William Glass, Roger I. Engelgau, Michael M. Mensah, George A. TI Implementation Research The Fourth Movement of the Unfinished Translation Research Symphony SO GLOBAL HEART LA English DT Article ID SYSTEMATIC ANALYSIS; BLOOD INSTITUTE; NATIONAL HEART; GLOBAL BURDEN; PUBLIC-HEALTH; UNITED-STATES; RISK-FACTORS; NIH ROADMAP; 21 REGIONS; LUNG C1 [Sampson, Uchechukwu K. A.; Engelgau, Michael M.; Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Chambers, David] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Riley, William] NIH, Off Behav & Social Sci Res, Bldg 10, Bethesda, MD 20892 USA. [Glass, Roger I.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Sampson, UKA (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. EM uchechukwu.sampson@nih.gov NR 41 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2211-8160 EI 2211-8179 J9 GLOB HEART JI Glob. Heart PD MAR PY 2016 VL 11 IS 1 BP 153 EP 158 DI 10.1016/j.gheart.2016.01.008 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV1II UT WOS:000382674100011 PM 27102036 ER PT J AU Mensah, GA AF Mensah, George A. TI Global Health Research SO GLOBAL HEART LA English DT Article ID CHRONIC DISEASES; NATIONAL HEART; MORTALITY; ALLIANCE; LUNG C1 [Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Mensah, George A.] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Mensah, GA (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA.; Mensah, GA (reprint author), NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. EM george.mensah@nih.gov NR 25 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2211-8160 EI 2211-8179 J9 GLOB HEART JI Glob. Heart PD MAR PY 2016 VL 11 IS 1 BP 159 EP 164 DI 10.1016/j.gheart.2016.01.005 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV1II UT WOS:000382674100012 PM 27102037 ER PT J AU Peprah, E Wiley, K Troyer, J Adebamowo, SN Adu, D Mayosi, BM Ramsay, M Motala, AA Adebamowo, C Ovbiagele, B Owolabi, M AF Peprah, Emmanuel Wiley, Ken Troyer, Jennifer Adebamowo, Sally N. Adu, Dwomoa Mayosi, Bongani M. Ramsay, Michele Motala, Ayesha A. Adebamowo, Clement Ovbiagele, Bruce Owolabi, Mayowa CA H3Africa Cardiovasc Dis Working Gr TI Building a Platform to Enable NCD Research to Address Population Health in Africa CVD Working Group Discussion at the Sixth H3Africa Consortium Meeting in Zambia SO GLOBAL HEART LA English DT Article ID SICKLE-CELL-DISEASE; SUB-SAHARAN AFRICA; MIDDLE-INCOME COUNTRIES; CARDIOVASCULAR-DISEASES; RISK-FACTORS; GENOMIC MEDICINE; KIDNEY-DISEASE; INTERVENTIONS; BURDEN; STROKE C1 [Peprah, Emmanuel] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wiley, Ken; Troyer, Jennifer; Adebamowo, Sally N.] NHGRI, NIH, Bethesda, MD 20892 USA. [Adu, Dwomoa] Univ Ghana, Dept Med & Therapeut, Accra, Ghana. [Mayosi, Bongani M.] Groote Schuur Hosp, Dept Med, Cape Town, South Africa. [Mayosi, Bongani M.] Univ Cape Town, Cape Town, South Africa. [Ramsay, Michele] Univ Witwatersrand, Sydney Brenner Inst Mol Biosci, Fac Hlth Sci, Johannesburg, South Africa. [Ramsay, Michele] Univ Witwatersrand, Div Human Genet, Fac Hlth Sci, Johannesburg, South Africa. [Motala, Ayesha A.] Univ KwaZulu Natal, Dept Endocrinol & Diabet, Sch Clin Med, Nelson R Mandela Campus, Kwa Zulu, South Africa. [Adebamowo, Clement] Univ Maryland, Dept Epidemiol & Publ Hlth, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Adebamowo, Clement] Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. [Adebamowo, Clement] Inst Human Virol, Strateg Informat Training & Res Off, Garki, Abuja, Nigeria. [Ovbiagele, Bruce] Med Univ South Carolina, Dept Neurol, Charleston, SC USA. [Owolabi, Mayowa] Univ Ibadan, Coll Med, Coll Med, Ibadan, Nigeria. RP Peprah, E (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. EM emmanuel.peprah@nih.gov FU Intramural NIH HHS [Z99 HL999999]; NHGRI NIH HHS [U54 HG006938, 1U54HG006947, U54 HG006939, U54 HG006947, U54 HG007479]; WETP NIH HHS [WT099316A1A]; Wellcome Trust [099313/B/12/2] NR 43 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2211-8160 EI 2211-8179 J9 GLOB HEART JI Glob. Heart PD MAR PY 2016 VL 11 IS 1 BP 165 EP 170 DI 10.1016/j.gheart.2015.11.002 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV1II UT WOS:000382674100013 PM 27102038 ER PT J AU Bassey-Archibong, BI Rayner, LGA Gardner, K Daniel, J AF Bassey-Archibong, Blessing I. Rayner, Lyndsay G. A. Gardner, Kevin Daniel, Juliet TI High expression of the transcription factor Kaiso correlates with aggressive breast cancers (BC) and racial disparity in BC outcomes in women of African ancestry SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Bassey-Archibong, Blessing I.; Rayner, Lyndsay G. A.; Daniel, Juliet] McMaster Univ, Hamilton, ON, Canada. [Gardner, Kevin] NIH, Bldg 10, Bethesda, MD 20892 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA B17 DI 10.1158/1538-7755.DISP15-B17 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300132 ER PT J AU Byrd, DA Agurs-Collins, T Berrigan, D Thompson, F AF Byrd, Doratha Armenthus Agurs-Collins, Tanya Berrigan, David Thompson, Francis TI Racial and ethnic differences in dietary intake, physical activity, and body mass index (BMI) among cancer survivors: 2005 and 2010 National Health Interview Surveys (NHIS) SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Byrd, Doratha Armenthus; Agurs-Collins, Tanya; Berrigan, David; Thompson, Francis] NCI, NIH, DHHS, Rockville, MD 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA PR07 DI 10.1158/1538-7755.DISP16-PR07 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300172 ER PT J AU Conley, BA AF Conley, Barbara A. TI NCI MATCH: A national precision medicine trial - Conception, development, and adjustment SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Conley, Barbara A.] NCI, Bethesda, MD 20892 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA IA38 DI 10.1158/1538-7755.DISP15-IA38 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300281 ER PT J AU Cropp, CD McDonnell, SK Middha, S DeRycke, M Karyadi, DM Schaid, D Thibodeau, SN Isaacs, WB Ostrander, EA Stanford, J Cooney, KA Bailey-Wilson, JE Carpten, JD AF Cropp, Cheryl D. McDonnell, Shannon K. Middha, Sumit DeRycke, Melissa Karyadi, Danielle M. Schaid, Daniel Thibodeau, Stephen N. Isaacs, William B. Ostrander, Elaine A. Stanford, Janet Cooney, Kathleen A. Bailey-Wilson, Joan E. Carpten, John D. TI Rare variant discovery in known cancer genes from whole-exome sequencing-of African American hereditary prostate cancer families SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Cropp, Cheryl D.; Carpten, John D.] Translat Genom Res Inst TGen, Phoenix, AZ USA. [McDonnell, Shannon K.; Middha, Sumit; DeRycke, Melissa; Schaid, Daniel; Thibodeau, Stephen N.] Mayo Clin, Rochester, MN USA. [Karyadi, Danielle M.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. [Isaacs, William B.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Stanford, Janet] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Cooney, Kathleen A.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, Baltimore, MD USA. NR 0 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 MAR PY 2016 VL 25 IS 3 SU S MA B40 DI 10.1158/1538-7755.DISP15-B40 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300181 ER PT J AU Geiger, AM AF Geiger, Ann M. TI NCORP cancer care delivery research: A new opportunity for studying cancer disparities SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Geiger, Ann M.] NCI, Rockville, MD 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA IA27 DI 10.1158/1538-7755.DISP15-IA27 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300245 ER PT J AU Jordan, S Tang, W Wallace, T Dorsey, T Yi, M Stephens, R Prokunina-Olsson, L Ambs, S AF Jordan, Symone Tang, Wei Wallace, Tiffany Dorsey, Tiffany Yi, Ming Stephens, Robert Prokunina-Olsson, Ludmila Ambs, Stefan TI An interferon A 4 genotype is linked to a gene expression signature in prostate tumors of African American men SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Jordan, Symone; Tang, Wei; Wallace, Tiffany; Dorsey, Tiffany; Ambs, Stefan] NCI, Human Carcinogenesis Lab, CCR, Bldg 37, Bethesda, MD 20892 USA. [Yi, Ming; Stephens, Robert] NCI, Adv Biomed Comp Ctr, Leidos Biomed Res, Frederick, MD 21701 USA. [Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, DCEG, Bethesda, MD 20892 USA. NR 0 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 MAR PY 2016 VL 25 IS 3 SU S MA B51 DI 10.1158/11538-7755.DISP15-B51 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300192 ER PT J AU Lowy, DR AF Lowy, Douglas R. TI Understanding and overcoming cancer disparities in the US and abroad SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Lowy, Douglas R.] NCI, Bethesda, MD 20892 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA IA11 DI 10.1158/1538-7755.DISP15-IA11 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300265 ER PT J AU Mitchell, KA Zingone, A Ryan, B AF Mitchell, Khadijah A. Zingone, Adriana Ryan, Brid TI Lung cancer in African Americans is characterized by histone modifying enzyme gene signatures SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Mitchell, Khadijah A.; Zingone, Adriana; Ryan, Brid] NCI, Bethesda, MD 20892 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA B30 DI 10.1158/1538-7755.DISP15-B30 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300144 ER PT J AU Ryan, BM AF Ryan, Brid M. TI Genetic, environmental, and biological contributions to racial disparities in lung cancer incidence SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res ID SERUM COTININE LEVELS; AFRICAN-AMERICAN; CARCINOGEN 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE; CHROMOSOME 15Q25; RISK; SMOKING; SUSCEPTIBILITY; HISTOLOGY; NICOTINE; SURVIVAL C1 [Ryan, Brid M.] NCI, Bethesda, MD 20892 USA. NR 21 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 MAR PY 2016 VL 25 IS 3 SU S MA IA02 DI 10.1158/1538-7755.DISP15-IA02 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300274 ER PT J AU Warner, WA Llanos, AAM Lee, TY Williams, TM Badal, KM Ret, VR Slovacek, S Toriola, AT Roach, A Martin, D AF Warner, Wayne A. Llanos, Adana A. M. Lee, Tammy Y. Williams, Tanisha M. Badal, Kimberly M. Ret, Veronica Roach Slovacek, Simeon Toriola, Adetunji T. Roach, Allana Martin, Damali TI Cancer incidence and mortality rates and trends in Trinidad and Tobago SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Warner, Wayne A.; Toriola, Adetunji T.] Washington Univ, Sch Med, St Louis, MO USA. [Llanos, Adana A. M.] Rutgers Sch Publ Hlth, New Brunswick, NJ USA. [Llanos, Adana A. M.] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Lee, Tammy Y.; Slovacek, Simeon] Calif State Univ Los Angeles, Los Angeles, CA 90032 USA. [Williams, Tanisha M.] Univ Connecticut, Storrs, CT USA. [Badal, Kimberly M.; Roach, Allana] Univ West Indies, Fac Med Sci, St Augustine, Trinid & Tobago. [Ret, Veronica Roach] Dr Elizabeth Quamina Canc Registry Trinidad & Tob, Mt Hope, Trinid & Tobago. [Martin, Damali] NCI, NIH, Rockville, MD 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA B46 DI 10.1158/1538-7755.DISP15-B46 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300185 ER PT J AU Akinboro, O Ottenbacher, A Martin, M Harrison, R James, T Martin, E Murdoch, J Linnear, K Cardarelli, K AF Akinboro, Oladimeji Ottenbacher, Allison Martin, Marcus Harrison, Roderick James, Thomas Martin, Eddilisa Murdoch, James Linnear, Kim Cardarelli, Kathryn TI Racial and Ethnic Disparities in Health and Health Care: an Assessment and Analysis of the Awareness and Perceptions of Public Health Workers Implementing a Statewide Community Transformation Grant in Texas SO JOURNAL OF RACIAL AND ETHNIC HEALTH DISPARITIES LA English DT Article DE Racial health disparities; Health care disparities; Minority health; Health care personnel; Public health practice; Public health workers ID MEDICAL-CARE; PERSPECTIVES; EQUITY; RACE AB Introduction Little is known about the awareness of public health professionals regarding racial and ethnic disparities in health in the United States of America (USA). Our study objective was to assess the awareness and perceptions of a group of public health workers in Texas regarding racial health disparities and their chief contributing causes. Methods We surveyed public health professionals working on a statewide grant in Texas, who were participants at health disparities' training workshops. Multivariable logistic regression was employed in examining the association between the participants' characteristics and their perceptions of the social determinants of health as principal causes of health disparities. Results There were 106 respondents, of whom 38 and 35 % worked in health departments and non-profit organizations, respectively. The racial/ethnic groups with the highest incidence of HIV/AIDS and hypertension were correctly identified by 63 and 50 % of respondents, respectively, but only 17, and 32 % were knowledgeable regarding diabetes and cancer, respectively. Seventy-one percent of respondents perceived that health disparities are driven by the major axes of the social determinants of health. Exposure to information about racial/ethnic health disparities within the prior year was associated with a higher odds of perceiving that social determinants of health were causes of health disparities (OR 9.62; 95 % CI 2.77, 33.41). Conclusion Among public health workers, recent exposure to information regarding health disparities may be associated with their perceptions of health disparities. Further research is needed to investigate the impact of such exposure on their long-term perception of disparities, as well as the equity of services and programs they administer. C1 [Akinboro, Oladimeji] Montefiore New Rochelle Hosp, Dept Med, 16 Guion Pl, New Rochelle, NY 10801 USA. [Ottenbacher, Allison] NCI, Behav Res Program, Rockville, MD USA. [Martin, Marcus; Harrison, Roderick; James, Thomas; Martin, Eddilisa; Murdoch, James] 2M Res Serv, Cedar Hill, TX USA. [James, Thomas] Univ Oklahoma, Norman, OK 73019 USA. [Murdoch, James] Univ Texas Dallas, Dallas, TX 75230 USA. [Linnear, Kim] Univ North Texas, Hlth Sci Ctr, Ft Worth, TX USA. [Cardarelli, Kathryn] Univ Kentucky, Coll Publ Hlth, Lexington, KY USA. [Akinboro, Oladimeji; Ottenbacher, Allison; Cardarelli, Kathryn] Univ North Texas, Hlth Sci Ctr, Texas Prevent Inst, Ctr Community Hlth, Ft Worth, TX USA. RP Akinboro, O (reprint author), Montefiore New Rochelle Hosp, Dept Med, 16 Guion Pl, New Rochelle, NY 10801 USA. EM oakinbor@montefiore.org OI Ottenbacher, Allison/0000-0002-8974-5580 NR 37 TC 0 Z9 0 U1 3 U2 4 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2197-3792 EI 2196-8837 J9 J RACIAL ETHN HEALTH JI J. Racial Ethn. Health Disparities PD MAR PY 2016 VL 3 IS 1 BP 46 EP 54 DI 10.1007/s40615-015-0111-1 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DT5FU UT WOS:000381507800005 PM 26896104 ER PT J AU McCarrey, AC An, Y Kitner-Triolo, MH Ferrucci, L Resnick, SM AF McCarrey, Anna C. An, Yang Kitner-Triolo, Melissa H. Ferrucci, Luigi Resnick, Susan M. TI Sex Differences in Cognitive Trajectories in Clinically Normal Older Adults SO PSYCHOLOGY AND AGING LA English DT Article DE aging; cognitive abilities; sex differences; longitudinal ID MINI-MENTAL STATE; CONGENITAL ADRENAL-HYPERPLASIA; ALZHEIMERS-DISEASE; GENDER-DIFFERENCES; AGE-DIFFERENCES; CORTICAL THICKNESS; COHORT DIFFERENCES; SPATIAL ABILITIES; DEMENTIA; POPULATION AB Age effects on cognitive functioning are well-documented, but effects of sex on trajectories of cognitive aging are less clear. We examined cognitive ability across a variety of measures for 1,065 to 2,127 participants (mean baseline age 64.1 to 69.7 years) from the Baltimore Longitudinal Study of Aging who were repeatedly tested over a mean follow-up interval of 3.0 to 9.0 years with a mean of 2.3 to 4.4 assessments. Memory and other cognitive tests were administered at each visit, assessing mental status, verbal learning and memory, figural memory, language, attention, perceptuomotor speed and integration, executive function, and visuospatial ability. Importantly, participants free from cognitive impairment at all time points were used in the analyses. Results showed that for all tests, higher age at baseline was significantly associated with lower scores, and performance declined over time. In addition, advancing age was associated with accelerated longitudinal declines in performance (trend for mental status). After adjusting for age, education, and race, sex differences were observed across most tests of specific cognitive abilities examined. At baseline, males outperformed females on the 2 tasks of visuospatial ability, and females outperformed males in most other tests of cognition. Sex differences in cognitive change over time indicated steeper rates of decline for men on measures of mental status, perceptuomotor speed and integration, and visuospatial ability, but no measures on which women showed significantly steeper declines. Our results highlight greater resilience to age-related cognitive decline in older women compared with men. C1 [McCarrey, Anna C.; An, Yang; Kitner-Triolo, Melissa H.; Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Ferrucci, Luigi] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Resnick, SM (reprint author), NIA, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM resnicks@mail.nih.gov FU National Institutes of Health, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 76 TC 5 Z9 5 U1 3 U2 5 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 EI 1939-1498 J9 PSYCHOL AGING JI Psychol. Aging PD MAR PY 2016 VL 31 IS 2 BP 166 EP 175 DI 10.1037/pag0000070 PG 10 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA DT8HJ UT WOS:000381730500003 PM 26796792 ER PT J AU Ford, EW Hesse, BW Huerta, TR AF Ford, Eric W. Hesse, Bradford W. Huerta, Timothy R. TI Personal Health Record Use in the United States: Forecasting Future Adoption Levels SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE personal health records; electronic health records; patient participation; technology diffusion; Bass modeling; PHR Adoption Forecasts ID ELECTRONIC PATIENT PORTALS; MEANINGFUL USE; INFORMATION; CARE; OUTCOMES; PROGRAM AB Background: Personal health records (PHRs) offer a tremendous opportunity to generate consumer support in pursing the triple aim of reducing costs, increasing access, and improving care quality. Moreover, surveys in the United States indicate that consumers want Web-based access to their medical records. However, concerns that consumers' low health information literacy levels and physicians' resistance to sharing notes will limit PHRs' utility to a relatively small portion of the population have reduced both the product innovation and policy imperatives. Objective: The purpose of our study was 3-fold: first, to report on US consumers' current level of PHR activity; second, to describe the roles of imitation and innovation influence factors in determining PHR adoption rates; and third, to forecast future PHR diffusion uptake among US consumers under 3 scenarios. Methods: We used secondary data from the Health Information National Trends Survey (HINTS) of US citizens for the survey years 2008, 2011, and 2013. Applying technology diffusion theory and Bass modeling, we evaluated 3 future PHR adoption scenarios by varying the introduction dates. Results: All models displayed the characteristic diffusion S-curve indicating that the PHR technology is likely to achieve significant market penetration ahead of meaningful use goals. The best-performing model indicates that PHR adoption will exceed 75% by 2020. Therefore, the meaningful use program targets for PHR adoption are below the rates likely to occur without an intervention. Conclusions: The promise of improved care quality and cost savings through better consumer engagement prompted the US Institute of Medicine to call for universal PHR adoption in 1999. The PHR products available as of 2014 are likely to meet and exceed meaningful use stage 3 targets before 2020 without any incentive. Therefore, more ambitious uptake and functionality availability should be incorporated into future goals. C1 [Ford, Eric W.] Johns Hopkins Univ, Dept Hlth Policy & Management, 624 N Broadway, Baltimore, MD 21205 USA. [Hesse, Bradford W.] NCI, Bethesda, MD 20892 USA. [Huerta, Timothy R.] Ohio State Univ, Coll Med, Dept Family Med, Columbus, OH 43210 USA. [Huerta, Timothy R.] Ohio State Univ, Coll Med, Dept Biomed Informat, Columbus, OH 43210 USA. RP Ford, EW (reprint author), Johns Hopkins Univ, Dept Hlth Policy & Management, 624 N Broadway, Baltimore, MD 21205 USA. EM ewford@gmail.com RI Huerta, Timothy/C-1748-2014; OI Hesse, Bradford/0000-0003-1142-1161; Ford, Eric/0000-0002-7885-0019 NR 33 TC 4 Z9 4 U1 5 U2 5 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD MAR PY 2016 VL 18 IS 3 AR e73 DI 10.2196/jmir.4973 PG 8 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA DS4VB UT WOS:000380778600004 PM 27030105 ER PT J AU Kotarek, J Stuart, C De Paoli, SH Simak, J Lin, TL Gao, YM Ovanesov, M Liang, YD Scott, D Brown, J Bai, Y Metcalfe, DD Marszal, E Ragheb, JA AF Kotarek, Joseph Stuart, Christine De Paoli, Silvia H. Simak, Jan Lin, Tsai-Lien Gao, Yamei Ovanesov, Mikhail Liang, Yideng Scott, Dorothy Brown, Janice Bai, Yun Metcalfe, Dean D. Marszal, Ewa Ragheb, Jack A. TI Subvisible Particle Content, Formulation, and Dose of an Erythropoietin Peptide Mimetic Product Are Associated With Severe Adverse Postmarketing Events SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE particle sizing; formulation; peptides; protein aggregation ID MAST-CELL ACTIVATION; POLYETHYLENE-GLYCOL; ANTIBODIES; RI AB Peginesatide (Omontys (R); Affymax, Inc., Cupertino, CA) was voluntarily withdrawn from the market less than a year after the product launch. Although clinical trials had demonstrated the drug to be safe and efficacious, 49 cases of anaphylaxis, including 7 fatalities, were reported not long after market introduction. Commercialization was initiated with a multiuse vial presentation, which differs in formulation from the single-use vial presentation used in phase 3 studies. Standard physical and chemical testing did not indicate any deviation from product specifications in either formulation. However, an analysis of subvisible particulates using nanoparticle tracking analysis and flow imaging revealed a significantly higher concentration of subvisible particles in the multiuse vial presentation linked to the hypersensitivity cases. Although it is unknown whether the elevated particulate content is causally related to these serious adverse events, this report illustrates the utility of characterizing subvisible particulates not captured by conventional light obscuration. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Kotarek, Joseph; Stuart, Christine; De Paoli, Silvia H.; Simak, Jan; Ovanesov, Mikhail; Liang, Yideng; Scott, Dorothy; Marszal, Ewa] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Lin, Tsai-Lien] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Gao, Yamei] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Brown, Janice] US FDA, Off New Drug Qual Assessment, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Bai, Yun; Metcalfe, Dean D.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ragheb, Jack A.] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Marszal, E (reprint author), US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA.; Ragheb, JA (reprint author), US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Ewa.Marszal@fda.hhs.gov; Jack.Ragheb@fda.hhs.gov FU US Department of Energy; US FDA; Division of Intramural Research, NIAID FX This project was supported in part by an appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US FDA. Additionally, portions of this work were supported by the Division of Intramural Research, NIAID. We thank David Frucht and Raymond Yin for generously donating the anti-PEG antibodies used in the study and the Takeda Pharmaceutical Company Ltd for providing product-related materials. We also acknowledge the numerous contributions of the entire FDA Omontys Task Force. NR 17 TC 6 Z9 6 U1 3 U2 5 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 MAR PY 2016 VL 105 IS 3 BP 1023 EP 1027 DI 10.1016/S0022-3549(15)00180-X PG 5 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DT8TT UT WOS:000381769100001 PM 26886324 ER PT J AU Yan, XT Chu, JH Gomez, J Koenigs, M Holm, C He, XX Perez, MF Zhao, HY Mane, S Martinez, FD Ober, C Nicolae, DL Barnes, KC London, SJ Gilliland, F Weiss, ST Raby, BA Cohn, L Chupp, GL AF Yan, Xiting Chu, Jen-Hwa Gomez, Jose Koenigs, Maria Holm, Carole He, Xiaoxuan Perez, Mario F. Zhao, Hongyu Mane, Shrikant Martinez, Fernando D. Ober, Carole Nicolae, Dan L. Barnes, Kathleen C. London, Stephanie J. Gilliland, Frank Weiss, Scott T. Raby, Benjamin A. Cohn, Lauren Chupp, Geoffrey L. TI Noninvasive Analysis of the Sputum Transcriptome Discriminates Clinical Phenotypes of Asthma SO ANNALS OF THE AMERICAN THORACIC SOCIETY LA English DT Meeting Abstract C1 [Yan, Xiting; Gomez, Jose; Koenigs, Maria; Holm, Carole; He, Xiaoxuan; Perez, Mario F.; Zhao, Hongyu; Mane, Shrikant; Cohn, Lauren; Chupp, Geoffrey L.] Yale Sch Med, New Haven, CT USA. [Chu, Jen-Hwa; Weiss, Scott T.; Raby, Benjamin A.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Chu, Jen-Hwa; Weiss, Scott T.; Raby, Benjamin A.] Harvard Med Sch, Boston, MA USA. [Martinez, Fernando D.] Univ Arizona, Tucson, AZ USA. [Ober, Carole; Nicolae, Dan L.] Univ Chicago, Chicago, IL 60637 USA. [Barnes, Kathleen C.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [London, Stephanie J.] NIH, Res Triangle Pk, NC USA. [Gilliland, Frank] Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90033 USA. EM geoffrey.chupp@yale.edu FU NHLBI NIH HHS [R01 HL118346]; NIEHS NIH HHS [P30 ES007048] NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1546-3222 EI 2325-6621 J9 ANN AM THORAC SOC JI Ann. Am. Thoracic Society PD MAR PY 2016 VL 13 SU 1 BP S104 EP S105 PG 3 WC Respiratory System SC Respiratory System GA DR6BQ UT WOS:000379986500034 PM 27027945 ER PT J AU Yang, IV Pedersen, BS Liu, AH O'Connor, GT Teach, SJ Kattan, M Misiak, RT Gruchalla, R Steinbach, SF Szefler, SJ Gill, MA Calatroni, A David, G Hennessy, CE Davidson, EJ Gergen, P Togias, A Busse, WW Schwartz, DA AF Yang, Ivana V. Pedersen, Brent S. Liu, Andrew H. O'Connor, George T. Teach, Stephen J. Kattan, Meyer Misiak, Rana T. Gruchalla, Rebecca Steinbach, Suzanne F. Szefler, Stanley J. Gill, Michelle A. Calatroni, Agustin David, Gloria Hennessy, Corinne E. Davidson, Elizabeth J. Gergen, Peter Togias, Alkis Busse, William W. Schwartz, David A. TI DNA Methylation Changes in Nasal Epithelia Are Associated with Allergic Asthma in the Inner City SO ANNALS OF THE AMERICAN THORACIC SOCIETY LA English DT Meeting Abstract C1 [Yang, Ivana V.; Pedersen, Brent S.; Hennessy, Corinne E.; Davidson, Elizabeth J.; Schwartz, David A.] Univ Colorado, Sch Med, Aurora, CO USA. [Yang, Ivana V.; Liu, Andrew H.; Szefler, Stanley J.; Schwartz, David A.] Natl Jewish Hlth, Denver, CO USA. [O'Connor, George T.; Steinbach, Suzanne F.] Boston Univ, Sch Med, Boston, MA USA. [Teach, Stephen J.] Childrens Natl Med Ctr, Washington, DC USA. [Kattan, Meyer] Columbia Univ, Med Ctr, New York, NY USA. [Misiak, Rana T.] Henry Ford Hosp, Detroit, MI USA. [Gruchalla, Rebecca; Gill, Michelle A.] Univ Texas SW Med Ctr Dallas, Dallas, TX USA. [Calatroni, Agustin; David, Gloria] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Gergen, Peter; Togias, Alkis] NIAID, Bethesda, MD USA. [Busse, William W.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. EM ivana.yang@ucdenver.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1546-3222 EI 2325-6621 J9 ANN AM THORAC SOC JI Ann. Am. Thoracic Society PD MAR PY 2016 VL 13 SU 1 BP S99 EP S100 PG 3 WC Respiratory System SC Respiratory System GA DR6BQ UT WOS:000379986500025 PM 27027970 ER PT J AU DiCarlo, AL Kaminski, JM Hatchett, RJ Maidment, BW AF DiCarlo, Andrea L. Kaminski, Joseph M. Hatchett, Richard J. Maidment, Bert W. TI Role of thrombocytopenia in radiation-induced mortality and review of therapeutic approaches targeting platelet regeneration after radiation exposure SO JOURNAL OF RADIATION ONCOLOGY LA English DT Review DE Radiation; Thrombocytopenia; Thrombopoietin; Platelets ID COLONY-STIMULATING FACTOR; BONE-MARROW-TRANSPLANTATION; TOTAL-BODY IRRADIATION; HUMAN MEGAKARYOCYTE GROWTH; MYELOSUPPRESSED RHESUS-MONKEYS; MURA CRITICALITY ACCIDENT; STEM-CELL TRANSPLANTATION; NONHUMAN-PRIMATES; HEMATOPOIETIC RECOVERY; MPL LIGAND AB Preclinical studies on irradiated animals show that thrombocytopenia can play a role in radiation mortality, particularly in animals receiving minimal supportive care. These findings are consistent with anecdotal evidence from the atomic bombings, where bleeding complications were noted often in patients. To evaluate the role of thrombocytopenia and hemorrhage in radiation-induced mortality, a review was conducted of publicly available pathology reports of patients who died following radiation exposure. Of the 42 reports identified with reasonably complete information, exposures resulted from nuclear detonation, contact with improperly disposed sources, radiotherapy, or industrial accidents. Consistent with animal data, a high incidence of bleeding was noted in the autopsy reports of the victims. Also presented is a review of animal model data on the use of various forms of thrombopoietin (TPO) as a treatment for hematopoietic acute radiation syndrome (ARS). Although animal studies suggested these approaches would increase platelet levels following lethal irradiation, their clinical development was halted due to lack of significant efficacy for chemotherapy-induced thrombocytopenia and safety concerns. Because there is currently no approved treatment stockpiled for radiation-induced thrombocytopenia, second-generation TPO mimetics and other novel platelet-promoting agents should be developed for this indication. C1 [DiCarlo, Andrea L.; Maidment, Bert W.] NIAID, Radiat Nucl Countermeasures Program, DAIT, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kaminski, Joseph M.] Georgia Regents Univ, Ctr Canc, Augusta, GA USA. [Hatchett, Richard J.] Dept Hlth & Human Serv HHS, BARDA, Washington, DC USA. RP DiCarlo, AL (reprint author), NIAID, Radiat Nucl Countermeasures Program, DAIT, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM cohena@niaid.nih.gov NR 131 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1948-7894 EI 1948-7908 J9 J RADIOL ONCOL JI J. RADIOL. ONCOL. PD MAR PY 2016 VL 5 IS 1 BP 19 EP 32 DI 10.1007/s13566-015-0201-z PG 14 WC Oncology SC Oncology GA DR1JX UT WOS:000379662900003 ER PT J AU Berger, KC Feldman, BM Wasserman, J Schramm, W Blanchette, V Fischer, K AF Berger, Karin C. Feldman, Brian M. Wasserman, Joan Schramm, Wolfgang Blanchette, Victor Fischer, Kathelijn CA Outcome Measures Expert Working Gr IPSG TI Securing reimbursement for patient centered haemophilia care: major collaborative efforts are needed SO HAEMATOLOGICA LA English DT Editorial Material ID DEVELOPING-COUNTRIES; IX; PRINCIPLES; QUALITY; RCTS C1 [Berger, Karin C.] Univ Hosp Munich, Dept Haematol Oncol, Munich, Germany. [Feldman, Brian M.] Univ Toronto, Div Rheumatol, Toronto, ON M5S 1A1, Canada. [Feldman, Brian M.] Univ Toronto, Res Inst, Hosp Sick Children, Dept Paediat,Med, Toronto, ON M5S 1A1, Canada. [Feldman, Brian M.] Univ Toronto, IHPME, Toronto, ON M5S 1A1, Canada. [Wasserman, Joan] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. [Schramm, Wolfgang] Univ Munich, Rudolf Marx Fdn, Munich, Germany. [Blanchette, Victor] Univ Toronto, Dept Paediat, Toronto, ON M5S 1A1, Canada. [Blanchette, Victor] Hosp Sick Children, Div Haematol Oncol, Paediat Thrombosis & Haemostasis Program, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. Univ Med Ctr Utrecht, Creveldklin & Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. RP Berger, KC (reprint author), Univ Hosp Munich, Dept Haematol Oncol, Munich, Germany. EM karin.berger@med.uni-muenchen.de NR 21 TC 0 Z9 0 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAR PY 2016 VL 101 IS 3 BP 266 EP 268 DI 10.3324/haematol.2015.139931 PG 3 WC Hematology SC Hematology GA DQ7MY UT WOS:000379392800017 PM 26928247 ER PT J AU Lipsky, AH Lozier, JN Wiestner, A AF Lipsky, Andrew H. Lozier, Jay N. Wiestner, Adrian TI Response to Comment on Incidence and Risk Factors of Bleeding-Related Adverse Events in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib SO HAEMATOLOGICA LA English DT Letter DE chronic lymphocytic leukemia; disorders of platelet function; laboratory hematology ID COLLAGEN C1 [Lipsky, Andrew H.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD USA. [Lozier, Jay N.] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Lipsky, Andrew H.] Montefiore Med Ctr, Dept Internal Med, New York, NY USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD USA. EM wiestnea@nhlbi.nih.gov FU Intramural NIH HHS NR 6 TC 1 Z9 1 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAR PY 2016 VL 101 IS 3 BP E124 EP E125 DI 10.3324/haematol.2015.140558 PG 2 WC Hematology SC Hematology GA DQ7MY UT WOS:000379392800015 PM 26928253 ER PT J AU Parham, GP Mwanahamuntu, MH Hicks, ML Henry-Tillman, R Chibwesha, CJ Chinula, L Oneko, OA Murokora, D Sahasrabuddhe, VV AF Parham, Groesbeck P. Mwanahamuntu, Mulindi H. Hicks, Michael L. Henry-Tillman, Ronda Chibwesha, Carla J. Chinula, Lameck Oneko, Olola Achieng Murokora, Daniel Sahasrabuddhe, Vikrant V. TI Population-level scale-up of surgery platforms for women's cancer care in low- and middle-income countries SO JOURNAL OF CANCER POLICY LA English DT Article DE Surgical care; Surgical training; Women's cancers; Low- and middle-income countries; Cancer care delivery ID BREAST-CANCER; MORTALITY; RESOURCE; ZAMBIA AB Surgery is a cornerstone of management of women's cancer care in low- and middle-income countries. As cancer incidence rates and disease burden rise rapidly even in the lowest income nations, the need for investing in surgical care platforms at all levels of the health system (primary health care clinics to tertiary hospitals) is being increasingly recognized. In this article, a conceptual framework for approaching scaling-up surgery platforms for women's cancer care in regions with least resources and substantial burden of disease is presented. A case is made for identifying highest priority conditions that can be managed by resource-appropriate and sustainable interventions. Core-competencies-based training of local health workers for targeted skills-building and utilizing innovative approaches to care delivery by harnessing and incorporating affordable technology for monitoring, outcomes evaluation and ongoing program adaptation are essential. Implementing surgical cancer care within a public health framework will help ensure services are integrated in a manner that strengthens health systems at all levels. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Parham, Groesbeck P.; Chibwesha, Carla J.; Chinula, Lameck] Univ N Carolina, 3009 Old Clin Bldg,Campus Box 7577, Chapel Hill, NC 27599 USA. [Parham, Groesbeck P.; Mwanahamuntu, Mulindi H.] Univ Zambia, POB 50110, Lusaka, Zambia. [Hicks, Michael L.] Michigan Canc Inst, 6019 Carmen Ct W, Orchard Lake, MI 48324 USA. [Henry-Tillman, Ronda] Univ Arkansas Med Sci, 4301 West Markham St, Little Rock, AR 72205 USA. [Chinula, Lameck] Kamuzu Cent Hosp, POB 149, Lilongwe, Malawi. [Oneko, Olola Achieng] Kilimanjaro Christian Med Ctr, POB 3010, Moshi, Tanzania. [Murokora, Daniel] Ugandan Womens Hlth Initiat, POB 32275, Kampala, Uganda. [Sahasrabuddhe, Vikrant V.] NCI, 9606 Med Ctr Dr,5E-338, Rockville, MD 20850 USA. RP Parham, GP (reprint author), Univ N Carolina, 3009 Old Clin Bldg,Campus Box 7577, Chapel Hill, NC 27599 USA. EM gparham@email.unc.edu NR 21 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 2213-5383 J9 J Cancer Policy JI J. CANCER POLICY PD MAR PY 2016 VL 7 BP 23 EP 27 DI 10.1016/j.jcpo.2015.12.002 PG 5 WC Health Policy & Services SC Health Care Sciences & Services GA DQ5NI UT WOS:000379251700004 ER PT J AU Fleming, KA AF Fleming, Kenneth A. TI Pathology and cancer policy SO JOURNAL OF CANCER POLICY LA English DT Article ID LABORATORIES; AFRICA AB Good quality pathology is a critical component of good quality cancer care. In much of the world, unfortunately, pathology provision is both of patchy distribution and of variable standard, undermining care of the cancer patient. This appears to be a result of a failure to recognise the critical importance of pathology with consequent low profile and low resource allocation. To address this, a campaign of advocacy with proposals for possible solutions is needed. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Fleming, Kenneth A.] NCI, Ctr Global Hlth, Washington, DC USA. [Fleming, Kenneth A.] Univ Oxford, Green Templeton Coll, Oxford OX1 2JD, England. RP Fleming, KA (reprint author), NCI, Ctr Global Hlth, Washington, DC USA.; Fleming, KA (reprint author), Univ Oxford, Green Templeton Coll, Oxford OX1 2JD, England. EM kenneth.fleming@medsci.ox.ac.uk NR 11 TC 0 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-5383 J9 J Cancer Policy JI J. CANCER POLICY PD MAR PY 2016 VL 7 BP 32 EP 35 DI 10.1016/j.jcpo.2015.12.005 PG 4 WC Health Policy & Services SC Health Care Sciences & Services GA DQ5NI UT WOS:000379251700006 ER PT J AU Topazian, H Cira, M Dawsey, SM Kibachio, J Kocholla, L Wangai, M Welch, J Williams, MJ Duncan, K Galassi, A AF Topazian, Hillary Cira, Mishka Dawsey, Sanford M. Kibachio, Joseph Kocholla, Lillian Wangai, Mary Welch, Jack Williams, Makeda J. Duncan, Kalina Galassi, Annette TI Joining forces to overcome cancer: The Kenya cancer research and control stakeholder program SO JOURNAL OF CANCER POLICY LA English DT Article AB Background: Cancer is the third leading cause of mortality in Kenya, accounting for 7% of annual deaths. The Kenyan Ministry of Health (MOH) is committed to reducing cancer mortality, as evidenced by policies such as the National Cancer Control Strategy (2011-2016). There are many Kenyan and international organizations devoted to this task; however, coordination is lacking among stakeholders, resulting in inefficient and overlapping expenditure of resources. Methods: The MOH and the NCI Center for Global Health collaboratively executed a two day workshop to improve coordination among government, NGO, and private organizations. Over 80 stakeholders participated from leading cancer research and control institutions in Kenya and the international sphere. Findings: Actionable recommendations include: establishment of a nationally representative population based cancer registry; enhanced training for community health workers, nurses, researchers, pathologists, and oncology specialists; a reconfigured referral process, including leveraging of existing resources to improve access to cancer care; and coordinated community outreach and education. The MOH is in the process of forming a Technical Working Group (TWG) and has elected a Board of Directors for the newly established Kenyan National Cancer Institute (KNCI), with both entities committed to advancing the cancer control work of the MOH. Interpretation: This stakeholder meeting enhanced in-country networks, identified priority needs and developed actionable proposals for coordinated improvement of cancer research and control. Active, persistent follow-up by the TWG, KNCI, and other partners will be needed to turn proposals into reality and ensure that partners' investments are integrated into larger cancer control efforts prioritized by MOH. Published by Elsevier Ltd. C1 [Topazian, Hillary; Welch, Jack; Williams, Makeda J.; Duncan, Kalina; Galassi, Annette] NCI, Ctr Global Hlth, Bethesda, MD 20892 USA. [Cira, Mishka] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Dawsey, Sanford M.; Kibachio, Joseph; Kocholla, Lillian; Wangai, Mary] Minist Hlth, Nairobi, Kenya. RP Galassi, A (reprint author), NCI, Ctr Global Hlth, Bethesda, MD 20892 USA. EM htopazian@gmail.com; mishka.cira@gmail.com; dawseys@mail.nih.gov; kibachiojoseph@gmail.com; Lilianak42@hotmail.com; mwangai@gmail.com; Jack.Welch@nih.gov; willimak@mail.nih.gov; Kalina.Duncan@nih.gov; agalassi57@gmail.com OI Galassi, Annette/0000-0002-0086-092X FU Intramural NIH HHS [Z99 CA999999] NR 12 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 2213-5383 J9 J Cancer Policy JI J. CANCER POLICY PD MAR PY 2016 VL 7 BP 36 EP 41 DI 10.1016/j.jcpo.2015.12.001 PG 6 WC Health Policy & Services SC Health Care Sciences & Services GA DQ5NI UT WOS:000379251700007 PM 26942109 ER PT J AU Rauschecker, M Abraham, SB Abel, BS Wesley, R Saverino, E Trivedi, A Heller, T Nieman, LK AF Rauschecker, Mitra Abraham, Smita Baid Abel, Brent S. Wesley, Robert Saverino, Elizabeth Trivedi, Apurva Heller, Theo Nieman, Lynnette K. TI Cosyntropin-Stimulated Serum Free Cortisol in Healthy, Adrenally Insufficient, and Mildly Cirrhotic Populations SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOSTEROID-BINDING GLOBULIN; PLASMA-FREE CORTISOL; SALIVARY CORTISOL AB Context: Serum free cortisol (SFF) responses to cosyntropin simulation test (CST) may more accurately assess adrenal function than total cortisol (TF). Objective: The objective of the study was to evaluate the diagnostic utility of SFF responses during a 250-mu g CST. Design: We recruited healthy volunteers (HV; n = 27), patients with primary and secondary adrenal insufficiency (n = 19 and n = 24, respectively), and subjects with Child-Pugh class A cirrhosis (CH; n = 15). Each received 250 mu g cosyntropin with measurement of ACTH and corticosteroid binding globulin (CBG) at time 0 and TF and SFF at 0, 30, and 60 minutes. Salivary cortisol was measured at all time points in CH subjects. Results: Peak SFF and TF were significantly higher in HVs vs both AI groups (P < .05). Peak SFF and TF (6.8 mu g/dL vs 2.2 mu g/dL; [188 nmol/L vs 62 nmol/L]; P < .01) were significantly higher in the secondary adrenal insufficiency vs primary adrenal insufficiency patients. The optimal peak SFF criterion to identify adrenal insufficiency patients vs HV was 0.9 mu g/dL (25 nmol/L) (sensitivity of 95%, specificity of 100%). Mean CBG and albumin levels were similar among all four groups. CH patients had a higher peak SFF than HV (2.4 vs 2.0 mu g/dL; P = .02. In the CH patients, peak salivary cortisol levels correlated well with peak SFF (r(s) = 0.84, P = .005). CBG levels were similar among the groups. Conclusion: We provide normative data for SFF values in HV and AI during the CST. Normal CBG levels in mild cirrhosis did not affect the interpretation of the CST. C1 [Rauschecker, Mitra; Abraham, Smita Baid; Abel, Brent S.; Saverino, Elizabeth; Nieman, Lynnette K.] NIDDK, Program Reprod & Adult Endocrinol, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Wesley, Robert] NIDDK, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Clin Epidemiol Serv, Liver Dis Branch,NIH, Bethesda, MD 20892 USA. [Trivedi, Apurva; Heller, Theo] NIDDK, Ctr Clin, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Trivedi, Apurva; Heller, Theo] NIDDK, Ctr Clin, Translat Hepatol Unit, NIH, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), R 1-3140,MSC 1109,10 Ctr Dr, Bethesda, MD 20892 USA. EM niemanl@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 14 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 MAR PY 2016 VL 101 IS 3 BP 1075 EP 1081 DI 10.1210/jc.2015-2285 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP9JA UT WOS:000378811300038 PM 26647150 ER PT J AU Torriani, M Srinivasa, S Fitch, KV Thomou, T Wong, K Petrow, E Kahn, CR Cypess, AM Grinspoon, SK AF Torriani, Martin Srinivasa, Suman Fitch, Kathleen V. Thomou, Thomas Wong, Kimberly Petrow, Eva Kahn, C. Ronald Cypess, Aaron M. Grinspoon, Steven K. TI Dysfunctional Subcutaneous Fat With Reduced Dicer and Brown Adipose Tissue Gene Expression in HIV-Infected Patients SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BEIGE ADIPOCYTES; LIPODYSTROPHY; DIFFERENTIATION; ADIPOGENESIS AB Context: HIV patients are at an increased risk for cardiometabolic disease secondary to depot-specific alterations in adipose function, but mechanisms remain poorly understood. Objective: The endoribonuclease Dicer has been linked to the modulation of brown and white adipocyte differentiation. We previously demonstrated that Dicer knockout mice undergo transformation of brown adipose tissue to white adipose tissue and develop a lipodystrophic phenotype. We hypothesized reduced Dicer and brown adipose tissue gene expression from nonlipomatous sc fat among HIV patients with a lipodystrophic phenotype. Design: Eighteen HIV (nine with and without lipodystrophic changes in fat distribution, characterized by excess dorsocervical adipose tissue [DCAT]) and nine non-HIV subjects underwent punch biopsy of abdominal sc fat to determine expression of Dicer and other adipose-related genes. Results: HIV subjects with long-duration antiretroviral use demonstrated excess DCAT vs non-HIV subjects (9.8 +/- 1.0 vs 6.6 +/- 0.8 cm(2), P = .02) with similar body mass index. Dicer expression was decreased in abdominal sc fat of HIV vs non-HIV (4.88 [1.91, 11.93] vs 17.69 [10.72, 47.91], P = .01), aswerePPAR alpha, ZIC1, PRDM16, DIO2, and HSP60 (all P <= .03). Moreover, the expression of Dicer (2.49 [0.02, 4.88] vs 11.20 [4.83, 21.45], P = .006), brown fat (PPAR alpha [P = .002], ZIC1 [P = .004], LHX8 [P = .03], PRDM16 [P = .0008], PAT2 [P = .008], P2RX5 [P = .02]), beige fat (TMEM26 [P = .004], CD137 [P = .008]), and other genes (DIO2 [P = .002], leptin [P = .003], HSP60 [P = .0004]) was further decreased in abdominal sc fat comparing HIV subjects with vs without excess DCAT. Down-regulation of Dicer in the abdominal sc fat correlated with the down-regulation of all brown and beige fat genes (all P <= .01). Conclusion: Our results demonstrate dysfunctional sc adipose tissue marked by reduced Dicer in relationship to the down-regulation of brown and beige fat-related genes in lipodystrophic HIV patients and may provide a novel mechanism for metabolic dysregulation. A strategy to increase browning of white adipose tissue may improve cardiometabolic health in HIV. C1 [Torriani, Martin; Srinivasa, Suman; Fitch, Kathleen V.; Wong, Kimberly; Petrow, Eva; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON207, Boston, MA 02114 USA. [Torriani, Martin] Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Thomou, Thomas; Kahn, C. Ronald; Cypess, Aaron M.] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. [Cypess, Aaron M.] NIDDK, Translat Physiol Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON207, Boston, MA 02114 USA. EM sgrinspoon@mgh.harvard.edu FU National Institutes of Health from the National Center for Research Resources [1UL1RR025758, 2P30AI060354, K23DK081604, M01RR01066, UL1TR001102]; National Center for Advancing Translational Sciences; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; [P30DK40561] FX This work was supported by the National Institutes of Health Grants 1UL1RR025758, 2P30AI060354 (to M.T.), K23DK081604 (to A.M.C.), M01RR01066, 1UL1RR025758, and UL1TR001102 (to the Harvard Catalyst/Harvard Clinical and Translational Science Center) from the National Center for Research Resources and National Center for Advancing Translational Sciences, and Grant P30DK40561, a pilot and feasibility grant to the Nutrition and Obesity Research Center at Harvard University, and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 28 TC 3 Z9 4 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 MAR PY 2016 VL 101 IS 3 BP 1225 EP 1234 DI 10.1210/jc.2015-3993 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP9JA UT WOS:000378811300056 PM 26756119 ER PT J AU Liu, J Haddad, EK Marceau, J Morabito, KM Rao, SS Filali-Mouhim, A Sekaly, RP Graham, BS AF Liu, Jie Haddad, Elias K. Marceau, Joshua Morabito, Kaitlyn M. Rao, Srinivas S. Filali-Mouhim, Ali Sekaly, Rafick-Pierre Graham, Barney S. TI A Numerically Subdominant CD8 T Cell Response to Matrix Protein of Respiratory Syncytial Virus Controls Infection with Limited Immunopathology SO PLOS PATHOGENS LA English DT Article ID ANTIGENIC-STIMULATION; VIRAL-INFECTION; DOWN-REGULATION; MEMORY; LUNG; MICE; EXPRESSION; APOPTOSIS; GENE; LYMPHOCYTES AB CD8 T cells are involved in pathogen clearance and infection-induced pathology in respiratory syncytial virus (RSV) infection. Studying bulk responses masks the contribution of individual CD8 T cell subsets to protective immunity and immunopathology. In particular, the roles of subdominant responses that are potentially beneficial to the host are rarely appreciated when the focus is on magnitude instead of quality of response. Here, by evaluating CD8 T cell responses in CB6F1 hybrid mice, in which multiple epitopes are recognized, we found that a numerically subdominant CD8 T cell response against DbM187 epitope of the virus matrix protein expressed high avidity TCR and enhanced signaling pathways associated with CD8 T cell effector functions. Each DbM187 T effector cell lysed more infected targets on a per cell basis than the numerically dominant KdM282 T cells, and controlled virus replication more efficiently with less pulmonary inflammation and illness than the previously well-characterized KdM282 T cell response. Our data suggest that the clinical outcome of viral infections is determined by the integrated functional properties of a variety of responding CD8 T cells, and that the highest magnitude response may not necessarily be the best in terms of benefit to the host. Understanding how to induce highly efficient and functional T cells would inform strategies for designing vaccines intended to provide T cell-mediated immunity. C1 [Liu, Jie; Marceau, Joshua; Morabito, Kaitlyn M.; Rao, Srinivas S.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Haddad, Elias K.] Drexel Univ, Div Infect Dis & HIV Med, Philadelphia, PA 19104 USA. [Filali-Mouhim, Ali] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Sekaly, Rafick-Pierre] Case Western Reserve Univ, Ctr AIDS Res, Cleveland, OH 44106 USA. RP Liu, J (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jieliu@mail.nih.gov; bgraham@nih.gov FU intramural research program; National Institute of Allergy and Infectious Diseases of the National Institute of Health FX This work was supported by intramural research program awarded to BSG by the National Institute of Allergy and Infectious Diseases of the National Institute of Health (http://www.niaid.nih.gov/researchfunding/Pages/default.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 2 Z9 2 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 MAR PY 2016 VL 12 IS 3 AR e1005486 DI 10.1371/journal.ppat.1005486 PG 25 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DP0CH UT WOS:000378154800023 PM 26943673 ER PT J AU Radoshitzky, SR Pegoraro, G Chi, XL Dong, L Chiang, CY Jozwick, L Clester, JC Cooper, CL Courier, D Langan, DP Underwood, K Kuehl, KA Sun, MG Cai, YY Yu, SQ Burk, R Zamani, R Kota, K Kuhn, JH Bavari, S AF Radoshitzky, Sheli R. Pegoraro, Gianluca Chi, Xiaoli Dong, Lian Chiang, Chih-Yuan Jozwick, Lucas Clester, Jeremiah C. Cooper, Christopher L. Courier, Duane Langan, David P. Underwood, Knashka Kuehl, Kathleen A. Sun, Mei G. Cai, Yingyun Yu, Shuiqing Burk, Robin Zamani, Rouzbeh Kota, Krishna Kuhn, Jens H. Bavari, Sina TI siRNA Screen Identifies Trafficking Host Factors that Modulate Alphavirus Infection SO PLOS PATHOGENS LA English DT Article ID SEMLIKI-FOREST-VIRUS; MICROTUBULE-DEPENDENT TRANSPORT; VENEZUELAN EQUINE ENCEPHALITIS; SMALL-MOLECULE INHIBITOR; VALLEY FEVER VIRUS; PLASMA-MEMBRANE; ACTIN CYTOSKELETON; ARP2/3 COMPLEX; SINDBIS VIRUS; CELLULAR RECEPTOR AB Little is known about the repertoire of cellular factors involved in the replication of pathogenic alphaviruses. To uncover molecular regulators of alphavirus infection, and to identify candidate drug targets, we performed a high-content imaging-based siRNA screen. We revealed an actin-remodeling pathway involving Rac1, PIP5K1-alpha, and Arp3, as essential for infection by pathogenic alphaviruses. Infection causes cellular actin rearrangements into large bundles of actin filaments termed actin foci. Actin foci are generated late in infection concomitantly with alphavirus envelope (E2) expression and are dependent on the activities of Rac1 and Arp3. E2 associates with actin in alphavirus-infected cells and co-localizes with Rac1-PIP5K1-alpha along actin filaments in the context of actin foci. Finally, Rac1, Arp3, and actin polymerization inhibitors interfere with E2 trafficking from the trans-Golgi network to the cell surface, suggesting a plausible model in which transport of E2 to the cell surface is mediated via Rac1- and Arp3-dependent actin remodeling. C1 [Radoshitzky, Sheli R.; Pegoraro, Gianluca; Chi, Xiaoli; Dong, Lian; Chiang, Chih-Yuan; Jozwick, Lucas; Clester, Jeremiah C.; Cooper, Christopher L.; Courier, Duane; Langan, David P.; Underwood, Knashka; Zamani, Rouzbeh; Kota, Krishna; Bavari, Sina] USAMRIID, Mol & Translat Sci Div, Frederick, MD 21702 USA. [Kuehl, Kathleen A.; Sun, Mei G.] USAMRIID, Div Pathol, Frederick, MD USA. [Cai, Yingyun; Yu, Shuiqing; Burk, Robin; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, Div Clin Res, NIH, Frederick, MD USA. RP Bavari, S (reprint author), USAMRIID, Mol & Translat Sci Div, Frederick, MD 21702 USA. EM sina.bavari.civ@mail.mil OI Pegoraro, Gianluca/0000-0003-2843-9464 FU Joint Science and Technology Office for Chemical and Biological Defense (JSTO-CBD) of the Defense Threat Reduction Agency (DTRA) (CCAR) [1323839, CB3849]; NIAID [HHSN272200700016I]; Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS); Battelle Memorial Institute; Tunnell Government Services; NIH/NIAID Integrated Research Facility at Fort Detrick [HHSN272200700016I] FX These studies were supported by The Joint Science and Technology Office for Chemical and Biological Defense (JSTO-CBD) of the Defense Threat Reduction Agency (DTRA) (proposal #1323839 and CCAR# CB3849) to SB (http://www.dtra.mil/). YC and JHK performed this work as employees of Tunnell Government Services Inc., and SY as an employee of Battelle Memorial Institute; all under Battelle's prime contract with NIAID, under Contract No. HHSN272200700016I. RB was supported by the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Battelle Memorial Institute and Tunnell Government Services provided support in the form of salaries, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. All work under contract HHSN272200700016I is performed under the agreement/understanding that it will belong to the client and will be affiliated directly to the NIH/NIAID Integrated Research Facility at Fort Detrick. The specific roles of these authors are articulated in the 'author contributions' section. NR 65 TC 3 Z9 3 U1 0 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 MAR PY 2016 VL 12 IS 3 AR e1005466 DI 10.1371/journal.ppat.1005466 PG 30 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DP0CH UT WOS:000378154800011 PM 27031835 ER PT J AU Wagh, K Bhattacharya, T Williamson, C Robles, A Bayne, M Garrity, J Rist, M Rademeyer, C Yoon, H Lapedes, A Gao, HM Greene, K Louder, MK Kong, R Karim, SA Burton, DR Barouch, DH Nussenzweig, MC Mascola, JR Morris, L Montefiori, DC Korber, B Seaman, MS AF Wagh, Kshitij Bhattacharya, Tanmoy Williamson, Carolyn Robles, Alex Bayne, Madeleine Garrity, Jetta Rist, Michael Rademeyer, Cecilia Yoon, Hyejin Lapedes, Alan Gao, Hongmei Greene, Kelli Louder, Mark K. Kong, Rui Karim, Salim Abdool Burton, Dennis R. Barouch, Dan H. Nussenzweig, Michel C. Mascola, John R. Morris, Lynn Montefiori, David C. Korber, Bette Seaman, Michael S. TI Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; MUCOSAL SHIV CHALLENGE; N-GLYCAN RECOGNITION; POTENT NEUTRALIZATION; HUMANIZED MICE; IN-VITRO; GP41-GP120 INTERFACE; IMPROVES PROTECTION; VACCINE DEVELOPMENT AB The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection. C1 [Wagh, Kshitij; Bhattacharya, Tanmoy; Yoon, Hyejin; Lapedes, Alan; Korber, Bette] Los Alamos Natl Lab, Div Theoret, Los Alamos, NM USA. [Bhattacharya, Tanmoy] Santa Fe Inst, Santa Fe, NM 87501 USA. [Williamson, Carolyn; Rademeyer, Cecilia] Univ Cape Town, Inst Infect Dis & Mol Med, Div Med Virol, ZA-7925 Cape Town, South Africa. [Williamson, Carolyn; Rademeyer, Cecilia] NHLS, Cape Town, South Africa. [Robles, Alex; Bayne, Madeleine; Garrity, Jetta; Rist, Michael; Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Gao, Hongmei; Greene, Kelli; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Louder, Mark K.; Kong, Rui; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Karim, Salim Abdool] Univ KwaZulu Natal, Durban Dept Immunol & Microbial Sci, Durban, South Africa. [Karim, Salim Abdool; Morris, Lynn] Univ KwaZulu Natal, Ctr AIDS Programme Res S Africa CAPRISA, Durban, South Africa. [Burton, Dennis R.] Scripps Res Inst, La Jolla, CA 92037 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, 1230 York Ave, New York, NY 10021 USA. [Morris, Lynn] Univ Witwatersrand, Natl Inst Communicable Dis, NHLS, Johannesburg 2050, South Africa. RP Seaman, MS (reprint author), Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. EM mseaman@bidmc.harvard.edu FU Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grant [1032144]; intramural research program of the Vaccine Research Center (VRC), NIAID, NIH; Center for Nonlinear Studies (CNLS) at Los Alamos National Laboratory FX This work was supported by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grant #1032144, and in part from the intramural research program of the Vaccine Research Center (VRC), NIAID, NIH. KW was supported by the Center for Nonlinear Studies (CNLS) at Los Alamos National Laboratory. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 87 TC 16 Z9 16 U1 1 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 MAR PY 2016 VL 12 IS 3 AR e1005520 DI 10.1371/journal.ppat.1005520 PG 27 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DP0CH UT WOS:000378154800037 PM 27028935 ER PT J AU Czajkowski, SM Lynch, MR Hall, KL Stipelman, BA Haverkos, L Perl, H Scott, MS Shirley, MC AF Czajkowski, Susan M. Lynch, Minda R. Hall, Kara L. Stipelman, Brooke A. Haverkos, Lynne Perl, Harold Scott, Marcia S. Shirley, Mariela C. TI Transdisciplinary translational behavioral (TDTB) research: opportunities, barriers, and innovations SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Transdisciplinary; Translational; Behavioral; NIH ID INTERVENTIONS; HEALTH; MODEL; DISSEMINATION; VARENICLINE; EFFICACY AB The translation of basic behavioral science discoveries into practical strategies represents a promising approach to developing more effective preventive interventions to improve health. Since translational research inevitably involves making use of diverse perspectives from multiple disciplines, it is best conducted as a transdisciplinary enterprise. In this paper, we discuss current strategies used by NIH to support transdisciplinary translational behavioral (TDTB) research, summarize successful efforts, and highlight challenges encountered in conducting such work (ranging from conceptual to organizational to methodological). Using examples from NIH-funded projects we illustrate the potential benefits of, and barriers to, pursuing this type of research and discuss next steps and potential future directions for NIH-supported TDTB research. C1 [Czajkowski, Susan M.; Hall, Kara L.; Stipelman, Brooke A.] NCI, NIH, Rockville, MD 20852 USA. [Lynch, Minda R.; Perl, Harold] NIDA, NIH, Rockville, MD USA. [Haverkos, Lynne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD USA. [Scott, Marcia S.; Shirley, Mariela C.] NIAAA, NIH, Rockville, MD 20852 USA. RP Czajkowski, SM (reprint author), NCI, NIH, Rockville, MD 20852 USA. EM Susan.Czajkowski@nih.gov NR 35 TC 3 Z9 3 U1 1 U2 2 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD MAR PY 2016 VL 6 IS 1 BP 32 EP 43 DI 10.1007/s13142-015-0367-3 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DO9ZU UT WOS:000378147900004 PM 27012251 ER PT J AU Vanyukov, MM Tarter, RE Conway, KP Kirillova, GP Chandler, RK Daley, DC AF Vanyukov, Michael M. Tarter, Ralph E. Conway, Kevin P. Kirillova, Galina P. Chandler, Redonna K. Daley, Dennis C. TI Risk and resistance perspectives in translation-oriented etiology research SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Review DE Resilience; Protective factors; Research paradigm; Phenotype measurement; Malleability ID SUBSTANCE USE DISORDERS; COCAINE DEPENDENCE; COMMON LIABILITY; ADDICTION; ALCOHOL; TRANSMISSION; WOMEN; MANIFESTATIONS; DYSREGULATION; INHERITANCE AB Risk for a disorder and the mechanisms that determine its elevation, risk factors, are the focus of medical research. Targeting risk factors should serve the goal of prevention and treatment intervention. Risk, however, is but one of the aspects of liability to a disorder, a latent trait that encompasses effects of all factors leading to or from the diagnostic threshold. The coequal but opposite aspect of liability is resistance to a disorder. The factors that increase resistance and thus enable prevention or recovery may differ from those that elevate risk. Accordingly, there are nontrivial differences between research perspectives that focus on risk and on resistance. This article shows how this distinction translates into goals and methods of research and practice, from the choice of potential mechanisms tested to the results sought in intervention. The resistance concept also differs from those of "resilience" and "protective factors," subsuming but not limited to them. The implications of the concept are discussed using substance use disorder as an example and substantiate the need for biomedical research and its translation to shift to the resistance perspective. C1 [Vanyukov, Michael M.; Tarter, Ralph E.; Kirillova, Galina P.; Daley, Dennis C.] Univ Pittsburgh, 3520 Forbes Ave,Suite 203, Pittsburgh, PA 15213 USA. [Conway, Kevin P.; Chandler, Redonna K.] NIDA, NIH, Baltimore, MD USA. RP Vanyukov, MM (reprint author), Univ Pittsburgh, 3520 Forbes Ave,Suite 203, Pittsburgh, PA 15213 USA. EM mmv@pitt.edu OI Conway, Kevin/0000-0002-7638-339X FU NIDA NIH HHS [P50 DA005605] NR 64 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD MAR PY 2016 VL 6 IS 1 BP 44 EP 54 DI 10.1007/s13142-015-0355-7 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DO9ZU UT WOS:000378147900005 PM 27012252 ER PT J AU Turkova, H Prodanov, T Maly, M Martucci, V Adams, K Widimsky, J Chen, CC Ling, A Kebebew, E Stratakis, CA Fojo, T Pacak, K AF Turkova, Hana Prodanov, Tamara Maly, Marek Martucci, Victoria Adams, Karen Widimsky, Jiri, Jr. Chen, Clara C. Ling, Alexander Kebebew, Electron Stratakis, Constantine A. Fojo, Tito Pacak, Karel TI CHARACTERISTICS AND OUTCOMES OF METASTATIC SDHB AND SPORADIC PHEOCHROMOCYTOMA/PARAGANGLIOMA: AN NATIONAL INSTITUTES OF HEALTH STUDY SO ENDOCRINE PRACTICE LA English DT Article ID SUCCINATE-DEHYDROGENASE; GERMLINE MUTATIONS; GENE-MUTATIONS; MALIGNANT PHEOCHROMOCYTOMAS; PLASMA METHOXYTYRAMINE; HEREDITARY FORMS; HIF2A MUTATIONS; MAX MUTATIONS; PRIMARY TUMOR; B GENE AB Objective: Overall about 10 to 20% of pheochromocytomas/paragangliomas (PHEOs/PGLs) are metastatic, with higher metastatic potential observed in succinate dehydrogenase subunit B/fumarate hydratase (SDHB/FH)-related tumors. Due to the improved availability of biochemical and genetic testing and the frequent use of anatomical/functional imaging, there is currently a higher detection rate of metastatic PHEO/PGL. Methods: A retrospective analysis of 132 patients (27 children, 105 adults) with metastatic PHEO/PGL diagnosed and treated from 2000 to 2014 was conducted. Results: Seventy-seven (58%) males and 55 (42%) females were included; 39 (30%) have died, with no sex preference. Seventy-three (55%) patients had SDHB mutations; 59 (45%) patients had apparently sporadic tumors (AST). SDHB patients had an average age at primary tumor diagnosis of 31 +/- 16 years compared to 40 +/- 15 years in AST patients (P<.001). The average metastatic interval (MI) decreased with increasing age in both SDHB and AST patients (P = .013 for both). Only 16% of all primary tumors were smaller than 4.5 cm. Eleven percent of patients had biochemically silent disease, more with SDHB. Of SDHB patients, 23% had metastatic tumors at first diagnosis, compared to 15% of AST patients. Five-and 10-year survival rates were significantly better for metastatic AST than SDHB patients (P = .01). Overall survival was significantly different between children and adults (P = .037); this was mostly attributed to the SDHB patients, in whom children had statistically significantly longer survival than adults (P = .006). The deceased patients all died due to the PHEO/PGL and mainly had noradrenergic phenotypes. Conclusion: In children, metastatic PHEOs/PGLs are mainly due to SDHB mutations; in adults they are equally distributed between in SDHB mutations and AST, with better 5- and 10-year survival rates for ASTs. In SDHB patients, children survive longer than adults. Primary metastatic tumors, most presenting as noradrenergic PGLs, are larger than 4.5 cm in >80% of patients. The frequency of metastatic tumors from primary AST increases with age, including a decreased MI compared to SDHB tumors. These results support several recommendations that are summarized in the Discussion. C1 [Turkova, Hana; Prodanov, Tamara; Martucci, Victoria; Adams, Karen; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Turkova, Hana] Gen Fac Hosp, Dept Oncol, Prague, Czech Republic. [Maly, Marek] Natl Inst Publ Hlth, Dept Biostat & Informat, Prague, Czech Republic. [Widimsky, Jiri, Jr.] Charles Univ Prague, Fac Med 1, Prague, Czech Republic. [Widimsky, Jiri, Jr.] Gen Fac Hosp, Dept Internal Med 3, Prague, Czech Republic. [Chen, Clara C.] NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. [Ling, Alexander] NIH, Dept Radiol, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Fojo, Tito] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver NICHD, Sect Med Neuroendocrinol, NIH, CRC, Bldg 10,1 East,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU NIH, Eunice Kennedy Shriver NICHD; NIH, NINDS; NIH, NHGRI FX This research was supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver NICHD, NINDS, and NHGRI. NR 54 TC 3 Z9 3 U1 3 U2 6 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD MAR PY 2016 VL 22 IS 3 BP 302 EP 314 DI 10.4158/EP15725.OR PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DO7NG UT WOS:000377968700003 PM 26523625 ER PT J AU Shimbo, T Takaku, M Wade, PA AF Shimbo, Takashi Takaku, Motoki Wade, Paul A. TI High-quality ChIP-seq analysis of MBD3 in human breast cancer cells SO GENOMICS DATA LA English DT Article DE ChIP-seq; Mi-2/NuRD; Breast cancer AB Chromatin accessibility is tightly regulated by multiple factors/mechanisms to establish different cell type-specific gene expression programs from a single genome. Dysregulation of this process can lead to diseases including cancer. The Mi-2/nucleosome remodeling and deacetylase (NuRD) complex is thought to orchestrate chromatin structure using its intrinsic nucleosome remodeling and histone deacetylase activities. However, the detailed mechanisms by which the NuRD complex regulates chromatin structure in vivo are not yet known. To explore the regulatory mechanisms of the NuRD complex, we mapped genome-wide localization of MBD3, a structural component of NuRD, in a human breast cancer cell line (MDA-MB-231) using a modified ChIP-seq protocol. Our data showed high quality localization information (i.e., high mapping efficiency and low PCR duplication rate) and excellent consistency between biological replicates. The data are deposited in the Gene Expression Omnibus (GSE76116). (C) Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/). C1 [Shimbo, Takashi; Takaku, Motoki; Wade, Paul A.] NIEHS, Epigenet & Stem Cell Biol Lab, Morrisville, NC 27560 USA. RP Wade, PA (reprint author), NIEHS, Epigenet & Stem Cell Biol Lab, Morrisville, NC 27560 USA. EM wadep2@niehs.nih.gov FU NIEHS NIH HHS [Z01 ES101965] NR 3 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-5960 J9 GENOM DATA JI Genom. Data PD MAR PY 2016 VL 7 BP 173 EP 174 DI 10.1016/j.gdata.2015.12.029 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA DO4NY UT WOS:000377761100054 PM 26981404 ER PT J AU Hays, RD Chawla, N Kent, EE Arora, NK AF Hays, Ron D. Chawla, Neetu Kent, Erin E. Arora, Neeraj K. TI Measurement equivalence of the Consumer Assessment of Healthcare Providers and Systems (CAHPS) Medicare survey items between non-Hispanic whites and Asians SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Univ Calif Los Angeles, Los Angeles, CA USA. Kaiser Permanente No Calif, Oakland, CA USA. NCI, NIH, Rockville, MD USA. Patient Centered Outcomes Res Inst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 259 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900249 ER PT J AU Kent, EE Mollica, M Gaillot, S Halpern, MT Hays, RD Lines, LM Topor, MA Yuan, G Schussler, NC Ramirez, E Smith, AW AF Kent, Erin E. Mollica, Michelle Gaillot, Sarah Halpern, Michael T. Hays, Ron D. Lines, Lisa M. Topor, Marie A. Yuan, Gigi Schussler, Nicola C. Ramirez, Edgardo Smith, Ashley Wilder TI Cancer registry-survey data linkages to measure patient-centered quality of care: SEER-MHOS and SEER-CAHPS SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 NCI, NIH, Rockville, MD USA. NCI, Rockville, MD USA. Ctr Medicare Serv, Baltimore, MD USA. Ctr Medicaid Serv, Baltimore, MD USA. Univ Arizona, Coll Publ Hlth, Tucson, AZ USA. Univ Calif Los Angeles, Los Angeles, CA USA. RTI Int, Waltham, MA USA. Informat Management Serv Inc, Rockville, MA USA. Informat Management Serv Inc, Rockville, MD USA. Informat Management Serv Inc, Calverton, MD USA. NCI, Bethesda, MD 20892 USA. RI Lines, Lisa/R-4983-2016 OI Lines, Lisa/0000-0002-9202-3466 NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 303 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900292 ER PT J AU Kenzik, K Richman, J Kent, EE Pisu, M Bhatia, S AF Kenzik, Kelly Richman, Joshua Kent, Erin E. Pisu, Maria Bhatia, Smita TI Impact of precancer multimorbidity clusters on survival and functional outcomes after cancer in older patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. Univ Alabama Birmingham, Birmingham, AL USA. NCI, NIH, Rockville, MD USA. Univ Alabama Birmingham, Ctr Comprehens Canc, Div Prevent Med, Birmingham, AL 35294 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 291 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900280 ER PT J AU Shak, S Petkov, V Miller, DP Howlader, N Gliner, N Howe, W Schussler, NC Cronin, K Baehner, FL Penberthy, L AF Shak, Steven Petkov, Valentina Miller, Dave P. Howlader, Nadia Gliner, Nathan Howe, Will Schussler, Nicola C. Cronin, Kathleen Baehner, Frederick L. Penberthy, Lynne TI Breast cancer specific mortality in patients with early-stage hormone receptor-positive invasive breast cancer and oncotype DX recurrence score results in the SEER database. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Genom Hlth Inc, Redwood City, CA USA. NCI, Bethesda, MD 20892 USA. Informat Management Serv Inc, Calverton, MD USA. Univ Calif San Francisco, Redwood City, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 176 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900172 ER PT J AU Spain, P Teixeira-Poit, S Halpern, MT Castro, K Das, IP Adjei, BA Clauser, S AF Spain, Pamela Teixeira-Poit, Stephanie Halpern, Michael T. Castro, Kathleen Das, Irene Prabhu Adjei, Brenda A. Clauser, Steven TI NCI Community Cancer Center Program (NCCCP): Understanding why hormonal therapy for breast cancer was considered but not administered. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 RTI Int, Res Triangle Pk, NC USA. Univ Arizona, Coll Publ Hlth, Tucson, AZ USA. NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. NCI, Rockville, MD USA. Patient Ctr Outcomes Res Inst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 74 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900073 ER PT J AU Teixeira-Poit, S Spain, P Halpern, MT Castro, KM Das, IP Adjei, BA Clauser, S AF Teixeira-Poit, Stephanie Spain, Pamela Halpern, Michael T. Castro, Kathleen M. Das, Irene Prabhu Adjei, Brenda A. Clauser, Steven TI NCI Community Cancer Center Program (NCCCP): Disparities in time between cancer diagnosis and treatment initiation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 RTI Int, Res Triangle Pk, NC USA. Univ Arizona, Coll Publ Hlth, Tucson, AZ USA. NCI, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. NCI, Rockville, MD USA. Patient Ctr Outcomes Res Inst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 279 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900269 ER PT J AU Chu, CY Stewart, PE Bestor, A Hansen, B Lin, T Gao, LH Norris, SJ Rosa, PA AF Chu, Chen-Yi Stewart, Philip E. Bestor, Aaron Hansen, Bryan Lin, Tao Gao, Lihui Norris, Steven J. Rosa, Patricia A. TI Function of the Borrelia burgdorferi FtsH Homolog Is Essential for Viability both In Vitro and In Vivo and Independent of HflK/C SO MBIO LA English DT Article ID OUTER SURFACE PROTEIN; ESCHERICHIA-COLI FTSH; HEAT-SHOCK; GENE-EXPRESSION; INFECTIOUS CYCLE; CIRCULAR PLASMID; LAC OPERATOR; MEMBRANE; DEGRADATION; COMPLEX AB In many bacteria, the FtsH protease and its modulators, HflK and HflC, form a large protein complex that contributes to both membrane protein quality control and regulation of the cellular response to environmental stress. Both activities are crucial to the Lyme disease pathogen Borrelia burgdorferi, which depends on membrane functions, such as motility, protein transport, and cell signaling, to respond to rapid changes in its environment. Using an inducible system, we demonstrate that FtsH production is essential for both mouse and tick infectivity and for in vitro growth of B. burgdorferi. FtsH depletion in B. burgdorferi cells resulted in membrane deformation and cell death. Overproduction of the protease did not have any detectable adverse effects on B. burgdorferi growth in vitro, suggesting that excess FtsH does not proteolytically overwhelm its substrates. In contrast, we did not observe any phenotype for cells lacking the protease modulators HflK and HflC (Delta HflK/C), although we examined morphology, growth rate, growth under stress conditions, and the complete mouse-tick infectious cycle. Our results demonstrate that FtsH provides an essential function in the life cycle of the obligate pathogen B. burgdorferi but that HflK and HflC do not detectably affect FtsH function. IMPORTANCE Lyme disease is caused by Borrelia burgdorferi, which is maintained in nature in an infectious cycle alternating between small mammals and Ixodes ticks. B. burgdorferi produces specific membrane proteins to successfully infect and persist in these diverse organisms. We hypothesized that B. burgdorferi has a specific mechanism to ensure that membrane proteins are properly folded and biologically active when needed and removed if improperly folded or dysfunctional. Our experiments demonstrate that FtsH, a protease that fulfills this role in other microorganisms, is essential to B. burgdorferi viability. Cells depleted of FtsH do not survive in laboratory culture medium and cannot colonize mice or ticks, revealing an absolute requirement for this protease. However, the loss of two potential modulators of FtsH activity, HflK and HflC, does not detectably affect B. burgdorferi physiology. Our results provide the groundwork for the identification of FtsH substrates that are critical for the bacterium's viability. C1 [Chu, Chen-Yi; Stewart, Philip E.; Bestor, Aaron; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, NIH, Hamilton, MT 59840 USA. [Hansen, Bryan] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. [Lin, Tao; Gao, Lihui; Norris, Steven J.] UTHealth, McGovern Med Sch, Dept Pathol & Lab Med, Houston, TX USA. RP Stewart, PE (reprint author), NIAID, Lab Zoonot Pathogens, NIH, Hamilton, MT 59840 USA. EM pestewart@niaid.nih.gov OI Norris, Steven/0000-0002-2501-8034 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) FX This work, including the efforts of Chen-Yi Chu, Philip E Stewart, Aaron Bestor, Bryan Hansen, and Patricia A Rosa, was funded by Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID). NR 50 TC 2 Z9 2 U1 2 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAR-APR PY 2016 VL 7 IS 2 AR e00404-16 DI 10.1128/mBio.00404-16 PG 10 WC Microbiology SC Microbiology GA DO4QT UT WOS:000377768700021 PM 27094329 ER PT J AU Memoli, MJ Shaw, PA Han, A Czajkowski, L Reed, S Athota, R Bristol, T Fargis, S Risos, K Powers, JH Davey, RT Taubenberger, JK AF Memoli, Matthew J. Shaw, Pamela A. Han, Alison Czajkowski, Lindsay Reed, Susan Athota, Rani Bristol, Tyler Fargis, Sarah Risos, Kyle Powers, John H. Davey, Richard T., Jr. Taubenberger, Jeffery K. TI Evaluation of Antihemagglutinin and Antineuraminidase Antibodies as Correlates of Protection in an Influenza A/H1N1 Virus Healthy Human Challenge Model SO MBIO LA English DT Article ID HEMAGGLUTINATION-INHIBITING ANTIBODY; UNITED-STATES; SEASONAL INFLUENZA; PANDEMIC H1N1; VACCINES; NEURAMINIDASE; INFECTION; IMMUNITY; SERUM; REPRODUCIBILITY AB Despite long-term investment, influenza continues to be a significant worldwide problem. The cornerstone of protection remains vaccination, and approved vaccines seek to elicit a hemagglutination inhibition (HAI) titer of >= 1:40 as the primary correlate of protection. However, recent poor vaccine performance raises questions regarding the protection afforded and whether other correlates of protection should be targeted. A healthy volunteer challenge study was performed with a wild-type 2009 A(H1N1) pdm influenza A challenge virus at the NIH Clinical Center to evaluate two groups of participants with HAI titers of >= 1:40 and < 1:40. The primary objective was to determine whether participants with HAI titers of >= 1:40 were less likely to develop mild to moderate influenza disease (MMID) after intranasal inoculation. HAI titers of >= 1:40 were protective against MMID but did not reduce the incidence of symptoms alone. Although the baseline HAI titer correlated with some reduction in disease severity measures, overall, the baseline NAI titer correlated more significantly with all disease severity metrics and had a stronger independent effect on outcome. This study demonstrates the importance of examining other immunological correlates of protection rather than solely HAI titers. This challenge study confirms the importance of NAI titer as a correlate and for the first time establishes that it can be an independent predictor of reduction of all aspects of influenza disease. This suggests that NAI titer may play a more significant role than previously thought and that neuraminidase immunity should be considered when studying susceptibility after vaccination and as a critical target in future influenza vaccine platforms. IMPORTANCE This study represents the first time the current gold standard for evaluating influenza vaccines as set by the U.S. Food and Drug Administration and the European Medicines Agency Committee for Medicinal Products for Human Use, a "protective" hemagglutination inhibition (HAI) titer of >= 1:40, has been evaluated in a well-controlled healthy volunteer challenge study since the cutoff was established. We used our established wild-type influenza A healthy volunteer human challenge model to evaluate how well this antibody titer predicts a reduction in influenza virus-induced disease. We demonstrate that although higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease. This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza. C1 [Memoli, Matthew J.; Han, Alison; Czajkowski, Lindsay; Reed, Susan; Athota, Rani; Bristol, Tyler; Fargis, Sarah; Risos, Kyle; Taubenberger, Jeffery K.] NIAID, Viral Pathogeness & Evolut Sect, Infect Dis Lab, Div Intramural Res,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Shaw, Pamela A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Powers, John H.] NIAID, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Davey, Richard T., Jr.] NIAID, Clin Res Sect, Lab Immunoregulat, Div Intramural Res,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Memoli, MJ (reprint author), NIAID, Viral Pathogeness & Evolut Sect, Infect Dis Lab, Div Intramural Res,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM memolim@niaid.nih.gov FU HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) [1 ZIA AI000986 09]; Biomedical Advanced Research and Development Authority FX This work, including the efforts of Matthew J. Memoli, Pamela A. Shaw, Alison Han, Lindsay Czajkowski, Susan Reed, Tyler Bristol, Sarah Fargis, Kyle Risos, John Powers, Richard T. Davey, and Jeffery K. Taubenberger, was funded by HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (1 ZIA AI000986 09).; Funding also received from Biomedical Advanced Research and Development Authority through an interagency agreement. NR 29 TC 8 Z9 8 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 MAR-APR PY 2016 VL 7 IS 2 AR e00417-16 DI 10.1128/mBio.00417-16 PG 12 WC Microbiology SC Microbiology GA DO4QT UT WOS:000377768700060 PM 27094330 ER PT J AU Singh, N Bubunenko, M Smith, C Abbott, DM Stringer, AM Shi, R Court, DL Wade, JT AF Singh, Navjot Bubunenko, Mikhail Smith, Carol Abbott, David M. Stringer, Anne M. Shi, Ronald Court, Donald L. Wade, Joseph T. TI SuhB Associates with Nus Factors To Facilitate 30S Ribosome Biogenesis in Escherichia coli SO MBIO LA English DT Article ID DEPENDENT TRANSCRIPTION TERMINATION; ANTITERMINATION IN-VITRO; LAMBDA N-PROTEIN; RNA-TRANSCRIPTION; PHAGE-LAMBDA; DEFECTIVE ANTITERMINATION; SENSITIVE GROWTH; SECY24 MUTATION; GENE-PRODUCT; ELONGATION AB A complex of highly conserved proteins consisting of NusB, NusE, NusA, and NusG is required for robust expression of rRNA in Escherichia coli. This complex is proposed to prevent Rho-dependent transcription termination by a process known as "antitermination." The mechanism of this antitermination in rRNA is poorly understood but requires association of NusB and NusE with a specific RNA sequence in rRNA known as BoxA. Here, we identify a novel member of the rRNA antitermination machinery: the inositol monophosphatase SuhB. We show that SuhB associates with elongating RNA polymerase (RNAP) at rRNA in a NusB-dependent manner. Although we show that SuhB is required for BoxA-mediated antitermination in a reporter system, our data indicate that the major function of the NusB/E/A/G/SuhB complex is not to prevent Rho-dependent termination of rRNA but rather to promote correct rRNA maturation. This occurs through formation of a SuhB-mediated loop between NusB/E/BoxA and RNAP/NusA/G. Thus, we have reassigned the function of these proteins at rRNA and identified another key player in this complex. IMPORTANCE As RNA polymerase transcribes the rRNA operons in E. coli, it complexes with a set of proteins called Nus that confer enhanced rates of transcription elongation, correct folding of rRNA, and rRNA assembly with ribosomal proteins to generate a fully functional ribosome. Four Nus proteins were previously known, NusA, NusB, NusE, and NusG; here, we discover and describe a fifth, SuhB, that is an essential component of this complex. We demonstrate that the main function of this SuhB-containing complex is not to prevent premature transcription termination within the rRNA operon, as had been long claimed, but to enable rRNA maturation and a functional ribosome fully competent for translation. C1 [Singh, Navjot; Smith, Carol; Abbott, David M.; Stringer, Anne M.; Shi, Ronald; Wade, Joseph T.] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12237 USA. [Bubunenko, Mikhail; Court, Donald L.] NCI, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Wade, Joseph T.] Univ Albany, Dept Biomed Sci, Albany, NY 12222 USA. RP Wade, JT (reprint author), New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12237 USA.; Wade, JT (reprint author), Univ Albany, Dept Biomed Sci, Albany, NY 12222 USA. EM joseph.wade@health.ny.gov FU National Institutes of Health through NIH Director's New Innovator Award Program [1DP2OD007188]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Trans National Institutes of Health/Food and Drug Administration Intramural Biodefense Program Grant of the National Institutes of Allergy and Infectious Disease FX This work was funded by the National Institutes of Health through the NIH Director's New Innovator Award Program (1DP2OD007188) to JTW. DLC was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and in part by a Trans National Institutes of Health/Food and Drug Administration Intramural Biodefense Program Grant of the National Institutes of Allergy and Infectious Disease. NR 65 TC 2 Z9 2 U1 1 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 MAR-APR PY 2016 VL 7 IS 2 AR e00114-16 DI 10.1128/mBio.00114-16 PG 9 WC Microbiology SC Microbiology GA DO4QT UT WOS:000377768700076 PM 26980831 ER PT J AU Tran, EEH Podolsky, KA Bartesaghi, A Kuybeda, O Grandinetti, G Wohlbold, TJ Tan, GS Nachbagauer, R Palese, P Krammer, F Subramaniam, S AF Tran, Erin E. H. Podolsky, Kira A. Bartesaghi, Alberto Kuybeda, Oleg Grandinetti, Giovanna Wohlbold, Teddy John Tan, Gene S. Nachbagauer, Raffael Palese, Peter Krammer, Florian Subramaniam, Sriram TI Cryo-electron Microscopy Structures of Chimeric Hemagglutinin Displayed on a Universal Influenza Vaccine Candidate SO MBIO LA English DT Article ID A VIRUSES; STALK ANTIBODIES; H5N1; TOMOGRAPHY; IMMUNITY; EPITOPE; CELLS; HEAD AB Influenza viruses expressing chimeric hemagglutinins (HAs) are important tools in the quest for a universal vaccine. Using cryo-electron tomography, we have determined the structures of a chimeric HA variant that comprises an H1 stalk and an H5 globular head domain (cH5/1 HA) in native and antibody-bound states. We show that cH5/1 HA is structurally different from native HA, displaying a 60 degrees rotation between the stalk and head groups, leading to a novel and unexpected "open" arrangement of HA trimers. cH5/1N1 viruses also display higher glycoprotein density than pH1N1 or H5N1 viruses, but despite these differences, antibodies that target either the stalk or head domains of hemagglutinins still bind to cH5/1 HA with the same consequences as those observed with native H1 or H5 HA. Our results show that a large range of structural plasticity can be tolerated in the chimeric spike scaffold without disrupting structural and geometric aspects of antibody binding. IMPORTANCE Chimeric hemagglutinin proteins are set to undergo human clinical trials as a universal influenza vaccine candidate, yet no structural information for these proteins is available. Using cryo-electron tomography, we report the first three-dimensional (3D) visualization of chimeric hemagglutinin proteins displayed on the surface of the influenza virus. We show that, unexpectedly, the chimeric hemagglutinin structure differs from those of naturally occurring hemagglutinins by displaying a more open head domain and a dramatically twisted head/stalk arrangement. Despite this unusual spatial relationship between head and stalk regions, virus preparations expressing the chimeric hemagglutinin are fully infectious and display a high glycoprotein density, which likely helps induction of a broadly protective immune response. C1 [Tran, Erin E. H.; Podolsky, Kira A.; Bartesaghi, Alberto; Kuybeda, Oleg; Grandinetti, Giovanna; Subramaniam, Sriram] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wohlbold, Teddy John; Tan, Gene S.; Nachbagauer, Raffael; Palese, Peter; Krammer, Florian] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. [Wohlbold, Teddy John] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, New York, NY 10029 USA. [Nachbagauer, Raffael] Univ Vienna, Fac Life Sci, Vienna, Austria. [Palese, Peter] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. RP Subramaniam, S (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ss1@nih.gov OI Palese, Peter/0000-0002-0337-5823; Krammer, Florian/0000-0003-4121-776X; Nachbagauer, Raffael/0000-0001-5568-5420 FU Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD; National Institute of Allergy and Infectious Diseases of the NIH [U19AI109946, P01 AI097092, T32 AI07647]; NIH Centers of Excellence for Influenza Research and Surveillance [HHSN266200700010C] FX This research was supported in part by funds from the Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD (to S.S.) and in part by the National Institute of Allergy and Infectious Diseases of the NIH under award U19AI109946 (P.P. and F.K.) and grant P01 AI097092 (P.P.) and T32 AI07647 (G.S.T.) and the NIH Centers of Excellence for Influenza Research and Surveillance contract HHSN266200700010C (P.P. and F.K.). NR 31 TC 2 Z9 2 U1 0 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 MAR-APR PY 2016 VL 7 IS 2 AR e00257-16 DI 10.1128/mBio.00257-16 PG 9 WC Microbiology SC Microbiology GA DO4QT UT WOS:000377768700086 PM 27006464 ER PT J AU Eng, J McClelland, RL Gomes, AS Hundley, WG Cheng, S Wu, CO Carr, JJ Shea, S Bluemke, DA Lima, JAC AF Eng, John McClelland, Robyn L. Gomes, Antoinette S. Hundley, W. Gregory Cheng, Susan Wu, Colin O. Carr, J. Jeffrey Shea, Steven Bluemke, David A. Lima, Joao A. C. TI Adverse Left Ventricular Remodeling and Age Assessed with Cardiac MR Imaging: The Multi-Ethnic Study of Atherosclerosis SO RADIOLOGY LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; CONGESTIVE-HEART-FAILURE; MAGNETIC-RESONANCE; EJECTION FRACTION; SYSTOLIC FUNCTION; ELDERLY COHORT; NORMAL VALUES; MASS; POPULATION; HYPERTENSION AB Purpose: To evaluate age-related left ventricular (LV) remodeling during longitudinal observation of a large cohort of asymptomatic individuals who were free of clinical cardiovascular disease at baseline. Materials and Methods: The applicable institutional review boards approved this study, and all participants gave informed consent. Cardiac magnetic resonance (MR) imaging was used to identify longitudinal changes in LV structure and function in 2935 participants who underwent baseline and follow-up cardiac MR imaging in the Multi-Ethnic Study of Atherosclerosis. Participants were free of clinical cardiovascular disease at baseline. Participants who experienced an incident coronary heart disease event were excluded. Data were analyzed with multivariable mixed-effects regression models in which the outcome was cardiac MR imaging measurement, and the covariates included follow-up time and cardiac risk factors. Results: Participants were aged 54-94 years at follow-up, and 53% of the participants were women. Median time between baseline and follow-up cardiac MR imaging was 9.4 years. Over this period, LV mass increased in men and decreased slightly in women (8.0 and -1.6 g per decade, respectively; P < .001). In both men and women, LV end-diastolic volume decreased (--9.8 and -13.3 mL per decade, respectively; P < .001), stroke volume decreased (-8.8 and -8.6 mL per decade, respectively; P < .001), and mass-to-volume ratio increased (0.14 and 0.11 g/mL per decade, respectively; P < .001). Change in LV mass was positively associated with systolic blood pressure and body mass index and negatively associated with treated hypertension and high-density lipoprotein cholesterol level. In men, the longitudinal LV mass increase was in contrast to a cross-sectional pattern of LV mass decrease. Conclusion: As patients age, the LV responds differently in its mass and volume between men and women, although both men and women experience increased concentric LV remodeling with age. In men, the opposition of longitudinal and cross-sectional changes in LV mass highlights the importance of longitudinal study. (C) RSNA, 2015 C1 [Eng, John] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, 600 N Wolfe St, Baltimore, MD 21287 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Div Cardiol, Dept Med, 600 N Wolfe St, Baltimore, MD 21287 USA. [McClelland, Robyn L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Gomes, Antoinette S.] UCLA Sch Med, Dept Radiol Sci, Los Angeles, CA USA. [Hundley, W. Gregory] Wake Forest Baptist Med Ctr, Dept Internal Med, Div Cardiol, Winston Salem, NC USA. [Cheng, Susan] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Wu, Colin O.] NHLBI, Off Biostat Res, Bldg 10, Bethesda, MD 20892 USA. [Carr, J. Jeffrey] Vanderbilt Univ, Sch Med, Dept Radiol, Nashville, TN 37212 USA. [Shea, Steven] Columbia Univ, Dept Med, New York, NY USA. [Shea, Steven] Columbia Univ, Dept Epidemiol, New York, NY USA. [Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Eng, J (reprint author), Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, 600 N Wolfe St, Baltimore, MD 21287 USA. EM jeng@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [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] FX This research was supported by the National Institutes of Health (grants 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). NR 36 TC 7 Z9 7 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAR PY 2016 VL 278 IS 3 BP 714 EP 722 DI 10.1148/radiol.2015150982 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DO3TC UT WOS:000377703400009 PM 26485617 ER PT J AU Ortiz, R Ballard, ED Machado-Vieira, R Saligan, LN Walitt, B AF Ortiz, R. Ballard, E. D. Machado-Vieira, R. Saligan, L. N. Walitt, B. TI Quantifying the influence of child abuse history on the cardinal symptoms of fibromyalgia SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Article DE fibromyalgia; pain; pain sensitivity; child abuse; child adversity; symptom profile ID QUALITY-OF-LIFE; SELF-REPORT QUESTIONNAIRE; AGE-RELATED DISEASE; MULTIDIMENSIONAL FATIGUE; PSYCHIATRIC-DISORDERS; PHYSICAL ABUSE; POSTTRAUMATIC-STRESS; COGNITIVE FUNCTION; PAIN SENSITIVITY; SEXUAL-ABUSE AB Objective. To quantify the influence of abuse, particularly in childhood, with pain sensitivity and other adverse symptoms experienced by women with fibromyalgia (FM). Methods. Subjects with FM completed a detailed abuse interview, dolorimetry, and questionnaire-based assessments of fatigue, cognitive self-appraisal, and depression. Student's t- and chi-square tests were used to analyse differences in FM symptoms between those with and without a history of childhood abuse. Linear regression was used to evaluate the relationship between abuse and symptom severity, adjusting for possible confounders. Results. In 111 women with FM, physical abuse during childhood demonstrated a clinically modest, yet statistically significant, association with increased tenderness as measured by pain pressure thresholds (beta=-0.25, p=0.011) and tender points (beta=.0.23, p=.022). Physical child abuse was also associated with cognitive language impairment after adjusting for depression (beta=0.27, p=0.001). While emotional child abuse was associated with fatigue, the association did not persist after adjustment for depressive symptoms. Conclusion. Group differences are of small magnitude and might not directly impact clinical practice, however, the experience of child abuse is associated with FM symptom severity and may shape the biological development of interoception in ways that predispose to pain and polysymptomatic distress. C1 [Ortiz, R.; Ballard, E. D.; Machado-Vieira, R.] NIMH, NIH, Bethesda, MD 20892 USA. [Saligan, L. N.; Walitt, B.] NINR, NIH, 10 Ctr Dr,Room 2-1339, Bethesda, MD 20892 USA. [Walitt, B.] Washington Hosp Ctr, Medstar Res Inst, Washington, DC 20010 USA. RP Walitt, B (reprint author), NINR, NIH, 10 Ctr Dr,Room 2-1339, Bethesda, MD 20892 USA. EM brian.walitt@nih.gov RI MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Georgetown Howard Universities Center for Clinical and Translational Science (GHUCCTS); NIH FX support for this study was provided by the Georgetown Howard Universities Center for Clinical and Translational Science (GHUCCTS).; Robin Ortiz was supported as an NIH research scholar. This was made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors; the other co-authors have declared no competing interests. NR 64 TC 0 Z9 0 U1 5 U2 5 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X EI 1593-098X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD MAR-APR PY 2016 VL 34 IS 2 SU 96 BP S59 EP S66 PG 8 WC Rheumatology SC Rheumatology GA DN7CT UT WOS:000377233600010 PM 26743156 ER PT J AU Harjutsalo, V Maric-Bilkan, C Forsblom, C Groop, PH AF Harjutsalo, Valma Maric-Bilkan, Christine Forsblom, Carol Groop, Per-Henrik CA FinnDiane Study Grp TI Age at menarche and the risk of diabetic microvascular complications in patients with type 1 diabetes SO DIABETOLOGIA LA English DT Article DE Age at menarche; Age at onset of diabetes; Delayed menarche; Diabetic nephropathy; Diabetic retinopathy; Puberty; Type 1 diabetes ID STAGE RENAL-DISEASE; METABOLIC-CONTROL; NATURAL-HISTORY; NEPHROPATHY; MELLITUS; PUBERTY; WOMEN; MICROALBUMINURIA; ADOLESCENTS; ONSET AB Aims/hypothesis The aim of this study was to evaluate the relationship among age at onset of diabetes, age at onset of menarche and risk of diabetic nephropathy and laser-treated retinopathy in type 1 diabetes. Methods Data related to age at menarche were collected through questionnaires and were available for 1,304 women who participated in the Finnish Diabetic Nephropathy Study (FinnDiane). A possible association between age at menarche and diabetic nephropathy and retinopathy was investigated. Results There was an inverse relationship between the age at onset of diabetes and age at menarche: the younger the age at onset of diabetes, the higher the age at menarche (p < 0.0001). A non-linear relationship between the age of menarche and risk of diabetic microvascular complications was found in patients with diabetes onset before menarche, but there was no such association in patients with diabetes onset after menarche. Women with delayed menarche (> mean age+ 2 years) had a 2.30 (95% CI 1.27, 4.17; p < 0.006) times higher risk of nephropathy compared with the women who underwent menarche at the mean age +/- 2 years. Delayed menarche also increased the risk of retinopathy (OR 2.34 [95% CI 1.36, 4.01]). After excluding patients with nephropathy, the OR for retinopathy was 2.11 (95% CI 1.15, 3.90). Earlier menarche (< mean age-2 years) did not have any effect on this risk. Conclusions/interpretation Delayed menarche was associated with an increased risk of diabetic nephropathy and retinopathy, whereas early menarche was not. Delayed menarche may be used as a new tool to identify women at risk of diabetic microvascular complications. C1 [Harjutsalo, Valma; Forsblom, Carol; Groop, Per-Henrik] Univ Helsinki, Biomedicum Helsinki, Folkhalsan Res Ctr, POB 63, FIN-00014 Helsinki, Finland. [Harjutsalo, Valma; Forsblom, Carol; Groop, Per-Henrik] Univ Helsinki, Abdominal Ctr Nephrol, FIN-00014 Helsinki, Finland. [Harjutsalo, Valma; Forsblom, Carol; Groop, Per-Henrik] Helsinki Univ Hosp, Helsinki, Finland. [Harjutsalo, Valma; Forsblom, Carol; Groop, Per-Henrik] Univ Helsinki, Res Program Unit, Diabet & Obes, FIN-00014 Helsinki, Finland. [Harjutsalo, Valma] Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland. [Maric-Bilkan, Christine] NHLBI, Vasc Biol & Hypertens Branch, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Groop, Per-Henrik] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. RP Groop, PH (reprint author), Univ Helsinki, Biomedicum Helsinki, Folkhalsan Res Ctr, POB 63, FIN-00014 Helsinki, Finland.; Groop, PH (reprint author), Univ Helsinki, Abdominal Ctr Nephrol, FIN-00014 Helsinki, Finland.; Groop, PH (reprint author), Helsinki Univ Hosp, Helsinki, Finland.; Groop, PH (reprint author), Univ Helsinki, Res Program Unit, Diabet & Obes, FIN-00014 Helsinki, Finland.; Groop, PH (reprint author), Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. EM per-henrik.groop@helsinki.fi FU Folkhalsan Research Foundation; Academy of Finland [134379]; Wilhelm and Else Stockmann Foundation; Liv och Halsa Foundation; Novo Nordisk Foundation FX This research was funded by grants from the Folkhalsan Research Foundation, the Academy of Finland (134379), the Wilhelm and Else Stockmann Foundation, the Liv och Halsa Foundation and the Novo Nordisk Foundation. The funding bodies were not involved in the design or conduct of the study. NR 47 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD MAR PY 2016 VL 59 IS 3 BP 472 EP 480 DI 10.1007/s00125-015-3816-0 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DN8BC UT WOS:000377302900010 PM 26607636 ER PT J AU Nair, AK Piaggi, P McLean, NA Kaur, M Kobes, S Knowler, WC Bogardus, C Hanson, RL Baier, LJ AF Nair, Anup K. Piaggi, Paolo McLean, Nellie A. Kaur, Manmeet Kobes, Sayuko Knowler, William C. Bogardus, Clifton Hanson, Robert L. Baier, Leslie J. TI Assessment of established HDL-C loci for association with HDL-C levels and type 2 diabetes in Pima Indians SO DIABETOLOGIA LA English DT Article DE CETP; HDL-C; HNF4A; KLF14; Lipids; Pima Indians; Type 2 diabetes ID CORONARY-HEART-DISEASE; GENETIC PREDISPOSITION; GLUCOSE-METABOLISM; INSULIN-RESISTANCE; RISK-FACTORS; CHOLESTEROL; MELLITUS; VARIANTS; POPULATION; WOMEN AB Aims/hypothesis Epidemiological studies in Pima Indians identified elevated levels of HDL-cholesterol (HDL-C) as a protective factor against type 2 diabetes risk in women. We assessed whether HDL-C-associated single-nucleotide polymorphisms (SNPs) also associate with type 2 diabetes in female Pima Indians. Methods Twenty-one SNPs in established HDL-C loci were initially analysed in 2,675 full-heritage Pima Indians. SNPs shown to associate with HDL-C (12 SNPs) were assessed for association with type 2 diabetes in 7,710 Pima Indians (55.6% female sex). The CETP locus provided the strongest evidence for association with HDL-C and was further interrogated by analysing tag SNPs. Results Twelve of the 21 SNPs analysed had a significant association with HDL-C in Pima Indians; five SNPs representing four loci (CETP, DOCK6, PPP1R3B and ABCA1) reached genome-wide significance. Three SNPs, at CETP, KLF14 and HNF4A, associated with type 2 diabetes only in female participants with the HDL-C-lowering allele increasing diabetes risk (p values: 3.2x10(-4) to 7.7x10(-5)); the association remained significant even after adjustment for HDL-C. Additional analysis across CETP identified rs6499863 as having the strongest association with type 2 diabetes in female participants (p = 5.0x10(-6)) and this association remained independent of the HDL-C association. Conclusions/interpretation SNPs at the CETP, HNF4A and KLF14 locus are associated with HDL-C levels and type 2 diabetes (in female participants). However, since HNF4A and KLF14 are established loci for type 2 diabetes, it is unlikely that HDL-C solely mediates these associations. C1 [Nair, Anup K.; Piaggi, Paolo; McLean, Nellie A.; Kaur, Manmeet; Kobes, Sayuko; Knowler, William C.; Bogardus, Clifton; Hanson, Robert L.; Baier, Leslie J.] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, 445 North 5th St, Phoenix, AZ 85004 USA. RP Baier, LJ (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, 445 North 5th St, Phoenix, AZ 85004 USA. EM lbaier@phx.niddk.nih.gov FU intramural research programme of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX The study was supported by the intramural research programme of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 44 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD MAR PY 2016 VL 59 IS 3 BP 481 EP 491 DI 10.1007/s00125-015-3835-x PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DN8BC UT WOS:000377302900011 PM 26670163 ER PT J AU Li, TM He, L Song, Y Villaruz, AE Joo, HS Liu, Q Zhu, YJ Wang, YA Qin, JX Otto, M Li, M AF Li, Tianming He, Lei Song, Yan Villaruz, Amer E. Joo, Hwang-Soo Liu, Qian Zhu, Yuanjun Wang, Yanan Qin, Juanxiu Otto, Michael Li, Min TI AraC-Type Regulator Rsp Adapts Staphylococcus aureus Gene Expression to Acute Infection SO INFECTION AND IMMUNITY LA English DT Article ID PHENOL-SOLUBLE MODULINS; POLYSACCHARIDE INTERCELLULAR ADHESIN/HEMAGGLUTININ; BIOFILM FORMATION; TRANSCRIPTIONAL REGULATORS; VIRULENCE DETERMINANTS; EPIDERMIDIS; PATHOGENESIS; DATABASE; SYSTEM; MODEL AB Staphylococcus aureus is an important human pathogen that can cause two categories of severe infections. Acute infections are characterized by pronounced toxin production, while chronic infections often involve biofilm formation. However, it is poorly understood how S. aureus controls the expression of genes associated with acute versus biofilm-associated virulence. We here identified an AraC-type transcriptional regulator, Rsp, that promotes the production of key toxins while repressing major biofilm-associated genes and biofilm formation. Genome-wide transcriptional analysis and modeling of regulatory networks indicated that upregulation of the accessory gene regulator (Agr) and downregulation of the ica operon coding for the biofilm exopolysaccharide polysaccharide intercellular adhesin (PIA) were central to the regulatory impact of Rsp on virulence. Notably, the Rsp protein directly bound to the agrP2 and icaADBC promoters, resulting in strongly increased levels of the Agr-controlled toxins phenol-soluble modulins (PSMs) and alpha-toxin and reduced production of PIA. Accordingly, Rsp was essential for the development of bacteremia and skin infection, representing major types of acute S. aureus infection. Our findings give important insight into how S. aureus adapts the expression of its broad arsenal of virulence genes to promote different types of disease manifestations and identify the Rsp regulator as a potential target for strategies to control acute S. aureus infection. C1 [Li, Tianming; He, Lei; Liu, Qian; Zhu, Yuanjun; Wang, Yanan; Qin, Juanxiu; Li, Min] Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Lab Med, Shanghai 200030, Peoples R China. [Song, Yan] Tongji Univ, Shanghai East Hosp, Sch Med, Dept Lab Med, Shanghai 200092, Peoples R China. [Villaruz, Amer E.; Joo, Hwang-Soo; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Bacteriol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Li, M (reprint author), Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Lab Med, Shanghai 200030, Peoples R China.; Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Bacteriol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov; ruth_limin@126.com OI Otto, Michael/0000-0002-2222-4115 FU Shanghai Committee of Science and Technology [14140901000]; Shanghai Shuguang Talent Project [12SG03]; National Natural Science Foundation of China (NSFC) [81322025, 81171623, 81371875, 81421001]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) [ZIA AI000904] FX Shanghai Committee of Science and Technology provided funding to Min Li under grant number 14140901000. Shanghai Shuguang Talent Project provided funding to Min Li under grant number 12SG03. National Natural Science Foundation of China (NSFC) provided funding to Min Li under grant numbers 81322025, 81171623, 81371875, and 81421001. Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) provided funding to Michael Otto under grant number ZIA AI000904. NR 46 TC 2 Z9 2 U1 0 U2 1 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 MAR PY 2016 VL 84 IS 3 BP 723 EP 734 DI 10.1128/IAI.01088-15 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DN5JS UT WOS:000377103300011 PM 26712209 ER PT J AU Zheng, MQ Horne, W McAleer, JP Pociask, D Eddens, T Good, M Gao, B Kolls, JK AF Zheng, Mingquan Horne, William McAleer, Jeremy P. Pociask, Derek Eddens, Taylor Good, Misty Gao, Bin Kolls, Jay K. TI Therapeutic Role of Interleukin 22 in Experimental Intra-abdominal Klebsiella pneumoniae Infection in Mice SO INFECTION AND IMMUNITY LA English DT Article ID MUCOSAL HOST-DEFENSE; IL-22; LIVER; CELLS; FUCOSYLATION; INFLAMMATION; HEPATOCYTES; PREVENTION; HEPATITIS; IMMUNITY AB Interleukin 22 (IL-22) is an IL-10-related cytokine produced by T helper 17 (Th17) cells and other immune cells that signals via IL-22 receptor alpha 1 (IL-22Ra1), which is expressed on epithelial tissues, as well as hepatocytes. IL-22 has been shown to have hepatoprotective effects that are mediated by signal transducer and activator of transcription 3 (STAT3) signaling. However, it is unclear whether IL-22 can directly regulate antimicrobial programs in the liver. To test this hypothesis, hepatocyte-specific IL-22Ra1 knockout (Il22Ra1(Hep-/-)) and Stat3 knockout (Stat3(Hep-/-)) mice were generated and subjected to intra-abdominal infection with Klebsiella pneumoniae, which results in liver injury and necrosis. We found that overexpression of IL-22 or therapeutic administration of recombinant IL-22 (rIL-22), given 2 h postinfection, significantly reduced the bacterial burden in both the liver and spleen. The antimicrobial activity of rIL-22 required hepatic Il22Ra1 and Stat3. Serum from rIL-22-treated mice showed potent bacteriostatic activity against K. pneumoniae, which was dependent on lipocalin 2 (LCN2). However, in vivo, rIL-22-induced antimicrobial activity was only partially reduced in LCN2-deficient mice. We found that rIL-22 also induced serum amyloid A2 (SAA2) and that SAA2 had anti-K. pneumoniae bactericidal activity in vitro. These results demonstrate that IL-22, through IL-22Ra1 and STAT3 singling, can induce intrinsic antimicrobial activity in the liver, which is due in part to LCN2 and SAA2. Therefore, IL-22 may be a useful adjunct in treating hepatic and intra-abdominal infections. C1 [Zheng, Mingquan; Horne, William; McAleer, Jeremy P.; Eddens, Taylor; Good, Misty; Kolls, Jay K.] Univ Pittsburgh, Childrens Hosp Pittsburgh, RK Mellon Fdn, UPMC,Pediat Res Inst, Pittsburgh, PA 15213 USA. [Pociask, Derek] Tulane Univ, Sch Med, Sect Pulm Dis Crit Care & Environm Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. [Eddens, Taylor] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA USA. [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. RP Kolls, JK (reprint author), Univ Pittsburgh, Childrens Hosp Pittsburgh, RK Mellon Fdn, UPMC,Pediat Res Inst, Pittsburgh, PA 15213 USA. EM jay.kolls@chp.edu FU HHS \ National Institutes of Health (NIH) [R37 HL079142]; HHS \ National Institutes of Health (NIH) \ NIAID [F30AI114146] FX HHS vertical bar National Institutes of Health (NIH) provided funding to Mingquan Zheng, William T Horne, Jeremy McAleer, Derek Pociask, and Jay Kolls under grant number R37 HL079142. HHS vertical bar National Institutes of Health (NIH) vertical bar NIAID provided funding to Taylor Eddens under grant number F30AI114146. NR 34 TC 4 Z9 4 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 MAR PY 2016 VL 84 IS 3 BP 782 EP 789 DI 10.1128/IAI.01268-15 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DN5JS UT WOS:000377103300017 PM 26729763 ER PT J AU Kim, YA Cho, DY Przytycka, TM AF Kim, Yoo-Ah Cho, Dong-Yeon Przytycka, Teresa M. TI Understanding Genotype-Phenotype Effects in Cancer via Network Approaches SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PROTEIN INTERACTION NETWORK; MUTATED DRIVER PATHWAYS; CANDIDATE DISEASE GENES; RARE DE-NOVO; MUTUAL EXCLUSIVITY; REGULATORY NETWORKS; FUNCTIONAL NETWORK; HIDDEN COMPONENTS; CORE PATHWAYS; WEB-SERVER C1 [Kim, Yoo-Ah; Cho, Dong-Yeon; Przytycka, Teresa M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RP Przytycka, TM (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM przytyck@ncbi.nlm.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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 86 TC 2 Z9 2 U1 1 U2 4 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 MAR PY 2016 VL 12 IS 3 AR e1004747 DI 10.1371/journal.pcbi.1004747 PG 15 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DM8AU UT WOS:000376583800049 PM 26963104 ER PT J AU Okamoto, KW Gould, F Lloyd, AL AF Okamoto, Kenichi W. Gould, Fred Lloyd, Alun L. TI Integrating Transgenic Vector Manipulation with Clinical Interventions to Manage Vector-Borne Diseases SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID TREATED BED NETS; AEDES-AEGYPTI; MALARIA CONTROL; PLASMODIUM-FALCIPARUM; DENGUE VIRUS; PATHOGEN TRANSMISSION; DEVELOPING-COUNTRIES; POPULATION-DYNAMICS; INFECTIOUS-DISEASES; DRUG DISCOVERY AB Many vector-borne diseases lack effective vaccines and medications, and the limitations of traditional vector control have inspired novel approaches based on using genetic engineering to manipulate vector populations and thereby reduce transmission. Yet both the short-and long-term epidemiological effects of these transgenic strategies are highly uncertain. If neither vaccines, medications, nor transgenic strategies can by themselves suffice for managing vector-borne diseases, integrating these approaches becomes key. Here we develop a framework to evaluate how clinical interventions (i.e., vaccination and medication) can be integrated with transgenic vector manipulation strategies to prevent disease invasion and reduce disease incidence. We show that the ability of clinical interventions to accelerate disease suppression can depend on the nature of the transgenic manipulation deployed (e.g., whether vector population reduction or replacement is attempted). We find that making a specific, individual strategy highly effective may not be necessary for attaining public-health objectives, provided suitable combinations can be adopted. However, we show how combining only partially effective antimicrobial drugs or vaccination with transgenic vector manipulations that merely temporarily lower vector competence can amplify disease resurgence following transient suppression. Thus, transgenic vector manipulation that cannot be sustained can have adverse consequences-consequences which ineffective clinical interventions can at best only mitigate, and at worst temporarily exacerbate. This result, which arises from differences between the time scale on which the interventions affect disease dynamics and the time scale of host population dynamics, highlights the importance of accounting for the potential delay in the effects of deploying public health strategies on long-term disease incidence. We find that for systems at the disease-endemic equilibrium, even modest perturbations induced by weak interventions can exhibit strong, albeit transient, epidemiological effects. This, together with our finding that under some conditions combining strategies could have transient adverse epidemiological effects suggests that a relatively long time horizon may be necessary to discern the efficacy of alternative intervention strategies. C1 [Okamoto, Kenichi W.; Gould, Fred; Lloyd, Alun L.] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Okamoto, Kenichi W.] Yale Univ, Yale Inst Biospher Studies, New Haven, CT USA. [Gould, Fred; Lloyd, Alun L.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Lloyd, Alun L.] N Carolina State Univ, Dept Math & Biomath, Grad Program, Raleigh, NC 27695 USA. RP Okamoto, KW (reprint author), N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA.; Okamoto, KW (reprint author), Yale Univ, Yale Inst Biospher Studies, New Haven, CT USA. EM kenichi.okamoto@yale.edu FU National Institutes of Health (NIH) [R01-AI091980, P01-AI098670]; W. M. Keck Foundation; National Science Foundation [RTG/DMS - 1246991] FX This research was funded by the National Institutes of Health (NIH) grants R01-AI091980 and P01-AI098670, the W. M. Keck Foundation and the National Science Foundation (RTG/DMS - 1246991). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 102 TC 0 Z9 0 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAR PY 2016 VL 12 IS 3 AR e1004695 DI 10.1371/journal.pcbi.1004695 PG 27 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DM8AU UT WOS:000376583800026 PM 26962871 ER PT J AU Nuermberger, E Sizemore, C Romero, K Hanna, D AF Nuermberger, Eric Sizemore, Christine Romero, Klaus Hanna, Debra TI Toward an Evidence-Based Nonclinical Road Map for Evaluating the Efficacy of New Tuberculosis (TB) Drug Regimens: Proceedings of a Critical Path to TB Drug Regimens-National Institute of Allergy and Infectious Diseases In Vivo Pharmacology Workshop for TB Drug Development SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Editorial Material ID HOLLOW-FIBER MODEL; ANTITUBERCULOSIS DRUGS; MYCOBACTERIUM-TUBERCULOSIS; MOUSE MODEL; PROGRESSION AB Novel tuberculosis (TB) drug regimens are urgently needed, and their development will be enabled by improved preclinical approaches that more effectively inform and ensure safe selection of clinical candidates and drug combination/regimens. An evidence-based approach for the assessment of nonclinical models supporting TB drug development has been proposed by a joint partnership between the National Institute of Allergy and Infectious Diseases (NIAID) and the Critical Path to TB Drug Regimens (CPTR) Consortium. C1 [Nuermberger, Eric] Johns Hopkins Univ, Ctr TB Res, Baltimore, MD USA. [Sizemore, Christine] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Romero, Klaus; Hanna, Debra] Crit Path Inst, Tucson, AZ USA. RP Hanna, D (reprint author), Crit Path Inst, Tucson, AZ USA. EM dhanna@c-path.org NR 17 TC 1 Z9 1 U1 2 U2 3 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 MAR PY 2016 VL 60 IS 3 BP 1177 EP 1182 DI 10.1128/AAC.02041-15 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DM6VM UT WOS:000376490800001 PM 26824941 ER PT J AU Maron, MI Magle, CT Czesny, B Turturice, BA Huang, RL Zheng, W Vaidya, AB Williamson, KC AF Maron, Maxim I. Magle, Crystal T. Czesny, Beata Turturice, Benjamin A. Huang, Ruili Zheng, Wei Vaidya, Akhil B. Williamson, Kim C. TI Maduramicin Rapidly Eliminates Malaria Parasites and Potentiates the Gametocytocidal Activity of the Pyrazoleamide PA21A050 SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PLASMODIUM-FALCIPARUM GAMETOCYTES; ANTIMALARIAL-DRUGS; MONENSIN; CULTURE; ERYTHROCYTES; TRANSMISSION; SALINOMYCIN; COMBINATION; HOMEOSTASIS; IONOPHORES AB New strategies targeting Plasmodium falciparum gametocytes, the sexual-stage parasites that are responsible for malaria transmission, are needed to eradicate this disease. Most commonly used antimalarials are ineffective against P. falciparum gametocytes, allowing patients to continue to be infectious for over a week after asexual parasite clearance. A recent screen for gameto-cytocidal compounds demonstrated that the carboxylic polyether ionophore maduramicin is active at low nanomolar concentrations against P. falciparum sexual stages. In this study, we showed that maduramicin has an EC50 (effective concentration that inhibits the signal by 50%) of 14.8 nM against late-stage gametocytes and significantly blocks in vivo transmission in a mouse model of malaria transmission. In contrast to other reported gametocytocidal agents, maduramicin acts rapidly in vitro, eliminating gametocytes and asexual schizonts in less than 12 h without affecting uninfected red blood cells (RBCs). Ring stage parasites are cleared by 24 h. Within an hour of drug treatment, 40% of the normally crescent-shaped gametocytes round up and become spherical. The number of round gametocytes increases to >60% by 2 h, even before a change in membrane potential as monitored by MitoProbe DiIC1 (5) is detectable. Maduramicin is not preferentially taken up by gametocyte-infected RBCs compared to uninfected RBCs, suggesting that gametocytes are more sensitive to alterations in cation concentration than RBCs. Moreover, the addition of 15.6 nM maduramicin enhanced the gametocytocidal activity of the pyrazoleamide PA21A050, which is a promising new antimalarial candidate associated with an increase in intracellular Na+ concentration that is proposed to be due to inhibition of PfATP4, a putative Na+ pump. These results underscore the importance of cation homeostasis in sexual as well as asexual intraerythrocytic-stage P. falciparum parasites and the potential of targeting this pathway for drug development. C1 [Maron, Maxim I.; Magle, Crystal T.; Czesny, Beata; Turturice, Benjamin A.; Williamson, Kim C.] Loyola Univ, Dept Biol, Chicago, IL 60626 USA. [Huang, Ruili; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Vaidya, Akhil B.] Drexel Univ, Dept Microbiol & Immunol, Ctr Mol Parasitol, Coll Med, Philadelphia, PA 19104 USA. [Maron, Maxim I.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Magle, Crystal T.] Hlth Sci Lib, Anschutz Med Campus, Aurora, CO USA. [Magle, Crystal T.] Univ Colorado, Anschutz Med Campus, Aurora, CO USA. [Turturice, Benjamin A.] Univ Illinois, Coll Med, Chicago, IL USA. [Williamson, Kim C.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. RP Williamson, KC (reprint author), Loyola Univ, Dept Biol, Chicago, IL 60626 USA. EM kim.williamson@usuhs.edu RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU National Institute of Allergy and Infectious Diseases (NIAID) [AI101396, AI114761, AI098413]; National Center for Advancing Translational Sciences (NCATS); Carbon Research Scholarship FX The National Institute of Allergy and Infectious Diseases (NIAID) provided funding to Kim C. Williamson and Akhil B. Vaidya under grant numbers AI101396 (K.C.W.), AI114761 (K.C.W.), and AI098413 (A.B.V.). The National Center for Advancing Translational Sciences (NCATS) provided intramural funding to Wei Zheng. M.I.M. received support from a Carbon Research Scholarship. NR 43 TC 0 Z9 0 U1 1 U2 4 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 MAR PY 2016 VL 60 IS 3 BP 1492 EP 1499 DI 10.1128/AAC.01928-15 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DM6VM UT WOS:000376490800039 ER PT J AU Del Prete, GQ Oswald, K Lara, A Shoemaker, R Smedley, J Macallister, R Coalter, V Wiles, A Wiles, R Li, Y Fast, R Kiser, R Lu, B Zheng, J Alvord, WG Trubey, CM Piatak, M Deleage, C Keele, BF Estes, JD Hesselgesser, J Geleziunas, R Lifson, JD AF Del Prete, Gregory Q. Oswald, Kelli Lara, Abigail Shoemaker, Rebecca Smedley, Jeremy Macallister, Rhonda Coalter, Vicky Wiles, Adam Wiles, Rodney Li, Yuan Fast, Randy Kiser, Rebecca Lu, Bing Zheng, Jim Alvord, W. Gregory Trubey, Charles M. Piatak, Michael, Jr. Deleage, Claire Keele, Brandon F. Estes, Jacob D. Hesselgesser, Joseph Geleziunas, Romas Lifson, Jeffrey D. TI Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID T-CELL-ACTIVATION; SUBEROYLANILIDE HYDROXAMIC ACID; HISTONE DEACETYLASE INHIBITORS; HIV-INFECTION; DEPSIPEPTIDE FR901228; LATENT INFECTION; RESIDUAL VIRUS; EXPRESSION; RESERVOIR; PHARMACOKINETICS AB Replication-competent human immunodeficiency virus (HIV) persists in infected people despite suppressive combination anti-retroviral therapy (cART), and it represents a major obstacle to HIV functional cure or eradication. We have developed a model of cART-mediated viral suppression in simian human immunodeficiency virus (SIV) mac239-infected Indian rhesus macaques and evaluated the impact of the histone deacetylase inhibitor (HDACi) romidepsin (RMD) on viremia in vivo. Eight macaques virologically suppressed to clinically relevant levels (< 30 viral RNA copies/ml of plasma), using a three-class five-drug cART regimen, received multiple intravenous infusions of either RMD (n = 5) or saline (n = 3) starting 31 to 54 weeks after cART initiation. In vivo RMD treatment resulted in significant transient increases in acetylated histone levels in CD4(+) T cells. RMD-treated animals demonstrated plasma viral load measurements for each 2-week treatment cycle that were significantly higher than those in saline control-treated animals during periods of treatment, suggestive of RMD-induced viral reactivation. However, plasma virus rebound was indistinguishable between RMD-treated and control-treated animals for a subset of animals released from cART. These findings suggest that HDACi drugs, such as RMD, can reactivate residual virus in the presence of suppressive antiviral therapy and may be a valuable component of a comprehensive HIV functional cure/eradication strategy. C1 [Del Prete, Gregory Q.; Oswald, Kelli; Lara, Abigail; Shoemaker, Rebecca; Coalter, Vicky; Wiles, Adam; Wiles, Rodney; Li, Yuan; Fast, Randy; Kiser, Rebecca; Trubey, Charles M.; Piatak, Michael, Jr.; Deleage, Claire; Keele, Brandon F.; Estes, Jacob D.; Lifson, Jeffrey D.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. [Smedley, Jeremy; Macallister, Rhonda] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Anim Sci Program, Frederick, MD USA. [Lu, Bing; Zheng, Jim; Hesselgesser, Joseph; Geleziunas, Romas] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA. [Alvord, W. Gregory] Data Management Serv Inc, Stat Consulting, Frederick, MD USA. [Smedley, Jeremy] Washington Natl Primate Res Ctr, Div Primate Resources, Seattle, WA USA. [Macallister, Rhonda] Oregon Natl Primate Res Ctr, Beaverton, OR USA. RP Lifson, JD (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. EM lifsonj@mail.nih.gov OI Smedley, Jeremy/0000-0003-3369-4662 FU federal funds from National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. NR 63 TC 4 Z9 4 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 MAR PY 2016 VL 60 IS 3 BP 1560 EP 1572 DI 10.1128/AAC.02625-15 PG 13 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DM6VM UT WOS:000376490800049 PM 26711758 ER PT J AU Sward, KA Rubin, S Jenkins, TL Newth, CJ Dean, JM AF Sward, Katherine A. Rubin, Sarah Jenkins, Tammara L. Newth, Christopher J. Dean, J. Michael CA Eunice Kennedy Shriver Natl Inst CPCCRN TI Case Study Semantic Annotation of a Pediatric Critical Care Research Study SO CIN-COMPUTERS INFORMATICS NURSING LA English DT Editorial Material ID INFRASTRUCTURE; STANDARDS C1 [Sward, Katherine A.] Univ Utah, Coll Nursing, Salt Lake City, UT 84112 USA. [Sward, Katherine A.; Dean, J. Michael] Univ Utah, Sch Med, Dept Biomed Informat, Salt Lake City, UT 84112 USA. [Rubin, Sarah; Newth, Christopher J.] Childrens Hosp Los Angeles, Dept Anesthesiol & Crit Care Med, Los Angeles, CA 90027 USA. [Rubin, Sarah; Newth, Christopher J.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Jenkins, Tammara L.] NICHHD, NICHD, Bethesda, MD 20892 USA. [Dean, J. Michael] Univ Utah, Sch Med, Dept Pediat, Div Pediat Crit Care, Salt Lake City, UT 84112 USA. RP Sward, KA (reprint author), Univ Utah, Salt Lake City, UT 84112 USA. EM kathy.sward@nurs.utah.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services [U10HD050096, U10HD049981, U10HD049983, U10HD050012, U10HD063108, U10HD063106, U10HD063114, U01HD049934]; KL2 Mentoring Research Career Development Award (National Center for Advancing Translational Science, National Institutes of Health) through Southern California Clinical and Translational Science Institute at U FX Supported, in part, by the following cooperative agreements from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services: U10HD050096, U10HD049981, U10HD049983, U10HD050012, U10HD063108, U10HD063106, U10HD063114, and U01HD049934. Sarah Rubin is a KL2 Scholar awarded under the KL2 Mentoring Research Career Development Award (National Center for Advancing Translational Science, National Institutes of Health) through Southern California Clinical and Translational Science Institute at University of Southern California, Keck School of Medicine. NR 17 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1538-2931 EI 1538-9774 J9 CIN-COMPUT INFORM NU JI CIN-Comput. Inform. Nurs. PD MAR PY 2016 VL 34 IS 3 BP 101 EP 104 PG 4 WC Computer Science, Interdisciplinary Applications; Medical Informatics; Nursing SC Computer Science; Medical Informatics; Nursing GA DM6KT UT WOS:000376461700001 PM 26958992 ER PT J AU Elshal, MF Aldahlawi, AM Saadah, OI McCoy, JP AF Elshal, M. F. Aldahlawi, A. M. Saadah, O. I. McCoy, J. P. TI Altered proportions of myeloid and plasmacytoid dendritic cells in children with inflammatory bowel disease SO JOURNAL OF CROHNS & COLITIS LA English DT Meeting Abstract C1 [Elshal, M. F.] King Abdulaziz Uinvers, Dept Biochem, Fac Sci, Jeddah, Saudi Arabia. [Elshal, M. F.; Aldahlawi, A. M.] King Abdulaziz Univ, Inflammatory Bowel Dis Res Grp, Jeddah 21413, Saudi Arabia. [Elshal, M. F.; Aldahlawi, A. M.] King Fahd Med Res Ctr, Immunol Unit, Jeddah, Saudi Arabia. [Elshal, M. F.] Sadat City Univ, Dept Mol Biol, Genet Engn & Biotechnol Res Inst, Cairo, Egypt. [Aldahlawi, A. M.] King Abdulaziz Univ, Fac Sci, Dept Biol Sci, Jeddah, Saudi Arabia. [Saadah, O. I.] King Abdulaziz Univ, Fac Med, Dept Paediat, Jeddah 21413, Saudi Arabia. [Saadah, O. I.] King Abdulaziz Uinvers, Inflammatory Bowel Dis Res Grp, Jeddah, Saudi Arabia. [McCoy, J. P.] NHLBI, NIH, Flow Cytometry Core, Bldg 10, Bethesda, MD 20892 USA. RI Genetic Engineering & Biotechnology, Research Institute /E-7221-2017; Fac Sci, KAU, Biol Sci Dept/L-4228-2013; Faculty of, Sciences, KAU/E-7305-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1873-9946 EI 1876-4479 J9 J CROHNS COLITIS JI J. Crohns Colitis PD MAR PY 2016 VL 10 SU 1 MA P085 BP S130 EP S131 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DJ8XF UT WOS:000374496600206 ER PT J AU Veenbergen, S Li, P Raatgeep, H Lindenbergh-Kortleve, D de Ruiter, L van Leeuwen, M Winter, D Simons-Oosterhuis, Y van Berkel, L Nugteren, S Arnold, J Wakabayashi, Y Zhu, J de Ridder, L Driessen, G Escher, J Leonard, W Samsom, J AF Veenbergen, S. Li, P. Raatgeep, H. Lindenbergh-Kortleve, D. de Ruiter, L. van Leeuwen, M. Winter, D. Simons-Oosterhuis, Y. van Berkel, L. Nugteren, S. Arnold, J. Wakabayashi, Y. Zhu, J. de Ridder, L. Driessen, G. Escher, J. Leonard, W. Samsom, J. TI Interleukin-10 inhibits human IFN gamma and IL-17-producing T helper cells indirectly by controlling antigen-presenting cell function SO JOURNAL OF CROHNS & COLITIS LA English DT Meeting Abstract C1 [Veenbergen, S.; Raatgeep, H.; Lindenbergh-Kortleve, D.; de Ruiter, L.; van Leeuwen, M.; Simons-Oosterhuis, Y.; van Berkel, L.; Nugteren, S.; Arnold, J.; Samsom, J.] Erasmus Univ, Med Ctr, Lab Paediat, Div Gastroenterol & Nutr, Rotterdam, Netherlands. [Li, P.; Leonard, W.] NHLBI, NIH, Lab Mol Immunol, Bldg 10, Bethesda, MD 20892 USA. [Winter, D.; de Ridder, L.; Escher, J.] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Paediat Gastroenterol, Rotterdam, Netherlands. [Wakabayashi, Y.; Zhu, J.] NHLBI, NIH, DNA Sequencing & Genom Core, Bldg 10, Bethesda, MD 20892 USA. [Driessen, G.] Erasmus Univ, Med Ctr, Dept Paediat Infect Dis & Immunol, Rotterdam, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1873-9946 EI 1876-4479 J9 J CROHNS COLITIS JI J. Crohns Colitis PD MAR PY 2016 VL 10 SU 1 MA DOP007 BP S28 EP S29 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DJ8XF UT WOS:000374496600038 ER PT J AU Fischbeck, KH AF Fischbeck, Kenneth H. TI Spinal and Bulbar Muscular Atrophy Overview SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Androgen receptor; Polyglutamine; Spinal and bulbarmuscular atrophy ID MOTOR-NEURON DEGENERATION; MUTANT ANDROGEN RECEPTOR; TRANSGENIC MOUSE MODEL; DISEASE; AUTOPHAGY; SBMA; LEUPRORELIN; PHENOTYPES; REPEAT; TRIAL AB Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by an expanded repeat in the androgen receptor gene. The mutant protein is toxic to motor neurons and muscle. The toxicity is ligand-dependent and likely involves aberrant interaction of the mutant androgen receptor with other nuclear factors leading to transcriptional dysregulation. Various therapeutic strategies have been effective in transgenic animal models, and the challenge now is to translate these strategies into safe and effective treatment in patients. C1 [Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, 35-2A1000,35 Convent Dr, Bethesda, MD 20892 USA. RP Fischbeck, KH (reprint author), NINDS, Neurogenet Branch, NIH, 35-2A1000,35 Convent Dr, Bethesda, MD 20892 USA. EM kf@ninds.nih.gov FU Intramural NIH HHS [ZIA NS003038-10] NR 27 TC 1 Z9 1 U1 4 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD MAR PY 2016 VL 58 IS 3 BP 317 EP 320 DI 10.1007/s12031-015-0674-7 PG 4 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DJ5YG UT WOS:000374286100002 PM 26547319 ER PT J AU McGuinness, WA Kobayashi, SD DeLeo, FR AF McGuinness, Will A. Kobayashi, Scott D. DeLeo, Frank R. TI Evasion of Neutrophil Killing by Staphylococcus aureus SO PATHOGENS LA English DT Review DE phagocytosis; neutrophil; Staphylococcus aureus; PMN; innate immunity ID CHEMOTAXIS INHIBITORY PROTEIN; LIPOTEICHOIC ACID; IMMUNE EVASION; UNITED-STATES; HOST-DEFENSE; IN-VIVO; CAPSULAR POLYSACCHARIDE; COMPLEMENT INHIBITOR; NASAL COLONIZATION; CLASS-II AB Staphylococcus aureus causes many types of infections, ranging from self-resolving skin infections to severe or fatal pneumonia. Human innate immune cells, called polymorphonuclear leukocytes (PMNs or neutrophils), are essential for defense against S. aureus infections. Neutrophils are the most prominent cell type of the innate immune system and are capable of producing non-specific antimicrobial molecules that are effective at eliminating bacteria. Although significant progress has been made over the past few decades, our knowledge of S. aureus-host innate immune system interactions is incomplete. Most notably, S. aureus has the capacity to produce numerous molecules that are directed to protect the bacterium from neutrophils. Here we review in brief the role played by neutrophils in defense against S. aureus infection, and correspondingly, highlight selected S. aureus molecules that target key neutrophil functions. C1 [McGuinness, Will A.; Kobayashi, Scott D.; DeLeo, Frank R.] NIAID, Bacteriol Lab, Rocky Mt Labs, NIH, 903 South 4th St, Hamilton, MT 59840 USA. RP DeLeo, FR (reprint author), NIAID, Bacteriol Lab, Rocky Mt Labs, NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM will.mcguinness@nih.gov; kobayashis@niaid.nih.gov; fdeleo@niaid.nih.gov NR 98 TC 2 Z9 2 U1 6 U2 8 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2076-0817 J9 PATHOGENS JI Pathogens PD MAR PY 2016 VL 5 IS 1 AR 32 DI 10.3390/pathogens5010032 PG 13 WC Microbiology SC Microbiology GA DI7LG UT WOS:000373680700003 ER PT J AU Beryozkin, A Levy, G Blumenfeld, A Meyer, S Namburi, P Morad, Y Gradstein, L Swaroop, A Banin, E Sharon, D AF Beryozkin, Avigail Levy, Gal Blumenfeld, Anat Meyer, Segev Namburi, Prasanthi Morad, Yair Gradstein, Libe Swaroop, Anand Banin, Eyal Sharon, Dror TI Genetic Analysis of the Rhodopsin Gene Identifies a Mosaic Dominant Retinitis Pigmentosa Mutation in a Healthy Individual SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE retinal degeneration; inherited blindness; genetic defects; rhodopsin; mosaicism ID FOUNDER MUTATION; PREVALENCE; FAMILIES; DISORDERS; REVEALS; ISRAELI; SCREEN AB PURPOSE. Retinitis pigmentosa (RP) is a group of clinically and genetically heterogeneous hereditary retinal diseases that result in blindness due to photoreceptor degeneration. Mutations in the rhodopsin (RHO) gene are the most common cause of autosomal dominant RP (adRP) and are responsible for 16% to 35% of adRP cases in the Western population. Our purpose was to investigate the contribution of RHO to adRP in the Israeli and Palestinian populations. METHODS. Thirty-two adRP families participated in the study. Mutation detection was performed by whole exome sequencing (WES) and Sanger sequencing of RHO exons. Fluorescence PCR reactions of serially diluted samples were used to predict the percentage of mosaic cells in blood samples. RESULTS. Eight RHO disease-causing mutations were identified in nine families, with only one novel mutation, c.548-638dup91bp, identified in a family where WES failed to detect any causal variant. Segregation analysis revealed that the origin of the mutation is in a mosaic healthy individual carrying the mutation in approximately 13% of blood cells. CONCLUSIONS. This is the first report of the mutation spectrum of a known adRP gene in the Israeli and Palestinian populations, leading to the identification of seven previously reported mutations and one novel mutation. Our study shows that RHO mutations are a major cause of adRP in this cohort and are responsible for 28% of adRP families. The novel mutation exhibits a unique phenomenon in which an unaffected individual is mosaic for an adRP-causing mutation. C1 [Beryozkin, Avigail; Levy, Gal; Blumenfeld, Anat; Meyer, Segev; Namburi, Prasanthi; Banin, Eyal; Sharon, Dror] Hadassah Hebrew Univ, Med Ctr, Dept Ophthalmol, Jerusalem, Israel. [Morad, Yair] Assaf Harofeh Med Ctr, Dept Ophthalmol, IL-70300 Zerifin, Israel. [Gradstein, Libe] Clalit Hlth Serv, Dept Ophthalmol, Beer Sheva, Israel. [Gradstein, Libe] Soroka Univ, Med Ctr, Beer Sheva, Israel. [Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. RP Banin, E; Sharon, D (reprint author), Hadassah Hebrew Univ, Med Ctr, Dept Ophthalmol, Jerusalem, Israel. EM banine@cc.huji.ac.il; dror.sharon1@gmail.com OI Swaroop, Anand/0000-0002-1975-1141 FU Foundation Fighting Blindness USA [BR-GE-0214-0639]; Bi-National USA-Israel Foundation (BSF) [2011202]; National Eye Institute; ERA-RARE RHORCOD grant; Yedidut Research grant FX Supported by the Foundation Fighting Blindness USA (BR-GE-0214-0639, DS and EB), the Bi-National USA-Israel Foundation (BSF-Grant No. 2011202, DS and AS), intramural research program of the National Eye Institute (AS), an ERA-RARE RHORCOD grant and the Yedidut Research grant (EB). NR 45 TC 1 Z9 1 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR PY 2016 VL 57 IS 3 BP 940 EP 947 DI 10.1167/iovs.15-18702 PG 8 WC Ophthalmology SC Ophthalmology GA DK4BE UT WOS:000374860600024 PM 26962691 ER PT J AU Hinshaw, SJH Ogbeifun, O Wandu, WS Lyu, CC Shi, GP Li, YC Qian, HH Gery, I AF Hinshaw, Samuel J. H. Ogbeifun, Osato Wandu, Wambui S. Lyu, Cancan Shi, Guangpu Li, Yichao