FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Markello, T Chen, D Kwan, JY Horkayne-Szakaly, I Morrison, A Simakova, O Maric, I Lozier, J Cullinane, AR Kilo, T Meister, L Pakzad, K Bone, W Chainani, S Lee, E Links, A Boerkoel, C Fischer, R Toro, C White, JG Gahl, WA Gunay-Aygun, M AF Markello, Thomas Chen, Dong Kwan, Justin Y. Horkayne-Szakaly, Iren Morrison, Alan Simakova, Olga Maric, Irina Lozier, Jay Cullinane, Andrew R. Kilo, Tatjana Meister, Lynn Pakzad, Kourosh Bone, William Chainani, Sanjay Lee, Elizabeth Links, Amanda Boerkoel, Cornelius Fischer, Roxanne Toro, Camillo White, James G. Gahl, William A. Gunay-Aygun, Meral TI York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1 SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE STIM1; York Platelet syndrome ID INHERITED THROMBOCYTOPENIC DISORDER; ELECTRON-DENSE CHAINS; TUBULAR-AGGREGATE MYOPATHY; CALCIUM SENSOR STIM1; LYMPHOCYTE FUNCTION; MEGAKARYOCYTES; GRANULES; CLUSTERS; BODIES; DEFICIENCY AB Store-operated Ca2+ entry is the major route of replenishment of intracellular Ca2+ in animal cells in response to the depletion of Ca2+ stores in the endoplasmic reticulum. It is primarily mediated by the Ca2+-selective release-activated Ca2+ (CRAC) channel, which consists of the pore-forming subunits ORAI1-3 and the Ca2+ sensors, STIM1 and STIM2. Recessive loss-of-function mutations in STIM1 or ORAI1 result in immune deficiency and non-progressive myopathy. Heterozygous gain-of-function mutations in STIM1 cause non-syndromic myopathies as well as syndromic forms of miosis and myopathy with tubular aggregates and Stormorken syndrome; some of these syndromic forms are associated with thrombocytopenia. Increased concentration of Ca2+ as a result of store-operated Ca2+ entry is essential for platelet activation. The York Platelet syndrome (YPS) is characterized by thrombocytopenia, striking ultrastructural platelet abnormalities including giant electron-opaque organelles and massive, multilayered target bodies and deficiency of platelet Ca2+ storage in delta granules. We present clinical and molecular findings in 7 YPS patients from 4 families, demonstrating that YPS patients have a chronic myopathy associated with rimmed vacuoles and heterozygous gain-of-function STIM1 mutations. These findings expand the phenotypic spectrum of STIM1-related human disorders and define the molecular basis of YPS. Published by Elsevier Inc. C1 [Markello, Thomas; Bone, William; Chainani, Sanjay; Lee, Elizabeth; Links, Amanda; Boerkoel, Cornelius; Toro, Camillo; Gahl, William A.] NIH, Undiagnosed Dis Program, Common Fund, Off Director, Bethesda, MD 20892 USA. [Chen, Dong] Mayo Clin, Div Hematopathol, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Kwan, Justin Y.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Horkayne-Szakaly, Iren; Morrison, Alan] Def Hlth Agcy, Joint Pathol Ctr, Silver Spring, MD 20910 USA. [Simakova, Olga; Maric, Irina; Lozier, Jay] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Cullinane, Andrew R.; Fischer, Roxanne; Gahl, William A.; Gunay-Aygun, Meral] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Kilo, Tatjana] Childrens Hopsital Westmead, Pediat Hematol, Westmead, NSW 2145, Australia. [Meister, Lynn] Joe DiMaggio Childrens Hosp, Pediat Hematol, Hollywood, FL 33021 USA. [Pakzad, Kourosh] Mem Healthcare Syst, Pathol Consultants South Broward, Hematopathol, Hollywood, FL 33021 USA. [White, James G.] Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 USA. RP Gunay-Aygun, M (reprint author), NHGRI, NIH, 10 Ctr Dr,Bldg 10,Rm 10C103C, Bethesda, MD 20892 USA. EM mgaygun@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 31 TC 16 Z9 16 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 BP 474 EP 482 DI 10.1016/j.ymgme.2014.12.307 PG 9 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800139 PM 25577287 ER PT J AU Couce, ML Boveda, MD Garcia-Jimemez, C Balmaseda, E Vives, I Castineiras, DE Fernandez-Marmiesse, A Fraga, JM Mudd, SH Corrales, FJ AF Couce, Maria L. Boveda, M. Dolores Garcia-Jimemez, Concepcion Balmaseda, Elena Vives, Inmaculada Castineiras, Daisy E. Fernandez-Marmiesse, Ana Fraga, Jose M. Mudd, S. Harvey Corrales, Fernando J. TI Clinical and metabolic findings in patients with methionine adenosyltransferase I/III deficiency detected by newborn screening (vol 110, pg 218, 2013) SO MOLECULAR GENETICS AND METABOLISM LA English DT Correction C1 [Couce, Maria L.] Univ Santiago de Compostela, Unit Diag & Treatment Congenital Metab Dis, Hlth Res Inst Santiago de Compostela IDIS, Dept Pediat,Hosp Clin,CIBERER, Santiago De Compostela 15706, A Coruna, Spain. [Boveda, M. Dolores; Castineiras, Daisy E.; Fernandez-Marmiesse, Ana] Univ Santiago, Unit Diag & Treatment Congenital Metab Dis, Metab Lab, Hosp Clin, Santiago De Compostela 15706, A Coruna, Spain. [Garcia-Jimemez, Concepcion] Hosp Miguel Servet, Serv Pediat, Metab Unit, Zaragoza, Spain. [Balmaseda, Elena] Complejo Hosp Univ Albacete, Serv Pediat, Metab Unit, Albacete, Spain. [Vives, Inmaculada] Hosp Univ Virgen de la Arrixaca, Serv Pediat, Metab Unit, Murcia, Spain. [Fraga, Jose M.] Univ Santiago, Unit Diag & Treatment Congenital Metab Dis, Dept Pediat, Hosp Clin, Santiago De Compostela 15706, A Coruna, Spain. [Mudd, S. Harvey] NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. [Corrales, Fernando J.] Univ Navarra, Ctr Appl Med Res, Div Hepatol & Gene Therapy, Proteon Unit, E-31080 Pamplona, Spain. RP Couce, ML (reprint author), Univ Santiago de Compostela, Unit Diag & Treatment Congenital Metab Dis, Hlth Res Inst Santiago de Compostela IDIS, Dept Pediat,Hosp Clin,CIBERER, A Choupana S-N, Santiago De Compostela 15706, A Coruna, Spain. NR 1 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 BP 486 EP 486 DI 10.1016/j.ymgme.2015.01.011 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800143 PM 25877476 ER PT J AU Wells, ML Washington, OL Hicks, SN Nobile, CJ Hartooni, N Wilson, GM Zucconi, BE Huang, WC Li, LP Fargo, DC Blackshear, PJ AF Wells, Melissa L. Washington, Onica L. Hicks, Stephanie N. Nobile, Clarissa J. Hartooni, Nairi Wilson, Gerald M. Zucconi, Beth E. Huang, Weichun Li, Leping Fargo, David C. Blackshear, Perry J. TI Post-transcriptional regulation of transcript abundance by a conserved member of the tristetraprolin family in Candida albicans SO MOLECULAR MICROBIOLOGY LA English DT Article ID MESSENGER-RNA; SCHIZOSACCHAROMYCES-POMBE; CONFORMATIONAL-CHANGES; BINDING; PROTEIN; PATHOGENICITY; EPIDEMIOLOGY; DEGRADATION; ASSOCIATION; RECRUITMENT AB Members of the tristetraprolin (TTP) family of CCCH tandem zinc finger proteins bind to AU-rich regions in target mRNAs, leading to their deadenylation and decay. Family members in Saccharomyces cerevisiae influence iron metabolism, whereas the single protein expressed in Schizosaccharomyces pombe, Zfs1, regulates cell-cell interactions. In the human pathogen Candida albicans, deep sequencing of mutants lacking the orthologous protein, Zfs1, revealed significant increases (>1.5-fold) in 156 transcripts. Of these, 113 (72%) contained at least one predicted TTP family member binding site in their 3UTR, compared with only 3 of 56 (5%) down-regulated transcripts. The zfs1/ mutant was resistant to 3-amino-1,2,4-triazole, perhaps because of increased expression of the potential target transcript encoded by HIS3. Sequences of the proteins encoded by the putative Zfs1 targets were highly conserved among other species within the fungal CTG clade, while the predicted Zfs1 binding sites in these mRNAs often disappeared' with increasing evolutionary distance from the parental species. C.albicansZfs1 bound to the ideal mammalian TTP binding site with high affinity, and Zfs1 was associated with target transcripts after co-immunoprecipitation. Thus, the biochemical activities of these proteins in fungi are highly conserved, but Zfs1-like proteins may target different transcripts in each species. C1 [Wells, Melissa L.; Washington, Onica L.; Hicks, Stephanie N.; Blackshear, Perry J.] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Huang, Weichun; Li, Leping] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Fargo, David C.] NIEHS, Integrat Bioinformat, Res Triangle Pk, NC 27709 USA. [Nobile, Clarissa J.] Univ Calif, Sch Nat Sci, Merced, CA 95343 USA. [Hartooni, Nairi] Univ Calif San Francisco, Microbiol & Immunol Dept, San Francisco, CA 94143 USA. [Wilson, Gerald M.; Zucconi, Beth E.] Univ Maryland, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences; NIH [R00AI100896, R01AI083311, R01CA102428] FX We thank the NIH Intramural Sequencing Center for performing the mRNA-Seq analysis and Tom Randall for assistance with tree generation. We are grateful for the availability of the Nikon Imaging Center (NIC) at UCSF, where confocal scanning laser microscopy images were acquired. We also thank Jessica Williams and Jim Westmoreland for critical comments on the manuscript, and Alexander Johnson for providing the wild-type and zfs1 Delta/Delta. mutant strains. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. CJN was supported by NIH grant R00AI100896; NH and CJN were supported by NIH grant R01AI083311 to Alexander Johnson; and GMW and BEZ were supported by NIH grant R01CA102428. NR 49 TC 6 Z9 6 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD MAR PY 2015 VL 95 IS 6 BP 1036 EP 1053 DI 10.1111/mmi.12913 PG 18 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA CD9FR UT WOS:000351403900010 PM 25524641 ER PT J AU Mattheisen, M Samuels, JF Wang, Y Greenberg, BD Fyer, AJ McCracken, JT Geller, DA Murphy, DL Knowles, JA Grados, MA Riddle, MA Rasmussen, SA McLaughlin, NC Nurmi, EL Askland, KD Qin, HD Cullen, BA Piacentini, J Pauls, DL Bienvenu, OJ Stewart, SE Liang, KY Goes, FS Maher, B Pulver, AE Shugart, YY Valle, D Lange, C Nestadt, G AF Mattheisen, M. Samuels, J. F. Wang, Y. Greenberg, B. D. Fyer, A. J. McCracken, J. T. Geller, D. A. Murphy, D. L. Knowles, J. A. Grados, M. A. Riddle, M. A. Rasmussen, S. A. McLaughlin, N. C. Nurmi, E. L. Askland, K. D. Qin, H-D Cullen, B. A. Piacentini, J. Pauls, D. L. Bienvenu, O. J. Stewart, S. E. Liang, K-Y Goes, F. S. Maher, B. Pulver, A. E. Shugart, Y. Y. Valle, D. Lange, C. Nestadt, G. TI Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS SO MOLECULAR PSYCHIATRY LA English DT Article ID FAMILY-BASED ASSOCIATION; TRANSPORTER GENE SLC1A1; TYROSINE PHOSPHATASES; EXCITATORY SYNAPSES; ANOREXIA-NERVOSA; PTP-SIGMA; VARIANTS; LINKAGE; LAR; BEHAVIORS AB Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family-and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P = 4.13 x 10(-7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P = 0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P = 0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P < 1 x 10(-6), experiment-wide significant), as well as OFCC1 (P = 6.29 x 10(-5)). The suggestive findings in this study await replication in larger samples. C1 [Mattheisen, M.] Aarhus Univ, Dept Biomed, DK-8000 Aarhus C, Denmark. [Mattheisen, M.] Aarhus Univ, Ctr Integrated Sequencing iSEQ, DK-8000 Aarhus C, Denmark. [Mattheisen, M.; Lange, C.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Mattheisen, M.; Lange, C.] Univ Bonn, Dept Genom Math, Bonn, Germany. [Samuels, J. F.; Wang, Y.; Grados, M. A.; Riddle, M. A.; Cullen, B. A.; Bienvenu, O. J.; Goes, F. S.; Pulver, A. E.; Nestadt, G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Greenberg, B. D.; Rasmussen, S. A.; McLaughlin, N. C.; Askland, K. D.] Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI USA. [Fyer, A. J.] Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, New York, NY USA. [McCracken, J. T.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Geller, D. A.; Pauls, D. L.; Stewart, S. E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Geller, D. A.; Pauls, D. L.; Stewart, S. E.] Harvard Univ, Sch Med, Boston, MA USA. [Murphy, D. L.] NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. [Knowles, J. A.] Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. [Qin, H-D] NIMH, Div Intramural Res Program, Unit Stat Genom, Intramural Res Program, Bethesda, MD 20892 USA. [Stewart, S. E.] Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. [Liang, K-Y; Maher, B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Valle, D.] Johns Hopkins Univ, Sch Med, Inst Human Genet, Baltimore, MD USA. RP Mattheisen, M (reprint author), Aarhus Univ, Dept Biomed, Wilhjelm Meyers 4, DK-8000 Aarhus C, Denmark. EM mm@hum-gen.au.dk; gnestadt@jhmi.edu RI Mattheisen, Manuel/B-4949-2012; OI Mattheisen, Manuel/0000-0002-8442-493X; Samuels, Jack/0000-0002-6715-7905; Stewart, S. Evelyn/0000-0002-0994-6383 FU NIMH [MH071507, MH079489, MH079487, MH079488, MH079494] FX The OCD Collaborative Genetics Association Study (OCGAS) is a collaborative research study and was funded by the following NIMH Grant Numbers: MH071507, MH079489, MH079487, MH079488 and MH079494. Y-YS and H-DQ were also supported by the Intramural Research Program of the NIMH. We thank the families who have participated in the study; David Houseman, PhD, Kathleen Merikangas, PhD, and Alec Wilson, PhD, for consultation; and the clinicians, study managers and clinical interviewers at the respective study sites for their efforts in participant recruitment and clinical assessments: Columbia University: Blair Simpson, MD, PhD, Julianna Stevens, BA Katie Buchholz; Johns Hopkins University: Graham Redgrave, MD, Krista Vermillion, BA, Janice Krasnow, PhD, Jana Drew, PhD, Melissa Meyers, PhD, and Margaret Schlossberg, PhD; Harvard/Massachusetts General Hospital: Elizabeth Mancuso, BA, Alyssa Faro, BA, Ashley Brown, BA, Kesley Ramsay, BA; National Institute of Mental Health (NIMH): Theresa B DeGuzman. NR 57 TC 33 Z9 33 U1 7 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2015 VL 20 IS 3 BP 337 EP 344 DI 10.1038/mp.2014.43 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CE4CV UT WOS:000351779300007 PM 24821223 ER PT J AU Zavala, B Zaghloul, K Brown, P AF Zavala, Baltazar Zaghloul, Kareem Brown, Peter TI The Subthalamic Nucleus, Oscillations, and Conflict SO MOVEMENT DISORDERS LA English DT Article DE subthalamic nucleus; deep brain stimulation; conflict; Parkinson's disease; impulsiveness ID DEEP BRAIN-STIMULATION; ANTERIOR CINGULATE CORTEX; HIGH-FREQUENCY STIMULATION; INFERIOR FRONTAL GYRUS; PARKINSONS-DISEASE; BASAL GANGLIA; RESPONSE-INHIBITION; DECISION-MAKING; COGNITIVE CONTROL; PATHOLOGICAL SYNCHRONIZATION AB The subthalamic nucleus (STN), which is currently the most common target for deep brain stimulation (DBS) for Parkinson's disease (PD), has received increased attention over the past few years for the roles it may play in functions beyond simple motor control. In this article, we highlight several of the theoretical, interventional, and electrophysiological studies that have implicated the STN in response inhibition. Most influential among this evidence has been the reported effect of STN DBS in increasing impulsive responses in the laboratory setting. Yet, how this relates to pathological impulsivity in patients' everyday lives remains uncertain. (c) 2015 International Parkinson and Movement Disorder Society C1 [Zavala, Baltazar; Brown, Peter] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurol, Expt Neurol Grp, Oxford OX3 9DU, England. [Zavala, Baltazar; Zaghloul, Kareem] NIH, Surg Neurol Branch, Bethesda, MD 20892 USA. RP Zavala, B (reprint author), BG 10 RM 3D20 MSC 1414,10 Ctr Dr, Bethesda, MD 20892 USA. EM baltazar.zavala@nih.gov RI Brown, Peter/J-4307-2016 OI Brown, Peter/0000-0002-5201-3044 FU Medical Research Council; National Institute for Health Research Oxford Biomedical Research Centre; National Institute of Neurological Disease and Stroke; National Institutes of Health Oxford-Cambridge fellowship FX Funding agencies: Dr. Brown is funded by the Medical Research Council and the National Institute for Health Research Oxford Biomedical Research Centre. Drs. Zavala and Zaghloul are funded by the National Institute of Neurological Disease and Stroke. Dr. Zavala is additionally supported by the National Institutes of Health Oxford-Cambridge fellowship. NR 88 TC 16 Z9 16 U1 8 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD MAR PY 2015 VL 30 IS 3 BP 328 EP 338 DI 10.1002/mds.26072 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA CD6BP UT WOS:000351173900006 PM 25688872 ER PT J AU Rogers, BM Soja, AJ Goulden, ML Randerson, JT AF Rogers, Brendan M. Soja, Amber J. Goulden, Michael L. Randerson, James T. TI Influence of tree species on continental differences in boreal fires and climate feedbacks SO NATURE GEOSCIENCE LA English DT Article ID INTERIOR ALASKA; BLACK SPRUCE; FOREST-FIRES; IMPACT; MANAGEMENT; EMISSIONS; WILDFIRES; SAVANNA; BALANCE AB Wildfires are common in boreal forests around the globe and strongly influence ecosystem processes. However, North American forests support more high-intensity crown fires than Eurasia, where lower-intensity surface fires are common. These two types of fire can result in different net effects on climate as a consequence of their contrasting impacts on terrestrial albedo and carbon stocks. Here we use remote-sensing imagery, climate reanalysis data and forest inventories to evaluate differences in boreal fire dynamics between North America and Eurasia and their key drivers. Eurasian fires were less intense, destroyed less live vegetation, killed fewer trees and generated a smaller negative shortwave forcing. As fire weather conditions were similar across continents, we suggest that different fire dynamics between the two continents resulted from their dominant tree species. In particular, species that have evolved to spread and be consumed by crown fires as part of their life cycle dominate North American boreal forests. In contrast, tree species that have evolved to resist and suppress crown fires dominate Eurasian boreal forests. We conclude that species-level traits must be considered in global evaluations of the effects of fire on emissions and climate. C1 [Rogers, Brendan M.; Goulden, Michael L.; Randerson, James T.] Univ Calif Irvine, Dept Earth Syst Sci, Irvine, CA 92697 USA. [Soja, Amber J.] NASA, Langley Res Ctr, Climate Sci Branch, NIA, Hampton, VA 23681 USA. [Soja, Amber J.] NASA, Langley Res Ctr, Chem & Dynam Branch, NIA, Hampton, VA 23681 USA. RP Rogers, BM (reprint author), Woods Hole Res Ctr, Falmouth, MA 02540 USA. EM brogers@whrc.org RI Goulden, Michael/B-9934-2008 FU US National Science Foundation (NSF); National Aeronautics and Space Administration (NASA); NSF [ID 2009067341]; Decadal and Regional Climate Prediction using Earth System Models award [AGS-1048890]; NASA Carbon Cycle program [NNX11AF96G]; NASA Atmosphere program [NNX10AT83G]; NASA Interdisciplinary Research in Earth Science program [NNH09ZDA-IDS-0116]; Carbon in Arctic Reservoirs Vulnerability Experiment (CARVE) FX This work was financially supported by the US National Science Foundation (NSF) and the National Aeronautics and Space Administration (NASA). NSF support included a Graduate Research Fellowship (ID 2009067341) to B.M.R. and a Decadal and Regional Climate Prediction using Earth System Models award to J.T.R. (AGS-1048890). This work was also supported by NASA Carbon Cycle (NNX11AF96G), Atmosphere (NNX10AT83G), and Interdisciplinary Research in Earth Science (NNH09ZDA-IDS-0116) programs, and the Carbon in Arctic Reservoirs Vulnerability Experiment (CARVE). We thank S. Conard, W. Kurz, S. Goetz and S. Davis for conversations on continental fire patterns, the National Research Council Canada for providing mapped forest inventory data, and the NASA LP DAAC for data distribution. NR 50 TC 23 Z9 23 U1 10 U2 39 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1752-0894 EI 1752-0908 J9 NAT GEOSCI JI Nat. Geosci. PD MAR PY 2015 VL 8 IS 3 BP 228 EP 234 DI 10.1038/NGEO2352 PG 7 WC Geosciences, Multidisciplinary SC Geology GA CD0NL UT WOS:000350770900023 ER PT J AU Ulrich, CM Wallen, GR Cui, NX Chittarns, J Sweet, M Plemmons, D AF Ulrich, Connie M. Wallen, Gwenyth R. Cui, Naixue Chittarns, Jesse Sweet, Monica Plemmons, Dena TI Establishing good collaborative research practices in the responsible conduct of research in nursing science SO NURSING OUTLOOK LA English DT Article DE Collaborative practices; Nursing science; Research integrity ID SCIENTIFIC MISCONDUCT; RESEARCH COORDINATORS; NONRESPONSE RATES; TELEPHONE SURVEY; NATIONAL-SURVEY; MISBEHAVIOR; HEALTH; IMPACT; BIAS AB Background: Team science is advocated to speed the pace of scientific discovery, yet the goals of collaborative practice in nursing science and the responsibilities of nurse stakeholders are sparse and inconclusive. The purpose of this study was to examine nurse scientists' views on collaborative research as part of a larger study on standards of scientific conduct. Methods: Web-based descriptive survey of nurse scientists randomly selected from 50 doctoral graduate programs in the United States. Results: Nearly forty percent of nurse respondents were not able to identify good collaborative practices for the discipline; more than three quarters did not know of any published guidelines available to them. Successful research collaborations were challenged by different expectations of authorship and data ownership, lack of timeliness and communication, poorly defined roles and responsibilities, language barriers, and when they involve junior and senior faculty working together on a project. Conclusion: Individual and organizational standards, practices, and policies for collaborative research needs clarification within the discipline. C1 [Ulrich, Connie M.; Cui, Naixue; Chittarns, Jesse] Univ Penn, Philadelphia, PA 19106 USA. [Wallen, Gwenyth R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Sweet, Monica; Plemmons, Dena] Univ Calif San Diego, San Diego, CA 92103 USA. RP Ulrich, CM (reprint author), Univ Penn, New Courtland Ctr Transit & Hlth, Sch Nursing, Dept Med Eth & Hlth Policy, Philadelphia, PA 19106 USA. EM culrich@nursing.upenn.edu; dplemmons@ucsd.edu FU National Institutes of Nursing Research [1R01NR009962-01A2] FX Supported by funding from the National Institutes of Nursing Research (1R01NR009962-01A2). NR 24 TC 2 Z9 2 U1 6 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD MAR-APR PY 2015 VL 63 IS 2 BP 171 EP 180 DI 10.1016/j.outlook.2014.10.007 PG 10 WC Nursing SC Nursing GA CD8CQ UT WOS:000351323200012 PM 25771191 ER PT J AU Owen, C Armstrong, AY AF Owen, Carter Armstrong, Alicia Y. TI Clinical Management of Leiomyoma SO OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Fibroids; Leiomyoma; Pathophysiology; Clinical management; Research ID UTERINE ARTERY EMBOLIZATION; PROGESTERONE-RECEPTOR MODULATORS; GONADOTROPIN-RELEASING-HORMONE; RANDOMIZED CONTROLLED-TRIAL; AFRICAN-AMERICAN WOMEN; TRANSVAGINAL SONOGRAPHY; WHITE WOMEN; HYSTEROSONOGRAPHIC EXAMINATION; FIBROID EMBOLIZATION; AROMATASE INHIBITOR AB Uterine leiomyoma, benign monoclonal tumors, afflict an estimated 60% of reproductive-aged women, with higher rates among African American women. Leiomyoma are associated with significant medical costs, impaired fertility potential, obstetric complications, and gynecologic morbidity. Currently, the effective clinical management of leiomyoma is limited by the fact that hysterectomy is the only cure. The purpose of this article is to provide the practitioner with a practical overview of the clinical management of this disease. C1 [Owen, Carter] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bethesda, MD 20892 USA. [Armstrong, Alicia Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Contracept Discovery & Dev Branch, NIH, Rockville, MD 20852 USA. RP Armstrong, AY (reprint author), Room 8813J,6100 Execut Blvd, Rockville, MD 20852 USA. EM armstroa@mail.nih.gov OI Owen, Carter Monique/0000-0002-5012-2706 NR 98 TC 9 Z9 9 U1 2 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8545 EI 1558-0474 J9 OBSTET GYN CLIN N AM JI Obstet. Gynecol. Clin. N. Am. PD MAR PY 2015 VL 42 IS 1 BP 67 EP + DI 10.1016/j.ogc.2014.09.009 PG 20 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CD2VK UT WOS:000350936900008 PM 25681841 ER PT J AU Kraemer, KH DiGiovanna, JJ AF Kraemer, Kenneth H. DiGiovanna, John J. TI Forty Years of Research on Xeroderma Pigmentosum at the US National Institutes of Health SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Review ID COCKAYNE-SYNDROME CELLS; DNA-REPAIR; SKIN-CANCER; COMPLEMENTATION GROUPS; GENETIC-HETEROGENEITY; DEFECTIVE REPAIR; SUN SENSITIVITY; DAMAGED DNA; MUTATIONS; PHOTOPRODUCTS AB In 1968, Dr. James Cleaver reported defective DNA repair in cultured cells from patients with xeroderma pigmentosum. This link between clinical disease and molecular pathophysiology has sparked interest in understanding not only the clinical characteristics of sun sensitivity, damage and cancer that occurred in XP patients but also the mechanisms underlying the damage and repair. While affected patients are rare, their exaggerated UV damage provides a window into the workings of DNA repair. These studies have clarified the importance of a functioning DNA repair system to the maintenance of skin and neurologic health in the general population. Understanding the role of damage in causing cancer, neurologic degeneration, hearing loss and internal cancers provides an opportunity for prevention and treatment. Characterizing complementation groups pointed to the importance of different underlying genes. Studying differences in cancer age of onset and underlying molecular signatures in cancers occurring either in XP patients or the general population has led to insights into differences in carcinogenic mechanisms. The accelerated development of cancers in XP has been used as a model to discover new cancer chemopreventive agents. An astute insight can be a tipping point triggering decades of productive inquiry. C1 [Kraemer, Kenneth H.; DiGiovanna, John J.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kraemer, KH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM kraemerk@nih.gov FU Center for Cancer Research, National Cancer Institute, NIH FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. We want to thank the many postdoctoral fellows, medical students and undergraduate summer students who worked in the laboratory. We are most grateful to the patients and their families who participated in these studies over the past four decades. NR 39 TC 3 Z9 3 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0031-8655 EI 1751-1097 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD MAR-APR PY 2015 VL 91 IS 2 BP 452 EP 459 DI 10.1111/php.12345 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CD5JM UT WOS:000351123900026 PM 25220021 ER PT J AU Weyemi, U Redon, CE Aziz, T Choudhuri, R Maeda, D Parekh, PR Bonner, MY Arbiser, JL Bonner, WM AF Weyemi, Urbain Redon, Christophe E. Aziz, Towqir Choudhuri, Rohini Maeda, Daisuke Parekh, Palak R. Bonner, Michael Y. Arbiser, Jack L. Bonner, William M. TI Inactivation of NADPH Oxidases NOX4 and NOX5 Protects Human Primary Fibroblasts from Ionizing Radiation-Induced DNA Damage SO RADIATION RESEARCH LA English DT Article ID OXIDATIVE STRESS; BLOOD-LYMPHOCYTES; BONE-MARROW; CELLS; GAMMA-H2AX; INJURY; INSTABILITY; INDUCTION; BIOLOGY AB Human exposure to ionizing radiation from medical procedures has increased sharply in the last three decades. Recent epidemiological studies suggest a direct relationship between exposure to ionizing radiation and health problems, including cancer incidence. Therefore, minimizing the impact of radiation exposure in patients has become a priority in the development of future clinical practices. Crucial players in radiation-induced DNA damage include reactive oxygen species (ROS), but the sources of these have remained elusive. To the best of our knowledge, we show here for the first time that two members of the ROS-generating NADPH oxidase family (NOXs), NOX4 and NOX5, are involved in radiation-induced DNA damage. Depleting these two NOXs in human primary fibroblasts resulted in reduced levels of DNA damage as measured by levels of radiation-induced foci, a marker of DNA double-strand breaks (DSBs) and the comet assay coupled with increased cell survival. NOX involvement was substantiated with fulvene-5, a NOXs-specific inhibitor. Moreover, fulvene-5 mitigated radiation-induced DNA damage in human peripheral blood mononuclear cells ex vivo. Our results provide evidence that the inactivation of NOXs protects cells from radiation-induced DNA damage and cell death. These findings suggest that NOXs inhibition may be considered as a future pharmacological target to help minimize the negative effects of radiation exposure for millions of patients each year. (C) 2015 by Radiation Research Society C1 [Weyemi, Urbain; Redon, Christophe E.; Aziz, Towqir; Choudhuri, Rohini; Maeda, Daisuke; Parekh, Palak R.; Bonner, William M.] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Bonner, Michael Y.; Arbiser, Jack L.] Emory Univ, Dept Dermatol, Atlanta, GA 30322 USA. [Bonner, Michael Y.; Arbiser, Jack L.] Emory Univ, Atlanta Vet Adm Med Ctr, Atlanta, GA 30322 USA. RP Weyemi, U (reprint author), NCI, Bldg 37,Room 5050A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM urbain.weyemi@nih.gov; bonnerw@mail.nih.gov RI Weyemi, Urbain/E-2083-2016 FU National Institute of Allergy and Infectious Diseases, Radiation/Nuclear Countermeasures Program; Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health FX This work was supported by the National Institute of Allergy and Infectious Diseases, Radiation/Nuclear Countermeasures Program and the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. NR 34 TC 4 Z9 4 U1 0 U2 3 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD MAR PY 2015 VL 183 IS 3 BP 262 EP 270 DI 10.1667/RR13799.1 PG 9 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA CE0EW UT WOS:000351478300003 PM 25706776 ER PT J AU Steinberg, ML de Chavez, P Baird, DD Carnethon, M Marsh, EE AF Steinberg, Marissa L. de Chavez, Peter Baird, Donna D. Carnethon, Mercedes Marsh, Erica E. TI Effect of Usage and Type of Hormonal Contraception (HC) on Anti-Mullerian Hormone (AMH) Levels in Young African American Women (AAW) SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Steinberg, Marissa L.; Marsh, Erica E.] Northwestern Univ, Obstet & Gynecol REI Div, Feinberg Sch Med, Chicago, IL 60611 USA. [de Chavez, Peter; Carnethon, Mercedes] Northwestern Univ, Preventat Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Baird, Donna D.] NIEHS, Epidemiol, Res Triangle Pk, NC 27709 USA. RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA O-016 BP 62A EP 62A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407200017 ER PT J AU Owen, CM Pal, L Mumford, SL Freeman, R Isaac, B McDonald, L Santoro, NF Taylor, HS Wolff, EF AF Owen, Carter M. Pal, Lubna Mumford, Sunni L. Freeman, Ruth Isaac, Barbara McDonald, Linda Santoro, Nanette F. Taylor, Hugh S. Wolff, Erin F. TI The Effects of Hormones on Skin Wrinkles and Rigidity Vary By Race: 4 Year Follow-Up for Skin Characteristics Ancillary Study of the KEEPS Trial SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Owen, Carter M.; Wolff, Erin F.] NICHD, PRAE, NIH, Bethesda, MD USA. [Pal, Lubna; McDonald, Linda; Taylor, Hugh S.] Yale SOM, Obstet & Gynecol, New Haven, CT USA. [Mumford, Sunni L.] NICHD, DIPHR, NIH, Bethesda, MD USA. [Freeman, Ruth; Isaac, Barbara] Albert Einstein COM, Obstet & Gynecol, Bronx, NY USA. [Santoro, Nanette F.] Univ Colorado Denver SOM, Obstet & Gynecol, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA O-020 BP 63A EP 63A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407200021 ER PT J AU Bernardi, LA de Chavez, PJ Ikhena, DE Baird, DD Carnethon, MR Marsh, EE AF Bernardi, Lia A. de Chavez, Peter J. Ikhena, Deborah E. Baird, Donna D. Carnethon, Mercedes R. Marsh, Erica E. TI The Weight Is Over: The Impact of Obesity on Antimullerian Hormone (AMH) in Young African American Women (AAW) SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Bernardi, Lia A.; Ikhena, Deborah E.; Marsh, Erica E.] Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Chicago, IL 60611 USA. [de Chavez, Peter J.; Carnethon, Mercedes R.] Northwestern Univ, Preventat Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Baird, Donna D.] NIEHS, Epidemiol, Res Triangle Pk, NC 27709 USA. RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA O-052 BP 73A EP 73A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407200053 ER PT J AU Plazyo, O Romero, R Miller, D Roumayah, T Gomez-Lopez, N AF Plazyo, Olesya Romero, Roberto Miller, Derek Roumayah, Tamara Gomez-Lopez, Nardhy TI Specific DAMPs Cause Sterile Inflammation of the Chorioamniotic Membranes and Adverse Perinatal Outcomes SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Plazyo, Olesya; Romero, Roberto; Miller, Derek; Roumayah, Tamara; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, Detroit, MI USA. [Plazyo, Olesya; Romero, Roberto; Miller, Derek; Roumayah, Tamara; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, Bethesda, MD USA. [Plazyo, Olesya; Miller, Derek; Roumayah, Tamara; Gomez-Lopez, Nardhy] WSU, OB GYN, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA O-074 BP 80A EP 80A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407200075 ER PT J AU Yu, J Vahidi, N Weitzel, P Decherney, A Tisdale, J Wolff, EF AF Yu, Jaclyn Vahidi, Nima Weitzel, Patrick Decherney, Alan Tisdale, John Wolff, Erin F. TI Premature Ovarian Insufficiency (POI) Is Associated With Abnormalities in Ovarian Stem Cells (OSC) in an Allogeneic Non-Human Primate (NHP) Transplant Model SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Yu, Jaclyn; Vahidi, Nima; Decherney, Alan; Wolff, Erin F.] NICHHD, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Weitzel, Patrick; Tisdale, John] NHLBI, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA O-087 BP 84A EP 85A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407200088 ER PT J AU Cox, J Malik, M Britten-Webb, J Patel, A Malik, S Segars, J Neiman, L Catherino, W AF Cox, Jeris Malik, Minnie Britten-Webb, Joy Patel, Amrita Malik, Shimona Segars, James Neiman, Lynnette Catherino, William TI Ulipristal Acetate Inhibits Extracellular Matrix Production in Human Leiomyomas In Vivo: A Laboratory Analysis of a Randomized Controlled Trial SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Cox, Jeris; Segars, James; Neiman, Lynnette; Catherino, William] NICHD, NIH, Bethesda, MD USA. [Cox, Jeris; Malik, Minnie; Britten-Webb, Joy; Patel, Amrita; Malik, Shimona; Catherino, William] USUHS, Obstet & Gynecol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA O-098 BP 88A EP 88A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407200099 ER PT J AU Ikhena, DE DeChavez, PJ Bernardi, LA Baird, D Carnethon, M Marsh, EE AF Ikhena, Deborah E. DeChavez, Peter J. Bernardi, Lia A. Baird, Donna Carnethon, Mercedes Marsh, Erica E. TI Is There a Relationship Between the Presence of Fibroids and Antimullerian Hormone (AMH) Concentrations in Young African American Women (AAW)? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Ikhena, Deborah E.; Bernardi, Lia A.; Marsh, Erica E.] Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Chicago, IL 60611 USA. [DeChavez, Peter J.; Carnethon, Mercedes] Northwestern Univ, Feinberg Sch Med, Preventat Med, Chicago, IL 60611 USA. [Baird, Donna] NIEHS, Epidemiol, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA O-100 BP 88A EP 89A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407200101 ER PT J AU Bolnick, AD Bolnick, JM Kilburn, BA Singh, M Hertz, M Jeelani, R Diamond, MP Drewlo, S Armant, DR AF Bolnick, Alan D. Bolnick, Jay M. Kilburn, Brian A. Singh, Manvinder Hertz, Michael Jeelani, Roohi Diamond, Michael P. Drewlo, Sascha Armant, D. Randall TI Low Molecular Weight Heparin Advances Extravillous Differentiation and Inhibits Cell Death in Human Trophoblast Cells Through HBEGF/ERBB Signaling SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Bolnick, Alan D.; Bolnick, Jay M.; Kilburn, Brian A.; Singh, Manvinder; Hertz, Michael; Jeelani, Roohi; Drewlo, Sascha; Armant, D. Randall] Wayne State Univ, Obstet & Gynecol, Detroit, MI USA. [Diamond, Michael P.] Georgia Regents Univ, Obstet & Gynecol, Augusta, GA USA. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA O-107 BP 91A EP 91A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407200108 ER PT J AU Manuck, T AF Manuck, T. TI Preterm Neonatal Death and Morbidity By Gestational Age: A Contemporary Cohort SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Manuck, T.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA O-131 BP 99A EP 99A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407201001 ER PT J AU Archer, DF Thomas, M Merkatz, R Creasy, G Roberts, K Blithe, D Conard, J Sitruk-Ware, R AF Archer, David F. Thomas, Michael Merkatz, Ruth Creasy, George Roberts, Kevin Blithe, Diana Conard, Jacqueline Sitruk-Ware, Regine TI Impact of a One-Year Contraceptive Vaginal Ring Delivering Nestorone and Ethinyl Estradiol on Hepatic Estrogen-Sensitive Proteins SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Archer, David F.] Eastern Virginia Med Sch, Obstet & Gynecol, Norfolk, VA 23501 USA. [Thomas, Michael] Ctr Reprod Hlth, Obstet & Gynecol, Cincinnati, OH USA. [Merkatz, Ruth; Creasy, George; Roberts, Kevin; Sitruk-Ware, Regine] Populat Counsil, Ctr Biomed Res, New York, NY USA. [Blithe, Diana] NICHD, NIH, Bethesda, MD USA. [Conard, Jacqueline] Hosp Cochin, Dept Biol Hematol, Paris, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA T-010 BP 111A EP 112A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407201040 ER PT J AU Frascoli, M Coniglio, L Tang, QZ Gomez-Lopez, N Romero, R MacKenzie, TC AF Frascoli, Michela Coniglio, Lacy Tang, Qizhi Gomez-Lopez, Nardhy Romero, Roberto MacKenzie, Tippi C. TI Evidence of Activation of T Cell-Mediated Immune Responses in the Fetal and Maternal Compartments in Preterm Labor SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Frascoli, Michela; Coniglio, Lacy; MacKenzie, Tippi C.] Univ Calif San Francisco, Eli & Edythe Broad Ctr Regenerat Med, San Francisco, CA 94143 USA. [Frascoli, Michela; Coniglio, Lacy; Tang, Qizhi; MacKenzie, Tippi C.] Univ Calif San Francisco, Surg, San Francisco, CA 94143 USA. [Gomez-Lopez, Nardhy; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Gomez-Lopez, Nardhy; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Obstet & Gynecol, Detroit, MI USA. [Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Immunol & Microbiol, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA T-047 BP 123A EP 123A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407201076 ER PT J AU Plazyo, O Romero, R Unkel, R Gomez-Lopez, N AF Plazyo, Olesya Romero, Roberto Unkel, Ronald Gomez-Lopez, Nardhy TI Differental Expression of Senescence Markers in Chorioamniotic Membranes in Spontaneous Term and Preterm Labor SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Plazyo, Olesya; Romero, Roberto; Unkel, Ronald; Gomez-Lopez, Nardhy] NICHD, PRB, NIH, Detroit, MI USA. [Plazyo, Olesya; Gomez-Lopez, Nardhy] WSU, OB GYN, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA T-053 BP 125A EP 125A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407201082 ER PT J AU Sanchez-Rodriguez, EN Romero, R Sahi, A Gomez-Lopez, N AF Sanchez-Rodriguez, Elly N. Romero, Roberto Sahi, Aashna Gomez-Lopez, Nardhy TI Pregnancy at Advanced Maternal Age Disrupts the T-Cell Repertoire at the Maternal-Fetal Interface and in the Offspring SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Sanchez-Rodriguez, Elly N.; Sahi, Aashna; Gomez-Lopez, Nardhy] WSU, OB GYN, Detroit, MI USA. [Romero, Roberto; Gomez-Lopez, Nardhy] NICHD, PRB, NIH, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA T-054 BP 125A EP 126A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407201083 ER PT J AU Esplin, S Manuck, T Varner, M Christensen, B Biggio, J Parry, S Bukowski, R Zhang, HP Andrews, W Saade, G Sadovsky, Y Ilekis, J Reddy, U AF Esplin, Sean Manuck, Tracy Varner, Michael Christensen, Bryce Biggio, Joseph Parry, Samuel Bukowski, Radek Zhang, Heping Andrews, William Saade, George Sadovsky, Yoel Ilekis, John Reddy, Uma TI Identification of Genetic Factors Associated With Spontaneous Preterm Birth With Features of Decidual Hemorrhage SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Esplin, Sean; Manuck, Tracy; Varner, Michael; Biggio, Joseph; Parry, Samuel; Bukowski, Radek; Zhang, Heping; Andrews, William; Saade, George; Sadovsky, Yoel; Ilekis, John; Reddy, Uma] NICHD, Genom & Prote Network Preterm Birth Res, Bethesda, MD USA. [Christensen, Bryce] Golden Helix, Stat, Bozeman, MT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA T-079 BP 133A EP 133A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407201108 ER PT J AU Mial, TN Kadam, L Romero, R Drewlo, S Gomez-Lopez, N AF Mial, Tara N. Kadam, Leena Romero, Roberto Drewlo, Sascha Gomez-Lopez, Nardhy TI Rosiglitazone Treatment Rapidly Controls the Systemic Pro-Inflammatory Response and Reduces the Rate of Infection-Induced Preterm Birth SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Mial, Tara N.; Kadam, Leena; Drewlo, Sascha; Gomez-Lopez, Nardhy] Wayne State Univ, OB GYN, Detroit, MI USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, Detroit, MI USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA T-091 BP 137A EP 137A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407201120 ER PT J AU Naik, A Romero, R Hassan, SS Unkel, R Gomez-Lopez, N AF Naik, Akshata Romero, Roberto Hassan, Sonia S. Unkel, Ronald Gomez-Lopez, Nardhy TI Vaginal Progesterone Administration Creates an Anti-Inflammatory Micro-Environment at the Maternal-Fetal Interface and Reduces the Rate of Endotoxin-Induced Preterm Birth SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Naik, Akshata; Romero, Roberto; Hassan, Sonia S.; Unkel, Ronald; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, Bethesda, MD USA. [Naik, Akshata; Hassan, Sonia S.; Gomez-Lopez, Nardhy] Wayne State Univ, OB GYN, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA T-093 BP 138A EP 138A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407201122 ER PT J AU Shachar, BZ Gajec, R AF Shachar, Bat Zion Gajec, Ryszard TI Heavy Metals and Risk for Spontaneous Preterm Birth SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Shachar, Bat Zion] NICHD, Eunice Kennedy Shriver, MFMU Network, Bethesda, MD USA. [Gajec, Ryszard] Stanford Univ, March Dimes Prematur Res Ctr, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA T-099 BP 140A EP 140A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407201128 ER PT J AU Manuck, T Esplin, MS Parry, S Zhang, H Biggio, J Bukowski, R Saade, G Andrews, W Baldwin, D Sadovsky, Y Huang, H Reddy, U Ilekis, J Varner, M AF Manuck, T. Esplin, M. S. Parry, S. Zhang, H. Biggio, J. Bukowski, R. Saade, G. Andrews, W. Baldwin, D. Sadovsky, Y. Huang, H. Reddy, U. Ilekis, J. Varner, M. TI Predictors of Response To Indomethacin for Acute Tocolysis SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Manuck, T.; Esplin, M. S.; Parry, S.; Zhang, H.; Biggio, J.; Bukowski, R.; Saade, G.; Andrews, W.; Baldwin, D.; Sadovsky, Y.; Huang, H.; Reddy, U.; Ilekis, J.; Varner, M.] NICHD, Genom & Prote Network Preterm Birth Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA T-142 BP 153A EP 153A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407201170 ER PT J AU Fritz, R Bolnick, A Bolnick, J Schloff, D Kilburn, B Drewlo, S Armant, DR AF Fritz, Rani Bolnick, Alan Bolnick, Jay Schloff, Deborah Kilburn, Brian Drewlo, Sascha Armant, D. Randall TI FISH Analysis After Trophoblast Retrieval and Isolation Form the Cervix (TRIC) Reveals Low Levels of Mosaicism in Extravillous Trophoblast Cells SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Fritz, Rani; Bolnick, Alan; Bolnick, Jay; Kilburn, Brian; Drewlo, Sascha; Armant, D. Randall] Wayne State Univ, Obstet & Gynecol, Detroit, MI USA. [Schloff, Deborah] Detroit Med Ctr, Cytogenet, Detroit, MI USA. [Armant, D. Randall] NICHD, Program Reprouct & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA T-204 BP 172A EP 172A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407201232 ER PT J AU Fritz, R Bolnick, J Bolnick, A Kilburn, B Singh, M Diamond, M Armant, DR AF Fritz, Rani Bolnick, Jay Bolnick, Alan Kilburn, Brian Singh, Manvinder Diamond, Michael Armant, D. Randall TI Trophoblast Retrieval and Isolation From the Cervix (TRIC) of Ongoing Pregnancies Is Unaffected By Body Mass Index, Gestational Age, Parity, or Maternal Age SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Fritz, Rani; Bolnick, Jay; Bolnick, Alan; Kilburn, Brian; Singh, Manvinder; Armant, D. Randall] Wayne State Univ, Obstet & Gynecol, Detroit, MI USA. [Diamond, Michael] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Armant, D. Randall] NICHHD, Program Adult & Reprod Endocrinol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA T-205 BP 173A EP 173A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407201233 ER PT J AU Link, MH Alvarez, MT Louis, GMB Peterson, CM Graves, SW AF Link, Megan H. Alvarez, Meihwa T. Louis, Germaine M. Buck Peterson, C. Matthew Graves, Steven W. TI Identification and Utilization of Peptide and Other Biochemical Markers for the Detection of Endometriosis SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Alvarez, Meihwa T.; Graves, Steven W.] Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA. [Link, Megan H.; Peterson, C. Matthew] Univ Utah, Obstet & Gynecol, Salt Lake City, UT USA. [Louis, Germaine M. Buck] NICHD, Div Intramural Populat Hlth Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA F-012 BP 208A EP 208A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202078 ER PT J AU Britten, JL Malik, M Patel, A Cox, J Catherino, WH AF Britten, Joy L. Malik, Minnie Patel, Amrita Cox, Jeris Catherino, William H. TI Aberrant Tri-Methylation of Histone 3 (H3) Correlates With Increased Extracellular Matrix Production in Leiomyoma Cells SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Britten, Joy L.; Malik, Minnie; Patel, Amrita; Cox, Jeris; Catherino, William H.] Uniformed Serv Univ Hlth Sci, Obstet & Gynecol, Bethesda, MD 20814 USA. [Cox, Jeris; Catherino, William H.] NICHHD, Obstet & Gynecol, Eunice Kennedy Shriver, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA F-024 BP 212A EP 212A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202090 ER PT J AU Fru, KN Millan, NM Conrey, A DeCherney, AH Tisdale, JF Wolff, EF AF Fru, Karenne N. Millan, Nicole M. Conrey, Anna DeCherney, Alan H. Tisdale, John F. Wolff, Erin F. TI Sickle Cell Disease Is Associated With an Increased Rate of Ovarian Dysfunction When the Fraction of Fetal Hemoglobin Is Low SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Fru, Karenne N.; Millan, Nicole M.; DeCherney, Alan H.; Wolff, Erin F.] NICHHD, NIH, Bethesda, MD 20892 USA. [Conrey, Anna; Tisdale, John F.] NHLBI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA F-029 BP 213A EP 214A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202095 ER PT J AU Royster, GD Csokmay, JM Yauger, BJ Chason, RJ DeCherney, AH McTear, C Hill, MJ AF Royster, G. Donald Csokmay, John M. Yauger, Belinda J. Chason, Rebecca J. DeCherney, Alan H. McTear, Coleen Hill, Micah J. TI Elevated Estradiol Levels (> 90th Percentile) At the Time of hCG Trigger During Controlled Ovarian Hyperstimulation Increases Obstetrical Risks Later in Pregnancy SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Royster, G. Donald; Csokmay, John M.; Yauger, Belinda J.; Chason, Rebecca J.; Hill, Micah J.] Walter Reed Natl Mil Med Ctr, OB GYN, Bethesda, MD USA. [Royster, G. Donald; DeCherney, Alan H.] NICHHD, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [McTear, Coleen] Madigan Army Med Ctr, OB GYN, Tacoma, WA 98431 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA F-065 BP 225A EP 225A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202131 ER PT J AU Abramovici, A AF Abramovici, Adi TI Maternal Tobacco Use and Associated Adverse Pregnancy Outcomes. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Abramovici, Adi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA F-179 BP 261A EP 261A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202245 ER PT J AU Dafashy, T Roman, C Kechichian, T Saade, GR Bytautiene, E AF Dafashy, Tamer Roman, Cintia Kechichian, Talar Saade, George R. Bytautiene, Egle TI AGE and Long Term Cardiovascular Outcomes Following Pregnancy Complications SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Dafashy, Tamer] Univ Texas Med Branch, NHLBI, MSRRP, Galveston, TX 77555 USA. [Roman, Cintia; Kechichian, Talar; Saade, George R.; Bytautiene, Egle] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA F-226 BP 275A EP 276A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202292 ER PT J AU Salafia, CM Randell, TL Shah, RG Merz, GS Misra, DP Katzmann, P Miller, RK Garcia, A Moye, J AF Salafia, Carolyn M. Randell, Taylor L. Shah, Ruchit G. Merz, George S. Misra, Dawn P. Katzmann, Philip Miller, Richard K. Garcia, Andrew Moye, John CA NCS Consortium TI Chorionic Plate Surface Vessel Networks and Murray's Law : Relationship of Vessel Numbers and Calibers SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Salafia, Carolyn M.; Merz, George S.] New York State Off Mental Retardat & Dev Disabil, Inst Basic Res, Placental Modulat, Staten Isl, NY USA. [Salafia, Carolyn M.; Randell, Taylor L.; Shah, Ruchit G.; Garcia, Andrew] Placental Analyt, R&D, Larchmont, NY USA. [Misra, Dawn P.] Wayne State Univ, Sch Med, Family Med & Publ Hlth Sci, Detroit, MI USA. [Katzmann, Philip; Miller, Richard K.] Univ Rochester, Sch Med, Obstet & Gynecol, Rochester, NY USA. [Moye, John; NCS Consortium] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA F-262 BP 286A EP 286A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202327 ER PT J AU Salafia, CM Zhou, D Shah, RG Kaneti, MC Lopriore, E Miller, RK Katzmann, P Moye, J AF Salafia, Carolyn M. Zhou, Danny Shah, Ruchit G. Kaneti, Moni C. Lopriore, Enrico Miller, Richard K. Katzmann, Philip Moye, John CA NCS Consortium TI Chorionic Vascular Network Characteristics in Monchorionic Twins Compared To Singleton Placentas SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Salafia, Carolyn M.] New York State Off Mental Retardat & Dev Disabil, Inst Basic Res, Placental Modulat, Staten Isl, NY USA. [Salafia, Carolyn M.; Shah, Ruchit G.; Kaneti, Moni C.] Placental Analyt, R&D, Larchmont, NY USA. [Zhou, Danny; Lopriore, Enrico] Leiden Univ, Neonatol, Leiden, Netherlands. [Miller, Richard K.; Katzmann, Philip] Univ Rochester, Sch Med, Obstet & Gynecol Anhd Pathol, Rochester, NY USA. [Miller, Richard K.; Katzmann, Philip; Moye, John; NCS Consortium] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA F-263 BP 286A EP 287A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202328 ER PT J AU Salafia, CM Shah, RG Merz, GS Misra, DP Miller, RK Katzmann, P Moye, J AF Salafia, Carolyn M. Shah, Ruchit G. Merz, George S. Misra, Dawn P. Miller, Richard K. Katzmann, Philip Moye, John CA NCS Consortium TI Mode Bifurcation Angles in Placental Chorionic Plate Vasculature Closely Follow Hydrodynamic Law SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Salafia, Carolyn M.; Merz, George S.] New York State Off Mental Retardat & Dev Disabil, Inst Basic Res, Placental Modulat, Staten Isl, NY USA. [Salafia, Carolyn M.; Shah, Ruchit G.] Placental Analyt, R&D, Larchmont, NY USA. [Misra, Dawn P.] Wayne State Univ, Sch Med, Family Med & Publ Hlth Sci, Detroit, MI USA. [Miller, Richard K.; Katzmann, Philip] Univ Rochester, Sch Med, Obstet & Gynecol, Rochester, NY USA. [Katzmann, Philip; Moye, John; NCS Consortium] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA F-261 BP 286A EP 286A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202326 ER PT J AU Plowden, TC Zarek, SM Mumford, SL Nieman, LK Armstrong, AY AF Plowden, Torie C. Zarek, Shvetha M. Mumford, Sunni L. Nieman, Lynnette K. Armstrong, Alicia Y. TI Bleeding Patterns in African American Versus Caucasian Women Treated With Ulipristal Acetate (UPA): Secondary Data Analysis of Two Randomized Controlled Trials. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Plowden, Torie C.; Zarek, Shvetha M.; Nieman, Lynnette K.; Armstrong, Alicia Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA S-021 BP 305A EP 305A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202384 ER PT J AU Zarek, SM Kim, JH Connell, MT Plowden, TC Segars, JH DeCherney, AH Wolff, EF AF Zarek, Shvetha M. Kim, Jeffrey H. Connell, Matthew T. Plowden, Torie C. Segars, James H. DeCherney, Alan H. Wolff, Erin F. TI Characterization of the Endometrial Microbiome. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Zarek, Shvetha M.; Connell, Matthew T.; Plowden, Torie C.; Segars, James H.; DeCherney, Alan H.; Wolff, Erin F.] NICHHD, Program Reprod & Adult Endocrinol, Eunice Kennedy Shriver, NIH, Bethesda, MD 20892 USA. [Kim, Jeffrey H.] Radiant Genom Inc, Emeryville, CA USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA S-037 BP 310A EP 310A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202400 ER PT J AU Stratton, P Giri, N Sklavos, MM Alter, BP Savage, S Pinto, LA AF Stratton, P. Giri, N. Sklavos, M. M. Alter, B. P. Savage, S. Pinto, L. A. TI Adult Males With Fanconi Anemia and Dyskeratosis Congenita But Not Diamond Blackfan Anemia Have Reduced Levels of Circulating Anti-Mullerian Hormone. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Stratton, P.] NICHD, PRAE, NIH, Bethesda, MD USA. [Giri, N.; Alter, B. P.; Savage, S.] NCI, CGB, DCEG, NIH, Bethesda, MD 20892 USA. [Sklavos, M. M.; Pinto, L. A.] FNLCR, Leidos Biomed Res, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA S-052 BP 315A EP 315A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202415 ER PT J AU Arenas-Hernandez, M St Louis, D Sanchez-Rodriguez, EN Romero, R Gomez-Lopez, N AF Arenas-Hernandez, Marcia St Louis, Derek Sanchez-Rodriguez, Elly N. Romero, Roberto Gomez-Lopez, Nardhy TI NKT-Activation Alters the Maternal T-Cell Repertoire and Causes Preterm Birth. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Arenas-Hernandez, Marcia; St Louis, Derek; Sanchez-Rodriguez, Elly N.; Gomez-Lopez, Nardhy] Wayne State Univ, OB GYN, Detroit, MI USA. [St Louis, Derek; Romero, Roberto; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, Detroit, MI USA. [St Louis, Derek; Romero, Roberto; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA S-066 BP 319A EP 319A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202429 ER PT J AU Furcron, AE Mial, TN Arenas-Hernandez, M Romero, R Hassan, SS Gomez-Lopez, N AF Furcron, Amy-Eunice Mial, Tara N. Arenas-Hernandez, Marcia Romero, Roberto Hassan, Sonia S. Gomez-Lopez, Nardhy TI Prenatal Stress Over Generations Disrupts the T-Cell Repertoire in Mothers and Neonates. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Furcron, Amy-Eunice; Mial, Tara N.; Arenas-Hernandez, Marcia; Hassan, Sonia S.; Gomez-Lopez, Nardhy] Wayne State Univ, OB GYN, Detroit, MI USA. [Romero, Roberto; Hassan, Sonia S.; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, Detroit, MI USA. [Romero, Roberto; Hassan, Sonia S.; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA S-069 BP 320A EP 320A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202432 ER PT J AU St Louis, D Arenas-Hernandez, M Plazyo, O Sanchez-Rodriguez, EN Romero, R Gomez-Lopez, N AF St Louis, Derek Arenas-Hernandez, Marcia Plazyo, Olesya Sanchez-Rodriguez, Elly N. Romero, Roberto Gomez-Lopez, Nardhy TI Rosiglitazone Rescues NKT Activation-Induced Preterm Birth. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [St Louis, Derek; Arenas-Hernandez, Marcia; Plazyo, Olesya; Sanchez-Rodriguez, Elly N.; Gomez-Lopez, Nardhy] WSU, OB GYN, Detroit, MI USA. [St Louis, Derek; Plazyo, Olesya; Romero, Roberto; Gomez-Lopez, Nardhy] NICHD, PRB, NIH, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA S-073 BP 321A EP 321A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202436 ER PT J AU Mial, TM Kot, C Robertson, SA Gomez-Lopez, N AF Mial, Tara M. Kot, Christopher Robertson, Sarah A. Gomez-Lopez, Nardhy TI A Reduction of Macrophage Populations at the Maternal-Fetal Interface in an Infectious, But Not in a Non-Infectious, Model of Preterm Birth. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Mial, Tara M.; Kot, Christopher; Gomez-Lopez, Nardhy] Wayne State Univ, OB GYN, Detroit, MI USA. [Kot, Christopher; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, Detroit, MI USA. [Robertson, Sarah A.] Univ Adelaide, OB GYN, Adelaide, SA, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA S-074 BP 322A EP 322A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202437 ER PT J AU Naik, A Romero, R Balancio, A Hassan, SS Gomez-Lopez, N AF Naik, Akshata Romero, Roberto Balancio, Amapola Hassan, Sonia S. Gomez-Lopez, Nardhy TI Human Chorionic Gonadotropin Drives a Macrophage M1-M2 Polarization at the Maternal-Fetal Interface and Reduces Th9 and Tc17 Cells in the Maternal Circulation. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Naik, Akshata; Romero, Roberto; Balancio, Amapola; Hassan, Sonia S.; Gomez-Lopez, Nardhy] WSU, OB GYN, Detroit, MI USA. [Naik, Akshata; Balancio, Amapola; Hassan, Sonia S.; Gomez-Lopez, Nardhy] NICHD, PRB, NIH, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA S-076 BP 322A EP 322A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202439 ER PT J AU Xu, Y Romero, R Mackenzie, TC Gomez-Lopez, N AF Xu, Yi Romero, Roberto Mackenzie, Tippi C. Gomez-Lopez, Nardhy TI Evidence of Maternal-Fetal Rejection in Spontaneous Preterm Labor: An Influx of CD8 T-EM Cells at the Maternal-Fetal Interface. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Xu, Yi; Romero, Roberto; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, Detroit, MI USA. [Mackenzie, Tippi C.] Univ Calif San Francisco, Surg, San Francisco, CA 94143 USA. [Gomez-Lopez, Nardhy] Wayne State Univ, OB GYN, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA S-081 BP 324A EP 324A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202444 ER PT J AU Yu, X Romero, R Price, M Mackenzie, TC Frascoli, M Gomez-Lopez, N AF Yu, Xi Romero, Roberto Price, Michael Mackenzie, Tippi C. Frascoli, Michela Gomez-Lopez, Nardhy TI A Reduction of CD71+Erythroid Cells in Term and Preterm Labor. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Yu, Xi; Romero, Roberto; Price, Michael; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, Detroit, MI USA. [Mackenzie, Tippi C.; Frascoli, Michela] Univ Calif San Francisco, Surg, San Francisco, CA 94143 USA. [Gomez-Lopez, Nardhy] Wayne State Univ, OB GYN, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA S-082 BP 324A EP 324A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202445 ER PT J AU Judy, AE AF Judy, Amy E. TI Maternal Height Is Protective Against Cesarean Delivery in Overweight and Obese Nulliparous Women. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Judy, Amy E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA S-142 BP 344A EP 344A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202505 ER PT J AU Manuck, T Esplin, MS Parry, S Zhang, H Biggio, J Bukowski, R Saade, G Sadovsky, Y Baldwin, D Andrews, W Huang, H Reddy, U Ilekis, J Varner, M AF Manuck, T. Esplin, M. S. Parry, S. Zhang, H. Biggio, J. Bukowski, R. Saade, G. Sadovsky, Y. Baldwin, D. Andrews, W. Huang, H. Reddy, U. Ilekis, J. Varner, M. TI Spontaneous Preterm Birth Phenotype and Neonatal Outcomes. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Manuck, T.; Esplin, M. S.; Parry, S.; Zhang, H.; Biggio, J.; Bukowski, R.; Saade, G.; Sadovsky, Y.; Baldwin, D.; Andrews, W.; Huang, H.; Reddy, U.; Ilekis, J.; Varner, M.] NICHD, Genom & Prote Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2015 VL 22 SU 1 MA S-146 BP 345A EP 345A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD9GW UT WOS:000351407202509 ER PT J AU Scheibye-Knudsen, M AF Scheibye-Knudsen, Morten TI Nourishing the Aging Brain SO SCIENTIST LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; COCKAYNE-SYNDROME; KETOGENIC DIET; MOUSE MODEL; DISEASE; NAD(+); SIRTUINS C1 NIA, Bethesda, MD 20892 USA. RP Scheibye-Knudsen, M (reprint author), NIA, Bethesda, MD 20892 USA. OI Scheibye-Knudsen, Morten/0000-0002-6637-1280 NR 12 TC 0 Z9 0 U1 0 U2 6 PU LABX MEDIA GROUP PI MIDLAND PA PO BOX 216, 478 BAY ST, MIDLAND, ONTARIO L4R 1K9, CANADA SN 0890-3670 EI 1547-0806 J9 SCIENTIST JI Scientist PD MAR PY 2015 VL 29 IS 3 BP 46 EP 51 PG 6 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA CD8GX UT WOS:000351334300011 ER PT J AU Mazza, F Ferrari, E Maineri, P Dozin, B Ratto, GB AF Mazza, Federico Ferrari, Enrico Maineri, Paola Dozin, Beatrice Ratto, Giovanni Battista TI Pleural lavage cytology predicts recurrence and survival, even in early non-small cell lung cancer SO SURGERY TODAY LA English DT Article DE Lung cancer; Lung resection; Staging; Prognosis; Cytology ID CISPLATIN TREATMENT; PROGNOSTIC-FACTOR; CARCINOMA; RESECTION; INDICATOR; EFFUSION AB Purpose The TNM staging remains the best prognostic descriptor of lung cancer; however, new independent prognostic factors are needed, particularly for early stage disease. Methods An evaluation of the pleural lavage cytology (PLC) was performed in 436 consecutive NSCLC patients who underwent surgical resection; clinical, pathological and follow-up data were available for 414 patients. Results The PLC was positive in 15 patients (3.6 %). The overall five-year survival was 35.9 % in PLC-positive and 57.8 % in PLC-negative patients (p = 0.004). To compare groups with the same prognostic characteristics, the analysis was restricted to p-stage I patients, but the survival remained worse in the PLC-positive patients (42.9 vs 69.4 %; p = 0.001). Recurrence was also observed more frequently in PLC-positive cases: 69.2 vs 34.5 %, OR 4.28 (95 % CI 1.29-14.18; p = 0.01). Among the PLC-positive patients, no difference between the local (44.4 %) and distant (55.6 %) relapse patterns was found (p = 0.82). The multivariate analysis identified four independent prognostic factors: age (p < 0.001), disease stage (p < 0.001), gender (p = 0.025) and PLC status (p = 0.012). Conclusions PLC is an independent prognostic factor for NSCLC. PLC-positive NSCLC patients have a worse overall survival and a higher recurrence rate, even in stage I disease. PLC-positive patients should be considered a high risk category, who should potentially be eligible for adjuvant therapy regardless of their p-stage. C1 [Mazza, Federico; Maineri, Paola] Santa Corona Hosp, Thorac Surg Unit, I-17027 Pietra Ligure, SV, Italy. [Ferrari, Enrico; Ratto, Giovanni Battista] AOU San Martino IST, Natl Canc Inst, Thorac Surg Unit, I-16132 Genoa, Italy. [Dozin, Beatrice] IRCCS AOU San Martino ST, Clin Epidemiol Unit, Genoa, Italy. RP Mazza, F (reprint author), Santa Corona Hosp, Thorac Surg Unit, Via 25 Aprile 38, I-17027 Pietra Ligure, SV, Italy. EM mazza-federico@libero.it NR 24 TC 6 Z9 6 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-1291 EI 1436-2813 J9 SURG TODAY JI Surg. Today PD MAR PY 2015 VL 45 IS 3 BP 322 EP 328 DI 10.1007/s00595-014-0915-3 PG 7 WC Surgery SC Surgery GA CD7OT UT WOS:000351280800009 PM 24817060 ER PT J AU Reiner, RC Smith, DL Gething, PW AF Reiner, Robert C., Jr. Smith, David L. Gething, Peter W. TI Climate change, urbanization and disease: summer in the city... SO TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE LA English DT Editorial Material DE Climate change; Composition of disease; Seasonality; Tropical climates; Urbanization ID MALARIA; MEGACITY; HEALTH AB Climate change and urbanization can alter the burden of human diseases. The tropics, a region that includes the poorest populations and highest disease burdens, are expected to get slightly hotter and substantially more urban. Studies have projected changing burdens under different climate or urbanization scenarios, but it remains unclear what will happen if both happen at once. Interactions could amplify disease burdens, improve health overall, or shift burdens around. Social planners need better data on contemporary seasonal disease incidence patterns across the spectrum of climate, urbanicity and socio-economic status. How climate change, urbanization and health interact must be understood to adequately plan for the future. C1 [Reiner, Robert C., Jr.; Smith, David L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Reiner, Robert C., Jr.] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN 47401 USA. [Smith, David L.; Gething, Peter W.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England. RP Reiner, RC (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM rcreiner@indiana.edu OI Gething, Peter/0000-0001-6759-5449 FU Medical Research Council NR 10 TC 2 Z9 2 U1 4 U2 27 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0035-9203 EI 1878-3503 J9 T ROY SOC TROP MED H JI Trans. Roy. Soc. Trop. Med. Hyg. PD MAR PY 2015 VL 109 IS 3 BP 171 EP 172 DI 10.1093/trstmh/tru194 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CD3LX UT WOS:000350981100002 PM 25491136 ER PT J AU Panch, SR Yau, YY West, K Diggs, K Sweigart, T Leitman, SF AF Panch, Sandhya R. Yau, Yu Ying West, Kamille Diggs, Karen Sweigart, Tamsen Leitman, Susan F. TI Initial serum ferritin predicts number of therapeutic phlebotomies to iron depletion in secondary iron overload SO TRANSFUSION LA English DT Article ID HEMATOPOIETIC-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; PERIPHERAL ARTERIAL-DISEASE; PORPHYRIA-CUTANEA-TARDA; FATTY LIVER-DISEASE; HEPATOCELLULAR-CARCINOMA; THALASSEMIA MAJOR; CLINICAL-TRIAL; HEMOCHROMATOSIS; TRANSFUSION AB BackgroundTherapeutic phlebotomy is increasingly used in patients with transfusional siderosis to mitigate organ injury associated with iron overload (IO). Laboratory response variables and therapy duration are not well characterized in such patients. Study Design and MethodsWe retrospectively evaluated 99 consecutive patients undergoing therapeutic phlebotomy for either transfusional IO (TIO, n=88; 76% had undergone hematopoietic transplantation) or nontransfusional indications (hyperferritinemia or erythrocytosis; n=11). Complete blood cell count, serum ferritin (SF), transferrin saturation, and transaminases were measured serially. Phlebotomy goal was an SF level of less than 300g/L. ResultsMean SF levels before phlebotomy among TIO and nontransfusional subjects were 3093 and 396g/L, respectively. Transfusion burden in the TIO group was 94108 (mean +/- SD) RBC units; approximately half completed therapy with 24 +/- 23 phlebotomies (range, 1-103). One-third were lost to follow-up. Overall, 15% had mild adverse effects, including headache, nausea, and dizziness, mainly during first phlebotomy. Prior transfusion burden correlated poorly with initial ferritin and total number of phlebotomies to target in the TIO group. However, number of phlebotomies to target was strongly correlated with initial SF (R-2=0.8; p<0.0001) in both TIO and nontransfusional groups. ALT decreased significantly with serial phlebotomy in all groups (mean initial and final values, 61 and 39U/L; p=0.03). ConclusionsInitial SF but not transfusion burden predicted number of phlebotomies to target in patients with TIO. Despite good treatment tolerance, significant losses to follow-up were noted. Providing patients with an estimated phlebotomy number and follow-up duration, and thus a finite endpoint, may improve compliance. Hepatic function improved with iron offloading. C1 [Yau, Yu Ying; West, Kamille; Diggs, Karen; Sweigart, Tamsen; Leitman, Susan F.] NHLBI, Dept Transfus Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Panch, Sandhya R.] NHLBI, Hematol Transfus Med, NIH, Bethesda, MD 20892 USA. RP Leitman, SF (reprint author), NIH Clin Ctr, Dept Transfus Med, Bldg 10,Room 1C-711, Bethesda, MD 20854 USA. EM sleitman@nih.gov FU Intramural NIH HHS [ZIA CL002107-14] NR 50 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD MAR PY 2015 VL 55 IS 3 BP 611 EP 622 DI 10.1111/trf.12854 PG 12 WC Hematology SC Hematology GA CD6BZ UT WOS:000351175100023 PM 25209879 ER PT J AU Lindblad, RW Ibenana, L Wagner, JE McKenna, DH Hei, DJ Hematti, P Couture, LA Silberstein, LE Armant, M Rooney, CM Gee, AP Welniak, LA Mondoro, TH Wood, DA Styers, D AF Lindblad, Robert W. Ibenana, Laarni Wagner, John E. McKenna, David H., Jr. Hei, Derek J. Hematti, Peiman Couture, Larry A. Silberstein, Leslie E. Armant, Myriam Rooney, Cliona M. Gee, Adrian P. Welniak, Lisbeth A. Mondoro, Traci Heath Wood, Deborah A. Styers, David TI Cell therapy product administration and safety: data capture and analysis from the Production Assistance for Cellular Therapies (PACT) program SO TRANSFUSION LA English DT Review ID STEM; DISEASE; TOLERANCE C1 [Lindblad, Robert W.; Ibenana, Laarni; Wood, Deborah A.; Styers, David] EMMES Corp, Rockville, MD 20850 USA. [Wagner, John E.; McKenna, David H., Jr.] Univ Minnesota, Minneapolis, MN USA. [Hei, Derek J.; Hematti, Peiman] Univ Wisconsin, Madison, WI USA. [Hematti, Peiman] UW Carbone Canc Ctr, Madison, WI USA. [Couture, Larry A.] City Hope Natl Med Ctr, Duarte, CA USA. [Silberstein, Leslie E.; Armant, Myriam] Childrens Hosp Boston, Boston, MA USA. [Rooney, Cliona M.; Gee, Adrian P.] Baylor Coll Med, Houston, TX 77030 USA. [Welniak, Lisbeth A.; Mondoro, Traci Heath] NHLBI, NIH, Bethesda, MD 20892 USA. RP Lindblad, RW (reprint author), EMMES Corp, 401 North Washington St,Suite 700, Rockville, MD 20850 USA. EM rlindblad@emmes.com FU National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services [HHSN268201000006C, HHSN268201000007C, HHSN268201000008C, HHSN268201000009C, HHSN268201000010C, HHSN268201000011C] FX The PACT program is supported with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services under Contract Numbers HHSN268201000006C, HHSN268201000007C, HHSN268201000008C, HHSN268201000009C, HHSN268201000010C, and HHSN268201000011C. NR 23 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD MAR PY 2015 VL 55 IS 3 BP 674 EP 679 DI 10.1111/trf.12881 PG 6 WC Hematology SC Hematology GA CD6BZ UT WOS:000351175100031 PM 25315143 ER PT J AU Sandler, SG Flegel, WA Westhoff, CM Denomme, GA Delaney, M Keller, MA Johnson, ST Katz, L Queenan, JT Vassallo, RR Simon, CD AF Sandler, S. Gerald Flegel, Willy A. Westhoff, Connie M. Denomme, Gregory A. Delaney, Meghan Keller, Margaret A. Johnson, Susan T. Katz, Louis Queenan, John T. Vassallo, Ralph R. Simon, Clayton D. TI It's time to phase in RHD genotyping for patients with a serologic weak D phenotype SO TRANSFUSION LA English DT Editorial Material ID ANTI-D IMMUNIZATION; RED-BLOOD-CELLS; AMINO-ACID SUBSTITUTIONS; MOLECULAR-BASIS; HEMOLYTIC-DISEASE; CLINICALLY RELEVANT; D ALLOIMMUNIZATION; D-VARIANTS; TRANSFUSION THERAPY; IMMUNE GLOBULIN C1 [Sandler, S. Gerald] MedStar Georgetown Univ Hosp, Dept Pathol & Lab Med, Washington, DC 20007 USA. [Queenan, John T.] MedStar Georgetown Univ Hosp, Dept Obstet & Gynecol, Washington, DC 20007 USA. [Flegel, Willy A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Westhoff, Connie M.] New York Blood Ctr, Immunohematol & Genom Lab, New York, NY 10021 USA. [Denomme, Gregory A.] BloodCtr Wisconsin, Diagnost Labs, Milwaukee, WI USA. [Johnson, Susan T.] BloodCtr Wisconsin, Clin Educ, Milwaukee, WI USA. [Delaney, Meghan] Puget Blood Ctr, Red Cell Genom Lab, Seattle, WA USA. [Delaney, Meghan] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Keller, Margaret A.] Amer Red Cross, Biomed Serv, Natl Mol Lab, Philadelphia, PA USA. [Vassallo, Ralph R.] Amer Red Cross, Biomed Serv, Med Off, Philadelphia, PA USA. [Katz, Louis] Amer Blood Ctr, Med Off, Washington, DC USA. [Simon, Clayton D.] Armed Serv Blood Program, Falls Church, VA USA. RP Sandler, SG (reprint author), MedStar Georgetown Univ Hosp, Dept Lab Med, 3800 Reservoir Rd NW, Washington, DC 20007 USA. EM sandlerg@gunet.georgetown.edu FU Intramural NIH HHS [Z99 CL999999] NR 148 TC 21 Z9 21 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD MAR PY 2015 VL 55 IS 3 BP 680 EP 689 DI 10.1111/trf.12941 PG 10 WC Hematology SC Hematology GA CD6BZ UT WOS:000351175100032 PM 25438646 ER PT J AU Lozano, M Cid, J Prowse, C McCullough, J Klein, HG Aubuchon, JP AF Lozano, Miguel Cid, Joan Prowse, Chris McCullough, Jeffrey Klein, Harvey G. Aubuchon, James P. TI Pathogen inactivation or pathogen reduction: proposal for standardization of nomenclature SO TRANSFUSION LA English DT Letter C1 [Lozano, Miguel; Cid, Joan] Univ Clin Hosp, Dept Hemotherapy & Hemostasis, Barcelona, Spain. [Prowse, Chris] Univ Edinburgh, Fac Med, Edinburgh, Midlothian, Scotland. [McCullough, Jeffrey] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Klein, Harvey G.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Aubuchon, James P.] Puget Sound Blood Ctr, Seattle, WA 98104 USA. RP Lozano, M (reprint author), Univ Clin Hosp, Dept Hemotherapy & Hemostasis, Barcelona, Spain. EM mlozano@clinic.ub.es RI Cid, Joan/F-7778-2016; OI Cid, Joan/0000-0001-5445-4508; Lozano, Miguel/0000-0003-2593-833X NR 4 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD MAR PY 2015 VL 55 IS 3 BP 690 EP 690 DI 10.1111/trf.12996 PG 1 WC Hematology SC Hematology GA CD6BZ UT WOS:000351175100033 PM 25677714 ER PT J AU Xu, WQ Gorman, K Santiago, JC Kluska, K Eiden, MV AF Xu, Wenqin Gorman, Kristen Santiago, Jan Clement Kluska, Kristen Eiden, Maribeth V. TI Genetic Diversity of Koala Retroviral Envelopes SO VIRUSES-BASEL LA English DT Article ID AMINO-ACID TRANSPORTER; APE LEUKEMIA-VIRUS; ENDOGENOUS RETROVIRUSES; PHASCOLARCTOS-CINEREUS; RECEPTOR; IDENTIFICATION; EVOLUTION; SUBGROUP; INVASION; GENOME AB Genetic diversity, attributable to the low fidelity of reverse transcription, recombination and mutation, is an important feature of infectious retroviruses. Under selective pressure, such as that imposed by superinfection interference, gammaretroviruses commonly adapt their envelope proteins to use alternative receptors to overcome this entry block. The first characterized koala retroviruses KoRV subgroup A (KoRV-A) were remarkable in their absence of envelope genetic variability. Once it was determined that KoRV-A was present in all koalas in US zoos, regardless of their disease status, we sought to isolate a KoRV variant whose presence correlated with neoplastic malignancies. More than a decade after the identification of KoRV-A, we isolated a second subgroup of KoRV, KoRV-B from koalas with lymphomas. The envelope proteins of KoRV-A and KoRV-B are sufficiently divergent to confer the ability to bind and employ distinct receptors for infection. We have now obtained a number of additional KoRV envelope variants. In the present studies we report these variants, and show that they differ from KoRV-A and KoRV-B envelopes in their host range and superinfection interference properties. Thus, there appears to be considerable variation among KoRVs envelope genes suggesting genetic diversity is a factor following the KoRV-A infection process. C1 [Xu, Wenqin; Gorman, Kristen; Santiago, Jan Clement; Kluska, Kristen; Eiden, Maribeth V.] NIMH, Sect Directed Gene Transfer, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Eiden, MV (reprint author), NIMH, Sect Directed Gene Transfer, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. EM xuwenqin@mail.nih.gov; klgorman11@yahoo.com; janclement.santiago@nih.gov; kristen.kluska@nih.gov; eidenm@mail.nih.gov FU NIMH FX We would like to thank James Nagle and Deborah Kauffman at the NINDS sequencing facility (National Institutes of Health) for their sequencing service; Cindy Stadler, (Los Angeles Zoo), and Geoff Pye, (San Diego Zoo) for generously providing the animal samples. Findings presented in this study are the results of the highly principled contributions of a number of members and outstanding students that have trained in the Eiden Laboratory including Jill Russ, David Kim, Aaron Yazdian, Craig Westover, Joseph Tran, and Deanna Myer. NIMH intramural funding supported this work. NR 26 TC 9 Z9 9 U1 1 U2 8 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD MAR PY 2015 VL 7 IS 3 BP 1258 EP 1270 DI 10.3390/v7031258 PG 13 WC Virology SC Virology GA CE6JP UT WOS:000351943000019 PM 25789509 ER PT J AU Kaufmann, P O'Rourke, PP AF Kaufmann, Petra O'Rourke, P. Pearl TI Central Institutional Review Board Review for an Academic Trial Network SO ACADEMIC MEDICINE LA English DT Editorial Material AB Problem Translating discoveries into therapeutics is often delayed by lengthy start-up periods for multicenter clinical trials. One cause of delay can be multiple institutional review board (IRB) reviews of the same protocol. Approach When developing the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT; hereafter, NN), the National Institute of Neurological Disorders and Stroke (NINDS) established a central IRB (CIRB) based at Massachusetts General Hospital, the academic medical center that received the NN clinical coordinating center grant. The 25 NN sites, located at U.S. academic institutions, agreed to required CIRB use for NN trials. Outcomes To delineate roles and establish legal relationships between the NN sites and the CIRB, the CIRB executed reliance agreements with the sites and their affiliates that hold federalwide assurance for the protection of human subjects (FWA); this took, on average, 84 days. The first NN protocol reviewed by the CIRB achieved full approval to allow participant enrollment within 56 days and went from grant award to the first patient visit in less than four months. The authors describe anticipated challenges related to institutional oversight responsibilities versus regulatory CIRB review as well as unanticipated challenges related to working with complex organizations that include multiple FWA-holding affiliates. Next Steps The authors anticipate that CIRB use will decrease NN trial start-up time and thus promote efficient trial implementation. They plan to collect data on timelines and costs associated with CIRB use. The NINDS plans to promote CIRB use in future initiatives. C1 [Kaufmann, Petra] Natl Ctr Adv Translat Sci, Div Clin Innovat, Bethesda, MD 20892 USA. [Kaufmann, Petra] NINDS, Off Clin Res, Bethesda, MD 20892 USA. [O'Rourke, P. Pearl] Partners HealthCare, Human Res Affairs, Boston, MA USA. [O'Rourke, P. Pearl] Partners HealthCare, Partners Human Embryon Stem Cell Res Oversight, Boston, MA USA. RP Kaufmann, P (reprint author), Natl Ctr Adv Translat Sci, Div Clin Innovat, 6701 Democracy Blvd,Room 934, Bethesda, MD 20892 USA. EM Petra.kaufman@nih.gov FU National Institute of Neurological Disorders and Stroke [NS-U01 NS077179] FX The central institutional review board is funded through a grant to the NeuroNEXT Clinical Coordinating Center at Massachusetts General Hospital from the National Institute of Neurological Disorders and Stroke (NS-U01 NS077179); this includes salary support for Dr. O'Rourke. NR 4 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD MAR PY 2015 VL 90 IS 3 BP 321 EP 323 DI 10.1097/ACM.0000000000000562 PG 3 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA CC7WT UT WOS:000350579800021 PM 25406606 ER PT J AU Lanken, PN Novack, DH Daetwyler, C Gallop, R Landis, JR Lapin, J Subramaniam, GA Schindler, BA AF Lanken, Paul N. Novack, Dennis H. Daetwyler, Christof Gallop, Robert Landis, J. Richard Lapin, Jennifer Subramaniam, Geetha A. Schindler, Barbara A. TI Efficacy of an Internet-Based Learning Module and Small-Group Debriefing on Trainees' Attitudes and Communication Skills Toward Patients With Substance Use Disorders: Results of a Cluster Randomized Controlled Trial SO ACADEMIC MEDICINE LA English DT Article ID PRIMARY-CARE; BRIEF INTERVENTION; PILOT TEST; DRUG-USE; HEALTH-PROFESSIONALS; ADDICTION MEDICINE; CLINICAL-TRIAL; UNITED-STATES; ALCOHOL-USE; ABUSE AB Purpose To examine whether an Internet-based learning module and small-group debriefing can improve medical trainees' attitudes and communication skills toward patients with substance use disorders (SUDs). Method In 2011-2012, 129 internal and family medicine residents and 370 medical students at two medical schools participated in a cluster randomized controlled trial, which assessed the effect of adding a two-part intervention to the SUDs curricula. The intervention included a self-directed, media-rich Internet-based learning module and a small-group, faculty-led debriefing. Primary study outcomes were changes in self-assessed attitudes in the intervention group (I-group) compared with those in the control group (C-group) (i.e., a difference of differences). For residents, the authors used real-time, Web-based interviews of standardized patients to assess changes in communication skills. Statistical analyses, conducted separately for residents and students, included hierarchical linear modeling, adjusted for site, participant type, cluster, and individual scores at baseline. Results The authors found no significant differences between the I- and C-groups in attitudes for residents or students at baseline. Compared with those in the C-group, residents, but not students, in the I-group had more positive attitudes toward treatment efficacy and self-efficacy at follow-up (P < .006). Likewise, compared with residents in the C-group, residents in the I-group received higher scores on screening and counseling skills during the standardized patient interview at follow-up (P = .0009). Conclusions This intervention produced improved attitudes and communication skills toward patients with SUDs among residents. Enhanced attitudes and skills may result in improved care for these patients. C1 [Lanken, Paul N.] Univ Penn, Professionalism & Humanism, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lanken, Paul N.] Univ Penn, Med & Med Eth & Hlth Policy, Perelman Sch Med, Philadelphia, PA 19104 USA. [Novack, Dennis H.] Drexel Univ, Coll Med, Med Educ, Philadelphia, PA 19104 USA. [Novack, Dennis H.] Drexel Univ, Coll Med, Med, Philadelphia, PA 19104 USA. [Daetwyler, Christof] Drexel Univ, Coll Med, Family Med & Community & Prevent Med, Philadelphia, PA 19104 USA. [Daetwyler, Christof] Drexel Univ, Coll Med, Online Resources Med Educ, Philadelphia, PA 19104 USA. [Gallop, Robert] W Chester Univ, Biostat, W Chester, PA 19380 USA. [Landis, J. Richard] Univ Penn, Div Biostat, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Landis, J. Richard] Univ Penn, Clin Res Comp Unit, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lapin, Jennifer] Univ Penn, Grad Med Educ Evaluat & Res, Off Evaluat & Assessment, Perelman Sch Med, Philadelphia, PA 19104 USA. [Subramaniam, Geetha A.] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. [Schindler, Barbara A.] Drexel Univ, Coll Med, Educ & Acad Affairs, Philadelphia, PA 19104 USA. [Schindler, Barbara A.] Drexel Univ, Coll Med, Psychiat & Pediat, Philadelphia, PA 19104 USA. RP Lanken, PN (reprint author), Hosp Univ Penn, 843 Gates Pavil,3400 Spruce St, Philadelphia, PA 19104 USA. EM paul.lanken@uphs.upenn.edu FU National Institutes of Health, National Institute on Drug Abuse [NIH HHSN271200900021C] FX National Institutes of Health, National Institute on Drug Abuse, contract no. NIH HHSN271200900021C. NR 58 TC 1 Z9 1 U1 3 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD MAR PY 2015 VL 90 IS 3 BP 345 EP 354 DI 10.1097/ACM.0000000000000506 PG 10 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA CC7WT UT WOS:000350579800025 PM 25295964 ER PT J AU Keselman, A Hundal, S Chentsova-Dutton, Y Bibi, R Edelman, JA AF Keselman, Alla Hundal, Savreen Chentsova-Dutton, Yulia Bibi, Raquel Edelman, Jay A. TI The Relationship between Biology Classes and Biological Reasoning and Common Heath Misconceptions SO AMERICAN BIOLOGY TEACHER LA English DT Article DE Biology education; health education; misconceptions; science in daily life ID HEALTH LITERACY; KNOWLEDGE; EVOLUTION; BELIEFS; SCIENCE; MODELS AB This study investigates the relationship among (1) college major, (2) knowledge used in reasoning about common health beliefs, and (3) judgment about the accuracy of those beliefs. Seventy-four college students, advanced biology and nonscience majors, indicated their agreement or disagreement with commonly believed, but often inaccurate, statements about health and explained their reasoning. The results indicated that while the direct impact of college-level biology coursework on judgment accuracy was minimal, biology major was associated with increased reliance on advanced biological reasoning, which mediated judgment accuracy. However, the overall association of advanced biological reasoning with judgment accuracy was small. The discussion calls for strengthening the science-daily life connection in biology education for majors and nonmajors. C1 [Keselman, Alla] Natl Lib Med, Div Specialized Informat Serv, Bethesda, MD 20892 USA. [Hundal, Savreen] Univ Maryland, Commun, College Pk, MD 20892 USA. [Chentsova-Dutton, Yulia] Georgetown Univ, Psychol, Washington, DC 20057 USA. [Bibi, Raquel] CUNY, Grad Ctr, Cognit Neurosci Subprogram Psychol, New York, NY USA. [Bibi, Raquel; Edelman, Jay A.] CUNY City Coll, Dept Biol, New York, NY 10031 USA. RP Keselman, A (reprint author), Natl Lib Med, Div Specialized Informat Serv, 6707 Democracy Blvd,Suite 510, Bethesda, MD 20892 USA. EM keselmana@mail.nih.gov; savreenhundal@gmail.com; yec2@georgetown.edu; rbibi@ccny.cuny.edu; jedelman@ccny.cuny.edu FU intramural research program of the National Library of Medicine, National Institutes of Health FX This study was supported by the intramural research program of the National Library of Medicine, National Institutes of Health. We thank Dr. David Kaufman for valuable discussions that helped refine the coding scheme. NR 22 TC 0 Z9 0 U1 1 U2 6 PU NATL ASSOC BIOLOGY TEACHERS INC PI RESTON PA 12030 SUNRISE VALLEY DR, #110, RESTON, VA 20191 USA SN 0002-7685 EI 1938-4211 J9 AM BIOL TEACH JI Am. Biol. Teach. PD MAR PY 2015 VL 77 IS 3 BP 170 EP 175 DI 10.1525/abt.2015.77.3.4 PG 6 WC Biology; Education, Scientific Disciplines SC Life Sciences & Biomedicine - Other Topics; Education & Educational Research GA CD3PN UT WOS:000350991200004 ER PT J AU Kabat, GC Matthews, CE Kamensky, V Hollenbeck, AR Rohan, TE AF Kabat, Geoffrey C. Matthews, Charles E. Kamensky, Victor Hollenbeck, Albert R. Rohan, Thomas E. TI Adherence to cancer prevention guidelines and cancer incidence, cancer mortality, and total mortality: a prospective cohort study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE body mass index; cancer incidence; cancer prevention guidelines; diet; physical activity ID HEALTHY FOOD CHOICES; RESEARCH FUND/AMERICAN INSTITUTE; LIFE-STYLE FACTORS; SOCIETY GUIDELINES; PHYSICAL-ACTIVITY; COMBINED IMPACT; RISK; NUTRITION; WOMEN; MEN AB Background: Several health agencies have issued guidelines promoting behaviors to reduce chronic disease risk; however, little is known about the impact of such guidelines, particularly on cancer incidence. Objective: The objective was to determine whether greater adherence to the American Cancer Society (ACS) cancer prevention guidelines is associated with a reduction in cancer incidence, cancer mortality, and total mortality. Design: The NIH-AARP Diet and Health Study, a prospective cohort study of 566,401 adults aged 50-71 y at recruitment in 1995-1996, was followed for a median of 10.5 y for cancer incidence, 12.6 y for cancer mortality, and 13.6 y for total mortality. Participants who reported a history of cancer or who had missing data were excluded, yielding 476,396 subjects for analysis. We constructed a 5-level score measuring adherence to ACS guidelines, which included baseline body mass index, physical activity, alcohol intake, and several aspects of diet. Cox proportional hazards models were used to compute HRs and 95% CIs for the association of the adherence score with cancer incidence, cancer mortality, and total mortality. All analyses included fine adjustment for cigarette smoking. Results: Among 476,396 participants, 73,784 incident first cancers, 16,193 cancer deaths, and 81,433 deaths from all causes were identified in the cohort. Adherence to ACS guidelines was associated with reduced risk of all cancers combined: HRs (95% CIs) for the highest compared with the lowest level of adherence were 0.90 (0.87, 0.93) in men and 0.81 (0.77, 0.84) in women. Fourteen of 25 specific cancer sites showed a reduction in risk associated with increased adherence. Adherence was also associated with reduced cancer mortality [HRs (95% CIs) were 0.75 (0.70, 0.80) in men and 0.76 (0.70, 0.83) in women] and reduced all-cause mortality [HRs (95% CIs) were 0.74 (0.72, 0.76) in men and 0.67 (0.65, 0.70) in women]. Conclusions: In both men and women, adherence to the ACS guidelines was associated with reductions in all-cancer incidence and the incidence of cancer at specific sites, as well as with reductions in cancer mortality and total mortality. These data suggest that, after accounting for cigarette smoking, adherence to a set of healthy behaviors may have considerable health benefits. C1 [Kabat, Geoffrey C.; Kamensky, Victor; Rohan, Thomas E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Kabat, GC (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM geoffrey.kabat@einstein.yu.edu FU Albert Einstein College of Medicine FX Supported by institutional funds from the Albert Einstein College of Medicine. NR 26 TC 15 Z9 17 U1 5 U2 9 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2015 VL 101 IS 3 BP 558 EP 569 DI 10.3945/ajcn.114.094854 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CC7HR UT WOS:000350538800020 PM 25733641 ER PT J AU Harmon, BE Boushey, CJ Shvetsov, YB Ettienne, R Reedy, J Wilkens, LR Le Marchand, L Henderson, BE Kolonel, LN AF Harmon, Brook E. Boushey, Carol J. Shvetsov, Yurii B. Ettienne, Reynolette Reedy, Jill Wilkens, Lynne R. Le Marchand, Loic Henderson, Brian E. Kolonel, Laurence N. TI Associations of key diet-quality indexes with mortality in the Multiethnic Cohort: the Dietary Patterns Methods Project SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE dietary indexes; epidemiology; multiethnic; risk factors; survival ID CORONARY-HEART-DISEASE; MAJOR CHRONIC DISEASE; GUIDELINES-FOR-AMERICANS; ALL-CAUSE MORTALITY; MEDITERRANEAN DIET; CARDIOVASCULAR-DISEASE; COLORECTAL-CANCER; ELDERLY-PEOPLE; BLOOD-PRESSURE; UNITED-STATES AB Background: Healthy dietary patterns have been linked positively with health and longevity. However, prospective studies in diverse populations in the United States addressing dietary patterns and mortality are limited. Objective: We assessed the ability of the following 4 diet-quality indexes [the Healthy Eating Index-2010 (HEI-2010), the Alternative HEI-2010 (AHEI-2010), the alternate Mediterranean diet score (aMED), and the Dietary Approaches to Stop Hypertension (DASH)] to predict the reduction in risk of mortality from all causes, cardiovascular disease (CVD), and cancer. Design: White, African American, Native Hawaiian, Japanese American, and Latino adults (n = 215,782) from the Multiethnic Cohort completed a quantitative food-frequency questionnaire. Scores for each dietary index were computed and divided into quintiles for men and women. Mortality was documented over 13-18 y of follow-up. HRs and 95% CIs were computed by using adjusted Cox models. Results: High HEI-2010, AHEI-2010, aMED, and DASH scores were all inversely associated with risk of mortality from all causes, CVD, and cancer in both men and women (P-trend < 0.0001 for all models). For men, the HEI-2010 was consistently associated with a reduction in risk of mortality for all causes (HR: 0.75; 95% CI: 0.71, 0.79), CVD (HR: 0.74; 95% CI: 0.69, 0.81), and cancer (HR: 0.76; 95% CI: 0.70, 0.83) when lowest and highest quintiles were compared. In women, the AHEI and aMED.showed large reductions for all-cause mortality (HR: 0.78; 95% CI: 0.74, 0.82), the AHEI showed large reductions for CVD (HR: 0.76; 95% CI: 0.69, 0.83), and the aMED showed large reductions for cancer (HR: 0.84; 95% CI: 0.76, 0: 92). Conclusion: These results, in a US multiethnic population, suggest that consuming a dietary pattern that achieves a high diet-quality index score is associated with lower risk of mortality from all causes, CVD, and cancer in adult men and women. C1 [Harmon, Brook E.; Boushey, Carol J.; Shvetsov, Yurii B.; Ettienne, Reynolette; Wilkens, Lynne R.; Le Marchand, Loic; Kolonel, Laurence N.] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA. [Reedy, Jill] NCI, Div Canc Control & Populat Sci, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Henderson, Brian E.] Univ So Calif, Los Angeles, CA USA. RP Boushey, CJ (reprint author), Univ Hawaii, Ctr Canc, Program Epidemiol, 701 Ilalo St,Room 525, Honolulu, HI 96813 USA. EM cjboushey@cc.hawaii.edu FU National Cancer Institute (NCI) [HHSN261201200423P]; NIH/NCI [P30 CA071789, 4R37 CA 54281]; [R25 CA 90956] FX Supported by the National Cancer Institute (NCI) (HHSN261201200423P) and in part by the NIH/NCI (P30 CA071789). The Multiethnic Cohort Study is supported by the NIH/NCI (4R37 CA 54281). BE Harmon and RE were recipients of the postdoctoral fellowship R25 CA 90956. NR 62 TC 41 Z9 41 U1 2 U2 20 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2015 VL 101 IS 3 BP 587 EP 597 DI 10.3945/ajcn.114.090688 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CC7HR UT WOS:000350538800023 PM 25733644 ER PT J AU Lavretsky, H Evans, JD Niederehe, G AF Lavretsky, Helen Evans, Jovier D. Niederehe, George TI SENIOR INVESTIGATOR WORKSHOP: RESEARCH AND FUNDING PRIORITIES AT NIMH IN 2015 AND BEYOND SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 27-30, 2015 CL New Orleans, LA SP Amer Assoc Geriatr Psychiat C1 [Lavretsky, Helen] Univ Calif Los Angeles, Los Angeles, CA USA. [Evans, Jovier D.; Niederehe, George] NIMH, Rockville, MD 20857 USA. RI Lavretsky, Helen/M-5711-2015 OI Lavretsky, Helen/0000-0001-9990-5085 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2015 VL 23 IS 3 SU S MA 323 BP S35 EP S36 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA CD1IV UT WOS:000350829500049 ER PT J AU Wong, LF Schliep, KC Silver, RM Mumford, SL Perkins, NJ Ye, A Galai, N Wactawski-Wende, J Lynch, AM Townsend, JM Faraggi, D Schisterman, EF AF Wong, Luchin F. Schliep, Karen C. Silver, Robert M. Mumford, Sunni L. Perkins, Neil J. Ye, Aijun Galai, Noya Wactawski-Wende, Jean Lynch, Anne M. Townsend, Janet M. Faraggi, David Schisterman, Enrique F. TI The effect of a very short interpregnancy interval and pregnancy outcomes following a previous pregnancy loss SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE interpregnancy interval; miscarriage; pregnancy loss; pregnancy outcomes; spontaneous abortion ID PERINATAL OUTCOMES; MISCARRIAGE; RISK; ABORTION; WOMEN AB OBJECTIVE: We sought to assess the relationship between a short interpregnancy interval (IPI) following a pregnancy loss and subsequent live birth and pregnancy outcomes. STUDY DESIGN: A secondary analysis of women enrolled in the Effects of Aspirin in Gestation and Reproduction trial with a human chorionic gonadotropin-positive pregnancy test and whose last reproductive outcome was a loss were included in this analysis (n = 677). IPI was defined as the time between last pregnancy loss and last menstrual period of the current pregnancy and categorized by 3-month intervals. Pregnancy outcomes include live birth, pregnancy loss, and any pregnancy complications. These were compared between IPI groups using multivariate relative risk estimation by Poisson regression. RESULTS: Demographic characteristics were similar between IPI groups. The mean gestational age of prior pregnancy loss was 8.6 +/- 2.8 weeks. The overall live birth rate was 76.5%, with similar live birth rates between those with IPI <= 3 months as compared to IPI > 3 months (adjusted relative risk [aRR], 1.07; 95% confidence interval [CI], 0.98-1.16). Rates were also similar for periimplantation loss (aRR, 0.95; 95% CI, 0.51-1.80), clinically confirmed loss (aRR, 0.75; 95% CI, 0.51-1.10), and any pregnancy complication (aRR, 0.88; 95% CI, 0.71-1.09) for those with IPI <= 3 months as compared to IPI > 3 months. CONCLUSION: Live birth rates and adverse pregnancy outcomes, including pregnancy loss, were not associated with a very short IPI after a prior pregnancy loss. The traditional recommendation to wait at least 3 months after a pregnancy loss before attempting a new pregnancy may not be warranted. C1 [Wong, Luchin F.; Silver, Robert M.] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Wong, Luchin F.; Silver, Robert M.] Intermt Healthcare, Dept Maternal Fetal Med, Salt Lake City, UT USA. [Schliep, Karen C.; Mumford, Sunni L.; Perkins, Neil J.; Ye, Aijun; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, Bethesda, MD USA. [Wactawski-Wende, Jean] SUNY Buffalo, Sch Med & Biomed Sci, Dept Epidemiol & Environm Hlth, Buffalo, NY 14260 USA. [Lynch, Anne M.] Univ Colorado, Sch Med, Dept Obstet & Gynecol, Denver, CO 80202 USA. [Townsend, Janet M.] Commonwealth Med Coll, Dept Family Community & Rural Hlth, Scranton, PA USA. [Galai, Noya; Faraggi, David] Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. RP Wong, LF (reprint author), Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. EM luchin.wong@hsc.utah.edu OI Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD [HHSN267200603423, HHSN267200603424, HHSN267200603426] FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, contract numbers HHSN267200603423, HHSN267200603424, and HHSN267200603426. NR 19 TC 0 Z9 0 U1 0 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2015 VL 212 IS 3 AR 375.e1 DI 10.1016/j.ajog.2014.09.020 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CC5DC UT WOS:000350377500035 PM 25246378 ER PT J AU Bhatt, N Dalal, M Tucker, W Obiyor, D Nussenblatt, R Sen, HN AF Bhatt, Nirali Dalal, Monica Tucker, William Obiyor, Dominic Nussenblatt, Robert Sen, H. Nida TI Subconjunctival Sirolimus in the Treatment of Autoimmune Non-necrotizing Anterior Scleritis: Results of a Phase I/II Clinical Trial SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID INFLAMMATORY DISEASE; METHOTREXATE THERAPY; TRIAMCINOLONE; EPISCLERITIS; UVEITIS AB PURPOSE: To investigate the safety, tolerability and efficacy of subconjunctival sirolimus injections as a treatment for active, autoimmune, non-necrotizing anterior scleritis. DESIGN: Phase I/IT, single-center, open-label, nonrandomized, prospective pilot study. METHODS: Five participants with active, autoimmune, non-necrotizing anterior scleritis with scleral inflammatory grade of >= 1+ in at least 1 quadrant with a history of flares were enrolled. A baseline injection was given, with the primary outcome measure of at least a 2-step reduction or reduction to grade zero in the study eye by 8 weeks. Secondary outcomes included changes in visual acuity and intraocular pressure,,ability to taper concomitant immunosuppressive regimen, and number of participants who experienced a disease flare requiring reinjection. Safety outcomes included the number and severity of systemic and ocular toxicities, and vision loss >= 15 ETDRS letters. The study included 6 visits over 4 months with an extension phase to 1 year for participants who met the primary outcome. RESULTS: All participants (N = 5, 100%; 95% CI [0.60, 1.00]) met the primary outcome in the study eye by the week 8 visit. There was no significant change in mean visual acuity or intraocular pressure. Three out of 5 patients (60%) experienced flares requiring reinjection. No systemic toxicities were observed. Two participants (40%) experienced a localized sterile inflammatory reaction at the site of the injection, which resolved without complication. CONCLUSIONS: Subconjunctival sirolimus leads to a short-term reduction in scleral inflammation, though relapses requiring reinjection do occur. There were no serious adverse events, though a local sterile conjunctival inflammatory reaction was observed. Published by Elsevier Inc. C1 [Bhatt, Nirali; Dalal, Monica; Tucker, William; Obiyor, Dominic; Nussenblatt, Robert; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), NEI, NIH, 10 Ctr Dr 10N109, Bethesda, MD 20892 USA. EM senh@nei.nih.gov FU National Eye Institute (NEI) Intramural Research Program, Bethesda, Maryland [Z99 EY999999, ZIA EY000516-01, ZIA EY000516-02, ZIA EY000516-03, ZIP EY000482-06] FX This research was supported by the National Eye Institute (NEI) Intramural Research Program, Bethesda, Maryland (grant numbers: Z99 EY999999, ZIA EY000516-01, ZIA EY000516-02, ZIA EY000516-03, and ZIP EY000482-06). NR 26 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD MAR PY 2015 VL 159 IS 3 BP 601 EP 606 DI 10.1016/j.ajo.2014.12.009 PG 6 WC Ophthalmology SC Ophthalmology GA CC1BV UT WOS:000350077100025 PM 25526946 ER PT J AU Dettmer, AM Rosenberg, K Menard, MT Suomi, SJ Meyer, JS Novak, MA AF Dettmer, Amanda M. Rosenberg, Kendra Menard, Mark T. Suomi, Stephen J. Meyer, Jerrold S. Novak, Melinda A. TI Differential maternal investment in rhesus monkey mothers with hair loss in the neonatal period SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract CT 84th Annual Meeting of the American-Association-of-Physical-Anthropologists CY MAR 25-28, 2015 CL St Louis, MO SP Amer Assoc Phys Anthropologists C1 [Dettmer, Amanda M.; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Bethesda, MD USA. [Rosenberg, Kendra; Menard, Mark T.; Meyer, Jerrold S.; Novak, Melinda A.] Univ Massachusetts Amherst, Dept Psychol, Amherst, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-9483 EI 1096-8644 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD MAR PY 2015 VL 156 SU 60 SI SI BP 119 EP 120 PG 2 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA CC8CE UT WOS:000350594900216 ER PT J AU Erkenswick, GA Watsa, M Gozalo, AS Parker, PG AF Erkenswick, Gideon A. Watsa, Mrinalini Gozalo, Alfonso S. Parker, Patricia G. TI A test of parasite-host specificity between two closely-related species of Neotropical primate, Saguinus fuscicollis and S. imperator SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract CT 84th Annual Meeting of the American-Association-of-Physical-Anthropologists CY MAR 25-28, 2015 CL St Louis, MO SP Amer Assoc Phys Anthropologists C1 [Erkenswick, Gideon A.; Parker, Patricia G.] Univ Missouri St Louis, Dept Biol, St Louis, MO USA. [Erkenswick, Gideon A.; Watsa, Mrinalini] Primates Peru Inc, Res Comm, Lima, Peru. [Watsa, Mrinalini] Washington Univ, Dept Anthropol, St Louis, MO 63130 USA. [Gozalo, Alfonso S.] Natl Inst Hlth, Comparat Med Branch, Bethesda, MD USA. [Parker, Patricia G.] St Louis Zoo, WildCare Inst, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-9483 EI 1096-8644 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD MAR PY 2015 VL 156 SU 60 SI SI BP 129 EP 130 PG 2 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA CC8CE UT WOS:000350594901016 ER PT J AU Feldblum, JT Krupenye, C Wroblewski, EE Rudicell, RS Hahn, BH Pusey, AE Gilby, IC AF Feldblum, Joseph T. Krupenye, Christopher Wroblewski, Emily E. Rudicell, Rebecca S. Hahn, Beatrice H. Pusey, Anne E. Gilby, Ian C. TI The adaptive value of male relationships in the chimpanzees of Gombe National Park, Tanzania SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract CT 84th Annual Meeting of the American-Association-of-Physical-Anthropologists CY MAR 25-28, 2015 CL St Louis, MO SP Amer Assoc Phys Anthropologists C1 [Feldblum, Joseph T.; Krupenye, Christopher; Pusey, Anne E.] Duke Univ, Dept Evolutionary Anthropol, Durham, NC 27706 USA. [Wroblewski, Emily E.] Stanford Univ, Dept Biol Struct, Stanford, CA 94305 USA. [Rudicell, Rebecca S.] Natl Inst Hlth, Vaccine Res Ctr, Bethesda, MD USA. [Rudicell, Rebecca S.] Sanofi, Paris, France. [Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Gilby, Ian C.] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-9483 EI 1096-8644 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD MAR PY 2015 VL 156 SU 60 SI SI BP 131 EP 131 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA CC8CE UT WOS:000350594901023 ER PT J AU Rubicz, R Shui, IM Zhao, SS Wright, JL Kolb, S Ostrander, EA Feng, ZD Fan, JB Stanford, JL AF Rubicz, Rohina Shui, Irene M. Zhao, Shanshan Wright, Jonathan L. Kolb, Suzanne Ostrander, Elaine A. Feng, Ziding Fan, Jian-Bing Stanford, Janet L. TI Health disparities in prostate cancer: Tumor epigenome profiling in African American vs European American men SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract CT 84th Annual Meeting of the American-Association-of-Physical-Anthropologists CY MAR 25-28, 2015 CL St Louis, MO SP Amer Assoc Phys Anthropologists C1 [Rubicz, Rohina; Shui, Irene M.; Zhao, Shanshan; Wright, Jonathan L.; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Wright, Jonathan L.] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Ostrander, Elaine A.] NHGRI, Canc Genet Branch, Bethesda, MD USA. [Feng, Ziding] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX USA. [Fan, Jian-Bing] Illumina Inc, Sci Res, San Diego, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-9483 EI 1096-8644 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD MAR PY 2015 VL 156 SU 60 SI SI BP 272 EP 272 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA CC8CE UT WOS:000350594902007 ER PT J AU Young, KL Justice, AE Highland, HM Graff, M Karaderi, T Heard-Costa, NL Pasko, D Turcot, V Lu, Y Southam, L Cupples, LA Liu, CT Fox, CS Winkler, TW Grarup, N Scott, RA Mccarthy, MM Mohlke, K Loos, RJF Borecki, I Lindgren, C North, KE AF Young, Kristin L. Justice, Anne E. Highland, Heather M. Graff, Misa Karaderi, T. Heard-Costa, Nancy L. Pasko, D. Turcot, Valerie Lu, Y. Southam, L. Cupples, L. A. Liu, Ching-Ti Fox, Caroline S. Winkler, Thomas W. Grarup, Niels Scott, Robert A. Mccarthy, M. M. Mohlke, Karen Loos, Ruth J. F. Borecki, Ingrid Lindgren, Cecelia North, Kari E. TI Transethnic meta-analysis of exomic variation contributing to central adiposity SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract CT 84th Annual Meeting of the American-Association-of-Physical-Anthropologists CY MAR 25-28, 2015 CL St Louis, MO SP Amer Assoc Phys Anthropologists C1 [Young, Kristin L.; Justice, Anne E.; Graff, Misa; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Young, Kristin L.] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Highland, Heather M.] Univ Texas Hlth Sci Ctr Houston, Univ Texas Grad Sch Biomed Sci Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA. [Karaderi, T.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England. [Heard-Costa, Nancy L.; Cupples, L. A.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Bethesda, MD USA. [Heard-Costa, Nancy L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Pasko, D.] Univ Exeter, Genet Complex Traits, Exeter EX4 4QJ, Devon, England. [Turcot, Valerie] Univ Montreal, Montreal Heart Inst, Montreal, PQ H3C 3J7, Canada. [Lu, Y.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Southam, L.] Wellcome Trust Sanger Inst, Cambridge, England. [Cupples, L. A.; Liu, Ching-Ti] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Winkler, Thomas W.] Univ Regensburg, Dept Genet Epidemiol, Inst Epidemiol & Prevent Med, D-93053 Regensburg, Germany. [Grarup, Niels] Univ Copenhagen, Novo Nordisk Fdn, Ctr Basic Metab Res, DK-1168 Copenhagen, Denmark. [Scott, Robert A.] Univ Cambridge, MRC, Epidemiol Unit, Cambridge CB2 1TN, England. [Mccarthy, M. M.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England. [Mohlke, Karen] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Borecki, Ingrid] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63130 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-9483 EI 1096-8644 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD MAR PY 2015 VL 156 SU 60 SI SI BP 330 EP 331 PG 2 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA CC8CE UT WOS:000350594902235 ER PT J AU Yuan, A Lee, Y Choi, U Moeckel, G Karihaloo, A AF Yuan, Amy Lee, Yashang Choi, Uimook Moeckel, Gilbert Karihaloo, Anil TI Chemokine receptor Cxcr4 contributes to kidney fibrosis via multiple effectors SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE chemokine (C-X-C motif) receptor 4; AMD-3100; kidney; fibrosis; macrophages; bone morphogenetic protein 7 ID EPITHELIAL-MESENCHYMAL TRANSITION; NF-KAPPA-B; MORPHOGENETIC PROTEIN-7 BMP7; SQUAMOUS-CELL CARCINOMA; HUMAN ENDOTHELIAL-CELLS; LUNG-CANCER CELLS; RENAL FIBROSIS; GROWTH-FACTOR; TRANSCRIPTIONAL REGULATION; PULMONARY-FIBROSIS AB Kidney fibrosis is the final common pathway for virtually every type of chronic kidney disease and is a consequence of a prolonged healing response that follows tissue inflammation. Chronic kidney inflammation ultimately leads to progressive tissue injury and scarring/fibrosis. Several pathways have been implicated in the progression of kidney fibrosis. In the present study, we demonstrate that G protein-coupled chemokine (C-X-C motif) receptor (CXCR) 4 was significantly upregulated after renal injury and that sustained activation of Cxcr4 expression augmented the fibrotic response. We demonstrate that after unilateral ureteral obstruction (UUO), both gene and protein expression of Cxcr4 were highly upregulated in tubular cells of the nephron. The increased Cxcr4 expression in tubules correlated with their increased dedifferentiated state, leading to increased mRNA expression of platelet-derived growth factor (PDGF)-alpha, transforming growth factor (TGF)-beta(1), and concurrent loss of bone morphogenetic protein 7 (Bmp7). Ablation of tubular Cxcr4 attenuated UUO-mediated fibrotic responses, which correlated with a significant reduction in PDGF-alpha and TGF-beta(1) levels and preservation of Bmp7 expression after UUO. Furthermore, Cxcr4(+) immune cells infiltrated the obstructed kidney and further upregulate their Cxcr4 expression. Genetic ablation of Cxcr4 from macrophages was protective against UUO-induced fibrosis. There was also reduced total kidney TGF-beta(1), which correlated with reduced Smad activation and alpha-smooth muscle actin levels. We conclude that chronic high Cxcr4 expression in multiple effector cell types can contribute to the pathogenesis of renal fibrosis by altering their biological profile. This study uncovered a novel cross-talk between Cxcr4-TGF-beta(1) and Bmp7 pathways and may provide novel targets for interrupting the progression of fibrosis. C1 [Choi, Uimook] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Moeckel, Gilbert] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Yuan, Amy; Lee, Yashang; Karihaloo, Anil] Yale Univ, Sch Med, Nephrol Sect, Dept Med, New Haven, CT 06520 USA. RP Karihaloo, A (reprint author), Yale Univ, Sch Med, Nephrol Sect, Dept Internal Med, New Haven, CT 06520 USA. EM anil.karihaloo@yale.edu FU George M. O'Brien Kidney Center at Yale (National Institute of Diabetes and Digestive and Kidney Diseases) [P30-DK-079310]; American Heart Association FX This work was supported by the George M. O'Brien Kidney Center at Yale (National Institute of Diabetes and Digestive and Kidney Diseases Grant P30-DK-079310) and a grant-in-aid from the American Heart Association (to A. Karihaloo). NR 87 TC 8 Z9 8 U1 1 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR 1 PY 2015 VL 308 IS 5 BP F459 EP F472 DI 10.1152/ajprenal.00146.2014 PG 14 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA CD1CP UT WOS:000350811800010 PM 25537742 ER PT J AU Jacobs, EJ Newton, CC Carter, BD Feskanich, D Freedman, ND Prentice, RL Flanders, WD AF Jacobs, Eric J. Newton, Christina C. Carter, Brian D. Feskanich, Diane Freedman, Neal D. Prentice, Ross L. Flanders, W. Dana TI What proportion of cancer deaths in the contemporary United States is attributable to cigarette smoking? SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Tobacco; Smoking; Cigarettes; Cancer; Mortality; Population attributable fraction ID RISK AB Purpose: The proportion of cancer deaths in the contemporary United States caused by cigarette smoking (the population attributable fraction [PM]) is not well documented. Methods: The PAF of all cancer deaths due to active cigarette smoking among adults 35 years and older in the United States in 2010 was calculated using age- and sex-specific smoking prevalence from the National Health Interview Survey (NHIS) and age- and sex-specific relative risks from the Cancer Prevention Study-II (for ages 35-54 years) and from the Pooled Contemporary Cohort data set (for ages 55 years and older). Results: The PAF for active cigarette smoking was 28.7% when estimated conservatively, including only deaths from the 12 cancers currently formally established as caused by smoking by the US Surgeon General. The PAF was 31.7% when estimated more comprehensively, including excess deaths from all cancers. These estimates do not include additional potential cancer deaths from environmental tobacco smoke or other type of tobacco use such as cigars, pipes, or smokeless tobacco. Conclusions: Cigarette smoking causes a large proportion of cancer deaths in the contemporary United States. Reducing smoking prevalence as rapidly as possible should be a top priority for the US public health efforts to prevent cancer deaths. (C) 2015 Elsevier Inc. All rights reserved. C1 [Jacobs, Eric J.; Newton, Christina C.; Carter, Brian D.; Flanders, W. Dana] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Feskanich, Diane] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Prentice, Ross L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Flanders, W. Dana] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. RP Jacobs, EJ (reprint author), Amer Canc Soc, Epidemiol Res Program, Natl Home Off, 250 Williams St, Atlanta, GA 30303 USA. EM Eric.Jacobs@cancer.org RI Freedman, Neal/B-9741-2015 OI Freedman, Neal/0000-0003-0074-1098 FU National Institutes of Health (NIH)-AARP Diet and Health Study; American Cancer Society (ACS) Cancer Prevention Study II Nutrition Cohort; Nurses' Health Study; NCI [P01 CA87969, UM1 CA167552]; National Heart, Lung, and Blood Institute [N01WH22110, N01WH32100-32102, N01WH32105, N01WH32106, N01WH32108, N01WH32109, N01WH32111, N01WH32112, N01WH32113, N01WH32115, N01WH32118, N01WH32119, N01WH32122, N01WH42107-N01WH42126, N01WH42129- N01WH42132, N01WH44221] FX Support for the National Institutes of Health (NIH)-AARP Diet and Health Study was provided by the Intramural Research Program of the National Cancer Institute, NIH. Support for the American Cancer Society (ACS) Cancer Prevention Study II Nutrition Cohort was provided by the Intramural Research Programs of the ACS. Support for the Nurses' Health Study and the Health Professionals Follow-up Study was provided by grants (P01 CA87969 and UM1 CA167552, respectively) from the NCI. Support for the Women's Health Initiative program is provided by contracts (N01WH22110, N01WH24152, N01WH32100-32102, N01WH32105, N01WH32106, N01WH32108, N01WH32109, N01WH32111, N01WH32112, N01WH32113, N01WH32115, N01WH32118,N01WH32119,N01WH32122, N01WH42107-N01WH42126, N01WH42129- N01WH42132, and N01WH44221) from the National Heart, Lung, and Blood Institute. NR 17 TC 7 Z9 7 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD MAR PY 2015 VL 25 IS 3 BP 179 EP 182 DI 10.1016/j.annepidem.2014.11.008 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CD0RQ UT WOS:000350782000006 PM 25487970 ER PT J AU Purdue, MP Hutchings, SJ Rushton, L Silverman, DT AF Purdue, Mark P. Hutchings, Sally J. Rushton, Lesley Silverman, Debra T. TI The proportion of cancer attributable to occupational exposures SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Population attributable fraction; Cancer; Occupational exposures ID GLOBAL BURDEN; UNITED-STATES; RISK-FACTORS; SHIFT WORK; BRITAIN; METAANALYSIS; METHODOLOGY; MORTALITY; DISEASE; INJURY AB Purpose: To review the literature on the estimation of the population attributable fraction (PAF) of cancer due to occupational exposures and to describe challenges in the estimation of this metric. To help illustrate the inherent challenges, we also estimate PAFs for selected cancers diagnosed in the United States in 2010 attributable to work as a painter (causally associated with bladder and lung cancer) and shift work (possibly associated with breast cancer). Methods: We reviewed and summarized previous reports providing quantitative estimates of PAF for total cancer due to occupational exposures. We calculated PAF estimates for painters and shift work using methodology from a detailed investigation of the occupational cancer burden in Great Britain, with adaptations made for the US population. Results: The estimated occupation-attributable fraction for total cancer generally ranged between 2% and 8% (men, 3%-14%; women, 1%-2%) based on previous reports. We calculated that employment as a painter accounted for a very small proportion of cancers of the bladder and lung diagnosed in the United States in 2010, with PAFs of 0.5% for each site. In contrast, our calculations suggest that the potential impact of shift work on breast cancer (if causal) could be substantial, with a PAF of 5.7%, translating to 11,777 attributable breast cancers. Conclusions: Continued efforts to estimate the occupational cancer burden will be important as scientific evidence and economic trends evolve. Such projects should consider the challenges involved in PAF estimation, which we summarize in this report. (C) 2015 Elsevier Inc. All rights reserved. C1 [Purdue, Mark P.; Silverman, Debra T.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Purdue, Mark P.] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada. [Hutchings, Sally J.; Rushton, Lesley] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England. [Hutchings, Sally J.; Rushton, Lesley] Univ London Imperial Coll Sci Technol & Med, MRC HPA, Ctr Environm & Hlth, London, England. RP Purdue, MP (reprint author), Ontario Inst Canc Res, 661 Univ Ave,Suite 510, Toronto, ON M5G 0A3, Canada. EM purduem@mail.nih.gov RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU Intramural NIH HHS [ZIA CP010123-15] NR 39 TC 6 Z9 6 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD MAR PY 2015 VL 25 IS 3 BP 188 EP 192 DI 10.1016/j.annepidem.2014.11.009 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CD0RQ UT WOS:000350782000008 PM 25487971 ER PT J AU Flegal, KM Panagiotou, OA Graubard, BI AF Flegal, Katherine M. Panagiotou, Orestis A. Graubard, Barry I. TI Estimating population attributable fractions to quantify the health burden of obesity SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Body mass index; Obesity; Body weight; Epidemiologic methods; Risk ID BODY-MASS INDEX; TYPE-2 DIABETES-MELLITUS; CORONARY-HEART-DISEASE; RISK-FACTORS; UNITED-STATES; LIFE-STYLE; PROSPECTIVE COHORT; CANCER INCIDENCE; EXCESS WEIGHT; ATHEROSCLEROSIS RISK AB Purpose: Obesity is a highly prevalent condition in the United States and elsewhere and is associated with increased mortality and morbidity. Here, we discuss some issues involved in quantifying the health burden of obesity using population attributable fraction (PAF) estimates and provide examples. Methods: We searched PubMed for articles reporting attributable fraction estimates for obesity. We reviewed eligible articles to identify methodological concerns and tabulated illustrative examples of PAF estimates for obesity relative to cancer, diabetes, cardiovascular disease, and all-cause mortality. Results: There is considerable variability among studies regarding the methods used for PAF calculation and the selection of appropriate counterfactuals. The reported estimates ranged from 5% to 15% for all-cause mortality, -0.2% to 8% for all-cancer incidence, 7% to 44% for cardiovascular disease incidence, and 3% to 83% for diabetes incidence. Conclusions: To evaluate a given estimate, it is important to consider whether the exposure and outcome were defined similarly for the PAF and for the relative risks, whether the relative risks were suitable for the population at hand, and whether PAF was calculated using correct methods. Strong causal assumptions are not necessarily warranted. In general, PAFs for obesity may be best considered as indicators of association. Published by Elsevier Inc. C1 [Flegal, Katherine M.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Panagiotou, Orestis A.; Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Flegal, KM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, 3311 Toledo Rd,Room 4336, Hyattsville, MD 20782 USA. EM kmf2@cdc.gov RI Panagiotou, Orestis/I-5934-2015; OI Panagiotou, Orestis/0000-0001-9604-8380; Flegal, Katherine/0000-0002-0838-469X FU Intramural NIH HHS [Z99 CA999999] NR 90 TC 10 Z9 10 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD MAR PY 2015 VL 25 IS 3 BP 201 EP 207 DI 10.1016/j.annepidem.2014.11.010 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CD0RQ UT WOS:000350782000010 PM 25511307 ER PT J AU Coren, LV Jain, S Trivett, MT Ohlen, C Ott, DE AF Coren, Lori V. Jain, Sumiti Trivett, Matthew T. Ohlen, Claes Ott, David E. TI Production of retroviral constructs for effective transfer and expression of T-cell receptor genes using Golden Gate cloning SO BIOTECHNIQUES LA English DT Article DE T-cell receptor; Golden Gate cloning; retroviral vector; gene engineering ID ANTIGEN RECEPTOR; ONE-POT AB Here we present an improved strategy for producing T-cell receptor (TCR)-expressing retroviral vectors using a Golden Gate cloning strategy. This method takes advantage of the modular nature of TCR genes by directly amplifying TCR alpha and beta variable regions from RNA or cDNA, then cloning and fusing them with their respective constant region genes resident in a retroviral TCR expression vector. Our one-step approach greatly streamlines the TCR vector production process in comparison to the traditional three-step procedure that typically involves cloning whole TCR genes, producing a TCR expression cassette, and constructing a retroviral construct. To date, we have generated TCR vectors that transferred seven functional human/rhesus macaque TCRs into primary T cells. The approach also holds promise for the assembly of other genes with defined variable regions, such as immunoglobulins. C1 [Coren, Lori V.; Jain, Sumiti; Trivett, Matthew T.; Ohlen, Claes; Ott, David E.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD 21701 USA. RP Ott, DE (reprint author), Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD 21701 USA. EM ottde@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank Hans-Peter Kleim for the Phoenix RD114 clone 22 packaging cell line. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. This paper is subject to the NIH Public Access Policy. NR 13 TC 1 Z9 1 U1 3 U2 10 PU BIOTECHNIQUES OFFICE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 EI 1940-9818 J9 BIOTECHNIQUES JI Biotechniques PD MAR PY 2015 VL 58 IS 3 BP 135 EP 139 DI 10.2144/000114265 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CD0WM UT WOS:000350794800006 PM 25757546 ER PT J AU Zhang, Z van Praag, H AF Zhang, Zhi van Praag, Henriette TI Maternal immune activation differentially impacts mature and adult-born hippocampal neurons in male mice SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Adult neurogenesis; Prenatal infection; Electrophysiology; Cognition; Hippocampus ID WORKING-MEMORY DEFICITS; MOUSE MODEL; DENTATE GYRUS; DOPAMINERGIC HYPERFUNCTION; RHESUS-MONKEY; ANIMAL-MODEL; SCHIZOPHRENIA; BRAIN; NEUROGENESIS; RATS AB Schizophrenia is associated with deficits in the hippocampus, a brain area important for learning and memory. The dentate gyrus (DG) of the hippocampus develops both before and after birth. To study the relative contribution of mature and adult-born DG granule cells to disease etiology, we compared both cell populations in a mouse model of psychiatric illness resulting from maternal immune activation. Polyriboinosinic-polyribocytidilic acid (PolyIC, 5 mg/kg) or saline was given on gestation day 15 to pregnant female C57Bl/6 mice. Male offspring (n = 105), was administered systemic bromodeoxyuridine (BrdU, 50 mg/kg) (n = 52) or intracerebral retroviral injection into the DG (n = 53), to label dividing cells at one month of age. Two months later behavioral tests were performed to evaluate disease phenotype. Immunohistochemistry and whole-cell patch clamping were used to assess morphological and physiological characteristics of DG cells. Three-month-old PolyIC exposed male offspring exhibited deficient pre-pulse inhibition, spatial maze performance and motor coordination, as well as increased depression-like behavior. Histological analysis showed reduced DG volume and parvalbumin positive interneuron number. Both mature and new hippocampal neurons showed modifications in intrinsic properties such as increased input resistance and lower current threshold, and decreased action potential number. Reduced GABAergic inhibitory transmission was observed only in mature DG neurons. Differential impairments in mature DG cells and adult-born new neurons may have implications for behavioral deficits associated with maternal immune activation. Published by Elsevier Inc. C1 [Zhang, Zhi; van Praag, Henriette] NIA, Neuroplast & Behav Unit, Lab Neurosci, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP van Praag, H (reprint author), NIA, Neuroplast & Behav Unit, Lab Neurosci, Biomed Res Ctr,NIH, Suite 100,251 Bayview Blvd, Baltimore, MD 21224 USA. EM vanpraagh@mail.nih.gov RI van Praag, Henriette/F-3939-2015 OI van Praag, Henriette/0000-0002-5727-434X FU Intramural Research Program of the National Institute on Aging FX This project was supported by the Intramural Research Program of the National Institute on Aging. We thank Sarah Collica, Ben Peterson and Jonathan Cheung for technical assistance and Linda R. Kitabayashi for help with preparation of photomicrographs. NR 66 TC 12 Z9 12 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD MAR PY 2015 VL 45 BP 60 EP 70 DI 10.1016/j.bbi.2014.10.010 PG 11 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA CC7BX UT WOS:000350523800008 PM 25449671 ER PT J AU Corrigan, F Wu, Y Tuke, J Coller, JK Rice, KC Diener, KR Hayball, JD Watkins, LR Somogyi, AA Hutchinson, MR AF Corrigan, Frances Wu, Yue Tuke, Jonathan Coller, Janet K. Rice, Kenner C. Diener, Kerrilyn R. Hayball, John D. Watkins, Linda R. Somogyi, Andrew A. Hutchinson, Mark R. TI Alcohol-induced sedation and synergistic interactions between alcohol and morphine: A key mechanistic role for Toll-like receptors and MyD88-dependent signaling SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Drug interactions; Toll like receptors; Myeloid differentiation factor 88; Cytokines; Naloxone; Drug overdose ID ETHANOL; MICE; ACTIVATION; OVERDOSE; DISEASE; DEATHS; RISK; RATS; PAIN AB Increasing evidence demonstrates induction of proinflammatory Toll-like receptor (TLR) 2 and TLR4 signaling by morphine and, TLR4 signaling by alcohol; thus indicating a common site of drug action and a potential novel innate immune-dependent hypothesis for opioid and alcohol drug interactions. Hence, the current study aimed to assess the role of TLR2, TLR4, MyD88 (as a critical TLR-signaling participant), NF-kappa B, Interleukin-1 beta (IL-1 beta; as a downstream proinflammatory effector molecule) and the mu opioid receptor (MOR; as a classical site for morphine action) in acute alcohol-induced sedation (4.5 g/kg) and alcohol (2.5 g/kg) interaction with morphine (5 mg/kg) by assessing the loss of righting reflex (LORR) as a measure of sedation. Wild-type male Balb/c mice and matched genetically-deficient TLR2, TLR4, and MyD88 strains were utilized, together with pharmacological manipulation of MOR, NF-kappa B, TLR4 and Interleukin-1 beta. Alcohol induced significant LORR in wild-type mice; this was halved by MyD88 and TLR4 deficiency, and surprisingly nearly completely eliminated by TLR2 deficiency. In contrast, the interaction between morphine and alcohol was found to be MOR-, NF-kappa B-, TLR2- and MyD88-dependent, but did not involve TLR4 or Interleukin-1 beta. Morphine-alcohol interactions caused acute elevations in microglial cell counts and NF-kappa B-p65 positive cells in the motor cortex in concordance with wild-type and TLR2 deficient mouse behavioral data, implicating neuroimmunopharmacological signaling as a pivotal mechanism in this clinically problematic drug-drug interaction. (C) 2014 Elsevier Inc. All rights reserved. C1 [Corrigan, Frances] Univ Adelaide, Sch Med Sci, Discipline Anat & Pathol, Adelaide, SA, Australia. [Wu, Yue; Coller, Janet K.; Somogyi, Andrew A.] Univ Adelaide, Sch Med Sci, Discipline Pharmacol, Adelaide, SA, Australia. [Tuke, Jonathan] Univ Adelaide, Sch Math Sci, Adelaide, SA, Australia. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Rockville, MD USA. [Rice, Kenner C.] NIAAA, NIH, Rockville, MD 20852 USA. [Diener, Kerrilyn R.] Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia. [Diener, Kerrilyn R.; Hayball, John D.] Hanson Inst, Expt Therapeut Lab, Adelaide, SA, Australia. [Diener, Kerrilyn R.; Hayball, John D.] Sansom Inst, Adelaide, SA, Australia. [Diener, Kerrilyn R.; Hayball, John D.] Univ S Australia, Sch Pharm & Med Sci, Adelaide, SA 5001, Australia. [Hayball, John D.] Univ Adelaide, Sch Med, Adelaide, SA, Australia. [Watkins, Linda R.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Watkins, Linda R.] Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA. [Somogyi, Andrew A.] Univ Adelaide, Ctr Translat Canc Res, Adelaide, SA, Australia. [Somogyi, Andrew A.] Univ Adelaide, Sch Med Sci, Discipline Physiol, Adelaide, SA, Australia. [Hutchinson, Mark R.] Royal Adelaide Hosp, Dept Clin Pharmacol, Adelaide, SA 5000, Australia. RP Hutchinson, MR (reprint author), Univ Adelaide, Sch Med Sci, Discipline Physiol, Adelaide, SA, Australia. EM mark.hutchinson@adelaide.edu.au RI Hayball, John/F-4137-2013; OI Hayball, John/0000-0002-3089-4506; Hutchinson, Mark/0000-0003-2154-5950 FU China Scholarship Council (CSC)-University of Adelaide; NHMRC ECR Fellowship; NIDA [DA024044] FX Yue Wu was the recipient of China Scholarship Council (CSC)-University of Adelaide Joint Postgraduate Scholarship. Mark R. Hutchinson is a NHMRC CJ Martin Fellow (ID 465423; 2007-2010) and an Australian Research Council Research Fellow (DP110100297). Janet K. Coller is a FTT Fricker Research Fellow (Medical Endowment Funds), Faculty of Health Sciences, University of Adelaide. Kerrilyn R. Diener is supported by a NHMRC ECR Fellowship. Linda Watkins is supported by a NIDA K05 award (DA024044). NR 39 TC 7 Z9 7 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD MAR PY 2015 VL 45 BP 245 EP 252 DI 10.1016/j.bbi.2014.12.019 PG 8 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA CC7BX UT WOS:000350523800025 PM 25542736 ER PT J AU Kundu, P Benson, BE Baldwin, KL Rosen, D Luh, WM Bandettini, PA Pine, DS Ernst, M AF Kundu, Prantik Benson, Brenda E. Baldwin, Katherine L. Rosen, Dana Luh, Wen-Ming Bandettini, Peter A. Pine, Daniel S. Ernst, Monique TI Robust resting state fMRI processing for studies on typical brain development based on multi-echo EPI acquisition SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Aging; BOLD; Coregistration; Denoising; T-2*; Functional connectivity; Seed-based; ICA; PCA ID INDEPENDENT COMPONENT ANALYSIS; BOLD-CONTRAST SENSITIVITY; FUNCTIONAL CONNECTIVITY; DIFFERENTIATING BOLD; HUMAN CONNECTOME; TIME-SERIES; SPIN-ECHO; ARTIFACT; CLASSIFIERS; ENHANCEMENT AB Several methodological challenges affect the study of typical brain development based on resting state blood oxygenation level dependent (BOLD) functional MRI (fMRI). One such challenge is mitigating artifacts such as those from head motion, known to be more substantial in younger subjects than older subjects. Other challenges include controlling for potential age-dependence in cerebrospinal fluid (CSF) volume affecting anatomical-functional coregistration; in vascular density affecting BOLD contrast-to-noise; and in CSF pulsation creating time series artifacts. Historically, these confounds have been approached through incorporating artifact-specific temporal and/or spatial filtering into preprocessing pipelines. However, such paths often come with new confounds or limitations. In this study we take the approach of a bottom-up revision of fMRI methodology based on acquisition of multi-echo fMRI and comprehensive utilization of the information in the TE-domain to enhance several aspects of fMRI analysis in the context of a developmental study. We show in a cohort of 25 healthy subjects, aged 9 to 43 years, that the analysis of multi-echo fMRI data eliminates a number of arbitrary processing steps such as bandpass filtering and spatial smoothing, while enabling procedures such as T-2* mapping, BOLD contrast normalization and signal dropout recovery, precise anatomical-functional coregistration based on T-2* measurements, automatic denoising through removing subject motion, scanner-related signal drifts and physiology, as well as statistical inference for seed-based connectivity. These enhancements are of both theoretical significance and practical benefit in the study of typical brain development. C1 [Kundu, Prantik; Baldwin, Katherine L.; Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. [Kundu, Prantik] Icahn Sch Med Mt Sinai, Sect Adv Funct Brain Imaging, New York, NY 10029 USA. [Benson, Brenda E.] NIMH, Sect Dev & Affect Neurosci, Emot & Dev Branch, Bethesda, MD 20892 USA. [Rosen, Dana; Pine, Daniel S.; Ernst, Monique] NIMH, Sect Neurobiol Fear & Anxiety, Emot & Dev Branch, Bethesda, MD 20892 USA. [Luh, Wen-Ming] Cornell Univ, Cornell MRI Facil, Ithaca, NY 14853 USA. [Bandettini, Peter A.] NIH, fMRI Core Facil, Bethesda, MD 20892 USA. RP Kundu, P (reprint author), NIMH, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. EM prantik.kundu@mssm.edu OI Kundu, Prantik/0000-0001-9367-3068 NR 43 TC 3 Z9 3 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 EI 1931-7565 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD MAR PY 2015 VL 9 IS 1 BP 56 EP 73 DI 10.1007/s11682-014-9346-4 PG 18 WC Neuroimaging SC Neurosciences & Neurology GA CD6AD UT WOS:000351169400006 PM 25592183 ER PT J AU Carter, MC Metcalfe, DD Clark, AS Wayne, AS Maric, I AF Carter, Melody C. Metcalfe, Dean D. Clark, Alicia S. Wayne, Alan S. Maric, Irina TI Abnormal bone marrow histopathology in paediatric mastocytosis SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE paediatrics; mastocytosis; childhood; bone marrow; myeloproliferative ID ACUTE MYELOID-LEUKEMIA; SYSTEMIC MASTOCYTOSIS; CUTANEOUS MASTOCYTOSIS; URTICARIA-PIGMENTOSA; SPECIMENS; MUTATION; T(8/21); CELLS; CHILD AB The diagnostic criteria for paediatric mastocytosis are largely based on adult studies and bone marrow findings are not well described in children. We evaluated use of the World Health Organization (WHO) criteria for the diagnosis of systemic disease in paediatric mastocytosis. In addition, we identified unique clinico-histopathological features within the biopsies. One hundred and thirteen children with paediatric mastocytosis were evaluated at the National Institutes of Health between 1986 and 2013. Complete bone marrow evaluations were performed in 50 cases. Seven children had repeat procedures. Bone marrows were analysed by histopathology, flow cytometry and for KIT D816V. Bone marrow biopsies displayed mild atypical haematopoietic maturation, increased haematogones and hypocellularity in a sub-set of patients with urticaria pigmentosa, diffuse cutaneous mastocytosis and indolent systemic mastocytosis. Hypocellularity was most pronounced in those with urticaria pigmentosa. Haematogones were highest, on average, in patients with diffuse cutaneous mastocytosis or mastocytomas. There was no evidence of peripheral blood cytopenias, myelodysplastic syndrome, myeloproliferative neoplasm or leukaemia within this cohort. The WHO criteria are applicable for the diagnosis of systemic mastocytosis in paediatrics. Although unsuspected bone marrow findings typically seen in myeloproliferative disorders are frequent in paediatric mastocytosis, patients within this study remained clinically stable without progression to a more aggressive variant. C1 [Carter, Melody C.; Metcalfe, Dean D.; Clark, Alicia S.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Maric, Irina] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wayne, Alan S.] Univ So Calif, Keck Sch Med, Div Hematol Oncol & Blood & Marrow Transplantat, Childrens Ctr Canc & Blood Dis,Childrens Hosp Los, Los Angeles, CA 90033 USA. RP Carter, MC (reprint author), Bldg 10-11C207,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. EM mcarter@niaid.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases; National Cancer Institute, Center for Cancer Research and Clinical Center, Warren Grant Magnuson Clinical Center, National Institutes of Health FX We gratefully acknowledge the study participants and their families, referring medical care teams and the faculty and staff of the NIH. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, Center for Cancer Research and Clinical Center, Warren Grant Magnuson Clinical Center, National Institutes of Health. NR 25 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAR PY 2015 VL 168 IS 6 BP 865 EP 873 DI 10.1111/bjh.13231 PG 9 WC Hematology SC Hematology GA CD4HN UT WOS:000351043400011 PM 25429914 ER PT J AU Pechanova, O Varga, ZV Cebova, M Giricz, Z Pacher, P Ferdinandy, P AF Pechanova, O. Varga, Z. V. Cebova, M. Giricz, Z. Pacher, P. Ferdinandy, P. TI Cardiac NO signalling in the metabolic syndrome SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review ID NITRIC-OXIDE SYNTHASE; SPONTANEOUSLY HYPERTENSIVE-RATS; ISCHEMIA-REPERFUSION INJURY; SOLUBLE GUANYLATE-CYCLASE; LEFT-VENTRICULAR FUNCTION; ACTIVATED PROTEIN-KINASE; MYOCARDIAL ISCHEMIA/REPERFUSION INJURY; ASYMMETRIC DIMETHYLARGININE ADMA; SUPEROXIDE-DISMUTASE ACTIVITY; CHOLESTEROL-ENRICHED DIET AB It is well documented that metabolic syndrome (i.e. a group of risk factors, such as abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides and low cholesterol level in high-density lipoprotein), which raises the risk for heart disease and diabetes, is associated with increased reactive oxygen and nitrogen species (ROS/RNS) generation. ROS/RNS can modulate cardiac NO signalling and trigger various adaptive changes in NOS and antioxidant enzyme expressions/activities. While initially these changes may represent protective mechanisms in metabolic syndrome, later with more prolonged oxidative, nitrosative and nitrative stress, these are often exhausted, eventually favouring myocardial RNS generation and decreased NO bioavailability. The increased oxidative and nitrative stress also impairs the NO-soluble guanylate cyclase (sGC) signalling pathway, limiting the ability of NO to exert its fundamental signalling roles in the heart. Enhanced ROS/RNS generation in the presence of risk factors also facilitates activation of redox-dependent transcriptional factors such as NF-B, promoting myocardial expression of various pro-inflammatory mediators, and eventually the development of cardiac dysfunction and remodelling. While the dysregulation of NO signalling may interfere with the therapeutic efficacy of conventional drugs used in the management of metabolic syndrome, the modulation of NO signalling may also be responsible for the therapeutic benefits of already proven or recently developed treatment approaches, such as ACE inhibitors, certain -blockers, and sGC activators. Better understanding of the above-mentioned pathological processes may ultimately lead to more successful therapeutic approaches to overcome metabolic syndrome and its pathological consequences in cardiac NO signalling. Linked ArticlesThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit C1 [Pechanova, O.; Cebova, M.] Slovak Acad Sci, Inst Normal & Pathol Physiol, Bratislava 81371, Slovakia. [Pechanova, O.; Cebova, M.] Slovak Acad Sci, Ctr Excellence Regulatory Role Nitr Oxide Civiliz, Bratislava 81371, Slovakia. [Pechanova, O.] Comenius Univ, Fac Nat Sci, Bratislava, Slovakia. [Varga, Z. V.; Giricz, Z.; Ferdinandy, P.] Semmelweis Univ, Dept Pharmacol & Pharmacotherapy, Cardiometab Res Grp, H-1085 Budapest, Hungary. [Pacher, P.] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. [Ferdinandy, P.] Pharmahungary Grp, Szeged, Hungary. RP Pechanova, O (reprint author), Slovak Acad Sci, Inst Normal & Pathol Physiol, Bratislava 81371, Slovakia. EM olga.pechanova@savba.sk RI Pacher, Pal/B-6378-2008; OI Pacher, Pal/0000-0001-7036-8108; Giricz, Zoltan/0000-0003-2036-8665 FU Hungarian Scientific Research Fund [OTKA K109737]; [APVV-0742-10]; [VEGA 2/0183/12]; [2/0144/14] FX This study was elaborated within the projects APVV-0742-10, VEGA 2/0183/12 and 2/0144/14, the New Horizons Grant of the European Foundation for the Study of Diabetes, Hungarian Scientific Research Fund (OTKA K109737) and COST Action BM1005, and the Intramural Program of NIH/NIAA. All authors contributed equally on literature search and metabolic syndrome models preparation. NR 219 TC 11 Z9 11 U1 2 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAR PY 2015 VL 172 IS 6 SI SI BP 1415 EP 1433 DI 10.1111/bph.12960 PG 19 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC7KL UT WOS:000350546100003 PM 25297560 ER PT J AU He, ZW Zhang, X Chen, C Wen, Z Hoopes, SL Zeldin, DC Wang, DW AF He, Zuowen Zhang, Xu Chen, Chen Wen, Zheng Hoopes, Samantha L. Zeldin, Darryl C. Wang, Dao Wen TI Cardiomyocyte-specific expression of CYP2J2 prevents development of cardiac remodelling induced by angiotensin II SO CARDIOVASCULAR RESEARCH LA English DT Article DE Epoxyeicosatrienoic acids; Cardiac hypertrophy; CYP2J2; Cardiac remodelling; Oxidative stress ID FACTOR-KAPPA-B; EPOXYEICOSATRIENOIC ACIDS; OXIDATIVE STRESS; HYPERTENSIVE-RATS; DIABETIC MICE; PPAR-GAMMA; HYPERTROPHY; GROWTH; FIBROBLASTS; ACTIVATION AB Cardiac remodelling is one of the key pathological changes that occur with cardiovascular disease. Previous studies have demonstrated the beneficial effects of CYP2J2 expression on cardiac injury. In the present study, we investigated the effects of cardiomyocyte-specific CYP2J2 expression and EET treatment on angiotensin II-induced cardiac remodelling and sought to determine the underlying molecular mechanisms involved in this process. Eight-week-old mice with cardiomyocyte-specific CYP2J2 expression (alpha MHC-CYP2J2-Tr) and wild-type (WT) control mice were treated with Ang-II. Ang-II treatment of WT mice induced changes in heart morphology, cardiac hypertrophy and dysfunction, as well as collagen accumulation; however, cardiomyocyte-specific expression of CYP2J2 attenuated these effects. The cardioprotective effects observed in alpha-MHC-CYP2J2-Tr mice were associated with peroxisome proliferator-activated receptor (PPAR)-gamma activation, reduced oxidative stress, reduced NF-kappa B p65 nuclear translocation, and inhibition of TGF-beta 1/smad pathway. The effects seen with cardiomyocyte-specific expression of CYP2J2 were partially blocked by treatment with PPAR-gamma antagonist GW9662. In in vitro studies, 11,12-EET(1 mu mol/L) treatment attenuated cardiomyocyte hypertrophy and remodelling-related protein (collagen I, TGF-beta 1, TIMP1) expression by inhibiting the oxidative stress-mediated NF-kappa B pathway via PPAR-gamma activation. Furthermore, conditioned media from neonatal cardiomyocytes treated with 11,12-EET inhibited activation of cardiac fibroblasts and TGF-beta 1/smad pathway. Cardiomyocyte-specific expression of CYP2J2 or treatment with EETs protects against cardiac remodelling by attenuating oxidative stress-mediated NF-kappa Bp65 nuclear translocation via PPAR-gamma activation. C1 [He, Zuowen; Chen, Chen; Wen, Zheng; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Internal Med, Wuhan 430030, Peoples R China. [He, Zuowen; Chen, Chen; Wen, Zheng; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Inst Hypertens, Wuhan 430030, Peoples R China. [Zhang, Xu] Tianjin Med Univ, Dept Physiol, Tianjin, Peoples R China. [Hoopes, Samantha L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Internal Med, 1095 Jiefang Ave, Wuhan 430030, Peoples R China. EM dwwang@tjh.tjmu.edu.cn FU NSFC [31130031]; National 973 Programs [2012CB518004, 2012CB517801]; NIH, National Institute of Environmental Health Sciences [Z01 ES025043]; Huazhong University of Science Technology; Innovation Foundation for Doctoral Dissertation of Huazhong University of Science and Technology, China FX This work was supported by NSFC Key Grant (No. 31130031) and National 973 Programs (No. 2012CB518004 and 2012CB517801). The work was also supported, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES025043 to D.C.Z.), Graduates' Innovation Fund of Huazhong University of Science & Technology and Innovation Foundation for Doctoral Dissertation of Huazhong University of Science and Technology, China. NR 43 TC 6 Z9 6 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 EI 1755-3245 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR 1 PY 2015 VL 105 IS 3 BP 304 EP 317 DI 10.1093/cvr/cvv018 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CD3VY UT WOS:000351013000009 PM 25618409 ER PT J AU Hu, JH Touch, P Zhang, JW Wei, H Liu, SH Lund, IK Hoyer-Hansen, G Dichek, DA AF Hu, Jie Hong Touch, Phanith Zhang, Jingwan Wei, Hao Liu, Shihui Lund, Ida K. Hoyer-Hansen, Gunilla Dichek, David A. TI Reduction of mouse atherosclerosis by urokinase inhibition or with a limited-spectrum matrix metalloproteinase inhibitor SO CARDIOVASCULAR RESEARCH LA English DT Article DE Atherosclerosis; Urokinase; Matrix metalloproteinases; Protease inhibition; Mouse models ID DEPENDENT ANTHRAX TOXIN; APOE-KNOCKOUT MICE; TARGETING PROTEASES; HUMAN COLLAGENASE-3; IN-VIVO; PLASMINOGEN; ACTIVATION; DISEASE; SURFACE; OVEREXPRESSION AB Elevated activity of urokinase plasminogen activator (uPA) and MMPs in human arteries is associated with accelerated atherosclerosis, aneurysms, and plaque rupture. We used Apoe-null mice with macrophage-specific uPA overexpression (SR-uPA mice; a well-characterized model of protease-accelerated atherosclerosis) to investigate whether systemic inhibition of proteolytic activity of uPA or a subset of MMPs can reduce protease-induced atherosclerosis and aortic dilation. SR-uPA mice were fed a high-fat diet for 10 weeks and treated either with an antibody inhibiting mouse uPA (mU1) or a control antibody. mU1-treated mice were also compared with PBS-treated non-uPA-overexpressing Apoe-null mice. Other SR-uPA mice were treated with one of three doses of a limited-spectrum synthetic MMP inhibitor (XL784) or vehicle. mU1 reduced aortic root intimal lesion area (20%; P = 0.05) and aortic root circumference (12%; P = 0.01). All XL784 doses reduced aortic root intimal lesion area (22-29%) and oil-red-O-positive lesion area (36-42%; P < 0.05 for all doses and both end points), with trends towards reduced aortic root circumference (6-10%). Neither mU1 nor XL784 significantly altered percent aortic surface lesion coverage. Several lines of evidence identified MMP-13 as a mediator of uPA-induced aortic MMP activity. Pharmacological inhibition of either uPA or selected MMPs decreased atherosclerosis in SR-uPA mice. uPA inhibition decreased aortic dilation. Differential effects of both agents on aortic root vs. distal aortic atherosclerosis suggest prevention of atherosclerosis progression vs. initiation. Systemic inhibition of uPA or a subset of MMPs shows promise for treating atherosclerosis. C1 [Hu, Jie Hong; Touch, Phanith; Zhang, Jingwan; Wei, Hao; Dichek, David A.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Liu, Shihui] NIAID, NIH, Bethesda, MD 20892 USA. [Lund, Ida K.; Hoyer-Hansen, Gunilla] Copenhagen Univ Hosp, Finsen Lab, Copenhagen, Denmark. [Lund, Ida K.; Hoyer-Hansen, Gunilla] Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark. RP Dichek, DA (reprint author), Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. EM ddichek@uw.edu FU John L. Locke Jr. Charitable Trust; National Heart, Lung and Blood Institute [R21HL113405] FX This study was supported by grants from the John L. Locke Jr. Charitable Trust and from the National Heart, Lung and Blood Institute (R21HL113405). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. NR 45 TC 2 Z9 2 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 EI 1755-3245 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR 1 PY 2015 VL 105 IS 3 BP 372 EP 382 DI 10.1093/cvr/cvv007 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CD3VY UT WOS:000351013000015 PM 25616415 ER PT J AU Oboti, L Perez-Gomez, A Keller, M Jacobi, E Birnbaumer, L Leinders-Zufall, T Zufall, F Chamero, P AF Oboti, Livio Perez-Gomez, Anabel Keller, Matthieu Jacobi, Eric Birnbaumer, Lutz Leinders-Zufall, Trese Zufall, Frank Chamero, Pablo TI A wide range of pheromone-stimulated sexual and reproductive behaviors in female mice depend on G protein Gao SO CHEMICAL SENSES LA English DT Meeting Abstract CT 24th Annual Meeting of the European-Chemoreception-Research-Organization (ECRO) CY SEP 10-13, 2014 CL Dijon, FRANCE SP European Chemorecept Res Org C1 [Oboti, Livio; Perez-Gomez, Anabel; Jacobi, Eric; Leinders-Zufall, Trese; Zufall, Frank; Chamero, Pablo] Univ Saarland, Dept Physiol, Sch Med, D-66424 Homburg, Germany. [Keller, Matthieu] Univ Tours, INRA, CNRS, Labe Physiol Reprod & Comportments,UMR 7247, F-37380 Nouzilly, France. [Birnbaumer, Lutz] NIH, Neurobiol Lab, Div Intramural Res, Res Triangle Pk, NC 27709 USA. RI Oboti, Livio/P-5876-2015; Leinders-Zufall, Trese/B-4103-2009 OI Oboti, Livio/0000-0001-7197-568X; Leinders-Zufall, Trese/0000-0002-0678-362X NR 0 TC 0 Z9 0 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0379-864X EI 1464-3553 J9 CHEM SENSES JI Chem. Senses PD MAR PY 2015 VL 40 IS 3 BP 213 EP 213 PG 1 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA CD3WX UT WOS:000351015600014 ER PT J AU Valencia, JC Steagall, WK Zhang, Y Fetsch, P Abati, A Tsukada, K Billings, E Hearing, VJ Yu, ZX Pacheco-Rodriguez, G Moss, J AF Valencia, Julio C. Steagall, Wendy K. Zhang, Yi Fetsch, Patricia Abati, Andrea Tsukada, Katsuya Billings, Eric Hearing, Vincent J. Yu, Zu-Xi Pacheco-Rodriguez, Gustavo Moss, Joel TI Antibody alpha PEP13h Reacts With Lymphangioleiomyomatosis Cells in Lung Nodules SO CHEST LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; SPORADIC PULMONARY LYMPHANGIOLEIOMYOMATOSIS; SMOOTH-MUSCLE-CELLS; GENE TSC2; PROTEIN; EXPRESSION; SIROLIMUS; MELANOSOMES; GROWTH; ANGIOMYOLIPOMA AB BACKGROUND: Lymphangioleiomyomatosis (LAM) is characterized by the proliferation in the lung, axial lymphatics (eg, lymphangioleiomyomas), and kidney (eg, angiomyolipomas) of abnormal smooth muscle-like LAM cells, which express melanoma antigens such as Pmel17/gp100 and have dysfunctional tumor suppressor tuberous sclerosis complex (TSC) genes TSC2 or TSC1. Histopathologic diagnosis of LAM in lung specimens is based on identification of the Pmel17 protein with the monoclonal antibody HMB-45. METHODS: We compared the sensitivity of HMB-45 to that of antipeptide antibody alpha PEP13h, which reacts with a C-terminal peptide of Pmel17. LAM lung nodules were laser-capture microdissected to identify proteins by Western blotting. RESULTS: HMB-45 recognized approximately 25% of LAM cells within the LAM lung nodules, whereas alpha PEP13h identified > 82% of LAM cells within these structures in approximately 90% of patients. Whereas HMB-45 reacted with epithelioid but not with spindle-shaped LAM cells, alpha PEP13h identified both spindle-shaped and epithelioid LAM cells, providing greater sensitivity for detection of all types of LAM cells. HMB-45 recognized Pmel17 in premelanosomal organelles; alpha PEP13h recognized proteins in the cytoplasm as well as in premelanosomal organelles. Both antibodies recognized a Pmel17 variant of approximately 50 kDa. CONCLUSIONS: Based on its sensitivity and specificity, alpha PEP13h may be useful in the diagnosis of LAM and more sensitive than HMB-45. C1 [Valencia, Julio C.; Steagall, Wendy K.; Zhang, Yi; Tsukada, Katsuya; Pacheco-Rodriguez, Gustavo; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Billings, Eric] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, Pathol Core, NIH, Bethesda, MD 20892 USA. [Hearing, Vincent J.] NCI, Pigment Cell Biol Sect, NIH, Bethesda, MD 20892 USA. [Fetsch, Patricia; Abati, Andrea] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Fetsch, Patricia; Abati, Andrea] NCI, Cytopathol Sect, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10-6D05,10 Ctr Dr,MSC 1590, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov FU National Cancer Institute; National Institutes of Health; National Heart, Lung, and Blood Institute FX The study was supported by the Intramural Research Program, National Institutes of Health; National Heart, Lung, and Blood Institute; and the National Cancer Institute. NR 43 TC 1 Z9 1 U1 0 U2 3 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD MAR PY 2015 VL 147 IS 3 BP 771 EP 777 DI 10.1378/chest.14-0380 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CC5RC UT WOS:000350419200056 PM 25411763 ER PT J AU Bansal, N Katz, R De Boer, IH Peralta, CA Fried, LF Siscovick, DS Rifkin, DE Hirsch, C Cummings, SR Harris, TB Kritchevsky, SB Sarnak, MJ Shlipak, MG Ix, JH AF Bansal, Nisha Katz, Ronit De Boer, Ian H. Peralta, Carmen A. Fried, Linda F. Siscovick, David S. Rifkin, Dena E. Hirsch, Calvin Cummings, Steven R. Harris, Tamara B. Kritchevsky, Stephen B. Sarnak, Mark J. Shlipak, Michael G. Ix, Joachim H. TI Development and Validation of a Model to Predict 5-Year Risk of Death without ESRD among Older Adults with CKD SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; MORTALITY RISK; OUTCOMES; ASSOCIATION; EVENTS; HEALTH; SCORES; AGE AB Background and objectives CKD is associated with mortality. Accurate prediction tools for mortality may guide clinical decision-making, particularly among elderly persons with CKD. Design, setting, participants, & measurements A prediction equation was developed for 5-year risk of mortality among participants with CKD in the Cardiovascular Health Study. Sixteen candidate predictor variables were explored, which included demographics, physical examination measures, comorbidity, medication use, and kidney function measures (eGFR calculated from serum creatinine and the CKD Epidemiology Collaboration equation and the urine albumin-to-creatinine ratio). Models were developed using Cox regression and evaluated using c statistics. A final parsimonious model was externally validated in an independent cohort of community-living elders with CKD in the Health, Aging, and Body Composition Study. Results The development cohort included 828 participants who had a mean age of 80 (+/- 5.6) years and an eGFR of 47 (+/- 11) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-51) mg/g. The validation cohort included 789 participants who had a mean age of 74 (+/- 2.8) years and an eGFR of 50 (+/- 9) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-42) mg/g. The final model for 5-year mortality risk induded age, sex, race, eGFR, urine albumin-to-creatinine ratio, smoking, diabetes mellitus, and history of heart failure and stroke (c statistic=0.72; 95% confidence interval, 0.68 to 0.74). When a point-based system was assigned for each of nine variables in the equation, the estimated risk of death within 5 years ranged from 3.8% among participants with the lowest scores to 83.6% among participants with nine points. The model performed fair in external validation (c statistic=0.69; 95% confidence interval, 0.64 to 0.74). Conclusions A simple prediction tool using nine readily available clinical variables can assist in predicting 5-year mortality risk in elderly patients with CKD, which may be useful in counseling patients and guiding clinical decision making. C1 [Bansal, Nisha; Katz, Ronit; De Boer, Ian H.] Univ Washington, Kidney Res Inst, Div Nephrol, Seattle, WA 98104 USA. [Peralta, Carmen A.; Shlipak, Michael G.] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Fried, Linda F.] Univ Pittsburgh, Div Nephrol, Pittsburgh, PA USA. [Siscovick, David S.] New York Acad Med, New York, NY USA. [Rifkin, Dena E.; Ix, Joachim H.] Univ Calif San Diego, Div Nephrol, San Diego, CA 92103 USA. [Hirsch, Calvin] Univ Calif Davis, Dept Med, Sacramento, CA 95817 USA. [Cummings, Steven R.] Calif Pacific Med Ctr, Res Inst, San Francisco Coordinating Ctr, San Francisco, CA USA. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Sarnak, Mark J.] Tufts Med Ctr, Div Nephrol, Boston, MA USA. RP Bansal, N (reprint author), Univ Washington, Kidney Res Inst, 325 9th Ave, Seattle, WA 98104 USA. EM nbansal@nephrology.washington.edu FU National Institute for Diabetes Digestive and Kidney Diseases [K23DK088865]; National Institutes on Aging (NIA) [R01AG027002]; American Heart Association Established Investigator Award [EIA18560026]; National Heart, Lung, and Blood Institute [HHSN268201200036C, HHSN268200800007C, N01-HC55222, N01-HC85079, N01-HC85080, N01-HC85081, N01-HC85082, N01-HC85083, N01-HC85086, HL080295]; NIA [AG023629, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute of Nursing Research (NINR) [R01-NR012459]; Intramural Research Program of the National Institutes of Health, NIA FX This work was supported by National Institute for Diabetes Digestive and Kidney Diseases Grant K23DK088865 (to N.B.), National Institutes on Aging (NIA) Grant R01AG027002 (to M.J.S.), and American Heart Association Established Investigator Award EIA18560026 (to J.H.I.). The Cardiovascular Health Study (CHS) research was supported by National Heart, Lung, and Blood Institute Contracts HHSN268201200036C, HHSN268200800007C, N01-HC55222, N01-HC85079, N01-HC85080, N01-HC85081, N01-HC85082, N01-HC85083, and N01-HC85086 and Grant HL080295, with additional contribution from the National Institute of Neurological Disorders and Stroke; additional support was provided by NIA Grant AG023629. The Health, Aging, and Body Composition Study research was supported by NIA Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; NIA Grant R01-AG028050; National Institute of Nursing Research (NINR) Grant R01-NR012459; and in part, the Intramural Research Program of the National Institutes of Health, NIA. NR 27 TC 10 Z9 10 U1 0 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAR PY 2015 VL 10 IS 3 BP 363 EP 371 DI 10.2215/CJN.04650514 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CC9QH UT WOS:000350705200006 PM 25710804 ER PT J AU Prevots, DR Marras, TK AF Prevots, D. Rebecca Marras, Theodore K. TI Epidemiology of Human Pulmonary Infection with Nontuberculous Mycobacteria A Review SO CLINICS IN CHEST MEDICINE LA English DT Review DE Epidemiology; Nontuberculous mycobacteria; Pulmonary disease; Global ID INTRACELLULARE COMPLEX DISEASE; HIV-NEGATIVE PATIENTS; LUNG-DISEASE; AVIUM COMPLEX; CLINICAL-RELEVANCE; UNITED-STATES; CYSTIC-FIBROSIS; RISK-FACTORS; RESPIRATORY-INFECTIONS; CHANGING EPIDEMIOLOGY AB Population-based data have documented a worldwide increase in the prevalence of human nontuberculous mycobacterial (NTM) infections since 2000. Mycobacterium avium complex is predominant in North America and East Asia, whereas in regions within Europe, M kansasii, M xenopi, and M malmoense are more common. Host factors important to the current epidemiology of NTM pulmonary disease include thoracic skeletal abnormalities, rheumatoid arthritis, and use of immunomodulatory drugs. Clustering of disease within families suggests a heritable genetic predisposition to disease susceptibility. Warm, humid environments with high atmospheric vapor pressure contribute to population risk. C1 [Prevots, D. Rebecca] NIAID, Epidemiol Unit, Lab Clin Infect Dis, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Marras, Theodore K.] Univ Toronto, Dept Med, Div Respirol, Toronto, ON M5T 2S8, Canada. [Marras, Theodore K.] Toronto Western Hosp, Toronto, ON M5T 2S8, Canada. RP Prevots, DR (reprint author), NIAID, Epidemiol Unit, Lab Clin Infect Dis, Div Intramural Res,NIH, 9000 Rockville Pike,Bldg 15B-1,8 West Dr,MSC 2665, Bethesda, MD 20892 USA. EM rprevots@niaid.nih.gov FU Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported in part by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health. We would also like to acknowledge Ms. Sara Strollo for her assistance with manuscript preparation. NR 88 TC 47 Z9 47 U1 2 U2 19 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-5231 EI 1557-8216 J9 CLIN CHEST MED JI Clin. Chest Med. PD MAR PY 2015 VL 36 IS 1 BP 13 EP 34 DI 10.1016/j.ccm.2014.10.002 PG 22 WC Respiratory System SC Respiratory System GA CC8IW UT WOS:000350612700004 PM 25676516 ER PT J AU Hamman, RF Horton, E Barrett-Connor, E Bray, GA Christophi, CA Crandall, J Florez, JC Fowler, S Goldberg, R Kahn, SE Knowler, WC Lachin, JM Murphy, MB Venditti, E AF Hamman, Richard F. Horton, Edward Barrett-Connor, Elizabeth Bray, George A. Christophi, Costas A. Crandall, Jill Florez, Jose C. Fowler, Sarah Goldberg, Ronald Kahn, Steven E. Knowler, William C. Lachin, John M. Murphy, Mary Beth Venditti, Elizabeth CA Diabet Prevention Program DPP Res TI Factors Affecting the Decline in Incidence of Diabetes in the Diabetes Prevention Program Outcomes Study (DPPOS) SO DIABETES LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; LIFE-STYLE INTERVENTION; FOLLOW-UP; WEIGHT-LOSS; FASTING GLUCOSE; PIMA-INDIANS; RISK; MELLITUS; ROSIGLITAZONE; PROGRESSION AB During the first 7 years of the Diabetes Prevention Program Outcomes Study (DPPOS), diabetes incidence rates, when compared with the Diabetes Prevention Program (DPP), decreased in the placebo (-42%) and metformin (-25%), groups compared with the rates in the intensive lifestyle intervention (+31%) group. Participants in the placebo and metformin groups were offered group intensive lifestyle intervention prior to entering the DPPOS. The following two hypotheses were explored to explain the rate differences: effective intervention (changes in weight and other factors due to intensive lifestyle intervention) and exhaustion of susceptible (changes in mean genetic and diabetes risk scores). No combination of behavioral risk factors (weight, physical activity, diet, smoking, and antidepressant or statin use) explained the lower DPPOS rates of diabetes progression in the placebo and metformin groups, whereas weight gain was the factor associated with higher rates of progression in the intensive lifestyle intervention group. Different patterns in the average genetic risk score over time were consistent with exhaustion of susceptibles. Results were consistent with exhaustion of susceptibles for the change in incidence rates, but not the availability of intensive lifestyle intervention to all persons before the beginning of the DPPOS. Thus, effective intervention did not explain the lower diabetes rates in the DPPOS among subjects in the placebo and metformin groups compared with those in the DPP. C1 [Hamman, Richard F.] Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO 80045 USA. [Horton, Edward] Joslin Diabet Ctr, Sect Clin Res, Boston, MA 02215 USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Bray, George A.] Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Christophi, Costas A.; Fowler, Sarah; Lachin, John M.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Crandall, Jill] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Goldberg, Ronald] Univ Miami, Sch Med, Diabet Res Inst, Miami, FL USA. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. [Knowler, William C.] NIDDK, Phoenix, AZ USA. [Murphy, Mary Beth] Univ Tennessee, Ctr Hlth Sci, Div Endocrinol, Memphis, TN 38163 USA. [Venditti, Elizabeth] Univ Pittsburgh, Western Psychiat Inst & Clin, Med Ctr Hlth Syst, Pittsburgh, PA 15213 USA. RP Hamman, RF (reprint author), Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO 80045 USA. EM dppmail@bsc.gwu.edu OI Lachin, John/0000-0001-9838-2841; Kahn, Steven/0000-0001-7307-9002 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Aging; National Eye Institute; National Heart, Lung, and Blood Institute; Office of Women's Health; National Institute on Minority Health and Health Disparities; Centers for Disease Control and Prevention; Department of Veterans Affairs; American Diabetes Association FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding of the clinical and coordinating centers that designed and undertook the study and collected, managed, analyzed, and interpreted the data. The General Clinical Research Center Program and the National Center for Research Resources supported data collection at many of the clinical centers. The study was funded by the NIDDK as a cooperative agreement The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and by the Indian Health Service. Funding was also provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute on Aging; the National Eye Institute; the National Heart, Lung, and Blood Institute; the Office of Women's Health; the National Institute on Minority Health and Health Disparities; the Centers for Disease Control and Prevention; the Department of Veterans Affairs; and the American Diabetes Association. The sponsor of this study was represented on the Steering Committee and played a part in the study design, how the study was performed, and the publication of the article. The funding agency was not represented on the writing group, although all members of the Steering Committee had input into the contents of the report. NR 32 TC 8 Z9 8 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD MAR PY 2015 VL 64 IS 3 BP 989 EP 998 DI 10.2337/db14-0333 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC3GX UT WOS:000350235900038 ER PT J AU Grant, BF Goldstein, RB Smith, SM Jung, JS Zhang, HT Chou, SP Pickering, RP Ruan, WJ Huang, BJ Saha, TD Aivadyan, C Greenstein, E Hasin, DS AF Grant, Bridget F. Goldstein, Rise B. Smith, Sharon M. Jung, Jeesun Zhang, Haitao Chou, Sanchen P. Pickering, Roger P. Ruan, Wenjun J. Huang, Boji Saha, Tulshi D. Aivadyan, Christina Greenstein, Eliana Hasin, Deborah S. TI The Alcohol Use Disorder and Associated Disabilities Interview Schedule-5 (AUDADIS-5): Reliability of substance use and psychiatric disorder modules in a general population sample SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Substance use disorders; Reliability; Mood disorders; Anxiety disorders; National Epidemiologic Survey on Alcohol and Related Conditions-III; Alcohol Use Disorder and Associated; Disabilities Interview Schedule-5 ID DSM-III-R; TEST-RETEST RELIABILITY; PERSONALITY-DISORDER; DRUG MODULES; DIAGNOSTIC INTERVIEW; COMMUNITY-SAMPLE; IV; AGREEMENT; VALIDITY; CIDI AB Background: The purpose of this study was to assess the test-retest reliability of substance use disorder and psychiatric modules in the Alcohol Use Disorder and Associated Disabilities Interview Schedule, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Version (AUDADIS-5). Methods: Kappa and intraclass correlation coefficients were calculated for DSM-5 substance use and psychiatric disorder diagnoses and dimensional criteria scales using a test-retest design among 1006 respondents drawn from the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III). Results: Reliabilities of substance use disorder diagnoses and associated criteria scales were generally good to excellent, while reliabilities for mood, anxiety and trauma and stress-related disorders and associated scales were generally in the fair to good range. Conclusions: The observed reliability of the DSM-5 diagnoses and dimensional scales for the substance use and psychiatric disorders found in this study indicates that the AUDADIS-5 can be a useful tool in various research settings, particularly in studies of the general population, the target population for which it was designed. Published by Elsevier Ireland Ltd. C1 [Grant, Bridget F.; Goldstein, Rise B.; Smith, Sharon M.; Jung, Jeesun; Zhang, Haitao; Chou, Sanchen P.; Pickering, Roger P.; Ruan, Wenjun J.; Huang, Boji; Saha, Tulshi D.] NIAAA, Div Intramural Clin & Biol Res, Lab Epidemiol & Biometry, Rockville, MD 20852 USA. [Aivadyan, Christina; Greenstein, Eliana; Hasin, Deborah S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Hasin, Deborah S.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Hasin, Deborah S.] Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. RP Grant, BF (reprint author), NIAAA, Div Intramural Clin & Biol Res, Lab Epidemiol & Biometry, 5635 Fishers Lane, Rockville, MD 20852 USA. EM bgrant@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institutes of Health; National Institute on Alcohol and Alcoholism; Intramural Program, NIAAA, National Institutes of Health; [HHSN275200900007C]; [K05AA014223] FX Support is acknowledged from the National Institutes of Health. Contract HHSN275200900007C, K05AA014223, and the New York State Psychiatric Institute (Hasin). The National Epidemiologic Survey on Alcohol Abuse and Related Conditions-III was sponsored by the National Institute on Alcohol and Alcoholism and funded, in part, by the Intramural Program, NIAAA, National Institutes of Health. NIAAA had no role in the study design, in the collection, analyses or interpretation of the data, in the writing of the report or the decision to submit the article for publication. NR 46 TC 23 Z9 23 U1 5 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAR 1 PY 2015 VL 148 BP 27 EP 33 DI 10.1016/j.drugalcdep.2014.11.026 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CC7DF UT WOS:000350527200003 PM 25595052 ER PT J AU Hasin, DS Greenstein, E Aivadyan, C Stohl, M Aharonovich, E Saha, T Goldstein, R Nunes, EV Jung, JS Zhang, HT Grant, BF AF Hasin, Deborah S. Greenstein, Eliana Aivadyan, Christina Stohl, Malki Aharonovich, Efrat Saha, Tulshi Goldstein, Rise Nunes, Edward V. Jung, Jeesun Zhang, Haitao Grant, Bridget F. TI The Alcohol Use Disorder and Associated Disabilities Interview Schedule-5 (AUDADIS-5): Procedural validity of substance use disorders modules through clinical re-appraisal in a general population sample SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Alcohol use disorder; Substance use disorder; Reliability; Validity; Alcohol Use Disorder and Associated; Disabilities Interview Schedule-5; Psychiatric Research Interview for Substance and Mental Disorders-5 ID PSYCHIATRIC RESEARCH INTERVIEW; DSM-IV ALCOHOL; FACE-TO-FACE; MENTAL-DISORDERS; DRUG MODULES; DIAGNOSTIC MODULES; UNITED-STATES; RELIABILITY; CONCORDANCE; PREVALENCE AB Background: The purpose of this study was to assess the procedural validity of the substance disorder modules of the lay-administered Alcohol Use Disorder and Associated Disabilities Interview Schedule, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Version (AUDADIS-5) through clinician re-appraisal re-interviews. Methods: The study employed a test-retest design among 712 respondents from the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III). A clinician-administered, semi-structured interview, the Psychiatric Research Interview for Substance and Mental Disorders, DSM-5 version (PRISM-5) was used as the re-appraisal. Kappa coeffients indicated concordance of the AUDADIS-5 and PRISM-5 for DSM-5 substance use disorder diagnoses, while intraclass correlation coefficients (ICC) indicated concordance on dimensional scales indicating the DSM-5 criteria count for each disorder. Results: With few exceptions, concordance of the AUDADIS-5 and the PRISM-5 for DSM-5 diagnoses of substance use disorders ranged from fair to good (k = 0.40-0.72). Concordance on dimensional scales was excellent (ICC >= 0.75) for the majority of DSM-5 SUD diagnoses, and fair to good (ICC = 0.43-0.72) for most of the rest. Conclusions: As indicated by concordance with a semi-structured clinician-administered re-appraisal, the procedural validity of the AUDADIS-5 DSM-5 substance use disorder diagnoses found in this study indicates that these AUDADIS-5 diagnoses are useful tools in epidemiologic studies. The considerably stronger concordance of the AUDADIS-5 and PRISM-5 dimensional DSM-5 SUD measures supports a current movement to place more emphasis on dimensional measures of psychopathology, and suggests that such measures may be more informative than binary diagnoses for research, and possibly for clinical purposes as well. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Hasin, Deborah S.; Aharonovich, Efrat; Nunes, Edward V.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Hasin, Deborah S.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Hasin, Deborah S.; Greenstein, Eliana; Aivadyan, Christina; Stohl, Malki; Aharonovich, Efrat; Nunes, Edward V.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Saha, Tulshi; Goldstein, Rise; Jung, Jeesun; Zhang, Haitao; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Bethesda, MD 20892 USA. RP Hasin, DS (reprint author), Columbia Univ, Med Ctr, Coll Phys & Surg, Dept Psychiat, 1051 Riverside Dr 123, New York, NY 10032 USA. EM deborah.hasin@gmail.com OI Goldstein, Rise/0000-0002-9603-9473 FU National Institutes of Health [HHSN275200900007C, K05AA014223, K24DA022412]; New York State Psychiatric Institute; National Institute on Alcohol Abuse and Alcoholism; Intramural Program, NIAAA, National Institutes of Health FX Support is acknowledged from the National Institutes of Health, Contract HHSN275200900007C, K05AA014223 (Hasin), K24DA022412 (Nunes) and the New York State Psychiatric Institute (Hasin, Nunes). The National Epidemiologic Survey on Alcohol and Related Conditions-Ill was sponsored by the National Institute on Alcohol Abuse and Alcoholism and funded, in part, by the Intramural Program, NIAAA, National Institutes of Health. No authors have any relevant financial interests. NR 49 TC 17 Z9 17 U1 2 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAR 1 PY 2015 VL 148 BP 40 EP 46 DI 10.1016/j.drugalcdep.2014.12.011 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CC7DF UT WOS:000350527200005 PM 25604321 ER PT J AU Dawson, DA Goldstein, RB Saha, TD Grant, BF AF Dawson, Deborah A. Goldstein, Rise B. Saha, Tulshi D. Grant, Bridget F. TI Changes in alcohol consumption: United States, 2001-2002 to 2012-2013 SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Alcohol consumption; Drinking trends; Heavy episodic drinking ID HEAVY DRINKING; US; DENSITY; ADULTS; TRENDS AB Background: Documenting changes in alcohol consumption is critical for assessing future health service and alcohol treatment needs, evaluating efforts to modify drinking behavior and understanding the impact of shifting demographics and social norms. For the period since 2000, published data on drinking trends have been scarce and inconsistent. Methods: Using data from two large, nationally representative surveys of U.S. adults (2001-2002 and 2012-2013) that contained virtually identical questions on consumption, we assessed differences by period in the prevalence of drinking, volume of intake, frequency of drinking and prevalence of >= monthly heavy episodic drinking (HED) and determined whether changes in consumption were consistent across beverage types and in population subgroups. Results: Between 2001-2002 and 2012-2013, the prevalence of drinking increased, as did volume and frequency of drinking and prevalence of >= monthly HED among drinkers. Increases were greater for women than men for all measures and smaller among the formerly married for consumption among drinkers. The increase in overall drinking prevalence was magnified among all race-ethnic minorities, whereas the increase in >= monthly HED was magnified only among Blacks (all relative to Whites). Conclusions: Our findings are suggestive of a "wetter" drinking climate in 2012-2013 than in 2001-2002, indicating the need for continued and expanded efforts to prevent chronic and episodic heavy alcohol consumption. Given the across-the-board increases in alcohol consumption in recent years, policy efforts that address drinking at the population level are supported, even if specific drinking behaviors and subgroups of drinkers are additionally targeted for individualized approaches. Published by Elsevier Ireland Ltd. C1 [Dawson, Deborah A.] Kelly Govt Serv, Bethesda, MD 20852 USA. [Dawson, Deborah A.; Goldstein, Rise B.; Saha, Tulshi D.; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. RP Goldstein, RB (reprint author), NIAAA, LEB, 5635 Fishers Lane,MSC 9304, Bethesda, MD 20892 USA. EM goldster@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism; National Institutes of Health; U.S. Department of Health and Human Services; Intramural Program of the National Institutes of Health FX The surveys on which this paper is based, the National Epidemiologic Surveys on Alcohol and Related Conditions (Wave 1 NESARC and NESARC-III), were sponsored by the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, U.S. Department of Health and Human Services, with supplemental support from the National Institute on Drug Abuse. This research was supported in part by the Intramural Program of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism. The NIH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 23 TC 18 Z9 18 U1 2 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAR 1 PY 2015 VL 148 BP 56 EP 61 DI 10.1016/j.drugalcdep.2014.12.016 PG 6 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CC7DF UT WOS:000350527200007 PM 25620731 ER PT J AU Marshall, BDL Operario, D Bryant, KJ Cook, RL Edelman, EJ Gaither, JR Gordon, AJ Kahler, CW Maisto, SA McGinnis, KA van den Berg, JJ Zaller, ND Justice, AC Fiellin, DA AF Marshall, Brandon D. L. Operario, Don Bryant, Kendall J. Cook, Robert L. Edelman, E. Jennifer Gaither, Julie R. Gordon, Adam J. Kahler, Christopher W. Maisto, Stephen A. McGinnis, Kathleen A. van den Berg, Jacob J. Zaller, Nickolas D. Justice, Amy C. Fiellin, David A. TI Drinking trajectories among HIV-infected men who have sex with men: A cohort study of United States veterans SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Alcohol; Men who have sex with men; Veterans; HIV infection; Trajectories; Trends ID POSTTRAUMATIC-STRESS-DISORDER; ALCOHOL-RELATED PROBLEMS; VA HEALTH-CARE; SUBSTANCE USE; POSITIVE MEN; AUDIT-C; SUPPORTED EMPLOYMENT; INVERSE PROBABILITY; MINORITY VETERANS; BINGE DRINKING AB Background: Although high rates of alcohol consumption and related problems have been observed among HIV-infected men who have sex with men (MSM), little is known about the long-term patterns of and factors associated with hazardous alcohol use in this population. We sought to identify alcohol use trajectories and correlates of hazardous alcohol use among HIV-infected MSM. Methods: Sexually active, HIV-infected MSM participating in the Veterans Aging Cohort Study were eligible for inclusion. Participants were recruited from VA infectious disease clinics in Atlanta, Baltimore, New York, Houston, Los Angeles, Pittsburgh, and Washington, DC. Data from annual self-reported assessments and group-based trajectory models were used to identify distinct alcohol use trajectories over an eight-year study period (2002-2010). We then used generalized estimate equations (GEE) to examine longitudinal correlates of hazardous alcohol use (defined as an AUDIT-C score >= 4). Results: Among 1065 participants, the mean age was 45.5 (SD = 9.2) and 606 (58.2%) were African American. Baseline hazardous alcohol use was reported by 309 (29.3%). Group-based trajectory modeling revealed a distinct group (12.5% of the sample) with consistently hazardous alcohol use, characterized by a mean AUDIT-C score of >5 at every time point. In a GEE-based multivariable model, hazardous alcohol use was associated with earning <$6000 annually, having an alcohol-related diagnosis, using cannabis, and using cocaine. Conclusions: More than 1 in 10 HIV-infected MSM US veterans reported consistent, long-term hazardous alcohol use. Financial insecurity and concurrent substance use were predictors of consistently hazardous alcohol use, and may be modifiable targets for intervention. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Marshall, Brandon D. L.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Operario, Don; Kahler, Christopher W.; van den Berg, Jacob J.] Brown Univ, Sch Publ Hlth, Dept Behav & Social Sci, Providence, RI 02912 USA. [Bryant, Kendall J.] NIAAA, Rockville, MD 20852 USA. [Cook, Robert L.] Univ Florida, Dept Epidemiol, Gainesville, FL 32610 USA. [Edelman, E. Jennifer; Justice, Amy C.; Fiellin, David A.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. [Edelman, E. Jennifer; Gaither, Julie R.; Justice, Amy C.; Fiellin, David A.] Yale Univ, Ctr Interdisciplinary Res AIDS, New Haven, CT 06510 USA. [Gaither, Julie R.] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT 06520 USA. [Gordon, Adam J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15206 USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. [Kahler, Christopher W.] Brown Univ, Sch Publ Hlth, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Kahler, Christopher W.] Brown Univ, Sch Publ Hlth, Alcohol Res Ctr HIV ARCH, Providence, RI 02912 USA. [Maisto, Stephen A.] Syracuse Univ, Dept Psychol, Syracuse, NY 13244 USA. [Maisto, Stephen A.] Syracuse VA Med Ctr, VA Ctr Integrated Healthcare, Syracuse, NY 13210 USA. [McGinnis, Kathleen A.; Justice, Amy C.] VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. [van den Berg, Jacob J.] Miriam Hosp, Div Infect Dis, Providence, RI 02906 USA. [Zaller, Nickolas D.] Univ Arkansas Med Sci, Dept Hlth Behav & Hlth Educ, Little Rock, AR 72205 USA. RP Marshall, BDL (reprint author), Brown Univ, Sch Publ Hlth, Dept Epidemiol, 121 South Main St,Box G-S-121-2, Providence, RI 02912 USA. EM brandon_marshall@brown.edu OI Fiellin, David/0000-0002-4006-010X; Justice, Amy/0000-0003-0139-5502 FU National Institute on Alcohol Abuse and Alcoholism [U24-AA022000, U10-AA013566, U01-AA020795, U01-AA020790, U24-AA020794, P01-AA019072]; National Institute of Allergy and Infectious Diseases [P30-AI042853]; NIAAA [U24-AA022002, K05-AA16928]; National Institute on Drug Abuse [F31-DA035567] FX This work was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (NIAAA: U24-AA022000, U10-AA013566, U01-AA020795, U01-AA020790, U24-AA020794, U10-AA013566, and P01-AA019072), the National Institute of Allergy and Infectious Diseases (P30-AI042853), and in kind by the U.S. Department of Veterans Affairs. Dr. Robert Cook is supported by the NIAAA (U24-AA022002). Ms. Julie Gaither is supported by the National Institute on Drug Abuse (F31-DA035567). Dr. Stephen Maisto is supported by the NIAAA (K05-AA16928). Dr. E. Jennifer Edelman is a Yale-Drug Abuse, Addiction, and HIV Research Scholar (K12-DA033312). The sponsors had no role in the study design; the collection, analysis and interpretation of data; the writing of the report; and in the decision to submit the article for publication. NR 65 TC 3 Z9 3 U1 4 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAR 1 PY 2015 VL 148 BP 69 EP 76 DI 10.1016/j.drugalcdep.2014.12.023 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CC7DF UT WOS:000350527200009 PM 25596785 ER PT J AU Vsevolozhskaya, OA Greenwood, MC Powell, SL Zaykin, DV AF Vsevolozhskaya, Olga A. Greenwood, Mark C. Powell, Scott L. Zaykin, Dmitri V. TI Resampling-based multiple comparison procedure with application to point-wise testing with functional data SO ENVIRONMENTAL AND ECOLOGICAL STATISTICS LA English DT Article DE Combining correlated p values; Functional data analysis; Multiple testing; Permutation procedure ID COMBINING P-VALUES; CASE-CONTROL ASSOCIATION; TRUNCATED PRODUCT; SCANS AB In this paper we describe a coherent multiple testing procedure for correlated test statistics such as are encountered in functional linear models. The procedure makes use of two different value combination methods: the Fisher combination method and the idak correction-based method. values for Fisher's and idak's test statistics are estimated through resampling to cope with the correlated tests. Building upon these two existing combination methods, we propose the smallest value as a new test statistic for each hypothesis. The closure principle is incorporated along with the new test statistic to obtain the overall value and appropriately adjust the individual values. Furthermore, a shortcut version for the proposed procedure is detailed, so that individual adjustments can be obtained even for a large number of tests. The motivation for developing the procedure comes from a problem of point-wise inference with smooth functional data where tests at neighboring points are related. A simulation study verifies that the methodology performs well in this setting. We illustrate the proposed method with data from a study on the aerial detection of the spectral effect of below ground carbon dioxide leakage on vegetation stress via spectral responses. C1 [Vsevolozhskaya, Olga A.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Greenwood, Mark C.] Montana State Univ, Dept Math Sci, Bozeman, MT 59717 USA. [Powell, Scott L.] Montana State Univ, Dept Land Resources & Environm Sci, Bozeman, MT 59717 USA. [Zaykin, Dmitri V.] NIEHS, Natl Inst Hlth, Bethesda, NC 27709 USA. RP Vsevolozhskaya, OA (reprint author), Michigan State Univ, Dept Epidemiol & Biostat, 909 Fee Rd, E Lansing, MI 48824 USA. EM vsevoloz@msu.edu FU U.S. Department of Energy; National Energy Technology Laboratory [DE-FE0000397]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX This work was carried out within the ZERT II project, with the support of the U.S. Department of Energy and the National Energy Technology Laboratory, under Award No. DE-FE0000397. However, any opinions, findings, conclusions, or recommendations expressed herein are those of the author(s) and do not necessarily reflect the views of the DOE. D.V.Z. was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 32 TC 1 Z9 1 U1 1 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1352-8505 EI 1573-3009 J9 ENVIRON ECOL STAT JI Environ. Ecol. Stat. PD MAR PY 2015 VL 22 IS 1 SI SI BP 45 EP 59 DI 10.1007/s10651-014-0282-7 PG 15 WC Environmental Sciences; Mathematics, Interdisciplinary Applications; Statistics & Probability SC Environmental Sciences & Ecology; Mathematics GA CC6RN UT WOS:000350495200005 PM 27695383 ER PT J AU ten Broeke, T van Spriel, A Sun, P Leusen, J AF ten Broeke, Toine van Spriel, Annemiek Sun, Peter Leusen, Jeanette TI Meeting Report on Immunoreceptors 2014 SO FASEB JOURNAL LA English DT Editorial Material ID T-CELLS; IN-VIVO; RECEPTORS; MHC; POLARIZATION; RECOGNITION; SPECIFICITY; ACTIVATION; PROMOTES; MEDIATE C1 [ten Broeke, Toine; Leusen, Jeanette] Univ Med Ctr Utrecht, Immunotherapy Grp, Lab Translat Immunol, NL-3584 CX Utrecht, Netherlands. [van Spriel, Annemiek] Radboud Univ Nijmegen, Med Ctr, Dept Tumor Immunol, Radboud Inst Mol Life Sci, NL-6525 ED Nijmegen, Netherlands. [Sun, Peter] NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. RP Leusen, J (reprint author), UMC Utrecht, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands. EM j.h.w.leusen@umcutrecht.nl RI van Spriel, Annemiek/O-1639-2013; OI Leusen, Jeanette/0000-0003-4982-6914 NR 30 TC 0 Z9 0 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD MAR PY 2015 VL 29 IS 3 BP 740 EP 744 DI 10.1096/fj.15-0302ufm PG 5 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA CC8QK UT WOS:000350633000002 PM 25733692 ER PT J AU Dillenburg-Pilla, P Patel, V Mikelis, CM Zarate-Blades, CR Doci, CL Amornphimoltham, P Wang, ZY Martin, D Leelahavanichkul, K Dorsam, RT Masedunskas, A Weigert, R Molinolo, AA Gutkind, JS AF Dillenburg-Pilla, Patricia Patel, Vyomesh Mikelis, Constantinos M. Zarate-Blades, Carlos Rodrigo Doci, Colleen L. Amornphimoltham, Panomwat Wang, Zhiyong Martin, Daniel Leelahavanichkul, Kantima Dorsam, Robert T. Masedunskas, Andrius Weigert, Roberto Molinolo, Alfredo A. Gutkind, J. Silvio TI SDF-1/CXCL12 induces directional cell migration and spontaneous metastasis via a CXCR4/G alpha i/mTORC1 axis SO FASEB JOURNAL LA English DT Article DE mTOR; rapamycin; cancer; lymphangiogenesis; chemotaxis ID MAMMALIAN TARGET; BREAST-CANCER; RAPID MOBILIZATION; CHEMOKINE RECEPTORS; HEMATOPOIETIC STEM; KINASE INHIBITOR; CXCR4 ANTAGONIST; PROGENITOR CELLS; KAPOSIS-SARCOMA; MTOR INHIBITION AB Multiple human malignancies rely on C-X-C motif chemokine receptor type 4 (CXCR4) and its ligand, SDF-1/CXCL12 (stroma cell-derived factor 1/C-X-C motif chemokine 12), to metastasize. CXCR4 inhibitors promote the mobilization of bone marrow stem cells, limiting their clinical application for metastasis prevention. We investigated the CXCR4-initiated signaling circuitry to identify new potential therapeutic targets. We used HeLa human cancer cells expressing high levels of CXCR4 endogenously. We found that CXCL12 promotes their migration in Boyden chamber assays and single cell tracking. CXCL12 activated mTOR (mechanistic target of rapamycin) potently in a pertussis-sensitive fashion. Inhibition of mTOR complex 1 (mTORC1) by rapamycin [drug concentration causing 50% inhibition (IC50) = 5 nM] and mTORC1/mTORC2 by Torin2 (IC50 = 6 nM), or by knocking downkey mTORC1/2 components, Raptor and Rictor, respectively, decreased directional cell migration toward CXCL12. We developed a CXCR4-mediated spontaneous metastasis model by implanting HeLa cells in the tongue of SCID-NOD mice, in which 80% of the animals develop lymph node metastasis. It is surprising that mTORC1 disruption by Raptor knockdown was sufficient to reduce tumor growth by 60% and spontaneous metastasis by 72%, which were nearly abolished by rapamycin. In contrast, disrupting mTORC2 had no effect in tumor growth or metastasis compared with control short hairpin RNAs. These data suggest that mTORC1 may represent a suitable therapeutic target in human malignancies using CXCR4 for their metastatic spread. C1 [Dillenburg-Pilla, Patricia; Patel, Vyomesh; Mikelis, Constantinos M.; Doci, Colleen L.; Amornphimoltham, Panomwat; Wang, Zhiyong; Martin, Daniel; Leelahavanichkul, Kantima; Dorsam, Robert T.; Masedunskas, Andrius; Weigert, Roberto; Molinolo, Alfredo A.; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Research, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. [Zarate-Blades, Carlos Rodrigo] US Natl Inst Hlth, Immunol Lab, NEI, Bethesda, MD USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Research, NIH, 30 Convent Dr,Bldg 30,Room 320, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Zarate-Blades, Carlos/C-9663-2015 OI Zarate-Blades, Carlos/0000-0002-7728-7869 FU Intramural Research Program of U.S. National Institutes of Health, National Institute of Dental and Craniofacial Research FX This research was supported by the Intramural Research Program of U.S. National Institutes of Health, National Institute of Dental and Craniofacial Research. The authors apologize to all of their colleagues for not citing some of their original studies as a result of space limitations. NR 54 TC 13 Z9 13 U1 1 U2 16 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD MAR PY 2015 VL 29 IS 3 BP 1056 EP 1068 DI 10.1096/fj.14-260083 PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA CC8QK UT WOS:000350633000029 PM 25466898 ER PT J AU Wolf, G Yang, P Fuchtbauer, AC Fuichtbauer, EM Silva, AM Park, C Wu, WR Nielsen, AL Pedersen, FS Macfarlan, TS AF Wolf, Gernot Yang, Peng Fuchtbauer, Annette C. Fuichtbauer, Ernst-Martin Silva, Andreia M. Park, Chungoo Wu, Warren Nielsen, Anders L. Pedersen, Finn S. Macfarlan, Todd S. TI The KRAB zinc finger protein ZFP809 is required to initiate epigenetic silencing of endogenous retroviruses SO GENES & DEVELOPMENT LA English DT Article DE endogenous retrovirus; epigenetic silencing; retrovirus restriction factors; KRAB zinc finger proteins ID EMBRYONIC STEM-CELLS; MURINE LEUKEMIA-VIRUS; DNA METHYLATION; CHROMATIN MODIFICATIONS; HEMATOPOIETIC STEM; PROGENITOR CELLS; GENE-EXPRESSION; CARCINOMA-CELLS; MUROID RODENTS; BINDING AB Retroviruses have been invading mammalian germlines for millions of years, accumulating in the form of endogenous retroviruses (ERVs) that account for nearly one-tenth of the mouse and human genomes. ERVs are epigenetically silenced during development, yet the cellular factors recognizing ERVs in a sequence-specific manner remain elusive. Here we demonstrate that ZFP809, a member of the Kruppel-associated box zinc finger protein (KRAB-ZFP) family, initiates the silencing of ERVs in a sequence-specific manner via recruitment of heterochromatin-inducing complexes. ZFP809 knockout mice display highly elevated levels of ZFP809-targeted ERVs in somatic tissues. ERV reactivation is accompanied by an epigenetic shift from repressive to active histone modifications but only slight destabilization of DNA methylation. Importantly, using conditional alleles and rescue experiments, we demonstrate that ZFP809 is required to initiate ERV silencing during embryonic development but becomes largely dispensable in somatic tissues. Finally, we show that the DNA-binding specificity of ZFP809 is evolutionarily conserved in the Muroidea superfamily of rodents and predates the endogenization of retroviruses presently targeted by ZFP809 in Mus musculus. In sum, these data provide compelling evidence that ZFP809 evolved to recognize foreign DNA and establish histone modification-based epigenetic silencing of ERVs. C1 [Wolf, Gernot; Yang, Peng; Park, Chungoo; Wu, Warren; Macfarlan, Todd S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Wolf, Gernot; Fuchtbauer, Annette C.; Fuichtbauer, Ernst-Martin; Silva, Andreia M.; Pedersen, Finn S.] Aarhus Univ, Dept Mol Biol & Genet, DK-8000 Aarhus C, Denmark. [Nielsen, Anders L.] Aarhus Univ, Dept Biomed, DK-8000 Aarhus C, Denmark. RP Macfarlan, TS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM todd.macfarlan@nih.gov RI Nielsen, Anders Lade/Q-9604-2016; OI Nielsen, Anders Lade/0000-0003-4372-9961; Macfarlan, Todd/0000-0003-2495-9809 FU Danish Council for Independent Research/Natural Sciences; Lundbeck Foundation; Danish Genetically Modified Animal Resource (DAGMAR); Danish Research School for Gene Medicine; National Institutes of Health [U01HG004085]; CSD (CHORI [Children's Hospital Oakland Research Institute]; Wellcome Trust Sanger Institute; University of California at Davis) Consortium [U01HG004080]; Eunice Kennedy Shriver National Institute of Child Health and Human Development DIR [HD008933] FX We thank members of the Macfarlan and Pedersen laboratories for useful discussions, and Lone Hojgaard, Alex Grinberg, Shery Rails, Lisa Williams-Simons, and Victoria Carter for technical assistance. We thank the Molecular Genomics Laboratory of the Eunice Kennedy Shriver National Institute of Child Health and Human Development for SOLiD sequencing and computational support (Steve Coon, Alan Pang, and James then). We thank Daniel Wolf and Stephen Goff for ZFP809 antibodies, and Yoichi Shinkai and Matthew Lorincz for Setdb1 conditional knockout MEFs. This work was supported by The Danish Council for Independent Research/Natural Sciences, The Lundbeck Foundation, The Danish Genetically Modified Animal Resource (DAGMAR), and the Danish Research School for Gene Medicine. National Institutes of Health grants to Velocigene at Regeneron, Inc. (U01HG004085) and the CSD (CHORI [Children's Hospital Oakland Research Institute], the Wellcome Trust Sanger Institute, and the University of California at Davis) Consortium (U01HG004080) funded the generation of gene-targeted ESCs in the ROMP Program, which are archived and distributed by the ROMP Repository at the University of California at Davis and CHORI (U42RR024244). T.S.M. is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development DIR grant HD008933. NR 61 TC 19 Z9 19 U1 2 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD MAR 1 PY 2015 VL 29 IS 5 BP 538 EP 554 DI 10.1101/gad.252767.114 PG 17 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA CD6HV UT WOS:000351191100008 PM 25737282 ER PT J AU Eckhoff, PA Tatem, AJ AF Eckhoff, Philip A. Tatem, Andrew J. TI Digital methods in epidemiology can transform disease control SO INTERNATIONAL HEALTH LA English DT Editorial Material DE Epidemiology; Genomics; GPS; Modelling; Phylogeography C1 [Eckhoff, Philip A.] Inst Dis Modeling, Bellevue, WA 98005 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden. RP Eckhoff, PA (reprint author), Inst Dis Modeling, Bellevue, WA 98005 USA. EM peckhoff@intven.com FU Global Good Fund in Bellevue, WA, USA; NIH/NIAID [U19AI089674]; Bill & Melinda Gates Foundation [OPP1106427, 1032350]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX PAE is supported by the Global Good Fund in Bellevue, WA, USA. AJT is supported by funding from NIH/NIAID [U19AI089674], the Bill & Melinda Gates Foundation [OPP1106427, 1032350] and the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 14 TC 1 Z9 1 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1876-3413 EI 1876-3405 J9 INT HEALTH JI Int. Health PD MAR PY 2015 VL 7 IS 2 SI SI BP 77 EP 78 DI 10.1093/inthealth/ihv013 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CC8QC UT WOS:000350632200001 PM 25733554 ER PT J AU Bharti, N Lu, X Bengtsson, L Wetter, E Tatem, AJ AF Bharti, Nita Lu, Xin Bengtsson, Linus Wetter, Erik Tatem, Andrew J. TI Remotely measuring populations during a crisis by overlaying two data sources SO INTERNATIONAL HEALTH LA English DT Article DE Crisis; Mobile phones; Movement; Population density; Satellite imagery ID NIGHTTIME LIGHTS IMAGERY; HUMAN MOBILITY; PREDICTABILITY; DYNAMICS; NIGER AB Background: Societal instability and crises can cause rapid, large-scale movements. These movements are poorly understood and difficult to measure but strongly impact health. Data on these movements are important for planning response efforts. We retrospectively analyzed movement patterns surrounding a 2010 humanitarian crisis caused by internal political conflict in Cote d'Ivoire using two different methods. Methods: We used two remote measures, nighttime lights satellite imagery and anonymized mobile phone call detail records, to assess average population sizes as well as dynamic population changes. These data sources detect movements across different spatial and temporal scales. Results: The two data sources showed strong agreement in average measures of population sizes. Because the spatiotemporal resolution of the data sources differed, we were able to obtain measurements on long- and short-term dynamic elements of populations at different points throughout the crisis. Conclusions: Using complementary, remote data sources to measure movement shows promise for future use in humanitarian crises. We conclude with challenges of remotely measuring movement and provide suggestions for future research and methodological developments. C1 [Bharti, Nita] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16801 USA. [Lu, Xin] Natl Univ Def Technol, Coll Informat Syst & Management, Changsha 410073, Hunan, Peoples R China. [Lu, Xin; Bengtsson, Linus; Wetter, Erik; Tatem, Andrew J.] Flowminder Fdn, S-17177 Stockholm, Sweden. [Lu, Xin; Bengtsson, Linus] Karolinska Inst, Dept Publ Hlth Sci, S-17177 Stockholm, Sweden. [Lu, Xin] Chinese Ctr Dis Control & Prevent, Key Lab Surveillance & Early Warning Infect Dis, Div Infect Dis, Beijing 102206, Peoples R China. [Wetter, Erik] Stockholm Sch Econ, Dept Management & Org, S-11383 Stockholm, Sweden. [Tatem, Andrew J.] Univ Southampton, Geog & Environm, Southampton SO17 1BJ, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Bharti, N (reprint author), Stanford Univ, Woods Inst Environm, Stanford, CA 94305 USA. EM nita@psu.edu FU Branco Weiss-The Society in Science; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NIH/NIAID [U19AI089674]; Bill & Melinda Gates Foundation [49446, 1032350]; National Natural Science Foundation of China [71301165] FX This work was supported by Branco Weiss-The Society in Science to NB. This work was also supported by RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; the Fogarty International Center, National Institutes of Health; NIH/NIAID [U19AI089674] and the Bill & Melinda Gates Foundation [#49446 and #1032350] to AT. This work was also supported by the National Natural Science Foundation of China [71301165] to XL. NR 51 TC 4 Z9 4 U1 0 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1876-3413 EI 1876-3405 J9 INT HEALTH JI Int. Health PD MAR PY 2015 VL 7 IS 2 SI SI BP 90 EP 98 DI 10.1093/inthealth/ihv003 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CC8QC UT WOS:000350632200005 PM 25733558 ER PT J AU Sedda, L Tatem, AJ Morley, DW Atkinson, PM Wardrop, NA Pezzulo, C Sorichetta, A Kuleszo, J Rogerse, DJ AF Sedda, Luigi Tatem, Andrew J. Morley, David W. Atkinson, Peter M. Wardrop, Nicola A. Pezzulo, Carla Sorichetta, Alessandro Kuleszo, Joanna Rogerse, David J. TI Poverty, health and satellite-derived vegetation indices: their inter-spatial relationship in West Africa SO INTERNATIONAL HEALTH LA English DT Article DE Child mortality; Geostatistics; Multidimensional Poverty Index; Normalized difference vegetation index; Nutrition; Poverty ID WATER MANAGEMENT; COUNTRIES; LEVEL; MODEL AB Background: Previous analyses have shown the individual correlations between poverty, health and satellite-derived vegetation indices such as the normalized difference vegetation index (NDVI). However, generally these analyses did not explore the statistical interconnections between poverty, health outcomes and NDVI. Methods: In this research aspatial methods (principal component analysis) and spatial models (variography, factorial kriging and cokriging) were applied to investigate the correlations and spatial relationships between intensity of poverty, health (expressed as child mortality and undernutrition), and NDVI for a large area of West Africa. Results: This research showed that the intensity of poverty (and hence child mortality and nutrition) varies inversely with NDVI. From the spatial point-of-view, similarities in the spatial variation of intensity of poverty and NDVI were found. Conclusions: These results highlight the utility of satellite-based metrics for poverty models including health and ecological components and, in general for large scale analysis, estimation and optimisation of multidimensional poverty metrics. However, it also stresses the need for further studies on the causes of the association between NDVI, health and poverty. Once these relationships are confirmed and better understood, the presence of this ecological component in poverty metrics has the potential to facilitate the analysis of the impacts of climate change on the rural populations afflicted by poverty and child mortality. C1 [Sedda, Luigi; Tatem, Andrew J.; Atkinson, Peter M.; Wardrop, Nicola A.; Pezzulo, Carla; Sorichetta, Alessandro; Kuleszo, Joanna] Univ Southampton, Geog & Environm, Southampton SO17 1BJ, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Flowminder Fdn, S-17177 Stockholm, Sweden. [Morley, David W.] MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, Sch Publ Hlth, Fac Med, London W2 1PG, England. [Rogerse, David J.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. RP Sedda, L (reprint author), Univ Southampton, Geog & Environm, Southampton SO17 1BJ, Hants, England. EM L.Sedda@soton.ac.uk OI Wardrop, Nicola/0000-0001-7401-4841 FU NIH/NIAID [U19AI089674]; Bill & Melinda Gates Foundation [OPP1106427, 1032350]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NERC ESPA DDDAC project [NE-J001570-1]; Medical Research Council [MR/J012343/1] FX This work was supported by NIH/NIAID [U19AI089674], the Bill & Melinda Gates Foundation [OPP1106427, 1032350], and the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health to AJT; by the NERC ESPA DDDAC project [NE-J001570-1] to PMA; and by Medical Research Council [project MR/J012343/1] to NAW and PMA. This work forms part of the WorldPop Project (www.worldpop.org.uk) and the Flowminder Foundation (www.flowminder.org). 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 4 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1876-3413 EI 1876-3405 J9 INT HEALTH JI Int. Health PD MAR PY 2015 VL 7 IS 2 SI SI BP 99 EP 106 DI 10.1093/inthealth/ihv005 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CC8QC UT WOS:000350632200006 PM 25733559 ER PT J AU Brady, OJ Godfray, HCJ Tatem, AJ Gething, PW Cohen, JM McKenzie, FE Perkins, TA Reiner, RC Tusting, LS Scott, TW Lindsay, SW Hay, SI Smith, DL AF Brady, Oliver J. Godfray, H. Charles J. Tatem, Andrew J. Gething, Peter W. Cohen, Justin M. McKenzie, F. Ellis Perkins, T. Alex Reiner, Robert C., Jr. Tusting, Lucy S. Scott, Thomas W. Lindsay, Steven W. Hay, Simon I. Smith, David L. TI Adult vector control, mosquito ecology and malaria transmission SO INTERNATIONAL HEALTH LA English DT Article DE Larval control; Malaria control policy; Micro-simulation models; Plasmodium falciparum; Plasmodium vivax; Vectorial capacity ID DYNAMICS; MODEL AB Background: Standard advice regarding vector control is to prefer interventions that reduce the lifespan of adult mosquitoes. The basis for this advice is a decades-old sensitivity analysis of 'vectorial capacity', a concept relevant for most malaria transmission models and based solely on adult mosquito population dynamics. Recent advances in micro-simulation models offer an opportunity to expand the theory of vectorial capacity to include both adult and juvenile mosquito stages in the model. Methods: In this study we revisit arguments about transmission and its sensitivity to mosquito bionomic parameters using an elasticity analysis of developed formulations of vectorial capacity. Results: We show that reducing adult survival has effects on both adult and juvenile population size, which are significant for transmission and not accounted for in traditional formulations of vectorial capacity. The elasticity of these effects is dependent on various mosquito population parameters, which we explore. Overall, control is most sensitive to methods that affect adult mosquito mortality rates, followed by blood feeding frequency, human blood feeding habit, and lastly, to adult mosquito population density. Conclusions: These results emphasise more strongly than ever the sensitivity of transmission to adult mosquito mortality, but also suggest the high potential of combinations of interventions including larval source management. This must be done with caution, however, as policy requires a more careful consideration of costs, operational difficulties and policy goals in relation to baseline transmission. C1 [Brady, Oliver J.; Gething, Peter W.; Hay, Simon I.; Smith, David L.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England. [Godfray, H. Charles J.] Univ Oxford, Dept Zool, Oxford, England. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.; McKenzie, F. Ellis; Perkins, T. Alex; Reiner, Robert C., Jr.; Scott, Thomas W.; Hay, Simon I.; Smith, David L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden. [Cohen, Justin M.] Clinton Hlth Access Initiat, Boston, MA USA. [Perkins, T. Alex] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. [Perkins, T. Alex] Univ Notre Dame, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Perkins, T. Alex; Reiner, Robert C., Jr.; Scott, Thomas W.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Reiner, Robert C., Jr.] Indiana Univ, Dept Epidemiol & Biostat, Bloomington, IN USA. [Tusting, Lucy S.] London Sch Hyg & Trop Med, Dept Dis Control, London WC1, England. [Lindsay, Steven W.] Univ Durham, Sch Biol Sci, Durham, England. [Smith, David L.] Sanaria Inst Global Hlth & Trop Med, Rockville, MD USA. RP Brady, OJ (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, S Parks Rd, Oxford, England. EM oliver.brady@zoo.ox.ac.uk RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Cohen, Justin/0000-0003-4481-6784; Tusting, Lucy/0000-0002-6897-8625; Gething, Peter/0000-0001-6759-5449; Brady, Oliver/0000-0002-3235-2129 FU Bill & Melinda Gates Foundation [OPP1110495, OPP1119467, OPP1106427, 1032350, OPP1053338]; National Institutes of Health/National Institute of Allergy and Infectious Diseases [U19AI089674]; British Biological Sciences Research Council (BBSRC) studentship; Wellcome Trust [095066]; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Leverhulme Centre for Integrative Research in Agriculture and Health; Foundation for the National Institutes of Health through the Vector-Based Control of Transmission: Discovery Research program of the Grand Challenges in Global Health initiative FX DLS, RCR and TAP received funding from the Bill & Melinda Gates Foundation [#OPP1110495]. DLS, AJT and SWL received funding from National Institutes of Health/National Institute of Allergy and Infectious Diseases [U19AI089674]. OJB is funded by a British Biological Sciences Research Council (BBSRC) studentship. SIH is funded by a Senior Research Fellowship from the Wellcome Trust [#095066] and supported by the Bill & Melinda Gates Foundation [#OPP1119467]. DLS, AJT, RCR, TAP, SWL, TWS and SIH acknowledge funding from the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. AJT is supported by funding from the Bill & Melinda Gates Foundation [OPP1106427, 1032350]. SWL acknowledges funding from the Bill & Melinda Gates Foundation [#OPP1053338]. LST acknowledges funding from the Leverhulme Centre for Integrative Research in Agriculture and Health. HCJG is supported by the Foundation for the National Institutes of Health through the Vector-Based Control of Transmission: Discovery Research program of the Grand Challenges in Global Health initiative. NR 33 TC 7 Z9 7 U1 1 U2 23 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1876-3413 EI 1876-3405 J9 INT HEALTH JI Int. Health PD MAR PY 2015 VL 7 IS 2 SI SI BP 121 EP 129 DI 10.1093/inthealth/ihv010 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CC8QC UT WOS:000350632200009 PM 25733562 ER PT J AU Hellings, JA Reed, G Cain, SE Zhou, XH Barth, FX Aman, MG Palaguachi, GI Mikhnev, D Teng, RJ Andridge, R Logan, M Butler, MG Han, JC AF Hellings, Jessica A. Reed, Gregory Cain, Sharon E. Zhou, Xinghua Barth, Francis X. Aman, Michael G. Palaguachi, Gladys I. Mikhnev, Dmytro Teng, Rujia Andridge, Rebecca Logan, Marilyn Butler, Merlin G. Han, Joan C. TI Loxapine Add-on for Adolescents and Adults with Autism Spectrum Disorders and Irritability SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID NEUROTROPHIC FACTOR BDNF; PERVASIVE DEVELOPMENTAL DISORDERS; MENTAL-RETARDATION; CHILDREN; SCHIZOPHRENIA; RISPERIDONE; BEHAVIOR; INDIVIDUALS; MULTICENTER; MEDICATIONS AB Objectives: Our clinical experience with low dose loxapine (5-15 mg/day) suggests promising efficacy and safety for irritability in autism spectrum disorders (ASD). We studied low dose loxapine prospectively in adolescents and adults with ASD and irritability. Additionally, we measured loxapine and metabolite concentrations, and brain-derived neurotrophic factor (BDNF) as a biomarker of neuromodulation. Methods: We performed a 12 week open trial of add-on loxapine in subjects, ages 13-65 years, diagnosed with ASD, and Aberrant Behavior Checklist-Irritability (ABC-I) subscale scores >14. Loxapine was dosed flexibly up to 15 mg daily, starting with 5 mg on alternate days. From weeks 1 to 6, other psychoactive medications were tapered if possible; from weeks 6 to 12, all medication doses were held stable. The primary outcome was the Clinical Global Impressions-Improvement subscale (CGI-I), ratings of Much Improved or Very Much Improved. Secondary outcomes were the ABC-I, Repetitive Behavior Scale-Revised, and Schalock Quality of Life scale. Serum BDNF and loxapine and metabolite concentrations were assayed. BDNF rs6265 was genotyped. Results: Sixteen subjects were enrolled; 12 completed all visits. Median age was 18 years (range 13-39). Median final loxapine dose was 7.5 mg/day (2.5-15). All 14 subjects (100%) with data at week 12 were rated as Much Improved on CGI-I at 12 weeks. Mean change on ABC-I at 12 weeks was -31%, p=0.01. Mean body mass index (BMI)-Z decreased between weeks 6 and 12, p=0.03. Side effects were minimal, and prolactin elevation occurred in only one subject. BDNF concentrations measured in 11 subjects increased significantly (p=0.04). Subjects with AG genotype for BDNF rs6265 required a lower dose of loxapine at study end, but had similar behavioral and BDNF concentration changes as the GG genotype. Conclusions: Low dose loxapine shows promise as a repurposed drug for irritability in ASD. Loxapine effects on BDNF warrant further study. C1 [Hellings, Jessica A.; Aman, Michael G.] Ohio State Univ, Nisonger Ctr, Columbus, OH 43210 USA. [Hellings, Jessica A.; Reed, Gregory; Cain, Sharon E.; Zhou, Xinghua; Barth, Francis X.; Logan, Marilyn; Butler, Merlin G.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Palaguachi, Gladys I.; Mikhnev, Dmytro; Teng, Rujia; Han, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Andridge, Rebecca] Ohio State Univ, Coll Publ Hlth, Columbus, OH 43210 USA. [Han, Joan C.] Univ Tennessee, Ctr Hlth Sci, Le Bonheur Childrens Hosp, Memphis, TN 38163 USA. RP Hellings, JA (reprint author), Ohio State Univ, Nisonger Ctr, Neurodev Psychiat Study Program, 395 McCampbell Hall,1581 Dodd Dr, Columbus, OH 43210 USA. EM Jessica.Hellings@osumc.edu RI Andridge, Rebecca/C-8457-2012 OI Andridge, Rebecca/0000-0001-9991-9647 FU Autism Speaks-Autism Treatment Network (ATN); Forest; National Institute of Mental Health (NIMH); Shire; Sunovion; Eunice Kennedy Shriver National Institute of Child Health and Human Development [1ZIAHD008898] FX Dr. Hellings is an investigator for studies funded by Autism Speaks-Autism Treatment Network (ATN), Forest, the National Institute of Mental Health (NIMH), Shire, and Sunovion; has been an advisor to Abbott Laboratories; and a consultant to Ferring Pharmaceuticals. Dr. Aman has received research contracts, consulted with, or served on advisory boards of Biomarin Pharmaceuticals, Bristol- Myers Squibb, CogState, Confluence Pharmaceutica, Coronado Bioscience, Forest Research, Hoffman LaRoche, Johnson & Johnson, Novartis, Pfizer, Prophase LLC, and Supernus Pharmaceutica. Dr. Cain has a conflict of interest for Shire. At the time of the research, Dr. Han was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1ZIAHD008898). No other authors have conflicts of interest. NR 47 TC 1 Z9 1 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD MAR 1 PY 2015 VL 25 IS 2 BP 150 EP 159 DI 10.1089/cap.2014.0003 PG 10 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA CD4MT UT WOS:000351057800008 PM 25782098 ER PT J AU Kopp, JB AF Kopp, Jeffrey B. TI Loss of Kruppel-like factor 6 cripples podocyte mitochondrial function SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID MESSENGER-RNA EXPRESSION; NEPHROTIC SYNDROME; PPAR-GAMMA; CELLS; DOXORUBICIN; METABOLISM; TRANSITION; DYNAMICS; DISEASES; GENOME AB Kruppel-like factors (KLFs) are zinc finger transcription factors that share homology in three C-terminal zinc finger domains. KLF family members are expressed in most if not all tissues and have diverse roles in organismal development and cell differentiation, function, and death. The glomerular podocyte is particularly sensitive to mitochondrial dysfunction, as seen in various genetic disorders manifesting as progressive glomerulosclerosis. In this issue of the JCI, Mallipattu and coworkers show that KLF6 expression is reduced in mouse and human glomerular disease. Podocyte-specific deletion of Klf6 expression in mice leads to mitochondrial dysfunction and apoptosis, followed by glomerulosclerosis. This is the first demonstration that defective transcriptional regulation of nuclear-encoded mitochondrial genes can result in experimental glomerular disease. C1 [Kopp, Jeffrey B.] NIDDK, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIH, 10 Ctr Dr,3N116, Bethesda, MD 20192 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU Intramural NIH HHS NR 33 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2015 VL 125 IS 3 BP 968 EP 971 DI 10.1172/JCI80280 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CC8KF UT WOS:000350616500012 PM 25689255 ER PT J AU Quinn, KM Zak, DE Costa, A Yamamoto, A Kastenmuller, K Hill, BJ Lynn, GM Darrah, PA Lindsay, RWB Wang, LS Cheng, C Nicosia, A Folgori, A Colloca, S Cortese, R Gostick, E Price, DA Gall, JGD Roederer, M Aderem, A Seder, RA AF Quinn, Kylie M. Zak, Daniel E. Costa, Andreia Yamamoto, Ayako Kastenmuller, Kathrin Hill, Brenna J. Lynn, Geoffrey M. Darrah, Patricia A. Lindsay, Ross W. B. Wang, Lingshu Cheng, Cheng Nicosia, Alfredo Folgori, Antonella Colloca, Stefano Cortese, Riccardo Gostick, Emma Price, David A. Gall, Jason G. D. Roederer, Mario Aderem, Alan Seder, Robert A. TI Antigen expression determines adenoviral vaccine potency independent of IFN and STING signaling SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID T-CELL RESPONSES; I INTERFERON; DENDRITIC CELLS; IMMUNE-RESPONSES; CHIMPANZEE ADENOVIRUS; INNATE IMMUNITY; TRANSGENE PRODUCT; CLONAL EXPANSION; MEMORY FORMATION; SYSTEMS BIOLOGY AB Recombinant adenoviral vectors (rAds) are lead vaccine candidates for protection against a variety of pathogens, including Ebola, HIV, tuberculosis, and malaria, due to their ability to potently induce T cell immunity in humans. However, the ability to induce protective cellular immunity varies among rAds. Here, we assessed the mechanisms that control the potency of CD8 T cell responses in murine models following vaccination with human-, chimpanzee-, and simian-derived rAds encoding SIV-Gag antigen (Ag). After rAd vaccination, we quantified Ag expression and performed expression profiling of innate immune response genes in the draining lymph node. Human-derived rAd5 and chimpanzee-derived chAd3 were the most potent rAds and induced high and persistent Ag expression with low innate gene activation, while less potent rAds induced less Ag expression and robustly induced innate immunity genes that were primarily associated with IFN signaling. Abrogation of type I IFN or stimulator of IFN genes (STING) signaling increased Ag expression and accelerated CD8 T cell response kinetics but did not alter memory responses or protection. These findings reveal that the magnitude of rAd-induced memory CD8 T cell immune responses correlates with Ag expression but is independent of IFN and STING and provide criteria for optimizing protective CD8 T cell immunity with rAd vaccines. C1 [Quinn, Kylie M.; Costa, Andreia; Yamamoto, Ayako; Kastenmuller, Kathrin; Hill, Brenna J.; Lynn, Geoffrey M.; Darrah, Patricia A.; Lindsay, Ross W. B.; Wang, Lingshu; Cheng, Cheng; Gall, Jason G. D.; Roederer, Mario; Seder, Robert A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Zak, Daniel E.; Aderem, Alan] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Nicosia, Alfredo; Folgori, Antonella; Colloca, Stefano] ReiThera Srl, Rome, Italy. [Nicosia, Alfredo] CEINGE Biotecnol Avanzate, Naples, Italy. [Nicosia, Alfredo] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy. [Cortese, Riccardo] Keires AG, Basel, Switzerland. [Gostick, Emma; Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF10 3AX, S Glam, Wales. RP Seder, RA (reprint author), NIAID, Vaccine Res Ctr, NIH, Bldg 40,Room 3512, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Foundation for the NIH; Bill & Melinda Gates Foundation [OPP1039775] FX We thank Pamela Troisch from the micro array core at the Institute for Systems Biology (Seattle, Washington, USA) for processing of the microarrays. This research has been supported in part by a grant from the Foundation for the NIH, with support from the Collaboration for AIDS Vaccine Discovery award (OPP1039775) from the Bill & Melinda Gates Foundation. D.A. Price is a Wellcome Trust Senior Investigator. NR 67 TC 19 Z9 19 U1 3 U2 23 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2015 VL 125 IS 3 BP 1129 EP 1146 DI 10.1172/JCI78280 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CC8KF UT WOS:000350616500028 PM 25642773 ER PT J AU Saleh, MA McMaster, WG Wu, J Norlander, AE Funt, SA Thabet, SR Kirabo, A Xiao, L Chen, W Itani, HA Michell, D Huan, TX Zhang, YH Takaki, S Titze, J Levy, D Harrison, DG Madhur, MS AF Saleh, Mohamed A. McMaster, William G. Wu, Jing Norlander, Allison E. Funt, Samuel A. Thabet, Salim R. Kirabo, Annet Xiao, Liang Chen, Wei Itani, Hana A. Michell, Danielle Huan, Tianxiao Zhang, Yahua Takaki, Satoshi Titze, Jens Levy, Daniel Harrison, David G. Madhur, Meena S. TI Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID II-INDUCED HYPERTENSION; VASCULAR DYSFUNCTION; PRESSURE; CELLS; TISSUES; DAMAGE; SCAN AB The lymphocyte adaptor protein LNK (also known as SH2B3) is primarily expressed in hematopoietic and endothelial cells, where it functions as a negative regulator of cytokine signaling and cell proliferation. Single-nucleotide polymorphisms in the gene encoding LNK are associated with autoimmune and cardiovascular disorders; however, it is not known how LNK contributes to hypertension. Here, we determined that loss of LNK exacerbates angiotensin II-induced (Ang II-induced) hypertension and the associated renal and vascular dysfunction. At baseline, kidneys from Lnk(-/-) mice exhibited greater levels of inflammation, oxidative stress, and glomerular injury compared with WT animals, and these parameters were further exacerbated by Ang H infusion. Aortas from Lnk(-/-) mice exhibited enhanced inflammation, reduced nitric oxide levels, and impaired endothelial-dependent relaxation. Bone marrow transplantation studies demonstrated that loss of LNK in hematopoietic cells is primarily responsible for the observed renal and vascular inflammation and predisposition to hypertension. Ang II infusion increased IFN-gamma-producing CD8(+) T cells in the spleen and kidneys of Lnk(-/-) mice compared with WT mice. Moreover, IFN-gamma deficiency resulted in blunted hypertension in response to Ang II infusion. Together, these results suggest that LNK is a potential therapeutic target for hypertension and its associated renal and vascular sequela. C1 [Saleh, Mohamed A.; McMaster, William G.; Wu, Jing; Norlander, Allison E.; Thabet, Salim R.; Kirabo, Annet; Xiao, Liang; Chen, Wei; Itani, Hana A.; Michell, Danielle; Zhang, Yahua; Titze, Jens; Harrison, David G.; Madhur, Meena S.] Vanderbilt Univ, Dept Med, Div Clin Pharmacol, Nashville, TN USA. [Saleh, Mohamed A.] Mansoura Univ, Fac Pharm, Dept Pharmacol & Toxicol, Mansoura, Egypt. [Funt, Samuel A.; Thabet, Salim R.] Emory Univ, Dept Med, Atlanta, GA 30322 USA. [Funt, Samuel A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Huan, Tianxiao; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Huan, Tianxiao; Levy, Daniel] NHLBI, Populat Sci Branch, Bethesda, MD 20892 USA. [Huan, Tianxiao; Levy, Daniel] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Takaki, Satoshi] Natl Ctr Global Hlth & Med, Res Inst, Dept Immune Regulat, Tokyo, Japan. RP Madhur, MS (reprint author), 2215 Garland Ave,P415D Med Res Bldg 4, Nashville, TN 37232 USA. EM meena.madhur@vanderbilt.edu OI Wu, Jing/0000-0003-2013-2863; Saleh, Mohamed/0000-0002-6405-6033 FU American Heart Association [14POST20420025]; NIH [HL105294, HL039006, P01 HL58000, GM015431, K08HL121671]; Vanderbilt Physician Scientist Development Award FX This work was supported by American Heart Association fellowship 14POST20420025 (to M.A. Saleh), NIH grants HL105294 and HL039006, Program Project grants P01 HL58000 and GM015431 (to D.G. Harrison), and NIH grant K08HL121671 and a Vanderbilt Physician Scientist Development Award (to M.S. Madhur). NR 24 TC 34 Z9 34 U1 0 U2 7 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2015 VL 125 IS 3 BP 1189 EP 1202 DI 10.1172/JCI76327 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CC8KF UT WOS:000350616500032 PM 25664851 ER PT J AU Dobenecker, MW Kim, JK Marcello, J Fang, TC Prinjha, R Bosselut, R Tarakhovsky, A AF Dobenecker, Marc-Werner Kim, Jong Kyong Marcello, Jonas Fang, Terry C. Prinjha, Rab Bosselut, Remy Tarakhovsky, Alexander TI Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID EMBRYONIC STEM-CELLS; MOLECULAR-MECHANISMS; NKT CELLS; LINEAGE; DEMETHYLASES; EFFECTOR; IMMUNITY; MOUSE; DIFFERENTIATION; EOMESODERMIN AB The fidelity of T cell immunity depends greatly on coupling T cell receptor signaling with specific T cell effector functions. Here, we describe a chromatin-based mechanism that enables integration of TCR specificity into definite T cell lineage commitment. Using natural killer T cells (iNKT cell) as a model of a T cell subset that differentiates in response to specific TCR signaling, we identified a key role of histone H3 lysine 27 trimethylation (H3K27me3) in coupling iNKT cell TCR specificity with the generation of iNKT cells. We found that the Zbtb16/PLZF gene promoter that drives iNKT cell differentiation possesses a bivalent chromatin state characterized by the simultaneous presence of negative and positive H3K27me3 and H3K4me3 modifications. Depletion of H3K27me3 at the Zbtb16/PLZF promoter leads to uncoupling of iNKT cell development from TCR specificity and is associated with accumulation of iNKT-like CD4(+) cells that express a non-iNKT cell specific T cell repertoire. In turn, stabilization of H3K27me3 leads to a drastic reduction of the iNKT cell population. Our data suggest that H3K27me3 levels at the bivalent Zbtb16/PLZF gene define a threshold enabling precise coupling of TCR specificity to lineage commitment. C1 [Dobenecker, Marc-Werner; Marcello, Jonas; Fang, Terry C.; Tarakhovsky, Alexander] Rockefeller Univ, Lab Immune Cell Epigenet & Signaling, New York, NY 10065 USA. [Kim, Jong Kyong; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Prinjha, Rab] GlaxoSmithKline R&D, Med Res Ctr, Epinova DPU, Immunoinflammat Therapy Area, Stevenage SG1 2NY, Herts, England. RP Dobenecker, MW (reprint author), Rockefeller Univ, Lab Immune Cell Epigenet & Signaling, New York, NY 10065 USA. EM dobenem@rockefeller.edu; tarakho@rockefeller.edu FU NIGMS NIH HHS [R01 GM112811] NR 48 TC 11 Z9 11 U1 1 U2 6 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 PY 2015 VL 212 IS 3 BP 297 EP 306 DI 10.1084/jem.20141499 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CD1ZN UT WOS:000350873300004 PM 25687282 ER PT J AU Padilla, LM Hansen, G Ruginski, IT Kramer, HS Thompson, WB Creem-Regehr, SH AF Padilla, Lace M. Hansen, Grace Ruginski, Ian T. Kramer, Heidi S. Thompson, William B. Creem-Regehr, Sarah H. TI The Influence of Different Graphical Displays on Nonexpert Decision Making Under Uncertainty SO JOURNAL OF EXPERIMENTAL PSYCHOLOGY-APPLIED LA English DT Article DE uncertainty; decision making; visualization ID VISUALIZING UNCERTAINTY; CONFIDENCE-INTERVALS; ERROR BARS; INFORMATION; FORECASTS; USER AB Understanding how people interpret and use visually presented uncertainty data is an important yet seldom studied aspect of data visualization applications. Current approaches in visualization often display uncertainty as an additional data attribute without a well-defined context. Our goal was to test whether different graphical displays (glyphs) would influence a decision about which of 2 weather forecasts was a more accurate predictor of an uncertain temperature forecast value. We used a statistical inference task based on fictional univariate normal distributions, each characterized by a mean and standard deviation. Participants viewed 1 of 5 different glyph types representing 2 weather forecast distributions. Three of these used variations in spatial encoding to communicate the distributions and the other 2 used nonspatial encoding (brightness or color). Four distribution pairs were created with different relative standard deviations (uncertainty of the forecasts). We found that there was a difference in how decisions were made with spatial versus nonspatial glyphs, but no difference among the spatial glyphs themselves. Furthermore, the effect of different glyph types changed as a function of the variability of the distributions. The results are discussed in the context of how visualizations might improve decision making under uncertainty. C1 [Padilla, Lace M.; Ruginski, Ian T.; Kramer, Heidi S.; Creem-Regehr, Sarah H.] Univ Utah, Dept Psychol, Salt Lake City, UT 84112 USA. [Hansen, Grace] NIH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. [Thompson, William B.] Univ Utah, Sch Comp, Salt Lake City, UT 84112 USA. RP Creem-Regehr, SH (reprint author), Univ Utah, Dept Psychol, 380 S 1530 East,Room 502, Salt Lake City, UT 84112 USA. EM sarah.creem@psych.utah.edu FU National Science Foundation [1212806] FX This research is based upon work supported by the National Science Foundation under Grant 1212806. We thank Mary Hegarty and Robert M. Kirby for comments on the manuscript. NR 34 TC 4 Z9 4 U1 2 U2 11 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1076-898X EI 1939-2192 J9 J EXP PSYCHOL-APPL JI J. Exp. Psychol.-Appl. PD MAR PY 2015 VL 21 IS 1 BP 37 EP 46 DI 10.1037/xap0000037 PG 10 WC Psychology, Applied SC Psychology GA CD3NO UT WOS:000350985700003 PM 25437794 ER PT J AU Taber, JM Leyva, B Persoskie, A AF Taber, Jennifer M. Leyva, Bryan Persoskie, Alexander TI Why do People Avoid Medical Care? A Qualitative Study Using National Data SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE Medical care avoidance; Health care barriers; Health care utilization; Qualitative ID HEALTH-CARE; BREAST-CANCER; COMMUNICATION INTERVENTIONS; TRENDS SURVEY; OLDER-ADULTS; INFORMATION; ACCESS; BARRIERS; PATIENT; DELAY AB Many studies have examined barriers to health care utilization, with the majority conducted in the context of specific populations and diseases. Less research has focused on why people avoid seeking medical care, even when they suspect they should go. The purpose of the study was to present a comprehensive description and conceptual categorization of reasons people avoid medical care. Data were collected as part of the 2008 Health Information National Trends Survey, a cross-sectional national survey. Participant-generated reasons for avoiding medical care were provided by 1,369 participants (40% male; M (age) =48.9; 75.1% non-Hispanic white, 7.4% non-Hispanic black, 8.5% Hispanic or Latino/a). Participants first indicated their level of agreement with three specific reasons for avoiding medical care; these data are reported elsewhere. We report responses to a follow-up question in which participants identified other reasons they avoid seeking medical care. Reasons were coded using a general inductive approach. Three main categories of reasons for avoiding medical care were identified. First, over one-third of participants (33.3% of 1,369) reported unfavorable evaluations of seeking medical care, such as factors related to physicians, health care organizations, and affective concerns. Second, a subset of participants reported low perceived need to seek medical care (12.2%), often because they expected their illness or symptoms to improve over time (4.0%). Third, many participants reported traditional barriers to medical care (58.4%), such as high cost (24.1%), no health insurance (8.3%), and time constraints (15.6%). We developed a conceptual model of medical care avoidance based on these results. Reasons for avoiding medical care were nuanced and highly varied. Understanding why people do not make it through the clinic door is critical to extending the reach and effectiveness of patient care, and these data point to new directions for research and strategies to reduce avoidance. C1 [Taber, Jennifer M.; Leyva, Bryan; Persoskie, Alexander] NCI, NIH, Bethesda, MD 20892 USA. RP Taber, JM (reprint author), NCI, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM Jennifer.taber@nih.gov NR 57 TC 4 Z9 4 U1 2 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAR PY 2015 VL 30 IS 3 BP 290 EP 297 DI 10.1007/s11606-014-3089-1 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CD2EG UT WOS:000350886500008 PM 25387439 ER PT J AU Liese, AD Krebs-Smith, SM Subar, AF George, SM Harmon, BE Neuhouser, ML Boushey, CJ Schap, TE Reedy, J AF Liese, Angela D. Krebs-Smith, Susan M. Subar, Amy F. George, Stephanie M. Harmon, Brook E. Neuhouser, Marian L. Boushey, Carol J. Schap, TusaRebecca E. Reedy, Jill TI The Dietary Patterns Methods Project: Synthesis of Findings across Cohorts and Relevance to Dietary Guidance SO JOURNAL OF NUTRITION LA English DT Article DE dietary guidance; dietary quality; dietary indices; mortality; cohorts; epidemiology ID HEALTHY EATING INDEX; FOOD-FREQUENCY QUESTIONNAIRE; MAJOR CHRONIC DISEASE; GUIDELINES-FOR-AMERICANS; RETIRED-PERSONS DIET; ALL-CAUSE MORTALITY; MEDITERRANEAN DIET; MEASUREMENT ERROR; WOMENS HEALTH; CARDIOVASCULAR-DISEASE AB The Dietary Patterns Methods Project (DPMP) was initiated in 2012 to strengthen research evidence on dietary indices, dietary patterns, and health for upcoming revisions of the Dietary Guidelines for Americans, given that the lack of consistent methodology has impeded development of consistent and reliable conclusions. DPMP investigators developed research questions and a standardized approach to index-based dietary analysis. This article presents a synthesis of findings across the cohorts. Standardized analyses were conducted in the NIH-AARP Diet and Health Study, the Multiethnic Cohort, and the Women's Health Initiative Observational Study (WHI-OS). Healthy Eating Index 2010, Alternative Healthy Eating Index 2010 (AHEI-2010), alternate Mediterranean Diet, and Dietary Approaches to Stop Hypertension (DASH) scores were examined across cohorts for correlations between pairs of indices; concordant classifications into index score quintiles; associations with all-cause, cardiovascular disease (CVD), and cancer mortality with the use of Cox proportional hazards models; and dietary intake of foods and nutrients corresponding to index quintiles. Across all cohorts in women and men, there was a high degree of correlation and consistent classifications between index pairs. Higher diet quality (top quintile) was significantly and consistently associated with an 11-28% reduced risk of death due to all causes, CVD, and cancer compared with the lowest quintile, independent of known confounders. This was true for all diet index-mortality associations, with the exception of AHEI-2010 and cancer mortality in WHI-OS women. In all cohorts, survival benefit was greater with a higher-quality diet, and relatively small intake differences distinguished the index quintiles. The reductions in mortality risk started at relatively lower levels of diet quality. Higher scores on each of the indices, signifying higher diet quality, were associated with marked reductions in mortality. Thus, the DPMP findings suggest that all 4 indices capture the essential components of a healthy diet. C1 [Liese, Angela D.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Liese, Angela D.] Univ S Carolina, Arnold Sch Publ Hlth, Ctr Res Nutr & Hlth Dispar, Columbia, SC 29208 USA. [Schap, TusaRebecca E.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Krebs-Smith, Susan M.; Subar, Amy F.; George, Stephanie M.; Reedy, Jill] NCI, Div Canc Control & Populat Sci, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Harmon, Brook E.; Boushey, Carol J.] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Liese, AD (reprint author), Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. EM liese@sc.edu FU NIH/National Cancer Institute (NCI) [4R37 CA 54281]; NCI [HHSN261201200423P]; NIH/NCI [P30 CA071789]; National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services [HHSN268201100046C, HHSN 268201100001C, HHSN268201100002C, HHSN2682011 00003C, HHSN26820110004C, HHSN271201100004C] FX Support for the Multiethnic Cohort comes from NIH/National Cancer Institute (NCI) 4R37 CA 54281, with additional support from the NCI (HHSN261201200423P) and NIH/NCI P30 CA071789. The Women's Health Initiative is funded by the National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN 268201100001C, HHSN268201100002C, HHSN2682011 00003C, HHSN26820110004C, and HHSN271201100004C. NR 50 TC 35 Z9 35 U1 5 U2 16 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD MAR PY 2015 VL 145 IS 3 BP 393 EP 402 DI 10.3945/jn.114.205336 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CC5RM UT WOS:000350420400005 PM 25733454 ER PT J AU Patel, SM Cobb, P Saydah, S Zhang, XP de Jesus, JM Cogswell, ME AF Patel, Sheena M. Cobb, Paul Saydah, Sharon Zhang, Xuanping de Jesus, Janet M. Cogswell, Mary E. TI Dietary Sodium Reduction Does Not Affect Circulating Glucose Concentrations in Fasting Children or Adults: Findings from a Systematic Review and Meta-Analysis SO JOURNAL OF NUTRITION LA English DT Article DE fasting glucose; insulin resistance; meta-analysis; sodium reduction; systematic review ID INSULIN SENSITIVITY; BLOOD-PRESSURE; SALT RESTRICTION; HYPERTENSIVE PATIENTS; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; DIABETES-MELLITUS; NACL RESTRICTION; PLASMA-GLUCOSE; SERUM-LIPIDS AB Background: Although evidence shows that reduced sodium intake lowers blood pressure, some studies suggest that sodium reduction may adversely affect insulin resistance and glucose tolerance. Objectives: The objectives were to assess the effects of sodium reduction on glucose tolerance, evaluate strengths and weaknesses of the relevant scientific literature, and provide direction for future research. Methods: We searched The Cochrane Library, MEDLINE, EMBASE, CINAHL, and Web of Science through August 2014. Both randomized and nonrandomized intervention trialswere included in ourmeta-analyses. The effects of sodium reduction on glucose tolerance were evaluated in 37 articles, but because of a lack of comparable data, 8 trials were excluded from the meta-analyses. Results: Participants were 10-79 y old, either primarily healthy or with hypertension. In meta-analyses of 20 randomized, crossover trials (n = 504 participants) and 9 nonrandomized crossover trials (n = 337), circulating glucose concentrations of fasting participants were not affected by reduction in sodium intake. In contrast, in meta-analyses of 19 of the 20 randomized, crossover trials (n = 494), fasting insulin concentrations were 9.53 pmol/L higher (95% CI: 5.04, 14.02 pmol/L higher) with sodium reduction. In 9 nonrandomized trials (n = 337), fasting insulin did not differ with reduced sodium intake. Results differed little when the analyses were restricted to studies with a low risk of bias and duration of >= 7 d. Conclusions: This meta-analysis revealed no evidence that, in trials with a short intervention and large reductions in sodium, circulating glucose concentrations differed between groups. Recommendations for future studies include extending intervention durations, ensuring comparability of groups at baseline through randomization, and assessing sodium intakes relevant to population sodium reduction. In addition, analyses on other metabolic variables were limited because of the number of trials reporting these outcomes and lack of consistency across measures, suggesting a need for comparable measures of glucose tolerance across studies. C1 [Patel, Sheena M.; Cobb, Paul; Cogswell, Mary E.] CDC, Div Heart Dis & Stroke Prevent, Atlanta, GA 30333 USA. [Saydah, Sharon; Zhang, Xuanping] CDC, Div Diabet Translat, Atlanta, GA 30333 USA. [Patel, Sheena M.] Oak Ridge Inst Sci & Educ, Atlanta, GA USA. [de Jesus, Janet M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Patel, SM (reprint author), CDC, Div Heart Dis & Stroke Prevent, Atlanta, GA 30333 USA. EM lsp7@cdc.gov FU Department of Energy; CDC FX Supported by appointment to the Research Participation Program (to SMP) for the CDC administered by the Oak Ridge Institute for Science and Education through an agreement between the Department of Energy and CDC. NR 59 TC 3 Z9 3 U1 5 U2 9 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD MAR PY 2015 VL 145 IS 3 BP 505 EP 513 DI 10.3945/jn.114.195982 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CC5RM UT WOS:000350420400019 PM 25733466 ER PT J AU Pfeiffer, CM Sternberg, MR Fazili, Z Yetley, EA Lacher, DA Bailey, RL Johnson, CL AF Pfeiffer, Christine M. Sternberg, Maya R. Fazili, Zia Yetley, Elizabeth A. Lacher, David A. Bailey, Regan L. Johnson, Clifford L. TI Unmetabolized Folic Acid Is Detected in Nearly All Serum Samples from US Children, Adolescents, and Adults SO JOURNAL OF NUTRITION LA English DT Article DE NHANES; serum folate; 5-methyltetrahydrofolate; unmetabolized folic acid; HPLC-tandem mass spectrometry ID TANDEM MASS-SPECTROMETRY; PRIMARY FOLATE FORMS; DIHYDROFOLATE-REDUCTASE; POSTMENOPAUSAL WOMEN; MICROBIOLOGIC ASSAY; UNITED-STATES; CORD BLOOD; NHANES; FORTIFICATION; PLASMA AB Background: Serum total folate consists mainly of 5-methyltetrahydrofolate (5-methylTHF). Unmetabolized folic acid (UMFA) may occur in persons consuming folic acid-fortified foods or supplements. Objectives: We describe serum 5-methylTHF and UMFA concentrations in the US population >= 1 y of age by demographic variables and fasting time, stratified by folic acid-containing dietary supplement use. We also evaluate factors associated with UMFA concentrations >1 nmol/L. Methods: Serum samples from the cross-sectional NHANES 2007-2008 were measured for 5-methylTHF (n = 2734) and UMFA (n = 2707) by HPLC-tandem mass spectrometry. Results: In supplement users compared with nonusers, we found significantly higher geometric mean concentrations of 5-methylTHF (48.4 and 30.7 nmol/L, respectively) and UMFA (1.54 and 0.794 nmol/L, respectively). UMFA concentrations were detectable (>0.3 nmol/L) in >95% of supplement users and nonusers, regardless of demographic or fasting characteristics; concentrations differed significantly by age and fasting time, but not by sex and race-ethnicity, both in supplement users and nonusers. The prevalence of UMFA concentrations >1 nmol/L was 33.2% overall and 21.0% in fasting (>= 8 h) adults (>= 20 y of age). Using multiple logistic regression analysis, UMFA concentrations >1 nmol/L were associated with being older, non-Hispanic black, nonfasting (<8 h), having smaller body surface area, higher total folic acid intake (diet and supplements), and higher red blood cell folate concentrations. In fasting adults, a decrease in the mean daily alcohol consumption was also associated with increased odds of UMFA concentrations >1 nmol/L. Conclusions: UMFA detection was nearly ubiquitous, and concentrations >1 nmol/L were largely but not entirely explained by fasting status and by total folic acid intake from diet and supplements. These new UMFA data in US persons >= 1 y of age provide much-needed information on this vitamer in a fortified population with relatively high use of dietary supplements. C1 [Pfeiffer, Christine M.; Sternberg, Maya R.; Fazili, Zia] CDC, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Yetley, Elizabeth A.; Bailey, Regan L.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Lacher, David A.; Johnson, Clifford L.] CDC, Natl Ctr Hlth Stat, Hyattsville, MD USA. RP Pfeiffer, CM (reprint author), CDC, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. EM CPfeiffer@cdc.gov NR 40 TC 15 Z9 15 U1 1 U2 7 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD MAR PY 2015 VL 145 IS 3 BP 520 EP 531 DI 10.3945/jn.114.201210 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CC5RM UT WOS:000350420400021 PM 25733468 ER PT J AU Bailey, RL Fakhouri, TH Park, Y Dwyer, JT Thomas, PR Gahche, JJ Miller, PE Dodd, KW Sempos, CT Murray, DM AF Bailey, Regan L. Fakhouri, Tala H. Park, Yikyung Dwyer, Johanna T. Thomas, Paul R. Gahche, Jaime J. Miller, Paige E. Dodd, Kevin W. Sempos, Christopher T. Murray, David M. TI Multivitamin-Mineral Use Is Associated with Reduced Risk of Cardiovascular Disease Mortality among Women in the United States SO JOURNAL OF NUTRITION LA English DT Article DE cardiovascular disease; dietary supplement; NHANES; mortality; multivitamin-mineral ID ANTIOXIDANT VITAMINS; DIETARY MAGNESIUM; CONTROLLED-TRIAL; HEALTH; CANCER; METAANALYSIS; PREVENTION; ADULTS; SUPPLEMENTS; PATTERNS AB Background: Multivitamin-mineral (MVM) products are the most commonly used supplements in the United States, followed by multivitamin (MV) products. Two randomized clinical trials (RCTs) did not show an effect of MVMs or MVs on cardiovascular disease (CVD) mortality; however, no clinical trial data are available for women with MVM supplement use and CVD mortality. Objective: The objective of this research was to examine the association between MVM and MV use and CVD-specific mortality among US adults without CVD. Methods: A nationally representative sample of adults from the restricted data NHANES III (1988-1994; n = 8678; age >= 40 y) were matched with mortality data reported by the National Death Index through 2011 to examine associations between MVM and MV use and CVD mortality by using Cox proportional hazards models, adjusting for multiple potential confounders. Results: We observed no significant association between CVD mortality and users of MVMs or MVs compared with nonusers; however, when users were classified by the reported length of time products were used, a significant association was found with MVM use of >3 y compared with nonusers (HR: 0.65; 95% CI: 0.49, 0.85). This finding was largely driven by the significant association among women (HR: 0.56; 95% CI: 0.37, 0.85) but not men (HR: 0.79; 95% CI: 0.44, 1.42). No significant association was observed for MV products and CVD mortality in fully adjusted models. Conclusions: In this nationally representative data set with detailed information on supplement use and CVD mortality data similar to 20 y later, we found an association between MVM use of >3 y and reduced CVD mortality risk for women when models controlled for age, race, education, body mass index, alcohol, aspirin use, serum lipids, blood pressure, and blood glucose/glycated hemoglobin. Our results are consistent with the 1 available RCT in men, indicating no relation with MVM use and CVD mortality. C1 [Bailey, Regan L.; Dwyer, Johanna T.; Thomas, Paul R.; Sempos, Christopher T.] NCI, Off Dietary Supplements, NIH, Bethesda, MD 20892 USA. [Murray, David M.] NCI, Off Dis Prevent, NIH, Bethesda, MD 20892 USA. [Park, Yikyung; Miller, Paige E.; Dodd, Kevin W.] NCI, Nihon Univ, Bethesda, MD 20892 USA. [Fakhouri, Tala H.; Gahche, Jaime J.] CDC, Natl Ctr Hlth Stat, Hyattsville, MD USA. RP Bailey, RL (reprint author), NCI, Off Dietary Supplements, NIH, Bethesda, MD 20892 USA. EM baileyr@mail.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769; Park, Yikyung/0000-0002-6281-489X FU NIH, Office of Dietary Supplements FX Supported by NIH, Office of Dietary Supplements. NR 30 TC 4 Z9 4 U1 0 U2 8 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD MAR PY 2015 VL 145 IS 3 BP 572 EP 578 DI 10.3945/jn.114.204743 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CC5RM UT WOS:000350420400027 PM 25733474 ER PT J AU Wood, WA Deal, AM Bennett, AV Mitchell, SA Abernethy, AP Basch, E Bailey, C Reeve, BB AF Wood, William A. Deal, Allison M. Bennett, Antonia V. Mitchell, Sandra A. Abernethy, Amy P. Basch, Ethan Bailey, Charlotte Reeve, Bryce B. TI Comparison of Seven-Day and Repeated 24-Hour Recall of Symptoms in the First 100 Days After Hematopoietic Cell Transplantation SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Hematopoietic stem cell transplantation; patient-reported outcomes; symptom burden; PRO-CTCAE ID PATIENT-REPORTED OUTCOMES; ALCOHOL-CONSUMPTION; PHYSICAL-ACTIVITY; DIARY; TOXICITY; INCONTINENCE; DESIGNS; HEALTH; PAIN AB Context. Patient-reported outcomes (PROs) provide a way to understand the effects of hematopoietic cell transplantation (HCT)-related stress on patients' lives. We previously reported that weekly collection of PROs is feasible. Objectives. Here, we report on the feasibility of daily patient-reported symptom collection and examine the relationship between daily vs. weekly symptom reporting over time. Methods. We analyzed data from 32 autologous and allogeneic HCT patients obtained until Day (D) +100. We used questions from the PRO version of the Common Terminology Criteria for Adverse Events to capture symptoms. Results. We found that overall rates of daily survey completion were moderate to high (range 67%-86%). The effect size of the difference between the maximum daily severity score and the weekly severity score ranged from 0.15 to 0.35, and the concordance correlation coefficient ranged from 0.513 to 0.834. Concordance of daily and weekly surveys was higher for maximum daily severity rating and mean daily severity rating than for minimum daily severity rating or most recent daily severity rating. Conclusion. We conclude that a seven-day recall period for symptom severity provides acceptable accuracy and precision in the first 100 days after HCT. Further studies to explore the utility of daily symptom reporting within specific clinical contexts may be warranted. (C) 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Wood, William A.; Bennett, Antonia V.; Basch, Ethan; Bailey, Charlotte; Reeve, Bryce B.] Univ N Carolina, Gillings Sch Global Publ Hlth, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Deal, Allison M.] Univ N Carolina, Gillings Sch Global Publ Hlth, Biostat Core Facil, Chapel Hill, NC 27599 USA. [Reeve, Bryce B.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, Chapel Hill, NC 27599 USA. [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Abernethy, Amy P.] Duke Univ, Med Ctr, Duke Canc Inst, Div Med Oncol, Durham, NC USA. RP Wood, WA (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Div Hematol & Oncol, Campus Box 7305,3rd Floor,Phys Off Bldg, Chapel Hill, NC 27599 USA. EM wawood@med.unc.edu OI Wood, William/0000-0001-7439-2543 FU National Institutes of Health [KL2TR000084] FX This work was supported by National Institutes of Health grant KL2TR000084. There are no conflicts of interest to report. NR 25 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD MAR PY 2015 VL 49 IS 3 BP 513 EP 520 DI 10.1016/j.jpainsymman.2014.06.011 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA CD2JN UT WOS:000350903800006 PM 25128608 ER PT J AU Kutney-Lee, A Brennan, CW Meterko, M Ersek, M AF Kutney-Lee, Ann Brennan, Caitlin W. Meterko, Mark Ersek, Mary TI Organization of Nursing and Quality of Care for Veterans at the End of Life SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Nursing care; palliative care; veterans; quality of care; end-of-life care; Department of Veterans Affairs ID PRACTICE ENVIRONMENT SCALE; CROSS-SECTIONAL SURVEYS; PATIENT SATISFACTION; FAMILY ASSESSMENT; HOSPITAL-CARE; UNITED-STATES; WORK INDEX; NATIONWIDE; OUTCOMES; PERSPECTIVES AB Context. The Veterans Health Administration (VA) has improved the quality of end-of-life (EOL) care over the past several years. Several structural and process variables are associated with better outcomes. Little is known, however, about the relationship between the organization of nursing care and EOL outcomes. Objectives. To examine the association between the organization of nursing care, including the nurse work environment and nurse staffing levels, and quality of EOL care in VA acute care facilities. Methods. Secondary analysis of linked data from the Bereaved Family Survey (BFS), electronic medical record, administrative data, and the VA Nursing Outcomes Database. The sample included 4908 veterans who died in one of 116 VA acute care facilities nationally between October 2010 and September 2011. Unadjusted and adjusted generalized estimating equations were used to examine associations between nursing and BFS outcomes. Results. BFS respondents were 17% more likely to give an excellent overall rating of the quality of EOL care received by the veteran in facilities with better nurse work environments (P <= 0.05). The nurse work environment also was a significant predictor of providers listening to concerns and providing desired treatments. Nurse staffing was significantly associated with an excellent overall rating, alerting of the family before death, attention to personal care needs, and the provision of emotional support after the patient's death. Conclusion. Improvement of the nurse work environment and nurse staffing in VA acute care facilities may result in enhanced quality of care received by hospitalized veterans at the EOL. (C) 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Kutney-Lee, Ann; Ersek, Mary] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Kutney-Lee, Ann; Ersek, Mary] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Brennan, Caitlin W.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Meterko, Mark] VA Boston Healthcare Syst, Boston, MA USA. [Meterko, Mark] Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Kutney-Lee, A (reprint author), Univ Penn, Sch Nursing, 418 Curie Blvd,Claire M Fagin Hall,Room 385, Philadelphia, PA 19104 USA. EM akutney@nursing.upenn.edu FU VA National Quality Scholars Program; NINR (Aiken, PI) [R01-NR-004513]; Robert Wood Johnson Foundation FX Dr. Brennan was supported by the VA National Quality Scholars Program. This work also was supported by NINR R01-NR-004513 (Aiken, PI) and the Robert Wood Johnson Foundation. The opinions expressed in this article are those of the authors alone and do not necessarily reflect the views of the Department of Veterans Affairs, National Institutes of Health, Public Health Service, Department of Health and Human Services, or the Robert Wood Johnson Foundation. The authors declare no conflicts of interest. NR 32 TC 3 Z9 3 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD MAR PY 2015 VL 49 IS 3 BP 570 EP 577 DI 10.1016/j.jpainsymman.2014.07.002 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA CD2JN UT WOS:000350903800013 PM 25116912 ER PT J AU Ambalavanan, N Cotten, CM Page, GP Carlo, WA Murray, JC Bhattacharya, S Mariani, TJ Cuna, AC Faye-Petersen, OM Kelly, D Higgins, RD AF Ambalavanan, Namasivayam Cotten, C. Michael Page, Grier P. Carlo, Waldemar A. Murray, Jeffrey C. Bhattacharya, Soumyaroop Mariani, Thomas J. Cuna, Alain C. Faye-Petersen, Ona M. Kelly, David Higgins, Rosemary D. CA Genomics & Cytokine Subcomm Eunice TI Integrated Genomic Analyses in Bronchopulmonary Dysplasia SO JOURNAL OF PEDIATRICS LA English DT Article ID WIDE ASSOCIATION; ALVEOLAR DEVELOPMENT; PRETERM INFANTS; LUNG GROWTH; GENES; SUSCEPTIBILITY; IDENTIFICATION; POLYMORPHISMS; POPULATION; MICRORNAS AB Objective To identify single-nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O-2 requirement at 36 weeks' postmenstrual age risk is strongly influenced by heritable factors. Study design A genome-wide scan was conducted on 1.2 million genotyped SNPs, and an additional 7 million imputed SNPs, using a DNA repository of extremely low birth weight infants. Genome-wide association and gene set analysis was performed for BPD or death, severe BPD or death, and severe BPD in survivors. Specific targets were validated via the use of gene expression in BPD lung tissue and in mouse models. Results Of 751 infants analyzed, 428 developed BPD or died. No SNPs achieved genome-wide significance (P < 10(-8)), although multiple SNPs in adenosine deaminase, CD44, and other genes were just below P < 10(-6). Of approximately 8000 pathways, 75 were significant at false discovery rate (FDR) < 0.1 and P < .001 for BPD/death, 95 for severe BPD/death, and 90 for severe BPD in survivors. The pathway with lowest FDR was miR-219 targets (P = 1.41E-08, FDR 9.5E-05) for BPD/death and phosphorous oxygen lyase activity (includes adenylate and guanylate cyclases) for both severe BPD/death (P = 5.68E-08, FDR 0.00019) and severe BPD in survivors (P = 3.91E-08, FDR 0.00013). Gene expression analysis confirmed significantly increased miR-219 and CD44 in BPD. Conclusions Pathway analyses confirmed involvement of known pathways of lung development and repair (CD44, phosphorus oxygen lyase activity) and indicated novel molecules and pathways (adenosine deaminase, targets of miR-219) involved in genetic predisposition to BPD. C1 [Ambalavanan, Namasivayam; Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL 35249 USA. [Cotten, C. Michael] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Page, Grier P.] RTI Int, Atlanta, GA USA. [Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Bhattacharya, Soumyaroop; Mariani, Thomas J.] Univ Rochester, Div Neonatol, Rochester, NY USA. [Bhattacharya, Soumyaroop; Mariani, Thomas J.] Univ Rochester, Program Pediat Mol & Personalized Med, Rochester, NY USA. [Cuna, Alain C.] Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA. [Faye-Petersen, Ona M.; Kelly, David] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35249 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Ambalavanan, N (reprint author), Univ Alabama Birmingham, Women & Infants Ctr, 176F Suite 9380,619 South 20th St, Birmingham, AL 35249 USA. EM nambalavanan@peds.uab.edu OI Bhattacharya, Soumyaroop/0000-0003-1140-7845; Ambalavanan, Namasivayam/0000-0003-0731-9092 FU National Institutes of Health (General Clinical Research Center) [M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587, UL1 RR24979]; National Institutes of Health (Eunice Kennedy Shriver NICHD) [U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34216, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40689, U10 HD53109] FX Supported by the National Institutes of Health (General Clinical Research Center M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587, UL1 RR24979) and the Eunice Kennedy Shriver NICHD (U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34216, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40689, U10 HD53109). J.M. received assistance for the GENEVA study from the National Human Genome Research Institute (U01 HG4423). Data collected at participating sites of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network were transmitted to RTI International, the data coordinating center for the network, which stored, managed, and analyzed the data for this study. The authors declare no conflicts of interest. NR 31 TC 20 Z9 22 U1 2 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD MAR PY 2015 VL 166 IS 3 BP 531 EP U803 DI 10.1016/j.jpeds.2014.09.052 PG 20 WC Pediatrics SC Pediatrics GA CC2ZL UT WOS:000350213600010 PM 25449221 ER PT J AU Lateef, TM Johann-Liang, R Kaulas, H Hasan, R Williams, K Caserta, V Nelson, KB AF Lateef, Tarannum M. Johann-Liang, Rosemary Kaulas, Himanshu Hasan, Rakibul Williams, Karen Caserta, Vito Nelson, Karin B. TI Seizures, Encephalopathy, and Vaccines: Experience in the National Vaccine Injury Compensation Program SO JOURNAL OF PEDIATRICS LA English DT Article ID SEVERE MYOCLONIC EPILEPSY; CHANNEL GENE SCN1A; DE-NOVO MUTATIONS; DRAVET-SYNDROME; PERTUSSIS VACCINATION; INFANCY; CHILDREN; IMMUNIZATION; INFLUENZA; POLICY AB Objectives To describe the demographic and clinical characteristics of children for whom claims were filed with the National Vaccine Injury Compensation Program (VICP) alleging seizure disorder and/or encephalopathy as a vaccine injury. Study design The National VICP within the Department of Health and Human Services compensates individuals who develop medical problems associated with a covered immunization. We retrospectively reviewed medical records of children younger than 2 years of age with seizures and/or encephalopathy allegedly caused by an immunization, where a claim was filed in the VICP between 1995 through 2005. Results The VICP retrieved 165 claims that had sufficient clinical information for review. Approximately 80% of these alleged an injury associated with whole-cell diphtheria, pertussis (whooping cough), and tetanus or tetanus, diphtheria toxoids, and acellular pertussis vaccine. Pre-existing seizures were found in 13% and abnormal findings on a neurologic examination before the alleged vaccine injury in 10%. A final diagnostic impression of seizure disorder was established in 69%, of whom 17% (28 patients) had myoclonic epilepsy, including possible severe myoclonic epilepsy of infancy. Specific conditions not caused by immunization, such as tuberous sclerosis and cerebral dysgenesis, were identified in 16% of subjects. Conclusion A significant number of children with alleged vaccine injury had pre-existing neurologic or neurodevelopmental abnormalities. Among those developing chronic epilepsy, many had clinical features suggesting genetically determined epilepsy. Future studies that include genotyping may allow more specific therapy and prognostication, and enhance public confidence in vaccination. C1 [Lateef, Tarannum M.; Kaulas, Himanshu; Hasan, Rakibul; Nelson, Karin B.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20012 USA. [Lateef, Tarannum M.; Kaulas, Himanshu; Hasan, Rakibul; Nelson, Karin B.] George Washington Univ, Sch Med, Washington, DC USA. [Johann-Liang, Rosemary; Williams, Karen; Caserta, Vito] Dept Hlth & Human Serv, Div Vaccine Injury Compensat, Rockville, MD USA. [Nelson, Karin B.] NINDS, NIH, Bethesda, MD 20892 USA. RP Lateef, TM (reprint author), Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20012 USA. EM tlateef@childrensnational.org NR 41 TC 3 Z9 3 U1 0 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD MAR PY 2015 VL 166 IS 3 BP 576 EP 581 DI 10.1016/j.jpeds.2014.10.054 PG 6 WC Pediatrics SC Pediatrics GA CC2ZL UT WOS:000350213600018 PM 25477158 ER PT J AU Zeller, MH Inge, TH Modi, AC Jenkins, TM Michalsky, MP Helmrath, M Courcoulas, A Harmon, CM Rofey, D Baughcum, A Austin, H Price, K Xanthakos, SA Brandt, ML Horlick, M Buncher, R AF Zeller, Meg H. Inge, Thomas H. Modi, Avani C. Jenkins, Todd M. Michalsky, Marc P. Helmrath, Michael Courcoulas, Anita Harmon, Carroll M. Rofey, Dana Baughcum, Amy Austin, Heather Price, Karin Xanthakos, Stavra A. Brandt, Mary L. Horlick, Mary Buncher, Ralph CA Teen Longitudinal Assessment Baria TI Severe Obesity and Comorbid Condition Impact on the Weight-Related Quality of Life of the Adolescent Patient SO JOURNAL OF PEDIATRICS LA English DT Article ID GASTRIC BYPASS-SURGERY; LONGITUDINAL ASSESSMENT; BARIATRIC SURGERY; EXTREME OBESITY; HEALTH; CHILDREN; OVERWEIGHT; YOUTH; PEDSQL(TM)-4.0; ASSOCIATIONS AB Objectives To assess links between comorbid health status, severe excess weight, and weight-related quality of life (WRQOL) in adolescents with severe obesity and undergoing weight-loss surgery (WLS) to inform clinical care. Study design Baseline (preoperative) data from Teen Longitudinal Assessment of Bariatric Surgery, a prospective multicenter observational study of 242 adolescents with severe obesity (Median(BMI) = 50.5 kg/m(2); Mean(age) = 17.1; 75.6% female; 71.9% white) undergoing WLS, were used to examine the impact of demographics, body mass index (BMI), presence/absence of 16 comorbid conditions, and a cumulative comorbidity load (CLoad) index on WRQOL scores (Impact of Weight on Quality of Life-Kids). Results WRQOL was significantly lower than reference samples of healthy weight, overweight, and obese samples. Of 16 comorbid conditions, the most prevalent were dyslipidemia (74.4%), chronic pain (58.3%), and obstructive sleep apnea (56.6%). Male subjects had a greater CLoad (P = .01) and BMI (P = .01), yet less impairment in total WRQOL (P < .01) than females. CLoad was a significant predictor of male WRQOL. For females, psychosocial (vs physical) comorbidities, BMI, and white race were significant predictors of WRQOL impairment. Less prevalent conditions (eg, stress urinary incontinence) also emerged as contributors to lower WRQOL. Conclusions WRQOL impairment is substantial for adolescents with severe obesity undergoing WLS, with predictors varying by sex. These patient-data highlight targets for education, support, and adjunctive care referrals before WLS. Furthermore, they provide a comprehensive empirical base for understanding heterogeneity in adolescent WRQOL outcomes after WLS, as weight and comorbidity profiles change over time. C1 [Zeller, Meg H.; Inge, Thomas H.; Modi, Avani C.; Jenkins, Todd M.; Helmrath, Michael; Xanthakos, Stavra A.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Michalsky, Marc P.; Baughcum, Amy] Nationwide Childrens Hosp, Columbus, OH USA. [Courcoulas, Anita; Rofey, Dana] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Harmon, Carroll M.; Austin, Heather] Univ Alabama Birmingham, Birmingham, AL USA. [Harmon, Carroll M.] SUNY Buffalo, Buffalo, NY 14260 USA. [Price, Karin; Brandt, Mary L.] Texas Childrens Hosp, Houston, TX 77030 USA. [Horlick, Mary] NIDDK, NIH, Bethesda, MD 20892 USA. [Buncher, Ralph] Univ Cincinnati, Cincinnati, OH USA. RP Zeller, MH (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Behav Med & Clin Psychol, 3333 Burnet Ave,MLC3015, Cincinnati, OH 45229 USA. EM meg.zeller@cchmc.org OI michalsky, marc/0000-0002-7119-3634 FU NCATS NIH HHS [UL1 TR000077, UL1 TR000077-04, UL1 TR001070, UL1 TR001425, UL1TR000005, UL1TR000165]; NCRR NIH HHS [UL1RR025755, M01-RR00188, UL1 RR024153]; NIDDK NIH HHS [P30 DK078392, P30 DK079626, U01 DK072493, U01DK072493, UM1 DK072493, UM1 DK095710, UM1DK072493, UM1DK095710] NR 44 TC 8 Z9 8 U1 2 U2 15 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD MAR PY 2015 VL 166 IS 3 BP 651 EP U962 DI 10.1016/j.jpeds.2014.11.022 PG 13 WC Pediatrics SC Pediatrics GA CC2ZL UT WOS:000350213600033 PM 25556022 ER PT J AU Krishnamurthy, U Neelavalli, J Mody, S Yeo, L Jella, PK Saleem, S Korzeniewski, SJ Cabrera, MD Ehterami, S Bahado-Singh, RO Katkuri, Y Haacke, EM Hernandez-Andrade, E Hassan, SS Romero, R AF Krishnamurthy, Uday Neelavalli, Jaladhar Mody, Swati Yeo, Lami Jella, Pavan K. Saleem, Sheena Korzeniewski, Steven J. Cabrera, Maria D. Ehterami, Shadi Bahado-Singh, Ray O. Katkuri, Yashwanth Haacke, Ewart M. Hernandez-Andrade, Edgar Hassan, Sonia S. Romero, Roberto TI MR imaging of the fetal brain at 1.5T and 3.0T field strengths: comparing specific absorption rate (SAR) and image quality SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE 3.0T; fetal imaging; fetal MRI; radio frequency energy; signal to noise; specific absorption rate ID MAGNETIC-RESONANCE-SPECTROSCOPY; CENTRAL-NERVOUS-SYSTEM; APPARENT DIFFUSION-COEFFICIENT; NMR RELAXATION-TIMES; HUMAN FETUS INUTERO; IN-UTERO; PRELIMINARY EXPERIENCE; 3 TESLA; 3-DIMENSIONAL ULTRASONOGRAPHY; TEMPERATURE ELEVATION AB Objectives: Our two objectives were to evaluate the feasibility of fetal brain magnetic resonance imaging (MRI) using a fast spin echo sequence at 3.0T field strength with low radio frequency (rf) energy deposition (as measured by specific absorption rate: SAR) and to compare image quality, tissue contrast and conspicuity between 1.5T and 3.0T MRI. Methods: T2 weighted images of the fetal brain at 1.5T were compared to similar data obtained in the same fetus using a modified sequence at 3.0T. Quantitative whole-body SAR and normalized image signal to noise ratio (SNR), a nominal scoring scheme based evaluation of diagnostic image quality, and tissue contrast and conspicuity for specific anatomical structures in the brain were compared between 1.5T and 3.0T. Results: Twelve pregnant women underwent both 1.5T and 3.0T MRI examinations. The image SNR was significantly higher (P=0.03) and whole-body SAR was significantly lower (P<0.0001) for images obtained at 3.0T compared to 1.5T. All cases at both field strengths were scored as having diagnostic image quality. Images from 3.0T MRI (compared to 1.5T) were equal (57%; 21/37) or superior (35%; 13/37) for tissue contrast and equal (61%; 20/33) or superior (33%, 11/33) for conspicuity. Conclusions: It is possible to obtain fetal brain images with higher resolution and better SNR at 3.0T with simultaneous reduction in SAR compared to 1.5T. Images of the fetal brain obtained at 3.0T demonstrated superior tissue contrast and conspicuity compared to 1.5T. C1 [Krishnamurthy, Uday; Neelavalli, Jaladhar; Mody, Swati; Jella, Pavan K.; Saleem, Sheena; Cabrera, Maria D.; Ehterami, Shadi; Katkuri, Yashwanth; Haacke, Ewart M.] Wayne State Univ, Sch Med, Dept Radiol, Detroit, MI 48201 USA. [Krishnamurthy, Uday; Neelavalli, Jaladhar; Haacke, Ewart M.] Wayne State Univ, Dept Biomed Engn, Detroit, MI 48201 USA. [Yeo, Lami; Korzeniewski, Steven J.; Hernandez-Andrade, Edgar; Hassan, Sonia S.; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Yeo, Lami; Korzeniewski, Steven J.; Hernandez-Andrade, Edgar; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Bahado-Singh, Ray O.] Oakland Univ, Dept Obstet & Gynecol, William Beaumont Sch Med, Rochester, MI 48063 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. RP Neelavalli, J (reprint author), Wayne State Univ, Sch Med, Dept Radiol, 4201 St Antoine, Detroit, MI 48201 USA. EM jneelava@med.wayne.edu OI Saleem, Sheena/0000-0002-6772-4981 FU National Institute of Child Health and Human Development [P3018205]; National Heart, Lung, and Blood Institute (NHLBI) [HSN275201300006C]; [1R42HL112580-01A1] FX Wayne State University's Perinatology Virtual Discovery Grant (made possible by W.K. Kellogg Foundation award), (Grant/Award Number: 'P3018205') National Institute of Child Health and Human Development, (Grant/Award Number: 'HSN275201300006C') National Heart, Lung, and Blood Institute (NHLBI), (Grant/Award Number: '1R42HL112580-01A1'). NR 121 TC 7 Z9 8 U1 2 U2 6 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD MAR PY 2015 VL 43 IS 2 BP 209 EP 220 DI 10.1515/jpm-2014-0268 PG 12 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA CC4QM UT WOS:000350338000012 PM 25324440 ER PT J AU Han, EY Ha, WH Jin, YW Bolch, WE Lee, C AF Han, Eun Young Ha, Wi-Ho Jin, Young-Woo Bolch, Wesley E. Lee, Choonsik TI Effective dose conversion coefficients for health care provider exposed to pediatric and adult victims in radiological dispersal device incident SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Article DE radiological dispersal device; effective dose; hybrid phantoms; Monte Carlo calculation ID HYBRID COMPUTATIONAL PHANTOMS AB After an incident of radiological dispersal devices (RDD), health care providers will be exposed to the contaminated patients in the extended medical treatments. Assessment of potential radiation dose to the health care providers will be crucial to minimize their health risk. In this study, we compiled a set of conversion coefficients (mSv MBq(-1) s(-1)) to readily estimate the effective dose from the time-integrated activity for the health care providers while they deal with internally contaminated patients at different ages. We selected Co-60, Ir-192, Am-241, Cs-137, and I-131 as the major radionuclides that may be used for RDD. We obtained the age-specific organ burdens after the inhalation of those radionuclides from the Dose and Risk Calculation Software (DCAL) program. A series of hybrid computational phantoms (1-, 5-, 10-, and 15 year-old, and adult males) were implemented in a general purpose Monte Carlo (MC) transport code, MCNPX v 2.7, to simulate an adult male health care provider exposed to contaminated patients at different ages. Two exposure scenarios were taken into account: a health care provider (a) standing at the side of patients lying in bed and (b) sitting face to face with patients. The conversion coefficients overall depended on radionuclides, the age of the patients, and the orientation of the patients. The conversion coefficient was greatest for Co-60 and smallest for Am-241. The dose from the 1 year-old patient phantom was up to three times greater than that from the adult patient phantom. The conversion coefficients were less dependent on the age of the patients in the scenario of a health care provider sitting face to face with patients. The dose conversion coefficients established in this study will be useful to readily estimate the effective dose to the health care providers in RDD events. C1 [Han, Eun Young] Univ Arkansas Med Sci, Dept Radiat Oncol, Little Rock, AR 72205 USA. [Ha, Wi-Ho; Jin, Young-Woo] Korea Inst Radiol & Med Sci, Natl Radiat Emergency Med Ctr, Seoul, South Korea. [Bolch, Wesley E.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. RP Han, EY (reprint author), Univ Arkansas Med Sci, Dept Radiat Oncol, Little Rock, AR 72205 USA. EM eyhan@uams.edu RI Lee, Choonsik/C-9023-2015 OI Lee, Choonsik/0000-0003-4289-9870 NR 19 TC 2 Z9 2 U1 0 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 EI 1361-6498 J9 J RADIOL PROT JI J. Radiol. Prot. PD MAR PY 2015 VL 35 IS 1 BP 37 EP 45 DI 10.1088/0952-4746/35/1/37 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA CC8SQ UT WOS:000350638900005 PM 25502317 ER PT J AU Little, MP AF Little, Mark P. TI Germline minisatellite mutations in the offspring of irradiated parents SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Editorial Material ID CHERNOBYL CLEANUP WORKERS; ATOMIC-BOMB SURVIVORS; NON-HODGKINS-LYMPHOMA; RADIATION-EXPOSURE; MICROSATELLITE MUTATIONS; NUCLEAR INDUSTRY; YOUNG-PEOPLE; NO EVIDENCE; LEUKEMIA; CHILDREN C1 NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. NR 34 TC 0 Z9 2 U1 0 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 EI 1361-6498 J9 J RADIOL PROT JI J. Radiol. Prot. PD MAR PY 2015 VL 35 IS 1 BP E1 EP E4 DI 10.1088/0952-4746/35/1/E1 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA CC8SQ UT WOS:000350638900001 PM 25485602 ER PT J AU Tan, S Yao, JH Flynn, JA Yao, L Ward, MM AF Tan, Sovira Yao, Jianhua Flynn, John A. Yao, Lawrence Ward, Michael M. TI Quantitation of Circumferential Syndesmophyte Height along the Vertebral Rim in Ankylosing Spondylitis Using Computed Tomography SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE ANKYLOSING SPONDYLITIS; SYNDESMOPHYTE; COMPUTED TOMOGRAPHY ID RADIOGRAPHIC PROGRESSION; CT; INDEX AB Objective. Using the 3-D imaging capability of computed tomography (CT), we developed an algorithm quantitating syndesmophyte height along the entire vertebral rim. We investigated its reliability and sensitivity to change, performed a 2-year longitudinal study, and compared it to CT measures of syndesmophyte volume. Methods. We performed thoracolumbar spine CT scans on 33 patients at baseline, Year 1, and Year 2, and computed syndesmophyte height in 4 intervertebral disc spaces (IDS). Height was computed every 5 degrees (72 angular sectors) along the vertebral rim. These 72 measures were summed to form the circumferential height per IDS, and results from 4 IDS were summed to provide results per patient. To assess reliability, we compared results between 2 scans performed on the same day in 9 patients. Validity was assessed by associations with spinal flexibility. Results. Coefficient of variation for circumferential syndesmophyte height was 0.893% per patient, indicating excellent reliability. Based on the Bland-Altman analysis, an increase in circumferential height of more than 3.44% per patient represented a change greater than measurement error. At years 1 and 2, mean (SD) circumferential syndesmophyte height increases were 10.2% (11.7%) and 16.1% (14.0%), respectively. Sensitivity to change was 0.72 and 0.87 at years 1 and 2, respectively. Circumferential syndesmophyte height correlated with the Schober test (r = -0.56, p = 0.0003) and lateral thoracolumbar flexion (r = -0.73, p < 0.0001). Conclusion. CT-based circumferential syndesmophyte height had excellent reliability and good sensitivity to change. It was more highly correlated with spine flexibility than syndesmophyte volume. The algorithm shows promise for longitudinal studies of syndesmophyte growth. C1 NIAMSD, Bethesda, MD 20892 USA. [Yao, Jianhua; Yao, Lawrence] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Flynn, John A.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RP Ward, MM (reprint author), NIAMSD, CRC, Bldg 10,Room 4-1339, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); US National Institutes of Health (NIH); Clinical Center, NIH; Johns Hopkins University School of Medicine General Clinical Research Center from National Center for Research Resources/NIH [M01-RR00052] FX Supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), US National Institutes of Health (NIH), and by the Clinical Center, NIH, and the Johns Hopkins University School of Medicine General Clinical Research Center (grant number M01-RR00052 from the National Center for Research Resources/NIH). NR 21 TC 1 Z9 1 U1 0 U2 1 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD MAR PY 2015 VL 42 IS 3 BP 472 EP 478 DI 10.3899/jrheum.140965 PG 7 WC Rheumatology SC Rheumatology GA CD0FM UT WOS:000350746000022 PM 25593240 ER PT J AU Rynn, MA Walkup, JT Compton, SN Sakolsky, DJ Sherrill, JT Shen, S Kendall, PC McCracken, J Albano, AM Piacentini, J Riddle, MA Keeton, C Waslick, B Chrisman, A Iyengar, S March, JS Birmaher, B AF Rynn, Moira A. Walkup, John T. Compton, Scott N. Sakolsky, Dara J. Sherrill, Joel T. Shen, Sa Kendall, Philip C. McCracken, James Albano, Anne Marie Piacentini, John Riddle, Mark A. Keeton, Courtney Waslick, Bruce Chrisman, Allan Iyengar, Satish March, John S. Birmaher, Boris TI Child/Adolescent Anxiety Multimodal Study: Evaluating Safety SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE anxiety; adverse events; selective serotonin reuptake inhibitors ID OBSESSIVE-COMPULSIVE DISORDER; RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL THERAPY; ADVERSE EVENTS; CHILD ANXIETY; PSYCHOTROPIC MEDICATIONS; DEPRESSIVE-DISORDERS; ADOLESCENTS; SERTRALINE; COMBINATION AB Objective: To evaluate the frequency of adverse events (AEs) across 4 treatment conditions in the Child/Adolescent Anxiety Multimodal Study (CAMS), and to compare the frequency of AEs between children and adolescents. Method: Participants ages 7 to 17 years (mean = 10.7 years) meeting the DSM-IV criteria for 1 or more of the following disorders: separation anxiety disorder, generalized anxiety disorder, or social phobia were randomized (2:2:2:1) to cognitive-behavioral therapy (CBT, n = 139), sertraline (SRT, n = 133), a combination of both (COMB, n = 140), or pill placebo (PBO, n = 76). Data on AEs were collected via a standardized inquiry method plus a self-report Physical Symptom Checklist (PSC). Results: There were no differences between the double-blinded conditions (SRT versus PBO) for total physical and psychiatric AEs or any individual physical or psychiatric AEs. The rates of total physical AEs were greater in the SRT-alone treatment condition when compared to CBT (p < .01) and COMB (p < .01). Moreover, those who received SRT alone reported higher rates of several physical AEs when compared to COMB and CBT. The rate of total psychiatric AEs was higher in children (<= 12 years) across all arms (31.7% versus 23.1%, p < .05). Total PSC scores decreased over time, with no significant differences between treatment groups. Conclusion: The results support the tolerability/safety of selective serotonin reuptake inhibitor (SSRI) treatment for anxiety disorders even after adjusting for the number of reporting opportunities, leading to no differences in overall rates of AEs. Few differences occurred on specific items. Additional monitoring of psychiatric AEs is recommended in children (<= 12 years). C1 [Rynn, Moira A.; Albano, Anne Marie] Columbia Univ, Med Ctr, New York State Psychiat Inst, New York, NY USA. [Walkup, John T.] Weill Cornell Med Coll, New York, NY USA. [Walkup, John T.] New York Presbyterian Hosp, New York, NY USA. [Compton, Scott N.; Chrisman, Allan; March, John S.] Duke Univ, Med Ctr, Durham, NC USA. [Sakolsky, Dara J.; Iyengar, Satish; Birmaher, Boris] Univ Pittsburgh, Western Psychiat Inst & Clin, Med Ctr, Pittsburgh, PA 15213 USA. [Sherrill, Joel T.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Shen, Sa] Univ Illinois, Champaign, IL USA. [Kendall, Philip C.] Temple Univ, Philadelphia, PA 19122 USA. [McCracken, James; Piacentini, John] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Riddle, Mark A.; Keeton, Courtney] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Waslick, Bruce] Baystate Med Ctr, Springfield, MA USA. RP Rynn, MA (reprint author), 1051 Riverside Dr,Mail Unit 78, New York, NY 10032 USA. EM rynnm@nyspi.columbiaedu FU NIMH [U01 MH64088, U01 MH064003, U01 MH63747, U01 MH64003, U01 MH64092, U01 MH64107, U01 MH064089] FX This research was supported by NIMH grants U01 MH64088 (J.P.), U01 MH064003 (S.C), U01 MH63747 (P.K.), U01 MH64003 (B B), U01 MH64092 (A M.A.), U01 MH64107 (J.M.), and U01 MH064089 (J.W.). Sertraline and matching placebo were supplied free of charge by Pfizer. NR 34 TC 6 Z9 7 U1 4 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAR PY 2015 VL 54 IS 3 BP 180 EP 190 DI 10.1016/j.jaac.2014.12.015 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA CC9RR UT WOS:000350709000005 PM 25721183 ER PT J AU Siegal-Willott, JL Jensen, N Kim, D Taliaferro, D Blankenship, T Malinsky, B Murray, S Eiden, MV Xu, WQ AF Siegal-Willott, Jessica L. Jensen, Nathaniel Kim, David Taliaferro, Dwayne Blankenship, Tiffany Malinsky, Becky Murray, Suzan Eiden, Maribeth V. Xu, Wenqin TI EVALUATION OF CAPTIVE GIBBONS (HYLOBATES SPP., NOMASCUS SPP., SYMPHALANGUS SPP.) IN NORTH AMERICAN ZOOLOGICAL INSTITUTIONS FOR GIBBON APE LEUKEMIA VIRUS (GALV) SO JOURNAL OF ZOO AND WILDLIFE MEDICINE LA English DT Article DE Gibbon; Hylobates; leukemia; Nomascus; retrovirus; Symphalangus ID C-TYPE VIRUS; HALLS ISLAND; RETROVIRUS; SEQUENCES; ONCOGENICITY; INFECTIONS; CATS AB This study evaluated 79 captive gibbons (Hylobates, Nomascus, and Symphalangus spp.) within 30 North American zoological institutions for evidence of exposure to and possible infection with gibbon ape leukemia virus (GALV). Enzyme-linked immunosorbent assays (ELISAs) on gibbon serum samples revealed the presence of antibodies against GALV antigens in 28% of animals, indicating previous exposure or possibly protective immunity to GALV. Virus detection in gibbon blood or serum using polymerase chain reaction (PCR) or co-culture of gibbon peripheral blood mononuclear cells with human cells was negative for all samples submitted. The majority (19/27, 70%) of animals with reported health conditions were clinically healthy at the time of sample collection. Historically accrued clinical data were used to assess association of diseases in gibbons antibody positive for GALV. The results suggest captive gibbons could mount an immune response to GALV and show no evidence of infection. There was no association with neoplastic conditions in seropositive animals. The potential role of gibbons as a reservoir for GALV and the role of GALV as an epizoonotic-zoonotic agent or as a contributor to gibbon ape morbidity and mortality are not substantiated by the study findings. C1 [Siegal-Willott, Jessica L.; Murray, Suzan] Smithsonian Inst, Natl Zool Pk, Dept Wildlife Hlth Serv, Washington, DC 20008 USA. [Malinsky, Becky] Smithsonian Inst, Natl Zool Pk, Anim Programs, Washington, DC 20008 USA. [Jensen, Nathaniel; Kim, David; Taliaferro, Dwayne; Blankenship, Tiffany; Eiden, Maribeth V.; Xu, Wenqin] NIMH, Sect Directed Gene Transfer, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Xu, WQ (reprint author), NIMH, Sect Directed Gene Transfer, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. EM xuwenqin@mail.nih.gov FU National Institute of Mental Health FX The authors thank Jim Nagle and Debbie Kauffmann at the National Institute of Neurological Disorders and Stroke sequencing facility (National Institutes of Health) for sequencing. We are grateful to Kristen Kluska for her editorial help. The authors also acknowledge the valuable information obtained in conversations with the late Alan Mootnick, whose broad knowledge of gibbon conservation practices in the United States was greatly appreciated. The authors thank Jay Petersen (gibbon Species Survival Plan coordinator) and Lisa Stevens (curator of primates, National Zoological Park) for their assistance with sample collection. The authors thank all of the participating institutions and their associated staff, including Binder Park Zoo, Birmingham Zoo, Blank Park Zoo, Brookfield Zoological Society, Dallas Zoo, Denver Zoo, Detroit Zoo, Fort Wayne Children's Zoo, Great Plains Zoo, Indianapolis Zoo, Jackson Zoological Park, Jacksonville Zoo, Los Angeles Zoo, Little Rock Zoo, Lion Country Safari Zoo, Nebraska Zoo, Phoenix Zoo, Pueblo Zoo, Rio Grande Zoo, Roger Williams Park Zoo, Sacramento Zoo, San Diego Zoo Safari Park, Seneca Park Zoo, Smithsonian Institution's National Zoological Park, Tulsa Zoo, Turtle Back Zoo, Utica Zoo, Woodland Park Zoo, and Zoo New England. This work was supported by the National Institute of Mental Health intramural funding. NR 28 TC 2 Z9 2 U1 1 U2 8 PU AMER ASSOC ZOO VETERINARIANS PI YULEE PA 581705 WHITE OAK ROAD, YULEE, FL 32097 USA SN 1042-7260 EI 1937-2825 J9 J ZOO WILDLIFE MED JI J. Zoo Wildl. Med. PD MAR PY 2015 VL 46 IS 1 BP 27 EP 33 DI 10.1638/2014-0034R.1 PG 7 WC Veterinary Sciences SC Veterinary Sciences GA CD2CG UT WOS:000350880800004 PM 25831573 ER PT J AU Madan, RA Gulley, JL AF Madan, Ravi A. Gulley, James L. TI Moving the goal posts in prostate cancer trials SO LANCET ONCOLOGY LA English DT Editorial Material ID MEN; ENZALUTAMIDE; CHEMOTHERAPY; ABIRATERONE; SURVIVAL; PHASE-3 C1 [Madan, Ravi A.; Gulley, James L.] NCI, NIH, Bethesda, MD 20892 USA. RP Madan, RA (reprint author), NCI, NIH, Ctr Dr, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 10 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD MAR PY 2015 VL 16 IS 3 BP 247 EP 249 DI 10.1016/S1470-2045(15)70071-9 PG 4 WC Oncology SC Oncology GA CC7WA UT WOS:000350577900039 PM 25701172 ER PT J AU Yu, P Petrus, MN Ju, W Zhang, M Conlon, KC Nakagawa, M Maeda, M Bamford, RN Waldmann, TA AF Yu, P. Petrus, M. N. Ju, W. Zhang, M. Conlon, K. C. Nakagawa, M. Maeda, M. Bamford, R. N. Waldmann, T. A. TI Augmented efficacy with the combination of blockade of the Notch-1 pathway, bortezomib and romidepsin in a murine MT-1 adult T-cell leukemia model SO LEUKEMIA LA English DT Article ID NF-KAPPA-B; ACUTE LYMPHOBLASTIC-LEUKEMIA; HISTONE DEACETYLASES; CANCER DEVELOPMENT; MULTIPLE-MYELOMA; ACTIVATION; LYMPHOMA; PROLIFERATION; RESISTANCE; APOPTOSIS AB Adult T-cell leukemia (ATL) is an aggressive malignancy caused by human T-cell lymphotropic virus-1. There is no accepted curative therapy for ATL. We have reported that certain ATL patients have increased Notch-1 signaling along with constitutive activation of the nuclear factor-kappa B pathway. Physical and functional interaction between these two pathways provides the rationale to combine the gamma-secretase inhibitor compound E with the proteasome inhibitor bortezomib. Moreover, romidepsin, a histone deacetylase inhibitor, has demonstrated major antitumor action in leukemia/lymphoma. In this study, we investigated the therapeutic efficacy of the single agents and the combination of these agents in a murine model of human ATL, the MT-1 model. Single and double agents inhibited tumor growth as monitored by tumor size (P < 0.05), and prolonged survival of leukemia-bearing mice (P < 0.05) compared with the control group. The combination of three agents significantly enhanced the antitumor efficacy as assessed by tumor size, tumor markers in the serum (human soluble interleukin-2 receptor-alpha and beta(2)-microglobulin) and survival of the MT-1 tumor-bearing mice, compared with all other treatment groups (P < 0.05). Improved therapeutic efficacy obtained by combining compound E, bortezomib and romidepsin supports a clinical trial of this combination in the treatment of ATL. C1 [Yu, P.; Petrus, M. N.; Ju, W.; Zhang, M.; Conlon, K. C.; Nakagawa, M.; Waldmann, T. A.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Zhang, M.] NCI, Lab Anim Sci Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Maeda, M.] Kyoto Univ, Inst Virus Res, Sakyo Ku, Kyoto 606, Japan. [Bamford, R. N.] Transponics, Jacobus, PA USA. RP Waldmann, TA (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, Bldg 10,Room 4N115,10 Ctr Dr, Bethesda, MD 20892 USA. EM tawald@mail.nih.gov FU Intramural Research Program of Center for Cancer Research, NCI, NIH FX This work was supported by the Intramural Research Program of Center for Cancer Research, NCI, NIH. NR 46 TC 4 Z9 5 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD MAR PY 2015 VL 29 IS 3 BP 556 EP 566 DI 10.1038/leu.2014.241 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA CD0BE UT WOS:000350734300005 PM 25118879 ER PT J AU Jukic, AMZ Steiner, AZ Baird, DD AF Jukic, Anne Marie Z. Steiner, Anne Z. Baird, Donna D. TI Association between serum 25-hydroxyvitamin D and ovarian reserve in premenopausal women SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Menopause; Follicle-stimulating hormone; Antimullerian hormone; Fecundability; Fertility ID FOLLICLE-STIMULATING-HORMONE; ANTI-MULLERIAN HORMONE; VITAMIN-D STATUS; NATURAL MENOPAUSE; ANTIMULLERIAN HORMONE; UTERINE LEIOMYOMA; AGE; SAMPLE; FECUNDABILITY; SMOKING AB Objective: Vitamin D has been linked to antimullerian hormone levels, suggesting a possible association with greater ovarian reserve, but large population-based studies are lacking. Our objective was to explore the association between vitamin D and follicle-stimulating hormone (FSH) in premenopausal women. Methods: The Uterine Fibroid Study (1996-1999) enrolled randomly selected 30- to 49-year-old members of a Washington, DC, health plan (N = 1,430). Women provided blood and urine samples in addition to questionnaire data. The vitamin D metabolite 25-hydroxyvitamin D (25(OH) D) was measured in stored plasma samples. Urinary FSH (mIU/mg creatinine) was measured by immunofluorometric assay. To obtain baseline measures, we limited this investigation to urine samples collected in the first 5 days of the menstrual cycle or 5 days before menses onset. In addition, postmenopausal women and women using oral contraceptives were excluded, leaving 527 women for analysis. FSH was creatinine-adjusted, normalized by log transformation, and modeled with multivariable linear regression. Results: The median 25(OH) D level was 12 ng/mL, with approximately 75% of participants below the recommended level of 20 ng/mL. FSH and 25(OH) D were inversely related. For every 10-ng/mL increase in 25(OH) D, urinary FSH decreased by 14% (95% CI, -23 to -5; P = 0.003). Conclusions: Vitamin D is inversely related to FSH. This is consistent with literature relating low vitamin D levels to lower antimullerian hormone levels. Prospective studies should investigate whether low vitamin D levels contribute to decreased ovarian reserve. C1 [Jukic, Anne Marie Z.; Baird, Donna D.] NIEHS, Epidemiol Branch, Durham, NC USA. [Steiner, Anne Z.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. RP Jukic, AMZ (reprint author), POB 12233, Durham, NC 27703 USA. EM jukica@niehs.nih.gov RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Z01ES0490003] FX This research was supported, in part, by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences (Z01ES0490003). NR 33 TC 2 Z9 2 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD MAR PY 2015 VL 22 IS 3 BP 312 EP 316 DI 10.1097/gme.0000000000000312 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CC8ZW UT WOS:000350658100012 PM 25093721 ER PT J AU Wickner, RB Shewmaker, FP Bateman, DA Edskes, HK Gorkovskiy, A Dayani, Y Bezsonov, EE AF Wickner, Reed B. Shewmaker, Frank P. Bateman, David A. Edskes, Herman K. Gorkovskiy, Anton Dayani, Yaron Bezsonov, Evgeny E. TI Yeast Prions: Structure, Biology, and Prion-Handling Systems SO MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS LA English DT Review ID BETA-SHEET STRUCTURE; HET-S PRION; TRANSCRIPTIONAL REGULATOR SFP1; PROTEIN-SYNTHESIS MACHINERY; NUCLEAR-MAGNETIC-RESONANCE; DISEASE-RELATED PROTEIN; TERMINATION FACTOR ERF3; 2-MU-M CIRCLE PLASMID; CHAIN RELEASE FACTOR; MESSENGER-RNA DECAY AB A prion is an infectious protein horizontally transmitting a disease or trait without a required nucleic acid. Yeast and fungal prions are nonchromosomal genes composed of protein, generally an altered form of a protein that catalyzes the same alteration of the protein. Yeast prions are thus transmitted both vertically (as genes composed of protein) and horizontally (as infectious proteins, or prions). Formation of amyloids (linear ordered beta-sheet-rich protein aggregates with beta -strands perpendicular to the long axis of the filament) underlies most yeast and fungal prions, and a single prion protein can have any of several distinct self-propagating amyloid forms with different biological properties (prion variants). Here we review the mechanism of faithful templating of protein conformation, the biological roles of these prions, and their interactions with cellular chaperones, the Btn2 and Cur1 aggregate-handling systems, and other cellular factors governing prion generation and propagation. Human amyloidoses include the PrP-based prion conditions and many other, more common amyloid-based diseases, several of which show prion-like features. Yeast prions increasingly are serving as models for the understanding and treatment of many mammalian amyloidoses. Patients with different clinical pictures of the same amyloidosis may be the equivalent of yeasts with different prion variants. C1 [Wickner, Reed B.; Bateman, David A.; Edskes, Herman K.; Gorkovskiy, Anton; Dayani, Yaron; Bezsonov, Evgeny E.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Shewmaker, Frank P.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov RI Gorkovskiy, Anton/J-8930-2016 OI Gorkovskiy, Anton/0000-0003-4811-2282 FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 216 TC 18 Z9 20 U1 3 U2 24 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1092-2172 EI 1098-5557 J9 MICROBIOL MOL BIOL R JI Microbiol. Mol. Biol. Rev. PD MAR PY 2015 VL 79 IS 1 BP 1 EP 17 DI 10.1128/MMBR.00041-14 PG 17 WC Microbiology SC Microbiology GA CD3KW UT WOS:000350978300001 PM 25631286 ER PT J AU Campo, JJ Aponte, JJ Skinner, J Nakajima, R Molina, DM Liang, L Sacarlal, J Alonso, PL Crompton, PD Felgner, PL Dobano, C AF Campo, Joe J. Aponte, John J. Skinner, Jeff Nakajima, Rie Molina, Douglas M. Liang, Li Sacarlal, Jahit Alonso, Pedro L. Crompton, Peter D. Felgner, Philip L. Dobano, Carlota TI RTS,S Vaccination Is Associated With Serologic Evidence of Decreased Exposure to Plasmodium falciparum Liver- and Blood-Stage Parasites SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID RTS,S/AS02A MALARIA VACCINE; RANDOMIZED CONTROLLED-TRIAL; HUMORAL IMMUNE-RESPONSES; PROTEIN MICROARRAYS; MOZAMBICAN CHILDREN; ACQUIRED-IMMUNITY; AFRICAN CHILDREN; PHASE-3 TRIAL; FOLLOW-UP; PROTECTION AB The leading malaria vaccine candidate, RTS,S, targets the sporozoite and liver stages of the Plasmodium falciparum life cycle, yet it provides partial protection against disease associated with the subsequent blood stage of infection. Antibodies against the vaccine target, the circumsporozoite protein, have not shown sufficient correlation with risk of clinical malaria to serve as a surrogate for protection. The mechanism by which a vaccine that targets the asymptomatic sporozoite and liver stages protects against disease caused by blood-stage parasites remains unclear. We hypothesized that vaccination with RTS, S protects from blood-stage disease by reducing the number of parasites emerging from the liver, leading to prolonged exposure to subclinical levels of blood-stage parasites that go undetected and untreated, which in turn boosts pre-existing antibody-mediated blood-stage immunity. To test this hypothesis, we compared antibody responses to 824 P. falciparum antigens by protein array in Mozambican children 6 months after receiving a full course of RTS, S (n = 291) versus comparator vaccine (n = 297) in a Phase IIb trial. Moreover, we used a nested case-control design to compare antibody responses of children who did or did not experience febrile malaria. Unexpectedly, we found that the breadth and magnitude of the antibody response to both liver and asexual blood-stage antigens was significantly lower in RTS, S vaccinees, with the exception of only four antigens, including the RTS, S circumsporozoite antigen. Contrary to our initial hypothesis, these findings suggest that RTS, S confers protection against clinical malaria by blocking sporozoite invasion of hepatocytes, thereby reducing exposure to the blood-stage parasites that cause disease. We also found that antibody profiles 6 months after vaccination did not distinguish protected and susceptible children during the subsequent 12-month follow-up period but were strongly associated with exposure. Together, these data provide insight into the mechanism by which RTS, S protects from malaria. C1 [Campo, Joe J.; Aponte, John J.; Alonso, Pedro L.; Dobano, Carlota] Univ Barcelona, Hosp Clin, ISGlobal, Barcelona Ctr Int Hlth Res CRESIB, Barcelona, Spain. [Campo, Joe J.; Aponte, John J.; Sacarlal, Jahit; Alonso, Pedro L.; Dobano, Carlota] Manhica Hlth Res Ctr, Manhica, Mozambique. [Skinner, Jeff; Crompton, Peter D.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Nakajima, Rie; Liang, Li; Felgner, Philip L.] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Molina, Douglas M.; Felgner, Philip L.] Antigen Discovery Inc, Irvine, CA USA. [Sacarlal, Jahit] Univ Eduardo Mondlane, Fac Med, Maputo, Mozambique. RP Campo, JJ (reprint author), Antigen Discovery Inc, 1 Technol Dr,Suite E309, Irvine, CA 92618 USA. EM jcampo@antigendiscovery.com RI Dobano, Carlota/N-4119-2014; Crompton, Peter/N-1130-2016; OI Dobano, Carlota/0000-0002-6751-4060; Skinner, Jeff/0000-0001-5697-0442 FU Program for Appropriate Technology in Health-Malaria Vaccine Initiative; Fundacion Ramon Areces; Agencia de Gestio d'Ajuts Universitaris i de Recerca [2010FI B 00168]; Instituto de Salud Carlos III [PS11/00423]; Spanish Ministry of Science and Innovation [RYC-2008-02631]; NIH [U54-AI065359, R44-AI066791, U19-AI089686, R01-AI095916] FX This work was supported by the Program for Appropriate Technology in Health-Malaria Vaccine Initiative; the Fundacion Ramon Areces; the Agencia de Gestio d'Ajuts Universitaris i de Recerca [2010FI B 00168 to JJC]; the Instituto de Salud Carlos III (grant PS11/00423); and the Spanish Ministry of Science and Innovation [RYC-2008-02631 to CD]. The following NIH funding contributed to the development and fabrication of the protein array chips used in this study: U54-AI065359, R44-AI066791, U19-AI089686, and R01-AI095916. The funders had no role in study design, data collection and analysis, or decision to publish. NR 44 TC 8 Z9 8 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD MAR PY 2015 VL 14 IS 3 BP 519 EP 531 DI 10.1074/mcp.M114.044677 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CC9EP UT WOS:000350671300007 PM 25547414 ER PT J AU Falcinelli, S Gowen, BB Trost, B Napper, S Kusalik, A Johnson, RF Safronetz, D Prescott, J Wahl-Jensen, V Jahrling, PB Kindrachuk, J AF Falcinelli, Shane Gowen, Brian B. Trost, Brett Napper, Scott Kusalik, Anthony Johnson, Reed F. Safronetz, David Prescott, Joseph Wahl-Jensen, Victoria Jahrling, Peter B. Kindrachuk, Jason TI Characterization of the Host Response to Pichinde Virus Infection in the Syrian Golden Hamster by Species-Specific Kinome Analysis SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID ADHESION MOLECULE-1 ICAM-1; NF-KAPPA-B; ENDOTHELIAL-CELLS; LASSA FEVER; VASCULAR-PERMEABILITY; HEMORRHAGIC-FEVER; IL-12 PRODUCTION; NUCLEAR-FACTOR; TNF-ALPHA; T-CELLS AB The Syrian golden hamster has been increasingly used to study viral hemorrhagic fever (VHF) pathogenesis and countermeasure efficacy. As VHFs are a global health concern, well-characterized animal models are essential for both the development of therapeutics and vaccines as well as for increasing our understanding of the molecular events that underlie viral pathogenesis. However, the paucity of reagents or platforms that are available for studying hamsters at a molecular level limits the ability to extract biological information from this important animal model. As such, there is a need to develop platforms/technologies for characterizing host responses of hamsters at a molecular level. To this end, we developed hamster-specific kinome peptide arrays to characterize the molecular host response of the Syrian golden hamster. After validating the functionality of the arrays using immune agonists of defined signaling mechanisms (lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-alpha), we characterized the host response in a hamster model of VHF based on Pichinde virus (PICV1) infection by performing temporal kinome analysis of lung tissue. Our analysis revealed key roles for vascular endothelial growth factor (VEGF), interleukin (IL) responses, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling, and Toll-like receptor (TLR) signaling in the response to PICV infection. These findings were validated through phosphorylation-specific Western blot analysis. Overall, we have demonstrated that hamster-specific kinome arrays are a robust tool for characterizing the species-specific molecular host response in a VHF model. Further, our results provide key insights into the hamster host response to PICV infection and will inform future studies with high-consequence VHF pathogens. C1 [Falcinelli, Shane; Johnson, Reed F.; Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, NIH, Bethesda, MD 20892 USA. [Gowen, Brian B.] Utah State Univ, Dept Anim Dairy & Vet Sci, Logan, UT 84322 USA. [Trost, Brett; Kusalik, Anthony] Univ Saskatchewan, Dept Comp Sci, Saskatoon, SK S7N 0W0, Canada. [Napper, Scott] Univ Saskatchewan, Dept Biochem, Saskatoon, SK S7N 0W0, Canada. [Napper, Scott] Univ Saskatchewan, Vaccine & Infect Dis Org Int Vaccine Ctr, Saskatoon, SK, Canada. [Safronetz, David; Prescott, Joseph] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Wahl-Jensen, Victoria; Jahrling, Peter B.; Kindrachuk, Jason] NIAID, Integrated Res Facil, NIH, Frederick, MD USA. [Wahl-Jensen, Victoria] Natl Biodef Anal & Countermeasures Ctr, Frederick, MD 21702 USA. RP Kindrachuk, J (reprint author), Integrated Res Facil, 8200 Res Plaza, Frederick, MD 21702 USA. EM kindrachuk.kenneth@nih.gov RI Trost, Brett/K-4127-2016; OI Trost, Brett/0000-0003-4863-7273; Kindrachuk, Jason/0000-0002-3305-7084 FU NIAID Division of Intramural Research; NIH [U54 AI-065357] FX This study was supported, in part, by the NIAID Division of Intramural Research. B. B. G. was supported by NIH grant U54 AI-065357 (Rocky Mountain RCE). NR 49 TC 7 Z9 7 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD MAR PY 2015 VL 14 IS 3 BP 646 EP 657 DI 10.1074/mcp.M114.045443 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CC9EP UT WOS:000350671300017 PM 25573744 ER PT J AU Lu, Q Insinna, C Ott, C Stauffer, J Pintado, PA Rahajeng, J Baxa, U Walia, V Cuenca, A Hwang, YS Daar, IO Lopes, S Lippincott-Schwartz, J Jackson, PK Caplan, S Westlake, CJ AF Lu, Quanlong Insinna, Christine Ott, Carolyn Stauffer, Jimmy Pintado, Petra A. Rahajeng, Juliati Baxa, Ulrich Walia, Vijay Cuenca, Adrian Hwang, Yoo-Seok Daar, Ira O. Lopes, Susana Lippincott-Schwartz, Jennifer Jackson, Peter K. Caplan, Steve Westlake, Christopher J. TI Early steps in primary cilium assembly require EHD1/EHD3-dependent ciliary vesicle formation SO NATURE CELL BIOLOGY LA English DT Article ID MOTHER CENTRIOLE; PRIMARY CILIOGENESIS; DISTINCT ROLES; EHD PROTEINS; GTPASE RAB8; MEMBRANE; TRANSPORT; DOCKING; COMPLEX; BIOGENESIS AB Membrane association with mother centriole (M-centriole) distal appendages is critical for ciliogenesis initiation. How the Rab GTPase Rab11-Rab8 cascade functions in early ciliary membrane assembly is unknown. Here, we show that the membrane shaping proteins EHD1 and EHD3, in association with the Rab11-Rab8 cascade, function in early ciliogenesis. EHD1 and EHD3 localize to preciliary membranes and the ciliary pocket. EHD-dependent membrane tubulation is essential for ciliary vesicle formation from smaller distal appendage vesicles (DAVs). Importantly, this step functions in M-centriole to basal body transformation and recruitment of transition zone proteins and IFT20. SNAP29, a SNARE membrane fusion regulator and EHD1-binding protein, is also required for DAV-mediated ciliary vesicle assembly. Interestingly, only after ciliary vesicle assembly is Rab8 activated for ciliary growth. Our studies uncover molecular mechanisms informing a previously uncharacterized ciliogenesis step, whereby EHD1 and EHD3 reorganize the M-centriole and associated DAVs before coordinated ciliary membrane and axoneme growth. C1 [Lu, Quanlong; Insinna, Christine; Stauffer, Jimmy; Walia, Vijay; Cuenca, Adrian; Hwang, Yoo-Seok; Daar, Ira O.; Westlake, Christopher J.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. [Ott, Carolyn; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Pintado, Petra A.] Univ Nova Lisboa, Fac Ciencias Med, CEDOC, P-1169056 Lisbon, Portugal. [Rahajeng, Juliati; Caplan, Steve] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA. [Rahajeng, Juliati; Caplan, Steve] Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE 68198 USA. [Baxa, Ulrich; Lopes, Susana] NCI, ATRF, Frederick Natl Lab, Frederick, MD 21701 USA. [Jackson, Peter K.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. RP Westlake, CJ (reprint author), NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM chris.westlake@nih.gov RI Lu, Quanlong/M-4436-2015; Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013; OI Lu, Quanlong/0000-0002-4261-5121; Lopes, Susana/0000-0002-6733-6356; Daar, Ira/0000-0003-2657-526X FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX We thank K. Nagashima and A. Kamata for help with IEM and EM, C. Lamont for data analysis, S. Lockett for help with SIM imaging, S. Specht for help with cell culture, A. Peden for SNAP29 antibodies, J. Goldenring for Rab11 antibodies, Z. Sun for the transgenic line and S. Burgess for assistance raising zebrafish embryos. We are grateful to J. Donaldson for critical reading of thismanuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. This project has also been funded in partwith federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. NR 58 TC 32 Z9 35 U1 4 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD MAR PY 2015 VL 17 IS 3 BP 228 EP + DI 10.1038/ncb3109 PG 22 WC Cell Biology SC Cell Biology GA CD0NE UT WOS:000350770200008 PM 25686250 ER PT J AU Paez-Segala, MG Sun, MG Shtengel, G Viswanathan, S Baird, MA Macklin, JJ Patel, R Allen, JR Howe, ES Piszczek, G Hess, HF Davidson, MW Wang, YL Looger, LL AF Paez-Segala, Maria G. Sun, Mei G. Shtengel, Gleb Viswanathan, Sarada Baird, Michelle A. Macklin, John J. Patel, Ronak Allen, John R. Howe, Elizabeth S. Piszczek, Grzegorz Hess, Harald F. Davidson, Michael W. Wang, Yalin Looger, Loren L. TI Fixation-resistant photoactivatable fluorescent proteins for CLEM SO NATURE METHODS LA English DT Article ID ELECTRON-MICROSCOPY; LOCALIZATION MICROSCOPY; SUPERRESOLUTION FLUORESCENCE; EOSFP; PEROXIDASE; CONVERSION; MARKER; BRIGHT AB Fluorescent proteins facilitate a variety of imaging paradigms in live and fixed samples. However, they lose their fluorescence after heavy fixation, hindering applications such as correlative light and electron microscopy (CLEM). Here we report engineered variants of the photoconvertible Eos fluorescent protein that fluoresce and photoconvert normally in heavily fixed (0.5-1% OsO4), plastic resin-embedded samples, enabling correlative super-resolution fluorescence imaging and high-quality electron microscopy. C1 [Paez-Segala, Maria G.; Sun, Mei G.; Shtengel, Gleb; Viswanathan, Sarada; Macklin, John J.; Patel, Ronak; Hess, Harald F.; Wang, Yalin; Looger, Loren L.] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Baird, Michelle A.; Allen, John R.; Howe, Elizabeth S.; Davidson, Michael W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32306 USA. [Baird, Michelle A.; Allen, John R.; Howe, Elizabeth S.; Davidson, Michael W.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Piszczek, Grzegorz] NHLBI, Bethesda, MD 20892 USA. RP Looger, LL (reprint author), Howard Hughes Med Inst, Janelia Farm Res Campus, Ashburn, VA 20147 USA. EM loogerl@janelia.hhmi.org FU Howard Hughes Medical Institute FX We thank D. Murphy and R. Fetter for helpful discussions. E. Betzig generously allowed use of his PALM microscope early in the project. S. Winfrey, H. White and A. Tkachuk assisted with cell culture. B. Kopek gave advice and technical support on PALM and CLEM. P. Rivlin gave advice on EM. P. Hulamm, L. Shao and T.-L. Chew provided technical support for imaging. T. Gallagher, M. Ramirez, P. Nguyen and K. McGowan aided in molecular biology. J. Marvin, J. Akerboom, M. Verdecia and E. Schreiter provided advice on biochemical characterization techniques. S. McKinney was helpful in the design of the anisotropy assay. Several members of the Davidson laboratory (FSU) assisted with characterization of the protein fusions: P. Cranfill, B. Sell, L. Case, J. Shirley, S. Gilbert, K. Hendrickson, R. Labaddan and R. Clarke. M.G.P.-S. thanks M. Reddy for guidance and mentoring in biochemistry and molecular biology. This work was supported by the Howard Hughes Medical Institute. NR 31 TC 21 Z9 22 U1 6 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD MAR PY 2015 VL 12 IS 3 BP 215 EP + DI 10.1038/NMETH.3225 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CC9EH UT WOS:000350670300019 PM 25581799 ER PT J AU Takebe, N McShane, L Conley, B AF Takebe, Naoko McShane, Lisa Conley, Barbara TI BIOMARKERS Exceptional responders-discovering predictive biomarkers SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID EVEROLIMUS AB Modern genomics technologies enable the identification of genetic alterations, even those present at a low frequency, and can contribute to unveiling the mechanistic rationale behind the unexpected clinical response of 'exceptional responders'. This approach will drive the identification of molecular biomarkers that can be integrated into clinical trials and predict response to a specific therapy. C1 [Takebe, Naoko; McShane, Lisa; Conley, Barbara] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20852 USA. RP Takebe, N (reprint author), NCI, Div Canc Treatment & Diag, NIH, 9609 Med Ctr Dr MSC9739, Bethesda, MD 20852 USA. EM takeben@mail.nih.gov NR 8 TC 6 Z9 6 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD MAR PY 2015 VL 12 IS 3 BP 132 EP 133 DI 10.1038/nrclinonc.2015.19 PG 2 WC Oncology SC Oncology GA CC9FG UT WOS:000350673000005 PM 25687910 ER PT J AU Humbard, MA Maurizi, MR AF Humbard, Matthew A. Maurizi, Michael R. TI The proteasome gets a grip on protein complexity SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID DEGRADATION C1 [Humbard, Matthew A.; Maurizi, Michael R.] NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Humbard, MA (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM maurizim@mail.nih.gov NR 8 TC 0 Z9 0 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAR PY 2015 VL 22 IS 3 BP 181 EP 183 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CC7ER UT WOS:000350531000005 PM 25736088 ER PT J AU Clausen, AR Lujan, SA Burkholder, AB Orebaugh, CD Williams, JS Clausen, MF Malc, EP Mieczkowski, PA Fargo, DC Smith, DJ Kunkel, TA AF Clausen, Anders R. Lujan, Scott A. Burkholder, Adam B. Orebaugh, Clinton D. Williams, Jessica S. Clausen, Maryam F. Malc, Ewa P. Mieczkowski, Piotr A. Fargo, David C. Smith, Duncan J. Kunkel, Thomas A. TI Tracking replication enzymology in vivo by genome-wide mapping of ribonucleotide incorporation SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID DNA-POLYMERASE-EPSILON; LEADING-STRAND DNA; MITOCHONDRIAL-DNA; MISMATCH REPAIR; SACCHAROMYCES-CEREVISIAE; RNASE H2; FORK; CONSEQUENCES; INSTABILITY; DELTA AB Ribonucleotides are frequently incorporated into DNA during replication in eukaryotes. Here we map genome-wide distribution of these ribonucleotides as markers of replication enzymology in budding yeast, using a new 5' DNA end-mapping method, hydrolytic end sequencing (HydEn-seq). HydEn-seq of DNA from ribonucleotide excision repair-deficient strains reveals replicase- and strand-specific patterns of ribonucleotides in the nuclear genome. These patterns support the roles of DNA polymerases a and 8 in lagging-strand replication and of DNA polymerase w in leading-strand replication. They identify replication origins, termination zones and variations in ribonucleotide incorporation frequency across the genome that exceed three orders of magnitude. HydEn-seq also reveals strand-specific 5' DNA ends at mitochondrial replication origins, thus suggesting unidirectional replication of a circular genome. Given the conservation of enzymes that incorporate and process ribonucleotides in DNA, HydEn-seq can be used to track replication enzymology in other organisms. C1 [Clausen, Anders R.; Lujan, Scott A.; Orebaugh, Clinton D.; Williams, Jessica S.; Kunkel, Thomas A.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Burkholder, Adam B.; Fargo, David C.] NIEHS, Integrat Bioinformat, NIH, Res Triangle Pk, NC 27709 USA. [Clausen, Maryam F.; Malc, Ewa P.; Mieczkowski, Piotr A.] Univ N Carolina, Dept Genet, High Throughput Sequencing Facil, Chapel Hill, NC USA. [Smith, Duncan J.] NYU, Dept Biol, Ctr Genom & Syst Biol, New York, NY 10003 USA. RP Kunkel, TA (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov OI Clausen, Anders Ranegaard/0000-0002-5069-0930; Smith, Duncan/0000-0002-0898-8629 FU Division of Intramural Research of the US National Institutes of Health (NIH), National Institute of Environmental Health Sciences [Z01 ES065070]; NIH [2R01GM052319-16A1] FX We thank M. Young and M. Longley for helpful comments on the manuscript. This work was supported by the Division of Intramural Research of the US National Institutes of Health (NIH), National Institute of Environmental Health Sciences (project Z01 ES065070 to T.A.K.) and by NIH grant 2R01GM052319-16A1 to P.A.M. NR 56 TC 45 Z9 45 U1 4 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAR PY 2015 VL 22 IS 3 BP 185 EP 191 DI 10.1038/nsmb.2957 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CC7ER UT WOS:000350531000006 PM 25622295 ER PT J AU Fenalti, G Zatsepin, NA Betti, C Giguere, P Han, GW Ishchenko, A Liu, W Guillemyn, K Zhang, H James, D Wang, D Weierstall, U Spence, JCH Boutet, S Messerschmidt, M Williams, GJ Gati, C Yefanov, OM White, TA Oberthuer, D Metz, M Yoon, CH Barty, A Chapman, HN Basu, S Coe, J Conrad, CE Fromme, R Fromme, P Tourwe, D Schiller, PW Roth, BL Ballet, S Katritch, V Stevens, RC Cherezov, V AF Fenalti, Gustavo Zatsepin, Nadia A. Betti, Cecilia Giguere, Patrick Han, Gye Won Ishchenko, Andrii Liu, Wei Guillemyn, Karel Zhang, Haitao James, Daniel Wang, Dingjie Weierstall, Uwe Spence, John C. H. Boutet, Sebastien Messerschmidt, Marc Williams, Garth J. Gati, Cornelius Yefanov, Oleksandr M. White, Thomas A. Oberthuer, Dominik Metz, Markus Yoon, Chun Hong Barty, Anton Chapman, Henry N. Basu, Shibom Coe, Jesse Conrad, Chelsie E. Fromme, Raimund Fromme, Petra Tourwe, Dirk Schiller, Peter W. Roth, Bryan L. Ballet, Steven Katritch, Vsevolod Stevens, Raymond C. Cherezov, Vadim TI Structural basis for bifunctional peptide recognition at human delta-opioid receptor SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID SERIAL FEMTOSECOND CRYSTALLOGRAPHY; MU AGONIST/DELTA ANTAGONIST; POTENT; TOLERANCE; DEPENDENCE; MORPHINE; BOND; DMT AB Bifunctional mu- and delta-opioid receptor (OR) ligands are potential therapeutic alternatives, with diminished side effects, to alkaloid opiate analgesics. We solved the structure of human delta-OR bound to the bifunctional delta-OR antagonist and mu-OR agonist tetrapeptide H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt and Tic. The observed receptor-peptide interactions are critical for understanding of the pharmacological profiles of opioid peptides and for development of improved analgesics. C1 [Fenalti, Gustavo; Han, Gye Won; Ishchenko, Andrii; Liu, Wei; Zhang, Haitao; Katritch, Vsevolod; Stevens, Raymond C.; Cherezov, Vadim] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Zatsepin, Nadia A.; James, Daniel; Wang, Dingjie; Weierstall, Uwe; Spence, John C. H.] Arizona State Univ, Dept Phys, Tempe, AZ 85287 USA. [Betti, Cecilia; Guillemyn, Karel; Tourwe, Dirk; Ballet, Steven] Vrije Univ Brussel, Dept Chem, Brussels, Belgium. [Betti, Cecilia; Guillemyn, Karel; Tourwe, Dirk; Ballet, Steven] Vrije Univ Brussel, Dept Bioengn Sci, Brussels, Belgium. [Giguere, Patrick; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC USA. [Giguere, Patrick; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Dept Pharmacol, Chapel Hill, NC USA. [Giguere, Patrick; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Div Chem Biol & Med Chem, Chapel Hill, NC USA. [Boutet, Sebastien; Messerschmidt, Marc; Williams, Garth J.] SLAC Natl Accelerator Lab, Linac Coherent Light Source, Menlo Pk, CA USA. [Gati, Cornelius; Yefanov, Oleksandr M.; White, Thomas A.; Oberthuer, Dominik; Metz, Markus; Yoon, Chun Hong; Barty, Anton; Chapman, Henry N.] Deutsch Elektronen Synchrotron DESY, Ctr Free Elect Laser Sci, Hamburg, Germany. [Oberthuer, Dominik] Univ Hamburg, Inst Biochem & Mol Biol, Hamburg, Germany. [Metz, Markus; Chapman, Henry N.] Univ Hamburg, Dept Phys, Hamburg, Germany. [Yoon, Chun Hong] European Xray Free Electron Laser Facil XFEL GmbH, Hamburg, Germany. [Basu, Shibom; Coe, Jesse; Conrad, Chelsie E.; Fromme, Raimund; Fromme, Petra] Arizona State Univ, Dept Chem & Biochem, Tempe, AZ USA. [Basu, Shibom; Coe, Jesse; Conrad, Chelsie E.; Fromme, Raimund; Fromme, Petra] Arizona State Univ, Biodesign Inst, Ctr Appl Struct Discovery, Tempe, AZ USA. [Schiller, Peter W.] Clin Res Inst Montreal, Lab Chem Biol & Peptide Res, Montreal, PQ H2W 1R7, Canada. RP Cherezov, V (reprint author), Univ So Calif, Bridge Inst, Los Angeles, CA 90033 USA. EM cherezov@usc.edu RI Messerschmidt, Marc/F-3796-2010; Barty, Anton/K-5137-2014; Zhang, Haitao/L-7612-2015; Roth, Bryan/F-3928-2010; Stevens, Raymond/K-7272-2015; Fromme, Raimund/C-8885-2012; Cherezov, Vadim/L-9812-2013; Chapman, Henry/G-2153-2010; Katritch, Vsevolod/Q-8357-2016 OI Messerschmidt, Marc/0000-0002-8641-3302; Barty, Anton/0000-0003-4751-2727; Stevens, Raymond/0000-0002-4522-8725; Fromme, Raimund/0000-0003-4835-1080; Cherezov, Vadim/0000-0002-5265-3914; Chapman, Henry/0000-0002-4655-1743; FU US National Institutes of Health (NIH); National Institute of General Medical Sciences grant [U54 GM094618, R01 GM108635, U54 GM094599, R01 GM095583, P41 GM103393]; US National Institute of Drug Abuse grant [P01 DA035764, R01 DA017204]; US National Institute of Mental Health Psychoactive Drug Screening Program; Michael Hooker Chair for Protein Therapeutics and Translational Proteomics; US National Science Foundation Science and Technology Center award [1231306]; Helmholtz Association; German Research Foundation (DFG) Cluster of Excellence 'Center for Ultrafast Imaging'; German Federal Ministry of Education and Research (BMBF) project [FKZ 05K12CH1, 05K2012]; PIER Helmholtz Graduate School; Marie Curie Initial Training Network NanoMem [317079]; Ministere du Developpement Economique, de l'Innovation et de l'Exportation du Quebec [PSR-SIIRI-417]; Research Foundation-Flanders (FWO Vlaanderen) [FWOAL570]; Canadian Institutes of Health Research (CIHR) [MOP-89716]; NIH [DA-004443]; US National Cancer Institute grant [Y1-CO-1020]; US National Institute of General Medical Sciences grant [Y1-GM-1104] FX This work was supported by US National Institutes of Health (NIH), National Institute of General Medical Sciences grants U54 GM094618 (R.C.S., V.C. and V.K.), R01 GM108635 (V.C.), U54 GM094599 (P.F.), R01 GM095583 (P.F.) and P41 GM103393 (S. Boutet); US National Institute of Drug Abuse grants P01 DA035764 (V.C., V.K., B.L.R. and R.C.S.) and R01 DA017204 (B.L.R.); the US National Institute of Mental Health Psychoactive Drug Screening Program (P.G. and B.L.R.); the Michael Hooker Chair for Protein Therapeutics and Translational Proteomics to B.L.R.; and US National Science Foundation Science and Technology Center award 1231306 (J.C.H.S., P.F. and U.W.). Parts of this work were supported by the Helmholtz Association, the German Research Foundation (DFG) Cluster of Excellence 'Center for Ultrafast Imaging' and the German Federal Ministry of Education and Research (BMBF) projects FKZ 05K12CH1 (H.N.C., A.B., C.G., O.M.Y., T.A.W., D.O. and M. Metz) and 05K2012 (D.O. and H.N.C.). C.G. thanks the PIER Helmholtz Graduate School and the Helmholtz Association for financial support. M. Metz. acknowledges support from the Marie Curie Initial Training Network NanoMem (grant no. 317079.). C.B., S. Ballet, D.T. and P.W.S. were supported by a collaboration convention between the Ministere du Developpement Economique, de l'Innovation et de l'Exportation du Quebec (PSR-SIIRI-417) and the Research Foundation-Flanders (FWO Vlaanderen, grant FWOAL570) and by grants to P.W.S. from the Canadian Institutes of Health Research (CIHR) (MOP-89716) and the NIH (DA-004443). We thank J. Velasquez, T. Trinh, M. Chu and A. Walker. Parts of this research were carried out at the Linac Coherent Light Source (LCLS), a US National User Facility operated by Stanford University on behalf of the US Department of Energy, Office of Basic Energy Sciences and at the GM/CA CAT, beamline 23ID-B, Advanced Photon Source, which is supported by the US National Cancer Institute grant Y1-CO-1020 and the US National Institute of General Medical Sciences grant Y1-GM-1104. NR 19 TC 39 Z9 39 U1 5 U2 37 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAR PY 2015 VL 22 IS 3 BP 265 EP 268 DI 10.1038/nsmb.2965 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CC7ER UT WOS:000350531000017 PM 25686086 ER PT J AU Basuli, F Li, CH Xu, BY Williams, M Wong, KR Coble, VL Vasalatiy, O Seidel, J Green, MV Griffiths, GL Choyke, PL Jagoda, EM AF Basuli, Falguni Li, Changhui Xu, Biying Williams, Mark Wong, Karen Coble, Vincent L. Vasalatiy, Olga Seidel, Jurgen Green, Michael V. Griffiths, Gary L. Choyke, Peter L. Jagoda, Elaine M. TI Synthesis of fluorine-18 radio-labeled serum albumins for PET blood pool imaging SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE [F-18]albumin; PET; Blood pool imaging ID LEFT-VENTRICULAR FUNCTION; POSITRON-EMISSION-TOMOGRAPHY; ONE-STEP RADIOSYNTHESIS; N-SUCCINIMIDYL; EJECTION FRACTION; LABELING PROTEINS; CLICK CHEMISTRY; PEPTIDES; ESTER; CYCLOADDITION AB We sought to develop a practical, reproducible and clinically translatable method of radiolabeling serum albumins with fluorine-18 for use as a PET blood pool imaging agent in animals and man. Fluorine-18 radiolabeled fluoronicotinic acid-2,3,5,6-tetrafluorophenyl ester, [F-18]F-Py-TFP was prepared first by the reaction of its quaternary ammonium triflate precursor with [F-18]tetrabutylammonium fluoride ([F-18]TBAF) according to a previously published method for peptides, with minor modifications. The incubation of [F-18]F-Py-TFP with rat serum albumin (RSA) in phosphate buffer (pH 9) for 15 mm at 37-40 degrees C produced fluorine-18-radiolabeled RSA and the product was purified using a mini-PD MiniTrap G-25 column. The overall radiochemical yield of the reaction was 18-35% (n = 30, uncorrected) in a 90-mM synthesis. This procedure, repeated with human serum albumin (HSA), yielded similar results. Fluorine-18-radiolabeled RSA demonstrated prolonged blood retention (biological half-life of 4.8 hours) in healthy awake rats. The distribution of major organ radioactivity remained relatively unchanged during the 4 hour observation periods either by direct tissue counting or by dynamic PET whole-body imaging except for a gradual accumulation of labeled metabolic products in the bladder. This manual method for synthesizing radiolabeled serum albumins uses fluorine-18, a widely available PET radio-nuclide, and natural protein available in both pure and recombinant forms which could be scaled up for widespread clinical applications. These preclinical biodistribution and PET imaging results indicate that [F-18]RSA is an effective blood pool imaging agent in rats and might, as [F-18]HSA, prove similarly useful as a clinical imaging agent. Published by Elsevier Inc C1 [Basuli, Falguni; Li, Changhui; Xu, Biying; Coble, Vincent L.; Vasalatiy, Olga] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20850 USA. [Williams, Mark; Wong, Karen; Seidel, Jurgen; Green, Michael V.; Choyke, Peter L.; Jagoda, Elaine M.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Griffiths, Gary L.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Res Directorate CMRP, Frederick, MD 21702 USA. [Seidel, Jurgen; Green, Michael V.] NCI, Leidos Biomed Res Inc, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Basuli, F (reprint author), NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20850 USA. EM bhattacharyyaf@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors thank Christine Enders for her excellent technical assistance. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 5 Z9 5 U1 3 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 EI 1872-9614 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD MAR PY 2015 VL 42 IS 3 BP 219 EP 225 DI 10.1016/j.nucmedbio.2014.11.011 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CD0RS UT WOS:000350782200003 PM 25533724 ER PT J AU Foster, DC Falsetta, ML Woeller, CF Pollock, SJ Song, K Bonham, A Haidaris, CG Stodgell, CJ Messing, SP Iadarola, M Phipps, RP AF Foster, David C. Falsetta, Megan L. Woeller, Collynn F. Pollock, Stephen J. Song, Kunchang Bonham, Adrienne Haidaris, Constantine G. Stodgell, Chris J. Messing, Susan P. Iadarola, Michael Phipps, Richard P. TI Site-specific mesenchymal control of inflammatory pain to yeast challenge in vulvodynia-afflicted and pain-free women SO PAIN LA English DT Article DE Vulvodynia; Vulvar vestibulitis; Localized provoked vulvodynia; Vestibulodynia; Vulvovaginal candidiasis; Fibroblast heterogeneity ID VULVAR VESTIBULITIS SYNDROME; CELL-WALL; FIBROBLAST HETEROGENEITY; RHEUMATOID-ARTHRITIS; ALBICANS; HYPERALGESIA; RELIABILITY; DYSPAREUNIA; MICROBIOTA; EXPRESSION AB Fibroblast strains were derived from 2 regions of the lower genital tract of localized provoked vulvodynia (LPV) cases and pain-free controls. Sixteen strains were derived from 4 cases and 4 controls, age and race matched, after presampling mechanical pain threshold assessments. Strains were challenged with 6 separate stimuli: live yeast species (Candida albicans, Candida glabrata, Candida tropicalis, and Saccharomyces cerevisiae), yeast extract (zymosan), or inactive vehicle. Production of prostaglandin E-2 (PGE(2)) and interleukin 6 (IL-6) were proinflammatory response measures. Highest IL-6 and PGE(2) occurred with vestibular strains after C albicans, C glabrata, and zymosan challenges, resulting in the ability to 'significantly predict IL-6 and PGE(2) production by genital tract location. After C albicans and C glabrata challenge of all 16 fibroblast strains, adjusting for dual sampling of subjects, PGE(2) and IL-6 production significantly predicted the presampling pain threshold from the genital tract site of sampling. At the same location of pain assessment and fibroblast sampling, in situ immunohistochemical (IHC)(+) fibroblasts for IL-6 and Cox-2 were quantified microscopically. The correlation between IL-6 production and IL-6 IHC(+) was statistically significant; however, biological significance is unknown because of the small number of IHC(+) IL-6 fibroblasts identified. A low fibroblast IL-6 IHC(+) count may result from most IL-6 produced by fibroblasts existing in a secreted extracellular state. Enhanced, site-specific, innate immune responsiveness to yeast pathogens by fibroblasts may be an early step in LPV pathogenesis. Fibroblast strain testing may offer an attractive and objective marker of LPV pathology in women with vulvodynia of inflammatory origin. C1 [Foster, David C.; Bonham, Adrienne; Stodgell, Chris J.] Univ Rochester, Sch Med & Dent, Dept Obstet & Gynecol, Rochester, NY 14642 USA. [Falsetta, Megan L.; Woeller, Collynn F.; Pollock, Stephen J.; Phipps, Richard P.] Univ Rochester, Sch Med & Dent, Dept Environm Med, Rochester, NY 14642 USA. [Song, Kunchang] Univ Rochester, Sch Med & Dent, Dept Pathol & Lab Med, Rochester, NY 14642 USA. [Haidaris, Constantine G.] Univ Rochester, Sch Med & Dent, Dept Microbiol & Immunol, Rochester, NY 14642 USA. [Messing, Susan P.] Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY 14642 USA. [Iadarola, Michael] NIH, Anesthesiol Res Labs, Dept Perioperat Med, Bethesda, MD 20892 USA. RP Foster, DC (reprint author), Univ Rochester, Strong Mem Hosp, Dept Obstet & Gynecol, 601 Elmwood Ave,Box 668, Rochester, NY 14642 USA. EM david_foster@urmc.rochester.edu OI Stodgell, Christopher/0000-0002-1666-5299; Pollock, Stephen/0000-0002-2091-1675 FU National Institutes of Health [HD069313 (NICHD)] FX Supported by National Institutes of Health grant No. HD069313 (NICHD). NR 72 TC 10 Z9 10 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD MAR PY 2015 VL 156 IS 3 BP 386 EP 396 DI 10.1097/01.j.pain.0000460320.95267.5d PG 11 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA CC7CW UT WOS:000350526300008 PM 25679469 ER PT J AU Gao, JJ Liu, R Zhao, E Huang, XM Nalls, MA Singleton, AB Chen, HL AF Gao, Jianjun Liu, Rui Zhao, Edward Huang, Xuemei Nalls, Michael A. Singleton, Andrew B. Chen, Honglei TI Head injury, potential interaction with genes, and risk for Parkinson's disease SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinson's disease; Head injury; Gene-environment interactions; Genome-wide association study ID TRAUMATIC BRAIN-INJURY; INFLAMMATION; METAANALYSIS; ASSOCIATION; EXPOSURE; SMOKING AB Introduction: To evaluate the association between head injury and Parkinson's disease (PD), focusing on the timing of head injury, and to explore potential interactions between head injury and genetic factors in PD etiology. Methods: The analysis included 507 PD cases and 1330 controls, all non-Hispanic Whites. Head injury was retrospectively asked, and genotyping was performed mainly as part of a previous GWAS. Results: We found a positive association between head injury and PD risk. Compared with no previous head injury, the odds ratio (OR) was 1.39 (95% confidence interval [CI]: 1.00, 1.94) for one and 2.33 (95% Cl: 1.25, 4.35) for two or more head injuries (P for trend = 0.0016). We further found that the higher risk was largely attributed to head injuries before age 30. Compared with no previous head injury, the OR was 2.04 (95% CI: 1.33, 3.14) for head injury that occurred before age 18, 1.39 (95% CI: 0.81, 2.36) for head injury between ages 18-<30, and 1.04(95% CI: 0.58, 1.87) for head injury that occurred at age 30 or older (P for trend = 0.001). Exploratory interaction analyses showed a significant interaction between head injury and a SNP at the RBMS3 locus (rs10510622, uncorrected P = 0.0001). No interaction was found with GWAS tag SNPs at or near the MAPT, SNCA, LRRK2, and HLA loci. Conclusion: Our study suggests that head injury early in life may be an important risk factor for PD. The potential interaction with RBMS3 needs confirmation. Published by Elsevier Ltd. C1 [Gao, Jianjun; Liu, Rui; Zhao, Edward; Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Nalls, Michael A.; Singleton, Andrew B.] NIA, Mol Genet Sect, Neurogenet Lab, Bethesda, MD 20892 USA. RP Gao, JJ (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM gaojianjunxf@gmail.com; chenh2@niehs.nih.gov RI Singleton, Andrew/C-3010-2009; OI Chen, Honglei/0000-0003-3446-7779 FU National Institute of Health [R01 NS060722]; National Institute of Environmental Health Sciences [Z01-ES-101986]; National Institute on Aging [Z01 AG000949-02]; National Cancer Institute [Z01 CP010196-02] FX This study was supported by the intramural research program of the National Institute of Health, The National Institute of Environmental Health Sciences [Z01-ES-101986], National Institute on Aging [Z01 AG000949-02], The National Cancer Institute [Z01 CP010196-02], and a National Institute of Health extramural grant [R01 NS060722 to X.H.] NR 24 TC 1 Z9 1 U1 0 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD MAR PY 2015 VL 21 IS 3 BP 292 EP 296 DI 10.1016/j.parkreldis.2014.12.033 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA CD2SU UT WOS:000350930100023 PM 25603768 ER PT J AU Armant, DR Fritz, R Kilburn, BA Kim, YM Nien, JK Maihle, NJ Romero, R Leach, RE AF Armant, D. R. Fritz, R. Kilburn, B. A. Kim, Y. M. Nien, J. K. Maihle, N. J. Romero, R. Leach, R. E. TI Reduced expression of the epidermal growth factor signaling system in preeclampsia SO PLACENTA LA English DT Article DE Preeclampsia; Epidermal growth factors; Placenta ID OXIDATIVE STRESS; FACTOR RECEPTOR; HUMAN-PLACENTA; TROPHOBLAST APOPTOSIS; EARLY-PREGNANCY; EGF; RETARDATION; CYTOTROPHOBLASTS; CELLS; ENDOMETRIAL AB Introduction: The epidermal growth factor (EGF) signaling system regulates trophoblast differentiation, and its disruption could contribute to perinatal disease. We hypothesized that this pathway is altered in preeclampsia, a disorder associated with trophoblast apoptosis and failure to invade and remodel the uterine spiral arteries. Methods: Six EGF family peptides and a truncated EGF receptor splice variant (p110/EGFR) were examined using immunohistochemistry in the trophoblast of placentas (N = 76) from women with preeclampsia, and compared to placentas from women of similar gestational age (GA) with preterm labor (PTL) or small for gestational age (SGA) fetuses, as well as normal term placentas. EGF, transforming growth factor-alpha (TGFA), and heparin-binding EGF-like growth factor (HBEGF) were evaluated using ELISA in maternal plasma from another 20 pregnancies with or without preeclampsia. Cell death was evaluated in the HTR-8/SVneo human cytotrophoblast cell line using TUNEL to evaluate the protective effects of EGF peptides. Results: Trophoblast HBEGF, TGFA, and EGF were significantly reduced in preeclampsia compared to PTL and SGA, while p110/EGFR accumulated significantly on the surface of the chorionic villi (p < 0.05). Plasma EGF levels were significantly decreased in preeclamptic patients, compared to non-preedamptic patients (p < 0.05). HBEGF, EGF, TGFA, epiregulin, and betacellulin each blocked cytotrophoblast cell death in vitro (p < 0.05). Discussion: Three members of the EGF family are dysregulated in placentas with preeclampsia, whereas p110/EGFR, a potential EGF receptor antagonist, is overexpressed. These findings are consistent with the concept that disruption of the EGF signaling system contributes to aberrant trophoblast development associated with preeclampsia. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Armant, D. R.; Fritz, R.; Kilburn, B. A.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Armant, D. R.] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Fritz, R.] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA. [Armant, D. R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Div Intramural Res, NIH, Bethesda, MD USA. [Kim, Y. M.; Nien, J. K.; Romero, R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Maihle, N. J.] Georgia Regents Univ, Ctr Canc, Augusta, GA USA. [Romero, R.] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, R.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Leach, R. E.] Michigan State Univ, Coll Human Med, Dept Obstet Gynecol & Reprod Biol, Grand Rapids, MI USA. [Leach, R. E.] Spectrum Hlth Med Grp, Dept Obstet Gynecol & Womens Hlth, Grand Rapids, MI USA. RP Armant, DR (reprint author), Wayne State Univ, Sch Med, CS Mott Ctr Human Growth & Dev, 275 E Hancock Ave, Detroit, MI 48201 USA. EM D.Armant@Wayne.edu OI Armant, D. Randall/0000-0001-5904-9325 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, (NICHD/NIH) Department of Health Human Services; NICHD/NIH as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research [U54HD40093]; NIH [HD045966, HD071408] FX This work was supported, in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, (NICHD/NIH) Department of Health & Human Services; by the NICHD/NIH through cooperative agreement U54HD40093 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research; and by NIH grants HD045966 and HD071408. NR 43 TC 8 Z9 8 U1 5 U2 10 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD MAR PY 2015 VL 36 IS 3 BP 270 EP 278 DI 10.1016/j.placenta.2014.12.006 PG 9 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA CD0QE UT WOS:000350778200003 PM 25589361 ER PT J AU Karlstetter, M Scholz, R Rutar, M Wong, WT Provis, JM Langmann, T AF Karlstetter, Marcus Scholz, Rebecca Rutar, Matt Wong, Wai T. Provis, Jan M. Langmann, Thomas TI Retinal microglia: Just bystander or target for therapy? SO PROGRESS IN RETINAL AND EYE RESEARCH LA English DT Article DE Retinal microglia; Retinal dystrophies; Age-related macular degeneration; Diabetic retinopathy; Glaucoma; Complement system; Aging; Neuroinflammation ID EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; OPTIC-NERVE HEAD; NECROSIS-FACTOR-ALPHA; CHOROIDAL NEOVASCULARIZATION MODEL; INDUCED PHOTORECEPTOR APOPTOSIS; ELEVATED HYDROSTATIC-PRESSURE; LINKED RETINITIS-PIGMENTOSA; ENDOTHELIAL GROWTH-FACTOR; FACTOR-H POLYMORPHISM; GANGLION-CELL LAYER AB Resident microglial cells can be regarded as the immunological watchdogs of the brain and the retina. They are active sensors of their neuronal microenvironment and rapidly respond to various insults with a morphological and functional transformation into reactive phagocytes. There is strong evidence from animal models and in situ analyses of human tissue that microglial reactivity is a common hallmark of various retinal degenerative and inflammatory diseases. These include rare hereditary retinopathies such as retinitis pigmentosa and X-linked juvenile retinoschisis but also comprise more common multifactorial retinal diseases such as age-related macular degeneration, diabetic retinopathy, glaucoma, and uveitis as well as neurological disorders with ocular manifestation. In this review, we describe how microglial function is kept in balance under normal conditions by cross-talk with other retinal cells and summarize how microglia respond to different forms of retinal injury. In addition, we present the concept that microglia play a key role in local regulation of complement in the retina and specify aspects of microglial aging relevant for chronic inflammatory processes in the retina. We conclude that this resident immune cell of the retina cannot be simply regarded as bystander of disease but may instead be a potential therapeutic target to be modulated in the treatment of degenerative and inflammatory diseases of the retina. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Karlstetter, Marcus; Scholz, Rebecca; Langmann, Thomas] Univ Cologne, Dept Ophthalmol, Lab Expt Immunol Eye, D-50931 Cologne, Germany. [Rutar, Matt; Provis, Jan M.] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 2601, Australia. [Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. RP Langmann, T (reprint author), Univ Cologne, Dept Ophthalmol, Lab Expt Immunol Eye, Kerpener Str 62, D-50931 Cologne, Germany. EM thomas.langmann@uk-koeln.de RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU DFG [LA1203/6-2, LA1203/8-1]; Hans und Marlies Stock-Foundation; Pro Retina Foundation; Novartis EYEnovative Program; Bayer Graduate Program in Pharmacology FX This work was supported by the DFG (LA1203/6-2 and LA1203/8-1), the Hans und Marlies Stock-Foundation, the Pro Retina Foundation, the Novartis EYEnovative Program, and the Bayer Graduate Program in Pharmacology. NR 354 TC 57 Z9 58 U1 8 U2 33 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1350-9462 J9 PROG RETIN EYE RES JI Prog. Retin. Eye Res. PD MAR PY 2015 VL 45 BP 30 EP 57 DI 10.1016/j.preteyeres.2014.11.004 PG 28 WC Ophthalmology SC Ophthalmology GA CD1LL UT WOS:000350836300002 PM 25476242 ER PT J AU Paksarian, D Eaton, WW Mortensen, PB Pedersen, CB AF Paksarian, Diana Eaton, William W. Mortensen, Preben B. Pedersen, Carsten B. TI Childhood Residential Mobility, Schizophrenia, and Bipolar Disorder: A Population-based Study in Denmark SO SCHIZOPHRENIA BULLETIN LA English DT Article DE epidemiology; residential mobility; childhood adversity ID PSYCHIATRIC-DISORDERS; ENVIRONMENTAL-FACTORS; RISK; COHORT; PSYCHOSIS; ADOLESCENCE; STRESS; FAMILY; MODEL; VICTIMIZATION AB Introduction: Childhood adversity is gaining increasing attention as a plausible etiological factor in the development of psychotic disorders. Childhood residential mobility is a potential risk factor that has received little attention in this context. Methods: We used registry data to estimate associations of residential mobility with narrow and broad schizophrenia and bipolar disorder across the course of childhood among 1.1 million individuals born in Denmark 1971-1991 and followed from age 15 through 2010. We assessed effect modification by sex, family history of mental disorder, the presence of siblings close in age, and distance moved. Results: In individual-year models adjusted for family history, urbanicity at birth, and parental age, mobility at all ages except the year of birth was associated with heightened risk of narrow and broad schizophrenia, and risk increased with age at moving and with the number of moves. Further adjustment for mobility at all ages 0-15 revealed associations mainly during the latter half of childhood, which were strongest during adolescence. Associations between mobility and bipolar disorder were fewer and weaker compared to schizophrenia. There was modest evidence of interaction with family history of psychiatric diagnosis, but little evidence for interaction by sex, the presence of closely-aged siblings, or distance moved. Schizophrenia associations did not appear attributable to increased mobility among adolescents with earlier onset. Conclusions: Mobility may increase risk for psychotic disorders, particularly schizophrenia. Children may be especially vulnerable during adolescence. Future research should investigate the importance of school changes and the potential for interaction with genetic risk. C1 [Paksarian, Diana; Eaton, William W.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Mortensen, Preben B.; Pedersen, Carsten B.] Aarhus Univ, Natl Ctr Register Based Res, Aarhus, Denmark. [Mortensen, Preben B.; Pedersen, Carsten B.] Aarhus Univ, Ctr Integrated Register Based Res, CIRRAU, Aarhus, Denmark. [Mortensen, Preben B.; Pedersen, Carsten B.] IPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Aarhus, Denmark. RP Paksarian, D (reprint author), NIMH, Genet Epidemiol Res Branch, Bldg 35,Room 2E422C,35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM diana.paksarian@nih.gov RI Mortensen, Preben/D-2358-2015; Pedersen, Carsten Bocker/B-8441-2013 OI Mortensen, Preben/0000-0002-5230-9865; Pedersen, Carsten Bocker/0000-0003-2077-8533 FU National Institute of Mental Health [5T32MH014592]; Intramural Research Program of the NIMH; National Institute on Drug Abuse [DA026652]; Stanley Medical Research Institute; Lundbeck Foundation FX National Institute of Mental Health (5T32MH014592); the Intramural Research Program of the NIMH; the National Institute on Drug Abuse (DA026652 to W.W.E.); the Stanley Medical Research Institute; and by The Lundbeck Foundation. NR 45 TC 9 Z9 9 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 IS 2 BP 346 EP 354 DI 10.1093/schbul/sbu074 PG 9 WC Psychiatry SC Psychiatry GA CD3LI UT WOS:000350979500009 PM 24903417 ER PT J AU Perkins, DO Jeffries, CD Addington, J Bearden, CE Cadenhead, KS Cannon, TD Cornblatt, BA Mathalon, DH McGlashan, TH Seidman, LJ Tsuang, MT Walker, EF Woods, SW Heinssen, R AF Perkins, Diana O. Jeffries, Clark D. Addington, Jean Bearden, Carrie E. Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. Mathalon, Daniel H. McGlashan, Thomas H. Seidman, Larry J. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. Heinssen, Robert TI Towards a Psychosis Risk Blood Diagnostic for Persons Experiencing High-Risk Symptoms: Preliminary Results From the NAPLS Project SO SCHIZOPHRENIA BULLETIN LA English DT Article DE clinical high risk; psychosis; prodrome; multiplex; risk prediction; malondialdehyde-modified low-density lipoprotein (MDA-LDL); immune; inflammation; oxidative stress ID HIGH-CLINICAL-RISK; OXIDATIVE STRESS; CORTISOL SECRETION; GROWTH-FACTOR; ROC CURVE; AT-RISK; SCHIZOPHRENIA; METAANALYSIS; VALIDATION; PRODROME AB Introduction: A barrier to preventative treatments for psychosis is the absence of accurate identification of persons at highest risk. A blood test that could substantially increase diagnostic accuracy would enhance development of psychosis prevention interventions. Methods: The North American Prodrome Longitudinal Study project is a multisite endeavor that aims to better understand predictors and mechanisms for the development of psychosis. In this study, we measured expression of plasma analytes reflecting inflammation, oxidative stress, hormones, and metabolism. A "greedy algorithm" selected analytes that best distinguished persons with clinical high-risk symptoms who developed psychosis (CHR-P; n = 32) from unaffected comparison (UC) subjects (n = 35) and from those who did not develop psychosis during a 2-year follow-up (CHR-NP; n = 40). Results: The classifier included 15 analytes (selected from 117), with an area under the receiver operating curve for CHR-P vs UC of 0.91 and CHR-P vs CHR-NP of 0.88. Randomly scrambled group membership followed by reconstructions of the entire classifier method yielded consistently weak classifiers, indicating that the true classifier is highly unlikely to be a chance occurrence. Such randomization methods robustly imply the assays contain consistent information distinguishing the groups which was not obscured by the data normalization method and was revealed by classifier construction. These results support the hypothesis that inflammation, oxidative stress, and dysregulation of hypothalamic-pituitary axes may be prominent in the earliest stages of psychosis. Conclusion: If confirmed in other groups of persons at elevated risk of psychosis, a multiplex blood assay has the potential for high clinical utility. C1 [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Jeffries, Clark D.] Univ N Carolina, Renaissance Comp Inst, Chapel Hill, NC USA. [Addington, Jean] Univ Calgary, Dept Psychiat, Hotchkiss Brain Inst, Calgary, AB T2N 1N4, Canada. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Cadenhead, Kristin S.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Cannon, Tyrone D.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Cannon, Tyrone D.; McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, Ctr Behav Genom, Inst Genom Med, La Jolla, CA 92093 USA. [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, Elaine F.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Heinssen, Robert] NIMH, Div Adult Translat Res & Treatment Dev, Bethesda, MD 20892 USA. RP Perkins, DO (reprint author), Univ N Carolina, Dept Psychiat, CB 7160, Chapel Hill, NC 27599 USA. EM diana_perkins@med.unc.edu FU National Institute of Mental Health [U01MH0818902, U01MH081984, P50MH066286, U01MH082022, U01MH081857, U01MH082004, U01MH081928, U01MH081988, U01MH066160]; San Francisco Foundation FX National Institute of Mental Health grants (U01MH0818902 to T.D.C., U01MH081984 to J.M.A., P50MH066286 to C.E.B., U01MH082022 to K.S.C., U01MH081857 to B.A.C., U01MH082004 to D.O.P., U01MH081928 to L.J.S., U01MH081988 to E.F.W., U01MH066160 to S.W.W.). The analysis of plasma samples was funded by a gift from an anonymous donor administered through the San Francisco Foundation (Perkins). NR 58 TC 36 Z9 36 U1 4 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 IS 2 BP 419 EP 428 DI 10.1093/schbul/sbu099 PG 10 WC Psychiatry SC Psychiatry GA CD3LI UT WOS:000350979500017 PM 25103207 ER PT J AU Buckley, PF Schooler, NR Goff, DC Hsiao, J Kopelowicz, A Lauriello, J Manschreck, T Mendelowitz, AJ Miller, DD Severe, JB Wilson, DR Ames, D Bustillo, J Mintz, J Kane, JM AF Buckley, Peter F. Schooler, Nina R. Goff, Donald C. Hsiao, John Kopelowicz, Alexander Lauriello, John Manschreck, Theo Mendelowitz, Alan J. Miller, Del D. Severe, Joanne B. Wilson, Daniel R. Ames, Donna Bustillo, Juan Mintz, Jim Kane, John M. CA PROACTIVE Study TI Comparison of SGA Oral Medications and a Long-Acting Injectable SGA: The PROACTIVE Study SO SCHIZOPHRENIA BULLETIN LA English DT Article DE relapse prevention; schizophrenia; psychotic symptoms; negative symptoms; clinical trial design ID RELAPSE PREVENTION; 1ST-EPISODE SCHIZOPHRENIA; RATING-SCALE; RISPERIDONE; ANTIPSYCHOTICS; TRIAL; STRATEGIES; PROGRAM; CARE AB Until relatively recently, long-acting injectable (LAI) formulations were only available for first-generation antipsychotics and their utilization decreased as use of oral second-generation antipsychotics (SGA) increased. Although registry-based naturalistic studies show LAIs reduce rehospitalization more than oral medications in clinical practice, this is not seen in recent randomized clinical trials. PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) relapse prevention study incorporated efficacy and effectiveness features. At 8 US academic centers, 305 patients with schizophrenia or schizoaffective disorder were randomly assigned to LAI risperidone (LAI-R) or physician's choice oral SGAs. Patients were evaluated during the 30-month study by masked, centralized assessors using 2-way video, and monitored biweekly by on-site clinicians and assessors who knew treatment assignment. Relapse was evaluated by a masked Relapse Monitoring Board. Differences between LAI-R and oral SGA treatment in time to first relapse and hospitalization were not significant. Psychotic symptoms and Brief Psychiatric Rating Scale total score improved more in the LAI-R group. In contrast, the LAI group had higher Scale for Assessment of Negative Symptoms Alogia scale scores. There were no other between-group differences in symptoms or functional improvement. Despite the advantage for psychotic symptoms, LAI-R did not confer an advantage over oral SGAs for relapse or rehospitalization. Biweekly monitoring, not focusing specifically on patients with demonstrated nonadherence to treatment and greater flexibility in changing medication in the oral treatment arm, may contribute to the inability to detect differences between LAI and oral SGA treatment in clinical trials. C1 [Buckley, Peter F.] Georgia Regents Univ, Med Coll Georgia, Augusta, GA 30912 USA. [Schooler, Nina R.] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Schooler, Nina R.; Mendelowitz, Alan J.; Kane, John M.] Zucker Hillside Hosp, Feinstein Inst Med Res, Glen Oaks, NY USA. [Goff, Donald C.] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. [Hsiao, John; Severe, Joanne B.] NIMH, Bethesda, MD 20892 USA. [Kopelowicz, Alexander; Ames, Donna] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Lauriello, John] Univ Missouri, Columbia Sch Med, Columbia, MO USA. [Manschreck, Theo] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Corrigan MH Ctr, Boston, MA 02215 USA. [Miller, Del D.] Univ Iowa, Dept Psychiat Res, Carver Coll Med, Iowa City, IA USA. [Wilson, Daniel R.] Univ Florida, Coll Med Jacksonville, Dept Anthropol, Jacksonville, FL USA. [Bustillo, Juan] Univ New Mexico, Sch Med, Dept Psychiat, Albuquerque, NM 87131 USA. [Mintz, Jim] Univ Texas San Antonio, Hlth Sci Ctr, San Antonio, TX USA. RP Buckley, PF (reprint author), Georgia Regents Univ, Med Coll Georgia, 1120 15th St,AA-1006, Augusta, GA 30912 USA. EM pbuckley@gru.edu RI Mintz, Jim/N-7385-2014 OI Mintz, Jim/0000-0002-8299-5851 FU National Institute of Mental Health [1 U01MH070023, 1 U01MH070011, 1 U01MH070009, 1 U01MH070012, 1 U01MH070008, 1 U01MH070017, 1 U01MH070007, 1 U01MH070010, 1 U01MH070016] FX Cooperative Agreement grants from the National Institute of Mental Health (1 U01MH070023) to N.R.S., J.M.K. (1 U01MH070011) to P.F.B. (1 U01MH070009) to D.C.G. (1 U01MH070012) to A.K. (1 U01MH070008) to J.L., J.B. (1 U01MH070017) to T.M. (1 U01MH070007) to A.J.M. (1 U01MH070010) to D.D.M. (1 U01MH070016) to D.R.W. NR 38 TC 16 Z9 16 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2015 VL 41 IS 2 BP 449 EP 459 DI 10.1093/schbul/sbu067 PG 11 WC Psychiatry SC Psychiatry GA CD3LI UT WOS:000350979500020 PM 24870446 ER PT J AU Healy, MW Hill, MJ Levens, ED AF Healy, Mae Wu Hill, Micah J. Levens, Eric D. TI Optimal Oocyte Retrieval and Embryo Transfer Techniques: Where We Are and How We Got Here SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE oocyte retrieval; embryo transfer; in vitro fertilization ID IN-VITRO FERTILIZATION; RANDOMIZED CONTROLLED-TRIAL; ASSISTED REPRODUCTIVE TECHNOLOGIES; HUMAN INVITRO FERTILIZATION; IMPROVES PREGNANCY RATES; CLINICAL PREGNANCY; TRANSFER CATHETER; CERVICAL-MUCUS; BED REST; BIRMINGHAM EXPERIENCE AB Oocyte retrieval is most safely accomplished with conscious sedation via a transvaginal approach under ultrasound guidance with low-pressure aspiration. Follicle flushing has not been shown to improve outcomes. The type of vaginal surgical preparation and the use of antibiotics have not been demonstrated to affect outcomes. As the final step in a rigorous assisted reproductive technology (ART) cycle, precise technique in embryo transfer is essential. Based on current findings, the recommended embryo transfer technique includes the use of an ultrasound-guided transcervical approach with a full bladder using a soft catheter. The transfer depth of the embryo should be in the mid-portion of the uterus with a quick steady insertion followed by pressure on the syringe during withdrawal of the catheter. It is acceptable to encourage immediate ambulation after embryo transfer. C1 [Healy, Mae Wu; Hill, Micah J.] NICHHD, Dept Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Levens, Eric D.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD 20850 USA. RP Levens, ED (reprint author), Shady Grove Fertil Reprod Sci Ctr, 15001 Shady Grove Rd,Suite 340, Rockville, MD 20850 USA. EM Eric.Levens@Integramed.com FU Program in Reproductive and Adult Endocrinology, NICHD, NIH, Bethesda, MD FX This work was supported, in part, by the Program in Reproductive and Adult Endocrinology, NICHD, NIH, Bethesda, MD. NR 109 TC 0 Z9 0 U1 1 U2 3 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 EI 1526-4564 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD MAR PY 2015 VL 33 IS 2 BP 83 EP 91 DI 10.1055/s-0035-1545365 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CD0HY UT WOS:000350752600005 PM 25734346 ER PT J AU Roy, AL Singer, DS AF Roy, Ananda L. Singer, Dinah S. TI Core promoters in transcription: old problem, new insights SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review DE transcription; core promoter; RNA Pol II; noncoding RNAs ID RNA-POLYMERASE-II; POL-II; DOWNSTREAM ELEMENT; GENOME-WIDE; CPG ISLANDS; INITIATION; CHROMATIN; COMPLEX; ENHANCERS; SEQUENCE AB Early studies established that transcription initiates within an approximately 50 bp DNA segment capable of nucleating the assembly of RNA polymerase II (Pol II) and associated general transcription factors (GTFs) necessary for transcriptional initiation; this region is called a core promoter. Subsequent analyses identified a series of conserved DNA sequence elements, present in various combinations or not at all, in core promoters. Recent genome-wide analyses have provided further insights into the complexity of core promoter architecture and function. Here we review recent studies that delineate the active role of core promoters in the transcriptional regulation of diverse physiological systems. C1 [Roy, Ananda L.] Tufts Univ, Sch Med, Dept Dev Mol & Chem Biol, Boston, MA 02111 USA. [Singer, Dinah S.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Roy, AL (reprint author), Tufts Univ, Sch Med, Dept Dev Mol & Chem Biol, Boston, MA 02111 USA. EM ananda.roy@tufts.edu; dinah.singer@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX D.S. is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 61 TC 10 Z9 10 U1 8 U2 42 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD MAR PY 2015 VL 40 IS 3 BP 165 EP 171 DI 10.1016/j.tibs.2015.01.007 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CC8IT UT WOS:000350612400006 PM 25680757 ER PT J AU Scheibye-Knudsen, M Fang, EF Croteau, DL Wilson, DM Bohr, VA AF Scheibye-Knudsen, Morten Fang, Evandro F. Croteau, Deborah L. Wilson, David M., III Bohr, Vilhelm A. TI Protecting the mitochondrial powerhouse SO TRENDS IN CELL BIOLOGY LA English DT Review DE mitochondria; DNA repair; mitophagy; reactive oxygen species; disease ID DNA MISMATCH-REPAIR; STRAND BREAK REPAIR; DAMAGED MITOCHONDRIA; COCKAYNE-SYNDROME; OXIDATIVE STRESS; EXCISION-REPAIR; ENDOPLASMIC-RETICULUM; MAMMALIAN-CELLS; MITOFUSIN 2; DISEASE AB Mitochondria are the oxygen-consuming power plants of cells. They provide a critical milieu for the synthesis of many essential molecules and allow for highly efficient energy production through oxidative phosphorylation. The use of oxygen is, however, a double-edged sword that on the one hand supplies ATP for cellular survival, and on the other leads to the formation of damaging reactive oxygen species (ROS). Different quality control pathways maintain mitochondria function including mitochondrial DNA (mtDNA) replication and repair, fusion-fission dynamics, free radical scavenging, and mitophagy. Further, failure of these pathways may lead to human disease. We review these pathways and propose a strategy towards a treatment for these often untreatable disorders. C1 [Scheibye-Knudsen, Morten; Fang, Evandro F.; Croteau, Deborah L.; Wilson, David M., III; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Scheibye-Knudsen, Morten/0000-0002-6637-1280 FU NIA/NIH FX We sincerely apologize to colleagues whose work we could not include due to space limitations. The research was supported entirely by the Intramural Research Program of the NIA/NIH. NR 106 TC 42 Z9 44 U1 9 U2 53 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD MAR PY 2015 VL 25 IS 3 BP 158 EP 170 DI 10.1016/j.tcb.2014.11.002 PG 13 WC Cell Biology SC Cell Biology GA CD2QZ UT WOS:000350925400006 PM 25499735 ER PT J AU Smith, JM Hedman, AC Sacks, DB AF Smith, Jessica M. Hedman, Andrew C. Sacks, David B. TI IQGAPs choreograph cellular signaling from the membrane to the nucleus SO TRENDS IN CELL BIOLOGY LA English DT Review DE IQGAP1; IQGAP2; IQGAP3; scaffold; signaling ID CALPONIN HOMOLOGY DOMAIN; BREAST-CANCER CELLS; RHO FAMILY GTPASES; HEPATOCELLULAR-CARCINOMA; PROTEIN IQGAP1; INTEGRATES CA2+/CALMODULIN; TYROSINE PHOSPHORYLATION; TRANSCRIPTION FACTOR; NEURITE OUTGROWTH; ERK1/2 ACTIVATION AB Since its discovery in 1994, recognized cellular functions for the scaffold protein IQGAP1 have expanded immensely. Over 100 unique IQGAP1-interacting proteins have been identified, implicating IQGAP1 as a critical integrator of cellular signaling pathways. Initial research established functions for IQGAP1 in cell-cell adhesion, cell migration, and cell signaling. Recent studies have revealed additional IQGAP1 binding partners, expanding the biological roles of IQGAP1. These include crosstalk between signaling cascades, regulation of nuclear function, and Wnt pathway potentiation. Investigation of the IQGAP2 and IQGAP3 homologs demonstrates unique functions, some of which differ from those of IQGAP1. Summarized here are recent observations that enhance our understanding of IQGAP proteins in the integration of diverse signaling pathways. C1 [Smith, Jessica M.; Hedman, Andrew C.; Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Sacks, DB (reprint author), NIH, Dept Lab Med, 10 Ctr Dr Bldg 10,Room 2C306, Bethesda, MD 20892 USA. EM sacksdb@mail.nih.gov OI Sacks, David/0000-0003-3100-0735 FU National Institutes of Health FX The authors apologize to those whose primary work was omitted due to space restrictions. This work was supported by the Intramural Research Program of the National Institutes of Health. NR 142 TC 16 Z9 17 U1 1 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD MAR PY 2015 VL 25 IS 3 BP 171 EP 184 DI 10.1016/j.tcb.2014.12.005 PG 14 WC Cell Biology SC Cell Biology GA CD2QZ UT WOS:000350925400007 PM 25618329 ER PT J AU Day, T Huijben, V Read, AF AF Day, Troy Huijben, Vie Read, Andrew F. TI Is selection relevant in the evolutionary emergence of drug resistance? SO TRENDS IN MICROBIOLOGY LA English DT Review DE evolutionary rescue; chemotherapy; antibiotics; mutant selection window ID VITRO DYNAMIC-MODEL; MUTANT PREVENTION CONCENTRATION; STAPHYLOCOCCUS-AUREUS; ANTIBIOTIC-RESISTANCE; WINDOW HYPOTHESIS; PSEUDOMONAS-AERUGINOSA; MALARIA PARASITES; FLUOROQUINOLONE; CIPROFLOXACIN; EXPOSURE AB The emergence of drug-resistant pathogens is often considered a canonical case of evolution by natural selection. Here we argue that the strength of selection can be a poor predictor of the rate of resistance emergence. It is possible for a resistant strain to be under negative selection and still emerge in an infection or spread in a population. Measuring the right parameters is a necessary first step toward the development of evidence-based resistance-management strategies. We argue that it is the absolute fitness of the resistant strains that matters most and that a primary determinant of the absolute fitness of a resistant strain is the ecological context in which it finds itself. C1 [Day, Troy] Queens Univ, Dept Math & Stat, Kingston, ON K7L 3N6, Canada. [Day, Troy] Queens Univ, Dept Biol, Kingston, ON K7L 3N6, Canada. [Day, Troy; Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Huijben, Vie] Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Barcelona, Spain. [Read, Andrew F.] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16802 USA. [Read, Andrew F.] Penn State Univ, Ctr Infect Dis Dynam, Dept Entomol, University Pk, PA 16802 USA. RP Day, T (reprint author), Queens Univ, Dept Math & Stat, Jeffery Hall, Kingston, ON K7L 3N6, Canada. EM tday@mast.queensu.ca FU Natural Sciences and Engineering Research Council of Canada; Society in Science-Branco Weiss Fellowship; Marie Curie IIF Fellowship; National Institute of General Medical Sciences [R01GM089932] FX For discussion, the authors thank W. Nelson and members of the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, the Department of Homeland Security, the Fogarty International Center, the National Institutes of Health, and particularly those at the Princeton RAPIDD workshop organized by J. Metcalf and R. Kouyos. They also thank G. Teitzel, D. Kennedy, B. Levin, and two anonymous referees for helpful comments on the manuscript. This research was supported by a grant from the Natural Sciences and Engineering Research Council of Canada (T.D.), a Society in Science-Branco Weiss Fellowship and Marie Curie IIF Fellowship (S.H.), and the National Institute of General Medical Sciences (R01GM089932) (A.F.R.). NR 37 TC 9 Z9 9 U1 3 U2 44 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X EI 1878-4380 J9 TRENDS MICROBIOL JI Trends Microbiol. PD MAR PY 2015 VL 23 IS 3 BP 126 EP 133 DI 10.1016/j.tim.2015.01.005 PG 8 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA CD2TZ UT WOS:000350933200003 PM 25680587 ER PT J AU Nelson, MI Vincent, AL AF Nelson, Martha I. Vincent, Amy L. TI Reverse zoonosis of influenza to swine: new perspectives on the human-animal interface SO TRENDS IN MICROBIOLOGY LA English DT Review DE influenza A virus; swine; pandemic; evolution; human-animal interface ID PANDEMIC H1N1 2009; COMPLETE GENOME SEQUENCE; NORTH-AMERICAN SWINE; A VIRUSES; UNITED-STATES; GENETIC-CHARACTERIZATION; SOUTHERN CHINA; RESPIRATORY-DISEASE; EQUINE INFLUENZA; PIG-POPULATION AB The origins of the 2009 influenza A (H1N1) pandemic in swine are unknown, highlighting gaps in our understanding of influenza A virus (IAV) ecology and evolution. We review how recently strengthened influenza virus surveillance in pigs has revealed that influenza virus transmission from humans to swine is far more frequent than swine-to-human zoonosis, and is central in seeding swine globally with new viral diversity. The scale of global human-to-swine transmission represents the largest 'reverse zoonosis' of a pathogen documented to date. Overcoming the bias towards perceiving swine as sources of human viruses, rather than recipients, is key to understanding how the bidirectional nature of the human-animal interface produces influenza threats to both hosts. C1 [Nelson, Martha I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Vincent, Amy L.] USDA ARS, Natl Anim Dis Ctr, Virus & Prion Res Unit, Ames, IA 50010 USA. RP Nelson, MI (reprint author), NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. EM nelsonma@mail.nih.gov FU Office of Global Affairs at the US Department of Health and Human Services (DHHS); USDA-ARS FX We would like to thank National Institutes of Health (NIH) intern Adaeze Ezeofor for her contributions to the organization and identification of the many journal references cited in this manuscript. We are also grateful to Drs Cecile Viboud (NIH) and Edward C. Holmes (University of Sydney) for their insightful comments on earlier drafts of this manuscript. This research was conducted within the context of the Multinational Influenza Seasonal Mortality Study (MISMS) (http://www.origem.info/misms/), an ongoing international collaborative effort to understand influenza epidemiology and evolution, led by the Fogarty International Center, NIH, with funding from the Office of Global Affairs at the US Department of Health and Human Services (DHHS) (M.I.N.). A.V. is funded by USDA-ARS. USDA is an equal opportunity provider and employer. Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the USDA. NR 135 TC 29 Z9 31 U1 5 U2 42 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X EI 1878-4380 J9 TRENDS MICROBIOL JI Trends Microbiol. PD MAR PY 2015 VL 23 IS 3 BP 142 EP 153 DI 10.1016/j.tim.2014.12.002 PG 12 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA CD2TZ UT WOS:000350933200005 PM 25564096 ER PT J AU Ambalavanan, N Carlo, WA Wrage, LA Das, A Laughon, M Cotten, CM Kennedy, KA Laptook, AR Shankaran, S Walsh, MC Higgins, RD AF Ambalavanan, Namasivayam Carlo, Waldemar A. Wrage, Lisa A. Das, Abhik Laughon, Matthew Cotten, C. Michael Kennedy, Kathleen A. Laptook, Abbot R. Shankaran, Seetha Walsh, Michele C. Higgins, Rosemary D. CA NICHD Neonatal Res Network TI PaCO2 in Surfactant, Positive Pressure, and Oxygenation Randomised Trial (SUPPORT) SO ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION LA English DT Article ID BIRTH-WEIGHT INFANTS; EXTREMELY PRETERM INFANTS; PERIVENTRICULAR LEUKOMALACIA; BRONCHOPULMONARY DYSPLASIA; PERMISSIVE HYPERCAPNIA; WEEKS GESTATION; CARBON-DIOXIDE; EARLY CPAP; HYPOCAPNIA; HEMORRHAGE AB Objective To determine the association of arterial partial pressure of carbon dioxide PaCO2 with severe intraventricular haemorrhage (sIVH), bronchopulmonary dysplasia (BPD), and neurodevelopmental impairment (NDI) at 18-22 months in premature infants. Design Secondary exploratory data analysis of Surfactant, Positive Pressure, and Oxygenation Randomised Trial (SUPPORT). Setting Multiple referral neonatal intensive care units. Patients 1316 infants 24 0/7 to 27 6/7 weeks gestation randomised to different oxygenation (SpO(2) target 85-89% vs 91-95%) and ventilation strategies. Main outcome measures Blood gases from postnatal day 0 to day 14 were analysed. Five PaCO2 variables were defined: minimum (Min), maximum (Max), SD, average (time-weighted), and a four level categorical variable (hypercapnic (highest quartile of Max PaCO2), hypocapnic (lowest quartile of Min PaCO2), fluctuators (hypercapnia and hypocapnia), and normocapnic (middle two quartiles of Max and Min PaCO2)). PaCO2 variables were compared for infants with and without sIVH, BPD and NDI (+/- death). Multivariable logistic regression models were developed for adjusted results. Results sIVH, BPD and NDI (+/- death) were associated with hypercapnic infants and fluctuators. Association of Max PaCO2 and outcomes persisted after adjustment (per 10 mm Hg increase: sIVH/death: OR 1.27 (1.13 to 1.41); BPD/death: OR 1.27 (1.12 to 1.44); NDI/death: OR 1.23 (1.10 to 1.38), death: OR 1.27 (1.12 to 1.44), all p<0.001). No interaction was found between PaCO2 category and SpO(2) treatment group for sIVH/death, NDI/death or death. Max PaCO2 was positively correlated with maximum FiO(2) (rs0.55, p<0.0001) and ventilator days (rs0.61, p<0.0001). Conclusions Higher PaCO2 was an independent predictor of sIVH/death, BPD/death and NDI/death. Further trials are needed to evaluate optimal PaCO2 targets for high-risk infants. C1 [Ambalavanan, Namasivayam; Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL 35249 USA. [Wrage, Lisa A.] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Das, Abhik] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. [Laughon, Matthew] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Cotten, C. Michael] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Kennedy, Kathleen A.] Univ Texas Med Sch Houston, Dept Pediat, Houston, TX USA. [Laptook, Abbot R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Walsh, Michele C.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Ambalavanan, N (reprint author), Univ Alabama Birmingham, Women & Infants Ctr, 176F Suite 9380,619 South 20th St, Birmingham, AL 35249 USA. EM ambal@uab.edu OI Freedman, Sharon/0000-0003-3615-3511; Ambalavanan, Namasivayam/0000-0003-0731-9092 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute (NHLBI) [U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27904, U10 HD34216, U10 HD36790, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40521, U10 HD40689, U10 HD53089, U10 HD53109, U10 HD53119, U10 HD53124]; National Institutes of Health [M01 RR30, M01 RR32, M01 RR39, M01 RR44, M01 RR54, M01 RR59, M01 RR64, M01 RR70, M01 RR80, M01 RR125, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587, UL1 TR93, UL1 TR142, UL1 TR442, UL1 TR454]; National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Heart, Lung, and Blood Institute (NHLBI) FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Heart, Lung, and Blood Institute (NHLBI) (U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27904, U10 HD34216, U10 HD36790, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40521, U10 HD40689, U10 HD53089, U10 HD53109, U10 HD53119, U10 HD53124) and the National Institutes of Health (M01 RR30, M01 RR32, M01 RR39, M01 RR44, M01 RR54, M01 RR59, M01 RR64, M01 RR70, M01 RR80, M01 RR125, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587, UL1 TR93, UL1 TR142, UL1 TR442, UL1 TR454). The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Heart, Lung, and Blood Institute (NHLBI) provided grant support for the Neonatal Research Network's SUPPORT Trial. The study sponsors were not involved in: (1) study design; (2) the collection, analysis, and interpretation of data; (3) the writing of the report; and (4) the decision to submit the paper for publication. No honorarium, grant, or other form of payment was given to anyone to produce the manuscript. NR 19 TC 3 Z9 3 U1 1 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1359-2998 EI 1468-2052 J9 ARCH DIS CHILD-FETAL JI Arch. Dis. Child.-Fetal Neonatal Ed. PD MAR PY 2015 VL 100 IS 2 BP F145 EP F149 DI 10.1136/archdischild-2014-306802 PG 5 WC Pediatrics SC Pediatrics GA CC6QO UT WOS:000350491900013 PM 25425651 ER PT J AU Brach, JS Lowry, K Perera, S Hornyak, V Wert, D Studenski, SA VanSwearingen, JM AF Brach, Jennifer S. Lowry, Kristin Perera, Subashan Hornyak, Victoria Wert, David Studenski, Stephanie A. VanSwearingen, Jessie M. TI Improving Motor Control in Walking: A Randomized Clinical Trial in Older Adults With Subclinical Walking Difficulty SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Aging; Exercise; Gait; Motor control; Rehabilitation ID CURVED-PATH WALKING; TEST-RETEST RELIABILITY; HARMONIC RATIOS; ACCELERATION PATTERNS; PHYSICAL PERFORMANCE; MOBILITY DISABILITY; PARKINSONS-DISEASE; BODY REORIENTATION; TIME VARIABILITY; GAIT VARIABILITY AB Objective: To test the proposed mechanism of action of a task-specific motor learning intervention by examining its effect on measures of the motor control of gait. Design: Single-blinded randomized clinical trial. Setting: University research laboratory. Participants: Adults (N=40) aged >= 65 years with gait speed >1.0m/s and impaired motor skill (figure-of-8 walk time >8s). Interventions: The 2 interventions included a task-oriented motor learning and a standard exercise program; both interventions included strength training. Both lasted 12 weeks, with twice-weekly, 1-hour, physical therapist supervised sessions. Main Outcome Measures: Two measures of the motor control of gait, gait variability and smoothness of walking, were assessed pre- and postintervention by assessors masked to the treatment arm. Results: Of 40 randomized subjects, 38 completed the trial (mean age +/- SD, 77.1 +/- 6.0y). The motor learning group improved more than the standard group in double-support time variability (.13m/s vs .05m/s; adjusted difference [AD]=.006, P=.03). Smoothness of walking in the anteroposterior direction improved more in the motor learning than standard group for all conditions (usual: AD=.53, P=.05; narrow: AD=.56, P=.01; dual task: AD=.57, P=.04). Smoothness of walking in the vertical direction also improved more in the motor learning than standard group for the narrow-path (AD=.71, P=.01) and dual-task (AD=.89, P=.01) conditions. Conclusions: Among older adults with subclinical walking difficulty, there is initial evidence that task-oriented motor learning exercise results in gains in the motor control of walking, while standard exercise does not. Task-oriented motor learning exercise is a promising intervention for improving timing and coordination deficits related to mobility difficulties in older adults, and needs to be evaluated in a definitive larger trial. (C) 2015 by the American Congress of Rehabilitation Medicine C1 [Brach, Jennifer S.; Hornyak, Victoria; Wert, David; VanSwearingen, Jessie M.] Univ Pittsburgh, Dept Phys Therapy, Pittsburgh, PA 15260 USA. [Lowry, Kristin] Des Moines Univ, Dept Phys Therapy, Des Moines, IA USA. [Perera, Subashan] Univ Pittsburgh, Div Geriatr Med, Pittsburgh, PA 15260 USA. [Studenski, Stephanie A.] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP Brach, JS (reprint author), Univ Pittsburgh, Dept Phys Therapy, 6035 Forbes Tower, Pittsburgh, PA 15260 USA. EM jbrach@pitt.edu FU Pittsburgh Older Americans Independence Center [NIA P30 AG024827]; Beeson Career Development Award [NIA K23 AG026766] FX Supported by the Pittsburgh Older Americans Independence Center (grant no. NIA P30 AG024827) and the Beeson Career Development Award (grant no. NIA K23 AG026766). NR 57 TC 6 Z9 6 U1 1 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD MAR PY 2015 VL 96 IS 3 BP 388 EP 394 DI 10.1016/j.apmr.2014.10.018 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA CC3QZ UT WOS:000350265400002 PM 25448244 ER PT J AU McEvoy, JW Blaha, MJ DeFilippis, AP Lima, JAC Bluemke, DA Hundley, WG Min, JK Shaw, LJ Lloyd-Jones, DM Barr, RG Budoff, MJ Blumenthal, RS Nasir, K AF McEvoy, John W. Blaha, Michael J. DeFilippis, Andrew P. Lima, Joao A. C. Bluemke, David A. Hundley, W. Gregory Min, James K. Shaw, Leslee J. Lloyd-Jones, Donald M. Barr, R. Graham Budoff, Matthew J. Blumenthal, Roger S. Nasir, Khurram TI Cigarette Smoking and Cardiovascular Events Role of Inflammation and Subclinical Atherosclerosis From the Multiethnic Study of Atherosclerosis SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE coronary artery disease; inflammation; smoking ID CORONARY-ARTERY CALCIFICATION; MALE BRITISH DOCTORS; LUNG-CANCER; COMPUTED-TOMOGRAPHY; HEART-DISEASE; RISK-FACTORS; MORTALITY; SMOKERS; METAANALYSIS; PROGRESSION AB Objectives To examine the contemporary effect of smoking in a multiethnic sample, and to explore the respective contributions of inflammation and subclinical atherosclerosis to the cardiovascular consequences of smoking. Approach and Results We studied 6814 participants free of cardiovascular disease and coronary heart disease (CHD) from the Multiethnic Study of Atherosclerosis. Smoking status and cumulative exposure were determined by self-report and confirmed by urinary cotinine. Multivariable Cox regression was used to estimate the association between smoking parameters and all-cause cardiovascular disease, all-cause CHD, and hard CHD events. We further adjusted for high-sensitivity C-reactive protein and coronary artery calcium (CAC) in hierarchical Cox models. We identified 3218 never smokers, 2607 former smokers, and 971 current smokers. Median follow-up was 10.2 years. Compared with never smokers, adjusted hazard ratios in current smokers were 1.7 (95% confidence interval, 1.3-2.2) for all-cause cardiovascular disease, 1.6 (1.1-2.1) for all-cause CHD, and 1.7 (1.2-2.4) for hard CHD. Similarly, among current smokers, hazard ratios were higher in the 4th versus 1st quartile of pack-years (eg, all-cause CHD hazard ratio=2.7 [1.1-6.6]). Both CAC>100 and high-sensitivity C-reactive protein 3 mg/L identified higher relative risk among current smokers (eg, all-cause CHD hazard ratio of 3.0 [1.5-6.0, compared with CAC=0] and 2.6 [1.4-4.8, compared with high-sensitivity C-reactive protein <2 mg/L], respectively). However, CAC was a stronger mediator of events and adversely modified the effect of smoking on events (eg, P-interaction=0.02 for hard CHD). Compared with never smokers, former smokers (median cessation interval=22 years) had similar adjusted hazard for events. Conclusions In this multiethnic cohort, current smoking and cumulative exposure remain important modifiable determinants of cardiovascular disease. Both high-sensitivity C-reactive protein 3 mg/L and, particularly, CAC>100 identified high-risk smokers who may benefit from more intensive smoking-cessation efforts. C1 [McEvoy, John W.; Blaha, Michael J.; DeFilippis, Andrew P.; Blumenthal, Roger S.; Nasir, Khurram] Johns Hopkins Univ, Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA. [Lima, Joao A. C.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD USA. [DeFilippis, Andrew P.] Univ Louisville, Div Cardiol, Rudd Heart & Lung Ctr, Louisville, KY 40292 USA. [Bluemke, David A.] NIH, Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Hundley, W. Gregory] Wake Forest Univ, Ctr Hlth, Div Cardiol, Winston Salem, NC 27109 USA. [Min, James K.] Cedars Sinai Med Ctr, Div Cardiol, Inst Heart, Los Angeles, CA 90048 USA. [Shaw, Leslee J.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Lloyd-Jones, Donald M.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Barr, R. Graham] Columbia Univ, Med Ctr, Dept Med, Div Gen Med,Div Pulm Allergy & Crit Care, New York, NY USA. [Barr, R. Graham] Columbia Univ, Dept Epidemiol, New York, NY USA. [Budoff, Matthew J.] Harbor UCLA, Los Angeles Biomed Res Inst, Torrance, CA USA. [Nasir, Khurram] Baptist Hlth South Florida, Ctr Wellness & Prevent, Miami, FL USA. [Nasir, Khurram] Baptist Hlth South Florida, Miami Cardiovasc Inst MCVI, Miami, FL USA. [Nasir, Khurram] Florida Int Univ, Dept Med, Herbert Wertheim Coll Med, Miami, FL 33199 USA. [Nasir, Khurram] Florida Int Univ, Dept Epidemiol, Robert Stempel Coll Publ Hlth, Miami, FL 33199 USA. RP Nasir, K (reprint author), Baptist Hlth South Florida, Ctr Wellness & Prevent, 1691 Michigan Ave,Suite 500, Miami Beach, FL 33139 USA. EM khurramn@baptisthealth.net OI McEvoy, John/0000-0001-6530-5479 FU American Heart Association Tobacco Regulation and Addiction Center (A-TRAC) [NIH 1 P50 HL120163-01]; Food and Drug Administration (FDA) Tobacco Centers of Regulatory Science for Research Relevant to the Family Smoking Prevention and Tobacco Control Act [P50]; National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95169]; Pollin Cardiovascular Prevention Fellowship; [R01-HL077612] FX This analysis was supported by funding from the American Heart Association Tobacco Regulation and Addiction Center (A-TRAC, NIH 1 P50 HL120163-01), a member of the Food and Drug Administration (FDA) Tobacco Centers of Regulatory Science for Research Relevant to the Family Smoking Prevention and Tobacco Control Act (P50). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the FDA. The Multiethnic Study of Atherosclerosis study which supplied the data for this analysis was supported by contracts N01-HC-95159 through N01-HC-95167 and N01-HC-95169 from the National Heart, Lung, and Blood Institute. The cotinine measurement was supported by contract R01-HL077612. Dr McEvoy is supported by the Pollin Cardiovascular Prevention Fellowship. NR 35 TC 11 Z9 13 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD MAR PY 2015 VL 35 IS 3 BP 700 EP 709 DI 10.1161/ATVBAHA.114.304562 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CC5JV UT WOS:000350395800029 PM 25573855 ER PT J AU Kavanaugh, A Cush, JJ Ahmed, MS Bermas, BL Chakravarty, E Chambers, C Clowse, M Curtis, JR Dao, K Hankins, GDV Koren, G Kim, SC Lapteva, L Mahadevan, U Moore, T Nolan, M Ren, ZX Sammaritano, LR Seymour, S Weisman, MH AF Kavanaugh, Arthur Cush, John J. Ahmed, Mahmoud S. Bermas, Bonnie L. Chakravarty, Eliza Chambers, Christina Clowse, Megan Curtis, Jeffrey R. Dao, Kathryn Hankins, Gary D. V. Koren, Gideon Kim, Seoyoung C. Lapteva, Larissa Mahadevan, Uma Moore, Thomas Nolan, Martha Ren, Zhaoxia Sammaritano, Lisa R. Seymour, Sally Weisman, Michael H. TI Proceedings From the American College of Rheumatology Reproductive Health Summit: The Management of Fertility, Pregnancy, and Lactation in Women With Autoimmune and Systemic Inflammatory Diseases SO ARTHRITIS CARE & RESEARCH LA English DT Article ID LATE-PRETERM INFANTS; BREAST-MILK; LUPUS-ERYTHEMATOSUS; BOWEL-DISEASE; NURSING MOTHERS; BIRTH OUTCOMES; MATERNAL SERUM; CROHNS-DISEASE; CHILDREN BORN; UNITED-STATES C1 [Kavanaugh, Arthur; Chambers, Christina] Univ Calif San Diego, La Jolla, CA 92093 USA. [Cush, John J.; Dao, Kathryn] Baylor Res Inst, Dallas, TX USA. [Ahmed, Mahmoud S.; Hankins, Gary D. V.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Bermas, Bonnie L.; Kim, Seoyoung C.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Chakravarty, Eliza] Oklahoma Med Res Fdn, Edmond, OK USA. [Clowse, Megan] Duke Univ, Med Ctr, Durham, NC USA. [Curtis, Jeffrey R.] Univ Alabama Birmingham, Birmingham, AL USA. [Koren, Gideon] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Lapteva, Larissa; Seymour, Sally] US FDA, Silver Spring, MD USA. [Mahadevan, Uma] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Moore, Thomas] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [Nolan, Martha] Soc Womens Hlth Res, Washington, DC USA. [Ren, Zhaoxia] NICHHD, NIH, Bethesda, MD 20892 USA. [Sammaritano, Lisa R.] Cornell Univ, Hosp Special Surg, Weill Med Coll, New York, NY 10021 USA. [Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Weisman, MH (reprint author), Cedars Sinai Med Ctr, Div Rheumatol, 8700 Beverly Blvd,B131, Los Angeles, CA 90048 USA. EM weisman@cshs.org OI Kim, Seoyoung/0000-0002-2517-3579 FU American College of Rheumatology FX The Reproductive Health Summit and preparation of this manuscript were supported by funding from the American College of Rheumatology. NR 106 TC 13 Z9 13 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD MAR PY 2015 VL 67 IS 3 BP 313 EP 325 DI 10.1002/acr.22516 PG 13 WC Rheumatology SC Rheumatology GA CC4BK UT WOS:000350295500001 PM 25385050 ER PT J AU Li, WW Rong, PF Yang, K Huang, P Sun, K Chen, XY AF Li, Wanwan Rong, Pengfei Yang, Kai Huang, Peng Sun, Kang Chen, Xiaoyuan TI Semimetal nanomaterials of antimony as highly efficient agent for photoacoustic imaging and photothermal therapy SO BIOMATERIALS LA English DT Article DE Semimetal; Antimony; Nanorod bundles; Photothermal therapy (PTT); Photoacoustic imaging (PAI) ID NEAR-INFRARED ABSORBENCY; REDUCED GRAPHENE OXIDE; CELLS IN-VIVO; CANCER-CELLS; GOLD NANORODS; CARBON NANOTUBES; FORMIC-ACID; NANOPARTICLES; ABLATION; NANOCRYSTALS AB In this study we report semimetal nanomaterials of antimony (Sb) as highly efficient agent for photo-acoustic imaging (PAI) and photothermal therapy (PTT). The Sb nanorod bundles have been synthesized through a facile route by mixing 1-octadecane (ODE) and oleyl amine (OAm) as the solvent. The aqueous dispersion of PEGylated Sb NPs, due to its broad and strong photoabsorption ranging from ultraviolet (UV) to near-infrared (NIR) wavelengths, is applicable as a photothermal agent driven by 808 nm laser with photothermal conversion efficiency up to 41%, noticeably higher than most of the PTT agents reported before. Our in vitro experiments also showed that cancer cell ablation effect of PEGylated Sb NPs was dependent on laser power. By intratumoral administration of PEGylated Sb NPs, 100% tumor ablation can be realized by using NIR laser irradiation with a lower power of 1 W/cm(2) for 5 min (or 0.5 W/cm(2) for 10 min) and no obvious toxic side effect is identified after photothermal treatment. Moreover, intense PA signal was also observed after intratumoral injection of PEGylated Sb NPs and NIR laser irradiation due to their strong NIR photoabsorption, suggesting PEGylated Sb NPs as a potential NIR PA agent. Based on the findings of this work, further development of using other semimetal nanocrystals as highly efficient NIR agents can be achieved for vivo tumor imaging and PTT. Published by Elsevier Ltd. C1 [Li, Wanwan; Sun, Kang] Shanghai Jiao Tong Univ, Sch Mat Sci & Engn, State Key Lab Met Matrix Composites, Shanghai 200240, Peoples R China. [Li, Wanwan; Rong, Pengfei; Yang, Kai; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Rong, Pengfei] Cent S Univ, State Key Lab Powder Met, Changsha 410083, Hunan, Peoples R China. [Rong, Pengfei; Huang, Peng] Cent S Univ, Xiangya Hosp 3, Dept Radiol, Changsha 410013, Hunan, Peoples R China. [Yang, Kai] Soochow Univ, SRMP, Suzhou 215123, Jiangsu, Peoples R China. [Yang, Kai] Soochow Univ, Sch Radiol & Interdisciplinary Sci RAD X, Suzhou 215123, Jiangsu, Peoples R China. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM wwli@sjtu.edu.cn; shawn.chen@nih.gov RI Huang, Peng/H-9985-2013; Huang, Peng/R-2480-2016 OI Huang, Peng/0000-0003-3651-7813 FU National Natural Science Foundation of China [50902093, 81371596, 81371645]; National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Basic Research Program of China (973 program) [2010CB933901, 2013CB733802, 2014CB744503] FX This work was supported in part, by the National Basic Research Program of China (973 program, 2010CB933901, 2013CB733802, 2014CB744503), the National Natural Science Foundation of China (Project No. 50902093, 81371596 and 81371645) and by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). NR 59 TC 21 Z9 22 U1 17 U2 152 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD MAR PY 2015 VL 45 BP 18 EP 26 DI 10.1016/j.biomaterials.2014.12.037 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CC2RD UT WOS:000350191400003 PM 25662491 ER PT J AU Skaar, JR Ferris, AL Wu, XL Saraf, A Khanna, KK Florens, L Washburn, MP Hughes, SH Pagano, M AF Skaar, Jeffrey R. Ferris, Andrea L. Wu, Xiaolin Saraf, Anita Khanna, Kum Kum Florens, Laurence Washburn, Michael P. Hughes, Stephen H. Pagano, Michele TI The Integrator complex controls the termination of transcription at diverse classes of gene targets SO CELL RESEARCH LA English DT Article DE Integrator; snRNA; histone; termination; RNA Polyermase II; processing ID RNA-POLYMERASE-II; DNA-DAMAGE RESPONSE; PROTEIN IDENTIFICATION TECHNOLOGY; HISTONE MESSENGER-RNAS; SMALL NUCLEAR-RNA; 3' END FORMATION; SNRNA GENES; PREMATURE TERMINATION; GENOMIC STABILITY; PAUSE SITES AB Complexes containing INTS3 and either NABP1 or NABP2 were initially characterized in DNA damage responses, but their biochemical function remained unknown. Using affinity purifications and HIV Integration targeting-sequencing (HIT-Seq), we find that these complexes are part of the Integrator complex, which binds RNA Polymerase II and regulates specific target genes. Integrator cleaves snRNAs as part of their processing to their mature form in a mechanism that is intimately coupled with transcription termination. However, HIT-Seq reveals that Integrator also binds to the 3' end of replication-dependent histones and promoter proximal regions of genes with polyadenylated transcripts. Depletion of Integrator subunits results in transcription termination failure, disruption of histone mRNA processing, and polyadenylation of snRNAs and histone mRNAs. Furthermore, promoter proximal binding of Integrator negatively regulates expression of genes whose transcripts are normally polyadenylated. Integrator recruitment to all three gene classes is DSIF-dependent, suggesting that Integrator functions as a termination complex at DSIF-dependent RNA Polymerase II pause sites. C1 [Skaar, Jeffrey R.; Pagano, Michele] NYU, Laura & Isaac Perlmutter Canc Ctr, Sch Med, Dept Pathol, New York, NY 10016 USA. [Pagano, Michele] Howard Hughes Med Inst, New York, NY 10016 USA. [Ferris, Andrea L.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. [Wu, Xiaolin] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD 21702 USA. [Saraf, Anita; Florens, Laurence; Washburn, Michael P.] Stowers Inst Med Res, Kansas City, MO 64110 USA. [Khanna, Kum Kum] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Washburn, Michael P.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66160 USA. RP Skaar, JR (reprint author), NYU, Laura & Isaac Perlmutter Canc Ctr, Sch Med, Dept Pathol, 522 First Ave, New York, NY 10016 USA. EM skaarlab@gmail.com OI pagano, michele/0000-0003-3210-2442; Florens, Laurence/0000-0002-9310-6650; Washburn, Michael/0000-0001-7568-2585 FU National Health and Medical Research Council of Australia; National Institutes of Health [R01-GM057587, R37-CA076584, R21-CA161108]; American Cancer Society; NIH [T32 CA009161]; Stowers Institute for Medical Research; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX We thank E McIntush/Bethyl Laboratories, Inc., CD Allis, W Wang and BD Dynlacht for antibodies, and CM Hughes, T Milne and S Buratowski for critical reading of the manuscript. We are grateful to J Meyer for his help with figure assembly. This work was funded by grants from the National Health and Medical Research Council of Australia to KKK and grants from the National Institutes of Health (R01-GM057587, R37-CA076584, and R21-CA161108) to MP. JRS is a Special Fellow of The Leukemia & Lymphoma Society, received support from the Mr. and Mrs. William G Campbell Postdoctoral Fellowship in Memory of Carolyn Cabott from the American Cancer Society, and is currently supported by NIH T32 CA009161 (Levy). A Saraf, L Florens, and MP Washburn are supported by the Stowers Institute for Medical Research. The Hughes laboratory was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. This project has been funded in part (XW) with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. NR 59 TC 14 Z9 14 U1 0 U2 2 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYANG ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 EI 1748-7838 J9 CELL RES JI Cell Res. PD MAR PY 2015 VL 25 IS 3 BP 288 EP 305 DI 10.1038/cr.2015.19 PG 18 WC Cell Biology SC Cell Biology GA CC7SN UT WOS:000350568800006 PM 25675981 ER PT J AU Schutz, B Schafer, MKH Gordes, M Eiden, LE Weihe, E AF Schuetz, Burkhard Schaefer, Martin K. -H. Goerdes, Markus Eiden, Lee E. Weihe, Eberhard TI Satb2-Independent Acquisition of the Cholinergic Sudomotor Phenotype in Rodents SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE Acetylcholine; Catecholamine; Cholinergic gene locus; Development; Neuropeptide; Sudomotor; Sympathetic ID VESICULAR ACETYLCHOLINE TRANSPORTER; POSTGANGLIONIC SYMPATHETIC NEURONS; SUPERIOR CERVICAL-GANGLION; PERIPHERAL NERVOUS-SYSTEM; SWEAT GLAND INNERVATION; NEUROTRANSMITTER PHENOTYPE; GENE LOCUS; DIFFERENTIATION; EXPRESSION; SATB2 AB Expression of Satb2 (Special AT-rich sequence-binding protein-2) elicits expression of the vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) in cultured rat sympathetic neurons exposed to soluble differentiation factors. Here, we determined whether or not Satb2 plays a similar role in cholinergic differentiation in vivo, by comparing the postnatal profile of Satb2 expression in the rodent stellate ganglion to that of VAChT and ChAT. Throughout postnatal development, VAChT and ChAT were found to be co-expressed in a numerically stable subpopulation of rat stellate ganglion neurons. Nerve fibers innervating rat forepaw sweat glands on P1 were VAChT immunoreactive, while ChAT was detectable at this target only after P5. The postnatal abundance of VAChT transcripts in the stellate ganglion was at maximum already on P1, whereas ChAT mRNA levels increased from low levels on P1 to reach maximum levels between P5 and P21. Satb2 mRNA was detected in cholinergic neurons in the stellate ganglion beginning with P8, thus coincident with the onset of unequivocal detection of ChAT immunoreactivity in forepaw sweat gland endings. Satb2 knockout mice exhibited no change in the P1 cholinergic VAChT/ChAT co-phenotype in stellate ganglion neurons. Thus, cholinergic phenotype maturation involves first, early target (sweat-gland)-independent expression and trafficking of VAChT, and later, potentially target- and Satb2-dependent elevation of ChAT mRNA and protein transport into sweat gland endings. In rat sudomotor neurons that, unlike mouse sudomotor neurons, co-express calcitonin gene-related peptide (CGRP), Satb2 may also be related to the establishment of species-specific neuropeptide co-phenotypes during postnatal development. C1 [Schuetz, Burkhard; Schaefer, Martin K. -H.; Goerdes, Markus; Weihe, Eberhard] Univ Marburg, Inst Anat & Cell Biol, Dept Mol Neurosci, D-35037 Marburg, Germany. [Eiden, Lee E.] NIMH, Mol Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Schutz, B (reprint author), Univ Marburg, Inst Anat & Cell Biol, Dept Mol Neurosci, Robert Koch Str 8, D-35037 Marburg, Germany. EM schuetzb@staff.uni-marburg.de; weihe@staff.uni-marburg.de OI Eiden, Lee/0000-0001-7524-944X FU LOEWE-Schwerpunkt 'Non-Neuronal Cholinergic Systems' of Justus Liebig University in Giessen, Germany FX The authors are grateful to Prof. Rudi Grosschedl (Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany) for providing Satb2 mutant mice. We also thank Marion Zibuschka, Carola Gackler, and Heidi Hlawaty for excellent technical assistance. Burkhard Schutz and Eberhard Weihe received financial support within the framework of LOEWE-Schwerpunkt 'Non-Neuronal Cholinergic Systems' of Justus Liebig University in Giessen, Germany. NR 37 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 EI 1573-6830 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD MAR PY 2015 VL 35 IS 2 BP 205 EP 216 DI 10.1007/s10571-014-0113-2 PG 12 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA CC3HG UT WOS:000350236800007 PM 25239161 ER PT J AU Balbus, JM Greenblatt, JB Chari, R Millstein, D Ebi, KL AF Balbus, John M. Greenblatt, Jeffery B. Chari, Ramya Millstein, Dev Ebi, Kristie L. TI A wedge-based approach to estimating health co-benefits of climate change mitigation activities in the United States (vol 127, pg 199, 2014) SO CLIMATIC CHANGE LA English DT Correction C1 [Balbus, John M.] NIEHS, Bethesda, MD 20892 USA. [Greenblatt, Jeffery B.; Millstein, Dev] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. [Chari, Ramya] RAND Corp, Santa Monica, CA USA. [Ebi, Kristie L.] Univ Washington, Seattle, WA 98195 USA. RP Balbus, JM (reprint author), NIEHS, 31 Ctr Dr,Room B1C02, Bethesda, MD 20892 USA. EM john.balbus@nih.gov NR 2 TC 0 Z9 0 U1 3 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-0009 EI 1573-1480 J9 CLIMATIC CHANGE JI Clim. Change PD MAR PY 2015 VL 129 IS 1-2 BP 363 EP 364 DI 10.1007/s10584-015-1336-z PG 2 WC Environmental Sciences; Meteorology & Atmospheric Sciences SC Environmental Sciences & Ecology; Meteorology & Atmospheric Sciences GA CC4VP UT WOS:000350352800027 ER PT J AU Scadding, GW Eifan, A Penagos, M Dumitru, A Switzer, A McMahon, O Phippard, D Togias, A Durham, SR Shamji, MH AF Scadding, G. W. Eifan, A. Penagos, M. Dumitru, A. Switzer, A. McMahon, O. Phippard, D. Togias, A. Durham, S. R. Shamji, M. H. TI Local and systemic effects of cat allergen nasal provocation SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Article DE cat allergy; nasal allergen challenge; tryptase; basophil; cytokine ID LOWER AIRWAYS; CHALLENGE; RHINITIS; RESPONSES; EXPOSURE; ASTHMA; INFLAMMATION; CHILDREN; RESPONSIVENESS; EOSINOPHILIA AB BackgroundCat allergen is widely distributed in homes and schools; allergic sensitization is common. ObjectiveTo develop a model of cat allergen nasal challenge to establish dose-response and time-course characteristics and investigate local and systemic biomarkers of allergic inflammation. MethodsNineteen cat-allergic individuals underwent titrated nasal challenge, range 0.243 to 14.6g/mL Fel d1, and matched diluent-only provocation. Clinical response to 8h was assessed by symptom scores and peak nasal inspiratory flow (PNIF). Nasal fluid was collected using polyurethane sponges and analysed by ImmunoCAP and multiplex assays. Whole blood flow cytometry for basophil surface CD63, CD107a, and CD203c was carried out at baseline and 6h post-challenge. ResultsA dose-response to allergen was seen in symptom scores and PNIF, maximal at 10000 BU/mL (4.87g/mL Fel d1), P<0.0001 vs. diluent. Nasal fluid tryptase was elevated at 5min after challenge (P<0.05 vs. diluent); eotaxin, IL-4, -5, -9, and -13 were increased at 8h (P<0.05 to P<0.0001 vs. diluent); TSLP was undetectable; IL-10, IL-17A, and IL-33 were unchanged compared to diluent challenge. Nasal fluid IL-5 and IL-13 correlated inversely with PNIF after challenge (IL-5, r=-0.79, P<0.0001; IL-13, r=-0.60, P=0.006). Surface expression of CD63 and CD107a was greater at 6h than at baseline, both in the presence (both P<0.05) and absence (CD63, P<0.01; CD107a, P<0.05) of in vitro allergen stimulation; no changes were seen on diluent challenge day. ConclusionsCat allergen nasal challenge produces local and systemic Th2-driven inflammatory responses and has potential as a surrogate outcome measure in clinical trials. C1 [Scadding, G. W.; Eifan, A.; Penagos, M.; Dumitru, A.; Switzer, A.; McMahon, O.; Durham, S. R.; Shamji, M. H.] Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. [Phippard, D.] Immune Tolerance Network, Bethesda, MD USA. [Togias, A.] NIAID, Bethesda, MD 20892 USA. [Shamji, M. H.] Univ London Imperial Coll Sci Technol & Med, Immunomodulat & Tolerance Grp, London SW7 2AZ, England. RP Shamji, MH (reprint author), Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Sir Alexander Fleming Bldg, London SW7 2AZ, England. EM m.shamji99@imperial.ac.uk OI Eifan, Aarif/0000-0003-4098-4211 FU Wellcome Trust NR 39 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0954-7894 EI 1365-2222 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD MAR PY 2015 VL 45 IS 3 BP 613 EP 623 DI 10.1111/cea.12434 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA CC6DT UT WOS:000350455800007 PM 25303516 ER PT J AU Barrenas, F Green, RR Thomas, MJ Law, GL Proll, SC Engelmann, F Messaoudi, I Marzi, A Feldmann, H Katze, MG AF Barrenas, Fredrik Green, Richard R. Thomas, Matthew J. Law, G. Lynn Proll, Sean C. Engelmann, Flora Messaoudi, Ilhem Marzi, Andrea Feldmann, Heinz Katze, Michael G. TI Next-Generation Sequencing Reveals a Controlled Immune Response to Zaire Ebola Virus Challenge in Cynomolgus Macaques Immunized with Vesicular Stomatitis Virus Expressing Zaire Ebola Virus Glycoprotein (VSV Delta G/EBOVgp) SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID NONHUMAN-PRIMATES; PROTECTION; INFECTION; CELLS AB Vesicular stomatitis virus expressing Zaire Ebola virus (EBOV) glycoprotein (VSV Delta G/EBOVgp) could be used as a vaccine to meet the 2014 Ebola virus outbreak. To characterize the host response to this vaccine, we used mRNA sequencing to analyze peripheral blood mononuclear cells (PBMCs) from cynomolgus macaques after VSV Delta G/EBOVgp immunization and subsequent EBOV challenge. We found a controlled transcriptional response that transitioned to immune regulation as the EBOV was cleared. This observation supports the safety of the vaccine. C1 [Barrenas, Fredrik; Green, Richard R.; Thomas, Matthew J.; Law, G. Lynn; Proll, Sean C.; Katze, Michael G.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Barrenas, Fredrik; Green, Richard R.; Thomas, Matthew J.; Law, G. Lynn; Proll, Sean C.; Katze, Michael G.] Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Barrenas, Fredrik] Uppsala Univ, Dept Cell & Mol Biol, Uppsala, Sweden. [Engelmann, Flora] Vaccine & Gene Therapy Inst, Beaverton, OR USA. [Messaoudi, Ilhem] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Katze, MG (reprint author), Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. EM honey@uw.edu FU NIH HHS [P51 OD010425] NR 14 TC 3 Z9 3 U1 1 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD MAR PY 2015 VL 22 IS 3 BP 354 EP 356 DI 10.1128/CVI.00733-14 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC4OW UT WOS:000350333700015 PM 25589554 ER PT J AU El-Maouche, D Collier, S Prasad, M Reynolds, JC Merke, DP AF El-Maouche, Diala Collier, Suzanne Prasad, Mala Reynolds, James C. Merke, Deborah P. TI Cortical bone mineral density in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency SO CLINICAL ENDOCRINOLOGY LA English DT Article ID CLINICAL-PRACTICE GUIDELINE; YOUNG-ADULT PATIENTS; BODY-COMPOSITION; CHILDREN; WOMEN; TURNOVER; DEHYDROEPIANDROSTERONE; REPLACEMENT; ANDROGENS; THERAPY AB BackgroundPrior studies reveal that bone mineral density (BMD) in congenital adrenal hyperplasia (CAH) is mostly in the osteopaenic range and is associated with lifetime glucocorticoid dose. The forearm, a measure of cortical bone density, has not been evaluated. ObjectiveWe aimed to evaluate BMD at various sites, including the forearm, and the factors associated with low BMD in CAH patients. MethodsEighty CAH adults (47 classic, 33 nonclassic) underwent dual-energy-x-ray absorptiometry and laboratory and clinical evaluation. BMD Z-scores at the AP spine, total hip, femoral neck, forearm and whole body were examined in relation to phenotype, body mass index, current glucocorticoid dose, average 5-year glucocorticoid dose, vitamin D, 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone and dehydroepiandrosterone sulphate (DHEAS). ResultsReduced BMD (T-score <-1 at hip, spine, or forearm) was present in 52% and was more common in classic than nonclassic patients (P=0005), with the greatest difference observed at the forearm (P=001). Patients with classic compared to nonclassic CAH, had higher 17-hydroxyprogesterone (P=0005), lower DHEAS (P=00002) and higher non-traumatic fracture rate (P=00005). In a multivariate analysis after adjusting for age, gender, height standard deviation, phenotype and cumulative glucocorticoid exposure, higher DHEAS was independently associated with higher BMD at the spine, radius and whole body. ConclusionClassic CAH patients have lower BMD than nonclassic patients, with the most affected area being the forearm. This first study of forearm BMD in CAH patients suggests that low DHEAS may be associated with weak cortical bone independent of glucocorticoid exposure. C1 [El-Maouche, Diala] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [El-Maouche, Diala; Collier, Suzanne; Merke, Deborah P.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Prasad, Mala; Reynolds, James C.] NIH, Radiol & Imaging Sci Dept, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Merke, DP (reprint author), NIH, Ctr Clin, Bldg 10,Room 1-2740,10 Ctr Dr,Mail Stop Code 1932, Bethesda, MD 20892 USA. EM dmerke@nih.gov OI El-Maouche, Diala/0000-0002-0936-2249 FU Eunice Kennedy Shriver National Institute of Child health and Human Development (NICHD); National Institutes of Health Clinical Center FX This work was supported by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child health and Human Development (NICHD) and the National Institutes of Health Clinical Center. DPM is a Commissioned Officer in the United States Public Health Service. NR 36 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD MAR PY 2015 VL 82 IS 3 BP 330 EP 337 DI 10.1111/cen.12507 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC1QE UT WOS:000350115600003 PM 24862755 ER PT J AU Mason, C Xiao, L Imayama, I Duggan, CR Campbell, KL Kong, A Wang, CY Alfano, CM Blackburn, GL Foster-Schubert, KE McTiernan, A AF Mason, Caitlin Xiao, Liren Imayama, Ikuyo Duggan, Catherine R. Campbell, Kristin L. Kong, Angela Wang, Ching-Yun Alfano, Catherine M. Blackburn, George L. Foster-Schubert, Karen E. McTiernan, Anne TI The effects of separate and combined dietary weight loss and exercise on fasting ghrelin concentrations in overweight and obese women: a randomized controlled trial SO CLINICAL ENDOCRINOLOGY LA English DT Article ID LONG-TERM REGULATION; BODY-WEIGHT; POSTMENOPAUSAL WOMEN; INSULIN SENSITIVITY; FOOD-INTAKE; FAT MASS; INTERVENTION; APPETITE; LEPTIN; HOMEOSTASIS AB ObjectiveCompensatory metabolic changes that accompany weight loss, for example, increased ghrelin, contribute to weight regain and difficulty in long-term weight loss maintenance; however, the separate effects of long-term caloric restriction and exercise on total circulating ghrelin in humans are unknown. DesignA 12-month randomized controlled trial comparing: i) dietary weight loss with a 10% weight loss goal (diet'; n=118); ii) moderate-to-vigorous intensity aerobic exercise for 45min/day, 5days/week (exercise'; n=117); iii) dietary weight loss and exercise (diet+exercise'; n=117); or iv) no-lifestyle-change control (n=87). Participants: 439 overweight or obese postmenopausal women (50-75 y). MeasurementsFasting total serum ghrelin was measured by radioimmunoassay at baseline and 12months. Fasting serum leptin, adiponectin and insulin were also measured. ResultsFasting total ghrelin significantly increased in the diet + exercise arm (+74%, P=0008) but not in either the diet (+65%, P=007) or exercise (+10%, P=053) arms compared with control. Greater weight loss was associated with increased ghrelin concentrations, regardless of intervention. Neither baseline ghrelin nor body composition modified the intervention effects on changes in total ghrelin. The 12-month change in total ghrelin was inversely associated with changes in leptin, insulin and insulin resistance, and positively associated with change in adiponectin. ConclusionsGreater weight loss, achieved through a reduced calorie diet or exercise, is associated with increased total ghrelin concentrations in overweight or obese postmenopausal women. C1 [Mason, Caitlin; Xiao, Liren; Imayama, Ikuyo; Duggan, Catherine R.; Wang, Ching-Yun; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Campbell, Kristin L.] Univ British Columbia, Dept Physiotherapy, Vancouver, BC V5Z 1M9, Canada. [Kong, Angela] Univ Illinois, Inst Hlth Res & Policy, Chicago, IL USA. [Wang, Ching-Yun; McTiernan, Anne] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. [Blackburn, George L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Nutr, Boston, MA 02215 USA. [Foster-Schubert, Karen E.] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. RP McTiernan, A (reprint author), Fred Hutchinson Canc Res Ctr, M4-B874,POB 19024, Seattle, WA 98109 USA. EM amctiern@fhcrc.org RI Duggan, Catherine/F-9414-2015; Biguzzi, Felipe/E-4724-2015 OI Duggan, Catherine/0000-0001-7369-4021; FU NIH [R01 CA102504, U54-CA116847, 5KL2RR025015-03, R25 CA94880, 2R25CA057699]; Canadian Institutes of Health Research Fellowship FX NIH grants R01 CA102504, U54-CA116847, 5KL2RR025015-03, R25 CA94880 and 2R25CA057699; and a Canadian Institutes of Health Research Fellowship. NR 35 TC 7 Z9 7 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD MAR PY 2015 VL 82 IS 3 BP 369 EP 376 DI 10.1111/cen.12483 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC1QE UT WOS:000350115600008 PM 24796864 ER PT J AU Dogan, BA Karakilic, E Tuna, MM Arduc, A Berker, D Guler, S AF Dogan, Bercem Aycicek Karakilic, Ersen Tuna, Mazhar Muslum Arduc, Ayse Berker, Dilek Gueler, Serdar TI Effect of androgen replacement therapy on atherosclerotic risk markers in young-to-middle-aged men with idiopathic hypogonadotropic hypogonadism SO CLINICAL ENDOCRINOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; LOW SERUM TESTOSTERONE; METABOLIC SYNDROME; ELDERLY-MEN; ENDOTHELIAL FUNCTION; INSULIN-RESISTANCE; OLDER MEN; CAROTID ATHEROSCLEROSIS; ENDOGENOUS TESTOSTERONE; CARDIOVASCULAR-DISEASE AB ObjectiveIdiopathic hypogonadotropic hypogonadism is a rare disorder. This study evaluated the effect of androgen replacement therapy on atherosclerotic risk markers in young-to-middle-aged men with this disorder. Design and methodsForty-three male patients aged 30 (range: 24-39years) who were newly diagnosed with idiopathic hypogonadotropic hypogonadism and 20 age-, sex- and weight-matched controls (range: 26-39years) were included in the study. Androgen replacement therapy was given according to the Algorithm of Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes (2010; Journal of Clinical Endocrinology and Metabolism, 95, 2536). The patients were assessed at a pretreatment visit and 3 and 6months after the treatment. Inflammatory markers and lipid parameters were evaluated. Endothelial function was assessed with brachial flow-mediated dilation of a brachial artery and high-resolution ultrasonography of the carotid intima-media thickness. ResultsThe carotid intima-media thickness (P<0001) was higher and the brachial flow-mediated diameter (P=0002) was lower in patients with idiopathic hypogonadotropic hypogonadism compared to the control subjects at the pretreatment visit. There was a negative correlation between the total testosterone level and carotid intima-media thickness (r=-0556, P=<0001). The carotid intima-media thickness and per cent flow-mediated diameter were significantly improved in the patient group 6months after the androgen replacement therapy (P=0002 and 0026, respectively). ConclusionsThis study indicated that low total testosterone levels can be considered a significant marker of atherosclerosis in patients with idiopathic hypogonadotropic hypogonadism and that androgen replacement therapy significantly reduces atherosclerotic risk markers in these patients after 6months. C1 [Dogan, Bercem Aycicek] Darica Farabi State Hosp, Dept Endocrinol & Metab Dis, TR-41000 Darica, Kocaeli, Turkey. [Karakilic, Ersen; Berker, Dilek] Ankara Numune Training & Res Hosp, Dept Endocrinol & Metab Dis, Ankara, Turkey. [Tuna, Mazhar Muslum] Dicle Univ, Dept Endocrinol & Metab Dis, Diyarbakir, Turkey. [Arduc, Ayse] NIDDK, Dept Diabet, Endocrine & Obes Branch, NIH, Bethesda, MD 20892 USA. [Gueler, Serdar] Hitit Univ, Dept Endocrinol & Metab Dis, Corum, Turkey. RP Dogan, BA (reprint author), Darica Farabi State Hosp, Dept Endocrinol & Metab, TR-41000 Darica, Kocaeli, Turkey. EM bercemay@gmail.com NR 43 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD MAR PY 2015 VL 82 IS 3 BP 422 EP 428 DI 10.1111/cen.12617 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC1QE UT WOS:000350115600014 PM 25280063 ER PT J AU Eisenhofer, G Darr, R Pamporaki, C Peitzsch, M Bornstein, S Lenders, JWM AF Eisenhofer, Graeme Darr, Roland Pamporaki, Christina Peitzsch, Mirko Bornstein, Stefan Lenders, Jacques W. M. TI Supine or Sitting? Economic and other considerations for use of plasma metanephrines for diagnosis of phaeochromocytoma SO CLINICAL ENDOCRINOLOGY LA English DT Letter C1 [Eisenhofer, Graeme; Peitzsch, Mirko] Tech Univ Dresden, Inst Clin Chem & Lab Med, D-01062 Dresden, Germany. [Eisenhofer, Graeme; Pamporaki, Christina; Bornstein, Stefan; Lenders, Jacques W. M.] Tech Univ Dresden, Dept Med 2, D-01062 Dresden, Germany. [Darr, Roland] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Lenders, Jacques W. M.] Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, Nijmegen, Netherlands. RP Eisenhofer, G (reprint author), Tech Univ Dresden, Inst Clin Chem & Lab Med, D-01062 Dresden, Germany. EM Graeme.Eisenhofer@uniklinikum-dresden.de RI Lenders, J.W.M./L-4487-2015 NR 5 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD MAR PY 2015 VL 82 IS 3 BP 463 EP 464 DI 10.1111/cen.12602 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC1QE UT WOS:000350115600020 PM 25186957 ER PT J AU Landon, MB Rice, MM Varner, MW Casey, BM Reddy, UM Wapner, RJ Rouse, DJ Biggio, JR Thorp, JM Chien, EK Saade, G Peaceman, AM Blackwell, SC VanDorsten, JP AF Landon, Mark B. Rice, Madeline Murguia Varner, Michael W. Casey, Brian M. Reddy, Uma M. Wapner, Ronald J. Rouse, Dwight J. Biggio, Joseph R., Jr. Thorp, John M. Chien, Edward K. Saade, George Peaceman, Alan M. Blackwell, Sean C. VanDorsten, J. Peter CA Eunice Kennedy Shriver Natl Inst TI Mild Gestational Diabetes Mellitus and Long-Term Child Health SO DIABETES CARE LA English DT Article ID BETA-CELL FUNCTION; GLUCOSE-TOLERANCE; MATERNAL OBESITY; INSULIN CONCENTRATIONS; BIRTH-WEIGHT; PREGNANCY; RISK; MOTHERS; WOMEN; HYPERGLYCEMIA AB OBJECTIVE To evaluate whether treatment of mild gestational diabetes mellitus (GDM) confers sustained offspring health benefits, including a lower frequency of obesity. RESEARCH DESIGN AND METHODS Follow-up study of children (ages 5-10) of women enrolled in a multicenter trial of treatment versus no treatment of mild GDM. Height, weight, blood pressure, waist circumference, fasting glucose, fasting insulin, triglycerides, and HDL cholesterol were measured. RESULTS Five hundred of 905 eligible offspring (55%) were enrolled. Maternal baseline characteristics were similar between the follow-up treated and untreated groups. The frequencies of BMI >= 95th (20.8% and 22.9%) and 85th (32.6% and 38.6%) percentiles were not significantly different in treated versus untreated offspring (P = 0.69 and P = 0.26). No associations were observed for BMI z score, log waist circumference, log triglycerides, HDL cholesterol, blood pressure, or log HOMA-estimated insulin resistance (HOMA-IR). The effect of treatment was different by sex for fasting glucose and log HOMA-IR (P for interaction = 0.002 and 0.02, respectively) but not by age-group (5-6 and 7-10 years) for any outcomes. Female offspring of treated women had significantly lower fasting glucose levels. CONCLUSIONS Although treatment for mild GDM has been associated with neonatal benefits, no reduction in childhood obesity or metabolic dysfunction in the offspring of treated women was found. However, only female offspring of women treated for mild GDM had lower fasting glucose. C1 [Landon, Mark B.] Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Rice, Madeline Murguia] George Washington Univ, Biostat Ctr, Washington, DC USA. [Varner, Michael W.] Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Casey, Brian M.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Wapner, Ronald J.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Rouse, Dwight J.] Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Biggio, Joseph R., Jr.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Thorp, John M.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Chien, Edward K.] Case Western Reserve Univ, Dept Obstet & Gynecol, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Saade, George] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Peaceman, Alan M.] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Blackwell, Sean C.] Univ Texas Houston, Hlth Sci Ctr, Childrens Mem Hermann Hosp, Dept Obstet & Gynecol, Houston, TX USA. [VanDorsten, J. Peter] Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. RP Landon, MB (reprint author), Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. EM mark.landon@osumc.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD-27915, HD-36801, HD-34208, HD-34116, HD-40485, HD-40500, HD-27869, HD-40560, HD-40544, HD-53097, HD-40512, HD-40545]; National Institutes of Health (NIH) National Center for Advancing Translational Sciences [UL1-TR-001070, UL1-TR-000439] FX This project was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-27915, HD-36801, HD-34208, HD-34116, HD-40485, HD-40500, HD-27869, HD-40560, HD-40544, HD-53097, HD-40512, and HD-40545) and the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (UL1-TR-001070 and UL1-TR-000439). Comments and views of the authors do not necessarily represent views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the NIH. NR 32 TC 27 Z9 28 U1 1 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2015 VL 38 IS 3 BP 445 EP 452 DI 10.2337/dc14-2159 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC4EN UT WOS:000350303700030 PM 25414152 ER PT J AU Abraham, TM Pencina, KM Pencina, MJ Fox, CS AF Abraham, Tobin M. Pencina, Karol M. Pencina, Michael J. Fox, Caroline S. TI Trends in Diabetes Incidence: The Framingham Heart Study SO DIABETES CARE LA English DT Article ID UNITED-STATES; US ADULTS; PREVALENCE; OBESITY; OVERWEIGHT; GLUCOSE AB OBJECTIVE Obesity and type 2 diabetes continue to increase in prevalence in the U.S. Whether diabetes incidence continues to increase in recent times is less well documented. We examined trends in diabetes incidence over the previous four decades. RESEARCH DESIGN AND METHODS Framingham Heart Study participants ages 40-55 years and free of diabetes at baseline (n = 4,795; mean age 45.3 years; 51.6% women) were followed for the development of diabetes in the 1970s, 1980s, 1990s, and 2000s. Diabetes was defined as either fasting glucose >= 126 mg/dL or use of antidiabetes medication. Poisson regression was used to calculate sex-specific diabetes incidence rates for a 47-year-old individual in each decade. Rates were also calculated among obese, overweight, and normal weight individuals. RESULTS The annualized rates of diabetes per 1,000 individuals were 2.6, 3.8, 4.7, and 3.0 (women) and 3.4, 4.5, 7.4, and 7.3 (men) in the 1970s, 1980s, 1990s, and 2000s, respectively. Compared with the 1970s, the age-and sex-adjusted relative risks of diabetes were 1.37 (95% CI 0.87-2.16; P = 0.17), 1.99 (95% CI 1.30-3.03; P = 0.001), and 1.81 (95% CI 1.16-2.82; P = 0.01) in the 1980s, 1990s, and 2000s, respectively. Compared with the 1990s, the relative risk of diabetes in the 2000s was 0.85 (95% CI 0.61-1.20; P = 0.36). CONCLUSIONS In our community-based sample, the risk of new-onset diabetes continued to be higher in the 2000s compared with the 1970s. In the past decade, diabetes incidence remained steady despite the ongoing trend of rising adiposity. C1 [Abraham, Tobin M.; Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Abraham, Tobin M.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Pencina, Karol M.] Boston Univ, Dept Math & Stat, Stat & Consulting Unit, Boston, MA 02215 USA. [Pencina, Michael J.] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Pencina, Michael J.] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] NHLBI, Bethesda, MD 20892 USA. RP Fox, CS (reprint author), Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, 75 Francis St, Boston, MA 02115 USA. EM foxca@nhlbi.nih.gov FU National Institutes of Health; [N01-HC-25195] FX The Framingham Heart Study of the National Heart, Lung, and Blood Institute is supported by contract N01-HC-25195. T.M.A. is supported by a National Institutes of Health-sponsored T32 training grant. NR 15 TC 14 Z9 14 U1 0 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2015 VL 38 IS 3 BP 482 EP 487 DI 10.2337/dc14-1432 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC4EN UT WOS:000350303700035 PM 25552418 ER PT J AU Groseth, A Wollenberg, KR Mampilli, V Shupert, T Weisend, C Guevara, C Kochel, TJ Tesh, RB Ebihara, H AF Groseth, Allison Wollenberg, Kurt R. Mampilli, Veena Shupert, Taylor Weisend, Carla Guevara, Carolina Kochel, Tadeusz J. Tesh, Robert B. Ebihara, Hideki TI Spatiotemporal Analysis of Guaroa Virus Diversity, Evolution, and Spread in South America SO EMERGING INFECTIOUS DISEASES LA English DT Article AB We conducted phylogeographic modeling to determine the introduction and spread of Guaroa virus in South America. The results suggest a recent introduction of this virus into regions of Peru and Bolivia over the past 60-70 years and emphasize the need for increased surveillance in surrounding areas. C1 [Groseth, Allison; Mampilli, Veena; Shupert, Taylor; Weisend, Carla; Ebihara, Hideki] NIH, Hamilton, MT USA. [Wollenberg, Kurt R.] NIH, Bethesda, MD 20892 USA. [Guevara, Carolina; Kochel, Tadeusz J.] US Naval Med Res Unit 6, Lima, Peru. [Tesh, Robert B.] Univ Texas Med Branch, Galveston, TX 77555 USA. RP Ebihara, H (reprint author), NIAID, Mol Virol & Host Pathogen Interact Unit, Virol Lab, NIH,Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM ebiharah@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases; NIH [HHSN272201000040I/HHSN200004/D04] FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases. R.B.T. was supported by NIH contract HHSN272201000040I/HHSN200004/D04. NR 12 TC 1 Z9 1 U1 0 U2 6 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAR PY 2015 VL 21 IS 3 BP 460 EP 463 DI 10.3201/eid2103.141351 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CC3SI UT WOS:000350269300011 PM 25695188 ER PT J AU Hensley, LE Dyall, J Olinger, GG Jahrling, PB AF Hensley, Lisa E. Dyall, Julie Olinger, Gene G., Jr. Jahrling, Peter B. TI Lack of Effect of Lamivudine on Ebola Virus Replication SO EMERGING INFECTIOUS DISEASES LA English DT Letter ID REVERSE-TRANSCRIPTASE; 5'-TRIPHOSPHATE C1 [Hensley, Lisa E.; Dyall, Julie; Olinger, Gene G., Jr.; Jahrling, Peter B.] NIH, Frederick, MD USA. RP Jahrling, PB (reprint author), NIAID, Integrated Res Facil, Div Clin Res, NIH, B8200 Res Plaza Dr, Frederick, MD 21702 USA. EM jahrlingp@niaid.nih.gov FU NIAID NIH HHS [HHSN272200700016I]; PHS HHS [HHSN272200700016I] NR 6 TC 9 Z9 9 U1 1 U2 11 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAR PY 2015 VL 21 IS 3 BP 550 EP 552 DI 10.3201/eid2103.141862 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CC3SI UT WOS:000350269300043 PM 25695153 ER PT J AU Perry, D Sperling, R Katz, R Berry, D Dilts, D Hanna, D Salloway, S Trojanowski, JQ Bountra, C Krams, M Luthman, J Potkin, S Gribkoff, V Temple, R Wang, Y Carrillo, MC Stephenson, D Snyder, H Liu, E Ware, T McKew, J Fields, FO Bain, LJ Bens, C AF Perry, Daniel Sperling, Reisa Katz, Russell Berry, Donald Dilts, David Hanna, Debra Salloway, Stephen Trojanowski, John Q. Bountra, Chas Krams, Michael Luthman, Johan Potkin, Steven Gribkoff, Val Temple, Robert Wang, Yaning Carrillo, Maria C. Stephenson, Diane Snyder, Heather Liu, Enchi Ware, Tony McKew, John Fields, F. Owen Bain, Lisa J. Bens, Cynthia TI Building a roadmap for developing combination therapies for Alzheimer's disease SO EXPERT REVIEW OF NEUROTHERAPEUTICS LA English DT Review DE Alzheimer' disease; combination therapy; collaboration; co-development; novel therapy ID HYPOTHETICAL MODEL; DYNAMIC BIOMARKERS AB Combination therapy has proven to be an effective strategy for treating many of the world's most intractable diseases. A growing number of investigators in academia, industry, regulatory agencies, foundations and advocacy organizations are interested in pursuing a combination approach to treating Alzheimer's disease. A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition, the Critical Path Institute and the Alzheimer's Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality. C1 [Sperling, Reisa] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Katz, Russell] US FDA, San Diego, CA USA. [Berry, Donald] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Dilts, David] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Hanna, Debra; Stephenson, Diane] Crit Path Inst, Tucson, AZ USA. [Salloway, Stephen] Brown Univ, Butler Hosp, Providence, RI 02912 USA. [Trojanowski, John Q.] Univ Penn, Sch Med, Dept Pathol & Lab Med,Inst Ageing, Alzheimers Dis Core Ctr,Ctr Neurodegenerat Dis Re, Philadelphia, PA 19104 USA. [Bountra, Chas] Univ Oxford, Oxford, England. [Krams, Michael] Janssen Pharmaceut, Philadelphia, PA USA. [Luthman, Johan] Eisai & Co Ltd, Philadelphia, PA USA. [Potkin, Steven] Univ Calif Irvine, Irvine, CA USA. [Gribkoff, Val] Elan, San Francisco, CA USA. [Temple, Robert; Wang, Yaning] US FDA, Silver Spring, MD USA. [Carrillo, Maria C.; Snyder, Heather] Alzheimers Assoc, Chicago, IL USA. [Liu, Enchi] Janssen Pharmaceut, San Francisco, CA USA. [Ware, Tony] Eli Lilly & Co, Indianapolis, IN 46285 USA. [McKew, John] NIH, Bethesda, MD 20892 USA. [Fields, F. Owen] Pfizer, Philadelphia, PA USA. [Perry, Daniel; Bens, Cynthia] Alliance Aging Res, Washington, DC 20006 USA. RP Bens, C (reprint author), Alliance Aging Res, Washington, DC 20006 USA. EM cbens@agingresearch.org FU Eli Lilly; Eisai; Avid; Janssen; Biogen Idec; Merck Lilly; Roche; Genentech; Alkermes; Forest; FORUM Pharmaceuticals; Lundbeck; Merck; Novartis; Otsuka; Sunovion; Takeda; Toyama; Vanda; Wellcome Trust; IMI; Abbvie; Bayer Healthcare; Boehringer Ingelheim; GSK; Pfizer FX JQ Trojanowski may accrue revenue on patents submitted by the University of Pennsylvania on methods and diagnostics that he invented. F Owen Fields is employed by Pfizer and has stock options in Pfizer. R Sperling has served as a consultant to Roche, Isis, Genentech, Janssen and has received research support from Eli Lilly, Eisai, Avid and Janssen. J Luthman is an employee of Eisai and owns shares in AstraZeneca and Merck. S Salloway has received research support from Biogen Idec, Merck Lilly, Roche and Genentech. J McKew was an employee of aTyr pharma at the time of publication. V Gribkoff was an employee of Elan at the time of the meeting. S Potkin has received grant support, funding, honoraria, consultancy fees from the following companies; Alkermes, Eli Lilly, Forest, FORUM Pharmaceuticals, Genentech, Janssen, Lundbeck, Merck, Novartis, Otsuka, Roche, Sunovion, Takeda, Toyama and Vanda. E Liu is an employee of Janssen. C Bountra is funded by the Wellcome Trust, IMI, Abbvie, Bayer Healthcare, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Merck, Novartis, Pfizer and Takeda. M Krams is employed by J&J. D Berry is co-owner of Berry Consultants, LLC. JA Ware is a full time employee of Eli Lilly. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 12 TC 6 Z9 6 U1 2 U2 12 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7175 EI 1744-8360 J9 EXPERT REV NEUROTHER JI Expert Rev. Neurother. PD MAR PY 2015 VL 15 IS 3 BP 327 EP 333 DI 10.1586/14737175.2015.996551 PG 7 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CC3KD UT WOS:000350245800010 PM 25708309 ER PT J AU Vuppalanchi, R Navarro, V Vega, M Bonkovsky, HL Seeff, L Serrano, J AF Vuppalanchi, Raj Navarro, Victor Vega, Maricruz Bonkovsky, Herbert L. Seeff, Leonard Serrano, Jose TI Herbal Dietary Supplement Associated Hepatotoxicity: An Upcoming Workshop and Need for Research SO GASTROENTEROLOGY LA English DT Editorial Material ID INDUCED LIVER-INJURY; NATIONAL-SURVEY C1 [Vuppalanchi, Raj] Indiana Univ, Div Gastroenterol & Hepatol, Indianapolis, IN 46204 USA. [Navarro, Victor; Vega, Maricruz; Seeff, Leonard] Einstein Med Ctr, Div Hepatol, Philadelphia, PA USA. [Bonkovsky, Herbert L.] Wake Forest Univ, Sch Med, Dept Internal Med, Sect Gastroenterol & Mol Med, Winston Salem, NC 27109 USA. [Bonkovsky, Herbert L.] Wake Forest Univ, Sch Med, Dept Internal Med, Sect Translat Sci, Winston Salem, NC 27109 USA. [Serrano, Jose] NIDDK, Bethesda, MD 20892 USA. RP Vuppalanchi, R (reprint author), Indiana Univ, Div Gastroenterol & Hepatol, Indianapolis, IN 46204 USA. OI Vuppalanchi, Raj/0000-0003-0637-1577 FU NCATS NIH HHS [UL1 TR001108]; NIDDK NIH HHS [1U01DK065176, U01 DK065201, U01 DK065184, 1U01DK065021, 1U01DK065201, U01 DK065238, U01 DK065211, U01 DK065193, U01 DK065176, 1U01DK065184, 1U01DK065193, 1U01DK065211, 1U01DK065238] NR 12 TC 2 Z9 2 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2015 VL 148 IS 3 BP 480 EP 482 DI 10.1053/j.gastro.2015.01.004 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CB9QX UT WOS:000349968200010 PM 25579757 ER PT J AU Contreras, AV Rangel-Escareno, C Torres, N Aleman-Escondrillas, G Ortiz, V Noriega, LG Torre-Villalvazo, I Granados, O Velazquez-Villegas, LA Tobon-Cornejo, S Gonzalez-Hirschfeld, D Recillas-Targa, F Tejero-Barrera, E Gonzalez, FJ Tovar, AR AF Contreras, Alejandra V. Rangel-Escareno, Claudia Torres, Nimbe Aleman-Escondrillas, Gabriela Ortiz, Victor Noriega, Lilia G. Torre-Villalvazo, Ivan Granados, Omar Velazquez-Villegas, Laura A. Tobon-Cornejo, Sandra Gonzalez-Hirschfeld, Diana Recillas-Targa, Felix Tejero-Barrera, Elizabeth Gonzalez, Frank J. Tovar, Armando R. TI PPAR alpha via HNF4 alpha regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis SO GENES AND NUTRITION LA English DT Article DE Amino acid catabolism; Body nitrogen; Ppara-null mice; Dietary protein/carbohydrate ratio ID ACTIVATED-RECEPTOR-ALPHA; SERINE DEHYDRATASE GENE; PEROXISOME PROLIFERATORS; CARBOHYDRATE-DIET; CYCLIC-AMP; LIVER; PROTEIN; RATS; MICE; AMINOTRANSFERASE AB The liver is the main organ involved in the metabolism of amino acids (AA), which are oxidized by amino acid catabolizing enzymes (AACE). Peroxisome proliferator-activated receptor-alpha (PPAR alpha) stimulates fatty acid beta-oxidation, and there is evidence that it can modulate hepatic AA oxidation during the transition of energy fuels. To understand the role and mechanism of PPAR alpha's regulation of AA catabolism, the metabolic and molecular adaptations of Ppara-null mice were studied. The role of PPAR alpha on AA metabolism was examined by in vitro and in vivo studies. In wild-type and Ppara-null mice, fed increasing concentrations of the dietary protein/carbohydrate ratio, we measured metabolic parameters, and livers were analyzed by microarray analysis, histology and Western blot. Functional enrichment analysis, EMSA and gene reporter assays were performed. Ppara-null mice presented increased expression of AACE in liver affecting AA, lipid and carbohydrate metabolism. Ppara-null mice had increased glucagon/ insulin ratio (7.2-fold), higher serum urea (73.1 %), lower body protein content (19.7 %) and decreased several serum AA in response to a high-protein/low-carbohydrate diet. A functional network of differentially expressed genes, suggested that changes in the expression of AACE were regulated by an interrelationship between PPAR alpha and HNF4 alpha. Our data indicated that the expression of AACE is down-regulated through PPAR alpha by attenuating HNF4 alpha transcriptional activity as observed in the serine dehydratase gene promoter. PPAR alpha via HNF4 alpha maintains body protein metabolic homeostasis by down-regulating genes involved in amino acid catabolism for preserving body nitrogen. C1 [Contreras, Alejandra V.] Univ Nacl Autonoma Mexico, Programa Doctorado Ciencias Biomed, Fac Med, Mexico City 04510, DF, Mexico. [Contreras, Alejandra V.; Tejero-Barrera, Elizabeth] Inst Nacl Med Genom, Lab Nutrigenet & Nutrigen, Mexico City 14610, DF, Mexico. [Rangel-Escareno, Claudia] Inst Nacl Med Genom, Dept Genom Computac, Mexico City 14610, DF, Mexico. [Torres, Nimbe; Aleman-Escondrillas, Gabriela; Ortiz, Victor; Noriega, Lilia G.; Torre-Villalvazo, Ivan; Granados, Omar; Velazquez-Villegas, Laura A.; Tobon-Cornejo, Sandra; Gonzalez-Hirschfeld, Diana; Tovar, Armando R.] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Fisiol Nutr, Mexico City 14000, DF, Mexico. [Recillas-Targa, Felix] Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Mexico City 04510, DF, Mexico. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Tovar, AR (reprint author), Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Fisiol Nutr, Vasco Quiroga 15 Col Secc 16, Mexico City 14000, DF, Mexico. EM tovar.ar@gmail.com RI Torre-Villalvazo, Ivan/M-2497-2014; Contreras, Alejandra Virginia/E-7815-2013 OI Torre-Villalvazo, Ivan/0000-0001-7412-1153; Contreras, Alejandra Virginia/0000-0003-3653-5958 FU Consejo Nacional de Ciencia y Tecnologia [54939]; Instituto Nacional de Medicina Genomica [16/2011/E] FX We thank Rafael Hernandez and Monica Guevara from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ) for animal care and Guillermo Ordaz from INCMNSZ for assistance in the handling of mice. This work is part of the Doctoral Thesis of A.V.C., who is student in the Programa de Doctorado en Ciencias Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM). This work was supported by Consejo Nacional de Ciencia y Tecnologia, Grant 54939 (to A.R.T.) and the Instituto Nacional de Medicina Genomica, Grant 16/2011/E (to A.V.C.). NR 52 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1555-8932 EI 1865-3499 J9 GENES NUTR JI Genes Nutr. PD MAR PY 2015 VL 10 IS 2 AR 3 DI 10.1007/s12263-014-0452-0 PG 16 WC Genetics & Heredity; Nutrition & Dietetics SC Genetics & Heredity; Nutrition & Dietetics GA CD0HN UT WOS:000350751500001 ER PT J AU Amendola, LM Dorschner, MO Robertson, PD Salama, JS Hart, R Shirts, BH Murray, ML Tokita, MJ Gallego, CJ Kim, DS Bennett, JT Crosslin, DR Ranchalis, J Jones, KL Rosenthal, EA Jarvik, ER Itsara, A Turner, EH Herman, DS Schleit, J Burt, A Jamal, SM Abrudan, JL Johnson, AD Conlin, LK Dulik, MC Santani, A Metterville, DR Kelly, M Foreman, AKM Lee, K Taylor, KD Guo, XQ Crooks, K Kiedrowski, LA Raffe, LJ Gordon, O Machini, K Desnick, R Biesecker, LG Lubitz, SA Mulchandani, S Cooper, GM Joffe, S Richards, CS Yang, YP Rotter, JI Rich, SS O'Donne, CJ Berg, JS Spinner, NB Evans, JP Fullerton, SM Leppig, KA Bennett, RL Bird, T Sybert, VP Grady, WM Tabor, HK Kim, JH Bamshad, MJ Wilfond, B Motulsky, AG Scott, R Pritchard, CC Walsh, TD Burke, W Raskind, WH Byers, P Hisama, FM Rehm, H Nickerson, DA Jarvik, GP AF Amendola, Laura M. Dorschner, Michael O. Robertson, Peggy D. Salama, Joseph S. Hart, Ragan Shirts, Brian H. Murray, Mitzi L. Tokita, Mari J. Gallego, Carlos J. Kim, Daniel Seung Bennett, James T. Crosslin, David R. Ranchalis, Jane Jones, Kelly L. Rosenthal, Elisabeth A. Jarvik, Ella R. Itsara, Andy Turner, Emily H. Herman, Daniel S. Schleit, Jennifer Burt, Amber Jamal, Seema M. Abrudan, Jenica L. Johnson, Andrew D. Conlin, Laura K. Dulik, Matthew C. Santani, Avni Metterville, Danielle R. Kelly, Melissa Foreman, Ann Katherine M. Lee, Kristy Taylor, Kent D. Guo, Xiuqing Crooks, Kristy Kiedrowski, Lesli A. Raffe, Leslie J. Gordon, Ora Machini, Kalotina Desnick, Robe Biesecker, Leslie G. Lubitz, Steven A. Mulchandani, Surabhi Cooper, Greg M. Joffe, Steven Richards, C. Sue Yang, Yaoping Rotter, Jerome I. Rich, Stephen S. O'Donne, Christopher J. Berg, Jonathan S. Spinner, Nancy B. Evans, James P. Fullerton, Stephanie M. Leppig, Kathleen A. Bennett, Robin L. Bird, Thomas Sybert, Virginia P. Grady, William M. Tabor, Holly K. Kim, Jerry H. Bamshad, Michael J. Wilfond, Benjamin Motulsky, Arno G. Scott, Ronald Pritchard, Colin C. Walsh, Tom D. Burke, Wylie Raskind, Wendy H. Byers, Peter Hisama, Fuki M. Rehm, Heidi Nickerson, Debbie A. Jarvik, Gail P. TI Actionable exomic incidental findings in 6503 participants: challenges of variant classification SO GENOME RESEARCH LA English DT Article ID MESSENGER-RNA DECAY; GENOMIC SEQUENCE; GENETIC-VARIANTS; MUTATIONS; IDENTIFICATION; INDIVIDUALS; INSIGHTS; DISEASE AB Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52(1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base. C1 [Amendola, Laura M.; Salama, Joseph S.; Hart, Ragan; Murray, Mitzi L.; Tokita, Mari J.; Gallego, Carlos J.; Bennett, James T.; Crosslin, David R.; Ranchalis, Jane; Rosenthal, Elisabeth A.; Jarvik, Ella R.; Itsara, Andy; Burt, Amber; Bennett, Robin L.; Sybert, Virginia P.; Motulsky, Arno G.; Scott, Ronald; Walsh, Tom D.; Burke, Wylie; Raskind, Wendy H.; Byers, Peter; Hisama, Fuki M.; Jarvik, Gail P.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Dorschner, Michael O.; Robertson, Peggy D.; Kim, Daniel Seung; Crosslin, David R.; Turner, Emily H.; Motulsky, Arno G.; Nickerson, Debbie A.; Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Dorschner, Michael O.; Shirts, Brian H.; Turner, Emily H.; Herman, Daniel S.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Dorschner, Michael O.; Raskind, Wendy H.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Murray, Mitzi L.; Schleit, Jennifer; Byers, Peter] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Bennett, James T.; Jones, Kelly L.; Tabor, Holly K.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Jamal, Seema M.; Scott, Ronald] Univ Washington, Dept Pediat, Div Med Genet, Seattle, WA 98195 USA. [Abrudan, Jenica L.] Childrens Hosp Philadelphia, Dept Genet, Philadelphia, PA 19104 USA. [Abrudan, Jenica L.; Conlin, Laura K.; Dulik, Matthew C.; Santani, Avni; Spinner, Nancy B.] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Johnson, Andrew D.; O'Donne, Christopher J.] NHLBI, Framingham Heart Study, Div Intramural Res, Framingham, MA 01702 USA. [Conlin, Laura K.; Santani, Avni; Spinner, Nancy B.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Dulik, Matthew C.] Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA. [Metterville, Danielle R.; Rehm, Heidi] Partners Healthcare, Mol Med Lab, Boston, MA 02115 USA. [Kelly, Melissa] Partners Healthcare Personalized Med, Boston, MA 02115 USA. [Foreman, Ann Katherine M.; Evans, James P.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Taylor, Kent D.; Guo, Xiuqing; Rotter, Jerome I.] Harbor UCLA, Los Angeles Biomed Res Inst, Translat Genom & Populat Sci, Torrance, CA 90502 USA. [Taylor, Kent D.; Guo, Xiuqing; Rotter, Jerome I.] Harbor UCLA, Dept Pediat, Torrance, CA 90502 USA. [Crooks, Kristy] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27514 USA. [Kiedrowski, Lesli A.] Univ Texas SW Med Ctr Dallas, Dept Canc Genet, Dallas, TX 75390 USA. [Raffe, Leslie J.; Gordon, Ora] Cedars Sinai Med Ctr, Med Genet Res Inst, Los Angeles, CA 90048 USA. [Machini, Kalotina] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Machini, Kalotina; Rehm, Heidi] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Desnick, Robe] Mt Sinai Hosp, Dept Genet & Genom Med, Div Med Genet, New York, NY 10029 USA. [Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Cooper, Greg M.] HudsonAlpha Inst Biotechnol Huntsville, Huntsville, AL 35806 USA. [Joffe, Steven] Univ Penn, Perelman Sch Med, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. [Richards, C. Sue] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA. [Yang, Yaoping] Harbor UCLA, Dept Pediat, Div Infect Dis, Torrance, CA 90502 USA. [Rich, Stephen S.] Harbor UCLA, Dept Pediat, Div Infect Dis, Torrance, CA 90502 USA. [Yang, Yaoping] Harbor UCLA, Los Angeles Biomed Res Inst, Torrance, CA 90502 USA. [Yang, Yaoping] Harbor UCLA, Dept Pediat, Torrance, CA 90502 USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [O'Donne, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Fullerton, Stephanie M.] Massachusetts Gen Hosp, Dept Bioeth & Humanities, Seattle, WA 98195 USA. [Leppig, Kathleen A.; Nickerson, Debbie A.] Grp Hlth Cooperat Puget Sound, Genet Serv, Seattle, WA 98112 USA. [Bird, Thomas] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Bird, Thomas] Vet Affairs Puget Sound Hlth Care Syst Geriatr Re, Seattle, WA 98108 USA. [Sybert, Virginia P.] Grp Hlth Cooperat Puget Sound, Dermatol, Seattle, WA 98112 USA. [Grady, William M.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Grady, William M.] Univ Washington, Dept Med, Div Gastroenterol, Seattle, WA 98195 USA. [Tabor, Holly K.; Wilfond, Benjamin] Seattle Childrens Res Inst, Treuman Katz Ctr Pediat Bioeth, Washington, DC 98105 USA. [Kim, Jerry H.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Wilfond, Benjamin] Univ Washington, Dept Pediat, Div Bioeth, Seattle, WA 98195 USA. RP Amendola, LM (reprint author), Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. EM pair@u.washington.edu RI Burke, William/C-1203-2012; Johnson, Andrew/G-6520-2013; OI Walsh, Tom/0000-0002-8875-0310; Lee, Kristy/0000-0002-8338-7989; Turner, Emily/0000-0001-9040-9229 FU NIH, NHGRI/NCI [U01HG006507, U01HG007307, U01HG006375, U01HG006485, U01HG006500, U01HG006546, UM1HG007301, UM1HG007292, U01HG006487, U01HG006492, U41HG006834]; NIH/NIGMS [T32 GM007454, 1K23HL114724, 5P30CA015704]; Burroughs Wellcome Fund (WMG); Washington State Life Sciences Discovery Fund [2065508]; National Heart, Lung, and Blood Institute (NHLBI); NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926]; Prostate Cancer Foundation Young Investigator Award FX We thank Joshua Akey for sharing his group's ancestry analyses. This work was funded by the NIH, NHGRI/NCI U01HG006507, U01HG007307, U01HG006375, U01HG006485, U01HG006500, U01HG006546, UM1HG007301, UM1HG007292, U01HG006487, U01HG006492, U41HG006834, U41HG006834, NIH/NIGMS T32 GM007454, 1K23HL114724, 5P30CA015704, Burroughs Wellcome Fund (WMG), and Washington State Life Sciences Discovery Fund (2065508, to the Northwest Institute of Genetic Medicine). The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI) and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO), and RC2 HL-102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). Dr. Pritchard is supported by a 2013 Prostate Cancer Foundation Young Investigator Award. The NEXT Medicine return of results committee included A.M., B.W., B.S., C.G., D.N., F.H., G.J, J.P.E., J.K., J.B., K.L., L.A., M.D., M.M., P.B., R.B., R.S., S.M.F., T.B., V.S., W.R., W.G., and W.B. The variant reviewers were A.J., A.D.J., A.S., B.S., C.G., D.H., D.K., ER., E.J., E.T., F.H., Gj., H.T., J.B., J.R., J.S., J.R., J.K., J.B., J.S., K.F., K.J., K.T., K.C., K.L., L.A., L.C., L.K., L.B., L.R., M.T., M.D., M.D., M.M., N.S., O.G., P.B., R.H., R.B., R.S., S.R., S.M., T.W., W.R., W.B., and X.G. NR 28 TC 57 Z9 57 U1 2 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD MAR PY 2015 VL 25 IS 3 BP 305 EP 315 DI 10.1101/gr.183483.114 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA CC7DA UT WOS:000350526700001 PM 25637381 ER PT J AU Taetzsch, T Levesque, S McGraw, C Brookins, S Luqa, R Bonini, MG Mason, RP Oh, U Block, ML AF Taetzsch, Thomas Levesque, Shannon McGraw, Constance Brookins, Savannah Luqa, Rafy Bonini, Marcelo G. Mason, Ronald P. Oh, Unsong Block, Michelle L. TI Redox Regulation of NF-kappa B p50 and M1 Polarization in Microglia SO GLIA LA English DT Article DE microglia; NF-kappa B p50; redox signaling; H2O2; CNS ID NADPH OXIDASE; DOPAMINERGIC NEUROTOXICITY; PARKINSONS-DISEASE; MACROPHAGE POLARIZATION; TARGETED DISRUPTION; SIGNALING PATHWAYS; NITRIC-OXIDE; ACTIVATION; LIPOPOLYSACCHARIDE; NEUROINFLAMMATION AB Redox-signaling is implicated in deleterious microglial activation underlying CNS disease, but how ROS program aberrant microglial function is unknown. Here, the oxidation of NF-kappa B p50 to a free radical intermediate is identified as a marker of dysfunctional M1 (pro-inflammatory) polarization in microglia. Microglia exposed to steady fluxes of H2O2 showed altered NF-kappa B p50 protein-protein interactions, decreased NF-kappa B p50 DNA binding, and augmented late-stage TNF alpha expression, indicating that H2O2 impairs NF-kappa B p50 function and prolongs amplified M1 activation. NF-kappa B p50(-/-) mice and cultures exhibited a disrupted M2 (alternative) response and impaired resolution of the M1 response. Persistent neuroinflammation continued 1 week after LPS (1 mg/kg, IP) administration in the NF-kappa B p50(-/-) mice. However, peripheral inflammation had already resolved in both strains of mice. Treatment with the spin-trap DMPO mildly reduced LPS-induced 22 h TNF alpha in the brain in NF-kappa B p50(+/+) mice. Interestingly, DMPO failed to reduce and strongly augmented brain TNF alpha production in NF-kappa B p50(-/-) mice, implicating a fundamental role for NF-kappa B p50 in the regulation of chronic neuroinflammation by free radicals. These data identify NF-kappa B p50 as a key redox-signaling mechanism regulating the M1/M2 balance in microglia, where loss of function leads to a CNS-specific vulnerability to chronic inflammation. C1 [Taetzsch, Thomas; Levesque, Shannon; McGraw, Constance; Brookins, Savannah; Luqa, Rafy] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Richmond, VA USA. [Bonini, Marcelo G.] Univ Illinois, Dept Med, Cardiol Sect, Chicago, IL USA. [Bonini, Marcelo G.] Univ Illinois, Dept Pharmacol, Chicago, IL USA. [Bonini, Marcelo G.] Univ Illinois, Dept Pathol, Chicago, IL USA. [Mason, Ronald P.] NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. [Oh, Unsong] Virginia Commonwealth Univ, Dept Neurol, Richmond, VA USA. [Block, Michelle L.] Indiana Univ Sch Med, Dept Anat & Cell Biol, Stark Neurosci Res Inst, Indianapolis, IN 46202 USA. RP Block, ML (reprint author), Indiana Univ Sch Med, Dept Anat & Cell Biol, Stark Neurosci Res Inst, Indianapolis, IN 46202 USA. EM mlblock@iupui.edu FU National Institute of Environmental Health Sciences/the National Institute of Health [R01ES016951]; NIH-NINDS Center core grant [5P30NS047463-02] FX Grant sponsor: National Institute of Environmental Health Sciences/the National Institute of Health; Grant number: R01ES016951.; Microscopy and stereology was performed at the VCU Department of Anatomy and Neurobiology Microscopy Facility, which is supported with funding from NIH-NINDS Center core grant (5P30NS047463-02). We thank Scott Henderson, PhD for his stereology expertise and technical assistance with this study. The authors thank Thurn Sams, Maria Bright, and Bryan Rohr for their assistance with maintenance and breeding of timed pregnant animals. NR 59 TC 9 Z9 9 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 EI 1098-1136 J9 GLIA JI Glia PD MAR PY 2015 VL 63 IS 3 BP 423 EP 440 DI 10.1002/glia.22762 PG 18 WC Neurosciences SC Neurosciences & Neurology GA CB9SU UT WOS:000349973600006 PM 25331559 ER PT J AU Meissner, EG Lee, YJ Osinusi, A Sims, Z Qin, J Sturdevant, D McHutchison, J Subramanian, M Sampson, M Naggie, S Patel, K Remaley, AT Masur, H Kottilil, S AF Meissner, Eric G. Lee, Yu-Jin Osinusi, Anu Sims, Zayani Qin, Jing Sturdevant, Dan McHutchison, John Subramanian, Mani Sampson, Maureen Naggie, Susanna Patel, Keyur Remaley, Alan T. Masur, Henry Kottilil, Shyam TI Effect of Sofosbuvir and Ribavirin Treatment on Peripheral and Hepatic Lipid Metabolism in Chronic Hepatitis C Virus, Genotype 1-Infected Patients SO HEPATOLOGY LA English DT Article ID INSULIN-RESISTANCE; VIROLOGICAL RESPONSE; LIVER; EXPRESSION; INFECTION; STEATOSIS; CHOLESTEROL; THERAPY; GENES; PEGINTERFERON AB Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral replication. Chronic HCV infection is associated with altered metabolism, including dyslipidemia and insulin resistance (IR), which contributes to disease progression and influences response to therapy. To further understand the impact of HCV infection on host metabolism, we examined changes in serum lipid profiles and intrahepatic expression of lipid-related genes during interferon (IFN)-free treatment of chronic HCV, genotype 1 infection with sofosbuvir and ribavirin (RBV), and explored associations with treatment outcome. Serum lipids (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TGs]) and hemoglobin A1C (HbA1C) were measured during treatment, while gene expression of lipid-related genes was assessed using paired pre- and end-of-treatment (EOT) liver biopsies from 8 patients (n=7 sustained virologic response [SVR]; n=1 relapse) and unpaired EOT liver biopsies from 25 patients (n=17 SVR; n=8 relapse). Serum LDL concentration and particle size increased early in therapy, whereas TG concentration and very-low-density lipoprotein particle size decreased concomitantly, irrespective of treatment outcome. Whereas LDL increased in patients regardless of treatment outcome, average LDL concentration was lower at baseline and post-treatment in patients who relapsed. Analysis of paired liver biopsies revealed altered expression of genes associated with lipid transport, assembly, and signaling. In unpaired EOT liver biopsies, intrahepatic expression of fatty acid metabolism and lipid transport genes was lower in patients who experienced treatment relapse. Conclusion: Clearance of HCV using an IFN-free antiviral regimen results in rapid changes in peripheral and intrahepatic metabolic pathways, implicating a direct effect of HCV replication on lipid homeostasis. (Hepatology 2015;61:790-801) C1 [Meissner, Eric G.; Lee, Yu-Jin; Osinusi, Anu; Qin, Jing; Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Osinusi, Anu] Univ Maryland, Sch Med, Inst Human Virol, Div Infect Dis, Baltimore, MD 21201 USA. [Sims, Zayani; Masur, Henry] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Sturdevant, Dan] NIAID, Genom Unit, Res Technol Sect, Rocky Mt Labs,NIH, Hamilton, MT USA. [McHutchison, John; Subramanian, Mani] Gilead Sci Inc, Foster City, CA 94404 USA. [Sampson, Maureen; Remaley, Alan T.] NHLBI, Lipoprotein Metab Sect, NIH, Bethesda, MD 20892 USA. [Naggie, Susanna; Patel, Keyur] Duke Univ, Duke Clin Res Inst, Durham, NC USA. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,Bldg 10,Room 11N204, Bethesda, MD 20892 USA. EM SKottilil@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Heart, Lung and Blood Institute; Clinical Research Center of the National Institutes of Health FX This project was funded by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, the National Heart, Lung and Blood Institute, and the Clinical Research Center of the National Institutes of Health. NR 48 TC 19 Z9 19 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD MAR PY 2015 VL 61 IS 3 BP 790 EP 801 DI 10.1002/hep.27424 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CC2BS UT WOS:000350150300012 PM 25203718 ER PT J AU Everhart, JE Ruhl, CE AF Everhart, James E. Ruhl, Constance E. TI Is There a Straightforward Relationship Between Hepatitis C Virus Infection and Diabetes? Reply SO HEPATOLOGY LA English DT Letter C1 [Everhart, James E.] NIDDK, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Ruhl, Constance E.] Social & Sci Syst Inc, Silver Spring, MD USA. RP Everhart, JE (reprint author), NIDDK, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. FU PHS HHS [HHSN276201200161U] NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD MAR PY 2015 VL 61 IS 3 BP 1098 EP 1098 DI 10.1002/hep.27124 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CC2BS UT WOS:000350150300051 PM 24623165 ER PT J AU Cheever, TR Berkley, D Braun, S Brown, RH Byrne, BJ Chamberlain, JS Cwik, V Duan, DS Federoff, HJ High, KA Kaspar, BK Klinger, KW Larkindale, J Lincecum, J Mavilio, F McDonald, CL McLaughlin, J McLeod, BW Mendell, JR Nuckolls, G Stedman, HH Tagle, DA Vandenberghe, LH Wang, H Wernett, PJ Wilson, JM Porter, JD Gubitz, AK AF Cheever, Thomas R. Berkley, Dale Braun, Serge Brown, Robert H. Byrne, Barry J. Chamberlain, Jeffrey S. Cwik, Valerie Duan, Dongsheng Federoff, Howard J. High, Katherine A. Kaspar, Brian K. Klinger, Katherine W. Larkindale, Jane Lincecum, John Mavilio, Fulvio McDonald, Cheryl L. McLaughlin, James McLeod, Bonnie Weiss Mendell, Jerry R. Nuckolls, Glen Stedman, Hansell H. Tagle, Danilo A. Vandenberghe, Luk H. Wang, Hao Wernett, Pamela J. Wilson, James M. Porter, John D. Gubitz, Amelie K. TI Perspectives on Best Practices for Gene Therapy Programs SO HUMAN GENE THERAPY LA English DT Article AB With recent successes in gene therapy trials for hemophilia and retinal diseases, the promise and prospects for gene therapy are once again garnering significant attention. To build on this momentum, the National Institute of Neurological Disorders and Stroke and the Muscular Dystrophy Association jointly hosted a workshop in April 2014 on "Best Practices for Gene Therapy Programs," with a focus on neuromuscular disorders. Workshop participants included researchers from academia and industry as well as representatives from the regulatory, legal, and patient advocacy sectors to cover the gamut from preclinical optimization to intellectual property concerns and regulatory approval. The workshop focused on three key issues in the field: (1) establishing adequate scientific premise for clinical trials in gene therapy, (2) addressing regulatory process issues, and (3) intellectual property and commercialization issues as they relate to gene therapy. The outcomes from the discussions at this workshop are intended to provide guidance for researchers and funders in the gene therapy field. C1 [Cheever, Thomas R.; Nuckolls, Glen; Wang, Hao; Wernett, Pamela J.; Porter, John D.; Gubitz, Amelie K.] NINDS, NIH, Bethesda, MD 20892 USA. [Berkley, Dale] NIH, Off Gen Counsel, Bethesda, MD 20892 USA. [Braun, Serge] Assoc Francaise Myopathies, F-91002 Evry, France. [Brown, Robert H.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. [Byrne, Barry J.] Univ Florida, Sch Med, Dept Pediat, Gainesville, FL 32610 USA. [Chamberlain, Jeffrey S.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Cwik, Valerie] Muscular Dystrophy Assoc, Tucson, AZ 85718 USA. [Duan, Dongsheng] Univ Missouri, Dept Mol Microbiol & Immunol, Columbia, MO 65212 USA. [Federoff, Howard J.] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20057 USA. [High, Katherine A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [High, Katherine A.] Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. [High, Katherine A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kaspar, Brian K.; Mendell, Jerry R.] Nationwide Childrens Hosp, Res Inst, Ctr Gene Therapy, Columbus, OH 43205 USA. [Klinger, Katherine W.] Genzyme Corp, Framingham, MA 01701 USA. [Larkindale, Jane] NMD Consulting, Tucson, AZ 85750 USA. [Lincecum, John] Amyotroph Lateral Sclerosis Therapy Dev Inst, Cambridge, MA 02139 USA. [Mavilio, Fulvio] Genethon, F-91002 Evry, France. [McDonald, Cheryl L.] NHLBI, NIH, Bethesda, MD 20892 USA. [McLaughlin, James] Voyager Therapeut, Cambridge, MA 02139 USA. [McLeod, Bonnie Weiss] Cooley LLP, Washington, DC 20001 USA. [Stedman, Hansell H.] Univ Penn, Perelman Sch Med, Dept Surg, Philadelphia, PA 19104 USA. [Tagle, Danilo A.] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Vandenberghe, Luk H.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Vandenberghe, Luk H.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Wilson, James M.] Univ Penn, Gene Therapy Program, Philadelphia, PA 19104 USA. RP Gubitz, AK (reprint author), NINDS, NIH, Room 2154,6001 Execut Blvd, Bethesda, MD 20892 USA. EM gubitza@ninds.nih.gov RI Kaspar, Brian/E-3349-2011; Wilson, James/F-9220-2011; OI Wilson, James/0000-0002-9630-3131; Mavilio, Fulvio/0000-0003-0459-4320 FU MDA; NINDS FX We would like to thank Wilson Bryan and Mercedes Serabian (CBER/FDA), and Marco Passini (Genzyme, a Sanofi Company) for their participation in the workshop. We would also like to thank Paul Muhlrad, formerly of the MDA, for his help with early stages of organizing the workshop. This workshop was supported by the MDA and NINDS. NR 4 TC 3 Z9 4 U1 0 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 EI 1557-7422 J9 HUM GENE THER JI Hum. Gene Ther. PD MAR 1 PY 2015 VL 26 IS 3 BP 127 EP 133 DI 10.1089/hum.2014.147 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CD4MV UT WOS:000351058000001 PM 25654329 ER PT J AU Felsburg, PJ De Ravin, SS Malech, HL Sorrentino, BP Burtner, C Kiem, HP AF Felsburg, Peter J. De Ravin, Suk See Malech, Harry L. Sorrentino, Brian P. Burtner, Christopher Kiem, Hans-Peter TI Gene Therapy Studies in a Canine Model of X-Linked Severe Combined Immunodeficiency SO HUMAN GENE THERAPY CLINICAL DEVELOPMENT LA English DT Review ID BONE-MARROW-TRANSPLANTATION; VECTOR INTEGRATION SITES; COMMON GAMMA-CHAIN; FOAMY VIRUS VECTOR; LENTIVIRAL VECTORS; IN-VIVO; GAMMARETROVIRAL VECTOR; IMMUNE RECONSTITUTION; REPOPULATING CELLS; HUMAN GENOME AB Since the occurrence of T cell leukemias in the original human gamma-retroviral gene therapy trials for X-linked severe combined immunodeficiency (XSCID), considerable effort has been devoted to developing safer vectors. This review summarizes gene therapy studies performed in a canine model of XSCID to evaluate the efficacy of gamma-retroviral, lentiviral, and foamy viral vectors for treating XSCID and a novel method of vector delivery. These studies demonstrate that durable T cell reconstitution and thymopoiesis with no evidence of any serious adverse events and, in contrast to the human XSCID patients, sustained marking in myeloid cells and B cells with reconstitution of normal humoral immune function can be achieved for up to 5 years without any pretreatment conditioning. The presence of sustained levels of gene-marked T cells, B cells, and more importantly myeloid cells for almost 5 years is highly suggestive of transduction of either multipotent hematopoietic stem cells or very primitive committed progenitors. C1 [Felsburg, Peter J.] Univ Penn, Sch Vet Med, Dept Clin Studies, Philadelphia, PA 19104 USA. [De Ravin, Suk See; Malech, Harry L.] NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Sorrentino, Brian P.] St Jude Childrens Res Hosp, Div Expt Hematol, Memphis, TN 38105 USA. [Burtner, Christopher; Kiem, Hans-Peter] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Kiem, Hans-Peter] Univ Washington, Dept Med, Seattle, WA 98109 USA. RP Felsburg, PJ (reprint author), Univ Penn, Sch Vet Med, Dept Clin Studies, 3900 Delancey St, Philadelphia, PA 19104 USA. EM felsburg@vet.upenn.edu OI Malech, Harry/0000-0001-5874-5775 FU NIH [RO1 AI43745, P01 AI097100] FX This study was supported by NIH Grants RO1 AI43745 and P01 AI097100. H.-P.K. is a Markey Molecular Medicine Investigator. The authors would like to thank Brian Hartnett, Douglas Kennedy, Jeffrey Kennedy, and Thomas O'Malley for technical assistance, and Patty O'Donnell for supervision of the XSCID dog colony. We would like to also thank Amgen for supplying cytokines, Takara Bio Inc. for supplying retronectin, and Dr. Linda Burkly of Biogen Idec for providing gamma c monoclonal antibody. NR 51 TC 1 Z9 1 U1 0 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2324-8637 EI 2324-8645 J9 HUM GENE THER CL DEV JI Hum. Gene Ther. Clin. Dev. PD MAR 1 PY 2015 VL 26 IS 1 BP 50 EP 56 DI 10.1089/humc.2015.004 PG 7 WC Biotechnology & Applied Microbiology; Critical Care Medicine; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; General & Internal Medicine; Research & Experimental Medicine GA CD3AW UT WOS:000350951100005 PM 25603151 ER PT J AU Wood, AR Tuke, MA Nalls, M Hernandez, D Gibbs, JR Lin, HX Xu, CS Li, QB Shen, J Jun, G Almeida, M Tanaka, T Perry, JRB Gaulton, K Rivas, M Pearson, R Curran, JE Johnson, MP Goring, HHH Duggirala, R Blangero, J Mccarthy, MI Bandinelli, S Murray, A Weedon, MN Singleton, A Melzer, D Ferrucci, L Frayling, TM AF Wood, Andrew R. Tuke, Marcus A. Nalls, Mike Hernandez, Dena Gibbs, J. Raphael Lin, Haoxiang Xu, Christopher S. Li, Qibin Shen, Juan Jun, Goo Almeida, Marcio Tanaka, Toshiko Perry, John R. B. Gaulton, Kyle Rivas, Manny Pearson, Richard Curran, Joanne E. Johnson, Matthew P. Goering, Harald H. H. Duggirala, Ravindranath Blangero, John Mccarthy, Mark I. Bandinelli, Stefania Murray, Anna Weedon, Michael N. Singleton, Andrew Melzer, David Ferrucci, Luigi Frayling, Timothy M. TI Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes SO HUMAN MOLECULAR GENETICS LA English DT Article ID WIDE ASSOCIATION; GENOTYPE IMPUTATION; IDENTIFICATION; VARIANTS; DISEASE; LOCI; SCHIZOPHRENIA; POPULATION; DISCOVERY; DECLINE AB study to test two primary hypotheses: (i) that sequencing would detect single low-frequency-large effect variants that explained similar amounts of phenotypic variance as single common variants, and (ii) that some common variant associations could be explained by low-frequency variants. We tested two sets of disease-related common phenotypes for which we had statistical power to detect large numbers of common variant-common phenotype associations-11 132 cis-gene expression traits in 450 individuals and 93 circulating biomarkers in all 680 individuals. From a total of 11 657 229 high-quality variants of which 6 129 221 and 5 528 008 were common and low frequency (<5%), respectively, low frequency-large effect associations comprised 7% of detectable cis-gene expression traits [89 of 1314 cis-eQTLs at P < 1 x 10(-06) (false discovery rate similar to 5%)] and one of eight biomarker associations at P < 8 x 10(-10). Very few (30 of 1232; 2%) common variant associations were fully explained by low-frequency variants. Our data show that whole-genome sequencing can identify low-frequency variants undetected by genotyping based approaches when sample sizes are sufficiently large to detect substantial numbers of common variant associations, and that common variant associations are rarely explained by single low-frequency variants of large effect. C1 [Wood, Andrew R.; Tuke, Marcus A.; Murray, Anna; Weedon, Michael N.; Frayling, Timothy M.] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England. [Nalls, Mike; Hernandez, Dena; Gibbs, J. Raphael; Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Hernandez, Dena; Gibbs, J. Raphael] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Hernandez, Dena; Gibbs, J. Raphael] UCL, Inst Neurol, Reta Lila Labs, London, England. [Lin, Haoxiang; Xu, Christopher S.; Li, Qibin; Shen, Juan] BGI Shenzhen, Shenzhen 518083, Peoples R China. [Jun, Goo] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Almeida, Marcio; Curran, Joanne E.; Johnson, Matthew P.; Goering, Harald H. H.; Duggirala, Ravindranath; Blangero, John] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Perry, John R. B.] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, MRC,Epidemiol Unit, Cambridge CB2 0QQ, England. [Gaulton, Kyle; Rivas, Manny; Pearson, Richard; Mccarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Gaulton, Kyle; Mccarthy, Mark I.] Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [Gaulton, Kyle; Mccarthy, Mark I.] Churchill Hosp, Oxford Natl Inst Hlth Res NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Bandinelli, Stefania] Tuscany Reg Hlth Agcy, Florence, Italy. [Bandinelli, Stefania] Univ Florence, IOT, Florence, Italy. [Bandinelli, Stefania] Univ Florence, Dept Med & Surg Crit Care, Florence, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Melzer, David] Univ Exeter, Inst Biomed & Clin Sci, Sch Med, Exeter, Devon, England. RP Frayling, TM (reprint author), Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England. EM a.r.wood@ex.ac.uk RI Singleton, Andrew/C-3010-2009; Jun, Goo/F-1941-2017; OI Jun, Goo/0000-0003-0891-0204; Murray, Anna/0000-0002-2351-2522; Melzer, David/0000-0002-0170-3838 FU Wellcome Trust [083270/Z/07/Z, 090367/Z/09/Z, WT097835MF, WT090367MA, 098381]; European Research Council [SZ-50371-GLUCOSEGENES-FP7-IDEAS-ERC]; NIH, National Institute on Aging [ZO1-AG000947, Z01-AG000185]; UK Medical Research Council; Italian Ministry of Health [ICS110.1/RF97.71]; US National Institute on Aging [263 MD 9164, 263 MD 821336]; NIH/NIDDK [DK085501, DK085524, DK085526, DK085545, DK085584]; Wellcome Trust FX This work was supported by Wellcome Trust grants: 083270/Z/07/Z and 090367/Z/09/Z. A.W. and T.F. are supported by the European Research Council grant: SZ-50371-GLUCOSEGENES-FP7-IDEAS-ERC. M.T., M.W. and A.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). M.T. is also supported through the Wellcome Trust grant WT090367MA. M.M. is a Wellcome Trust Senior Investigator and is supported by the Wellcome Trust grant 098381. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (ZO1-AG000947 and Z01-AG000185) and in part by the UK Medical Research Council. The InCHIANTI study baseline (1998-2000) was supported as a 'targeted project' (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (contracts: 263 MD 9164 and 263 MD 821336). A portion of this study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov). We thank the T2D-GENES consortium for whole-genome sequencing in the San Antonio Family Heart Study. Sequence data were generated by the T2D-GENES consortium with support from NIH/NIDDK U01's DK085501, DK085524, DK085526, DK085545 and DK085584. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. NR 37 TC 1 Z9 1 U1 0 U2 8 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 1 PY 2015 VL 24 IS 5 BP 1504 EP 1512 DI 10.1093/hmg/ddu560 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CC1ZB UT WOS:000350142800025 PM 25378555 ER PT J AU Mayer-Barber, KD Sher, A AF Mayer-Barber, Katrin D. Sher, Alan TI Cytokine and lipid mediator networks in tuberculosis SO IMMUNOLOGICAL REVIEWS LA English DT Review DE tuberculosis; cytokines; eicosanoids; lipoxins; prostaglandins; host-directed therapy ID TUMOR-NECROSIS-FACTOR; MYCOBACTERIUM-TUBERCULOSIS; INTERFERON-GAMMA; PULMONARY TUBERCULOSIS; IMMUNE-RESPONSE; IL-1-BETA PRODUCTION; IFN-GAMMA; ANTIMICROBIAL IMMUNITY; ALVEOLAR MACROPHAGES; ACTIVE TUBERCULOSIS AB A major approach for immunologic intervention in tuberculosis involves redirecting the outcome of the host immune response from the induction of disease to pathogen control. Cytokines and lipid mediators known as eicosanoids play key roles in regulating this balance and as such represent important targets for immunologic intervention. While the evidence for cytokine/eicosanoid function derives largely from the investigation of murine and zebrafish experimental infection models, clinical studies have confirmed the existence of many of the same pathways in tuberculosis patients. Here, we summarize new data that reveal important intersections between the cytokine and eicosanoid networks in the host response to mycobacteria and discuss how targeting this crosstalk can promote resistance to lethal Mycobacterium tuberculosis infection. This approach could lead to new host-directed therapies to be used either as an adjunct for improving the efficacy of standard antibiotic treatment or for the management of drug-resistant infections. C1 [Mayer-Barber, Katrin D.; Sher, Alan] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Sher, A (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bldg 50,Room 6140, Bethesda, MD 20892 USA. EM asher@niaid.nih.gov FU Intramural Research Program of the NIAID FX We thank Anne O'Garra, Andrea Cooper, Charles Serhan, Maziar Divangahi and Heinz Remold for their stimulating discussions and Daniel Barber and Bruno Andrade for their helpful comments on the manuscript. K. D. M.-B. and A. S. are supported by the Intramural Research Program of the NIAID. The authors have no conflicts of interest to declare. NR 111 TC 17 Z9 18 U1 3 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD MAR PY 2015 VL 264 IS 1 SI SI BP 264 EP 275 DI 10.1111/imr.12249 PG 12 WC Immunology SC Immunology GA CC2HX UT WOS:000350167200018 PM 25703565 ER PT J AU Lenaerts, A Barry, CE Dartois, V AF Lenaerts, Anne Barry, Clifton E., III Dartois, Veronique TI Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses SO IMMUNOLOGICAL REVIEWS LA English DT Review DE tuberculosis; immunopathology; lesion dynamics; biomarkers; animal models ID ANAEROBIC NITRATE REDUCTASE; MYCOBACTERIUM-BOVIS BCG; GUINEA-PIG MODEL; PULMONARY TUBERCULOSIS; RABBIT MODEL; MOUSE MODEL; LATENT TUBERCULOSIS; INNATE IMMUNITY; IN-VITRO; NONREPLICATING PERSISTENCE AB Tuberculosis (TB) lesions are extremely complex and dynamic. Here, we review the multiple types and fates of pulmonary lesions that form following infection by Mycobacterium tuberculosis and the impact of this spatial and temporal heterogeneity on the bacteria they harbor. The diverse immunopathology of granulomas and cavities generates a plethora of microenvironments to which M.tuberculosis bacilli must adapt. This in turn affects the replication, metabolism, and relative density of bacterial subpopulations, and consequently their respective susceptibility to chemotherapy. We outline recent developments that support a paradigm shift in our understanding of lesion progression. The simple model according to which lesions within a single individual react similarly to the systemic immune response no longer prevails. Host-pathogen interactions within lesions are a dynamic process, driven by subtle and local differences in signaling pathways, resulting in diverging trajectories of lesions within a single host. The spectrum of TB lesions is a continuum with a large overlap in the lesion types found in latently infected and active TB patients. We hope this overview will guide TB researchers in the design, choice of read-outs, and interpretation of future studies in the search for predictive biomarkers and novel therapies. C1 [Lenaerts, Anne] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Dartois, Veronique] Rutgers State Univ, Publ Hlth Res Inst, New Jersey Med Sch, Newark, NJ 07103 USA. RP Dartois, V (reprint author), Rutgers State Univ, Publ Hlth Res Inst, New Jersey Med Sch, 225 Warren St, Newark, NJ 07103 USA. EM veronique.dartois@rutgers.edu RI Barry, III, Clifton/H-3839-2012; Lenaerts, Anne/F-1353-2017 FU TB Drug Accelerator program of the Bill and Melinda Gates Foundation; NIH/NIAID IDIQ Contract [HHSN272201000009I/01]; Intramural Research Program of the NIH, NIAID; NIH [1R01AI111967-01, 1R01AI106398-01] FX The authors are funded by the TB Drug Accelerator program of the Bill and Melinda Gates Foundation, as well as NIH/NIAID IDIQ Contract, Task Order HHSN272201000009I/01 (Anne Lenaerts), the Intramural Research Program of the NIH, NIAID (Clifton Barry) and NIH grants 1R01AI111967-01 and 1R01AI106398-01 (Veronique Dartois). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does it mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The authors have no conflicts of interest to declare. NR 143 TC 44 Z9 44 U1 7 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD MAR PY 2015 VL 264 IS 1 SI SI BP 288 EP 307 DI 10.1111/imr.12252 PG 20 WC Immunology SC Immunology GA CC2HX UT WOS:000350167200020 PM 25703567 ER PT J AU Nathan, C Barry, CE AF Nathan, Carl Barry, Clifton E., III TI TB drug development: immunology at the table SO IMMUNOLOGICAL REVIEWS LA English DT Review DE drug resistance; immunopathology; non-replication; persistence; phenotypic tolerance; viable but non-culturable ID NITRIC-OXIDE SYNTHASE; MYCOBACTERIUM-TUBERCULOSIS; ISOCITRATE LYASE; PULMONARY TUBERCULOSIS; BACTERIAL PERSISTENCE; NUTRIENT STARVATION; HUMAN MACROPHAGES; TUBERCLE-BACILLI; EXPRESSION; INFECTION AB Our understanding of the host-pathogen relationship in tuberculosis (TB) can help guide drug discovery in at least two ways. First, the recognition that host immunopathology affects lesional TB drug distribution means that pharmacokinetic evaluation of drug candidates needs to move beyond measurements of drug levels in blood, whole lungs, or alveolar epithelial lining fluid to include measurements in specific types of lesions. Second, by restricting the replication of M.tuberculosis (Mtb) subpopulations in latent TB infection and in active disease, the host immune response puts Mtb into a state associated with phenotypic tolerance to TB drugs selected for their activity against replicating Mtb. This has spurred a major effort to conduct high throughput screens in vitro for compounds that can kill Mtb when it is replicating slowly if at all. Each condition used in vitro to slow Mtb's replication and thereby model the phenotypically drug-tolerant state has advantages and disadvantages. Lead candidates emerging from such in vitro studies face daunting challenges in the design of proof-of-concept studies in animal models. Moreover, some non-replicating subpopulations of Mtb fail to resume replication when plated on agar, although their viability is demonstrable by other means. There is as yet no widely replicated assay in which to screen compounds for their ability to kill this viable but non-culturable' subpopulation. Despite these hurdles, drugs that can kill slowly replicating or non-replicating Mtb may offer our best hope for treatment-shortening combination chemotherapy of TB. C1 [Nathan, Carl] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA. [Barry, Clifton E., III] NIAIID, TB Res Sect, Bethesda, MD 20892 USA. RP Nathan, C (reprint author), Weill Cornell Med Coll, Dept Microbiol & Immunol, 1300 York Ave, New York, NY 10065 USA. EM cnathan@med.cornell.edu RI Barry, III, Clifton/H-3839-2012 FU Bill and Melinda Gates Foundation; NIH [RO1 AI64768, RO1 AI105807, U19 AI111143]; Milstein Program in Translational Medicine; William Randolph Hearst Foundation FX Preparation of this review was supported by grants from the Bill and Melinda Gates Foundation and NIH (RO1 AI64768, RO1 AI105807 and U19 AI111143) and by the Milstein Program in Translational Medicine. The Department of Microbiology and Immunology at Weil Cornell Medical College is supported by the William Randolph Hearst Foundation. We thank K. Burns-Huang for review of the manuscript. The authors have no conflicts of interest to declare. NR 68 TC 10 Z9 10 U1 2 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD MAR PY 2015 VL 264 IS 1 SI SI BP 308 EP 318 DI 10.1111/imr.12275 PG 11 WC Immunology SC Immunology GA CC2HX UT WOS:000350167200021 PM 25703568 ER PT J AU Santosh, KC Candemir, S Jaeger, S Karargyris, A Antani, S Thoma, GR AF Santosh, K. C. Candemir, Sema Jaeger, Stefan Karargyris, Alexandros Antani, Sameer Thoma, George R. TI Automatically Detecting Rotation in Chest Radiographs Using Principal Rib-Orientation Measure for Quality Control SO INTERNATIONAL JOURNAL OF PATTERN RECOGNITION AND ARTIFICIAL INTELLIGENCE LA English DT Article DE Chest radiographs; automation; pattern recognition; quality control; generalized line histogram; rib-orientation; rotation detection ID SEGMENTATION AB We present a novel method for detecting rotated lungs in chest radiographs for quality control and augmenting automated abnormality detection. The method computes a principal rib-orientation measure using a generalized line histogram technique for quality control, and therefore augmenting automated abnormality detection. To compute the line histogram, we use line seed filters as kernels to convolve with edge images, and extract a set of lines from the posterior rib-cage. After convolving kernels in all possible orientations in the range [0 degrees; 180 degrees], we measure the angle with maximum magnitude in the line histogram. This measure provides an approximation of the principal chest rib-orientation for each lung. A chest radiograph is upright if the difference between the orientation angles of both lungs with respect to the horizontal axis is negligible. We validate our method on sets of normal and abnormal images and argue that rib orientation can be used for rotation detection in chest radiographs as an aid in quality control during image acquisition. It can also be used for training and testing data sets for computer aided diagnosis research, for example. In our experiments, we achieve a maximum accuracy of approximately 90%. C1 [Santosh, K. C.; Candemir, Sema; Jaeger, Stefan; Karargyris, Alexandros; Antani, Sameer; Thoma, George R.] NIH, Natl Lib Med, Bethesda, MD 20894 USA. RP Santosh, KC (reprint author), NIH, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM santosh.kc@nih.gov; sema.candemir@nih.gov; stefan.jaeger@nih.gov; alex.karargyris@nih.gov; sameer.antani@nih.gov; george.thoma@nih.gov OI Santosh, K.C./0000-0003-4176-0236 FU Intramural Research Program of the National Institutes of Health (NIH); National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM), and Lister Hill National Center for Biomedical Communications (LHNCBC). The authors would like to thank the NIH Fellows Editorial Board for their editorial assistance. NR 28 TC 3 Z9 3 U1 0 U2 1 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA 5 TOH TUCK LINK, SINGAPORE 596224, SINGAPORE SN 0218-0014 EI 1793-6381 J9 INT J PATTERN RECOGN JI Int. J. Pattern Recognit. Artif. Intell. PD MAR PY 2015 VL 29 IS 2 AR 1557001 DI 10.1142/S0218001415570013 PG 19 WC Computer Science, Artificial Intelligence SC Computer Science GA CD0IW UT WOS:000350755900008 ER PT J AU Eishingdrelo, H Sun, W Li, H Wang, L Eishingdrelo, A Dai, S McKew, JC Zheng, W AF Eishingdrelo, Haifeng Sun, Wei Li, Hua Wang, Li Eishingdrelo, Alex Dai, Sheng McKew, John C. Zheng, Wei TI ERK and beta-Arrestin Interaction: A Converging Point of Signaling Pathways for Multiple Types of Cell Surface Receptors SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE beta-arrestin; extracellular signal-regulated kinases; ERK; protein-protein interactions ID G-PROTEIN; KINASE; ACTIVATION; SCAFFOLDS; SUPERFAMILY; EXPRESSION; LIGANDS; ASSAY; EGF AB beta-Arrestin, a signal adaptor protein, mediates intracellular signal transductions through protein-protein interactions by bringing two or more proteins in proximity. Extracellular signal-regulated kinase (ERK), a protein kinase in the family of mitogen-activated protein kinases (MAPKs), is involved in various receptor signal pathways. Interaction of ERK with -arrestin or formation of ERK/-arrestin signal complex occurs in response to activation of a variety of cell surface receptors. The ERK/-arrestin signal complex may be a common transducer to converge a variety of extracellular stimuli to similar downstream intracellular signaling pathways. By using a cell-based protein-protein interaction LinkLight assay technology, we demonstrate a direct interaction between ERK and -arrestin in response to extracellular stimuli, which can be sensitively and quantitatively monitored. Activations of G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs), and cytokine receptors promote formation of the ERK/-arrestin signal complex. Our data indicate that the ERK/-arrestin signal complex is a common transducer that participates in a variety of receptor signaling pathways. Furthermore, we demonstrate that receptor antagonists or kinase inhibitors can block the agonist-induced ERK and -arrestin interaction. Thus, the ERK/-arrestin interaction assay is useful for screening of new receptor modulators. C1 [Eishingdrelo, Haifeng; Li, Hua; Wang, Li; Eishingdrelo, Alex] BioInvenu Corp, E Hanover, NJ 07936 USA. [Sun, Wei; Dai, Sheng; McKew, John C.; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Eishingdrelo, H (reprint author), BioInvenu Corp, 50 Williams Pkwy, E Hanover, NJ 07936 USA. EM haifeng.eishingdrelo@bioinvenu.com; wzheng@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU NIH/NIMH SBIR [R43MH101903]; Therapeutics for Rare and Neglected Diseases at the National Center for Advancing Translational Sciences FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the NIH/NIMH SBIR grant (R43MH101903) awarded to H.E. and was supported by the Intramural Research Programs of Therapeutics for Rare and Neglected Diseases at the National Center for Advancing Translational Sciences. NR 30 TC 2 Z9 2 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 EI 1552-454X J9 J BIOMOL SCREEN JI J. Biomol. Screen PD MAR PY 2015 VL 20 IS 3 BP 341 EP 349 DI 10.1177/1087057114557233 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA CC4GL UT WOS:000350310000004 PM 25361946 ER PT J AU Murthy, SB Moradiya, Y Shah, S Shastri, A Bershad, EM Suarez, JI AF Murthy, Santosh B. Moradiya, Yogesh Shah, Shreyansh Shastri, Aditi Bershad, Eric M. Suarez, Jose I. TI In-hospital outcomes of thrombolysis for acute ischemic stroke in patients with primary brain tumors SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Acute stroke; Nationwide inpatient sample; Primary brain tumors; Thrombolysis ID PLASMINOGEN-ACTIVATOR USE; INTRAVENOUS THROMBOLYSIS; INTRACRANIAL MENINGIOMA; ADMINISTRATIVE DATA; UNITED-STATES; THERAPY; ELIXHAUSER; HEMORRHAGE; ALTEPLASE; ACCURACY AB Data on thrombolysis outcomes in patients with primary brain tumors are limited. Our aim was to study stroke outcomes following thrombolysis in these patients in a population-based study. Patients with acute ischemic stroke who received thrombolysis were identified from the 2002-2011 USA Nationwide Inpatient Sample. We compared demographics, comorbidities, and outcomes between primary brain tumor-associated strokes (BTS) and non-brain tumor associated strokes (NBTS). The main outcomes were inpatient mortality, home discharge and intracranial hemorrhage (ICH) rate. Of the 124,083 thrombolysis-treated stroke patients, 416 (0.34%) had brain tumors. In adjusted analysis, inpatient mortality (odds ratio [OR]: 0.98; 95% confidence interval [CI]: 0.77-1.26, p = 0.918), rate of home discharge (OR: 1.15; 95% Cl: 0.87-1.53, p = 0.40) and rate of ICH (OR: 0.94; 95% CI: 0.62-1.44, p = 0.801) were similar between BTS and NBTS. Analysis of brain tumor subtypes showed that compared to NBTS, malignant BTS were independently associated with higher in-hospital mortality (OR: 2.51; 95% CI: 1.66-3.79, p <0.001), lower home discharge (OR: 0.36, 95% CI: 0.18-0.72, p = 0.004), and increased risk of ICH (OR: 2.33, 95% Cl: 1.49-3.65, p < 0.001). Additionally, among the BTS, intraparenchymal location of tumor was associated with higher mortality (OR: 2.51; 95% CI: 1.20-5.23, p = 0.014) and lower home discharge (OR: 0.26; 95% CI: 0.13-0.53, p < 0.001). Thrombolytic therapy for acute stroke appears to be safe in patients with primary brain tumors, with similar rates of ICH. Malignant BTS have worse outcomes, while benign BTS have outcomes comparable to NBTS. Careful consideration of tumor pathology may aid selection of patients with poor thrombolysis outcomes. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Murthy, Santosh B.; Moradiya, Yogesh] Johns Hopkins Univ, Sch Med, Div Neurosci Crit Care, Baltimore, MD 21287 USA. [Shah, Shreyansh] NIH, Dept Vasc Neurol, Bethesda, MD 20892 USA. [Shastri, Aditi] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Hematol & Oncol, Bronx, NY 10467 USA. [Bershad, Eric M.; Suarez, Jose I.] Baylor Coll Med, Dept Vasc Neurol & Neurocrit Care, Houston, TX 77030 USA. RP Murthy, SB (reprint author), Johns Hopkins Univ, Sch Med, Div Neurosci Crit Care, 600 N Wolf St,Meyer 8-140, Baltimore, MD 21287 USA. EM santoshbmurthy@gmail.com NR 35 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD MAR PY 2015 VL 22 IS 3 BP 474 EP 478 DI 10.1016/j.jocn.2014.09.016 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CC6YN UT WOS:000350515000007 PM 25564270 ER PT J AU Hwang, IY Park, C Harrison, K Boularan, C Gales, C Kehrl, JH AF Hwang, Il-Young Park, Chung Harrison, Kathleen Boularan, Cedric Gales, Celine Kehrl, John H. TI An Essential Role for RGS Protein/G alpha(i2) Interactions in B Lymphocyte-Directed Cell Migration and Trafficking SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROTEIN ALPHA-SUBUNITS; CHEMOKINE RECEPTOR; SIGNALING KINETICS; ORGANS; DESENSITIZATION; ACTIVATION; REGULATORS; SPHINGOSINE-1-PHOSPHATE; CHEMOATTRACTANTS; UBIQUITINATION AB Chemokines engage B lymphocyte surface receptors, triggering heterotrimeric G protein Gai subunit guanine nucleotide exchange. RGS proteins limit the duration that Gai subunits remain GTP bound, and the loss of an individual RGS protein typically enhances chemokine receptor signaling. In this study, we show that B cells carrying a GaG alpha(G184S/G184S)(i2) mutation that disables all RGS protein/Gai2 interactions exhibit an unexpectedly severe reduction in chemokine receptor signaling. The Ga alpha(G184S/G184S)(i2) B cells have markedly elevated basal calcium levels, but poor chemokine-induced increases, enhanced nonspecific migration, but extremely poor chemotaxis. In striking contrast, the Ga alpha(G184S/G184S)(i2) B cells exhibited enhanced sensitivity to sphingosine 1-phosphate (S1P). S1P elicited heightened intracellular calcium responses and enhanced S1P-triggered cell migration. Mice with the G alpha(G184S/G184S)(i2) mutation displayed excessive numbers of germinal center-like structures; abnormal serum Ig profiles; and aberrant B lymphocyte trafficking. These findings establish an essential role for RGS proteins in B cell chemoattractant signaling and for the proper position of B lymphocytes in lymphoid organs. C1 [Hwang, Il-Young; Park, Chung; Harrison, Kathleen; Boularan, Cedric; Kehrl, John H.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Boularan, Cedric; Gales, Celine] Inst Malad Metabol & Cardiovasc, INSERM, U1048, F-31432 Toulouse 4, France. RP Kehrl, JH (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 11B08,10 Ctr Dr MSC 1876, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov FU intramural program of the National Institutes of Allergy and Infectious Diseases FX This work was supported by the intramural program of the National Institutes of Allergy and Infectious Diseases. NR 54 TC 7 Z9 7 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 1 PY 2015 VL 194 IS 5 BP 2128 EP 2139 DI 10.4049/jimmunol.1401952 PG 12 WC Immunology SC Immunology GA CC0KI UT WOS:000350023900014 PM 25617475 ER PT J AU Paschall, AV Zhang, RH Qi, CF Bardhan, K Peng, L Lu, GM Yang, JJ Merad, M McGaha, T Zhou, G Mellor, A Abrams, SI Morse, HC Ozato, K Xiong, HB Liu, KB AF Paschall, Amy V. Zhang, Ruihua Qi, Chen-Feng Bardhan, Kankana Peng, Liang Lu, Geming Yang, Jianjun Merad, Miriam McGaha, Tracy Zhou, Gang Mellor, Andrew Abrams, Scott I. Morse, Herbert C., III Ozato, Keiko Xiong, Huabao Liu, Kebin TI IFN Regulatory Factor 8 Represses GM-CSF Expression in T Cells To Affect Myeloid Cell Lineage Differentiation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SEQUENCE-BINDING-PROTEIN; INNATE IMMUNE-SYSTEM; SUPPRESSOR-CELLS; TRANSCRIPTION FACTORS; MONOCYTE DIFFERENTIATION; CUTTING EDGE; DENDRITIC CELLS; TARGET GENES; IRF FAMILY; IN-VIVO AB During hematopoiesis, hematopoietic stem cells constantly differentiate into granulocytes and macrophages via a distinct differentiation program that is tightly controlled by myeloid lineage-specific transcription factors. Mice with a null mutation of IFN regulatory factor 8 (IRF8) accumulate CD11b(+)Gr1(+) myeloid cells that phenotypically and functionally resemble tumorinduced myeloid-derived suppressor cells (MDSCs), indicating an essential role of IRF8 in myeloid cell lineage differentiation. However, IRF8 is expressed in various types of immune cells, and whether IRF8 functions intrinsically or extrinsically in regulation of myeloid cell lineage differentiation is not fully understood. In this study, we report an intriguing finding that, although IRF8-deficient mice exhibit deregulated myeloid cell differentiation and resultant accumulation of CD11b(+)Gr1(+) MDSCs, surprisingly, mice with IRF8 deficiency only in myeloid cells exhibit no abnormal myeloid cell lineage differentiation. Instead, mice with IRF8 deficiency only in T cells exhibited deregulated myeloid cell differentiation and MDSC accumulation. We further demonstrated that IRF8-deficient T cells exhibit elevated GM-CSF expression and secretion. Treatment of mice with GM-CSF increased MDSC accumulation, and adoptive transfer of IRF8-deficient T cells, but not GM-CSF-deficient T cells, increased MDSC accumulation in the recipient chimeric mice. Moreover, overexpression of IRF8 decreased GM-CSF expression in T cells. Our data determine that, in addition to its intrinsic function as an apoptosis regulator in myeloid cells, IRF8 also acts extrinsically to repress GM-CSF expression in T cells to control myeloid cell lineage differentiation, revealing a novel mechanism that the adaptive immune component of the immune system regulates the innate immune cell myelopoiesis in vivo. C1 [Paschall, Amy V.; Bardhan, Kankana; Liu, Kebin] Georgia Regents Univ, Dept Biochem & Mol Biol, Med Coll Georgia, Augusta, GA 30912 USA. [Paschall, Amy V.; McGaha, Tracy; Zhou, Gang; Mellor, Andrew; Liu, Kebin] Georgia Regents Univ, Ctr Canc, Canc Immunol Inflammat & Tolerance Program, Augusta, GA 30912 USA. [Paschall, Amy V.; Liu, Kebin] Charlie Norwood VA Med Ctr, Augusta, GA 30904 USA. [Zhang, Ruihua; Peng, Liang; Lu, Geming; Yang, Jianjun; Merad, Miriam; Xiong, Huabao] Mt Sinai Sch Med, Inst Immunol, New York, NY 10029 USA. [Qi, Chen-Feng; Morse, Herbert C., III] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Abrams, Scott I.] Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14263 USA. [Ozato, Keiko] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Programs Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Xiong, HB (reprint author), Mt Sinai Sch Med, Inst Immunol, New York, NY 10029 USA. EM huabao.xiong@mssm.edu; kliu@gru.edu OI Liu, Kebin/0000-0003-1965-7240 FU National Institutes of Health [CA133085, CA185909, CA182518, DK072201, AI091871, AI104688, CA140622]; Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; VA Merit Review Award [BX001962] FX This work was supported by National Institutes of Health Grants CA133085, CA185909, and CA182518 (to K.L.); DK072201, AI091871, and AI104688 (to H.X.); and CA140622 (to S.I.A.); and in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (to H.C.M.), the National Institute of Child Health and Human Development (to K.O.), and VA Merit Review Award BX001962 (to K.L.). NR 73 TC 12 Z9 12 U1 1 U2 8 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 1 PY 2015 VL 194 IS 5 BP 2369 EP 2379 DI 10.4049/jimmunol.1402412 PG 11 WC Immunology SC Immunology GA CC0KI UT WOS:000350023900037 PM 25646302 ER PT J AU Feldman, S Achour, I Wuerffel, R Kumar, S Gerasimova, T Sen, R Kenter, AL AF Feldman, Scott Achour, Ikbel Wuerffel, Robert Kumar, Satyendra Gerasimova, Tatiana Sen, Ranjan Kenter, Amy L. TI Constraints Contributed by Chromatin Looping Limit Recombination Targeting during Ig Class Switch Recombination SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; RNA-POLYMERASE-II; GENE-EXPRESSION; CIRCULAR DNA; 3D STRUCTURE; TRANSCRIPTION; LOCUS; ACTIVATION; CELLS; IL-4 AB Engagement of promoters with distal elements in long-range looping interactions has been implicated in regulation of Ig class switch recombination (CSR). The principles determining the spatial and regulatory relationships among Igh transcriptional elements remain poorly defined. We examined the chromosome conformation of C region (C-H) loci that are targeted for CSR in a cytokine-dependent fashion in mature B lymphocytes. Germline transcription (GLT) of the gamma 1 and epsilon C-H loci is controlled by two transcription factors, IL-4-inducible STAT6 and LPS-activated NF-kappa B. We showed that although STAT6 deficiency triggered loss of GLT, deletion of NF-kappa B p50 abolished both GLT and gamma 1 locus: enhancer looping. Thus, chromatin looping between C-H loci and Igh enhancers is independent of GLT production and STAT6, whereas the establishment and maintenance of these chromatin contacts requires NF-kappa B p50. Comparative analysis of the endogenous gamma 1 locus and a knock-in heterologous promoter in mice identified the promoter per se as the interactive looping element and showed that transcription elongation is dispensable for promoter/enhancer interactions. Interposition of the LPS-responsive heterologous promoter between the LPS-inducible gamma 3 and gamma 2b loci altered GLT expression and essentially abolished direct IgG2b switching while maintaining a sequential mu ->gamma 3 ->gamma 2b format. Our study provides evidence that promoter/enhancer looping interactions can introduce negative constraints on distal promoters and affect their ability to engage in germline transcription and determine CSR targeting. C1 [Feldman, Scott; Achour, Ikbel; Wuerffel, Robert; Kumar, Satyendra; Kenter, Amy L.] Univ Illinois, Coll Med, Dept Microbiol & Immunol, Chicago, IL 60612 USA. [Gerasimova, Tatiana; Sen, Ranjan] NIA, Gene Regulat Sect, Lab Cellular & Mol Biol, NIH, Baltimore, MD 21224 USA. RP Kenter, AL (reprint author), Univ Illinois, Coll Med, Dept Microbiol & Immunol, 835 South Wolcott Ave,M-C 790, Chicago, IL 60612 USA. EM star1@uic.edu FU National Institutes of Health Grant [AI052400]; Intramural Research Program of the National Institute on Aging FX This work was supported by National Institutes of Health Grant AI052400 (to A.L.K.) and by the Intramural Research Program of the National Institute on Aging (to R.S.). NR 46 TC 6 Z9 6 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 1 PY 2015 VL 194 IS 5 BP 2380 EP 2389 DI 10.4049/jimmunol.1401170 PG 10 WC Immunology SC Immunology GA CC0KI UT WOS:000350023900038 PM 25624452 ER PT J AU Kutty, G Davis, AS Ma, L Taubenberger, JK Kovacs, JA AF Kutty, Geetha Davis, A. Sally Ma, Liang Taubenberger, Jeffery K. Kovacs, Joseph A. TI Pneumocystis Encodes a Functional Endo-beta-1,3-glucanase That is Expressed Exclusively in Cysts SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE cell wall; endo-beta-1,3-glucanase; Eng; glucan; Pneumocystis ID MAJOR SURFACE GLYCOPROTEIN; SCHIZOSACCHAROMYCES-POMBE; SACCHAROMYCES-CEREVISIAE; CELL-SEPARATION; CARINII; ANTIGENS; GENES; WALL; PNEUMONIA; SEPTUM AB beta-1,3-glucan is a major cell wall component of Pneumocystis cysts. We have characterized endo-beta-1,3-glucanase (Eng) from 3 species of Pneumocystis. The gene eng is a single-copy gene that encodes a protein containing 786 amino acids in P. carinii and P. murina, and 788 amino acids in P. jirovecii, including a signal peptide for the former 2 but not the latter. Recombinant Eng expressed in Escherichia coli was able to solubilize the major surface glycoprotein of Pneumocystis, thus potentially facilitating switching of the expressed major surface glycoprotein (Msg) variant. Confocal immunofluorescence analysis of P. murina-infected mouse lung sections localized Eng exclusively to the cyst form of Pneumocystis. No Eng was detected after mice were treated with caspofungin, a beta-1,3-glucan synthase inhibitor that is known to reduce the number of cysts. Thus, Eng is a cyst-specific protein that may play a role in Msg variant expression in Pneumocystis. C1 [Kutty, Geetha; Ma, Liang; Kovacs, Joseph A.] NIH, Crit Care Med Dept, Ctr Clin, Bethesda, MD 20892 USA. [Davis, A. Sally; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), Bldg 10,Rm 2C145,MSC 1662, Bethesda, MD 20892 USA. EM jkovacs@nih.gov FU National Institutes of Health (NIH) Clinical Center; National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Intramural Research Programs of the National Institutes of Health (NIH) Clinical Center and the National Institute of Allergy and Infectious Diseases, NIH. NR 26 TC 2 Z9 2 U1 0 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 1 PY 2015 VL 211 IS 5 BP 719 EP 728 DI 10.1093/infdis/jiu517 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC3CL UT WOS:000350222000007 PM 25231017 ER PT J AU Estes, JD Reilly, C Trubey, CM Fletcher, CV Cory, TJ Piatak, M Russ, S Anderson, J Reimann, TG Star, R Smith, A Tracy, RP Berglund, A Schmidt, T Coalter, V Chertova, E Smedley, J Haase, AT Lifson, JD Schacker, TW AF Estes, Jacob D. Reilly, Cavan Trubey, Charles M. Fletcher, Courtney V. Cory, Theodore J. Piatak, Michael, Jr. Russ, Samuel Anderson, Jodi Reimann, Thomas G. Star, Robert Smith, Anthony Tracy, Russell P. Berglund, Anna Schmidt, Thomas Coalter, Vicky Chertova, Elena Smedley, Jeremy Haase, Ashley T. Lifson, Jeffrey D. Schacker, Timothy W. TI Antifibrotic Therapy in Simian Immunodeficiency Virus Infection Preserves CD4(+) T-Cell Populations and Improves Immune Reconstitution With Antiretroviral Therapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; fibrosis; immune reconstitution; fibroblastic reticular cell network; T-cell depletion ID LYMPHATIC TISSUE FIBROSIS; FIBROBLASTIC RETICULAR CELLS; COLLAGEN DEPOSITION; LIVER FIBROSIS; NODE CORTEX; PIRFENIDONE; AGENT; RATS; PROLIFERATION; HOMEOSTASIS AB Even with prolonged antiretroviral therapy (ART), many human immunodeficiency virus-infected individuals have <500 CD4(+) T cells/mu L, and CD4(+) T cells in lymphoid tissues remain severely depleted, due in part to fibrosis of the paracortical T-cell zone (TZ) that impairs homeostatic mechanisms required for T-cell survival. We therefore used antifibrotic therapy in simian immunodeficiency virus-infected rhesus macaques to determine whether decreased TZ fibrosis would improve reconstitution of peripheral and lymphoid CD4(+) T cells. Treatment with the antifibrotic drug pirfenidone preserved TZ architecture and was associated with significantly larger populations of CD4(+) T cells in peripheral blood and lymphoid tissues. Combining pirfenidone with an ART regimen was associated with greater preservation of CD4(+) T cells than ART alone and was also associated with higher pirfenidone concentrations. These data support a potential role for antifibrotic drug treatment as adjunctive therapy with ART to improve immune reconstitution. C1 [Russ, Samuel; Anderson, Jodi; Reimann, Thomas G.; Berglund, Anna; Schmidt, Thomas; Schacker, Timothy W.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Smith, Anthony; Haase, Ashley T.] Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. [Reilly, Cavan] Univ Minnesota, Dept Biostat, Minneapolis, MN 55455 USA. [Estes, Jacob D.; Trubey, Charles M.; Piatak, Michael, Jr.; Coalter, Vicky; Chertova, Elena; Smedley, Jeremy; Lifson, Jeffrey D.] Frederick Natl Lab, Leidos Biomed Res, Bethesda, MD USA. [Star, Robert] NIDDK, NIH, Bethesda, MD 20892 USA. [Fletcher, Courtney V.; Cory, Theodore J.] Univ Nebraska Med Ctr, Coll Pharm, Omaha, NE USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol & Lab Med, Burlington, VT USA. RP Schacker, TW (reprint author), Univ Minnesota, MMC 250,516 Delaware St, Minneapolis, MN 55455 USA. EM schacker@umn.edu FU National Institutes of Health [R01AI054232, K24AI056986, R01AI093319, AI028246, AI048484, AI056997]; National Cancer Institute [HHSN261200800001E] FX This work was supported by the National Institutes of Health (grants R01AI054232, K24AI056986, and R01AI093319 to P. I. S.; and grants AI028246, AI048484, and AI056997 to A. T. H.) and the National Cancer Institute (grant HHSN261200800001E). NR 37 TC 11 Z9 11 U1 1 U2 5 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 1 PY 2015 VL 211 IS 5 BP 744 EP 754 DI 10.1093/infdis/jiu519 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC3CL UT WOS:000350222000010 PM 25246534 ER PT J AU Tenorio, AR Chan, ES Bosch, RJ Macatangay, BJC Read, SW Yesmin, S Taiwo, B Margolis, DM Jacobson, JM Landay, AL Wilson, CC AF Tenorio, Allan R. Chan, Ellen S. Bosch, Ronald J. Macatangay, Bernard J. C. Read, Sarah W. Yesmin, Suria Taiwo, Babafemi Margolis, David M. Jacobson, Jeffrey M. Landay, Alan L. Wilson, Cara C. CA A5286 Team TI Rifaximin has a Marginal Impact on Microbial Translocation, T-cell Activation and Inflammation in HIV-Positive Immune Non-responders to Antiretroviral Therapy - ACTG A5286 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; immune nonresponders to ART; microbial translocation; immune activation; inflammation; rifaximin ID IMMUNOLOGICAL RECOVERY; PREDICT MORTALITY; INFECTED PATIENTS; LYMPHOID-TISSUE; GUT MICROBIOTA; PLASMA-LEVELS; PILOT TRIAL; IMMUNODEFICIENCY; ENDOTOXEMIA; SUPPRESSION AB Background. Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART). Methods. HIV-positive adults receiving ART for >= 96 weeks with undetectable viremia for >= 48 weeks and CD4(+) T-cell counts <350 cells/mm(3) were randomized 2:1 to rifaximin versus no study treatment for 4 weeks. T-cell activation, LPS, and soluble CD14 were measured at baseline and at weeks 2, 4, and 8. Wilcoxon rank sum tests compared changes between arms. Results. Compared with no study treatment (n = 22), rifaximin (n = 43) use was associated with a significant difference between study arms in the change from baseline to week 4 for CD8(+)T-cell activation (median change, 0.0% with rifaximin vs +0.6% with no treatment; P=.03). This difference was driven by an increase in the no-study-treatment arm because there was no significant change within the rifaximin arm. Similarly, although there were significant differences between study arms in change from baseline to week 2 for LPS and soluble CD14, there were no significant changes within the rifaximin arm. Conclusions. In immune nonresponders to ART, rifaximin minimally affected microbial translocation and CD8(+)T-cell activation. C1 [Tenorio, Allan R.] Rush Univ, Med Ctr, Dept Med, Chicago, IL 60612 USA. [Landay, Alan L.] Rush Univ, Med Ctr, Dept Immunol & Microbiol, Chicago, IL 60612 USA. [Taiwo, Babafemi] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Chan, Ellen S.; Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Macatangay, Bernard J. C.] Univ Pittsburgh, Sch Med, Div Infect Dis, Philadelphia, PA USA. [Jacobson, Jeffrey M.] Drexel Univ, Div Infect Dis & HIV, Philadelphia, PA 19104 USA. [Read, Sarah W.] NIAID, HIV Res Branch, TRP, Div AIDS,NIH, Bethesda, MD 20892 USA. [Yesmin, Suria] ACTG Operat Ctr, Social & Sci Syst, Silver Spring, MD USA. [Margolis, David M.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Wilson, Cara C.] Univ Colorado Denver, Dept Med, Aurora, CO USA. RP Tenorio, AR (reprint author), 600 S Paulina St,Ste 143 AAC, Chicago, IL 60612 USA. EM astenorio@gmail.com FU National Institute of Health [AI068636, AI068634, AI069452, A1025439, AI069424, AI069447, AI069419, AI069532, AI069470, AI069494, AI069511-08, AI069439, AI069418, AI069556]; National Institute of Health. [AI069477, AI069501, AI069471, AI069412, AI069502, AI69501, AI069423, AI069415, AI069481, AI069534, AI069503, AI069432, TR001082, RR024160, TR001070, TR000439, TR001111, Al050404, AI073961, AI50410, AI045008] FX This work was supported by grants from the National Institute of Health (AI068636 to the ACTG Network Leadership; AI068634 and AI068636 to ACTG Statistical Data Analysis Center [E. S. C. and R. J. B.]; AI068636 to A. L. L.; AI069452, A1025439, AI069424, AI069447, AI069419, AI069418, AI069532, AI069470, AI069494, AI069511-08, AI069439, AI069471, AI069418, AI069556, AI069477, AI069494, AI069439, AI069501, AI069471, AI069412, AI069412, AI069412, AI069502, AI069494, AI69501, AI069423, AI069415, AI069481, AI069534, AI069503 and AI069432 to the ACTG clinical research sites; TR001082, RR024160, TR001070, TR000439 and TR001111 to the Clinical and Translational Science Centers; and Al050404, AI073961, AI50410 and AI045008 to the Centers for AIDS Research). NR 35 TC 14 Z9 14 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 1 PY 2015 VL 211 IS 5 BP 780 EP 790 DI 10.1093/infdis/jiu515 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC3CL UT WOS:000350222000013 PM 25214516 ER PT J AU Ballerini, C Baldi, G Aldinucci, A Maggi, P AF Ballerini, Clara Baldi, Giovanni Aldinucci, Alessandra Maggi, Pietro TI Nanomaterial Applications in Multiple Sclerosis Inflamed Brain SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Article DE Nanotechnology; Nanomaterials; Imaging; Therapy; Brain inflammation; Multiple sclerosis ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; IRON-OXIDE NANOPARTICLES; SPINAL-CORD-INJURY; T-CELL TOLERANCE; IN-VIVO TRACKING; MONOCYTE INFILTRATION; STEM-CELLS; MRI AB In the last years scientific progress in nanomaterials, where size and shape make the difference, has increased their utilization in medicine with the development of a promising new translational science: nanomedicine. Due to their surface and core biophysical properties, nanomaterials hold the promise for medical applications in central nervous system (CNS) diseases: inflammatory, degenerative and tumors. The present review is focused on nanomaterials at the neuro-immune interface, evaluating two aspects: the possible CNS inflammatory response induced by nanomaterials and the developments of nanomaterials to improve treatment and diagnosis of neuroinflammatory diseases, with a focus on multiple sclerosis (MS). Indeed, nanomedicine allows projecting new ways of drug delivery and novel techniques for CNS imaging. Despite the wide field of application in neurological diseases of nanomaterials, our topic here is to review the more recent development of nanomaterials that cross blood brain barrier (BBB) and reach specific target during CNS inflammatory diseases, a crucial strategy for CNS early diagnosis and drug delivery, indeed the main challenges of nanomedicine. C1 [Ballerini, Clara; Aldinucci, Alessandra] Univ Florence, Dept Neurofarba, I-50137 Florence, Italy. [Baldi, Giovanni] Ce Ri Col Res Ctr Colorobbia, Florence, Italy. [Maggi, Pietro] Univ Libre Bruxelles Bruxelles Be, Hop Erasme, Brussels, Belgium. [Maggi, Pietro] NINDS, NIH Bethesda US, Bethesda, MD 20892 USA. RP Ballerini, C (reprint author), Univ Florence, Dept Neurofarba, Viale Pieraccini 6, I-50137 Florence, Italy. EM clara.ballerini@unifi.it OI ballerini, clara/0000-0002-7812-9029 NR 94 TC 2 Z9 2 U1 5 U2 49 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD MAR PY 2015 VL 10 IS 1 BP 1 EP 13 DI 10.1007/s11481-015-9588-y PG 13 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CC4PK UT WOS:000350335100001 PM 25616566 ER PT J AU Lonser, RR Sarntinoranont, M Morrison, PF Oldfield, EH AF Lonser, Russell R. Sarntinoranont, Malisa Morrison, Paul F. Oldfield, Edward H. TI Convection-enhanced delivery to the central nervous system SO JOURNAL OF NEUROSURGERY LA English DT Review DE convection-enhanced delivery; drug delivery; central nervous system; technique; bulk flow ID RECURRENT MALIGNANT GLIOMA; NEURONAL CEROID-LIPOFUSCINOSIS; PHASE-I TRIAL; IL4-PSEUDOMONAS EXOTOXIN NBI-3001; DIRECT INTERSTITIAL INFUSION; VIRUS-SIZED PARTICLES; GENE-THERAPY; BRAIN-STEM; REAL-TIME; PARKINSONS-DISEASE AB Convection-enhanced delivery (CED) is a bulk flow driven process. Its properties permit direct, homogeneous, targeted perfusion of CNS regions with putative therapeutics while bypassing the blood-brain barrier. Development of surrogate imaging tracers that are co-infused during drug delivery now permit accurate, noninvasive real-time tracking of convective infusate flow in nervous system tissues. The potential advantages of CED in the CNS over other currently available drug delivery techniques, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation, have led to its application in research studies and clinical trials. The authors review the biophysical principles of convective flow and the technology, properties, and clinical applications of convective delivery in the CNS. C1 [Lonser, Russell R.] Ohio State Univ, Wexner Med Ctr, Dept Neurol Surg, Columbus, OH 43210 USA. [Lonser, Russell R.; Oldfield, Edward H.] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. [Morrison, Paul F.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Sarntinoranont, Malisa] Univ Florida, Dept Mech & Aerosp Engn, Gainesville, FL USA. [Oldfield, Edward H.] Univ Virginia, Hlth Sci Ctr, Dept Neurol Surg, Charlottesville, VA USA. RP Lonser, RR (reprint author), Ohio State Univ, Wexner Med Ctr, Dept Neurol Surg, 410 W 10th Ave,Doan Hall N1047, Columbus, OH 43210 USA. EM russell.lonser@osumc.edu NR 117 TC 14 Z9 15 U1 2 U2 17 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD MAR PY 2015 VL 122 IS 3 BP 697 EP 706 DI 10.3171/2014.10.JNS14229 PG 10 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA CC3RJ UT WOS:000350266600029 PM 25397365 ER PT J AU Nansel, T Haynie, D Lipsky, L Mehta, S Laffel, L AF Nansel, Tonja Haynie, Denise Lipsky, Leah Mehta, Sanjeev Laffel, Lori TI Little Variation in Diet Cost Across Wide Ranges of Overall Dietary Quality among Youth with Type 1 Diabetes SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Type 1 diabetes; Cost; Spending; Adolescents; Children ID LOW-INCOME WOMEN; ENERGY-DENSE DIETS; SOCIOECONOMIC-STATUS; NUTRITIONAL QUALITY; NUTRIENT DATABASE; FOOD-CONSUMPTION; AMERICAN WOMEN; HEALTHFUL DIET; CHILDREN; ADOLESCENTS AB We examined the association of diet quality with diet cost in a sample of youth with type 1 diabetes, for whom diet is an important component of medical management. Differences in food group spending by diet quality were also examined to identify potential budgetary reallocation to improve overall diet quality. Families of 252 youth with type 1 diabetes aged 8 to 18 years completed 3-day youth diet records. Cost of each food reported was calculated based on the average price obtained from two online grocery stores. Diet cost was estimated as average daily cost of foods consumed. The Healthy Eating Index 2005 (HEI2005), Nutrient Rich Foods Index version 9.3, and Whole Plant Food Density scores were evaluated. Differences in mean daily diet cost across tertiles of HEI2005, Nutrient Rich Foods Index version 9.3, and Whole Plant Food Density were modest, with none reaching statistical significance. Those in the upper tertile of HEI2005 spent more on whole fruit, whole grains, lean meat, and low-fat dairy, and less on high-fat meat and high-fat dairy compared with those in the lower tertiles. Higher-quality diets can be obtained at comparable costs to lesser-quality diets, suggesting that cost need not be an insurmountable barrier to more healthful eating. Reallocation of spending may increase overall quality without substantially increasing overall spending. Findings suggest potential strategies for assisting families of youth with type 1 diabetes in identifying cost-effective ways to achieve a more healthful diet. C1 [Nansel, Tonja; Haynie, Denise; Lipsky, Leah] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Mehta, Sanjeev; Laffel, Lori] Harvard Univ, Sch Med, Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Boston, MA 02115 USA. RP Nansel, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B13, Bethesda, MD 20892 USA. EM nanselt@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595; Haynie, Denise/0000-0002-8270-6079; Lipsky, Leah/0000-0003-2645-4388 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Program [HHSN267200703434C] FX This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Program (contract no. HHSN267200703434C). NR 55 TC 4 Z9 4 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD MAR PY 2015 VL 115 IS 3 BP 433 EP U115 DI 10.1016/j.jand.2014.07.035 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CC3FM UT WOS:000350231700014 PM 25266245 ER PT J AU Barrett, L Trehanpati, N Poonia, S Daigh, L Sarin, SK Masur, H Kottilil, S AF Barrett, L. Trehanpati, N. Poonia, S. Daigh, L. Sarin, S. Kumar Masur, H. Kottilil, S. TI Hepatic compartmentalization of exhausted and regulatory cells in HIV/HCV-coinfected patients SO JOURNAL OF VIRAL HEPATITIS LA English DT Article DE HCV; HIV; intrahepatic immunity; T cell ID C VIRUS-INFECTION; CD8 T-CELLS; NATURAL-HISTORY; PD-1 EXPRESSION; HCV INFECTION; LIVER; FIBROSIS; IMMUNITY; HIV AB Accelerated intrahepatic hepatitis C virus (HCV) pathogenesis is likely the result of dysregulation within both the innate and adaptive immune compartments, but the exact contribution of peripheral blood and liver lymphocyte subsets remains unclear. Prolonged activation and expansion of immunoregulatory cells have been thought to play a role. We determined immune cell subset frequency in contemporaneous liver and peripheral blood samples from chronic HCV-infected and HIV/HCV-coinfected individuals. Peripheral blood mononuclear cells (PBMC) and biopsy-derived liver-infiltrating lymphocytes from 26 HIV/HCV-coinfected, 10 chronic HCV-infected and 10 HIV-infected individuals were assessed for various subsets of T and B lymphocytes, dendritic cell, natural killer (NK) cell and NK T-cell frequency by flow cytometry. CD8(+) T cells expressing the exhaustion marker PD-1 were increased in HCV-infected individuals compared with uninfected individuals (P=0.02), and HIV coinfection enhanced this effect (P=0.005). In the liver, regulatory CD4(+)CD25(+)Foxp3(+) T cells, as well as CD4(+)CD25(+)PD1(+) T cells, were more frequent in HIV/HCV-coinfected than in HCV-monoinfected samples (P<0.001). HCV was associated with increased regulatory T cells, PD-1(+) T cells and decreased memory B cells, regardless of HIV infection (P0.005 for all). Low CD8(+) expression was observed only in PD-1(+)CD8(+) T cells from HCV-infected individuals and healthy controls (P=0.002) and was associated with enhanced expansion of exhausted CD8(+) T cells when exposed in vitro to PHA or CMV peptides. In conclusion, in HIV/HCV coinfection, ongoing HCV replication is associated with increased regulatory and exhausted T cells in the periphery and liver that may impact control of HCV. Simultaneous characterization of liver and peripheral blood highlights the disproportionate intrahepatic compartmentalization of immunoregulatory T cells, which may contribute to establishment of chronicity and hepatic fibrogenesis in HIV coinfection. C1 [Barrett, L.; Poonia, S.; Daigh, L.; Masur, H.; Kottilil, S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Trehanpati, N.; Sarin, S. Kumar] Inst Liver & Biliary Sci, New Delhi, India. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Rm11N204,9000 Rockville Pike, Bethesda, MD 20892 USA. EM SKottilil@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 20 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1352-0504 EI 1365-2893 J9 J VIRAL HEPATITIS JI J. Viral Hepatitis PD MAR PY 2015 VL 22 IS 3 BP 281 EP 288 DI 10.1111/jvh.12291 PG 8 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA CC7KN UT WOS:000350546300008 PM 25174689 ER PT J AU Rasmussen, AL Tchitchek, N Safronetz, D Carter, VS Williams, CM Haddock, E Korth, MJ Feldmann, H Katze, MG AF Rasmussen, Angela L. Tchitchek, Nicolas Safronetz, David Carter, Victoria S. Williams, Christopher M. Haddock, Elaine Korth, Marcus J. Feldmann, Heinz Katze, Michael G. TI Delayed Inflammatory and Cell Death Responses Are Associated with Reduced Pathogenicity in Lujo Virus-Infected Cynomolgus Macaques SO JOURNAL OF VIROLOGY LA English DT Article ID CDNA MICROARRAY DATA; ENDEMIC LASSA FEVER; MAST-CELLS; IMMUNE-RESPONSES; DENDRITIC CELLS; MONKEYS; NORMALIZATION; MACROPHAGES; EXPRESSION; INFLUENZA AB To identify host factors associated with arenavirus virulence, we used a cynomolgus macaque model to evaluate the pathogenesis of Lujo virus (LUJV), a recently emerged arenavirus that caused an outbreak of severe viral hemorrhagic fever in southern Africa. In contrast to human cases, LUJV caused mild, nonlethal illness in macaques. We then compared this to contrasting clinical outcomes during arenavirus infection, specifically to samples obtained from macaques infected with three highly pathogenic lines of Lassa virus (LASV), the causative agent of Lassa fever (LF). We assessed gene expression in peripheral blood mononuclear cells (PBMC) and determined genes that significantly changed expression relative to that in uninfected animals over the course of infection. We detected a 72-h delay in the induction of host responses to infection during LUJV infection compared to that of the animals infected with LASV. This included genes associated with inflammatory and antiviral responses and was particularly apparent among groups of genes promoting cell death. We also observed early differential expression of a subset of genes specific to LUJV infection that accounts for the delayed inflammatory response. Cell type enrichment analysis suggested that host response induction delay and an LUJV-specific profile are due to a different proportion of natural killer cells responding in LUJV infection than that in the LASV-infected animals. Together, these data indicate that delayed proinflammatory and proapoptotic host responses to arenavirus infection could ameliorate disease severity. This conclusion provides insight into the cellular and molecular mechanisms of arenaviral hemorrhagic fever and suggests potential strategies for therapeutic development. IMPORTANCE Old World arenaviruses are significant human pathogens that often are associated with high mortality. However, mechanisms underlying disease severity and virulence in arenavirus hemorrhagic fever are largely unknown, particularly regarding host responses that contribute to pathogenicity. This study describes a comparison between Lujo and Lassa virus infection in cynomolgus macaques. Lujo virus-infected macaques developed only mild illness, while Lassa virus-infected macaques developed severe illness consistent with Lassa fever. We determined that mild disease is associated with a delay in host expression of genes linked to virulence, such as those causing inflammation and cell death, and with distinct cell types that may mediate this delay. This is the first study to associate the timing and directionality of gene expression with arenaviral pathogenicity and disease outcome and evokes new potential approaches for developing effective therapeutics for treating these deadly emerging pathogens. C1 [Rasmussen, Angela L.; Tchitchek, Nicolas; Carter, Victoria S.; Williams, Christopher M.; Korth, Marcus J.; Katze, Michael G.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Safronetz, David; Haddock, Elaine; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Katze, Michael G.] Washington Natl Primate Res Ctr, Seattle, WA USA. RP Katze, MG (reprint author), Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. EM honey@uw.edu OI Rasmussen, Angela/0000-0001-9462-3169; Tchitchek, Nicolas/0000-0003-3307-0446 FU National Institute of Allergy and Infectious Diseases [P51 OD010425, U54 AI081680, U19 AI109761]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported in part by awards P51 OD010425, U54 AI081680, and U19 AI109761 from the National Institute of Allergy and Infectious Diseases and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 44 TC 3 Z9 3 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2015 VL 89 IS 5 BP 2543 EP 2552 DI 10.1128/JVI.02246-14 PG 10 WC Virology SC Virology GA CC2XD UT WOS:000350207400010 PM 25520505 ER PT J AU Kailasan, S Halder, S Gurda, B Bladek, H Chipman, PR McKenna, R Brown, K Agbandje-McKenna, M AF Kailasan, Shweta Halder, Sujata Gurda, Brittney Bladek, Heather Chipman, Paul R. McKenna, Robert Brown, Kevin Agbandje-McKenna, Mavis TI Structure of an Enteric Pathogen, Bovine Parvovirus SO JOURNAL OF VIROLOGY LA English DT Article ID ADENOASSOCIATED VIRUS TYPE-2; MINK DISEASE PARVOVIRUS; MINUTE VIRUS; PHOSPHOLIPASE-A2 ACTIVITY; FUNCTIONAL IMPLICATIONS; 3-DIMENSIONAL STRUCTURE; ELECTRON-MICROSCOPY; CELLULAR RECEPTOR; CAPSID PROTEINS; HUMAN BOCAVIRUS AB Bovine parvovirus (BPV), the causative agent of respiratory and gastrointestinal disease in cows, is the type member of the Bocaparvovirus genus of the Parvoviridae family. Toward efforts to obtain a template for the development of vaccines and small-molecule inhibitors for this pathogen, the structure of the BPV capsid, assembled from the major capsid viral protein 2 (VP2), was determined using X-ray crystallography as well as cryo-electron microscopy and three-dimensional image reconstruction (cryoreconstruction) to 3.2-and 8.8-angstrom resolutions, respectively. The VP2 region ordered in the crystal structure, from residues 39 to 536, conserves the parvoviral eight-stranded jellyroll motif and an alpha A helix. The BPV capsid displays common parvovirus features: a channel at and depressions surrounding the 5-fold axes and protrusions surrounding the 3-fold axes. However, rather than a depression centered at the 2-fold axes, a raised surface loop divides this feature in BPV. Additional observed density in the capsid interior in the cryo-reconstructed map, compared to the crystal structure, is interpreted as 10 additional N-terminal residues, residues 29 to 38, that radially extend the channel under the 5-fold axis, as observed for human bocavirus 1 (HBoV1). Surface loops of various lengths and conformations extend from the core jellyroll motif of VP2. These loops confer the unique surface topology of the BPV capsid, making it strikingly different from HBoV1 as well as the type members of other Parvovirinae genera for which structures have been determined. For the type members, regions structurally analogous to those decorating the BPV capsid surface serve as determinants of receptor recognition, tissue and host tropism, pathogenicity, and antigenicity. IMPORTANCE Bovine parvovirus (BPV), identified in the 1960s in diarrheic calves, is the type member of the Bocaparvovirus genus of the nonenveloped, single-stranded DNA (ssDNA) Parvoviridae family. The recent isolation of human bocaparvoviruses from children with severe respiratory and gastrointestinal infections has generated interest in understanding the life cycle and pathogenesis of these emerging viruses. We have determined the high-resolution structure of the BPV capsid assembled from its predominant capsid protein VP2, known to be involved in a myriad of functions during host cell entry, pathogenesis, and antigenicity for other members of the Parvovirinae. Our results show the conservation of the core secondary structural elements and the location of the N-terminal residues for the known bocaparvovirus capsid structures. However, surface loops with high variability in sequence and conformation give BPV a unique capsid surface topology. Similar analogous regions in other Parvovirinae type members are important as determinants of receptor recognition, tissue and host tropism, pathogenicity, and antigenicity. C1 [Kailasan, Shweta; Halder, Sujata; Gurda, Brittney; Bladek, Heather; Chipman, Paul R.; McKenna, Robert; Agbandje-McKenna, Mavis] Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. [Kailasan, Shweta; Halder, Sujata; Gurda, Brittney; Bladek, Heather; Chipman, Paul R.; McKenna, Robert; Agbandje-McKenna, Mavis] Univ Florida, McKnight Brain Inst, Gainesville, FL USA. [Brown, Kevin] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Agbandje-McKenna, M (reprint author), Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. EM mckenna@ufl.edu OI Gurda, Brittney /0000-0002-0174-9385 FU UF College of Medicine and Division of Sponsored Programs; UF College of Medicine and McKnight Brain Institute FX We thank the UF Interdisciplinary Center for Biotechnology Research Electron Microscopy core for cryo-electron microscopy access (funded by the UF College of Medicine and Division of Sponsored Programs).; This project was funded by the UF College of Medicine and McKnight Brain Institute (to M.A.-M.). NR 71 TC 3 Z9 3 U1 3 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2015 VL 89 IS 5 BP 2603 EP 2614 DI 10.1128/JVI.03157-14 PG 12 WC Virology SC Virology GA CC2XD UT WOS:000350207400015 PM 25520501 ER PT J AU Kong, R Louder, MK Wagh, K Bailer, RT deCamp, A Greene, K Gao, HM Taft, JD Gazumyan, A Liu, C Nussenzweig, MC Korber, B Montefiori, DC Mascola, JR AF Kong, Rui Louder, Mark K. Wagh, Kshitij Bailer, Robert T. deCamp, Allan Greene, Kelli Gao, Hongmei Taft, Justin D. Gazumyan, Anna Liu, Cassie Nussenzweig, Michel C. Korber, Bette Montefiori, David C. Mascola, John R. TI Improving Neutralization Potency and Breadth by Combining Broadly Reactive HIV-1 Antibodies Targeting Major Neutralization Epitopes SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN GP120; HUMAN MONOCLONAL-ANTIBODIES; PROXIMAL EXTERNAL REGION; MUCOSAL SHIV CHALLENGE; N-GLYCAN RECOGNITION; INFECTION IN-VIVO; PASSIVE TRANSFER; GP41-GP120 INTERFACE; VACCINE DEVELOPMENT AB The isolation of broadly neutralizing HIV-1 monoclonal antibodies (MAbs) to distinct epitopes on the viral envelope glycoprotein (Env) provides the potential to use combinations of MAbs for prevention and treatment of HIV-1 infection. Since many of these MAbs have been isolated in the last few years, the potency and breadth of MAb combinations have not been well characterized. In two parallel experiments, we examined the in vitro neutralizing activities of double-, triple-, and quadruple-MAb combinations targeting four distinct epitopes, including the CD4-binding site, the V1V2-glycan region, the V3-glycan supersite, and the gp41 membrane-proximal external region (MPER), using a panel of 125 Env-pseudotyped viruses. All MAb combinations showed substantially improved neutralization breadth compared to the corresponding single MAbs, while the neutralization potency of individual MAbs was maintained. At a 50% inhibitory concentration (IC50) cutoff of 1 mu g/ml per antibody, double-MAb combinations neutralized 89 to 98% of viruses, and triple combinations neutralized 98 to 100%. Overall, the improvement of neutralization breadth was closely predicted by an additive-effect model and explained by complementary neutralization profiles of antibodies recognizing distinct epitopes. Subtle but consistent favorable interactions were observed in some MAb combinations, whereas less favorable interactions were observed on a small subset of viruses that are highly sensitive to V3-glycan MAbs. These data demonstrate favorable in vitro combinations of broadly neutralizing HIV-1 MAbs and suggest that such combinations could have utility for HIV-1 prevention and treatment. IMPORTANCE Over the last 5 years, numerous broadly reactive HIV-1-neutralizing MAbs have been isolated from B cells of HIV-1-infected donors. Each of these MAbs binds to one of the major vulnerable sites (epitopes) on the surface of the viral envelope glycoprotein. Since antibodies to distinct viral epitopes could theoretically act together to provide greater potency and breadth of virus neutralization, we tested physical mixtures of double, triple, and quadruple combinations of neutralizing MAbs targeting four major epitopes on HIV-1 Env. When tested together, antibody combinations showed substantially improved neutralization breadth compared to single MAbs. This improvement could be explained by the complementary neutralization profiles of individual MAbs. We further demonstrated that each antibody maintained its full neutralization potency when used in combination with other MAbs. These data provide a rationale for clinical use of antibody-based combinations for HIV-1 prevention and therapy. C1 [Kong, Rui; Louder, Mark K.; Bailer, Robert T.; Taft, Justin D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Wagh, Kshitij; Korber, Bette] Los Alamos Natl Lab, Div Theoret, Los Alamos, NM USA. [deCamp, Allan] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Greene, Kelli; Gao, Hongmei; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Greene, Kelli; Gao, Hongmei; Montefiori, David C.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. [Gazumyan, Anna; Liu, Cassie; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. RP Montefiori, DC (reprint author), Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. EM monte@duke.edu; jmascola@nih.gov OI Korber, Bette/0000-0002-2026-5757 FU intramural research program of the Vaccine Research Center, NIAID, NIH; Bill and Melinda Gates Foundation (Collaboration for AIDS Vaccine Discovery) [1032144]; Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery grant (CHAVI-ID) [UM1 AI100645] FX This work was funded by the intramural research program of the Vaccine Research Center, NIAID, NIH, and by a grant from the Bill and Melinda Gates Foundation (Collaboration for AIDS Vaccine Discovery; no. 1032144). B.K. and K.W. were also partially supported in this work through a Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery grant (CHAVI-ID; UM1 AI100645). NR 82 TC 29 Z9 29 U1 1 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2015 VL 89 IS 5 BP 2659 EP 2671 DI 10.1128/JVI.03136-14 PG 13 WC Virology SC Virology GA CC2XD UT WOS:000350207400019 PM 25520506 ER PT J AU Ryder, AB Buonocore, L Vogel, L Nachbagauer, R Krammer, F Rose, JK AF Ryder, Alex B. Buonocore, Linda Vogel, Leatrice Nachbagauer, Raffael Krammer, Florian Rose, John K. TI A Viable Recombinant Rhabdovirus Lacking Its Glycoprotein Gene and Expressing Influenza Virus Hemagglutinin and Neuraminidase Is a Potent Influenza Vaccine SO JOURNAL OF VIROLOGY LA English DT Article ID VESICULAR-STOMATITIS-VIRUS; REPLICATION-COMPETENT VECTOR; HIGHLY PATHOGENIC PHENOTYPE; NEUTRALIZING ANTIBODIES; IMMUNE-RESPONSES; ENVELOPE GLYCOPROTEINS; SEASONAL INFLUENZA; NONHUMAN-PRIMATES; GENOMIC RNA; IN-VIVO AB The emergence of novel influenza viruses that cause devastating human disease is an ongoing threat and serves as an impetus for the continued development of novel approaches to influenza vaccines. Influenza vaccine development has traditionally focused on producing humoral and/or cell-mediated immunity, often against the viral surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). Here, we describe a new vaccine candidate that utilizes a replication-defective vesicular stomatitis virus (VSV) vector backbone that lacks the native G surface glycoprotein gene (VSV Delta G). The expression of the H5 HA of an H5N1 highly pathogenic avian influenza virus (HPAIV), A/Vietnam/1203/04 (VN1203), and the NA of the mouse-adapted H1N1 influenza virus A/PuertoRico/8/34 (PR8) in the VSV Delta G vector restored the ability of the recombinant virus to replicate in cell culture, without the requirement for the addition of trypsin. We show here that this recombinant virus vaccine candidate was nonpathogenic in mice when given by either the intramuscular or intranasal route of immunization and that the in vivo replication of VSV Delta G-H5N1 is profoundly attenuated. This recombinant virus also provided protection against lethal H5N1 infection after a single dose. This novel approach to vaccination against HPAIVs may be widely applicable to other emerging strains of influenza virus. IMPORTANCE Preparation for a potentially catastrophic influenza pandemic requires novel influenza vaccines that are safe, can be produced and administered quickly, and are effective, both soon after administration and for a long duration. We have created a new influenza vaccine that utilizes an attenuated vesicular stomatitis virus (VSV) vector, to deliver and express influenza virus proteins against which vaccinated animals develop potent antibody responses. The influenza virus hemagglutinin and neuraminidase proteins, expressed on the surface of VSV particles, allowed this vaccine to grow in cell culture and induced a potent antibody response in mice that was effective against infection with a lethal influenza virus. The mice showed no adverse reactions to the vaccine, and they were protected against an otherwise lethal influenza infection after only 14 days postvaccination and after as many as 140 days postvaccination. The ability to rapidly produce this safe and effective vaccine in cell culture is additionally advantageous. C1 [Ryder, Alex B.; Buonocore, Linda; Rose, John K.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Ryder, Alex B.] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA. [Vogel, Leatrice] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Nachbagauer, Raffael; Krammer, Florian] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. [Nachbagauer, Raffael] Univ Vienna, Fac Life Sci, Vienna, Austria. RP Rose, JK (reprint author), Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. EM john.rose@yale.edu OI Krammer, Florian/0000-0003-4121-776X; Nachbagauer, Raffael/0000-0001-5568-5420 FU NIH [R01-AI080781]; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), NIH; Yale University School of Medicine NRSA training grant [5T32HL007974-13]; Erwin Schrodinger fellowship from the Austrian Science Fund (FWF) [J3232] FX This study was supported by NIH grant R01-AI080781 and by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), NIH. Alex B. Ryder was supported by Yale University School of Medicine NRSA training grant 5T32HL007974-13. Florian Krammer was supported by an Erwin Schrodinger fellowship (J3232) from the Austrian Science Fund (FWF). NR 66 TC 5 Z9 5 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2015 VL 89 IS 5 BP 2820 EP 2830 DI 10.1128/JVI.03246-14 PG 11 WC Virology SC Virology GA CC2XD UT WOS:000350207400033 PM 25540378 ER PT J AU Majerciak, V Pripuzova, N Chan, C Temkin, N Specht, SI Zheng, ZM AF Majerciak, Vladimir Pripuzova, Natalia Chan, Calvin Temkin, Nicholas Specht, Suzanne I. Zheng, Zhi-Ming TI Stability of Structured Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Is Regulated by Protein Phosphorylation and Homodimerization SO JOURNAL OF VIROLOGY LA English DT Article ID MESSENGER-RNA EXPORT; KINASE CK2 PHOSPHORYLATION; NUCLEAR-RNA; CASEIN KINASE; LIVING CELLS; VIRUS; EXPRESSION; BINDING; ICP27; CLEAVAGE AB Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 plays an essential role in KSHV lytic infection by promoting viral gene expression at the posttranscriptional level. Using bioinformatic and biochemical approaches, we determined that ORF57 contains two structurally and functionally distinct domains: a disordered nonstructural N-terminal domain (amino acids [aa] 1 to 152) and a structured alpha-helix-rich C-terminal domain (aa 153 to 455). The N-terminal domain mediates ORF57 interaction with several RNA-protein complexes essential for ORF57 to function. The N-terminal phosphorylation by cellular casein kinase II (CKII) at S21, T32, and S43, and other cellular kinases at S95 and S97 residues in proximity of the caspase-7 cleavage site, 30-DETD-33, inhibits caspase-7 digestion of ORF57. The structured C-terminal domain mediates homodimerization of ORF57, and the critical region for this function was mapped carefully to alpha-helices 7 to 9. Introduction of point mutations into alpha-helix 7 at ORF57 aa 280 to 299, a region highly conserved among ORF57 homologues from other herpesviruses, inhibited ORF57 homodimerization and led to proteasome-mediated degradation of ORF57 protein. Thus, homodimerization of ORF57 via its C terminus prevents ORF57 from degrading and allows two structure-free N termini of the dimerized ORF57 to work coordinately for host factor interactions, leading to productive KSHV lytic infection and pathogenesis. IMPORTANCE KSHV is a human oncogenic virus linked to the development of several malignancies. KSHV-mediated oncogenesis requires both latent and lytic infection. The KSHV ORF57 protein is essential for KSHV lytic replication, as it regulates the expression of viral lytic genes at the posttranscriptional level. This report provides evidence that the structural conformation of the ORF57 protein plays a critical role in regulation of ORF57 stability. Phosphorylation by CKII on the identified serine/threonine residues at the N-terminal unstructured domain of ORF57 prevents its digestion by caspase-7. The C-terminal domain of ORF57, which is rich in alpha-helices, contributes to homodimerization of ORF57 to prevent proteasome-mediated protein degradation. Elucidation of the ORF57 structure not only enables us to better understand ORF57 stability and functions but also provides an important tool for us to modulate ORF57's activity with the aim to inhibit KSHV lytic replication. C1 [Majerciak, Vladimir; Pripuzova, Natalia; Chan, Calvin; Temkin, Nicholas; Zheng, Zhi-Ming] NCI, Tumor Virus RNA Biol Sect, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21701 USA. [Specht, Suzanne I.] NCI, Lab Cell & Dev Signaling, NIH, Frederick, MD 21701 USA. RP Zheng, ZM (reprint author), NCI, Tumor Virus RNA Biol Sect, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21701 USA. EM zhengt@exchange.nih.gov FU intramural research programs of the National Cancer Institute, National Institutes of Health FX This work was supported by the intramural research programs of the National Cancer Institute, National Institutes of Health. Calvin Chan and Nicholas Temkin took part in the NIH Summer Internship Program in Biomedical Research. NR 71 TC 6 Z9 6 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2015 VL 89 IS 6 BP 3256 EP 3274 DI 10.1128/JVI.03721-14 PG 19 WC Virology SC Virology GA CC2XQ UT WOS:000350208900022 PM 25568207 ER PT J AU Lingemann, M Surman, S Amaro-Carambot, E Schaap-Nutt, A Collins, PL Munir, S AF Lingemann, Matthias Surman, Sonja Amaro-Carambot, Emerito Schaap-Nutt, Anne Collins, Peter L. Munir, Shirin TI The Aberrant Gene-End Transcription Signal of the Matrix M Gene of Human Parainfluenza Virus Type 3 Downregulates Fusion F Protein Expression and the F-Specific Antibody Response In Vivo SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; VESICULAR STOMATITIS-VIRUS; HEMAGGLUTININ-NEURAMINIDASE; MESSENGER-RNA; SENDAI-VIRUS; INTERGENIC REGIONS; ACTIVATION; INFECTION; GLYCOPROTEIN; REPLICATION AB Human parainfluenza virus type 3 (HPIV3), a paramyxovirus, is a major viral cause of severe lower respiratory tract disease in infants and children. The gene-end (GE) transcription signal of the HPIV3 matrix (M) protein gene is identical to those of the nucleoprotein and phosphoprotein genes except that it contains an apparent 8-nucleotide insert. This was associated with an increased synthesis of a readthrough transcript of the M gene and the downstream fusion (F) protein gene. We hypothesized that this insert may function to downregulate the expression of F protein by interfering with termination/reinitiation at the M-F gene junction, thus promoting the production of M-F readthrough mRNA at the expense of monocistronic F mRNA. To test this hypothesis, two similar recombinant HPIV3 viruses from which this insert in the M-GE signal was removed were generated. The M-GE mutants exhibited a reduction in M-F readthrough mRNA and an increase in monocistronic F mRNA. This resulted in a substantial increase in F protein synthesis in infected cells as well as enhanced incorporation of F protein into virions. The efficiency of mutant virus replication was similar to that of wild-type (wt) HPIV3 both in vitro and in vivo. However, the F-protein-specific serum antibody response in hamsters was increased for the mutants compared to wt HPIV3. This study identifies a previously undescribed viral mechanism for attenuating the host adaptive immune response. Repairing the M-GE signal should provide a means to increase the antibody response to a live attenuated HPIV3 vaccine without affecting viral replication and attenuation. IMPORTANCE The HPIV3 M-GE signal was previously shown to contain an apparent 8-nucleotide insert that was associated with increased synthesis of a readthrough mRNA of the M gene and the downstream F gene. However, whether this had any significant effect on the synthesis of monocistronic F mRNA or F protein, virus replication, virion morphogenesis, and immunogenicity was unknown. Here, we show that the removal of this insert shifts F gene transcription from readthrough M-F mRNA to monocistronic F mRNA. This resulted in a substantial increase in the amount of F protein expressed in the cell and packaged in the virus particle. This did not affect virus replication but increased the F-specific antibody response in hamsters. Thus, in wild-type HPIV3, the aberrant M-GE signal operates a previously undescribed mechanism that reduces the expression of a major neutralization and protective antigen, resulting in reduced immunogenicity. This has implications for the design of live attenuated HPIV3 vaccines; specifically, the antibody response against F can be elevated by "repairing" the M-GE signal to achieve higher-level F antigen expression, with no effect on attenuation. C1 [Lingemann, Matthias; Surman, Sonja; Amaro-Carambot, Emerito; Schaap-Nutt, Anne; Collins, Peter L.; Munir, Shirin] NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Munir, S (reprint author), NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM munirs@niaid.nih.gov FU Intramural Research Program of the NIAID, NIH FX This study was supported by the Intramural Research Program of the NIAID, NIH. NR 41 TC 0 Z9 0 U1 2 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2015 VL 89 IS 6 BP 3318 EP 3331 DI 10.1128/JVI.03148-14 PG 14 WC Virology SC Virology GA CC2XQ UT WOS:000350208900027 PM 25589643 ER PT J AU Qiu, Q Xu, ZL Tian, J Moitra, R Gunti, S Notkins, AL Byrnes, AP AF Qiu, Qi Xu, Zhili Tian, Jie Moitra, Rituparna Gunti, Sreenivasulu Notkins, Abner L. Byrnes, Andrew P. TI Impact of Natural IgM Concentration on Gene Therapy with Adenovirus Type 5 Vectors SO JOURNAL OF VIROLOGY LA English DT Article ID IN-VIVO; POLYREACTIVE ANTIBODIES; CELL-DEVELOPMENT; KUPFFER CELLS; B-CELLS; MICE; COMPLEMENT; HEXON; LIVER; MACROPHAGES AB Natural IgM inhibits gene transfer by adenovirus type 5 (Ad5) vectors. We show that polyreactive natural IgM antibodies bind to Ad5 and that inhibition of liver transduction by IgM depends on Kupffer cells. By manipulating IgM concentration in vivo, we demonstrate that IgM inhibits liver transduction in a concentration-dependent manner. We further show that differences in natural IgM between BALB/c and C57BL/6 mice contribute to lower efficiency of Ad5 gene transfer in BALB/c mice. C1 [Qiu, Qi; Xu, Zhili; Tian, Jie; Moitra, Rituparna; Byrnes, Andrew P.] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Gunti, Sreenivasulu; Notkins, Abner L.] Natl Inst Dent & Craniofacial Res, Expt Med Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. RP Byrnes, AP (reprint author), US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Andrew.Byrnes@FDA.HHS.gov OI Byrnes, Andrew/0000-0003-1135-2629 FU U.S. Food and Drug Administration (FDA); FDA's Critical Path program; Oak Ridge Institute for Science and Education FX Funding was provided by the U.S. Food and Drug Administration (FDA), including the FDA's Critical Path program. This project was supported in part by fellowships administered by the Oak Ridge Institute for Science and Education. NR 28 TC 2 Z9 3 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2015 VL 89 IS 6 BP 3412 EP 3416 DI 10.1128/JVI.03217-14 PG 5 WC Virology SC Virology GA CC2XQ UT WOS:000350208900034 PM 25552715 ER PT J AU Baz, M Subbarao, K AF Baz, Mariana Subbarao, Kanta TI An addition to treatment options for avian influenza A H5N1? SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material ID CONVALESCENT PLASMA; INFECTION; VIRUSES; HUMANS C1 [Baz, Mariana; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Baz, M (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov NR 12 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD MAR PY 2015 VL 15 IS 3 BP 251 EP 253 DI 10.1016/S1473-3099(15)70019-8 PG 3 WC Infectious Diseases SC Infectious Diseases GA CC3SA UT WOS:000350268500003 PM 25662593 ER PT J AU Xue, H Inati, S Sorensen, TS Kellman, P Hansen, MS AF Xue, Hui Inati, Souheil Sorensen, Thomas Sangild Kellman, Peter Hansen, Michael S. TI Distributed MRI Reconstruction Using Gadgetron-Based Cloud Computing SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE Gadgetron; distributed computing; nonlinear MRI reconstruction; open-source software ID COMMODITY GRAPHICS HARDWARE; CARTESIAN SENSE; ACQUISITIONS; GRAPPA AB PurposeTo expand the open source Gadgetron reconstruction framework to support distributed computing and to demonstrate that a multinode version of the Gadgetron can be used to provide nonlinear reconstruction with clinically acceptable latency. MethodsThe Gadgetron framework was extended with new software components that enable an arbitrary number of Gadgetron instances to collaborate on a reconstruction task. This cloud-enabled version of the Gadgetron was deployed on three different distributed computing platforms ranging from a heterogeneous collection of commodity computers to the commercial Amazon Elastic Compute Cloud. The Gadgetron cloud was used to provide nonlinear, compressed sensing reconstruction on a clinical scanner with low reconstruction latency (eg, cardiac and neuroimaging applications). ResultsThe proposed setup was able to handle acquisition and 1(1)-SPIRiT reconstruction of nine high temporal resolution real-time, cardiac short axis cine acquisitions, covering the ventricles for functional evaluation, in under 1 min. A three-dimensional high-resolution brain acquisition with 1 mm(3) isotropic pixel size was acquired and reconstructed with nonlinear reconstruction in less than 5 min. ConclusionA distributed computing enabled Gadgetron provides a scalable way to improve reconstruction performance using commodity cluster computing. Nonlinear, compressed sensing reconstruction can be deployed clinically with low image reconstruction latency. Magn Reson Med 73:1015-1025, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Xue, Hui; Hansen, Michael S.] NHLBI, Magnet Resonance Technol Program, NIH, Bethesda, MD 20814 USA. [Inati, Souheil] NIMH, NIH, Bethesda, MD 20892 USA. [Sorensen, Thomas Sangild] Aarhus Univ, Dept Comp Sci, Aarhus, Denmark. [Sorensen, Thomas Sangild] Aarhus Univ, Dept Clin Med, Aarhus, Denmark. [Kellman, Peter] NHLBI, Med Signal & Image Proc Program, NIH, Bethesda, MD 20892 USA. RP Xue, H (reprint author), NHLBI, Magnet Resonance Technol Program, NIH, 10 Ctr Dr, Bethesda, MD 20814 USA. EM hui.xue@nih.gov RI Hansen, Michael/J-5391-2015; OI Hansen, Michael/0000-0002-8087-8731; Sorensen, Thomas Sangild/0000-0002-8482-7667 FU National Heart, Lung and Blood Institute Intramural Research Program FX Grant sponsor: National Heart, Lung and Blood Institute Intramural Research Program. NR 23 TC 7 Z9 7 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD MAR PY 2015 VL 73 IS 3 BP 1015 EP 1025 DI 10.1002/mrm.25213 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CC3VV UT WOS:000350279900013 PM 24687458 ER PT J AU Hansen, MS Inati, SJ Kellman, P AF Hansen, Michael S. Inati, Souheil J. Kellman, Peter TI Noise Propagation in Region of Interest Measurements SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE region of interest measurement; standard deviation; confidence interval; signal to noise ratio; parallel imaging ID RECONSTRUCTIONS; UNCERTAINTY; GRAPPA; RATIO AB PurposeThe purpose of this work was to develop and validate a technique for predicting the standard deviation (SD) associated with thermal noise propagation in region of interest measurements. Theory and MethodsStandard methods for error propagation estimation were used to derive equations for the SDs of linear combinations of complex, magnitude, or phase pixel values. The equations were applied to common imaging scenarios in which the image pixels were correlated due to anisotropic pixel resolutions and parallel imaging. All SD estimates were evaluated efficiently using only vector-vector multiplications and Fourier transforms. The estimated SDs were compared to those obtained using repeated experiments and pseudo replica reconstructions. ResultsThe proposed method was able to predict region of interest SDs in all the tested analysis scenarios. Positive and negative noise correlations caused by different parallel-imaging aliasing point spread functions were accurately predicted, and the method predicted the confidence intervals (CI) of time-intensity curves for in vivo cardiac perfusion measurements. ConclusionAn intuitive technique for region of interest CIs was developed and validated using phantom experiments and in vivo data. Magn Reson Med 73:1300-1308, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Hansen, Michael S.; Kellman, Peter] NHLBI, NIH, Bethesda, MD 20814 USA. [Inati, Souheil J.] NIMH, NIH, Bethesda, MD 20892 USA. RP Hansen, MS (reprint author), NHLBI, NIH, Bldg 10,B1D405,9000 Rockville Pike, Bethesda, MD 20814 USA. EM michael.hansen@nih.gov RI Hansen, Michael/J-5391-2015 OI Hansen, Michael/0000-0002-8087-8731 FU National Institutes of Health; National Heart, Lung, and Blood Institute; National Institute of Mental Health FX This research was supported by the Intramural Research Program of the National Institutes of Health; the National Heart, Lung, and Blood Institute; and the National Institute of Mental Health. NR 14 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD MAR PY 2015 VL 73 IS 3 BP 1300 EP 1308 DI 10.1002/mrm.25194 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CC3VV UT WOS:000350279900044 PM 24634307 ER PT J AU Walia, JS Altaleb, N Bello, A Kruck, C LaFave, MC Varshney, GK Burgess, SM Chowdhury, B Hurlbut, D Hemming, R Kobinger, GP Triggs-Raine, B AF Walia, Jagdeep S. Altaleb, Naderah Bello, Alexander Kruck, Christa LaFave, Matthew C. Varshney, Gaurav K. Burgess, Shawn M. Chowdhury, Biswajit Hurlbut, David Hemming, Richard Kobinger, Gary P. Triggs-Raine, Barbara TI Long-Term Correction of Sandhoff Disease Following Intravenous Delivery of rAAV9 to Mouse Neonates SO MOLECULAR THERAPY LA English DT Article ID TAY-SACHS-DISEASE; CENTRAL-NERVOUS-SYSTEM; GENE-TRANSFER; HEPATOCELLULAR-CARCINOMA; HETEROZYGOTE DETECTION; GM2 GANGLIOSIDOSIS; INTEGRATION SITES; IN-VIVO; MICE; MODELS AB G(M2) gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in p-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb(-/-)) of the G(M2) gangliosidoses, we tested the potential of systemically delivered adeno-associated virus 9 (AAV9) expressing Hexb cDNA to correct the neurological phenotype. Neonatal or adult SD and normal mice were intravenously injected with AAV9-HexB or -LacZ and monitored for serum P-hexosaminidase activity, motor function, and sur-vival. Brain G(M2) ganglioside, beta-hexosaminidase activity, and inflammation were assessed at experimental week 43, or an earlier humane end point. SD mice injected with AAV9-LacZ died by 17 weeks of age, whereas all neonatal AAV9-HexB treated SD mice survived until 43 weeks (P < 0.0001) with only three exhibiting neurological dysfunction. SD mice treated as adults with AAV9-HexB died between 17 and 35 weeks. Neonatal SD-HexB-treated mice had a significant increase in brain beta-hexosanninidase activity, and a reduction in G(M2) ganglioside storage and neuroinflannnnation compared to adult SD-HexB- and SD-LacZ-treated groups. However, at 43 weeks, 8 of 10 neonatal-HexB injected control and SD mice exhibited liver or lung tumors. This study demonstrates the potential for long-term correction of SD and other G(M2) gangliosidoses through early rAAV9 based systemic gene therapy. C1 [Walia, Jagdeep S.] Queens Univ, Dept Pediat, Kingston, ON K7L 3N6, Canada. [Walia, Jagdeep S.; Altaleb, Naderah; Kruck, Christa; Chowdhury, Biswajit; Hemming, Richard; Triggs-Raine, Barbara] Univ Manitoba, Dept Biochem & Med Genet, Winnipeg, MB R3E 0J9, Canada. [Walia, Jagdeep S.; Triggs-Raine, Barbara] Univ Manitoba, Dept Pediat & Child Hlth, Winnipeg, MB R3E 0J9, Canada. [Walia, Jagdeep S.; Triggs-Raine, Barbara] Manitoba Inst Child Hlth, Winnipeg, MB, Canada. [Bello, Alexander; Kobinger, Gary P.] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0J9, Canada. [Bello, Alexander; Kobinger, Gary P.] Publ Hlth Agcy Canada, Special Pathogens Program, Winnipeg, MB, Canada. [LaFave, Matthew C.; Varshney, Gaurav K.; Burgess, Shawn M.] NHGRI, Dev Genom Sect, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Hurlbut, David] Queens Univ, Dept Pathol & Mol Med, Kingston, ON, Canada. RP Triggs-Raine, B (reprint author), Univ Manitoba, Dept Biochem & Med Genet, 745 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada. EM Barbara.Triggs-Raine@med.umanitoba.ca RI Varshney, Gaurav/L-5261-2014; OI Burgess, Shawn/0000-0003-1147-0596; Triggs-Raine, Barbara/0000-0003-4719-6779; Varshney, Gaurav K./0000-0002-0429-1904 FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; Public Health Agency of Canada; Manitoba Institute of Child Health; Manitoba Medical Service Foundation; Saudi Arabian Cultural Bureau in Canada FX The authors thank Xin-Min Li for access to open-field testing equipment and ANY-maze software. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (SB), by the Public Health Agency of Canada (GK) and by grants from the Manitoba Institute of Child Health and The Manitoba Medical Service Foundation to JW/BTR. NA was supported by funding from the Saudi Arabian Cultural Bureau in Canada. The work was primarily done in Winnipeg, Manitoba, Canada. The authors declare no conflict of interest. NR 50 TC 14 Z9 14 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAR PY 2015 VL 23 IS 3 BP 414 EP 422 DI 10.1038/mt.2014.240 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CC3RM UT WOS:000350267000002 PM 25515709 ER PT J AU Waterfall, JJ Meltzer, PS AF Waterfall, Joshua J. Meltzer, Paul S. TI Avalanching mutations in biallelic mismatch repair deficiency syndrome SO NATURE GENETICS LA English DT News Item ID DNA-POLYMERASE; CANCER; NEUROFIBROMATOSIS; CARCINOMA C1 [Waterfall, Joshua J.; Meltzer, Paul S.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Waterfall, JJ (reprint author), NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM pmeltzer@mail.nih.gov NR 13 TC 1 Z9 1 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2015 VL 47 IS 3 BP 194 EP 196 DI 10.1038/ng.3227 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA CC4MQ UT WOS:000350327900007 PM 25711864 ER PT J AU Miotto, O Amato, R Ashley, EA MacInnis, B Almagro-Garcia, J Amaratunga, C Lim, P Mead, D Oyolal, SO Dhorda, M Imwong, M Woodrow, C Manske, M Stalker, J Drury, E Campino, S Amenga-Etego, L Thanh, TNN Tran, HT Ringwald, P Bethellm, D Nosten, F Phyo, AP Pukrittayakamee, S Chotivanich, K Chuor, CM Nguon, C Suon, S Sreng, S Newton, PN Mayxay, M Khanthavong, M Hongvanthong, B Htut, Y Han, KT Kyaw, MP Faiz, MA Fanello, CI Onyamboko, M Mokuolu, OA Jacob, CG Takala-Harrison, S Plowe, CV Day, NP Dondorp, AM Spencer, CCA McVean, G Fairhurst, RM White, NJ Kwiatkowski, DP AF Miotto, Olivo Amato, Roberto Ashley, Elizabeth A. MacInnis, Bronwyn Almagro-Garcia, Jacob Amaratunga, Chanaki Lim, Pharath Mead, Daniel Oyolal, Samuel O. Dhorda, Mehul Imwong, Mallika Woodrow, Charles Manske, Magnus Stalker, Jim Drury, Eleanor Campino, Susana Amenga-Etego, Lucas Thuy-Nhien Nguyen Thanh Hien Tinh Tran Ringwald, Pascal Bethellm, Delia Nosten, Francois Phyo, Aung Pyae Pukrittayakamee, Sasithon Chotivanich, Kesinee Chuor, Char Meng Nguon, Chea Suon, Seila Sreng, Sokunthea Newton, Paul N. Mayxay, Mayfong Khanthavong, Maniphone Hongvanthong, Bouasy Htut, Ye Han, Kay Thwe Kyaw, Myat Phone Faiz, Md Abul Fanello, Caterina I. Onyamboko, Marie Mokuolu, Olugbenga A. Jacob, Christopher G. Takala-Harrison, Shannon Plowe, Christopher V. Day, Nicholas P. Dondorp, Arjen M. Spencer, Chris C. A. McVean, Gilean Fairhurst, Rick M. White, Nicholas J. Kwiatkowski, Dominic P. TI Genetic architecture of artemisinin-resistant Plasmodium falciparum SO NATURE GENETICS LA English DT Article ID CHLOROQUINE RESISTANCE; PARASITE CLEARANCE; DRUG-RESISTANCE; PFMDR2 GENE; MALARIA; SPREAD; EPIDEMIOLOGY; INDIVIDUALS; MUTATIONS; PROVINCE AB We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population. C1 [Miotto, Olivo; Amato, Roberto; MacInnis, Bronwyn; Almagro-Garcia, Jacob; Mead, Daniel; Oyolal, Samuel O.; Manske, Magnus; Stalker, Jim; Drury, Eleanor; Campino, Susana; Kwiatkowski, Dominic P.] Wellcome Trust Sanger Inst, Hinxton, Cambs, England. [Miotto, Olivo; Amato, Roberto; MacInnis, Bronwyn; Almagro-Garcia, Jacob; Manske, Magnus; Stalker, Jim; Campino, Susana; Amenga-Etego, Lucas; Spencer, Chris C. A.; McVean, Gilean; Kwiatkowski, Dominic P.] Univ Oxford, Ctr Genom & Global Hlth, MRC, Oxford, England. [Miotto, Olivo; Ashley, Elizabeth A.; Woodrow, Charles; Nosten, Francois; Phyo, Aung Pyae; Fanello, Caterina I.; Day, Nicholas P.; Dondorp, Arjen M.; White, Nicholas J.] Mahidol Univ, Fac Trop Med, Matlidol Oxtord Trop Med Res Unit, Bangkok 10700, Thailand. [Amato, Roberto; Almagro-Garcia, Jacob; Spencer, Chris C. A.; McVean, Gilean; Kwiatkowski, Dominic P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Ashley, Elizabeth A.; Dhorda, Mehul; Woodrow, Charles; Hien Tinh Tran; Nosten, Francois; Phyo, Aung Pyae; Newton, Paul N.; Mayxay, Mayfong; Fanello, Caterina I.; Onyamboko, Marie; Day, Nicholas P.; Dondorp, Arjen M.; White, Nicholas J.] Univ Oxford, Ctr Trop Med, Nuffield Dept Med, Oxford, England. [Amaratunga, Chanaki; Lim, Pharath; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, US NIH, Bethesda, MD 20892 USA. [Lim, Pharath; Chuor, Char Meng; Nguon, Chea; Suon, Seila; Sreng, Sokunthea] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. [Dhorda, Mehul; Jacob, Christopher G.; Takala-Harrison, Shannon; Plowe, Christopher V.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Dhorda, Mehul] Mahidol Univ, Asia Reg Ctr, WWARN, Bangkok 10700, Thailand. [Imwong, Mallika; Pukrittayakamee, Sasithon; Chotivanich, Kesinee] Mahidol Univ, Fac Trop Med, Bangkok 10700, Thailand. [Amenga-Etego, Lucas] Navrongo Hlth Res Ctr, Navrongo, Ghana. [Thuy-Nhien Nguyen Thanh; Hien Tinh Tran] Univ Oxford, Clin Res Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam. [Ringwald, Pascal] WHO, Global Malaria Programme, CH-1211 Geneva, Switzerland. [Bethellm, Delia] USAMC AFRIMS, Dept Immunol & Med, Bangkok, Thailand. [Nosten, Francois; Phyo, Aung Pyae] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Shoklo Malaria Res Unit, Mae Sot, Thailand. [Newton, Paul N.; Mayxay, Mayfong] Mahosot Hosp, Lao Oxford Mahosot Wellcome Trust Res Unit LOMWRU, Viangchan, Laos. [Mayxay, Mayfong] Univ Hlth Sci, Fac Postgrad Studies, Viangchan, Laos. [Khanthavong, Maniphone; Hongvanthong, Bouasy] Minist Hlth, Ctr Mahariol Parasitol & Entomol, Viangchan, Laos. [Htut, Ye; Han, Kay Thwe; Kyaw, Myat Phone] Dept Med Res, Yarigon, Myanmar. [Faiz, Md Abul] Malaria Res Grp & Dev Care Fdn, Dhaka, Bangladesh. [Onyamboko, Marie] Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Mokuolu, Olugbenga A.] Univ Ilorin, Dept Paediat & Child Hlth, Ilorin, Nigeria. [Plowe, Christopher V.] Univ Maryland, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21201 USA. [McVean, Gilean] Univ Oxford, Dept Stat, Oxford, England. RP Kwiatkowski, DP (reprint author), Wellcome Trust Sanger Inst, Hinxton, Cambs, England. EM dominic@sanger.ac.uk OI Nosten, Francois/0000-0002-7951-0745; Amato, Roberto/0000-0001-8633-9221; Miotto, Olivo/0000-0001-8060-6771; Oyola, Samuel O./0000-0002-6425-7345; 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; Woodrow, Charles/0000-0002-5134-7165 FU Wellcome Trust; Wellcome Trust Sanger Institute [098051]; Wellcome Trust Centre for Human Genetics [090532/Z/09/Z]; Resource Centre for Genomic Epidemiology of Malaria [090770/Z/09/Z]; Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme; UK Medical Research Council [G0600718]; Bill and Melinda Gates Foundation [OPP1040463]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases; US National Institutes of Health; Department for International Development [PO5408] FX We thank the following colleagues for their efforts in support of this work: P. Vauterin, G. Band and Q.S. Le; J. Anderson, D. Dek, S. Duong, R. Gwadz, S. Mao, V. Ou, B. Sam, C. Sopha, V. Try and T. Wellems; the personnel at Phuoc Long Hospital, Bu Gia Map Health Station, Malaria Control Center of Binh Phuoc Province, Vietnam; M. Phommasansack, B. Phimphalat and C. Vilayhong; and A.K. Tshefu. Special thanks are given to V. Cornelius and K. Johnson for their continual support of the analysis group. The sequencing for this study was funded by the Wellcome Trust through core funding of the Wellcome Trust Sanger Institute (098051). The Wellcome Trust also supports the Wellcome Trust Centre for Human Genetics (090532/Z/09/Z), the Resource Centre for Genomic Epidemiology of Malaria (090770/Z/09/Z) and the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme. The Centre for Genomics and Global Health is supported by the UK Medical Research Council (G0600718). This work was funded in part by the Bill and Melinda Gates Foundation (OPP1040463), the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health and the Department for International Development (PO5408). P.R. is a staff member of the World Health Organization. The views expressed in this publication are those of the authors and do not necessarily reflect the positions, decisions, policies or views of their employers or of the funding organizations. NR 42 TC 96 Z9 101 U1 3 U2 51 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2015 VL 47 IS 3 BP 226 EP + DI 10.1038/ng.3189 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA CC4MQ UT WOS:000350327900012 PM 25599401 ER PT J AU Merker, M Blin, C Mona, S Duforet-Frebourg, N Lecher, S Willery, E Blum, MGB Ruch-Gerdes, S Mokrousov, I Aleksic, E Allix-Beguec, C Antierens, A Augustynowicz-Kopec, E Banff', M Barletta, F Beckr, HP Barry, CE Bonnet, M Borroni, E Campos-Herrero, I Cirillo, D Cox, H Crowe, S Crudu, V Die, R Drobniewski, F Fauville-Dufaux, M Gagneuxr, S Ghebremichael, S Hanekom, M Hoffner, S Jiao, WW Kalon, S Kohl, TA Kontsevaya, I Lillebaek, T Maeda, S Nikolayevskyy, V Rasmussen, M Rastogi, N Samper, S Sanchez-Padilla, E Savic, B Shamputa, IC Shen, A Sng, LH Stakenas, P Toit, K Varaine, F Vukovic, D Wahl, C Warren, R Supply, P Niemann, S Wirth, T AF Merker, Matthias Blin, Camille Mona, Stefano Duforet-Frebourg, Nicolas Lecher, Sophie Willery, Eve Blum, Michael G. B. Ruech-Gerdes, Sabine Mokrousov, Igor Aleksic, Eman Allix-Beguec, Caroline Antierens, Annick Augustynowicz-Kopec, Ewa Banff', Marie Barletta, Francesca Beckr, Hans Peter Barry, Clifton E., III Bonnet, Maryline Borroni, Emanuele Campos-Herrero, Isolina Cirillo, Daniela Cox, Helen Crowe, Suzanne Crudu, Valeriu Die, Roland Drobniewski, Francis Fauville-Dufaux, Maryse Gagneuxr, Sebastien Ghebremichael, Solomon Hanekom, Madeleine Hoffner, Sven Jiao, Wei-wei Kalon, Stobdan Kohl, Thomas A. Kontsevaya, Irina Lillebaek, Troels Maeda, Shinji Nikolayevskyy, Vladyslav Rasmussen, Michael Rastogi, Nalin Samper, Sofia Sanchez-Padilla, Elisabeth Savic, Branislava Shamputa, Isdore Chola Shen, Adong Sng, Li-Hwei Stakenas, Petras Toit, Kadri Varaine, Francis Vukovic, Dragana Wahl, Celine Warren, Robin Supply, Philip Niemann, Stefan Wirth, Thierrv TI Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage SO NATURE GENETICS LA English DT Article ID DRUG-RESISTANT TUBERCULOSIS; NEW-YORK-CITY; MUTATION-RATE; MAXIMUM-LIKELIHOOD; SOUTH-AFRICA; MCE OPERONS; STRAINS; POPULATION; EMERGENCE; TRANSMISSION AB Mycobacterium tuberculosis strains of the Beijing lineage are globally distributed and are associated with the massive spread of multidrug-resistant (MDR) tuberculosis in Eurasia. Here we reconstructed the biogeographical structure and evolutionary history of this lineage by genetic analysis of 4,987 isolates from 99 countries and whole-genome sequencing of 110 representative isolates. We show that this lineage initially originated in the Far East, from where it radiated worldwide in several waves. We detected successive increases in population size for this pathogen over the last 200 years, practically coinciding with the Industrial Revolution, the First World War and HIV epidemics. Two MDR clones of this lineage started to spread throughout central Asia and Russia concomitantly with the collapse of the public health system in the former Soviet Union. Mutations identified in genes putatively under positive selection and associated with virulence might have favored the expansion of the most successful branches of the lineage. C1 [Merker, Matthias; Kohl, Thomas A.] Mol Mycobacteriol Res Ctr Borstel, Borstel, Germany. [Blin, Camille; Mona, Stefano] Ecole Prat Flautes Etud, Lab Biol Integrat Populat Evolut Mol, Paris, France. [Blin, Camille; Mona, Stefano; Wirth, Thierrv] Univ Paris 06, Sorbonne Univ, Ecole Prat Hautes Etud,UMR CNRS 7205, Inst Systemat Evolut Biodivers,Museum Natl Hist N, Paris, France. [Duforet-Frebourg, Nicolas; Blum, Michael G. B.] Univ Grenoble 1, CNRS, Lab Techn Ingn Med Complexite Informat Math & App, Grenoble, France. [Lecher, Sophie; Willery, Eve; Supply, Philip] Ctr Infect & Immun Lille, INSERM, U1019, Lille, France. [Lecher, Sophie; Willery, Eve; Supply, Philip] CNRS, UMR 8204, Lille, France. [Lecher, Sophie; Willery, Eve; Supply, Philip] Univ Lille Nord, Ctr Infect & Immun Lille, Lille, France. [Lecher, Sophie; Willery, Eve; Supply, Philip] Inst Pasteur, Ctr Infect & Immun Lille, F-59019 Lille, France. Res Ctr Borstel, Natl Reference Ctr Mycobacteria, Borstel, Germany. [Mokrousov, Igor] St Petersburg Pasteur Inst, Lab Mol Microbiol, St Petersburg, Russia. [Aleksic, Eman] Burnet Inst, Ctr Biomed Res, Melbourne, Vic, Australia. [Allix-Beguec, Caroline; Wahl, Celine; Supply, Philip] Genoscreen, Lille, France. [Antierens, Annick] Med Sans Frontieres Switzerland, Dept Med, Geneva, Switzerland. [Augustynowicz-Kopec, Ewa] Natl TB & Lung Dis Res Inst, Dept Microbiol, Warsaw, Poland. [Banff', Marie] Univ Bern, Inst Social & Prevent Med, Bern, Switzerland. [Barletta, Francesca] Univ Peruana Cayetano Heredia, Inst Med Trop Alexander von Humboldt, Mol Epidemiol Unit TB, Lima, Peru. [Beckr, Hans Peter; Gagneuxr, Sebastien] Swiss Trop & Publ Hlth Inst, Dept Med Parasitol & Infect Biol, Basel, Switzerland. [Barry, Clifton E., III; Shamputa, Isdore Chola] NIAID, TB Res Sect, US NIH, Bethesda, MD 20892 USA. [Bonnet, Maryline; Sanchez-Padilla, Elisabeth] Epictr, Clin Res Dept, Paris, France. [Borroni, Emanuele; Cirillo, Daniela] Ist Sci San Raffaele, Emerging Bacterial Pathogens Unit, I-20132 Milan, Italy. [Campos-Herrero, Isolina] Hosp Univ Gran Canaria Dr Negrin, Dept Microbiol, Las Palmas Gran Canaria, Spain. [Cox, Helen] Univ Cape Town, Div Med Microbiol, ZA-7925 Cape Town, South Africa. [Crowe, Suzanne] Alfred Hosp, Dept Infect Dis, Melbourne, Vic, Australia. [Crowe, Suzanne] Monash Univ, Cent Clin Sch, Melbourne, Vic 3004, Australia. [Crudu, Valeriu] Phthysiopneumol Inst, Natl TB Reference Lab, Kishinev, Moldova. [Die, Roland] Schleswig Holstein Univ Hosp, Inst Epidemiol, Kiel, Germany. [Drobniewski, Francis; Nikolayevskyy, Vladyslav] Barts & London Queen Marys Sch Med & Dent, Publ Hlth England Natl Mycobacterial Reference, London, England. Barts & London Queen Marys Sch Med & Dent, Publ Hlth England Natl Mycobacterial Reference &, London, England. [Drobniewski, Francis; Nikolayevskyy, Vladyslav] Barts & London Queen Marys Sch Med & Dent, Human Immunodeficiency Virus Grp, London, England. [Drobniewski, Francis; Nikolayevskyy, Vladyslav] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis, London, England. [Fauville-Dufaux, Maryse] TB & Mycobacteria Sci Inst Publ Hlth, Brussels, Belgium. [Ghebremichael, Solomon] Publ Hlth Agcy Sweden, Dept Microbiol, Solna, Sweden. [Hanekom, Madeleine; Warren, Robin] Univ Stellenbosch, Fac Med & Hlth Sci, Ctr TB Res,Div Mol Biol & Human Genet, Ctr Excellence Biomed TB Res,MRC,Natl Res Fdn,Dep, Cape Town, South Africa. [Hoffner, Sven] Swedish Inst Communicable Dis Control, Dept Diagnost & Vaccinol, Solna, Sweden. [Jiao, Wei-wei; Shen, Adong] Capital Med Univ, Beijing Childrens Hosp, Beijing Pediat Res Inst, Key Lab Major Dis Children, Beijing, Peoples R China. [Jiao, Wei-wei; Shen, Adong] Capital Med Univ, Beijing Childrens Hosp, Beijing Pediat Res Inst, Natl Key Discipline Pediat,Minist Educ, Beijing, Peoples R China. [Kalon, Stobdan] US Agcy Int Dev Qual Hlth Care Project, Bishkek, Kyrgyzstan. [Kontsevaya, Irina] Sarnara Oblast TB Serv, Samara, Russia. [Lillebaek, Troels; Rasmussen, Michael] Statens Serum Inst, Int Reference Lab Mycobacteriol, DK-2300 Copenhagen, Denmark. [Maeda, Shinji] Japan Anti TB Assoc, Res Inst TB, Tokyo, Japan. [Rastogi, Nalin] WHO, Inst Paslieur Guadeloupe, Supranat TB Reference Lab, Abymes, France. [Samper, Sofia] Hosp Univ Miguel Servet, Inst Invest Sanit Aragon, Zaragoza, Spain. [Savic, Branislava; Vukovic, Dragana] Univ Belgrade, Fac Med, Inst Microbiol & Immunol, Belgrade, Serbia. [Sng, Li-Hwei] Singapore Gen Hosp, Dept Pathol, Cent TB Lab, Singapore, Singapore. [Stakenas, Petras] Vilnius Univ, Inst Biotechnol, Dept Immunol & Cell Biol, Vilnius, Lithuania. [Toit, Kadri] Tartu Univ Hosp, United Labs, Tartu, Estonia. [Varaine, Francis] Med Sans Frontieres, Dept Med, Paris, France. [Niemann, Stefan] German Ctr Infect Res, Borstel Site, Borstel, Germany. RP Wirth, T (reprint author), Ecole Prat Flautes Etud, Lab Biol Integrat Populat Evolut Mol, Paris, France. EM philip.supply@ibl.cnrs.fr; sniemann@fz-borstel.de; wirth@rnram.fr RI Wirth, Thierry/B-4915-2008; Niemann, Stefan/C-9327-2011; BLUM, Michael/F-9978-2010; Barry, III, Clifton/H-3839-2012; Merker, Matthias/P-7399-2015; Mokrousov, Igor/J-3640-2014; OI BLUM, Michael/0000-0003-4174-7373; Merker, Matthias/0000-0003-1386-2331; Mokrousov, Igor/0000-0001-5924-0576; Nikolayevskyy, Vladyslav/0000-0002-9502-0332; Kontsevaya, Irina/0000-0003-3421-7550; Rastogi, Nalin/0000-0002-7199-7747 FU European Community [278864]; European Union [223681]; Action Transversale du Museum National d'Histoire Naturelle 'Les Microorganismes; Acteurs Cles dans les Ecosystemes FX We gratefully acknowledge L. Cowan and J. Posey (US Centers for Disease Control and Prevention) for pros ding us with significant amounts of genot)iping data for M. tuberculosis Beijing isolates. We thank T. Ubben, I. Radzio, F Struwe-Sonnenschein and). Zallet (Research Center Borstel) for excellent technical assistance. We acknowledge J. Peh for her assistance and support in the study and I. Comas for statistical advice. Parts of this work have been supported by grants from the European Community's Seventh ilramework Programme (FP7120072013) under grant agreement 278864 in the framework ot. the European Union PathoNGenTrace project and grant agreement 223681 in the framework of the TB-PAN-NET project. We also thank Action Transversale du Museum National d'Histoire Naturelle 'Les Microorganismes, Acteurs Cles dans les Ecosystemes' for financial support. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 78 TC 78 Z9 80 U1 8 U2 43 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2015 VL 47 IS 3 BP 242 EP + PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CC4MQ UT WOS:000350327900014 PM 25599400 ER PT J AU Rosenberg, AZ Naicker, S Winkler, CA Kopp, JB AF Rosenberg, Avi Z. Naicker, Saraladevi Winkler, Cheryl A. Kopp, Jeffrey B. TI HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatment SO NATURE REVIEWS NEPHROLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHRONIC KIDNEY-DISEASE; IMMUNE-COMPLEX GLOMERULONEPHRITIS; ACTIVE ANTIRETROVIRAL THERAPY; TUBULAR EPITHELIAL-CELLS; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; RAPAMYCIN-INDUCED MODULATION; LUPUS-LIKE FEATURES; INFECTED PATIENTS; RENAL-DISEASE AB HIV is a highly adaptive, rapidly evolving virus, which is associated with renal diseases including collapsing glomerulopathy-the classic histomorphological form of HIV-associated nephropathy. Other nephropathies related to viral factors include HIV-immune-complex kidney disease and thrombotic microangiopathy. The distribution of HIV-associated kidney diseases has changed over time and continues to vary across geographic regions worldwide. The reasons for this diversity are complex and include a critical role of APOL1 variants and possibly other genetic factors, disparities in access to effective antiviral therapies, and likely other factors that we do not yet fully understand. The mechanisms responsible for HIVAN, including HIV infection of podocytes and tubular epithelial cells, the molecules responsible for HIV entry, and diverse mechanisms of cell injury, have been the focus of much study. Although combined antiretroviral therapy is effective at preventing and reversing HIVAN, focal segmental glomerulosclerosis, arterionephrosclerosis and diabetic nephropathy are increasingly common in individuals who have received such therapy for many years. These diseases are associated with metabolic syndrome, obesity and premature ageing. Future directions for HIV-related kidney disease will involve regular screening for drug nephrotoxicity and incipient renal disease, as well as further research into the mechanisms by which chronic inflammation can lead to glomerular disease. C1 [Rosenberg, Avi Z.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. [Naicker, Saraladevi] Univ Witwatersrand, Fac Hlth Sci, Sch Clin Med, ZA-2193 Johannesburg, South Africa. [Winkler, Cheryl A.] NCI, Basic Res Lab, Ctr Canc Res, Leidos Biomed Res,Frederick Natl Lab, Frederick, MD 21702 USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIDDK, Kidney Dis Sect, NIH, 10 Ctr Dr,3N116, Bethesda, MD 20892 USA. EM jeffreyk@intra.niddk.nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X; Rosenberg, Avi/0000-0003-2356-950X FU Intramural Research Programs of the National Cancer Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health, USA; Medical Research Council; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; National Research Foundation of South Africa FX The authors' work is supported in part by the Intramural Research Programs of the National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, and National Institutes of Health, USA, and by the Medical Research Council and National Research Foundation of South Africa. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. Content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, USA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The authors note with regret the recent untimely death of Linda Kao, a pioneering and generous researcher who made many important contributions to the field of human genetics, in particular to the discovery of the chromosome 22 locus that includes APOL1 as a risk factor for HIVAN. NR 133 TC 15 Z9 18 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD MAR PY 2015 VL 11 IS 3 BP 150 EP 160 DI 10.1038/nrneph.2015.9 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA CC4QC UT WOS:000350336900007 PM 25686569 ER PT J AU Pownall, HJ Bray, GA Wagenknecht, LE Walkup, MP Heshka, S Hubbard, VS Hill, J Kahn, SE Nathan, DM Schwartz, AV Johnson, KC AF Pownall, Henry J. Bray, George A. Wagenknecht, Lynne E. Walkup, Michael P. Heshka, Stanley Hubbard, Van S. Hill, James Kahn, Steven E. Nathan, David M. Schwartz, Anne V. Johnson, Karen C. TI Changes in Body Composition Over 8 Years in a Randomized Trial of a Lifestyle Intervention: The Look AHEAD Study SO OBESITY LA English DT Article ID TYPE-2 DIABETES-MELLITUS; X-RAY ABSORPTIOMETRY; DISEASE RISK-FACTORS; WEIGHT-LOSS; CARDIOVASCULAR-DISEASE; FAT DISTRIBUTION; GENERAL-POPULATION; INSULIN-RESISTANCE; OLDER-ADULTS; OBESE WOMEN AB ObjectiveTo determine the effects of an intensive lifestyle intervention versus a comparison group on body composition in obese or overweight persons with type 2 diabetes at baseline and at 1, 4, and 8 years. MethodsBody composition was measured by dual-energy X-ray absorptiometry in a subset of 1019 Look AHEAD study volunteers randomized to intervention or comparison groups. The intervention was designed to achieve and maintain 7% weight loss through increased physical activity and reduced caloric intake. The comparison group received social support and diabetes education. ResultsAt 1 year, the intervention group lost fat (5.60.2 kg) and lean mass (2.3 +/- 0.1 kg) but regained fat (approximate to 100%) and lost lean mass between years 1 and 8. Between baseline and year 8, weight loss was greater in intervention versus comparison groups (4.0 +/- 0.4 vs. 2.3 +/- 0.4 kg); comparison group weight loss was mostly lean mass (2.1 +/- 0.17 kg). Fat mass in the intervention group was lower than that of the comparison group at all post-baseline time points. ConclusionsReduced fat mass may place the intervention group at a lower risk of obesity-linked sequelae, a hypothesis that can be tested by future studies of this cohort. C1 [Pownall, Henry J.] Houston Methodist Res Inst, Div Atherosclerosis, Dept Cardiol, Houston, TX USA. [Pownall, Henry J.] Baylor Coll Med, Houston, TX 77030 USA. [Bray, George A.] Pennington Biomed Res Ctr, Div Clin Obes, Baton Rouge, LA 70808 USA. [Wagenknecht, Lynne E.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Walkup, Michael P.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Heshka, Stanley] St Lukes Roosevelt Hosp, Dept Med, New York, NY 10025 USA. [Hubbard, Van S.] NIH, Bethesda, MD 20892 USA. [Hill, James] Univ Colorado, Anschutz Hlth & Wellness Ctr, Denver, CO 80202 USA. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Div Metab Endocrinol & Nutr, Dept Med, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. [Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Schwartz, Anne V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. RP Wagenknecht, LE (reprint author), Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. EM lwgnkcht@wakehealth.edu OI Kahn, Steven/0000-0001-7307-9002 FU National Institutes of Health (NIH) through National Institute of Diabetes and Digestive and Kidney Diseases [DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, DK56992]; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; NIH Office of Research on Women's Health; Centers for Disease Control and Prevention; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Johns Hopkins Medical Institutions Bayview General Clinical Research Center [M01RR02719]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center; Massachusetts Institute of Technology General Clinical Research Center [M01RR01066]; University of Colorado Health Sciences Center General Clinical Research Center [M01RR00051]; Clinical Nutrition Research Unit [P30 DK48520]; University of Tennessee at Memphis General Clinical Research Center [M01RR0021140]; University of Pittsburgh General Clinical Research Center (GCRC) [M01RR000056]; Clinical Translational Research Center (CTRC) - Clinical & Translational Science Award [UL1 RR 024153]; NIH [DK 046204]; VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; Frederic C. Bartter General Clinical Research Center [M01RR01346] FX This research was supported by the National Institutes of Health (NIH) through cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases: DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, and DK56992. Additional funding was provided by the National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; NIH Office of Research on Women's Health; the Centers for Disease Control and Prevention; and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The Indian Health Service (I.H.S.) provided personnel, medical oversight, and use of facilities. Additional support provided by The Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01RR02719); the Massachusetts General Hospital Mallinckrodt General Clinical Research Center and the Massachusetts Institute of Technology General Clinical Research Center (M01RR01066); the University of Colorado Health Sciences Center General Clinical Research Center (M01RR00051) and Clinical Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR0021140); the University of Pittsburgh General Clinical Research Center (GCRC) (M01RR000056), the Clinical Translational Research Center (CTRC) funded by the Clinical & Translational Science Award (UL1 RR 024153) and NIH grant (DK 046204); the VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; and the Frederic C. Bartter General Clinical Research Center (M01RR01346). The following organizations have committed to make major contributions to Look AHEAD: FedEx Corporation; Health Management Resources; LifeScan, Inc., a Johnson & Johnson Company; OPTIFAST (R) of Nestle HealthCare Nutrition, Inc.; Hoffmann-La Roche Inc.; Abbott Nutrition; and Slim-Fast Brand of Unilever North America. Some of the information contained herein was derived from data provided by the Bureau of Vital Statistics, New York City Department of Health and Mental Hygiene. The opinions expressed in this article are those of the authors and do not necessarily reflect the views of the funding sources. NR 40 TC 8 Z9 8 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD MAR PY 2015 VL 23 IS 3 BP 565 EP 572 DI 10.1002/oby.21005 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CC3LG UT WOS:000350249700011 PM 25707379 ER PT J AU Racz, GZ Zheng, C Goldsmith, CM Baum, BJ Cawley, NX AF Racz, G. Z. Zheng, C. Goldsmith, C. M. Baum, B. J. Cawley, N. X. TI Toward gene therapy for growth hormone deficiency via salivary gland expression of growth hormone SO ORAL DISEASES LA English DT Article DE gene therapy; gene engineering; endocrinology; cell biology ID DOMINANT GH DEFICIENCY; SECRETORY PATHWAYS; ADENOVIRAL VECTOR; MEDIATED TRANSFER; PROTEINS; ERYTHROPOIETIN; MUTATION; FUSION; IDENTIFICATION; GRANULES AB OBJECTIVES: Salivary glands are useful targets for gene therapeutics. After gene transfer into salivary glands, regulated secretory pathway proteins, such as human growth hormone, are secreted into saliva, whereas constitutive secretory pathway proteins, such as erythropoietin, are secreted into the bloodstream. Secretion of human growth hormone (hGH) into the saliva is not therapeutically useful. In this study, we attempted to redirect the secretion of transgenic hGH from the saliva to the serum by site-directed mutagenesis. MATERIALS AND METHODS: We tested hGH mutants first in vitro with AtT20 cells, a model endocrine cell line that exhibits polarized secretion of regulated secretory pathway proteins. Selected mutants were further studied in vivo using adenoviral-mediated gene transfer to rat submandibular glands. RESULTS: We identified two mutants with differences in secretion behavior compared to wild-type hGH. One mutant, Delta N1-6, was detected in the serum of transduced rats, demonstrating that expression of this mutant in the salivary gland resulted in its secretion through the constitutive secretory pathway. CONCLUSION: This study demonstrates that mutagenesis of therapeutic proteins normally destined for the regulated secretory pathway may result in their secretion via the constitutive secretory pathway into the circulation for potential therapeutic benefit. C1 [Racz, G. Z.; Zheng, C.; Goldsmith, C. M.; Baum, B. J.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Cawley, N. X.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Neurobiol, NIH, Bethesda, MD USA. RP Racz, GZ (reprint author), Semmelweis Univ, Dept Oral Biol, Nagyvarad Ter 4, H-1089 Budapest, Hungary. EM gabor.z.racz@gmail.com FU Division of Intramural Research, National Institute of Dental and Craniofacial Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, and Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. We thank Dr. Yuval Samuni for helpful discussions. NR 31 TC 1 Z9 1 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD MAR PY 2015 VL 21 IS 2 BP 149 EP 155 DI 10.1111/odi.12217 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CB9XC UT WOS:000349986500003 PM 24320050 ER PT J AU Short, D Gilsanz, V Kalkwarf, H Lappe, J Oberfield, S Shepherd, J Winer, K Zemel, B Hangartner, T AF Short, D. F. Gilsanz, V. Kalkwarf, H. J. Lappe, J. M. Oberfield, S. Shepherd, J. A. Winer, K. K. Zemel, B. S. Hangartner, T. N. TI Anthropometric models of bone mineral content and areal bone mineral density based on the bone mineral density in childhood study SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Anthropometrics; Bone growth; Bone mineral density; Model fitting ID X-RAY ABSORPTIOMETRY; PEDIATRIC OFFICIAL POSITIONS; PUBERTAL CHILDREN; MASS; ADOLESCENTS; PREDICTION; DENSITOMETRY; SEX; AGE AB A Summary New models describing anthropometrically adjusted normal values of bone mineral density and content in children have been created for the various measurement sites. The inclusion of multiple explanatory variables in the models provides the opportunity to calculate Z-scores that are adjusted with respect to the relevant anthropometric parameters. Introduction Previous descriptions of children's bone mineral measurements by age have focused on segmenting diverse populations by race and sex without adjusting for anthropometric variables or have included the effects of a single anthropometric variable. Methods We applied multivariate semi-metric smoothing to the various pediatric bone-measurement sites using data from the Bone Mineral Density in Childhood Study to evaluate which of sex, race, age, height, weight, percent body fat, and sexual maturity explain variations in the population's bone mineral values. By balancing high adjusted R-2 values with clinical needs, two models are examined. Results At the spine, whole body, whole body sub head, total hip, hip neck, and forearm sites, models were created using sex, race, age, height, and weight as well as an additional set of models containing these anthropometric variables and percent body fat. For bone mineral density, weight is more important than percent body fat, which is more important than height. For bone mineral content, the order varied by site with body fat being the weakest component. Including more anthropometrics in the model reduces the overlap of the critical groups, identified as those individuals with a Z-score below -2, from the standard sex, race, and age model. Conclusions If body fat is not available, the simpler model including height and weight should be used. The inclusion of multiple explanatory variables in the models provides the opportunity to calculate Z-scores that are adjusted with respect to the relevant anthropometric parameters. C1 [Short, D. F.; Hangartner, T. N.] Wright State Univ, Dayton, OH 45435 USA. [Gilsanz, V.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Kalkwarf, H. J.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Lappe, J. M.] Creighton Univ, Omaha, NE 68178 USA. [Oberfield, S.] Columbia Univ, New York, NY USA. [Shepherd, J. A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Winer, K. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Zemel, B. S.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Short, D (reprint author), Wright State Univ, Dayton, OH 45435 USA. EM david.short@wright.edu FU NIDDK NIH HHS [T32 DK065522] NR 18 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD MAR PY 2015 VL 26 IS 3 BP 1099 EP 1108 DI 10.1007/s00198-014-2916-x PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC2ZP UT WOS:000350214100027 PM 25311106 ER PT J AU Liu, JC Ridge, JA Brizel, DM O'Sullivan, B Cohen, EW Mann, BS Adelstein, DJ AF Liu, Jeffrey C. Ridge, John A. Brizel, David M. O'Sullivan, Brian Cohen, Ezra W. Mann, Bhupinder S. Adelstein, David J. TI Current Status of Clinical Trials in Head and Neck Cancer 2014 SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Review DE clinical trial; head and neck neoplasms; human papilloma virus; oropharyngeal carcinoma; review ID SQUAMOUS-CELL CARCINOMA; ADVANCED NASOPHARYNGEAL CARCINOMA; HUMAN-PAPILLOMAVIRUS; TRANSORAL RESECTION; CHEMOTHERAPY; CHEMORADIOTHERAPY; SURVIVAL AB Introduction The last few years have seen significant increase in the number of available clinical trials in head and neck cancer. It has been difficult to stay abreast of these efforts because multiple cooperative groups and institutions are engaged in their recruitment. This review presents the state of the art of available clinical trials organized around major research themes. Data Sources Published literature, published cooperative group monographs, expert review. Review Methods Initial themes in head and neck cancer clinical trial development were first identified along with examples. Opinions from an international panel of multidisciplinary experts were then solicited. Results/Discussion Current major themes of head and neck clinical trials centered on 5 major themes: (1) recognition of human papillomavirus oropharynx cancer and optimal treatment strategies, (2) defining the role of transoral surgery in head and neck cancer treatment, (3) improving postoperative adjuvant treatment, (4) investigation of rare malignancies, and (5) the importance of biomarker-driven, innovative, and targeted therapy investigation. Conclusions A number of exciting clinical trials are currently in development or accrual with the potential for tremendous impact and improvement of the treatment of head and neck cancer. Implications for Practice Awareness by practicing otolaryngologists and trainees of these current themes will be essential for study accrual, success, and improvement in the care of head and neck cancer. C1 [Liu, Jeffrey C.; Ridge, John A.] Fox Chase Canc Ctr, Head & Neck Surg Sect, Philadelphia, PA 19111 USA. [Liu, Jeffrey C.] Temple Univ, Sch Med, Dept Otolaryngol, Philadelphia, PA 19140 USA. [Brizel, David M.] Duke Canc Inst, Dept Radiat Oncol, Durham, NC USA. [O'Sullivan, Brian] Univ Toronto, Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON, Canada. [Cohen, Ezra W.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Mann, Bhupinder S.] NCI, Bethesda, MD 20892 USA. [Adelstein, David J.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. RP Liu, JC (reprint author), Temple Univ, Sch Med, Otolaryngol Head & Neck Surg, 3440 North Broad St,Kresge West,Third Floor, Philadelphia, PA 19140 USA. EM Jeffrey.Liu@temple.edu NR 17 TC 2 Z9 2 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD MAR PY 2015 VL 152 IS 3 BP 410 EP 417 DI 10.1177/0194599814566595 PG 8 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA CC6LS UT WOS:000350477100005 PM 25605695 ER PT J AU Hogue, CJR Parker, CB Willinger, M Temple, JR Bann, CM Silver, RM Dudley, DJ Moore, JL Coustan, DR Stoll, BJ Reddy, UM Varner, MW Saade, GR Conway, D Goldenberg, RL AF Hogue, Carol J. R. Parker, Corette B. Willinger, Marian Temple, Jeff R. Bann, Carla M. Silver, Robert M. Dudley, Donald J. Moore, Janet L. Coustan, Donald R. Stoll, Barbara J. Reddy, Uma M. Varner, Michael W. Saade, George R. Conway, Deborah Goldenberg, Robert L. CA Eunice Kennedy Shriver Natl Inst TI The Association of Stillbirth with Depressive Symptoms 6-36 Months Post-Delivery SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE Stillbirth; depression; grief; follow-up studies; African Americans ID EDINBURGH POSTNATAL DEPRESSION; MARGINAL STRUCTURAL MODELS; POSTPARTUM DEPRESSION; PERINATAL DEPRESSION; PREGNANCY; WOMEN; RISK; SCALE; VALIDATION; EXPERIENCE AB Background: Stillbirths (>= 20 weeks' gestation), which account for about 1 in 200 US pregnancies, may grieve parents deeply. Unresolved grief may lead to persistent depression. Methods: We compared depressive symptoms in 2009 (6-36 months after index delivery) among consenting women in the Stillbirth Collaborative Research Network's population-based case-control study conducted 2006-08 (n=275 who delivered a stillbirth and n=522 who delivered a healthy livebirth (excluding livebirths<37 weeks, infants who had been admitted to a neonatal intensive care unit or who died). Women scoring>12 on the Edinburgh Depression Scale were classified as currently depressed. Crude (cOR) and adjusted (aOR) odds ratios and 95% confidence intervals [CI] were computed from univariate and multivariable logistic models, with weighting for study design and differential consent. Marginal structural models examined potential selection bias due to low follow-up. Results: Current depression was more likely in women with stillbirth (14.8%) vs. healthy livebirth (8.3%, cOR 1.90 [95% CI 1.20, 3.02]). However, after control for history of depression and factors associated with both depression and stillbirth, the stillbirth association was no longer significant (aOR 1.35 [95% CI 0.79, 2.30]). Conversely, for the 76% of women with no history of depression, a significant association remained after adjustment for confounders (aOR 1.98 [95% CI 1.02, 3.82]). Conclusions: Improved screening for depression and referral may be needed for women's health care. Research should focus on defining optimal methods for support of women suffering stillbirth so as to lower the risk of subsequent depression. C1 [Hogue, Carol J. R.; Stoll, Barbara J.] Emory Univ, Sch Publ Hlth, Atlanta, GA 30322 USA. [Hogue, Carol J. R.; Stoll, Barbara J.] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Parker, Corette B.; Bann, Carla M.; Moore, Janet L.] Res Triangle Inst, Stat & Epidemiol, Res Triangle Pk, NC 27709 USA. [Willinger, Marian; Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Temple, Jeff R.; Saade, George R.] Univ Texas Med Branch, Obstet & Gynecol, Galveston, TX 77555 USA. [Silver, Robert M.; Varner, Michael W.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Dudley, Donald J.; Conway, Deborah] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Coustan, Donald R.] Brown Univ, Obstet & Gynecol, Providence, RI 02912 USA. [Goldenberg, Robert L.] Columbia Univ, Med Ctr, Obstet & Gynecol, New York, NY USA. RP Hogue, CJR (reprint author), Emory Univ, Rollins Sch Publ Hlth, Mailstop CNR 3005,1518 Clifton Rd NE, Atlanta, GA 30322 USA. EM chogue@emory.edu RI Temple, Jeff/A-7666-2009; Varner, Michael/K-9890-2013 OI Temple, Jeff/0000-0003-3193-0510; Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Office of Research in Women's Health, National Institutes of Health [U10-HD045953, U10-HD045925, U10-HD045952, U10-HD045955, UK10-HD045944, U10-HD045954] FX This study was supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health and with supplemental funding from the Office of Research in Women's Health, National Institutes of Health: U10-HD045953 (Brown University, Rhode Island); U10-HD045925 (Emory University, Georgia); U10-HD045952 (University of Texas Medical Branch at Galveston); U10-HD045955 (University of Texas Health Sciences Center at San Antonio); UK10-HD045944 (University of Utah Health Sciences Center); U10-HD045954 (RTI International, North Carolina). NR 35 TC 5 Z9 5 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD MAR PY 2015 VL 29 IS 2 BP 131 EP 143 DI 10.1111/ppe.12176 PG 13 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA CC3TU UT WOS:000350273800005 PM 25682858 ER PT J AU Lesher, LL Matyas, RA Sjaarda, LA Newman, SL Silver, RM Galai, N Hovey, KM Wactawski-Wende, J Emerick, L Lynch, AM Mead, B Townsend, JM Perkins, NJ Mumford, SL Stanford, J Schisterman, EF AF Lesher, Laurie L. Matyas, Rebecca A. Sjaarda, Lindsey A. Newman, Sarah L. Silver, Robert M. Galai, Noya Hovey, Kathleen M. Wactawski-Wende, Jean Emerick, Leah Lynch, Anne M. Mead, Betsy Townsend, Janet M. Perkins, Neil J. Mumford, Sunni L. Stanford, Joseph Schisterman, Enrique F. TI Recruitment for Longitudinal, Randomised Pregnancy Trials Initiated Preconception: Lessons from the Effects of Aspirin in Gestation and Reproduction Trial SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE research subject recruitment; preconception; low-dose aspirin; pregnancy ID LOW-DOSE ASPIRIN; DESIGN AB BackgroundRecruitment into large, preconception randomised clinical trials (RCT) is challenging. We describe clinic and community-based preconception recruitment strategies for the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial and highlight approaches that were and were not successful. This longitudinal RCT was conducted at four major sites in the US. Eligible women had one to two prior pregnancy losses and were actively trying to become pregnant. MethodsProvider/clinic and community-based outreach strategies were utilised, and the recruitment rate and costs of methods were assessed. ResultsA screening questionnaire was completed by 5485 women; 42.4% (n=2323) screened were initially eligible, of whom 50.7% (n=1228) were randomised. Provider/clinic-based recruitment yielded the highest number eligible of those screened (30.1%) and also the most randomised participants overall (40.3%). The next highest yield came from direct mail and brochures/flyers at 13.1% and 12.5% of women randomised, respectively. However, direct mailings cost $720 per participant randomised. Other than word of mouth, provider/clinic-based recruitment was the most cost effective method, costing an average of $60 per randomised participant. Web-based recruitment yielded 4.7% of participants at a cost of $278 per randomised participant. ConclusionsProvider and clinic-based recruitment was the most effective and cost-efficient method of recruitment in a preconception intervention study of reproduction among women. C1 [Lesher, Laurie L.; Newman, Sarah L.; Silver, Robert M.; Stanford, Joseph] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Matyas, Rebecca A.; Sjaarda, Lindsey A.; Perkins, Neil J.; Mumford, Sunni L.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Galai, Noya] Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. [Hovey, Kathleen M.; Wactawski-Wende, Jean] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY 14260 USA. [Emerick, Leah; Lynch, Anne M.] Univ Colorado, Dept Obstet & Gynecol, Denver, CO 80202 USA. [Mead, Betsy; Townsend, Janet M.] Commonwealth Med Coll, Dept Family Community & Rural Hlth, Scranton, PA USA. [Stanford, Joseph] Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, 6100 Execut Blvd,7B03M, Rockville, MD 20852 USA. EM schistee@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health, Bethesda, MD, USA) [HHSN267200603423, HHSN267200603424, HHSN267200603426] FX We sincerely thank the EAGeR participants for their extraordinary commitment to the study, all of the EAGeR investigators and staff who devoted their time and energy to the success of this trial, and the members of the data safety monitoring board for continuous oversight, constant support, and advice throughout the trial. This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health, Bethesda, MD, USA; contract numbers HHSN267200603423, HHSN267200603424, and HHSN267200603426). We declare we have no competing interests. NR 14 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD MAR PY 2015 VL 29 IS 2 BP 162 EP 167 DI 10.1111/ppe.12177 PG 6 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA CC3TU UT WOS:000350273800010 PM 25682951 ER PT J AU Dickson, PE Ndukum, J Wilcox, T Clark, J Roy, B Zhang, LF Li, Y Lin, DT Chesler, EJ AF Dickson, Price E. Ndukum, Juliet Wilcox, Troy Clark, James Roy, Brittany Zhang, Lifeng Li, Yun Lin, Da-Ting Chesler, Elissa J. TI Association of novelty-related behaviors and intravenous cocaine self-administration in Diversity Outbred mice SO PSYCHOPHARMACOLOGY LA English DT Article DE Addiction; Behavior; Cocaine; Genetics; Novelty; Anxiety; Self-administration; Diversity Outbred; Diversity Outcross ID QUANTITATIVE-TRAIT-LOCI; RECOMBINANT INBRED MICE; PROGRESSIVE RATIO SCHEDULES; COLLABORATIVE CROSS; SENSATION SEEKING; SEX-DIFFERENCES; C57BL/6J MICE; PERIADOLESCENT MICE; GENETIC-ANALYSIS; MOUSE STRAINS AB The preference for and reaction to novelty are strongly associated with addiction to cocaine and other drugs. However, the genetic variants and molecular mechanisms underlying these phenomena remain largely unknown. Although the relationship between novelty- and addiction-related traits has been observed in rats, studies in mice have failed to demonstrate this association. New, genetically diverse, high-precision mouse populations including Diversity Outbred (DO) mice provide an opportunity to assess an expanded range of behavioral variation enabling detection of associations of novelty- and addiction-related traits in mice. To examine the relationship between novelty- and addiction-related traits, male (n = 51) and female (n = 47) DO mice were tested on open field exploration, hole board exploration, and novelty preference followed by intravenous cocaine self-administration (IVSA; ten 2-h sessions of fixed ratio 1 and one 6-h session of progressive ratio). We observed high variation of cocaine IVSA in DO mice with 43 % reaching and 57 % not reaching conventional acquisition criteria. As a group, mice that did not reach these criteria still demonstrated significant lever discrimination. Mice experiencing catheter occlusion or other technical issues (n = 17) were excluded from the analysis. Novelty-related behaviors were positively associated with cocaine IVSA. Multivariate analysis of associations among novelty- and addiction-related traits revealed a large degree of shared variance (45 %). Covariation among cocaine IVSA and novelty-related phenotypes in DO mice indicates that this relationship is amenable to genetic dissection. The high genetic precision and phenotypic diversity in the DO may facilitate discovery of previously undetectable mechanisms underlying predisposition to develop addiction disorders. C1 [Dickson, Price E.; Ndukum, Juliet; Wilcox, Troy; Clark, James; Roy, Brittany; Chesler, Elissa J.] Jackson Lab, Bar Harbor, ME 04609 USA. [Zhang, Lifeng; Li, Yun; Lin, Da-Ting] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Chesler, EJ (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM lind3@mail.nih.gov; Elissa.Chesler@jax.org FU Jackson Laboratory; NIDA; IRP; NIDA Drug Supply Program, Cancer Center Core Grant [CA034196]; NIGMS [P50 GM076468] FX The authors gratefully acknowledge support from The Jackson Laboratory to EJC, NIDA, IRP to DTL; NIDA Drug Supply Program, Cancer Center Core Grant CA034196; and NIGMS P50 GM076468. We would also like to thank Dr. Yavin Shaham of NIDA IRP and Dr. Guy Mittleman at Ball State University for their consultation on the mouse IVSA procedure and Andree Lapierre of JAX Surgical Services for consultation on mouse surgical techniques for the study. NR 102 TC 4 Z9 4 U1 2 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2015 VL 232 IS 6 BP 1011 EP 1024 DI 10.1007/s00213-014-3737-5 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CC4CR UT WOS:000350298900003 PM 25238945 ER PT J AU Popik, P Holuj, M Nikiforuk, A Kos, T Trullas, R Skolnick, P AF Popik, Piotr Holuj, Malgorzata Nikiforuk, Agnieszka Kos, Tomasz Trullas, Ramon Skolnick, Phil TI 1-Aminocyclopropanecarboxylic acid (ACPC) produces procognitive but not antipsychotic-like effects in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE 1-Aminocyclopropanecarboxylic acid; ACPC; Strychnine-insensitive glycine/NMDA site; Learning; Memory; Cognitive flexibility; Attentional set-shifting test; Schizophrenia; Animal models; Prefrontal cortex; Attention; Impulsivity; Five-choice serial reaction time task (5-CSRTT) ID D-ASPARTATE RECEPTOR; INSENSITIVE GLYCINE RECEPTORS; D-CYCLOSERINE; NEGATIVE SYMPTOMS; D-SERINE; PREPULSE INHIBITION; PARTIAL AGONIST; EXHIBIT ANTIDEPRESSANT; SELECTIVE INHIBITOR; OBJECT RECOGNITION AB In addition to the negative and positive symptoms of schizophrenia, cognitive deficits, including prefrontal cortical dysfunction, are now recognized as core features of this disorder. Compounds increasing the NMDA receptor function via the strychnine-insensitive glycine receptors have been proposed as potential antipsychotics. Depending on the ambient concentrations of glutamate and glycine, 1-aminocyclopropanecarboxylic acid (ACPC) behaves as either a partial agonist or a functional antagonist at the strychnine-insensitive glycine receptors. We investigated the procognitive and antipsychotic-like effects of ACPC in rats treated with phencyclidine (PCP) or ketamine (KET), compounds that produce psychotic-like symptoms in humans and laboratory animals. Cognitive effects were investigated in the novel object recognition (NOR) and attentional set-shifting tests (ASST). In addition, the effects of ACPC were investigated in PCP-induced hyperactivity, conditioned avoidance response (CAR), and prepulse inhibition (PPI) tests. The effects on attention and impulsivity were measured in the five-choice serial reaction time task (5-CSRTT). ACPC (200-400 mg/kg) inhibited memory fading in naive rats and like clozapine prevented PCP- and KET-induced amnesia in the NOR. In naive animals, ACPC at 400 but not 200 mg/kg enhanced cognitive flexibility in the ASST, as the animals required fewer trials to reach the criteria during the extra-dimensional phase. In contrast, ACPC did not affect PCP-induced hyperactivity, CAR, and PPI as well as attention and impulsivity in the 5-CSRTT. The present study demonstrates that ACPC enhanced both object recognition memory and cognitive flexibility dependent on the prefrontal cortex, but did not affect impulsivity nor exhibit an antipsychotic-like profile. C1 [Popik, Piotr; Holuj, Malgorzata; Nikiforuk, Agnieszka; Kos, Tomasz] Polish Acad Sci, Inst Pharmacol, Behav Neurosci & Drug Dev, PL-31343 Krakow, Poland. [Trullas, Ramon] CSIC, IDIBAPS, Barcelona 08036, Spain. [Skolnick, Phil] NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. RP Popik, P (reprint author), Polish Acad Sci, Inst Pharmacol, Behav Neurosci & Drug Dev, 12 Smetna St, PL-31343 Krakow, Poland. EM nfpopik@cyf-kr.edu.pl RI Popik, Piotr/R-5383-2016; Trullas, Ramon/D-2197-2016 OI Popik, Piotr/0000-0003-0722-1263; Trullas, Ramon/0000-0001-7951-9881 FU Institute of Pharmacology, Polish Academy of Sciences; [SAF2011-23550] FX This study was supported by the Statutory Funds of the Institute of Pharmacology, Polish Academy of Sciences. RT is supported by grant SAF2011-23550. The technical help of Dr K. Fijal in performing the PPI experiment is appreciated. NR 67 TC 3 Z9 3 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2015 VL 232 IS 6 BP 1025 EP 1038 DI 10.1007/s00213-014-3738-4 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CC4CR UT WOS:000350298900004 PM 25260339 ER PT J AU Cippitelli, A Ayanwuyi, LO Barbier, E Domi, E Lerma-Cabrera, JM Carvajal, F Scuppa, G Li, HW Ubaldi, M Heilig, M Roberto, M Ciccocioppo, R AF Cippitelli, Andrea Ayanwuyi, Lydia O. Barbier, Estelle Domi, Esi Lerma-Cabrera, Jose M. Carvajal, Francisca Scuppa, Giulia Li, Hongwu Ubaldi, Massimo Heilig, Markus Roberto, Marisa Ciccocioppo, Roberto TI Polymorphism in the corticotropin-releasing factor receptor 1 (CRF1-R) gene plays a role in shaping the high anxious phenotype of Marchigian Sardinian alcohol-preferring (msP) rats SO PSYCHOPHARMACOLOGY LA English DT Article DE CRF; SNP; Anxiety; msP; Defensive burying; Restraint; Alcoholism; Abuse ID DEFENSIVE BURYING PARADIGM; IMPAIRED STRESS-RESPONSE; ANXIETY-RELATED BEHAVIOR; ELEVATED PLUS-MAZE; STRIA TERMINALIS; BED NUCLEUS; ETHANOL WITHDRAWAL; FACTOR ANTAGONIST; DEPENDENT RATS; CRHR1 GENE AB Marchigian Sardinian alcohol-preferring (msP) rats exhibit innate preference for alcohol along with anxious phenotype. In these animals, two single-nucleotide polymorphisms in position -1,836 and -2,097 from the first start codon of the CRF1-R transcript have been found. Here, we examined whether these point mutations account for the heightened anxiety-like behavior and stress responsiveness of msP rats. We rederived the msP rats to obtain two distinct lines carrying the wild-type (GG) and point mutations (AA), respectively. CRF1-R gene expression analysis revealed significant dysregulation of the system in the extended amygdala of AA rats. At the behavioral level, using the elevated plus maze, we found that both AA and GG lines had higher basal anxiety compared to Wistar rats. In the defensive burying test, AA rats showed decreased burying behavior compared to the GG and the unselected Wistar lines. Freezing/immobility did not differ among AA and GG but was higher than that of Wistars. The selective CRF1-R antagonist antalarmin (0, 10, and 20 mg/kg) reduced burying behavior in Wistar animals. However, antalarmin (10 mg/kg) tended to increase rather than reducing this behavior when tested in the msP lines, an effect that appeared more marked in the GG as compared to the AA line. The present data suggest that rats with msP genetic background are more anxious and show different sensitivity to stress and CRF1-R blockade than Wistars. The point mutations occurring in the CRF1-R gene do not seem to influence basal anxiety while they appear to affect active responses to stress. C1 [Cippitelli, Andrea; Ayanwuyi, Lydia O.; Domi, Esi; Lerma-Cabrera, Jose M.; Carvajal, Francisca; Scuppa, Giulia; Li, Hongwu; Ubaldi, Massimo; Ciccocioppo, Roberto] Univ Camerino, Sch Pharm, Pharmacol Unit, I-62032 Camerino, MC, Italy. [Barbier, Estelle; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Roberto, Marisa] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. RP Ciccocioppo, R (reprint author), Univ Camerino, Sch Pharm, Pharmacol Unit, Bldg Expt Med,Via Madonna delle Carceri, I-62032 Camerino, MC, Italy. EM roberto.ciccocioppo@unicam.it RI Carvajal, Maria Francisca/D-5382-2013; OI Carvajal, Maria Francisca/0000-0002-4507-2863; Heilig, Markus/0000-0003-2706-2482; Ubaldi, Massimo/0000-0002-4089-2483 FU National Institutes of Health from the National Institute on Alcohol Abuse and Alcoholism [RO1 AA017447, RO1 AA014351] FX We are thankful to Rina Righi and Mariangela Fiorelli for animal care and Marino Cucculelli and Alfredo Fiorelli for technical support. This work was supported by the National Institutes of Health, grant RO1 AA017447, and RO1 AA014351 from the National Institute on Alcohol Abuse and Alcoholism. NR 67 TC 3 Z9 3 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2015 VL 232 IS 6 BP 1083 EP 1093 DI 10.1007/s00213-014-3743-7 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CC4CR UT WOS:000350298900009 PM 25260340 ER PT J AU French, A Bravery, C Smith, J Chandra, A Archibald, P Gold, JD Artzi, N Kim, HW Barker, RW Meissner, A Wu, JC Knowles, JC Williams, D Garcia-Cardena, G Sipp, D Oh, S Loring, JF Rao, MS Reeve, B Wall, I Carr, AJ Bure, K Stacey, G Karp, JM Snyder, EY Brindley, DA AF French, Anna Bravery, Christopher Smith, James Chandra, Amit Archibald, Peter Gold, Joseph D. Artzi, Natalie Kim, Hae-Won Barker, Richard W. Meissner, Alexander Wu, Joseph C. Knowles, Jonathan C. Williams, David Garcia-Cardena, Guillermo Sipp, Doug Oh, Steve Loring, Jeanne F. Rao, Mahendra S. Reeve, Brock Wall, Ivan Carr, Andrew J. Bure, Kim Stacey, Glyn Karp, Jeffrey M. Snyder, Evan Y. Brindley, David A. TI Enabling Consistency in Pluripotent Stern Cell-Derived Products for Research and Development and Clinical Applications Through Material Standards SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article ID MINIMUM INFORMATION; LINES; GUIDELINES; DISEASE; ES AB There is a need for physical standards (reference materials) to ensure both reproducibility and consistency in the production of somatic cell types from human pluripotent stem cell (hPSC) sources. We have outlined the need for reference materials (RMs) in relation to the unique properties and concerns surrounding hPSC-derived products and suggest in-house approaches to RM generation relevant to basic research, drug screening, and therapeutic applications. hPSCs have an unparalleled potential as a source of somatic cells for drug screening, disease modeling, and therapeutic application. Undefined variation and product variability after differentiation to the lineage or cell type of interest impede efficient translation and can obscure the evaluation of clinical safety and efficacy. Moreover, in the absence of a consistent population, data generated from in vitro studies could be unreliable and irreproducible. Efforts to devise approaches and tools that facilitate improved consistency of hPSC-derived products, both as development tools and therapeutic products, will aid translation. Standards exist in both written and physical form; however, because many unknown factors persist in the field, premature written standards could inhibit rather than promote innovation and translation. We focused on the derivation of physical standard RMs. We outline the need for RMs and assess the approaches to in-house RM generation for hPSC-derived products, a critical tool for the analysis and control of product variation that can be applied by researchers and developers. We then explore potential routes for the generation of RMs, including both cellular and noncellular materials and novel methods that might provide valuable tools to measure and account for variation. Multiparametric techniques to identify "signatures" for therapeutically relevant cell types, such as neurons and cardiomyocytes that can be derived from hPSCs, would be of significant utility, although physical RMs will be required for clinical purposes. C1 [French, Anna; Smith, James; Barker, Richard W.; Wall, Ivan; Carr, Andrew J.; Brindley, David A.] Univ Oxford, Ctr Adv Sustainable Med Innovat, Oxford UCL, Oxford OX3 7LG, England. [Carr, Andrew J.] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Nuffield Orthopaed Ctr, Oxford OX3 7LG, England. [Brindley, David A.] Univ Oxford, Said Business Sch, Oxford OX3 7LG, England. [Bravery, Christopher] Consulting Adv Biol Ltd, London, England. [Chandra, Amit; Archibald, Peter] Univ Loughborough, Wolfson Sch Mech & Mfg Engn, Ctr Biol Engn, Loughborough, Leics, England. [Gold, Joseph D.; Wu, Joseph C.] Stanford Univ, Sch Med, Stanford Cardiovasc Inst, Stanford, CA USA. [Wu, Joseph C.] Stanford Univ, Sch Med, Dept Med, Stanford, CA USA. [Meissner, Alexander; Garcia-Cardena, Guillermo] Stanford Univ, Sch Med, Dept Radiol, Stanford, CA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA USA. [Artzi, Natalie] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Kim, Hae-Won] Dankook Univ, Dept Dent Biomat, Sch Dent, Cheonan, South Korea. [Knowles, Jonathan C.; Wall, Ivan] Dankook Univ, Dept Nanobiomed Sci, Plus NBM Global Res Ctr Regenerat Med BK21, Cheonan, South Korea. [Wall, Ivan] Dankook Univ, Biomat & Tissue Engn Lab, Dept Nanobiomed Sci, Cheonan, South Korea. [Wall, Ivan] Dankook Univ, WCU Res Ctr, Cheonan, South Korea. [Meissner, Alexander; Reeve, Brock; Karp, Jeffrey M.; Brindley, David A.] Harvard Univ, Stem Cell Inst, Cambridge, MA USA. [Meissner, Alexander; Garcia-Cardena, Guillermo] Broad Inst MIT & Harvard, Cambridge, MA USA. [Meissner, Alexander; Brindley, David A.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Knowles, Jonathan C.] UCL, Div Biomat & Tissue Engn, UCL Eastman Dent Inst, London, England. [Wall, Ivan] UCL, Dept Biochem Engn, London, England. [Brindley, David A.] UCL, Ctr Behav Med, UCL Sch Pharm, London, England. [Garcia-Cardena, Guillermo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Excellence Vasc Biol,Dept Pathol, Boston, MA 02115 USA. [Karp, Jeffrey M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Regenerat Therapeut, Boston, MA 02115 USA. [Karp, Jeffrey M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Biomed Engn, Boston, MA 02115 USA. [Garcia-Cardena, Guillermo] Harvard Univ, Sch Med, Program Dev & Regenerat Biol, Boston, MA USA. [Sipp, Doug] RIKEN, Ctr Dev Biol, Kobe, Hyogo, Japan. [Oh, Steve] ASTAR, Bioproc Technol Inst, Singapore, Singapore. [Loring, Jeanne F.] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. [Loring, Jeanne F.] Scripps Res Inst, Ctr Regenerat Med, La Jolla, CA 92037 USA. [Rao, Mahendra S.] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Bure, Kim] TAP Biosyst, Royston, England. [Stacey, Glyn] Natl Inst Biol Stand & Controls, Ctr MHRA, S Mimms, Herts, England. [Karp, Jeffrey M.] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Snyder, Evan Y.] Sanford Burnham Med Res Inst, La Jolla, CA USA. [Snyder, Evan Y.] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA. [Snyder, Evan Y.] Sanford Consortium Regenerat Med, La Jolla, CA USA. [Brindley, David A.] Stanford UCSF FDA, CERSI, San Francisco, CA USA. RP French, A (reprint author), Univ Oxford, Ctr Adv Sustainable Med Innovat, Oxford UCL, Old Rd Campus, Oxford OX3 7LG, England. EM anna.french@casmi.org.uk; esnyder@sanfordburnham.org; david.brindley@ndorms.ox.ac.uk RI Sipp, Douglas/C-9218-2017 OI Sipp, Douglas/0000-0002-5979-0938 FU GE Healthcare; Centre for Commercialization of Regenerative Medicine; TAP Biosystems (now Sartorius Stedim), Lonza; California Institute for Regenerative Medicine; SENS Research Foundation; UK Cell Therapy Catapult; NIH Center for Regenerative Medicine; New York Stem Cell Foundation; ThermoFisher Scientific; Eisai; Medipost (U.S.); Medipost (Korea); Celgene; Roche; Oxford Biomedica; Oxford-UCL Centre for the Advancement of Sustainable Medical Innovation; Technology Strategy Board FX We express our sincere thanks to the following organizations that have contributed to the consortium as funding and events partners-without whom the consortium and the benefits it will bring to stem cell translation would be constrained: GE Healthcare, Centre for Commercialization of Regenerative Medicine, TAP Biosystems (now Sartorius Stedim), Lonza, California Institute for Regenerative Medicine, SENS Research Foundation, UK Cell Therapy Catapult, NIH Center for Regenerative Medicine, New York Stem Cell Foundation, ThermoFisher Scientific, Eisai, Medipost (U.S.), Medipost (Korea), Celgene, Roche, and Oxford Biomedica. Additionally, the Oxford-UCL Centre for the Advancement of Sustainable Medical Innovation is a past recipient of funding from the Technology Strategy Board to support an investigation into cell therapy regulation. We also extend our sincere thanks to Dr. Peter Andrews (Sheffield University) and Dr. Sue Dopson (University of Oxford) for contributing to this research. NR 33 TC 8 Z9 9 U1 2 U2 5 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD MAR PY 2015 VL 4 IS 3 BP 217 EP 223 DI 10.5966/sctm.2014-0233 PG 7 WC Cell & Tissue Engineering SC Cell Biology GA CC6YL UT WOS:000350514800014 PM 25650438 ER PT J AU Efthymiou, AG Steiner, J Pavan, WJ Wincovitch, S Larson, DM Porter, FD Rao, MS Malik, N AF Efthymiou, Anastasia G. Steiner, Joe Pavan, William J. Wincovitch, Stephen Larson, Denise M. Porter, Forbes D. Rao, Mahendra S. Malik, Nasir TI Rescue of an In Vitro Neuron Phenotype Identified in Niemann-Pick Disease, Type C1 Induced Pluripotent Stem Cell-Derived Neurons by Modulating the WNT Pathway and Calcium Signaling SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Niemann-pick disease, type C1; Disease modeling; Neural stem cells; WNT signaling; Calcium signaling ID LYSOSOMAL STORAGE DISEASES; CHOLESTEROL ACCUMULATION; DEFINED CONDITIONS; PURKINJE-CELLS; LIPID STORAGE; MOUSE MODEL; NPC1; FIBROBLASTS; CURCUMIN; MICE AB Niemann-Pick disease, type Cl (NPC1) is a familial disorder that has devastating consequences on postnatal development with multisystem pffects, including neurodegeneration. There is no Food and Drug Administration-approved treatment option for NPC1; however, several potentially therapeutic compounds have been identified in assays using yeast, rodent models, and NPC1 human fibroblasts. Although these discoveries were made in fibroblasts from NPC1 subjects and were in some instances validated in animal models of the disease, testing these drugs on a cell type more relevant for NPC1 neurological disease would greatly facilitate both study of the disease and identification of more relevant therapeutic compounds. Toward this goal, we have generated an induced pluripotent stem cell line from a subject homozygous for the most frequent NPC1 mutation (p.I1061T) and subsequently created a stable line of neural stem cells (NSCs). These NSCs were then used to create neurons as an appropriate disease model. NPC1 neurons display a premature cell death phenotype, and gene expression analysis of these cells suggests dysfunction of important signaling pathways, including calcium and WNT. The clear readout from these cells makes them ideal candidates for high-throughput screening and will be a valuable tool to better understand the development of NPC1 in neural cells, as well as to develop better therapeutic options for NPC1. C1 [Efthymiou, Anastasia G.; Malik, Nasir] NIAMSD, Bethesda, MD 20892 USA. [Steiner, Joe] NINDS, NeuroTherapeut Dev Unit, Bethesda, MD 20892 USA. [Pavan, William J.; Wincovitch, Stephen; Larson, Denise M.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Rao, Mahendra S.] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Malik, N (reprint author), NIAMSD, NIH, 50 South Dr,Room 1142, Bethesda, MD 20892 USA. EM malikn@mail.nih.gov OI Efthymiou, Anastasia/0000-0002-1769-5078 FU NIH Common Fund; National Institute of Child Health and Human Development FX This work was supported by the NIH Common Fund and the intramural research program of the National Institute of Child Health and Human Development. NR 43 TC 6 Z9 6 U1 0 U2 4 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD MAR PY 2015 VL 4 IS 3 BP 230 EP 238 DI 10.5966/sctm.2014-0127 PG 9 WC Cell & Tissue Engineering SC Cell Biology GA CC6YL UT WOS:000350514800016 PM 25637190 ER PT J AU Holliday, EG Traylor, M Malik, R Bevan, S Falcone, G Hopewell, JC Cheng, YC Cotlarciuc, I Bis, JC Boerwinkle, E Boncoraglio, GB Clarke, R Cole, JW Fornage, M Furie, KL Ikram, MA Jannes, J Kittner, SJ Lincz, LF Maguire, JM Meschia, JF Mosley, TH Nalls, MA Oldmeadow, C Parati, EA Psaty, BM Rothwell, PM Seshadri, S Scott, RJ Sharma, P Sudlow, C Wiggins, KL Worrall, BB Rosand, J Mitchell, BD Dichgans, M Markus, HS Levi, C Attia, J Wray, NR AF Holliday, Elizabeth G. Traylor, Matthew Malik, Rainer Bevan, Steve Falcone, Guido Hopewell, Jemma C. Cheng, Yu-Ching Cotlarciuc, Ioana Bis, Joshua C. Boerwinkle, Eric Boncoraglio, Giorgio B. Clarke, Robert Cole, John W. Fornage, Myriam Furie, Karen L. Ikram, M. Arfan Jannes, Jim Kittner, Steven J. Lincz, Lisa F. Maguire, Jane M. Meschia, James F. Mosley, Thomas H. Nalls, Mike A. Oldmeadow, Christopher Parati, Eugenio A. Psaty, Bruce M. Rothwell, Peter M. Seshadri, Sudha Scott, Rodney J. Sharma, Pankaj Sudlow, Cathie Wiggins, Kerri L. Worrall, Bradford B. Rosand, Jonathan Mitchell, Braxton D. Dichgans, Martin Markus, Hugh S. Levi, Christopher Attia, John Wray, Naomi R. CA Australian Stroke Genetics Collabo Wellcome Trust Case Control Consor Int Stroke Genetics Consortium TI Genetic Overlap Between Diagnostic Subtypes of Ischemic Stroke SO STROKE LA English DT Article DE atherosclerosis; genetic epidemiology; lacunar stroke ID GENOME-WIDE ASSOCIATION; COMPLEX TRAITS; METAANALYSIS; VARIANTS; LINKAGE AB Background and Purpose-Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. Methods-Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. Results-High genetic correlation was identified between LAA and SVD using linear mixed models (r(g)=0.96, SE=0.47, P=9x10(-4)) and profile scores (r(g)=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1x10(-7)) for single nucleotide polymorphisms near the opioid receptor mu 1 (OPRM1) gene. Conclusions-Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes. C1 [Holliday, Elizabeth G.; Attia, John] Univ Newcastle, Sch Med & Publ Hlth, Callaghan, NSW 2308, Australia. [Lincz, Lisa F.; Scott, Rodney J.] Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW 2308, Australia. [Maguire, Jane M.] Univ Newcastle, Sch Nursing & Midwifery, Callaghan, NSW 2308, Australia. [Holliday, Elizabeth G.; Oldmeadow, Christopher; Attia, John] Hunter Med Res Inst, Publ Hlth Res Program, Clin Res Design IT & Stat Support Unit, Newcastle, NSW, Australia. [Traylor, Matthew; Bevan, Steve; Markus, Hugh S.] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 1TN, England. [Malik, Rainer; Dichgans, Martin] Univ Munich, Klinikum Univ Mun Chen, Inst Stroke & Dementia Res, Munich, Germany. [Falcone, Guido; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Falcone, Guido; Rosand, Jonathan] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Hopewell, Jemma C.; Clarke, Robert] Univ Oxford, Clin Trial Serv Unit, Oxford OX1 2JD, England. [Hopewell, Jemma C.; Clarke, Robert] Univ Oxford, Epidemiol Studies Unit, Oxford OX1 2JD, England. [Rothwell, Peter M.] Univ Oxford, Nuffield Dept Clin Neurosci, Stroke Prevent Res Unit, Oxford OX1 2JD, England. [Cheng, Yu-Ching; Mitchell, Braxton D.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Cole, John W.; Kittner, Steven J.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Cotlarciuc, Ioana] Univ London Imperial Coll Sci Technol & Med, ICCRU, London, England. [Bis, Joshua C.; Psaty, Bruce M.; Wiggins, Kerri L.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Boerwinkle, Eric; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Boerwinkle, Eric; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Boncoraglio, Giorgio B.; Parati, Eugenio A.] IRCCS Ist Neurol Carlo Besta, Dept Cerebrovasc Dis, Milan, Italy. [Cole, John W.; Kittner, Steven J.] Vet Affairs Med Ctr, Dept Neurol, Baltimore, MD USA. [Furie, Karen L.] Rhode Isl Hosp, Dept Neurol, Providence, RI USA. [Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Jannes, Jim] Univ Adelaide, Sch Med, Adelaide, SA 5005, Australia. [Lincz, Lisa F.] Calvary Mater Newcastle Hosp, Hunter Haematol Res Grp, Newcastle, NSW, Australia. [Lincz, Lisa F.; Maguire, Jane M.; Scott, Rodney J.; Levi, Christopher] Hunter Med Res Inst, Newcastle, NSW, Australia. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med Geriatr, Jackson, MS 39216 USA. [Nalls, Mike A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Psaty, Bruce M.] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Scott, Rodney J.] John Hunter Hosp, NSW Pathol, Newcastle, NSW, Australia. [Levi, Christopher] John Hunter Hosp, Dept Neurol, Newcastle, NSW, Australia. [Sharma, Pankaj] Royal Holloway Univ London ICR2UL & Ashford, Inst Cardiovasc Res, London, England. [Sharma, Pankaj] St Peters Hosp, Chertsey, England. [Sudlow, Cathie] Univ Edinburgh, Div Clin Neurosci, Edinburgh EH8 9YL, Midlothian, Scotland. [Worrall, Bradford B.] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Worrall, Bradford B.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Dichgans, Martin] Munich Cluster Syst Neurol SyNergy, Munich, Germany. [Wray, Naomi R.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. EM liz.holliday@newcastle.edu.au RI Boncoraglio, Giorgio/B-8647-2011; Wray, Naomi/C-8639-2015; OI Wray, Naomi/0000-0001-7421-3357; Seshadri, Sudha/0000-0001-6135-2622; Ikram, Mohammad Arfan/0000-0003-0372-8585; Traylor, Matthew/0000-0001-6624-8621; Bevan, Steve/0000-0003-0490-6830; Mitchell, Braxton/0000-0003-4920-4744 FU British Heart Foundation [FS/14/55/30806]; NHGRI NIH HHS [U01 HG005160]; NIA NIH HHS [R01 AG033193]; NIDCD NIH HHS [L30 DC006823]; NINDS NIH HHS [K08 NS045802, U01 NS069208]; The Dunhill Medical Trust [OSRP2/1006]; Wellcome Trust [095626] NR 30 TC 11 Z9 11 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD MAR PY 2015 VL 46 IS 3 BP 615 EP + DI 10.1161/STROKEAHA.114.007930 PG 22 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CC3XP UT WOS:000350284900015 PM 25613305 ER PT J AU Lutsep, HL Barnwell, SL Larsen, DT Lynn, MJ Hong, M Turan, TN Derdeyn, CP Fiorella, D Janis, LS Chimowitz, MI AF Lutsep, Helmi L. Barnwell, Stanley L. Larsen, Darren T. Lynn, Michael J. Hong, Mindy Turan, Tanya N. Derdeyn, Colin P. Fiorella, David Janis, L. Scott Chimowitz, Marc I. CA SAMMPRIS Investigators TI Outcome in Patients Previously on Antithrombotic Therapy in the SAMMPRIS Trial Subgroup Analysis SO STROKE LA English DT Article DE antiplatelet agents; intracranial arteriosclerosis; stroke ID INTRACRANIAL ARTERIAL-STENOSIS; AGGRESSIVE MEDICAL-MANAGEMENT; RECURRENT STROKE; RISK AB Background and Purpose-Stenting has been used as a rescue therapy in patients with intracranial arterial stenosis and a transient ischemic attack or stroke when on antithrombotic therapy (AT). We determined whether the stenting versus aggressive medical therapy for intracranial arterial stenosis (SAMMPRIS) trial supported this approach by comparing the treatments within subgroups of patients whose qualifying event (QE) occurred on versus off of AT. Methods-The primary outcome, 30-day stroke and death and later strokes in the territory of the qualifying artery, was compared between (1) percutaneous transluminal angioplasty and stenting plus aggressive medical therapy (PTAS) versus aggressive medical management therapy alone (AMM) for patients whose QE occurred on versus off AT and between (2) patients whose QE occurred on versus off AT separately for the treatment groups. Results-Among the 284/451 (63%) patients who had their QE on AT, the 2-year primary end point rates were 15.6% for those randomized to AMM (n=140) and 21.6% for PTAS (n=144; P=0.043, log-rank test). In the 167 patients not on AT, the 2-year primary end point rates were 11.6% for AMM (n=87) and 18.8% for PTAS (n=80; P=0.31, log-rank test). Within both treatment groups, there was no difference in the time to the primary end point between patients who were on or off AT (AMM, P=0.96; PTAS, P=0.52; log-rank test). Conclusions-SAMMPRIS results indicate that the benefit of AMM over PTAS is similar in patients on versus off AT at the QE and that failure of AT is not a predictor of increased risk of a primary end point. C1 [Lutsep, Helmi L.; Larsen, Darren T.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Barnwell, Stanley L.] Oregon Hlth & Sci Univ, Dept Neurol Surg, Portland, OR 97239 USA. [Barnwell, Stanley L.] Oregon Hlth & Sci Univ, Dotter Intervent Inst, Portland, OR 97239 USA. [Lynn, Michael J.; Hong, Mindy] Emory Univ, Dept Biostat & Bioinformat, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Turan, Tanya N.; Chimowitz, Marc I.] Med Univ S Carolina, Dept Neurol, Charleston, SC USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Fiorella, David] SUNY Stony Brook, Dept Neurol Surg, Stony Brook, NY 11794 USA. [Janis, L. Scott] NIH, Bethesda, MD 20892 USA. RP Lutsep, HL (reprint author), Oregon Hlth & Sci Univ, Oregon Stroke Ctr, 3181 SW Sam Jackson Pk Rd,CR131, Portland, OR 97239 USA. EM lutseph@ohsu.edu OI Turan, Tanya/0000-0001-5399-8845; Derdeyn, Colin/0000-0002-5932-2683 FU NEI NIH HHS [P30 EY006360, U10 EY013287, UG1 EY013287]; NINDS NIH HHS [K23 NS069668, U01 NS058728] NR 9 TC 6 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD MAR PY 2015 VL 46 IS 3 BP 775 EP 779 DI 10.1161/STROKEAHA.114.007752 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CC3XP UT WOS:000350284900039 PM 25593135 ER PT J AU Tsivgoulis, G Psaltopoulou, T Wadley, VG Alexandrov, AV Howard, G Unverzagt, FW Moy, C Howard, VJ Kissela, B Judd, SE AF Tsivgoulis, Georgios Psaltopoulou, Theodora Wadley, Virginia G. Alexandrov, Andrei V. Howard, George Unverzagt, Frederick W. Moy, Claudia Howard, Virginia J. Kissela, Brett Judd, Suzanne E. TI Adherence to a Mediterranean Diet and Prediction of Incident Stroke SO STROKE LA English DT Article DE diet, Mediterranean; hemorrhagic disorders; patient adherence; stroke; transient ischemic attack ID INTIMA-MEDIA THICKNESS; CORONARY-HEART-DISEASE; COGNITIVE IMPAIRMENT; CEREBROVASCULAR-DISEASE; NORTHERN MANHATTAN; RACIAL-DIFFERENCES; RISK-FACTORS; STYLE DIET; METAANALYSIS; POPULATION AB Background and Purpose-There are limited data on the potential association of adherence to Mediterranean diet (MeD) with incident stroke. We sought to assess the longitudinal association between greater adherence to MeD and risk of incident stroke. Methods-We prospectively evaluated a population-based cohort of 30 239 individuals enrolled in REasons for Geographic and Racial Differences in Stroke (REGARDS) study, after excluding participants with stroke history, missing demographic data or food frequency questionnaires, and unavailable follow-up information. Adherence to MeD was categorized using MeD score. Incident stroke was adjudicated by expert panel review of medical records during a mean follow-up period of 6.5 years. Results-Incident stroke was identified in 565 participants (2.8%; 497 and 68 cases of ischemic stroke [IS] and hemorrhagic stroke, respectively) of 20 197 individuals fulfilling the inclusion criteria. High adherence to MeD (MeD score, 5-9) was associated with lower risk of incident IS in unadjusted analyses (hazard ratio, 0.83; 95% confidence interval, 0.70-1.00; P=0.046). The former association retained its significance (hazard ratio, 0.79; 95% confidence interval, 0.65-0.96; P=0.016) after adjustment for demographics, vascular risk factors, blood pressure levels, and antihypertensive medications. When MeD was evaluated as a continuous variable, a 1-point increase in MeD score was independently associated with a 5% reduction in the risk of incident IS (95% confidence interval, 0-11%). We documented no association of adherence to MeD with incident hemorrhagic stroke. There was no interaction of race (P=0.37) on the association of adherence to MeD with incident IS. Conclusions-High adherence to MeD seems to be associated with a lower risk of incident IS independent of potential confounders. Adherence to MeD is not related to the risk of incident hemorrhagic stroke. C1 [Tsivgoulis, Georgios] Univ Athens, Sch Med, Dept Neurol 2, Attikon Hosp, Athens 15344, Greece. [Psaltopoulou, Theodora] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, Athens 15344, Greece. [Tsivgoulis, Georgios; Alexandrov, Andrei V.] Univ Tennessee, Ctr Hlth Sci, Dept Neurol, Memphis, TN 38163 USA. [Tsivgoulis, Georgios] St Annes Univ Hosp, Int Clin Res Ctr, Brno, Czech Republic. [Wadley, Virginia G.] Univ Alabama Birmingham, Dept Med, Birmingham, AL USA. [Howard, George; Judd, Suzanne E.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL USA. [Howard, Virginia J.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL USA. [Unverzagt, Frederick W.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Moy, Claudia] NINDS, NIH, Bethesda, MD 20892 USA. [Kissela, Brett] Univ Cincinnati, Dept Neurol, Cincinnati, OH 45221 USA. RP Tsivgoulis, G (reprint author), Univ Athens, Sch Med, Dept Neurol 2, Iras 39, Athens 15344, Greece. EM tsivgoulisgiorg@yahoo.gr OI Alexandrov, Andrei V/0000-0001-8871-1023; Kissela, Brett/0000-0002-9773-4013 FU NCATS NIH HHS [UL1 TR000077, UL1 TR001425]; NINDS NIH HHS [R01 NS041588, U01 NS041588] NR 38 TC 8 Z9 8 U1 1 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD MAR PY 2015 VL 46 IS 3 BP 780 EP + DI 10.1161/STROKEAHA.114.007894 PG 12 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CC3XP UT WOS:000350284900040 PM 25628306 ER PT J AU Cui, X Chopp, M Zacharek, A Karasinska, JM Cui, YS Ning, RZ Zhang, Y Wang, Y Chen, JL AF Cui, Xu Chopp, Michael Zacharek, Alex Karasinska, Joanna M. Cui, Yisheng Ning, Ruizhuo Zhang, Yi Wang, Yun Chen, Jieli TI Deficiency of Brain ATP-Binding Cassette Transporter A-1 Exacerbates Blood-Brain Barrier and White Matter Damage After Stroke SO STROKE LA English DT Article DE aquaporin 4; ATP binding cassette transporter A-1; blood-brain barrier; insulin-like growth factor binding protein 1; stroke; white matter ID CEREBRAL-ISCHEMIA; ABCA1; EXPRESSION; NEUROINFLAMMATION; PERICYTES; SYSTEM; AQUAPORIN-4; INTEGRITY; DISEASE; INJURY AB Background and Purpose-The ATP-binding cassette transporter A-1 (ABCA1) gene is a key target of the transcription factors liver X receptors. Liver X receptor activation has anti-inflammatory and neuroprotective effects in animal ischemic stroke models. Here, we tested the hypothesis that brain ABCA1 reduces blood-brain barrier (BBB) and white matter (WM) impairment in the ischemic brain after stroke. Methods-Adult brain-specific ABCA1-deficient (ABCA1(-B/-B)) and floxed-control (ABCA1(fl/fl)) mice were subjected to permanent distal middle cerebral artery occlusion and were euthanized 7 days after distal middle cerebral artery occlusion. Functional outcome, infarct volume, BBB leakage, and WM damage were analyzed. Results-Compared with ABCA1(fl/fl) mice, ABCA1(-B/-B) mice showed marginally (P=0.052) increased lesion volume but significantly increased BBB leakage and WM damage in the ischemic brain and more severe neurological deficits. Brain ABCA1-deficient mice exhibited increased the level of matrix metalloproteinase-9 and reduced the level of insulin-ike growth factor 1 in the ischemic brain. BBB leakage was inversely correlated (r=-0.073; P<0.05) with aquaporin-4 expression. Reduction of insulin-like growth factor 1 and aquaporin-4, but upregulation of matrix metalloproteinase-9 expression were also found in the primary astrocyte cultures derived from ABCA1(-B/-B) mice. Cultured primary cortical neurons derived from C57BL/6 wild-type mice with ABCA1(-B/-B) astrocyte-conditioned medium exhibited decreased neurite outgrowth compared with culture with ABCA1(fl/fl) astrocyte-conditioned medium. ABCA1(-B/-B) primary cortical neurons show significantly decreased neurite outgrowth, which was attenuated by insulin-like growth factor 1 treatment. Conclusions-We demonstrate that brain ABCA1 deficiency increases BBB leakage, WM/axonal damage, and functional deficits after stroke. Concomitant reduction of insulin-like growth factor 1 and upregulation of matrix metalloproteinase-9 may contribute to brain ABCA1 deficiency-induced BBB and WM/axonal damage in the ischemic brain. C1 [Cui, Xu; Chopp, Michael; Zacharek, Alex; Cui, Yisheng; Ning, Ruizhuo; Zhang, Yi; Chen, Jieli] Henry Ford Hosp, Dept Neurol, Detroit, MI 48202 USA. [Chopp, Michael] Oakland Univ, Dept Phys, Rochester, MI USA. [Wang, Yun] NIDA, Neural Protect & Regenerat Sect, Ctr Neuropsychiat Res, NIH, Baltimore, MD USA. [Karasinska, Joanna M.] Univ British Columbia, Dept Med Genet, Ctr Mol Med & Therapeut, Vancouver, BC, Canada. RP Cui, X (reprint author), Henry Ford Hosp, E&R Bldg,Room 3029,2799 West Grand Blvd, Detroit, MI 48202 USA. EM tcui@neuro.hfh.edu; jieli@neuro.hfh.edu FU NIA NIH HHS [R01 AG031811, R01 AG037506]; NINDS NIH HHS [R41 NS080329, R01 NS083078, 1R41NS080329-01A1] NR 35 TC 10 Z9 10 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD MAR PY 2015 VL 46 IS 3 BP 827 EP 834 DI 10.1161/STROKEAHA.114.007145 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CC3XP UT WOS:000350284900047 PM 25593138 ER PT J AU Riley, WT Keberlein, P Sorenson, G Mohler, S Tye, B Ramirez, AS Carroll, M AF Riley, William T. Keberlein, Pamela Sorenson, Gigi Mohler, Sailor Tye, Blake Ramirez, A. Susana Carroll, Mark TI Program Evaluation of Remote Heart Failure Monitoring: Healthcare Utilization Analysis in a Rural Regional Medical Center SO TELEMEDICINE AND E-HEALTH LA English DT Article DE cardiology/cardiovascular; telecardiology; mobile health; telemedicine; home health monitoring ID MANAGEMENT; DISEASE; TRIAL AB Background: Remote monitoring for heart failure (HF) has had mixed and heterogeneous effects across studies, necessitating further evaluation of remote monitoring systems within specific healthcare systems and their patient populations. "Care Beyond Walls and Wires," a wireless remote monitoring program to facilitate patient and care team co-management of HF patients, served by a rural regional medical center, provided the opportunity to evaluate the effects of this program on healthcare utilization. Materials and Methods: Fifty HF patients admitted to Flagstaff Medical Center (Flagstaff, AZ) participated in the project. Many of these patients lived in underserved and rural communities, including Native American reservations. Enrolled patients received mobile, broadband-enabled remote monitoring devices. A matched cohort was identified for comparison. Results: HF patients enrolled in this program showed substantial and statistically significant reductions in healthcare utilization during the 6 months following enrollment, and these reductions were significantly greater compared with those who declined to participate but not when compared with a matched cohort. Conclusions: The findings from this project indicate that a remote HF monitoring program can be successfully implemented in a rural, underserved area. Reductions in healthcare utilization were observed among program participants, but reductions were also observed among a matched cohort, illustrating the need for rigorous assessment of the effects of HF remote monitoring programs in healthcare systems. C1 [Riley, William T.] NCI, NIH, Rockville, MD 20850 USA. [Keberlein, Pamela; Sorenson, Gigi; Carroll, Mark] Northern Arizona Healthcare, Flagstaff Med Ctr, Flagstaff, AZ USA. [Mohler, Sailor] Zephyr Technol, Annapolis, MD USA. [Tye, Blake] Qualcomm, San Diego, CA USA. [Ramirez, A. Susana] Univ Calif Merced, Merced, CA USA. RP Riley, WT (reprint author), NCI, 9609 Med Ctr Dr,MSC 9761, Rockville, MD 20850 USA. EM wiriley@mail.nih.gov NR 16 TC 1 Z9 1 U1 1 U2 10 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 EI 1556-3669 J9 TELEMED E-HEALTH JI Telemed. e-Health PD MAR 1 PY 2015 VL 21 IS 3 BP 157 EP 162 DI 10.1089/tmj.2014.0093 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CD2CZ UT WOS:000350882900004 PM 25025239 ER PT J AU Hullsiek, KH Kagan, JM Engen, N Grarup, J Hudson, F Denning, ET Carey, C Courtney-Rodgers, D Finley, EB Jansson, PO Pearson, MT Peavy, DE Belloso, WH AF Hullsiek, Katherine Huppler Kagan, Jonathan M. Engen, Nicole Grarup, Jesper Hudson, Fleur Denning, Eileen T. Carey, Catherine Courtney-Rodgers, David Finley, Elizabeth B. Jansson, Per O. Pearson, Mary T. Peavy, Dwight E. Belloso, Waldo H. CA INSIGHT START Monitoring Substudy TI Investigating the Efficacy of Clinical Trial Monitoring Strategies: Design and Implementation of the Cluster Randomized START Monitoring Substudy SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE data monitoring; centralized monitoring; on-site monitoring; quality assurance; clinical trials ID QUALITY; FRAUD; COSTS AB Background: Trial monitoring protects participant safety and study integrity. While monitors commonly go on site to verify source data, there is little evidence that this practice is efficient or effective. An ongoing international HIV treatment trial (START) provides an opportunity to explore the usefulness of different monitoring approaches. Methods: All START sites are centrally monitored and required to follow a local monitoring plan requiring specific quality assurance activities. In addition, sites were randomized (1:1) to receive, or not receive, annual on-site monitoring. The study will determine if on-site monitoring increases the identification of major protocol deviations (eligibility or consent violations, improper study drug use, primary or serious event underreporting, data alteration or fraud). Results: The START study completed enrollment in December 2013, with planned follow-up through December 2016. The monitoring study is ongoing at 196 sites in 34 countries. Results are expected when the START study concludes in December 2016. C1 [Hullsiek, Katherine Huppler; Engen, Nicole; Denning, Eileen T.] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Kagan, Jonathan M.] NIAID, Div Clin Res, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Grarup, Jesper; Jansson, Per O.; Pearson, Mary T.] Univ Copenhagen, Rigshosp, Dept Infect Dis & Rheumatol, Copenhagen HIV Programme, DK-1168 Copenhagen, Denmark. [Hudson, Fleur] UCL, MRC, Clin Trials Unit, London, England. [Carey, Catherine; Courtney-Rodgers, David] Univ New S Wales, Kirby Inst, Sydney, NSW, Australia. [Finley, Elizabeth B.] Washington DC Vet Affairs Med Ctr, Washington, DC USA. [Peavy, Dwight E.] Newark EMA Hlth Serv Council, Newark, NJ USA. [Belloso, Waldo H.] CICAL, Buenos Aires, DF, Argentina. [Belloso, Waldo H.] Hosp Italiano Buenos Aires, Buenos Aires, DF, Argentina. RP Hullsiek, KH (reprint author), 2221 Univ Ave SE,Suite 200, Minneapolis, MN 55422 USA. EM kathy-h@ccbr.umn.edu FU National Institute of Allergy and Infectious Diseases [U01AI068641] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Grant support was received from the National Institute of Allergy and Infectious Diseases (grant number U01AI068641). NR 32 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD MAR PY 2015 VL 49 IS 2 BP 225 EP 233 DI 10.1177/2168479014555912 PG 9 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA CC6RF UT WOS:000350494000003 PM 25973346 ER PT J AU Kirchner, TR Villanti, AC Cantrell, J Anesetti-Rothermel, A Ganz, O Conway, KP Vallone, DM Abrams, DB AF Kirchner, Thomas R. Villanti, Andrea C. Cantrell, Jennifer Anesetti-Rothermel, Andrew Ganz, Ollie Conway, Kevin P. Vallone, Donna M. Abrams, David B. TI Tobacco retail outlet advertising practices and proximity to schools, parks and public housing affect Synar underage sales violations in Washington, DC SO TOBACCO CONTROL LA English DT Article ID FAMILY SMOKING PREVENTION; YOUTH ACCESS; CONTROL ACT; EXPOSURE; DENSITY; ASSOCIATIONS; CESSATION; PROGRAMS AB Objective To examine the cross-sectional association between illicit sales of tobacco to minors, Washington DC tobacco outlet advertising practices, retail store type, the demographic make-up of the area surrounding each outlet, and the proximity of each outlet to high schools, recreational parks and public housing. Participants Seven hundred and fifty tobacco outlets in the DC area, n=347 of which were randomly selected for inspection by the Synar Inspection Program in 2009-2010. Main outcome measures The presence of tobacco advertisements on the interior and exterior of each outlet, and illicit tobacco sales to Synar Inspection Program youth volunteers. Results The presence of tobacco advertisements on the exterior of gas stations was much greater than on other retail store types (OR=6.68; 95% CI 4.05 to 11.01), as was the absence of any advertisements at bars or restaurants that sold tobacco (OR=0.33; 95% CI 0.22 to 0.52). Exterior tobacco advertisements were also more likely in predominantly African-American areas of the city (OR=3.11; 95% CI 2.28 to 4.25), and particularly likely on storefronts located closer to parks (OR=1.87; 95% CI 1.06 to 3.28). Illicit sales to minors were more common at gas stations (OR=3.01; 95% CI 1.5 to 6.3), outlets that displayed exterior tobacco advertisements closer to parks (OR=3.36; 95% CI 1.38 to 8.21), and outlets located closer to high schools in majority African-American block groups (OR=1.29; 95% CI 1.07 to 1.58). Conclusions Findings demonstrate that while illicit tobacco sales to minors are occurring at acceptably low rates by Synar standards, illicit sales vary considerably by retail store type, advertising approach and proximity to high schools, parks and African-American residential areas. Future work may help inform regulatory efforts to reduce youth access at the neighbourhood, city, state and national levels. C1 [Kirchner, Thomas R.; Villanti, Andrea C.; Anesetti-Rothermel, Andrew; Abrams, David B.] Legacy, Steven A Schroeder Natl Inst Tobacco Res & Policy, Washington, DC 20036 USA. [Kirchner, Thomas R.; Villanti, Andrea C.; Cantrell, Jennifer; Ganz, Ollie; Vallone, Donna M.; Abrams, David B.] Johns Hopkins Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. [Kirchner, Thomas R.; Vallone, Donna M.; Abrams, David B.] Georgetown Univ, Med Ctr, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Cantrell, Jennifer] Legacy, Dept Res & Evaluat, Washington, DC 20036 USA. [Anesetti-Rothermel, Andrew] W Virginia Univ, Sch Publ Hlth, Dept Epidemiol, Morgantown, WV 26506 USA. [Conway, Kevin P.] NIDA, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Kirchner, TR (reprint author), Legacy, Steven A Schroeder Natl Inst Tobacco Res & Policy, 1724 Massachusetts Ave,NW, Washington, DC 20036 USA. EM tkirchner@legacyforhealth.org OI Conway, Kevin/0000-0002-7638-339X; Villanti, Andrea/0000-0003-3104-966X FU National Institute on Drug Abuse, National Institutes of Health; Food and Drug Administration, Department of Health and Human Services [HHSN271201100027C]; American Legacy Foundation; Centers for Disease Control and Prevention CPPW Contract from the DC Department of Health (DC DoH) [PO358719] FX This project has been funded in whole, or in part, with federal funds from the National Institute on Drug Abuse, National Institutes of Health, and the Food and Drug Administration, Department of Health and Human Services under Contract #HHSN271201100027C. Funding for the primary data collection was provided by the American Legacy Foundation. The project was also funded by the Centers for Disease Control and Prevention CPPW Contract from the DC Department of Health (DC DoH contract #PO358719) (PI: Kirchner). NR 24 TC 5 Z9 5 U1 1 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 EI 1468-3318 J9 TOB CONTROL JI Tob. Control PD MAR PY 2015 VL 24 IS E1 BP E52 EP E58 DI 10.1136/tobaccocontrol-2013-051239 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CC1UW UT WOS:000350131200010 PM 24570101 ER PT J AU Edmondson, EF Bright, JM Halsey, CH Ehrhart, EJ AF Edmondson, E. F. Bright, J. M. Halsey, C. H. Ehrhart, E. J. TI Pathologic and Cardiovascular Characterization of Pheochromocytoma-Associated Cardiomyopathy in Dogs SO VETERINARY PATHOLOGY LA English DT Article DE canine; cardiomyocyte necrosis; cardiomyopathy; catecholamine; pheochromocytoma ID CATECHOLAMINE-INDUCED CARDIOMYOPATHY; INDUCED MYOCARDIAL NECROSIS; CONTRACTION BAND LESIONS; HEART-RATE-VARIABILITY; DILATED CARDIOMYOPATHY; ATRIOVENTRICULAR-BLOCK; ISOPROTERENOL; REVERSIBILITY; ARRHYTHMIAS; INJURY AB Pheochromocytoma-associated catecholamine-induced cardiomyopathy is a well-known entity in man, nonhuman primates, and mice but has not been described in dogs. In this retrospective study, 9 dogs were identified with pheochromocytomas and concurrent cardiovascular pathology observed histologically (n = 6), echocardiographically (n = 4), and/or electrocardiographically (n = 5). Cardiac lesions included multifocal cardiomyocyte necrosis with contraction bands, cardiomyocyte degeneration, myocardial hemorrhage, lymphohistiocytic myocarditis, and interstitial fibrosis. Clinical procedures, including electrocardiographic and echocardiographic examinations, Doppler blood pressure measurement, and auscultation, were available for 5 dogs and consistently revealed concentric or mixed (eccentric and concentric) ventricular hypertrophy. Additional changes observed included arrhythmias, systemic hypertension, and heart murmurs. The myocardial lesions observed in this series of dogs are similar to those observed in humans with pheochromocytoma-associated catecholamine-induced cardiomyopathy. Since the clinical manifestations of catecholamine-induced cardiac disease are amenable to medical treatment, recognition of this cardiomyopathy has the potential to reduce morbidity and mortality in dogs with pheochromocytoma. C1 [Edmondson, E. F.; Ehrhart, E. J.] Colorado State Univ, Dept Microbiol Immunol & Pathol, Coll Vet Med & Biomed Sci, Flint Anim Canc Ctr, Ft Collins, CO 80521 USA. [Bright, J. M.] Colorado State Univ, Dept Clin Sci, Coll Vet Med & Biomed Sci, Ft Collins, CO 80521 USA. [Halsey, C. H.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Edmondson, EF (reprint author), Colorado State Univ, Dept Microbiol Immunol & Pathol, Coll Vet Med & Biomed Sci, Flint Anim Canc Ctr, 506 S Whitcomb St, Ft Collins, CO 80521 USA. EM elijah.edmondson@colostate.edu NR 38 TC 3 Z9 3 U1 3 U2 16 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 EI 1544-2217 J9 VET PATHOL JI Vet. Pathol. PD MAR PY 2015 VL 52 IS 2 BP 338 EP 343 DI 10.1177/0300985814533805 PG 6 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA CC7NX UT WOS:000350556100012 PM 24810909 ER PT J AU Gao, X Qu, HY Ai, CZ Cao, YF Huang, T Chen, JX Zeng, J Sun, XY Hong, M Gonzalez, FJ Liu, ZY Fang, ZZ AF Gao, Xin Qu, Hengyan Ai, Chun-Zhi Cao, Yun-Feng Huang, Ting Chen, Jian-Xing Zeng, Jia Sun, Xiao-Yu Hong, Mo Gonzalez, Frank J. Liu, Zeyuan Fang, Zhong-Ze TI Regulation profile of phosphatidylcholines (PCs) and lysophosphatidylcholines (LPCs) components towards UDP-glucuronosyltransferases (UGTs) isoforms SO XENOBIOTICA LA English DT Article DE Allosteric activation; lysophosphatidylcholines; phosphatidylcholine; UDP-glucuronosyltransferases ID ACID; IDENTIFICATION; PHOSPHOLIPIDS; INHIBITION AB 1. Endogenous compounds have been reported to be the regulators of UDP-glucuronosyltransferases (UGTs) isoforms. This study aims to investigate the regulatory effects of the activity of UGT isoforms by two important lipid components phosphatidylcholine (PC) and lysophosphatidylcholines (LPC) using in vitro incubation system. 2. UGTs supersomes-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as the probe reaction to evaluate the inhibition of compounds towards UGT isoforms except UGT1A4, and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation reaction was utilized to phenotype the activity of UGT1A4. 3. About 50 mu M of LPC15:0, LPC16:0, LPC17:0, LPC18:0, LPC18:1 and PC16:0, 2:0 exhibited inhibition towards more than 90% activity of UGT isoforms, and other LPC and PC components showed negligible inhibitory potential towards all the UGT isoforms. UGT1A6 and UGT1A8 were identified to be the most sensitive UGT isoforms susceptible for the inhibition by LPC15:0, LPC16:0, LPC17:0, LPC18:0, LPC18:1 and PC16:0, 2:0, indicating the strong influence of these LPC and PC components towards UGT1A6 and UGT1A8-catalyzed metabolic reaction when the concentrations of these components increased. C1 [Gao, Xin; Qu, Hengyan; Liu, Zeyuan] Acad Mil Med Sci, Affiliated Hosp, Dept Clin Pharmacol, Beijing, Peoples R China. [Fang, Zhong-Ze] Tianjin Med Univ, Sch Publ Hlth, Dept Toxicol, Tianjin, Peoples R China. [Ai, Chun-Zhi; Sun, Xiao-Yu; Hong, Mo] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian, Peoples R China. [Ai, Chun-Zhi; Sun, Xiao-Yu; Hong, Mo] Liaoning Med Univ, Affiliated Hosp 1, Dalian, Peoples R China. [Cao, Yun-Feng; Huang, Ting; Chen, Jian-Xing; Zeng, Jia] Shanghai Inst Planned Parenthood Res, Shanghai Engn & Technol Res Ctr Reprod Hlth Drug, Key Lab Contracept & Devices Res NPFPC, Shanghai, Peoples R China. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Fang, ZZ (reprint author), Tianjin Med Univ, Sch Publ Hlth, Dept Toxicol, 22 Qixiangtai Rd, Tianjin 300070, Peoples R China. EM gaoxinwjyxy@163.com; fangzhongze@tijmu.edu.cn FU National Natural Science Foundation of China [81202586] FX The authors have declared no conflict of interest. This work was supported by the National Natural Science Foundation of China (No. 81202586). NR 21 TC 12 Z9 12 U1 4 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0049-8254 EI 1366-5928 J9 XENOBIOTICA JI Xenobiotica PD MAR PY 2015 VL 45 IS 3 BP 197 EP 206 DI 10.3109/00498254.2014.966174 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CC6CH UT WOS:000350451700002 PM 25259654 ER PT J AU Vincent, HK AF Vincent, Heather K. TI Designing Running Programs for Obese Individuals SO ACSMS HEALTH & FITNESS JOURNAL LA English DT Editorial Material C1 [Vincent, Heather K.] Univ Florida, NIH, Gainesville, FL 32611 USA. RP Vincent, HK (reprint author), UF Hlth Sports Performance Ctr, Gainesville, FL 32607 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1091-5397 EI 1536-593X J9 ACSMS HEALTH FIT J JI ACSMS Health Fit. J. PD MAR-APR PY 2015 VL 19 IS 2 BP 36 EP 38 PG 3 WC Sport Sciences SC Sport Sciences GA CC2BN UT WOS:000350149700010 ER PT J AU Schubauer-Berigan, MK Anderson, JL Hein, MJ Little, MP Sigurdson, AJ Pinkerton, LE AF Schubauer-Berigan, Mary K. Anderson, Jeri L. Hein, Misty J. Little, Mark P. Sigurdson, Alice J. Pinkerton, Lynne E. TI Breast Cancer Incidence in a Cohort of US Flight Attendants SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE flight crew; ionizing radiation; cosmic; circadian rhythm disruption; cohort studies ID CIRCADIAN-RHYTHM DISRUPTION; COSMIC-RADIATION EXPOSURE; AIRLINE CABIN CREW; REPRODUCTIVE FACTORS; QUALITY FACTOR; NIGHT WORK; RISK; MORTALITY; COUNTRIES; ALTITUDES AB BackgroundFlight attendants may have elevated breast cancer incidence (BCI). We evaluated BCI's association with cosmic radiation dose and circadian rhythm disruption among 6,093 female former U.S. flight attendants. MethodsWe collected questionnaire data on BCI and risk factors for breast cancer from 2002-2005. We conducted analyses to evaluate (i) BCI in the cohort compared to the U.S. population; and (ii) exposure-response relations. We applied an indirect adjustment to estimate whether parity and age at first birth (AFB) differences between the cohort and U.S. population could explain BCI that differed from expectation. ResultsBCI was elevated but may be explained by lower parity and older AFB in the cohort than among U.S. women. BCI was not associated with exposure metrics in the cohort overall. Significant positive associations with both were observed only among women with parity of three or more. ConclusionsFuture cohort analyses may be informative on the role of these occupational exposures and non-occupational risk factors. Am. J. Ind. Med. 58:252-266, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Schubauer-Berigan, Mary K.; Anderson, Jeri L.; Hein, Misty J.; Pinkerton, Lynne E.] NIOSH, Div Surveillance Hazard Evaluat & Field Studies, Industrywide Studies Branch, Cincinnati, OH 45226 USA. [Little, Mark P.; Sigurdson, Alice J.] NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Schubauer-Berigan, MK (reprint author), NIOSH, Div Surveillance Hazard Evaluat & Field Studies, Industrywide Studies Branch, Cincinnati, OH 45226 USA. EM zcg3@cdc.gov OI Little, Mark/0000-0003-0980-7567 FU National Cancer Institute; Office of Women's Health of the U.S. Department of Health and Human Services FX The authors thank many able colleagues currently or formerly employed at NIOSH, including Steven Allee, Faith Armstrong, Christine Gersic, Stacy Kramer, Zachary Zivkovich, and others, for their assistance in collecting, coding, cleaning, and programming of data for the study. We thank researchers at Battelle and Westat for assistance with the administration of the questionnaire and medical record follow-back and coding. Martha Waters, Robert Daniels, and Elizabeth Whelan of NIOSH and Elaine Ron (deceased) of NCI provided input into the dosimetry, design, or interpretation of the study. We thank Lian Luo and James Yiin for creating the SEER-based breast cancer incidence rate file. The study was funded, in part, by an interagency agreement with the National Cancer Institute and the Office of Women's Health of the U.S. Department of Health and Human Services. NR 41 TC 5 Z9 6 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 EI 1097-0274 J9 AM J IND MED JI Am. J. Ind. Med. PD MAR PY 2015 VL 58 IS 3 BP 252 EP 266 DI 10.1002/ajim.22419 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CC0ZN UT WOS:000350068700002 PM 25678455 ER PT J AU Hohenadel, K Raj, P Demers, PA Zahm, SH Blair, A AF Hohenadel, Karin Raj, Priyanka Demers, Paul A. Zahm, Shelia Hoar Blair, Aaron TI The Inclusion of Women in Studies of Occupational Cancer: A Review of the Epidemiologic Literature From 1991-2009 SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Review DE workplace; occupations; neoplasms; women's health ID GENDER-DIFFERENCES; HEALTH; EXPOSURE; SEX AB IntroductionSince the early 1990s, researchers have been concerned with the low rate at which women are included in epidemiologic studies of occupational cancer. A previous evaluation determined that one-third of articles published between 1970 and 1990 included women. MethodsTo assess whether there has been an improvement in recent years, papers on occupational cancer between 1991 and 2009 were reviewed in fifteen journals. ResultsThe proportion of articles that included men remained stable around 90%, while the proportion of articles that included women increased substantially, from 39% in 1991-1995 to 62% in 2006-2009. Articles that assessed risk among men only or men and women presented a higher number of risk estimates and were more likely to evaluate dose-response relationships than studies including women. ConclusionsDespite advances in the inclusion of women in studies of occupational cancer, disparities remain in the number of studies of occupational cancer and depth of analysis in studies that included women. Am. J. Ind. Med. 58:276-281, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Hohenadel, Karin; Raj, Priyanka; Demers, Paul A.] Occupat Canc Res Ctr, Toronto, ON M5G 1X3, Canada. [Demers, Paul A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Zahm, Shelia Hoar; Blair, Aaron] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Hohenadel, K (reprint author), Occupat Canc Res Ctr, Ontario 505 Univ Ave,17th Floor, Toronto, ON M5G 1X3, Canada. EM Karin.hohenadel@utoronto.ca FU Occupational Cancer Research Centre in Toronto, Canada FX Contract grant sponsor: The Occupational Cancer Research Centre in Toronto, Canada. NR 17 TC 2 Z9 2 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 EI 1097-0274 J9 AM J IND MED JI Am. J. Ind. Med. PD MAR PY 2015 VL 58 IS 3 BP 276 EP 281 DI 10.1002/ajim.22424 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CC0ZN UT WOS:000350068700004 PM 25678456 ER PT J AU Stateman, WA Henkin, RI Knoppel, AB Flegel, WA AF Stateman, William A. Henkin, Robert I. Knoeppel, Alexandra B. Flegel, Willy A. TI Erythrocyte membrane antigen frequencies in patients with Type II congenital smell loss SO AMERICAN JOURNAL OF OTOLARYNGOLOGY LA English DT Article ID HORMONE-RELEASING HORMONE; KALLMANN-SYNDROME; HYPOGONADOTROPIC HYPOGONADISM; DIGENIC MUTATIONS; GENETIC-BASIS; NASAL MUCUS; ANOSMIA; DYSFUNCTION; HYPOSMIA; TASTE AB Objective: The objective of this study was to determine whether there are genetic factors associated with Type II congenital smell loss. Study design: The expression frequencies of 16 erythrocyte antigens among patients with Type II congenital smell loss were determined and compared to those of a large control group. Methods: Blood samples were obtained from 99 patients with Type II congenital smell loss. Presence of the erythrocyte surface antigens A, B, M, N, S, s, Fy(a), Fy(b), D, C, c, E, e, K, Jk(a), and Jk(b) was analyzed by blood group serology. Comparisons of expression frequencies of these antigens were made between the patients and a large control group. Results: Patients tested for the Duffy b antigen (Fy(b) haplotype) exhibited a statistically significant 11% decrease in expression frequency compared to the controls. There were no significant differences between patients and controls in the expression frequencies for all other erythrocyte antigens (A, B, M, N, S, s, Fy(a), D, C, c, E, e, K, Jk(a), or Jk(b)). Conclusions: These findings describe the presence of a previously unrevealed genetic tendency among patients with Type II congenital smell loss related to erythrocyte surface antigen expression. The deviation in expression rate of Duffy b suggests a target gene and chromosome region in which future research into this form of congenital smell loss may reveal a more specific genetic basis for Type II congenital smell loss. (C) 2015 Elsevier Inc. All rights reserved. C1 [Stateman, William A.; Henkin, Robert I.; Knoeppel, Alexandra B.] Ctr Mol Nutr & Sensory Disorders, Taste & Smell Clin, Washington, DC 20016 USA. [Flegel, Willy A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Henkin, RI (reprint author), Ctr Mol Nutr & Sensory Disorders, 5125 MacArthur Blvd NW,20, Washington, DC 20016 USA. EM wstateman@gmail.com; doc@tasteandsmell.com; abknoppel@gmail.com; flegelwa@cc.nth.gov OI Knoppel, Alexandra/0000-0003-2504-7350 FU Intramural Research Program of the NIH Clinical Center FX This research was supported in part by the Intramural Research Program of the NIH Clinical Center. NR 47 TC 3 Z9 3 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0196-0709 EI 1532-818X J9 AM J OTOLARYNG JI Am. J. Otolaryngol. PD MAR-APR PY 2015 VL 36 IS 2 BP 146 EP 152 DI 10.1016/j.amjoto.2014.10.006 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA CB9FJ UT WOS:000349937100006 PM 25456515 ER PT J AU Gu, FY Han, JL Laden, F Pan, A Caporaso, NE Stampfer, MJ Kawachi, I Rexrode, KM Willett, WC Hankinson, SE Speizer, FE Schernhammer, ES AF Gu, Fangyi Han, Jiali Laden, Francine Pan, An Caporaso, Neil E. Stampfer, Meir J. Kawachi, Ichiro Rexrode, Kathryn M. Willett, Walter C. Hankinson, Susan E. Speizer, Frank E. Schernhammer, Eva S. TI Total and Cause-Specific Mortality of US Nurses Working Rotating Night Shifts SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID BREAST-CANCER RISK; ISCHEMIC-HEART-DISEASE; CIRCADIAN DISRUPTION; LUNG-CANCER; NORWEGIAN NURSES; FOLLOW-UP; WOMEN; HEALTH; SLEEP; OCCUPATION AB Background: Rotating night shift work imposes circadian strain and is linked to the risk of several chronic diseases. Purpose: To examine associations between rotating night shift work and all-cause; cardiovascular disease (CVD); and cancer mortality in a prospective cohort study of 74,862 registered U.S. nurses from the Nurses' Health Study. Methods: Lifetime rotating night shift work (defined as >= 3 nights/month) information was collected in 1988. During 22 years (1988-2010) of follow-up, 14,181 deaths were documented, including 3,062 CVD and 5,413 cancer deaths. Cox proportional hazards models estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs. Results: All-cause and CVD mortality were significantly increased among women with >= 5 years of rotating night shift work, compared to women who never worked night shifts. Specifically, for women with 6-14 and >= 15 years of rotating night shift work, the HRs were 1.11 (95% CI=1.06, 1.17) and 1.11 (95% CI=1.05, 1.18) for all-cause mortality and 1.19 (95% CI=1.07, 1.33) and 1.23 (95% CI=1.09, 1.38) for CVD mortality. There was no significant association between rotating night shift work and all-cancer mortality (HR >= 15years=1.08, 95% CI=0.98, 1.19) or mortality of any individual cancer, with the exception of lung cancer (HR >= 15years=1.25, 95% CI=1.04, 1.51). Conclusions: Women working rotating night shifts for >= 5 years have a modest increase in all-cause and CVD mortality; those working >= 15 years of rotating night shift work have a modest increase in lung cancer mortality. These results add to prior evidence of a potentially detrimental effect of rotating night shift work on health and longevity. (C) 2015 American Journal of Preventive Medicine. All rights reserved. C1 [Gu, Fangyi; Caporaso, Neil E.] NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD 20892 USA. [Han, Jiali; Stampfer, Meir J.; Hankinson, Susan E.; Speizer, Frank E.; Schernhammer, Eva S.] Channing Div Network Med, Boston, MA 02115 USA. [Han, Jiali] Brigham & Womens Hosp, Dept Dermatol, Clin Res Program, Boston, MA 02115 USA. [Rexrode, Kathryn M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Schernhammer, Eva S.] Brigham & Womens Hosp, Dept Med, Div Sleep Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Laden, Francine] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Laden, Francine; Stampfer, Meir J.; Schernhammer, Eva S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kawachi, Ichiro] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hankinson, Susan E.] Univ Massachusetts, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Han, Jiali] Indiana Univ, Simon Canc Ctr, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46204 USA. [Pan, An] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Pan, An] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore 117595, Singapore. [Pan, An] Natl Univ Hlth Syst, Singapore, Singapore. [Schernhammer, Eva S.] Appl Canc Res Inst Translat Res Vienna ACR ITR VI, Vienna, Austria. RP Schernhammer, ES (reprint author), Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. EM eva.schernhammer@channing.harvard.edu RI Pan, An/C-5572-2011; OI Pan, An/0000-0002-1089-7945; Rexrode, Kathryn/0000-0003-3387-8429 FU National Cancer Institute [CA50385, CA87969]; NIH Heart, Lung and Blood Institute [HL034594]; CDC/The National Institute for Occupational Safety and Health [OH009803]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute FX This research was supported by National Cancer Institute grants CA50385 and CA87969, NIH Heart, Lung and Blood Institute grant HL034594, and CDC/The National Institute for Occupational Safety and Health grant OH009803. Gu was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. We would like to thank the participants and staff of the Nurses' Health Study cohort for their valuable contributions as well as the following state cancer registries for their help: Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Nebraska, New Hampshire, New Jersey, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, Washington, and Wyoming. The authors assume full responsibility for analyses and interpretation of these data. We also thank Tricia Li for help with SAS programming. The authors report no conflicts of interest. No financial disclosures were reported by the authors of this paper. The authors alone are responsible for the content and writing of the paper. The sponsors had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. Researchers of this article are independent of sponsors. This manuscript is an honest, accurate, and transparent account of the study being reported. No important aspects of the study have been omitted. Any discrepancies from the study as planned have been explained. NR 60 TC 9 Z9 9 U1 7 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAR PY 2015 VL 48 IS 3 BP 241 EP 252 DI 10.1016/j.amepre.2014.10.018 PG 12 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CB6LZ UT WOS:000349739800001 PM 25576495 ER PT J AU Dettmer, AM Woodward, RA Suom, SJ AF Dettmer, Amanda M. Woodward, Ruth A. Suom, Stephen J. TI Reproductive Consequences of a Matrilineal Overthrow in Rhesus Monkeys SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE macaque; primate; violence; overthrow; reproduction; fitness ID MACACA-MULATTA; GROUP FISSION; GROUP-SIZE; MACAQUES; PRIMATES; COMPETITION; POPULATION; AGGRESSION; FASCICULARIS; MORTALITY AB Matrilineal overthrows in macaque societies are rare but devastating events, often resulting in severe morbidity, mortality, and loss of individual and group fitness. The handful of documented macaque overthrows provides scant evidence to reveal the severity or longevity of reproductive consequences resulting from such violent events. We analyzed archival records from semi-free ranging rhesus monkeys, Macaca mulatta, across 6 years (55N107, from 2007 to 2012) during which time a matrilineal overthrow occurred (in 2009) to test the hypothesis that extremely violent interactions such as a matrilineal overthrow would significantly reduce reproductive fitness for the involved matrilines and for the troop collectively. The matrilineal overthrow resulted in a significant increase in infant loss for the population from the previous year ((2)=8.117, df=1, P=0.004), as evidenced by the fact that in 2009, but not in other years, the proportion of infants lost was greater than the proportion of viable infants ((2)=4.55, df=1, P=0.03). Moreover, the deposed matriline suffered 100% infant loss in 2009, a significant change from the previous year ((2)=7.87, df=1, P=0.005) while the attacking matriline suffered 50% infant loss (also a significant change from the previous year; (2)=4.44, df=1, P=0.035), with the uninvolved, lowest-ranking matriline showing no change in infant loss from the previous year ((2)=0.008, df=1, P=0.93). The deposed matriline did not produce viable offspring again until 3 years later. We further found that rates of severe fighting (as indicated by the number of fight wounds requiring medical treatment) were positively correlated with infant loss across the 6 years of the study (r([s])=0.943, P=0.005). Our data indicate that extreme periods of intra-group conflict, such as the matrilineal overthrow, have marked short-term consequences for individual fitness, and may be extreme examples of the long-term influences that group violence exerts on the mean fitness within a primate troop. Am. J. Primatol. 77:346-352, 2015. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Dettmer, Amanda M.; Suom, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Poolesville, MD USA. [Woodward, Ruth A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Res Anim Management Branch, NIH, Poolesville, MD USA. RP Dettmer, AM (reprint author), NIH, Anim Ctr, POB 529, Poolesville, MD 20837 USA. EM dettmera@mail.nih.gov FU Intramural NIH HHS [ZIA HD001107-31] NR 36 TC 3 Z9 3 U1 4 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAR PY 2015 VL 77 IS 3 BP 346 EP 352 DI 10.1002/ajp.22350 PG 7 WC Zoology SC Zoology GA CB8OU UT WOS:000349891000012 PM 25382028 ER PT J AU Robinson, DG Schooler, NR John, M Correll, CU Marcy, P Addington, J Brunette, MF Estroff, SE Mueser, KT Penn, D Robinson, J Rosenheck, RA Severe, J Goldstein, A Azrin, S Heinssen, R Kane, JM AF Robinson, Delbert G. Schooler, Nina R. John, Majnu Correll, Christoph U. Marcy, Patricia Addington, Jean Brunette, Mary F. Estroff, Sue E. Mueser, Kim T. Penn, David Robinson, James Rosenheck, Robert A. Severe, Joanne Goldstein, Amy Azrin, Susan Heinssen, Robert Kane, John M. TI Prescription Practices in the Treatment of First-Episode Schizophrenia Spectrum Disorders: Data From the National RAISE-ETP Study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID ANTIPSYCHOTIC-DRUGS; REGRESSION-MODELS; PSYCHOSIS; RISPERIDONE; OLANZAPINE; EFFICACY; TRIAL; HALOPERIDOL; MEDICATIONS; DISPARITIES AB Objective: Treatment guidelines suggest distinctive medication strategies for first-episode and multiepisode patients with schizophrenia. To assess the extent to which community clinicians adjust their usual treatment regimens for first-episode patients, the authors examined prescription patterns and factors associated with prescription choice in a national cohort of early-phase patients. Method: Prescription data at study entry were obtained from 404 participants in the Recovery After an Initial Schizophrenia Episode Project's Early Treatment Program (RAISE-ETP), a nationwide multisite effectiveness study for patients with first-episode schizophrenia spectrum disorders. Treatment with antipsychotics did not exceed 6 months at study entry. Results: The authors identified 159 patients (39.4% of the sample) who might benefit from changes in their psychotropic prescriptions. Of these, 8.8% received prescriptions for recommended antipsychotics at higher than recommended dosages; 32.1% received prescriptions for olanzapine (often at high dosages), 23.3% for more than one antipsychotic, 36.5% for an antipsychotic and also an antidepressant without a clear indication, 10.1% for psychotropic medications without an antipsychotic, and 1.2% for stimulants. Multivariate analysis showed evidence for sex, age, and insurance status effects on prescription practices. Racial and ethnic effects consistent with effects reported in previous studies of multiepisode patients were found in univariate analyses. Despite some regional variations in prescription practices, no region consistently had different practices from the others. Diagnosis had limited and inconsistent effects. Conclusions: Besides prescriber education, policy makers may need to consider not only patient factors but also service delivery factors in efforts to improve prescription practices for first-episode schizophrenia patients. C1 [Robinson, Delbert G.] Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY 11030 USA. Hofstra North Shore LIJ Sch Med, Dept Psychiat, Hempstead, NY USA. Hofstra North Shore LIJ Sch Med, Dept Mol Med, Hempstead, NY USA. North Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Psychiat Res, Glen Oaks, NY USA. Suny Downstate Med Ctr, New York, NY USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Univ Calgary, Dept Psychiat, Hotchkiss Brain Inst, Calgary, AB, Canada. Geisel Sch Med, Hanover, NH USA. Univ N Carolina, Dept Social Med, Chapel Hill, NC USA. Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. Boston Univ, Ctr Psychiat Rehabil, Dept Occupat Therapy, Boston, MA 02215 USA. Boston Univ, Ctr Psychiat Rehabil, Dept Psychiat, Boston, MA 02215 USA. Boston Univ, Dept Psychol, Ctr Psychiat Rehabil, Boston, MA 02215 USA. Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. NYU, Langone Med Ctr, Dept Psychiat & Adolescent & Child Psychiat, New York, NY USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. NIMH, Bethesda, MD 20892 USA. RP Robinson, DG (reprint author), Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY 11030 USA. EM drobinso@nshs.edu FU NIMH [HHSN-271-2009-00019C]; NIMH Advanced Centers for Interventions and Services Research award [P30MH090590]; Bristol-Myers Squibb; Janssen; Otsuka; Genentech; Neurocrine; Feinstein Institute for Medical Research; Janssen/Johnson Johnson; NIMH; NARSAD FX Funding for the RAISE-ETP study was provided by NIMH contract HHSN-271-2009-00019C (principal investigator, Dr. Kane). Additional support for the analyses in this study was provided by an NIMH Advanced Centers for Interventions and Services Research award (P30MH090590; principal investigator, Dr. Kane).; Dr. D. Robinson has served as a consultant to Asubio and Shire and has received grants from Bristol-Myers Squibb, Janssen, and Otsuka. Dr. Schooler has served as a consultant to Amgen, Eli Lilly, EnVivo (Forum), Genentech/Roche, Graham Boechk Foundation, Janssen Psychiatry, Lundbeck International Neuroscience Foundations, Shire, and Sunovion and has received grants from Genentech, Neurocrine, and Otsuka. Dr. Correll has been a consultant or adviser to, or has received honoraria from, Actelion, Alexza, American Academy of Child and Adolescent Psychiatry, Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Janssen/Johnson & Johnson, Lundbeck, MedAvante, Medscape, Merck, NIMH, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva, and Vanda and has received grant support from Bristol-Myers Squibb, Feinstein Institute for Medical Research, Janssen/Johnson & Johnson, NIMH, NARSAD, and Otsuka. Ms. Marcy owns stock in Pfizer. Dr. Kane has served as a consultant or on the speakers bureau for Alkermes, Bristol-Myers Squibb, Eli Lilly, EnVivo Pharmaceuticals (Forum), Forest, Genentech, Intracellular Therapeutics, Janssen, Johnson & Johnson, Lundbeck, Otsuka, Reviva, and Roche, and he is a shareholder in MedAvante. The other authors report no financial relationships with commercial interests. NR 33 TC 19 Z9 19 U1 6 U2 15 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAR PY 2015 VL 172 IS 3 BP 237 EP 248 DI 10.1176/appi.ajp.2014.13101355 PG 12 WC Psychiatry SC Psychiatry GA CC0DW UT WOS:000350007000009 PM 25727536 ER PT J AU Dickinson, D AF Dickinson, Dwight TI The Measure of Madness: Philosophy of Mind, Cognitive Neuroscience, and Delusional Thought SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Book Review C1 [Dickinson, Dwight] NIMH, Clin & Translat Neurosci Branch, Psychosis & Cognit Studies Sect, Bethesda, MD 20892 USA. RP Dickinson, D (reprint author), NIMH, Clin & Translat Neurosci Branch, Psychosis & Cognit Studies Sect, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAR PY 2015 VL 172 IS 3 BP 297 EP 298 DI 10.1176/appi.ajp.2014.14121521 PG 2 WC Psychiatry SC Psychiatry GA CC0DW UT WOS:000350007000020 PM 25727545 ER PT J AU Pantin, JM Hoyt, RF Aras, O Sato, N Chen, MY Hunt, T Clevenger, R Eclarinal, P Adler, S Choyke, P Childs, RW AF Pantin, J. M. Hoyt, R. F., Jr. Aras, O. Sato, N. Chen, M. Y. Hunt, T. Clevenger, R. Eclarinal, P. Adler, S. Choyke, P. Childs, R. W. TI Optimization of Intrabone Delivery of Hematopoietic Progenitor Cells in a Swine Model Using Cell Radiolabeling with [89]zirconium SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE animal models: porcine; basic (laboratory) research; science; bone marrow; clinical research; practice; hematology; oncology; diagnostic techniques and imaging: positron emission tomography; graft survival; graft-versus-host disease (GVHD); hematopoietic stem cell transplantation; monitoring: physiologic; xenotransplantation ID UMBILICAL-CORD BLOOD; BONE-MARROW-TRANSPLANTATION; MESENCHYMAL STEM-CELLS; VERSUS-HOST-DISEASE; IN-VIVO; INTRAFEMORAL TRANSPLANTATION; ENHANCE ENGRAFTMENT; STROMAL CELLS; INJECTION; INFUSION AB Intrabone (IB) hematopoietic cell transplantation (HCT) of umbilical cord blood in humans remains experimental and the technique has not been optimized. It is unknown whether hematopoietic progenitor cells (HPCs) injected IB are initially retained in the marrow or rapidly enter into the venous circulation before homing to the marrow. To develop an IB-injection technique that maximizes HPC marrow-retention, we tracked radiolabeled human HPCs following IB-injection into swine. We developed a method to radionuclide-label HPCs using a long-lived positron emitter Zr-89 and protamine sulfate that resulted in cellular-retention of low-dose radioactivity. This approach achieved radioactivity levels sufficient for detection by positron emission tomography with both high sensitivity and spatial resolution when fused with computed tomography. We found that conditions utilized in pilot IB-HCT clinical trials conducted by others led to both rapid drainage into the central venous circulation and cellular extravasation into surrounding muscle and soft tissues. By optimizing the needle design, using continuous real-time intra-marrow pressure monitoring, and by reducing the infusion-volume and infusion-rate, we overcame this limitation and achieved high retention of HPCs in the marrow. This method of IB cellular delivery is readily applicable in the clinic and could be utilized in future investigational IB-HCT trials aimed at maximizing marrow retention of HPCs. The authors report a novel method of hematopoietic progenitor cell labeling and in vivo tracking, and develop a technique that utilizes real-time intramarrow pressure monitoring to optimize the retention of hematopoietic progenitor cells in the bone marrow following intrabone transplantation. See accompanying videos of dynamic 3D CT angiography in online supporting information and in the AJT Video Library. C1 [Pantin, J. M.] Georgia Regents Univ, Div Hematol & Med Oncol, Augusta, GA USA. [Pantin, J. M.; Childs, R. W.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Hoyt, R. F., Jr.; Hunt, T.; Clevenger, R.] NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. [Hoyt, R. F., Jr.] Frederick Natl Lab, Leidos Biomed Res Inc, Lab Anim Sci Program, Frederick, MD USA. [Aras, O.] NIH, Imaging Sci Training Program, Dept Diagnost Radiol, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Sato, N.; Choyke, P.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chen, M. Y.] NHLBI, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Eclarinal, P.; Adler, S.] Leidos Biomed Res Inc, Reston, VA USA. RP Childs, RW (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM childsr@nih.gov RI kiaie, robabeh/I-2157-2016; kiaie, fatemeh/I-6083-2016; OI kiaie, robabeh/0000-0001-5251-3201; Pantin, Jeremy/0000-0001-7536-0623 FU Division of Intramural Research (DIR) of the NHLBI; NCI FX This work was supported by the Division of Intramural Research (DIR) of the NHLBI and the NCI. Peter Herscovitch, M.D., Dale Kiesewetter, Ph.D., Chang Paik Ph.D., Eric Munger, Karen Wong, Karen Keeran, Gayle Nugent, Arthur Zetts, Kenneth Jeffries, Shawn Kozlov, Gideon Kwarteng, Lawrence Szajek, Ph.D., Joseph Frank, M.D., M.S., Thomas Philbeck, Ph.D., and Hahn Khuu, M.D., were all instrumental in the completion of this project. NR 42 TC 4 Z9 4 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2015 VL 15 IS 3 BP 606 EP 617 DI 10.1111/ajt.13007 PG 12 WC Surgery; Transplantation SC Surgery; Transplantation GA CB9UD UT WOS:000349977700009 PM 25656824 ER PT J AU Sobota, RS Shriner, D Kodaman, N Goodloe, R Zheng, W Gao, YT Edwards, TL Amos, CI Williams, SM AF Sobota, Rafal S. Shriner, Daniel Kodaman, Nuri Goodloe, Robert Zheng, Wei Gao, Yu-Tang Edwards, Todd L. Amos, Christopher I. Williams, Scott M. TI Addressing Population-Specific Multiple Testing Burdens in Genetic Association Studies SO ANNALS OF HUMAN GENETICS LA English DT Article DE Genome-wide threshold; GWAS; HapMap; linkage disequilibrium; autocorrelation ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; BREAST-CANCER SURVIVAL; IDENTIFIES 3; MELANOMA; LOCI; VARIANTS; ERROR; SCANS; SNP AB The number of effectively independent tests performed in genome-wide association studies (GWAS) varies by population, making a universal P-value threshold inappropriate. We estimated the number of independent SNPs in Phase 3 HapMap samples by: (1) the LD-pruning function in PLINK, and (2) an autocorrelation-based approach. Autocorrelation was also used to estimate the number of independent SNPs in whole genome sequences from 1000 Genomes. Both approaches yielded consistent estimates of numbers of independent SNPs, which were used to calculate new population-specific thresholds for genome-wide significance. African populations had the most stringent thresholds (1.49 x 10(-7) for YRI at r(2) = 0.3), East Asian populations the least (3.75 x 10(-7) for JPT at r(2) = 0.3). We also assessed how using population-specific significance thresholds compared to using a single multiple testing threshold at the conventional 5 x 10(-8) cutoff. Applied to a previously published GWAS of melanoma in Caucasians, our approach identified two additional genes, both previously associated with the phenotype. In a Chinese breast cancer GWAS, our approach identified 48 additional genes, 19 of which were in or near genes previously associated with the phenotype. We conclude that the conventional genome-wide significance threshold generates an excess of Type 2 errors, particularly in GWAS performed on more recently founded populations. C1 [Sobota, Rafal S.; Kodaman, Nuri; Goodloe, Robert] Vanderbilt Univ, Med Ctr, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN USA. [Sobota, Rafal S.; Kodaman, Nuri; Amos, Christopher I.; Williams, Scott M.] Dartmouth Coll, Geisel Sch Med, Dept Genet, Hanover, NH 03755 USA. [Shriner, Daniel] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Zheng, Wei; Edwards, Todd L.] Vanderbilt Univ, Dept Med, Div Epidemiol, Ctr Human Genet Res, Nashville, TN USA. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. RP Williams, SM (reprint author), Dartmouth Coll, Geisel Sch Med, Dept Genet, HB-6044, Hanover, NH 03755 USA. EM scott.williams@dartmouth.edu FU Center for Research on Genomics and Global Health (CRGGH); National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [Z01HG200362]; Public Health Service from the National Institute of General Medical Studies [T32 GM07347]; NIH [P20 GM103534] FX The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. This research was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). This work was supported by Public Health Service award T32 GM07347 from the National Institute of General Medical Studies for the Vanderbilt Medical-Scientist Training Program. SMW was partially supported by NIH grant P20 GM103534. NR 39 TC 8 Z9 8 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0003-4800 EI 1469-1809 J9 ANN HUM GENET JI Ann. Hum. Genet. PD MAR PY 2015 VL 79 IS 2 BP 136 EP 147 DI 10.1111/ahg.12095 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA CB9MQ UT WOS:000349956200006 PM 25644736 ER PT J AU Steele, JC Guella, I Szu-Tu, C Lin, MK Thompson, C Evans, DM Sherman, HE Vilarino-Guell, C Gwinn, K Morris, H Dickson, DW Farrer, MJ AF Steele, John C. Guella, Ilaria Szu-Tu, Chelsea Lin, Michelle K. Thompson, Christina Evans, Daniel M. Sherman, Holly E. Vilarino-Gueell, Carles Gwinn, Katrina Morris, Huw Dickson, Dennis W. Farrer, Matthew J. TI Defining Neurodegeneration on Guam by Targeted Genomic Sequencing SO ANNALS OF NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; PARKINSONISM-DEMENTIA COMPLEX; MOTOR-NEURON DISEASE; FRONTOTEMPORAL DEMENTIA; MUTATIONS; ALS/PDC; PDC; HYPOTHESIS; CHAMORROS; DIAGNOSIS AB ObjectiveAmyotrophic lateral sclerosis/parkinsonism-dementia complex has been described in Guam, Western Papua, and the Kii Peninsula of Japan. The etiology and pathogenesis of this complex neurodegenerative disease remains enigmatic. MethodsIn this study, we have used targeted genomic sequencing to evaluate the contribution of genetic variability in the pathogenesis of amyotrophic lateral sclerosis, parkinsonism, and dementia in Guamanian Chamorros. ResultsGenes previously linked to or associated with amyotrophic lateral sclerosis, parkinsonism, dementia, and related neurodegenerative syndromes were sequenced in Chamorro subjects living in the Mariana Islands. Homozygous PINK1 p.L347P, heterozygous DCTN1 p.T54I, FUS p.P431L, and HTT (42 CAG repeats) were identified as pathogenic mutations. InterpretationThe findings explain the clinical, pathologic, and genetic heterogeneity observed in some multi-incident families and contribute to the excess incidence of neurodegeneration previously reported on Guam. Ann Neurol 2015;77:458-468 C1 [Steele, John C.] Micronesian Hlth Study II, Tamuning, GU USA. [Guella, Ilaria; Szu-Tu, Chelsea; Lin, Michelle K.; Thompson, Christina; Evans, Daniel M.; Sherman, Holly E.; Vilarino-Gueell, Carles; Farrer, Matthew J.] Univ British Columbia, Djavad Mowafhagian Ctr Brain Heath, Vancouver, BC V6T 1Z3, Canada. [Gwinn, Katrina] NINDS, NIH, Bethesda, MD 20892 USA. [Morris, Huw] UCL, Inst Neurol, London, England. [Dickson, Dennis W.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. RP Farrer, MJ (reprint author), Univ British Columbia, Djavad Mowafhagian Ctr Brain Heath, Ctr Appl Neurogenet, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada. EM mfarrer@can.ubc.ca RI Vilarino-Guell, Carles/D-8628-2011; Morris, Huw/B-8527-2008; OI Vilarino-Guell, Carles/0000-0002-5612-5940; Morris, Huw/0000-0002-5473-3774; Gwinn, Katrina/0000-0002-8277-651X FU Canada Excellence Research Chairs program; Cundill Foundation; Cure PSP Society FX This study was supported by the Canada Excellence Research Chairs program (M.J.F.), the Cundill Foundation (M.J.F.), and Leading Edge Endowment Funds for next generation sequencing and genetic analyses (M.J.F.). J.C.S.'s institution received a grant from the Cure PSP Society. NR 42 TC 7 Z9 7 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD MAR PY 2015 VL 77 IS 3 BP 458 EP 468 DI 10.1002/ana.24346 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CC6EC UT WOS:000350456800010 PM 25558820 ER PT J AU Parikh, NI Gerschenson, M Bennett, K Gangcuangco, LMM Lopez, MS Mehta, NN Playford, MP Nakamoto, BK Seto, TB Chow, DC Shikuma, CM AF Parikh, Nisha I. Gerschenson, Mariana Bennett, Kara Gangcuangco, Louie Mar M. Lopez, Mary S. Mehta, Nehal N. Playford, Martin P. Nakamoto, Beau K. Seto, Todd B. Chow, Dominic C. Shikuma, Cecilia M. TI Lipoprotein concentration, particle number, size and cholesterol efflux capacity are associated with mitochondrial oxidative stress and function in an HIV positive cohort SO ATHEROSCLEROSIS LA English DT Article DE Atherosclerosis; Cardiovascular disease; Lipids; NMR spectroscopy; Oxidative phosphorylation; Cholesterol efflux capacity; HDL ID HIGH-DENSITY-LIPOPROTEIN; INFLAMMATORY MARKERS; METABOLIC SYNDROME; DISEASE; HYPERCHOLESTEROLEMIA; PROFILES; RISK AB Background: Association of lipoprotein particle size/number and HDL function with mitochondrial oxidative stress and function may underlie the excess cardiovascular (CVD) risk in HIV. Methods and results: Among HIV infected individuals on stable highly active antiretroviral therapy, we related standard and novel lipid measures [plasma total cholesterol, triglycerides, HDL-C, LDL-C, lipoprotein particle (-P) subclass size and number and HDL function (via cholesterol-efflux capacity)] with oxidative stress [peripheral blood mononuclear cell's mitochondrial-specific 8-oxo-deoxyguanine (8-oxo-dG)] and function markers [oxidative phosphorylation (OXPHOS) NADH dehydrogenase (Complex I) and cytochrome c oxidase (Complex IV) enzyme activities]. Multivariable-adjusted logistic and linear regression analyses were employed adjusting for age, gender, CD4 nadir, viral load, smoking, diabetes, HOMA-IR, hypertension and lipid medications. Among 150 HIV-infected persons (mean age 52 years, 12% women, median CD4 count 524 cell/mm3), low HDL-C and high total cholesterol/HDL-C ratio were related to PBMC 8-oxo-deoxyguanine (p = 0.01 and 0.02 respectively). Large HDL-P and HDL-P size were inversely related to PBMC 8-oxo-deoxyguanine (p = 0.04). Small LDL-P (p = 0.01) and total LDL-P (p = 0.01) were related to decreased OXPHOS Complex I activity. LDL-P was related to decreased OXPHOS Complex IV activity (p = 0.02). Cholesterol efflux capacity was associated with increased OXPHOS Complex IV activity. Conclusions: HDL concentration and particle size and number are related to decreased PBMC mitochondrial oxidative stress whereas HDL function is positively related to mitochondrial oxidative function. The association we find between atherogenic lipoprotein profile and increased oxidative stress and function suggests these pathways may be important in the pathogenesis of cardiometabolic disease in HIV disease. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Parikh, Nisha I.; Bennett, Kara; Gangcuangco, Louie Mar M.; Nakamoto, Beau K.; Chow, Dominic C.; Shikuma, Cecilia M.] Univ Hawaii, John A Burns Sch Med, Dept Med, Hawaii Ctr AIDS, Honolulu, HI 96822 USA. [Parikh, Nisha I.] Univ Calif San Francisco, Div Cardiovasc, Dept Med, San Francisco, CA 94143 USA. [Gerschenson, Mariana; Lopez, Mary S.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Mehta, Nehal N.; Playford, Martin P.] NHLBI, Sect Inflammat & Cardiometabol Dis, NIH, Bethesda, MD 20892 USA. [Seto, Todd B.] Queens Med Ctr, Div Cardiovasc, Honolulu, HI USA. [Nakamoto, Beau K.] Straub Clin & Hosp, Dept Neurol, Honolulu, HI USA. RP Parikh, NI (reprint author), Univ Calif San Francisco, Div Cardiovasc, Dept Med, San Francisco, CA 94143 USA. EM nparikh@medicine.uscf.edu FU NIH [U54RR026136, U54MD007584, R01HL095135, K23 HL088981, P20MD000173, G12MD007601, P30103341] FX This work was supported by NIH grants U54RR026136, U54MD007584, R01HL095135 (CMS), K23 HL088981 (DC), P20MD000173, G12MD007601, P30103341 (MG). NR 23 TC 4 Z9 4 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAR PY 2015 VL 239 IS 1 BP 50 EP 54 DI 10.1016/j.atherosclerosis.2014.12.005 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CB6RH UT WOS:000349753800008 PM 25574857 ER PT J AU Salem, GH Dennis, JU Krynitsky, J Garmendia-Cedillos, M Swaroop, K Malley, JD Pajevic, S Abuhatzira, L Bustin, M Gillet, JP Gottesman, MM Mitchell, JB Pohida, TJ AF Salem, Ghadi H. Dennis, John U. Krynitsky, Jonathan Garmendia-Cedillos, Marcial Swaroop, Kanchan Malley, James D. Pajevic, Sinisa Abuhatzira, Liron Bustin, Michael Gillet, Jean-Pierre Gottesman, Michael M. Mitchell, James B. Pohida, Thomas J. TI SCORHE: A novel and practical approach to video monitoring of laboratory mice housed in vivarium cage racks SO BEHAVIOR RESEARCH METHODS LA English DT Article DE Video monitoring; Home-cage behavior; Mouse behavior; Mouse activity profiling ID MOUSE MODELS; BEHAVIOR; TRACKING; SYSTEM; HUNTINGTONS; AUTOMATION; RODENTS; BLIND; LIGHT AB The System for Continuous Observation of Rodents in Home-cage Environment (SCORHE) was developed to demonstrate the viability of compact and scalable designs for quantifying activity levels and behavior patterns for mice housed within a commercial ventilated cage rack. The SCORHE in-rack design provides day- and night-time monitoring with the consistency and convenience of the home-cage environment. The dual-video camera custom hardware design makes efficient use of space, does not require home-cage modification, and is animal-facility user-friendly. Given the system's low cost and suitability for use in existing vivariums without modification to the animal husbandry procedures or housing setup, SCORHE opens up the potential for the wider use of automated video monitoring in animal facilities. SCORHE's potential uses include day-to-day health monitoring, as well as advanced behavioral screening and ethology experiments, ranging from the assessment of the short- and long-term effects of experimental cancer treatments to the evaluation of mouse models. When used for phenotyping and animal model studies, SCORHE aims to eliminate the concerns often associated with many mouse-monitoring methods, such as circadian rhythm disruption, acclimation periods, lack of night-time measurements, and short monitoring periods. Custom software integrates two video streams to extract several mouse activity and behavior measures. Studies comparing the activity levels of ABCB5 knockout and HMGN1 overexpresser mice with their respective C57BL parental strains demonstrate SCORHE's efficacy in characterizing the activity profiles for singly- and doubly-housed mice. Another study was conducted to demonstrate the ability of SCORHE to detect a change in activity resulting from administering a sedative. C1 [Salem, Ghadi H.; Krynitsky, Jonathan; Garmendia-Cedillos, Marcial; Swaroop, Kanchan; Malley, James D.; Pajevic, Sinisa; Pohida, Thomas J.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Dennis, John U.] SAIC Frederick, Lab Anim Sci Program, Bethesda, MD USA. [Abuhatzira, Liron; Bustin, Michael] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gillet, Jean-Pierre; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Salem, GH (reprint author), NIH, Div Computat Biosci, Ctr Informat Technol, 12 South Dr,Bldg 12A,Room 2025, Bethesda, MD 20892 USA. EM salem@exchange.nih.gov RI Bustin, Michael/G-6155-2015 FU Intramural NIH HHS [Z99 CT999999] NR 30 TC 2 Z9 2 U1 3 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1554-351X EI 1554-3528 J9 BEHAV RES METHODS JI Behav. Res. Methods PD MAR PY 2015 VL 47 IS 1 BP 235 EP 250 DI 10.3758/s13428-014-0451-5 PG 16 WC Psychology, Mathematical; Psychology, Experimental SC Psychology GA CB9US UT WOS:000349979400018 PM 24706080 ER PT J AU Pavletic, SZ Vogelsang, GB Lee, SJ AF Pavletic, Steven Z. Vogelsang, Georgia B. Lee, Stephanie J. TI 2014 National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: Preface to the Series SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Editorial Material ID WORKING GROUP-REPORT; CHRONIC GVHD; DIAGNOSIS C1 [Pavletic, Steven Z.] Natl Canc Inst, Bethesda, MD 20892 USA. [Vogelsang, Georgia B.] Johns Hopkins Sch Med, Baltimore, MD USA. [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Pavletic, SZ (reprint author), Natl Canc Inst, 9000 Rockville Pike,10-CRC-3-3330, Bethesda, MD 20892 USA. EM pavletis@mail.nih.gov NR 10 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2015 VL 21 IS 3 BP 387 EP 388 DI 10.1016/j.bbmt.2014.12.035 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CC0EV UT WOS:000350009500003 PM 25572033 ER PT J AU Jagasia, MH Greinix, HT Arora, M Williams, KM Wolff, D Cowen, EW Palmer, J Weisdorf, D Treister, NS Cheng, GS Kerr, H Stratton, P Duarte, RF McDonald, GB Inamoto, Y Vigorito, A Arai, S Datiles, MB Jacobsohn, D Heller, T Kitko, CL Mitchell, SA Martin, PJ Shulman, H Wu, RS Cutler, CS Vogelsang, GB Lee, SJ Pavletic, SZ Flowers, MED AF Jagasia, Madan H. Greinix, Hildegard T. Arora, Mukta Williams, Kirsten M. Wolff, Daniel Cowen, Edward W. Palmer, Jeanne Weisdorf, Daniel Treister, Nathaniel S. Cheng, Guang-Shing Kerr, Holly Stratton, Pamela Duarte, Rafael F. McDonald, George B. Inamoto, Yoshihiro Vigorito, Afonso Arai, Sally Datiles, Manuel B. Jacobsohn, David Heller, Theo Kitko, Carrie L. Mitchell, Sandra A. Martin, Paul J. Shulman, Howard Wu, Roy S. Cutler, Corey S. Vogelsang, Georgia B. Lee, Stephanie J. Pavletic, Steven Z. Flowers, Mary E. D. TI National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; National Institutes of Health; Diagnosis; Staging ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; CHRONIC GVHD CONSORTIUM; RISK-FACTORS; NONRELAPSE MORTALITY; SURVIVAL; SEVERITY; OUTCOMES; SCORE; ORGAN AB The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Jagasia, Madan H.] Vanderbilt Univ, Med Ctr, Dept Hematol & Oncol, Nashville, TN 37235 USA. [Greinix, Hildegard T.] Med Univ Vienna, Dept Internal Med, Vienna, Austria. [Arora, Mukta; Weisdorf, Daniel] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Williams, Kirsten M.; Cowen, Edward W.; Pavletic, Steven Z.] Ctr Canc Res, Natl Canc Inst, NIH, Bethesda, MD USA. [Williams, Kirsten M.; Jacobsohn, David] Childrens Natl Hlth Syst, Dept Blood & Marrow Transplantat, Washington, DC USA. [Weisdorf, Daniel] Univ Regensburg, Dept Internal Med, D-93053 Regensburg, Germany. [Palmer, Jeanne] Mayo Clin Arizona, Dept Hematol Oncol Blood & Marrow Transplant, Phoenix, AZ USA. [Treister, Nathaniel S.] Brigham & Womens Hosp, Dept Surg, Div Oral Med & Dent, Boston, MA 02115 USA. [Cheng, Guang-Shing; McDonald, George B.; Martin, Paul J.; Shulman, Howard; Lee, Stephanie J.; Flowers, Mary E. D.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Kerr, Holly] BC Canc Agcy, Dept Hematol, Vancouver, BC, Canada. [Stratton, Pamela] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. [Duarte, Rafael F.] Inst Catala Oncol, Dept Hematol, Barcelona, Spain. [Inamoto, Yoshihiro] Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo, Japan. [Vigorito, Afonso] Hemoctr Unicamp, Hematol & Hemotherapy Ctr, Campinas, SP, Brazil. [Arai, Sally] Stanford Univ, Med Ctr, Dept Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Datiles, Manuel B.] NIH, Natl Eye Inst, Eye Clin, Bethesda, MD 20892 USA. [Heller, Theo] NIH, Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Branch, Bethesda, MD 20892 USA. [Kitko, Carrie L.] Univ Michigan, Ctr Comprehens Canc, Blood & Marrow Transplant Program, Ann Arbor, MI 48109 USA. [Mitchell, Sandra A.] NIH, Dept Appl Res Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Wu, Roy S.] NIH, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Cutler, Corey S.] Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA USA. [Vogelsang, Georgia B.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. RP Flowers, MED (reprint author), Fred Hutchinson Canc Res Ctr, D5-290 POB 19024, Seattle, WA 98109 USA. EM mflowers@fredhutch.org OI Datiles, Manuel III B./0000-0003-4660-1664 FU NIH's National Cancer Institute, Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research, National Center for Advancing Translational Sciences; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; National Cancer Institute [CA18029, CA118953]; National Institutes of Health FX This project was supported by the NIH's National Cancer Institute, Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research, National Center for Advancing Translational Sciences; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources. This work was also supported in part by grants CA18029 and CA118953 from the National Cancer Institute and the National Institutes of Health. The authors want to acknowledge the following individuals and organizations that, by their participation, made this project possible: American Society for Blood and Marrow Transplantation, Center for International Bone and Marrow Transplant Research, US Chronic GVHD Consortium (supported by ORDR/NCATS and NCI), German-Austrian-Swiss chronic GVHD Consortium, National Marrow Donor Program, the Health Resources and Services Administration, Division of Transplantation, US Department of Human Health and Services, Canadian Blood and Marrow Transplant Group, European Group for Blood and Marrow Transplantation, Pediatric Blood and Marrow Transplant Consortium, and the representatives of the Brazilian Chronic GVHD consortium (Drs. Maria Claudia Moreira, Marcia de Matos Silva and Vaneuza Funke) and Deutsche Jose Carreras Leukamie-Stiftung. The authors would like to thank Dr. Joseph Antin (Dana Farber Cancer Center, Boston, MA) and Dr. Gerard Socie (University Paris VII & AP-HP, Hospital Saint Louis, Paris, France) for their critical review of the manuscript. The authors also thank Marcie Hall for careful review of the manuscript. The organizers are in debt to patients and patient and research advocacy groups, who made this process much more meaningful by their engagement. Acknowledgement goes to the Meredith Cowden GVHD foundation for facilitating the initial planning meeting in Cleveland in November of 2013 in conjunction with the National GVHD Symposium. The project group also recognizes the contributions of numerous colleagues in the field of blood and marrow transplantation in the US and internationally, medical specialists and consultants, the pharmaceutical industry, and the NIH and US Food and Drug Administration professional staff for their intellectual input, dedication, and enthusiasm on the road to completion of these documents. For their expert contributions to this 2014 NIH Consensus Diagnosis and Staging Working Group document special acknowledgements go to Drs. Mark Schubert, Fred Hutchinson Cancer Research Center in Seattle, WA, Tina Dietrich-Ntoukas, University of Regensburg, Germany, Janine Clayton, National Eye Institute, NIH, Bethesda, MD, Melissa A. Merideth, National Human Genome Research Institute, NIH, Bethesda, MD, Tajana Klepac Pulanic, Community Health Center East, Zagreb, Croatia, and Robert Knobler, University of Vienna, Austria. NR 51 TC 87 Z9 90 U1 6 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2015 VL 21 IS 3 BP 389 EP 401 DI 10.1016/j.bbmt.2014.12.001 PG 13 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CC0EV UT WOS:000350009500004 PM 25529383 ER PT J AU Kent, EE Ambs, A Mitchell, SA Clauser, SB Smith, AW Hays, RD AF Kent, Erin E. Ambs, Anita Mitchell, Sandra A. Clauser, Steven B. Smith, Ashley Wilder Hays, Ron D. TI Health-Related Quality of Life in Older Adult Survivors of Selected Cancers: Data From the SEER-MHOS Linkage SO CANCER LA English DT Article DE epidemiology; neoplasms; older adult; quality of life; rare diseases ID ELDERLY-PATIENTS; OUTCOMES RESEARCH; LUNG-CANCER; POPULATION; INSTRUMENTS AB BACKGROUNDResearch on health-related quality of life (HRQOL) among older adult cancer survivors is mostly confined to breast cancer, prostate cancer, colorectal cancer, and lung cancer, which account for 63% of all prevalent cancers. Much less is known about HRQOL in the context of less common cancer sites. METHODSHRQOL was examined with the 36-Item Short Form Health Survey, version 1, and the Veterans RAND 12-Item Health Survey in patients with selected cancers (kidney cancer, bladder cancer, pancreatic cancer, upper gastrointestinal cancer, cancer of the oral cavity and pharynx, uterine cancer, cervical cancer, thyroid cancer, melanoma, chronic leukemia, non-Hodgkin lymphoma, and multiple myeloma) and in individuals without cancer on the basis of data linked from the Surveillance, Epidemiology, and End Results cancer registry system and the Medicare Health Outcomes Survey. Scale scores, Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, and a utility metric (Short Form 6D/Veterans RAND 6D), adjusted for sociodemographic characteristics and other chronic conditions, were calculated. A 3-point difference in the scale scores and a 2-point difference in the PCS and MCS scores were considered to be minimally important differences. RESULTSData from 16,095 cancer survivors and 1,224,549 individuals without a history of cancer were included. The results indicated noteworthy deficits in physical health status. Mental health was comparable, although scores for the Role-Emotional and Social Functioning scales were worse for patients with most types of cancer versus those without cancer. Survivors of multiple myeloma and pancreatic malignancies reported the lowest scores, with their PCS/MCS scores less than those of individuals without cancer by 3 or more points. CONCLUSIONSHRQOL surveillance efforts revealed poor health outcomes among many older adults and specifically among survivors of multiple myeloma and pancreatic cancer. Cancer 2015;121:758-765. (c) 2014 American Cancer Society. The health-related quality of life of older adult survivors of less common cancers is compared to the health-related quality of life of older individuals with no cancer history on the basis of data from the Surveillance, Epidemiology, and End Results/Medicare Health Outcomes Survey linked data resource. Inferior health-related quality of life (particularly impaired physical health) is found among survivors of several cancer types; the greatest deficits are reported by those with multiple myeloma and pancreatic cancer. C1 [Kent, Erin E.; Ambs, Anita; Mitchell, Sandra A.; Clauser, Steven B.; Smith, Ashley Wilder] NCI, Appl Res Program, Rockville, MD 20850 USA. [Hays, Ron D.] Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA. RP Kent, EE (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM erin.kent@nih.gov FU National Institute on Aging [P30-AG021684]; National Institute on Minority Health and Health Disparities [P20MD000182] FX Ron D. Hays was supported in part by grants from the National Institute on Aging (P30-AG021684) and the National Institute on Minority Health and Health Disparities (P20MD000182). NR 39 TC 8 Z9 8 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD MAR 1 PY 2015 VL 121 IS 5 BP 758 EP 765 DI 10.1002/cncr.29119 PG 8 WC Oncology SC Oncology GA CB9WY UT WOS:000349986100016 PM 25369293 ER PT J AU Yang, HP Schneider, SS Chisholm, CM Browne, EP Mahmood, S Gierach, GL Lenington, S Anderton, DL Sherman, ME Arcaro, KF AF Yang, Hannah P. Schneider, Sallie Smith Chisholm, Christina M. Browne, Eva P. Mahmood, Sidra Gierach, Gretchen L. Lenington, Sarah Anderton, Douglas L. Sherman, Mark E. Arcaro, Kathleen F. TI Association of TGF-beta 2 levels in breast milk with severity of breast biopsy diagnosis SO CANCER CAUSES & CONTROL LA English DT Article DE TGF-beta 2; Breast milk; Breast cancer; Epidemiology ID GROWTH-FACTOR-BETA; CANCER-ASSOCIATED PROTEINS; TGF-BETA; DIFFERENTIAL EXPRESSION; MAMMARY-GLAND; WOMEN; INFANT; CARCINOGENESIS; PREGNANCY; RISK AB TGF-beta plays a dual role in breast carcinogenesis, acting at early stages as tumor-suppressors and later as tumor-promoters. TGF-beta isoforms are expressed in breast tissues and secreted in milk, suggesting that analysis of levels in milk might be informative for breast cancer risk. Accordingly, we assessed TGF-beta 2 levels in milk from women who had undergone a breast biopsy and related the concentrations to diagnosis. Milk donated by women who had undergone or were scheduled for a breast biopsy was shipped on ice for processing and testing. Breast cancer risk factors were obtained through a self-administered questionnaire, and biopsy diagnoses were extracted from pathology reports. TGF-beta 2 levels in milk, assessed as absolute levels and in relation to total protein, were analyzed in bilateral samples donated by 182 women. Linear regression was used to estimate relationships of log-transformed TGF-beta 2 levels and TGF-beta 2/ total protein ratios to biopsy category. Milk TGF-beta 2 levels from biopsied and non-biopsied breasts within women were highly correlated (r (2) = 0.77). Higher mean TGF-beta 2 milk levels (based on average of bilateral samples) were marginally associated with more severe breast pathological diagnosis, after adjusting for duration of nursing current child (adjusted p trend = 0.07). Our exploratory analysis suggests a borderline significant association between higher mean TGF-beta 2 levels in breast milk and more severe pathologic diagnoses. Further analysis of TGF-beta signaling in milk may increase understanding of postpartum remodeling and advance efforts to analyze milk as a means of assessing risk of breast pathology. C1 [Yang, Hannah P.; Gierach, Gretchen L.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Schneider, Sallie Smith] Pioneer Valley Life Sci Inst, Springfield, MA USA. [Chisholm, Christina M.; Browne, Eva P.; Lenington, Sarah; Arcaro, Kathleen F.] Univ Massachusetts, Amherst, MA 01003 USA. [Mahmood, Sidra] Mt Holyoke Coll, S Hadley, MA 01075 USA. [Anderton, Douglas L.] Univ S Carolina, Columbia, SC 29208 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Yang, HP (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 7E-238, Bethesda, MD 20892 USA. EM yanghan@mail.nih.gov RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU CDMRP [W81XWH-08-1-0721]; Avon Foundation for Women; Intramural Research Program of NCI's Division of Cancer Epidemiology and Genetics FX This work was supported by awards from the CDMRP (W81XWH-08-1-0721) and The Avon Foundation for Women to KFA and the Intramural Research Program of NCI's Division of Cancer Epidemiology and Genetics. NR 29 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAR PY 2015 VL 26 IS 3 BP 345 EP 354 DI 10.1007/s10552-014-0498-8 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CB9OP UT WOS:000349961500003 PM 25604865 ER PT J AU Weitmann, K Hirt, C Schwarz, S Rabkin, C Dolken, G Hoffmann, W AF Weitmann, Kerstin Hirt, Carsten Schwarz, Sabine Rabkin, Charles Doelken, Gottfried Hoffmann, Wolfgang TI Influence of reproductive history and exogenous hormone use on prevalence and frequency of circulating t(14;18)-positive cells in a population-based cross-sectional study SO CANCER CAUSES & CONTROL LA English DT Article DE t(14;18) translocation; Healthy individuals; Reproductive history; Exogenous hormone use ID NON-HODGKIN-LYMPHOMA; POLYMERASE-CHAIN-REACTION; HEALTHY-INDIVIDUALS; FOLLICULAR LYMPHOMA; B-CELL; PERIPHERAL-BLOOD; UNITED-STATES; SEX-HORMONES; RISK; WOMEN AB The t(14;18) translocation might represent an intermediate step in the pathogenesis of follicular lymphoma (FL), one of the most common subtypes of non-Hodgkin lymphoma. Circulating t(14;18)-positive cells can also be detected in 30-60 % of healthy individuals at low frequencies. Some studies found a negative association between reproductive factors or use of menopausal hormone therapy (MHT) with FL. The objective of this study was to evaluate whether there is an association between number of frequencies, oral contraceptive (OC) use, menopausal status and MHT, and t(14;18) prevalence and frequency in a representative population analysis based on an epidemiologic study in the northeastern part of Germany. The analysis is based on results of buffy coat samples from 1,981 women of the Study of Health in Pomerania (SHIP-0) and data obtained in standardized face-to-face interviews. For prevalence, odds ratios (OR) and 95 % confidence intervals (CI) were calculated using unconditional logistic regression. Frequency data were analyzed using negative binomial regression. The multivariable models included age, number of pregnancies, menopausal status (premenopausal, natural, medical/surgical menopause), OC use and MHT as a measure for exogenous hormone exposure use. We found no association between reproductive history and combined exogenous hormone use on the prevalence of circulating t(14;18)-positive cells. Modeling MHT and OC use separately in a sensitivity analysis, the MHT parameter yielded statistical significance [OR 1.37 (95 % CI 1.04;1.81)]. t(14;18) frequency was associated with use of OC [incidence rate ratio (IRR) for ever use 3.18 (95 % CI 1.54;6.54)], current use [IRR 3.86 (1.56;9.54)], > 10 years use [IRR 3.93 (1.67;9.23)] and MHT [restricted to postmenopausal women; IRR 2.63 (95 % CI 1.01;6.85)] in bivariate age-adjusted analyses. In the multivariable model, medical/surgical menopause [IRR 2.46 (1.11;5.44)] and the category ever use of OC and MHT were statistically significant [IRR 2.41 (1.09;5.33)]. Exogenous hormone use might be a risk factor for t(14;18) frequency rather than for t(14;18) prevalence. Further research on healthy individuals carrying a t(14;18) translocation and possible risk factors for malignant lymphoma is necessary to determine the additional molecular or immunological events that have to occur to develop FL. C1 [Weitmann, Kerstin; Doelken, Gottfried; Hoffmann, Wolfgang] Univ Med Greifswald, Inst Community Med, Dept Epidemiol Hlth Care & Community Hlth, D-17487 Greifswald, Germany. [Hirt, Carsten] Univ Med Greifswald, Dept Haematol & Oncol, D-17487 Greifswald, Germany. [Schwarz, Sabine] German Agcy Qual Med AZQ, Berlin, Germany. [Rabkin, Charles] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Weitmann, K (reprint author), Univ Med Greifswald, Inst Community Med, Dept Epidemiol Hlth Care & Community Hlth, Ellernholzstr 1-2, D-17487 Greifswald, Germany. EM kerstin.weitmann@uni-greifswald.de FU Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania FX The authors greatly acknowledge the excellent technical assistance of Ute Pett, who prepared the biosamples. SHIP is part of the Community Medicine Research net of the University Medicine Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grants Nos. 01ZZ9603, 01ZZ0103, 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. NR 55 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAR PY 2015 VL 26 IS 3 BP 455 EP 465 DI 10.1007/s10552-015-0525-4 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CB9OP UT WOS:000349961500013 PM 25634026 ER PT J AU O'Mara, A AF O'Mara, Ann TI What Is Cancer Nursing Research? SO CANCER NURSING LA English DT Editorial Material ID PRESERVES MUSCLE MASS; LEWIS LUNG-CARCINOMA; MICE BEARING; GASTROCNEMIUS-MUSCLE; B16 MELANOMA C1 NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP O'Mara, A (reprint author), NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0162-220X EI 1538-9804 J9 CANCER NURS JI Cancer Nurs. PD MAR-APR PY 2015 VL 38 IS 2 BP 81 EP 82 DI 10.1097/NCC.0000000000000228 PG 2 WC Oncology; Nursing SC Oncology; Nursing GA CB8UV UT WOS:000349907900007 PM 25689041 ER PT J AU Mazan-Mamczarz, K Peroutka, RJ Steinhardt, JJ Gidoni, M Zhang, YQ Lehrmann, E Landon, AL Dai, BJ Houng, S Muniandy, PA Efroni, S Becker, KG Gartenhaus, RB AF Mazan-Mamczarz, Krystyna Peroutka, Raymond J. Steinhardt, James J. Gidoni, Moriah Zhang, Yongqing Lehrmann, Elin Landon, Ari L. Dai, Bojie Houng, Simone Muniandy, Parameswary A. Efroni, Sol Becker, Kevin G. Gartenhaus, Ronald B. TI Distinct inhibitory effects on mTOR signaling by ethanol and INK128 in diffuse large B-cell lymphoma SO CELL COMMUNICATION AND SIGNALING LA English DT Article DE mTOR signaling; Translation; EtOH; INK128; DLBCL; Gene expression ID NON-HODGKIN-LYMPHOMA; MESSENGER-RNA TRANSLATION; ALCOHOL-CONSUMPTION; MAMMALIAN TARGET; STRESS GRANULES; RAPAMYCIN MTOR; ANTITUMOR-ACTIVITY; P70S6 KINASE; PHOSPHORYLATION; RISK AB Background: The mechanistic target of rapamycin, (mTOR) kinase plays a pivotal role in controlling critical cellular growth and survival pathways, and its aberrant induction is implicated in cancer pathogenesis. Therefore, suppression of active mTOR signaling has been of great interest to researchers; several mTOR inhibitors have been discovered to date. Ethanol (EtOH), similar to pharmacologic mTOR inhibitors, has been shown to suppress the mTOR signaling pathway, though in a non-catalytic manner. Despite population studies showing that the consumption of EtOH has a protective effect against hematological malignancies, the mechanisms behind EtOH's modulation of mTOR activity in cells and its downstream consequences are largely unknown. Here we evaluated the effects of EtOH on the mTOR pathway, in comparison to the active-site mTOR inhibitor INK128, and compared translatome analysis of their downstream effects in diffuse large B-cell lymphoma (DLBCL). Results: Treatment of DLBCL cells with EtOH suppressed mTORC1 complex formation while increasing AKT phosphorylation and mTORC2 complex assembly. INK128 completely abrogated AKT phosphorylation without affecting the structure of mTORC1/2 complexes. Accordingly, EtOH less profoundly suppressed cap-dependent translation and global protein synthesis, compared to a remarkable inhibitory effect of INK128 treatment. Importantly, EtOH treatment induced the formation of stress granules, while INK128 suppressed their formation. Microarray analysis of polysomal RNA revealed that although both agents primarily affected cell growth and survival, EtOH and INK128 regulated the synthesis of mostly distinct genes involved in these processes. Though both EtOH and INK128 inhibited cell cycle, proliferation and autophagy, EtOH, in contrast to INK128, did not induce cell apoptosis. Conclusion: Given that EtOH, similar to pharmacologic mTOR inhibitors, inhibits mTOR signaling, we systematically explored the effect of EtOH and INK128 on mTOR signal transduction, components of the mTORC1/2 interaction and their downstream effectors in DLBCL malignancy. We found that EtOH partially inhibits mTOR signaling and protein translation, compared to INK128' s complete mTOR inhibition. Translatome analysis of mTOR downstream target genes established that differential inhibition of mTOR by EtOH and INK128 distinctly modulates translation of specific subsets of mRNAs involved in cell growth and survival, leading to differential cellular response and survival. C1 [Mazan-Mamczarz, Krystyna; Peroutka, Raymond J.; Steinhardt, James J.; Landon, Ari L.; Dai, Bojie; Houng, Simone; Muniandy, Parameswary A.; Gartenhaus, Ronald B.] Univ Maryland, Dept Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Gidoni, Moriah; Efroni, Sol] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-5290002 Ramat Gan, Israel. [Zhang, Yongqing; Lehrmann, Elin; Becker, Kevin G.] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA. [Gartenhaus, Ronald B.] Vet Adm Med Ctr, Baltimore, MD 21201 USA. RP Gartenhaus, RB (reprint author), Univ Maryland, Dept Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. EM rgartenhaus@som.umaryland.edu FU Department of Veterans Affairs (Merit Review Award) FX We are grateful to the University of Maryland Greenebaum Cancer Center Core Flow Cytometry Facility for performing flow cytometric analyses. We also thank our colleague W. H. Wood for providing expert technical assistance. This work was supported in part by the Department of Veterans Affairs (Merit Review Award; R. B. G) and the National institutes of Health (R01AA017972 and R01CA164311; R. B. G). This research was also supported in part by the Intramural Research Program at the National Institute on Aging, National Institutes of Health (Y. Z., E. L., K. G. B). NR 59 TC 4 Z9 4 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-811X J9 CELL COMMUN SIGNAL JI Cell Commun. Signal. PD MAR 1 PY 2015 VL 13 AR 15 DI 10.1186/s12964-015-0091-0 PG 17 WC Cell Biology SC Cell Biology GA CC6SU UT WOS:000350499400001 PM 25849580 ER PT J AU Eiden, RD Molnar, DS Granger, DA Colder, CR Schuetze, P Huestis, MA AF Eiden, Rina D. Molnar, Danielle S. Granger, Douglas A. Colder, Craig R. Schuetze, Pamela Huestis, Marilyn A. TI Prenatal Tobacco Exposure and Infant Stress Reactivity: Role of Child Sex and Maternal Behavior SO DEVELOPMENTAL PSYCHOBIOLOGY LA English DT Article DE infant cortisol; prenatal tobacco exposure; sex differences; mother-infant interactions ID PITUITARY-ADRENAL AXIS; ADRENOCORTICAL RESPONSES; INDIVIDUAL-DIFFERENCES; 6-MONTH-OLD INFANTS; CORTISOL REACTIVITY; SALIVARY CORTISOL; ALLOSTATIC LOAD; CORD BLOOD; SMOKING; PREGNANCY AB This study examined the association between prenatal tobacco exposure (PTE) and infant cortisol reactivity at 9 months of infant age. Child sex and maternal parenting behavior were hypothesized moderators. The sample included 217 (148 tobacco-exposed, 69 non-exposed) mother-child dyads. Data used were obtained from pregnancy assessments, mother-infant feeding interactions at 2 months, and salivary cortisol at four time points in response to frustration at 9 months. Results indicated a significant association between PTE and infant cortisol that was moderated by infant sex and maternal intrusiveness. That is, PTE boys had lower cortisol than control boys, but there was no association between PTE and cortisol among girls. There was a significant association between PTE and cortisol among infants of intrusive mothers, but not among infants with non-intrusive mothers. Thus, PTE was associated with cortisol hypo-reactivity such that boys and non-exposed infants experiencing high maternal intrusiveness were at greater risk. (c) 2015 Wiley Periodicals, Inc. Dev Psychobiol 57: 212-225, 2015. C1 [Eiden, Rina D.; Molnar, Danielle S.] SUNY Buffalo, Res Inst Addict, Buffalo, NY 14260 USA. [Granger, Douglas A.] Arizona State Univ, Inst Interdisciplinary Salivary Biosci Res, Tempe, AZ USA. [Granger, Douglas A.] Johns Hopkins Univ, Sch Nursing, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Colder, Craig R.] SUNY Buffalo, Dept Psychol, Buffalo, NY 14260 USA. [Schuetze, Pamela] SUNY Coll Buffalo, Dept Psychol, Buffalo, NY 14222 USA. [Huestis, Marilyn A.] NIDA, NIH, Baltimore, MD USA. RP Eiden, RD (reprint author), 1021 Main St, Buffalo, NY 14203 USA. EM eiden@ria.buffalo.edu FU National Institute on Drug Abuse at the National Institutes of Health [R01DA019632]; Intramural Research Program FX The authors are grateful to the families who participated in the study and to Research Technicians for data collection and coding. Special thanks goes to Dr. Amol Lele at Women and Children's Hospital of Buffalo for her collaboration on data collection. The study was supported by the National Institute on Drug Abuse at the National Institutes of Health under award number R01DA019632 and the Intramural Research Program. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 52 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1630 EI 1098-2302 J9 DEV PSYCHOBIOL JI Dev. Psychobiol. PD MAR PY 2015 VL 57 IS 2 BP 212 EP 225 DI 10.1002/dev.21284 PG 14 WC Developmental Biology; Psychology SC Developmental Biology; Psychology GA CB9QW UT WOS:000349968100007 PM 25650169 ER PT J AU Bianconi, SE Cross, JL Wassif, CA Porter, FD AF Bianconi, Simona E. Cross, Joanna L. Wassif, Christopher A. Porter, Forbes D. TI Pathogenesis, epidemiology, diagnosis and clinical aspects of Smith-Lemli-Opitz syndrome SO EXPERT OPINION ON ORPHAN DRUGS LA English DT Review DE cholesterol metabolism; congenital malformation syndrome; 7-dehydrocholesterol reductase; inborn error of metabolism; malformation syndrome; Smith-Lemli-Opitz syndrome ID CHROMATOGRAPHY-MASS-SPECTROMETRY; DEFECTIVE CHOLESTEROL-BIOSYNTHESIS; SYNDROME SLOS; REDUCTASE GENE; 7-DEHYDROCHOLESTEROL REDUCTASE; DELTA-7-STEROL REDUCTASE; ADRENAL INSUFFICIENCY; SIMVASTATIN TREATMENT; SYNDROME FIBROBLASTS; DIETARY-CHOLESTEROL AB Introduction: Smith-Lemli-Opitz syndrome (SLOS) is a malformation syndrome inherited in an autosomal recessive fashion. It is due to a metabolic defect in the conversion of 7-dehydrocholesterol to cholesterol, which leads to an accumulation of 7-dehydrocholesterol and frequently a deficiency of cholesterol. The syndrome is characterized by typical dysmorphic facial features, multiple malformations, and intellectual disability. Areas covered: In this paper we provide an overview of the clinical phenotype and discuss how the manifestations of the syndrome vary depending on the age of the patients. We then explore the underlying biochemical defect and pathophysiological alterations that may contribute to the many disease manifestations. Subsequently we explore the epidemiology and succinctly discuss population genetics as they relate to SLOS. The next section presents the diagnostic possibilities. Thereafter, the treatment and management as is standard of care are presented. Expert opinion: Even though the knowledge of the underlying molecular mutations and the biochemical alterations is being rapidly accumulated, there is currently no efficacious therapy addressing neurological dysfunction. We discuss the difficulty of treating this disorder, which manifests as a combination of a malformation syndrome and an inborn error of metabolism. A very important factor in developing new therapies is the need to rigorously establish efficacy in controlled trials. C1 [Bianconi, Simona E.] NICHHD, Program Dev Endocrinol & Genet, Sect Mol Dysmorphol, Bethesda, MD 20892 USA. [Cross, Joanna L.; Wassif, Christopher A.] NICHHD, Program Dev Endocrinol & Genet, Sect Mol Dysmorphol, Bethesda, MD 20892 USA. [Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Porter, FD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, 10 Ctr Dr,Bld 10,CRC,Rm 2571, Bethesda, MD 20892 USA. EM fdporter@mail.nih.gov OI Wassif, Christopher/0000-0002-2524-1420 FU Wellcome Trust/NIH Studentship; intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX JL Cross is co-supervised in her studies by Professor Frances Platt, University of Oxford, and is a recipient of a Wellcome Trust/NIH Studentship. FD Porter, CA Wassif and S Bianconi are supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 114 TC 5 Z9 5 U1 3 U2 13 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 2167-8707 J9 EXPERT OPIN ORPHAN D JI Exp. Opin. Orphan Drugs PD MAR PY 2015 VL 3 IS 3 BP 267 EP 280 DI 10.1517/21678707.2015.1014472 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC1MZ UT WOS:000350106400004 PM 25734025 ER PT J AU Potter, WZ AF Potter, William Z. TI Optimizing early Go/No Go decisions in CNS drug development SO EXPERT REVIEW OF CLINICAL PHARMACOLOGY LA English DT Editorial Material DE brain target engagement; CNS drug development; Go/No Go decisions; mechanistic hypotheses; RDoC ID DISEASE AB Go/No Go decisions concerning development of any single compound determine investment in increasingly costly studies from Phases I-III. Such decisions are problematic for CNS drug development where the variety of molecular targets in the brain have stimulated decades of studies without major therapeutic advances. Many costly studies do not even yield interpretable results as to whether the mechanism being pursued has therapeutic potential. Therefore, both industry and the public sector have implemented a decision making strategy based on whether a compound can test a molecular hypothesis of drug action. One requires, at a minimum, compelling evidence in humans that a compound both interacts with its presumed molecular targets in brain and ideally documents a CNS functional consequence of the interaction prior to efficacy studies. This strategy will much more quickly rule out ineffective mechanisms although it does not address the problem of poorly predictive models of novel CNS drug efficacy. C1 NIMH, Bethesda, MD 20892 USA. RP Potter, WZ (reprint author), NIMH, Bethesda, MD 20892 USA. EM bill.potter@nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 9 TC 2 Z9 2 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1751-2433 EI 1751-2441 J9 EXPERT REV CLIN PHAR JI Expert Rev. Clin. Pharmacol. PD MAR PY 2015 VL 8 IS 2 BP 155 EP 157 DI 10.1586/17512433.2015.991715 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC0JW UT WOS:000350022600001 PM 25537256 ER PT J AU Coyne, KS Sexton, CC Thompson, C Bavendam, T Brubaker, L AF Coyne, Karin S. Sexton, Chris C. Thompson, Christine Bavendam, Tamara Brubaker, Linda TI Development and psychometric evaluation of the urgency questionnaire for evaluating severity and health-related quality of life impact of urinary urgency in overactive bladder SO INTERNATIONAL UROGYNECOLOGY JOURNAL LA English DT Article DE OAB; Qualitative; Questionnaire; Urinary urgency; Validation; Symptoms; HRQL ID TRACT SYMPTOMS; TEST-RETEST; OAB-Q; RELIABILITY; PERCEPTION; VALIDATION; SENSATION; WOMEN; SCALE; USIQ AB Urinary urgency is the cardinal symptom of overactive bladder (OAB). However, there is no single instrument that assesses the context, severity, intensity, and daily life impact of urinary urgency. The purpose of this manuscript is to describe the methods and results of the qualitative and quantitative research conducted to develop a new tool for this purpose, the Urgency Questionnaire (UQ). Qualitative data from interviews with patients with urinary urgency were used to develop and refine the items and response options of the UQ. Three studies were used to evaluate psychometric properties: a clinical trial of tolterodine (Detrol; n = 974); a psychometric validation study (n = 163); and a test-retest validation study (n = 47). Item and exploratory factor analysis (EFA) were performed to assess the subscale structure, and the psychometric performance of the resulting scales was evaluated. Fifteen Likert-scale items and four VAS questions were retained. A four-factor solution was shown to best fit the data, with the subscales: Impact on Daily Activities, Time to Control Urgency, Nocturia, and Fear of Incontinence. All subscales and VAS items demonstrated good reliability (Cronbach's alpha 0.79-0.94), convergent and discriminant validity, and responsiveness to change. The UQ differentiated between OAB patients and controls. The results provide quantitative evidence that urinary urgency, as assessed by the UQ, is a pathological sensation distinctive from the normal urge to void and suggest that the UQ might be a reliable, valid, and responsive instrument for evaluating the severity and HRQL impact of urinary urgency in OAB. C1 [Coyne, Karin S.; Sexton, Chris C.; Thompson, Christine] Evidera, Bethesda, MD 20814 USA. [Bavendam, Tamara] NIDDK, NIH, Bethesda, MD 20892 USA. [Brubaker, Linda] Loyola Univ Chicago, Stritch Sch Med, Maywood, IL USA. RP Coyne, KS (reprint author), Evidera, 7101 Wisconsin Ave,Suite 600, Bethesda, MD 20814 USA. EM karin.coyne@evidera.com FU Pfizer FX Funding for this work was provided by Pfizer. NR 35 TC 2 Z9 2 U1 1 U2 2 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-3462 EI 1433-3023 J9 INT UROGYNECOL J JI Int. Urogynecol. J. PD MAR PY 2015 VL 26 IS 3 BP 373 EP 382 DI 10.1007/s00192-014-2435-5 PG 10 WC Obstetrics & Gynecology; Urology & Nephrology SC Obstetrics & Gynecology; Urology & Nephrology GA CB9MV UT WOS:000349956700010 PM 24942375 ER PT J AU Bian, JH Du, SY Wu, Y Cao, YF Nie, XH He, H You, ZB AF Bian, Jiang-Hui Du, Shou-Yang Wu, Yan Cao, Yi-Fan Nie, Xu-Heng He, Hui You, Zhi-Bing TI Maternal effects and population regulation: maternal density-induced reproduction suppression impairs offspring capacity in response to immediate environment in root voles Microtus oeconomus SO JOURNAL OF ANIMAL ECOLOGY LA English DT Article DE ecological stressor; environmental mismatch; glucocorticoid metabolites; maternal matching; none-genetic phenotypic effects; population self-regulation ID PREDATOR-INDUCED STRESS; LIFE-HISTORY TRAITS; CLETHRIONOMYS-GLAREOLUS; CHITTY HYPOTHESIS; SMALL MAMMALS; BANK VOLES; CYCLES; ECOLOGY; HORMONES; DYNAMICS AB 1. The hypothesis that maternal effects act as an adaptive bridge in translating maternal environments into offspring phenotypes, and thereby affecting population dynamics has not been studied in the well-controlled fields. In this study, the effects of maternal population density on offspring stress axis, reproduction and population dynamics were studied in root voles (Microtus oeconomus). Parental enclosures for breeding offspring were established by introducing six adults per sex into each of 4 (low density) and 30 adults per sex into each of another 4 (high density) enclosures. Live-trapping started 2weeks after. Offspring captured at age of 20-30 days were removed to the laboratory, housed under laboratory conditions until puberty, and subsequently used to establish offspring populations in these same enclosures, after parental populations had been removed. [Correction added on 8 January 2015 after first online publication: 10-20 days' has been changed to 20-30 days.'] Offspring from each of the two parental sources were assigned into four enclosures with two for each of the two density treatments used in establishing parental populations (referred to as LL and LH for maternally unstressed offspring, assigned in low and highdensity, and HL and HH for maternally stressed offspring, assigned in low and high density). Faecal corticosterone metabolites (FCM) levels, offspring reproduction traits and population dynamics were tested following repeated live-trapping over two seasons. Differential fluctuations in population size were observed between maternally density-stressed and density-unstressed offspring. Populations in LL and LH groups changed significantly in responding to initial density and reached the similar levels at beginning of the second trapping season. Populations in HL and HH groups, however, were remained relatively steady, and in HL group, the low population size was sustained until end of experiment. Maternal density stress was associated with FCM elevations, reproduction suppression and body mass decrease at sexual maturity in offspring. The FCM elevations and reproduction suppression were independent of offspring population density and correlated with decreased offspring quality. These findings indicate that intrinsic state alterations induced by maternal stress impair offspring capacity in response to immediate environment, and these alterations are likely mediated by maternal stress system. The maladaptive reproduction suppression seen in HL group suggests intrinsic population density as one of ecological factors generating delayed density-dependent effects. C1 [Bian, Jiang-Hui; Du, Shou-Yang; Cao, Yi-Fan; Nie, Xu-Heng; He, Hui] Chinese Acad Sci, Northwest Inst Plateau Biol, Key Lab Adaptat & Evolut Plateau Biota, Xining 810001, Peoples R China. [Du, Shou-Yang; Nie, Xu-Heng; He, Hui] Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China. [Wu, Yan] Hangzhou Normal Univ, Sch Life & Environm Sci, Hangzhou 310012, Zhejiang, Peoples R China. [You, Zhi-Bing] NIDA, Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Bian, JH (reprint author), Chinese Acad Sci, Northwest Inst Plateau Biol, Key Lab Adaptat & Evolut Plateau Biota, Xining 810001, Peoples R China. EM bjh@nwipb.cas.cn FU National Natural Science Foundation of China [31170394]; Natural Science Foundation of Qinghai Province [2014-ZJ-913] FX This work was funded by the National Natural Science Foundation of China (Grant No., 31170394) and the Natural Science Foundation of Qinghai Province (Grant No., 2014-ZJ-913). We sincerely thank Drs Lowell Getz at Department of Animal Biology, University of Illinois and Rudy Boonstra at Centre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto, Scarborough for their critical comments and careful editing the manuscript. We thank Dr. De-Hua Wang at Institute of Zoology, Chinese Academy of Science for his valuable suggestions in conducting this study. The use of animals in this study adhered to China ethical guidelines for animal use in research and to the institutional guidelines on animal research. NR 66 TC 6 Z9 6 U1 5 U2 45 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-8790 EI 1365-2656 J9 J ANIM ECOL JI J. Anim. Ecol. PD MAR PY 2015 VL 84 IS 2 BP 326 EP 336 DI 10.1111/1365-2656.12307 PG 11 WC Ecology; Zoology SC Environmental Sciences & Ecology; Zoology GA CB9RB UT WOS:000349968700002 PM 25327547 ER PT J AU Dize, L Gaydos, CA Quinn, TC West, SK AF Dize, L. Gaydos, C. A. Quinn, T. C. West, S. K. TI Stability of Chlamydia trachomatis on Storage of Dry Swabs for Accurate Detection by Nucleic Acid Amplification Tests SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Letter ID ELIMINATION C1 [Dize, L.; Gaydos, C. A.; Quinn, T. C.] Johns Hopkins Univ, Div Infect Dis, Int Sexually Transmitted Dis Res Lab, Baltimore, MD 21205 USA. [West, S. K.] Johns Hopkins Univ, Wilmer Eye Inst, Dana Ctr Prevent Ophthalmol, Baltimore, MD 21218 USA. [Quinn, T. C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Dize, L (reprint author), Johns Hopkins Univ, Div Infect Dis, Int Sexually Transmitted Dis Res Lab, Baltimore, MD 21205 USA. FU NEI NIH HHS [U10 EY022584]; NIAID NIH HHS [UM1 AI068613] NR 2 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 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2015 VL 53 IS 3 BP 1046 EP 1047 DI 10.1128/JCM.03218-14 PG 2 WC Microbiology SC Microbiology GA CC2WD UT WOS:000350204600052 PM 25540399 ER PT J AU Li, C Shi, C Kim, J Chen, Y Ni, S Jiang, L Zheng, C Li, D Hou, J Taichman, RS Sun, H AF Li, C. Shi, C. Kim, J. Chen, Y. Ni, S. Jiang, L. Zheng, C. Li, D. Hou, J. Taichman, R. S. Sun, H. TI Erythropoietin Promotes Bone Formation through EphrinB2/EphB4 Signaling SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE osteoblast; skeletal; osteogenesis; hematopoietic growth factors; hormones; cytokines ID RESORPTION; RECEPTOR; MICROENVIRONMENT; ANGIOGENESIS; HOMEOSTASIS; GROWTH; MICE AB Recent studies have demonstrated that erythropoietin (EPO) has extensive nonhematopoietic biological functions. However, little is known about how EPO regulates bone formation, although several studies suggested that EPO can affect bone homeostasis. In this study, we investigated the effects of EPO on the communication between osteoclasts and osteoblasts through the ephrinB2/EphB4 signaling pathway. We found that EPO slightly promotes osteoblastic differentiation with the increased expression of EphB4 in ST2 cells. However, EPO increased the expression of Nfatc1 and ephrinB2 but decreased the expression of Mmp9 in RAW264.7 cells, resulting in an increase of ephrinB2-expressing osteoclasts and a decrease in resorption activity. The stimulation of ephrinB2/EphB4 signaling via ephrinB2-Fc significantly promoted EPO-mediated osteoblastic differentiation in ST2 cells. EphB4 knockdown through EphB4 shRNA inhibited EPO-mediated osteoblastic phenotypes. Furthermore, in vivo assays clearly demonstrated that EPO efficiently induces new bone formation in the alveolar bone regeneration model. Taken together, these results suggest that ephrinB2/EphB4 signaling may play an important role in EPO-mediated bone formation. C1 [Li, C.; Shi, C.; Ni, S.; Jiang, L.; Li, D.; Hou, J.; Sun, H.] Jilin Univ, Sch & Hosp Stomatol, Changchun 130023, Jilin Province, Peoples R China. [Kim, J.; Taichman, R. S.] Univ Michigan, Sch Dent, Dept Periodont & Oral Med, Ann Arbor, MI 48109 USA. [Chen, Y.] First Peoples Hosp Chenzhou, Dept Stomatol, Chenzhou, Hunan, Peoples R China. [Zheng, C.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Sun, H (reprint author), Jilin Univ, Dept Oral Pathol, Sch & Hosp Stomatol, Changchun 130021, Peoples R China. EM rtaich@umich.edu; hcsun@mail.jlu.edu.cn OI Taichman, Russell S./0000-0002-7890-0020 FU National Natural Science Foundation of China [81271111]; National Institutes of Health [DE022493, DE020721]; Ministry of Education of China [20120061130010] FX This work was supported by grants from the National Natural Science Foundation of China (No. 81271111), the National Institutes of Health (DE022493, DE020721), and the Ministry of Education of China (No. 20120061130010). The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 23 TC 6 Z9 9 U1 2 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD MAR PY 2015 VL 94 IS 3 BP 455 EP 463 DI 10.1177/0022034514566431 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CC2CB UT WOS:000350151400009 PM 25586589 ER PT J AU Salahuddin, T Natarajan, B Selwaness, M Sadek, A Playford, M Doveikis, J Bluemke, D Mehta, NN AF Salahuddin, Taufiq Natarajan, Balaji Selwaness, Mariana Sadek, Ahmed Playford, Martin Doveikis, Julia Bluemke, David Mehta, Nehal N. TI VASCULAR INFLAMMATION IN THE AORTA IS RELATED TO CORONARY PLAQUE BURDEN IN PSORIASIS SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 [Salahuddin, Taufiq; Natarajan, Balaji; Sadek, Ahmed; Playford, Martin; Doveikis, Julia; Mehta, Nehal N.] NHLBI, Bethesda, MD 20892 USA. [Selwaness, Mariana; Bluemke, David] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2015 VL 63 IS 3 MA 3 BP 569 EP 569 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA CC1RM UT WOS:000350120400023 ER PT J AU Natarajan, B Salahuddin, T Playford, M Herscovitch, P Mehta, N AF Natarajan, Balaji Salahuddin, Taufiq Playford, Martin Herscovitch, Peter Mehta, Nehal TI INSULIN RESISTANCE DETERMINES SEVERITY OF VASCULAR INFLAMMATION BY 18-FLUORODEOXY GLUCOSE PET-CT IN PSORIASIS SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 [Natarajan, Balaji; Salahuddin, Taufiq; Playford, Martin; Mehta, Nehal] NHLBI, Div Inflammat & Cardiometab Dis, Bethesda, MD 20892 USA. [Herscovitch, Peter] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2015 VL 63 IS 3 MA 28 BP 581 EP 581 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA CC1RM UT WOS:000350120400060 ER PT J AU Hansen, MS Kellman, P AF Hansen, Michael S. Kellman, Peter TI Image Reconstruction: An Overview for Clinicians SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Review DE image reconstruction; signal to noise ratio; point spread function; Gibbs ringing; raw data filtering; noise correlation ID TO-NOISE RATIO; NUCLEAR-MAGNETIC-RESONANCE; FAST FOURIER-TRANSFORMS; K-SPACE TRAJECTORIES; PHASED-ARRAY; THERMAL AGITATION; MRI; BLAST; SENSE; CONDUCTORS AB Image reconstruction plays a critical role in the clinical use of magnetic resonance imaging (MRI). The MRI raw data is not acquired in image space and the role of the image reconstruction process is to transform the acquired raw data into images that can be interpreted clinically. This process involves multiple signal processing steps that each have an impact on the image quality. This review explains the basic terminology used for describing and quantifying image quality in terms of signal-to-noise ratio and point spread function. In this context, several commonly used image reconstruction components are discussed. The image reconstruction components covered include noise prewhitening for phased array data acquisition, interpolation needed to reconstruct square pixels, raw data filtering for reducing Gibbs ringing artifacts, Fourier transforms connecting the raw data with image space, and phased array coil combination. The treatment of phased array coils includes a general explanation of parallel imaging as a coil combination technique. The review is aimed at readers with no signal processing experience and should enable them to understand what role basic image reconstruction steps play in the formation of clinical images and how the resulting image quality is described. J. Magn. Reson. Imaging 2014. (c) 2014 Wiley Periodicals, Inc. J. Magn. Reson. Imaging 2015;41:573-585. (c) 2014 Wiley Periodicals, Inc. C1 [Hansen, Michael S.; Kellman, Peter] NHLBI, NIH, Bethesda, MD 20814 USA. RP Hansen, MS (reprint author), NHLBI, NIH, Bldg 10,B1D405,9000 Rockville Pike, Bethesda, MD 20814 USA. EM michael.hansen@nih.gov RI Hansen, Michael/J-5391-2015 OI Hansen, Michael/0000-0002-8087-8731 FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health FX Contract grant sponsor: Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. NR 77 TC 2 Z9 2 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD MAR PY 2015 VL 41 IS 3 BP 573 EP 585 DI 10.1002/jmri.24687 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CB9QT UT WOS:000349967700002 PM 24962650 ER PT J AU Nguyen, TH Bryant, H Shapsa, A Street, H Mani, V Fayad, ZA Frank, JA Tsimikas, S Briley-Saebo, KC AF Nguyen, Tuyen H. Bryant, Henry Shapsa, Ari Street, Hannah Mani, Venkatesh Fayad, Zahi A. Frank, Joseph A. Tsimikas, Sotirios Briley-Saebo, Karen C. TI Manganese G8 Dendrimers Targeted to Oxidation-Specific Epitopes: In Vivo MR Imaging of Atherosclerosis SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE G8 dendrimers; manganese; oxidation-specific epitopes ID PAMAM DENDRIMERS; CONTRAST AGENTS; RAT MYOCARDIUM; LESIONS; TOXICITY; RELAXATION; MECHANISMS; RELAXIVITY; ANTIBODIES; THERAPY AB PurposeTo determine if manganese (Mn) G8 dendrimers targeted to oxidation-specific epitopes (OSE) allow for in vivo detection of atherosclerotic lesions. Materials and MethodsOSE have been identified as key factors in atherosclerotic plaque progression and destabilization. Mn offers a potentially clinically translatable alternative to gadolinium-based agents when bioretention and potential toxicity of gadolinium is anticipated. However, to be effective, high payloads of Mn must accumulate intracellularly in macrophages. It was hypothesized that G8 dendrimers targeted to OSE may allow delivery of high Mn payloads, thereby enabling in vivo detection of macrophage-rich plaques. G8 dendrimers were modified to allow conjugation with MnDTPA (758 Mn ion) and the antibody MDA2 that is targeted to malondialdehyde (MDA)-lysine epitopes. Both the untargeted and targeted G8 dendrimers were characterized and their in vivo efficacy evaluated in apoE(-/-) mice over a 96-hour time period after bolus administration of a 0.05 mmol Mn/kg dose using a clinical MR system (3T). ResultsSignificant enhancement (normalized enhancement >60%, P=0.0013) of atherosclerotic lesions was observed within a 72-hour time period following administration of the targeted dendrimers. The presence of Mn within atherosclerotic lesions was confirmed using spectroscopic methods (>8 g Mn/g). Limited signal attenuation (<18%) and Mn deposition (<1 g Mn/g) was observed in the arterial wall following injection of the untargeted material. ConclusionThis study demonstrates that manganese-labeled dendrimers, allowing a high Mn payload, targeted to OSE may allow in vivo image of atherosclerotic lesions. J. Magn. Reson. Imaging 2015;41:797-805. (c) 2014 Wiley Periodicals, Inc. C1 [Nguyen, Tuyen H.; Shapsa, Ari; Street, Hannah; Mani, Venkatesh; Fayad, Zahi A.] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, New York, NY 10029 USA. [Nguyen, Tuyen H.; Shapsa, Ari; Street, Hannah; Mani, Venkatesh; Fayad, Zahi A.] Icahn Sch Med Mt Sinai, Dept Radiol, New York, NY 10029 USA. [Bryant, Henry; Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Tsimikas, Sotirios] Univ Calif San Diego, Vasc Med Program, La Jolla, CA 92093 USA. [Briley-Saebo, Karen C.] NYU, Coll Dent, Dept Basic Sci & Craniofacial Biol, New York, NY 10029 USA. RP Briley-Saebo, KC (reprint author), NYU, Coll Dent, One Gustave Levy Pl,Box 1234, New York, NY 10029 USA. EM kcs3@nyu.edu OI Briley, Karen/0000-0001-5402-8779; Mani, Venkatesh/0000-0002-0432-2918 FU National Institutes of Health (NIH) [R21 HL091399-01A2]; NIH/NHLBI [R01 HL71021, R01 HL78667, R01 EB009638]; NIH (NHLBI) [R01-HL119828, R01HL093767, P01-HL055798]; NIH Training Grant [T32 GM062754] FX Contract grant sponsor: National Institutes of Health (NIH); Contract grant numbers: R21 HL091399-01A2 (to Briley-Saebo), NIH/NHLBI R01 HL71021, NIH/NHLBI R01 HL78667, NIH/NIBIB R01 EB009638 (to Fayad), NIH (NHLBI) grants R01-HL119828, R01HL093767, P01-HL055798 (to Tsimikas), NIH Training Grant T32 GM062754 (to Nguyen). NR 32 TC 6 Z9 7 U1 3 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD MAR PY 2015 VL 41 IS 3 BP 797 EP 805 DI 10.1002/jmri.24606 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CB9QT UT WOS:000349967700027 PM 24610640 ER PT J AU Mangino, M Christiansen, L Stone, R Hunt, SC Horvath, K Eisenberg, DTA Kimura, M Petersen, I Kark, JD Herbig, U Reiner, AP Benetos, A Codd, V Nyholt, DR Sinnreich, R Christensen, K Nassar, H Hwang, SJ Levy, D Bataille, V Fitzpatrick, AL Chen, W Berenson, GS Samani, NJ Martin, NG Tishkoff, S Schork, NJ Kyvik, KO Dalgard, C Spector, TD Aviv, A AF Mangino, Massimo Christiansen, Lene Stone, Rivka Hunt, Steven C. Horvath, Kent Eisenberg, Dan T. A. Kimura, Masayuki Petersen, Inge Kark, Jeremy D. Herbig, Utz Reiner, Alex P. Benetos, Athanase Codd, Veryan Nyholt, Dale R. Sinnreich, Ronit Christensen, Kaare Nassar, Hisham Hwang, Shih-Jen Levy, Daniel Bataille, Veronique Fitzpatrick, Annette L. Chen, Wei Berenson, Gerald S. Samani, Nilesh J. Martin, Nicholas G. Tishkoff, Sarah Schork, Nicholas J. Kyvik, Kirsten Ohm Dalgard, Christine Spector, Timothy D. Aviv, Abraham TI DCAF4, a novel gene associated with leucocyte telomere length SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID TERT PROMOTER MUTATIONS; BREAST-CANCER RISK; FAMILIAL MELANOMA; LUNG-CANCER; METAANALYSIS; GENOME; DNA; EXPRESSION; VARIANTS; PROTEIN AB Background Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR). Results Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p= 6.4x10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p= 4.1x10(-3) and 2x10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97x10(-169) to 3.42x10(-24). Conclusions We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population. C1 [Mangino, Massimo; Bataille, Veronique; Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Mangino, Massimo] Guys & St Thomas Fdn Trust, Biomed Res Ctr, NIHR, London, England. [Christiansen, Lene; Petersen, Inge; Christensen, Kaare; Kyvik, Kirsten Ohm] Univ Southern Denmark, Epidemiol Unit, Danish Aging Res Ctr, Odense, Denmark. [Christiansen, Lene; Petersen, Inge; Christensen, Kaare; Kyvik, Kirsten Ohm] Univ Southern Denmark, Danish Twin Registry, Inst Publ Hlth, Odense, Denmark. [Christiansen, Lene; Christensen, Kaare] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Christiansen, Lene; Christensen, Kaare] Odense Univ Hosp, Dept Clin Biochem & Pharmacol, DK-5000 Odense, Denmark. [Stone, Rivka; Horvath, Kent; Kimura, Masayuki; Herbig, Utz; Aviv, Abraham] Rutgers State Univ, New Jersey Med Sch, Ctr Human Dev & Aging, Newark, NJ 07102 USA. [Hunt, Steven C.] Univ Utah, Dept Med, Cardiovasc Genet Div, Salt Lake City, UT 84112 USA. [Eisenberg, Dan T. A.] Univ Washington, Dept Anthropol, Seattle, WA 98195 USA. [Eisenberg, Dan T. A.] Univ Washington, Ctr Studies Demog & Ecol, Seattle, WA 98195 USA. [Kark, Jeremy D.; Sinnreich, Ronit] Hebrew Univ Jerusalem, Hadassah Sch Publ Hlth & Community Med, Epidemiol Unit, Jerusalem, Israel. [Reiner, Alex P.; Fitzpatrick, Annette L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98104 USA. [Benetos, Athanase] Univ Lorraine, INSERM, U961, Dept Geriatr, Nancy, France. [Codd, Veryan; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Codd, Veryan; Samani, Nilesh J.] Glenfield Hosp, Leicester Cardiovasc Biomed Res Unit, NIHR, Leicester, Leics, England. [Nyholt, Dale R.; Martin, Nicholas G.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Nassar, Hisham] Hadassah Univ, Med Ctr, Dept Cardiol, Jerusalem, Israel. [Hwang, Shih-Jen; Levy, Daniel] NHLBI, Populat Sci Branch, Bethesda, MD 20892 USA. [Hwang, Shih-Jen; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Bataille, Veronique] West Herts NHS Trust, Dept Dermatol, Watford, Herts, England. [Chen, Wei; Berenson, Gerald S.] Tulane Univ, Ctr Cardiovasc Hlth, New Orleans, LA USA. [Tishkoff, Sarah] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Schork, Nicholas J.] Scripps Res Inst, Dept Mol & Expt Med, San Diego, CA USA. [Kyvik, Kirsten Ohm] Univ Southern Denmark, Inst Reg Hlth Serv Res, Odense, Denmark. [Kyvik, Kirsten Ohm] Odense Univ Hosp, Odense Patient Data Explorat Network OPEN, DK-5000 Odense, Denmark. [Dalgard, Christine] Univ Southern Denmark, Inst Publ Hlth, Odense, Denmark. RP Aviv, A (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Ctr Human Dev & Aging, 185 S Orange Ave, Newark, NJ 07103 USA. EM massimo.mangino@kcl.ac.uk; avivab@umdnj.edu RI Christensen, Kaare/C-2360-2009; Kyvik, Kirsten /K-5680-2016; mangino, massimo/F-5134-2011 OI Christensen, Kaare/0000-0002-5429-5292; Kyvik, Kirsten /0000-0003-2981-0245; mangino, massimo/0000-0002-2167-7470 FU Wellcome Trust [076113/C/04/Z]; European Community's Seventh Framework Programme (FP7); National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust; King's College London; ERC Advanced Principal Investigator award; National Institute of Environmental Health Science [5R01ES021724]; National Institute on Aging [2R01AG016592]; NIH [N01-HC-25195, R01AG20132, R01AG21593, R01AG030678]; National Heart, Lung, and Blood Institute; Center for Population Studies of the NHLBI; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756]; National Institute on Aging (NIA) [AG023629]; British Heart Foundation (BHF); BHF; NIHR Leicester Cardiovascular Biomedical Research Unit; NIHR Senior Investigator award; US-Israel Binational Science Foundation; Israel Science Foundation; US-AID Program for Middle Eastern Regional Cooperation; French Fondation pour la Recherche Medicale [FRM DCV2007-0409250]; Plan Pluriformation [PPF815 PSVT-2005]; Australian Research Council [A7960034, A79906588, A79801419, DP0212016, DP0343921]; European Community; ENGAGE project [HEALTH-F4-2007-201413]; National Health and Medical Research Council (NHMRC)-European Union Collaborative Research Grant [496739]; NHMRC Fellowship [619667]; ARC Future Fellowship [FT0991022, FT110100548]; NHMRC (Medical Bioinformatics Genomics Proteomics Program) [389891]; Netherlands Scientific Organisation [NWO 480-05-003]; NIHR programme grant [RP-PG-0310-1002]; [HL54471]; [HL54472]; [HL54473]; [HL54495]; [HL54496]; [HL54509]; [HL54515]; [HL055673] FX King's College LondonTwinsUK. The study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. TDS is holder of an ERC Advanced Principal Investigator award. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. The Bogalusa Heart Study. This study was supported by grants 5R01ES021724 from National Institute of Environmental Health Science, and 2R01AG016592 from the National Institute on Aging. The Framingham Heart Study. Supported by NIH contract N01-HC-25195. This project was supported in part by intramural funding from the National Heart, Lung, and Blood Institute and the Center for Population Studies of the NHLBI. CHS. Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of CHS investigators and institutions can be found at http://chs-nhlbi.org/. The Center of Human Development and Aging. AA grant support: NIH: Human Telomere Genetics R01AG20132; Telomeres & Vascular Aging, R01AG21593; Leukocyte Telomere Dynamics, Gender, Menopause, Insulin Resistance, R01AG030678. BHF-FHS. The British Heart Foundation Family Heart Study (BHF-FHS) was funded by the British Heart Foundation (BHF). Genotyping of the BHF-FHS study was undertaken as part of the WTCCC and funded by the Wellcome Trust. NJS holds a chair funded by the BHF and VC is funded by the BHF. VC and NJS are supported by the NIHR Leicester Cardiovascular Biomedical Research Unit and NJS holds an NIHR Senior Investigator award. The Jerusalem LRC Longitudinal Study The study was funded by the US-Israel Binational Science Foundation and the Israel Science Foundation. Palestinian-Israeli Jerusalem Risk Factor Study. The study was funded by the US-AID Program for Middle Eastern Regional Cooperation. ADELAHYDE-Nancy study and ERA-France study. The study received support from the French Fondation pour la Recherche Medicale (FRM DCV2007-0409250) and the Plan Pluriformation (PPF815 PSVT-2005). Special thanks to Ms Cynthia Thiriot (INSERM U961, Nancy France) for her contribution to the geotyping of French cohorts. Hypertension Genetic Epidemiology Network Study (HyperGEN). HyperGEN was supported by cooperative agreements HL54471, HL54472, HL54473, HL54495, HL54496, HL54509, HL54515 and grant HL055673. HyperGEN investigators and institutions can be found at http://www.biostat.wustl.edu/hypergen/hypergen.shtml. Queensland Institute of Medical Research (QIMR). We thank Marlene Grace, Ann Eldridge, and Kerrie McAloney for sample collection; Megan Campbell, Lisa Bowdler, Sara Smith, Steven Crooks, and staff of the Molecular Epidemiology Laboratory for sample processing and preparation; Harry Beeby, David Smyth, and Daniel Park for IT/database support; Scott Gordon for his substantial efforts involving the QC and preparation of the GWA data; and the twins and their families for their participation.; We acknowledge support from the Australian Research Council (A7960034, A79906588, A79801419, DP0212016, and DP0343921). Telomere length assessment was co-funded by the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413 and National Health and Medical Research Council (NHMRC)-European Union Collaborative Research Grant 496739. GWM was supported by an NHMRC Fellowship (619667), DRN (FT0991022) and SEM (FT110100548) were supported by an ARC Future Fellowship. Genotyping was funded by the NHMRC (Medical Bioinformatics Genomics Proteomics Program, 389891). Genotype imputation was carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organisation (NWO 480-05-003). UKBS. The UK Blood Services collection of Common Controls (UKBS-CC collection) is supported by the Wellcome Trust grant 076113/C/04/Z and the collection was established as part of the Wellcome Trust Case Control Consortium. WHO is supported by a NIHR programme grant to NHSBT (RP-PG-0310-1002) and is a NIHR Senior Investigator. NR 55 TC 10 Z9 11 U1 0 U2 6 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD MAR PY 2015 VL 52 IS 3 BP 157 EP 162 DI 10.1136/jmedgenet-2014-102681 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA CB8JD UT WOS:000349874700003 PM 25624462 ER PT J AU Yao, W Bekmezian, S Hardy, D Kushner, HW Miller, AJ Huang, JC Lee, JS AF Yao, William Bekmezian, Sona Hardy, Dan Kushner, Harvey W. Miller, Arthur J. Huang, John C. Lee, Janice S. TI Cone-Beam Computed Tomographic Comparison of Surgically Assisted Rapid Palatal Expansion and Multipiece Le Fort I Osteotomy SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID MAXILLARY EXPANSION; STABILITY AB Purpose: To examine and compare the skeletal and dental effects of surgically assisted rapid palatal expansion (SARPE) and multipiece Le Fort osteotomy using cone-beam computed tomography (CBCT). Materials and Methods: This was a prospective cohort study. Patients underwent SARPE or multipiece Le Fort I osteotomy to address maxillary transverse deficiency. CBCT scans were taken preoperatively, immediately postoperatively or after retention, and at least 6 months postoperatively. Four landmark measurements and ratios of dental-to-skeletal change were used to follow skeletal and dental widths in the posterior and anterior maxillary regions. Wilcoxon signed-rank test and Wilcoxon 2-sample rank-sum test were used to compare the landmark measurements and the ratio of dental-to-skeletal change for the 2 surgeries. A P value less than .05 was statistically significant. Results: Thirteen patients (mean, 28.3 yr old; 7 women) were enrolled: 9 were treated by multipiece Le Fort I osteotomy and 4 were treated by SARPE. The ratios of dental-to-skeletal expansion in the posterior maxilla for the Le Fort procedure and SARPE were 0.70 +/- 0.41 and 25.20 +/- 15.8, respectively, and the dental-to-skeletal relapses were 1.17 +/- 0.80 and -3.63 +/- 3.70, respectively. The ratios of dental-to-skeletal expansion in the anterior maxilla for the Le Fort procedure and SARPE were 0.58 +/- 0.38 and 31.80 +/- 59.4, respectively, and the dental-to-skeletal relapses were 2.25 +/- 3.41 and 4.86 +/- 8.10, respectively. Conclusion: There was greater correlation between dental and skeletal changes in the multipiece Le Fort procedure, indicating bodily separation of the segments, whereas the SARPE showed noteworthy dental and skeletal tipping. Dental relapse was greater than skeletal relapse for these 2 procedures. Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons C1 [Yao, William; Bekmezian, Sona; Hardy, Dan; Miller, Arthur J.; Huang, John C.] Univ Calif San Francisco, Div Orthodont, Dept Orofacial Sci, San Francisco, CA 94143 USA. [Kushner, Harvey W.] Biomed Comp Res Inst, Philadelphia, PA USA. [Lee, Janice S.] NIDCR, NIH, Bethesda, MD 20892 USA. RP Lee, JS (reprint author), NIDCR, NIH, 10 Ctr Dr,Bldg 10,Room 5-2531 North East Atrium, Bethesda, MD 20892 USA. EM art.miller@ucsf.edu OI Bekmezian, Sona/0000-0002-7604-5462 NR 23 TC 2 Z9 2 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD MAR PY 2015 VL 73 IS 3 BP 499 EP 508 DI 10.1016/j.joms.2014.08.024 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CB6UM UT WOS:000349762200019 PM 25488314 ER PT J AU Abulseoud, OA Cuellar-Barboza, A Karpyak, V AF Abulseoud, Osama A. Cuellar-Barboza, Alfredo Karpyak, Victor TI Regarding Cuellar-Barboza AB, et al. Change in consumption patterns for treatment-seeking patients with alcohol use disorder post-bariatric surgery. J Psychosom Res 2014; 10.1016/j.jpsychores.2014.06.019. [Epub ahead of print] Response SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Letter C1 [Abulseoud, Osama A.; Cuellar-Barboza, Alfredo; Karpyak, Victor] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 55904 USA. [Abulseoud, Osama A.] NIDA, IRP, NIH, Baltimore, MD 21224 USA. [Cuellar-Barboza, Alfredo] UANL Hosp Univ, Monterrey 64630, NL, Mexico. RP Abulseoud, OA (reprint author), Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 55904 USA. EM Osama.abulseoud@nih.gov NR 4 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 EI 1879-1360 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD MAR PY 2015 VL 78 IS 3 BP 299 EP 300 DI 10.1016/j.jpsychores.2015.01.005 PG 2 WC Psychiatry SC Psychiatry GA CC2PE UT WOS:000350186300015 PM 25604438 ER PT J AU Crews, DC Kuczmarski, MF Miller, ER Zonderman, AB Evans, MK Powe, NR AF Crews, Deidra C. Kuczmarski, Marie Fanelli Miller, Edgar R., III Zonderman, Alan B. Evans, Michele K. Powe, Neil R. TI Dietary Habits, Poverty, and Chronic Kidney Disease in an Urban Population SO JOURNAL OF RENAL NUTRITION LA English DT Article ID GLOMERULAR-FILTRATION-RATE; FOOD INSECURITY; BLOOD-PRESSURE; LOW-INCOME; ACID LOAD; SOCIOECONOMIC-STATUS; RACIAL-DIFFERENCES; PHYSICAL-ACTIVITY; SUBGROUP ANALYSIS; CLINICAL-TRIAL AB Background: Poverty is associated with chronic kidney disease (CKD) in the United States and worldwide. Poor dietary habits may contribute to this disparity. Study Design: Cross-sectional study. Setting and Participants: A total of 2,058 community-dwelling adults aged 30 to 64 years residing in Baltimore City, Maryland. Predictors: Adherence to the Dietary Approaches to Stop Hypertension (DASH) diet. DASH scoring based on 9 target nutrients (total fat, saturated fat, protein, fiber, cholesterol, calcium, magnesium, sodium, and potassium); adherence defined as score >= 4.5 of maximum possible score of 9. Poverty (self-reported household income <125% of 2004 Department of Health and Human Services guideline) and nonpoverty (>= 125% of guideline). Outcomes and Measurements: CKD defined as estimated glomerular filtration rate < 60mL/minute/1.73m(2) (CKD epidemiology collaboration equation). Multivariable logistic regression was used to calculate adjusted odds ratios (AORs) for relation of DASH score tertile and CKD, stratified by poverty status. Results: Among 2,058 participants (mean age 48 years; 57% black; 44% male; 42% with poverty), median DASH score was low, 1.5 (interquartile range, 1-2.5). Only 5.4% were adherent. Poverty, male sex, black race, and smoking were more prevalent among the lower DASH score tertiles, whereas higher education and regular health care were more prevalent among the highest DASH score tertile (P < . 05 for all). Fiber, calcium, magnesium, and potassium intake were lower, and cholesterol higher, among the poverty compared with nonpoverty group (P < .05 for all), with no difference in sodium intake. A total of 5.6% of the poverty and 3.8% of the nonpoverty group had CKD (P = .05). The lowest DASH tertile (compared with the highest) was associated with more CKD among the poverty (AOR 3.15, 95% confidence interval 1.51-6.56), but not among the nonpoverty group (AOR 0.73, 95% confidence interval 0.37-1.43; P interaction = .001). Conclusions: Poor dietary habits are strongly associated with CKD among the urban poor and may represent a target for interventions aimed at reducing disparities in CKD. (C) 2015 by the National Kidney Foundation, Inc. All rights reserved C1 [Crews, Deidra C.] Johns Hopkins Univ, Sch Med, Div Nephrol, Dept Med, Baltimore, MD 21224 USA. [Crews, Deidra C.; Miller, Edgar R., III] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [Kuczmarski, Marie Fanelli] Univ Delaware, Dept Behav Hlth & Nutr, Newark, DE USA. [Miller, Edgar R., III] Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Dept Med, Baltimore, MD 21224 USA. [Miller, Edgar R., III] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Zonderman, Alan B.; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Powe, Neil R.] Univ Calif San Francisco, Dept Med, San Francisco Gen Hosp, San Francisco, CA USA. RP Crews, DC (reprint author), Johns Hopkins Univ, Sch Med, Div Nephrol, Dept Med,Johns Hopkins Bayview Med Ctr, 301 Mason F Lord Dr,Suite 2500, Baltimore, MD 21224 USA. EM dcrews1@jhmi.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health; Harold Amos Medical Faculty Development Program; Robert Wood Johnson Foundation; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K23DK097184]; National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK78124] FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. Dr. D.C.C. was supported by the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation and grant K23DK097184 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health. Dr. N.R.P. was partially supported by grant R01 DK78124 from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 50 TC 10 Z9 10 U1 0 U2 16 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1051-2276 EI 1532-8503 J9 J RENAL NUTR JI J. Renal Nutr. PD MAR PY 2015 VL 25 IS 2 BP 103 EP 110 DI 10.1053/j.jrn.2014.07.008 PG 8 WC Nutrition & Dietetics; Urology & Nephrology SC Nutrition & Dietetics; Urology & Nephrology GA CB9NV UT WOS:000349959400006 PM 25238697 ER PT J AU Ascierto, ML Bozzano, F Bedognetti, D Marras, F Schechterly, C Matsuura, K Picciotto, A Marenco, S Zhao, YD DeGiorgi, V Sommariva, M Moretta, L Wang, E Alter, HJ Marincola, FM De Maria, A AF Ascierto, Maria Libera Bozzano, Federica Bedognetti, Davide Marras, Francesco Schechterly, Cathy Matsuura, Kentaro Picciotto, Antonino Marenco, Simona Zhao, Yingdong DeGiorgi, Valeria Sommariva, Michele Moretta, Lorenzo Wang, Ena Alter, Harvey J. Marincola, Francesco M. De Maria, Andrea TI Inherent transcriptional signatures of NK cells are associated with response to IFN alpha plus rivabirin therapy in patients with Hepatitis C Virus SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE NK cells; HCV infection; Clinical response; Regulation of NK cells ID NATURAL-KILLER-CELLS; DENDRITIC CELLS; ACTIVATING RECEPTORS; INFLUENZA INFECTION; TRIGGERING RECEPTOR; HCV INFECTION; NKP46; CYTOTOXICITY; EXPRESSION; LYSIS AB Background: Differences in the expression of Natural Killer cell receptors have been reported to reflect divergent clinical courses in patients with chronic infections or tumors. However, extensive molecular characterization at the transcriptional level to support this view is lacking. The aim of this work was to characterize baseline differences in purified NK cell transcriptional activity stratified by response to treatment with PEG-IFNa/RBV in patients chronically infected with HCV. Methods: To this end we here studied by flow cytometer and gene expression profile, phenotypic and transcriptional characteristics of purified NK cells in patients chronically infected with HCV genotype-1 virus who were subsequently treated with PEG-IFNa/RBV. Results were further correlated with divergent clinical response obtained after treatment. Results: The pre-treatment transcriptional patterns of purified NK cells from patients subsequently undergoing a sustained virologic response (SVR) clearly segregated from those of non-responder (NR) patients. A set of 476 transcripts, including molecules involved in RNA processing, ubiquitination pathways as well as HLA class II signalling were differently expressed among divergent patients. In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D. A complex relationship was observed that suggested for extensive post-transcriptional editing. Only a small number of the NK cell transcripts identified were correlated with chronic HCV infection/replication indicating that inherent transcriptional activity prevails over environment effects such as viral infection. Conclusions: Collectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage. C1 [Ascierto, Maria Libera; Bozzano, Federica; De Maria, Andrea] Univ Genoa, Dept Hlth Sci, Genoa, Italy. [Ascierto, Maria Libera] Johns Hopkins Med, Dept Oncol, Baltimore, MD 21231 USA. [Bozzano, Federica; De Maria, Andrea] Univ Genoa, Dept Expt Med, Genoa, Italy. [Bedognetti, Davide; Wang, Ena; Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Marras, Francesco; Moretta, Lorenzo] Ist Giannina Gaslin, Genoa, Italy. [Schechterly, Cathy; Matsuura, Kentaro; DeGiorgi, Valeria; Sommariva, Michele; Alter, Harvey J.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Picciotto, Antonino; Marenco, Simona; De Maria, Andrea] IRCCS Az Osp Univ San Martino, IST Ist Nazl Ric Sul Cancro, Genoa, Italy. [Zhao, Yingdong] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [De Maria, Andrea] Univ Genoa, I-16132 Genoa, Italy. RP Ascierto, ML (reprint author), Univ Genoa, Dept Hlth Sci, Genoa, Italy. EM asciertoml@jhu.edu; de-maria@unige.it RI de maria, andrea/F-7116-2016; Sommariva, Michele/C-1174-2017 OI de maria, andrea/0000-0001-5782-333X; Sommariva, Michele/0000-0002-7622-0996 FU Associazione Italiana per la Ricerca sul Cancro (AIRC) Projects Ministero della Salute Grant [RF2006]; Ricerca Oncologica Project Grant [RO strategici 3/07]; Istituto Superiore di Sanita (ISS) Programma nazionale di ricerca sull'AIDS Grants [40G.41, 45G.11, 40D61, 40H69, 40H23]; Ministero della Salute Grant [RF-2010-2316197]; NIH FX The present work was partly supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) Projects Ministero della Salute Grant RF2006; Ricerca Oncologica Project 2006-08 Grant RO strategici 3/07; Istituto Superiore di Sanita (ISS) Programma nazionale di ricerca sull'AIDS Grants 40G.41, 45G.11, 40D61, 40H69, and 40H23; and Ministero della Salute Grant RF-2010-2316197, and NIH intramural support. NR 42 TC 0 Z9 0 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAR 1 PY 2015 VL 13 AR 77 DI 10.1186/s12967-015-0428-x PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CC6WE UT WOS:000350508900002 PM 25849716 ER PT J AU Volpato, S Bazzano, S Fontana, A Ferrucci, L Pilotto, A AF Volpato, Stefano Bazzano, Salvatore Fontana, Andrea Ferrucci, Luigi Pilotto, Alberto CA Mpi-Triveneto Study Grp TI Multidimensional Prognostic Index Predicts Mortality and Length of Stay During Hospitalization in the Older Patients: A Multicenter Prospective Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE MPI; Prognosis; Hospital; Mortality; Aging ID COMPREHENSIVE GERIATRIC ASSESSMENT; SHORT-TERM MORTALITY; SURVIVAL ANALYSIS; ELDERLY PATIENTS; RECLASSIFICATION; DISCRIMINATION; VALIDATION; HAZARDS; DISEASE; ADULTS AB Background. The Multidimensional Prognostic Index (MPI) is a validated predictive tool for long-term mortality based on information collected in a standardized Comprehensive Geriatric Assessment. We investigated whether the MPI is an effective predictor of intrahospital mortality and length of hospital stay after admission to acute geriatric wards. Methods. Prospective study of 1,178 older patients (702 women and 476 men, 85.0 +/- 6.8 years) admitted to 20 geriatrics units. Within 48 hours from admission, the MPI, according to an earlier validated algorithm, was calculated. Subjects were divided into three groups of MPI score, low-risk (MPI-1 value <= 0.33), moderate-risk (MPI-2 value 0.34-0.66), and severe-risk of mortality (MPI-3 value >= 0.67), on the basis of earlier established cut-offs. Associations with in-hospital mortality and length of stay were examined using multivariable Cox regression models and adjusted Poisson linear mixed-effects models, respectively. Results. At admission, 23.6% subjects had a MPI-1 score, 33.8% had a MPI-2 score, and 42.6% had a MPI-3 score. Subjects with higher MPI score at admission were older (p <.001), more frequently women (p <.001) and had higher prevalence of common chronic conditions. After adjustment for age, gender, and diseases, patients included in the MPI-2 and MPI-3 groups had a significantly higher risk for intrahospital mortality (hazard ratio: 3.48, 95% confidence intervals: 1.02-11.88, p = .047; hazard ratio: 8.31, 95% confidence intervals: 2.54-27.19, p <.001) than patients included in the MPI-1 group, respectively. In multivariable model, length of stay significantly increased across the three MPI groups (11.29 [0.5], 13.73 [1.3], and 15.30 [1.4] days, respectively [p < .0001]). Conclusions. In older acute care inpatients, MPI score assessed at hospital admission is an independent predictor of in-hospital mortality and the length of hospital stay. C1 [Volpato, Stefano] Univ Ferrara, Dept Med Sci, I-44100 Ferrara, Italy. [Bazzano, Salvatore; Pilotto, Alberto] Azienda ULSS 16 Padova, Geriatr Unit, Padua, Italy. [Bazzano, Salvatore; Pilotto, Alberto] Sci Inst Res & Care, Geriatr Gerontol Res Unit, San Giovanni Rotondo, Italy. [Fontana, Andrea] Sci Inst Res & Care, Unit Biostat, San Giovanni Rotondo, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Volpato, S (reprint author), Univ Ferrara, Dept Med Sci, Via Savonarola 9, I-44100 Ferrara, Italy. EM vlt@unife.it RI Fontana, Andrea/J-8584-2016 OI Fontana, Andrea/0000-0002-6660-5315 NR 33 TC 4 Z9 4 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2015 VL 70 IS 3 BP 323 EP 329 DI 10.1093/gerona/glu167 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CC1RZ UT WOS:000350122200007 ER PT J AU Rejeski, WJ Bray, GA Chen, SH Clark, JM Evans, M Hill, JO Jakicic, JM Johnson, KC Neiberg, R Ip, EH AF Rejeski, W. Jack Bray, George A. Chen, Shyh-Huei Clark, Jeanne M. Evans, Mary Hill, James O. Jakicic, John M. Johnson, Karen C. Neiberg, Rebecca Ip, Edward H. CA Look AHEAD Res Grp TI Aging and Physical Function in Type 2 Diabetes: 8 Years of an Intensive Lifestyle Intervention SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Diabetes; Obesity; Functional performance ID QUALITY-OF-LIFE; OBESE OLDER-ADULTS; LOOK-AHEAD TRIAL; WEIGHT-LOSS; KNEE OSTEOARTHRITIS; CLINICAL-TRIAL; HEALTH; INDIVIDUALS; EXERCISE; PREVALENCE AB Background. Compared with adults without type 2 diabetes mellitus, those with the disease experience more limitations in their physical functioning (PF). Look AHEAD is a large multicenter trial that examined the effects of an intensive lifestyle intervention (ILI) for weight loss on cardiovascular outcomes compared with diabetes support and education (DSE). Although the current study compared treatment differences between ILI and DSE on PF, the primary goal was to examine whether this effect was moderated by age and history of cardiovascular disease at enrollment. Methods. Overweight or obese adults with type 2 diabetes mellitus (n = 5,145) were randomly assigned to either ILI or DSE. The mean (+/- SD) age and % females in ILI was 58.9 years (+/- 6.9) and 59.8%; it was 58.6 years (6.8) and 59.5% in DSE. Analysis in 4,998 participants assessed the differential rates of decline in PF across a period of 8 years for the ILI and DSE groups. Results. ILI resulted in improved PF compared with DSE after 1 year (p < .0001) and was maintained across time. Within the ILI, older adults experienced greater improvements than younger adults (p < .0001). By year 2, persons in ILI with preexisting cardiovascular disease were no different in PF than in DSE participants with preexisting cardiovascular disease. Conclusion. With the exception of persons who had a history of cardiovascular disease, ILI slowed the decline in PF with type 2 diabetes mellitus despite weight regain, an effect that was stronger for older than younger participants and could translate into reductions in falls and disability. C1 [Rejeski, W. Jack] Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC 27109 USA. [Bray, George A.] Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Chen, Shyh-Huei; Neiberg, Rebecca; Ip, Edward H.] Wake Forest Univ, Sch Med, Dept Biostat Sci, Winston Salem, NC 27109 USA. [Clark, Jeanne M.] Johns Hopkins Sch Med, Div Gen Internal Med, Baltimore, MD USA. [Evans, Mary] NIDDK, Bethesda, MD 20892 USA. [Hill, James O.] Univ Colorado, Sch Med, Dept Pediat & Med, Denver, CO USA. [Jakicic, John M.] Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA 15260 USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. RP Rejeski, WJ (reprint author), Wake Forest Univ, Dept Hlth & Exercise Sci, POB 7868, Winston Salem, NC 27109 USA. EM rejeski@wfu.edu FU National Institutes of Health through National Institute of Diabetes and Digestive and Kidney Diseases [DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, DK56992]; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; NIH Office of Research on Women's Health; Centers for Disease Control and Prevention; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Johns Hopkins Medical Institutions Bayview General Clinical Research Center [M01RR02719]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center; Massachusetts Institute of Technology General Clinical Research Center [M01RR01066]; University of Colorado Health Sciences Center General Clinical Research Center [M01RR00051]; Clinical Nutrition Research Unit [P30 DK48520]; University of Tennessee at Memphis General Clinical Research Center [M01RR0021140]; University of Pittsburgh General Clinical Research Center (GCRC) [M01RR000056]; Clinical Translational Research Center (CTRC) - Clinical & Translational Science Award [UL1 RR 024153]; NIH [DK 046204]; VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; Frederic C. Bartter General Clinical Research Center [M01RR01346]; [R21AG042761-01] FX This project was funded by the National Institutes of Health through cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases: DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, and DK56992. Additional funding was provided by the National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; NIH Office of Research on Women's Health; and the Centers for Disease Control and Prevention. This research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The Indian Health Service (I.H.S.) provided personnel, medical oversight, and use of facilities. The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the I.H.S. or other funding sources. Additional support was received from The Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01RR02719); the Massachusetts General Hospital Mallinckrodt General Clinical Research Center and the Massachusetts Institute of Technology General Clinical Research Center (M01RR01066); the University of Colorado Health Sciences Center General Clinical Research Center (M01RR00051) and Clinical Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR0021140); the University of Pittsburgh General Clinical Research Center (GCRC) (M01RR000056), the Clinical Translational Research Center (CTRC) funded by the Clinical & Translational Science Award (UL1 RR 024153) and NIH grant (DK 046204); the VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; the Frederic C. Bartter General Clinical Research Center (M01RR01346); and a methodological grant awarded to E.H.I., R21AG042761-01. The following organizations have committed to make major contributions to Look AHEAD: FedEx Corporation; Health Management Resources; LifeScan, Inc., a Johnson & Johnson Company; OPTIFAST (R) of Nestle HealthCare Nutrition, Inc.; Hoffmann-La Roche Inc.; Abbott Nutrition; and Slim-Fast Brand of Unilever North America. Some of the information contained herein was derived from data provided by the Bureau of Vital Statistics, New York City Department of Health and Mental Hygiene. NR 34 TC 4 Z9 4 U1 1 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2015 VL 70 IS 3 BP 343 EP 351 DI 10.1093/gerona/glu083 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CC1RZ UT WOS:000350122200010 PM 24986062 ER PT J AU Koyama, A Houston, DK Simonsick, EM Lee, JS Ayonayon, HN Shahar, DR Rosano, C Satterfield, S Yaffe, K AF Koyama, Alain Houston, Denise K. Simonsick, Eleanor M. Lee, Jung Sun Ayonayon, Hilsa N. Shahar, Danit R. Rosano, Caterina Satterfield, Suzanne Yaffe, Kristine TI Association Between the Mediterranean Diet and Cognitive Decline in a Biracial Population SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Epidemiology; Nutrition; Cognitive aging; Alzheimers; Cognition ID MENTAL-STATE-EXAM; ALZHEIMERS-DISEASE; CARDIOVASCULAR-DISEASE; ADHERENCE; RISK; DEMENTIA; HEALTH; MEDDIETSCORE; IMPAIRMENT; AMERICANS AB Background. Results from numerous studies suggest protective effects of the Mediterranean diet for cardiovascular disease, cancer, and mortality. Evidence for an association with a decreased risk of cognitive decline is less consistent and studies are limited by a lack of diversity in their populations. Methods. We followed 2,326 older adults (38.2% black, 51.3% female, aged 70-79 at baseline) over 8 years in a prospective cohort study in the United States (Health, Aging and Body Composition study). To measure adherence to a Mediterranean diet, we calculated race-specific tertiles of the MedDiet score (range: 0-55) using baseline food frequency questionnaires. Cognitive decline was assessed using repeated Modified Mini Mental State Examination scores over the study. We used linear mixed models to assess the association between MedDiet score and trajectory of cognitive decline. Results. Among blacks, participants with high MedDiet scores had a significantly lower mean rate of decline on the Modified Mini Mental State Examination score compared with participants with lower MedDiet scores (middle and bottom tertiles). The mean difference in points per year was 0.22 (95% confidence interval: 0.05-0.39; p = .01) after adjustment for age, sex, education, body mass index, current smoking, physical activity, depression, diabetes, total energy intake, and socioeconomic status. No association between MedDiet scores and change in Modified Mini Mental State Examination score was seen among white participants (p = .14). Conclusions. Stronger adherence to the Mediterranean diet may reduce the rate of cognitive decline among black, but not white older adults. Further studies in diverse populations are needed to confirm this association and pinpoint mechanisms that may explain these results. C1 [Koyama, Alain] Northern Calif Inst Res & Educ, San Francisco, CA USA. [Koyama, Alain; Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Houston, Denise K.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Lee, Jung Sun] Univ Georgia, Athens, GA 30602 USA. [Ayonayon, Hilsa N.; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Shahar, Danit R.] Ben Gurion Univ Negev, Fac Hlth Sci, Dept Epidemiol & Hlth Evaluat, S Daniel Int Ctr Hlth & Nutr, IL-84105 Beer Sheva, Israel. [Rosano, Caterina] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15260 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Koyama, A (reprint author), San Francisco VA Med Ctr, 4150 Clement St,VAMC 116H, San Francisco, CA 94121 USA. EM akk412@mail.harvard.edu OI Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010 FU National Institute of Aging [K24 AG 031155, R01 AG 026720]; Alzheimer's Association [IIRG-08-88872]; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; NINR [R01-NR012459]; Intramural Research Program of the NIH, National Institute on Aging FX Funded in part by grants K24 AG 031155 and R01 AG 026720 from the National Institute of Aging and grant IIRG-08-88872 from the Alzheimer's Association. This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106, NIA grant R01-AG028050, and NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 39 TC 4 Z9 4 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2015 VL 70 IS 3 BP 352 EP 357 DI 10.1093/gerona/glu097 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CC1RZ UT WOS:000350122200011 PM 24994847 ER PT J AU Brown, P AF Brown, Patricia TI A word from OLAW SO LAB ANIMAL LA English DT Editorial Material C1 NIH, OLAW, OER, OD,HHS, Washington, DC 20001 USA. RP Brown, P (reprint author), NIH, OLAW, OER, OD,HHS, Washington, DC 20001 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 EI 1548-4475 J9 LAB ANIMAL JI Lab Anim. PD MAR PY 2015 VL 44 IS 3 BP 88 EP 88 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA CC2SP UT WOS:000350195200015 ER PT J AU Narver, HL AF Narver, Heather Lyons TI Nalbuphine, a non-controlled opioid analgesic, and its potential use in research mice SO LAB ANIMAL LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; BUPRENORPHINE; NALOXONE; MODEL; PAIN; BUTORPHANOL; PARTURITION; MORPHINE; NAUSEA; LABOR AB Nalbuphine is an inexpensive, non-controlled, opioid analgesic that has been in clinical use for decades. A kappa opioid receptor agonist and mu opioid receptor antagonist, nalbuphine causes fewer adverse effects than other opioid analgesics. The author reviews the characteristics of nalbuphine, analyzes studies of nalbuphine in mice and explores the potential use of nalbuphine to treat pain in research mice. In analgesiometric studies in mice, nalbuphine ameliorates both somatic and visceral pain. Nalbuphine seems to have a broad range of safe doses for subcutaneous administration in mice. Unlike non-steroidal anti-inflammatory drugs, nalbuphine does not antagonize prostaglandins or impede labor in mice. Although additional study is needed before clinical use can be recommended, evidence presented here suggests that nalbuphine might be an effective analgesic for dystocia (or difficult birth) and other painful conditions in research mice. C1 NINDS, Anim Hlth & Care Sect, NIH, Bethesda, MD 20892 USA. RP Narver, HL (reprint author), NINDS, Anim Hlth & Care Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM narverh@mail.nih.gov NR 39 TC 1 Z9 1 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 EI 1548-4475 J9 LAB ANIMAL JI Lab Anim. PD MAR PY 2015 VL 44 IS 3 BP 110 EP 114 PG 5 WC Veterinary Sciences SC Veterinary Sciences GA CC2SP UT WOS:000350195200022 ER PT J AU Eytan, DF Snow, GE Carlson, SG Schiltz, S Chen, Z Van Waes, C AF Eytan, Danielle F. Snow, Grace E. Carlson, Sophie G. Schiltz, Stephen Chen, Zhong Van Waes, Carter TI Combination Effects of SMAC Mimetic Birinapant With TNF alpha, TRAIL, and Docetaxel in Preclinical Models of HNSCC SO LARYNGOSCOPE LA English DT Article DE Inhibitor of Apoptosis; second mitochondria-derived activator of caspases; cell death; squamous carcinoma ID SQUAMOUS-CELL CARCINOMA; NF-KAPPA-B; SOLID TUMORS; PHASE-I; CANCER; APOPTOSIS; DEATH; HEAD; NECK; INFLAMMATION AB Objectives/HypothesisHead and neck squamous cell carcinoma (HNSCC) cells are resistant to cell death induced by tumor necrosis factor ligands such as tumor necrosis factor (TNF) or TNF-related apoptosis-inducing ligand (TRAIL) and cytotoxic chemotherapies. Recently, genetic alterations in cell death pathways, including inhibitor of apoptosis proteins, have been demonstrated in HNSCC. We investigated the effects of birinapant, a novel, second mitochondria-derived activator of caspases (SMAC)-mimetic that targets inhibitor of apoptosis proteins, alone and in combination with TNF, TRAIL, or chemotherapy docetaxel. Study DesignExperimental study using human HNSCC cell lines in vitro and xenograft mouse model in vivo. MethodsA panel of HNSCC cell lines with varying genetic alterations in cell death pathway components were treated with birinapantTNF, TRAIL, and docetaxel and were assessed for effects on cell density, cell cycle, and death. Synergism was determined at varying concentrations of treatments using the Chou-Talalay method. Combination studies using birinapantdocetaxel were performed in a xenograft mouse model. ResultsBirinapant, alone or in combination with TNF or TRAIL, decreased cell density in cell lines, with IC(50)s ranging from 0.5 nM to>1 mu M. Birinapant alone or with TNF significantly increased subG0 cell death in different lines. Docetaxel showed synergism with birinapant +/- TNF in vitro. Birinapant monotherapy-inhibited growth in a tumor xenograft model resistant to docetaxel, and combination treatment further delayed growth. ConclusionsBirinapant alone or in combination with TNF or TRAIL and docetaxel decreased cell density, increased cell death, and displayed antitumor activity in a preclinical HNSCC xenograft exhibiting aberrations in cell death pathway components and docetaxel resistance. C1 [Eytan, Danielle F.; Snow, Grace E.; Carlson, Sophie G.; Schiltz, Stephen; Chen, Zhong; Van Waes, Carter] Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Bethesda, MD 20892 USA. [Eytan, Danielle F.; Snow, Grace E.] NIH, Med Res Scholars Program, Bethesda, MD 20892 USA. [Eytan, Danielle F.] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. RP Van Waes, C (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, CRC Rm 4-2732,10 Ctr Dr, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov FU NIDCD intramural projects [ZIA-DC-000016, 73, 74]; NIH-Medical Research Scholars Program FX Supported by NIDCD intramural projects (ZIA-DC-000016, 73, 74) and the NIH-Medical Research Scholars Program (D.F.E., G.E.S.). Birinapant was provided to NIDCD and authors (D.F.E., G.E.S., S.G.C., S.S., Z.C., C.V.W.) for research under a Materials Transfer Agreement with the National Cancer Institute and TetraLogic Pharmaceuticals (Malvern, PA). NR 24 TC 5 Z9 5 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD MAR PY 2015 VL 125 IS 3 BP E118 EP E124 DI 10.1002/lary.25056 PG 7 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA CB9PN UT WOS:000349964100005 PM 25431358 ER PT J AU Barry, CE AF Barry, Clifton E., III TI Timing is everything for compassionate use of delamanid SO NATURE MEDICINE LA English DT Letter ID MULTIDRUG-RESISTANT; TUBERCULOSIS C1 NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. RP Barry, CE (reprint author), NIAID, TB Res Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM cbarry@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012 NR 6 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD MAR PY 2015 VL 21 IS 3 BP 211 EP 211 DI 10.1038/nm.3823 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CC4YG UT WOS:000350362000008 PM 25742452 ER PT J AU Coll, RC Robertson, AAB Chae, JJ Higgins, SC Munoz-Planillo, R Inserra, MC Vetter, I Dungan, LS Monks, BG Stutz, A Croker, DE Butler, MS Haneklaus, M Sutton, CE Nunez, G Latz, E Kastner, DL Mills, KHG Masters, SL Schroder, K Cooper, MA O'Neill, LAJ AF Coll, Rebecca C. Robertson, Avril A. B. Chae, Jae Jin Higgins, Sarah C. Munoz-Planillo, Raul Inserra, Marco C. Vetter, Irina Dungan, Lara S. Monks, Brian G. Stutz, Andrea Croker, Daniel E. Butler, Mark S. Haneklaus, Moritz Sutton, Caroline E. Nunez, Gabriel Latz, Eicke Kastner, Daniel L. Mills, Kingston H. G. Masters, Seth L. Schroder, Kate Cooper, Matthew A. O'Neill, Luke A. J. TI A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases SO NATURE MEDICINE LA English DT Article ID DIFFERENTIAL REQUIREMENT; NALP3 INFLAMMASOME; AUTOIMMUNE ENCEPHALOMYELITIS; CYTOPLASMIC DNA; CELL-DEATH; T-CELLS; ACTIVATION; IL-1-BETA; INTERLEUKIN-1; MECHANISMS AB The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1 beta (IL-1 beta) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease. C1 [Coll, Rebecca C.; Higgins, Sarah C.; Dungan, Lara S.; Haneklaus, Moritz; Sutton, Caroline E.; Mills, Kingston H. G.; O'Neill, Luke A. J.] Univ Dublin Trinity Coll, Trinity Biomed Sci Inst, Sch Biochem & Immunol, Dublin 2, Ireland. [Coll, Rebecca C.; Robertson, Avril A. B.; Inserra, Marco C.; Vetter, Irina; Croker, Daniel E.; Butler, Mark S.; Schroder, Kate; Cooper, Matthew A.] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia. [Chae, Jae Jin; Kastner, Daniel L.] NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Munoz-Planillo, Raul; Nunez, Gabriel] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA. [Munoz-Planillo, Raul; Nunez, Gabriel] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI USA. [Inserra, Marco C.; Vetter, Irina] Univ Queensland, Sch Pharm, Brisbane, Qld, Australia. [Monks, Brian G.; Stutz, Andrea; Latz, Eicke] Univ Bonn, Univ Hosp, Inst Innate Immun, Bonn, Germany. [Latz, Eicke] Univ Massachusetts, Sch Med, Dept Infect Dis & Immunol, Worcester, MA USA. [Latz, Eicke] German Ctr Neurodegenerat Dis, Bonn, Germany. [Masters, Seth L.] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia. RP O'Neill, LAJ (reprint author), Univ Dublin Trinity Coll, Trinity Biomed Sci Inst, Sch Biochem & Immunol, Dublin 2, Ireland. EM m.cooper@imb.uq.edu.au; laoneill@tcd.ie RI Butler, Mark/D-9973-2011; Schroder, Kate/C-6132-2008; Croker, Daniel/N-7134-2013; Coll, Rebecca/J-2124-2014; Cooper, Matthew/C-7988-2009; Vetter, Irina/A-6035-2010; Robertson, Avril/A-4043-2012; OI Butler, Mark/0000-0001-6689-4236; Mills, Kingston/0000-0003-3646-8222; Schroder, Kate/0000-0001-9261-3805; Croker, Daniel/0000-0001-9533-4019; Coll, Rebecca/0000-0002-7359-6023; Vetter, Irina/0000-0002-3594-9588; Robertson, Avril/0000-0002-9652-8357; masters, seth/0000-0003-4763-576X; Cooper, Matthew/0000-0003-3147-3460 FU Science Foundation Ireland [G20598, 11/PI/1036, 07/SRC/B1144]; Intramural Research Program of the National Human Genome Research Institute, US National Institutes of Health; Australian Research Council [FT130101215, FT130100361]; US National Institutes of Health [DK091191, DK095782]; German Research Foundation [SFB645, SFB670, SFB704, TRR57]; European Research Council (ERC, InflammAct); Excellence Cluster ImmunoSensation; VESKI innovation fellowship; National Health and Medical Research Council of Australia [1032065, 1057815]; Queensland Smart Futures Fund; ERC Advanced Grant [E12435] FX We thank A. Kitanovic (German Center for Neurodegenerative Diseases) for image analysis (Fig. 3c), S. Corr (Trinity College Dublin) for providing S. typhimurium UK-1 strain and H.M. Hoffman (University of California, San Diego) for providing Nlrp3 (A350VneoR) mice. This work was supported by the following funding bodies, grants and fellowships. L.A.J.O'N. and R.C.C.: Science Foundation Ireland (G20598). D.L.K. and J.J.C.: Intramural Research Program of the National Human Genome Research Institute, US National Institutes of Health. S.C.H., C.E.S. and K.H.G.M.: Science Foundation Ireland (11/PI/1036) and (07/SRC/B1144). I.V.: Australian Research Council (FT130101215). G.N.: US National Institutes of Health (DK091191) and (DK095782). E.L.: German Research Foundation (SFB645, SFB670, SFB704, TRR57), European Research Council (ERC, InflammAct) and Excellence Cluster ImmunoSensation. S.L.M.: VESKI innovation fellowship and National Health and Medical Research Council of Australia (1032065) and (1057815). K.S.: Queensland Smart Futures Fund and Australian Research Council (FT130100361). L.A.J.O'N.: ERC Advanced Grant (E12435). NR 59 TC 155 Z9 163 U1 31 U2 123 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD MAR PY 2015 VL 21 IS 3 BP 248 EP + DI 10.1038/nm.3806 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CC4YG UT WOS:000350362000017 PM 25686105 ER PT J AU Youm, YH Nguyen, KY Grant, RW Goldberg, EL Bodogai, M Kim, D D'Agostino, D Planavsky, N Lupfer, C Kanneganti, TD Kang, S Horvath, TL Fahmy, TM Crawford, PA Biragyn, A Alnemri, E Dixit, VD AF Youm, Yun-Hee Nguyen, Kim Y. Grant, Ryan W. Goldberg, Emily L. Bodogai, Monica Kim, Dongin D'Agostino, Dominic Planavsky, Noah Lupfer, Christopher Kanneganti, Thirumala D. Kang, Seokwon Horvath, Tamas L. Fahmy, Tarek M. Crawford, Peter A. Biragyn, Arya Alnemri, Emad Dixit, Vishwa Deep TI The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease SO NATURE MEDICINE LA English DT Article ID CALORIE RESTRICTION; OXIDATIVE STRESS; INNATE IMMUNITY; ACTIVATION; RECEPTOR; BODY; MECHANISMS; CRYSTALS; BODIES AB The ketone bodies beta-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP(1). BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet(2). Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown(2-6). We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K+ efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1 beta and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1 beta secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome. C1 [Youm, Yun-Hee; Nguyen, Kim Y.; Goldberg, Emily L.; Horvath, Tamas L.; Dixit, Vishwa Deep] Yale Univ, Sch Med, Comparat Med Sect, New Haven, CT 06510 USA. [Youm, Yun-Hee; Nguyen, Kim Y.; Goldberg, Emily L.; Horvath, Tamas L.; Dixit, Vishwa Deep] Yale Univ, Sch Med, Program Integrat Cell Signaling & Neurobiol Metab, New Haven, CT USA. [Grant, Ryan W.] Purdue Univ, Dept Nutr Sci, W Lafayette, IN 47907 USA. [Bodogai, Monica] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Kim, Dongin; Fahmy, Tarek M.] Yale Univ, Dept Biomed Engn, New Haven, CT USA. [D'Agostino, Dominic] Univ S Florida, Dept Mol Pharmacol & Physiol, Tampa, FL USA. [Planavsky, Noah] Yale Univ, Dept Geol & Geophys, New Haven, CT USA. [Lupfer, Christopher; Kanneganti, Thirumala D.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN USA. [Kang, Seokwon; Alnemri, Emad] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA. [Crawford, Peter A.] Sanford Burnham Med Res Inst, Diabet & Obes Res Ctr, Orlando, FL USA. [Dixit, Vishwa Deep] Yale Univ, Sch Med, Dept Immunol, New Haven, CT USA. RP Dixit, VD (reprint author), Yale Univ, Sch Med, Comparat Med Sect, New Haven, CT 06510 USA. EM vishwa.dixit@yale.edu RI D'Agostino, Dominic/I-6194-2012; OI Grant, Ryan/0000-0002-8940-4196 FU National Institute on Aging-Intramural Research Program; Office of Naval Research (ONR) [N000141310062]; National Institutes of Health [AG043608, AG31797, DK090556, AI105097] FX We thank M. Koch, Y. Kui, P. Chang and D. Albarado for technical assistance, and V.M. Dixit (Genentech) and R. Medzhitov (Yale School of Medicine) for helpful discussions and for providing knockout mice. Salmonella typhimurium and Francisella tularensis (U112) were provided by D. Monack (Stanford University School of Medicine) and J. Teale (University of Texas at San Antonio). M.B. and A.B. were supported by the National Institute on Aging-Intramural Research Program. D.D'A. was supported by the Office of Naval Research (ONR) Grant N000141310062. V.D.D. was supported in part by the grants from National Institutes of Health (AG043608, AG31797, DK090556 and AI105097). NR 35 TC 90 Z9 94 U1 11 U2 67 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD MAR PY 2015 VL 21 IS 3 BP 263 EP + DI 10.1038/nm.3804 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CC4YG UT WOS:000350362000019 PM 25686106 ER PT J AU Zhang, SL Qi, J Li, XP Wang, HL Britt, JP Hoffman, AF Bonci, A Lupica, CR Morales, M AF Zhang, Shiliang Qi, Jia Li, Xueping Wang, Hui-Ling Britt, Jonathan P. Hoffman, Alexander F. Bonci, Antonello Lupica, Carl R. Morales, Marisela TI Dopaminergic and glutamatergic microdomains in a subset of rodent mesoaccumbens axons SO NATURE NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; RELEASE GLUTAMATE; NUCLEUS-ACCUMBENS; RAT-BRAIN; NEURONS; INNERVATION; PROJECTIONS; SYNAPSES; MIDBRAIN AB Mesoaccumbens fibers are thought to co-release dopamine and glutamate. However, the mechanism is unclear, and co-release by mesoaccumbens fibers has not been documented. Using electron microcopy, we found that some mesoaccumbens fibers have vesicular transporters for dopamine (VMAT2) in axon segments that are continuous with axon terminals that lack VMAT2, but contain vesicular glutamate transporters type 2 (VGIuT2). In vivo overexpression of VMAT2 did not change the segregation of the two vesicular types, suggesting the existence of highly regulated mechanisms for maintaining this segregation. The mesoaccumbens axon terminals containing VGIuT2 vesicles make asymmetric synapses, commonly associated with excitatory signaling. Using optogenetics, we found that dopamine and glutamate were released from the same mesoaccumbens fibers. These findings reveal a complex type of signaling by mesoaccumbens fibers in which dopamine and glutamate can be released from the same axons, but are not normally released at the same site or from the same synaptic vesicles. C1 [Zhang, Shiliang; Qi, Jia; Li, Xueping; Wang, Hui-Ling; Morales, Marisela] NIDA, Neuronal Networks Sect, US Natl Inst Hlth, Baltimore, MD 21224 USA. [Britt, Jonathan P.; Bonci, Antonello] NIDA, Synapt Plast Sect, US Natl Inst Hlth, Baltimore, MD USA. [Hoffman, Alexander F.; Lupica, Carl R.] NIDA, Electrophysiol Res Sect, US Natl Inst Hlth, Baltimore, MD USA. RP Morales, M (reprint author), NIDA, Neuronal Networks Sect, US Natl Inst Hlth, Baltimore, MD 21224 USA. EM mmorales@intra.nida.nih.gov RI Hoffman, Alexander/H-3035-2012; Britt, Jonathan/D-8877-2011 OI Hoffman, Alexander/0000-0002-2676-0628; Britt, Jonathan/0000-0003-3044-9565 FU National Institute on Drug Abuse; [NS050274] FX The viral packaging and in vitro testing of the AAV-DIO-VMAT2(Myc) vector were done by the National Institute on Drug Abuse Intramural Research Program Optogenetics and Transgenic Technology Core (OTTC). We thank O. Kiehn and L. Borgius (Karolinska Institutet) for providing the Vglut2-Cre transgenic mice and K. Deisseroth (Stanford University) for the Th-Cre transgenic rats. Resources for three-dimensional analysis were supported by NS050274. The Intramural Research Program of the National Institute on Drug Abuse supported this work. NR 21 TC 47 Z9 47 U1 1 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD MAR PY 2015 VL 18 IS 3 BP 386 EP 392 DI 10.1038/nn.3945 PG 7 WC Neurosciences SC Neurosciences & Neurology GA CC2SO UT WOS:000350195100018 PM 25664911 ER PT J AU Koonin, EV Krupovic, M AF Koonin, Eugene V. Krupovic, Mart TI Evolution of adaptive immunity from transposable elements combined with innate immune systems SO NATURE REVIEWS GENETICS LA English DT Article ID CRISPR-CAS SYSTEMS; V(D)J RECOMBINATION; RNA-INTERFERENCE; MOBILE ELEMENTS; COMPARATIVE GENOMICS; ARGONAUTE PROTEINS; DEFENSE SYSTEMS; GENE-REGULATION; CELLULAR GENES; DNA AB Adaptive immune systems in prokaryotes and animals give rise to long-term memory through modification of specific genomic loci, such as by insertion of foreign (viral or plasmid) DNA fragments into clustered regularly interspaced short palindromic repeat (CRISPR) loci in prokaryotes and by V(D)J recombination of immunoglobulin genes in vertebrates. Strikingly, recombinases derived from unrelated mobile genetic elements have essential roles in both prokaryotic and vertebrate adaptive immune systems. Mobile elements, which are ubiquitous in cellular life forms, provide the only known, naturally evolved tools for genome engineering that are successfully adopted by both innate immune systems and genome-editing technologies. In this Opinion article, we present a general scenario for the origin of adaptive immunity from mobile elements and innate immune systems. C1 [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Krupovic, Mart] Inst Pasteur, Unite Biol Mol Gene Chez Extremophiles, F-75015 Paris, France. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov; krupovic@pasteur.fr RI Krupovic, Mart/I-4209-2012 OI Krupovic, Mart/0000-0001-5486-0098 FU US Department of Health and Human Services FX The authors thank K. Makarova for critical reading of the manuscript and comments. E.V.K is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 108 TC 34 Z9 34 U1 15 U2 83 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD MAR PY 2015 VL 16 IS 3 BP 184 EP 192 DI 10.1038/nrg3859 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA CB8PR UT WOS:000349893500012 PM 25488578 ER PT J AU Kourrich, S Calu, DJ Bonci, A AF Kourrich, Said Calu, Donna J. Bonci, Antonello TI Intrinsic plasticity: an emerging player in addiction SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID NUCLEUS-ACCUMBENS NEURONS; COCAINE-SEEKING BEHAVIOR; SELF-ADMINISTRATION SESSIONS; PAVLOVIAN APPROACH BEHAVIOR; CUE-INDUCED REINSTATEMENT; GOAL-DIRECTED BEHAVIORS; MEDIUM SPINY NEURONS; SIGMA-1 RECEPTOR; AMPA RECEPTORS; K+ CHANNELS AB Exposure to drugs of abuse, such as cocaine, leads to plastic changes in the activity of brain circuits, and a prevailing view is that these changes play a part in drug addiction. Notably, there has been intense focus on drug-induced changes in synaptic excitability and much less attention on intrinsic excitability factors (that is, excitability factors that are remote from the synapse). Accumulating evidence now suggests that intrinsic factors such as K+ channels are not only altered by cocaine but may also contribute to the shaping of the addiction phenotype. C1 [Kourrich, Said] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Calu, Donna J.; Bonci, Antonello] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Bonci, Antonello] Johns Hopkins Univ, Sch Med, Solomon H Snyder Neurosci Inst, Baltimore, MD USA. RP Kourrich, S (reprint author), Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. EM Said.Kourrich@UTSouthwestern.edu; antonello.bonci@nih.gov OI Calu, Donna/0000-0003-2377-9494 NR 184 TC 30 Z9 30 U1 4 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD MAR PY 2015 VL 16 IS 3 BP 173 EP + DI 10.1038/nrn3877 PG 12 WC Neurosciences SC Neurosciences & Neurology GA CC1NR UT WOS:000350108400012 PM 25697160 ER PT J AU Buchner, A Krumova, P Ganesan, S Bahr, M Eckermann, K Weishaupt, JH AF Buchner, Anja Krumova, Petranka Ganesan, Sundar Baehr, Mathias Eckermann, Katrin Weishaupt, Jochen H. TI Sumoylation of p35 Modulates p35/Cyclin-Dependent Kinase (Cdk) 5 Complex Activity SO NEUROMOLECULAR MEDICINE LA English DT Article DE Sumoylation; p35/Cdk5 activity; FRET/FLIM; Oxidative stress ID CYCLIN-DEPENDENT KINASE-5; NEURONAL-SPECIFIC ACTIVATOR; NUCLEAR-PORE COMPLEX; PARKINSONS-DISEASE; NEURITE OUTGROWTH; MOUSE MODEL; CELL-DEATH; SUMO; PROTEIN; PHOSPHORYLATION AB Cyclin-dependent kinase (Cdk) 5 is critical for central nervous system development and neuron-specific functions including neurite outgrowth as well as synaptic function and plasticity. Cdk5 activity requires association with one of the two regulatory subunits, called p35 and p39. p35 redistribution as well as misregulation of Cdk5 activity is followed by cell death in several models of neurodegeneration. Posttranslational protein modification by small ubiquitin-related modifier (SUMO) proteins (sumoylation) has emerged as key regulator of protein targeting and protein/protein interaction. Under cell-free in vitro conditions, we found p35 covalently modified by SUMO1. Using both biochemical and FRET-/FLIM-based approaches, we demonstrated that SUMO2 is robustly conjugated to p35 in cells and identified the two major SUMO acceptor lysines in p35, K246 and K290. Furthermore, different degrees of oxidative stress resulted in differential p35 sumoylation, linking oxidative stress that is encountered in neurodegenerative diseases to the altered activity of Cdk5. Functionally, sumoylation of p35 increased the activity of the p35/Cdk5 complex. We thus identified a novel neuronal SUMO target and show that sumoylation is a likely candidate mechanism for the rapid modulation of p35/Cdk5 activity in physiological situations as well as in disease. C1 [Buchner, Anja; Krumova, Petranka; Baehr, Mathias; Eckermann, Katrin; Weishaupt, Jochen H.] Univ Med Ctr Gottingen, Dept Neurol, D-37073 Gottingen, Germany. [Buchner, Anja; Eckermann, Katrin] Ctr Nanoscale Microscopy & Mol Physiol Brain CNMP, Gottingen, Germany. [Ganesan, Sundar] NIH, Bethesda, MD 20892 USA. RP Eckermann, K (reprint author), Univ Med Ctr Gottingen, Dept Neurol, Waldweg 33, D-37073 Gottingen, Germany. EM keckerm@gwdg.de; jochen.weishaupt@uni-ulm.de RI Baehr, Mathias/K-2188-2014 FU Cluster of Excellence; DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) FX We thank Christine Poser and Claudia Fokken for excellent technical support. We thank Ron Hay (University of Dundee, Dundee, UK) for providing us with the His6-SUMO1 and His6-SUMO2 plasmids, Frauke Melchior (ZMBH, Heidelberg, Germany) for the components used for the in vitro sumoylation assay and Gertrude Bunt (University Medical Center Gottingen, Gottingen, Germany) for mVenus and mTFP plasmids. This work was supported by the Cluster of Excellence and DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB). NR 56 TC 3 Z9 3 U1 1 U2 6 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 EI 1559-1174 J9 NEUROMOL MED JI Neuromol. Med. PD MAR PY 2015 VL 17 IS 1 BP 12 EP 23 DI 10.1007/s12017-014-8336-4 PG 12 WC Neurosciences SC Neurosciences & Neurology GA CB8VW UT WOS:000349910700002 PM 25391294 ER PT J AU Harmon, QE Huang, L Umbach, DM Klungsoyr, K Engel, SM Magnus, P Skjaerven, R Zhang, J Wilcox, AJ AF Harmon, Quaker E. Huang, Lisu Umbach, David M. Klungsoyr, Kari Engel, Stephanie M. Magnus, Per Skjaerven, Rolv Zhang, Jun Wilcox, Allen J. TI Risk of Fetal Death With Preeclampsia SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID MEDICAL BIRTH REGISTRY; GESTATIONAL-AGE; HYPERTENSIVE DISORDERS; PERINATAL EPIDEMIOLOGY; STILLBIRTH; PREGNANCY; MORTALITY; NORWAY AB OBJECTIVE: To estimate gestational age-specific risks of fetal death in pregnancies complicated by preeclampsia. METHODS: Population-based cohort study comprising all singleton births (N=554,333) without preexisting chronic hypertension recorded in the Norwegian Medical Birth Registry from 1999 to 2008. Additional data come from a subset of preeclamptic pregnancies enrolled in the Norwegian Mother and Child Cohort Study with available medical records (n=3,037). The risk of fetal death, expressed per 1,000 fetuses exposed to preeclampsia, was calculated using a life table approach. RESULTS: Preeclampsia was recorded in 3.8% (n=21,020) of all pregnancies. Risk of stillbirth was 3.6 per 1,000 overall and 5.2 per 1,000 among pregnancies with preeclampsia (relative risk 1.45, 95% confidence interval [CI] 1.20-1.76). However, relative risk of stillbirth was markedly elevated with preeclampsia in early pregnancy. At 26 weeks of gestation, there were 11.6 stillbirths per 1,000 pregnancies with preeclampsia compared with 0.1 stillbirths per 1,000 pregnancies without (relative risk 86, 95% CI 46-142). Fetal risk with preeclampsia declined as pregnancy advanced, but at 34 weeks of gestation remained more than sevenfold higher than pregnancies without preeclampsia. CONCLUSION: For clinical purposes, the fetal risk of death associated with preeclampsia begins when preeclampsia becomes clinically apparent. Using a method that takes into account the clinical diagnosis of preeclampsia and the population of fetuses at risk, we find a remarkably high relative risk of fetal death among pregnancies diagnosed with preeclampsia in the preterm period. C1 NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. Xinhua Hosp, Shanghai, Peoples R China. Shanghai Jiao Tong Univ, Sch Med, MOE Shanghai Key Lab Childrens Environm Hlth, Shanghai 200030, Peoples R China. Norwegian Inst Publ Hlth, Med Birth Registry Norway, Bergen, Norway. Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. Norwegian Inst Publ Hlth, Oslo, Norway. RP Wilcox, AJ (reprint author), NIEHS, Epidemiol Branch, POB 12233,MD A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wilcox@niehs.nih.gov OI Harmon, Quaker/0000-0002-5866-848X; Wilcox, Allen/0000-0002-3376-1311 FU Norwegian Ministry of Health; Ministry of Education and Research, National Institutes of Health, National Institute of Environmental Health Sciences [N01-ES-75558]; National Institutes of Health, National Institute of Neurological Disorders and Stroke [1 UO1 NS 047537-01, 2 UO1 NS 047537-06A1]; Norwegian Research Council/FUGE [151918/S10]; National Institute of Child Health and Human Development [R01HD058008]; Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES044003] FX The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, National Institutes of Health, National Institute of Environmental Health Sciences (contract no. N01-ES-75558), National Institutes of Health, National Institute of Neurological Disorders and Stroke (grant no. 1 UO1 NS 047537-01, grant no. 2 UO1 NS 047537-06A1), and the Norwegian Research Council/FUGE (grant no. 151918/S10). The validation of preeclampsia diagnoses was funded by the National Institute of Child Health and Human Development (R01HD058008, Principal Investigator S.M.E.). This research was supported in part (Allen J. Wilcox, David M. Umbach, Quaker E. Harmon) by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES044003). NR 27 TC 12 Z9 12 U1 3 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2015 VL 125 IS 3 BP 628 EP 635 DI 10.1097/AOG.0000000000000696 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CC1QY UT WOS:000350118100016 PM 25730226 ER PT J AU Bailit, JL Grobman, WA Rice, MM Reddy, UM Wapner, RJ Varner, MW Leveno, KJ Iams, JD Tita, ATN Saade, G Rouse, DJ Blackwell, SC AF Bailit, Jennifer L. Grobman, William A. Rice, Madeline Murguia Reddy, Uma M. Wapner, Ronald J. Varner, Michael W. Leveno, Kenneth J. Iams, Jay D. Tita, Alan T. N. Saade, George Rouse, Dwight J. Blackwell, Sean C. CA Eunice Kennedy Shriver Natl Inst TI Morbidly Adherent Placenta Treatments and Outcomes SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID ACCRETA AB OBJECTIVE: To describe recent maternal and neonatal delivery outcomes among women with a morbidly adherent placenta in major centers across the United States. METHODS: This study reviewed a cohort of 115,502 women and their neonates born in 25 hospitals in the United States between March 2008 and February 2011 from the Assessment of Perinatal EXcellence data set. All cases of morbidly adherent placenta were identified. Maternal demographics, procedures undertaken, and maternal and neonatal outcomes were analyzed. RESULTS: There were 158 women with a morbidly adherent placenta (1/731 births, 95% confidence interval 1/632-866). Eighteen percent of women with a morbidly adherent placenta were nulliparous and 37% had no prior cesarean delivery. Only 53% (84/158) were suspected to have a morbidly adherent placenta before delivery. Women with a prenatally suspected morbidly adherent placenta experienced large blood loss (33%), hysterectomy (92%), and intensive care unit admission (39%) compared with 19%, 45%, and 22%, respectively, in those not suspected prenatally to have a morbidly adherent placenta (P<.05 for all). CONCLUSION: Eighteen percent of women with a morbidly adherent placenta were nulliparous. Half of the morbidly adherent placenta cases were suspected before delivery and outcomes were poorer in this group, probably because the more clinically significant morbidly adherent placentas are more likely to be suspected before delivery. C1 [Bailit, Jennifer L.] Case Western Reserve Univ, Dept Obstet, MetroHlth Med Ctr, Cleveland, OH 44107 USA. [Bailit, Jennifer L.] Case Western Reserve Univ, Dept Gynecol, MetroHlth Med Ctr, Cleveland, OH 44107 USA. Northwestern Univ, Prentice Womens Hosp, Chicago, IL 60611 USA. Columbia Univ, New York, NY USA. Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ Texas Med Branch, Galveston, TX 77555 USA. Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Alabama Birmingham, Birmingham, AL USA. Brown Univ, Providence, RI 02912 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Bailit, JL (reprint author), Case Western Reserve Univ, Dept Obstet, MetroHlth Med Ctr, 2500 MetroHlth Dr, Cleveland, OH 44107 USA. EM jbailit@metrohealth.org RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118]; National Center for Research Resources (NCRR) [UL1 RR024989, 5UL1 RR025764]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118) and the National Center for Research Resources (NCRR; UL1 RR024989; 5UL1 RR025764). Sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. NR 8 TC 10 Z9 10 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2015 VL 125 IS 3 BP 683 EP 689 DI 10.1097/AOG.0000000000000680 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CC1QY UT WOS:000350118100023 PM 25730233 ER PT J AU Stratton, P Khachikyan, I Sinaii, N Ortiz, R Shah, J AF Stratton, Pamela Khachikyan, Izabella Sinaii, Ninet Ortiz, Robin Shah, Jay TI Association of Chronic Pelvic Pain and Endometriosis With Signs of Sensitization and Myofascial Pain SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID QUALITY-OF-LIFE; VAGINAL HYPERALGESIA; PRESSURE-PAIN; FIBROMYALGIA; HEALTH; WOMEN; SENSITIVITY; DYSFUNCTION; DIAGNOSIS; LOCATION AB OBJECTIVE: To evaluate sensitization, myofascial trigger points, and quality of life in women with chronic pelvic pain with and without endometriosis. METHODS: A cross-sectional prospective study of women aged 18-50 years with pain suggestive of endometriosis and healthy, pain-free volunteers without a history of endometriosis. Patients underwent a physiatric neuromusculoskeletal assessment of clinical signs of sensitization and myofascial trigger points in the abdominopelvic region. Pain symptoms, psychosocial, and quality-of-life measures were also assessed. All participants with pain underwent laparoscopic excision of suspicious lesions to confirm endometriosis diagnosis by histologic evaluation. RESULTS: Patients included 18 with current, biopsyproven endometriosis, 11 with pain only, and 20 healthy volunteers. The prevalence of sensitization as measured by regional allodynia and hyperalgesia was similar in both pain groups (83 and 82%) but much lower among healthy volunteers (15%, P<.001). Nearly all women with pain had myofascial trigger points (94 and 91%). Adjusting for study group, those with high anxiety (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.004-1.099, P=.031) and depression (OR 1.06, 95% CI 1.005-1.113, P=.032) scores were more likely to have sensitization. Pain patients with any history of endometriosis had the highest proportion of sensitization compared with the others (87% compared with 67% compared with 15%; P<.001). Adjusting for any history of endometriosis, those with myofascial trigger points were most likely sensitized (OR 9.41, 95% CI 1.77-50.08, P=.009). CONCLUSION: Sensitization and myofascial trigger points were common in women with pain regardless of whether they had endometriosis at surgery. Those with any history of endometriosis were most likely to have sensitization. Traditional methods of classifying endometriosis-associated pain based on disease, duration, and anatomy are inadequate and should be replaced by a mechanism-based evaluation, as our study illustrates. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. NIH, Biostat & Clin Epidemiol Serv, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Stratton, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Gynecol Consult Serv, Program Reprod & Adult Endocrinol, CRC, Bldg 10,Room 1-3140,10 Ctr Dr MSC 1109, Bethesda, MD 20892 USA. EM ps79c@nih.gov FU National Institutes of Health, Clinical Center; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Funded by the Intramural Program of the National Institutes of Health, Clinical Center, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and clinical trial NCT00073801. NR 41 TC 13 Z9 13 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2015 VL 125 IS 3 BP 719 EP 728 DI 10.1097/AOG.0000000000000663 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CC1QY UT WOS:000350118100027 PM 25730237 ER PT J AU Shea, MK Kritchevsky, SB Hsu, FC Nevitt, M Booth, SL Kwoh, CK McAlindon, TE Vermeer, C Drummen, N Harris, TB Womack, C Loeser, RF AF Shea, M. K. Kritchevsky, S. B. Hsu, F. -C. Nevitt, M. Booth, S. L. Kwoh, C. K. McAlindon, T. E. Vermeer, C. Drummen, N. Harris, T. B. Womack, C. Loeser, R. F. CA Hlth ABC Study TI The association between vitamin K status and knee osteoarthritis features in older adults: The Health, Aging and Body Composition Study SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Osteoarthritis; Nutrition; Phylloquinone; Vitamin K; Matrix gla protein; Epidemiology ID MATRIX GLA PROTEIN; BONE MORPHOGENETIC PROTEIN-2; COMMUNITY-DWELLING ADULTS; ARTICULAR-CARTILAGE; ELDERLY PERSONS; MENISCAL TEAR; CALCIUM; SYMPTOMS; CALCIFICATION; DEPOSITION AB Background: Vitamin K-dependent (VKD) proteins, including the mineralization inhibitor matrix-gla protein (MGP), are found in joint tissues including cartilage and bone. Previous studies suggest low vitamin K status is associated with higher osteoarthritis (OA) prevalence and incidence. Objective: To clarify what joint tissues vitamin K is relevant to in OA, we investigated the cross-sectional and longitudinal association between vitamin K status and knee OA structural features measured using magnetic resonance imaging (MRI). Methods: Plasma phylloquinone (PK, vitamin K1) and dephosphorylated-uncarboxylated MGP ((dp) ucMGP) were measured in 791 older community-dwelling adults who had bilateral knee MRIs (mean +/- SD age = 74 +/- 3 y; 67% female). The adjusted odds ratios (and 95% confidence intervals) [OR (95%CI)] for presence and progression of knee OA features according to vitamin K status were calculated using marginal models with generalized estimating equations (GEEs), adjusted for age, sex, body mass index (BMI), triglycerides and other pertinent confounders. Results: Longitudinally, participants with very low plasma PK (<0.2 nM) were more likely to have articular cartilage and meniscus damage progression after 3 years [OR (95% CIs): 1.7(1.0-3.0), 2.6(1.3-5.2) respectively] compared to sufficient PK (>= 1.0 nM). Higher plasma (dp) ucMGP (reflective of lower vitamin K status) was associated with higher odds of meniscus damage, osteophytes, bone marrow lesions, and subarticular cysts cross-sectionally [ORs (95% CIs) comparing highest to lowest quartile: 1.6(1.1-2.3); 1.7(1.1-2.5); 1.9(1.3-2.8); 1.5(1.0-2.1), respectively]. Conclusion: Community-dwelling men and women with very low plasma PK were more likely to have progression of articular cartilage and meniscus damage. Plasma (dp) ucMGP was associated with presence of knee OA features but not progression. Future studies are needed to clarify mechanisms underlying vitamin Ks role in OA. (C) 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Shea, M. K.; Booth, S. L.] Tufts Univ, USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Kritchevsky, S. B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Hsu, F. -C.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Nevitt, M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kwoh, C. K.] Univ Arizona, Div Rheumatol, Tucson, AZ USA. [McAlindon, T. E.] Tufts Med Ctr, Div Rheumatol, Boston, MA USA. [Vermeer, C.; Drummen, N.] VitaK, Maastricht, Netherlands. [Harris, T. B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Womack, C.] Univ Tennessee, Dept Prevent Med, Hlth Sci Ctr, Memphis, TN USA. [Loeser, R. F.] Univ N Carolina, Div Rheumatol Allergy & Immunol, Chapel Hill, NC USA. RP Shea, MK (reprint author), Tufts Univ, USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. EM kyla.shea@tufts.edu OI Vermeer, Cees/0000-0002-2300-8561 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institute of Arthritis Musculoskeletal and Skin Diseases [R21AR062284, K01AR063167]; Arthritis Foundation; U.S. Department of Agriculture, Agricultural Research Service [58-1950-7-707] FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, and contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; the National Institute of Arthritis Musculoskeletal and Skin Diseases (R21AR062284 and K01AR063167), a New Investigator Grant from the Arthritis Foundation and the U.S. Department of Agriculture, Agricultural Research Service under Cooperative Agreement No. 58-1950-7-707. NR 42 TC 8 Z9 8 U1 1 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD MAR PY 2015 VL 23 IS 3 BP 370 EP 378 DI 10.1016/j.joca.2014.12.008 PG 9 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA CB9PF UT WOS:000349963300005 PM 25528106 ER PT J AU Chong, CR Linnoila, I Janne, PA Johnson, BE Sholl, LM AF Chong, Curtis R. Linnoila, Ilona Jaenne, Pasi A. Johnson, Bruce E. Sholl, Lynette M. TI Pathologic Classification of Pulmonary Carcinoid Cell Lines SO PANCREAS LA English DT Meeting Abstract C1 [Chong, Curtis R.; Jaenne, Pasi A.; Johnson, Bruce E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Linnoila, Ilona] NCI, Bethesda, MD 20892 USA. [Sholl, Lynette M.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD MAR PY 2015 VL 44 IS 2 BP 347 EP 347 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CB6XF UT WOS:000349769400030 ER PT J AU Torre, P Yao, TJ Zeldow, B Williams, P Hoffman, HJ Siberry, GK AF Torre, Peter, III Yao, Tzy-Jyun Zeldow, Bret Williams, Paige Hoffman, Howard J. Siberry, George K. CA HIV AIDS Cohort Study PHACS TI Distortion Product Otoacoustic Emission Data in Perinatally HIV-infected and HIV-exposed but Uninfected Children and Adolescents in the Pediatric HIV/AIDS Cohort Study SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE perinatal HIV infection; perinatal HIV exposure; otoacoustic emissions; antiretroviral therapy AB The effect of perinatal HIV infection and exposure on sub-clinical auditory function can be measured with distortion product otoacoustic emissions (DPOAEs). DPOAEs were obtained at 4 frequency bins (1, 2, 3 and 4 kHz) and categorized by a signal-to-noise ratio. HIV infection was not associated with poorer DPOAEs. Among HIV-infected children, HIV viral load >= 400 copies/mL had significantly lower odds of better DPOAEs. C1 [Torre, Peter, III] San Diego State Univ, Sch Speech Language & Hearing Sci, San Diego, CA 92182 USA. [Yao, Tzy-Jyun; Zeldow, Bret; Williams, Paige] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, Bethesda, MD USA. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Torre, P (reprint author), San Diego State Univ, Sch Speech Language & Hearing Sci, 5500 Campanile Dr,SLHS 244, San Diego, CA 92182 USA. EM ptorre@mail.sdsu.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; Harvard University School of Public Health [HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3]; Tulane University School of Medicine [HD052104, 3U01 HD052104-06S1, 3U01HD052104-06S1] FX The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3) (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104, 3U01 HD052104-06S1) (Principal Investigator: Russell Van Dyke: Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Julie Davidson). The Pediatric HIV/AIDS Cohort Study (PHACS) was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3) and the Tulane University School of Medicine (HD052104, 3U01HD052104-06S1). The authors have no conflicts of interest to disclose. NR 10 TC 2 Z9 2 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD MAR PY 2015 VL 34 IS 3 BP 276 EP 278 DI 10.1097/INF.0000000000000598 PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA CB8VM UT WOS:000349909700017 PM 25742077 ER PT J AU Yeganeh, N Watts, HD Camarca, M Soares, G Joao, E Pilotto, JH Gray, G Theron, G Santos, B Fonseca, R Kreitchmann, R Pinto, J Mussi-Pinhata, M Ceriotto, M Machado, DM Veloso, VG Grinzstejn, B Morgado, MG Bryson, Y Mofenson, LM Nielsen-Saines, K AF Yeganeh, Nava Watts, Heather D. Camarca, Margaret Soares, Gabriel Joao, Esau Pilotto, Jose Henrique Gray, Glenda Theron, Gerhard Santos, Breno Fonseca, Rosana Kreitchmann, Regis Pinto, Jorge Mussi-Pinhata, Marisa Ceriotto, Mariana Machado, Daisy Maria Veloso, Valdilea G. Grinzstejn, Beatriz Morgado, Mariza G. Bryson, Yvonne Mofenson, Lynne M. Nielsen-Saines, Karin CA NICHD HPTP 040 P1043 Study Team TI Syphilis in HIV-infected Mothers and Infants Results from the NICHD/HPTN 040 Study SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE HIV mother to child transmission; congenital syphilis; prenatal care ID HUMAN-IMMUNODEFICIENCY-VIRUS; SERONEGATIVE SECONDARY SYPHILIS; TO-CHILD TRANSMISSION; CD4 CELL COUNTS; CONGENITAL-SYPHILIS; MATERNAL SYPHILIS; RISK-FACTORS; VIRAL LOAD; PREGNANCY; IDENTIFICATION AB Background: Untreated syphilis during pregnancy is associated with spontaneous abortion, stillbirth, prematurity and infant mortality. Syphilis may facilitate HIV transmission, which is especially concerning in low-and middle-income countries where both diseases are common. Methods: We performed an analysis of data available from NICHD/HPTN 040 (P1043), a study focused on the prevention of intrapartum HIV transmission to 1684 infants born to 1664 untreated HIV-infected women. This analysis evaluates risk factors and outcomes associated with a syphilis diagnosis in this cohort of HIV-infected women and their infants. Results: Approximately, 10% of women (n = 171) enrolled had serological evidence of syphilis without adequate treatment documented and 1.4% infants (n = 24) were dually HIV and syphilis infected. Multivariate logistic analysis showed that compared with HIV-infected women, co-infected women were significantly more likely to self-identify as non-white (adjusted odds ratio [AOR] 2.5, 95% CI: 1.5-4.2), to consume alcohol during pregnancy (AOR 1.5, 95% CI: 1.1-2.1) and to transmit HIV to their infants (AOR 2.1, 95% CI: 1.3-3.4), with 88% of HIV infections being acquired in utero. As compared with HIV-infected or HIV-exposed infants, co-infected infants were significantly more likely to be born to mothers with venereal disease research laboratory titers >= 1:16 (AOR 3, 95% CI: 1.1-8.2) and higher viral loads (AOR 1.5, 95% CI: 1.1-1.9). Of 6 newborns with symptomatic syphilis, 2 expired shortly after birth, and 2 were HIV-infected. Conclusion: Syphilis continues to be a common co-infection in HIV-infected women and can facilitate in utero transmission of HIV to infants. Most infants are asymptomatic at birth, but those with symptoms have high mortality rates. C1 [Yeganeh, Nava; Soares, Gabriel; Bryson, Yvonne; Nielsen-Saines, Karin] David Geffen UCLA Sch Med, Los Angeles, CA USA. [Watts, Heather D.; Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Camarca, Margaret] WESTAT Corp, Rockville, MD 20850 USA. [Joao, Esau] Hosp Fed Serv Estado, Rio De Janeiro, Brazil. [Pilotto, Jose Henrique] Hosp Geral Nova Iguacu, Nova Iguacu, Brazil. [Pilotto, Jose Henrique] Fundacao Oswaldo Cruz Fiocruz, Inst Oswaldo Cruz, Lab AIDS & Immnol Mol, Rio De Janeiro, Brazil. [Gray, Glenda] Univ Witwatersrand, Perinatal HIV Res Unit, Chris Hani Baragwanath Hosp, Johannesburg, South Africa. [Theron, Gerhard] Univ Stellenbosch, Tygerberg Hosp, Cape Town, South Africa. [Santos, Breno] Hosp Conceicao, Porto Alegre, RS, Brazil. [Fonseca, Rosana] Hosp Femina, Oporto, Portugal. [Kreitchmann, Regis] Irmandade Santa Casa Misericordia Porto Alegre, Porto Alegre, RS, Brazil. [Pinto, Jorge] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Mussi-Pinhata, Marisa] Univ Sao Paulo, BR-14049 Ribeirao Preto, SP, Brazil. [Ceriotto, Mariana] Fdn Maternal & Infant Hlth FUNDASAMIN, Buenos Aires, DF, Argentina. [Machado, Daisy Maria] Univ Fed Sao Paulo, Escola Paulista Med, Sao Paulo, Brazil. [Veloso, Valdilea G.; Grinzstejn, Beatriz; Morgado, Mariza G.] Fundacao Oswaldo Cruz Fiocruz, Lab Pesquisa Clin DST & AIDS, Inst Pesquisa Clin Evandro Chagas, Rio De Janeiro, Brazil. RP Yeganeh, N (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Div Infect Dis, MDCC 22-442 10833,Le Conte Ave, Los Angeles, CA 90095 USA. EM nyeganeh@mednet.ucla.edu FU NICHD [HHSN267200800001C, U01 AI047986]; UCLA Center for AIDS Research; UCLA AIDS Institute [5P30 AI28697]; Boehringer Ingelheim Pharmaceuticals Inc. (BIPI); GlaxoSmithKline on behalf of ViiV Healthcare FX The NICHD HPTN 040 study was supported by NICHD Contract # HHSN267200800001C (NICHD Control # N01-HD-8-0001) and U01 AI047986 (Brazilian AIDS Prevention Trials International Network), NIAID/NIH. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) (U01 AI068634), the Eunice Kennedy Skiver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (AI068632). This subanalysis was supported by the UCLA Center for AIDS Research and UCLA AIDS Institute (5P30 AI28697). In addition, the study was supported in part by Boehringer Ingelheim Pharmaceuticals Inc. (BIPI), and GlaxoSmithKline on behalf of ViiV Healthcare. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and were fully responsible for all aspects of manuscript development. Boehringer-Ingelheim Pharmaceuticals, Inc and GlaxoSmithKline were given the opportunity to check the data used in the present manuscript for factual accuracy only. We thank the patients and their families who enrolled in this trial; and Marita McDonough and Lauren Petrella from Boehringer Ingelheim Pharmaceuticals and Helen Watson from GlaxoSmithKline (on behalf of ViiV Healthcare) for assistance with the donation of study drugs from their respective companies for the conduct of the study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or US Department of Health and Human Services. NR 32 TC 10 Z9 11 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD MAR PY 2015 VL 34 IS 3 BP E52 EP E57 DI 10.1097/INF.0000000000000578 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA CB8VM UT WOS:000349909700004 PM 25742089 ER PT J AU Costa, VD Bradley, MM Lang, PJ AF Costa, Vincent D. Bradley, Margaret M. Lang, Peter J. TI From threat to safety: Instructed reversal of defensive reactions SO PSYCHOPHYSIOLOGY LA English DT Article DE Fear inhibition; Emotion regulation; Instructed fear; Threat of shock; Anticipation; Reversal learning ID FEAR-RELEVANT STIMULI; POTENTIATED STARTLE; ELECTRODERMAL RESPONSES; EMOTION REGULATION; AFFECTIVE PICTURE; EXTINCTION; REFLEX; SHOCK; PREPAREDNESS; ACQUISITION AB Cues that signal the possibility of receiving an electric shock reliably induce defensive activation. To determine whether cues can also easily reverse defensive reactions, a threat reversal paradigm was developed in which a cue signaling threat of shock reversed its meaning across the course of the study. This allowed us to contrast defensive reactions to threat cues that became safe cues, with responses to cues that continued to signal threat or safety. Results showed that, when participants were instructed that a previously threatening cue now signaled safety, there was an immediate and complete attenuation of defensive reactions compared to threat cues that maintained their meaning. These findings highlight the role that language can play both in instantiating and attenuating defensive reactions, with implications for understanding emotion regulation, social communication, and clinical phenomena. C1 [Costa, Vincent D.; Bradley, Margaret M.; Lang, Peter J.] Univ Florida, Ctr Study Emot & Attent, Gainesville, FL USA. [Costa, Vincent D.] NIMH, NIH, Bethesda, MD 20892 USA. RP Costa, VD (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49 Room B1EE17, Bethesda, MD 20892 USA. EM atsocvd@gmail.com OI Costa, Vincent/0000-0002-5412-8945 FU National Institute of Dental and Craniofacial Research [R01 DE 13956]; National Institute of Mental Health [P50 MH 72850, F31 MH 080551] FX This research was supported by grants from the National Institute of Dental and Craniofacial Research (R01 DE 13956) awarded to MMB, and from the National Institute of Mental Health awarded to PJL and MMB (P50 MH 72850) and to VDC (F31 MH 080551). NR 46 TC 4 Z9 4 U1 5 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD MAR PY 2015 VL 52 IS 3 BP 325 EP 332 DI 10.1111/psyp.12359 PG 8 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA CC0QD UT WOS:000350039700003 PM 25250656 ER PT J AU Puchner, SB Lu, MT Mayrhofer, T Liu, T Pursnani, A Ghoshhajra, BB Truong, QA Wiviott, SD Fleg, JL Hoffmann, U Ferencik, M AF Puchner, Stefan B. Lu, Michael T. Mayrhofer, Thomas Liu, Ting Pursnani, Amit Ghoshhajra, Brian B. Truong, Quynh A. Wiviott, Stephen D. Fleg, Jerome L. Hoffmann, Udo Ferencik, Maros TI High-Risk Coronary Plaque at Coronary CT Angiography Is Associated with Nonalcoholic Fatty Liver Disease, Independent of Coronary Plaque and Stenosis Burden: Results from the ROMICAT II Trial SO RADIOLOGY LA English DT Article ID SPIRAL COMPUTED-TOMOGRAPHY; HEPATIC STEATOSIS; INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC LESIONS; REACTIVE PROTEIN; UNITED-STATES; POPULATION; CALCIFICATION; SEVERITY; SCORE AB Purpose: To determine the association between nonalcoholic fatty liver disease (NAFLD) and the presence of high-risk coronary atherosclerotic plaque as assessed with coronary computed tomographic (CT) angiography. Materials and Methods: This study was approved by the local ethics committees; informed consent was obtained. Patients randomized to the coronary CT angiography arm of the Rule Out Myocardial Infarction using Computer Assisted Tomography, or ROMICAT, II trial who underwent both nonenhanced CT to assess calcium score and contrast material-enhanced coronary CT angiography were included. Readers assessed coronary CT angiography images for the presence of coronary plaque, significant stenosis (>= 50%), and high-risk plaque features (positive remodeling, CT attenuation < 30 HU, napkin-ring sign, spotty calcium). NAFLD was defined as hepatic steatosis at nonenhanced CT (liver minus spleen CT attenuation < 1 HU) without evidence of clinical liver disease, liver cirrhosis, or alcohol abuse. To determine the association between high-risk plaque and NAFLD, univariable and multivariable logistic regression analyses were performed, with high-risk plaque as a dependent variable and NAFLD, traditional risk factors, and extent of coronary atherosclerosis as independent variables. Results: Overall, 182 (40.9%) of 445 patients had CT evidence of NAFLD. High-risk plaque was more frequent in patients with NAFLD than in patients without NAFLD (59.3% vs 19.0%, respectively; P < .001). The association between NAFLD and high-risk plaque (odds ratio, 2.13; 95% confidence interval: 1.18, 3.85) persisted after adjusting for the extent and severity of coronary atherosclerosis and traditional risk factors. Conclusion: NAFLD is associated with advanced high-risk coronary plaque, independent of traditional cardiovascular risk factors and the extent and severity of coronary artery disease. (C) RSNA, 2014. C1 [Puchner, Stefan B.; Lu, Michael T.; Mayrhofer, Thomas; Liu, Ting; Pursnani, Amit; Ghoshhajra, Brian B.; Truong, Quynh A.; Hoffmann, Udo; Ferencik, Maros] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Puchner, Stefan B.; Lu, Michael T.; Mayrhofer, Thomas; Liu, Ting; Pursnani, Amit; Ghoshhajra, Brian B.; Truong, Quynh A.; Hoffmann, Udo; Ferencik, Maros] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Truong, Quynh A.; Ferencik, Maros] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Puchner, Stefan B.] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Vienna, Austria. [Wiviott, Stephen D.] Harvard Univ, Brigham & Womens Hosp, Div Cardiovasc Med, Sch Med, Boston, MA 02115 USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Puchner, SB (reprint author), Massachusetts Gen Hosp, Dept Radiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM sbpuchner@mgh.harvard.edu FU national Instittute of Health [U01HL092040, U01HL092022, 5T32 HL076136, 5K24HL113128, K23HL098370, L30HL093896] FX This research was supported by the national Instittute of Health (grant nos. U01HL092040, U01HL092022, 5T32 HL076136, 5K24HL113128, K23HL098370, L30HL093896, and 5T32 HL076136) NR 35 TC 18 Z9 18 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAR PY 2015 VL 274 IS 3 BP 693 EP 701 DI 10.1148/radiol.14140933 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CB9YK UT WOS:000349990500008 PM 25369449 ER PT J AU Michalopoulou, PG Averbeck, BB Kalpakidou, AK Evans, S Bobin, T Kapur, S Shergill, SS AF Michalopoulou, Panayiota G. Averbeck, Bruno B. Kalpakidou, Anastasia K. Evans, Simon Bobin, Tracey Kapur, Shitij Shergill, Sukhwinder S. TI The effects of a single dose of oxytocin on working memory in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Letter ID VASOPRESSIN; DOPAMINE C1 [Michalopoulou, Panayiota G.; Kalpakidou, Anastasia K.; Bobin, Tracey; Kapur, Shitij] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, Sect Schizophrenia Imaging & Therapeut, London SE5 8AF, England. [Averbeck, Bruno B.] NIMH, Neuropsychol Lab, Div Intramural Res Programs, Bethesda, MD 20892 USA. [Evans, Simon] Univ Sussex, Sch Psychol, Brighton, E Sussex, England. [Shergill, Sukhwinder S.] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, Cognit Schizophrenia & Imaging Lab, London SE5 8AF, England. RP Michalopoulou, PG (reprint author), Kings Coll London, Inst Psychiat Psychol & Neurosci, POB 053,16 Crespigny Pk, London SE5 8AF, England. EM panayiota.michalopoulou@kcl.ac.uk OI Kapur, Shitij/0000-0002-2231-2924 FU Intramural NIH HHS [ZIA MH002928-07]; Medical Research Council [G0701748] NR 10 TC 2 Z9 2 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR PY 2015 VL 162 IS 1-3 BP 62 EP 63 DI 10.1016/j.schres.2014.12.029 PG 2 WC Psychiatry SC Psychiatry GA CB9QI UT WOS:000349966400011 PM 25579054 ER PT J AU Magnus, MC Haberg, SE Karlstad, O Nafstad, P London, SJ Nystad, W AF Magnus, Maria C. Haberg, Siri E. Karlstad, Oystein Nafstad, Per London, Stephanie J. Nystad, Wenche TI Grandmother's smoking when pregnant with the mother and asthma in the grandchild: the Norwegian Mother and Child Cohort Study SO THORAX LA English DT Article ID IN-UTERO EXPOSURE; MATERNAL SMOKING; LUNG-FUNCTION; DNA METHYLATION; TOBACCO-SMOKE; COTININE CONCENTRATIONS; ADULT DISEASE; BIRTH COHORT; WEIGHT-GAIN; ORIGINS AB Background A trans-generational influence of prenatal tobacco smoke exposure on asthma development has been proposed but the evidence remains sparse. Methods We examined the grandmother's smoking when pregnant with the mother in relation to asthma outcomes in the grandchild (current asthma at 36 months (N=53 169, cases=3013), current asthma at 7 years (N=25 394, cases=1265) and dispensed asthma medications at 7 years in the Norwegian Prescription Database (N=45 607, cases=1787)) within the Norwegian Mother and Child Cohort Study (MoBa). We calculated adjusted RR (adj. RR) and 95% CIs using log binomial regression. Results A total of 23.5% of mothers reported that their mother smoked when pregnant with them. The grandmother's smoking when pregnant with the mother was positively associated with asthma at 36 months (adj. RR 1.15 (95% CI 1.06 to 1.24)), asthma at 7 years (adj. RR 1.21 (95% CI 1.07 to 1.37)) and dispensed asthma medications at 7 years (adj. RR 1.15 (95% CI 1.04 to 1.26)). This positive association did not differ significantly by the mother's smoking status when pregnant with the child (p values for multiplicative interaction >0.1). Conclusions The grandmother's smoking when pregnant with the mother increased the risk of asthma in the grandchild independent of the mother's smoking status. However, given limited information on the grandmother's socioeconomic status, asthma status and other factors, unmeasured confounding may be present. C1 [Magnus, Maria C.; Nafstad, Per; Nystad, Wenche] Norwegian Inst Publ Hlth, Dept Chron Dis, Div Epidemiol, N-0403 Oslo, Norway. [Haberg, Siri E.] Norwegian Inst Publ Hlth, Inst Management & Staff, N-0403 Oslo, Norway. [Karlstad, Oystein] Norwegian Inst Publ Hlth, Dept Pharmacoepidemiol, Div Epidemiol, N-0403 Oslo, Norway. [Nafstad, Per] Univ Oslo, Fac Med, Dept Community Med, Oslo, Norway. [London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Magnus, MC (reprint author), Norwegian Inst Publ Hlth, Dept Chron Dis, Div Epidemiol, POB 4404, N-0403 Oslo, Norway. EM maria.christine.magnus@fhi.no OI Karlstad, Oystein/0000-0003-1204-787X; London, Stephanie/0000-0003-4911-5290 FU NIH (NIH/NIEHS) [N01-ES-75558]; NIH (NIH/NINDS) [1 UO1 NS 047537-01, 2 UO1 NS 047537-06A1]; Norwegian Research Council/FUGE [151918/S10]; Intramural Research Program of the NIH, NIEHS [ZIA ES049019]; Norwegian Extra-Foundation for Health and Rehabilitation [2011.2.0218] FX The Norwegian Mother and Child Cohort Study is supported by NIH (NIH/NIEHS contract number N01-ES-75558, NIH/NINDS grant no. 1 UO1 NS 047537-01 and grant no. 2 UO1 NS 047537-06A1) and the Norwegian Research Council/FUGE (grant no. 151918/S10). Supported in part by the Intramural Research Program of the NIH, NIEHS (ZIA ES049019). Ms Magnus is also supported by the Norwegian Extra-Foundation for Health and Rehabilitation (grant no. 2011.2.0218). NR 35 TC 15 Z9 16 U1 1 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 EI 1468-3296 J9 THORAX JI Thorax PD MAR PY 2015 VL 70 IS 3 BP 237 EP 243 DI 10.1136/thoraxjnl-2014-206438 PG 7 WC Respiratory System SC Respiratory System GA CB8AL UT WOS:000349850300009 PM 25572596 ER PT J AU Koh, C Heller, T AF Koh, C. Heller, T. TI Letter: the potential success of long-term therapy of chronic delta hepatitis with peginterferon alfa - authors' reply SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Letter ID MANAGEMENT; VIRUS C1 [Koh, C.; Heller, T.] NIDDK, Translat Hepatol Unit, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Koh, C (reprint author), NIDDK, Translat Hepatol Unit, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM kohchris@mail.nih.gov; TheoH@intra.niddk.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD MAR PY 2015 VL 41 IS 6 BP 595 EP 596 DI 10.1111/apt.13079 PG 2 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA CB4SA UT WOS:000349617000014 PM 25659215 ER PT J AU Kitagaki, J Shi, GB Miyauchi, S Murakami, S Yang, YL AF Kitagaki, Jirouta Shi, Genbin Miyauchi, Shizuka Murakami, Shinya Yang, Yili TI Cyclic depsipeptides as potential cancer therapeutics SO ANTI-CANCER DRUGS LA English DT Review DE aplidine; cancer therapy; cryptophycin 1; cyclic depsipeptides; kahalalide F; LY355703; PM02734; romidepsin ID HISTONE DEACETYLASE INHIBITOR; SOUTHWEST-ONCOLOGY-GROUP; ADVANCED SOLID TUMORS; CELL LUNG-CANCER; PHASE-II TRIAL; CRYPTOPHYCIN ANALOG LY355703; CHROMOBACTERIUM-VIOLACEUM NO-968; BISINTERCALATOR NATURAL-PRODUCTS; REFRACTORY MULTIPLE-MYELOMA; NON-HODGKINS-LYMPHOMA AB Cyclic depsipeptides are polypeptides in which one or more amino acid is replaced by a hydroxy acid, resulting in the formation of at least one ester bond in the core ring structure. Many natural cyclic depsipeptides possessing intriguing structural and biological properties, including antitumor, antifungal, antiviral, antibacterial, anthelmintic, and anti-inflammatory activities, have been identified from fungi, plants, and marine organisms. In particular, the potent effects of cyclic depsipeptides on tumor cells have led to a number of clinical trials evaluating their potential as chemotherapeutic agents. Although many of the trials have not achieved the desired results, romidepsin (FK228), a bicyclic depsipeptide that inhibits histone deacetylase, has been shown to have clinical efficacy in patients with refractory cutaneous T-cell lymphoma and has received Food and Drug Administration approval for use in treatment. In this review, we discuss antitumor cyclic depsipeptides that have undergone clinical trials and focus on their structural features, mechanisms, potential applications in chemotherapy, and pharmacokinetic and toxicity data. The results of this study indicate that cyclic depsipeptides could be a rich source of new cancer therapeutics. C1 [Kitagaki, Jirouta; Miyauchi, Shizuka; Murakami, Shinya] Osaka Univ, Dept Periodontol, Div Oral Biol & Dis Control, Grad Sch Dent, Suita, Osaka 565, Japan. [Kitagaki, Jirouta] Osaka Univ, Challenge Intractable Oral Dis, Ctr Translat Dent Res, Dent Hosp, Suita, Osaka 565, Japan. [Shi, Genbin] NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21701 USA. [Yang, Yili] Second Mil Med Univ, Shanghai Changzheng Hosp, Ctr Translat Med, Shanghai, Peoples R China. RP Yang, YL (reprint author), Shanghai Changzheng Hosp, Ctr Translat Med, 800 Xiangyin Rd, Shanghai 200433, Peoples R China. EM nathanyang@hotmail.com FU [25862045]; [23249086] FX The authors started this work while both J.K. and Y.Y. were working at the Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health. They thank Dr Alan O. Perantoni for the encouragement and support. This work was supported in part by a Grant-in Aid for Scientific Research (No. 25862045, 23249086) to J.K. and S.M. NR 126 TC 6 Z9 6 U1 6 U2 65 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0959-4973 EI 1473-5741 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD MAR PY 2015 VL 26 IS 3 BP 259 EP 271 DI 10.1097/CAD.0000000000000183 PG 13 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA CB1KC UT WOS:000349385100002 PM 25419631 ER PT J AU Jerome, GJ Ko, SU Kauffman, D Studenski, SA Ferrucci, L Simonsick, EM AF Jerome, Gerald J. Ko, Seung-uk Kauffman, Danielle Studenski, Stephanie A. Ferrucci, Luigi Simonsick, Eleanor M. TI Gait characteristics associated with walking speed decline in older adults: Results from the Baltimore Longitudinal Study of Aging SO ARCHIVES OF GERONTOLOGY AND GERIATRICS LA English DT Article DE Gait; Stride length; Cadence; Aging; Functional decline ID RANDOMIZED CONTROLLED-TRIAL; MEANINGFUL CHANGE; CLINICAL-TRIAL; AGE; PERFORMANCE; PATTERNS; EXERCISE; PARAMETERS; MORTALITY; CADENCE AB Background: Understanding the mechanisms that contribute to walking speed decline can provide needed insight for developing targeted interventions to reduce the rate and likelihood of decline. Objective: Examine the association between gait characteristics and walking speed decline in older adults. Methods: Participants in the Baltimore Longitudinal Study of Aging aged 60 to 89 were evaluated in the gait laboratory which used a three dimensional motion capture system and force platforms to assess cadence, stride length, stride width, percent of gait cycle in double stance, anterior-posterior mechanical work expenditure (MWE), and medial-lateral MWE. Usual walking speed was assessed over 6 m at baseline and follow-up. Gait characteristics associated with meaningful decline (decline >= 0.05 m/s/y) in walking speed were evaluated by logistic regression adjusted for age, sex, race, height, weight, initial walking speed and follow-up time. Results: Among 362 participants, the average age was 72.4 (SD = 8.1) years, 51% were female, 27% were black and 23% were identified has having meaningful decline in usual walking speed with an average follow-up time of 3.2 (1.1) years. In the fully adjusted model, faster cadence [ORadj = 0.65, 95% CI (0.43,0.97)] and longer strides [ORadj = 0.87, 95% CI (0.83,0.91)] were associated with lower odds of decline. However age [ORadj = 1.04, 95% CI (0.99,1.10)] was not associated with decline when controlling for gait characteristics and other demographics. Conclusion: A sizable proportion of healthy older adults experienced walking speed decline over an average of 3 years. Longer stride and faster cadence were protective against meaningful decline in usual walking speed. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Jerome, Gerald J.] Towson Univ, Dept Kinesiol, Towson, MD 21252 USA. [Ko, Seung-uk] Chonnam Natl Univ, Dept Mech Engn, Yeosu, South Korea. [Kauffman, Danielle; Studenski, Stephanie A.; Ferrucci, Luigi; Simonsick, Eleanor M.] NIA, Longitudinal Sect, NIH, Baltimore, MD 21224 USA. RP Jerome, GJ (reprint author), Towson Univ, Dept Kinesiol, Towson, MD 21252 USA. EM gjerome@towson.edu FU Intramural Research Program of the National Institute on Aging [Z01 AG000015-50] FX This research was supported by the Intramural Research Program of the National Institute on Aging (Z01 AG000015-50). NR 26 TC 9 Z9 9 U1 5 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-4943 EI 1872-6976 J9 ARCH GERONTOL GERIAT JI Arch. Gerontol. Geriatr. PD MAR-APR PY 2015 VL 60 IS 2 BP 239 EP 243 DI 10.1016/j.archger.2015.01.007 PG 5 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CB5VF UT WOS:000349695000002 PM 25614178 ER PT J AU Banks, N Bryant, J Fischer, R Huizing, M Gahl, WA Gunay-Aygun, M AF Banks, Nicole Bryant, Joy Fischer, Roxanne Huizing, Marjan Gahl, William A. Gunay-Aygun, Meral TI Pregnancy in autosomal recessive polycystic kidney disease SO ARCHIVES OF GYNECOLOGY AND OBSTETRICS LA English DT Article DE Autosomal recessive polycystic kidney disease (ARPKD); Renal disease and pregnancy; Liver disease and pregnancy; Ciliopathy ID LIVER AB Autosomal recessive polycystic kidney disease (ARPKD) is the most common childhood-onset ciliopathy. As treatments improve, more women are reaching reproductive age, but little is known about ARPKD and pregnancy. In our ongoing study on ARPKD and other ciliopathies, 12 females over 18 years of age were identified and systematically evaluated. Six had children; four carried pregnancies and delivered, one used assisted reproductive technology and had a surrogate carry the pregnancy, and one adopted. We report the outcomes of four pregnancies with live birth deliveries and two women who chose alternate family building options. Patient one was diagnosed at 6 months, and at age 21 had a pregnancy complicated by transient worsening of renal function (creatinine increase from 1.15 to 1.78 mg/dL). Patient two was diagnosed with ARPKD at age seven and had an uncomplicated pregnancy at age 23. Patient three was diagnosed incidentally with ARPKD at age 23, 3 months after completion of an uncomplicated pregnancy. Patient four who had an uncomplicated pregnancy at age 33 was diagnosed with ARPKD at age 46. Women with ARPKD face reproductive decisions largely bereft of information about the pregnancies of other ARPKD patients. We report four cases of pregnancy and ARPKD to expand current knowledge and encourage further research. C1 [Banks, Nicole; Bryant, Joy; Fischer, Roxanne; Huizing, Marjan; Gahl, William A.; Gunay-Aygun, Meral] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Gahl, William A.; Gunay-Aygun, Meral] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Gunay-Aygun, M (reprint author), NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, 10 Ctr Dr,Bldg 10,Room 10C103CA, Bethesda, MD 20892 USA. EM mgaygun@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute; Office of Rare Diseases, National Institutes of Health, Bethesda, Maryland, USA FX This research was supported, in part, by the Intramural Research Program of the National Human Genome Research Institute and the Office of Rare Diseases, National Institutes of Health, Bethesda, Maryland, USA, and clinical trial NCT00068224. The authors thank the Autosomal Recessive Polycystic Kidney Disease/Congenital Hepatic Fibrosis Alliance for their extensive support and the patients and their families who generously participated in this investigation. NR 9 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0932-0067 EI 1432-0711 J9 ARCH GYNECOL OBSTET JI Arch. Gynecol. Obstet. PD MAR PY 2015 VL 291 IS 3 BP 705 EP 708 DI 10.1007/s00404-014-3445-8 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CB3TP UT WOS:000349552000036 PM 25214022 ER PT J AU Komatsu, M Kimura, T Yazaki, M Tanaka, N Yang, Y Nakajima, T Horiuchi, A Fang, ZZ Joshita, S Matsumoto, A Umemura, T Tanaka, E Gonzalez, FJ Ikeda, SI Aoyama, T AF Komatsu, Michiharu Kimura, Takefumi Yazaki, Masahide Tanaka, Naoki Yang, Yang Nakajima, Takero Horiuchi, Akira Fang, Zhong-Ze Joshita, Satoru Matsumoto, Akihiro Umemura, Takeji Tanaka, Eiji Gonzalez, Frank J. Ikeda, Shu-Ichi Aoyama, Toshifumi TI Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPAR alpha SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE Urea cycle disorder; SLC25A13; NAFLD; PPAR alpha; Mitochondrial beta-oxidation; JNK ID FATTY LIVER-DISEASE; ASPARTATE-GLUTAMATE CARRIER; CITRIN DEFICIENCY; SLC25A13 GENE; NONALCOHOLIC STEATOHEPATITIS; HEPATOCELLULAR-CARCINOMA; HEPATIC STEATOSIS; UREA CYCLE; MICE; EXPRESSION AB SLC25A13 (citrin or aspartate glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty add (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (camitine palmitoyl-CoA transferase 1 alpha, medium-and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial beta-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor a (PPAR alpha), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARa expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPAR alpha. Collectively, down-regulation of PPARa is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPAR alpha. (C) 2014 Elsevier B.V. All rights reserved. C1 [Komatsu, Michiharu; Kimura, Takefumi; Tanaka, Naoki; Joshita, Satoru; Matsumoto, Akihiro; Umemura, Takeji; Tanaka, Eiji] Shinshu Univ, Sch Med, Dept Med Gastroenterol, Matsumoto, Nagano 3908621, Japan. [Kimura, Takefumi; Tanaka, Naoki; Yang, Yang; Nakajima, Takero; Aoyama, Toshifumi] Shinshu Univ, Sch Med, Dept Metab Regulat, Matsumoto, Nagano 3908621, Japan. [Yazaki, Masahide; Ikeda, Shu-Ichi] Shinshu Univ, Sch Med, Dept Med Neurol & Rheumatol, Matsumoto, Nagano 3908621, Japan. [Yazaki, Masahide] Shinshu Univ, Inst Biomed Sci, Dept Biol Sci Intractable Neurol Dis, Matsumoto, Nagano 3908621, Japan. [Horiuchi, Akira] Showa Man Gen Hosp, Ctr Digest Dis, Tokyo, Japan. [Fang, Zhong-Ze] Tianjin Med Univ, Sch Publ Hlth, Dept Toxicol, Tianjin, Peoples R China. [Gonzalez, Frank J.] Natl Canc Inst, Natl Inst Hlth, Ctr Canc Res, Lab Metab, Rockville, MD USA. RP Tanaka, N (reprint author), Shinshu Univ, Sch Med, Dept Metab Regulat, Matsumoto, Nagano 3908621, Japan. EM naopi@shinshu-u.ac.jp NR 50 TC 7 Z9 7 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD MAR PY 2015 VL 1852 IS 3 BP 473 EP 481 DI 10.1016/j.bbadis.2014.12.011 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CB6LR UT WOS:000349739000010 PM 25533124 ER PT J AU Resnik, DB Elliott, KC AF Resnik, David B. Elliott, Kevin C. TI BISPHENOL A AND RISK MANAGEMENT ETHICS SO BIOETHICS LA English DT Article DE Bisphenol A; risk management; ethics; regulation; low dose effects; endocrine disruptors ID ENDOCRINE-DISRUPTING CHEMICALS; BROMINATED FLAME RETARDANTS; NONMONOTONIC DOSE-RESPONSES; WIDESPREAD EXPOSURE; HEALTH; CARCINOGENESIS; HORMESIS; SCIENCE; SAFETY; LEVEL AB It is widely recognized that endocrine disrupting compounds, such as Bisphenol A, pose challenges for traditional paradigms in toxicology, insofar as these substances appear to have a wider range of low-dose effects than previously recognized. These compounds also pose challenges for ethics and policymaking. When a chemical does not have significant low-dose effects, regulators can allow it to be introduced into commerce or the environment, provided that procedures and rules are in place to keep exposures below an acceptable level. This option allows society to maximize the benefits from the use of the chemical while minimizing risks to human health or the environment, and it represents a compromise between competing values. When it is not possible to establish acceptable exposure levels for chemicals that pose significant health or environmental risks, the most reasonable options for risk management may be to enact either partial or complete bans on their use. These options create greater moral conflict than other risk management strategies, leaving policymakers difficult choices between competing values. C1 [Resnik, David B.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Elliott, Kevin C.] Michigan State Univ, Lyman Briggs Coll, E Lansing, MI 48824 USA. [Elliott, Kevin C.] Michigan State Univ, Dept Fisheries & Wildlife, E Lansing, MI 48824 USA. RP Resnik, DB (reprint author), NIEHS, NIH, 111 Alexander Dr,Box 12233,MD CU 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-05] NR 56 TC 1 Z9 2 U1 2 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-9702 EI 1467-8519 J9 BIOETHICS JI Bioethics PD MAR PY 2015 VL 29 IS 3 BP 182 EP 189 DI 10.1111/bioe.12079 PG 8 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA CB4XL UT WOS:000349631600006 PM 24471646 ER PT J AU Rais-Bahrami, S Siddiqui, MM Vourganti, S Turkbey, B Rastinehad, AR Stamatakis, L Truong, H Walton-Diaz, A Hoang, AN Nix, JW Merino, MJ Wood, BJ Simon, RM Choyke, PL Pinto, PA AF Rais-Bahrami, Soroush Siddiqui, M. Minhaj Vourganti, Srinivas Turkbey, Baris Rastinehad, Ardeshir R. Stamatakis, Lambros Truong, Hong Walton-Diaz, Annerleim Hoang, Anthony N. Nix, Jeffrey W. Merino, Maria J. Wood, Bradford J. Simon, Richard M. Choyke, Peter L. Pinto, Peter A. TI Diagnostic value of biparametric magnetic resonance imaging (MRI) as an adjunct to prostate-specific antigen (PSA)-based detection of prostate cancer in men without prior biopsies SO BJU INTERNATIONAL LA English DT Article DE PSA; PSA density; prostate cancer detection; MRI ID TRANSRECTAL ULTRASOUND BIOPSY; RADICAL PROSTATECTOMY; ACTIVE SURVEILLANCE; MORTALITY; PREDICTION AB Objectives To determine the diagnostic yield of analysing biparametric (T2-and diffusion-weighted) magnetic resonance imaging (B-MRI) for prostate cancer detection compared with standard digital rectal examination (DRE) and prostate-specific antigen (PSA)-based screening. Patients and Methods Review of patients who were enrolled in a trial to undergo multiparametric-prostate (MP)-MRI and MR/ultrasound fusion-guided prostate biopsy at our institution identified 143 men who underwent MP-MRI in addition to standard DRE and PSA-based prostate cancer screening before any prostate biopsy. Patient demographics, DRE staging, PSA level, PSA density (PSAD), and B-MRI findings were assessed for association with prostate cancer detection on biopsy. Results Men with detected prostate cancer tended to be older, with a higher PSA level, higher PSAD, and more screen-positive lesions (SPL) on B-MRI. B-MRI performed well for the detection of prostate cancer with an area under the curve (AUC) of 0.80 (compared with 0.66 and 0.74 for PSA level and PSAD, respectively). We derived combined PSA and MRI-based formulas for detection of prostate cancer with optimised thresholds. (i) for PSA and B-MRI: PSA level + 6 x (the number of SPL) > 14 and (ii) for PSAD and B-MRI: 14 x (PSAD) + (the number of SPL) > 4.25. AUC for equations 1 and 2 were 0.83 and 0.87 and overall accuracy of prostate cancer detection was 79% in both models. Conclusions The number of lesions positive on B-MRI outperforms PSA alone in detection of prostate cancer. Furthermore, this imaging criteria coupled as an adjunct with PSA level and PSAD, provides even more accuracy in detecting clinically significant prostate cancer. C1 [Rais-Bahrami, Soroush; Siddiqui, M. Minhaj; Vourganti, Srinivas; Rastinehad, Ardeshir R.; Stamatakis, Lambros; Truong, Hong; Walton-Diaz, Annerleim; Hoang, Anthony N.; Nix, Jeffrey W.; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.; Pinto, Peter A.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. [Simon, Richard M.] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov OI Siddiqui, Mohummad/0000-0002-4484-6820; Rais-Bahrami, Soroush/0000-0001-9466-9925 FU Howard Hughes Medical Institute; Intramural NIH HHS NR 20 TC 25 Z9 25 U1 3 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD MAR PY 2015 VL 115 IS 3 BP 381 EP 388 DI 10.1111/bju.12639 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CC1OQ UT WOS:000350111100014 PM 24447678 ER PT J AU Rajaram, M AF Rajaram, Megha TI Breast Cancer in the Eighteenth Century SO BRITISH JOURNAL FOR THE HISTORY OF SCIENCE LA English DT Book Review C1 [Rajaram, Megha] NCI, Bethesda, MD 20892 USA. RP Rajaram, M (reprint author), NCI, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0007-0874 EI 1474-001X J9 BRIT J HIST SCI JI Br. J. Hist. Sci. PD MAR PY 2015 VL 48 IS 1 BP 177 EP 178 DI 10.1017/S000708741400096X PG 2 WC History & Philosophy Of Science SC History & Philosophy of Science GA CB5MJ UT WOS:000349671200009 ER PT J AU Memoli, MJ Czajkowski, L Reed, S Athota, R Bristol, T Proudfoot, K Fargis, S Stein, M Dunfee, RL Shaw, PA Davey, RT Taubenberger, JK AF Memoli, Matthew J. Czajkowski, Lindsay Reed, Susan Athota, Rani Bristol, Tyler Proudfoot, Kathleen Fargis, Sarah Stein, Matthew Dunfee, Rebecca L. Shaw, Pamela A. Davey, Richard T. Taubenberger, Jeffery K. TI Validation of the Wild-type Influenza A Human Challenge Model H1N1pdMIST: An A(H1N1) pdm09 Dose-Finding Investigational New Drug Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE influenza; H1N1; healthy volunteer; influenza A; challenge ID EXPERIMENTAL-INFECTION; VIRUS; VOLUNTEERS; OSELTAMIVIR; RESPONSES; ANTIBODY; CELL; VACCINATION; ANTIVIRALS; IMMUNITY AB Background. Healthy volunteer wild-type influenza challenge models offer a unique opportunity to evaluate multiple aspects of this important virus. Such studies have not been performed in the United States in more than a decade, limiting our capability to investigate this virus and develop countermeasures. We have completed the first ever wild-type influenza A challenge study under an Investigational New Drug application (IND). This dose-finding study will lead to further development of this model both for A(H1N1)pdm09 and other strains of influenza. Methods. Volunteers were admitted to an isolation unit at the National Institutes of Health Clinical Center for a minimum of 9 days. A reverse genetics, cell-based, Good Manufacturing Practice (GMP)-produced, wild-type A (H1N1) pdm09 virus was administered intranasally. Escalating doses were given until a dose was reached that produced disease in a minimum of 60% of volunteers. Results. An optimal dose of 107 tissue culture infectious dose 50 was reached that caused mild to moderate influenza disease in 69% of individuals with mean viral shedding for 4-5 days and significant rises in convalescent influenza antibody titers. Viral shedding preceded symptoms by 12-24 hours and terminated 2-3 days prior to symptom resolution, indicating that individuals may be infectious before symptom development. As expected, nasal congestion and rhinorrhea were most common, but interestingly, fever was observed in only 10% of individuals. Conclusions. This study represents the first healthy volunteer influenza challenge model using a GMP-produced wild-type virus under an IND. This unique clinical research program will facilitate future studies of influenza pathogenesis, animal model validation, and the rapid, efficient, and cost-effective evaluation of efficacy of novel vaccines and therapeutics. C1 [Memoli, Matthew J.; Czajkowski, Lindsay; Reed, Susan; Athota, Rani; Bristol, Tyler; Proudfoot, Kathleen; Fargis, Sarah; Stein, Matthew; Dunfee, Rebecca L.; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Shaw, Pamela A.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Davey, Richard T.] NIAID, Clin Res Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Memoli, MJ (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, MSC 3203,33 North Dr, Bethesda, MD 20892 USA. EM memolim@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID); NIAID Extramural Clinical Research Acceleration Program FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), as well as the NIAID Extramural Clinical Research Acceleration Program. NR 37 TC 14 Z9 14 U1 0 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 1 PY 2015 VL 60 IS 5 BP 693 EP 702 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CB6VY UT WOS:000349766100006 PM 25416753 ER PT J AU Lough, ME Seidel, GD AF Lough, Mary E. Seidel, Geoffrey D. TI Legal and Clinical Issues in Genetics and Genomics SO CLINICAL NURSE SPECIALIST LA English DT Editorial Material C1 [Lough, Mary E.] Stanford Healthcare, Stanford, CA USA. [Lough, Mary E.] Stanford Univ, Stanford, CA 94305 USA. [Seidel, Geoffrey D.] Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Leidos Biomed Res Inc, Frederick, MD USA. RP Lough, ME (reprint author), Stanford Hlth Care, Nursing Educ & Practice, 300 Pasteur Dr,H0105,MC 5221, Stanford, CA 94070 USA. EM Mlough@stanfordhealthcare.org FU PHS HHS [HHSN261200800001E] NR 11 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0887-6274 EI 1538-9782 J9 CLIN NURSE SPEC JI Clin. Nurse Spec. PD MAR-APR PY 2015 VL 29 IS 2 BP 68 EP 70 DI 10.1097/NUR.0000000000000101 PG 3 WC Nursing SC Nursing GA CB3XT UT WOS:000349563500143 PM 25654702 ER PT J AU Benson, BE Guyer, AE Nelson, EE Pine, DS Ernst, M AF Benson, Brenda E. Guyer, Amanda E. Nelson, Eric E. Pine, Daniel S. Ernst, Monique TI Role of contingency in striatal response to incentive in adolescents with anxiety SO COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE LA English DT Article DE Anxiety; Self-control; Agency; Reward; Caudate ID BEHAVIORAL-INHIBITION; MOTIVATED BEHAVIOR; SOCIAL ANXIETY; EMOTIONAL DISORDERS; ATTENTIONAL BIAS; BASAL GANGLIA; REWARD; UNCERTAINTY; CORTEX; VISUALIZATION AB This study examines the effect of contingency on reward function in anxiety. We define contingency as the aspect of a situation in which the outcome is determined by one's action-that is, when there is a direct link between one's action and the outcome of the action. Past findings in adolescents with anxiety or at risk for anxiety have revealed hypersensitive behavioral and neural responses to higher value rewards with correct performance. This hypersensitivity to highly valued (salient) actions suggests that the value of actions is determined not only by outcome magnitude, but also by the degree to which the outcome is contingent on correct performance. Thus, contingency and incentive value might each modulate reward responses in unique ways in anxiety. Using fMRI with a monetary reward task, striatal response to cue anticipation is compared in 18 clinically anxious and 20 healthy adolescents. This task manipulates orthogonally reward contingency and incentive value. Findings suggest that contingency modulates the neural response to incentive magnitude differently in the two groups. Specifically, during the contingent condition, right-striatal response tracks incentive value in anxious, but not healthy, adolescents. During the noncontingent condition, striatal response is bilaterally stronger to low than to high incentive in anxious adolescents, while healthy adolescents exhibit the expected opposite pattern. Both contingency and reward magnitude differentiate striatal activation in anxious versus healthy adolescents. These findings may reflect exaggerated concern about performance and/or alterations of striatal coding of reward value in anxious adolescents. Abnormalities in reward function in anxiety may have treatment implications. C1 [Benson, Brenda E.; Nelson, Eric E.; Pine, Daniel S.; Ernst, Monique] NIMH, Sect Dev & Affect Neurosci, Davis, MD 20892 USA. [Guyer, Amanda E.] Univ Calif Davis, Ctr Mind & Brain, Davis, CA 95616 USA. RP Ernst, M (reprint author), NIMH, Sect Dev & Affect Neurosci, 15K North Dr Bethesda, Davis, MD 20892 USA. EM ernstm@mail.nih.gov OI Nelson, Eric/0000-0002-3376-2453 FU Intramural Research Program of the National Institute of Mental Health (National Institutes of Health) FX This work was supported by the Intramural Research Program of the National Institute of Mental Health (National Institutes of Health). We wish to thank the subjects and their families. We also wish to thank Rista Plate, Allison M Detloff, and Nevia Pavletic for their help in the study and manuscript preparation. NR 53 TC 2 Z9 2 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-7026 EI 1531-135X J9 COGN AFFECT BEHAV NE JI Cogn. Affect. Behav. Neurosci. PD MAR PY 2015 VL 15 IS 1 BP 155 EP 168 DI 10.3758/s13415-014-0307-6 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CB6ST UT WOS:000349757700013 PM 25183555 ER PT J AU Wallin, MT Oh, U Nyalwidhe, J Semmes, J Kislinger, T Coffman, P Kurtzke, JF Jacobson, S AF Wallin, M. T. Oh, U. Nyalwidhe, J. Semmes, J. Kislinger, T. Coffman, P. Kurtzke, J. F. Jacobson, S. TI Serum proteomic analysis of a pre-symptomatic multiple sclerosis cohort SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE epidemiology; multiple sclerosis; proteomics ID CEREBROSPINAL-FLUID; IDENTIFICATION; BIOMARKERS; PROTEINS; EAE; MS AB Background and purposeSusceptibility to multiple sclerosis (MS) is determined by environmental and genetic factors, but the cause remains unknown. Changes to the proteome prior to first symptom onset may reflect the underlying pathophysiology of the disease. MethodsThis preliminary study utilized pre-symptomatic and post-symptomatic serum from a sample of 100 incident population-based US military veterans with MS along with 100 matched healthy controls. All samples were obtained from the Department of Defense Serum Repository. Multidimensional protein identification technology tandem mass spectrometry analysis was performed on tryptic peptides of lectin-captured glycosylated serum proteins following albumin/immunoglobulin G depletion. Identified proteins were analyzed with the Ingenuity Pathway Analysis program. ResultsThe mean intervals between first symptom onset and the collection of pre-symptomatic and post-symptomatic sera were -6.0 and +1.1years, respectively. Pre-symptomatic proteins from the MS group were differentially regulated compared with both control groups indicating that proteomic changes are detected prior to symptom onset. Pathway analysis showed that proteins involved in the complement and coagulation pathways and lipid transport are significantly altered in the serum of subjects with MS compared with healthy donors. ConclusionsCompared with healthy controls, differential proteomic changes were noted in the serum of patients with MS that preceded the onset of symptomatic disease. Further work is in progress to confirm or refute these findings. C1 [Wallin, M. T.; Coffman, P.; Kurtzke, J. F.] VA Multiple Sclerosis Ctr Excellence East, Washington, DC USA. [Wallin, M. T.; Kurtzke, J. F.] Georgetown Univ, Sch Med, Washington, DC USA. [Oh, U.] Virginia Commonwealth Univ, Sch Med, Richmond, VA USA. [Nyalwidhe, J.; Semmes, J.] Eastern Virginia Med Sch, Leroy T Canoles Jr Canc Res Ctr, Norfolk, VA 23501 USA. [Kislinger, T.] Univ Toronto, Toronto, ON, Canada. [Jacobson, S.] NINDS, NIH, Bethesda, MD 20892 USA. RP Wallin, MT (reprint author), VA Med Ctr, Neurol Serv, 127,50 Irving St NW, Washington, DC 20422 USA. EM mitchell.wallin@va.gov FU National Multiple Sclerosis Society [PP1368]; VA Merit Review [EPID-009-06F]; NIH CTSA [KL2TR000057]; VA Multiple Sclerosis Center of Excellence - East FX The following members of the Walter Reed Medical Center Neurology Department were collaborators on this project: Steven Lewis, Anthony Frattalone and Daniel Correa. Data were obtained from the Defense Medical Surveillance Center, Silver Spring, MD. Serum specimens were from the DoDSR, Silver Spring, MD (data from 1987 to 2007, released in 2010). Support for this study was provided by a National Multiple Sclerosis Society Pilot Grant (PP1368) and in part by VA Merit Review (EPID-009-06F), NIH CTSA (KL2TR000057 to U.O.) and the VA Multiple Sclerosis Center of Excellence - East. NR 20 TC 3 Z9 3 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 EI 1468-1331 J9 EUR J NEUROL JI Eur. J. Neurol. PD MAR PY 2015 VL 22 IS 3 BP 591 EP 599 DI 10.1111/ene.12534 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CB5OA UT WOS:000349676000027 PM 25104396 ER PT J AU Paul, L Jacques, PF Aviv, A Vasan, RS D'Agostino, RB Levy, D Selhub, J AF Paul, Ligi Jacques, Paul F. Aviv, Abraham Vasan, Ramachandran S. D'Agostino, Ralph B. Levy, Daniel Selhub, Jacob TI High plasma folate is negatively associated with leukocyte telomere length in Framingham Offspring cohort SO EUROPEAN JOURNAL OF NUTRITION LA English DT Article DE Telomere length; Folate; Multivitamins; Folic acid fortification ID FOLIC-ACID SUPPLEMENTATION; BREAST-CANCER; ALZHEIMERS-DISEASE; PERNICIOUS-ANEMIA; HUMAN FIBROBLASTS; MULTIVITAMIN USE; MAMMALIAN-CELLS; RISK; HOMOCYSTEINE; METABOLISM AB Shortening of telomeres, the protective structures at the ends of eukaryotic chromosomes, is associated with age-related pathologies. Telomere length is influenced by DNA integrity and DNA and histone methylation. Folate plays a role in providing precursors for nucleotides and methyl groups for methylation reactions and has the potential to influence telomere length. We determined the association between leukocyte telomere length and long-term plasma folate status (mean of 4 years) in Framingham Offspring Study (n = 1,044, females = 52.1 %, mean age 59 years) using data from samples collected before and after folic acid fortification. Leukocyte telomere length was determined by Southern analysis and fasting plasma folate concentration using microbiological assay. There was no significant positive association between long-term plasma folate and leukocyte telomere length among the Framingham Offspring Study participants perhaps due to their adequate folate status. While the leukocyte telomere length in the second quintile of plasma folate was longer than that in the first quintile, the difference was not statistically significant. The leukocyte telomere length of the individuals in the fifth quintile of plasma folate was shorter than that of those in the second quintile by 180 bp (P < 0.01). There was a linear decrease in leukocyte telomere length with higher plasma folate concentrations in the upper four quintiles of plasma folate (P for trend = 0.001). Multivitamin use was associated with shorter telomeres in this cohort (P = 0.015). High plasma folate status possibly resulting from high folic acid intake may interfere with the role of folate in maintaining telomere integrity. C1 [Paul, Ligi; Jacques, Paul F.; Selhub, Jacob] Tufts Univ, JM USDA HNRC, Boston, MA 02111 USA. [Aviv, Abraham] Univ Med & Dent New Jersey, Ctr Human Dev & Aging, Newark, NJ 07103 USA. [Vasan, Ramachandran S.; D'Agostino, Ralph B.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. RP Paul, L (reprint author), Tufts Univ, JM USDA HNRC, 711 Washington St, Boston, MA 02111 USA. EM Ligi.Paul_Pottenplackel@tufts.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU United States Department of Agriculture [51520-008-04S]; National Heart Lung and Blood Institute, Framingham Heart Study (NHLBI/NIH) [N01-HC-25195]; Boston University School of Medicine FX Support from United States Department of Agriculture Cooperative Agreement 51520-008-04S, National Heart Lung and Blood Institute, Framingham Heart Study (NHLBI/NIH Contract #N01-HC-25195) and Boston University School of Medicine. Any opinions, findings, conclusion or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the United States Department of Agriculture. NR 51 TC 5 Z9 5 U1 0 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1436-6207 EI 1436-6215 J9 EUR J NUTR JI Eur. J. Nutr. PD MAR PY 2015 VL 54 IS 2 BP 235 EP 241 DI 10.1007/s00394-014-0704-1 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CB6WF UT WOS:000349766800008 PM 24793435 ER PT J AU Hosgood, HD Song, MS Hsiung, CA Yin, ZH Shu, XO Wang, ZM Chatterjee, N Zheng, W Caporaso, N Burdette, L Yeager, M Berndt, SI Landi, MT Chen, CJ Chang, GC Hsiao, CF Tsai, YH Chien, LH Chen, KY Huang, MS Su, WC Chen, YM Chen, CH Yang, TY Wang, CL Hung, JY Lin, CC Perng, RP Chen, CY Chen, KC Li, YJ Yu, CJ Chen, YS Chen, YH Tsai, FY Kim, C Seow, WJ Bassig, BA Wu, W Guan, P He, QC Gao, YT Cai, QY Chow, WH Xiang, YB Lin, DX Wu, C Wu, YL Shin, MH Hong, YC Matsuo, K Chen, KX Wong, MP Lu, DR Jin, L Wang, JC Seow, A Wu, TC Shen, HB Fraumeni, JF Yang, PC Chang, IS Zhou, BS Chanock, SJ Rothman, N Lan, Q AF Hosgood, H. Dean, III Song, Minsun Hsiung, Chao Agnes Yin, Zhihua Shu, Xiao-Ou Wang, Zhaoming Chatterjee, Nilanjan Zheng, Wei Caporaso, Neil Burdette, Laurie Yeager, Meredith Berndt, Sonja I. Landi, Maria Teresa Chen, Chien-Jen Chang, Gee-Chen Hsiao, Chin-Fu Tsai, Ying-Huang Chien, Li-Hsin Chen, Kuan-Yu Huang, Ming-Shyan Su, Wu-Chou Chen, Yuh-Min Chen, Chung-Hsing Yang, Tsung-Ying Wang, Chih-Liang Hung, Jen-Yu Lin, Chien-Chung Perng, Reury-Perng Chen, Chih-Yi Chen, Kun-Chieh Li, Yao-Jen Yu, Chong-Jen Chen, Yi-Song Chen, Ying-Hsiang Tsai, Fang-Yu Kim, Christopher Seow, Wei Jie Bassig, Bryan A. Wu, Wei Guan, Peng He, Qincheng Gao, Yu-Tang Cai, Qiuyin Chow, Wong-Ho Xiang, Yong-Bing Lin, Dongxin Wu, Chen Wu, Yi-Long Shin, Min-Ho Hong, Yun-Chul Matsuo, Keitaro Chen, Kexin Wong, Maria Pik Lu, Dara Jin, Li Wang, Jiu-Cun Seow, Adeline Wu, Tangchun Shen, Hongbing Fraumeni, Joseph F., Jr. Yang, Pan-Chyr Chang, I-Shou Zhou, Baosen Chanock, Stephen J. Rothman, Nathaniel Lan, Qing TI Interactions between household air pollution and GWAS-identified lung cancer susceptibility markers in the Female Lung Cancer Consortium in Asia (FLCCA) SO HUMAN GENETICS LA English DT Article ID GENE-ENVIRONMENT INDEPENDENCE; COAL COMBUSTION EMISSIONS; XUAN-WEI; POOLED ANALYSIS; NEVER SMOKERS; RISK; INDOOR; CHINA; ASSOCIATION; ADENOCARCINOMA AB We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene-HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n = 3; 1,731 cases; 1,349 controls). Coal use was associated with a 30 % increased risk of lung cancer (OR 1.3, 95 % CI 1.0-1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations. C1 [Hosgood, H. Dean, III] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Hosgood, H. Dean, III; Song, Minsun; Chatterjee, Nilanjan; Caporaso, Neil; Berndt, Sonja I.; Landi, Maria Teresa; Kim, Christopher; Seow, Wei Jie; Bassig, Bryan A.; Fraumeni, Joseph F., Jr.; Chanock, Stephen J.; Rothman, Nathaniel; Lan, Qing] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Hsiung, Chao Agnes; Hsiao, Chin-Fu; Chien, Li-Hsin; Chen, Yi-Song; Chen, Ying-Hsiang] Natl Hlth Res Inst, Inst Populat Hlth Sci, Zhunan, Taiwan. [Yin, Zhihua; Wu, Wei; Guan, Peng; He, Qincheng; Zhou, Baosen] China Med Univ, Sch Publ Hlth, Dept Epidemiol, Shenyang 110001, Peoples R China. [Shu, Xiao-Ou; Zheng, Wei; Cai, Qiuyin] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol, Nashville, TN USA. [Shu, Xiao-Ou; Zheng, Wei; Cai, Qiuyin] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Wang, Zhaoming; Burdette, Laurie; Yeager, Meredith] Natl Canc Inst Frederick, Core Genotype Facil, SAIC Frederick, NIH, Frederick, MD USA. [Chen, Chien-Jen; Li, Yao-Jen] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan. [Chang, Gee-Chen] Natl Yang Ming Univ, Sch Med, Dept Med, Taipei 112, Taiwan. [Chang, Gee-Chen; Yang, Tsung-Ying; Chen, Kun-Chieh] Taichung Vet Gen Hosp, Div Chest Med, Taichung, Taiwan. [Tsai, Ying-Huang] Chang Gung Mem Hosp, Dept Resp Therapy, Chiayi, Taiwan. [Chen, Kuan-Yu; Yu, Chong-Jen] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan. [Huang, Ming-Shyan; Hung, Jen-Yu] Kaohsiung Med Univ, Sch Med, Kaohsiung Med Univ Hosp, Dept Internal Med, Kaohsiung, Taiwan. [Su, Wu-Chou; Lin, Chien-Chung] Cheng Kung Univ, Coll Med, Natl Cheng Kung Univ Hosp, Dept Internal Med, Tainan, Taiwan. [Chen, Yuh-Min; Perng, Reury-Perng] Taipei Vet Gen Hosp, Chest Dept, Taipei, Taiwan. [Chen, Chung-Hsing; Tsai, Fang-Yu; Chang, I-Shou] Natl Hlth Res Inst, Natl Inst Canc Res, Zhunan, Taiwan. [Wang, Chih-Liang] Chang Gung Mem Hosp, Dept Pulm & Crit Care, Taoyuan, Taiwan. [Chen, Chih-Yi] China Med Univ & Hosp, Ctr Canc, Taichung, Taiwan. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Lin, Dongxin; Wu, Chen] Chinese Acad Med Sci, State Key Lab Mol Oncol, Beijing 100730, Peoples R China. [Lin, Dongxin; Wu, Chen] Chinese Acad Med Sci, Dept Etiol & Carcinogenesis, Canc Inst & Hosp, Beijing 100730, Peoples R China. [Lin, Dongxin; Wu, Chen] Peking Union Med Coll, Beijing 100021, Peoples R China. [Wu, Yi-Long] Guangdong Acad Med Sci, Med Res Ctr, Guangdong Lung Canc Inst, Guangzhou, Guangdong, Peoples R China. [Wu, Yi-Long] Guangdong Acad Med Sci, Ctr Canc, Guangdong Gen Hosp, Guangzhou, Guangdong, Peoples R China. [Shin, Min-Ho] Chonnam Natl Univ, Sch Med, Dept Prevent Med, Kwangju, South Korea. [Hong, Yun-Chul] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Matsuo, Keitaro] Kyushu Univ, Dept Prevent Med, Fac Med Sci, Fukuoka 812, Japan. [Chen, Kexin] Tianjin Med Univ, Canc Inst & Hosp, Dept Epidemiol & Biostat, Tianjin, Peoples R China. [Wong, Maria Pik] Univ Hong Kong, LKS Fac Med, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Lu, Dara; Jin, Li; Wang, Jiu-Cun] Fudan Univ, Minist Educ, Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Lu, Dara; Jin, Li; Wang, Jiu-Cun] Fudan Univ, State Key Lab Genet Engn, Sch Life Sci, Shanghai 200433, Peoples R China. [Seow, Adeline] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Wu, Tangchun] Huazhong Univ Sci & Technol, Inst Occupat Med, Wuhan 430074, Peoples R China. [Wu, Tangchun] Huazhong Univ Sci & Technol, Minist Educ, Key Lab Environm & Hlth, Sch Publ Hlth, Wuhan 430074, Peoples R China. [Shen, Hongbing] Nanjing Med Univ, Minist Educ, Key Lab Modern Toxicol, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Nanjing, Jiangsu, Peoples R China. [Yang, Pan-Chyr] Natl Taiwan Univ, Coll Med, Dept Internal Med, Taipei, Taiwan. RP Hosgood, HD (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, 1300 Morris Pk Ave Belfer 1309, Bronx, NY 10461 USA. EM dean.hosgood@einstein.yu.edu RI Hsiung, Chao Agnes/E-3994-2010; Chang, I-Shou/D-2084-2010; Hsiao, Chin-Fu/E-3993-2010; Chen, Chien-Jen/C-6976-2008; Jin, Li/C-1468-2009; Wang, Jiucun/J-8744-2012; OI Jin, Li/0000-0002-4546-2415; Wang, Jiucun/0000-0003-2765-0620; Yu, Chong-Jen/0000-0001-5664-9392; YANG, PAN-CHYR/0000-0001-6330-6048 FU NCI; National Research Program for Biopharmaceuticals in Taiwan [MOHW103-TDU-PB-211-144003]; Taiwan Bioinformatics Institute [NSC 102-2319-B-400-001] FX This work was supported by the NCI intramural system. GELAC was supported in part by grants from the National Research Program for Biopharmaceuticals in Taiwan (MOHW103-TDU-PB-211-144003) and by Taiwan Bioinformatics Institute Core Facility (NSC 102-2319-B-400-001). NR 41 TC 3 Z9 3 U1 1 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD MAR PY 2015 VL 134 IS 3 BP 333 EP 341 DI 10.1007/s00439-014-1528-z PG 9 WC Genetics & Heredity SC Genetics & Heredity GA CB3UR UT WOS:000349555000007 PM 25566987 ER PT J AU Huan, TX Liu, CY Joehanes, R Zhang, XL Chen, BH Johnson, AD Yao, C Courchesne, P O'Donnell, CJ Munson, PJ Levy, D AF Huan, Tianxiao Liu, Chunyu Joehanes, Roby Zhang, Xiaoling Chen, Brian H. Johnson, Andrew D. Yao, Chen Courchesne, Paul O'Donnell, Christopher J. Munson, Peter J. Levy, Daniel TI A systematic heritability analysis of the human whole blood transcriptome SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; CORONARY-HEART-DISEASE; HUMAN GENE-EXPRESSION; SUSCEPTIBILITY LOCI; INDIVIDUALS; PRESSURE; DISCOVERY; FRAMEWORK; VARIANTS AB Genome-wide expressio n quantitative trait locus (eQTL) mapping may reveal common genetic variants regulating gene expression. In addition to mapping eQTLs, we systematically evaluated the heritability of the whole blood transcriptome in 5,626 participants from the Framingham Heart Study. Of all gene expression measurements, about 40 % exhibit evidence of being heritable [ > 0, (p < 0.05)], the average heritability was estimated to be 0.13, and 10 % display > 0.2. To identify the role of eQTLs in promoting phenotype differences and disease susceptibility, we investigated the proportion of cis/trans eQTLs in different heritability categories and discovered that genes with higher heritability are more likely to have cis eQTLs that explain large proportions of variance in the expression of the corresponding genes. Single cis eQTLs explain 0.33-0.53 of variance in transcripts on average, whereas single trans eQTLs only explain 0.02-0.07. The top cis eQTLs tend to explain more variance in the corresponding gene when its is greater. Taking body mass index (BMI) as a case study, we cross-linked cis/trans eQTLs with both GWAS SNPs and differentially expressed genes for BMI. We discovered that BMI GWAS SNPs in 16p11.2 (e.g., rs7359397) are associated with several BMI differentially expressed genes in a cis manner (e.g. SULT1A1, SPNS1, and TUFM). These BMI signature genes explain a much larger proportion of variance in BMI than do the GWAS SNPs. Our results shed light on the impact of eQTLs on the heritability of the human whole blood transcriptome and its relations to phenotype differences. C1 [Huan, Tianxiao; Liu, Chunyu; Zhang, Xiaoling; Chen, Brian H.; Johnson, Andrew D.; Yao, Chen; Courchesne, Paul; O'Donnell, Christopher J.; Levy, Daniel] NHLBI, Framingham Heart Study, Populat Sci Branch, Framingham, MA 01702 USA. [Huan, Tianxiao; Liu, Chunyu; Joehanes, Roby; Chen, Brian H.; Yao, Chen; Courchesne, Paul; Levy, Daniel] NHLBI, Div Intramural Res, Populat Sci Branch, Bethesda, MD 20892 USA. [Joehanes, Roby; Munson, Peter J.] NIH, Div Computat Biosci, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, Populat Sci Branch, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM huant@mail.nih.gov; Levyd@nih.gov RI Johnson, Andrew/G-6520-2013 FU Intramural NIH HHS [Z01 HL006001-01, Z01 HL006001-02, ZIA HL006001-03] NR 38 TC 2 Z9 2 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD MAR PY 2015 VL 134 IS 3 BP 343 EP 358 DI 10.1007/s00439-014-1524-3 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA CB3UR UT WOS:000349555000008 PM 25585846 ER PT J AU Rimoin, AW Hoff, NA Djoko, CF Kisalu, NK Kashamuka, M Tamoufe, U LeBreton, M Kayembe, PK Muyembe, JJ Kitchen, CR Saylors, K Fair, J Doshi, R Papworth, E Mpoudi-Ngole, E Grillo, MP Tshala, F Peeters, M Wolfe, ND AF Rimoin, A. W. Hoff, N. A. Djoko, C. F. Kisalu, N. K. Kashamuka, M. Tamoufe, U. LeBreton, M. Kayembe, P. K. Muyembe, J. J. Kitchen, C. R. Saylors, K. Fair, J. Doshi, R. Papworth, E. Mpoudi-Ngole, E. Grillo, M. P. Tshala, F. Peeters, M. Wolfe, N. D. TI HIV infection and risk factors among the armed forces personnel stationed in Kinshasa, Democratic Republic of Congo SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE Africa; syphilis (Treponema pallidum); HIV (Human immunodeficiency virus); AIDS; prevalence; sexual behaviour; epidemiology ID IMMUNODEFICIENCY-VIRUS-INFECTION; POPULATIONS; DIVERSITY; HIV/AIDS; AFRICA; PREVALENCE; PREVENTION; KNOWLEDGE; COUNTRIES; SERVICES AB Despite recent declines in HIV incidence, sub-Saharan Africa remains the most heavily affected region in the global HIV/AIDS epidemic. Estimates of HIV prevalence in African military personnel are scarce and inconsistent. We conducted a serosurvey between June and September 2007 among 4043 Armed Forces personnel of the Democratic Republic of Congo (FARDC) stationed in Kinshasa, Democratic Republic of Congo (DRC) to determine the prevalence of HIV and syphilis infections and describe associated risk behaviours. Participants provided blood for HIV and syphilis testing and responded to a demographic and risk factor questionnaire. The prevalence of HIV was 3.8% and the prevalence of syphilis was 11.9%. Women were more likely than men to be HIV positive, (7.5% vs. 3.6% respectively, aOR: 1.66, 95% C. I: 1.21-2.28, p<0.05). Factors significantly associated with HIV infection included gender and self-reported genital ulcers in the 12 months before date of enrollment. The prevalence of HIV in the military appears to be higher than the general population in DRC (3.8% vs. 1.3%, respectively), with women at increased risk of infection. C1 [Rimoin, A. W.; Hoff, N. A.; Doshi, R.] Univ Calif Los Angeles, Los Angeles Fielding Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90005 USA. [Djoko, C. F.; Tamoufe, U.; LeBreton, M.; Saylors, K.; Fair, J.; Wolfe, N. D.] Metabiota, San Francisco, CA USA. [Djoko, C. F.; Tamoufe, U.; LeBreton, M.; Saylors, K.; Fair, J.; Wolfe, N. D.] Metabiota, Yaounde, Cameroon. [Kisalu, N. K.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Kashamuka, M.; Kayembe, P. K.] Univ Kinshasa, Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO. [Muyembe, J. J.] Natl Inst Biomed Res, Kinshasa, DEM REP CONGO. [Kitchen, C. R.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90005 USA. [Papworth, E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Mpoudi-Ngole, E.] CREMER IMPM IRD, Virol Lab, Yaounde, Cameroon. [Grillo, M. P.] Naval Hlth Res Ctr, Dept Def HIV AIDS Prevent Program DHAPP, San Diego, CA USA. [Tshala, F.] Minist Def, Mil Hlth Serv, Kinshasa, DEM REP CONGO. [Peeters, M.] IRD, Lab Retrovirus, UMR 145, Montpellier, France. [Peeters, M.] Univ Montpellier I, Montpellier, France. [Wolfe, N. D.] Stanford Univ, Program Human Biol, Stanford, CA 94305 USA. RP Rimoin, AW (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, CHS 41-245, Los Angeles, CA 90005 USA. EM arimoin@ucla.edu OI Kayembe Kalambayi, Patrick/0000-0002-5693-2144 FU Department of Defense HIV/AIDS Prevention Program (DHAPP), Naval Health Research Center, San Diego, CA; National Institutes of Health (NIH) Fogarty International Center (FIC) AIDS International Training and Research Program [2 D 43 TW000010-16/17]; NIH [DP1-OD000370]; DoD HIV/AIDS Prevention Program (DHAPP); Henry M. Jackson Foundation for the Advancement of Military Medicine, google.org; Skoll Foundation; Global Emerging Infections Surveillance and Response System (GEIS) - a Division of the United States Armed Forces Health Surveillance Center FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by the Department of Defense HIV/AIDS Prevention Program (DHAPP), Naval Health Research Center, San Diego, CA. CFD was supported, in part, by funds from the National Institutes of Health (NIH) Fogarty International Center (FIC) AIDS International Training and Research Program (2 D 43 TW000010-16/17). NDW is supported by the NIH Director's Pioneer Award (DP1-OD000370). GVF is supported by the DoD HIV/AIDS Prevention Program (DHAPP), the Henry M. Jackson Foundation for the Advancement of Military Medicine, google.org, The Skoll Foundation, and the Global Emerging Infections Surveillance and Response System (GEIS) - a Division of the United States Armed Forces Health Surveillance Center. NR 37 TC 2 Z9 2 U1 2 U2 7 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0956-4624 EI 1758-1052 J9 INT J STD AIDS JI Int. J. STD AIDS PD MAR PY 2015 VL 26 IS 3 BP 187 EP 195 DI 10.1177/0956462414533672 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CB3WY UT WOS:000349561300007 PM 24828556 ER PT J AU Ferrazzano, G Conte, A Fabbrini, G Bologna, M Macerollo, A Defazio, G Hallett, M Berardelli, A AF Ferrazzano, Gina Conte, Antonella Fabbrini, Giovanni Bologna, Matteo Macerollo, Antonella Defazio, Giovanni Hallett, Mark Berardelli, Alfredo TI Botulinum toxin and blink rate in patients with blepharospasm and increased blinking SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID SOMATOSENSORY TEMPORAL DISCRIMINATION; SPONTANEOUS EYEBLINK ACTIVITY; PARKINSONS-DISEASE; MOVEMENT-DISORDERS; HEMIFACIAL SPASM; EYE SYMPTOMS; DYSTONIA; NEUROTOXIN; REFLEX AB Objective The aim of the study was to investigate the effect of botulinum toxin (BoNT) on blink rate (BR) in patients with blepharospasm (BSP) and increased blinking (IB). Methods 37 patients with a clinical diagnosis of primary BSP (19 patients had tonic orbicularis oculi (OO) spasms and 18 patients had clonic OO spasms) and 8 patients with IB were included in this case-control study. All subjects underwent a standardised video protocol and clinical evaluation with a validated questionnaire designed to identify eye symptoms and Blepharospasm Disability Index (BSDI) before and 1 month after BoNT injection. BR was measured from the video recording before and after BoNT. BR in BSP and IB patients was compared with that from a group of healthy subjects and from a group of patients with hemifacial spasm (HFS). BR in HFS was also measured before and after BoNT. Results BR was increased in patients with IB and in BSP patients with clonic spasms but not in BSP patients with tonic spasms. BoNT reduced BR in patients with IB and in patients with clonic spasms, but not in patients with tonic spasms. BoNT left BR in patients with HFS unchanged. Changes in BR after BoNT were also independent of the presence of ocular symptoms. Despite the differential response of BR, BoNT significantly reduced BSDI in patients with BSP and IB. Conclusions BoNT differentially modulates BR in patients with BSP and IB depending on the baseline BR. BoNT injection reduces BR only when the blink generator is overactive, possibly influencing tear film retention. C1 [Ferrazzano, Gina; Conte, Antonella; Fabbrini, Giovanni; Berardelli, Alfredo] Univ Roma La Sapienza, Dept Neurol & Psychiat, I-00185 Rome, Italy. [Conte, Antonella; Fabbrini, Giovanni; Bologna, Matteo; Berardelli, Alfredo] IRCCS Neuromed Inst, Pozzilli, IS, Italy. [Macerollo, Antonella; Defazio, Giovanni] Aldo Moro Univ Bari, Dept Neurosci & Sensory Organs, Bari, Italy. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Berardelli, A (reprint author), Univ Roma La Sapienza, Dept Neurol & Psychiat, Viale Univ 30, I-00185 Rome, Italy. EM alfredo.berardelli@uniroma1.it RI Bologna, Matteo/K-7886-2016 OI Bologna, Matteo/0000-0003-0165-0833 FU Benign Essential Blepharospasm Research Foundation FX Benign Essential Blepharospasm Research Foundation. NR 43 TC 2 Z9 2 U1 1 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD MAR PY 2015 VL 86 IS 3 BP 336 EP 340 DI 10.1136/jnnp-2014-307821 PG 5 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA CB6EX UT WOS:000349720800018 PM 24963123 ER PT J AU Sargen, MR Kanetsky, PA Newton-Bishop, J Hayward, NK Mann, GJ Gruis, NA Tucker, MA Goldstein, AM Bianchi-Scarra, G Puig, S Elder, DE AF Sargen, Michael R. Kanetsky, Peter A. Newton-Bishop, Julia Hayward, Nicholas K. Mann, Graham J. Gruis, Nelleke A. Tucker, Margaret A. Goldstein, Alisa M. Bianchi-Scarra, Giovanna Puig, Susana Elder, David E. TI Histologic features of melanoma associated with CDKN2A genotype SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE CDKN2A; classification and regression tree analysis; familial melanoma; genetic testing; histology; pagetoid scatter; pigmentation; sporadic melanoma ID POPULATION-BASED SAMPLE; MORPHOLOGIC FEATURES; MALIGNANT-MELANOMA; MUTATION CARRIERS; BREAST-CANCER; CLASSIFICATION; PATHOLOGY; BRCA1; MITF; CONSORTIUM AB Background: Inherited susceptibility genes have been associated with histopathologic characteristics of tumors. Objective: We sought to identify associations between histology of melanomas and CDKN2A genotype. Methods: This was a case-control study design comparing 28 histopathologic tumor features among individuals with sporadic melanomas (N = 81) and cases from melanoma families with (N = 123) and without (N = 120) CDKN2A germline mutations. Results: Compared with CDKN2A(-) cases, mutation carriers tended to have histologic features of superficial spreading melanoma subtype including higher pigmentation (P-trend = .02) and increased pagetoid scatter (Ptrend = .07) after adjusting for age at diagnosis, sex, and American Joint Committee on Cancer thickness category. Similar associations were observed when comparing mutation carriers with a combined group of CDKN2A(-) (wild type) and sporadic melanomas. The presence of spindle cell morphology in the vertical growth phase was also an important predictor of genotype. Of the 15 cases with this phenotype, none were observed to harbor a CDKN2A mutation. Limitations: Our study examined rare mutations and may have been underpowered to detect small, but biologically significant associations between histology and genotype. Conclusion: Familial melanomas with CDKN2A mutations preferentially express a histologic phenotype of dense pigmentation, high pagetoid scatter, and a non-spindle cell morphology in the vertical growth phase. C1 [Sargen, Michael R.] Emory Univ Hosp, Dept Dermatol, Atlanta, GA 30322 USA. [Kanetsky, Peter A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Newton-Bishop, Julia] Univ Leeds, Leeds Inst Canc & Pathol, Epidemiol & Biostat Sect, Leeds LS2 9JT, W Yorkshire, England. [Hayward, Nicholas K.] Queensland Inst Med Res, Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Mann, Graham J.] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Mann, Graham J.] Univ Sydney, Melanoma Inst Australia, Sydney, NSW 2006, Australia. [Gruis, Nelleke A.] Leiden Univ, Med Ctr, Dept Dermatol, NL-2300 RA Leiden, Netherlands. [Tucker, Margaret A.; Goldstein, Alisa M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bianchi-Scarra, Giovanna] Univ Genoa, Dept Internal Med & Med Specialties DiMI, Ist Ricovero & Cura Carattere Sci Azienda Osped U, I-16126 Genoa, Italy. [Puig, Susana] Univ Barcelona, Hosp Clin Barcelona, Inst Recerca Biomed August Pi I Sunyer, E-08007 Barcelona, Spain. [Puig, Susana] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades, Barcelona, Spain. [Elder, David E.] Hosp Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Sargen, MR (reprint author), Dermatol Residency Training Program, 1525 Clifton Rd,Floor 1,Suite 100, Atlanta, GA 30322 USA. EM michael.sargen@emory.edu RI hayward, nicholas/C-1367-2015; OI hayward, nicholas/0000-0003-4760-1033; Gruis, Nelleke/0000-0002-5210-9150; Newton Bishop, Julia/0000-0001-9147-6802; Puig, Susana/0000-0003-1337-9745 FU National Cancer Institute of the US National Institutes of Health [R01 CA83115]; Spanish Fondo de Investigaciones Sanitarias [09/01393, 12/00840]; Centro de Investigaciones Biomedicas en Red (CIBER) de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) Sociedades de Garantia Reciproca (SGR) of the Catalan Government, Spain [1337]; European Commission (Melanoma Genetics Consortium, GenoMEL) [LSHC-CT-2006-018702]; Cancer Research UK [C588/A4994, C588/A10589]; National Health and Medical Research Council of Australia (NHMRC); NHMRC [402761, 633004]; Cancer Institute New South Wales [05/TPG/1-01, 10/TPG/1-02] FX Research at each of the participating institutions is funded by the National Cancer Institute of the US National Institutes of Health (R01 CA83115). The research at the Melanoma Unit in Barcelona is partially funded by Spanish Fondo de Investigaciones Sanitarias (grants 09/01393 and 12/00840); Centro de Investigaciones Biomedicas en Red (CIBER) de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) 2009 Sociedades de Garantia Reciproca (SGR) 1337 of the Catalan Government, Spain; European Commission under the 6th Framework Program, Contract No. LSHC-CT-2006-018702 (Melanoma Genetics Consortium, GenoMEL). The Leeds research group is partially funded by Cancer Research UK (C588/A4994 and C588/A10589). Research at QIMR Berghofer Medical Research Institute is partially funded by the National Health and Medical Research Council of Australia (NHMRC). Work in Sydney was also funded by program grants of NHMRC (402761, 633004) and Cancer Institute New South Wales (05/TPG/1-01, 10/TPG/1-02). NR 31 TC 7 Z9 7 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2015 VL 72 IS 3 BP 496 EP U175 DI 10.1016/j.jaad.2014.11.014 PG 19 WC Dermatology SC Dermatology GA CB6US UT WOS:000349762800025 PM 25592620 ER PT J AU Zuo, RC Schwartz, DM Lee, CCR Anadkat, MJ Cowen, EW Naik, HB AF Zuo, Rena C. Schwartz, Daniella M. Lee, Chyi-Chia Richard Anadkat, Milan J. Cowen, Edward W. Naik, Haley B. TI Palmoplantar pustules and osteoarticular pain in a 42-year-old woman SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material DE autoinflammatory; chronic recurrent multifocal osteomyelitis; neutrophilic dermatoses; palmoplantar pustulosis; synovitis-acne-pustulosis-hyperostosis-osteitis ID RECURRENT MULTIFOCAL OSTEOMYELITIS; SAPHO-SYNDROME; OSTEITIS SAPHO; FOLLOW-UP; ACNE; HYPEROSTOSIS; SYNOVITIS; ARTHRITIS; CHILDHOOD; CHILDREN C1 [Zuo, Rena C.; Cowen, Edward W.; Naik, Haley B.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Schwartz, Daniella M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Anadkat, Milan J.] Washington Univ, Sch Med, Div Dermatol, St Louis, MO 63110 USA. RP Naik, HB (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Bldg 10-Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM haley.naik@nih.gov FU Howard Hughes Medical Institute; Intramural NIH HHS [Z99 CA999999] NR 36 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2015 VL 72 IS 3 BP 550 EP 553 DI 10.1016/j.jaad.2014.07.014 PG 4 WC Dermatology SC Dermatology GA CB6US UT WOS:000349762800031 PM 25127881 ER PT J AU Singleton, A AF Singleton, Andrew TI A new gene for Parkinson's disease: should we care? SO LANCET NEUROLOGY LA English DT Editorial Material ID DROSOPHILA-PINK1; INTERACTS; RISK C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Singleton, A (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov NR 8 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD MAR PY 2015 VL 14 IS 3 BP 239 EP 240 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CB4JM UT WOS:000349594000004 ER PT J AU Villarino, AV Laurence, A AF Villarino, Alejandro V. Laurence, Arian TI IL-1 watches the watchmen SO NATURE IMMUNOLOGY LA English DT Editorial Material ID RETINOIC ACID; DIFFERENTIATION; EXPRESSION; RESPONSES; CELLS C1 [Villarino, Alejandro V.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Laurence, Arian] Freeman Rd Hosp, Northern Ctr Canc Care, Newcastle Upon Tyne, Tyne & Wear, England. RP Villarino, AV (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM alejandro.villarino@nih.gov; arian.laurence@nuth.nhs.uk RI Laurence, Arian/A-8770-2009; OI Laurence, Arian/0000-0003-0942-8292; Villarino, Alejandro/0000-0001-8068-2176 NR 10 TC 0 Z9 0 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2015 VL 16 IS 3 BP 226 EP 227 DI 10.1038/ni.3105 PG 2 WC Immunology SC Immunology GA CB7XN UT WOS:000349842100005 PM 25689436 ER PT J AU Vasanthakumar, A Moro, K Xin, AN Liao, Y Gloury, R Kawamoto, S Fagarasan, S Mielke, LA Afshar-Sterle, S Masters, SL Nakae, S Saito, H Wentworth, JM Li, P Liao, W Leonard, WJ Smyth, GK Shi, W Nutt, SL Koyasu, S Kallies, A AF Vasanthakumar, Ajithkumar Moro, Kazuyo Xin, Annie Liao, Yang Gloury, Renee Kawamoto, Shimpei Fagarasan, Sidonia Mielke, Lisa A. Afshar-Sterle, Shoukat Masters, Seth L. Nakae, Susumu Saito, Hirohisa Wentworth, John M. Li, Peng Liao, Wei Leonard, Warren J. Smyth, Gordon K. Shi, Wei Nutt, Stephen L. Koyasu, Shigeo Kallies, Axel TI The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells SO NATURE IMMUNOLOGY LA English DT Article ID LYMPHOID-CELLS; REG CELLS; DIFFERENTIATION; INFLAMMATION; INTERLEUKIN-33; EXPRESSION; CYTOKINES; BLIMP-1; OBESITY; FAMILY AB Foxp3(+) regulatory T (T-reg) cells in visceral adipose tissue (VAT-T-reg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-gamma; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-T-reg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-T-reg differentiation through direct regulation of ST2 and PPAR-gamma expression. IL-33 administration induced vigorous population expansion of VAT-T-reg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-T-reg cell homeostasis. C1 [Vasanthakumar, Ajithkumar; Xin, Annie; Liao, Yang; Gloury, Renee; Mielke, Lisa A.; Afshar-Sterle, Shoukat; Masters, Seth L.; Wentworth, John M.; Smyth, Gordon K.; Shi, Wei; Nutt, Stephen L.; Kallies, Axel] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia. [Vasanthakumar, Ajithkumar; Xin, Annie; Liao, Yang; Gloury, Renee; Mielke, Lisa A.; Afshar-Sterle, Shoukat; Masters, Seth L.; Wentworth, John M.; Nutt, Stephen L.; Kallies, Axel] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia. [Moro, Kazuyo; Koyasu, Shigeo] RIKEN, Ctr Integrat Med Sci, Lab Immune Cell Syst, Yokohama, Kanagawa, Japan. [Moro, Kazuyo; Nakae, Susumu] Japan Sci & Technol Agcy, Precursory Res Embryon Sci & Technol PRESTO, Tokyo, Japan. [Moro, Kazuyo] Yokohama City Univ, Grad Sch Med Life Sci, Dept Med Life Sci, Div Immunobiol, Yokohama, Kanagawa 232, Japan. [Kawamoto, Shimpei; Fagarasan, Sidonia] RIKEN, Res Ctr Integrat Med Sci, Lab Mucosal Immun, Yokohama, Kanagawa, Japan. [Nakae, Susumu] Univ Tokyo, Inst Med Sci, Ctr Expt Med & Syst Biol, Lab Syst Biol, Tokyo, Japan. [Saito, Hirohisa] Natl Res Inst Child Hlth & Dev, Dept Allergy & Immunol, Tokyo, Japan. [Li, Peng; Liao, Wei; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Li, Peng; Liao, Wei; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. [Shi, Wei] Univ Melbourne, Dept Comp & Informat Syst, Parkville, Vic 3052, Australia. [Smyth, Gordon K.] Univ Melbourne, Dept Math & Stat, Parkville, Vic 3052, Australia. [Koyasu, Shigeo] Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo, Japan. RP Kallies, A (reprint author), Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia. EM kallies@wehi.edu.au RI Moro, Kazuyo/A-5987-2016; Koyasu, Shigeo/J-5583-2015; Fagarasan, Sidonia/A-5258-2016; Smyth, Gordon/B-5276-2008 OI Nutt, Stephen/0000-0002-0020-6637; masters, seth/0000-0003-4763-576X; Koyasu, Shigeo/0000-0001-9585-3038; Fagarasan, Sidonia/0000-0003-2086-6402; Smyth, Gordon/0000-0001-9221-2892 FU National Health and Medical Research Council of Australia; Sylvia and Charles Viertel Foundation; Australian Research Council; Diabetes Australia Research Trust; PRESTO from the Japan Science and Technology Agency; Japan Society for the Promotion of Science [22229004]; Division of Intramural Research, National Heart, Blood, and Lung Institute, US National Institutes of Health; [26293110] FX We thank P. O'Brien for assistance with tissue collection, S. Wada for animal care, M. Febbraio and A. Lew for critical advice, E. Cretney for mice and E. Bandala-Sanchez, V. Bryant and J. Brady for reagents. We are grateful to K. Nakanishi (Hyogo College of Medicine), T. Mak (The Campbell Family Institute for Breast Cancer Research), and U. Klein (Columbia University) for mice. Supported by the National Health and Medical Research Council of Australia (A.K., S.L.N. and G.K.S.), the Sylvia and Charles Viertel Foundation (A.K.), the Australian Research Council (A.K. and S.L.N.), the Diabetes Australia Research Trust (J. M. W.), PRESTO from the Japan Science and Technology Agency (K.M.), and a Grant-in Aid for Scientific Research (B) (26293110 to K.M.) and a Grant-in-Aid for Scientific Research (S) (22229004 to S. Koyasu) from the Japan Society for the Promotion of Science. W.L., P.L. and W.J.L. are supported by the Division of Intramural Research, National Heart, Blood, and Lung Institute, US National Institutes of Health. This study was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure Support scheme. NR 65 TC 68 Z9 69 U1 4 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2015 VL 16 IS 3 BP 276 EP U239 DI 10.1038/ni.3085 PG 12 WC Immunology SC Immunology GA CB7XN UT WOS:000349842100011 PM 25599561 ER PT J AU Robinette, ML Fuchs, A Cortez, VS Lee, JS Wang, YM Durum, SK Gilfillan, S Colonna, M AF Robinette, Michelle L. Fuchs, Anja Cortez, Victor S. Lee, Jacob S. Wang, Yaming Durum, Scott K. Gilfillan, Susan Colonna, Marco CA Immunological Genome Consortium TI Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets SO NATURE IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; REGULATORY T-CELLS; ADAPTIVE IMMUNITY; GENE-EXPRESSION; FACTOR GATA3; IN-VIVO; RECEPTOR; BET; INFLAMMATION; DIFFERENTIATION AB The recognized diversity of innate lymphoid cells (ILCs) is rapidly expanding. Three ILC classes have emerged, ILC1, ILC2 and ILC3, with ILC1 and ILC3 including several subsets. The classification of some subsets is unclear, and it remains controversial whether natural killer (NK) cells and ILC1 cells are distinct cell types. To address these issues, we analyzed gene expression in ILCs and NK cells from mouse small intestine, spleen and liver, as part of the Immunological Genome Project. The results showed unique gene-expression patterns for some ILCs and overlapping patterns for ILC1 cells and NK cells, whereas other ILC subsets remained indistinguishable. We identified a transcriptional program shared by small intestine ILCs and a core ILC signature. We revealed and discuss transcripts that suggest previously unknown functions and developmental paths for ILCs. C1 [Robinette, Michelle L.; Cortez, Victor S.; Wang, Yaming; Gilfillan, Susan; Colonna, Marco] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. [Fuchs, Anja] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Lee, Jacob S.] Merck Res Labs, Palo Alto, CA USA. [Durum, Scott K.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Colonna, M (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. EM mcolonna@wustl.edu OI Colonna, Marco/0000-0001-5222-4987 FU US National Institutes of Health [R24A1072073, 1U01A1095542, R01DE021255, R21CA16719, T32 GM07200, T32 AI 7172-34] FX We thank our colleagues in the ImmGen consortium, especially C. Benoist and L. Lanier, for input and discussion; the core ImmGen team, K. Rothamel and A. Rhodes, for contributions and technical assistance; M. Artyomov, G. Krishnan and J. Siegel for computational assistance; D. Sojka for discussion; E. Lantelme and D. Brinja for sorting assistance; P. Wang for microscopy assistance; and eBioscience and Affymetrix for support of the ImmGen Project. Supported by the US National Institutes of Health (R24A1072073 to the ImmGen Consortium; 1U01A1095542, R01DE021255 and R21CA16719 to the Colonna laboratory; MSTP T32 GM07200 to M. L. R.; and Infectious Disease Training Grant T32 AI 7172-34 to V.S.C.). NR 51 TC 105 Z9 106 U1 8 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2015 VL 16 IS 3 BP 306 EP U142 DI 10.1038/ni.3094 PG 13 WC Immunology SC Immunology GA CB7XN UT WOS:000349842100014 PM 25621825 ER PT J AU Sotiras, A Resnick, SM Davatzikos, C AF Sotiras, Aristeidis Resnick, Susan M. Davatzikos, Christos TI Finding imaging patterns of structural covariance via Non-Negative Matrix Factorization SO NEUROIMAGE LA English DT Article DE Data analysis; Structural covariance; Non-Negative Matrix Factorization; Principal Component Analysis; Independent Component Analysis; Diffusion Tensor Imaging; Fractional anisotropy; Structural Magnetic Resonance Imaging; Gray matter; RAVENS ID INDEPENDENT COMPONENT ANALYSIS; CANONICAL CORRELATION-ANALYSIS; VOXEL-BASED MORPHOMETRY; PARTIAL LEAST-SQUARES; DEFORMATION-BASED MORPHOMETRY; MAGNETIC-RESONANCE IMAGES; FUNCTIONAL CONNECTIVITY; HUMAN BRAIN; PRINCIPAL COMPONENTS; ELASTIC REGISTRATION AB In this paper, we investigate the use of Non-Negative Matrix Factorization (NNMF) for the analysis of structural neuroimaging data. The goal is to identify the brain regions that co-vary across individuals in a consistent way, hence potentially being part of underlying brain networks or otherwise influenced by underlying common-mechanisms such as genetics and pathologies. NNMF offers a directly data-drivenway of extracting relatively localized co-varying structural regions, thereby transcending limitations of Principal Component Analysis (PCA), Independent Component Analysis (ICA) and other related methods that tend to produce dispersed components of positive and negative loadings. In particular, leveraging upon the well known ability of NNMF to produce parts-based representations of image data, we derive decompositions that partition the brain into regions that vary in consistent ways across individuals. Importantly, these decompositions achieve dimensionality reduction via highly interpretable ways and generalize well to new data as shown via split-sample experiments. We empirically validate NNMF in two data sets: i) a Diffusion Tensor (DT) mouse brain development study, and ii) a structural Magnetic Resonance (sMR) study of human brain aging. We demonstrate the ability of NNMF to produce sparse parts-based representations of the data at various resolutions. These representations seem to follow what we know about the underlying functional organization of the brain and also capture some pathological processes. Moreover, we show that these low dimensional representations favorably compare to descriptions obtained with more commonly used matrix factorization methods like PCA and ICA. (C) 2014 Elsevier Inc. All rights reserved. C1 [Sotiras, Aristeidis; Davatzikos, Christos] Univ Penn, Ctr Biomed Image Comp & Analyt, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. RP Sotiras, A (reprint author), Univ Penn, Ctr Biomed Image Comp & Analyt, Sect Biomed Image Anal, 3600 Market St,Suite 380, Philadelphia, PA 19106 USA. EM Aristeidis.Sotiras@uphs.upenn.edu FU National Institutes of Health [R01-MH070365, R01-AG014971]; Baltimore Longitudinal Study of Aging [HHSN271201300284] FX This work was partially supported by the National Institutes of Health (grant numbers R01-MH070365 and R01-AG014971) and the Baltimore Longitudinal Study of Aging under contract HHSN271201300284. NR 93 TC 7 Z9 8 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD MAR PY 2015 VL 108 BP 1 EP 16 DI 10.1016/j.neuroimage.2014.11.045 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CB4SO UT WOS:000349618600001 PM 25497684 ER PT J AU Jarcho, JM Tanofsky-Kraff, M Nelson, EE Engel, SG Vannucci, A Field, SE Romer, AL Hannallah, L Brady, S Demidowich, AP Shomaker, LB Courville, AB Pine, DS Yanovski, JA AF Jarcho, Johanna M. Tanofsky-Kraff, Marian Nelson, Eric E. Engel, Scott G. Vannucci, Anna Field, Sara E. Romer, Adrienne L. Hannallah, Louise Brady, SheilaM. Demidowich, Andrew P. Shomaker, Lauren B. Courville, Amber B. Pine, Daniel S. Yanovski, Jack A. TI Neural activation during anticipated peer evaluation and laboratory meal intake in overweight girls with and without loss of control eating SO NEUROIMAGE LA English DT Article DE Loss of control eating; Adolescents; Social distress; Anxiety; Neural activation; Food intake ID PEDIATRIC ANXIETY DISORDERS; EARLY-CHILDHOOD TEMPERAMENT; RESEARCH DOMAIN CRITERIA; REWARD BRAIN-REGIONS; PREFRONTAL CORTEX; ADOLESCENT GIRLS; BULIMIA-NERVOSA; PALATABLE FOOD; WEIGHT-GAIN; EMOTION REGULATION AB The interpersonal model of loss of control (LOC) eating proposes that socially distressing situations lead to anxious states that trigger excessive food consumption. Self-reports support these links, but the neurobiological underpinnings of these relationships remain unclear. We therefore examined brain regions associated with anxiety in relation to LOC eating and energy intake in the laboratory. Twenty-two overweight and obese (BMIz: 1.9 +/- 0.4) adolescent (15.8 +/- 1.6 y) girls with LOC eating (LOC+, n = 10) and without LOC eating (LOC-, n = 12) underwent functional magnetic resonance imaging (fMRI) during a simulated peer interaction chatroom paradigm. Immediately after the fMRI scan, girls consumed lunch ad libitum from a 10,934-kcal laboratory buffet meal with the instruction to "let yourself go and eat as much as you want." Pre-specified hypotheses regarding activation of five regions of interest were tested. Analysis of fMRI data revealed a significant group by peer feedback interaction in the ventromedial prefrontal cortex (vmPFC), such that LOC+ had less activity following peer rejection (vs. acceptance), while LOC-had increased activity (p < .005). Moreover, functional coupling between vmPFC and striatum for peer rejection (vs. acceptance) interacted with LOC status: coupling was positive for LOC+, but negative in LOC-(p < .005). Activity of fusiform face area (FFA) during negative peer feedback from high-value peers also interacted with LOC status (p < .005). A positive association between FFA activation and intake during the meal was observed among only those with LOC eating. In conclusion, overweight and obese girls with LOC eating may be distinguished by a failure to engage regions of prefrontal cortex implicated in emotion regulation in response to social distress. The relationship between FFA activation and food intake supports the notion that heightened sensitivity to incoming interpersonal cues and perturbations in socio-emotional neural circuits may lead to overeating in order to cope with negative affect elicited by social discomfort in susceptible youth. Published by Elsevier Inc. C1 [Jarcho, Johanna M.; Nelson, Eric E.; Romer, Adrienne L.; Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, NIH, Bethesda, MD 20892 USA. [Tanofsky-Kraff, Marian; Vannucci, Anna; Field, Sara E.; Hannallah, Louise] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Tanofsky-Kraff, Marian; Vannucci, Anna; Field, Sara E.; Hannallah, Louise; Brady, SheilaM.; Demidowich, Andrew P.; Shomaker, Lauren B.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Engel, Scott G.] Neuropsychiat Res Inst, Fargo, ND 58103 USA. [Engel, Scott G.] Univ N Dakota, Sch Med & Hlth Sci, Fargo, ND 58103 USA. [Courville, Amber B.] NIH, Dept Nutr, Ctr Clin, DHHS, Bethesda, MD 20892 USA. RP Tanofsky-Kraff, M (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM marian.tanofsky-kraff@usuhs.edu OI Yanovski, Jack/0000-0001-8542-1637; Jarcho, Johanna/0000-0001-9075-6968; Nelson, Eric/0000-0002-3376-2453 FU NIDDK [1R01DK080906]; USUHS [R072IC]; NIH [Z99 MH999999, Z99 HD999999]; NIH from the NICHD [1ZIAHD000641]; Bench to Bedside Program of the NIH; Office of Behavioral and Social Sciences Research (OBSSR) of the NIH; Human Imaging Core Facility of the Center for Neuroscience and Regenerative Medicine FX Research support: NIDDK 1R01DK080906 (to MTK); USUHS grant R072IC (to MTK); NIH Intramural Research Program Z99 MH999999 (JMJ, EEN, and DSP) and Z99 HD999999 (JAY); NIH grant 1ZIAHD000641 from the NICHD (to JAY); the Bench to Bedside Program and the Office of Behavioral and Social Sciences Research (OBSSR) of the NIH (to JAY and MTK); and Human Imaging Core Facility of the Center for Neuroscience and Regenerative Medicine. NR 121 TC 6 Z9 6 U1 7 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD MAR PY 2015 VL 108 BP 343 EP 353 DI 10.1016/j.neuroimage.2014.12.054 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CB4SO UT WOS:000349618600034 PM 25550068 ER PT J AU Lui, JLC Chau, M Chen, WP Cheung, CSF Hanson, J Rodriguez-Canales, J Nilsson, O Baron, J AF Lui, Julian C. Chau, Michael Chen, Weiping Cheung, Crystal S. F. Hanson, Jeffrey Rodriguez-Canales, Jaime Nilsson, Ola Baron, Jeffrey TI Spatial regulation of gene expression during growth of articular cartilage in juvenile mice SO PEDIATRIC RESEARCH LA English DT Article ID SUPERFICIAL ZONE; SPEMANN ORGANIZER; BETA-CATENIN; PROTEIN; PLATE; CHONDROGENESIS; CHONDROCYTES; OSTEOARTHRITIS; TGF-BETA-1; CELLS AB BACKGROUND: In juvenile mammals, the epiphyses of long bones grow by chondrogenesis within the articular cartilage. A better understanding of the molecular mechanisms that regulate the growth of articular cartilage may give insight into the antecedents of joint disease, such as osteoarthritis. METHODS: We used laser capture microdissection to isolate chondrocytes from the superficial, middle, and deep zones of growing tibial articular cartilage in the 1-wk-old mouse and then investigated expression patterns by microarray. To identify molecular markers for each zone of the growing articular cartilage, we found genes showing zone-specific expression and confirmed by real-time PCR and in situ hybridization. RESULTS: Bioinformatic analyses implicated ephrin receptor signaling, Wnt signaling, and bone morphogenetic protein signaling in the spatial regulation of chondrocyte differentiation during growth. Molecular markers were identified for superficial (e.g., Cilp, Prg4), middle (Cxcl14,Tnn), and deep zones (Sfrp5, Frzb). Comparison between juvenile articular and growth plate cartilage revealed that the superficial-to-deep zone transition showed similarity with the hypertrophic-to-resting zone transition. CONCLUSION: Laser capture microdissection combined with microarray analysis identified novel signaling pathways that are spatially regulated in growing mouse articular cartilage and revealed similarities between the molecular architecture of the growing articular cartilage and that of growth plate cartilage. C1 [Lui, Julian C.; Cheung, Crystal S. F.; Nilsson, Ola; Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Chau, Michael; Nilsson, Ola] Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Mol Med, Stockholm, Sweden. [Chau, Michael; Nilsson, Ola] Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit, Stockholm, Sweden. [Chau, Michael; Nilsson, Ola] Karolinska Univ Hosp, Stockholm, Sweden. [Chen, Weiping] Natl Inst Diabet & Digest & Kidney Dis NIDDK, Genom Core Lab, NIH, Bethesda, MD USA. [Hanson, Jeffrey; Rodriguez-Canales, Jaime] NCI, Laser Capture Microdissect Core Facil, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Lui, JLC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. EM luichunk@mail.nih.gov RI Lui, Chun Kin Julian/E-2253-2012; OI Nilsson, Ola/0000-0002-9986-8138 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute, NIH FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Cancer Institute, NIH. NR 39 TC 4 Z9 4 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0031-3998 EI 1530-0447 J9 PEDIATR RES JI Pediatr. Res. PD MAR PY 2015 VL 77 IS 3 BP 406 EP 415 DI 10.1038/pr.2014.208 PG 10 WC Pediatrics SC Pediatrics GA CB3GD UT WOS:000349515300002 PM 25521919 ER PT J AU Kong, L Wilson, IA Kwong, PD AF Kong, Leopold Wilson, Ian A. Kwong, Peter D. TI Crystal structure of a fully glycosylated HIV-1 gp120 core reveals a stabilizing role for the glycan at Asn262 SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE HIV-1 gp120; glycan shield; role of N262 ID NEUTRALIZING ANTIBODIES; ENVELOPE GLYCOPROTEIN; TARGET; TRIMER; BROAD AB The crystal structure of a fully glycosylated HIV-1 gp120 core in complex with CD4 receptor and Fab 17b at 4.5-angstrom resolution reveals 9 of the 15 N-linked glycans of core gp120 to be partially ordered. The glycan at position Asn262 had the most extensive and well-ordered electron density, and a GlcNAc(2)Man(7) was modeled. The GlcNAc stem of this glycan is largely buried in a cleft in gp120, suggesting a role in gp120 folding and stability. Its arms interact with the stems of neighboring glycans from the oligomannose patch, which is a major target for broadly neutralizing antibodies. Proteins 2015; 83:590-596. (c) 2014 Wiley Periodicals, Inc. C1 [Kong, Leopold; Kwong, Peter D.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Kong, Leopold; Wilson, Ian A.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Kong, Leopold; Wilson, Ian A.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Kong, Leopold; Wilson, Ian A.] Scripps Res Inst, Collaborat AIDS Vaccine Discovery, La Jolla, CA 92037 USA. [Kong, Leopold; Wilson, Ian A.] Scripps Res Inst, Scripps Ctr HIV AIDS Vaccine Immunol & Immunogen, La Jolla, CA 92037 USA. [Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. RP Kwong, PD (reprint author), Vaccine Res Ctr, Bldg 40,Room 4508,40 Convent Dr, Bethesda, MD 20892 USA. EM wilson@scripps.edu; pdkwong@nih.gov FU NIH [RO1 AI084817]; Scripps CHAVI-ID [UM1 AI100663]; Joint Center for Structural Genomics [GM U54 GM94586]; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]; Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH; Skaggs Institute; International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium; International AIDS Vaccine Initiative's (IAVI's) Collaboration for AIDS Vaccine Discovery; American Foundation for AIDS Research for a Mathilde Krim Fellowship in Basic Biomedical Research FX Grant sponsor: NIH; Grant number: RO1 AI084817; Grant sponsor: Scripps CHAVI-ID; Grant number: UM1 AI100663; Grant sponsor: The Joint Center for Structural Genomics; Grant number: GM U54 GM94586; Grant sponsor: US Department of Energy, Basic Energy Sciences, Office of Science; Grant number: W-31-109-Eng-38; Grant sponsor: Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH; Grant sponsor: Skaggs Institute; Grant sponsors: International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium and Collaboration for AIDS Vaccine Discovery; Grant sponsor: American Foundation for AIDS Research for a Mathilde Krim Fellowship in Basic Biomedical Research. NR 20 TC 10 Z9 10 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD MAR PY 2015 VL 83 IS 3 BP 590 EP 596 DI 10.1002/prot.24747 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CB1LO UT WOS:000349389200017 PM 25546301 ER PT J AU Stephan, MA Heckel, B Song, S Cohen, LG AF Stephan, Marianne A. Heckel, Brittany Song, Sunbin Cohen, Leonardo G. TI Crossmodal encoding of motor sequence memories SO PSYCHOLOGICAL RESEARCH-PSYCHOLOGISCHE FORSCHUNG LA English DT Article ID PITCH HEIGHT; MUSIC; REACTIVATION; PIANISTS; IMAGERY; STROKE; BRAIN AB In this study, we tested the hypothesis that exposure to specific auditory sequences could lead to the crossmodal induction of new motor memories. Twenty young, healthy participants memorized a melody without moving. Each tone in the memorized melody had previously been associated with a particular finger movement. For ten of the participants, the contour of the melody memorized was congruent to a subsequently performed, but never practiced, finger movement sequence (C group, n = 10). For the other ten participants, the melody memorized was incongruent to the subsequent finger movement sequence (InC group, n = 10). Results showed faster performance of the movement sequence in the C group than in the InC group. This difference in motor performance was most pronounced 6 h after melody learning and then dissipated over 30 days. These results provide evidence of a specific, crossmodal encoding of a movement sequence representation through an auditory sequence with the effect on motor performance lasting for several hours. The findings of this study are significant, as the formation of new motor memories through exposure to auditory stimuli may be useful in rehabilitation settings where the initial encoding of motor memories through physical training is disrupted. C1 [Stephan, Marianne A.; Heckel, Brittany; Song, Sunbin; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. RP Stephan, MA (reprint author), Concordia Univ, Lab Motor Learning & Neural Plast, Dept Psychol, 7141 Sherbrooke St West, Montreal, PQ H4B 1R6, Canada. EM marianne.stephan@alumni.ethz.ch; blh25@georgetown.edu; songss@ninds.nih.gov; cohenl@ninds.nih.gov FU Swiss Foundation for Grants in Biology and Medicine (SFGBM); Swiss National Science Foundation (SNSF); Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health FX This research was supported by the Swiss Foundation for Grants in Biology and Medicine (SFGBM) and the Swiss National Science Foundation (SNSF), as well as by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health. We are grateful to Virginia Penhune and Rachel Brown for their helpful suggestions and discussions. Furthermore, we thank Steven Livingstone and another anonymous reviewer for their constructive comments. NR 28 TC 2 Z9 2 U1 0 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-0727 EI 1430-2772 J9 PSYCHOL RES-PSYCH FO JI Psychol. Res.-Psychol. Forsch. PD MAR PY 2015 VL 79 IS 2 BP 318 EP 326 DI 10.1007/s00426-014-0568-2 PG 9 WC Psychology, Experimental SC Psychology GA CB6WV UT WOS:000349768400014 PM 24771059 ER PT J AU Grant, KB Agarwal, HK Shih, JH Bernardo, M Pang, YX Daar, D Merino, MJ Wood, BJ Pinto, PA Choyke, PL Turkbey, B AF Grant, Kinzya B. Agarwal, Harsh K. Shih, Joanna H. Bernardo, Marcelino Pang, Yuxi Daar, Dagane Merino, Maria J. Wood, Bradford J. Pinto, Peter A. Choyke, Peter L. Turkbey, Baris TI Comparison of calculated and acquired high b value diffusion-weighted imaging in prostate cancer SO ABDOMINAL IMAGING LA English DT Article DE Prostate cancer; MRI; Diffusion-weighted imaging; High b value ID 3 T; TUMOR-DETECTION; DIAGNOSTIC-ACCURACY; CLINICAL UTILITY; AGGRESSIVENESS; KURTOSIS; BIOPSIES; MRI; FUSION AB To determine whether the performance of calculated high b value diffusion-weighted images (DWI) derived from regular lower b value DWI using exponential diffusion decay models (intravoxel incoherent motion = IVIM and diffusional kurtosis = DK) is comparable to acquired high b value DWI in prostate cancer detection. One hundred six patients underwent diagnostic multiparametric prostate MRI at 3T using an endorectal coil. Five b value (b = 0, 188, 375, 563, 750 s/mm(2)) DWI and high b value (b = 0, 1000 and 2000 s/mm(2)) DWI were acquired. Calculated high b value (b = 1000 s/mm(2) and b = 2000 s/mm(2)) DWI were derived from the DWI dataset using DK and IVIM models. Calculated and acquired high b value DWI images were compared for lesion visibility and image quality by two experienced radiologists (1 and 6 years of experience). GEE with Wald test was used to compare the image quality among the four calculated high b value DWI by comparing the proportion of lesions in each model which were comparable to the acquired images. This comparison was done for all lesions and by lesion location (PZ or CG; low apical/anterior or apical/mid/base) More lesions were visible on acquired b = 2000 s/mm(2) compared to b = 1000 s/mm(2) DWI. Calculated high b value DWI using the IVIM model had approximately the same number of lesions as acquired high b value DWI, whereas the DK model had fewer lesions than acquired images. The image quality of calculated high b value DWI was comparable to that of acquired images, and the highest quality images were obtained with b1000(IVIM). The image quality of calculated b1000(IVIM) was the same as that of acquired DWI in apical/mid/base (98%) locations and comparable in low apical and anterior (95.4%) locations. The image quality of calculated b2000(IVIM) was inferior in both apical/mid/base (86.2%) locations and comparable in low apical and anterior (83.9%) locations. Calculated high b value DWI obtained using IVIM model has same lesion visibility as that of acquired DWI. The image quality of calculated high b value DWI relative to corresponding acquired DWI decreases with increase in b value. C1 [Grant, Kinzya B.; Agarwal, Harsh K.; Bernardo, Marcelino; Daar, Dagane; Choyke, Peter L.; Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Agarwal, Harsh K.] Philips Res North Amer, Briarcliff Manor, NY USA. [Shih, Joanna H.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Bernardo, Marcelino; Daar, Dagane] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Bethesda, MD USA. [Pang, Yuxi] Philips Healthcare, Cleveland, OH USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Ctr Clin, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Bethesda, MD 20892 USA. [Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, NIH, 10 Ctr Dr,MSC 1182,Bldg 10,Room B3B85, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov NR 33 TC 10 Z9 11 U1 3 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 EI 1432-0509 J9 ABDOM IMAGING JI Abdom. Imaging PD MAR PY 2015 VL 40 IS 3 BP 578 EP 586 DI 10.1007/s00261-014-0246-2 PG 9 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA CB1CJ UT WOS:000349363900015 PM 25223523 ER PT J AU Baird, JH Minniti, CP Lee, JM Tian, X Wu, CL Jackson, M Alam, S Taylor, JG Kato, GJ AF Baird, John H. Minniti, Caterina P. Lee, Jung-Min Tian, Xin Wu, Colin Jackson, Mary Alam, Shoaib Taylor, James G. Kato, Gregory J. TI Oscillatory haematopoiesis in adults with sickle cell disease treated with hydroxycarbamide SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE sickle cell disease; oscillatory haematopoiesis; hydroxycarbamide; complete peripheral blood count; periodicity ID CHRONIC GRANULOCYTIC-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; PLATELET COUNT OSCILLATIONS; CHRONIC MYELOID-LEUKEMIA; TIME-SERIES ANALYSIS; POLYCYTHEMIA-VERA; CYCLIC HEMATOPOIESIS; SPECTRAL-ANALYSIS; SPACED DATA; HYDROXYUREA AB Hydroxycarbamide therapy has been associated with significant oscillations in peripheral blood counts from myeloid, lymphoid and erythroid lineages in patients with polycythaemia vera and chronic myeloid leukaemia. We retrospectively evaluated serial blood counts over an 8-year period from 44 adult patients with sickle cell disease receiving hydroxycarbamide. Platelet counts, leucocyte counts, haemoglobin values and reticulocyte counts, apportioned by hydroxycarbamide status, were analysed using a Lomb-Scargle periodogram algorithm. Significant periodicities were present in one or more counts in 38 patients receiving hydroxycarbamide for a mean duration of 481years. Platelet and leucocyte counts oscillated in 568% and 523% of patients, respectively. These oscillations generally became detectable within days of initiating therapy. During hydroxycarbamide therapy, the predominant periods of oscillation were 27 +/- 1d for platelet counts and 15 +/- 1d for leucocyte counts. Despite an absolute decrease in leucocyte and platelet counts during hydroxycarbamide treatment, the amplitudes between nadirs and zeniths remained similar regardless of exposure. Our observations appear consistent with previously proposed models of cyclic haematopoiesis, and document that hydroxycarbamide-induced oscillations in blood counts are innocuous phenomena not limited to myeloproliferative disorders as described previously. We speculate the known cell cycle inhibitory properties of hydroxycarbamide may accentuate otherwise latent constitutive oscillatory haematopoiesis. C1 [Baird, John H.; Minniti, Caterina P.; Jackson, Mary; Taylor, James G.] NHLBI, Hematol Branch, Bethesda, MD USA. [Lee, Jung-Min] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Tian, Xin; Wu, Colin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Alam, Shoaib] NHLBI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. [Kato, Gregory J.] Univ Pittsburgh, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15261 USA. [Kato, Gregory J.] Univ Pittsburgh, Heart Lung Blood & Vasc Med Inst, Pittsburgh, PA 15261 USA. RP Kato, GJ (reprint author), Univ Pittsburgh, Dept Med, Div Hematol Oncol, 200 Lothrop St,BST E1240, Pittsburgh, PA 15261 USA. EM katogj@upmc.edu RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Taylor, James/0000-0002-4421-1809 FU Division of Intramural Research of the National Heart, Lung and Blood Institute [1 ZIA HL006014-03]; Clinical Research Training Program; National Institutes of Health (NIH); Pfizer Inc. FX JHB and GJK designed the research study, analysed the data and wrote the manuscript; CPM, JML, SA, MJ, JGT, and GJK acquired the data for the study; JML, XT, and CW assisted in the analysis and interpretation of the data. All authors reviewed and approved the manuscript. This research was supported by the Division of Intramural Research of the National Heart, Lung and Blood Institute (1 ZIA HL006014-03). Fellowship funding of JHB was provided by the Clinical Research Training Program, a public-private partnership supported jointly by the National Institutes of Health (NIH) and Pfizer Inc. (via a grant to the Foundation for NIH from Pfizer Inc.). The authors thank Mary K. Hall for expert protocol management; protocol coordinators James Nichols, Catherine Seamon, Marlene Peters-Lawrence, and Darlene Allen for assistance in patient recruitment and data collection; and Cindy Clark, NIH Library Writing Center, for manuscript editing assistance. NR 39 TC 1 Z9 1 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAR PY 2015 VL 168 IS 5 BP 737 EP 746 DI 10.1111/bjh.13203 PG 10 WC Hematology SC Hematology GA CB4PW UT WOS:000349611300015 PM 25377027 ER PT J AU Bond, DA Dunavin, N Otterson, GA AF Bond, David Alan Dunavin, Neil Otterson, Gregory Alan TI Mutational Profiling of Second Primary Lung Cancers in Patients Who Have Received Radiation for the Treatment of Hodgkin's Disease SO CANCER INVESTIGATION LA English DT Article DE Second malignancy; Lung adenocarcinoma; Hodgkin's; EGFR; KRAS; ALK ID CLINICAL-COURSE; LYMPHOMA; SURVIVORS; CHEMOTHERAPY; KRAS AB Lung cancer (LC) represents the most common solid tumor in survivors of Hodgkin's disease (HD), and the assessment of the mutational status of oncogenic driver mutations in LC is now standard. We compiled clinical and mutation data (EGFR, KRAS, and ALK) from the medical records of patients with LC and a remote history of HD. 13 cases of LC following HD were seen, including seven with mutational data. Two had EGFR mutations, none had KRAS mutations or ALK translocations. Our conclusions are limited by the small sample size, however this report reinforces the need to identify driver mutations in lung cancers. C1 [Bond, David Alan] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Dunavin, Neil] NIH, Hematol Branch, Bethesda, MD 20892 USA. [Otterson, Gregory Alan] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Otterson, GA (reprint author), Ohio State Univ, Ctr Comprehens Canc, 320 W 10th Ave,B 450B Starling Loving Hall, Columbus, OH 43210 USA. EM Greg.Otterson@osumc.edu NR 18 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0735-7907 EI 1532-4192 J9 CANCER INVEST JI Cancer Invest. PD MAR PY 2015 VL 33 IS 3 BP 86 EP 88 DI 10.3109/07357907.2014.1000494 PG 3 WC Oncology SC Oncology GA CB3MS UT WOS:000349532900006 PM 25615851 ER PT J AU Gow, RV Hibbeln, JR Parletta, N AF Gow, Rachel V. Hibbeln, Joseph R. Parletta, Natalie TI Current evidence and future directions for research with omega-3 fatty acids and attention deficit hyperactivity disorder SO CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE LA English DT Review DE attention deficit hyperactivity disorder; docosahexaenoic acid; eicosapentaenoic acid; highly unsaturated fatty acids; omega-3 fatty acids ID POLYUNSATURATED FATTY-ACIDS; CALLOUS-UNEMOTIONAL TRAITS; RANDOMIZED CONTROLLED-TRIALS; PLACEBO-CONTROLLED TRIAL; DEFICIT/HYPERACTIVITY DISORDER; ANTISOCIAL-BEHAVIOR; DOUBLE-BLIND; CHILDREN; SUPPLEMENTATION; ADHD AB Purpose of review Nutritional insufficiencies of nutrients such as omega-3 highly unsaturated fatty acids (HUFAs), vitamins and minerals have been linked to suboptimal developmental outcomes including attention deficit hyperactivity disorder (ADHD). Although the predominant treatment is currently psychostimulant medications, randomized clinical trials with omega-3 HUFAs have reported small-to-modest effects in reducing symptoms of ADHD in children despite arguable individual methodological and design misgivings. Recent findings This review presents, discusses and critically evaluates data and findings from meta-analytic and systematic reviews and clinical trials published within the last 12 months. Recent trajectories of this research are discussed, such as comparing eicosapentaenoic acid and docosahexaenoic acid and testing the efficacy of omega-3 HUFAs as an adjunct to methylphenidate. Discussion includes highlighting limitations and potential future directions such as addressing variable findings by accounting for other nutritional deficiencies and behavioural food intolerances. Summary The authors conclude that given the current economic burden of ADHD, estimated in the region of $77 billion in the USA alone, in addition to the fact that a proportion of patients with ADHD are either treatment resistant, nonresponders or withdraw from medication because of adverse side-effects, the investigation of nonpharmacological interventions including omega-3 HUFAs in clinical practice warrants extrapolating. C1 [Gow, Rachel V.; Hibbeln, Joseph R.] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Parletta, Natalie] Univ S Australia, Sch Populat Hlth, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia. RP Parletta, N (reprint author), Univ S Australia, Sch Populat Hlth, GPO Box 2471, Adelaide, SA 5001, Australia. EM natalie.parletta@unisa.edu.au OI Parletta, Natalie/0000-0003-2322-5555 FU National Health and Medical Research Council [320860, 631947]; Equazen; Novasel; Vifor Pharma; Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism; Barlean's Organic Oils FX N.P. (formerly Sinn) is supported by National Health and Medical Research Council Program Grant funding (# 320860 and 631947). She has received supplements and cash contributions for her research from Equazen, Novasel and Vifor Pharma. They played no role in study design, analysis or publication. J.R.H. and R.V.G. are provided with support by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism. RVG receives a research gift/stipend from Barlean's Organic Oils. NR 28 TC 6 Z9 6 U1 6 U2 34 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1363-1950 EI 1473-6519 J9 CURR OPIN CLIN NUTR JI Curr. Opin. Clin. Nutr. Metab. Care PD MAR PY 2015 VL 18 IS 2 BP 133 EP 138 DI 10.1097/MCO.0000000000000140 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CB1QE UT WOS:000349402000005 PM 25581035 ER PT J AU Taylor-Fishwick, DA Weaver, J Glenn, L Kuhn, N Rai, G Jadhav, A Simeonov, A Dudda, A Schmoll, D Holman, TR Maloney, DJ Nadler, JL AF Taylor-Fishwick, David A. Weaver, Jessica Glenn, Lindsey Kuhn, Norine Rai, Ganesha Jadhav, Ajit Simeonov, Anton Dudda, Angela Schmoll, Dieter Holman, Theodore R. Maloney, David J. Nadler, Jerry L. TI Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction SO DIABETOLOGIA LA English DT Article DE 12-Lipoxygenase; Cytokines; Diabetes; Drug discovery; Inhibitors; Islets ID INSULIN-RESISTANCE; MOUSE MODEL; MICE; STRESS; EXPRESSION; POTENT; ONSET; 12/15-LIPOXYGENASE; LIPOXYGENASES; MACROPHAGES AB Islet inflammation leads to loss of functional pancreatic beta cell mass. Increasing evidence suggests that activation of 12-lipoxygenase leads to inflammatory beta cell loss. This study evaluates new specific small-molecule inhibitors of 12-lipoxygenase for protecting rodent and human beta cells from inflammatory damage. Mouse beta cell lines and mouse and human islets were treated with inflammatory cytokines IL-1 beta, TNF alpha and IFN gamma in the absence or presence of novel selective 12-lipoxygenase inhibitors. Glucose-stimulated insulin secretion (GSIS), gene expression, cell survival and 12-S-hydroxyeicosatetraenoic acid (12-S-HETE) levels were evaluated using established methods. Pharmacokinetic analysis was performed with the lead inhibitor in CD1 mice. Inflammatory cytokines led to the loss of human beta cell function, elevated cell death, increased inflammatory gene expression and upregulation of 12-lipoxygenase expression and activity (measured by 12-S-HETE generation). Two 12-lipoxygenase inhibitors, Compounds 5 and 9, produced a concentration-dependent reduction of stimulated 12-S-HETE levels. GSIS was preserved in the presence of the 12-lipoxygenase inhibitors. 12-Lipoxygenase inhibition preserved survival of primary mouse and human islets. When administered orally, Compound 5 reduced plasma 12-S-HETE in CD1 mice. Compounds 5 and 9 preserved the function and survival of human donor islets exposed to inflammatory cytokines. Selective inhibition of 12-lipoxygenase activity confers protection to beta cells during exposure to inflammatory cytokines. These concept validation studies identify 12-lipoxygenase as a promising target in the prevention of loss of functional beta cells in diabetes. C1 [Taylor-Fishwick, David A.; Weaver, Jessica] Eastern Virginia Med Sch, Dept Microbiol & Mol Cell Biol, Norfolk, VA 23507 USA. [Taylor-Fishwick, David A.; Glenn, Lindsey; Kuhn, Norine; Nadler, Jerry L.] Eastern Virginia Med Sch, Dept Internal Med, Norfolk, VA 23507 USA. [Taylor-Fishwick, David A.; Nadler, Jerry L.] Eastern Virginia Med Sch, Strelitz Diabet Ctr, Norfolk, VA 23507 USA. [Rai, Ganesha; Jadhav, Ajit; Simeonov, Anton; Maloney, David J.] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Dudda, Angela] Sanofi, DSAR Drug Disposit, Frankfurt, Germany. [Schmoll, Dieter] Sanofi, R&D, Diabet Div, Frankfurt, Germany. [Holman, Theodore R.] UCSC, Dept Biochem, Santa Cruz, CA USA. RP Taylor-Fishwick, DA (reprint author), Eastern Virginia Med Sch, Dept Microbiol & Mol Cell Biol, 700 W Olney Rd, Norfolk, VA 23507 USA. EM TaylorD@evms.edu OI Taylor-Fishwick, David/0000-0002-6720-7482 FU Intramural NIH HHS; NIMH NIH HHS [U54MH084681] NR 38 TC 8 Z9 8 U1 0 U2 7 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 2015 VL 58 IS 3 BP 549 EP 557 DI 10.1007/s00125-014-3452-0 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CA9LD UT WOS:000349244100016 PM 25417214 ER PT J AU Chung, ST Hsia, DS Chacko, SK Rodriguez, LM Haymond, MW AF Chung, Stephanie T. Hsia, Daniel S. Chacko, Shaji K. Rodriguez, Luisa M. Haymond, Morey W. TI Increased gluconeogenesis in youth with newly diagnosed type 2 diabetes SO DIABETOLOGIA LA English DT Article DE Fasting hyperglycaemia; Gluconeogenesis; Glucose production; Paediatric type 2 diabetes ID HEPATIC GLUCOSE-PRODUCTION; FATTY LIVER-DISEASE; INSULIN SENSITIVITY; POSTPRANDIAL HYPERGLYCEMIA; INDIRECT CALORIMETRY; NONDIABETIC HUMANS; LIPID-METABOLISM; FASTED STATE; MELLITUS; GLYCOGENOLYSIS AB The role of increased gluconeogenesis as an important contributor to fasting hyperglycaemia at diabetes onset is not known. We evaluated the contribution of gluconeogenesis and glycogenolysis to fasting hyperglycaemia in newly diagnosed youths with type 2 diabetes following an overnight fast. Basal rates (mu mol kg(FFM) (-1) min(-1)) of gluconeogenesis ((H2O)-H-2), glycogenolysis and glycerol production ([H-2(5)] glycerol) were measured in 18 adolescents (nine treatment naive diabetic and nine normal-glucose-tolerant obese adolescents). Type 2 diabetes was associated with higher gluconeogenesis (9.2 +/- 0.6 vs 7.0 +/- 0.3 mu mol kg(FFM) (-1) min(-1), p < 0.01), plasma fasting glucose (7.0 +/- 0.6 vs 5.0 +/- 0.2 mmol/l, p = 0.004) and insulin (300 +/- 30 vs 126 +/- 31 pmol/l, p = 0.001). Glucose production and glycogenolysis were similar between the groups (15.4 +/- 0.3 vs 12.4 +/- 1.4 mu mol kg(FFM) (-1) min(-1), p = 0.06; and 6.2 +/- 0.8 vs 5.3 +/- 0.7 mu mol kg(FFM) (-1) min(-1), p = 0.5, respectively). After controlling for differences in adiposity, gluconeogenesis, glycogenolysis and glucose production were higher in diabetic youth (p a parts per thousand currency signaEuro parts per thousand 0.02). Glycerol concentration (84 +/- 6 vs 57 +/- 6 mu mol/l, p = 0.01) and glycerol production (5.0 +/- 0.3 vs 3.6 +/- 0.5 mu mol kg(FFM) (-1) min(-1), p = 0.03) were 40% higher in youth with diabetes. The increased glycerol production could account for only similar to 1/3 of substrate needed for the increased gluconeogenesis in diabetic youth. Increased gluconeogenesis was a major contributor to fasting hyperglycaemia and hepatic insulin resistance in newly diagnosed untreated adolescents and was an early pathological feature of type 2 diabetes. Increased glycerol availability may represent a significant source of new carbon substrates for increased gluconeogenesis but would not account for all the carbons required to sustain the increased rates. C1 [Chung, Stephanie T.] NIDDK, NIH, Bethesda, MD 20892 USA. [Chung, Stephanie T.; Hsia, Daniel S.; Chacko, Shaji K.; Rodriguez, Luisa M.; Haymond, Morey W.] Baylor Coll Med, USDA ARS, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Chung, Stephanie T.; Hsia, Daniel S.; Chacko, Shaji K.; Rodriguez, Luisa M.; Haymond, Morey W.] Baylor Coll Med, USDA ARS, Div Pediat Diabet Endocrinol & Metab, Houston, TX 77030 USA. RP Chung, ST (reprint author), NIDDK, NIH, 10 Ctr Dr Bld 10 CRC,RM 5-5740,MSC 1612, Bethesda, MD 20892 USA. EM chungst@niddk.nih.gov FU Intramural NIH HHS [Z99 DK999999]; NIDDK NIH HHS [R01DK 55478, R01 DK055478] NR 50 TC 3 Z9 3 U1 0 U2 8 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 2015 VL 58 IS 3 BP 596 EP 603 DI 10.1007/s00125-014-3455-x PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CA9LD UT WOS:000349244100021 PM 25447079 ER PT J AU Schliep, KC Mumford, SL Vladutiu, CJ Ahrens, KA Perkins, NJ Sjaarda, LA Kissell, KA Prasad, A Wactawski-Wende, J Schisterman, EF AF Schliep, Karen C. Mumford, Sunni L. Vladutiu, Catherine J. Ahrens, Katherine A. Perkins, Neil J. Sjaarda, Lindsey A. Kissell, Kerri A. Prasad, Ankita Wactawski-Wende, Jean Schisterman, Enrique F. TI Perceived Stress, Reproductive Hormones, and Ovulatory Function A Prospective Cohort Study SO EPIDEMIOLOGY LA English DT Article ID MARGINAL STRUCTURAL MODELS; PSYCHOSOCIAL STRESS; PSYCHOLOGICAL STRESS; PREMENOPAUSAL WOMEN; MENSTRUAL-CYCLE; CASE-CROSSOVER; FERTILITY; BIOCYCLE; PROBABILITY; ANOVULATION AB Background: Stress has been shown to suppress ovulation in experimental models, but its effect on human reproduction at the population level is unclear. Methods: Healthy women (n = 259), aged 18-44 years from Western New York, were followed for 2 menstrual cycles (2005-2007). Women completed daily perceived stress assessments, a 4-item Perceived Stress Scale (PSS-4) up to 4 times each cycle, and a 14-item PSS at baseline. Mixed model analyses were used to assess effects of stress on log reproductive hormone concentrations and sporadic anovulation. Results: High versus low daily stress was associated with lower estradiol (-9.5% [95% confidence interval (CI) = -15.6% to -3.0%]), free estradiol (-10.4% [-16.5% to -3.9%]), and luteinizing hormone (-14.8% [-21.3% to -7.7%]) and higher follicle-stimulating hormone (6.2% [95% CI = 2.0% to 10.5%]) after adjusting for age, race, percent body fat, depression score, and time-varying hormones and vigorous exercise. High versus low daily stress was also associated with lower luteal progesterone (-10.4% [95% CI = -19.7% to -0.10%]) and higher odds of anovulation (adjusted odds ratio = 2.2 [95% CI = 1.0 to 4.7]). For each unit increase in daily stress level, women had a 70% higher odds of an anovulatory episode (odds ratio = 1.7 [1.1 to 2.4]). Similar but attenuated results were found for the association between the PSS-4 and reproductive hormones, while null findings were found for the baseline PSS. Conclusion: Daily perceived stress does appear to interfere with menstrual cycle function among women with no known reproductive disorders, warranting further research to explore potential population-level impacts and causal biologic mechanisms. C1 [Schliep, Karen C.; Mumford, Sunni L.; Ahrens, Katherine A.; Perkins, Neil J.; Sjaarda, Lindsey A.; Kissell, Kerri A.; Prasad, Ankita; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. [Vladutiu, Catherine J.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Kissell, Kerri A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Rockville, MD 20852 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Buffalo, NY 14260 USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, 6100 Execut Blvd,7B03, Rockville, MD 20852 USA. EM mumfords@mail.nih.gov FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [HHSN275200403394C]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; National Heart, Lung, and Blood Institute, National Institutes of Health [T32-HL007055] FX Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institutes of Health (contract number: HHSN275200403394C).; K.C.S., S.L.M., K.A.A., N.J.P., L.A.S., K.A.K., A.P., and E.F.S. received support from the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health for the submitted work. C.J.V. received support from grant T32-HL007055 from the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 39 TC 6 Z9 6 U1 3 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD MAR PY 2015 VL 26 IS 2 BP 177 EP 184 DI 10.1097/EDE.0000000000000238 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CB1PO UT WOS:000349400300023 PM 25643098 ER PT J AU Wesolowski, A O'Meara, WP Tatem, AJ Ndege, S Eagle, N Buckee, CO AF Wesolowski, Amy O'Meara, Wendy Prudhomme Tatem, Andrew J. Ndege, Samson Eagle, Nathan Buckee, Caroline O. TI Quantifying the Impact of Accessibility on Preventive Healthcare in Sub-Saharan Africa Using Mobile Phone Data SO EPIDEMIOLOGY LA English DT Article ID SYSTEMATIC ANALYSIS; UNDER-5 MORTALITY; CHILD-MORTALITY; ACCESS; KENYA; FACILITY; DISTANCE; POVERTY; MALARIA AB Background: Poor physical access to health facilities has been identified as an important contributor to reduced uptake of preventive health services and is likely to be most critical in low-income settings. However, the relation among physical access, travel behavior, and the uptake of healthcare is difficult to quantify. Methods: Using anonymized mobile phone data from 2008 to 2009, we analyze individual and spatially aggregated travel patterns of 14,816,521 subscribers across Kenya and compare these measures to (1) estimated travel times to health facilities and (2) data on the uptake of 2 preventive healthcare interventions in an area of western Kenya: childhood immunizations and antenatal care. Results: We document that long travel times to health facilities are strongly correlated with increased mobility in geographically isolated areas. Furthermore, we found that in areas with equal physical access to healthcare, mobile phone-derived measures of mobility predict which regions are lacking preventive care. Conclusions: Routinely collected mobile phone data provide a simple and low-cost approach to mapping the uptake of preventive healthcare in low-income settings. C1 [Wesolowski, Amy] Carnegie Mellon Univ, Dept Engn & Publ Policy, Pittsburgh, PA 15213 USA. [Wesolowski, Amy; Eagle, Nathan; Buckee, Caroline O.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wesolowski, Amy; Buckee, Caroline O.] Harvard Univ, Sch Publ Hlth, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. [O'Meara, Wendy Prudhomme] Duke Univ, Dept Med, Durham, NC USA. [O'Meara, Wendy Prudhomme] Duke Global Hlth Inst, Durham, NC USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Ndege, Samson] Moi Univ, Sch Publ Hlth, Eldoret, Kenya. [Eagle, Nathan] Northeastern Univ, Dept Comp Sci, Boston, MA 02115 USA. RP Buckee, CO (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM cbuckee@hsph.harvard.edu FU NSF [0750271]; James S. McDonnell Foundation; Bill & Melinda Gates Foundation [49446, OPP1032350]; NIH/NIAID [U19AI089674]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Models of Infectious Disease Agent Study program [1U54GM088558]; Abbott Laboratories; Purpleville Foundation; Global Business Coalition FX A.W. was supported by the NSF (#0750271) and the James S. McDonnell Foundation. A.J.T. acknowledges support from Bill & Melinda Gates Foundation (#49446 and #OPP1032350), NIH/NIAID (U19AI089674), and the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. C.O.B. was supported by the Models of Infectious Disease Agent Study program (cooperative agreement 1U54GM088558). The other authors have no conflicts of interest to report. The Home-based Counseling and Testing program was supported by grants from Abbott Laboratories, the Purpleville Foundation, and the Global Business Coalition. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the 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 31 TC 3 Z9 3 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD MAR PY 2015 VL 26 IS 2 BP 223 EP 228 DI 10.1097/EDE.0000000000000239 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CB1PO UT WOS:000349400300029 PM 25643101 ER PT J AU Aweeka, FT Hu, C Huang, L Best, BM Stek, A Lizak, P Burchett, SK Read, JS Watts, H Mirochnick, M Capparelli, EV AF Aweeka, F. T. Hu, C. Huang, L. Best, B. M. Stek, A. Lizak, P. Burchett, S. K. Read, J. S. Watts, H. Mirochnick, M. Capparelli, E. V. CA Int Maternal Pediat Adolescent TI Alteration in cytochrome P450 3A4 activity as measured by a urine cortisol assay in HIV-1-infected pregnant women and relationship to antiretroviral pharmacokinetics SO HIV MEDICINE LA English DT Article DE antiretrovirals; cortisol; cytochrome p450; pharmacokinetics; pregnancy ID CYP3A ACTIVITY; 6-BETA-HYDROXYCORTISOL/CORTISOL RATIO; LOPINAVIR EXPOSURE; NELFINAVIR; VARIABILITY; INDUCTION; MIDAZOLAM; EXCRETION; CHINESE; IMPACT AB ObjectivesPregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4). The urinary ratio of 6- hydroxycortisol to cortisol (6HF:F) is a marker of CYP3A4 induction. We sought to evaluate its change in antiretroviral (ARV)-treated HIV-1-infected women and to relate this change to ARV pharmacokinetics. MethodsWomen receiving various ARVs had pharmacokinetic evaluations during the third trimester of pregnancy (>30 weeks) and postpartum with determination of 6HF:F carried out on the same days. The Wilcoxon signed rank test was used to compare the ratio antepartum to postpartum. The relationship between the change in ratio and the change in pharmacokinetics was analysed using Kendall's tau. Results6HF:F ratios were available for 107 women antepartum, with 54 having postpartum values. The ratio was higher antepartum (P=0.033) (median comparison 1.35; 95% confidence interval 1.01, 1.81). For 71 women taking a protease inhibitor (PI), the antepartum vs. postpartum 6HF:F comparison was marginally significant (P=0.058). When the change in the 6HF:F ratio was related to the change in the dose-adjusted ARV area under the plasma concentration vs. time curve (AUC) between antepartum and postpartum, the 35 subjects in the lopinavir/ritonavir (LPV/r) arms demonstrated an inverse relationship (P=0.125), albeit this correlation did not reach statistical significance. ConclusionsA 35% increase in the urinary 6HF:F ratio was measured during late pregnancy compared with postpartum, indicating that CYP3A induction occurs during pregnancy. The trend towards an inverse relationship between the change in the 6HF:F ratio and the change in the LPV AUC antepartum vs. postpartum suggests that CYP3A induction may be one mechanism behind altered LPV exposure during pregnancy. C1 [Aweeka, F. T.; Huang, L.; Lizak, P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hu, C.] Univ Arizona, Tucson, AZ USA. [Best, B. M.; Capparelli, E. V.] Univ Calif San Diego, San Diego, CA 92103 USA. [Stek, A.] Univ So Calif, Los Angeles, CA USA. [Burchett, S. K.] Childrens Hosp, Boston, MA 02115 USA. [Read, J. S.; Watts, H.] NICHHD, Bethesda, MD 20892 USA. [Mirochnick, M.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Aweeka, FT (reprint author), Univ Calif San Francisco, Drug Res Unit, 521 Parnassus Ave, San Francisco, CA 94143 USA. EM faweeka@sfghsom.ucsf.edu RI Hu, Chengcheng/A-8391-2017 FU Pediatric AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases [U01 AI04189, U01 AI41089, U01 AI27560-18, U01 AI32907]; General Clinical Research Center Units - National Center for Research Resources [M01 RR00533, M01 RR01271]; Pediatric/Perinatal HIV Clinical Trials Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3365]; Pediatric Pharmacology Research Unit Network of the National Institute for Child Health and Human Development [U01-HD-031318-11] FX This study was supported in part by the Pediatric AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases (grants U01 AI04189, U01 AI41089, U01 AI27560-18 and U01 AI32907), the General Clinical Research Center Units funded by the National Center for Research Resources (grants M01 RR00533 and M01 RR01271), the Pediatric/Perinatal HIV Clinical Trials Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract N01-HD-3-3365), and the Pediatric Pharmacology Research Unit Network of the National Institute for Child Health and Human Development (grant U01-HD-031318-11). NR 26 TC 2 Z9 2 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-2662 EI 1468-1293 J9 HIV MED JI HIV Med. PD MAR PY 2015 VL 16 IS 3 BP 176 EP 183 DI 10.1111/hiv.12195 PG 8 WC Infectious Diseases SC Infectious Diseases GA CB2CR UT WOS:000349434800005 PM 25407158 ER PT J AU Heller, ER Khan, SG Kuschal, C Tamura, D DiGiovanna, JJ Kraemer, KH AF Heller, Elizabeth R. Khan, Sikandar G. Kuschal, Christiane Tamura, Deborah DiGiovanna, John J. Kraemer, Kenneth H. TI Mutations in the TTDN1 Gene Are Associated with a Distinct Trichothiodystrophy Phenotype SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID XERODERMA-PIGMENTOSUM; DNA-REPAIR; BRITTLE HAIR; MENTAL-RETARDATION; SHORT STATURE; PHOTOSENSITIVITY; MANIFESTATIONS; ABNORMALITIES; IMPAIRMENT; PREGNANCY AB Trichothiodystrophy (TTD) is a rare multisystem disorder, characterized by sulfur-deficient hair with alternating dark and light "tiger tail" banding on polarized light microscopy. TTD is caused by mutations in DNA repair/transcription genes XPD, XPB or TTDA, and in TTDN1, a gene of unknown function. Although most of the TTD patients are photosensitive, patients with TTDN1 mutations were reported to be nonphotosensitive. We followed a cohort of 36 TTD patients from 2001 to 2013. We describe five patients from four families with defects in the TTDN1 gene: four had no photosensitivity, and one patient exhibited cutaneous burning. Deep phenotyping of our cohort revealed differences between the patients with and without TTDN1 mutations. Delayed bone age and seizure disorders were overrepresented in the TTDN1 group (P=0.009 and P=0.024, respectively), whereas some characteristic TTD clinical, laboratory, and imaging findings were absent. The three oldest TTDN1 patients displayed autistic behaviors in contrast to the characteristic friendly, socially interactive personality in the other patients. DNA sequencing revealed deletion mutations in TTDN1 ranging in size from a single base pair to over 120 kb. These data identify a distinct phenotype relationship in TTD caused by TTDN1 mutations and suggest a different mechanism of disease. C1 [Heller, Elizabeth R.; Khan, Sikandar G.; Kuschal, Christiane; Tamura, Deborah; DiGiovanna, John J.; Kraemer, Kenneth H.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kraemer, KH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Bldg 37,Room 4002, Bethesda, MD 20892 USA. EM kraemerk@nih.gov OI Kuschal, Christiane/0000-0001-6113-3585 FU NIH; Pfizer; Doris Duke Charitable Foundation; Alexandria Real Estate Equities; Howard Hughes Medical Institute; Mr and Mrs Joel S Marcus; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research 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, The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, and Mr and Mrs Joel S Marcus, and the Howard Hughes Medical Institute, as well as other private donors. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Carine Nadem and Jared Jagdeo for their help with DNA sequencing, Daniel Edelman, Holly Stevenson, and Yonghong Wang of the NCI Clinical Molecular Profiling Core for assistance with aCGH studies, and John Crawford and Mary King, photographers, and Alan Hoofring, lead medical illustrator, of the NIH Medical Arts and Photography group for assistance with Figures 1 and 2. We are indebted to our patients and families for their gracious participation. NR 30 TC 5 Z9 5 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2015 VL 135 IS 3 BP 734 EP 741 DI 10.1038/id.2014.440 PG 8 WC Dermatology SC Dermatology GA CB2AH UT WOS:000349428600016 PM 25290684 ER PT J AU Qian, Y Jeong, JS Abdeladhim, M Valenzuela, JG Aoki, V Hans-Filhio, G Rivitti, EA Diaz, LA AF Qian, Ye Jeong, Joseph S. Abdeladhim, Maha Valenzuela, Jesus G. Aoki, Valeria Hans-Filhio, Gunter Rivitti, Evandro A. Diaz, Luis A. CA Cooperative Grp Fogo Selvagem Res TI IgE Anti-LJM11 Sand Fly Salivary Antigen May Herald the Onset of Fogo Selvagem in Endemic Brazilian Regions SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID PEMPHIGUS; AUTOANTIBODIES; EPITOPE C1 [Qian, Ye; Jeong, Joseph S.; Diaz, Luis A.] Univ N Carolina, Dept Dermatol, Chapel Hill, NC 27514 USA. [Abdeladhim, Maha; Valenzuela, Jesus G.] NIAID, Vector Biol Sect, LMVR, NIH, Rockville, MD USA. [Aoki, Valeria; Rivitti, Evandro A.] Univ Sao Paulo, Dept Dermatol, Sao Paulo, Brazil. [Hans-Filhio, Gunter] Univ Fed Mato Grosso do Sul, Dept Dermatol, Campo Grande, Brazil. RP Qian, Y (reprint author), Univ N Carolina, Dept Dermatol, Chapel Hill, NC 27514 USA. EM ye_qian@med.unc.edu RI Aoki, Valeria/H-1415-2012 FU NIAMS NIH HHS [K01 AR056378, K01-AR056378, R01 AR032599, R01-AR32599] NR 13 TC 4 Z9 4 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2015 VL 135 IS 3 BP 913 EP 915 DI 10.1038/jid.2014.430 PG 3 WC Dermatology SC Dermatology GA CB2AH UT WOS:000349428600039 PM 25285921 ER PT J AU Eggly, S Manning, MA Slatcher, RB Berg, RA Wessel, DL Newth, CJL Shanley, TP Harrison, R Dalton, H Dean, JM Doctor, A Jenkins, T Meert, KL AF Eggly, Susan Manning, Mark A. Slatcher, Richard B. Berg, Robert A. Wessel, David L. Newth, Christopher J. L. Shanley, Thomas P. Harrison, Rick Dalton, Heidi Dean, J. Michael Doctor, Allan Jenkins, Tammara Meert, Kathleen L. TI Language Analysis as a Window to Bereaved Parents' Emotions During a Parent-Physician Bereavement Meeting SO JOURNAL OF LANGUAGE AND SOCIAL PSYCHOLOGY LA English DT Article DE bereavement; language analysis; health; family; physician; meaning making; actor-partner interdependence ID INTENSIVE-CARE-UNIT; CHILDS DEATH; FOLLOW-UP; MEANING RECONSTRUCTION; POSITIVE EMOTIONS; GRIEF; MODEL; SENSE; LIFE; EXPRESSION AB Parent-physician bereavement meetings may benefit parents by facilitating sense making, which is associated with healthy adjustment after a traumatic event. Prior research suggests a reciprocal relationship between sense making and positive emotions. We analyzed parents' use of emotion words during bereavement meetings to better understand parents' emotional reactions during the meeting and how their emotional reactions related to their appraisals of the meeting. Parents' use of positive emotion words increased, suggesting the meetings help parents make sense of the death. Parents' use of positive emotion words was negatively related to their own and/or their spouse's appraisals of the meeting, suggesting that parents who have a positive emotional experience during the meeting may also have a short-term negative reaction. Language analysis can be an effective tool to understand individuals' ongoing emotions and meaning making processes during interventions to reduce adverse consequences of a traumatic event, such as a child's death. C1 [Eggly, Susan; Manning, Mark A.] Wayne State Univ, Karmanos Canc Inst, Dept Oncol, Detroit, MI 48201 USA. [Slatcher, Richard B.] Wayne State Univ, Dept Psychol, Detroit, MI 48201 USA. [Berg, Robert A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Wessel, David L.] Childrens Natl Med Ctr, Hosp Serv, Washington, DC 20010 USA. [Wessel, David L.] Childrens Natl Med Ctr, Specialty Serv, Washington, DC 20010 USA. [Newth, Christopher J. L.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Shanley, Thomas P.] Univ Michigan, CS Mott Childrens Hosp, Ann Arbor, MI 48109 USA. [Harrison, Rick] Univ Calif Los Angeles, Mattel Childrens Hosp, Los Angeles, CA USA. [Dalton, Heidi] Phoenix Childrens Hosp, Phoenix, AZ USA. [Dean, J. Michael] Univ Utah, Div Pediat Crit Care, Salt Lake City, UT USA. [Dean, J. Michael] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Doctor, Allan] St Louis Childrens Hosp, Div Pediat Crit Care Med, St Louis, MO 63178 USA. [Jenkins, Tammara] NICHHD, Bethesda, MD 20892 USA. [Meert, Kathleen L.] Childrens Hosp Michigan, Div Crit Care Med, Detroit, MI 48201 USA. RP Eggly, S (reprint author), Wayne State Univ, Karmanos Canc Inst, 4100 John R St,MM03CB, Detroit, MI 48201 USA. EM egglys@karmanos.org OI Doctor, Allan/0000-0002-6096-6400; Eggly, Susan/0000-0002-8137-6098 FU NICHD NIH HHS [U10 HD063114, U10 HD063108, U10 HD049981, U10 HD063106, UG1 HD050096, U01 HD049934, U10 HD050012, U10 HD050096] NR 37 TC 1 Z9 1 U1 3 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0261-927X EI 1552-6526 J9 J LANG SOC PSYCHOL JI J. Lang. Soc. Psychol. PD MAR PY 2015 VL 34 IS 2 BP 181 EP 199 DI 10.1177/0261927X14555549 PG 19 WC Communication; Linguistics; Psychology, Social SC Communication; Linguistics; Psychology GA CB0MH UT WOS:000349319800004 PM 26726278 ER PT J AU de Guglielmo, G Melis, M De Luca, MA Kallupi, M Li, HW Niswender, K Giordano, A Senzacqua, M Somaini, L Cippitelli, A Gaitanaris, G Demopulos, G Damadzic, R Tapocik, J Heilig, M Ciccocioppo, R AF de Guglielmo, Giordano Melis, Miriam De Luca, Maria Antonietta Kallupi, Marsida Li, Hong Wu Niswender, Kevin Giordano, Antonio Senzacqua, Martina Somaini, Lorenzo Cippitelli, Andrea Gaitanaris, George Demopulos, Gregory Damadzic, Ruslan Tapocik, Jenica Heilig, Markus Ciccocioppo, Roberto TI PPAR gamma Activation Attenuates Opioid Consumption and Modulates Mesolimbic Dopamine Transmission SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS; DRUG-ABUSE; NEURONS; ADDICTION; DARPP-32; RECEPTORS; RAT; MECHANISM; MORPHINE AB PPAR gamma is one of the three isoforms identified for the peroxisome proliferator-activated receptors (PPARs) and is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. PPAR gamma has been long studied for its role in adipogenesis and glucose metabolism, but the discovery of the localization in ventral tegmental area (VTA) neurons opens new vistas for a potential role in the regulation of reward processing and motivated behavior in drug addiction. Here, we demonstrate that activation of PPAR gamma by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. These effects are associated with a marked reduction of heroin-induced increase in phosphorylation of DARPP-32 protein in the nucleus accumbens (NAc) and with a marked and selective reduction of acute heroin-induced elevation of extracellular dopamine (DA) levels in the NAc shell, as measured by in vivo microdialysis. Through ex vivo electrophysiology in acute midbrain slices, we also show that stimulation of PPAR gamma attenuates opioid-induced excitation of VTA DA neurons via reduction of presynaptic GABA release from the rostromedial tegmental nucleus (RMTg). Consistent with this finding, site-specific microinjection of pioglitazone into the RMTg but not into the VTA reduced heroin taking. Our data illustrate that activation of PPAR gamma may represent a new pharmacotherapeutic option for the treatment of opioid addiction. C1 [de Guglielmo, Giordano; Kallupi, Marsida; Li, Hong Wu; Cippitelli, Andrea; Ciccocioppo, Roberto] Univ Camerino, Sch Pharm, Pharmacol Unit, I-62032 Camerino, Macerata, Italy. [Melis, Miriam; De Luca, Maria Antonietta] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy. [De Luca, Maria Antonietta] INN, Cagliari, Italy. [Niswender, Kevin] Tennessee Valley Healthcare Syst, Nashville, TN USA. [Niswender, Kevin] Vanderbilt Univ, Sch Med, Dept Med, Div Diabet Endocrinol & Metab, Nashville, TN 37212 USA. [Giordano, Antonio; Senzacqua, Martina] Univ Politecn Marche, Sect Neurosci & Cell Biol, Dept Expt & Clin Med, Ancona, Italy. [Somaini, Lorenzo] ASL 12 Biella, Hlth Local Unit, Addict Treatment Ctr, Biella, Italy. [Gaitanaris, George; Demopulos, Gregory] Omeros Corp, Seattle, WA USA. [Damadzic, Ruslan; Tapocik, Jenica; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. RP Ciccocioppo, R (reprint author), Univ Camerino, Sch Pharm, Dept Expt Med & Publ Hlth, Pharmacol Unit, Via Madonna Carceri 9, I-62032 Camerino, Macerata, Italy. EM roberto.ciccocioppo@unicam.it OI Heilig, Markus/0000-0003-2706-2482 FU University of Camerino; Omeros FX This study was supported by the University of Camerino (to RC). Dr Demopulos is the Chairman and CEO of Omeros Corporation and Dr Gaitanaris is Chief Scientific Officer of Omeros Corporation. Omeros exclusively controls the intellectual property rights directed to the use of PPAR gamma receptor agonists for the treatment of addiction and addictive behaviors obtained from the University of Camerino and Dr Ciccocioppo. Dr Ciccocioppo is the inventor on a number of patent applications, which have been assigned to Omeros, relating to the therapeutic use of PPAR gamma agonists in addiction. He is entitled to receive payments and royalties from Omeros under such licensing arrangement. NR 52 TC 7 Z9 7 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2015 VL 40 IS 4 BP 927 EP 937 DI 10.1038/npp.2014.268 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CB3DS UT WOS:000349509000014 PM 25311134 ER PT J AU Pecina, M Love, T Stohler, CS Goldman, D Zubieta, JK AF Pecina, Marta Love, Tiffany Stohler, Christian S. Goldman, David Zubieta, Jon-Kar TI Effects of the Mu Opioid Receptor Polymorphism (OPRM1 A118G) on Pain Regulation, Placebo Effects and Associated Personality Trait Measures SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISM; MORPHINE CONSUMPTION; INDIVIDUAL-DIFFERENCES; DOPAMINE TRANSMISSION; AFFECTIVE DIMENSIONS; INDUCED ANALGESIA; SOCIAL REJECTION; VARIANT A118G; RESPONSES; REWARD AB Mu-opioid receptors (MOPRs) are critically involved in the modulation of pain and analgesia, and represent a candidate mechanism for the development of biomarkers of pain conditions and their responses to treatment. To further understand the human implications of genetic variation within the opioid system in pain and opioid-mediated placebo responses, we investigated the association between the functional single-nucleotide polymorphism (SNP) in the mu-opioid receptor gene (OPRM1), A118G, and psychophysical responses, personality traits, and neurotransmitter systems (dopamine (DA), opioid) related to pain and placebo analgesia. OPRM1 G carriers, compared with AA homozygotes, showed an overall reduction of baseline mu-opioid receptor availability in regions implicated in pain and affective regulation. In response to a sustained painful stimulus, we found no effect of Al I 8G on pain-induced endogenous opioid release. Instead, AA homozygotes showed a blunted DA response in the nucleus accumbens (NAc) in response to the pain challenge. After placebo administration, G carriers showed more pronounced mood disturbances and lower placebo-induced mu-opioid system activation in the anterior insula (aINS), the amygdala (AMY), the NAc, the thalamus (THA), and the brainstem, as well as lower levels of DA D-2/3 activation in the NAc. At a trait level, G carriers reported higher NEO-Neuroticism scores; a personality trait previously associated with increased pain and lower placebo responses, which were negatively correlated with baseline, mu-opioid receptor availability in the aINS and subgenual anterior cingulate cortex (sgACC). Our results demonstrate that the A118G OPRM1 polymorphism contributes to interindividual variations in the function of neurotransmitters responsive to pain (endogenous opioid and dopamine), as well as their regulation through cognitive-emotional influences in the context of therapeutic expectations, the so-called placebo effect. These effects are relevant to human vulnerability to disease processes where these neurotransmitters have a role, such as persistent pain, mood, and substance use disorders, and responses to their treatments. C1 [Pecina, Marta; Love, Tiffany; Zubieta, Jon-Kar] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Stohler, Christian S.] Columbia Univ, Coll Dent Med, New York, NY USA. [Goldman, David] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. [Zubieta, Jon-Kar] Univ Michigan, Sch Med, Dept Radiol, Ann Arbor, MI 48109 USA. RP Zubieta, JK (reprint author), Univ Michigan, Mol & Behav Neurosci Inst, 205 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM zubieta@umich.edu RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Love, Tiffany/0000-0001-9299-3190 FU Phil F. Jenkins Foundation; [R01 DA 022520]; [R01 DA 27494] FX Work was supported by R01 DA 022520, R01 DA 27494 (JKZ), and the Phil F. Jenkins Foundation. The authors declare no conflict of interest. NR 58 TC 24 Z9 24 U1 3 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2015 VL 40 IS 4 BP 957 EP 965 DI 10.1038/npp.2014.272 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CB3DS UT WOS:000349509000017 PM 25308352 ER PT J AU Zhang, HY Bi, GH Li, X Li, J Qu, H Zhang, SJ Li, CY Onaivi, ES Gardner, EL Xi, ZX Liu, QR AF Zhang, Hai-Ying Bi, Guo-Hua Li, Xia Li, Jie Qu, Hong Zhang, Shi-Jian Li, Chuan-Yun Onaivi, Emmanuel S. Gardner, Eliot L. Xi, Zheng-Xiong Liu, Qing-Rong TI Species Differences in Cannabinoid Receptor 2 and Receptor Responses to Cocaine Self-Administration in Mice and Rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; CB2 RECEPTOR; PHARMACOLOGICAL CHARACTERIZATION; SWISS-MODEL; ENDOCANNABINOID SYSTEM; INTRANASAL DELIVERY; SELECTIVE LIGANDS; PLACE PREFERENCE; MESSENGER-RNA; BRAIN AB The discovery of functional cannabinoid receptors 2 (CB(2)Rs) in brain suggests a potential new therapeutic target for neurological and psychiatric disorders, However, recent findings in experimental animals appear controversial. Here we report that there are significant species differences in CB2R mRNA splicing and expression, protein sequences, and receptor responses to CB2R ligands in mice and rats. Systemic administration of JWH133, a highly selective CB2R agonist, significantly and dose-dependently inhibited intravenous cocaine self-administration under a fixed ratio (FR) schedule of reinforcement in mice, but not in rats. However, under a progressive ratio (PR) schedule of reinforcement, JWHI33 significantly increased breakpoint for cocaine self-administration in rats, but decreased it in mice. To explore the possible reasons for these conflicting findings, we examined CB2R gene expression and receptor structure in the brain. We found novel rat-specific.CB2c and CB2D mRNA isoforms in addition to CB2A and CB2B mRNA isoforms. In situ hybridization RNAscope assays found higher levels of CB2R mRNA in different brain regions and cell types in mice than in rats. By comparing CB2R-encoding regions, we observed a premature stop codon in the mouse CB2R gene that truncated 13 amino-acid residues including a functional autophosphorylation site in the intracellular C-terminus. These findings suggest that species differences in the splicing and expression of CB2R genes and receptor structures may in part explain the different effects of CB2R-selective ligands on cocaine self-administration in mice and rats. C1 [Zhang, Hai-Ying; Bi, Guo-Hua; Li, Xia; Li, Jie; Gardner, Eliot L.; Xi, Zheng-Xiong] NIDA, Neuroropsychopharmacol Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Qu, Hong] Peking Univ, Ctr Bioinformat, Coll Life Sci, Beijing 100871, Peoples R China. [Zhang, Shi-Jian; Li, Chuan-Yun] Inst Mol Med, Beijing Key Lab Cardiometab Mol Med, Beijing, Peoples R China. [Zhang, Shi-Jian; Li, Chuan-Yun] Peking Univ, Beijing 100871, Peoples R China. [Onaivi, Emmanuel S.] William Paterson Univ, Dept Biol, Wayne, NJ USA. [Liu, Qing-Rong] NIDA, Neurobiol Relapse Sect, Behav Neurosci Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Xi, ZX (reprint author), NIDA, Neuroropsychopharmacol Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program, Baltimore, MD 21224 USA. EM zxi@intra.nida.nih.gov; qliu@intra.nida.nih.gov RI Liu, Qing-Rong/A-3059-2012; OI Liu, Qing-Rong/0000-0001-8477-6452; Zhang, Haiying/0000-0003-0593-5940 FU National Institute on Drug Abuse, National Institute of Health (NIDA-NIH); National Natural Science Foundation of China [31171270]; National Key Basic Research Program of China [2012CB518004, 2013CB531202]; NIDA-NIH; NIH [DA032890] FX We gratefully acknowledge Dr Yavin Shaham, chief of the Behavioral Neuroscience Research Branch, Intramural Research Program, NIDA-NIH, for invaluable advice on statistical analysis. H-YZ, G-HB, XL, JL, Z-XX, ELG, and Q-RL are supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institute of Health (NIDA-NIH). HQ is supported by the National Natural Science Foundation of China (31171270), and C-YL and S-JZ are supported by the National Key Basic Research Program of China (2012CB518004 and 2013CB531202). ESO acknowledges Guest Researcher support at NIDA-NIH and NIH grant DA032890. NR 76 TC 6 Z9 6 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2015 VL 40 IS 4 BP 1037 EP 1051 DI 10.1038/npp.2014.297 PG 15 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CB3DS UT WOS:000349509000025 PM 25374096 ER PT J AU Wakaskar, RR Bathena, SPR Tallapaka, SB Ambardekar, VV Gautam, N Thakare, R Simet, SM Curran, SM Singh, RK Dong, YX Vetro, JA AF Wakaskar, Rajesh R. Bathena, Sai Praneeth R. Tallapaka, Shailendra B. Ambardekar, Vishakha V. Gautam, Nagsen Thakare, Rhishikesh Simet, Samantha M. Curran, Stephen M. Singh, Rakesh K. Dong, Yuxiang Vetro, Joseph A. TI Peripherally Cross-Linking the Shell of Core-Shell Polymer Micelles Decreases Premature Release of Physically Loaded Combretastatin A4 in Whole Blood and Increases its Mean Residence Time and Subsequent Potency Against Primary Murine Breast Tumors After IV Administration SO PHARMACEUTICAL RESEARCH LA English DT Article DE drug delivery; peripheral shell cross-linking; pluronic F127; poloxamer 407; polymer nanocarriers; premature drug release; vascular disrupting agents ID BLOCK-COPOLYMER MICELLES; DRUG-DELIVERY; IN-VITRO; TRIBLOCK COPOLYMERS; LINKED MICELLES; SOLUBILIZATION; ACCUMULATION; DOXORUBICIN; PHOSPHATE; DESIGN AB Determine the feasibility and potential benefit of peripherally cross-linking the shell of core-shell polymer micelles on the premature release of physically loaded hydrophobic drug in whole blood and subsequent potency against solid tumors. Individual Pluronic F127 polymer micelles (F127 PM) peripherally cross-linked with ethylenediamine at 76% of total PEO blocks (X-F127 PM) were physically loaded with combretastatin A4 (CA4) by the solid dispersion method and compared to CA4 physically loaded in uncross-linked F127 PM, CA4 in DMSO in vitro, or water-soluble CA4 phosphate (CA4P) in vivo. X-F127 PM had similar CA4 loading and aqueous solubility as F127 PM up to 10 mg CA4 / mL at 22.9 wt% and did not aggregate in PBS or 90% (v/v) human serum at 37A degrees C for at least 24 h. In contrast, X-F127 PM decreased the unbound fraction of CA4 in whole blood (fu) and increased the mean plasma residence time and subsequent potency of CA4 against the vascular function and growth of primary murine 4T1 breast tumors over CA4 in F127 PM and water-soluble CA4P after IV administration. Given that decreasing the fu is an indication of decreased drug release, peripherally cross-linking the shell of core-shell polymer micelles may be a simple approach to decrease premature release of physically loaded hydrophobic drug in the blood and increase subsequent potency in solid tumors. C1 [Wakaskar, Rajesh R.; Vetro, Joseph A.] Univ Nebraska Med Ctr, Ctr Drug Delivery & Nanomed, Omaha, NE 68198 USA. [Wakaskar, Rajesh R.; Bathena, Sai Praneeth R.; Tallapaka, Shailendra B.; Gautam, Nagsen; Thakare, Rhishikesh; Curran, Stephen M.; Dong, Yuxiang; Vetro, Joseph A.] Univ Nebraska Med Ctr, Coll Pharm, Dept Pharmaceut Sci, Omaha, NE 68198 USA. [Ambardekar, Vishakha V.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Canc Res Technol Program, Frederick, MD 21702 USA. [Simet, Samantha M.] Univ Nebraska Med Ctr, Dept Pulm Crit Care Sleep & Allergy, Coll Med, Omaha, NE 68198 USA. [Singh, Rakesh K.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. RP Vetro, JA (reprint author), Univ Nebraska Med Ctr, Coll Pharm, Dept Pharmaceut Sci, 986025 Nebraska Med Ctr, Omaha, NE 68198 USA. EM jvetro@unmc.edu RI Vetro, Joseph/K-3171-2013 OI Vetro, Joseph/0000-0003-2446-9797 FU NIH COBRE grant [2P20GM103480-06]; NIH [1U54CA163120-01]; UNMC Predoctoral Fellowships; NIH (SIG program); UNMC Program of Excellence (POE); Nebraska Research Initiative (NRI) FX This work was supported by NIH COBRE grant 2P20GM103480-06 (Nebraska Center for Nanomedicine) (RRW, RKS, JAV), NIH 1U54CA163120-01 grant (RKS), and UNMC Predoctoral Fellowships (SPRB, ST, VVA). The Nanoimaging Core Facility was supported by the NIH (SIG program), the UNMC Program of Excellence (POE), and the Nebraska Research Initiative (NRI). The Authors would also like to acknowledge Todd A. Wyatt, PhD and the VA Nebraska-Western Iowa Health Care System Research Service for providing access to and assistance with the Electric Cell Impedance Sensing apparatus. NR 47 TC 3 Z9 4 U1 2 U2 14 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD MAR PY 2015 VL 32 IS 3 BP 1028 EP 1044 DI 10.1007/s11095-014-1515-z PG 17 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA CB0ZX UT WOS:000349357300022 PM 25223962 ER PT J AU Street, AE Gilman, SE Rosellini, AJ Stein, MB Bromet, EJ Cox, KL Colpe, LJ Fullerton, CS Gruber, MJ Heeringa, SG Lewandowski-Romps, L Little, RJA Naifeh, JA Nock, MK Sampson, NA Schoenbaum, M Ursano, RJ Zaslavsky, AM Kessler, RC AF Street, A. E. Gilman, S. E. Rosellini, A. J. Stein, M. B. Bromet, E. J. Cox, K. L. Colpe, L. J. Fullerton, C. S. Gruber, M. J. Heeringa, S. G. Lewandowski-Romps, L. Little, R. J. A. Naifeh, J. A. Nock, M. K. Sampson, N. A. Schoenbaum, M. Ursano, R. J. Zaslavsky, A. M. Kessler, R. C. CA Army STARRS Collaborators TI Understanding the elevated suicide risk of female soldiers during deployments SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Army; Army STARRS; epidemiology; gender; military; risk factors; suicide ID SERVICEMEMBERS ARMY STARRS; MENTAL-HEALTH; GENDER-DIFFERENCES; OEF/OIF VETERANS; UNITED-STATES; US ARMY; MILITARY PERSONNEL; COMBAT DEPLOYMENT; SEXUAL-HARASSMENT; RESILIENCE AB Background. The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) has found that the proportional elevation in the US Army enlisted soldier suicide rate during deployment (compared with the never-deployed or previously deployed) is significantly higher among women than men, raising the possibility of gender differences in the adverse psychological effects of deployment. Method. Person-month survival models based on a consolidated administrative database for active duty enlisted Regular Army soldiers in 2004-2009 (n = 975 057) were used to characterize the gender x deployment interaction predicting suicide. Four explanatory hypotheses were explored involving the proportion of females in each soldier's occupation, the proportion of same-gender soldiers in each soldier's unit, whether the soldier reported sexual assault victimization in the previous 12 months, and the soldier's pre-deployment history of treated mental/behavioral disorders. Results. The suicide rate of currently deployed women (14.0/100 000 person-years) was 3.1-3.5 times the rates of other (i.e. never-deployed/previously deployed) women. The suicide rate of currently deployed men (22.6/100 000 personyears) was 0.9-1.2 times the rates of other men. The adjusted (for time trends, sociodemographics, and Army career variables) female: male odds ratio comparing the suicide rates of currently deployed v. other women v. men was 2.8 (95% confidence interval 1.1-6.8), became 2.4 after excluding soldiers with Direct Combat Arms occupations, and remained elevated (in the range 1.9-2.8) after adjusting for the hypothesized explanatory variables. Conclusions. These results are valuable in excluding otherwise plausible hypotheses for the elevated suicide rate of deployed women and point to the importance of expanding future research on the psychological challenges of deployment for women. C1 [Street, A. E.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Street, A. E.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Gilman, S. E.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Gilman, S. E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Rosellini, A. J.; Gruber, M. J.; Sampson, N. A.; Zaslavsky, A. M.; Kessler, R. C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Stein, M. B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, M. B.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Stein, M. B.] VA San Diego Healthcare Syst, San Diego, CA USA. [Bromet, E. J.] SUNY Stony Brook, Sch Med, Dept Psychiat, Stony Brook, NY 11794 USA. [Cox, K. L.] US Army Publ Hlth Command, Aberdeen Proving Ground, MD USA. [Colpe, L. J.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Fullerton, C. S.; Naifeh, J. A.; Ursano, R. J.] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Sch Med, Ctr Study Traumat Stress, Bethesda, MD 20814 USA. [Heeringa, S. G.; Lewandowski-Romps, L.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Little, R. J. A.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Nock, M. K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Schoenbaum, M.] NIMH, Off Sci Policy Planning & Commun, Bethesda, MD 20892 USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM kessler@hcp.med.harvard.edu RI Gilman, Stephen/E-7632-2010 OI Gilman, Stephen/0000-0002-8331-6419 FU Department of the Army; US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) [U01MH087981] FX Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, NIMH, the Department of the Army, or the DoD. Co-principal investigators are: Robert J. Ursano, MD (Uniformed Services University of the Health Sciences) and Murray B. Stein, MD, MPH (University of California San Diego and VA San Diego Healthcare System). Site principal investigators are: Steven Heeringa, PhD (University of Michigan) and Ronald C. Kessler, PhD (Harvard Medical School). NIMH collaborating scientists are: Lisa J. Colpe, PhD, MPH and Michael Schoenbaum, PhD. Army liaisons/consultants are: Col. Steven Cersovsky, MD, MPH (US Army Public Health Command; USAPHC); Kenneth Cox, MD, MPH (USAPHC). Other team members: Pablo A. Aliaga, MA (Uniformed Services University of the Health Sciences); Col. David M. Benedek, MD (Uniformed Services University of the Health Sciences); Susan Borja, PhD (NIMH); Gregory G. Brown, PhD (University of California San Diego); Laura Campbell-Sills, PhD (University of California San Diego); Catherine L. Dempsey, PhD, MPH (Uniformed Services University of the Health Sciences); Richard Frank, PhD (Harvard Medical School); Carol S. Fullerton, PhD (Uniformed Services University of the Health Sciences); Nancy Gebler, MA (University of Michigan); Robert K. Gifford, PhD (Uniformed Services University of the Health Sciences); Stephen E. Gilman, ScD (Harvard School of Public Health); Marjan G. Holloway, PhD (Uniformed Services University of the Health Sciences); Paul E. Hurwitz, MPH (Uniformed Services University of the Health Sciences); Sonia Jain, PhD (University of California San Diego); Tzu-Cheg Kao, PhD (Uniformed Services University of the Health Sciences); Karestan C. Koenen, PhD (Columbia University); Lisa Lewandowski-Romps, PhD (University of Michigan); Holly Herberman Mash, PhD (Uniformed Services University of the Health Sciences); James E. McCarroll, PhD, MPH (Uniformed Services University of the Health Sciences); Katie A. McLaughlin, PhD (Harvard Medical School); James A. Naifeh, PhD (Uniformed Services University of the Health Sciences); Matthew K. Nock, PhD (Harvard University); Rema Raman, PhD (University of California San Diego); Sherri Rose, PhD (Harvard Medical School); Anthony Joseph Rosellini, PhD (Harvard Medical School); Nancy A. Sampson, BA (Harvard Medical School); LCDR Patcho Santiago, MD, MPH (Uniformed Services University of the Health Sciences); Michaelle Scanlon, MBA (NIMH); Jordan Smoller, MD, ScD (Harvard Medical School); Michael L. Thomas, PhD (University of California San Diego); Patti L. Vegella, MS, MA (Uniformed Services University of the Health Sciences); Christina Wassel, PhD (University of Pittsburgh); and Alan M. Zaslavsky, PhD (Harvard Medical School). A complete list of Army STARRS publications can be found at http://www.ARMYSTARRS.org. As a cooperative agreement, scientists employed by NIMH (L. J. Colpe and M. Schoenbaum) and Army liaisons/consultants (Col. Steven Cersovsky, MD, MPH USAPHC and Kenneth Cox, MD, MPH USAPHC) collaborated to develop the study protocol and data collection instruments, supervise data collection, plan and supervise data analyses, interpret results, and prepare reports.; Although a draft of this manuscript was submitted to the Army and NIMH for review and comment prior to submission, this was with the understanding that comments would be no more than advisory. NR 46 TC 9 Z9 9 U1 4 U2 18 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD MAR PY 2015 VL 45 IS 4 BP 717 EP 726 DI 10.1017/S003329171400258X PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CB4SR UT WOS:000349618900004 PM 25359554 ER PT J AU Meade, JA Free, RB Miller, NR Chun, LS Doyle, TB Moritz, AE Conroy, JL Watts, VJ Sibley, DR AF Meade, Julie A. Free, R. Benjamin Miller, Nicole R. Chun, Lani S. Doyle, Trevor B. Moritz, Amy E. Conroy, Jennie L. Watts, Val J. Sibley, David R. TI (-)-Stepholidine is a potent pan-dopamine receptor antagonist of both G protein- and beta-arrestin-mediated signaling SO PSYCHOPHARMACOLOGY LA English DT Article DE Stepholidine; Dopamine; Antipsychotic; beta-arrestin; Receptor ID L-STEPHOLIDINE; D1 RECEPTOR; FUNCTIONAL SELECTIVITY; COUPLED RECEPTORS; BIASED LIGANDS; DUAL ACTIONS; D-1; AGONIST; BINDING; PHARMACOLOGY AB (-)-Stepholidine is a tetrahydroberberine alkaloid that is known to interact with dopamine receptors and has also been proposed as a novel antipsychotic agent. Its suggested novelty lies in the fact that it has been proposed to have D1-like receptor agonist and D2-like receptor antagonist properties. Thus, it might be effective in treating both positive and negative (cognition) symptoms of schizophrenia. However, its activity on specific dopamine receptor subtypes has not been clarified, especially with respect to its ability to activate D1-like receptors. We wished to examine the affinity and functional activity of (-)-stepholidine at each of the human dopamine receptor subtypes expressed in a defined cellular environment. D1-D5 dopamine receptors were stably expressed in cell lines and their interactions with (-)-stepholidine were examined using radioligand binding and various functional signaling assays. Radioligand binding assays were also performed using bovine striatal membranes. (-)-Stepholidine exhibited high (nM) affinity for D1 and D5 receptors, somewhat lower (two- to four-fold) affinity for D2 and D3 receptors, and low micromolar affinity for D4 receptors. Functionally, (-)-stepholidine was ineffective in activating G protein-mediated signaling of D1-like and D2 receptors and was also ineffective in stimulating beta-arrestin recruitment to any dopamine receptor subtype. It did, however, antagonize all of these responses. It also antagonized D1-D2 heteromer-mediated Ca2+ mobilization. Radioligand binding assays of D1-like receptors in brain membranes also indicated that (-)-stepholidine binds to the D1 receptor with antagonist-like properties. (-)-Stepholidine is a pan-dopamine receptor antagonist and its in vivo effects are largely mediated through dopamine receptor blockade with potential cross-talk to other receptors or signaling proteins. C1 [Meade, Julie A.; Free, R. Benjamin; Miller, Nicole R.; Chun, Lani S.; Doyle, Trevor B.; Moritz, Amy E.; Conroy, Jennie L.; Sibley, David R.] NIH, Natl Inst Neurol Disorders & Stroke, Mol Neuropharmacol Sect, Bethesda, MD 20892 USA. [Chun, Lani S.] Johns Hopkins Univ, Dev Biol & Biophys Program, Baltimore, MD USA. [Doyle, Trevor B.; Watts, Val J.] Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. RP Sibley, DR (reprint author), NIH, Natl Inst Neurol Disorders & Stroke, Mol Neuropharmacol Sect, 5625 Fishers Lane,Room 4S-04, Bethesda, MD 20892 USA. EM sibleyd@helix.nih.gov FU National Institute of Neurological Disorders and Stroke (NINDS) FX This work was supported, in part, by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS). All authors declare no conflicts of interest. The authors would like to thank Dr. Peter W. Dematteo (NIDA) for optical rotation analysis and NMR confirmation of (-)stepholidine batches, and Mr. Bryce Adams for technical assistance. NR 51 TC 5 Z9 5 U1 3 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2015 VL 232 IS 5 BP 917 EP 930 DI 10.1007/s00213-014-3726-8 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CB1HD UT WOS:000349377000009 PM 25231919 ER PT J AU Jasinska, AJ Chen, BT Bonci, A Stein, EA AF Jasinska, Agnes J. Chen, Billy T. Bonci, Antonello Stein, Elliot A. TI Dorsal medial prefrontal cortex (MPFC) circuitry in rodent models of cocaine use: implications for drug addiction therapies SO ADDICTION BIOLOGY LA English DT Review DE Addiction; cocaine; medial prefrontal cortex; prelimbic cortex ID VENTRAL TEGMENTAL AREA; LONG-TERM POTENTIATION; DOPAMINE NEURONS; COGNITIVE CONTROL; BASOLATERAL AMYGDALA; NUCLEUS-ACCUMBENS; HUMAN BRAIN; CLINICAL-IMPLICATIONS; SEEKING BEHAVIOR; CINGULATE CORTEX AB Although the importance of the medial prefrontal cortex (MPFC) in cocaine addiction is well established, its precise contribution to cocaine seeking, taking and relapse remains incompletely understood. In particular, across two different models of cocaine self-administration, pharmacological or optogenetic activation of the dorsal MPFC has been reported to sometimes promote and sometimes inhibit cocaine seeking. We highlight important methodological differences between the two experimental paradigms and propose a framework to potentially reconcile the apparent discrepancy. We also draw parallels between these pre-clinical models of cocaine self-administration and human neuro-imaging studies in cocaine users, and argue that both lines of evidence point to dynamic interactions between cue-reactivity processes and control processes within the dorsal MPFC circuitry. From a translational perspective, these findings underscore the importance of interventions and therapeutics targeting not just a brain region, but a specific computational process within that brain region, and may have implications for the design and implementation of more effective treatments for human cocaine addiction. C1 [Jasinska, Agnes J.; Chen, Billy T.; Bonci, Antonello; Stein, Elliot A.] NIDA, Intramural Res Program, Baltimore, MD USA. [Bonci, Antonello] Johns Hopkins Univ, Sch Med, Solomon Snyder Dept Neurosci, Baltimore, MD USA. [Bonci, Antonello] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. RP Jasinska, AJ (reprint author), NIDA, NIH, Neuroimaging Res Branch, Baltimore, MD 20892 USA. EM agnesjasinska11@gmail.com; EStein@intra.nida.nih.gov FU Intramural Research Program of NIDA, NIH FX This work was supported by the Intramural Research Program of NIDA, NIH. NR 99 TC 8 Z9 8 U1 2 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2015 VL 20 IS 2 BP 215 EP 226 DI 10.1111/adb.12132 PG 12 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA CB0HG UT WOS:000349305900001 PM 24620898 ER PT J AU Daut, RA Busch, EF Ihne, J Fisher, D Mishina, M Grant, SGN Camp, M Holmes, A AF Daut, Rachel A. Busch, Erica F. Ihne, Jessica Fisher, Daniel Mishina, Masayoshi Grant, Seth G. N. Camp, Marguerite Holmes, Andrew TI Tolerance to ethanol intoxication after chronic ethanol: role of GluN2A and PSD-95 SO ADDICTION BIOLOGY LA English DT Article DE chronic ethanol; GluN2A and PSD-95; tolerance ID CHRONIC INTERMITTENT ETHANOL; NMDA RECEPTOR NR2A; MICE; DEPENDENCE; ASSOCIATION; ALCOHOLISM; MODULATION; SUBUNIT AB The neural and genetic factors underlying chronic tolerance to alcohol are currently unclear. The GluN2AN-methyl-D-aspartate receptors (NMDAR) subunit and the NMDAR-anchoring protein PSD-95 mediate acute alcohol intoxication and represent putative mechanisms mediating tolerance. We found that chronic intermittent ethanol exposure (CIE) did not produce tolerance [loss of righting reflex (LORR)] or withdrawal-anxiety in C57BL/6J, GluN2A or PSD-95 knockout mice assayed 2-3 days later. However, significant tolerance to LORR was evident 1 day after CIE in C57BL/6J and PSD-95 knockouts, but absent in GluN2A knockouts. These data suggest a role for GluN2A in tolerance, extending evidence that human GluN2A gene variation is involved in alcohol dependence. C1 [Daut, Rachel A.; Busch, Erica F.; Ihne, Jessica; Fisher, Daniel; Camp, Marguerite; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. [Mishina, Masayoshi] Ritsumeikan Univ, Res Org Sci & Technol, Brain Sci Lab, Kusatsu, Japan. [Grant, Seth G. N.] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Grant, Seth G. N.] Univ Edinburgh, Ctr Neuroregenerat, Edinburgh, Midlothian, Scotland. RP Holmes, A (reprint author), 5625 Fishers Lane Room 2N09, Rockville, MD 20852 USA. EM Andrew.Holmes@nih.gov OI Reed, Jessica/0000-0003-0550-7284 FU NIAAA Intramural Research Program FX We are very grateful to Dr. Howard Becker, Dr. Marcelo Lopez, Dr. Nicolas Jury, Miss Benita Hurd and Miss Erica Sagalyn for valuable assistance with the CIE procedure. Research was supported by the NIAAA Intramural Research Program. NR 14 TC 5 Z9 5 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2015 VL 20 IS 2 BP 259 EP 262 DI 10.1111/adb.12110 PG 4 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA CB0HG UT WOS:000349305900005 PM 24397780 ER PT J AU DePoy, L Daut, R Wright, T Camp, M Crowley, N Noronha, B Lovinger, D Holmes, A AF DePoy, Lauren Daut, Rachel Wright, Tara Camp, Marguerite Crowley, Nicole Noronha, Bianca Lovinger, David Holmes, Andrew TI Chronic alcohol alters rewarded behaviors and striatal plasticity SO ADDICTION BIOLOGY LA English DT Article DE Alcohol; dorsolateral striatum; reward ID ETHANOL EXPOSURE; DEPENDENCE; RESCUE; MICE AB Chronic intermittent ethanol (CIE) alters neural functions and behaviors mediated by the dorsolateral striatum (DLS) and prefrontal cortex. Here, we examined the effects of prolonged (16-bout) CIE on DLS plasticity and DLS-mediated behaviors. Ex vivo electrophysiological recordings revealed loss in efficacy of DLS synaptically induced activation and absent long-term depression after CIE. CIE increased two-bottle choice drinking and impaired Pavlovian-to-instrumental transfer but not discriminated approach. These data suggest prolonged CIE impaired DLS plasticity, to produce associated changes in drinking and cue-controlled reward-seeking. Given recent evidence that less-prolonged CIE can promote certain dorsal striatal-mediated behaviors, CIE may drive chronicity-dependent adaptations in corticostriatal systems regulating behavior. C1 [DePoy, Lauren; Daut, Rachel; Wright, Tara; Camp, Marguerite; Noronha, Bianca; Holmes, Andrew] NIAAA, NIH, Lab Behav & Genom Neurosci, Bethesda, MD USA. [Crowley, Nicole; Lovinger, David] NIAAA, NIH, Lab Integrat Neurosci, Bethesda, MD USA. RP DePoy, L (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, 954 Gatewood Rd, Atlanta, GA 30329 USA. EM ldebrou@emory.edu FU NIAAA Intramural Research Program FX We are very grateful to Miss B. Hurd for valuable assistance with the CIE procedure and Mr. R.E. Cruz for facilitating the writing of the manuscript. Research supported by the NIAAA Intramural Research Program. NR 20 TC 9 Z9 9 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2015 VL 20 IS 2 BP 345 EP 348 DI 10.1111/adb.12131 PG 4 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA CB0HG UT WOS:000349305900014 PM 24666522 ER PT J AU Carroll, AJ Sutherland, MT Salmeron, BJ Ross, TJ Stein, EA AF Carroll, Allison J. Sutherland, Matthew T. Salmeron, Betty Jo Ross, Thomas J. Stein, Elliot A. TI Greater externalizing personality traits predict less error-related insula and anterior cingulate cortex activity in acutely abstinent cigarette smokers SO ADDICTION BIOLOGY LA English DT Article DE Anterior cingulate cortex; errors; functional magnetic resonance imaging (fMRI) impulsivity; insula; nicotine abstinence ID TOBACCO CRAVING QUESTIONNAIRE; DEFAULT-MODE; FUNCTIONAL CONNECTIVITY; ANTISOCIAL-BEHAVIOR; NEURAL MECHANISMS; COGNITIVE CONTROL; DECISION-MAKING; DRUG-ADDICTION; FRONTAL-CORTEX; BRAIN NETWORKS AB Attenuated activity in performance-monitoring brain regions following erroneous actions may contribute to the repetition of maladaptive behaviors such as continued drug use. Externalizing is a broad personality construct characterized by deficient impulse control, vulnerability to addiction and reduced neurobiological indices of error processing. The insula and dorsal anterior cingulate cortex (dACC) are regions critically linked with error processing as well as the perpetuation of cigarette smoking. As such, we examined the interrelations between externalizing tendencies, erroneous task performance, and error-related insula and dACC activity in overnight-deprived smokers (n=24) and non-smokers (n=20). Participants completed a self-report measure assessing externalizing tendencies (Externalizing Spectrum Inventory) and a speeded Flanker task during functional magnetic resonance imaging scanning. We observed that higher externalizing tendencies correlated with the occurrence of more performance errors among smokers but not non-smokers. Suggesting a neurobiological contribution to such suboptimal performance among smokers, higher externalizing also predicted less recruitment of the right insula and dACC following error commission. Critically, this error-related activity fully mediated the relationship between externalizing traits and error rates. That is, higher externalizing scores predicted less error-related right insula and dACC activity and, in turn, less error-related activity predicted more errors. Relating such regional activity with a clinically relevant construct, less error-related right insula and dACC responses correlated with higher tobacco craving during abstinence. Given that inadequate error-related neuronal responses may contribute to continued drug use despite negative consequences, these results suggest that externalizing tendencies and/or compromised error processing among subsets of smokers may be relevant factors for smoking cessation success. C1 [Carroll, Allison J.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Carroll, Allison J.; Sutherland, Matthew T.; Salmeron, Betty Jo; Ross, Thomas J.; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. [Sutherland, Matthew T.] Florida Int Univ, Dept Phys, Miami, FL 33199 USA. RP Sutherland, MT (reprint author), Florida Int Univ, Dept Phys, Acad Hlth Ctr 4, RM 313,11200 SW 8th St, Miami, FL 33199 USA. EM masuther@fiu.edu RI Salmeron, Betty Jo/M-1793-2016; OI Salmeron, Betty Jo/0000-0003-1699-9333; Ross, Thomas/0000-0002-7745-3572 FU National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services (NIDA-IRP/NIH/DHHS) FX This work was supported by the National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services (NIDA-IRP/NIH/DHHS). We thank Eliscia Smith, Angela Neal, Kimberly Slater, Loretta Spurgeon, and the NIDA-IRP nurses and recruitment staff for assistance with data collection. NR 68 TC 5 Z9 6 U1 3 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2015 VL 20 IS 2 BP 377 EP 389 DI 10.1111/adb.12118 PG 13 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA CB0HG UT WOS:000349305900018 PM 24354662 ER PT J AU Beasley, CR Jenkins, RA Valenti, M AF Beasley, Christopher R. Jenkins, Richard A. Valenti, Maria TI Special Section on LGBT Resilience Across Cultures: Introduction SO AMERICAN JOURNAL OF COMMUNITY PSYCHOLOGY LA English DT Article DE LGBT; Resilience; Culture; Prevention; Promotion AB This special section addresses a gap area of resilience and LGBT well-being. Although comprehensive global diversity regarding LGBT resilience was challenging to find, the special section includes representation from outside the US (Israel and Hong Kong), ethnic/racially diverse domestic populations, immigration, and one population for which LGBT identities might be considered marginalized-Christians in the US. The full range of LGBT identities are represented in the issue along with persons identifying as queer or questioning, although transgendered people were less well represented than lesbian, gay or bisexual identities. C1 [Beasley, Christopher R.] Washington Coll, Chestertown, MD USA. [Jenkins, Richard A.] NIDA, Dept Behav Sci & Hlth, Bethesda, MD 20892 USA. [Valenti, Maria] Educ Dev Ctr, Waltham, MA USA. RP Jenkins, RA (reprint author), NIDA, Dept Behav Sci & Hlth, Bethesda, MD 20892 USA. EM cbeasley2@washcoll.edu; jenkinsri@nida.nih.gov NR 18 TC 4 Z9 4 U1 2 U2 15 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0562 EI 1573-2770 J9 AM J COMMUN PSYCHOL JI Am. J. Community Psychol. PD MAR PY 2015 VL 55 IS 1-2 BP 164 EP 166 DI 10.1007/s10464-015-9701-7 PG 3 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Social Work SC Public, Environmental & Occupational Health; Psychology; Social Work GA CA6KW UT WOS:000349023400015 PM 25566819 ER PT J AU Bissonette, GB Schoenbaum, G Roesch, MR Powell, EM AF Bissonette, Gregory B. Schoenbaum, Geoffrey Roesch, Matthew R. Powell, Elizabeth M. TI Interneurons Are Necessary for Coordinated Activity During Reversal Learning in Orbitofrontal Cortex SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Autism; Interneuron; OFC; Parvalbumin; Plaur; Reversal learning; Schizophrenia ID PLASMINOGEN-ACTIVATOR RECEPTOR; GROWTH FACTOR/SCATTER FACTOR; MEDIAL PREFRONTAL CORTEX; BASOLATERAL AMYGDALA; GABAERGIC INTERNEURONS; BEHAVIORAL FLEXIBILITY; COGNITIVE INFLEXIBILITY; CORTICAL-LESIONS; BIPOLAR DISORDER; DECISION-MAKING AB BACKGROUND: Cerebral cortical gamma-aminobutyric acidergic interneuron dysfunction is hypothesized to lead to cognitive deficits comorbid with human neuropsychiatric disorders, including schizophrenia, autism, and epilepsy. We have previously shown that mice that harbor mutations in the Plaur gene, which is associated with schizophrenia, have deficits in frontal cortical parvalbumin-expressing interneurons. Plaur mice have impaired reversal learning, similar to deficits observed in patients with schizophrenia. METHODS: We examined the role of parvalbumin interneurons in orbitofrontal cortex during reversal learning by recording single unit activity from 180 control and 224 Plaur mouse neurons during a serial reversal task. Neural activity was analyzed during correct and incorrect decision choices and reward receipt. RESULTS: Neurons in control mice exhibited strong phasic responses both during discrimination and reversal learning to decisions and rewards, and the strength of the response was correlated with behavioral performance. Although baseline firing was significantly enhanced in Plaur mice, neural selectivity for correct or erroneous decisions was diminished and not correlated with behavior, and reward encoding was downscaled. In addition, Plaur mice showed a significant reduction in the number of neurons that encoded expected outcomes across task phases during the decision period. CONCLUSIONS: These data indicate that parvalbumin interneurons are necessary for the representation of outcomes in orbitofrontal cortex. Deficits in inhibition blunt selective neural firing during key decisions, contributing to behavioral inflexibility. These data provide a potential explanation for disorders of cognitive control that accompany the loss of these gamma-aminobutyric acidergic interneurons in human neuropsychiatric disorders, such as autism, epilepsy, and schizophrenia. C1 [Bissonette, Gregory B.; Powell, Elizabeth M.] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Bissonette, Gregory B.; Powell, Elizabeth M.] Univ Maryland, Program Neurosci, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Baltimore, MD USA. [Bissonette, Gregory B.; Roesch, Matthew R.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Powell, Elizabeth M.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. RP Powell, EM (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, HSF 2 S251,20 Penn St, Baltimore, MD 21201 USA. EM epowe001@umaryland.edu OI Bissonette, Gregory/0000-0003-4478-652X FU National Alliance for Research on Schizophrenia and Depression Young Investigator Award; National Institute on Drug Abuse Grants [DA108826, DA015718, DA031695] FX Financial support for this study was provided by National Alliance for Research on Schizophrenia and Depression Young Investigator Award (EMP) and National Institute on Drug Abuse Grants DA108826 (Principal Investigator [PI]: EMP), DA015718 (PI: GS), and DA031695 (PI: MRR). NR 72 TC 19 Z9 19 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 1 PY 2015 VL 77 IS 5 BP 454 EP 464 DI 10.1016/j.biopsych.2014.07.023 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CA8XH UT WOS:000349203800008 PM 25193243 ER PT J AU Lin, Y Damjanovic, A Metter, EJ Nguyen, H Truong, T Najarro, K Morris, C Longo, DL Zhan, M Ferrucci, L Hodes, RJ Weng, NP AF Lin, Yun Damjanovic, Amanda Metter, E. Jeffrey Huy Nguyen Thai Truong Najarro, Kevin Morris, Christa Longo, Dan L. Zhan, Ming Ferrucci, Luigi Hodes, Richard J. Weng, Nan-ping TI Age-associated telomere attrition of lymphocytes in vivo is co-ordinated with changes in telomerase activity, composition of lymphocyte subsets and health conditions SO CLINICAL SCIENCE LA English DT Article DE aging; glucose; interleukin 6 (IL-6); lymphocyte; telomerase; telomere length ID T-CELLS; REVERSE-TRANSCRIPTASE; HEMATOPOIETIC-CELLS; LENGTH; EXPRESSION; CHROMOSOME; DYNAMICS; DIFFERENTIATION; ACTIVATION; MORTALITY AB Telomeres are essential in maintaining chromosome integrity and in controlling cellular replication. Attrition of telomere length in peripheral blood mononuclear cells (PBMCs) with age is well documented from cross-sectional studies. But the actual in vivo changes in telomere lengths and its relationship with the contributing factors within the individuals with age have not been fully addressed. In the present paper, we report a longitudinal analysis of telomere length in the PBMCs, lymphocytes and monocytes of 216 human subjects aged from 20-90 years assessed at 0-, 5- and 12-year follow-up. For the 5- and 12-year follow-up, telomere length in the PBMCs decreased in 34% and 46%, exhibited no detectable change in 56% and 47% and increased in 10% and 7% of the subjects respectively. The rate of telomere change was distinct for T-cells, B-cells and monocytes for any given subject. Telomerase activity declined with age in the resting T-cells and B-cells and the activated T-cells. Finally, a significant portion of telomere attrition in T-cells with age was explained by a decline in the telomerase activity, decreased naive cells and the change in physiological conditions such as elevated blood glucose and interleukin (IL)-6 levels. These findings show that changes in the telomere length of the PBMCs with age in vivo occur at different rates in different individuals and cell types and reveal that changes in the telomere length in the T-cells with age is influenced by the telomerase activity, naive T-cell percentage and changes in health conditions. C1 [Lin, Yun; Damjanovic, Amanda; Huy Nguyen; Thai Truong; Najarro, Kevin; Weng, Nan-ping] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Metter, E. Jeffrey; Ferrucci, Luigi] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Morris, Christa] NIA, Flow Cytometry Unit, NIH, Baltimore, MD 21224 USA. [Longo, Dan L.] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Zhan, Ming] NIA, Bioinformat Unit, NIH, Baltimore, MD 21224 USA. [Hodes, Richard J.] NIA, Bethesda, MD 20892 USA. [Hodes, Richard J.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Weng, NP (reprint author), NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. EM Wengn@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 44 TC 23 Z9 23 U1 1 U2 31 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0143-5221 EI 1470-8736 J9 CLIN SCI JI Clin. Sci. PD MAR PY 2015 VL 128 IS 6 BP 367 EP 377 DI 10.1042/CS20140481 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CB1CU UT WOS:000349365100004 PM 25317735 ER PT J AU Fedorova, OV Lakatta, EG Bagrov, AY Melander, O AF Fedorova, Olga V. Lakatta, Edward G. Bagrov, Alexei Y. Melander, Olle TI Plasma level of the endogenous sodium pump ligand marinobufagenin is related to the salt-sensitivity in men SO JOURNAL OF HYPERTENSION LA English DT Article DE dietary sodium; marinobufagenin; salt sensitivity; sex specificity ID REDUCED DIETARY-SODIUM; LOWERS BLOOD-PRESSURE; NA/K-ATPASE; K+-ATPASE; HYPERTENSION; INHIBITORS; RAT; BUFODIENOLIDE; PROGESTERONE; RESTRICTION AB Objective: Salt-induced elevation of the endogenous digitalis like sodium pump ligand marinobufagenin (MBG) in the Dahl salt-sensitive rats resulted in elevated blood pressure (BP). Here, we tested, in humans, whether MBG levels are related to ambulatory 24-h BP (ABP), controlled long-term increase of salt-intake induces changes in MBG and any salt-induced change in MBG is related to salt sensitivity. Methods: Thirty-nine healthy individuals (53 +/- 11 years old; 20 men and 19 women) had a total daily NaCl intake of 50 mmol (low-salt) and 150 mmol (high-salt) for 4 weeks each, in a random order. ABP and MBG in plasma and urine were measured at baseline (unstandardized salt intake) and after high and low-salt intake. Results: At baseline, plasma MBG (P-MBG) was related to 24-h SBP (r = 0.43, P = 0.007) and DBP (r = 0.32, P = 0.047), whereas 24-h urinary excretion of MBG (UE-MBG) was related to 24-h DBP only (r = 0.42, P = 0.008). Sex-specific analyses revealed that these relationships were significant in men only. Compared with low-salt, high-salt diet increased P-MBG (P = 0.029), mainly driven by results in men. Male P-MBG responders vs. nonresponders (above vs. below median of high-salt induced P-MBG increase) had markedly enhanced SBP (10.4 +/- 6.4 vs. 1.0 +/- 6.0 mmHg; P = 0.003) and DBP (6.7 +/- 5.0 vs. +/- 0.6 +/- 3.6 mmHg; P = 0.001) salt sensitivity. Conclusion: In men, MBG increases with 24-h ABP, and similar to Dahl salt-sensitive rats, 4 weeks of high-salt induced MBG response is accompanied by marked salt sensitivity. However, these patterns seem to be sex-specific and are not observed in women. C1 [Fedorova, Olga V.; Lakatta, Edward G.; Bagrov, Alexei Y.] NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. [Melander, Olle] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Melander, Olle] Skane Univ Hosp, Dept Internal Med, Malmo, Sweden. RP Fedorova, OV (reprint author), NIA, Lab Cardiovasc Sci, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM fedorovo@mail.nih.gov FU National Institute on Aging, NIH FX This study was supported in part by Intramural Research Program, National Institute on Aging, NIH. The authors gratefully acknowledge excellent technical support by Anton Bzhelyanskiy. NR 28 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD MAR PY 2015 VL 33 IS 3 BP 534 EP 541 DI 10.1097/HJH.0000000000000437 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CA6EX UT WOS:000349003300015 PM 25479026 ER PT J AU Friedmann, PD Wilson, D Knudsen, HK Ducharme, LJ Welsh, WN Frisman, L Knight, K Lin, HJ James, A Albizu-Garcia, CE Pankow, J Hall, EA Urbine, TF Abdel-Salam, S Duvall, JL Vocci, FJ AF Friedmann, Peter D. Wilson, Donna Knudsen, Hannah K. Ducharme, Lori J. Welsh, Wayne N. Frisman, Linda Knight, Kevin Lin, Hsiu-Ju James, Amy Albizu-Garcia, Carmen E. Pankow, Jennifer Hall, Elizabeth A. Urbine, Terry F. Abdel-Salam, Sami Duvall, Jamieson L. Vocci, Frank J. TI Effect of an Organizational Linkage Intervention on Staff Perceptions of Medication-Assisted Treatment and Referral Intentions in Community Corrections SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Opioid-related disorders; Alcohol-related disorders; Opiate substitution treatment; Attitudes; Criminal justice ID SUBSTANCE-ABUSE TREATMENT; HEALTH-CARE PROFESSIONALS; DRUG-ABUSE; TREATMENT PROGRAMS; PROBATION OFFICERS; UNITED-STATES; USE DISORDERS; BEHAVIOR; PHARMACOTHERAPY; ATTITUDES AB Introduction: Medication-assisted treatment (MAT) is effective for alcohol and opioid use disorders but it is stigmatized and underutilized in criminal justice settings. Methods: This study cluster-randomized 20 community corrections sites to determine whether an experimental implementation strategy of training and an organizational linkage intervention improved staff perceptions of MAT and referral intentions more than training alone. The 3-hour training was designed to address deficits in knowledge, perceptions and referral information, and the organizational linkage intervention brought together community corrections and addiction treatment agencies in an interagency strategic planning and implementation process over 12 months. Results: Although training alone was associated with increases in familiarity with pharmacotherapy and knowledge of where to refer clients, the experimental intervention produced significantly greater improvements in functional attitudes (e.g. that MAT is helpful to clients) and referral intentions. Corrections staff demonstrated greater improvements in functional perceptions and intent to refer opioid dependent clients for MAT than did treatment staff. Conclusion: Knowledge, perceptions and information training plus interorganizational strategic planning intervention is an effective means to change attitudes and intent to refer clients for medication assisted treatment in community corrections settings, especially among corrections staff. Published by Elsevier Inc. C1 [Friedmann, Peter D.] Providence Veteran Affairs Med Ctr, Providence, RI USA. [Friedmann, Peter D.] Brown Univ, Providence, RI 02912 USA. [Friedmann, Peter D.; Wilson, Donna] Rhode Isl Hosp, Providence, RI 02903 USA. [Knudsen, Hannah K.; Duvall, Jamieson L.] Univ Kentucky, Lexington, KY USA. [Ducharme, Lori J.] NIDA, Bethesda, MD 20892 USA. [Welsh, Wayne N.] Temple Univ, Philadelphia, PA 19122 USA. [Frisman, Linda; Lin, Hsiu-Ju; James, Amy] Univ Connecticut, Storrs, CT USA. [Knight, Kevin; Pankow, Jennifer] Texas Christian Univ, Ft Worth, TX 76129 USA. [Albizu-Garcia, Carmen E.] Univ Puerto Rico, San Juan, PR 00936 USA. [Hall, Elizabeth A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Urbine, Terry F.] Arizona State Univ, Tempe, AZ USA. [Abdel-Salam, Sami] W Chester Univ, W Chester, PA 19380 USA. [Vocci, Frank J.] Friends Res Inst, Baltimore, MD USA. RP Friedmann, PD (reprint author), Rhode Isl Hosp, Plain St Bldg,593 Eddy St, Providence, RI 02903 USA. EM pfriedmann@lifespan.org FU U.S. Department of Health and Human Services; National Institutes of Health; National Institute on Drug Abuse FX This study was funded under a cooperative agreement from the U.S. Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse. The authors gratefully acknowledge the collaborative contributions by NIDA; the Coordinating Center, AMAR International, Inc.; and the Research Centers participating in CJ-DATS. The Research Centers include: Arizona State University and Maricopa County Adult Probation (U01DA025307); University of Connecticut and the Connecticut Department of Correction (U01DA016194); University of Delaware and the Delaware Department of Corrections (U01DA016230); Friends Research Institute (U01DA025233) and the Maryland Department of Public Safety Correctional Services' Division of Parole and Probation; University of Kentucky and the Kentucky Department of Corrections (U01DA016205); National Development and Research Institutes, Inc. and the Colorado Department of Corrections (U01DA016200); Rhode Island Hospital, Brown University, University of Rhode Island, the Rhode Island Department of Corrections, University of Puerto Rico and the Puerto Rico Department of Corrections and Rehabilitation (U01DA016191); Texas Christian University and the Illinois Department of Corrections (U01DA016190); Temple University and the Pennsylvania Department of Corrections (U01DA025284); and the University of California at Los Angeles and the State of New Mexico Corrections Department (U01DA016211). The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, NIDA, the Department of Veteran Affairs or other CJ-DATS parties. NR 49 TC 5 Z9 5 U1 4 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD MAR PY 2015 VL 50 BP 50 EP 58 DI 10.1016/j.jsat.2014.10.001 PG 9 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA CA0PM UT WOS:000348619300008 PM 25456091 ER PT J AU Salotti, J Sakchaisri, K Tourtellotte, WG Johnson, PF AF Salotti, Jacqueline Sakchaisri, Krisada Tourtellotte, Warren G. Johnson, Peter F. TI An Arf-Egr-C/EBP beta Pathway Linked to Ras-Induced Senescence and Cancer SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ONCOGENE-INDUCED SENESCENCE; MESSENGER-RNA EXPRESSION; SQUAMOUS-CELL CARCINOMA; EPIDERMAL GROWTH-FACTOR; GENE-EXPRESSION; TRANSCRIPTION FACTOR; DOWN-REGULATION; IN-VITRO; NGFI-A; TUMOR-SUPPRESSOR AB Oncogene-induced senescence (OIS) protects normal cells from transformation by Ras, whereas cells lacking p14/p19(Arf) or other tumor suppressors can be transformed. The transcription factor C/EBP beta is required for OIS in primary fibroblasts but is downregulated by H-Ras(V12) in immortalized NIH 3T3 cells through a mechanism involving p19(Arf) loss. Here, we report that members of the serum-induced early growth response (Egr) protein family are also downregulated in 3T3(Ras) cells and directly and redundantly control Cebpb gene transcription. Egr1, Egr2, and Egr3 recognize three sites in the Cebpb promoter and associate transiently with this region after serum stimulation, coincident with Cebpb induction. Codepletion of all three Egrs prevented Cebpb expression, and serum induction of Egrs was significantly blunted in 3T3(Ras) cells. Egr2 and Egr3 levels were also reduced in Ras(V12)-expressing p19(Arf) null mouse embryonic fibroblasts (MEFs), and overall Egr DNA-binding activity was suppressed in Arf-deficient but not wild-type (WT) MEFs, leading to Cebpb downregulation. Analysis of human cancers revealed a strong correlation between EGR levels and CEBPB expression, regardless of whether CEBPB was increased or decreased in tumors. Moreover, overexpression of Egrs in tumor cell lines induced CEBPB and inhibited proliferation. Thus, our findings identify the Arf-Egr-C/EBP beta axis as an important determinant of cellular responses (senescence or transformation) to oncogenic Ras signaling. C1 [Salotti, Jacqueline; Sakchaisri, Krisada; Johnson, Peter F.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Tourtellotte, Warren G.] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. RP Johnson, PF (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. EM johnsope@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 75 TC 4 Z9 4 U1 0 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR PY 2015 VL 35 IS 5 BP 866 EP 883 DI 10.1128/MCB.01489-14 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CB0FE UT WOS:000349300200009 PM 25535333 ER PT J AU Withycombe, JS Smith, LM Meza, JL Merkle, C Faulkner, MS Ritter, L Seibel, NL Moore, K AF Withycombe, Janice S. Smith, Lynette M. Meza, Jane L. Merkle, Carrie Faulkner, Melissa Spezia Ritter, Leslie Seibel, Nita L. Moore, Ki TI Weight Change During Childhood Acute Lymphoblastic Leukemia Induction Therapy Predicts Obesity: A Report From the Children's Oncology Group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE acute lymphoblastic leukemia; childhood; obesity; weight gain ID BODY-MASS INDEX; HEALTH CONSEQUENCES; SURVIVORS; ADOLESCENTS; METAANALYSIS; LYMPHOMA; CANCER; OVERWEIGHT; COHORT; GAIN AB BackgroundObesity is a well documented problem associated with childhood acute lymphoblastic leukemia (ALL) with increasing body mass index often observed during therapy. This study aims to evaluate if weight gain, early in therapy, is predictive of obesity at the end of treatment. ProcedureIn this secondary analysis, data from 1,017 high-risk ALL patients previously treated on a Children's Oncology Group protocol (CCG study 1961) were reviewed. Logistic regression was used to examine whether change in BMI z-score at Induction or Delayed Intensification (DI) 1 were predictive of obesity at the end of therapy. ResultsThe BMI z-score at the beginning of Induction and the change in BMI z-score during Induction were both significant predictors of obesity at the end of therapy. The change in BMI z-score during cycle 1 of DI was not found to be associated with obesity. ConclusionsIt is well know that obesity at the beginning of therapy is predictive of obesity at the end of ALL therapy. The new, and more important, finding from this study is that even after adjusting for baseline weight, the increase in BMI z-scores during induction was an independent predictor of obesity at the end of therapy. Most researchers agree that prevention is the best form of treatment for obesity as it is difficult to reverse once it is present. This study suggests that monitoring weight trends during Induction may be useful in guiding healthcare practitioners in identifying which patients are at highest risk for obesity development so that early intervention may occur. Pediatr Blood Cancer 2015;62:434-439. (c) 2014 Wiley Periodicals, Inc. C1 [Withycombe, Janice S.] Palmetto Hlth, Childrens Canc Ctr, Columbia, SC 29203 USA. [Smith, Lynette M.; Meza, Jane L.] Univ Nebraska Med Ctr, Dept Biostat, Omaha, NE USA. [Merkle, Carrie; Ritter, Leslie; Moore, Ki] Univ Arizona, Coll Nursing, Tucson, AZ 85721 USA. [Faulkner, Melissa Spezia] Emory Sch Nursing, Atlanta, GA USA. [Seibel, Nita L.] NCI, Bethesda, MD 20892 USA. [Seibel, Nita L.] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Withycombe, JS (reprint author), Palmetto Hlth, Childrens Canc Ctr, 9 Richland Med Pk Dr,Suite 400, Columbia, SC 29203 USA. EM Janice.Withycombe@PalmettoHealth.org FU American Cancer Society Doctoral Degree Scholarship in Cancer Nursing [119073-DSCN-10-090-01-SCN]; National Cancer Institute - Children's Oncology Group [U10CA098543] FX Grant sponsor: American Cancer Society Doctoral Degree Scholarship in Cancer Nursing; Grant number: 119073-DSCN-10-090-01-SCN; Grant sponsor: National Cancer Institute - Children's Oncology Group; Grant number: U10CA098543 NR 32 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAR PY 2015 VL 62 IS 3 BP 434 EP 439 DI 10.1002/pbc.25316 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CA4BU UT WOS:000348850100011 PM 25407299 ER PT J AU Wagner, LM Fouladi, M Ahmed, A Krailo, MD Weigel, B DuBois, SG Doyle, LA Chen, H Blaney, SM AF Wagner, Lars M. Fouladi, Maryam Ahmed, Atif Krailo, Mark D. Weigel, Brenda DuBois, Steven G. Doyle, L. Austin Chen, Helen Blaney, Susan M. TI Phase II Study of Cixutumumab in Combination With Temsirolimus in Pediatric Patients and Young Adults With Recurrent or Refractory Sarcoma: A Report From the Children's Oncology Group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE cixutumumab; pediatric sarcoma; Phase II; temsirolimus ID IGF-1R ANTIBODY CIXUTUMUMAB; PRECLINICAL TESTING PROGRAM; RENAL-CELL CARCINOMA; SOFT-TISSUE SARCOMA; RECEPTOR ANTIBODY; EWINGS-SARCOMA; SOLID TUMORS; MONOCLONAL-ANTIBODY; FAMILY TUMORS; OPEN-LABEL AB BackgroundThe combined inhibition of insulin-growth factor type 1 receptor (IGF-1R) and the mammalian target of rapamycin (mTOR) has shown activity in preclinical models of pediatric sarcoma and in adult sarcoma patients. We evaluated the activity of the anti-IGF-1R antibody cixutumumab with the mTOR inhibitor temsirolimus in patients with relapsed or refractory Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, and other soft tissue sarcoma, using the recommended dosages from a pediatric phase I trial. MethodsCixutumumab 6mg/kg and temsirolimus 8mg/m(2) were administered intravenously once weekly in 4-week cycles to patients <30 years. Temsirolimus was escalated to 10mg/m(2) for subsequent cycles in patients who did not experience unacceptable first-cycle toxicity. A two-stage design was used to identify a response rate <10 or >35% for each tumor-specific cohort. Tumor tissue was analyzed by immunohistochemistry for potential biomarkers of response. ResultsForty-three evaluable patients received a median of 2 cycles (range 1-7). No objective responses were observed, and 16% of patients were progression-free at 12 weeks. Dose-limiting toxicity was observed in 15 (16%) of 92 cycles. The most common toxicities were mucositis, electrolyte disturbances, and myelosuppression. The majority of patients receiving a second cycle were not eligible for temsirolimus escalation due to first-cycle toxicity. The lack of objective responses precluded correlation with tissue biomarkers. ConclusionsDespite encouraging preclinical data, the combination of cixutumumab and temsirolimus did not result in objective responses in this phase II trial of pediatric and young adults with recurrent or refractory sarcoma. Pediatr Blood Cancer 2015;62:440-444. (c) 2014 Wiley Periodicals, Inc. C1 [Wagner, Lars M.; Fouladi, Maryam] Cincinnati Childrens Hosp Med Ctr, Div Oncol, Cincinnati, OH 45229 USA. [Ahmed, Atif] Childrens Mercy Hosp, Dept Pathol, Kansas City, MO 64108 USA. [Krailo, Mark D.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Weigel, Brenda] Univ Minnesota, Div Pediat Hematol Oncol, Minneapolis, MN USA. [DuBois, Steven G.] Univ Calif San Francisco, San Francisco Sch Med, Div Pediat Hematol Oncol, San Francisco, CA 94143 USA. [Doyle, L. Austin; Chen, Helen] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Blaney, Susan M.] Texas Childrens Hosp, Baylor Coll Med, Div Hematol Oncol, Houston, TX 77030 USA. RP Wagner, LM (reprint author), Univ Kentucky Pediat Hematol Oncol, 740 S Limestone,Off J-457, Lexington, KY 40502 USA. EM lars.wagner@uky.edu OI Ahmed, Atif/0000-0002-8791-5785 FU Chair's Grant [CA98543]; NCTN Operation Center [CA180886]; Statistics and Data Center [CA98413]; NCTN Statistics and Data Center [CA180899] FX Grant sponsor: Chair's Grant; Grant number: CA98543; Grant sponsor: NCTN Operation Center; Grant number: CA180886; Grant sponsor: Statistics and Data Center; Grant number: CA98413; Grant sponsor: NCTN Statistics and Data Center; Grant number: CA180899 NR 29 TC 18 Z9 18 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAR PY 2015 VL 62 IS 3 BP 440 EP 444 DI 10.1002/pbc.25334 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CA4BU UT WOS:000348850100012 PM 25446280 ER PT J AU Glover, J Krailo, M Tello, T Marina, N Janeway, K Barkauskas, D Fan, TM Gorlick, R Khanna, C AF Glover, Jason Krailo, Mark Tello, Tanya Marina, Neyssa Janeway, Katherine Barkauskas, Don Fan, Timothy M. Gorlick, Richard Khanna, Chand CA COG Osteosarcoma Biol Grp TI A Summary of the Osteosarcoma Banking Efforts: A Report From the Children's Oncology Group and the QuadW Foundation SO PEDIATRIC BLOOD & CANCER LA English DT Article DE banking; biology; bone; osteosarcoma; sarcoma ID REDUCED FOLATE CARRIER; OSTEOGENIC-SARCOMA; METASTATIC OSTEOSARCOMA; SURVIVAL; CHEMOTHERAPY; METHYLATION; DIAGNOSIS; SURGERY; TARGETS; SAMPLES AB BackgroundSurvival rates of patients with osteosarcoma have remained stagnant over the last thirty years. Better understanding of biology, new therapeutics, and improved biomarkers are needed. The Children's Oncology Group (COG) addressed this need by developing one of the largest osteosarcoma biorepositories ever, containing over 15,000 tumor and tissue samples from over 1,500 patients. ProcedureThe biology study P9851 and the banking study AOST06B1 has enrolled 1,787 patients (as of September, 2013). Clinical information was lacking on 510 patients on P9851, who were not enrolled on a concurrent therapeutic trial. The value of these specimens was diminished. The lack of statistical support available for biology projects slowed the analysis of several critical studies. The QuadW Foundation, CureSearch, and the COG formed the Childhood Sarcoma Biostatistics and Annotation Office (CSBAO) to provide the infrastructure and address these needs by linking clinically annotated patient data to archived tissue samples and to develop biostatistical support for childhood sarcoma research. ResultsOriginally 5.3% of samples from the 510 patients on P9851 not enrolled on a therapeutic study had full clinical annotation. The efforts of the CSBAO have linked clinical annotation to 90.8% of those specimens and provided statistical analyses to several studies that had used COG samples. As a result, 24 biology studies in osteosarcoma have been completed and published in peer-reviewed journals. ConclusionsThese samples and in-silico data are available to the research community for basic and translational science projects to improve the biological understanding and treatment of patients affected by osteosarcoma. Pediatr Blood Cancer 2015;62:450-455. (c) 2014 Wiley Periodicals, Inc. C1 [Glover, Jason] Randall Childrens Hosp, Childrens Canc & Blood Disorders Program, Portland, OR USA. [Krailo, Mark; Tello, Tanya] Childrens Oncol Grp, Monrovia, CA USA. [Marina, Neyssa] Stanford Univ, Dept Pediat Hematol Oncol, Palo Alto, CA 94304 USA. [Janeway, Katherine] Dana Farber Boston Childrens Canc & Blood Disorde, Dept Pediat Oncol, Boston, MA USA. [Barkauskas, Don] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Fan, Timothy M.] Univ Illinois, Dept Vet Clin Med, Urbana, IL 61801 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Div Pediat Hematol & Oncol, Bronx, NY USA. [Khanna, Chand] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Glover, J (reprint author), Randall Childrens Hosp, 3rd Floor,2801 N Gantenbein Ave, Portland, OR 97223 USA. EM jglover@lhs.org FU WWWW (QuadW) Foundation, Inc.; [U10 CA98543]; [U24 CA114766] FX Grant sponsor: The Chair's; Grant number: U10 CA98543; Grant sponsor: Human Specimen Banking; Grant number: U24 CA114766; Grant sponsor: WWWW (QuadW) Foundation, Inc. (www.QuadW.org) NR 30 TC 6 Z9 6 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAR PY 2015 VL 62 IS 3 BP 450 EP 455 DI 10.1002/pbc.25346 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CA4BU UT WOS:000348850100014 PM 25611047 ER PT J AU Mertes, CM Schneider, A Sulla-Menashe, D Tatem, AJ Tan, B AF Mertes, C. M. Schneider, A. Sulla-Menashe, D. Tatem, A. J. Tan, B. TI Detecting change in urban areas at continental scales with MODIS data SO REMOTE SENSING OF ENVIRONMENT LA English DT Article DE Urban areas; Urbanization; Cities; Land cover; Change detection; Classification; Machine learning; Decision trees; Data fusion; Decision fusion ID LAND-COVER CLASSIFICATION; NIGHTTIME LIGHT DATA; REMOTELY-SENSED DATA; TIME-SERIES; UNITED-STATES; URBANIZATION DYNAMICS; SURFACE-TEMPERATURE; SATELLITE DATA; RESOLUTION; IMAGERY AB Urbanization is one of the most important components of global environmental change, yet most of what we know about urban areas is at the local scale. Remote sensing of urban expansion across large areas provides information on the spatial and temporal patterns of growth that are essential for understanding differences in socioeconomic and political factors that spur different forms of development, as well the social, environmental, and climatic impacts that result. However, mapping urban expansion globally is challenging: urban areas have a small footprint compared to other land cover types, their features are small, they are heterogeneous in both material composition and configuration, and the form and rates of new development are often highly variable across locations. Here we demonstrate a methodology for monitoring urban land expansion at continental to global scales using Moderate Resolution Imaging Spectroradiometer (MODIS) data. The new method focuses on resolving the spectral and temporal ambiguities between urban/non-urban land and stable/changed areas by: (1) spatially constraining the study extent to known locations of urban land; (2) integrating multi-temporal data from multiple satellite data sources to classify c. 2010 urban extent; and (3) mapping newly built areas (2000-2010) within the 2010 urban land extent using a multi-temporal composite change detection approach based on MODIS 250 m annual maximum enhanced vegetation index (EVI). We test the method in 15 countries in East-Southeast Asia experiencing different rates and manifestations of urban expansion. A two-tiered accuracy assessment shows that the approach characterizes urban change across a variety of socioeconomic/political and ecological/climatic conditions with good accuracy (70-91% overall accuracy by country, 69-89% by biome). The 250 m EVI data not only improve the classification results, but are capable of distinguishing between change and no-change areas in urban areas. Over 80% of the error in the change detection can be related to definitional issues or error propagation, rather than algorithm error. As such, these methods hold great potential for routine monitoring of urban change, as well as for providing a consistent and up-todate dataset on urban extent and expansion for a rapidly evolving region. (C) 2014 Published by Elsevier Inc. C1 [Mertes, C. M.; Schneider, A.] Ctr Sustainabil & Global Environm, Nelson Inst Environm Studies, Madison, WI 53726 USA. [Mertes, C. M.; Schneider, A.] Univ Wisconsin, Dept Geog, Madison, WI 53726 USA. [Sulla-Menashe, D.] Boston Univ, Dept Earth & Environm, Boston, MA 02215 USA. [Tatem, A. J.] Univ Southampton, Dept Geog & Environm, Southampton SO17 1BJ, Hants, England. [Tatem, A. J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tan, B.] NASA, Goddard Space Flight Ctr, Greenbelt, MD 20771 USA. RP Mertes, CM (reprint author), Ctr Sustainabil & Global Environm, Nelson Inst Environm Studies, Madison, WI 53726 USA. EM cmertes@wisc.edu FU World Bank FX The authors wish to thank Phil Townsend, Mutlu Ozdogan, Caitlin Kontgis, and two anonymous reviewers for comments on an earlier draft of this manuscript. The authors are grateful to Sarah Graves, Jo Horton, James Rollo, and Ian Schelly for technical support, assistance in data collection, and cartographic expertise. This work was funded in part by support from the World Bank. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 101 TC 21 Z9 21 U1 15 U2 112 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0034-4257 EI 1879-0704 J9 REMOTE SENS ENVIRON JI Remote Sens. Environ. PD MAR 1 PY 2015 VL 158 BP 331 EP 347 DI 10.1016/j.rse.2014.09.023 PG 17 WC Environmental Sciences; Remote Sensing; Imaging Science & Photographic Technology SC Environmental Sciences & Ecology; Remote Sensing; Imaging Science & Photographic Technology GA CA4MR UT WOS:000348879100024 ER PT J AU Pongpiachan, S Tipmanee, D Khumsup, C Kittikoon, I Hirunyatrakul, P AF Pongpiachan, Siwatt Tipmanee, Danai Khumsup, Chukkapong Kittikoon, Itthipon Hirunyatrakul, Phoosak TI Assessing risks to adults and preschool children posed by PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) during a biomass burning episode in Northern Thailand SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Forest fire; PAHs; Northern Thailand; PM2.5; Risk assessment ID SEASONAL-VARIATION; CANCER-RISK; CHEMICAL CHARACTERISTICS; ATMOSPHERIC PARTICLES; VERTICAL-DISTRIBUTION; SOURCE APPORTIONMENT; PARTICULATE MATTER; METROPOLITAN-AREA; TRAFFIC EMISSIONS; SIZE DISTRIBUTION AB To investigate the potential cancer risk resulting from biomass burning,. polycydic aromatic hydrocarbons (PAHs) bound to fine particles (PM2.5) were assessed in nine administrative northern provinces (NNP) of Thailand, before (N-I) and after (N-II) a haze episode. The average values of Sigma 3,4-ring PAHs and B[a]P-Equivaient concentrations in world urban cities were significantly (p < 0.05) much higher than those in samples collected from northern provinces during both sampling periods. Application of diagnostic binary ratios of PAHs underlined the predominant contribution of vehicular exhaust to PM2.5-bound PAH levels in NNP areas, even in the middle of the agricultural waste burning period. The proximity of N-I and N-II values in three-dimensional (3D) principal component analysis (PCA) plots also supports this conclusion. Although the excess cancer risk in NNP areas is much lower than those of other urban area and industrialized cities, there are nevertheless some concerns relating to adverse health impacts on preschool children due to non-dietary exposure to PAHs in home environments. (C) 2014 Elsevier B.V. All rights reserved. C1 [Pongpiachan, Siwatt] NIDA, Sch Social & Environm Dev, NIDA Ctr Res & Dev Disaster Prevent & Management, Bangkok 10240, Thailand. [Tipmanee, Danai] Chulalongkorn Univ, Grad Sch, Int Postgrad Program Environm Management, Bangkok, Thailand. [Tipmanee, Danai] Chulalongkorn Univ, Ctr Excellence Environm & Hazardous Waste Managem, Bangkok, Thailand. [Khumsup, Chukkapong; Kittikoon, Itthipon; Hirunyatrakul, Phoosak] Bara Sci Co Ltd, Bangkok 10500, Thailand. RP Pongpiachan, S (reprint author), NIDA, Sch Social & Environm Dev, NIDA Ctr Res & Dev Disaster Prevent & Management, 118 Moo 3,Sereethai Rd, Bangkok 10240, Thailand. EM pongpiajun@gmail.com FU National Institute of Development Administration (NIDA) Research Center FX This project was financed by the National Institute of Development Administration (NIDA) Research Center. The authors acknowledge Assist Prof. Dr. Torpong Kreetachart from the School of Energy and Environment (SEEN), University of Phayao, for his contribution to laboratory work. The authors are grateful for the kind support of the Pollution Control Department, Ministry of Natural Resources and Environment, which provided meteorological data. Ms. Chomsri Choochuay, Ms. jittiphan Chonchalar, Ms. Panatda Kanchai, and Ms. Tidarat Ponpiboon are acknowledged for their assistance with field samplings. NR 79 TC 12 Z9 12 U1 12 U2 72 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD MAR 1 PY 2015 VL 508 BP 435 EP 444 DI 10.1016/j.scitotenv.2014.12.019 PG 10 WC Environmental Sciences SC Environmental Sciences & Ecology GA CA8TZ UT WOS:000349195100047 PM 25506906 ER PT J AU Sander, LD Newell, K Ssebbowa, P Serwadda, D Quinn, TC Gray, RH Wawer, MJ Mondo, G Reynolds, S AF Sander, Laura D. Newell, Kevin Ssebbowa, Paschal Serwadda, David Quinn, Thomas C. Gray, Ronald H. Wawer, Maria J. Mondo, George Reynolds, Steven TI Hypertension, cardiovascular risk factors and antihypertensive medication utilisation among HIV-infected individuals in Rakai, Uganda SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Article DE hypertension prevalence; treatment; HIV; Rakai; Uganda; prevalence de l'hypertension; traitement; VIH; Rakai; Ouganda; prevalencia de hipertension; tratamiento; VIH; Rakai; Uganda ID SUB-SAHARAN AFRICA; INCOME COUNTRIES; PREVALENCE; DISEASES; COHORT; EPIDEMIOLOGY; ASSOCIATION; PREVENTION; THERAPY; BURDEN AB ObjectivesTo assess the prevalence of hypertension, elevated blood pressure and cardiovascular risk factors among HIV-positive individuals in rural Rakai District, Uganda. MethodsWe assessed 426 HIV-positive individuals in Rakai, Uganda from 2007 to 2010. Prevalence of hypertension and elevated blood pressure assessed by clinical measurement was compared to clinician-recorded hypertension in case report forms. Multiple logistic regression and z-tests were used to examine the association of hypertension and elevated blood pressure with age, sex, body mass index (BMI), CD4 cell count and antiretroviral treatment (ART) use. For individuals on antihypertensives, medication utilisation was reviewed. ResultsThe prevalence of hypertension (two elevated blood pressure readings at different time points) was 8.0% (95% CI: 5.4-10.6%), and that of elevated blood pressure (one elevated blood pressure reading) was 26.3% (95% CI: 22.1-30.5%). Age 50years and higher BMI were positively associated with elevated blood pressure. ART use, time on ART and CD4 cell count were not associated with hypertension. Eighty-three percent of subjects diagnosed with hypertension were on antihypertensive medications, most commonly beta-blockers and calcium channel blockers. ConclusionsHypertension is common among HIV-positive individuals in rural Uganda. ObjectifsEvaluer la prevalence de l'hypertension, de l'elevation de la pression arterielle et les facteurs de risque cardiovasculaire chez les personnes VIH-positives dans le district rural de Rakai, en Ouganda. MethodesNous avons evalue 426 personnes VIH-positives a Rakai, en Ouganda de 2007 a 2010. La prevalence de l'hypertension et de la pression arterielle elevee evaluees par mesure clinique a ete comparee a l'hypertension enregistree par un clinicien dans les formulaires de rapport de cas. La regression logistique multiple et les z-tests ont ete utilises pour examiner l'association entre l'hypertension et l'elevation de la pression arterielle avec l'age, le genre sexuel, l'indice de masse corporelle, la numeration des CD4 et l'utilisation de traitement antiretroviral (ART). Pour les individus sous antihypertenseurs, l'utilisation des medicaments a ete analysee. ResultatsLa prevalence de l'hypertension (deux valeurs elevees de lecture de la pression arterielle a differents points dans le temps) etait de 8,0% (IC95%: 5,4 a 10,6%) et celle de la pression arterielle elevee (une valeur elevee de lecture de la pression arterielle) etait de 26,3% (IC95%: 22,1 a 30,5%). L'age 50 ans et un indice de masse corporelle eleve etaient positivement associes a la pression arterielle elevee. L'utilisation d'ART, la duree sous ART et la numeration des CD4 n'etaient pas associees a l'hypertension. 83% des sujets ayant recu un diagnostic d'hypertension etaient sous medicaments antihypertenseurs, le plus souvent des betabloquants et des bloqueurs des canaux calciques. ConclusionsL'hypertension est frequente chez les personnes VIH-positives en zone rurale, en Ouganda. ObjetivosEvaluar la prevalencia de hipertension, presion sanguinea elevada y factores de riesgo cardiovascular en individuos VIH positivos del distrito rural de Rakai, Uganda. MetodosHemos evaluado a 426 individuos VIH-positivos en Rakai, Uganda entre el 2007 y el 2010. Se compararon la prevalencia de hipertension y de presion sanguinea elevada segun pruebas clinicas, con los informes clinicos de hipertension recogidos por los medicos en los cuadernos de recogida de datos. Mediante regresion logistica multiple y z-test se examinaron las asociaciones entre hipertension y presion sanguinea con la edad, el sexo, el indice de masa corporal, conteo de CD4 y uso de terapia antirretroviral. Para individuos recibiendo antihipertensivos, se reviso el uso de medicamentos. ResultadosLa prevalencia de hipertension (dos lecturas de presion sanguinea elevada en diferentes puntos de tiempo) era del 8.0% (IC 95%: 5.4-10.6%), y la de una presion sanguinea elevada (una lectura de presion sanguinea) era del 26.3% (IC 95%: 22.1-30.5%). Tener una edad 50 anos y un mayor indice de masa corporal estaban asociados de forma positiva con una presion sanguinea elevada. El uso de TAR, el tiempo recibiendo TAR, y el conteo de celulas CD4 no estaban asociadas con la hipertension. Un 83% de los sujetos diagnosticados con hipertension estaban recibiendo medicacion antihipertensiva, principalmente betabloqueantes y bloqueadores del canal de calcio. ConclusionesLa hipertension es comun entre individuos VIH positivos en zonas rurales de Uganda. C1 [Sander, Laura D.; Gray, Ronald H.; Wawer, Maria J.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Newell, Kevin] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD USA. [Ssebbowa, Paschal; Mondo, George] Rakai Hlth Sci Program, Kalisizo, Uganda. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Quinn, Thomas C.; Reynolds, Steven] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Quinn, Thomas C.; Reynolds, Steven] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Sander, LD (reprint author), 1000 E Eager St, Baltimore, MD 21202 USA. EM lsander@jhmi.edu FU National Institutes of Health (NIH) Office of Disease Prevention; National Institute of Allergy and Infectious Diseases, NIH; PEPFAR through CDC Uganda; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Supported by The National Institutes of Health (NIH) Office of Disease Prevention and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. Support for HIV care and treatment was provided by PEPFAR through CDC Uganda. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organisations imply endorsement by the U.S. Government. NR 39 TC 1 Z9 1 U1 3 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1360-2276 EI 1365-3156 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD MAR PY 2015 VL 20 IS 3 BP 391 EP 396 DI 10.1111/tmi.12443 PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CA1ID UT WOS:000348665100014 PM 25430847 ER PT J AU Czerwinski, A Basava, C Dauter, M Dauter, Z AF Czerwinski, Andrzej Basava, Channa Dauter, Miroslawa Dauter, Zbigniew TI Crystal structure of N-{N-[N-acetyl-(S)-leucyl]-(S)-leucyl}norleucinal (ALLN), an inhibitor of proteasome SO ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS LA English DT Article DE crystal structure; proteasome inhibitor; hydrogen bonding; antiparallel beta-sheet ID CANCER-THERAPY; 20S PROTEASOME; DISEASE; SYSTEM; TARGET AB The title compound, C20H37N3O4, also known by the acronym ALLN, is a tripeptidic inhibitor of the proteolytic activity of the proteasomes, enzyme complexes implicated in several neurodegenerative diseases and other disorders, including cancer. The crystal structure of ALLN, solved from synchrotron radiation diffraction data, revealed the molecules in extended conformation of the backbone and engaging all peptide N and O atoms in intermolecular hydrogen bonds forming an infinite antiparallel beta-sheet. C1 [Czerwinski, Andrzej; Basava, Channa] Peptides Int Inc, Louisville, KY 40299 USA. [Dauter, Miroslawa] Argonne Natl Lab, Basic Sci Program, Leidos Biomed Res Inc, Argonne, IL 60439 USA. [Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab, Argonne, IL 60439 USA. RP Dauter, Z (reprint author), NCI, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab, Argonne, IL 60439 USA. EM dauter@anl.gov NR 23 TC 1 Z9 1 U1 0 U2 2 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2056-9890 J9 ACTA CRYSTALLOGR E JI Acta Crystallogr. Sect. E.-Crystallogr. Commun. PD MAR PY 2015 VL 71 BP 254 EP + DI 10.1107/S2056989015002091 PN 3 PG 10 WC Crystallography SC Crystallography GA DD5OK UT WOS:000369973400058 PM 25844180 ER PT J AU Cuthbert, BN AF Cuthbert, Bruce N. TI Research Domain Criteria: toward future psychiatric nosologies SO DIALOGUES IN CLINICAL NEUROSCIENCE LA English DT Article DE psychiatric diagnosis; psychiatric nosology; RDoC; Research Domain Criteria ID RDOC FRAMEWORK; DIAGNOSTIC-CRITERIA; DSM-V; PSYCHOPATHOLOGY; CLASSIFICATION; NEUROSCIENCE; PERSONALITY; PERSPECTIVE; CHALLENGES; DISORDERS AB The Research Domain Criteria (RDoC) project was initiated by the National Institute of Mental Health (NIMH) in early 2009 as the implementation of Goal 1.4 of its just-issued strategic plan. In keeping with the NIMH mission, to "transform the understanding and treatment of mental illnesses through basic and clinical research," RDoC was explicitly conceived as a research-related initiative. The statement of the relevant goal in the strategic plan reads: " Develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures." Due to the novel approach that RDoC takes to conceptualizing and studying mental disorders, it has received widespread attention, well beyond the borders of the immediate research community. This review discusses the rationale for the experimental framework that RDoC has adopted, and its implications for the nosology of mental disorders in the future. (C) 2015, AICH - Servier Research Group C1 [Cuthbert, Bruce N.] NIMH, 6001 Execut Blvd,Room 8151,MSC 9632, Bethesda, MD 20892 USA. RP Cuthbert, BN (reprint author), NIMH, 6001 Execut Blvd,Room 8151,MSC 9632, Bethesda, MD 20892 USA. EM bcuthber@mail.nih.gov NR 40 TC 26 Z9 26 U1 2 U2 2 PU INST CONFERENCE HIPPOCRATE PI SURESNESS-CEDEX PA 50 RUE CARNOT, SURESNESS-CEDEX, 92284, FRANCE SN 1294-8322 EI 1958-5969 J9 DIALOGUES CLIN NEURO JI Dialogues Clin. Neurosci. PD MAR PY 2015 VL 17 IS 1 BP 89 EP 97 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EF2RU UT WOS:000390172800010 PM 25987867 ER PT J AU Guo, MZ Alumkal, J Drachova, T Gao, D Marina, SS Jen, J Herman, JG AF Guo, Mingzhou Alumkal, Joshi Drachova, Tatiana Gao, Dan Marina, Serban S. Jen, Jin Herman, James G. TI CHFR Methylation Strongly Correlates with Methylation of DNA Damage Repair and Apoptotic Pathway Genes in Non-Small Cell Lung Cancer SO DISCOVERY MEDICINE LA English DT Article ID CPG ISLAND HYPERMETHYLATION; MITOTIC STRESS CHECKPOINT; ANEMIA-BRCA PATHWAY; PROMOTER HYPERMETHYLATION; EPIGENETIC INACTIVATION; ABERRANT METHYLATION; COLORECTAL-CANCER; GASTRIC-CANCER; PHENOTYPE; SURVIVAL AB DNA methylation occurs commonly in non-small cell lung cancer (NSCLC). We sought to determine the frequency and relationship of methylation of key genes involved in the pathways of mitotic checkpoint control, DNA damage repair, apoptosis, and growth factor signaling in these patients. We analyzed the DNA methylation status of eight genes (CHFR, FANCF, MGMT, p16, DAPK, ASC or TMS-1, RAR-B, and CRBP1) using nested methylation-specific PCR (MSP) on over 314 paraffin-embedded, human non-small cell lung cancer samples. We determined the methylation frequency of each gene in addition to the association of the methylation of each gene with other members of the panel. Methylation was a common event in these samples. Our methylation analysis showed frequencies of methylation of 10% for CHFR, 14% for FANCF, 30% for MGMT, 29% for p16, 17% for DAPK, 33% for ASC, 38% for RAR-B, and 7% for CRBP1. There was a strong correlation between methylation of the mitotic G2-M checkpoint gene, CHFR, and methylation of other genes in our panel involved in DNA damage repair (FANCF and MGMT) and apoptosis (DAPK and ASC) but not with other genes in our panel, including p16 (the G1-S checkpoint gene), CRBP1, or RAR-B. In addition, MGMT methylation strongly correlated with the pro-apoptotic gene, ASC. There are distinct associations of methylated genes in non-small cell lung cancer involving DNA damage repair, apoptosis, and the G2-M mitotic checkpoint control. Further studies are warranted to determine whether these methylation patterns have implications for prognosis in addition to prediction of response to chemotherapeutic agents commonly used in the treatment of non-small cell lung cancer, such as radiotherapy and platinum-or taxane-based chemotherapy. C1 [Guo, Mingzhou] Chinese Peoples Liberat Army Gen Hosp, Dept Gastroenterol & Hepatol, Beijing 100853, Peoples R China. [Alumkal, Joshi] Johns Hopkins Univ, Dept Oncol, Sch Med, Baltimore, MD 21287 USA. [Alumkal, Joshi] Oregon Clin & Translat Res Inst, Portland, OR 97239 USA. [Drachova, Tatiana] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gao, Dan] Nankai Univ, Coll Med, Tianjin 300071, Peoples R China. [Marina, Serban S.; Jen, Jin] Mayo Clin, Med Genome Facil Gene Express Core, Rochester, MN 55905 USA. [Herman, James G.] Univ Pittsburgh, Ctr Canc, Hillman Canc Ctr, Pittsburgh, PA 15213 USA. RP Herman, JG (reprint author), Univ Pittsburgh, Ctr Canc, Hillman Canc Ctr, Pittsburgh, PA 15213 USA. EM jen.jin@mayo.edu; hermanj3@upmc.edu FU NCI NIH HHS [R21 CA127055, R33 CA127055] NR 50 TC 4 Z9 4 U1 1 U2 4 PU DISCOVERY MEDICINE PI TIMONIUM PA 10 GERARD AVE, STE 201, TIMONIUM, MD 21093 USA SN 1539-6509 EI 1944-7930 J9 DISCOV MED JI Discov. Med. PD MAR PY 2015 VL 19 IS 104 BP 151 EP 158 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CL4KM UT WOS:000356921400001 PM 25828518 ER PT J AU Briggs, J AF Briggs, Josephine TI Americans' Active Quest for Health Through Complementary and Integrative Medicine SO GENERATIONS-JOURNAL OF THE AMERICAN SOCIETY ON AGING LA English DT Article ID LOW-BACK-PAIN; MINDFULNESS MEDITATION; ACUPUNCTURE; TRIAL C1 [Briggs, Josephine] NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA. RP Briggs, J (reprint author), NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA. NR 14 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC AGING PI SAN FRANCISCO PA 833 MARKET ST, STE 511, SAN FRANCISCO, CA 94103-1824 USA SN 0738-7806 J9 GENERATIONS JI Generations-J. Am. Soc. Aging PD SPR PY 2015 VL 39 IS 1 BP 56 EP 64 PG 9 WC Gerontology SC Geriatrics & Gerontology GA DE1HR UT WOS:000370378300012 ER PT J AU Garcia, AJ Pindolia, DK Lopiano, KK Tatem, AJ AF Garcia, Andres J. Pindolia, Deepa K. Lopiano, Kenneth K. Tatem, Andrew J. TI Modeling internal migration flows in sub-Saharan Africa using census microdata SO MIGRATION STUDIES LA English DT Article ID GRAVITY MODEL; HUMAN MOBILITY; HUMAN MOVEMENT; POPULATION-MOVEMENTS; LABOR MIGRATION; BURKINA-FASO; WEST-AFRICA; MALARIA; TRANSMISSION; PATTERNS AB Globalization and the expansion of transport networks has transformed migration into a major policy issue because of its effects on a range of phenomena, including resource flows in economics, urbanization, as well as the epidemiology of infectious diseases. Quantifying and modeling human migration can contribute towards a better understanding of the nature of migration and help develop evidence-based interventions for disease control policy, economic development, and resource allocation. In this study we paired census microdata from 10 countries in sub-Saharan Africa with additional spatial datasets to develop models for the internal migration flows in each country, including key drivers that reflect the changing social, demographic, economic, and environmental landscapes. We assessed how well these gravity-type spatial interaction models can both explain and predict migration. Results show that the models can explain up to 87 percent of internal migration, can predict future within-country migration with correlations of up to 0.91, and can also predict migration in other countries with correlations of up to 0.72. Findings show that such models are useful tools for understanding migration as well as predicting flows in regions where data are sparse, and can contribute towards strategic economic development, planning, and disease control targeting. C1 [Garcia, Andres J.; Pindolia, Deepa K.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Garcia, Andres J.; Pindolia, Deepa K.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Pindolia, Deepa K.] Clinton Hlth Access Initiat, Boston, MA USA. [Lopiano, Kenneth K.] Univ Florida, Dept Stat, Gainesville, FL 32611 USA. [Lopiano, Kenneth K.] Stat & Appl Math Sci Inst, Res Triangle Pk, NC USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Karolinska Inst, Flowminder Fdn, SE-17177 Stockholm, Sweden. RP Garcia, AJ (reprint author), Univ Florida, Dept Geog, Gainesville, FL 32611 USA. EM andygarcia@gmail.com NR 70 TC 4 Z9 4 U1 5 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2049-5838 EI 2049-5846 J9 MIGR STUD JI Migr. Stud. PD MAR PY 2015 VL 3 IS 1 BP 89 EP 110 DI 10.1093/migration/mnu036 PG 22 WC Demography SC Demography GA DE3LS UT WOS:000370531200005 ER PT J AU Resnik, DB AF Resnik, David B. TI Paternalism and Utilitarianism in Research with Human Participants SO HEALTH CARE ANALYSIS LA English DT Article DE Informed consent; Justice; Paternalism; Research participation; Risks; Utilitarianism ID RESEARCH ETHICS AB In this article I defend a rule utilitarian approach to paternalistic policies in research with human participants. Some rules that restrict individual autonomy can be justified on the grounds that they help to maximize the overall balance of benefits over risks in research. The consequences that should be considered when formulating policy include not only likely impacts on research participants, but also impacts on investigators, institutions, sponsors, and the scientific community. The public reaction to adverse events in research (such as significant injury to participants or death) is a crucial concern that must be taken into account when assessing the consequences of different policy options, because public backlash can lead to outcomes that have a negative impact on science, such as cuts in funding, overly restrictive regulation and oversight, and reduced willingness of individuals to participate in research. I argue that concern about the public reaction to adverse events justifies some restrictions on the risks that competent, adult volunteers can face in research that offers them no significant benefits. The paternalism defended here is not pure, because it involves restrictions on the rights of investigators in order to protect participants. It also has a mixed rationale, because individual autonomy may be restricted not only to protect participants from harm but also to protect other stakeholders. Utility is not the sole justification for paternalistic research policies, since other considerations, such as justice and respect for individual rights/autonomy, must also be taken into account. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Box 12233,Mail Drop CU 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-04, ZIA ES102646-03] NR 28 TC 1 Z9 1 U1 1 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1065-3058 EI 1573-3394 J9 HEALTH CARE ANAL JI Health Care Anal. PD MAR PY 2015 VL 23 IS 1 BP 19 EP 31 DI 10.1007/s10728-012-0233-0 PG 13 WC Ethics; Health Policy & Services; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Biomedical Social Sciences GA AZ7RF UT WOS:000348414900002 PM 23076346 ER PT J AU Besio, R Maruelli, S Gioia, R Villa, I Grabowski, P Gallagher, O Bishop, NJ Foster, S De Lorenzi, E Colombo, R Diaz, JLD Moore-Barton, H Deshpande, C Aydin, HI Tokatli, A Kwiek, B Kasapkara, CS Adisen, EO Gurer, MA Di Rocco, M Phang, JM Gunn, TM Tenni, R Rossi, A Forlino, A AF Besio, Roberta Maruelli, Silvia Gioia, Roberta Villa, Isabella Grabowski, Peter Gallagher, Orla Bishop, Nicholas J. Foster, Sarah De Lorenzi, Ersilia Colombo, Raffaella Dapena Diaz, Jose Luis Moore-Barton, Haether Deshpande, Charu Aydin, Halil Ibrahim Tokatli, Aysegul Kwiek, Bartlomiej Kasapkara, Cigdem Seher Adisen, Esra Ozsoy Gurer, Mehmet Ali Di Rocco, Maja Phang, James M. Gunn, Teresa M. Tenni, Ruggero Rossi, Antonio Forlino, Antonella TI Lack of prolidase causes a bone phenotype both in human and in mouse SO BONE LA English DT Article DE Prolidase; Prolidase deficiency; Bone phenotype; Growth plate; Collagen ID OSTEOGENESIS IMPERFECTA; IN-VIVO; EXTRACELLULAR-MATRIX; COMPUTED-TOMOGRAPHY; MURINE MODEL; DEFICIENCY; TISSUE; VASCULARIZATION; TRANSPLANTATION; FIBROBLASTS AB The degradation of the main fibrillar collagens, collagens I and II, is a crucial process for skeletal development. The most abundant dipeptides generated from the catabolism of collagens contain proline and hydroxyproline. In humans, prolidase is the only enzyme able to hydrolyze dipeptides containing these amino acids at their C-terminal end, thus being a key player in collagen synthesis and turnover. Mutations in the prolidase gene cause prolidase deficiency (PD), a rare recessive disorder. Here we describe 12 PD patients, 9 of whom were molecularly characterized in this study. Following a retrospective analysis of all of them a skeletal phenotype associated with short stature, hypertelorism, nose abnormalities, microcephaly, osteopenia and genu valgum, independent of both the type of mutation and the presence of the mutant protein was identified. In order to understand the molecular basis of the bone phenotype associated with PD, we analyzed a recently identified mouse model for the disease, the dark-like (dal) mutant. The dal/dal mice showed a short snout, they were smaller than controls, their femurs were significantly shorter and pQCT and mu CT analyses of long bones revealed compromised bone properties at the cortical and at the trabecular level in both male and female animals. The differences were more pronounce at 1 month being the most parameters normalized by 2 months of age. A delay in the formation of the second ossification center was evident at postnatal day 10. Our work reveals that reduced bone growth was due to impaired chondrocyte proliferation and increased apoptosis rate in the proliferative zone associated with reduced hyperthrophic zone height. These data suggest that lack of prolidase, a cytosolic enzyme involved in the final stage of protein catabolism, is required for normal skeletogenesis especially at early age when the requirement for collagen synthesis and degradation is the highest. (C) 2014 Elsevier Inc. All rights reserved. C1 [Besio, Roberta; Maruelli, Silvia; Gioia, Roberta; Tenni, Ruggero; Rossi, Antonio; Forlino, Antonella] Univ Pavia, Dept Mol Med, I-27100 Pavia, Italy. [Villa, Isabella] Ist Sci San Raffaele, Bone Metab Unit, I-20132 Milan, Italy. [Grabowski, Peter; Gallagher, Orla; Bishop, Nicholas J.; Foster, Sarah] Univ Sheffield, Sheffield, S Yorkshire, England. [De Lorenzi, Ersilia; Colombo, Raffaella] Univ Pavia, Dept Drug Sci, I-27100 Pavia, Italy. [Dapena Diaz, Jose Luis] Hosp Univ Vall dHebron, Barcelona, Spain. [Moore-Barton, Haether; Deshpande, Charu] Guys & St Thomas NHS Fdn Trust, Dept Clin Genet, London, England. [Aydin, Halil Ibrahim] Turgut Ozal Univ, Dept Pediat, Ankara, Turkey. [Tokatli, Aysegul] Hacettepe Univ, Dept Pediat, Ankara, Turkey. [Kwiek, Bartlomiej] Med Univ Warsaw, Dept Dermatol, Warsaw, Poland. [Kasapkara, Cigdem Seher; Adisen, Esra Ozsoy; Gurer, Mehmet Ali] Gazi Univ Hosp, Pediat Metab Unit, Ankara, Turkey. [Di Rocco, Maja] Gaslini Inst, Dept Pediat, Unit Rare Dis, Genoa, Italy. [Phang, James M.] NCI, Basic Res Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Gunn, Teresa M.] McLaughlin Res Inst, Great Falls, MT USA. RP Forlino, A (reprint author), Univ Pavia, Dept Mol Med, Biochem Unit, Via Taramelli 3b, I-27100 Pavia, Italy. EM aforlino@unipv.it RI Forlino, Antonella/H-5385-2015; Rossi, Antonio/E-9935-2012; Dapena Diaz, Jose Luis/E-6159-2016; OI Forlino, Antonella/0000-0002-6385-1182; Dapena Diaz, Jose Luis/0000-0002-6711-7479; Colombo, Raffaella/0000-0001-9675-6598; De Lorenzi, Ersilia/0000-0002-5450-7208; Gunn, Teresa/0000-0003-2688-6420 FU FONDAZIONE CARIPLO [2013-0612, 2011-0270]; European Community [602300] FX The authors wish to acknowledge Mr Angelo Gallanti, Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy, for the tissue culture support and Dr Alessandro Rubinacci, MD, Head of the Bone Metabolic Unit, San Raffaele Scientific Institute, Milan, Italy, for the helpful discussion of the data. This work was supported by FONDAZIONE CARIPLO 2013-0612 to A.F., the European Community's Seventh Framework Programme under grant agreement n. 602300 (SYBIL) to A.R. and A.F. and FONDAZIONE CARIPLO 2011-0270 to R.T. NR 41 TC 2 Z9 2 U1 1 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD MAR PY 2015 VL 72 BP 53 EP 64 DI 10.1016/j.bone.2014.11.009 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AZ1OK UT WOS:000348007900007 PM 25460580 ER PT J AU Gasque, KCS Foster, BL Kuss, P Yadav, MC Liu, J Kiffer-Moreira, T van Elsas, A Hatch, N Somerman, MJ Milian, JL AF Gasque, Kellen C. S. Foster, Brian L. Kuss, Pia Yadav, Manisha C. Liu, Jin Kiffer-Moreira, Tina van Elsas, Andrea Hatch, Nan Somerman, Martha J. Milian, Jose Luis TI Improvement of the skeletal and dental hypophosphatasia phenotype in Alpl(-/-) mice by administration of soluble (non-targeted) chimeric alkaline phosphatase SO BONE LA English DT Article DE Enzyme replacement; Hypophosphatasia; Rickets; Osteomalacia; Craniosynostosis; Seizures ID ENZYME-REPLACEMENT THERAPY; INFANTILE HYPOPHOSPHATASIA; MISSENSE MUTATIONS; MOUSE MODEL; MURINE HYPOPHOSPHATASIA; VASCULAR CALCIFICATION; ARTERIAL CALCIFICATION; INTRAVENOUS-INFUSION; BONE MINERALIZATION; DEFICIENT MICE AB Hypophosphatasia (HFP) results from ALPL gene mutations, which lead to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP), and accumulation of inorganic pyrophosphate, a potent inhibitor of mineralization that is also a natural substrate of TNAP, in the extracellular space. HPP causes mineralization disorders including soft bones (rickets or osteomalacia) and defects in teeth and periodontal tissues. Enzyme replacement therapy using mineral-targeting recombinant TNAP has proven effective in preventing skeletal and dental defects in TNAP knockout (Alpl(-/-)) mice, a model for life-threatening HPP. Here, we show that the administration of a soluble, intestinal-like chimeric alkaline phosphatase (ChimAP) improves the manifestations of HPP in Alpl(-/-) mice. Mice received daily subcutaneous injections of ChimAP at doses of 1, 8 or 16 mg/kg, from birth for up to 53 days. Lifespan and body weight of Alpl(-/-) mice were normalized, and vitamin B6-associated seizures were absent with 16 mg/kg/day of ChimAP. Radiographs, mu CT and histological analyses documented improved mineralization in cortical and trabecular bone and secondary ossification centers in long bones of ChimAP16-treated mice. There was no evidence of craniosynostosis in the ChimAP16-treated mice and we did not detect ectopic calcification by radiography and histology in the aortas, stomachs, kidneys or lungs in any of the treatment groups. Molar tooth development and function improved with the highest ChimAP dose, including enamel, dentin, and tooth morphology. Cementum remained deficient and alveolar bone mineralization was reduced compared to controls, though ChimAP-treated Alpl(-/-) mice featured periodontal attachment and retained teeth. This study provides the first evidence for the pharmacological efficacy of ChimAP for use in the treatment of skeletal and dental manifestations of HPP. (C) 2014 Elsevier Inc. All rights reserved. C1 [Gasque, Kellen C. S.; Kuss, Pia; Yadav, Manisha C.; Kiffer-Moreira, Tina; Milian, Jose Luis] Sanford Burnham Med Res Inst, Sanford Childrens Hlth Res Ctr, La Jolla, CA 92037 USA. [Foster, Brian L.; Somerman, Martha J.] NIAMSD, Lab Oral Connect Tissue Biol, NIH, Bethesda, MD 20892 USA. [Liu, Jin; Hatch, Nan] Univ Michigan, Sch Dent, Dept Orthodont & Pediat Dent, Ann Arbor, MI 48109 USA. [van Elsas, Andrea] AM Pharma BV, Bunnik, Netherlands. RP Milian, JL (reprint author), Sanford Burnham Med Res Inst, Sanford Childrens Hlth Res Ctr, La Jolla, CA 92037 USA. EM millan@sanfordburnham.org RI Foster, Brian/H-8375-2015 OI Foster, Brian/0000-0003-3444-0576 FU National Institute of Dental and Craniofacial Research (NIDCR) of the National Institutes of Health (NIH) [DE12889]; AM-Pharma (Bunnik, The Netherlands); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/NIH [AR066110]; NIAMS; CNPq - Ciencias sem fronteiras FX This work was funded by grant DE12889 (JLM) from the National Institute of Dental and Craniofacial Research (NIDCR) of the National Institutes of Health (NIH), a grant from AM-Pharma (Bunnik, The Netherlands) (JLM), grant AR066110 (BLF) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/NIH, and funding from the intramural research program of NIAMS (MJS). KCSG was partially supported by a fellowship from CNPq - Ciencias sem fronteiras. We acknowledge the expert technical contributions of the Histology Facility at SBMRI Lake Nona, as well as Nasrin Kalantari Pour at NIAMS for dental histology. We thank Kenn Holmbeck (NIDCR/NIH) and Lyudmila Lukashova (Hospital for Special Surgery, New York, NY) for assistance in mu CT scanning and analysis of mandibles. We also thank Diana Sandoval from the Animal facility at SBMRI La Jolla for excellent help with animal breeding, maintenance and injections. NR 59 TC 9 Z9 9 U1 3 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD MAR PY 2015 VL 72 BP 137 EP 147 DI 10.1016/j.bone.2014.11.017 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AZ1OK UT WOS:000348007900017 PM 25433339 ER PT J AU Patel, NN Angiuli, E Gamba, P Gaughan, A Lisini, G Stevens, FR Tatem, AJ Trianni, G AF Patel, Nirav N. Angiuli, Emanuele Gamba, Paolo Gaughan, Andrea Lisini, Gianni Stevens, Forrest R. Tatem, Andrew J. Trianni, Giovanna TI Multitemporal settlement and population mapping from Landsat using Google Earth Engine SO INTERNATIONAL JOURNAL OF APPLIED EARTH OBSERVATION AND GEOINFORMATION LA English DT Article DE Landsat; Multitemporal; Population mapping; Google Earth Engine; Settlement mapping; Urbanization; Spatial demography ID REMOTELY-SENSED DATA; URBAN-GROWTH; SATELLITE IMAGERY; COVER CHANGE; CITIES; AREAS; MAPS; CENSUS; SPRAWL; SPACE AB As countries become increasingly urbanized, understanding how urban areas are changing within the landscape becomes increasingly important. Urbanized areas are often the strongest indicators of human interaction with the environment, and understanding how urban areas develop through remotely sensed data allows for more sustainable practices. The Google Earth Engine (GEE) leverages cloud computing services to provide analysis capabilities on over 40 years of Landsat data. As a remote sensing platform, its ability to analyze global data rapidly lends itself to being an invaluable tool for studying the growth of urban areas. Here we present (i) An approach for the automated extraction of urban areas from Landsat imagery using GEE, validated using higher resolution images, (ii) a novel method of validation of the extracted urban extents using changes in the statistical performance of a high resolution population mapping method. Temporally distinct urban extractions were classified from the GEE catalog of Landsat 5 and 7 data over the Indonesian island of Java by using a Normalized Difference Spectral Vector (NDSV) method. Statistical evaluation of all of the tests was performed, and the value of population mapping methods in validating these urban extents was also examined. Results showed that the automated classification from GEE produced accurate urban extent maps, and that the integration of GEE-derived urban extents also improved the quality of the population mapping outputs. (C) 2014 Elsevier B.V. All rights reserved. C1 [Patel, Nirav N.] George Mason Univ, Dept Geog & Geoinformat Sci, Fairfax, VA 22030 USA. [Angiuli, Emanuele; Gamba, Paolo; Lisini, Gianni; Trianni, Giovanna] Univ Pavia, Dept Elect Biomed & Comp Engn, I-27100 Pavia, Italy. [Gaughan, Andrea; Stevens, Forrest R.] Univ Louisville, Dept Geog & Geosci, Louisville, KY 40205 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton SO17 1BJ, Hants, England. [Tatem, Andrew J.] Fogarty Int Ctr, NIH, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Flowminder Fdn, S-17177 Stockholm, Sweden. RP Patel, NN (reprint author), 13706 Sun Court, Tampa, FL 33624 USA. EM niravpate165@gmail.com RI Gamba, Paolo/G-1959-2010; OI Gamba, Paolo/0000-0002-9576-6337; Stevens, Forrest/0000-0002-9328-3753 FU CARIPLO Foundation [2009-2936]; Google Foundation; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Bill and Melinda Gates Foundation [49446, 1032350] FX The work by NNP during his stay at the University of Pavia was supported by the CARIPLO Foundation, Project 2009-2936 for the Internationalization of the PhD programs in ICT and Bioengineering of the University of Pavia. PG acknowledges support from the Google Foundation for the preliminary phase of this research. AJT acknowledges funding support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and is also supported by grants from the Bill and Melinda Gates Foundation (#49446, #1032350). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work forms an output of the WorldPop project (www.worldpop.org.uk) and Flowminder Foundation (www.flowminder.org). NR 44 TC 7 Z9 7 U1 19 U2 77 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0303-2434 J9 INT J APPL EARTH OBS JI Int. J. Appl. Earth Obs. Geoinf. PD MAR PY 2015 VL 35 BP 199 EP 208 DI 10.1016/j.jag.2014.09.005 PN B PG 10 WC Remote Sensing SC Remote Sensing GA AY4XC UT WOS:000347577400005 ER PT J AU Zhou, CK Littman, AJ Levine, PH Hoffman, HJ Cleary, SD White, E Cook, MB AF Zhou, Cindy Ke Littman, Alyson J. Levine, Paul H. Hoffman, Heather J. Cleary, Sean D. White, Emily Cook, Michael B. TI Male Pattern Baldness in Relation to Prostate Cancer Risks: An Analysis in the VITamins and Lifestyle (VITAL) Cohort Study SO PROSTATE LA English DT Article DE male pattern baldness; prostate cancer; androgen; cohort study ID ENDOGENOUS SEX-HORMONES; EARLY-ONSET BALDNESS; ANDROGENETIC ALOPECIA; SERUM TESTOSTERONE; HAIR LOSS; MEN; METAANALYSIS; POLYMORPHISMS; EPIDEMIOLOGY; FINASTERIDE AB BACKGROUNDMale pattern baldness and prostate cancer may share common pathophysiological mechanisms in terms of advancing age, heritability, and endogenous hormones. Results from previous epidemiologic studies are inconsistent. Therefore, we investigated the association of prostate cancer risks with male pattern baldness at age 30 years, age 45 years, and baseline (median age=60.5 years) in the VITamins And Lifestyle (VITAL) cohort study. METHODSWe included 32,583 men who were aged 50-76 years and without prior cancer diagnosis (excluding non-melanoma skin cancer) at the start of follow-up. First primary incident prostate cancers were ascertained via linkage to the western Washington Surveillance, Epidemiology, and End Results (SEER) program. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regressions with adjustment for potential confounders. RESULTSDuring follow-up (median=9 years), 2,306 incident prostate cancers were diagnosed. Male pattern baldness at age 30 years, age 45 years, and baseline were not statistically significantly associated with overall or subtypes of prostate cancer. CONCLUSIONThis study did not provide support for the hypothesis that male pattern baldness may be a marker for subsequent prostate cancer. Previous evidence indicates that a distinct class of frontal with vertex balding may be associated with increased risk of aggressive prostate cancer, but all such balding classes were captured as a single exposure category by the VITAL cohort questionnaire. Prostate 75:415-423, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Zhou, Cindy Ke; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zhou, Cindy Ke; Levine, Paul H.; Hoffman, Heather J.; Cleary, Sean D.] George Washington Univ, Dept Epidemiol & Biostat, Washington, DC USA. [Littman, Alyson J.; White, Emily] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Littman, Alyson J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [White, Emily] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. RP Cook, MB (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 7-E106,MSC 9774, Bethesda, MD 20892 USA. EM michael.cook@nih.gov RI Zhou, Cindy /H-2165-2015; Cook, Michael/A-5641-2009 OI Zhou, Cindy /0000-0003-4814-4305; Cook, Michael/0000-0002-0533-7302 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX Grant sponsor: Intramural Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 50 TC 3 Z9 3 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD MAR 1 PY 2015 VL 75 IS 4 BP 415 EP 423 DI 10.1002/pros.22927 PG 9 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA AY8OA UT WOS:000347811800008 PM 25492530 ER PT J AU Conway, DI Brenner, DR McMahon, AD Macpherson, LMD Agudo, A Ahrens, W Bosetti, C Brenner, H Castellsague, X Chen, C Curado, MP Curioni, OA Dal Maso, L Daudt, AW de Gois, JF D'Souza, G Edefonti, V Fabianova, E Fernandez, L Franceschi, S Gillison, M Hayes, RB Healy, CM Herrero, R Holcatova, I Jayaprakash, V Kelsey, K Kjaerheim, K Koifman, S La Vecchia, C Lagiou, P Lazarus, P Levi, F Lissowska, J Luce, D Macfarlane, TV Mates, D Matos, E McClean, M Menezes, AM Menvielle, G Merletti, F Morgenstern, H Moysich, K Muller, H Muscat, J Olshan, AF Purdue, MP Ramroth, H Richiardi, L Rudnai, P Schantz, S Schwartz, SM Shangina, O Simonato, L Smith, E Stucker, I Sturgis, EM Szeszenia-Dabrowska, N Talamini, R Thomson, P Vaughan, TL Wei, QY Winn, DM Wunsch, V Yu, GP Zhang, ZF Zheng, TZ Znaor, A Boffetta, P Chuang, SC Ghodrat, M Lee, YCA Hashibe, M Brennan, P AF Conway, David I. Brenner, Darren R. McMahon, Alex D. Macpherson, Lorna M. D. Agudo, Antonio Ahrens, Wolfgang Bosetti, Cristina Brenner, Hermann Castellsague, Xavier Chen, Chu Curado, Maria Paula Curioni, Otavio A. Dal Maso, Luigino Daudt, Alexander W. de Gois Filho, Jose F. D'Souza, Gypsyamber Edefonti, Valeria Fabianova, Eleonora Fernandez, Leticia Franceschi, Silvia Gillison, Maura Hayes, Richard B. Healy, Claire M. Herrero, Rolando Holcatova, Ivana Jayaprakash, Vijayvel Kelsey, Karl Kjaerheim, Kristina Koifman, Sergio La Vecchia, Carlo Lagiou, Pagona Lazarus, Philip Levi, Fabio Lissowska, Jolanta Luce, Daniele Macfarlane, Tatiana V. Mates, Dana Matos, Elena McClean, Michael Menezes, Ana M. Menvielle, Gwenn Merletti, Franco Morgenstern, Hal Moysich, Kirsten Mueller, Heiko Muscat, Joshua Olshan, Andrew F. Purdue, Mark P. Ramroth, Heribert Richiardi, Lorenzo Rudnai, Peter Schantz, Stimson Schwartz, Stephen M. Shangina, Oxana Simonato, Lorenzo Smith, Elaine Stucker, Isabelle Sturgis, Erich M. Szeszenia-Dabrowska, Neonila Talamini, Renato Thomson, Peter Vaughan, Thomas L. Wei, Qingyi Winn, Deborah M. Wunsch-Filho, Victor Yu, Guo-Pei Zhang, Zuo-Feng Zheng, Tongzhang Znaor, Ariana Boffetta, Paolo Chuang, Shu-Chun Ghodrat, Marianoosh Lee, Yuan-Chin Amy Hashibe, Mia Brennan, Paul TI Estimating and explaining the effect of education and income on head and neck cancer risk: INHANCE consortium pooled analysis of 31 case-control studies from 27 countries SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE head and neck cancer; socioeconomic inequalities; epidemiology ID UPPER AERODIGESTIVE TRACT; SOCIOECONOMIC INEQUALITIES; HUMAN-PAPILLOMAVIRUS; ORAL-CANCER; OROPHARYNGEAL-CANCER; CIGARETTE-SMOKING; EPIDEMIOLOGY CONSORTIUM; OCCUPATIONAL EXPOSURES; INTERNATIONAL HEAD; ALCOHOL-DRINKING AB Low socioeconomic status has been reported to be associated with head and neck cancer risk. However, previous studies have been too small to examine the associations by cancer subsite, age, sex, global region and calendar time and to explain the association in terms of behavioral risk factors. Individual participant data of 23,964 cases with head and neck cancer and 31,954 controls from 31 studies in 27 countries pooled with random effects models. Overall, low education was associated with an increased risk of head and neck cancer (OR = 2.50; 95% CI = 2.02 - 3.09). Overall one-third of the increased risk was not explained by differences in the distribution of cigarette smoking and alcohol behaviors; and it remained elevated among never users of tobacco and nondrinkers (OR = 1.61; 95% CI = 1.13 - 2.31). More of the estimated education effect was not explained by cigarette smoking and alcohol behaviors: in women than in men, in older than younger groups, in the oropharynx than in other sites, in South/Central America than in Europe/North America and was strongest in countries with greater income inequality. Similar findings were observed for the estimated effect of low versus high household income. The lowest levels of income and educational attainment were associated with more than 2-fold increased risk of head and neck cancer, which is not entirely explained by differences in the distributions of behavioral risk factors for these cancers and which varies across cancer sites, sexes, countries and country income inequality levels. What's new? Head and neck cancer is among the most common and increasing cancers in the world. Besides smoking, alcohol drinking, and human papilloma virus infections, low socioeconomic status has been implicated as one of the most important risk factors for this cancer type. This large multinational study authoritatively confirmed that lower education status and lower income are associated with increased risk for head and neck cancer development. Smoking and alcohol consumption could not entirely explain the risk associated with low socioeconomic factors, and therefore, as the authors argue, need to be more explicitly recognized in the etiology associated with head and neck cancer. C1 [Conway, David I.; McMahon, Alex D.; Macpherson, Lorna M. D.] Univ Glasgow, Glasgow Dent Sch, Coll Med Vet & Life Sci, Glasgow G2 3JZ, Lanark, Scotland. [Brenner, Darren R.; Franceschi, Silvia; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Agudo, Antonio] Catalan Inst Oncol ICO, Environm & Canc Epidemiol Res Program, Unit Nutr, Barcelona, Spain. [Ahrens, Wolfgang] BIPS Inst Epidemiol & Prevent Res, Bremen, Germany. [Ahrens, Wolfgang] Univ Bremen, Inst Stat, D-28359 Bremen, Germany. [Bosetti, Cristina; La Vecchia, Carlo; Mueller, Heiko] IRCCS Ist Ric Farmacol Mario Negri, Dept Epidemiol, Milan, Italy. [Brenner, Hermann] German Canc Res Ctr, Heidelberg, Germany. [Castellsague, Xavier] ICO, IDIBELL, CIBER ESP, Barcelona, Catalonia, Spain. [Chen, Chu; Schwartz, Stephen M.; Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Curado, Maria Paula; Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Curioni, Otavio A.] Hosp Heliopolis, Sao Paulo, Brazil. [Dal Maso, Luigino; Talamini, Renato] Ctr Riferimento Oncol IRCCS, Epidemiol & Biostat Unit, Aviano, Italy. [Daudt, Alexander W.] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [de Gois Filho, Jose F.] Inst Canc Arnaldo Viera de Carvalho, Sao Paulo, Brazil. [D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Edefonti, Valeria] Univ Milan, Dept Clin Sci & Community Hlth, I-20122 Milan, Italy. [Fabianova, Eleonora] Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Fernandez, Leticia] Inst Oncol & Radiobiol, Havana, Cuba. [Gillison, Maura] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Hayes, Richard B.] NYU, Sch Med, Div Epidemiol, New York, NY 10003 USA. [Healy, Claire M.] Univ Dublin Trinity Coll, Sch Dent Sci, Dublin 2, Ireland. [Herrero, Rolando] Int Agcy Res Canc, Prevent & Implementat Grp, F-69372 Lyon, France. [Holcatova, Ivana] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic. [Jayaprakash, Vijayvel; Moysich, Kirsten] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Kelsey, Karl] Brown Univ, Providence, RI 02912 USA. [Kjaerheim, Kristina] Canc Registry Norway, Oslo, Norway. [Koifman, Sergio] Fundacao Oswaldo Cruz, Escola Nacl Saude Publ, Rio De Janeiro, Brazil. [Lagiou, Pagona] Univ Athens, Sch Med, GR-11527 Athens, Greece. [Lazarus, Philip] Washington State Univ, Coll Pharm, Spokane, WA USA. [Levi, Fabio] CHU Vaudois, Inst Med Sociale & Prevent IUMSP, CH-1011 Lausanne, Switzerland. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Luce, Daniele; Menvielle, Gwenn; Stucker, Isabelle] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, U1018, Villejuif, France. [Macfarlane, Tatiana V.] Univ Aberdeen, Sch Dent, Aberdeen, Scotland. [Mates, Dana] Natl Inst Publ Hlth, Bucharest, Romania. [Matos, Elena] Univ Buenos Aires, Inst Oncol Angel H Roffo, RA-1053 Buenos Aires, DF, Argentina. [McClean, Michael] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Menezes, Ana M.] Univ Fed Pelotas, Capao Do Leao, RS, Brazil. [Merletti, Franco; Richiardi, Lorenzo] Univ Turin, Dept Med Sci, I-10124 Turin, Italy. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Muscat, Joshua] Penn State Coll Med, Hershey, PA USA. [Olshan, Andrew F.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Purdue, Mark P.] NCI, Bethesda, MD 20892 USA. [Ramroth, Heribert] Heidelberg Univ, Inst Publ Hlth, D-69115 Heidelberg, Germany. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Schantz, Stimson] New York Eye & Ear Infirm, New York, NY USA. [Shangina, Oxana] Russian Acad Med Sci, Canc Res Ctr, Moscow, Russia. [Simonato, Lorenzo] Univ Padua, Dept Mol Med, Lab Publ Hlth & Populat Studies, I-35100 Padua, Italy. [Smith, Elaine] Univ Iowa, Coll Publ Hlth, Iowa City, IA 52242 USA. [Sturgis, Erich M.; Wei, Qingyi] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Szeszenia-Dabrowska, Neonila] Inst Occupat Med, Lodz, Poland. [Thomson, Peter] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Winn, Deborah M.] NCI, NIH, Bethesda, MD 20892 USA. [Wunsch-Filho, Victor] Univ Sao Paulo, Fac Saude Publ, Dept Epidemiol, BR-05508 Sao Paulo, Brazil. [Yu, Guo-Pei] New York Med Coll, Valhalla, NY 10595 USA. [Yu, Guo-Pei] Peking Univ, Med Informat Ctr, Beijing 100871, Peoples R China. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Zheng, Tongzhang] Yale Univ, New Heaven, CT USA. [Znaor, Ariana] Croatian Natl Inst Publ Hlth, Croatian Natl Canc Registry, Zagreb, Croatia. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Chuang, Shu-Chun] Natl Hlth Res Inst, Inst Populat Hlth Sci, Div Hlth Policy Translat, Miaoli, Taiwan. [Ghodrat, Marianoosh; Lee, Yuan-Chin Amy; Hashibe, Mia] Univ Utah, Sch Med, Salt Lake City, UT USA. [Levi, Fabio] Univ Lausanne, Lausanne, Switzerland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. RP Conway, DI (reprint author), Univ Glasgow, Sch Dent, 378 Sauchiehall St, Glasgow G2 3JZ, Lanark, Scotland. EM david.conway@glasgow.ac.uk RI Chuang, Shu-Chun/N-3358-2013; McClean, Michael/J-2934-2015; Castellsague Pique, Xavier/N-5795-2014; Menezes, Ana/G-7266-2012; Menvielle, Gwenn/E-7201-2017; LUCE, Daniele/J-9125-2015; Szeszenia-Dabrowska, Neonila/F-7190-2010; Curado, Maria Paula/M-6200-2013; Purdue, Mark/C-9228-2016; Agudo, Antonio/J-1805-2016; Brenner, Hermann/B-4627-2017; Thomson, Peter/L-7719-2016; OI Luce, Daniele/0000-0002-1708-4584; Ahrens, Wolfgang/0000-0003-3777-570X; Castellsague Pique, Xavier/0000-0002-0802-3595; Agudo, Antonio/0000-0001-9900-5677; Curado, Maria Paula/0000-0001-8172-2483; Purdue, Mark/0000-0003-1177-3108; Brenner, Hermann/0000-0002-6129-1572; mates, dana/0000-0002-6219-9807; dal maso, luigino/0000-0001-6163-200X; Thomson, Peter/0000-0002-2007-7975; Macfarlane, Tatiana/0000-0002-9392-0812; richiardi, lorenzo/0000-0003-0316-9402; La Vecchia, Carlo/0000-0003-1441-897X; Kjaerheim, Kristina/0000-0003-0691-3735; EDEFONTI, VALERIA CARLA/0000-0002-1995-1477; Hayes, Richard/0000-0002-0918-661X; Healy, Claire M/0000-0001-7940-4611 FU UICC Yamagiwa-Yoshida Memorial International Cancer Study; International Agency for Research on Cancer, Lyon, France Visiting Scientist Award; INHANCE Pooled Data Coordination; NCI [R03CA113157]; NIDCR [R03DE016611]; Italian Association for Research on Cancer (AIRC) [10068]; Italian Ministry of Research [PRIN 2009 X8YCBN]; Swiss League against Cancer; Swiss Research against Cancer/Oncosuisse, Switzerland FX Grant sponsor(s): UICC Yamagiwa-Yoshida Memorial International Cancer Study grant; International Agency for Research on Cancer, Lyon, France Visiting Scientist Award; INHANCE Pooled Data Coordination Grant sponsor: NCI; Grant number: R03CA113157; and Grant sponsor: NIDCR; Grant number: R03DE016611; Individual Studies funded by the following: Aviano, Milan (1984-1989) Study, Milan (2006-2009) Study and Italy Multicenter Study Grant sponsors: Italian Association for Research on Cancer (AIRC); Grant number: 10068; Grant sponsor: Italian Ministry of Research; Grant number: PRIN 2009 X8YCBN; Grant sponsor: Swiss League against Cancer and the Swiss Research against Cancer/Oncosuisse, Switzerland; Grant numbers: KFS-700 and OCS-1633; Central Europe Study Grant sponsor: World Cancer Research Fund and the European Commission INCO- COPERNICUS Program Central Europe; Grant number: IC15- CT98- 0332; Western Europe Study Grant sponsors: European Commission's 5th Framework Programme; Grant number: QLK1- 2001- 00182, and RegionPiemonte and Padova University; Grant number: CPDA057222; Germany- Saarland Study Grant sponsor: Ministry of Science, Research and Arts Baden- Wurttemberg; Germany- Heidelberg Study Grant sponsor: German Ministry of Education and Research; Grant number: 01GB9702/ 3; France (2001- 2007) Study Grant sponsors: French National Cancer Institute (INCA); French Agency for Food, Environmental and Occupational Health and Safety (ANSES); French Association for Research on Cancer (ARC); Fondation pour la Recherche Medicale ( FRM); French Institute for Public Health Surveillance (InVS); Fondation de France; Ministry of Health; International Multicenter Study Grant sponsor: Fondo de Investigaciones Sanitarias ( FIS) of the Spanish Government; Grant numbers: FIS 97/ 0024, FIS 97/ 0662 and BAE 01/ 5013, and International Union Against Cancer ( UICC) and Yamagiwa- Yoshida Memorial International Cancer Study Grant; Boston Study Grant sponsor: NIH US; Grant numbers: R01CA078609 and R01CA100679; Baltimore Study Grant sponsor: NIDCR; Grant number: DE016631; HOTSPOT Study Grant sponsor: Johns Hopkins Richard Gelb Cancer Prevention Award; New York Multicenter Study Grant sponsor: National Institutes of Health ( NIH) US; Grant numbers: P01CA068384 and R01DA026815; Seattle ( 1985- 1995) Study Grant sponsor: NIH US; Grant numbers: R01CA048996 and R01DE012609; Iowa Study Grant sponsor: NIH US; Grant numbers: NIDCR R01DE11979, NIDCR R01DE13110 and NIH FIRCA TW01500 and Veterans affairs Merit Review Funds; North Carolina ( 1994- 1997) Study Grant sponsor: NIH, US; Grant number: R01CA061188 and Grant sponsor: National Institute of Environmental Health Sciences; Grant number: P30ES010126; North Carolina ( 2002- 2012) Study Grant sponsor: NIH, US; Grant number: R01CA90731; Seattle- Leo Study Grant sponsor: NIH; Grant number: R01CA030022; Tampa Study Grant sponsor: NIH, US; Grant numbers: P01CA068384, K07CA104231 and R01DE013158; Los Angeles Study Grant sponsor: NIH, US; Grant numbers: P50CA090388, R01DA011386, R03CA077954, T32CA009142, U01CA096134 and R21ES011667 and the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; Houston Study Grant sponsor: NIH, US; Grant numbers: R01ES011740 and R01CA100264; Puerto Rico Study Grant sponsor: NIH NCI and NIDCR intramural programs; MSKCC Study Grant sponsor: NIH, US; Grant number: R01CA051845; Latin America Study Grant sponsors: Fondo para la investigacion Cientifica y Tecnologica (FONCYT) Argentina, IMIM (Barcelona), and Fundac, ao de Amparoa Pesquisa no Estado de Sao; Paulo (FAPESP); Grant number: 01/ 01768- 2; and Grant sponsor: European Commission; Grant number: IC18- CT97- 0222; Sao Paulo Study Grant sponsor: Fundacao de Amparoa Pesquisa no Estado de Sao Paulo (FAPESP); Grant number: 10/ 51168- 0 NR 45 TC 17 Z9 17 U1 2 U2 31 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 1 PY 2015 VL 136 IS 5 BP 1125 EP 1139 DI 10.1002/ijc.29063 PG 15 WC Oncology SC Oncology GA AW5ZY UT WOS:000346350500038 PM 24996155 ER PT J AU Reigstad, MM Larsen, IK Myklebust, TA Robsahm, TE Oldereid, NB Omland, AK Vangen, S Brinton, LA Storeng, R AF Reigstad, Marte Myhre Larsen, Inger Kristin Myklebust, Tor Age Robsahm, Trude Eid Oldereid, Nan Birgitte Omland, Anne Katerine Vangen, Siri Brinton, Louise Annette Storeng, Ritsa TI Risk of breast cancer following fertility treatment-A registry based cohort study of parous women in Norway SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast cancer; assisted reproductive technology; ART; in vitro fertilization; IVF; hormones; risk; malignancy; cancer ID IN-VITRO FERTILIZATION; ASSISTED REPRODUCTIVE TECHNOLOGY; OVULATION-STIMULATING DRUGS; MEDICAL BIRTH REGISTRY; POSSIBLE ASSOCIATION; GYNECOLOGIC CANCERS; INFERTILE WOMEN; OVARIAN-CANCER; UNITED-STATES; GAVE BIRTH AB Despite increasing numbers of women availing themselves of assisted reproductive technology (ART), effects on cancer risk remain unresolved. Given hormonal exposures, breast cancer risk is of particular concern. The aim of this study is to investigate breast cancer risk amongst women giving birth following ART as compared to that amongst women who gave birth without ART. Data on all women who gave birth in Norway with or without ART, between 1984 and 2010 were obtained from the Medical Birth Registry of Norway (MBRN). 808,834 women eligible for study were linked to the Cancer Registry of Norway. Cox proportional models computed hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer between the two groups, adjusting for age, parity, age at first birth, calendar period and region of residence. In total, 8,037 women were diagnosed with breast cancer during the study period, 138 ART women and 7,899 unexposed. Total follow-up time was 12,401,121 person-years (median 16.0); median age at entry was 32.5 years (range18.6-49.9) for ART women and 26.3 (range 10.5-54.6) for unexposed. Women exposed to ART had an elevated risk of breast cancer (adjusted HR 1.20, 95% CI 1.01-1.42). Subgroup analyses gave an HR of 1.30 (95% CI 1.07-1.57) for women treated with IVF and 1.35 (95 % CI 1.07-1.71) for women with follow-up >10 years, compared with controls. Our findings of increased risk in the study population warrant continued monitoring of women treated with ART as this population advances into more typical cancer age ranges. What's new? Assisted reproductive technology (ART) typically involves the use of hormonal therapy, suggesting possible effects on cancer risk for infertile women. But whether ART is associated with increased or decreased risk of breast cancer in particular is unclear. Here, based on data from the Cancer Registry of Norway and the Medical Birth Registry of Norway, women who give birth following ART are at increased risk of breast cancer compared with women who give birth without ART. The rise in risk was greatest amongst women who were followed for more than 10 years and women who used in-vitro fertilization specifically. C1 [Reigstad, Marte Myhre; Vangen, Siri; Storeng, Ritsa] Oslo Univ Hosp, Norwegian Natl Advisory Unit Womens Hlth, Rikshosp, N-0424 Oslo, Norway. [Larsen, Inger Kristin; Myklebust, Tor Age; Robsahm, Trude Eid] Inst Populat Based Canc Res, Canc Registry Norway, Dept Is Inst Populat Based Res, Oslo, Norway. [Oldereid, Nan Birgitte; Omland, Anne Katerine] Oslo Univ Hosp, Sect Reprod Med, Rikshosp, N-0424 Oslo, Norway. [Brinton, Louise Annette] NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Bethesda, MD 20892 USA. RP Reigstad, MM (reprint author), Oslo Univ Hosp, Norwegian Natl Advisory Unit Womens Hlth, Rikshosp, POB 4950 Nydalen, N-0424 Oslo, Norway. EM martereigstad@gmail.com RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU Intramural NIH HHS [ZIA CP010128-18] NR 46 TC 12 Z9 12 U1 3 U2 22 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 1 PY 2015 VL 136 IS 5 BP 1140 EP 1148 DI 10.1002/ijc.29069 PG 9 WC Oncology SC Oncology GA AW5ZY UT WOS:000346350500039 PM 25042052 ER PT J AU Han, Y Signorello, LB Strom, SS Kittles, RA Rybicki, BA Stanford, JL Goodman, PJ Berndt, SI Carpten, J Casey, G Chu, LS Conti, DV Rand, KA Diver, WR Hennis, AJM John, EM Kibel, AS Klein, EA Kolb, S Le Marchand, L Leske, MC Murphy, AB Neslund-Dudas, C Park, JY Pettaway, C Rebbeck, TR Gapstur, SM Zheng, SL Wu, SY Witte, JS Xu, JF Isaacs, W Ingles, SA Hsing, A Easton, DF Eeles, RA Schumacher, FR Chanock, S Nemesure, B Blot, WJ Stram, DO Henderson, BE Haiman, CA AF Han, Ying Signorello, Lisa B. Strom, Sara S. Kittles, Rick A. Rybicki, Benjamin A. Stanford, Janet L. Goodman, Phyllis J. Berndt, Sonja I. Carpten, John Casey, Graham Chu, Lisa Conti, David V. Rand, Kristin A. Diver, W. Ryan Hennis, Anselm J. M. John, Esther M. Kibel, Adam S. Klein, Eric A. Kolb, Suzanne Le Marchand, Loic Leske, M. Cristina Murphy, Adam B. Neslund-Dudas, Christine Park, Jong Y. Pettaway, Curtis Rebbeck, Timothy R. Gapstur, Susan M. Zheng, S. Lilly Wu, Suh-Yuh Witte, John S. Xu, Jianfeng Isaacs, William Ingles, Sue A. Hsing, Ann Easton, Douglas F. Eeles, Rosalind A. Schumacher, Fredrick R. Chanock, Stephen Nemesure, Barbara Blot, William J. Stram, Daniel O. Henderson, Brian E. Haiman, Christopher A. CA PRACTICAL Consortium ELLIPSE GAME-ON Consortium TI Generalizability of established prostate cancer risk variants in men of African ancestry SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE prostate cancer; genetic risk variant; generalizability; African ancestry ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; SEQUENCE VARIANTS; IDENTIFICATION; REPLICATION AB Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p<0.05, with the most statistically significant variants being rs116041037 (p=3.7 x 10(-26)) and rs6983561 (p=1.1 x 10(-16)) at 8q24, as well as rs7210100 (p=5.4 x 10(-8)) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p<0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR)=1.12, p=7.3 x 10(-98)]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry. C1 [Han, Ying; Casey, Graham; Conti, David V.; Rand, Kristin A.; Ingles, Sue A.; Schumacher, Fredrick R.; Stram, Daniel O.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Signorello, Lisa B.] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Strom, Sara S.] Univ Texas MD Anderson Canc Ctr, Div Canc Prevent & Populat Sci, Dept Epidemiol, Houston, TX 77030 USA. [Kittles, Rick A.] Univ Illinois, Dept Med, Chicago, IL USA. [Rybicki, Benjamin A.; Neslund-Dudas, Christine] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Stanford, Janet L.; Kolb, Suzanne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Goodman, Phyllis J.] SWOG Stat Ctr, Seattle, WA USA. [Berndt, Sonja I.; Chanock, Stephen] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Carpten, John] Translat Genom Res Inst, Phoenix, AZ USA. [Casey, Graham; Schumacher, Fredrick R.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Chu, Lisa; John, Esther M.; Hsing, Ann] Canc Prevent Inst Calif, Fremont, CA USA. [Diver, W. Ryan; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Hennis, Anselm J. M.; Leske, M. Cristina; Wu, Suh-Yuh; Nemesure, Barbara] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Hennis, Anselm J. M.] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Hennis, Anselm J. M.] Univ W Indies, Fac Med Sci, Bridgetown, Barbados. [Hennis, Anselm J. M.] Minist Hlth, Bridgetown, Barbados. [John, Esther M.; Hsing, Ann] Stanford Univ, Sch Med, Div Epidemiol, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [John, Esther M.; Hsing, Ann] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. [Kibel, Adam S.] Brigham & Womens Hosp, Div Urol Surg, Dana Farber Canc Inst, Boston, MA 02115 USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Le Marchand, Loic] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. [Murphy, Adam B.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Park, Jong Y.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Pettaway, Curtis] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Rebbeck, Timothy R.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Zheng, S. Lilly; Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Witte, John S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Inst Human Genet, San Francisco, CA 94143 USA. [Witte, John S.] Univ Calif San Francisco, Dept Urol, Inst Human Genet, San Francisco, CA USA. [Isaacs, William] Johns Hopkins Hosp & Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Eeles, Rosalind A.] Inst Canc Res, London SW3 6JB, England. [Eeles, Rosalind A.] Inst Canc Res, Sutton, Surrey, England. [Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv Fdn Trust, London, England. [Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv Fdn Trust, Sutton, Surrey, England. [Blot, William J.] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Blot, William J.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. RP Haiman, CA (reprint author), Harlyne Norris Res Tower,1450 Biggy St,Room 1504, Los Angeles, CA 90033 USA. EM haiman@usc.edu OI Eeles, Rosalind/0000-0002-3698-6241 FU National Institutes of Health (NIH) [CA63464, CA54281, CA1326792, CA148085, HG004726] FX Grant sponsor: National Institutes of Health (NIH); Grant number: CA63464, CA54281, CA1326792, CA148085, HG004726 NR 25 TC 20 Z9 20 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD MAR 1 PY 2015 VL 136 IS 5 BP 1210 EP 1217 DI 10.1002/ijc.29066 PG 8 WC Oncology SC Oncology GA AW5ZY UT WOS:000346350500046 PM 25044450 ER PT J AU Cahoon, EK Pfeiffer, RM Wheeler, DC Arhancet, J Lin, SW Alexander, BH Linet, MS Freedman, DM AF Cahoon, Elizabeth K. Pfeiffer, Ruth M. Wheeler, David C. Arhancet, Juan Lin, Shih-Wen Alexander, Bruce H. Linet, Martha S. Freedman, D. Michal TI Relationship between ambient ultraviolet radiation and non-Hodgkin lymphoma subtypes: A US population-based study of racial and ethnic groups SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE ultraviolet radiation; non-Hodgkin lymphoma; race ID CIRCULATING 25-HYDROXYVITAMIN D; VITAMIN-D; UNITED-STATES; SUN EXPOSURE; EPIDEMIOLOGIC RESEARCH; INTERLYMPH CONSORTIUM; MALIGNANT-LYMPHOMA; RISK; SUNLIGHT; CANCER AB Associations between ultraviolet radiation (UVR) exposure and non-Hodgkin lymphoma (NHL) have been inconsistent, but few studies have examined these associations for specific subtypes or across race/ethnicities. We evaluated the relationship between ambient UVR exposure and subtype-specific NHL incidence for whites, Hispanics and blacks in the United States for years 2001-2010 (n=187,778 cases). Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for UVR quintiles using Poisson regression. Incidence was lower for the highest UVR quintile for chronic/small lymphocytic/leukemia (CLL/SLL) (IRR=0.87, 95% CI: 0.77-0.97), mantle cell (IRR=0.82, 95% CI: 0.69-0.97), lymphoplasmacytic (IRR=0.58, 95% CI: 0.42-0.80), mucosa-associated lymphoid tissue (MZLMALT) (IRR=0.74, 95% CI: 0.60-0.90), follicular (FL) (IRR=0.76, 95% CI: 0.68-0.86), diffuse large B-cell (IRR=0.84, 95% CI: 0.76-0.94;), peripheral T-cell other (PTCL) (IRR=0.76, 95% CI: 0.61-0.95) and PTCL not otherwise specified (PNOS) (IRR=0.77, 95% CI: 0.61-0.98). Trends were significant for MZLMALT, FL, DLBCL, BNOS and PTCL, with FL and DLBCL still significant after Bonferroni correction. We found interaction by race/ethnicity for CLL/SLL, FL, Burkitt, PNOS and MF/SS, with CLL/SLL and FL still significant after Bonferroni correction. Some B-cell lymphomas (CLL/SLL, FL and Burkitt) suggested significant inverse relationships in whites and Hispanics, but not in blacks. Some T-cell lymphomas suggested the most reduced risk for the highest quintile of UVR among blacks (PNOS and MF/SS), though trends were not significant. These findings strengthen the case for an inverse association of UVR exposure, support modest heterogeneity between NHL subtypes and suggest some differences by race/ethnicity. What's new? Studies have yielded mix results as to whether exposure to ultraviolet radiation (UVR) increases or decreases risk of non-Hodgkin lymphoma (NHL). In the present analysis of data from population-based cancer registries in the United States, increasing ambient UVR exposure was associated with a reduction in risk of most NHL subtypes, The reduction occurred for all races, including non-Hispanic whites, Hispanic whites, and blacks. The findings emphasize the importance of exploring NHL etiology according to subtypes and across races and ethnicities, as NHL is increasingly recognized as comprising a diverse group of cancers, each potentially involving unique mechanisms. C1 [Cahoon, Elizabeth K.; Linet, Martha S.; Freedman, D. Michal] NCI, Radiat Epidemiol Branch, DCEG, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, DCEG, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Wheeler, David C.] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA USA. [Arhancet, Juan] Rocky Vista Univ, Coll Osteopath Med, Parker, CO USA. [Lin, Shih-Wen] NCI, Nutr Epidemiol Branch, DCEG, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. RP Cahoon, EK (reprint author), NCI, Radiat Epidemiol Branch, DCEG, NIH, 9609 Med Ctr Dr,Room 7E560,MSC 9778, Bethesda, MD 20892 USA. EM khaykin@hotmail.com FU NIH; National Cancer Institute FX Grant sponsor: Intramural Research Program of the NIH and the National Cancer Institute NR 48 TC 4 Z9 4 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD MAR 1 PY 2015 VL 136 IS 5 BP E432 EP E441 DI 10.1002/ijc.29237 PG 10 WC Oncology SC Oncology GA AW5ZY UT WOS:000346350500020 PM 25258118 ER PT J AU Felix, AS Gaudet, MM La Vecchia, C Nagle, CM Shu, XO Weiderpass, E Adami, HO Beresford, S Bernstein, L Chen, C Cook, LS De Vivo, I Doherty, JA Friedenreich, CM Gapstur, SM Hill, D Horn-Ross, PL Lacey, JV Levi, F Liang, XL Lu, LG Magliocco, A McCann, SE Negri, E Olson, SH Palmer, JR Patel, AV Petruzella, S Prescott, J Risch, HA Rosenberg, L Sherman, ME Spurdle, AB Webb, PM Wise, LA Xiang, YB Xu, WH Yang, HP Yu, H Zeleniuch-Jacquotte, A Brinton, LA AF Felix, Ashley S. Gaudet, Mia M. La Vecchia, Carlo Nagle, Christina M. Shu, Xiao Ou Weiderpass, Elisabete Adami, Hans Olov Beresford, Shirley Bernstein, Leslie Chen, Chu Cook, Linda S. De Vivo, Immaculata Doherty, Jennifer A. Friedenreich, Christine M. Gapstur, Susan M. Hill, Dierdre Horn-Ross, Pamela L. Lacey, James V. Levi, Fabio Liang, Xiaolin Lu, Lingeng Magliocco, Anthony McCann, Susan E. Negri, Eva Olson, Sara H. Palmer, Julie R. Patel, Alpa V. Petruzella, Stacey Prescott, Jennifer Risch, Harvey A. Rosenberg, Lynn Sherman, Mark E. Spurdle, Amanda B. Webb, Penelope M. Wise, Lauren A. Xiang, Yong-Bing Xu, Wanghong Yang, Hannah P. Yu, Herbert Zeleniuch-Jacquotte, Anne Brinton, Louise A. TI Intrauterine devices and endometrial cancer risk: A pooled analysis of the Epidemiology of Endometrial Cancer Consortium SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE contraception; pooled analysis; endometrial neoplasm; etiology ID MENSTRUAL BLOOD-LOSS; BODY IRON STORES; PROGESTERONE-RECEPTORS; CONTRACEPTIVE-DEVICE; REPRODUCTIVE FACTORS; UNITED-STATES; BREAST-CANCER; ESTROGEN-RECEPTORS; STEROID-RECEPTORS; CHINESE WOMEN AB Intrauterine devices (IUDs), long-acting and reversible contraceptives, induce a number of immunological and biochemical changes in the uterine environment that could affect endometrial cancer (EC) risk. We addressed this relationship through a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We combined individual-level data from 4 cohort and 14 case-control studies, in total 8,801 EC cases and 15,357 controls. Using multivariable logistic regression, we estimated pooled odds ratios (pooled-ORs) and 95% confidence intervals (CIs) for EC risk associated with ever use, type of device, ages at first and last use, duration of use and time since last use, stratified by study and adjusted for confounders. Ever use of IUDs was inversely related to EC risk (pooled-OR=0.81, 95% CI=0.74-0.90). Compared with never use, reduced risk of EC was observed for inert IUDs (pooled-OR=0.69, 95% CI=0.58-0.82), older age at first use (35 years pooled-OR=0.53, 95% CI=0.43-0.67), older age at last use (45 years pooled-OR=0.60, 95% CI=0.50-0.72), longer duration of use (10 years pooled-OR=0.61, 95% CI=0.52-0.71) and recent use (within 1 year of study entry pooled-OR=0.39, 95% CI=0.30-0.49). Future studies are needed to assess the respective roles of detection biases and biologic effects related to foreign body responses in the endometrium, heavier bleeding (and increased clearance of carcinogenic cells) and localized hormonal changes. What's new? Are IUDs associated with endometrial cancer? Around the world, the intrauterine device is gaining popularity as a long-term birth control strategy. Positioned as it is embedded in the uterine lining, an IUD could affect endometrial tissue. This study builds on previous work by considering the type of device used, in addition to factors such as duration of use. The authors found that women who had used an IUD, particularly an inert IUD, had less risk of endometrial cancer. The longer the device was used, they found, the more the cancer risk decreased. C1 [Felix, Ashley S.; Yang, Hannah P.; Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Felix, Ashley S.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Gaudet, Mia M.; Gapstur, Susan M.; Patel, Alpa V.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [La Vecchia, Carlo] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Nagle, Christina M.; Webb, Penelope M.] QIMR Berghofer Med Res Inst, Dept Populat Hlth, Herston, Qld, Australia. [Shu, Xiao Ou] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA. [Shu, Xiao Ou] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Weiderpass, Elisabete; Adami, Hans Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Arctic Univ Norway, Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Dept Genet Epidemiol, Helsinki, Finland. [Adami, Hans Olov; De Vivo, Immaculata; Prescott, Jennifer] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Beresford, Shirley; Chen, Chu; Doherty, Jennifer A.; Hill, Dierdre] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Bernstein, Leslie; Lacey, James V.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA. [Cook, Linda S.] Univ New Mexico, Albuquerque, NM 87131 USA. [De Vivo, Immaculata; Prescott, Jennifer] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [De Vivo, Immaculata; Prescott, Jennifer] Harvard Univ, Sch Med, Boston, MA USA. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Dept Community & Family Med, Lebanon, NH USA. [Friedenreich, Christine M.] Alberta Hlth Serv CancerControl Alberta, Edmonton, AB, Canada. [Horn-Ross, Pamela L.] Canc Prevent Inst Calif, Fremont, CA USA. [Levi, Fabio] Univ Lausanne Hosp, Inst Social & Prevent Med IUMSP, Vaud Canc Registry & Canc Epidemiol Unit, Lausanne, Switzerland. [Liang, Xiaolin; Olson, Sara H.; Petruzella, Stacey] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Lu, Lingeng; Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Magliocco, Anthony] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [McCann, Susan E.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Negri, Eva] Ist Ric Farmacol Mario Negri, Dept Epidemiol, Milan, Italy. [Palmer, Julie R.; Rosenberg, Lynn; Wise, Lauren A.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Sherman, Mark E.] NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Spurdle, Amanda B.] QIMR Berghofer Med Res Inst, Genet & Computat Biol Div, Herston, Qld, Australia. [Xiang, Yong-Bing] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Shanghai Canc Inst, Shanghai, Peoples R China. [Xu, Wanghong] Fudan Univ, Sch Publ Hlth, Dept Epidemiol, Shanghai 200433, Peoples R China. [Yu, Herbert] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. RP Felix, AS (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM ashley.felix@nih.gov RI Brinton, Louise/G-7486-2015; Felix, Ashley/A-3240-2016; Weiderpass, Elisabete/M-4029-2016; Spurdle, Amanda/A-4978-2011; OI Brinton, Louise/0000-0003-3853-8562; Weiderpass, Elisabete/0000-0003-2237-0128; Spurdle, Amanda/0000-0003-1337-7897; La Vecchia, Carlo/0000-0003-1441-897X; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; ALBERTA; NIH [R01 CA082838]; Alberta Innovates-Health Solutions; Alberta Cancer Foundation; ANECS: National Health and Medical Research Council (NHMRC) [339435]; NHMRC [552429]; BWHS: NCI [R03-CA169888, R01CA58420, UM1-CA164974]; CECS: NIH [R01 CA098346]; NIH; Associazione Italiana per la Ricerca sul Cancro FX This work was supported in part by an Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. We thank the many individuals who participated and the numerous institutions and their staff who supported the individual studies. We also thank Dr. Leah Mechanic at NCI's Division of Cancer Control and Population Sciences for her support of the E2C2 activities. The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. Individual studies were funded by the following grants and agencies: ALBERTA: Cancer Institute of Canada with funds from the Canadian Cancer Society and the Canadian Institute for Health Research, NIH Grant No. R01 CA082838, C.F. is supported by career awards from Alberta Innovates-Health Solutions and the Alberta Cancer Foundation through the Weekend to End Women's Cancers Breast Cancer Chair, L. S. C. was supported through the Canada Research Chairs program; ANECS: National Health and Medical Research Council (NHMRC), Grant No. 339435 of Australia and the Cancer Councils of Queensland and Tasmania; P. M. W. and A. B. S. are supported by Fellowships from the NHMRC and C. M. N. is funded by NHMRC Program Grant No. 552429; BWHS: NCI Grants No. R03-CA169888 (PI: Wise), R01CA58420 (PI: Rosenberg), and UM1-CA164974 (PI: Rosenberg); CECS: NIH Grant No. R01 CA098346; CPS-II: The American Cancer Society (ACS) funds the creation, maintenance and updating of the Cancer Prevention Study-II (CPS-II) cohort; CTS: NIH Grants No. R01CA91019 and R01CA77398; EDGE: NIH Grants No. R01 CA83918 and P30CA008748; FHCRC: NIH Grants No. R35 CA 39779, R01 CA 47749, R01 CA 75977, N01 HD 2 3166, K05 CA 92002, CA 105212, R01 CA87538, and funds from the Fred Hutchinson Cancer Research Center; MILANO: Italian Cancer Research Association (AIRC) Grant No. 10068; NHS: NIH Grants No. P01 CA87262 and R01 CA082838; NYU: NIH/ NCI Grants No. R01 CA098661, R01 CA08121, and Center Grant P30 CA016087; SECS: NIH Grant No. R01 CA092585; SWEC: Swiss National Science Foundation Grant 32.9495.88 and the Swiss National Research Foundation grant OCS 1633-02-2005; US: Intramural Research Funds of the NCI, NIH, Department of Health and Human Services; WLHS: Swedish Research Council, Swedish Cancer Society, and Distinguished Professor Award at Karolinska Institutet to H. O. A (Dnr: 2368-10-221). NR 77 TC 4 Z9 4 U1 1 U2 19 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 1 PY 2015 VL 136 IS 5 BP E410 EP E422 DI 10.1002/ijc.29229 PG 13 WC Oncology SC Oncology GA AW5ZY UT WOS:000346350500018 PM 25242594 ER PT J AU Li, ML Huang, CH Deng, W Ma, XH Han, YY Wang, Q Li, Z Guo, WJ Li, YF Jiang, LJ Lei, W Hu, X Gong, QY Merikangas, KR Palaniyappan, L Li, T AF Li, Mingli Huang, Chaohua Deng, Wei Ma, Xiaohong Han, Yuanyuan Wang, Qiang Li, Zhe Guo, Wanjun Li, Yinfei Jiang, Lijun Lei, Wei Hu, Xun Gong, Qiyong Merikangas, Kathleen Ries Palaniyappan, Lena Li, Tao TI Contrasting and convergent patterns of amygdala connectivity in mania and depression: A resting-state study SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Depression; Mania; Functional connectivity; Amygdala ID BIPOLAR DISORDER; FUNCTIONAL CONNECTIVITY; EMOTION; BRAIN; HIPPOCAMPUS; ACTIVATION; MEMORIES; UNIPOLAR; DEFICITS; CORTEX AB Background: wlVlania and depression in bipolar disorder (BP) manifest two extremes of aberrant emotional, physiologic and behavioral arousal states despite similarities in treatment response and neurocognitive deficits. We used resting-state functional magnetic resonance imaging (rsliV1Rl) to explore the common and unique abnormal functional connectivity underlying acute manic or depressed state in BR Methods: 18 Patients with bipolar mania (BM), 10 patients with bipolar depression (BD) and 28 healthy controls underwent resting-state functional magnetic resonance imaging scanning. Left and right amygdala seed-to-voxel based functional connectivity were assessed and compared among the three groups. The relationships between aberrant functional connectivity and the severity of clinical symptoms, number of episodes, illness duration were investigated. Results: Compared to healthy controls, both BM and BD groups showed reduced functional connectivity between bilateral amygdala and inferior frontal gyrus (orbital), striatum, right lingual gyros and posterior cerebellar lobe. Furthermore right amygdala-hippocampal connectivity was decreased in BD but increased in BM. No significant correlations were found between strength of abnormal functional connectivity and clinical characteristic in BD or BM. Limitations: No euthymic subjects were recruited, and the patients in current study were all on medication. Conclusions: The presence of substantial overlap in the pattern of disturbed connectivity between amygdala and frontal, striatal, lingual and cerebellar regions suggests mood state independent clysconnectivity. The contrasting pattern of functional connectivity between right amygclala and hippocarnpus in BD arid BM provides a novel lead to the probable mechanistic differences in these two extremes of mood states. (C) 2014 Elsevier B.V. All rights reserved. C1 [Li, Mingli; Huang, Chaohua; Deng, Wei; Han, Yuanyuan; Wang, Qiang; Li, Zhe; Guo, Wanjun; Li, Yinfei; Jiang, Lijun; Lei, Wei; Li, Tao] Sichuan Univ, West China Hosp, Mental Hlth Ctr, Chengdu 610041, Sichuan, Peoples R China. [Li, Mingli; Huang, Chaohua; Deng, Wei; Han, Yuanyuan; Wang, Qiang; Li, Zhe; Guo, Wanjun; Li, Yinfei; Jiang, Lijun; Lei, Wei; Li, Tao] Sichuan Univ, Psychiat Lab, West China Hosp, Chengdu 610041, Sichuan, Peoples R China. [Li, Mingli; Ma, Xiaohong; Wang, Qiang; Guo, Wanjun; Li, Yinfei; Jiang, Lijun; Lei, Wei; Li, Tao] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Sichuan, Peoples R China. [Hu, Xun] Sichuan Univ, West China Hosp, Huaxi BioBank, Chengdu 610041, Sichuan Provinc, Peoples R China. [Gong, Qiyong] Sichuan Univ, West China Hosp, Huaxi MRI Ctr, Chengdu 610041, Sichuan Provinc, Peoples R China. [Merikangas, Kathleen Ries] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [Palaniyappan, Lena] Univ Nottingham, Div Psychiat & Appl Pyschol, Inst Mental Hlth, Ctr Translat Neuroimaging, Nottingham NG7 2RD, England. RP Palaniyappan, L (reprint author), Univ Nottingham, Div Psychiat & Appl Pyschol, Inst Mental Hlth, Ctr Translat Neuroimaging, Nottingham NG7 2RD, England. EM Lena.Palaniyappan@nottingham.ac.uk; litaohx@scu.edu.cn RI Palaniyappan, Lena/L-8911-2016 OI Palaniyappan, Lena/0000-0003-1640-7182 FU National Nature Science Foundation of China [81261120415, 91332205]; Wellcome Trust [WT096002/z/11]; China Postdoctoral Science Foundation [2013M540712]; Chinese Society of Psychiatry-Servier Youth Scientific Research Fund FX This work was partly funded by National Nature Science Foundation of China (81261120415, 91332205, TL), Wellcome Trust Fellowship WT096002/z/11 to LP, China Postdoctoral Science Foundation (Grant No. 2013M540712, ML) and Chinese Society of Psychiatry-Servier Youth Scientific Research Fund to ML. The granting agencies had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 28 TC 5 Z9 6 U1 3 U2 24 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAR 1 PY 2015 VL 173 BP 53 EP 58 DI 10.1016/j.jad.2014.10.044 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AX0LI UT WOS:000346643500009 PM 25462396 ER PT J AU Yu, B Russanova, VR Gravina, S Hartley, S Mullikin, JC Ignezweski, A Graham, J Segars, JH DeCherney, AH Howard, BH AF Yu, Bo Russanova, Valya R. Gravina, Silvia Hartley, Stephen Mullikin, James C. Ignezweski, Alice Graham, James Segars, James H. DeCherney, Alan H. Howard, Bruce H. TI DNA methylome and transcriptome sequencing in human ovarian granulosa cells links age-related changes in gene expression to gene body methylation and 3 '-end GC density SO ONCOTARGET LA English DT Article DE DNA methylation; transcription end site; fertility; ovarian granulosa cell; transcriptome ID ANTI-MULLERIAN HORMONE; RNA-SEQ EXPERIMENTS; NATURAL MENOPAUSE; HUMAN GENOME; CANCER; TISSUE; MECHANISMS; PATTERNS; LOCI; HYPERMETHYLATION AB Diminished ovarian function occurs early and is a primary cause for age-related decline in female fertility; however, its underlying mechanism remains unclear. This study investigated the roles that genome and epigenome structure play in age-related changes in gene expression and ovarian function, using human ovarian granulosa cells as an experimental system. DNA methylomes were compared between two groups of women with distinct age-related differences in ovarian functions, using both Methylated DNA Capture followed by Next Generation Sequencing (MethylCap-seq) and Reduced Representation Bisulfite Sequencing (RRBS); their transcriptomes were investigated using mRNA-seq. Significant, non-random changes in transcriptome and DNA methylome features are observed in human ovarian granulosa cells as women age and their ovarian functions deteriorate. The strongest correlations between methylation and the age-related changes in gene expression are not confined to the promoter region; rather, high densities of hypomethylated CpG-rich regions spanning the gene body are preferentially associated with gene down-regulation. This association is further enhanced where CpG regions are localized near the 3'-end of the gene. Such features characterize several genes crucial in age-related decline in ovarian function, most notably the AMH (Anti-Mullerian Hormone) gene. The genomewide correlation between the density of hypomethylated intragenic and 3'-end regions and gene expression suggests previously unexplored mechanisms linking epigenome structure to age-related physiology and pathology. C1 [Yu, Bo] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10461 USA. [Russanova, Valya R.; Howard, Bruce H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Gravina, Silvia] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA. [Hartley, Stephen; Mullikin, James C.] NHGRI, Comparat Genom Unit, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Ignezweski, Alice; Graham, James] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD 20850 USA. [Segars, James H.; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Yu, B (reprint author), Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10461 USA. EM boyumich2@gmail.com NR 60 TC 7 Z9 7 U1 6 U2 9 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB 28 PY 2015 VL 6 IS 6 BP 3627 EP 3643 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CF6WB UT WOS:000352696200017 PM 25682867 ER PT J AU Teplyuk, NM Uhlmann, EJ Wong, AHK Karmali, P Basu, M Gabriely, G Jain, A Wang, Y Chiocca, EA Stephens, R Marcusson, E Yi, M Krichevsky, AM AF Teplyuk, Nadiya M. Uhlmann, Erik J. Wong, Andus Hon-Kit Karmali, Priya Basu, Meenakshi Gabriely, Galina Jain, Anant Wang, Yang Chiocca, E. Antonio Stephens, Robert Marcusson, Eric Yi, Ming Krichevsky, Anna M. TI MicroRNA-10b inhibition reduces E2F1-mediated transcription and miR-15/16 activity in glioblastoma SO ONCOTARGET LA English DT Article DE miR-10b; E2F1 transcription; p21; glioblastoma; cell cycle ID CANCER-CELL-PROLIFERATION; HUMAN GLIOMA-CELLS; MIR-B-10 EXPRESSION; GENE-EXPRESSION; BREAST-CANCER; BRAIN-TUMORS; INVASION; PROTEIN; PROMOTES; APOPTOSIS AB MicroRNA-10b (miR-10b) is commonly elevated in glioblastoma (GBM), while not expressed in normal brain tissues. Targeted inhibition of miR-10b has pleiotropic effects on GBM derived cell lines, it reduces GBM growth in animal models, but does not affect normal neurons and astrocytes. This data raises the possibility of developing miR-10b-targeting GBM therapy. However, the mechanisms contributing to miR-10b-mediated glioma cell survival and proliferation are unexplored. We found that inhibition of miR-10b has distinct effects on specific glioma cell lines. In cells expressing high levels of tumor suppressor p21WAF1/Cip1, it represses E2F1-mediated transcription, leading to down-regulation of multiple E2F1 target genes encoding for S-phase specific proteins, epigenetic modulators, and miRNAs (e.g. miR-15/16), and thereby stalling progression through the S-phase of cell cycle. Subsequently, miR-15/16 activities are reduced and many of their direct targets are de-repressed, including ubiquitin ligase FBXW7 that destabilizes Cyclin E. Conversely, GBM cells expressing low p21 level, or after p21 knock-down, exhibit weaker or no E2F1 response to miR-10b inhibition. Comparative analysis of The Cancer Genome Atlas revealed a strong correlation between miR-10b and multiple E2F target genes in GBM and low-grade glioma. Taken together, these findings indicate that miR-10b regulates E2F1-mediated transcription in GBM, in a p21-dependent fashion. C1 [Teplyuk, Nadiya M.; Uhlmann, Erik J.; Wong, Andus Hon-Kit; Basu, Meenakshi; Gabriely, Galina; Jain, Anant; Wang, Yang; Krichevsky, Anna M.] Harvard Univ, Sch Med, Dept Neurol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Karmali, Priya; Marcusson, Eric] Regulus Therapeut Inc, San Diego, CA USA. [Chiocca, E. Antonio] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA 02115 USA. [Stephens, Robert; Yi, Ming] Leidos Biomed Res Inc, Canc Res & Technol Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Krichevsky, AM (reprint author), Harvard Univ, Sch Med, Dept Neurol, Brigham & Womens Hosp, Boston, MA 02115 USA. EM akrichevsky@rics.bwh.harvard.edu FU NIH/NCI [RO1CA138734]; Sontag Foundation Distinguished Scientist Award; National Brain Tumor Society; Brain Science Foundation FX This work was supported by NIH/NCI grant RO1CA138734, Sontag Foundation Distinguished Scientist Award, grants from National Brain Tumor Society (to AMK), and Brain Science Foundation (to AMK, NMT, and EJU). NR 58 TC 11 Z9 11 U1 0 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 FEB 28 PY 2015 VL 6 IS 6 BP 3770 EP 3783 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CF6WB UT WOS:000352696200027 PM 25738367 ER PT J AU Shu, X Purdue, MP Ye, YQ Wood, CG Chen, M Wang, ZM Albanes, D Pu, X Huang, MS Stevens, VL Diver, WR Gapstur, SM Virtamo, J Chow, WH Tannir, NM Dinney, CP Rothman, N Chanock, SJ Wu, XF AF Shu, Xiang Purdue, Mark P. Ye, Yuanqing Wood, Christopher G. Chen, Meng Wang, Zhaoming Albanes, Demetrius Pu, Xia Huang, Maosheng Stevens, Victoria L. Diver, W. Ryan Gapstur, Susan M. Virtamo, Jarmo Chow, Wong-Ho Tannir, Nizar M. Dinney, Colin P. Rothman, Nathaniel Chanock, Stephen J. Wu, Xifeng TI Multilevel-analysis identify a cis-expression quantitative trait locus associated with risk of renal cell carcinoma SO ONCOTARGET LA English DT Article DE RCC; GWAS; GSEA; eQTL ID GENOME-WIDE ASSOCIATION; GENE-EXPRESSION; SUSCEPTIBILITY LOCI; GENOTYPE IMPUTATION; FAMILY-HISTORY; KIDNEY CANCER; COPY-NUMBER; GERMLINE; PATHWAY; DISEASE AB We conducted multilevel analyses to identify potential susceptibility loci for renal cell carcinoma (RCC), which may be overlooked in traditional genome-wide association studies (GWAS). A gene set enrichment analysis was performed utilizing a GWAS dataset comprised of 894 RCC cases and 1,516 controls using GenGen, SNP ratio test, and ALIGATOR. The antigen processing and presentation pathway was consistently significant (P = 0.001, = 0.004, and < 0.001, respectively). Versatile gene-based association study approach was applied to the top-ranked pathway and identified the driven genes. By comparing the expression of the genes in RCC tumor and adjacent normal tissues, we observed significant overexpression of HLA genes in tumor tissues, which was also supported by public databases. We sought to validate genetic variants in antigen processing and presentation pathway in an independent GWAS dataset comprised of 1,311 RCC cases and 3,424 control subjects from the National Cancer Institute; one SNP, rs1063355, was significant in both populations (Pmeta-analysis = 9.15 x 10(square 4), P-heterogeneity = 0.427). Strong correlation indicated that rs1063355 was a cis-expression quantitative trait loci which associated with HLA-DQB1 expression (Spearman's rank r = square 0.59, p = 5.61 x 10(square 6)). The correlation was further validated using a public dataset. Our results highlighted the role of immune-related pathway and genes in the etiology of RCC. C1 [Shu, Xiang; Ye, Yuanqing; Chen, Meng; Pu, Xia; Huang, Maosheng; Chow, Wong-Ho; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Purdue, Mark P.; Albanes, Demetrius; Rothman, Nathaniel; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Wood, Christopher G.; Dinney, Colin P.] Univ Texas MD Anderson Canc Ctr, Urol, Houston, TX 77030 USA. [Wang, Zhaoming] SAIC Frederick Inc, Natl Canc Inst Frederick, Canc Genom Res Lab, Frederick, MD USA. [Stevens, Victoria L.; Diver, W. Ryan; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Tannir, Nizar M.] Univ Texas MD Anderson Canc Ctr, Genitourinary Med Oncol, Houston, TX 77030 USA. RP Wu, XF (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. EM xwu@mdanderson.org RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU National Institutes of Health [R01 CA170298]; University of Texas MD Anderson Cancer Center, Duncan Family Institute for Cancer Prevention FX This work was supported in part by grants from the National Institutes of Health (R01 CA170298); and by the University of Texas MD Anderson Cancer Center, Duncan Family Institute for Cancer Prevention institutional support for the Center for Translational and Public Health Genomics. NR 51 TC 0 Z9 0 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 FEB 28 PY 2015 VL 6 IS 6 BP 4097 EP 4109 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CF6WB UT WOS:000352696200050 PM 25784652 ER PT J AU Lindenberg, L Thomas, A Adler, S Mena, E Kurdziel, K Maltzman, J Wallin, B Hoffman, K Pastan, I Paik, CH Choyke, P Hassan, R AF Lindenberg, Liza Thomas, Anish Adler, Stephen Mena, Esther Kurdziel, Karen Maltzman, Julia Wallin, Bruce Hoffman, Kimberly Pastan, Ira Paik, Chang Hum Choyke, Peter Hassan, Raffit TI Safety and biodistribution of In-111-amatuximab in patients with mesothelin expressing cancers using Single Photon Emission Computed Tomography-Computed Tomography (SPECT-CT) imaging SO ONCOTARGET LA English DT Article DE In-111-Amatuximab; radioimmunoconjugates; mesothelioma; pancreatic cancer; mesothelin ID MONOCLONAL-ANTIBODY MORAB-009; OVARIAN-CANCER; SERUM MESOTHELIN; BREAST-CANCER; BINDING; CA125/MUC16; MARKER; TUMOR AB Amatuximab is a chimeric high-affinity monoclonal IgG1/k antibody targeting mesothelin that is being developed for treatment of mesothelin-expressing cancers. Considering the ongoing clinical development of amatuximab in these cancers, our objective was to characterize the biodistribution, and dosimetry of (111)Indium (In-111) radiolabelled amatuximab in mesothelin-expressing cancers. Between October 2011 and February 2013, six patients including four with malignant mesothelioma and two with pancreatic adenocarcinoma underwent Single Photon Emission Computed Tomography-Computed Tomography (SPECT/CT) imaging following administration of In-111 amatuximab. SPECT/CT images were obtained at 2-4 hours, 24-48 hours and 96-168 hours after radiotracer injection. In all patients, tumor to background ratios (TBR) consistently met or exceeded an uptake of 1.2 (range 1.2-62.0) which is considered the minimum TBR that can be visualized. TBRs were higher in tumors of patients with mesothelioma than pancreatic adenocarcinoma. In-111-amatuximab uptake was noted in both primary tumors and metastatic sites. The radiotracer dose was generally well-tolerated and demonstrated physiologic uptake in the heart, liver, kidneys and spleen. This is the first study to show tumor localization of an anti-mesothelin antibody in humans. Our results show that (111) In-amatuximab was well tolerated with a favorable dosimetry profile. It localizes to mesothelin expressing cancers with a higher uptake in mesothelioma than pancreatic cancer. C1 [Lindenberg, Liza; Kurdziel, Karen; Choyke, Peter] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Thomas, Anish; Hassan, Raffit] NCI, Thorac & GI Oncol Branch, NIH, Bethesda, MD 20892 USA. [Adler, Stephen] NCI, Mol Imaging Program, SAIC Frederick Inc, NCI Frederick, Frederick, MD 21701 USA. [Mena, Esther] Johns Hopkins Univ, Dept Radiol & Radiol Sci, Baltimore, MD USA. [Maltzman, Julia; Wallin, Bruce; Hoffman, Kimberly] Morphotek, Exton, PA USA. [Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Paik, Chang Hum] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NCI, Thorac & GI Oncol Branch, NIH, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov OI Thomas, Anish/0000-0003-3293-3115 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Morphotek, Inc.; National Cancer Institute FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and in part by Morphotek, Inc., under a Cooperative Research and Development Agreement with National Cancer Institute. NR 27 TC 8 Z9 8 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 FEB 28 PY 2015 VL 6 IS 6 BP 4496 EP 4504 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CF6WB UT WOS:000352696200081 PM 25756664 ER PT J AU Kim, RG Smith, OK Wong, WC Ryan, AM Ryan, MC Aladjem, MI AF Kim, RyangGuk Smith, Owen K. Wong, Wing Chung Ryan, Alex M. Ryan, Michael C. Aladjem, Mirit I. TI ColoWeb: a resource for analysis of colocalization of genomic features SO BMC GENOMICS LA English DT Article DE ChIP-seq; Epigenetics; Genomics; Sequencing; Web service ID REPLICATION ORIGINS; DNA; CHROMATIN; WIDE; GENOMEINSPECTOR; METHYLATION; SEQUENCES; ELEMENTS; BINDING; UPDATE AB Background: Next-generation sequencing techniques such as ChIP-seq allow researchers to investigate the genomic position of nuclear components and events. These experiments provide researchers with thousands of regions of interest to probe in order to identify biological relevance. As the cost of sequencing decreases and its robustness increases, more and more researchers turn to genome-wide studies to better understand the genomic elements they are studying. One way to interpret the output of sequencing studies is to investigate how the element of interest localizes in relationship to genome annotations and the binding of other nuclear components. Colocalization of genomic features could indicate cooperation and provide evidence for more detailed investigations. Although there are several existing tools for visualizing and analyzing colocalization, either they are difficult to use for experimental researchers, not well maintained, or without measurements for colocalization strength. Here we describe an online tool, ColoWeb, designed to allow experimentalists to compare their datasets to existing genomic features in order to generate hypotheses about biological interactions easily and quickly. Results: ColoWeb is a web-based service for evaluating the colocation of genomic features. Users submit genomic regions of interest, for example, a set of locations from a ChIP-seq analysis. ColoWeb compares the submitted regions of interest to the location of other genomic features such as transcription factors and chromatin modifiers. To facilitate comparisons among various genomic features, the output consists of both graphical representations and quantitative measures of the degree of colocalization between user's genomic regions and selected features. Frequent colocation may indicate a biological relationship. Conclusion: ColoWeb is a biologist-friendly web service that can quickly provide an assessment of thousands of genomic regions to identify colocated genomic features. ColoWeb is freely available at: http://projects.insilico.us.com/ColoWeb. C1 [Smith, Owen K.; Aladjem, Mirit I.] Natl Canc Inst, DNA Replicat Grp, Mol Pharmacol Lab, Dev Therapeut Branch,NIH, Bethesda, MD 20892 USA. [Kim, RyangGuk; Wong, Wing Chung; Ryan, Alex M.; Ryan, Michael C.] Silico Solut, Falls Church, VA USA. RP Aladjem, MI (reprint author), Natl Canc Inst, DNA Replicat Grp, Mol Pharmacol Lab, Dev Therapeut Branch,NIH, Bethesda, MD 20892 USA. EM aladjemm@mail.nih.gov FU NIH, Center for Cancer Research, National Cancer Institute FX We would like to thank our interns Jack Lynch, Sepehr An-saripour, and Alex Ryan for their work on the initial version of ColoWeb and Drs. Haiqing Fu, Ya Zhang and Koichi Utani for helpful comments. This work was supported by the intramural research program of the NIH, Center for Cancer Research, National Cancer Institute. NR 21 TC 4 Z9 4 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD FEB 28 PY 2015 VL 16 AR 142 DI 10.1186/s12864-015-1345-3 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CD4EK UT WOS:000351035200001 PM 25887597 ER PT J AU Stoddard, J Hsu, D Reynolds, RC Brotman, MA Ernst, M Pine, DS Leibenluft, E Dickstein, DP AF Stoddard, Joel Hsu, Derek Reynolds, Richard C. Brotman, Melissa A. Ernst, Monique Pine, Daniel S. Leibenluft, Ellen Dickstein, Daniel P. TI Aberrant amygdala intrinsic functional connectivity distinguishes youths with bipolar disorder from those with severe mood dysregulation SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Irritability; Functional connectivity; Magnetic resonance imaging; Bipolar disorder; Child ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; RESTING-STATE; RATING-SCALE; EMOTIONAL LABILITY; CHILDREN; MANIA; RELIABILITY; ACTIVATION; DEPRESSION; PHENOTYPES AB It remains unclear the degree to which youths with episodic mania (bipolar disorder; BD) vs. those with chronic, severe irritability (severe mood dysregulation, SMD) should be placed in similar or distinct diagnostic groups. Addressing this clinically meaningful question requires greater understanding of the neural alterations underlying both disorders. We evaluated resting state functional magnetic resonance imaging data of 53 youths (14 BD, 20 healthy volunteers (HV), and 19 SMD, ages 9-18.5 years). Seed regions of interest were the bilateral basolateral, superficial and centromedial amygdala, defined using the Juelich probabilistic atlas. We found a significant between-group difference in functional connectivity between the left basolateral amygdala and the medial aspect of the left frontal pole plus the posterior cingulate/precuneus. This finding was driven by hyperconnectivity among BD vs. HV or SIVID youths. As with earlier data, these findings suggest that the pathophysiology of BD and SMD may differ. Published by Elsevier Ireland Ltd. C1 [Stoddard, Joel; Hsu, Derek; Brotman, Melissa A.; Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Reynolds, Richard C.] NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Ernst, Monique; Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Emot & Dev Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Dickstein, Daniel P.] Brown Univ, Alpert Med Sch, Dept Psychiat & Human Behav, PediMIND Program, Providence, RI 02912 USA. RP Stoddard, J (reprint author), NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM joel.stoddard@nih.gov RI Dickstein, Daniel/L-3210-2016; Brotman, Melissa/H-7409-2013 OI Dickstein, Daniel/0000-0003-1647-5329; FU Intramural Research Program, National Institute of Mental Health (NIMH) FX This research was supported by the Intramural Research Program, National Institute of Mental Health (NIMH). We thank the children and families who participated in this study, and the staff of the Emotion and Development Branch at NIMH. NR 41 TC 9 Z9 10 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD FEB 28 PY 2015 VL 231 IS 2 BP 120 EP 125 DI 10.1016/j.pscychresns.2014.11.006 PG 6 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CA3YN UT WOS:000348841200004 PM 25544024 ER PT J AU Garfinkel, BP Melamed-Book, N Anuka, E Bustin, M Orly, J AF Garfinkel, Benjamin P. Melamed-Book, Naomi Anuka, Eli Bustin, Michael Orly, Joseph TI HP1BP3 is a novel histone H1 related protein with essential roles in viability and growth SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CHROMATIN IN-VIVO; LINKER-HISTONE; TERMINAL DOMAIN; HETEROCHROMATIN PROTEIN-1; PRIMARY DETERMINANT; FUNCTIONAL-ANALYSIS; MOUSE DEVELOPMENT; LIVING CELLS; BINDING; PHOSPHORYLATION AB The dynamic architecture of chromatin is vital for proper cellular function, and is maintained by the concerted action of numerous nuclear proteins, including that of the linker histone H1 variants, the most abundant family of nucleosome-binding proteins. Here we show that the nuclear protein HP1BP3 is widely expressed in most vertebrate tissues and is evolutionarily and structurally related to the H1 family. HP1BP3 contains three globular domains and a highly positively charged C-terminal domain, resembling similar domains in H1. Fluorescence recovery after photobleaching (FRAP) studies indicate that like H1, binding of HP1BP3 to chromatin depends on both its C and N terminal regions and is affected by the cell cycle and post translational modifications. HP1BP3 contains functional motifs not found in H1 histones, including an acidic stretch and a consensus HP1-binding motif. Transcriptional profiling of HeLa cells lacking HP1BP3 showed altered expression of 383 genes, suggesting a role for HP1BP3 in modulation of gene expression. Significantly, Hp1bp(3-/-) mice present a dramatic phenotype with 60% of pups dying within 24 h of birth and the surviving animals exhibiting a lifelong 20% growth retardation. We suggest that HP1BP3 is a ubiquitous histone H1 like nuclear protein with distinct and non-redundant functions necessary for survival and growth. C1 [Garfinkel, Benjamin P.; Anuka, Eli; Orly, Joseph] Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel. [Melamed-Book, Naomi] Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Bioimaging Unit, IL-91904 Jerusalem, Israel. [Bustin, Michael] NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Garfinkel, BP (reprint author), Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel. EM benny.garfinkel@mail.huji.ac.il; orly@vms.huji.ac.il RI Bustin, Michael/G-6155-2015; OI Garfinkel, Benjamin/0000-0002-2790-1349 FU United States-Israel Binational Science Foundation [2009326]; Israel Science Foundation [677/12] FX The United States-Israel Binational Science Foundation [2009326 to J.O. and M.B.] and The Israel Science Foundation [677/12 to J.O.]. Funding for open access charge: The United States-Israel Binational Science Foundation [2009326 to J.O. and M.B.]. NR 85 TC 6 Z9 6 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 27 PY 2015 VL 43 IS 4 BP 2074 EP 2090 DI 10.1093/nar/gkv089 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CE5LK UT WOS:000351876500014 PM 25662603 ER PT J AU Chen, MC Murat, P Abecassis, K Ferre-D'Amare, AR Balasubramanian, S AF Chen, Michael C. Murat, Pierre Abecassis, Keren Ferre-D'Amare, Adrian R. Balasubramanian, Shankar TI Insights into the mechanism of a G-quadruplex-unwinding DEAH-box helicase SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SMALL-MOLECULE; TETRAMOLECULAR QUADRUPLEX; SUBSTRATE-SPECIFICITY; INTERACTING LIGANDS; RESOLVING ACTIVITY; DNA STRUCTURES; RNA HELICASES; MAJOR SOURCE; INHIBITION; FAMILY AB The unwinding of nucleic acid secondary structures within cells is crucial to maintain genomic integrity and prevent abortive transcription and translation initiation. DHX36, also known as RHAU or G4R1, is a DEAH-box ATP-dependent helicase highly specific for DNA and RNA G-quadruplexes (G4s). A fundamental mechanistic understanding of the interaction between helicases and their G4 substrates is important to elucidate G4 biology and pave the way toward G4-targeted therapies. Here we analyze how the thermodynamic stability of G4 substrates affects binding and unwinding by DHX36. We modulated the stability of the G4 substrates by varying the sequence and the number of G-tetrads and by using small, G4stabilizing molecules. We found an inverse correlation between the thermodynamic stability of the G4 substrates and rates of unwinding by DHX36. In stark contrast, the ATPase activity of the helicase was largely independent of substrate stability pointing toward a decoupling mechanism akin to what has been observed for many double-stranded DEAD-box RNA helicases. Our study provides the first evidence that DHX36 uses a local, non-processive mechanism to unwind G4 substrates, reminiscent of that of eukaryotic initiation factor 4A (eIF4A) on double-stranded substrates. C1 [Chen, Michael C.; Murat, Pierre; Abecassis, Keren; Balasubramanian, Shankar] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Chen, Michael C.; Ferre-D'Amare, Adrian R.] NHLBI, Bethesda, MD 20892 USA. [Balasubramanian, Shankar] Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Cambridge, England. RP Balasubramanian, S (reprint author), Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England. EM adrian.ferre@nih.gov; sb10031@cam.ac.uk FU Cancer Research UK and ERC (Balasubramanian group); Cambridge Trust studentship; Intramural Program of the National Heart, Lung and Blood Institute, NIH; ALS on the Berkeley Center for Structural Biology beamlines, US National Institutes of Health (NIH); NIH Oxford Cambridge Scholars Program; University of Cambridge FX Cancer Research UK and ERC (Balasubramanian group); Cambridge Trust studentship (to M.C.C.); Intramural Program of the National Heart, Lung and Blood Institute, NIH; ALS on the Berkeley Center for Structural Biology beamlines, US National Institutes of Health (NIH); NIH Oxford Cambridge Scholars Program [to M.C.C.]. Funding for open access charge: University of Cambridge. NR 51 TC 16 Z9 16 U1 3 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 27 PY 2015 VL 43 IS 4 BP 2223 EP 2231 DI 10.1093/nar/gkv051 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CE5LK UT WOS:000351876500026 PM 25653156 ER PT J AU Caglayan, M Horton, JK Prasad, R Wilson, SH AF Caglayan, Melike Horton, Julie K. Prasad, Rajendra Wilson, Samuel H. TI Complementation of aprataxin deficiency by base excision repair enzymes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA-POLYMERASE-BETA; STRAND-BREAK REPAIR; ATAXIA-OCULOMOTOR APRAXIA; LYASE ACTIVITY; DAMAGE; GENE; SITE; APE1; REQUIREMENT; MECHANISM AB Abortive ligation during base excision repair (BER) leads to blocked repair intermediates containing a 5' -adenylated-deoxyribose phosphate (5'-AMP-dRP) group. Aprataxin (APTX) is able to remove the AMP group allowing repair to proceed. Earlier results had indicated that purified DNA polymerase beta (pol beta) removes the entire 5'-AMP-dRP group through its lyase activity and flap endonuclease 1 (FEN1) excises the 5'-AMP-dRP group along with one or two nucleotides. Here, using cell extracts from APTX-deficient cell lines, human Ataxia with Oculomotor Apraxia Type 1 (AOA1) and DT40 chicken B cell, we found that pol beta and FEN1 enzymatic activities were prominent and strong enough to complement APTX deficiency. In addition, pol beta, APTX and FEN1 coordinate with each other in processing of the 5'-adenylated dRP-containing BER intermediate. Finally, other DNA polymerases and a repair factor with dRP lyase activity (pol lambda, pol iota, pol theta and Ku70) were found to remove the 5'-adenylated-dRP group from the BER intermediate. However, the activities of these enzymes were weak compared with those of pol beta and FEN1. C1 [Caglayan, Melike; Horton, Julie K.; Prasad, Rajendra; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES050158, ES050159] FX Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES050158, ES050159 to S.H.W.]. Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES050158, ES050159 to S.H.W]. NR 28 TC 7 Z9 7 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 27 PY 2015 VL 43 IS 4 BP 2271 EP 2281 DI 10.1093/nar/gkv079 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CE5LK UT WOS:000351876500030 PM 25662216 ER PT J AU Zhang, F Saini, AK Shin, BS Nanda, J Hinnebusch, AG AF Zhang, Fan Saini, Adesh K. Shin, Byung-Sik Nanda, Jagpreet Hinnebusch, Alan G. TI Conformational changes in the P site and mRNA entry channel evoked by AUG recognition in yeast translation preinitiation complexes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID 40S RIBOSOMAL-SUBUNIT; START CODON SELECTION; INITIATION-FACTORS EIF1; IN-VIVO; SCANNING MECHANISM; CRYSTAL-STRUCTURE; BINDING; RECRUITMENT; RESIDUES; RELEASE AB The translation preinitiation complex (PIC) is thought to assume an open conformation when scanning the mRNA leader, with AUG recognition evoking a closed conformation and more stable P site interaction of Met-tRNAi; however, physical evidence is lacking that AUG recognition constrains interaction of mRNA with the 40S binding cleft. We compared patterns of hydroxyl radical cleavage of rRNA by Fe(II)-BABE tethered to unique sites in eIF1A in yeast PICs reconstituted with mRNA harboring an AUG or near-cognate (AUC) start codon. rRNA residues in the P site display reduced cleavage in AUG versus AUC PICs; and enhanced cleavage in the AUC complexes was diminished by mutations of scanning enhancer elements of eIF1A that increase near-cognate recognition in vivo. This suggests that accessibility of these rRNA residues is reduced by accommodation of Met-tRNAi in the P site (PIN state) and by their interactions with the anticodon stem of Met-tRNAi. Our cleavage data also provide evidence that AUG recognition evokes dissociation of eIF1 from its 40S binding site, ejection of the eIF1A-CTT from the P-site and rearrangement to a closed conformation of the entry channel with reduced mobility of mRNA. C1 [Zhang, Fan; Saini, Adesh K.; Shin, Byung-Sik; Hinnebusch, Alan G.] NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Saini, Adesh K.] Shoolini Univ Biotechnol & Management Sci, Dept Biotechnol, Solan 173212, Himachal Prades, India. [Nanda, Jagpreet] NICHD, Lab Mech & Regulat Prot Synth, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov RI university, shoolini/K-9336-2015 FU Intramural Research Program of the NIH [GM62128]; Department of Science and Technology, Government of India [Int/NZ/P-2/13]; Intramural Research Program of the National Institutes of Health FX Intramural Research Program of the NIH [GM62128 to Jon R. Lorsch and J.N.]; Department of Science and Technology, Government of India [Int/NZ/P-2/13 to A.K.S.]. Funding for open access charge: Intramural Research Program of the National Institutes of Health. NR 36 TC 8 Z9 8 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 27 PY 2015 VL 43 IS 4 BP 2293 EP 2312 DI 10.1093/nar/gkv028 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CE5LK UT WOS:000351876500032 PM 25670678 ER PT J AU Bates, PA Depaquit, J Galati, EAB Kamhawi, S Maroli, M McDowell, MA Picado, A Ready, PD Salomon, OD Shaw, JJ Traub-Cseko, YM Warburg, A AF Bates, Paul A. Depaquit, Jerome Galati, Eunice A. B. Kamhawi, Shaden Maroli, Michele McDowell, Mary Ann Picado, Albert Ready, Paul D. Salomon, O. Daniel Shaw, Jeffrey J. Traub-Csekoe, Yara M. Warburg, Alon TI Recent advances in phlebotomine sand fly research related to leishmaniasis control SO PARASITES & VECTORS LA English DT Review DE Phlebotomine sand flies; Human leishmaniasis; Vector control; Leishmaniasis control; ISOPS ID LUTZOMYIA-LONGIPALPIS; VISCERAL LEISHMANIASIS; DIPTERA-PSYCHODIDAE; FLIES; INFECTION; TRANSMISSION; VECTORS; CLASSIFICATION; IDENTIFICATION; PREVENTION AB Phlebotomine sand flies are the subject of much research because of the role of their females as the only proven natural vectors of Leishmania species, the parasitic protozoans that are the causative agents of the neglected tropical disease leishmaniasis. Activity in this field was highlighted by the eighth International Symposium on Phlebotomine Sand flies (ISOPS) held in September 2014, which prompted this review focusing on vector control. Topics reviewed include: Taxonomy and phylogenetics, Vector competence, Genetics, genomics and transcriptomics, Eco-epidemiology, and Vector control. Research on sand flies as leishmaniasis vectors has revealed a diverse array of zoonotic and anthroponotic transmission cycles, mostly in subtropical and tropical regions of Africa, Asia and Latin America, but also in Mediterranean Europe. The challenge is to progress beyond descriptive eco-epidemiology, in order to separate vectors of biomedical importance from the sand fly species that are competent vectors but lack the vectorial capacity to cause much human disease. Transmission modelling is required to identify the vectors that are a public health priority, the ones that must be controlled as part of the integrated control of leishmaniasis. Effective modelling of transmission will require the use of entomological indices more precise than those usually reported in the leishmaniasis literature. C1 [Bates, Paul A.] Univ Lancaster, Fac Hlth & Med, Div Biomed & Life Sci, Lancaster, England. [Depaquit, Jerome] Univ Reims, USC Transmiss Vectorielle & Epidemiosurveillance, ANSES, F-51096 Reims, France. [Galati, Eunice A. B.] Univ Sao Paulo, Fac Saude Publ, Dept Epidemiol, BR-01246904 Sao Paulo, Brazil. [Kamhawi, Shaden] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Maroli, Michele] Ist Super Sanita, I-00161 Rome, Italy. [McDowell, Mary Ann] Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Picado, Albert] Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, E-08036 Barcelona, Spain. [Ready, Paul D.] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Dis Control, London WC1E 7HT, England. [Salomon, O. Daniel] Consejo Nacl Invest Cient & Tecn, Natl Inst Trop Med MOH, Puerto Iguazu, Argentina. [Shaw, Jeffrey J.] Univ Sao Paulo, Inst Biomed Sci, Sao Paulo, Brazil. [Traub-Csekoe, Yara M.] Inst Oswaldo Cruz, Lab Biol Mol Parasitas & Vetores, Rio De Janeiro, RJ, Brazil. [Warburg, Alon] Hebrew Univ Jerusalem, Inst Med Res Israel Canada, Kuvin Ctr Study Infect & Trop Dis, IL-91120 Jerusalem, Israel. RP Ready, PD (reprint author), London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Dis Control, Keppel St, London WC1E 7HT, England. EM Paul.Ready@lshtm.ac.uk RI Traub-Cseko, Yara/F-2723-2015; GALATI, EUNICE/D-2720-2016; OI Bates, Paul/0000-0001-6861-5421; Picado, Albert/0000-0001-7344-628X FU WHO; PAHO; CONICET (Argentina); Bayer; IDEXX Laboratories; Arcuri; Chemotechnica; Mundo Sano; MSD Health FX ISOPS VIII was organized by Instituto Nacional de Medicina Tropical and Ministerio de Salud (Argentina), co-organized by Red de Investigacion de las Leishmaniasis en Argentina, supported by WHO, PAHO and CONICET (Argentina), and sponsored by Bayer, IDEXX Laboratories, Arcuri, Chemotechnica, Mundo Sano, and MSD Health. NR 50 TC 15 Z9 15 U1 6 U2 21 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 FEB 27 PY 2015 VL 8 AR 131 DI 10.1186/s13071-015-0712-x PG 8 WC Parasitology SC Parasitology GA CD4GI UT WOS:000351040200001 PM 25885217 ER PT J AU Wang, WM Zhao, ZL Ma, SR Yu, GT Liu, B Zhang, L Zhang, WF Kulkarni, AB Sun, ZJ Zhao, YF AF Wang, Wei-Ming Zhao, Zhi-Li Ma, Si-Rui Yu, Guang-Tao Liu, Bing Zhang, Lu Zhang, Wen-Feng Kulkarni, Ashok B. Sun, Zhi-Jun Zhao, Yi-Fang TI Epidermal Growth Factor Receptor Inhibition Reduces Angiogenesis via Hypoxia-Inducible Factor-1 alpha and Notch1 in Head Neck Squamous Cell Carcinoma SO PLOS ONE LA English DT Article ID GAMMA-SECRETASE; MOUSE MODEL; CANCER; PATHWAY; CHEMOTHERAPY; ACTIVATION; CETUXIMAB; RESISTANCE; SURVIVAL; VEGF AB Angiogenesis, a marker of cancer development, affects response to radiotherapy sensibility. This preclinical study aims to understand the receptor tyrosine kinase-mediated angiogenesis in head neck squamous cell carcinoma (HNSCC). The receptor tyrosine kinase activity in a transgenic mouse model of HNSCC was assessed. The anti-tumorigenetic and anti-angiogenetic effects of cetuximab-induced epidermal growth factor receptor (EGFR) inhibition were investigated in xenograft and transgenic mouse models of HNSCC. The signaling transduction of Notch1 and hypoxia-inducible factor-1 alpha (HIF-1 alpha) was also analyzed. EGFR was overexpressed and activated in the Tgfbr1/ Pten deletion (2cKO) mouse model of HNSCC. Cetuximab significantly delayed tumor onset by reducing tumor angiogenesis. This drug exerted similar effects on heterotopic xenograft tumors. In the human HNSCC tissue array, increased EGFR expression correlated with increased HIF-1 alpha and micro vessel density. Cetuximab inhibited tumor-induced angiogenesis in vitro and in vivo by significantly downregulating HIF-1 alpha and Notch1. EGFR is involved in the tumor angiogenesis of HNSCC via the HIF-1 alpha and Notch1 pathways. Therefore, targeting EGFR by suppressing hypoxiaand Notch-induced angiogenesis may benefit HNSCC therapy. C1 [Wang, Wei-Ming; Zhao, Zhi-Li; Ma, Si-Rui; Yu, Guang-Tao; Zhang, Lu; Sun, Zhi-Jun; Zhao, Yi-Fang] Wuhan Univ, Minist Educ, State Key Lab Breeding Base Basic Sci Stomatol, Wuhan 430072, Peoples R China. [Wang, Wei-Ming; Zhao, Zhi-Li; Ma, Si-Rui; Yu, Guang-Tao; Zhang, Lu; Sun, Zhi-Jun; Zhao, Yi-Fang] Wuhan Univ, Minist Educ, Key Lab Oral Biomed, Wuhan 430072, Peoples R China. [Wang, Wei-Ming; Zhao, Zhi-Li; Ma, Si-Rui; Liu, Bing; Zhang, Wen-Feng; Sun, Zhi-Jun; Zhao, Yi-Fang] Wuhan Univ, Sch & Hosp Stomatol, Dept Oral & Maxillofacial Head & Neck Oncol, Wuhan 430072, Peoples R China. [Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Sun, ZJ (reprint author), Wuhan Univ, Minist Educ, State Key Lab Breeding Base Basic Sci Stomatol, Wuhan 430072, Peoples R China. EM zhijundejia@163.com; yifang@whu.edu.cn FU National Natural Science Foundation of China [81072203, 81272963, 81371106, 81272946, 81170977, 81472528]; program for new century excellent talents in university, ministry of education of China [NCET-13-0439] FX This work was funded by National Natural Science Foundation of China (81072203, 81272963) to Z.-J. Sun, (81371106) to L. Zhang, (81272946) to W.-F. Zhang, and (81170977) to Y.-F. Zhao. Z.-J. Sun is supported by program for new century excellent talents in university (NCET-13-0439), ministry of education of China. Support also came from National Natural Science Foundation of China (81472528) to Z.-J. Sun. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 6 Z9 9 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 27 PY 2015 VL 10 IS 2 AR e0119723 DI 10.1371/journal.pone.0119723 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC3LS UT WOS:000350251200072 PM 25723392 ER PT J AU Danthi, NS Wu, CO DiMichele, DM Hoots, WK Lauer, MS AF Danthi, Narasimhan S. Wu, Colin O. DiMichele, Donna M. Hoots, W. Keith Lauer, Michael S. TI Citation Impact of NHLBI R01 Grants Funded Through the American Recovery and Reinvestment Act as Compared to R01 Grants Funded Through a Standard Payline SO CIRCULATION RESEARCH LA English DT Article DE bibliometrics; economics ID BIOMEDICAL-RESEARCH; PERCENTILE RANKING AB Rationale: The American Recovery and Reinvestment Act (ARRA) allowed National Heart, Lung, and Blood Institute to fund R01 grants that fared less well on peer review than those funded by meeting a payline threshold. It is not clear whether the sudden availability of additional funding enabled research of similar or lesser citation impact than already funded work. Objective: To compare the citation impact of ARRA-funded de novo National Heart, Lung, and Blood Institute R01 grants with concurrent de novo National Heart, Lung, and Blood Institute R01 grants funded by standard payline mechanisms. Methods and Results: We identified de novo (type 1) R01 grants funded by National Heart, Lung, and Blood Institute in fiscal year 2009: these included 458 funded by meeting Institute's published payline and 165 funded only because of ARRA funding. Compared with payline grants, ARRA grants received fewer total funds (median values, $1.03 versus $1.87 million; P<0.001) for a shorter duration (median values including no-cost extensions, 3.0 versus 4.9 years; P<0.001). Through May 2014, the payline R01 grants generated 3895 publications, whereas the ARRA R01 grants generated 996. Using the InCites database from Thomson-Reuters, we calculated a normalized citation impact for each grant by weighting each article for the number of citations it received normalizing for subject, article type, and year of publication. The ARRA R01 grants had a similar normalized citation impact per $1 million spent as the payline grants (median values [interquartile range], 2.15 [0.73-4.68] versus 2.03 [0.75-4.10]; P=0.61). The similar impact of the ARRA grants persisted even after accounting for potential confounders. Conclusions: Despite shorter durations and lower budgets, ARRA R01 grants had comparable citation outcomes per $million spent to that of contemporaneously funded payline R01 grants. C1 [Danthi, Narasimhan S.; Wu, Colin O.; Lauer, Michael S.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [DiMichele, Donna M.; Hoots, W. Keith] NHLBI, Div Blood Dis & Disorders, NIH, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 11 TC 3 Z9 3 U1 0 U2 2 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 FEB 27 PY 2015 VL 116 IS 5 BP 784 EP 788 DI 10.1161/CIRCRESAHA.116.305894 PG 5 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA CC5JR UT WOS:000350395400008 PM 25722441 ER PT J AU Patel, KM Strong, A Tohyama, J Jin, XT Morales, CR Billheimer, J Millar, J Kruth, H Rader, DJ AF Patel, Kevin M. Strong, Alanna Tohyama, Junichiro Jin, Xueting Morales, Carlos R. Billheimer, Jeffery Millar, John Kruth, Howard Rader, Daniel J. TI Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis SO CIRCULATION RESEARCH LA English DT Article DE atherosclerosis; foam cell; low-density lipoprotein cholesterol; macrophage; receptor-mediated endocytosis ID CORONARY-ARTERY-DISEASE; FAMILIAL HYPERCHOLESTEROLEMIA; HYPERLIPIDEMIC MICE; MOUSE MODELS; CHOLESTEROL; LOCI; ASSOCIATION; PROSAPOSIN; COMPLEXITY; VARIANTS AB Rationale: Noncoding gene variants at the SORT1 locus are strongly associated with low-density lipoprotein cholesterol (LDL-C) levels, as well as with coronary artery disease. SORT1 encodes a protein called sortilin, and hepatic sortilin modulates LDL metabolism by targeting apolipoprotein B-containing lipoproteins to the lysosome. Sortilin is also expressed in macrophages, but its role in macrophage uptake of LDL and in atherosclerosis independent of plasma LDL-C levels is unknown. Objective: To determine the effect of macrophage sortilin expression on LDL uptake, foam cell formation, and atherosclerosis. Methods and Results: We crossed Sort1(-/-) mice onto a humanized Apobec1(-/-); hAPOB transgenic background and determined that Sort1 deficiency on this background had no effect on plasma LDL-C levels but dramatically reduced atherosclerosis in the aorta and aortic root. To test whether this effect was a result of macrophage sortilin deficiency, we transplanted Sort1(-/-);LDLR-/- or Sort1(+/+);LDLR-/- bone marrow into Ldlr(-/-) mice and observed a similar reduction in atherosclerosis in mice lacking hematopoetic sortilin without an effect on plasma LDL-C levels. In an effort to determine the mechanism by which hematopoetic sortilin deficiency reduced atherosclerosis, we found no effect of sortilin deficiency on macrophage recruitment or lipopolysaccharide-induced cytokine release in vivo. In contrast, sortilin-deficient macrophages had significantly reduced uptake of native LDL ex vivo and reduced foam cell formation in vivo, whereas sortilin overexpression in macrophages resulted in increased LDL uptake and foam cell formation. Conclusions: Macrophage sortilin deficiency protects against atherosclerosis by reducing macrophage uptake of LDL. Sortilin-mediated uptake of native LDL into macrophages may be an important mechanism of foam cell formation and contributor to atherosclerosis development. C1 [Patel, Kevin M.; Strong, Alanna; Tohyama, Junichiro; Billheimer, Jeffery; Millar, John; Rader, Daniel J.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Jin, Xueting; Kruth, Howard] NHLBI, Sect Expt Atherosclerosis, NIH, Bethesda, MD 20892 USA. [Morales, Carlos R.] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada. RP Rader, DJ (reprint author), Univ Penn, Perelman Sch Med, Smilow Ctr Translat Res 11 125, 3400 Civic Ctr Blvd, Philadelphia, PA 19104 USA. EM rader@mail.med.upenn.edu FU National Heart, Lung, and Blood Institute [R01HL109489]; National Institute of General Medical Sciences [T32GM008076-30] FX This work was supported by R01HL109489 from the National Heart, Lung, and Blood Institute (D.J. Rader) and T32GM008076-30 from the National Institute of General Medical Sciences (K.M. Patel). NR 21 TC 18 Z9 20 U1 1 U2 16 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 FEB 27 PY 2015 VL 116 IS 5 BP 789 EP 796 DI 10.1161/CIRCRESAHA.116.305811 PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA CC5JR UT WOS:000350395400009 PM 25593281 ER PT J AU Drechsler, M de jong, R Rossaint, J Viola, JR Leoni, G Wang, JM Grommes, J Hinkel, R Kupatt, C Weber, C Doring, Y Zarbock, A Soehnlein, O AF Drechsler, Maik de Jong, Renske Rossaint, Jan Viola, Joana R. Leoni, Giovanna Wang, Ji Ming Grommes, Jochen Hinkel, Rabea Kupatt, Christian Weber, Christian Doering, Yvonne Zarbock, Alexander Soehnlein, Oliver TI Annexin A1 Counteracts Chemokine-Induced Arterial Myeloid Cell Recruitment SO CIRCULATION RESEARCH LA English DT Article DE annexin A1; atherosclerosis; chemokine; leukocytes ID PROTEIN-COUPLED RECEPTOR; SMOOTH-MUSCLE-CELLS; MYOCARDIAL-INFARCTION; CLASSICAL MONOCYTES; APOE(-/-) MICE; IN-VIVO; ATHEROSCLEROSIS; INFLAMMATION; ADHESION; RESOLUTION AB Rationale: Chemokine-controlled arterial leukocyte recruitment is a crucial process in atherosclerosis. Formyl peptide receptor 2 (FPR2) is a chemoattractant receptor that recognizes proinflammatory and proresolving ligands. The contribution of FPR2 and its proresolving ligand annexin A1 to atherosclerotic lesion formation is largely undefined. Objective: Because of the ambivalence of FPR2 ligands, we here investigate the role of FPR2 and its resolving ligand annexin A1 in atherogenesis. Methods and Results: Deletion of FPR2 or its ligand annexin A1 enhances atherosclerotic lesion formation, arterial myeloid cell adhesion, and recruitment. Mechanistically, we identify annexin A1 as an endogenous inhibitor of integrin activation evoked by the chemokines CCL5, CCL2, and CXCL1. Specifically, the annexin A1 fragment Ac2-26 counteracts conformational activation and clustering of integrins on myeloid cells evoked by CCL5, CCL2, and CXCL1 through inhibiting activation of the small GTPase Rap1. In vivo administration of Ac2-26 largely diminishes arterial recruitment of myeloid cells in a FPR2-dependent fashion. This effect is also observed in the presence of selective antagonists to CCR5, CCR2, or CXCR2, whereas Ac2-26 was without effect when all 3 chemokine receptors were antagonized simultaneously. Finally, repeated treatment with Ac2-26 reduces atherosclerotic lesion sizes and lesional macrophage accumulation. Conclusions: Instructing the annexin A1-FPR2 axis harbors a novel approach to target arterial leukocyte recruitment. With the ability of Ac2-26 to counteract integrin activation exerted by various chemokines, delivery of Ac2-26 may be superior in inhibition of arterial leukocyte recruitment when compared with blocking individual chemokine receptors. C1 [Drechsler, Maik; de Jong, Renske; Viola, Joana R.; Leoni, Giovanna; Grommes, Jochen; Weber, Christian; Doering, Yvonne; Soehnlein, Oliver] Ludwig Maximilians Univ Munchen, Inst Cardiovasc Prevent IPEK, D-80336 Munich, Germany. [Drechsler, Maik; Soehnlein, Oliver] Univ Amsterdam, Acad Med Ctr, Dept Pathol, NL-1105 AZ Amsterdam, Netherlands. [Rossaint, Jan; Zarbock, Alexander] Univ Munster, Dept Anaesthesiol, D-48149 Munster, Germany. [Rossaint, Jan; Zarbock, Alexander] Max Planck Inst, Munster, Germany. [Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Frederick, MD 21701 USA. [Grommes, Jochen] Univ Hosp RWTH Aachen, European Vasc Ctr Aachen Maastricht, Aachen, Germany. [Hinkel, Rabea; Kupatt, Christian] Ludwig Maximilians Univ Munchen, Klinikum Grosshadern, Med Klin & Poliklin 1, D-80336 Munich, Germany. [Hinkel, Rabea; Kupatt, Christian; Weber, Christian; Soehnlein, Oliver] Partner Site Munich Heart Alliance, DZHK, Munich, Germany. RP Soehnlein, O (reprint author), Ludwig Maximilians Univ Munchen, IPEK, Pettenkoferstr 9, D-80336 Munich, Germany. EM oliver.soehnlein@gmail.com RI Drechsler, Maik/C-3829-2008; Hinkel, Rabea/I-9165-2014; OI Hinkel, Rabea/0000-0002-2936-0400; Weber, Christian/0000-0003-4610-8714 FU DFG (Deutsche Forschungsgemeinschaft) [SO876/3-1, SO876/6-1, FOR809, SFB914 TP B08, SFB1123 TP A06, ZA428/6-1, SFB1009 TP A05]; Else Kroner Fresenius Stiftung; NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek; VIDI) [91712303]; LMUexcellence; FoFoLe program of the Ludwig-Maximilians-Universitat Munchen FX The study was supported by the DFG (Deutsche Forschungsgemeinschaft; SO876/3-1, SO876/6-1, FOR809, SFB914 TP B08, SFB1123 TP A06, ZA428/6-1, SFB1009 TP A05), the Else Kroner Fresenius Stiftung, the NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek; VIDI project 91712303), the LMUexcellence and the FoFoLe program of the Ludwig-Maximilians-Universitat Munchen. NR 43 TC 27 Z9 28 U1 0 U2 10 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 FEB 27 PY 2015 VL 116 IS 5 BP 827 EP 835 DI 10.1161/CIRCRESAHA.116.305825 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA CC5JR UT WOS:000350395400013 PM 25520364 ER PT J AU Vallabhaneni, H Zhou, F Maul, RW Sarkar, J Yin, JH Lei, M Harrington, L Gearhart, PJ Liu, Y AF Vallabhaneni, Haritha Zhou, Fang Maul, Robert W. Sarkar, Jaya Yin, Jinhu Lei, Ming Harrington, Lea Gearhart, Patricia J. Liu, Yie TI Defective Repair of Uracil Causes Telomere Defects in Mouse Hematopoietic Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SISTER-CHROMATID EXCHANGE; SINGLE-STRANDED-DNA; ABERRANT HOMOLOGOUS RECOMBINATION; BASE EXCISION-REPAIR; TETRAHYMENA TELOMERASE; REVERSE-TRANSCRIPTASE; LENGTH REGULATOR; FRAGILE SITES; POT1 PROTEINS; STEM-CELLS AB Calcium transients in the cell nucleus evoked by synaptic activity in hippocampal neurons function as a signaling end point in synapse-to-nucleus communication. As an important regulator of neuronal gene expression, nuclear calcium is involved in the conversion of synaptic stimuli into functional and structural changes of neurons. Here we identify two synaptic organizers, Lrrtm1 and Lrrtm2, as targets of nuclear calcium signaling. Expression of both Lrrtm1 and Lrrtm2 increased in a synaptic NMDA receptor- and nuclear calcium-dependent manner in hippocampal neurons within 2-4 h after the induction of action potential bursting. Induction of Lrrtm1 and Lrrtm2 occurred independently of the need for new protein synthesis and required calcium/calmodulin-dependent protein kinases and the nuclear calcium signaling target CREB-binding protein. Analysis of reporter gene constructs revealed a functional cAMP response element in the proximal promoter of Lrrtm2, indicating that at least Lrrtm2 is regulated by the classical nuclear Ca2+ /calmodulin-dependent protein kinase IV-CREB/CREB-binding protein pathway. These results suggest that one mechanism by which nuclear calcium signaling controls neuronal network function is by regulating the expression of Lrrtm1 and Lrrtm2. C1 [Vallabhaneni, Haritha; Zhou, Fang; Sarkar, Jaya; Yin, Jinhu; Liu, Yie] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Maul, Robert W.; Gearhart, Patricia J.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Lei, Ming] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Natl Ctr Prot Sci Shanghai,State Key Lab Mol Biol, Shanghai 200031, Peoples R China. [Harrington, Lea] Univ Montreal, Inst Res Immunol & Canc, Dept Med, Montreal, PQ H3C 3J7, Canada. RP Gearhart, PJ (reprint author), NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. EM gearhartp@mail.nih.gov; liuyie@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, NIA FX The work was supported entirely by the Intramural Research Program of the National Institutes of Health, NIA. NR 68 TC 4 Z9 4 U1 1 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 FEB 27 PY 2015 VL 290 IS 9 BP 5502 EP 5511 DI 10.1074/jbc.M114.607101 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CC0RS UT WOS:000350044200022 PM 25572391 ER PT J AU Drew, BG Hamidi, H Zhou, ZQ Villanueva, CJ Krum, SA Calkin, AC Parks, BW Ribas, V Kalajian, NY Phun, J Daraei, P Christofk, HR Hewitt, SC Korach, KS Tontonoz, P Lusis, AJ Slamon, DJ Hurvitz, SA Hevener, AL AF Drew, Brian G. Hamidi, Habib Zhou, Zhenqi Villanueva, Claudio J. Krum, Susan A. Calkin, Anna C. Parks, Brian W. Ribas, Vicent Kalajian, Nareg Y. Phun, Jennifer Daraei, Pedram Christofk, Heather R. Hewitt, Sylvia C. Korach, Kenneth S. Tontonoz, Peter Lusis, Aldons J. Slamon, Dennis J. Hurvitz, Sara A. Hevener, Andrea L. TI Estrogen Receptor (ER)alpha-regulated Lipocalin 2 Expression in Adipose Tissue Links Obesity with Breast Cancer Progression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INSULIN-RESISTANCE; ALPHA GENE; METABOLIC SYNDROME; LUNG METASTASIS; INFLAMMATION; CELLS; MICE; FAT; ADIPOCYTES; BINDING AB Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of estrogen receptor (ER)alpha promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissue-specific sites of ER alpha action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERa in adipose tissue we generated fat-specific ERa knock-out (FERKO) 'mice. Herein we show that ERa deletion increased adipocyte size, fat pad weight, and tissue expression and circulating levels of the secreted glycoprotein, lipocalin 2 (Lcn2), an adipokine previously associated with BrCA development. Chromatin immunoprecipitation and luciferase reporter studies showed that ER alpha binds the Lcn2 promoter to repress its expression. Because adipocytes constitute an important cell type of the breast microenvironment, we examined the impact of adipocyte ERa deletion on cancer cell behavior. Conditioned medium from ER alpha-null adipocytes and medium containing pure Lcn2 increased proliferation and migration of a subset of BrCA cells in culture. The proliferative and promigratory effects of ER alpha-deficient adipocyte-conditioned medium on BrCA cells was reversed by Lcn2 deletion. BrCA cell responsiveness to exogenous Lcn2 was heightened in cell types where endogenous Lcn2 expression was minimal, but components of the Lcn2 signaling pathway were enriched, i.e. SLC22A17 and 3 -hydroxybutyrate dehydrogenase (BDH2). In breast tumor biopsies from women diagnosed with BrCA we found that BDH2 expression was positively associated with adiposity and circulating Lcn2 levels. Collectively these data suggest that reduction of ERa expression in adipose tissue promotes adiposity and is linked with the progression and severity of BrCA via increased adipocyte-specific Lcn2 production and enhanced tumor cell Lcn2 sensitivity. C1 [Drew, Brian G.; Zhou, Zhenqi; Ribas, Vicent; Kalajian, Nareg Y.; Phun, Jennifer; Daraei, Pedram; Hevener, Andrea L.] Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol Diabet & Hypertens, Dept Med, Los Angeles, CA 90095 USA. [Hamidi, Habib; Slamon, Dennis J.; Hurvitz, Sara A.] Univ Calif Los Angeles, Div Hematol Oncol, Los Angeles, CA 90095 USA. [Hamidi, Habib; Christofk, Heather R.; Slamon, Dennis J.; Hurvitz, Sara A.; Hevener, Andrea L.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Villanueva, Claudio J.; Calkin, Anna C.; Tontonoz, Peter] Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Krum, Susan A.] Univ Calif Los Angeles, Dept Orthopaed Surg, Orthopaed Hosp, Los Angeles, CA 90095 USA. [Krum, Susan A.] Univ Calif Los Angeles, Orthopaed Hosp, Res Ctr, Los Angeles, CA 90095 USA. [Parks, Brian W.; Lusis, Aldons J.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. [Christofk, Heather R.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Hewitt, Sylvia C.; Korach, Kenneth S.] NIEHS, Receptor Biol Sect, Reprod & Dev Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Slamon, Dennis J.; Hurvitz, Sara A.] Translat Res Oncol US, Los Angeles, CA 90095 USA. [Hevener, Andrea L.] Iiris Cantor UCLA Womens Hlth Ctr, Los Angeles, CA 90095 USA. RP Hevener, AL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol Diabet & Hypertens, 900 Vet Ave,Warren Hall Suite 24-130, Los Angeles, CA 90095 USA. EM ahevener@mednet.ucla.edu RI Ribas, Vicent/K-1390-2014; OI Ribas, Vicent/0000-0003-3380-2256; Korach, Kenneth/0000-0002-7765-418X FU UCLA Jonsson Comprehensive Cancer Center; UCLA Iris Cantor Women's Health Foundation; UCSD-UCLA Diabetes Research Center FX We are grateful for the continued support of our research from the UCLA Jonsson Comprehensive Cancer Center, the UCLA Iris Cantor Women's Health Foundation, and the UCSD-UCLA Diabetes Research Center. Intellectual contributions by Richard Finn, Jerrold Olefsky, Ronald Evans, Hussy Cohen, and Chris Glass were also helpful in advancing this research. We are grateful for the technical support from Rima Boyadjian (UCLA Inflammation Core), the UCLA Tissue Procurement and Histology Core, and the UCSD Moores Cancer Center Histology and Immunohistochemistry Shared Resource directed by Nissi Varki. NR 61 TC 8 Z9 8 U1 0 U2 8 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 FEB 27 PY 2015 VL 290 IS 9 BP 5566 EP 5581 DI 10.1074/jbc.M114.606459 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CC0RS UT WOS:000350044200028 PM 25468909 ER PT J AU Roos, P Orlando, PA Fagerstrom, RM Pepper, JW AF Roos, Patrick Orlando, Paul A. Fagerstrom, Richard M. Pepper, John W. TI In North America, Some Ovarian Cancers Express the Oncogenes of Preventable Human Papillomavirus HPV-18 SO SCIENTIFIC REPORTS LA English DT Article ID CERVICAL-CANCER; DNA LEVELS; RNA-SEQ; E6; PREVALENCE; E7; CLASSIFICATION; METAANALYSIS; INTEGRATION; LANDSCAPE AB Some researchers in other regions have recommended human papillomavirus (HPV) vaccination to reduce risk of ovarian cancer, but not in North America, where evidence has previously suggested no role for HPV in ovarian cancer. Here we use a large sample of ovarian cancer transcriptomes (RNA-Seq) from The Cancer Genome Atlas (TCGA) database to address whether HPV is involved with ovarian cancer in North America. We estimate that a known high-risk type of HPV (type 18) is present and active in 1.5% of cases of ovarian epithelial cancers in the US and Canada. Our detection methods were verified by negative and positive controls, and our sequence matches indicated high validity, leading to strong confidence in our conclusions. Our results indicate that previous reports of zero prevalence of HPV in North American cases of ovarian cancer should not be considered conclusive. This is important because currently used vaccines protect against the HPV-18 that is active in ovarian tumors and, therefore, may reduce risk in North America of cancers of the ovaries as well as of the cervix and several other organ sites. C1 [Roos, Patrick; Fagerstrom, Richard M.; Pepper, John W.] NCI, Biometry Res Grp, Canc Prevent Div, Rockville, MD 20850 USA. [Orlando, Paul A.] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Pepper, John W.] Santa Fe Inst, Santa Fe, NM 87501 USA. RP Pepper, JW (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM pepperjw@mail.nih.gov NR 28 TC 0 Z9 0 U1 1 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 FEB 27 PY 2015 VL 5 AR 8645 DI 10.1038/srep08645 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC4BF UT WOS:000350295000001 PM 25721614 ER PT J AU Lewis, DEA Le, P Adhya, S AF Lewis, Dale E. A. Phuoc Le Adhya, Sankar TI Differential Role of Base Pairs on gal Promoters Strength SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE transcription; CRP; promoter; galactose; TG-motif ID COLI RNA-POLYMERASE; AMP RECEPTOR PROTEIN; CAP-DEPENDENT PROMOTERS; GALACTOSE OPERON PROMOTERS; OPEN COMPLEX-FORMATION; ESCHERICHIA-COLI; TRANSCRIPTION INITIATION; CYCLIC-AMP; OVERLAPPING PROMOTERS; STRUCTURAL BASIS AB Sequence alignments of promoters in prokaryotes postulated that the frequency of occurrence of a base pair at a given position of promoter elements reflects its contribution to intrinsic promoter strength. We directly assessed the contribution of the four base pairs in each position in the intrinsic promoter strength by keeping the context constant in Escherichia coil cAMP-CRP (cAMP receptor protein) regulated gal promoters by in vitro transcription assays. First, we show that base pair frequency within known consensus elements correlates well with promoter strength. Second, we observe some substitutions upstream of the ex-10 TG motif that are important for promoter function. Although the galP1 and P2 promoters overlap, only three positions where substitutions inactivated both promoters were found. We propose that RNA polymerase binds to the - 12T base pair as part of double-stranded DNA while opening base pairs from - 11A to +3 to form the single-stranded transcription bubble DNA during isomerization. The cAMP-CRP complex rescued some deleterious substitutions in the promoter region. The base pair roles and their flexibilities reported here for Escherichia coil gal promoters may help construction of synthetic promoters in gene circuitry experiments in which overlapping promoters with differential controls may be warranted. Published by Elsevier Ltd. C1 [Lewis, Dale E. A.; Phuoc Le; Adhya, Sankar] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Lewis, DEA (reprint author), 37 Convent Dr,Room 5138, Bethesda, MD 20892 USA. EM Lewisdal@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research FX We thank Maxim Soukhodolets and Mofang Liu for preparing the CRP and Debbie Hinton, Susan Garges, and Stephen Busby for critical reading of the manuscript. The authors would like to thank Cindy Clark, National Institutes of Health Library Writing Center, for manuscript editing assistance. This work was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research. The authors have no conflict of interest to declare. NR 94 TC 1 Z9 1 U1 1 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 27 PY 2015 VL 427 IS 4 BP 792 EP 806 DI 10.1016/j.jmb.2014.12.010 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CC1BO UT WOS:000350076400009 PM 25543084 ER PT J AU Falzarano, D Feldmann, H AF Falzarano, Darryl Feldmann, Heinz TI Delineating Ebola entry SO SCIENCE LA English DT Editorial Material ID NIEMANN-PICK C1; VIRUS INFECTION C1 [Falzarano, Darryl] Univ Saskatchewan, Int Vaccine Ctr, Vaccine & Infect Dis Org, Saskatoon, SK, Canada. [Feldmann, Heinz] NIAID, Lab Virol, Div Intramural Res, NIH, Hamilton, MT USA. RP Falzarano, D (reprint author), Univ Saskatchewan, Int Vaccine Ctr, Vaccine & Infect Dis Org, Saskatoon, SK, Canada. EM feldmannh@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 10 TC 3 Z9 4 U1 0 U2 13 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD FEB 27 PY 2015 VL 347 IS 6225 BP 947 EP 948 DI 10.1126/science.aaa8121 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB9NQ UT WOS:000349958900017 PM 25722396 ER PT J AU Crucitti, GC Metifiot, M Pescatori, L Messore, A Madia, VN Pupo, G Saccoliti, F Scipione, L Tortorella, S Esposito, F Corona, A Cadeddu, M Marchand, C Pommier, Y Tramontano, E Costi, R Di Santo, R AF Crucitti, Giuliana Cuzzucoli Metifiot, Mathieu Pescatori, Luca Messore, Antonella Madia, Valentina Noemi Pupo, Giovanni Saccoliti, Francesco Scipione, Luigi Tortorella, Silvano Esposito, Francesca Corona, Angela Cadeddu, Marta Marchand, Christophe Pommier, Yves Tramontano, Enzo Costi, Roberta Di Santo, Roberto TI Structure-Activity Relationship of Pyrrolyl Diketo Acid Derivatives as Dual Inhibitors of HIV-1 Integrase and Reverse Transcriptase Ribonuclease H Domain SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID VIRUS TYPE-1 INTEGRASE; RNASE-H; MONOAMINE-OXIDASE; STRAND TRANSFER; HYDROXYTROPOLONES; REPLICATION; RALTEGRAVIR; POLYMERASE; RESISTANT; 3-KINASE AB The development of HIV-1 dual inhibitors is a highly innovative approach aimed at reducing drug toxic side effects as well as therapeutic costs. HIV-1 integrase (IN) and reverse transcriptase-associated ribonuclease H (RNase H) are both selective targets for HIV-1 chemotherapy, and the identification of dual IN/RNase H inhibitors is an attractive strategy for new drug development. We newly synthesized pyrrolyl derivatives that exhibited good potency against IN and a moderate inhibition of the RNase H function of RT, confirming the possibility of developing dual HIV-1 IN/RNase H inhibitors and obtaining new information for the further development of more effective dual HIV-1 inhibitors. C1 [Crucitti, Giuliana Cuzzucoli; Pescatori, Luca; Messore, Antonella; Madia, Valentina Noemi; Pupo, Giovanni; Saccoliti, Francesco; Scipione, Luigi; Tortorella, Silvano; Costi, Roberta; Di Santo, Roberto] Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur, Fdn Cenci Bolognetti, I-00185 Rome, Italy. [Marchand, Christophe; Pommier, Yves] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Esposito, Francesca; Corona, Angela; Cadeddu, Marta; Tramontano, Enzo] Univ Cagliari, Dept Life & Environm Sci, I-09124 Cagliari, Italy. RP Costi, R (reprint author), Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur, Fdn Cenci Bolognetti, I-00185 Rome, Italy. EM roberta.costi@uniroma1.it RI Corona, Angela/G-7327-2014; Marchand, Christophe/D-8559-2016; Pescatori, Luca/H-5917-2016; Tramontano, Enzo/B-4919-2012; Esposito, Francesca/I-8879-2012; OI scipione, luigi/0000-0002-2006-7005; Corona, Angela/0000-0002-6630-8636; Pescatori, Luca/0000-0003-4734-7856; Tramontano, Enzo/0000-0002-4849-0980; Madia, Valentina Noemi/0000-0002-5724-612X; Esposito, Francesca/0000-0001-9725-7977; COSTI, Roberta/0000-0002-1314-9029; TORTORELLA, Silvano/0000-0002-3279-9182; Di Santo, Roberto/0000-0002-4279-7666 FU Italian MIUR [ISS 40H4, 2010W2KM5L_002]; FP7 CHAARM project; NIH Intramural Research Program, Center for Cancer Research, National Cancer Institute FX The authors thank the Italian MIUR for financial support, ISS 40H4, PRIN 2010-2011 (Grant 2010W2KM5L_002). R.D.S. and R.C. thank the FP7 CHAARM project for support. This work was also supported by the NIH Intramural Research Program, Center for Cancer Research, National Cancer Institute. NR 48 TC 12 Z9 13 U1 3 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 26 PY 2015 VL 58 IS 4 BP 1915 EP 1928 DI 10.1021/jm501799k PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CD6GD UT WOS:000351186700021 ER PT J AU Cheng, JJ Giguere, PM Onajole, OK Lv, W Gaisin, A Gunosewoyo, H Schmerberg, CM Pogorelov, VM Rodriguiz, RM Vistoli, G Wetsel, WC Roth, BL Kozikowski, AP AF Cheng, Jianjun Giguere, Patrick M. Onajole, Oluseye K. Lv, Wei Gaisin, Arsen Gunosewoyo, Hendra Schmerberg, Claire M. Pogorelov, Vladimir M. Rodriguiz, Ramona M. Vistoli, Giulio Wetsel, William C. Roth, Bryan L. Kozikowski, Alan P. TI Optimization of 2-Phenylcyclopropylmethylamines as Selective Serotonin 2C Receptor Agonists and Their Evaluation as Potential Antipsychotic Agents SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RATIONAL DRUG DESIGN; IN-VIVO; 5-HT2C AGONIST; IDENTIFICATION; LORCASERIN; LIGANDS; BINDING; OBESITY AB The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of beta(2)-adrenergic receptor and 5-HT2B receptor. C1 [Cheng, Jianjun; Onajole, Oluseye K.; Lv, Wei; Gaisin, Arsen; Gunosewoyo, Hendra; Kozikowski, Alan P.] Univ Illinois, Dept Med Chem & Pharmacognosy, Coll Pharm, Drug Discovery Program, Chicago, IL 60612 USA. [Giguere, Patrick M.; Roth, Bryan L.] Univ N Carolina, NIMH, Psychoact Drug Screening Program, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Giguere, Patrick M.; Roth, Bryan L.] Univ N Carolina, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Schmerberg, Claire M.; Pogorelov, Vladimir M.; Rodriguiz, Ramona M.] Duke Univ, Dept Psychiat & Behav Sci, Mouse Behav & Neuroendocrine Anal Core Facil, Med Ctr, Durham, NC 27710 USA. [Vistoli, Giulio] Univ Milan, Dipartimento Sci Farmaceut, I-20133 Milan, Italy. [Wetsel, William C.] Duke Univ, Med Ctr, Mouse Behav & Neuroendocrine Anal Core Facil, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Wetsel, William C.] Duke Univ, Med Ctr, Mouse Behav & Neuroendocrine Anal Core Facil, Dept Cell Biol, Durham, NC 27710 USA. [Wetsel, William C.] Duke Univ, Med Ctr, Mouse Behav & Neuroendocrine Anal Core Facil, Dept Neurobiol, Durham, NC 27710 USA. RP Kozikowski, AP (reprint author), Univ Illinois, Dept Med Chem & Pharmacognosy, Coll Pharm, Drug Discovery Program, 833 South Wood St, Chicago, IL 60612 USA. EM kozikowa@uic.edu RI Roth, Bryan/F-3928-2010; OI Schmerberg, Claire/0000-0001-5171-7659; Vistoli, Giulio/0000-0002-3939-5172; Gunosewoyo, Hendra/0000-0003-3897-1948 FU National Institute of Health (NIH) [R01MH99993]; NIMH Psychoactive Drug Screening Program FX Financial support from the National Institute of Health (NIH) (no. R01MH99993) and NIMH Psychoactive Drug Screening Program is gratefully acknowledged. NR 32 TC 9 Z9 9 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 26 PY 2015 VL 58 IS 4 BP 1992 EP 2002 DI 10.1021/jm5019274 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CD6GD UT WOS:000351186700027 PM 25633969 ER PT J AU Ayithan, N Bradfute, SB Anthony, SM Stuthman, KS Bavari, S Bray, M Ozato, K AF Ayithan, Natarajan Bradfute, Steven B. Anthony, Scott M. Stuthman, Kelly S. Bavari, Sina Bray, Mike Ozato, Keiko TI Virus-Like Particles Activate Type I Interferon Pathways to Facilitate Post-Exposure Protection against Ebola Virus Infection SO PLOS ONE LA English DT Article ID NF-KAPPA-B; DENDRITIC CELLS REQUIRES; TOLL-LIKE RECEPTOR; FILOVIRUS INFECTION; REGULATORY FACTOR-8; HEMORRHAGIC-FEVER; INFLAMMASOME ACTIVATION; CYTOKINE EXPRESSION; NEGATIVE REGULATION; IMMUNE-RESPONSES AB Ebola virus (EBOV) causes a severe hemorrhagic disease with high fatality. Virus-like particles (VLPs) are a promising vaccine candidate against EBOV. We recently showed that VLPs protect mice from lethal EBOV infection when given before or after viral infection. To elucidate pathways through which VLPs confer post-exposure protection, we investigated the role of type I interferon (IFN) signaling. We found that VLPs lead to accelerated induction of IFN stimulated genes (ISGs) in liver and spleen of wild type mice, but not in Ifnar(-/-)mice. Accordingly, EBOV infected Ifnar(-/-)mice, unlike wild type mice succumbed to death even after VLP treatment. The ISGs induced in wild type mice included anti-viral proteins and negative feedback factors known to restrict viral replication and excessive inflammatory responses. Importantly, proinflammatory cytokine/chemokine expression was much higher in WT mice without VLPs than mice treated with VLPs. In EBOV infected Ifnar(-/-)mice, however, uninhibited viral replication and elevated proinflammatory factor expression ensued, irrespective of VLP treatment, supporting the view that type I IFN signaling helps to limit viral replication and attenuate inflammatory responses. Further analyses showed that VLP protection requires the transcription factor, IRF8 known to amplify type I IFN signaling in dendritic cells and macrophages, the probable sites of initial EBOV infection. Together, this study indicates that VLPs afford post-exposure protection by promoting expeditious initiation of type I IFN signaling in the host. C1 [Ayithan, Natarajan; Ozato, Keiko] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Bradfute, Steven B.; Anthony, Scott M.; Stuthman, Kelly S.; Bavari, Sina] US Army, Med Inst Infect Dis, Ft Detrick, MD USA. [Bray, Mike] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD USA. RP Ozato, K (reprint author), NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM ozatok@nih.gov FU Intramural Program of NICHD; Trans-NIH FDA intramural Bio-defense Program, NIH FX This work was supported by the Intramural Program of NICHD and the Trans-NIH FDA intramural Bio-defense Program, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 6 Z9 6 U1 2 U2 13 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 FEB 26 PY 2015 VL 10 IS 2 AR UNSP e0118345 DI 10.1371/journal.pone.0118345 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC2ZH UT WOS:000350213200048 PM 25719445 ER PT J AU Malachowa, N Kobayashi, SD Sturdevant, DE Scott, DP Deleo, FR AF Malachowa, Natalia Kobayashi, Scott D. Sturdevant, Daniel E. Scott, Dana P. DeLeo, Frank R. TI Insights into the Staphylococcus aureus-Host Interface: Global Changes in Host and Pathogen Gene Expression in a Rabbit Skin Infection Model SO PLOS ONE LA English DT Article ID SOFT-TISSUE INFECTIONS; PANTON-VALENTINE LEUKOCIDIN; HUMAN ENDOTHELIAL-CELLS; ONCOSTATIN-M; EMERGENCY-DEPARTMENT; VIRULENCE DETERMINANTS; ADHESION MOLECULES; T-CELLS; USA300; KERATINOCYTES AB Staphylococcus aureus is an important cause of human skin and soft tissue infections (SSTIs) globally. Notably, 80% of all SSTIs are caused by S. aureus, of which similar to 63% are abscesses and/or cellulitis. Although progress has been made, our knowledge of the host and pathogen factors that contribute to the pathogenesis of SSTIs is incomplete. To provide a more comprehensive view of this process, we monitored changes in the S. aureus transcriptome and selected host proinflammatory molecules during abscess formation and resolution in a rabbit skin infection model. Within the first 24 h, S. aureus transcripts involved in DNA repair, metabolite transport, and metabolism were up-regulated, suggesting an increase in the machinery encoding molecules involved in replication and cell division. There was also increased expression of genes encoding virulence factors, namely secreted toxins and fibronectin and/or fibrinogen-binding proteins. Of the host genes tested, we found that transcripts encoding IL-8, IL1 beta, oncostatin M-like, CCR1, CXCR1 (IL8RA), CCL4 (MIP-1 beta) and CCL3 (MIP1 alpha)-like proteins were among the most highly up-regulated transcripts during S. aureus abscess formation. Our findings provide additional insight into the pathogenesis of S. aureus SSTIs, including a temporal component of the host response. These results serve as a springboard for future studies directed to better understand how/why mild or moderate SSTIs progress to invasive disease. C1 [Malachowa, Natalia; Kobayashi, Scott D.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Sturdevant, Daniel E.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. [Scott, Dana P.] NIAID, Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Deleo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU US National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the US National Institute of Allergy and Infectious Diseases, 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 37 TC 7 Z9 7 U1 2 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 26 PY 2015 VL 10 IS 2 AR e0117713 DI 10.1371/journal.pone.0117713 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC2ZH UT WOS:000350213200028 PM 25719526 ER PT J AU Sokolnikov, M Preston, D Gilbert, E Schonfeld, S Koshurnikova, N AF Sokolnikov, Mikhail Preston, Dale Gilbert, Ethel Schonfeld, Sara Koshurnikova, Nina TI Radiation Effects on Mortality from Solid Cancers Other than Lung, Liver, and Bone Cancer in the Mayak Worker Cohort: 1948-2008 SO PLOS ONE LA English DT Article ID ATOMIC-BOMB SURVIVORS; PLUTONIUM EXCRETION; NUCLEAR-COMPLEX; EXPOSURE; MODEL; RISK; DOSIMETRY; DISEASES; URINE; PA AB Radiation effects on mortality from solid cancers other than lung, liver, and bone cancer in the Mayak worker cohort: 1948-2008. The cohort of Mayak Production Association (PA) workers in Russia offers a unique opportunity to study the effects of prolonged low dose rate external gamma exposures and exposure to plutonium in a working age population. We examined radiation effects on the risk of mortality from solid cancers excluding sites of primary plutonium deposition (lung, liver, and bone surface) among 25,757 workers who were first employed in 1948-1982. During the period 1948-2008, there were 1,825 deaths from cancers other than lung, liver and bone. Using colon dose as a representative external dose, a linear dose response model described the data well. The excess relative risk per Gray for external gamma exposure was 0.16 (95% CI: 0.07 - 0.26) when unadjusted for plutonium exposure and 0.12 (95% CI 0.03 - 0.21) when adjusted for plutonium dose and monitoring status. There was no significant effect modification by sex or attained age. Plutonium exposure was not significantly associated with the group of cancers analyzed after adjusting for monitoring status. Site-specific risks were uncertainly estimated but positive for 13 of the 15 sites evaluated with a statistically significant estimate only for esophageal cancer. Comparison with estimates based on the acute exposures in atomic bomb survivors suggests that the excess relative risk per Gray for prolonged external exposure in Mayak workers may be lower than that for acute exposure but, given the uncertainties, the possibility of equal effects cannot be dismissed. C1 [Sokolnikov, Mikhail; Koshurnikova, Nina] Southern Urals Biophys Inst, Lab Epidemiol, Ozyorsk, Russia. [Preston, Dale] Hirosoft Int, Eureka, CA USA. [Gilbert, Ethel; Schonfeld, Sara] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Schonfeld, Sara] Int Agcy Res Canc, Sect Environm & Radiat, F-69372 Lyon, France. RP Sokolnikov, M (reprint author), Southern Urals Biophys Inst, Lab Epidemiol, Ozyorsk, Russia. EM sokolnikov@subi.su FU US Department of Energy Joint Coordinating Committee for Radiation Effects Research [DE-HS0000091]; US National Cancer Institute [HHSN261200900090C]; Russian Federal Government FX The study was funded by the following sources: US Department of Energy Joint Coordinating Committee for Radiation Effects Research contract DE-HS0000091, US National Cancer Institute contract No HHSN261200900090C, and Russian Federal Government contract "Radiation Epidemiology." The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 11 Z9 12 U1 0 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 FEB 26 PY 2015 VL 10 IS 2 AR e0117784 DI 10.1371/journal.pone.0117784 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC2ZH UT WOS:000350213200032 PM 25719381 ER PT J AU Collins, FS Varmus, H AF Collins, Francis S. Varmus, Harold TI A New Initiative on Precision Medicine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Collins, Francis S.] NIH, Bethesda, MD 20892 USA. [Varmus, Harold] NCI, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 740 Z9 809 U1 65 U2 203 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 FEB 26 PY 2015 VL 372 IS 9 BP 793 EP 795 DI 10.1056/NEJMp1500523 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CB8SQ UT WOS:000349901700001 PM 25635347 ER PT J AU Du Toit, G Roberts, G Sayre, PH Bahnson, HT Radulovic, S Santos, AF Brough, HA Phippard, D Basting, M Feeney, M Turcanu, V Sever, ML Lorenzo, MG Plaut, M Lack, G AF Du Toit, George Roberts, Graham Sayre, Peter H. Bahnson, Henry T. Radulovic, Suzana Santos, Alexandra F. Brough, Helen A. Phippard, Deborah Basting, Monica Feeney, Mary Turcanu, Victor Sever, Michelle L. Lorenzo, Margarita Gomez Plaut, Marshall Lack, Gideon CA LEAP Study Team TI Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ORAL IMMUNOTHERAPY; FOOD ALLERGY; CHILDREN; PROTEIN; PREVALENCE; RESPONSES; FORMULAS AB BACKGROUND The prevalence of peanut allergy among children in Western countries has doubled in the past 10 years, and peanut allergy is becoming apparent in Africa and Asia. We evaluated strategies of peanut consumption and avoidance to determine which strategy is most effective in preventing the development of peanut allergy in infants at high risk for the allergy. METHODS We randomly assigned 640 infants with severe eczema, egg allergy, or both to consume or avoid peanuts until 60 months of age. Participants, who were at least 4 months but younger than 11 months of age at randomization, were assigned to separate study cohorts on the basis of preexisting sensitivity to peanut extract, which was determined with the use of a skin-prick test - one consisting of participants with no measurable wheal after testing and the other consisting of those with a wheal measuring 1 to 4 mm in diameter. The primary outcome, which was assessed independently in each cohort, was the proportion of participants with peanut allergy at 60 months of age. RESULTS Among the 530 infants in the intention-to-treat population who initially had negative results on the skin-prick test, the prevalence of peanut allergy at 60 months of age was 13.7% in the avoidance group and 1.9% in the consumption group (P<0.001). Among the 98 participants in the intention-to-treat population who initially had positive test results, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P = 0.004). There was no significant between-group difference in the incidence of serious adverse events. Increases in levels of peanut-specific IgG4 antibody occurred predominantly in the consumption group; a greater percentage of participants in the avoidance group had elevated titers of peanut-specific IgE antibody. A larger wheal on the skin-prick test and a lower ratio of peanut-specific IgG4: IgE were associated with peanut allergy. CONCLUSIONS The early introduction of peanuts significantly decreased the frequency of the development of peanut allergy among children at high risk for this allergy and modulated immune responses to peanuts. C1 [Du Toit, George; Radulovic, Suzana; Santos, Alexandra F.; Brough, Helen A.; Basting, Monica; Feeney, Mary; Turcanu, Victor; Lack, Gideon] Kings Coll London, Div Asthma Allergy & Lung Biol, Dept Pediat Allergy, London WC2R 2LS, England. [Du Toit, George; Radulovic, Suzana; Santos, Alexandra F.; Brough, Helen A.; Basting, Monica; Feeney, Mary; Turcanu, Victor; Lack, Gideon] Guys & St Thomas Natl Hlth Serv Fdn Trust, London, England. [Roberts, Graham] Univ Southampton, Southampton, Hants, England. [Roberts, Graham] Natl Inst Hlth Res, Resp Biomed Res Unit, Southampton, Hants, England. [Roberts, Graham] David Hide Ctr, Newport, Wight, England. [Sayre, Peter H.] Univ Calif San Francisco, Div Hematol Oncol, Dept Med, San Francisco, CA 94143 USA. [Phippard, Deborah] Univ Calif San Francisco, Immune Tolerance Network, San Francisco, CA 94143 USA. [Bahnson, Henry T.; Sever, Michelle L.] Rho Fed Syst Div, Chapel Hill, NC USA. [Lorenzo, Margarita Gomez; Plaut, Marshall] NIAID, Bethesda, MD 20892 USA. RP Lack, G (reprint author), Guys & St Thomas NHS Fdn Trust, Childrens Allergy Unit, 2nd Fl,South Wing,Westminster Bridge Rd, London SE1 7EH, England. FU National Institute of Allergy and Infectious Diseases FX Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00329784.) NR 32 TC 253 Z9 259 U1 27 U2 77 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 FEB 26 PY 2015 VL 372 IS 9 BP 803 EP 813 DI 10.1056/NEJMoa1414850 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CB8SQ UT WOS:000349901700005 PM 25705822 ER PT J AU Grady, C AF Grady, Christine TI Enduring and Emerging Challenges of Informed Consent SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID DECISION-MAKING; CLINICAL-TRIALS; UNITED-STATES; HEALTH-CARE; PATIENT; PERSPECTIVE; SUPPORT; QUALITY; FORMS; INTERVENTIONS C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Grady, C (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10-1C118, Bethesda, MD 20892 USA. EM cgrady@nih.gov NR 74 TC 25 Z9 25 U1 3 U2 24 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 FEB 26 PY 2015 VL 372 IS 9 BP 855 EP 862 DI 10.1056/NEJMra1411250 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CB8SQ UT WOS:000349901700010 PM 25714163 ER PT J AU Subramanian, M Francis, P Bilke, S Li, XL Hara, T Lu, X Jones, MF Walker, RL Zhu, Y Pineda, M Lee, C Varanasi, L Yang, Y Martinez, LA Luo, J Ambs, S Sharma, S Wakefield, LM Meltzer, PS Lal, A AF Subramanian, M. Francis, P. Bilke, S. Li, X. L. Hara, T. Lu, X. Jones, M. F. Walker, R. L. Zhu, Y. Pineda, M. Lee, C. Varanasi, L. Yang, Y. Martinez, L. A. Luo, J. Ambs, S. Sharma, S. Wakefield, L. M. Meltzer, P. S. Lal, A. TI A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis SO ONCOGENE LA English DT Article ID P53 MUTANTS; TARGET RECOGNITION; MICRORNA TARGETS; BREAST-CANCER; P73 FUNCTION; EXPRESSION; ACTIVATION; P63; MYC; PROLIFERATION AB Most p53 mutations in human cancers are missense mutations resulting in a full-length mutant p53 protein. Besides losing tumor suppressor activity, some hotspot p53 mutants gain oncogenic functions. This effect is mediated in part, through gene expression changes due to inhibition of p63 and p73 by mutant p53 at their target gene promoters. Here, we report that the tumor suppressor microRNA let-7i is downregulated by mutant p53 in multiple cell lines expressing endogenous mutant p53. In breast cancer patients, significantly decreased let-7i levels were associated with missense mutations in p53. Chromatin immunoprecipitation and promoter luciferase assays established let-7i as a transcriptional target of mutant p53 through p63. Introduction of let-7i to mutant p53 cells significantly inhibited migration, invasion and metastasis by repressing a network of oncogenes including E2F5, LIN28B, MYC and NRAS. Our findings demonstrate that repression of let-7i expression by mutant p53 has a key role in enhancing migration, invasion and metastasis. C1 [Subramanian, M.; Francis, P.; Bilke, S.; Li, X. L.; Hara, T.; Jones, M. F.; Walker, R. L.; Zhu, Y.; Pineda, M.; Meltzer, P. S.; Lal, A.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Lu, X.; Sharma, S.] Howard Univ, Dept Biochem & Mol Biol, Coll Med, Washington, DC 20059 USA. [Lee, C.; Luo, J.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Varanasi, L.; Martinez, L. A.] Univ Mississippi, Med Ctr, Inst Canc, Dept Biochem, Jackson, MS 39216 USA. [Yang, Y.; Wakefield, L. M.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Ambs, S.] NCI, Lab Human Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Lal, A (reprint author), NCI, Regulatory RNAs & Canc Sect, Genet Branch, NIH, Bldg 37,Room 6134,37 Convent Dr, Bethesda, MD 20892 USA. EM ashish.lal@nih.gov OI Sharma, Sudha/0000-0003-2765-2482 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Institute of General Medical Sciences of the National Institutes of Health [SC1GM093999] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Sudha Sharma was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number SC1GM093999. We thank K Prasanth, W Bodmer, B Hassel, M Thomas, J Lieberman and M Gorospe for their comments on this manuscript. We thank B Vogelstein for the DLD1 isogenic cell lines, K Vousden for the H1299-EV and H1299-p53R273H cells, S O'Hara for the pGL4-let-7i and Z Mourelators for the Ago2 (2A8) antibody. NR 53 TC 12 Z9 12 U1 1 U2 10 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 FEB 26 PY 2015 VL 34 IS 9 BP 1094 EP 1104 DI 10.1038/onc.2014.46 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA CC1RY UT WOS:000350122100003 PM 24662829 ER PT J AU Yapici, NB Bi, Y Li, PF Chen, X Yan, X Mandalapu, SR Faucett, M Jockusch, S Ju, JF Gibson, KM Pavan, WJ Bi, LR AF Yapici, Nazmiye B. Bi, Yue Li, Pengfei Chen, Xin Yan, Xin Mandalapu, Srinivas Rao Faucett, Megan Jockusch, Steffen Ju, Jingfang Gibson, K. Michael Pavan, William J. Bi, Lanrong TI Highly Stable and Sensitive Fluorescent Probes (LysoProbes) for Lysosomal Labeling and Tracking SO SCIENTIFIC REPORTS LA English DT Article ID POTENTIAL THERAPEUTIC TARGET; CANCER-THERAPY; AUTOPHAGY; PH; CELLS; MITOCHONDRIA; ORGANELLES; DISEASES AB We report the design, synthesis and application of several new fluorescent probes (LysoProbes I-VI) that facilitate lysosomal pH monitoring and characterization of lysosome-dependent apoptosis. LysoProbes are superior to commercially available lysosome markers since the fluorescent signals are both stable and highly selective, and they will aid in characterization of lysosome morphology and trafficking. We predict that labeling of cancer cells and solid tumor tissues with LysoProbes will provide an important new tool for monitoring the role of lysosome trafficking in cancer invasion and metastasis. C1 [Yapici, Nazmiye B.; Chen, Xin; Yan, Xin; Mandalapu, Srinivas Rao; Faucett, Megan; Bi, Lanrong] Michigan Technol Univ, Dept Chem, Houghton, MI 49931 USA. [Bi, Yue; Li, Pengfei] HeBei Med Univ, Hosp 2, Shijiazhuang 050000, Peoples R China. [Jockusch, Steffen] Columbia Univ, Dept Chem, New York, NY 10027 USA. [Ju, Jingfang] Stony Brook Med, Translat Res Lab, Stony Brook, NY 11794 USA. [Gibson, K. Michael] Washington State Univ, Coll Pharm, Spokane, WA 99202 USA. [Pavan, William J.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Ju, JF (reprint author), Stony Brook Med, Translat Res Lab, Stony Brook, NY 11794 USA. EM jingfang.ju@stonybrookmedicine.edu; mike.gibson@wsu.edu; lanrong@mtu.edu OI Ju, Jingfang/0000-0002-4821-7458; Yapici, Nazmiye/0000-0002-3449-9562 FU NIH [GM088795-01]; NSF [1048655]; NASA [MSGC R85197]; MIIE [1204010]; VPR-SI fund [R01386]; Research Excellence Fund [R01121, R01323] FX The authors acknowledge the support of NIH (GM088795-01), NSF (No. 1048655), NASA (#MSGC R85197), MIIE (#1204010), VPR-SI fund (#R01386), and the Research Excellence Fund (#R01121 and #R01323). The authors are particularly thankful to Dr. Bruce Seely for his ongoing support of our work. NR 30 TC 8 Z9 8 U1 7 U2 52 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 26 PY 2015 VL 5 AR 8576 DI 10.1038/srep08576 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB9PL UT WOS:000349963900001 PM 25715948 ER PT J AU Kim, MS Lapkouski, M Yang, W Gellert, M AF Kim, Min-Sung Lapkouski, Mikalai Yang, Wei Gellert, Martin TI Crystal structure of the V(D)J recombinase RAG1-RAG2 SO NATURE LA English DT Article ID DNA HAIRPIN FORMATION; AMINO-ACID-RESIDUES; SINGLE ACTIVE-SITE; MUTATIONAL ANALYSIS; BINDING DOMAIN; RAG2 PROTEINS; COMPLEX; TRANSPOSITION; CLEAVAGE; RAG1/2 AB V(D)J recombination in the vertebrate immune system generates a highly diverse population of immunoglobulins and T-cell receptors by combinatorial joining of segments of coding DNA. The RAG1-RAG2 protein complex initiates this site-specific recombination by cutting DNA at specific sites flanking the coding segments. Here we report the crystal structure of the mouse RAG1-RAG2 complex at 3.2A resolution. The 230-kilodalton RAG1-RAG2 heterotetramer is 'Y-shaped', with the amino-terminal domains of the two RAG1 chains forming an intertwined stalk. Each RAG1-RAG2 heterodimer composes one arm of the 'Y', with the active site in the middle and RAG2 at its tip. The RAG1-RAG2 structure rationalizes more than 60 mutations identified in immunodeficient patients, as well as a large body of genetic and biochemical data. The architectural similarity between RAG1 and the hairpin-forming transposases Hermes and Tn5 suggests the evolutionary conservation of these DNA rearrangements. C1 [Kim, Min-Sung; Lapkouski, Mikalai; Yang, Wei; Gellert, Martin] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM wei.yang@nih.gov; gellert@helix.nih.gov RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We thank G. Grundy and S. Ramon-Maiques for the pioneering work that made this study possible, and D. Leahy for editing the manuscript The research was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 45 TC 33 Z9 34 U1 0 U2 16 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 FEB 26 PY 2015 VL 518 IS 7540 BP 507 EP 511 DI 10.1038/nature14174 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC1JP UT WOS:000350097300040 PM 25707801 ER PT J AU Chang, CC Chow, CC Tellier, LCAM Vattikuti, S Purcell, SM Lee, JJ AF Chang, Christopher C. Chow, Carson C. Tellier, Laurent C. A. M. Vattikuti, Shashaank Purcell, Shaun M. Lee, James J. TI Second-generation PLINK: rising to the challenge of larger and richer datasets SO GIGASCIENCE LA English DT Article DE GWAS; Population genetics; Whole-genome sequencing; High-density SNP genotyping; Computational statistics ID HARDY-WEINBERG EQUILIBRIUM; GENOME-WIDE ASSOCIATION; FISHERS EXACT TEST; LINKAGE DISEQUILIBRIUM; CONTINGENCY-TABLES; EXACT TESTS; ALGORITHM; PERMUTATION; PERFORMANCE; IDENTITY AB Background: PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for faster and scalable implementations of key functions, such as logistic regression, linkage disequilibrium estimation, and genomic distance evaluation. In addition, GWAS and population-genetic data now frequently contain genotype likelihoods, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1's primary data format. Findings: To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, O(root n)-time/constant-space Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. We have also developed an extension to the data format which adds low-overhead support for genotype likelihoods, phase, multiallelic variants, and reference vs. alternate alleles, which is the basis of our planned second release ( PLINK 2.0). Conclusions: The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use. C1 [Chang, Christopher C.] Complete Genom, Mountain View, CA 94043 USA. [Chang, Christopher C.; Tellier, Laurent C. A. M.] BGI Cognit Genom Lab, Shenzhen 518083, Peoples R China. [Chow, Carson C.; Vattikuti, Shashaank; Lee, James J.] NIDDK, Math Biol Sect, LBM, NIH, Bethesda, MD 20892 USA. [Tellier, Laurent C. A. M.] Univ Copenhagen, Bioinformat Ctr, DK-2200 Copenhagen, Denmark. [Purcell, Shaun M.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Purcell, Shaun M.] Icahn Sch Med Mt Sinai, Div Psychiat Genom, Dept Psychiat, New York, NY 10029 USA. [Purcell, Shaun M.] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Purcell, Shaun M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Lee, James J.] Univ Minnesota Twin Cities, Dept Psychol, Minneapolis, MN 55455 USA. RP Chang, CC (reprint author), Complete Genom, 2071 Stierlin Court, Mountain View, CA 94043 USA. EM chrchang@alumni.caltech.edu FU BGI Hong Kong; Shenzhen Municipal Government of China [CXB201108250094A]; Intramural Research Program of the NIH, NIDDK FX Christopher Chang and Laurent Tellier were supported by BGI Hong Kong and Shenzhen Municipal Government of China grant CXB201108250094A. Carson Chow and Shashaank Vattikuti were supported by the Intramural Research Program of the NIH, NIDDK. NR 44 TC 184 Z9 184 U1 16 U2 31 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND EI 2047-217X J9 GIGASCIENCE JI GigaScience PD FEB 25 PY 2015 VL 4 AR 7 DI 10.1186/s13742-015-0047-8 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX4IB UT WOS:000365662000001 PM 25722852 ER PT J AU Davis, SK Gebreab, SY Xu, RH Riestra, P Khan, RJ Sumner, AE Hickson, D Bidulescu, A AF Davis, Sharon K. Gebreab, Samson Y. Xu, Ruihua Riestra, Pia Khan, Rumana J. Sumner, Anne E. Hickson, DeMarc Bidulescu, Aurelian TI Association of adiponectin with type 2 diabetes and hypertension in African American men and women: the Jackson Heart Study SO BMC CARDIOVASCULAR DISORDERS LA English DT Article DE Biomarkers; Types 2 diabetes; Hypertension; African Americans ID CARDIOVASCULAR-DISEASE; PLASMA ADIPONECTIN; METABOLIC SYNDROME; RISK; DETERMINANTS; ADIPOSITY; GLUCOSE; PROTEIN; COHORT; WHITE AB Background: Adiponectin is a biomarker that is associated with type 2 diabetes and hypertension. Lower circulating level is a risk factor. Higher levels are protective. African Americans have a higher prevalence of type 2 diabetes and hypertension and lower levels of adiponectin when compared to other racial/ ethnic groups. Little is known about the association of adiponectin on these health outcomes among African Americans. The purpose of the study was to assess the association of adiponectin on type 2 diabetes and hypertension likelihood among African American men and women in the Jackson Heart Study. Methods: Separate multivariate logistic regressions were conducted stratified by sex based on cross-sectional data with type 2 diabetes and hypertension as the outcomes. Adiponectin was divided into four quartiles with the highest quartile as the reference. Data was collected from 2000-2004 on 3,663 participants. Data analysis was conducted in calendar year 2014. Two-tailed P < .05 was established as level of significance. Results: In the adjusted multivariate models, adiponectin level was inversely associated with type 2 diabetes among women (odds ratio [OR], 95% confidence interval [CI] = 1.47, [1.02, 2.11], P = .04). There was no association among men. Women with the lowest level of adiponectin were less likely to be hypertensive (OR, 95% CI = 0.66, [0.46, 0.95], p = .02). There was no association among men. Conclusion: Findings reveal differential associations between levels of adiponectin with type 2 diabetes and hypertension likelihood among African American women. More research is needed to elucidate this differential association. C1 [Davis, Sharon K.; Gebreab, Samson Y.; Xu, Ruihua; Riestra, Pia; Khan, Rumana J.] NHGRI, Genom Metab Cardiovasc & Inflammatory Dis Branch, Social Epidemiol Res Unit, Bethesda, MD 20892 USA. [Sumner, Anne E.] NIDDK, Sect Ethn & Hlth, Bethesda, MD 20892 USA. [Hickson, DeMarc] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Bidulescu, Aurelian] Indiana Univ, Sch Publ Hlth, Bloomington, IN 47405 USA. RP Davis, SK (reprint author), NHGRI, Genom Metab Cardiovasc & Inflammatory Dis Branch, Social Epidemiol Res Unit, 10 Ctr Dr, Bethesda, MD 20892 USA. EM sharon.davis@nih.gov; samson.gebreab@nih.gov FU National Heart, Lung and Blood Institute [HHSN268201300046C, HHSN26820130047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities; PHS Award from the National Institutes of Health, National Center for Research Resources [UL1 RR025008]; NIH grant by the National Heart, Lung and Blood Institute [UH1 HL073461]; National Human Genome Research Institute, National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Disorders, National Institutes of Health FX Funding for the Jackson Heart Study was supported by contracts HHSN268201300046C, HHSN26820130047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung and Blood Institute and the National Institute on Minority Health and Health Disparities.; The adiponectin measurements were partially supported by PHS Award UL1 RR025008 from the National Institutes of Health, National Center for Research Resources and by the NIH grant UH1 HL073461 provided by the National Heart, Lung and Blood Institute.; Sharon K Davis, Samson Gebreab, Ruihua Xu, Pia Riestra, and Rumana Khan are supported by the intramural program of the National Human Genome Research Institute, National Institutes of Health. Anne Sumner is supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Disorders, National Institutes of Health. NR 35 TC 4 Z9 4 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2261 J9 BMC CARDIOVASC DISOR JI BMC Cardiovasc. Disord. PD FEB 25 PY 2015 VL 15 AR 13 DI 10.1186/s12872-015-0005-5 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CC8LA UT WOS:000350619000001 PM 25885320 ER PT J AU Root, DH Hoffman, AF Good, CH Zhang, SL Gigante, E Lupica, CR Morales, M AF Root, David H. Hoffman, Alexander F. Good, Cameron H. Zhang, Shiliang Gigante, Eduardo Lupica, Carl R. Morales, Marisela TI Norepinephrine Activates Dopamine D-4 Receptors in the Rat Lateral Habenula SO JOURNAL OF NEUROSCIENCE LA English DT Article DE addiction; depression; dopamine; habenula; locus ceruleus; ventral tegmental area ID VENTRAL TEGMENTAL AREA; NEGATIVE REWARD SIGNALS; NORADRENERGIC INNERVATION; SUBSTANTIA-NIGRA; DORSAL RAPHE; NEURONS; COCAINE; NORADRENALINE; BRAIN; STIMULATION AB The lateral habenula (LHb) is involved in reward and aversion and is reciprocally connected with dopamine (DA)-containing brain regions, including the ventral tegmental area (VTA). We used a multidisciplinary approach to examine the properties of DA afferents to the LHb in the rat. We find that >90% of VTA tyrosine hydroxylase (TH) neurons projecting to the LHb lack vesicular monoamine transporter 2(VMAT2) mRNA, and there is little coexpression ofTHandVMAT2protein in this mesohabenular pathway. Consistent with this, electrical stimulation of LHb did not evoke DA-like signals, assessed with fast-scan cyclic voltammetry. However, electrophysiological currents that were inhibited by L741,742, a DA-D-4-receptor antagonist, were observed in LHb neurons when DA uptake or degradation was blocked. To prevent DA activation of D-4 receptors, we repeated this experiment in LHb slices from DA-depleted rats. However, this did not disrupt D-4 receptor activation initiated by the dopamine transporter inhibitor, GBR12935. As the LHb is also targeted by noradrenergic afferents, we examined whether GBR12935 activation of DA-D-4 receptors occurred in slices depleted of norepinephrine (NE). Unlike DA, NE depletion prevented the activation of DA-D-4 receptors. Moreover, direct application of NE elicited currents in LHb neurons that were blocked by L741,742, and GBR12935 was found to be a more effective blocker of NE uptake than the NE-selective transport inhibitor nisoxetine. These findings demonstrate that NE is released in the rat LHb under basal conditions and that it activates DA-D-4 receptors. Therefore, NE may be an important regulator of LHb function. C1 [Root, David H.; Zhang, Shiliang; Gigante, Eduardo; Morales, Marisela] NIDA, Neuronal Networks Sect, Integrat Neurosci Res Branch, Baltimore, MD 21224 USA. [Hoffman, Alexander F.; Good, Cameron H.; Lupica, Carl R.] NIDA, Electrophysiol Res Sect, Cellular Neurobiol Res Branch, Baltimore, MD 21224 USA. RP Lupica, CR (reprint author), NIDA, Electrophysiol Res Sect, Cellular Neurobiol Branch, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM clupica@intra.nida.nih.gov; mmorales@intra.nida.nih.gov RI Hoffman, Alexander/H-3035-2012 OI Hoffman, Alexander/0000-0002-2676-0628 FU National Institute on Drug Abuse Intramural Research Program FX This work was supported by the National Institute on Drug Abuse Intramural Research Program. Viruses were packaged by the National Institute on Drug Abuse Optogenetic and Transgenic Technology Core. NR 55 TC 18 Z9 19 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 FEB 25 PY 2015 VL 35 IS 8 BP 3460 EP 3469 DI 10.1523/JNEUROSCI.4525-13.2015 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CD0CV UT WOS:000350738800017 PM 25716845 ER PT J AU Craig, MT McBain, CJ AF Craig, Michael T. McBain, Chris J. TI Fast Gamma Oscillations Are Generated Intrinsically in CA1 without the Involvement of Fast-Spiking Basket Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article DE axo-axonic; basket; gamma; interneurons; oscillation; trilaminar ID HIPPOCAMPUS IN-VITRO; NETWORK OSCILLATIONS; PYRAMIDAL CELLS; GABAERGIC INTERNEURONS; FREQUENCY OSCILLATIONS; RECEPTOR-ACTIVATION; RAT; RHYTHMS; NEURONS; INHIBITION AB Information processing in neuronal networks relies on the precise synchronization of ensembles of neurons, coordinated by the diverse family of inhibitory interneurons. Cortical interneurons can be usefully parsed by embryonic origin, with the vast majority arising from either the caudal or medial ganglionic eminences (CGE and MGE). Here, we examine the activity of hippocampal interneurons during gamma oscillations in mouse CA1, using an in vitro model where brief epochs of rhythmic activity were evoked by local application of kainate. We found that this CA1 KA-evoked gamma oscillation was faster than that in CA3 and, crucially, did not appear to require the involvement of fast-spiking basket cells. In contrast to CA3, we also found that optogenetic inhibition of pyramidal cells in CA1 did not significantly affect the power of the oscillation, suggesting that excitation may not be essential for gamma genesis in this region. We found that MGE-derived interneurons were generally more active than CGE interneurons during CA1 gamma, although a group of CGE-derived interneurons, putative trilaminar cells, were strongly phase-locked with gamma oscillations and, together with MGE-derived axo-axonic and bistratified cells, provide attractive candidates for being the driver of this locally generated, predominantly interneuron-driven model of gamma oscillations. C1 [Craig, Michael T.; 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 RI Craig, Michael/E-7070-2011 OI Craig, Michael/0000-0001-8481-6709 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Award FX This work was supported a Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Award to C.J.M. NR 48 TC 12 Z9 12 U1 0 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 25 PY 2015 VL 35 IS 8 BP 3616 EP 3624 DI 10.1523/JNEUROSCI.4166-14.2015 PG 9 WC Neurosciences SC Neurosciences & Neurology GA CD0CV UT WOS:000350738800032 PM 25716860 ER PT J AU Li, JY Valentin, A Ng, S Beach, RK Alicea, C Bergamaschi, C Felber, BK Pavlakis, GN AF Li, Jinyao Valentin, Antonio Ng, Sinnie Beach, Rachel Kelly Alicea, Candido Bergamaschi, Cristina Felber, Barbara K. Pavlakis, George N. TI Differential effects of IL-15 on the generation, maintenance and cytotoxic potential of adaptive cellular responses induced by DNA vaccination SO VACCINE LA English DT Article DE IL-15; Knock out; DNA vaccine; Immune response; Cytotoxic potential; HIV ID CD8(+) T-CELLS; HOMEOSTATIC PROLIFERATION; IMMUNE-RESPONSES; CUTTING EDGE; MEMORY; INFECTION; INTERLEUKIN-15; SURVIVAL; MICE; IL-15R-ALPHA AB IL-15 is an important cytokine for the regulation of lymphocyte homeostasis. However, the role of IL-15 in the generation, maintenance and cytotoxic potential of antigen specific T cells is not fully understood. Because the route of antigenic delivery and the vaccine modality could influence the IL-15 requirement for mounting and preserving cytotoxic T cell responses, we have investigated the immunogenicity of DNA-based vaccines in IL-15 KO mice. DNA vaccination with SIV Gag induced antigen-specific CD4(+) and CD8(+) T cells in the absence of IL-15. However, the absolute number of antigen-specific CD8(+) T cells was decreased in IL-15 KO mice compared to WT animals, suggesting that IL-15 is important for the generation of maximal number of antigen-specific CD8(+) T cells. Interestingly, antigen-specific memory CD8 cells could be efficiently boosted 8 months after the final vaccination in both WT and KO strains of mice, suggesting that the maintenance of antigen-specific long-term memory T cells induced by DNA vaccination is comparable in the absence and presence of IL-15. Importantly, boosting by DNA 8-months after vaccination revealed severely reduced granzyme B content in CD8(+) T cells of IL-15 KO mice compared to WT mice. This suggests that the cytotoxic potential of the long-term memory CD8(+) T cells is impaired. These results suggest that IL-15 is not essential for the generation and maintenance of adaptive cellular responses upon DNA vaccination, but it is critical for the preservation of maximal numbers and for the activity of cytotoxic CD8(+) T cells. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license C1 [Li, Jinyao; Valentin, Antonio; Ng, Sinnie; Beach, Rachel Kelly; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Beach, Rachel Kelly; Alicea, Candido; Bergamaschi, Cristina; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. RP Valentin, A (reprint author), NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. EM antonio.valentin@nih.gov; george.pavlakis@nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH) FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH). NR 46 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD FEB 25 PY 2015 VL 33 IS 9 BP 1188 EP 1196 DI 10.1016/j.vaccine.2014.12.046 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CC2QO UT WOS:000350189900014 PM 25559187 ER PT J AU Perkins, RB Zisblatt, L Legler, A Trucks, E Hanchate, A Gorin, SS AF Perkins, Rebecca B. Zisblatt, Lara Legler, Aaron Trucks, Emma Hanchate, Amresh Gorin, Sherri Sheinfeld TI Effectiveness of a provider-focused intervention to improve HPV vaccination rates in boys and girls SO VACCINE LA English DT Article DE HPV vaccination; Provider education; Intervention; Quality improvement ID HUMAN-PAPILLOMAVIRUS VACCINATION; CONTINUING MEDICAL-EDUCATION; OF-THE-LITERATURE; UNITED-STATES; DECISION-MAKING; IMMUNIZATION; ADOLESCENTS; PHYSICIAN; HEALTH; RECOMMENDATIONS AB Background: HPV vaccination is universally recommended for boys and girls, yet vaccination rates remain low nationwide. Methods: We conducted a provider-focused intervention that included repeated contacts, education, individualized feedback, and strong quality improvement incentives to raise HPV vaccination rates at two federally qualified community health centers. To estimate the effectiveness of the intervention, rates of initiation of vaccination, and completion of the next needed HPV vaccination (dose 1, 2 or 3) among boys and girls ages 11-21 were compared at baseline and two follow-up periods in two intervention health centers (n = 4093 patients) and six control health centers (n = 9025 patients). We conducted multivariable logistic regression accounting for clustering by practice. Results: Girls and boys in intervention practices significantly increased HPV vaccine initiation during the active intervention period relative to control practices (girls OR 1.6, boys OR 11; p < 0.001 for both). Boys at intervention practices were also more likely to continue to initiate vaccination during the post-intervention/maintenance period (OR 8.5; p < 0.01). Girls and boys at intervention practices were more also likely to complete their next needed HPV vaccination (dose 1, 2 or 3) than those at control practices (girls OR 1.4, boys OR 23; p < 0.05 for both). These improvements were sustained for both boys and girls in the post-intervention/maintenance period (girls OR 1.6, boys OR 25; p < 0.05 for both). Conclusions: Provider-focused interventions including repeated contacts, education, individualized feedback, and strong quality improvement incentives have the potential to produce sustained improvements in HPV vaccination rates. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Perkins, Rebecca B.] Boston Univ, Sch Med, Boston Med Ctr, Dept Obstet & Gynecol, Boston, MA 02118 USA. [Zisblatt, Lara; Trucks, Emma] Boston Univ, Sch Med Continuing Med Educ, Boston, MA 02118 USA. [Legler, Aaron] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Hanchate, Amresh] Boston Univ, Sch Med, Vet Affairs Boston Healthcare Syst, Boston, MA 02118 USA. [Gorin, Sherri Sheinfeld] NCI, Leidos Biomed Res Inc SAICI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Gorin, Sherri Sheinfeld] Herbert Irving Comprehens Canc Ctr, New York, NY USA. RP Perkins, RB (reprint author), Boston Univ, Sch Med, Boston Med Ctr, Dept Obstet & Gynecol, 85 E Concord St 6th Floor, Boston, MA 02118 USA. EM rbperkin@bu.edu FU American Cancer Society Mentored Research Scholar Grant [MRSG-09-151-01]; Glaxo-Smith-Kline FX The work of Dr. Perkins, Dr. Hanchate, and Mr. Legler on this study was supported by American Cancer Society Mentored Research Scholar Grant (MRSG-09-151-01). The Boston University Continuing Medical Education Office, which employs Dr. Zisblatt and Ms. Trucks, received an unrestricted educational grant from Glaxo-Smith-Kline that partially supported this work. The funders had no role in the design of the intervention, the design of the study, or the writing of the manuscript. Thank you to Dr. Rebecca A. Silliman for her review of drafts of this article. Thank you to Drs. Huy Nguyen, Holly Goodale, Peter Loewenthan, and Karen Kennedy for their enthusiastic leadership in the HPV vaccine interventions. NR 39 TC 18 Z9 18 U1 4 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD FEB 25 PY 2015 VL 33 IS 9 BP 1223 EP 1229 DI 10.1016/j.vaccine.2014.11.021 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CC2QO UT WOS:000350189900018 PM 25448095 ER PT J AU Fagnan, DE Yang, NN McKew, JC Lo, AW AF Fagnan, David E. Yang, N. Nora McKew, John C. Lo, Andrew W. TI Financing translation: Analysis of the NCATS rare-diseases portfolio SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article AB The portfolio of the National Center for Advancing Translational Sciences (NCATS) rare-diseases therapeutic development program comprises 28 research projects initiated at the preclinical stage. Historical data reveal substantially lower costs and higher success rates but longer preclinical timelines for the NCATS projects relative to the industry averages for early-stage translational medical research and development (R&D) typically cited in literature. Here, we evaluate the potential risks and rewards of investing in a portfolio of rare-disease therapeutics. Using a "megafund" financing structure, NCATS data, and valuation estimates from a panel of industry experts, we simulate a hypothetical megafund in which senior and junior debt yielded 5 and 8%, respectively. The simulated expected return to equity was 14.7%, corresponding to a modified internal rate of return of 21.6%. These returns and the likelihood of private-sector funding can be enhanced through third-party funding guarantees from philanthropies, patient advocacy groups, and government agencies. C1 [Fagnan, David E.; Lo, Andrew W.] MIT, Ctr Operat Res, Cambridge, MA 02142 USA. [Fagnan, David E.; Lo, Andrew W.] MIT, Sloan Sch Management, Cambridge, MA 02142 USA. [Fagnan, David E.; Lo, Andrew W.] MIT, Lab Financial Engn, Cambridge, MA 02142 USA. [Yang, N. Nora; McKew, John C.] US Natl Inst Hlth, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Lo, Andrew W.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Lo, Andrew W.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Lo, Andrew W.] AlphaSimplex Grp LLC, Cambridge, MA 02142 USA. RP Lo, AW (reprint author), MIT, Ctr Operat Res, Cambridge, MA 02142 USA. EM alo-admin@mit.edu FU MIT Laboratory for Financial Engineering; NIH, NCATS FX We gratefully acknowledge research support from the MIT Laboratory for Financial Engineering. This research was supported in part by the Intramural Research Program of the NIH, NCATS. NR 10 TC 2 Z9 2 U1 1 U2 7 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 FEB 25 PY 2015 VL 7 IS 276 AR 276ps3 DI 10.1126/scitranslmed.aaa2360 PG 7 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CB8TD UT WOS:000349903100003 PM 25717096 ER PT J AU Brownstein, KJ Knight, M Ito, Y Rottinghaus, GE Folk, WR AF Brownstein, Korey J. Knight, Martha Ito, Yoichiro Rottinghaus, George E. Folk, William R. TI Isolation of the Predominant Cycloartane Glycoside, Sutherlandioside B, from Sutherlandia frutescens (L.) R.Br. by Spiral Countercurrent Chromatography SO JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES LA English DT Article DE spiral countercurrent chromatography; spiral tubing support rotor; Sutherlandia frutescens; n-butanol-aqueous solvent systems; cycloartane glycoside; sutherlandioside ID SUPPORT AB The introduction to high-speed countercurrent chromatography of a spiral tubing support rotor has enabled the application of more polar volatile solvent systems for natural products separation, especially water soluble compounds and their metabolites. Here is reported the use of spiral countercurrent chromatography with the spiral tubing support rotor to fractionate extracts of the African medicinal plant Sutherlandia frutescens (L.) R.Br. A two-phase solvent system of ethyl acetate, methanol, water, and n-butanol, with the lower aqueous phase mobile, separated sutherlandioside B efficiently from other compounds. The purity of sutherlandioside B was determined by high-performance liquid chromatography and mass spectrometry analysis. Sufficient quantities of sutherlandioside B can be purified by this method for use in cell culture assays and the development of a sensitive antibody by which to detect the consumption and metabolism in vivo of this novel botanical. C1 [Brownstein, Korey J.; Folk, William R.] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. [Knight, Martha] CC Biotech LLC, Rockville, MD USA. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Ctr Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Rottinghaus, George E.] Univ Missouri, Vet Med Diagnost Lab, Columbia, MO USA. RP Folk, WR (reprint author), Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. EM folkw@missouri.edu OI Knight, Martha/0000-0003-4863-8858 FU NIH/National Center for Complementary and Alternative Medicine/Office of Dietary Supplements/National Cancer Center/Fogarty International Center [5U19AT003264, 1P50AT600273] FX This publication was supported by research funded by the NIH/National Center for Complementary and Alternative Medicine/Office of Dietary Supplements/National Cancer Center/Fogarty International Center grants 5U19AT003264 and 1P50AT600273. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, ODS, NCI, FIC, or the National Institutes of Health. NR 17 TC 2 Z9 2 U1 0 U2 22 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1082-6076 EI 1520-572X J9 J LIQ CHROMATOGR R T JI J. Liq. Chromatogr. Relat. Technol. PD FEB 25 PY 2015 VL 38 IS 4 BP 423 EP 429 DI 10.1080/10826076.2014.913518 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AU1HK UT WOS:000345371500001 PM 25646069 ER PT J AU Morgan, DL Merrick, BA Gerrish, KE Stockton, PS Wang, Y Foley, JF Gwinn, WM Kelly, FL Palmer, SM Ton, TVT Flake, GP AF Morgan, Daniel L. Merrick, B. Alex Gerrish, Kevin E. Stockton, Patricia S. Wang, Yu Foley, Julie F. Gwinn, William M. Kelly, Francine L. Palmer, Scott M. Ton, Thai-Vu T. Flake, Gordon P. TI Gene Expression in Obliterative Bronchiolitis-Like Lesions in 2,3-Pentanedione-Exposed Rats SO PLOS ONE LA English DT Article ID GROWTH-FACTOR-BETA; BRONCHOALVEOLAR LAVAGE FLUID; LUNG-TRANSPLANT RECIPIENTS; TGF-BETA; PULMONARY-FIBROSIS; FIBROBLAST PROLIFERATION; MEDIATED FIBROSIS; EPITHELIAL-CELLS; AIRWAY DISEASE; TENASCIN-C AB Obliterative bronchiolitis (OB) is an irreversible lung disease characterized by progressive fibrosis in the small airways with eventual occlusion of the airway lumens. OB is most commonly associated with lung transplant rejection; however, OB has also been diagnosed in workers exposed to artificial butter flavoring (ABF) vapors. Research has been limited by the lack of an adequate animal model of OB, and as a result the mechanism(s) is unclear and there are no effective treatments for this condition. Exposure of rats to the ABF component, 2,3-pentanedione (PD) results in airway lesions that are histopathologically similar to those in human OB. We used this animal model to evaluate changes in gene expression in the distal bronchi of rats with PD-induced OB. Male Wistar Han rats were exposed to 200 ppm PD or air 6 h/d, 5 d/wk for 2-wks. Bronchial tissues were laser microdissected from serial sections of frozen lung. In exposed lungs, both fibrotic and non-fibrotic airways were collected. Following RNA extraction and microarray analysis, differential gene expression was evaluated. In non-fibrotic bronchi of exposed rats, 4683 genes were significantly altered relative to air-exposed controls with notable down-regulation of many inflammatory cytokines and chemokines. In contrast, in fibrotic bronchi, 3807 genes were significantly altered with a majority of genes being up-regulated in affected pathways. Tgf-beta 2 and downstream genes implicated in fibrosis were significantly up-regulated in fibrotic lesions. Genes for collagens and extracellular matrix proteins were highly up-regulated. In addition, expression of genes for peptidases and peptidase inhibitors were significantly altered, indicative of the tissue remodeling that occurs during airway fibrosis. Our data provide new insights into the molecular mechanisms of OB. This new information is of potential significance with regard to future therapeutic targets for treatment. C1 [Morgan, Daniel L.; Merrick, B. Alex; Stockton, Patricia S.; Wang, Yu; Foley, Julie F.; Gwinn, William M.; Ton, Thai-Vu T.; Flake, Gordon P.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Gerrish, Kevin E.] NIEHS, Div Intramural Res, Res Triangle Pk, NC 27709 USA. [Kelly, Francine L.; Palmer, Scott M.] Duke Univ, Med Ctr, Durham, NC USA. RP Morgan, DL (reprint author), NIEHS, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM morgan3@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS); National Institutes of Health (NIH) FX This work was funded by the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). This article is the work product of a group of employees of the NIEHS; however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 4 Z9 5 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 FEB 24 PY 2015 VL 10 IS 2 AR e0118459 DI 10.1371/journal.pone.0118459 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC9IY UT WOS:000350683900058 PM 25710175 ER PT J AU Pedone, C Roshanravan, B Scarlata, S Patel, KV Ferrucci, L Incalzi, RA AF Pedone, Claudio Roshanravan, Baback Scarlata, Simone Patel, Kushang V. Ferrucci, Luigi Incalzi, Raffaele Antonelli TI Longitudinal Association between Serum Leptin Concentration and Glomerular Filtration Rate in Humans SO PLOS ONE LA English DT Article ID CHRONIC KIDNEY-DISEASE; BODY-MASS INDEX; STAGE RENAL-DISEASE; METABOLIC SYNDROME; OBESITY; RISK; MICROALBUMINURIA; ADIPONECTIN; ADULTS; CKD AB Background Obesity is a risk factor for decline in glomerular filtration rate (GFR). One proposed mechanism leading to glomerulopathy is an increase in leptin levels. However, the association between leptin and GFR has never been demonstrated. The aim of this study is to verify whether higher levels of leptin are associated with longitudinal changes of estimated GFR (eGFR). Methods and findings We selected 744 participants in the InCHIANTI study (416 women). The association between eGFR and leptin changes over a 6-years follow-up was assessed using random effect models including leptin as a time-varying covariate and adjusted for potential confounders. We also compared the proportion of patients with rapid decline of renal function across tertiles of change in serum leptin between baseline and 6-years follow-up. Mean baseline eGFR was 82.2 ml/min/1.73 m, 78.7 ml/min/1.73 m, and 75.4 ml/min/1.73 m in the first, second and third tertile of baseline serum leptin concentration, respectively. After adjustment for potential confounders, leptin concentration was inversely associated with changes of eGFR over time (beta for log-leptin: -1.288, 95% CI: -2.079 - -0.497). Relative to baseline levels, the estimated change in eGFR for unit-increase in log-leptin was -1.9% (95% CI: -2.977 - -0.761). After stratification by sex, the results were confirmed in women only. In women we also found an association between increasing leptin concentration over time and rapid decline of renal function. Conclusions In women, serum leptin may contribute to eGFR decline independently from obesity and diabetes mellitus, although a cause-effect relationship cannot be established due to the observational nature of our study. A better characterization of adipokine profile of obese individuals may shed light on the accelerated renal function decline reported in a proportion of high-risk obese individuals. C1 [Pedone, Claudio; Scarlata, Simone; Incalzi, Raffaele Antonelli] Campus Biomed Univ, Unit Geriatr, Rome, Italy. [Roshanravan, Baback] Univ Washington, Dept Med, Div Nephrol, Kidney Res Inst, Seattle, WA 98195 USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Ferrucci, Luigi] NIA, Longitudinal Study Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Incalzi, Raffaele Antonelli] S Raffaele Cittadella Carita Fdn, Taranto, Italy. RP Pedone, C (reprint author), Campus Biomed Univ, Unit Geriatr, Rome, Italy. EM c.pedone@unicampus.it RI Scarlata, Simone/G-6490-2010; OI Scarlata, Simone/0000-0002-2704-2708; Pedone, Claudio/0000-0003-1847-9032; Antonelli Incalzi, Raffaele/0000-0003-2100-2075 FU NIDDK NIH HHS [L30 DK099909, K23 DK099442] NR 42 TC 2 Z9 2 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 FEB 24 PY 2015 VL 10 IS 2 AR UNSP e0117828 DI 10.1371/journal.pone.0117828 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC9IY UT WOS:000350683900040 PM 25710704 ER PT J AU Barkhof, F Reich, DS AF Barkhof, Frederik Reich, Daniel S. TI Can leptomeningeal enhancement be linked to multiple sclerosis? SO NEUROLOGY LA English DT Editorial Material ID BRAIN AB Multiple sclerosis (MS) is an inflammatory, immune-mediated disease of the CNS that classically was thought to involve primarily the white matter. More recently, gray matter involvement has been recognized, in part through the use of new MRI techniques. However, MRI is far from perfect for detecting neocortical tissue damage in MS, particularly confluent subpial demyelination that can be quite extensive.(1) Subpial lesions seem to be especially prominent in cases of progressive MS, in which disability accumulates relentlessly over time, and they are thus thought to play a pathogenic role. C1 [Barkhof, Frederik] Vrije Univ Amsterdam, Med Ctr, Dept Radiol & Nucl Med, Amsterdam, Netherlands. [Reich, Daniel S.] NINDS, Neuroradiol Unit, NIH, Bethesda, MD 20892 USA. RP Barkhof, F (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Radiol & Nucl Med, Amsterdam, Netherlands. EM f.barkhof@vumc.nl RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 14 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 24 PY 2015 VL 84 IS 8 BP 762 EP 763 DI 10.1212/WNL.0000000000001292 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CC6GQ UT WOS:000350463800006 PM 25616481 ER PT J AU LeWitt, PA Kim, S AF LeWitt, Peter A. Kim, Scott TI The pharmacodynamics of placebo Expectation effects of price as a proxy for efficacy SO NEUROLOGY LA English DT Editorial Material ID PARKINSONS-DISEASE; DECEPTION AB For shoppers of luxury goods, satisfaction with a purchase might be proportionate to its expense. Suppose, however, that a patient's perception of medication benefit is similarly governed by its cost: does that make sense? Espay et al.,(1) reporting in the current issue of Neurology (R), would have us think so. Their research takes the study of placebo effect to a new dimension of inquiry by investigating treatment cost as a determinant of antiparkinsonian control. In this small but well-designed study, the authors conclude that price does matter as to how patients with Parkinson disease (PD) perceive benefit. This may be bad news for health care providers committed to cost control, especially if such a mindset assumes better results should arise from more expensive drugs. C1 [LeWitt, Peter A.] Henry Ford West Bloomfield Hosp, Parkinsons Dis & Movement Disorders Ctr, Dept Neurol, West Bloomfield Township, MI USA. [LeWitt, Peter A.] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Kim, Scott] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP LeWitt, PA (reprint author), Henry Ford West Bloomfield Hosp, Parkinsons Dis & Movement Disorders Ctr, Dept Neurol, West Bloomfield Township, MI USA. EM plewitt1@hfhs.org NR 6 TC 1 Z9 1 U1 0 U2 3 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 FEB 24 PY 2015 VL 84 IS 8 BP 766 EP 767 DI 10.1212/WNL.0000000000001294 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CC6GQ UT WOS:000350463800008 PM 25632090 ER PT J AU Zeng, XK Han, LL Singh, SR Liu, HH Neumuller, RA Yan, D Hu, YH Liu, Y Liu, W Lin, XH Hou, SX AF Zeng, Xiankun Han, Lili Singh, Shree Ram Liu, Hanhan Neumueller, Ralph A. Yan, Dong Hu, Yanhui Liu, Ying Liu, Wei Lin, Xinhua Hou, Steven X. TI Genome-wide RNAi Screen Identifies Networks Involved in Intestinal Stem Cell Regulation in Drosophila SO CELL REPORTS LA English DT Article ID TRANSGENIC RNAI; SELF-RENEWAL; BACTERIAL-INFECTION; MIDGUT HOMEOSTASIS; MULTIPLE PATHWAYS; MEDIATOR COMPLEX; PROLIFERATION; TRANSCRIPTION; DIVISION; GROWTH AB The intestinal epithelium is the most rapidly self-renewing tissue in adult animals and maintained by intestinal stem cells (ISCs) in both Drosophila and mammals. To comprehensively identify genes and pathways that regulate ISC fates, we performed a genome-wide transgenic RNAi screen in adult Drosophila intestine and identified 405 genes that regulate ISC maintenance and lineage-specific differentiation. By integrating these genes into publicly available interaction databases, we further developed functional networks that regulate ISC self-renewal, ISC proliferation, ISC maintenance of diploid status, ISC survival, ISC-to-enterocyte (EC) lineage differentiation, and ISC-to-enteroendocrine (EE) lineage differentiation. By comparing regulators among ISCs, female germline stem cells, and neural stem cells, we found that factors related to basic stem cell cellular processes are commonly required in all stem cells, and stem-cell-specific, niche-related signals are required only in the unique stem cell type. Our findings provide valuable insights into stem cell maintenance and lineage-specific differentiation. C1 [Zeng, Xiankun; Singh, Shree Ram; Liu, Hanhan; Liu, Ying; Liu, Wei; Hou, Steven X.] NCI, Basic Res Lab, NIH, Frederick, MD 21702 USA. [Han, Lili; Lin, Xinhua] Chinese Acad Sci, Inst Zool, Key Lab Stem Cell & Dev Biol, Beijing 100864, Peoples R China. [Lin, Xinhua] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA. [Neumueller, Ralph A.; Yan, Dong; Hu, Yanhui] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Neumueller, Ralph A.] Univ Munich, Gene Ctr, D-81377 Munich, Germany. [Neumueller, Ralph A.] Univ Munich, Dept Biochem, D-81377 Munich, Germany. RP Hou, SX (reprint author), NCI, Basic Res Lab, NIH, Frederick, MD 21702 USA. EM hous@mail.nih.gov RI Singh, Shree Ram/B-7614-2008; Liu, Ying /K-8883-2016 OI Singh, Shree Ram/0000-0001-6545-583X; FU Intramural Research Program of the National Cancer Institute; Nature Sciences Foundation of China [31030049, 81361120382, 31271582]; Strategic Priority Research Program of the Chinese Academy of Sciences [XDA01010101] FX We thank Shigeo Hayashi, Tiffany Cook, VDRC, the Bloomington Stock Centers, and TRiP at Harvard Medical School for fly stocks; Barry Dickson, Tiffany Cook, and DSHB for antibodies; and S. Lockett for help with the confocal microscope. Work in the laboratory of S.X.H. was supported by the Intramural Research Program of the National Cancer Institute; work in the laboratory of X.L. was supported by grants from the Nature Sciences Foundation of China (31030049, 81361120382, and 31271582) and the Strategic Priority Research Program of the Chinese Academy of Sciences Grant (XDA01010101). NR 66 TC 14 Z9 14 U1 1 U2 11 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 FEB 24 PY 2015 VL 10 IS 7 BP 1226 EP 1238 DI 10.1016/j.celrep.2015.01.051 PG 13 WC Cell Biology SC Cell Biology GA CB8YP UT WOS:000349918700017 PM 25704823 ER PT J AU Volkow, ND Baler, R AF Volkow, Nora D. Baler, Ruben TI Beliefs modulate the effects of drugs on the human brain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID REWARD; ADDICTION C1 [Volkow, Nora D.; Baler, Ruben] NIDA, NIH, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, NIH, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 12 TC 2 Z9 2 U1 0 U2 5 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 FEB 24 PY 2015 VL 112 IS 8 BP 2301 EP 2302 DI 10.1073/pnas.1500552112 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB8WE UT WOS:000349911700022 PM 25673784 ER PT J AU Hariharan, P Balasubramaniam, D Peterkofsky, A Kaback, HR Guana, L AF Hariharan, Parameswaran Balasubramaniam, Dhandayuthapani Peterkofsky, Alan Kaback, H. Ronald Guana, Lan TI Thermodynamic mechanism for inhibition of lactose permease by the phosphotransferase protein IIA(Glc) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ITC; PTS; sugar/cation symport; protein-protein interactions; protein conformation ID ESCHERICHIA-COLI; MELIBIOSE PERMEASE; SALMONELLA-TYPHIMURIUM; CATABOLITE REPRESSION; ENZYME IIA(GLC); CONFORMATIONAL FLEXIBILITY; MEMBRANE-VESICLES; SUGAR BINDING; SYSTEM; PHOSPHOENOLPYRUVATE AB In a variety of bacteria, the phosphotransferase protein IIA(Glc) plays a key regulatory role in catabolite repression in addition to its role in the vectorial phosphorylation of glucose catalyzed by the phosphoenolpyruvate: carbohydrate phosphotransferase system (PTS). The lactose permease (LacY) of Escherichia coli catalyzes stoichiometric symport of a galactoside with an H+, using a mechanism in which sugar- and H+-binding sites become alternatively accessible to either side of the membrane. Both the expression (via regulation of cAMP levels) and the activity of LacY are subject to regulation by IIA(Glc) (inducer exclusion). Here we report the thermodynamic features of the IIA(Glc)-LacY interaction as measured by isothermal titration calorimetry (ITC). The studies show that IIA(Glc) binds to LacY with a K-d of about 5 mu M and a stoichiometry of unity and that binding is driven by solvation entropy and opposed by enthalpy. Upon IIA(Glc) binding, the conformational entropy of LacY is restrained, which leads to a significant decrease in sugar affinity. By suppressing conformational dynamics, IIA(Glc) blocks inducer entry into cells and favors constitutive glucose uptake and utilization. Furthermore, the studies support the notion that sugar binding involves an induced-fit mechanism that is inhibited by IIA(Glc) binding. The precise mechanism of the inhibition of LacY by IIA(Glc) elucidated by ITC differs from the inhibition of melibiose permease (MelB), supporting the idea that permeases can differ in their thermodynamic response to binding IIA(Glc). C1 [Hariharan, Parameswaran; Guana, Lan] Texas Tech Univ, Hlth Sci Ctr, Sch Med, Ctr Membrane Prot Res,Dept Cell Physiol & Mol Bio, Lubbock, TX 79430 USA. [Balasubramaniam, Dhandayuthapani; Kaback, H. Ronald] Univ Calif Los Angeles, Dept Physiol, Los Angeles, CA 90095 USA. [Kaback, H. Ronald] Univ Calif Los Angeles, Dept Microbiol Immunol, Los Angeles, CA 90095 USA. [Kaback, H. Ronald] Univ Calif Los Angeles, Dept Mol Genet, Los Angeles, CA 90095 USA. [Kaback, H. Ronald] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [Peterkofsky, Alan] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Kaback, HR (reprint author), Univ Calif Los Angeles, Dept Physiol, Los Angeles, CA 90095 USA. EM rkaback@mednet.ucla.edu; lan.guan@ttuhsc.edu RI Parameswaran, Hariharan/P-2496-2015; OI Parameswaran, Hariharan/0000-0002-6020-1547; Guan, Lan/0000-0002-2274-361X FU National Science Foundation [MCB-1158085]; National Institutes of Health [R01 DK051131, R01 DK069463, R01 GM095538]; National Heart, Lung, and Blood Institute (the intramural research program) FX This work was supported by the National Science Foundation (Grant MCB-1158085 to L.G.), the National Institutes of Health (Grants R01 DK051131 and R01 DK069463 to H.R.K.; Grant R01 GM095538 to L.G.), and the National Heart, Lung, and Blood Institute (the intramural research program) (A.P.). NR 55 TC 4 Z9 4 U1 0 U2 10 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 FEB 24 PY 2015 VL 112 IS 8 BP 2407 EP 2412 DI 10.1073/pnas.1500891112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB8WE UT WOS:000349911700041 PM 25675534 ER PT J AU Bemben, MA Nguyen, QA Wang, TG Li, Y Nicoll, RA Roche, KW AF Bemben, Michael A. Quynh-Anh Nguyen Wang, Tongguang Li, Yan Nicoll, Roger A. Roche, Katherine W. TI Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autism; neuroligin; synaptogenesis; development; synaptic adhesion molecule ID SYNAPTIC-TRANSMISSION; CELL-ADHESION; DE-NOVO; RECEPTOR; NLGN4; PHOSPHORYLATION; NEUREXINS; NUMBER; PSD-95; GENES AB Autism spectrum disorders (ASDs) comprise a highly heritable, multifarious group of neurodevelopmental disorders, which are characterized by repetitive behaviors and impairments in social interactions. Point mutations have been identified in X-linked Neuroligin (NLGN) 3 and 4X genes in patients with ASDs and all of these reside in their extracellular domains except for a single point mutation in the cytoplasmic domain of NLGN4X in which an arginine is mutated to a cysteine (R704C). Here we show that endogenous NLGN4X is robustly phosphorylated by protein kinase C (PKC) at T707, and R704C completely eliminates T707 phosphorylation. Endogenous NLGN4X is intensely phosphorylated on T707 upon PKC stimulation in human neurons. Furthermore, a phosphomimetic mutation at T707 has a profound effect on NLGN4X-mediated excitatory potentiation. Our results now establish an important interplay between a genetic mutation, a key posttranslational modification, and robust synaptic changes, which can provide insights into the synaptic dysfunction of ASDs. C1 [Bemben, Michael A.; Roche, Katherine W.] NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. [Bemben, Michael A.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Quynh-Anh Nguyen; Nicoll, Roger A.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Quynh-Anh Nguyen; Nicoll, Roger A.] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA. [Wang, Tongguang] NINDS, Translat Neurosci Ctr, NIH, Bethesda, MD 20892 USA. [Li, Yan] NINDS, Protein Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. RP Nicoll, RA (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. EM nicoll@cmp.ucsf.edu; rochek@ninds.nih.gov OI Roche, Katherine/0000-0001-7282-6539 FU NIMH NIH HHS [R37 MH038256] NR 32 TC 7 Z9 9 U1 1 U2 6 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 FEB 24 PY 2015 VL 112 IS 8 BP 2551 EP 2556 DI 10.1073/pnas.1500501112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB8WE UT WOS:000349911700065 PM 25675530 ER PT J AU Shah, MR Cook, N Wong, R Hsue, P Ridker, P Currier, J Shurin, S AF Shah, Monica R. Cook, Nakela Wong, Renee Hsue, Priscilla Ridker, Paul Currier, Judith Shurin, Susan TI Stimulating High Impact HIV-Related Cardiovascular Research Recommendations From a Multidisciplinary NHLBI Working Group on HIV-Related Heart, Lung, and Blood Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE acquired immunodeficiency syndrome; cardiovascular disease; coronary artery disease; disease progression; inflammation; risk factors ID IMMUNODEFICIENCY-VIRUS-INFECTION; ANTIRETROVIRAL THERAPY; RISK-FACTORS; MYOCARDIAL-INFARCTION; GENERAL-POPULATION; INFLAMMATION; ATHEROSCLEROSIS; DEATH; ADULTS; PATHOGENESIS AB The clinical challenges confronting patients with human immunodeficiency virus (HIV) have shifted from acquired immunodeficiency syndrome (AIDS)-related illnesses to chronic diseases, such as coronary artery disease, chronic lung disease, and chronic anemia. With the growing burden of HIV-related heart, lung, and blood (HLB) disease, the National Heart, Lung, and Blood Institute (NHLBI) recognizes it must stimulate and support HIV-related HLB research. Because HIV offers a natural, accelerated model of common pathological processes, such as inflammation, HIV-related HLB research may yield important breakthroughs for all patients with HLB disease. This paper summarizes the cardiovascular recommendations of an NHLBI Working Group, Advancing HIV/AIDS Research in Heart, Lung, and Blood Diseases, charged with identifying scientific priorities in HIV-related HLB disease and developing recommendations to promote multidisciplinary collaboration among HIV and HLB investigators. The working group included multidisciplinary sessions, as well as HLB breakout sessions for discussion of disease-specific issues, with common themes about scientific priorities and strategies to stimulate HLB research emerging in all 3 groups. (C) 2015 by the American College of Cardiology Foundation. C1 [Shah, Monica R.; Cook, Nakela; Wong, Renee] NHLBI, Bethesda, MD 20892 USA. [Hsue, Priscilla] Univ Calif San Francisco, Sch Med, Div Cardiol, San Francisco, CA USA. [Ridker, Paul] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Currier, Judith] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Infect Dis, Los Angeles, CA 90095 USA. [Shurin, Susan] NCI, Bethesda, MD 20892 USA. RP Shah, MR (reprint author), NHLBI, 6701 Rockledge Dr,Room 8173, Bethesda, MD 20892 USA. EM shahmr@nhlbi.nih.gov FU Gilead; Amgen FX Dr. Hsue has received consulting fees from Gilead and Amgen. Dr. Ridker is listed as a coinventor on patents held by the Brigham and Women's Hospital and licensed to Seimens and AstraZeneca relating to the use of inflammatory biomarkers in cardiovascular disease and diabetes. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 59 TC 5 Z9 6 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 24 PY 2015 VL 65 IS 7 BP 738 EP 744 DI 10.1016/j.jacc.2014.12.014 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CB1BR UT WOS:000349362000011 PM 25677433 ER PT J AU Yaniv, Y Tsutsui, K Lakatta, EG AF Yaniv, Yael Tsutsui, Kenta Lakatta, Edward G. TI Potential effects of intrinsic heart pacemaker cell mechanisms on dysrhythmic cardiac action potential firing SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE arrhythmias; atrial fibrillation; coupled-clock pacemaker system; heart rate variability; sinus node disease ID TACHYCARDIA-BRADYCARDIA SYNDROME; SINOATRIAL NODE DYSFUNCTION; NONSELECTIVE CATION CHANNEL; ACUTE MYOCARDIAL-INFARCTION; SICK SINUS SYNDROME; RATE-VARIABILITY; ATRIAL-FIBRILLATION; VENTRICULAR-FIBRILLATION; CONGENITAL DEAFNESS; CATHETER ABLATION AB The heart's regular electrical activity is initiated by specialized cardiac pacemaker cells residing in the sinoatrial node. The rate and rhythm of spontaneous action potential firing of sinoatrial node cells are regulated by stochastic mechanisms that determine the level of coupling of chemical to electrical clocks within cardiac pacemaker cells. This coupled-clock system is modulated by autonomic signaling from the brain via neurotransmitter release from the vagus and sympathetic nerves. Abnormalities in brain-heart clock connections or in any molecular clock activity within pacemaker cells lead to abnormalities in the beating rate and rhythm of the pacemaker tissue that initiates the cardiac impulse. Dysfunction of pacemaker tissue can lead to tachy-brady heart rate alternation or exit block that leads to long atrial pauses and increases susceptibility to other cardiac arrhythmia. Here we review evidence for the idea that disturbances in the intrinsic components of pacemaker cells may be implemented in arrhythmia induction in the heart. C1 [Yaniv, Yael] Technion Israel Inst Technol, Biomed Engn Fac, IL-3200003 Haifa, Israel. [Tsutsui, Kenta; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Biomed Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Yaniv, Y (reprint author), Technion Israel Inst Technol, Biomed Engn Fac, IL-3200003 Haifa, Israel. EM yaely@bm.technion.ac.il; lakattae@grc.nia.nih.gov FU Intramural Research Program of the NIH; National Institute on Aging; Technion VPR Fund -Krbling Biomedical Engineering Research Fund; NSFC-ISF joint research program [398/14] FX This research was partially supported by the Intramural Research Program of the NIH, National Institute on Aging, by Technion VPR Fund -Krbling Biomedical Engineering Research Fund (YY) and by NSFC-ISF joint research program, No. 398/14 (YY). NR 84 TC 3 Z9 3 U1 0 U2 4 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 FEB 23 PY 2015 VL 6 AR 47 DI 10.3389/fphys.2015.00047 PG 8 WC Physiology SC Physiology GA CG0CB UT WOS:000352933100001 PM 25755643 ER PT J AU Winter, PW Chandris, P Fischer, RS Wu, YC Waterman, CM Shroff, H AF Winter, Peter W. Chandris, Panagiotis Fischer, Robert S. Wu, Yicong Waterman, Clare M. Shroff, Hari TI Incoherent structured illumination improves optical sectioning and contrast in multiphoton super-resolution microscopy SO OPTICS EXPRESS LA English DT Article ID 2-PHOTON MICROSCOPY; LIGHT; RESOLUTION AB Three-dimensional super-resolution imaging in thick, semi-transparent biological specimens is hindered by light scattering, which increases background and degrades both contrast and optical sectioning. We describe a simple method that mitigates these issues, improving image quality in our recently developed two-photon instant structured illumination microscope without requiring any hardware modifications to the instrument. By exciting the specimen with three laterally-structured, phase-shifted illumination patterns and post-processing the resulting images, we digitally remove both scattered and out-of-focus emissions that would otherwise contaminate our raw data. We demonstrate the improved performance of our approach in biological samples, including pollen grains, primary mouse aortic endothelial cells cultured in a three-dimensional collagen matrix and live tumor-like cell spheroids. (C) 2015 Optical Society of America C1 [Winter, Peter W.; Chandris, Panagiotis; Wu, Yicong; Shroff, Hari] Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD 20892 USA. [Fischer, Robert S.; Waterman, Clare M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Winter, PW (reprint author), Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD 20892 USA. EM peter.winter@nih.gov RI Shroff, Hari/E-7247-2016; OI Shroff, Hari/0000-0003-3613-8215; Waterman, Clare/0000-0001-6142-6775 FU National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health; National Heart, Lung, and Blood Institute of the National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering (P.W.W., P.C., Y.W., and H.S.), and the National Heart, Lung, and Blood Institute (R.S.F. and C.M.W.) of the National Institutes of Health. The NIH does not endorse or recommend any commercial products, processes, or services. The views and opinions of authors expressed here do not necessarily state or reflect those of the U.S. government and they may not be used for advertising or product endorsement purposes. We thank Christian Combs and Daniela Malide for help in rendering 3D data. NR 12 TC 5 Z9 5 U1 2 U2 19 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD FEB 23 PY 2015 VL 23 IS 4 BP 5327 EP 5334 DI 10.1364/OE.23.005327 PG 8 WC Optics SC Optics GA CD1ZH UT WOS:000350872700141 PM 25836564 ER PT J AU Chen, B Miller, AL Rebelatto, M Brewah, Y Rowe, DC Clarke, L Czapiga, M Rosenthal, K Imamichi, T Chen, Y Chang, CS Chowdhury, PS Naiman, B Wang, Y Yang, D Humbles, AA Herbst, R Sims, GP AF Chen, Bo Miller, Allison L. Rebelatto, Marlon Brewah, Yambasu Rowe, Daniel C. Clarke, Lori Czapiga, Meggan Rosenthal, Kim Imamichi, Tomozumi Chen, Yan Chang, Chew-Shun Chowdhury, Partha S. Naiman, Brian Wang, Yue Yang, De Humbles, Alison A. Herbst, Ronald Sims, Gary P. TI S100A9 Induced Inflammatory Responses Are Mediated by Distinct Damage Associated Molecular Patterns (DAMP) Receptors In Vitro and In Vivo SO PLOS ONE LA English DT Article ID GLYCATION END-PRODUCTS; BRONCHOALVEOLAR LAVAGE FLUID; INTERSTITIAL LUNG-DISEASES; ACTIVATED PROTEIN-KINASE; CALCIUM-BINDING PROTEIN; GROUP BOX-1 PROTEIN; ENDOTHELIAL-CELLS; CHEMOTACTIC ACTIVITY; RAGE; EXPRESSION AB Release of endogenous damage associated molecular patterns (DAMPs), including members of the S100 family, are associated with infection, cellular stress, tissue damage and cancer. The extracellular functions of this family of calcium binding proteins, particularly S100A8, S100A9 and S100A12, are being delineated. They appear to mediate their functions via receptor for advanced glycation endproducts (RAGE) or TLR4, but there remains considerable uncertainty over the relative physiological roles of these DAMPs and their pattern recognition receptors. In this study, we surveyed the capacity of S100 proteins to induce proinflammatory cytokines and cell migration, and the contribution RAGE and TLR4 to mediate these responses in vitro. Using adenoviral delivery of murine S100A9, we also examined the potential for S100A9 homodimers to trigger lung inflammation in vivo. S100A8, S100A9 and S100A12, but not the S100A8/ A9 heterodimer, induced modest levels of TLR4-mediated cytokine production from human PBMC. In contrast, for most S100s including S100A9, RAGE blockade inhibited S100-mediated cell migration of THP1 cells and major leukocyte populations, whereas TLR4-blockade had no effect. Intranasal administration of murine S100A9 adenovirus induced a specific, time-dependent predominately macrophage infiltration that coincided with elevated S100A9 levels and proinflammatory cytokines in the BAL fluid. Inflammatory cytokines were markedly ablated in the TLR4-defective mice, but unexpectedly the loss of TLR4 signaling or RAGE-deficiency did not appreciably impact the S100A9-mediated lung pathology or the inflammatory cell infiltrate in the alveolar space. These data demonstrate that physiological levels of S100A9 homodimers can trigger an inflammatory response in vivo, and despite the capacity of RAGE and TLR4 blockade to inhibit responses in vitro, the response is predominately independent of both these receptors. C1 [Chen, Bo; Miller, Allison L.; Rebelatto, Marlon; Brewah, Yambasu; Rowe, Daniel C.; Clarke, Lori; Czapiga, Meggan; Rosenthal, Kim; Imamichi, Tomozumi; Chen, Yan; Chang, Chew-Shun; Chowdhury, Partha S.; Naiman, Brian; Wang, Yue; Humbles, Alison A.; Herbst, Ronald; Sims, Gary P.] MedImmune LLC, Gaithersburg, MD 20878 USA. [Imamichi, Tomozumi] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Appl & Dev Directorate, Lab Human Retrovirol, Frederick, MD 21702 USA. [Yang, De] NCI, Mol Immunoregulat Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Sims, GP (reprint author), MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878 USA. EM simsg@medimmune.com FU MedImmune LLC FX This work was sponsored by MedImmune LLC. The funder provided support in the form of salaries for authors BC, ALM, MR, YB, DCR, LC MC, KR, YC, CSC, PSC, BN, YW, AAH, RH and GPS but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the author contributions section. NR 60 TC 12 Z9 12 U1 0 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 FEB 23 PY 2015 VL 10 IS 2 AR e0115828 DI 10.1371/journal.pone.0115828 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC9BI UT WOS:000350662100019 PM 25706559 ER PT J AU Erinosho, TO Pinard, CA Nebeling, LC Moser, RP Shaikh, AR Resnicow, K Oh, AY Yaroch, AL AF Erinosho, Temitope O. Pinard, Courtney A. Nebeling, Linda C. Moser, Richard P. Shaikh, Abdul R. Resnicow, Ken Oh, April Y. Yaroch, Amy L. TI Development and Implementation of the National Cancer Institute's Food Attitudes and Behaviors Survey to Assess Correlates of Fruit and Vegetable Intake in Adults SO PLOS ONE LA English DT Article ID SELF-DETERMINATION THEORY; HEALTHFUL DIETARY CHANGE; PSYCHOLOGICAL-FACTORS; PSYCHOSOCIAL FACTORS; AFRICAN-AMERICANS; US ADULTS; CONSUMPTION; MOTIVATION; EAT; RELIABILITY AB Background Low fruit and vegetable (FV) intake is a leading risk factor for chronic disease globally as well as in the United States. Much of the population does not consume the recommended servings of FV daily. This paper describes the development of psychosocial measures of FV intake for inclusion in the U.S. National Cancer Institute's 2007 Food Attitudes and Behaviors Survey. Methods This was a cross-sectional study among 3,397 adults from the United States. Scales included conventional constructs shown to be correlated with fruit and vegetable intake (FVI) in prior studies (e.g., self-efficacy, social support), and novel constructs that have been measured in few-to-no studies (e.g., views on vegetarianism, neophobia). FVI was assessed with an eight-item screener. Exploratory factor analysis, Cronbach's alpha, and regression analyses were conducted. Results Psychosocial scales with Cronbach's alpha >= 0.68 were self-efficacy, social support, perceived barriers and benefits of eating FVs, views on vegetarianism, autonomous and controlled motivation, and preference for FVs. Conventional scales that were associated (p<0.05) with FVI were self-efficacy, social support, and perceived barriers to eating FVs. Novel scales that were associated (p<0.05) with FVI were autonomous motivation, and preference for vegetables. Other single items that were associated (p<0.05) with FVI included knowledge of FV recommendations, FVI "while growing up", and daily water consumption. Conclusion These findings may inform future behavioral interventions as well as further exploration of other potential factors to promote and support FVI. C1 [Erinosho, Temitope O.] Univ N Carolina, Chapel Hill, NC USA. [Pinard, Courtney A.; Yaroch, Amy L.] Gretchen Swanson Ctr Nutr, Omaha, NE 68114 USA. [Nebeling, Linda C.; Moser, Richard P.; Shaikh, Abdul R.] US Natl Canc Inst, Rockville, MD USA. [Resnicow, Ken] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Oh, April Y.] SAIC Frederick Inc, Clin Monitoring Res Program, Natl Canc Inst Frederick, Frederick, MD USA. RP Pinard, CA (reprint author), Gretchen Swanson Ctr Nutr, Omaha, NE 68114 USA. EM cpinard@centerfornutrition.org NR 56 TC 3 Z9 3 U1 3 U2 17 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 FEB 23 PY 2015 VL 10 IS 2 AR UNSP e0115017 DI 10.1371/journal.pone.0115017 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC9BI UT WOS:000350662100006 PM 25706120 ER PT J AU Iijima, S Matsuura, K Watanabe, T Onomoto, K Fujita, T Ito, K Iio, E Miyaki, T Fujiwara, K Shinkai, N Kusakabe, A Endo, M Nojiri, S Joh, T Tanaka, Y AF Iijima, Sayuki Matsuura, Kentaro Watanabe, Tsunamasa Onomoto, Koji Fujita, Takashi Ito, Kyoko Iio, Etsuko Miyaki, Tomokatsu Fujiwara, Kei Shinkai, Noboru Kusakabe, Atsunori Endo, Mio Nojiri, Shunsuke Joh, Takashi Tanaka, Yasuhito TI Influence of Genes Suppressing Interferon Effects in Peripheral Blood Mononuclear Cells during Triple Antiviral Therapy for Chronic Hepatitis C SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; PEGYLATED INTERFERON; VIRUS-INFECTION; STIMULATED GENES; ADAPTER PROTEIN; DENDRITIC CELLS; INTERLEUKIN 28B; INNATE IMMUNITY; IL28B GENOTYPE; HCV INFECTION AB The levels of expression of interferon-stimulated genes (ISGs) in liver are associated with response to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV). However, associations between the responses of ISGs to IFN-based therapy and treatment efficacy or interleukin-28B (IL28B) genotype have not yet been determined. Therefore, we investigated the early responses of ISGs and interferon-lambdas (IFN-lambda s) in peripheral blood mononuclear cells (PBMCs) during PEG-IFN/RBV plus NS3/4 protease inhibitor (PI) therapy. We prospectively enrolled 50 chronic hepatitis C patients with HCV genotype 1, and collected PBMCs at baseline, 8 and 24 h after the initial administration of PEG-IFN/RBV/PI. Levels of mRNAs for selected ISGs and IFN-lambda s were evaluated by real-time PCR. All 31 patients with a favorable IL28B genotype and 13 of 19 with an unfavorable genotype achieved sustained virological responses (SVR). Levels of mRNA for A20, SOCS1, and SOCS3, known to suppress antiviral activity by interfering with the IFN signaling pathway, as well as IRF1 were significantly higher at 8 h in patients with an unfavorable IL28B genotype than in those with a favorable one (P = 0.007, 0.026, 0.0004, 0.0006, respectively), especially in the non-SVR group. Particularly, the fold-change of IRF1 at 8 h relative to baseline was significantly higher in non-SVR than in SVR cases with an unfavorable IL28B genotype (P = 0.035). In conclusion, levels of several mRNAs of genes suppressing antiviral activity in PBMCs during PEG-IFN/RBV/PI differed according to IL28B genotypes, paralleling treatment efficacy. C1 [Iijima, Sayuki; Matsuura, Kentaro; Watanabe, Tsunamasa; Ito, Kyoko; Iio, Etsuko; Tanaka, Yasuhito] Nagoya City Univ, Grad Sch Med Sci, Dept Virol, Nagoya, Aichi, Japan. [Iijima, Sayuki; Matsuura, Kentaro; Watanabe, Tsunamasa; Ito, Kyoko; Iio, Etsuko; Tanaka, Yasuhito] Nagoya City Univ, Grad Sch Med Sci, Liver Unit, Nagoya, Aichi, Japan. [Matsuura, Kentaro; Iio, Etsuko; Fujiwara, Kei; Shinkai, Noboru; Endo, Mio; Nojiri, Shunsuke; Joh, Takashi] Nagoya City Univ, Grad Sch Med Sci, Dept Gastroenterol & Metab, Nagoya, Aichi, Japan. [Matsuura, Kentaro] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Onomoto, Koji; Fujita, Takashi] Kyoto Univ, Inst Virus Res, Mol Genet Lab, Kyoto 606, Japan. [Miyaki, Tomokatsu] Toyokawa City Hosp, Div Internal Med, Toyokawa, Japan. [Kusakabe, Atsunori] Nagoya Daini Red Cross Hosp, Div Gastroenterol, Nagoya, Aichi, Japan. RP Tanaka, Y (reprint author), Nagoya City Univ, Grad Sch Med Sci, Dept Virol, Nagoya, Aichi, Japan. EM ytanaka@med.nagoya-cu.ac.jp FU Ministry of Health, Labour and Welfare of Japan [H25-kanen-ippan-005]; Uehara Memorial Foundation FX This study was supported in part by a grant-in-aid from the Ministry of Health, Labour and Welfare of Japan (H25-kanen-ippan-005) and The Uehara Memorial Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 3 Z9 3 U1 0 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 FEB 23 PY 2015 VL 10 IS 2 AR e0118000 DI 10.1371/journal.pone.0118000 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC9BI UT WOS:000350662100136 PM 25706116 ER PT J AU Kaul, S Mittal, SK Feigenbaum, L Kruhlak, MJ Roche, PA AF Kaul, Sunil Mittal, Sharad K. Feigenbaum, Lionel Kruhlak, Michael J. Roche, Paul A. TI Expression of the SNARE Protein SNAP-23 Is Essential for Cell Survival SO PLOS ONE LA English DT Article ID T-CELLS; MOLECULAR-MECHANISMS; PLATELET EXOCYTOSIS; CYTOTOXIC-LINEAGE; GLUCOSE-UPTAKE; MAST-CELLS; SYNTAXIN 2; DIFFERENTIATION; THYMOCYTES; PROMOTES AB Members of the SNARE-family of proteins are known to be key regulators of the membrane-membrane fusion events required for intracellular membrane traffic. The ubiquitously expressed SNARE protein SNAP-23 regulates a wide variety of exocytosis events and is essential for mouse development. Germline deletion of SNAP-23 results in early embryonic lethality in mice, and for this reason we now describe mice and cell lines in which SNAP-23 can be conditionally-deleted using Cre-lox technology. Deletion of SNAP-23 in CD19-Cre expressing mice prevents B lymphocyte development and deletion of SNAP-23 using a variety of T lymphocyte-specific Cre mice prevents T lymphocyte development. Acute depletion of SNAP-23 in mouse fibroblasts leads to rapid apoptotic cell death. These data highlight the importance of SNAP-23 for cell survival and describe a mouse in which specific cell types can be eliminated by expression of tissue-specific Cre-recombinase. C1 [Kaul, Sunil; Mittal, Sharad K.; Kruhlak, Michael J.; Roche, Paul A.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Feigenbaum, Lionel] Frederick Natl Lab Canc Res, Leidos Biomed Res, Frederick, MD USA. RP Roche, PA (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM paul.roche@nih.gov FU National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 2 Z9 2 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 23 PY 2015 VL 10 IS 2 AR e0118311 DI 10.1371/journal.pone.0118311 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC9BI UT WOS:000350662100166 PM 25706117 ER PT J AU Li, F Lee, JH Grishaev, A Ying, JF Bax, A AF Li, Fang Lee, Jung Ho Grishaev, Alexander Ying, Jinfa Bax, Ad TI High Accuracy of Karplus Equations for Relating Three-Bond J Couplings to Protein Backbone Torsion Angles SO CHEMPHYSCHEM LA English DT Article DE backbone torsion angles; DFT calculations; Karplus equation; NMR spectroscopy; protein structure ID RESIDUAL DIPOLAR COUPLINGS; NUCLEAR-MAGNETIC-RESONANCE; NMR-SPECTROSCOPY; PEPTIDE-BOND; RING SIZE; CONSTANTS; DYNAMICS; UBIQUITIN; MACROMOLECULES; ALIGNMENT AB (3)J(CC) and (3)J(HNH) couplings are related to the intervening backbone torsion angle phi by standard Karplus equations. Although these couplings are known to be affected by parameters other than phi, including H-bonding, valence angles and residue type, experimental results and quantum calculations indicate that the impact of these latter parameters is typically very small. The solution NMR structure of protein GB3, newly refined by using extensive sets of residual dipolar couplings, yields 50-60% better Karplus equation agreement between phi angles and experimental (3)J(CC) and (3)J(HNH) values than does the high-resolution X-ray structure. In intrinsically disordered proteins, (3)J(CC) and (3)J(HNH) couplings can be measured at even higher accuracy, and the impact of factors other than the intervening torsion angle on (3)J will be smaller than in folded proteins, making these couplings exceptionally valuable reporters on the ensemble of phi angles sampled by each residue. C1 [Li, Fang; Lee, Jung Ho; Grishaev, Alexander; Ying, Jinfa; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Intramural Antiviral Target Program of the Office of the Director, NIH; KVSTA Fellowship; China Scholarship Council FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by the Intramural Antiviral Target Program of the Office of the Director, NIH. J.H. Lee is the recipient of a KVSTA Fellowship and F. Li acknowledges financial support from the China Scholarship Council. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland. (http://biowulf.nih.gov). NR 46 TC 11 Z9 11 U1 2 U2 18 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1439-4235 EI 1439-7641 J9 CHEMPHYSCHEM JI ChemPhysChem PD FEB 23 PY 2015 VL 16 IS 3 BP 572 EP 578 DI 10.1002/cphc.201402704 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA CB9PM UT WOS:000349964000010 PM 25511552 ER PT J AU Kim, S Lu, ZY Wilbur, J AF Kim, Sun Lu, Zhiyong Wilbur, John TI Identifying named entities from PubMed (R) for enriching semantic categories SO BMC BIOINFORMATICS LA English DT Article DE Semantic term extraction; Natural language processing; Machine learning ID BIOMEDICAL TEXT; TERM IDENTIFICATION; CONCEPT EXTRACTION; BIOLOGICAL TEXTS; RECOGNITION; SYSTEM AB Background: Controlled vocabularies such as the Unified Medical Language System (UMLS (R)) and Medical Subject Headings (MeSH (R)) are widely used for biomedical natural language processing (NLP) tasks. However, the standard terminology in such collections suffers from low usage in biomedical literature, e.g. only 13% of UMLS terms appear in MEDLINE (R). Results: We here propose an efficient and effective method for extracting noun phrases for biomedical semantic categories. The proposed approach utilizes simple linguistic patterns to select candidate noun phrases based on headwords, and a machine learning classifier is used to filter out noisy phrases. For experiments, three NLP rules were tested and manually evaluated by three annotators. Our approaches showed over 93% precision on average for the headwords, "gene", "protein", "disease", "cell" and "cells". Conclusions: Although biomedical terms in knowledge-rich resources may define semantic categories, variations of the controlled terms in literature are still difficult to identify. The method proposed here is an effort to narrow the gap between controlled vocabularies and the entities used in text. Our extraction method cannot completely eliminate manual evaluation, however a simple and automated solution with high precision performance provides a convenient way for enriching semantic categories by incorporating terms obtained from the literature. C1 [Kim, Sun; Lu, Zhiyong; Wilbur, John] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Wilbur, J (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM wilbur@ncbi.nlm.nih.gov FU NIH, National Library of Medicine FX The authors are supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 46 TC 2 Z9 2 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD FEB 21 PY 2015 VL 16 AR 57 DI 10.1186/s12859-015-0487-2 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA CC5AY UT WOS:000350370600001 PM 25887671 ER PT J AU Greene, JM Levy, D Fung, KL Souza, PS Gottesman, MM Lavi, O AF Greene, James M. Levy, Doron Fung, King Leung Souza, Paloma S. Gottesman, Michael M. Lavi, Orit TI Modeling intrinsic heterogeneity and growth of cancer cells SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Agent-based model; Asynchronization; Integro-differential equations; Delay-differential equations; Cell density ID DRUG-RESISTANCE; MULTIDRUG-RESISTANCE; APOPTOSIS; DYNAMICS AB Intratumoral heterogeneity has been found to be a major cause of drug resistance. Cell-to-cell variation increases as a result of cancer-related alterations, which are acquired by stochastic events and further induced by environmental signals. However, most cellular mechanisms include natural fluctuations that are closely regulated, and thus lead to asynchronization of the cells, which causes intrinsic heterogeneity in a given population. Here, we derive two novel mathematical models, a stochastic agent-based model and an integro-differential equation model, each of which describes the growth of cancer cells as a dynamic transition between proliferative and quiescent states. These models are designed to predict variations in growth as a function of the intrinsic heterogeneity emerging from the durations of the cell-cycle and apoptosis, and also include cellular density dependencies. By examining the role all parameters play in the evolution of intrinsic tumor heterogeneity, and the sensitivity of the population growth to parameter values, we show that the cell-cycle length has the most significant effect on the growth dynamics. In addition, we demonstrate that the agent-based model can be approximated well by the more computationally efficient integro-differential equations when the number of cells is large. This essential step in cancer growth modeling will allow us to revisit the mechanisms of multidrug resistance by examining spatiotemporal differences of cell growth while administering a drug among the different sub-populations in a single tumor, as well as the evolution of those mechanisms as a function of the resistance level. Published by Elsevier Ltd. C1 [Greene, James M.; Levy, Doron] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Greene, James M.; Levy, Doron] Univ Maryland, Ctr Sci Computat & Math Modeling CSCAMM, College Pk, MD 20742 USA. [Fung, King Leung; Souza, Paloma S.; Gottesman, Michael M.; Lavi, Orit] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lavi, O (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 2112, Bethesda, MD 20892 USA. EM orit.lavi@nih.gov RI Silva de Souza, Paloma/C-3091-2015 OI Silva de Souza, Paloma/0000-0002-1360-1134 FU Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute; UMD-NCI Partnership for Cancer Technology; NSF/NIGMS program [DMS-0758374]; John Simon Guggenheim Memorial Foundation FX We would like to thank George Leiman, Carol Cardarelli, and all members of the Gottesman lab, Subhadra Banerjee and Karen Wolcott from the NCI FACS Core Facility, for their helpful assistance and discussions. This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute and was supported in part by a seed grant from the UMD-NCI Partnership for Cancer Technology. The work of DL was supported in part by the joint NSF/NIGMS program under Grant Number DMS-0758374, and by the John Simon Guggenheim Memorial Foundation. NR 23 TC 2 Z9 3 U1 0 U2 20 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 EI 1095-8541 J9 J THEOR BIOL JI J. Theor. Biol. PD FEB 21 PY 2015 VL 367 BP 262 EP 277 DI 10.1016/j.jtbi.2014.11.017 PG 16 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA CB3DT UT WOS:000349509100021 PM 25457229 ER PT J AU Kochenderfer, JN Dudley, ME Kassim, SH Somerville, RPT Carpenter, RO Stetler-Stevenson, M Yang, JC Phan, GQ Hughes, MS Sherry, RM Raffeld, M Feldman, S Lu, L Li, YF Ngo, LT Goy, A Feldman, T Spaner, DE Wang, ML Chen, CC Kranick, SM Nath, A Nathan, DAN Morton, KE Toomey, MA Rosenberg, SA AF Kochenderfer, James N. Dudley, Mark E. Kassim, Sadik H. Somerville, Robert P. T. Carpenter, Robert O. Stetler-Stevenson, Maryalice Yang, James C. Phan, Giao Q. Hughes, Marybeth S. Sherry, Richard M. Raffeld, Mark Feldman, Steven Lu, Lily Li, Yong F. Ngo, Lien T. Goy, Andre Feldman, Tatyana Spaner, David E. Wang, Michael L. Chen, Clara C. Kranick, Sarah M. Nath, Avindra Nathan, Debbie-Ann N. Morton, Kathleen E. Toomey, Mary Ann Rosenberg, Steven A. TI Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma and Indolent B-Cell Malignancies Can Be Effectively Treated With Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SUPPRESSOR-CELLS; CANCER-PATIENTS; CENTRAL MEMORY; TRANSPLANTATION; THERAPY; LYMPHOCYTES; LEUKEMIA; ANTIBODY; CD19; PERSISTENCE AB Purpose T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19(+) B-cell malignancies. Patients and Methods We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. Results Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/L. Conclusion This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach. (C) 2014 by American Society of Clinical Oncology C1 [Kochenderfer, James N.; Dudley, Mark E.; Kassim, Sadik H.; Somerville, Robert P. T.; Carpenter, Robert O.; Stetler-Stevenson, Maryalice; Yang, James C.; Phan, Giao Q.; Hughes, Marybeth S.; Sherry, Richard M.; Raffeld, Mark; Feldman, Steven; Lu, Lily; Li, Yong F.; Ngo, Lien T.; Nathan, Debbie-Ann N.; Morton, Kathleen E.; Toomey, Mary Ann; Rosenberg, Steven A.] NCI, Bethesda, MD 20892 USA. [Chen, Clara C.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Kranick, Sarah M.; Nath, Avindra] NINDS, NIH, Bethesda, MD 20892 USA. [Goy, Andre; Feldman, Tatyana] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Spaner, David E.] Sunybrook Odette Canc Ctr, Toronto, ON, Canada. [Wang, Michael L.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Kochenderfer, JN (reprint author), NIH, CRC, 10 Ctr Dr,Room 3-3330, Bethesda, MD 20892 USA. EM kochendj@mail.nih.gov FU Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH); NCI, NIH [HHSN261200800001E]; Kite Pharma; Surgery Branch, NCI FX Supported in part by intramural funding for the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH); by federal funds from the NCI, NIH, under Contract No. HHSN261200800001E; and by Kite Pharma through a cooperative research and development agreement with the Surgery Branch, NCI. NR 46 TC 233 Z9 248 U1 9 U2 55 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 FEB 20 PY 2015 VL 33 IS 6 BP 540 EP U31 DI 10.1200/JCO.2014.56.2025 PG 11 WC Oncology SC Oncology GA CF4MS UT WOS:000352523800007 PM 25154820 ER PT J AU Gruschus, JM Jiang, ZP Yap, TL Hill, SA Grishaev, A Piszczek, G Sidransky, E Lee, JC AF Gruschus, James M. Jiang, Zhiping Yap, Thai Leong Hill, Stephanie A. Grishaev, Alexander Piszczek, Grzegorz Sidransky, Ellen Lee, Jennifer C. TI Dissociation of glucocerebrosidase dimer in solution by its co-factor, saposin C SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Gaucher disease; Parkinson disease; NMR; AUC; alpha-synuclein ID ACID BETA-GLUCOSIDASE; SPHINGOLIPID ACTIVATOR PROTEIN; ALPHA-SYNUCLEIN; ANALYTICAL ULTRACENTRIFUGATION; PARKINSONS-DISEASE; GAUCHER-DISEASE; MUTATIONS; INTERFACE; BINDING; MOUSE AB Mutations in the gene for the lysosomal enzyme glucocerebrosidase (GCase) cause Gaucher disease and are the most common risk factor for Parkinson disease (PD). Analytical ultracentrifugation of 8 mu M GCase shows equilibrium between monomer and dimer forms. However, in the presence of its co-factor saposin C (Sap C), only monomer GCase is seen. Isothermal calorimetry confirms that Sap C associates with GCase in solution in a 1:1 complex (K-d = 2.1 +/- 1.1 mu M). Saturation cross-transfer NMR determined that the region of Sap C contacting GCase includes residues 63-66 and 74-76, which is distinct from the region known to enhance GCase activity. Because alpha-synuclein (alpha-syn), a protein closely associated with PD etiology, competes with Sap C for GCase binding, its interaction with GCase was also measured by ultracentrifugation and saturation cross-transfer. Unlike Sap C, binding of a-syn to GCase does not affect multimerization. However, adding alpha-syn reduces saturation cross-transfer from Sap C to GCase, confirming displacement. To explore where Sap C might disrupt multimeric GCase, GCase x-ray structures were analyzed using the program PISA, which predicted stable dimer and tetramer forms. For the most frequently predicted multimer interface, the GCase active sites are partially buried, suggesting that Sap C might disrupt the multimer by binding near the active site. Published by Elsevier Inc. C1 [Gruschus, James M.; Jiang, Zhiping; Yap, Thai Leong; Hill, Stephanie A.; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Grishaev, Alexander] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Piszczek, Grzegorz] NHLBI, Biophys Core, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Gruschus, JM (reprint author), NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. EM gruschuj@helix.nih.gov; leej4@mail.nih.gov RI Lee, Jennifer/E-9658-2015 OI Lee, Jennifer/0000-0003-0506-8349 FU Intramural Research Program at the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Human Genome Research Institute (NHGRI); U.S. Department of Energy [W-31-109-ENG-38] FX This work was supported by the Intramural Research Program at the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Human Genome Research Institute (NHGRI). Recombinant GCase was a gift from Protalix Biotherapeutics (Carmiel, Israel). The Sap C plasmid was provided by Gilbert Prive (University of Toronto, Toronto, ON). We thank Nico Tjandra (NHLBI) for his advice regarding the NMR experiments and the use of NMR spectrometers, and Duck-Yeon Lee (NHLBI Biochemistry Core Facility) for his assistance with the mass spectrometry and analysis. We thank S. Seifert and X. Zuo for assistance with SAXS data collection and gratefully acknowledge use of the Advanced Photon Source, supported by the U.S. Department of Energy, contract No. W-31-109-ENG-38, and the shared scattering beamline resource allocated under the PUP-77 agreement between NCI, NIH, and the Argonne National Laboratory. NR 30 TC 5 Z9 5 U1 3 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 20 PY 2015 VL 457 IS 4 BP 561 EP 566 DI 10.1016/j.bbrc.2015.01.024 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CD1MK UT WOS:000350838800012 PM 25600808 ER PT J AU D'Souza, MP Yang, OO AF D'Souza, Marie Patricia Yang, Otto O. TI Adenovirus vectors as HIV-1 vaccines: where are we? What next? SO AIDS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYTOTOXIC T-LYMPHOCYTES; GAG/POL/NEF VACCINE; HVTN 503/PHAMBILI; IMMUNE-RESPONSES; RHESUS MACAQUES; CELL RESPONSES; INFECTED CELLS; EFFICACY TRIAL; SOUTH-AFRICA C1 [D'Souza, Marie Patricia] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Yang, Otto O.] Univ Calif Los Angeles, Div Infect Dis, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Yang, Otto O.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Yang, Otto O.] AIDS Healthcare Fdn, Los Angeles, CA USA. RP Yang, OO (reprint author), Univ Calif Los Angeles, Div Infect Dis, BSRB 173,615 Charles E Young Dr South, Los Angeles, CA 90095 USA. EM oyang@mednet.ucla.edu FU AIDS Healthcare Foundation; NIH Vaccine Trials Network FX O.O.Y.'s contribution to this article was supported by grants from AIDS Healthcare Foundation and the NIH Vaccine Trials Network. M.P.D'S. and O.O.Y. had equal roles in conceiving and writing this manuscript. NR 55 TC 1 Z9 1 U1 3 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD FEB 20 PY 2015 VL 29 IS 4 BP 395 EP 400 DI 10.1097/QAD.0000000000000548 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA CA6FG UT WOS:000349004400001 PM 25630039 ER PT J AU Tan, HY Yong, YK Andrade, BB Shankar, EM Ponnampalavanar, S Omar, SFS Narendran, G Kamarulzaman, A Swaminathan, S Sereti, I Crowe, SM French, MA AF Tan, Hong Yien Yong, Yean Kong Andrade, Bruno B. Shankar, Esaki M. Ponnampalavanar, Sasheela Omar, Sharifah F. S. Narendran, Gopalan Kamarulzaman, Adeeba Swaminathan, Soumya Sereti, Irini Crowe, Suzanne M. French, Martyn A. TI Plasma interleukin-18 levels are a biomarker of innate immune responses that predict and characterize tuberculosis-associated immune reconstitution inflammatory syndrome SO AIDS LA English DT Article DE antiretroviral therapy; CXCL10; HIV; interferon-gamma; interleukin-18; interleukin-18 binding protein; sCD14; tuberculosis-associated immune reconstitution inflammatory syndrome; tuberculosis ID IL-18 BINDING-PROTEIN; HIV-INFECTED PATIENTS; CD4(+) T-CELLS; ANTIRETROVIRAL THERAPY; RESTORATION DISEASE; RISK-FACTORS; GENE-EXPRESSION; TH1 CYTOKINE; PATHOGENESIS; DEFINITIONS AB Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a substantial problem in HIV/TB coinfected patients commencing antiretroviral therapy (ART). The immunopathogenesis of TB-IRIS includes increased production of proinflammatory chemokines and cytokines, including interleukin-18, which is a signature cytokine of the nucleotide-binding domain and leucine-rich repeat pyrin containing protein-3 inflammasome. We compared plasma levels of interleukin-18 and other biomarkers of monocyte/macrophage activation in the prediction and characterization of TB-IRIS. Methods: Biomarkers were assayed pre-ART and during TB-IRIS, or equivalent time-point, in a case-control study of Malaysian HIV patients with paradoxical or unmasking TB-IRIS (n = 15), TB no IRIS (n = 14), and no TB or IRIS (n = 15). Findings for interleukin-18 were verified in another cohort of patients with paradoxical TB-IRIS (n = 26) and their controls (n = 22) from India. Results: Interleukin-18 was higher in TB-IRIS patients pre-ART and during the event in both Malaysian patients (P < 0.0001) and Indian patients (P < 0.01). CXCL10 was higher pre-ART (P < 0.001), mainly in paradoxical TB-IRIS patients, and during TB-IRIS (P < 0.001), whereas CXCL8 was only higher during TB-IRIS (P < 0.001). Soluble(s) CD14 was increased in all patients with HIV/TB coinfection pre-ART and during TB-IRIS or equivalent time-point, compared with patients without TB. In contrast, interferon-g was lower before and during TB-IRIS. By receiver operating curve analysis, CXCL10, and/or interleukin-18 pre-ART were predictive of TB-IRIS. Conclusion: Plasma interleukin-18 levels pre-ART are candidate biomarkers for predicting paradoxical and unmasking TB-IRIS and should be investigated for risk stratification and elucidation of disease pathogenesis. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved. C1 [Tan, Hong Yien; Yong, Yean Kong; Shankar, Esaki M.; Ponnampalavanar, Sasheela; Omar, Sharifah F. S.; Kamarulzaman, Adeeba] Univ Malaya, Fac Med, Ctr Excellence Res AIDS CERiA, Kuala Lumpur, Malaysia. [Andrade, Bruno B.; Sereti, Irini] NIAID, NIH, Bethesda, MD 20892 USA. [Shankar, Esaki M.] Univ Malaya, Fac Med, Med Ctr, TIDREC,Dept Med Microbiol, Kuala Lumpur, Malaysia. [Ponnampalavanar, Sasheela; Omar, Sharifah F. S.; Kamarulzaman, Adeeba] Univ Malaya, Dept Med, Med Ctr, Infect Dis Unit, Kuala Lumpur, Malaysia. [Narendran, Gopalan; Swaminathan, Soumya] Natl Inst Res TB, Madras, Tamil Nadu, India. [Crowe, Suzanne M.] Macfarlane Burnet Inst Med Res & Publ Hlth, Ctr Biomed Res, Melbourne, Vic, Australia. [Crowe, Suzanne M.] Alfred Hosp, Infect Dis Unit, Melbourne, Vic, Australia. [Crowe, Suzanne M.] Monash Univ, Dept Infect Dis, Melbourne, Vic 3004, Australia. [French, Martyn A.] Univ Western Australia, Sch Pathol & Lab Med, Perth, WA 6009, Australia. [French, Martyn A.] Royal Perth Hosp, Dept Clin Immunol, Perth, WA 6001, Australia. [French, Martyn A.] PathWest Lab Med, Perth, WA, Australia. RP French, MA (reprint author), Univ Western Australia, Sch Pathol & Lab Med, Level 2,MRF Bldg,50 Murray St, Perth, WA 6000, Australia. EM martyn.french@uwa.edu.au RI Yong, Yean Kong/Q-5318-2016; Yong, Yean Kong/B-9202-2017 OI Yong, Yean Kong/0000-0002-8409-6251 FU University of Malaya, Ministry of Education High Impact Research Grant [H-20001-E000001]; University of Malaya; Australian National Health and Medical Research Council (NHMRC); NIAID/NIH; NIH FX Source of funding: This work was supported by a University of Malaya, Ministry of Education High Impact Research Grant (H-20001-E000001). H.Y.T. was funded by the Graduate Research Assistantship Schemes 2010-2012, University of Malaya. S.M.C. is supported by an Australian National Health and Medical Research Council (NHMRC) Principal Research Fellowship. The work of B.B.A. and I.S. is supported by the Intramural Research Program of NIAID/NIH and the study conducted on patients in the Chennai cohort was supported in part by the NIH Intramural-to-India Program 2008. NR 44 TC 11 Z9 12 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD FEB 20 PY 2015 VL 29 IS 4 BP 421 EP 431 DI 10.1097/QAD.0000000000000557 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA CA6FG UT WOS:000349004400004 PM 25565499 ER PT J AU Li, Y Graubard, BI Huang, P Gastwirth, JL AF Li, Y. Graubard, B. I. Huang, P. Gastwirth, J. L. TI Extension of the Peters-Belson method to estimate health disparities among multiple groups using logistic regression with survey data SO STATISTICS IN MEDICINE LA English DT Article DE Taylor linearization; complex survey data; multinomial logistic regression; proportional odds logistic regression; unexplained disparity ID BLINDER-OAXACA DECOMPOSITION; MODELS; EMPLOYMENT AB Determining the extent of a disparity, if any, between groups of people, for example, race or gender, is of interest in many fields, including public health for medical treatment and prevention of disease. An observed difference in the mean outcome between an advantaged group (AG) and disadvantaged group (DG) can be due to differences in the distribution of relevant covariates. The Peters-Belson (PB) method fits a regression model with covariates to the AG to predict, for each DG member, their outcome measure as if they had been from the AG. The difference between the mean predicted and the mean observed outcomes of DG members is the (unexplained) disparity of interest. We focus on applying the PB method to estimate the disparity based on binary/multinomial/proportional odds logistic regression models using data collected from complex surveys with more than one DG. Estimators of the unexplained disparity, an analytic variance-covariance estimator that is based on the Taylor linearization variance-covariance estimation method, as well as a Wald test for testing a joint null hypothesis of zero for unexplained disparities between two or more minority groups and a majority group, are provided. Simulation studies with data selected from simple random sampling and cluster sampling, as well as the analyses of disparity in body mass index in the National Health and Nutrition Examination Survey 1999-2004, are conducted. Empirical results indicate that the Taylor linearization variance-covariance estimation is accurate and that the proposed Wald test maintains the nominal level. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Li, Y.; Huang, P.] Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. [Graubard, B. I.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Gastwirth, J. L.] George Washington Univ, Dept Stat, Washington, DC 20052 USA. RP Li, Y (reprint author), Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. EM yli6@umd.edu FU Intramural NIH HHS [Z99 CA999999] NR 34 TC 0 Z9 0 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD FEB 20 PY 2015 VL 34 IS 4 BP 595 EP 612 DI 10.1002/sim.6357 PG 18 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA AZ7TM UT WOS:000348420600005 PM 25382235 ER PT J AU Kreitman, RJ AF Kreitman, Robert J. TI Removing a hair of doubt about BRAF targeting SO BLOOD LA English DT Editorial Material ID CELL LEUKEMIA C1 NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NIH, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 0 U2 1 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 FEB 19 PY 2015 VL 125 IS 8 BP 1199 EP 1200 PG 2 WC Hematology SC Hematology GA CD1FI UT WOS:000350819600002 PM 25700421 ER PT J AU Uldrick, TS Little, RF AF Uldrick, Thomas S. Little, Richard F. TI How I treat classical Hodgkin lymphoma in patients infected with human immunodeficiency virus SO BLOOD LA English DT Review ID EPSTEIN-BARR-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; STEM-CELL TRANSPLANTATION; POSITRON-EMISSION-TOMOGRAPHY; REED-STERNBERG CELLS; INTERNATIONAL PROGNOSTIC SCORE; TUMOR-ASSOCIATED MACROPHAGES; AIDS MALIGNANCY CONSORTIUM; LATENT MEMBRANE PROTEIN-1; ITALIAN COOPERATIVE GROUP AB HIV-associated classical Hodgkin lymphoma (HIV-cHL) is an important complication of HIV disease in the era of effective combination anti retroviral therapy(cART). Generally, newly diagnosed HIV-cHL should be managed with curative intent. With modern HIV therapeutics, HIV-cHL treatment outcomes are largely comparable to those of the background population with cHL (non HIV-cHL). To achieve these outcomes, particular attention must be given to managing HIV. This management includes understanding HIV as a comorbid condition with a spectrum of impact that is unique to each patient. Meticulous attention to drug-drug interactions is required to avoid toxicity and pharmacokinetic effects that can undermine cure. Relapsed and refractory HIV-cHL poses additional therapeutic challenges. The standard management in this setting should also be based on that for non HIV-cHL, and includes the use of salvage chemotherapy followed by autologous stem cell transplant in chemosensitive disease. The role of allogeneic hematopoietic stem cell transplant is less clear but may be useful in select cases. Newer agents with activity in cHL are being tested as part of primary and salvage therapy and are also highly relevant for HIV-cHL. C1 [Uldrick, Thomas S.; Little, Richard F.] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Little, Richard F.] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Little, RF (reprint author), 9609 Med Ctr Dr,MSC 9739, Bethesda, MD 20892 USA. EM richard_little@nih.gov FU National Institutes of Health; Cancer Therapy Evaluation Program of the National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health and the Cancer Therapy Evaluation Program of the National Cancer Institute. NR 88 TC 12 Z9 12 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 19 PY 2015 VL 125 IS 8 BP 1226 EP 1235 DI 10.1182/blood-2014-08-551598 PG 10 WC Hematology SC Hematology GA CD1FI UT WOS:000350819600008 PM 25499453 ER PT J AU Lozier, JN Calvo, KR AF Lozier, Jay N. Calvo, Katherine R. TI Effect of viral decontamination measures on Wright-stained blood smears SO BLOOD LA English DT Letter ID EBOLA; INACTIVATION; VIRUSES; MARBURG; LASSA C1 [Lozier, Jay N.; Calvo, Katherine R.] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Lozier, JN (reprint author), NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Room 2C306,MSC 1508,10 Ctr Dr, Bethesda, MD 20892 USA. EM lozierjn@cc.nih.gov FU CLC NIH HHS [CL080014]; Intramural NIH HHS NR 6 TC 1 Z9 1 U1 1 U2 2 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 FEB 19 PY 2015 VL 125 IS 8 BP 1350 EP 1351 PG 2 WC Hematology SC Hematology GA CD1FI UT WOS:000350819600021 PM 25700425 ER PT J AU Kaur, H De Muyt, A Lichten, M AF Kaur, Hardeep De Muyt, Arnaud Lichten, Michael TI Top3-Rmi1 DNA Single-Strand Decatenase Is Integral to the Formation and Resolution of Meiotic Recombination Intermediates SO MOLECULAR CELL LA English DT Article ID TOPOISOMERASE-III-ALPHA; SACCHAROMYCES-CEREVISIAE; HOMOLOGOUS RECOMBINATION; GENOME STABILITY; JOINT MOLECULES; SGS1 HELICASE; MUS81/MMS4 ENDONUCLEASE; MITOTIC RECOMBINATION; SYNDROME GENES; BUDDING YEAST AB The topoisomerase III (Top3)-Rmi1 heterodimer, which catalyzes DNA single-strand passage, forms a conserved complex with the Bloom's helicase (BLM, Sgs1 in budding yeast). This complex has been proposed to regulate recombination by disassembling double Holliday junctions in a process called dissolution. Top3-Rmi1 has been suggested to act at the end of this process, resolving hemicatenanes produced by earlier BLM/Sgs1 activity. We show here that, to the contrary, Top3-Rmi1 acts in all meiotic recombination functions previously associated with Sgs1, most notably as an early recombination intermediate chaperone, promoting regulated crossover and noncrossover recombination and preventing aberrant recombination intermediate accumulation. In addition, we show that Top3-Rmi1 has important Sgs1-independent functions that ensure complete recombination intermediate resolution and chromosome segregation. These findings indicate that Top3-Rmi1 activity is important throughout recombination to resolve strand crossings that would otherwise impede progression through both early steps of pathway choice and late steps of intermediate resolution. C1 [Kaur, Hardeep; De Muyt, Arnaud; Lichten, Michael] NCI, Lab Biochem & Mol Biol, Bethesda, MD 20892 USA. RP Lichten, M (reprint author), NCI, Lab Biochem & Mol Biol, Bethesda, MD 20892 USA. EM mlichten@helix.nih.gov RI Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 FU Intramural Research Program of the NIH through the Center for Cancer Research at the National Cancer Institute FX We thank Angelika Amon, Ian Hickson, and Alain Nicolas for plasmids used in strain construction, Shangming Tang, Neil Hunter, and Wolf-Dietrich Heyer for communicating unpublished data, and Dhruba Chattoraj, Jianhong Chen, Julia Cooper, Michael Klutstein, Bruce Paterson, and Yikang Rong for comments. This work was supported by the Intramural Research Program of the NIH through the Center for Cancer Research at the National Cancer Institute. NR 66 TC 18 Z9 18 U1 2 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 FEB 19 PY 2015 VL 57 IS 4 BP 583 EP 594 DI 10.1016/j.molcel.2015.01.020 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CC0BR UT WOS:000350000500004 PM 25699707 ER PT J AU Gostic, KM Kucharski, AJ Lloyd-Smith, JO AF Gostic, Katelyn M. Kucharski, Adam J. Lloyd-Smith, James O. TI Effectiveness of traveller screening for emerging pathogens is shaped by epidemiology and natural history of infection SO ELIFE LA English DT Article ID ACUTE RESPIRATORY SYNDROME; MARBURG HEMORRHAGIC-FEVER; INFLUENZA-A H7N9; MIDDLE-EAST; SYNDROME CORONAVIRUS; VIRUS-INFECTION; INTERNATIONAL AIRPORT; MERS CORONAVIRUS; RISK-FACTORS; EBOLA-VIRUS AB During outbreaks of high-consequence pathogens, airport screening programs have been deployed to curtail geographic spread of infection. The effectiveness of screening depends on several factors, including pathogen natural history and epidemiology, human behavior, and characteristics of the source epidemic. We developed a mathematical model to understand how these factors combine to influence screening outcomes. We analyzed screening programs for six emerging pathogens in the early and late stages of an epidemic. We show that the effectiveness of different screening tools depends strongly on pathogen natural history and epidemiological features, as well as human factors in implementation and compliance. For pathogens with longer incubation periods, exposure risk detection dominates in growing epidemics, while fever becomes a better target in stable or declining epidemics. For pathogens with short incubation, fever screening drives detection in any epidemic stage. However, even in the most optimistic scenario arrival screening will miss the majority of cases. C1 [Gostic, Katelyn M.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Kucharski, Adam J.] Ctr Math Modelling Infect Dis, Dept Infect Dis Epidemiol, London Sch Trop Hyg & Med, London, England. [Lloyd-Smith, James O.] Fogarty Int Ctr, Natl Inst Hlth, Bethesda, MD USA. RP Gostic, KM (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. EM kgostic@ucla.edu RI Lloyd-Smith, James/K-4080-2012 OI Lloyd-Smith, James/0000-0001-7941-502X FU National Institutes of Health [T32-GM008185]; Medical Research Council [MR/K021524/1]; U.S. Department of Homeland Security; Fogarty International Center; National Science Foundation [EF-0928690] FX National Institutes of Health T32-GM008185 Katelyn M Gostic; Medical Research Council MR/K021524/1 Adam J Kucharski; U.S. Department of Homeland Security RAPIDD Program James O Lloyd-Smith, Adam J Kucharski; Fogarty International Center RAPIDD Program James O Lloyd-Smith, Adam J Kucharski; National Science Foundation EF-0928690 James O Lloyd-Smith; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 51 TC 1 Z9 1 U1 1 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 FEB 19 PY 2015 VL 4 AR e05564 DI 10.7554/eLife.05564 PG 16 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CB7QA UT WOS:000349821200001 ER PT J AU Blair, RJR Leibenluft, E Pine, DS AF Blair, R. James R. Leibenluft, Ellen Pine, Daniel S. TI Conduct Disorder and Callous-Unemotional Traits in Youth REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Blair, R. James R.; Leibenluft, Ellen; Pine, Daniel S.] NIMH, Bethesda, MD 20892 USA. RP Blair, RJR (reprint author), NIMH, Bethesda, MD 20892 USA. EM jamesblair@mail.nih.gov NR 1 TC 3 Z9 3 U1 3 U2 17 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 FEB 19 PY 2015 VL 372 IS 8 BP 784 EP 784 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CB7PB UT WOS:000349818700023 PM 25693027 ER PT J AU Kundaje, A Meuleman, W Ernst, J Bilenky, M Yen, A Heravi-Moussavi, A Kheradpour, P Zhang, Z Wang, J Ziller, MJ Amin, V Whitaker, JW Schultz, MD Ward, LD Sarkar, A Quon, G Sandstrom, RS Eaton, ML Wu, YC Pfenning, AR Wang, X Claussnitzer, M Liu, Y Coarfa, C Harris, RA Shoresh, N Epstein, CB Gjoneska, E Leung, D Xie, W Hawkins, RD Lister, R Hong, C Gascard, P Mungall, AJ Moore, R Chuah, E Tam, A Canfield, TK Hansen, RS Kaul, R Sabo, PJ Bansal, MS Carles, A Dixon, JR Farh, KH Feizi, S Karlic, R Kim, AR Kulkarni, A Li, D Lowdon, R Elliott, G Mercer, TR Neph, SJ Onuchic, V Polak, P Rajagopal, N Ray, P Sallari, RC Siebenthall, KT Sinnott-Armstrong, NA Stevens, M Thurman, RE Wu, J Zhang, B Zhou, X Beaudet, AE Boyer, LA De Jager, PL Farnham, PJ Fisher, SJ Haussler, D Jones, SJM Li, W Marra, MA McManus, MT Sunyaev, S Thomson, JA Tlsty, TD Tsai, LH Wang, W Waterland, RA Zhang, MQ Chadwick, LH Bernstein, BE Costello, JF Ecker, JR Hirst, M Meissner, A Milosavljevic, A Ren, B Stamatoyannopoulos, JA Wang, T Kellis, M AF Kundaje, Anshul Meuleman, Wouter Ernst, Jason Bilenky, Misha Yen, Angela Heravi-Moussavi, Alireza Kheradpour, Pouya Zhang, Zhizhuo Wang, Jianrong Ziller, Michael J. Amin, Viren Whitaker, John W. Schultz, Matthew D. Ward, Lucas D. Sarkar, Abhishek Quon, Gerald Sandstrom, Richard S. Eaton, Matthew L. Wu, Yi-Chieh Pfenning, Andreas R. Wang, Xinchen Claussnitzer, Melina Liu, Yaping Coarfa, Cristian Harris, R. Alan Shoresh, Noam Epstein, Charles B. Gjoneska, Elizabeta Leung, Danny Xie, Wei Hawkins, R. David Lister, Ryan Hong, Chibo Gascard, Philippe Mungall, Andrew J. Moore, Richard Chuah, Eric Tam, Angela Canfield, Theresa K. Hansen, R. Scott Kaul, Rajinder Sabo, Peter J. Bansal, Mukul S. Carles, Annaick Dixon, Jesse R. Farh, Kai-How Feizi, Soheil Karlic, Rosa Kim, Ah-Ram Kulkarni, Ashwinikumar Li, Daofeng Lowdon, Rebecca Elliott, GiNell Mercer, Tim R. Neph, Shane J. Onuchic, Vitor Polak, Paz Rajagopal, Nisha Ray, Pradipta Sallari, Richard C. Siebenthall, Kyle T. Sinnott-Armstrong, Nicholas A. Stevens, Michael Thurman, Robert E. Wu, Jie Zhang, Bo Zhou, Xin Beaudet, Arthur E. Boyer, Laurie A. De Jager, Philip L. Farnham, Peggy J. Fisher, Susan J. Haussler, David Jones, Steven J. M. Li, Wei Marra, Marco A. McManus, Michael T. Sunyaev, Shamil Thomson, James A. Tlsty, Thea D. Tsai, Li-Huei Wang, Wei Waterland, Robert A. Zhang, Michael Q. Chadwick, Lisa H. Bernstein, Bradley E. Costello, Joseph F. Ecker, Joseph R. Hirst, Martin Meissner, Alexander Milosavljevic, Aleksandar Ren, Bing Stamatoyannopoulos, John A. Wang, Ting Kellis, Manolis CA Roadmap Epigenomics Consortium TI Integrative analysis of 111 reference human epigenomes SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; EMBRYONIC STEM-CELLS; DYNAMIC DNA METHYLATION; CHROMATIN-STATE; HISTONE MODIFICATIONS; RISK LOCI; TRANSCRIPTION FACTORS; ALZHEIMERS-DISEASE; REGULATORY REGIONS; MAMMALIAN GENOMES AB The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease. C1 [Kundaje, Anshul; Meuleman, Wouter; Ernst, Jason; Yen, Angela; Kheradpour, Pouya; Zhang, Zhizhuo; Wang, Jianrong; Ward, Lucas D.; Sarkar, Abhishek; Quon, Gerald; Eaton, Matthew L.; Wu, Yi-Chieh; Pfenning, Andreas R.; Wang, Xinchen; Claussnitzer, Melina; Liu, Yaping; Bansal, Mukul S.; Feizi, Soheil; Kim, Ah-Ram; Sallari, Richard C.; Sinnott-Armstrong, Nicholas A.; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Kundaje, Anshul; Meuleman, Wouter; Ernst, Jason; Yen, Angela; Kheradpour, Pouya; Zhang, Zhizhuo; Wang, Jianrong; Ziller, Michael J.; Ward, Lucas D.; Sarkar, Abhishek; Quon, Gerald; Eaton, Matthew L.; Wu, Yi-Chieh; Pfenning, Andreas R.; Wang, Xinchen; Claussnitzer, Melina; Liu, Yaping; Shoresh, Noam; Epstein, Charles B.; Gjoneska, Elizabeta; Bansal, Mukul S.; Farh, Kai-How; Feizi, Soheil; Kim, Ah-Ram; Polak, Paz; Sallari, Richard C.; Sinnott-Armstrong, Nicholas A.; De Jager, Philip L.; Sunyaev, Shamil; Tsai, Li-Huei; Bernstein, Bradley E.; Meissner, Alexander; Kellis, Manolis] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Kundaje, Anshul] Stanford Univ, Dept Genet, Dept Comp Sci, Stanford, CA 94305 USA. [Ernst, Jason] Univ Calif Davis, Dept Biol Chem, Los Angeles, CA 90095 USA. [Bilenky, Misha; Heravi-Moussavi, Alireza; Mungall, Andrew J.; Moore, Richard; Chuah, Eric; Tam, Angela; Jones, Steven J. M.; Marra, Marco A.; Hirst, Martin] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada. [Ziller, Michael J.; Meissner, Alexander] Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Amin, Viren; Coarfa, Cristian; Harris, R. Alan; Onuchic, Vitor; Milosavljevic, Aleksandar] Baylor Coll Med, Epigenome Ctr, Houston, TX 77030 USA. [Whitaker, John W.; Leung, Danny; Xie, Wei; Hawkins, R. David; Dixon, Jesse R.; Rajagopal, Nisha; Wang, Wei; Ren, Bing] Univ Calif San Diego, Inst Genom Med, Dept Cellular & Mol Med, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Schultz, Matthew D.; Lister, Ryan; Ecker, Joseph R.] Howard Hughes Med Inst, Genom Anal Lab, La Jolla, CA 92037 USA. [Schultz, Matthew D.; Lister, Ryan; Ecker, Joseph R.] Salk Inst Biol Studies, La Jolla, CA 92037 USA. [Sandstrom, Richard S.; Canfield, Theresa K.; Sabo, Peter J.; Neph, Shane J.; Siebenthall, Kyle T.; Thurman, Robert E.; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Wang, Xinchen; Boyer, Laurie A.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Gjoneska, Elizabeta; Tsai, Li-Huei] MIT, Picower Inst Learning & Memory, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Leung, Danny; Xie, Wei; Hawkins, R. David; Dixon, Jesse R.; Rajagopal, Nisha; Ren, Bing] Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Hong, Chibo; Costello, Joseph F.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Neurosurg, San Francisco, CA 94158 USA. [Gascard, Philippe; Tlsty, Thea D.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. [Hansen, R. Scott; Kaul, Rajinder] Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98121 USA. [Bansal, Mukul S.] Univ Connecticut, Dept Comp Sci & Engn, Storrs, CT 06269 USA. [Carles, Annaick; Hirst, Martin] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V6T 1Z4, Canada. [Carles, Annaick; Hirst, Martin] Univ British Columbia, Ctr High Throughput Biol, Vancouver, BC V6T 1Z4, Canada. [Karlic, Rosa] Univ Zagreb, Div Biol, Dept Mol Biol, Bioinformat Grp, Zagreb 10000, Croatia. [Kulkarni, Ashwinikumar; Ray, Pradipta; Zhang, Michael Q.] Univ Texas Dallas, Dept Mol & Cell Biol, Ctr Syst Biol, NSERL, Dallas, TX 75080 USA. [Li, Daofeng; Lowdon, Rebecca; Elliott, GiNell; Stevens, Michael; Zhang, Bo; Zhou, Xin; Wang, Ting] Washington Univ, Dept Genet, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA. [Mercer, Tim R.] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia. [Polak, Paz; De Jager, Philip L.; Sunyaev, Shamil] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wu, Jie] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. [Wu, Jie] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Beaudet, Arthur E.] Baylor Coll Med, Mol & Human Genet Dept, Houston, TX 77030 USA. [De Jager, Philip L.; Sunyaev, Shamil] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Farnham, Peggy J.] Univ So Calif, Keck Sch Med, Dept Biochem, Los Angeles, CA 90089 USA. [Fisher, Susan J.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Haussler, David] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Jones, Steven J. M.] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada. [Jones, Steven J. M.; Marra, Marco A.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 1Z4, Canada. [Li, Wei] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [McManus, Michael T.] Univ Calif San Francisco, Ctr Diabet, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Thomson, James A.] Univ Wisconsin, Madison, WI 53715 USA. [Waterland, Robert A.] Baylor Coll Med, USDA ARS, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Zhang, Michael Q.] Tsinghua Univ, Bioinformat Div, Ctr Synthet & Syst Biol, TNLIST, Beijing 100084, Peoples R China. [Chadwick, Lisa H.] NIEHS, Res Triangle Pk, NC 27709 USA. [Bernstein, Bradley E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bernstein, Bradley E.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Thomson, James A.] Morgridge Inst Res, Madison, WI 53707 USA. [Stevens, Michael] Washington Univ, Dept Comp Sci & Engn, St Louis, MO 63130 USA. RP Kundaje, A (reprint author), MIT, Comp Sci & Artificial Intelligence Lab, 32 Vassar St, Cambridge, MA 02139 USA. EM manoli@mit.edu RI Wang, Tao/E-5900-2015; Chen, Zhao/I-5625-2014; Lister, Ryan/B-5168-2012; Li, Daofeng/E-5386-2011; Ecker, Joseph/B-9144-2008; Hariharan, Manoj/N-2855-2015; Hirst, Martin/B-7684-2016; Marra, Marco/B-5987-2008; Jones, Steven/C-3621-2009; Zhang, Bo/A-6874-2011; OI Meuleman, Wouter/0000-0002-1196-5401; Pelizzola, Mattia/0000-0001-6672-9636; Ward, Lucas/0000-0002-8017-809X; Tsai, Linus/0000-0002-0134-6949; Mattick, John/0000-0002-7680-7527; Gu, Junchen/0000-0002-0928-7453; /0000-0002-3447-9801; Wu, Jie/0000-0002-0989-8115; Wang, Tao/0000-0002-1646-6863; Subramanian, Sai Lakshmi/0000-0003-1384-0722; Lister, Ryan/0000-0001-6637-7239; Li, Daofeng/0000-0001-7492-3703; Ecker, Joseph/0000-0001-5799-5895; Hariharan, Manoj/0000-0002-1006-5372; Zhang, Bo/0000-0003-2962-5314; Farnham, Peggy/0000-0003-4469-7914; Robinson, Joshua/0000-0002-2421-4535 FU NIH Common Fund as part of the NIH Roadmap Epigenomics Program [U01ES017155, U01ES017154, U01ES017166, U01ES017156, U01DA025956]; NHGRI [RC1HG005334, R01HG004037, R01HG004037-S1, RO1NS078839]; NIH [ES017166, F32HL110473, K99HL119617]; NSFC [91019016]; NBRPC [2012CB316503]; NSF CAREER [1254200]; [5R24HD000836]; [P30AG10161]; [R01AG15819]; [R01AG17917]; [U01AG46152] FX This work was supported by the NIH Common Fund as part of the NIH Roadmap Epigenomics Program through U01ES017155 (B.B. and A.M.), U01ES017154 (J.C. and M.M.), U01ES017166 (B.R.), U01ES017156 (J.S.), U01DA025956 (A.M. and A.B.), and by NHGRI through RC1HG005334, R01HG004037 and R01HG004037-S1 (M.K.), RO1NS078839 (L.-H.T.), and by NIH ES017166, NSFC 91019016 and NBRPC 2012CB316503 (M.Q.Z.). Sample procurement was supported by grants 5R24HD000836 (I.A.G.) for staged fetal tissues; P30AG10161, R01AG15819, R01AG17917 (D.A.B.) and U01AG46152 (P.L.D. and D.A.B.) for adult brain samples. This work was also supported by NIH fellowship grants F32HL110473 and K99HL119617 (S.L.), and NSF CAREER award 1254200 (J.E.). We acknowledge program leadership by members of the NIH Epigenomics Workgroup, especially J.S. Satterlee, F.L. Tyson, J. Rutter, K.A. McAllister, A. Haugen, C. Colvis (NCATS), J. Battey (NIDCD), L. Birnbaum (NIEHS) and N. Volkow (NIDA). We acknowledge feedback from our External Scientific Panel members M. Bartolomei, S. Baylin, S. Beck, A. Chakravarti, L. Jackson-Grusby, J. Lieb, S. Peckman, J. Quackenbush and S. Stice. NR 112 TC 311 Z9 313 U1 21 U2 163 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 FEB 19 PY 2015 VL 518 IS 7539 BP 317 EP 330 DI 10.1038/nature14248 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB3SA UT WOS:000349547400028 ER PT J AU Dixon, JR Jung, I Selvaraj, S Shen, Y Antosiewicz-Bourget, JE Lee, AY Ye, Z Kim, A Rajagopal, N Xie, W Diao, YR Liang, J Zhao, HM Lobanenkov, VV Ecker, JR Thomson, JA Ren, B AF Dixon, Jesse R. Jung, Inkyung Selvaraj, Siddarth Shen, Yin Antosiewicz-Bourget, Jessica E. Lee, Ah Young Ye, Zhen Kim, Audrey Rajagopal, Nisha Xie, Wei Diao, Yarui Liang, Jing Zhao, Huimin Lobanenkov, Victor V. Ecker, Joseph R. Thomson, James A. Ren, Bing TI Chromatin architecture reorganization during stem cell differentiation SO NATURE LA English DT Article ID HUMAN GENOME; GENE-EXPRESSION; HISTONE MODIFICATIONS; DNA METHYLATION; REGULATORY DNA; NUCLEAR LAMINA; ENHANCERS; ORGANIZATION; PRINCIPLES; LANDSCAPE AB Higher-order chromatin structure is emerging as an important regulator of gene expression. Although dynamic chromatin structures have been identified in the genome, the full scope of chromatin dynamics during mammalian development and lineage specification remains to be determined. By mapping genome-wide chromatin interactions in human embryonic stem(ES) cells and four human ES-cell-derived lineages, we uncover extensive chromatin reorganization during lineage specification. We observe that although self-associating chromatin domains are stable during differentiation, chromatin interactions both within and between domains change in a striking manner, altering 36% of active and inactive chromosomal compartments throughout the genome. By integrating chromatin interaction maps with haplotype-resolved epigenome and transcriptome data sets, we find widespread allelic bias in gene expression correlated with allele-biased chromatin states of linked promoters and distal enhancers. Our results therefore provide a global view of chromatin dynamics and a resource for studying long-range control of gene expression in distinct human cell lineages. C1 [Dixon, Jesse R.; Jung, Inkyung; Selvaraj, Siddarth; Shen, Yin; Lee, Ah Young; Ye, Zhen; Kim, Audrey; Rajagopal, Nisha; Diao, Yarui; Ren, Bing] Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Dixon, Jesse R.] Univ Calif San Diego, Med Scientist Training Program, La Jolla, CA 92093 USA. [Selvaraj, Siddarth] Univ Calif San Diego, Bioinformat & Syst Biol Grad Program, La Jolla, CA 92093 USA. [Antosiewicz-Bourget, Jessica E.; Thomson, James A.] Morgridge Inst Res, Madison, WI 53715 USA. [Xie, Wei] Tsinghua Univ, Tsinghua Univ Peking Univ Ctr Life Sci, Sch Life Sci, Beijing 100084, Peoples R China. [Liang, Jing; Zhao, Huimin] Univ Illinois, Dept Chem & Biomol Engn, Urbana, IL 61801 USA. [Lobanenkov, Victor V.] NIAID, Lab Immunogenet, Twinbrook NIAID Facil 1, Rockville, MD 20852 USA. [Ecker, Joseph R.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. [Thomson, James A.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, Madison, WI 53706 USA. [Thomson, James A.] Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA. [Ren, Bing] Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, Inst Genom Med, La Jolla, CA 92093 USA. RP Ren, B (reprint author), Ludwig Inst Canc Res, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM biren@ucsd.edu RI Ecker, Joseph/B-9144-2008; OI Ecker, Joseph/0000-0001-5799-5895; Lobanenkov, Victor/0000-0001-6665-3635 FU Ludwig Institute for Cancer Research; NIH Roadmap Epigenome Project [U01 ES017166, R01 ES024984]; California Institute of Regenerative Medicine [RN2-00905]; Human Frontier Science Program [LT000576/2014-L] FX We thank the members of the Ren laboratory for support and suggestions throughout the course of this work. This work is funded in part by the Ludwig Institute for Cancer Research, the NIH Roadmap Epigenome Project (U01 ES017166 and R01 ES024984), and the California Institute of Regenerative Medicine (RN2-00905). Y.D. is supported by a postdoctoral fellowship from the Human Frontier Science Program (LT000576/2014-L). NR 45 TC 152 Z9 155 U1 23 U2 119 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 FEB 19 PY 2015 VL 518 IS 7539 BP 331 EP 336 DI 10.1038/nature14222 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB3SA UT WOS:000349547400029 PM 25693564 ER PT J AU Ren, JK Briones, V Barbour, S Yu, WS Han, YX Terashima, M Muegge, K AF Ren, Jianke Briones, Victorino Barbour, Samantha Yu, Weishi Han, Yixing Terashima, Minoru Muegge, Kathrin TI The ATP binding site of the chromatin remodeling homolog Lsh is required for nucleosome density and de novo DNA methylation at repeat sequences SO NUCLEIC ACIDS RESEARCH LA English DT Article ID FAMILY-MEMBER; SNF2 FAMILY; IN-VITRO; GENE-EXPRESSION; GENOME; METHYLTRANSFERASES; ELEMENTS; ISWI; TRANSCRIPTION; MECHANISMS AB Lsh, a chromatin remodeling protein of the SNF2 family, is critical for normal heterochromatin structure. In particular, DNA methylation at repeat elements, a hallmark of heterochromatin, is greatly reduced in Lsh(-)/(-) (KO) cells. Here, we examined the presumed nucleosome remodeling activity of Lsh on chromatin in the context of DNA methylation. We found that dynamic CG methylation was dependent on Lsh in embryonic stem cells. Moreover, we demonstrate that ATP function is critical for de novo methylation at repeat sequences. The ATP binding site of Lsh is in part required to promote stable association of the DNA methyltransferase 3b with the repeat locus. By performing nucleosome occupancy assays, we found distinct nucleosome occupancy in KO ES cells compared to WT ES cells after differentiation. Nucleosome density was restored to wild-type level by re-expressing wild-type Lsh but not the ATP mutant in KO ES cells. Our results suggest that ATP-dependent nucleosome remodeling is the primary molecular function of Lsh, which may promote de novo methylation in differentiating ES cells. C1 [Ren, Jianke; Briones, Victorino; Barbour, Samantha; Yu, Weishi; Han, Yixing; Terashima, Minoru; Muegge, Kathrin] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Muegge, Kathrin] Leidos Biomed Res Inc, Basic Sci Program, Mouse Canc Genet Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Muegge, K (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. EM Kathrin.Muegge@nih.gov FU NIH, Frederick National Lab, Center for Cancer Research; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; National Cancer Institute FX This research was supported by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. This project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. Funding for open access charge: National Cancer Institute Institutional charges. NR 68 TC 11 Z9 11 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 18 PY 2015 VL 43 IS 3 BP 1444 EP 1455 DI 10.1093/nar/gku1371 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CE2HZ UT WOS:000351638000018 PM 25578963 ER PT J AU Hirota, K Yoshikiyo, K Guilbaud, G Tsurimoto, T Murai, J Tsuda, M Phillips, LG Narita, T Nishihara, K Kobayashi, K Yamada, K Nakamura, J Pommier, Y Lehmann, A Sale, JE Takeda, S AF Hirota, Kouji Yoshikiyo, Kazunori Guilbaud, Guillaume Tsurimoto, Toshiki Murai, Junko Tsuda, Masataka Phillips, Lara G. Narita, Takeo Nishihara, Kana Kobayashi, Kaori Yamada, Kouich Nakamura, Jun Pommier, Yves Lehmann, Alan Sale, Julian E. Takeda, Shunichi TI The POLD3 subunit of DNA polymerase delta can promote translesion synthesis independently of DNA polymerase zeta SO NUCLEIC ACIDS RESEARCH LA English DT Article ID IMMUNOGLOBULIN GENE CONVERSION; BREAK-INDUCED REPLICATION; BASE EXCISION-REPAIR; SACCHAROMYCES-CEREVISIAE; SOMATIC HYPERMUTATION; ACCESSORY SUBUNITS; DAMAGE TOLERANCE; REV1 PROTEIN; HUMAN-CELLS; POL32 AB The replicative DNA polymerase Pol delta consists of a catalytic subunit POLD1/p125 and three regulatory subunits POLD2/p50, POLD3/p66 and POLD4/p12. The ortholog of POLD3 in Saccharomyces cerevisiae, Pol32, is required for a significant proportion of spontaneous and UV-induced mutagenesis through its additional role in translesion synthesis (TLS) as a subunit of DNA polymerase zeta. Remarkably, chicken DT40 B lymphocytes deficient in POLD3 are viable and able to replicate undamaged genomic DNA with normal kinetics. Like its counterpart in yeast, POLD3 is required for fully effective TLS, its loss resulting in hypersensitivity to a variety of DNA damaging agents, a diminished ability to maintain replication fork progression after UV irradiation and a significant decrease in abasic site-induced mutagenesis in the immunoglobulin loci. However, these defects appear to be largely independent of Pol zeta, suggesting that POLD3 makes a significant contribution to TLS independently of Pol zeta in DT40 cells. Indeed, combining pol eta pol zeta and pold3 mutations results in synthetic lethality. Additionally, we show in vitro that POLD3 promotes extension beyond an abasic by the Pol delta holoenzyme suggesting that while POLD3 is not required for normal replication, it may help Pol delta to complete abasic site bypass independently of canonical TLS polymerases. C1 [Hirota, Kouji; Yoshikiyo, Kazunori; Murai, Junko; Tsuda, Masataka; Narita, Takeo; Nishihara, Kana; Takeda, Shunichi] Kyoto Univ, Grad Sch Med, Dept Radiat Genet, Sakyo Ku, Kyoto 6068501, Japan. [Hirota, Kouji; Kobayashi, Kaori] Tokyo Metropolitan Univ, Dept Chem, Grad Sch Sci & Engn, Hachioji, Tokyo 1920397, Japan. [Guilbaud, Guillaume; Phillips, Lara G.; Sale, Julian E.] MRC, Mol Biol Lab, Cambridge CB2 0QH, England. [Tsurimoto, Toshiki; Pommier, Yves] Kyushu Univ, Sch Sci, Dept Biol, Higashi Ku, Fukuoka 8128581, Japan. [Murai, Junko] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yamada, Kouich] Natl Inst Hlth & Nutr, Div Genet Biochem, Tokyo 1628636, Japan. [Nakamura, Jun] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. [Lehmann, Alan] Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England. RP Takeda, S (reprint author), Kyoto Univ, Grad Sch Med, Dept Radiat Genet, Sakyo Ku, Kyoto 6068501, Japan. EM jes@mrc-lmb.cam.ac.uk; stakeda@rg.med.kyoto-u.ac.jp RI U-ID, Kyushu/C-5291-2016 FU JSPS KAKENHI [20770147, 22687001, 25281021, 20241012, 23221005, 21114509, 24114509, 26116518]; Uehara Memorial Foundation; Naito Foundation; National Institutes of Health [P30 ES10126, P42 ES05948]; Medical Research Council [U105178808]; Fanconi Anemia Research Fund FX Grant-in-Aid for Scientific Research on Innovative Areas [21114509, 24114509, 26116518], JSPS KAKENHI [20770147, 22687001, 25281021] and, grants from the Uehara Memorial Foundation and the Naito Foundation [to K.H.]; JSPS KAKENHI [20241012, 23221005 to S.T.]; National Institutes of Health Grants [P30 ES10126, P42 ES05948 to J.N.]; LMB from the Medical Research Council [U105178808] and Fanconi Anemia Research Fund [to G.G., L.G.P. and J.E.S.]. NR 59 TC 12 Z9 12 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 18 PY 2015 VL 43 IS 3 BP 1671 EP 1683 DI 10.1093/nar/gkv023 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CE2HZ UT WOS:000351638000035 PM 25628356 ER PT J AU Busser, BW Haimovich, J Huang, D Ovcharenko, I Michelson, AM AF Busser, Brian W. Haimovich, Julian Huang, Di Ovcharenko, Ivan Michelson, Alan M. TI Enhancer modeling uncovers transcriptional signatures of individual cardiac cell states in Drosophila SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GENOME-WIDE DISCOVERY; REGULATORY NETWORKS; CHROMATIN STATE; BINDING; SPECIFICITY; INTEGRATION; PROMOTERS; DIVISION; DATABASE; PATHWAY AB Here we used discriminative training methods to uncover the chromatin, transcription factor (TF) binding and sequence features of enhancers underlying gene expression in individual cardiac cells. We used machine learning with TF motifs and ChIP data for a core set of cardiogenic TFs and histone modifications to classify Drosophila cell-type-specific cardiac enhancer activity. We show that the classifier models can be used to predict cardiac cell subtype cis-regulatory activities. Associating the predicted enhancers with an expression atlas of cardiac genes further uncovered clusters of genes with transcription and function limited to individual cardiac cell subtypes. Further, the cell-specific enhancer models revealed chromatin, TF binding and sequence features that distinguish enhancer activities in distinct subsets of heart cells. Collectively, our results show that computational modeling combined with empirical testing provides a powerful platform to uncover the enhancers, TF motifs and gene expression profiles which characterize individual cardiac cell fates. C1 [Busser, Brian W.; Haimovich, Julian; Michelson, Alan M.] NHLBI, Lab Dev Syst Biol, Genet & Dev Biol Ctr, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Huang, Di; Ovcharenko, Ivan] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Michelson, AM (reprint author), NHLBI, Lab Dev Syst Biol, Genet & Dev Biol Ctr, Div Intramural Res,NIH, Bldg 10, Bethesda, MD 20892 USA. EM busserbw@nhlbi.nih.gov; ovcharen@nih.gov; michelsonam@nhlbi.nih.gov FU National Heart Lung and Blood Institute Division of Intramural Research; Intramural Research Program of the National Institutes of Health, National Library of Medicine; National Institutes of Health FX National Heart Lung and Blood Institute Division of Intramural Research (to A.M.); Intramural Research Program of the National Institutes of Health, National Library of Medicine (to I.O.). Funding for open access charge: National Institutes of Health. NR 43 TC 3 Z9 3 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 18 PY 2015 VL 43 IS 3 BP 1726 EP 1739 DI 10.1093/nar/gkv011 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CE2HZ UT WOS:000351638000039 PM 25609699 ER PT J AU Gassman, NR Coskun, E Stefanick, DF Horton, JK Jaruga, P Dizdaroglu, M Wilson, SH AF Gassman, Natalie R. Coskun, Erdem Stefanick, Donna F. Horton, Julie K. Jaruga, Pawel Dizdaroglu, Miral Wilson, Samuel H. TI Bisphenol A Promotes Cell Survival Following Oxidative DNA Damage in Mouse Fibroblasts SO PLOS ONE LA English DT Article ID BASE-EXCISION-REPAIR; BREAST-CANCER; GLYCOSYLASE; EXPOSURE; ENZYME; NEIL1; IDENTIFICATION; GENOTOXICITY; EXPRESSION; RESPONSES AB Bisphenol A (BPA) is a biologically active industrial chemical used in production of consumer products. BPA has become a target of intense public scrutiny following concerns about its association with human diseases such as obesity, diabetes, reproductive disorders, and cancer. Recent studies link BPA with the generation of reactive oxygen species, and base excision repair (BER) is responsible for removing oxidatively induced DNA lesions. Yet, the relationship between BPA and BER has yet to be examined. Further, the ubiquitous nature of BPA allows continuous exposure of the human genome concurrent with the normal endogenous and exogenous insults to the genome, and this co-exposure may impact the DNA damage response and repair. To determine the effect of BPA exposure on base excision repair of oxidatively induced DNA damage, cells compromised in double-strand break repair were treated with BPA alone or co-exposed with either potassium bromate (KBrO3) or laser irradiation as oxidative damaging agents. In experiments with KBrO3, co-treatment with BPA partially reversed the KBrO3-induced cytotoxicity observed in these cells, and this was coincident with an increase in guanine base lesions in genomic DNA. The improvement in cell survival and the increase in oxidatively induced DNA base lesions were reminiscent of previous results with alkyl adenine DNA glycosylase-deficient cells, suggesting that BPA may prevent initiation of repair of oxidized base lesions. With laser irradiation-induced DNA damage, treatment with BPA suppressed DNA repair as revealed by several indicators. These results are consistent with the hypothesis that BPA can induce a suppression of oxidized base lesion DNA repair by the base excision repair pathway. C1 [Gassman, Natalie R.; Stefanick, Donna F.; Horton, Julie K.; Wilson, Samuel H.] NIEHS, Genom Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Coskun, Erdem; Jaruga, Pawel; Dizdaroglu, Miral] NIST, Biomol Measurement Div, Gaithersburg, MD 20899 USA. [Coskun, Erdem] Gazi Univ, Fac Pharm, Ankara, Turkey. RP Wilson, SH (reprint author), NIEHS, Genom Integr & Struct Biol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov RI Jaruga, Pawel/M-4378-2015; OI Gassman, Natalie/0000-0002-8488-2332 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES050158, Z01-ES050159]; [1K99ES023813-01] FX This research was supported by Research Project Numbers Z01-ES050158 and Z01-ES050159 in the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NRG is funded by 1K99ES023813-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Certain commercial equipment or materials are identified in this paper in order to specify adequately the experimental procedure. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose. NR 41 TC 4 Z9 4 U1 4 U2 21 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 FEB 18 PY 2015 VL 10 IS 2 AR e0118819 DI 10.1371/journal.pone.0118819 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC0WZ UT WOS:000350061500131 PM 25693136 ER PT J AU Duy, J Koehler, JW Honko, AN Minogue, TD AF Duy, Janice Koehler, Jeffrey W. Honko, Anna N. Minogue, Timothy D. TI Optimized microRNA purification from TRIzol-treated plasma SO BMC GENOMICS LA English DT Article DE microRNA; TRIzol; Ebola virus; RNA extraction; Plasma; Biomarker; RT-PCR; Nonhuman primate ID CIRCULATING MICRORNAS; BLOOD; EXTRACTION; EXPRESSION; MIRNAS; QUANTIFICATION; PCR; RNA; CHALLENGES; BIOMARKERS AB Background: MicroRNAs (miRNAs) represent new and potentially informative diagnostic targets for disease detection and prognosis. However, little work exists documenting the effect of TRIzol, a common viral inactivation and nucleic acid extraction reagent, on miRNA purification. Here, we developed an optimized protocol for miRNA extraction from plasma samples by evaluating five different RNA extraction kits, TRIzol phase separation, purification additives, and initial plasma sample volume. This method was then used for downstream profiling of plasma miRNAs found in archived samples from one nonhuman primate (NHP) experimentally challenged with Ebola virus by the aerosol route. Results: Comparison of real-time RT-PCR results for spiked-in and endogenous miRNA sequences determined extraction efficiencies from five different RNA purification kits. These experiments showed that 50 mu L plasma processed using the QIAGEN miRNeasy Mini Kit with 5 mu g of glycogen as a co-precipitant yielded the highest recovery of endogenous miRNAs. Using this optimized protocol, miRNAs from archived plasma samples of one rhesus macaque challenged with aerosolized Ebola virus was profiled using a targeted real-time PCR array. A total of 519 of the 752 unique miRNAs assayed were present in the plasma samples at day 0 and day 7 (time of death) post-exposure. Statistical analyses revealed 25 sequences significantly up- or down-regulated between day 0 and day 7 post infection, validating the utility of the extraction method for plasma miRNA profiling. Conclusions: This study contributes to the knowledgebase of circulating miRNA extraction methods and expands on the potential applications of cell-free miRNA profiling for diagnostics and pathogenesis studies. Specifically, we optimized an extraction protocol for miRNAs from TRIzol-inactivated plasma samples that can be used for highly pathogenic viruses. C1 [Duy, Janice; Koehler, Jeffrey W.; Minogue, Timothy D.] US Army, Diagnost Syst Div, Res Inst Infect Dis, Frederick, MD 21701 USA. [Honko, Anna N.] NIAID, Integrated Res Facil, NIH, Frederick, MD 21701 USA. [Honko, Anna N.] US Army, Virol Div, Med Inst Infect Dis, Frederick, MD 21701 USA. RP Minogue, TD (reprint author), US Army, Diagnost Syst Div, Res Inst Infect Dis, 1425 Porter St, Frederick, MD 21701 USA. EM timothy.d.minogue.civ@mail.mil OI Honko, Anna/0000-0001-9165-148X; Koehler, Jeffrey/0000-0003-3225-6599 FU Defense Threat Reduction Agency (DTRA) under USAMRIID project [1442078] FX The authors would like to thank USAMRIID Veterinary Medicine Corps for blood samples from healthy nonhuman primates, and Dr. Samuel Dickson for his help with statistical analyses. Research was conducted under an IACUC approved protocol in compliance with the Animal Welfare Act, PHS Policy, and other Federal statutes and regulations relating to animals and experiments involving animals. The facility where this research was conducted is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, National Research Council, 2011. This research was funded by the Defense Threat Reduction Agency (DTRA) under USAMRIID project number 1442078. The opinions, interpretations, conclusions, and recommendations contained herein are those of the authors and are not necessarily endorsed by the U.S. Army. NR 44 TC 4 Z9 4 U1 4 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD FEB 18 PY 2015 VL 16 AR 95 DI 10.1186/s12864-015-1299-5 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CC2GP UT WOS:000350163500002 PM 25765146 ER PT J AU Apps, MAJ Lesage, E Ramnani, N AF Apps, Matthew A. J. Lesage, Elise Ramnani, Narender TI Vicarious Reinforcement Learning Signals When Instructing Others SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cingulate; fMRI; prediction error; reinforcement learning; social; teaching ID ANTERIOR CINGULATE CORTEX; MEDIAL PREFRONTAL CORTICES; OLD-WORLD MONKEY; PREDICTION ERRORS; RHESUS-MONKEY; ORBITOFRONTAL CORTEX; SOCIAL-BEHAVIOR; NEURAL MECHANISMS; MACAQUE MONKEY; REWARD AB Reinforcement learning (RI.) theory posits that learning is driven by discrepancies between the predicted and actual outcomes of actions (prediction errors [PEs]). In social environments, learning is often guided by similar RL mechanisms. For example, teachers monitor the actions of students and provide feedback to them. This feedback evokes PEs in students that guide their learning. We report the first study that investigates the neural mechanisms that underpin RL signals in the brain of a teacher. Neurons in the anterior cingulate cortex (ACC) signal PEs when learning from the outcomes of one's own actions but also signal infonuation when outcomes are received by others. Does a teacher's ACC signal PEs when monitoring a student's learning? Using fMRI, we studied brain activity in human subjects (teachers) as they taught a confederate (student) action outcome associations by p ro v iding pos it ive or negative feedback. We examined activity time-locked to the students' responses, when teachers infer student predictions and know actual outcomes. We fitted a RL-based computational model to the behavior of the student to characterize their learning, and examined whether a teacher's ACC signals when a student's predictions are wrong. In line with our hypothesis, activity in the teacher's ACC covaried with the PE values in the model. Additionally, activity in the teacher's insula and ventromedial prefrontal cortex covaried with the predicted value according to the student. Our findings highlight that the ACC signals PEs vicariously for others' erroneous predictions, when monitoring and instructing their learning. These results su : :est that RL mechanisms, processed vicariously, may underpin and facilitate teaching behaviors. C1 [Apps, Matthew A. J.] John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England. [Apps, Matthew A. J.] Univ Oxford, Dept Expt Psychol, Oxford OX1 2JD, England. [Apps, Matthew A. J.; Lesage, Elise; Ramnani, Narender] Univ London, Royal Holloway, Dept Psychol, Surrey TW20 0EX, England. [Lesage, Elise] NIDA, Intramural Res Program, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. RP Apps, MAJ (reprint author), John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Level 6,West Wing, Oxford OX3 9DU, England. EM matthew.apps@ndcn.ox.ac.uk FU ESRC 1+3 PhD Studentship FX This work was supported by an ESRC 1+3 PhD Studentship to M.A.J.A., supervised by NR. We thank Ari Lingeswaran for help with MRI data collection; and Eden Hardmann and Arleta Woznica for acting as confederates. NR 68 TC 14 Z9 14 U1 4 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 FEB 18 PY 2015 VL 35 IS 7 BP 2904 EP 2913 DI 10.1523/JNEUROSCI.3669-14.2015 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CB9ZD UT WOS:000349992800008 PM 25698730 ER PT J AU Volkow, ND Wang, GJ Kojori, ES Fowler, JS Benveniste, H Tomasi, D AF Volkow, Nora D. Wang, Gene-Jack Kojori, Ehsan Shokri Fowler, Joanna S. Benveniste, Helene Tomasi, Dardo TI Alcohol Decreases Baseline Brain Glucose Metabolism More in Heavy Drinkers Than Controls But Has No Effect on Stimulation-Induced Metabolic Increases SO JOURNAL OF NEUROSCIENCE LA English DT Article DE acetate metabolism; alcoholism; glial metabolism; glycolysis; positron emission tomography ID POSITRON-EMISSION-TOMOGRAPHY; ETHANOL WITHDRAWAL SYNDROME; FRONTAL HYPOMETABOLISM; CEREBRAL METABOLISM; NEURAL ACTIVITY; ACETATE; ACTIVATION; RAT; PET; DEGENERATION AB During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-(18)FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD(20 +/- 13%) than controls (9 +/- 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 +/- 12%) compared with NS in both groups (15 +/- 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal. C1 [Volkow, Nora D.; Wang, Gene-Jack; Kojori, Ehsan Shokri; Tomasi, Dardo] NIAAA, Bethesda, MD 20892 USA. [Fowler, Joanna S.] Brookhaven Natl Lab, Dept Biosci, Upton, NY 11973 USA. [Benveniste, Helene] Stony Brook Med, Dept Anesthesiol, Stony Brook, NY 11794 USA. RP Volkow, ND (reprint author), NIDA, NIH, 6001 Execut Blvd,Room 5274, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov RI Tomasi, Dardo/J-2127-2015 FU National Institutes of Health FX This work was supported by the National Institutes of Health Intramural Research Program. We thank Christopher Wong, Dave Alexoff, Colleen Shea, Pauline Carter, Karen Torres Apelskog, and Ruben Baler for their contributions. NR 42 TC 1 Z9 2 U1 1 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 18 PY 2015 VL 35 IS 7 BP 3248 EP 3255 DI 10.1523/JNEUROSCI.4877-14.2015 PG 8 WC Neurosciences SC Neurosciences & Neurology GA CB9ZD UT WOS:000349992800037 PM 25698759 ER PT J AU Geisler, BP Raad, RA Esaian, D Sharon, E Schwartz, DR AF Geisler, Benjamin P. Raad, Roy A. Esaian, Diana Sharon, Elad Schwartz, David R. TI Apical ballooning and cardiomyopathy in a melanoma patient treated with ipilimumab: a case of takotsubo-like syndrome SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Takotsubo cardiomyopathy; Ipilimumab [Supplementary concept]; Melanoma; Drug-related side effects and adverse reactions ID POSITRON-EMISSION-TOMOGRAPHY; TAKO-TSUBO CARDIOMYOPATHY; MYOCARDITIS; MIMICKING; DIAGNOSIS; CTLA-4 AB Although animal studies have shown that the immunomodulator ipilimumab causes inflammation of the myocardium, clinically significant myocarditis has been observed only infrequently. We report a case of suspected acute coronary syndrome without a culprit lesion on cardiac angiography and takotsubo cardiomyopathy (TC)-like appearance on echocardiography in a patient with metastatic melanoma who received four standard doses of ipilimumab. Apical ballooning, hyperdynamic basal wall motion, systolic anterior motion of the mitral valve, and associated severe left ventricular outflow tract obstruction were present. Restaging with positron emission tomography-computed tomography done soon after discharge incidentally revealed increased fludeoxyglucose uptake in the apex. This case illustrates that a TC-like syndrome might be caused by autoimmune myocarditis after ipilimumab treatment although this was not biopsy-confirmed. Post-marketing surveillance should capture cardiac events occurring in patients treated with ipilimumab to better document and clarify a relationship to the drug, and biopsies should be considered. Physicians utilizing this novel agent should be aware of the potential for immune-related adverse events. C1 [Geisler, Benjamin P.; Raad, Roy A.; Esaian, Diana; Schwartz, David R.] NYU, Sch Med, New York, NY 10016 USA. [Sharon, Elad] NCI, Bethesda, MD 20892 USA. RP Geisler, BP (reprint author), NYU, Sch Med, New York, NY 10016 USA. EM bgeisler@post.harvard.edu OI Geisler, Benjamin/0000-0003-1704-6067; Raad, Roy A./0000-0001-7561-6983 NR 16 TC 8 Z9 8 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD FEB 17 PY 2015 VL 3 AR 4 DI 10.1186/s40425-015-0048-2 PG 4 WC Oncology SC Oncology GA CU7RZ UT WOS:000363740500002 PM 25705383 ER PT J AU Jury, NJ McCormick, BA Horseman, ND Benoit, SC Gregerson, KA AF Jury, Nicholas J. McCormick, Betsy A. Horseman, Nelson D. Benoit, Stephen C. Gregerson, Karen A. TI Enhanced Responsiveness to Selective Serotonin Reuptake Inhibitors during Lactation SO PLOS ONE LA English DT Article ID NEUROENDOCRINE STRESS RESPONSES; DORSAL RAPHE NUCLEUS; FORCED SWIMMING TEST; POSTPARTUM DEPRESSION; MATERNAL-BEHAVIOR; MAJOR DEPRESSION; POSTNATAL DEPRESSION; PLASMA TRYPTOPHAN; CONTAINING FIBERS; BODY-TEMPERATURE AB The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence has cast doubt on the effectiveness of SSRIs, these results support their therapeutic use in the treatment of PPD. C1 [Jury, Nicholas J.; Horseman, Nelson D.; Gregerson, Karen A.] Univ Cincinnati, Coll Med, Neurosci Grad Program, Cincinnati, OH 45267 USA. [Gregerson, Karen A.] Univ Cincinnati, Div Pharmaceut Sci, James L Winkle Coll Pharm, Cincinnati, OH 45267 USA. [Horseman, Nelson D.; Gregerson, Karen A.] Univ Cincinnati, Dept Mol & Cellular Physiol, Cincinnati, OH 45267 USA. [McCormick, Betsy A.] Univ Cincinnati, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Cincinnati, OH 45267 USA. [Benoit, Stephen C.] Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH 45267 USA. RP Jury, NJ (reprint author), NIAAA, Lab Behav & Genom Neurosci, NIH, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM Nick.Jury@nih.gov OI Jury, Nicholas/0000-0002-4233-117X FU National Institutes of Health [DK-54966]; United States Department of Agriculture NRI grant [2007-35206-17898]; National Institutes of Health training grant [DK-059803] FX KAG received National Institutes of Health grant DK-54966. NDH received United States Department of Agriculture NRI grant #2007-35206-17898. NJJ received a predoctoral fellowship on National Institutes of Health training grant DK-059803. The funders had a significant role in study design, data collection, analysis, decision to publish, and preparation of the manuscript. NR 97 TC 1 Z9 1 U1 5 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 17 PY 2015 VL 10 IS 2 AR e0117339 DI 10.1371/journal.pone.0117339 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC4KQ UT WOS:000350322700036 PM 25689282 ER PT J AU Stevens, FR Gaughan, AE Linard, C Tatem, AJ AF Stevens, Forrest R. Gaughan, Andrea E. Linard, Catherine Tatem, Andrew J. TI Disaggregating Census Data for Population Mapping Using Random Forests with Remotely-Sensed and Ancillary Data SO PLOS ONE LA English DT Article ID RESOLUTION SATELLITE IMAGERY; LAND-COVER; KENYA; SURFACES; RISK; MAPS AB High resolution, contemporary data on human population distributions are vital for measuring impacts of population growth, monitoring human-environment interactions and for planning and policy development. Many methods are used to disaggregate census data and predict population densities for finer scale, gridded population data sets. We present a new semi-automated dasymetric modeling approach that incorporates detailed census and ancillary data in a flexible, "Random Forest" estimation technique. We outline the combination of widely available, remotely-sensed and geospatial data that contribute to the modeled dasymetric weights and then use the Random Forest model to generate a gridded prediction of population density at similar to 100 m spatial resolution. This prediction layer is then used as the weighting surface to perform dasymetric redistribution of the census counts at a country level. As a case study we compare the new algorithm and its products for three countries (Vietnam, Cambodia, and Kenya) with other common gridded population data production methodologies. We discuss the advantages of the new method and increases over the accuracy and flexibility of those previous approaches. Finally, we outline how this algorithm will be extended to provide freely-available gridded population data sets for Africa, Asia and Latin America. C1 [Stevens, Forrest R.; Gaughan, Andrea E.] Univ Louisville, Dept Geog & Geosci, Louisville, KY 40292 USA. [Linard, Catherine] Fonds Natl Rech Sci FRS FNRS, B-1000 Brussels, Belgium. [Linard, Catherine] Univ Libre Bruxelles, Biol Control & Spatial Ecol, B-1050 Brussels, Belgium. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton SO17 1BJ, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Stevens, FR (reprint author), Univ Louisville, Dept Geog & Geosci, Louisville, KY 40292 USA. EM forrest.stevens@louisville.edu OI Stevens, Forrest/0000-0002-9328-3753 FU RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Bill and Melinda Gates Foundation [49446, 1032350] FX AJT acknowledges funding support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and is also supported by grants from the Bill and Melinda Gates Foundation (#49446 and #1032350). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 34 Z9 36 U1 2 U2 14 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 FEB 17 PY 2015 VL 10 IS 2 AR UNSP e0107042 DI 10.1371/journal.pone.0107042 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC4KQ UT WOS:000350322700001 PM 25689585 ER PT J AU Anderson, AH Yang, W Townsend, RR Pan, Q Chertow, GM Kusek, JW Charleston, J He, J Kallem, R Lash, JP Miller, ER Rahman, M Steigerwalt, S Weir, M Wright, JT Feldman, HI AF Anderson, Amanda H. Yang, Wei Townsend, Raymond R. Pan, Qiang Chertow, Glenn M. Kusek, John W. Charleston, Jeanne He, Jiang Kallem, RadhaKrishna Lash, James P. Miller, Edgar R., III Rahman, Mahboob Steigerwalt, Susan Weir, Matthew Wright, Jackson T., Jr. Feldman, Harold I. CA Chronic Renal Insufficiency Cohort TI Time-Updated Systolic Blood Pressure and the Progression of Chronic Kidney Disease A Cohort Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RENAL-INSUFFICIENCY COHORT; MARGINAL STRUCTURAL MODELS; CONVERTING ENZYME-INHIBITION; INVERSE PROBABILITY WEIGHTS; BASE-LINE CHARACTERISTICS; DIABETIC-NEPHROPATHY; HYPERTENSION; TRIAL; RISK; MEN AB Background: Previous reports of the longitudinal association between achieved blood pressure (BP) and end-stage renal disease (ESRD) among patients with chronic kidney disease (CKD) have not incorporated time-updated BP with appropriate covariate adjustment. Objective: To assess the association between baseline and time-updated systolic blood pressure (SBP) with CKD progression. Design: Observational, prospective cohort study. (ClinicalTrials.gov: NCT00304148) Setting: 7 U.S. clinical centers. Patients: Patients in the Chronic Renal Insufficiency Cohort Study (n = 3708) followed for a median of 5.7 years (25th to 75th percentile, 4.6 to 6.7 years). Measurements: The mean of 3 seated SBP measurements made up the visit-specific SBP. Time-updated SBP was the mean of that and all previous visits. Outcomes were ESRD and the composite end point of ESRD or halving of the estimated glomerular filtration rate. Analyses investigating baseline and time-updated SBP used Cox proportional hazards models and marginal structural models, respectively. Results: Systolic blood pressure was 130 mm Hg or greater at all visits in 19.2% of patients. The hazard ratio for ESRD among patients with SBP of was 1.46 (95% CI, 1.13 to 1.88) using only baseline data and 2.37 (CI, 1.48 to 3.80) using time-updated data. Among patients with SBP of 140 mm Hg or greater, corresponding hazard ratios were 1.46 (CI, 1.18 to 1.88) and 3.37 (CI, 2.26 to 5.03) for models using only baseline data and those using time-updated data, respectively. Limitation: Blood pressure was measured once annually, and the cohort was not a random sample. Conclusion: Time-updated SBP greater than 130 mm Hg was more strongly associated with CKD progression than analyses based on baseline SBP. C1 [Anderson, Amanda H.; Yang, Wei; Pan, Qiang; Feldman, Harold I.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Townsend, Raymond R.] Univ Penn, Perelman Sch Med, Renal Hypertens Div, Philadelphia, PA 19104 USA. [Chertow, Glenn M.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Kusek, John W.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. [Charleston, Jeanne] Johns Hopkins Univ ProHlth, Baltimore, MD 21207 USA. [He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA 70112 USA. [Kallem, RadhaKrishna] Univ Penn, Perelman Sch Med, Smilow Ctr Translat Res, Renal Hypertens Div, Philadelphia, PA 19104 USA. [Lash, James P.] Univ Illinois, Dept Med, Med Ctr, Nephrol Sect, Chicago, IL 60612 USA. [Miller, Edgar R., III] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Rahman, Mahboob; Wright, Jackson T., Jr.] Case Western Reserve Univ, Univ Hosp, Case Med Ctr, Div Nephrol & Hypertens, Cleveland, OH 44106 USA. [Steigerwalt, Susan] Renaissance Renal Res Inst, Detroit, MI 48336 USA. [Weir, Matthew] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. RP Anderson, AH (reprint author), Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, 819 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM andersah@mail.med.upenn.edu FU National Institute of Diabetes and Digestive and Kidney Diseases FX National Institute of Diabetes and Digestive and Kidney Diseases. NR 37 TC 14 Z9 16 U1 2 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 17 PY 2015 VL 162 IS 4 BP 258 EP + DI 10.7326/M14-0488 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CC3FU UT WOS:000350232500015 PM 25686166 ER PT J AU Korn, EL Freidlin, B AF Korn, E. L. Freidlin, B. TI Evaluation of chemoresponse assays as predictive markers SO BRITISH JOURNAL OF CANCER LA English DT Article DE analytic methods; chemoresponse assay; chemosensitivity assay; predictive marker; personalised medicine ID RECURRENT OVARIAN-CANCER AB Background: A chemoresponse assay that can be used to predict which patients will respond to which drugs would be useful in directing treatment. Two new analytic methods to assess the predictive ability of a chemoresponse assay have been proposed by Tian et al. Methods: Three examples in which a hypothetical assay has no predictive ability are considered to evaluate the properties of the proposed analytic methods. Results: For these specific examples, the proposed methods incorrectly suggest that the assay is predictive. Conclusions: The examples presented here demonstrate that it can be challenging to evaluate the predictive value of a chemoresponse assay. C1 [Korn, E. L.; Freidlin, B.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Korn, EL (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, MSC 9735, Bethesda, MD 20892 USA. EM korne@ctep.nci.nih.gov NR 6 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 17 PY 2015 VL 112 IS 4 BP 621 EP 623 DI 10.1038/bjc.2014.661 PG 3 WC Oncology SC Oncology GA CB8SY UT WOS:000349902600002 PM 25584494 ER PT J AU Nagao, K Udey, MC AF Nagao, Keisuke Udey, Mark C. TI Mushrooming Insights into Skin Dendritic Cell Physiology SO IMMUNITY LA English DT Editorial Material ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; IMMUNITY; RESIDENT AB Mechanisms responsible for protective immunity against epicutaneous Candida infections are incompletely characterized. In this issue of Immunity, Kashem et al. demonstrate that different Candida life forms engage selected skin dendritic cell subsets in distinct compartments, resulting in qualitatively different immune responses. C1 [Nagao, Keisuke; Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Nagao, K (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM keisuke.nagao@nih.gov; udeym@mail.nih.gov RI Nagao, Keisuke/J-5116-2013 OI Nagao, Keisuke/0000-0002-7005-3138 NR 10 TC 1 Z9 1 U1 1 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 FEB 17 PY 2015 VL 42 IS 2 BP 210 EP 213 DI 10.1016/j.immuni.2015.01.025 PG 5 WC Immunology SC Immunology GA CB8XT UT WOS:000349916400005 PM 25692697 ER PT J AU Nielles-Vallespin, S Kellman, P Hsu, LY Arai, AE AF Nielles-Vallespin, Sonia Kellman, Peter Hsu, Li-Yueh Arai, Andrew E. TI FLASH proton density imaging for improved surface coil intensity correction in quantitative and semi-quantitative SSFP perfusion cardiovascular magnetic resonance SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Myocardial perfusion; Quantitative perfusion; Cardiovascular magnetic resonance; Surface coil correction; Proton density frames; Balanced Steady State Free Precession (SSFP); Fast Low Angle SHot (FLASH) ID MYOCARDIAL 1ST-PASS PERFUSION; STATE FREE PRECESSION; MRI; SEQUENCES; HUMANS; GRAPPA; ARRAY AB Background: A low excitation flip angle (a < 10 degrees) steady-state free precession (SSFP) proton-density (PD) reference scan is often used to estimate the B-1-field inhomogeneity for surface coil intensity correction (SCIC) of the saturation-recovery (SR) prepared high flip angle (a = 40-50 degrees) SSFP myocardial perfusion images. The different SSFP off-resonance response for these two flip angles might lead to suboptimal SCIC when there is a spatial variation in the background B-0-field. The low flip angle SSFP-PD frames are more prone to parallel imaging banding artifacts in the presence of off-resonance. The use of FLASH-PD frames would eliminate both the banding artifacts and the uneven frequency response in the presence of off-resonance in the surface coil inhomogeneity estimate and improve homogeneity of semi-quantitative and quantitative perfusion measurements. Methods: B-0-field maps, SSFP and FLASH-PD frames were acquired in 10 healthy volunteers to analyze the SSFP off-resonance response. Furthermore, perfusion scans preceded by both FLASH and SSFP-PD frames from 10 patients with no myocardial infarction were analyzed semi-quantitatively and quantitatively (rest n = 10 and stress n = 1). Intra-subject myocardial blood flow (MBF) coefficient of variation (CoV) over the whole left ventricle (LV), as well as intra-subject peak contrast (CE) and upslope (SLP) standard deviation (SD) over 6 LV sectors were investigated. Results: In the 6 out of 10 cases where artifacts were apparent in the LV ROI of the SSFP-PD images, all three variability metrics were statistically significantly lower when using the FLASH-PD frames as input for the SCIC (CoVMBF-FLASH = 0.3 +/- 0.1, CoVMBF-SSFP = 0.4 +/- 0.1, p = 0.03; SDCE-FLASH = 10 +/- 2, SDCE-SSFP = 32 +/- 7, p = 0.01; SDSLP-FLASH = 0.02 +/- 0.01, SDSLP-SSFP = 0.06 +/- 0.02, p = 0.03). Example rest and stress data sets from the patient pool demonstrate that the low flip angle SSFP protocol can exhibit severe ghosting artifacts originating from off-resonance banding artifacts at the edges of the field of view that parallel imaging is not able to unfold. These artifacts lead to errors in the quantitative perfusion maps and the semi-quantitative perfusion indexes, such as false positives. It is shown that this can be avoided by using FLASH-PD frames as input for the SCIC. Conclusions: FLASH-PD images are recommended as input for SCIC of SSFP perfusion images instead of low flip angle SSFP-PD images. C1 [Nielles-Vallespin, Sonia; Kellman, Peter; Hsu, Li-Yueh; Arai, Andrew E.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Nielles-Vallespin, S (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM sonia.nielles-vallespin@nih.gov FU National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS [HL004607-14CPB] FX Supported by the National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS (HL004607-14CPB). NR 17 TC 1 Z9 1 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD FEB 17 PY 2015 VL 17 AR 16 DI 10.1186/s12968-015-0120-6 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CB9IR UT WOS:000349945700001 PM 25827180 ER PT J AU Nettiksimmons, J Ayonayon, H Harris, T Phillips, C Rosano, C Satterfield, S Yaffe, K AF Nettiksimmons, Jasmine Ayonayon, Hilsa Harris, Tamara Phillips, Caroline Rosano, Caterina Satterfield, Suzanne Yaffe, Kristine CA Hlth ABC Study TI Development and validation of risk index for cognitive decline using blood-derived markers SO NEUROLOGY LA English DT Article ID CARDIOVASCULAR HEALTH COGNITION; C-REACTIVE PROTEIN; ALZHEIMERS-DISEASE; SERUM-ALBUMIN; OLDER-ADULTS; TELOMERE LENGTH; CYSTATIN-C; A-BETA; DEMENTIA; INTERLEUKIN-6 AB Objective:We sought to develop and validate a risk index for prospective cognitive decline in older adults based on blood-derived markers.Methods:The index was based on 8 markers that have been previously associated with cognitive aging: APOE genotype, plasma -amyloid 42/40 ratio, telomere length, cystatin C, glucose, C-reactive protein, interleukin-6, and albumin. The outcome was person-specific cognitive slopes (Modified Mini-Mental State Examination) from 11 years of follow-up. A total of 1,445 older adults comprised the development sample. An index based on dichotomized markers was divided into low-, medium-, and high-risk categories; the risk categories were validated with the remaining sample (n = 739) using linear regression. Amyloid was measured on a subsample (n = 865) and was included only in a secondary index.Results:The risk categories showed significant differences from each other and were predictive of prospective cognitive decline in the validation sample, even after adjustment for age and baseline cognitive score: the low-risk group (24.8%) declined 0.32 points/y (95% confidence interval [CI]: -0.46, -0.19), the medium-risk group (58.7%) declined 0.55 points/y (95% CI: -0.65, 0.45), and the high-risk group (16.6%) declined 0.69 points/y (95% CI: -0.85, -0.54). Using the secondary index, which included -amyloid 42/40 (validation n = 279), the low-risk group (26.9%) declined 0.20 points/y (95% CI: -0.42, 0.01), the medium-risk group (61.3%) declined 0.55 points/y (95% CI: -0.72, -0.38), and the high-risk group (11.8%) declined 0.83 points/y (95% CI: -1.14, -0.51).Conclusions:A risk index based on 8 blood-based markers was modestly able to predict cognitive decline over an 11-year follow-up. Further validation in other cohorts is necessary. C1 [Nettiksimmons, Jasmine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Ayonayon, Hilsa] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Harris, Tamara] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. [Phillips, Caroline] NIA, Neuroepidemiol Sect, Bethesda, MD 20892 USA. [Rosano, Caterina] Univ Pittsburgh, Ctr Aging & Populat Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Satterfield, Suzanne] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Knoxville, TN 37996 USA. [Yaffe, Kristine] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Neurol, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Nettiksimmons, J (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. EM jasmine.nettiksimmons@ucsf.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050, K24AG031155]; National Institute of Nursing Research [R01-NR012459]; NIH, NIA; American Health Assistance Foundation [A201-0029] FX National Institute on Aging (NIA) contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106; NIA grant R01-AG028050; National Institute of Nursing Research grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, NIA, and by grant A201-0029 from the American Health Assistance Foundation. Dr. Yaffe is supported in part by a NIA grant (K24AG031155). NR 36 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 17 PY 2015 VL 84 IS 7 BP 696 EP 702 DI 10.1212/WNL.0000000000001263 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CB7XV UT WOS:000349843000014 PM 25609760 ER PT J AU Oh, J Sotirchos, ES Saidha, S Whetstone, A Chen, M Newsome, SD Zackowski, K Balcer, LJ Frohman, E Prince, J Diener-West, M Reich, DS Calabresi, PA AF Oh, Jiwon Sotirchos, Elias S. Saidha, Shiv Whetstone, Anna Chen, Min Newsome, Scott D. Zackowski, Kathy Balcer, Laura J. Frohman, Elliot Prince, Jerry Diener-West, Marie Reich, Daniel S. Calabresi, Peter A. TI Relationships between quantitative spinal cord MRI and retinal layers in multiple sclerosis SO NEUROLOGY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; NEUROMYELITIS-OPTICA; AXONAL LOSS; REPRODUCIBILITY; HETEROGENEITY; DEMYELINATION; SEGMENTATION; PATHOGENESIS; PHENOTYPE; PATHOLOGY AB Objective:To assess relationships between spinal cord MRI (SC-MRI) and retinal measures, and to evaluate whether these measures independently relate to clinical disability in multiple sclerosis (MS).Methods:One hundred two patients with MS and 11 healthy controls underwent 3-tesla brain and cervical SC-MRI, which included standard T1- and T2-based sequences and diffusion-tensor and magnetization-transfer imaging, and optical coherence tomography with automated segmentation. Clinical assessments included visual acuity (VA), Expanded Disability Status Scale, MS functional composite, vibration sensation threshold, and hip-flexion strength. Regions of interest circumscribing SC cross-sections at C3-4 were used to obtain cross-sectional area (CSA), fractional anisotropy (FA), perpendicular diffusivity (), and magnetization transfer ratio. Multivariable regression assessed group differences and SC, retinal, and clinical relationships.Results:In MS, there were correlations between SC-CSA, SC-FA, SC-(perpendicular to), and peripapillary retinal nerve fiber layer (pRNFL) (p = 0.01, p = 0.002, p = 0.001, respectively) after adjusting for age, sex, prior optic neuritis, and brain atrophy. In multivariable clinical models, when SC-CSA, pRNFL, and brain atrophy were included simultaneously, SC-CSA and pRNFL retained independent relationships with low-contrast VA (p = 0.04, p = 0.002, respectively), high-contrast VA (p = 0.06, p = 0.008), and vibration sensation threshold (p = 0.01, p = 0.05). SC-CSA alone retained independent relationships with Expanded Disability Status Scale (p = 0.001), hip-flexion strength (p = 0.001), and MS functional composite (p = 0.004).Conclusions:In this cross-sectional study of patients with MS, correlations exist between SC-MRI and retinal layers, and both exhibit independent relationships with clinical dysfunction. These findings suggest that the SC and optic nerve reflect ongoing global pathologic processes that supplement measures of whole-brain atrophy, highlighting the importance of combining measures from unique compartments to facilitate a thorough examination of regional and global disease processes that contribute to clinical disability in MS. C1 [Oh, Jiwon; Sotirchos, Elias S.; Saidha, Shiv; Whetstone, Anna; Newsome, Scott D.; Zackowski, Kathy; Reich, Daniel S.; Calabresi, Peter A.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Chen, Min; Prince, Jerry] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Prince, Jerry] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA. [Zackowski, Kathy] Johns Hopkins Univ, Dept Phys Med & Rehabil, Baltimore, MD USA. [Chen, Min; Diener-West, Marie; Reich, Daniel S.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Reich, Daniel S.] Johns Hopkins Univ, Dept Radiol & Radiol Sci, Baltimore, MD USA. [Oh, Jiwon] Univ Toronto, St Michaels Hosp, Dept Med, Div Neurol, Toronto, ON M5S 1A1, Canada. [Zackowski, Kathy] Kennedy Krieger Inst, Mot Anal Lab, Baltimore, MD USA. [Balcer, Laura J.] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Frohman, Elliot] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Frohman, Elliot] Univ Texas SW Med Ctr Dallas, Dept Ophthalmol, Dallas, TX 75390 USA. [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Bethesda, MD 20892 USA. RP Calabresi, PA (reprint author), Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. EM joh20@jhu.edu; pcalabr1@jhmi.edu RI Reich, Daniel/E-5701-2010; OI Reich, Daniel/0000-0002-2628-4334; Sotirchos, Elias/0000-0002-8812-1637 FU Multiple Sclerosis Society of Canada Transitional Career Development Award; NIH [R01NS08234 R01 NS082347, K01 HDO49476]; National Institute of Neurological Disorders and Stroke FX Multiple Sclerosis Society of Canada Transitional Career Development Award (to J.O.), NIH R01NS08234 R01 NS082347 to P.A.C., NIH K01 HDO49476 to K.Z., Intramural Research Program of the National Institute of Neurological Disorders and Stroke (to D.S.R.). NR 33 TC 7 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 17 PY 2015 VL 84 IS 7 BP 720 EP 728 DI 10.1212/WNL.0000000000001257 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA CB7XV UT WOS:000349843000017 PM 25609766 ER PT J AU Hoppe, T Minton, AP AF Hoppe, Travis Minton, Allen P. TI An Equilibrium Model for the Combined Effect of Macromolecular Crowding and Surface Adsorption on the Formation of Linear Protein Fibrils SO BIOPHYSICAL JOURNAL LA English DT Article ID ISLET AMYLOID POLYPEPTIDE; SELF-ASSOCIATION; PHYSIOLOGICAL CONSEQUENCES; HARD-WALL; DIFFUSION; POLYMERIZATION; CONFINEMENT; TUBULIN; FTSZ AB The formation of linear protein fibrils has previously been shown to be enhanced by volume exclusion or crowding in the presence of a high concentration of chemically inert protein or polymer, and by adsorption to membrane surfaces. An equilibrium mesoscopic model for the combined effect of both crowding and adsorption upon the fibrillation of a dilute tracer protein is presented. The model exhibits behavior that differs qualitatively from that observed in the presence of crowding or adsorption alone. The model predicts that in a crowded solution, at critical values of the volume fraction of crowder or intrinsic energy of the tracer-wall interaction, the tracer protein will undergo an extremely cooperative transition-approaching a step function-from existence as a slightly self-associated species in solution to existence as a highly self-associated and completely adsorbed species. Criteria for a valid experimental test of these predictions are presented. C1 [Hoppe, Travis; Minton, Allen P.] NIDDK, Sect Phys Biochem, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDK, Sect Phys Biochem, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM minton@helix.nih.gov OI Hoppe, Travis/0000-0002-4694-3050; Minton, Allen/0000-0001-8459-1247 FU Intramural Research Division of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX This research was supported by the Intramural Research Division of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. (http://biowulf.nih.gov). NR 38 TC 4 Z9 4 U1 3 U2 26 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 17 PY 2015 VL 108 IS 4 BP 957 EP 966 DI 10.1016/j.bpj.2014.12.033 PG 10 WC Biophysics SC Biophysics GA CB5IJ UT WOS:000349660400022 PM 25692600 ER PT J AU Alberts, B Kirschner, MW Tilghman, S Varmus, H AF Alberts, Bruce Kirschner, Marc W. Tilghman, Shirley Varmus, Harold TI Opinion: Addressing systemic problems in the biomedical research enterprise SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material C1 [Alberts, Bruce] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA. [Kirschner, Marc W.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Tilghman, Shirley] Princeton Univ, Dept Mol Biol, Princeton, NJ 08540 USA. [Varmus, Harold] Natl Canc Inst, Bethesda, MD 20892 USA. RP Alberts, B (reprint author), Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA. EM bruce.alberts@ucsf.edu NR 4 TC 11 Z9 12 U1 1 U2 9 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 FEB 17 PY 2015 VL 112 IS 7 BP 1912 EP 1913 DI 10.1073/pnas.1500969112 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB2GV UT WOS:000349446000031 PM 25691698 ER PT J AU Weyemi, U Redon, CE Aziz, T Choudhuri, R Maeda, D Parekh, PR Bonner, MY Arbiser, JL Bonner, WM AF Weyemi, Urbain Redon, Christophe E. Aziz, Towqir Choudhuri, Rohini Maeda, Daisuke Parekh, Palak R. Bonner, Michael Y. Arbiser, Jack L. Bonner, William M. TI NADPH oxidase 4 is a critical mediator in Ataxia telangiectasia disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ataxia telangiectasia; NOX4; ROS; neurodegeneration; DNA damage ID ATM-DEFICIENT MICE; INCREASED OXIDATIVE STRESS; N-ACETYL CYSTEINE; DNA-DAMAGE; NOX FAMILY; SENESCENCE; ROS; LYMPHOMA; GENE; PROTEINS AB Ataxia telangiectasia (A-T), a rare autosomal recessive disorder characterized by progressive cerebellar degeneration and a greatly increased incidence of cancer among other symptoms, is caused by a defective or missing ataxia telangiectasia mutated (ATM) gene. The ATM protein has roles in DNA repair and in the regulation of reactive oxygen species (ROS). Here, we provide, to our knowledge, the first evidence that NADPH oxidase 4 (NOX4) is involved in manifesting A-T disease. We showed that NOX4 expression levels are higher in A-T cells, and that ATM inhibition leads to increased NOX4 expression in normal cells. A-T cells exhibit elevated levels of oxidative DNA damage, DNA double-strand breaks and replicative senescence, all of which are partially abrogated by down-regulation of NOX4 with siRNA. Sections of degenerating cerebelli from A-T patients revealed elevated NOX4 levels. ATM-null mice exhibit A-T disease but they die from cancer before the neurological symptoms are manifested. Injecting Atm-null mice with fulvene-5, a specific inhibitor of NOX4 and NADPH oxidase 2 (NOX2), decreased their elevated cancer incidence to that of the controls. We conclude that, in A-T disease in humans and mice, NOX4 may be critical mediator and targeting it will open up new avenues for therapeutic intervention in neurodegeneration. C1 [Weyemi, Urbain; Redon, Christophe E.; Aziz, Towqir; Choudhuri, Rohini; Maeda, Daisuke; Parekh, Palak R.; Bonner, William M.] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Bonner, Michael Y.; Arbiser, Jack L.] Emory Univ, Dept Dermatol, Atlanta, GA 30322 USA. [Bonner, Michael Y.; Arbiser, Jack L.] Emory Univ, Atlanta Vet Adm Med Ctr, Atlanta, GA 30322 USA. RP Weyemi, U (reprint author), NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. EM weyemiurbain@yahoo.fr; bonnerw@mail.nih.gov RI Weyemi, Urbain/E-2083-2016 FU National Institute of Allergy and Infectious Diseases, Radiation/Nuclear Countermeasures Program; Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health FX Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD. We thank Dr. Simone Difilippantonio, Dr. Diana Haines, Mrs. Christina Robinson, and the other members of the Laboratory of Animal Sciences Program and Pathology Histotechnology Laboratory staff (National Cancer Institute-Frederick) for help with animal maintenance and histological analysis. We also thank Dr. Lino Tessarollo of the Mouse Cancer Genetics Program (National Cancer Institute-Frederick) for help with motor coordination tests and Mrs. Jennifer E. Dwyer of the Laboratory of Cancer Biology and Genetics (National Cancer Institute) for help with immunohistochemistry slides scanning. This work was supported by the National Institute of Allergy and Infectious Diseases, Radiation/Nuclear Countermeasures Program and the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. NR 42 TC 2 Z9 2 U1 0 U2 0 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 FEB 17 PY 2015 VL 112 IS 7 BP 2121 EP 2126 DI 10.1073/pnas.1418139112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB2GV UT WOS:000349446000071 PM 25646414 ER PT J AU Catalan, MA Kondo, Y Pena-Munzenmayer, G Jaramillo, Y Liu, F Choi, S Crandall, E Borok, Z Flodby, P Shull, GE Melvin, JE AF Catalan, Marcelo A. Kondo, Yusuke Pena-Munzenmayer, Gaspar Jaramillo, Yasna Liu, Frances Choi, Sooji Crandall, Edward Borok, Zea Flodby, Per Shull, Gary E. Melvin, James E. TI A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE acinar cell; secretion; Cl- channel; Tmem16A/Ano1; Cftr channel ID ACTIVATED CHLORIDE CHANNEL; REGULATED ANION CHANNEL; SUBMANDIBULAR-GLAND; ESSENTIAL COMPONENT; MEMBRANE-PROTEIN; CYSTIC-FIBROSIS; KNOCKOUT MICE; CL-CURRENT; CELLS; CFTR AB Activation of an apical Ca2+-activated Cl- channel (CaCC) triggers the secretion of saliva. It was previously demonstrated that CaCC-mediated Cl- current and Cl- efflux are absent in the acinar cells of systemic Tmem16A (Tmem16A Cl- channel) null mice, but salivation was not assessed in fully developed glands because Tmem16A null mice die within a few days after birth. To test the role of Tmem16A in adult salivary glands, we generated conditional knockout mice lacking Tmem16A in acinar cells (Tmem16A(-/-)). Ca2+-dependent salivation was abolished in Tmem16A(-/-) mice, demonstrating that Tmem16A is obligatory for Ca2+-mediated fluid secretion. However, the amount of saliva secreted by Tmem16A(-/-) mice in response to the beta-adrenergic receptor agonist isoproterenol (IPR) was comparable to that seen in controls, indicating that Tmem16A does not significantly contribute to cAMP-induced secretion. Furthermore, IPR-stimulated secretion was unaffected in mice lacking Cftr (Cftr(Delta F508/Delta F508)) or ClC-2 (Clcn2(-/-)) Cl- channels. The time course for activation of IPR-stimulated fluid secretion closely correlated with that of the IPR-induced cell volume increase, suggesting that acinar swelling may activate a volume-sensitive Cl- channel. Indeed, Cl- channel blockers abolished fluid secretion, indicating that Cl(-)channel activity is critical for IPR-stimulated secretion. These data suggest that beta-adrenergic-induced, cAMP-dependent fluid secretion involves a volume-regulated anion channel. In summary, our results using acinar-specific Tmem16A(-/-) mice identify Tmem16A as the Cl- channel essential for muscarinic, Ca2+-dependent fluid secretion in adult mouse salivary glands. C1 [Catalan, Marcelo A.; Kondo, Yusuke; Pena-Munzenmayer, Gaspar; Jaramillo, Yasna; Liu, Frances; Choi, Sooji; Melvin, James E.] Natl Inst Dent & Craniofacial Res, Secretory Mech & Dysfunct Sect, NIH, Bethesda, MD 20892 USA. [Catalan, Marcelo A.; Kondo, Yusuke] Kyushu Dent Univ, Dept Oral Reconstruct & Rehabil, Kitakyushu, Fukuoka 8038580, Japan. [Crandall, Edward; Borok, Zea; Flodby, Per] Univ So Calif, Will Rogers Inst Pulm Res Ctr, Div Pulm & Crit Care Med, Los Angeles, CA 90033 USA. [Shull, Gary E.] Univ Cincinnati, Dept Mol Genet Biochem & Microbiol, Coll Med, Cincinnati, OH 45267 USA. RP Catalan, MA (reprint author), Natl Inst Dent & Craniofacial Res, Secretory Mech & Dysfunct Sect, NIH, Bethesda, MD 20892 USA. EM marcelo.catalan@nih.gov; james.melvin@nih.gov OI Borok, Zea/0000-0001-8673-8177; Catalan, Marcelo/0000-0003-3544-2821 FU Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH); Hastings Foundation; Whittier Foundation; NIH [DK050594] FX We thank the University of Cincinnati Animal Core Facility for the design and generation of the exon 12-floxed Tmem16A mouse. The Secretory Mechanisms and Dysfunction Section is supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH). Z.B., E.C., and P.F. were supported by the Hastings and Whittier Foundations and the NIH. G.E.S. was supported by NIH Grant DK050594. NR 41 TC 15 Z9 15 U1 0 U2 7 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 FEB 17 PY 2015 VL 112 IS 7 BP 2263 EP 2268 DI 10.1073/pnas.1415739112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB2GV UT WOS:000349446000095 PM 25646474 ER PT J AU Klebba, JE Buster, DW McLamarrah, TA Rusan, NM Rogers, GC AF Klebba, Joseph E. Buster, Daniel W. McLamarrah, Tiffany A. Rusan, Nasser M. Rogers, Gregory C. TI Autoinhibition and relief mechanism for Polo-like kinase 4 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autoinhibition; centriole; centrosome; Polo box; Polo-like kinase 4 ID CENTRIOLE DUPLICATION; MITOTIC ENTRY; BOX DOMAIN; PLK4; CENTROSOME; CELLS; BIOGENESIS; PROTEINS; BINDING; PHOSPHORYLATION AB Polo-like kinase 4 (Plk4) is a master regulator of centriole duplication, and its hyperactivity induces centriole amplification. Homodimeric Plk4 has been shown to be ubiquitinated as a result of autophosphorylation, thus promoting its own degradation and preventing centriole amplification. Unlike other Plks, Plk4 contains three rather than two Polo box domains, and the function of its third Polo box (PB3) is unclear. Here, we performed a functional analysis of Plk4's structural domains. Like other Plks, Plk4 possesses a previously unidentified autoinhibitory mechanism mediated by a linker (L1) near the kinase domain. Thus, autoinhibition is a conserved feature of Plks. In the case of Plk4, autoinhibition is relieved after homodimerization and is accomplished by PB3 and by autophosphorylation of L1. In contrast, autophosphorylation of the second linker promotes separation of the Plk4 homodimer. Therefore, autoinhibition delays the multiple consequences of activation until Plk4 dimerizes. These findings reveal a complex mechanism of Plk4 regulation and activation which govern the process of centriole duplication. C1 [Klebba, Joseph E.; Buster, Daniel W.; McLamarrah, Tiffany A.; Rogers, Gregory C.] Univ Arizona, Ctr Canc, Dept Cellular & Mol Med, Tucson, AZ 85724 USA. [Rusan, Nasser M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Rogers, GC (reprint author), NHLBI, NIH, Bethesda, MD 20892 USA. EM gcrogers@email.arizona.edu RI Rusan, Nasser/P-3511-2016 FU National Cancer Institute (NCI) Grant [P30 CA23074]; NCI/NIH Gastrointestinal Specialized Programs of Research Excellence Grant [P50 CA95060]; National Science Foundation Grant [1158151]; Arizona Biomedical Research Commission Grant [1210]; Phoenix Friends; Division of Intramural Research at the NIH/National Heart, Lung, and Blood Institute Project [1ZIAHL006104] FX We thank P. Krieg and S. Rogers for comments on the manuscript, D. Morgan for use of his facilities, and S. Aguirre for technical assistance. G.C.R. was supported by National Cancer Institute (NCI) Grant P30 CA23074, NCI/NIH Gastrointestinal Specialized Programs of Research Excellence Grant P50 CA95060, National Science Foundation Grant 1158151, the Arizona Biomedical Research Commission Grant 1210, and the Phoenix Friends. N.M.R. is supported by the Division of Intramural Research at the NIH/National Heart, Lung, and Blood Institute Project 1ZIAHL006104. NR 54 TC 12 Z9 12 U1 0 U2 7 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 FEB 17 PY 2015 VL 112 IS 7 BP E657 EP E666 DI 10.1073/pnas.1417967112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB2GV UT WOS:000349446000009 PM 25646492 ER PT J AU Reeb-Sutherland, BC Williams, LR Degnan, KA Perez-Edgar, K Chronis-Tuscano, A Leibenluft, E Pine, DS Pollak, SD Fox, NA AF Reeb-Sutherland, Bethany C. Williams, Lela Rankin Degnan, Kathryn A. Perez-Edgar, Koraly Chronis-Tuscano, Andrea Leibenluft, Ellen Pine, Daniel S. Pollak, Seth D. Fox, Nathan A. TI Identification of emotional facial expressions among behaviorally inhibited adolescents with lifetime anxiety disorders SO COGNITION & EMOTION LA English DT Article DE Recognition; Temperament; Children; Face processing; Social anxiety ID SOCIAL ANXIETY; RECOGNITION; CHILDHOOD; CHILDREN; DEFICITS; THREAT; BIASES; SPECIFICITY; FACES AB The current study examined differences in emotion expression identification between adolescents characterised with behavioural inhibition (BI) in childhood with and without a lifetime history of anxiety disorder. Participants were originally assessed for BI during toddlerhood and for social reticence during childhood. During adolescence, participants returned to the laboratory and completed a facial emotion identification task and a clinical psychiatric interview. Results revealed that behaviorally inhibited adolescents with a lifetime history of anxiety disorder displayed a lower threshold for identifying fear relative to anger emotion expressions compared to non-anxious behaviorally inhibited adolescents and non-inhibited adolescents with or without anxiety. These findings were specific to behaviorally inhibited adolescents with a lifetime history of social anxiety disorder. Thus, adolescents with a history of both BI and anxiety, specifically social anxiety, are more likely to differ from other adolescents in their identification of fearful facial expressions. This offers further evidence that perturbations in the processing of emotional stimuli may underlie the aetiology of anxiety disorders. C1 [Reeb-Sutherland, Bethany C.] Florida Int Univ, Dept Psychol, Miami, FL 33199 USA. [Williams, Lela Rankin] Arizona State Univ, Sch Social Work, Phoenix, AZ USA. [Degnan, Kathryn A.; Fox, Nathan A.] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. [Perez-Edgar, Koraly] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Chronis-Tuscano, Andrea] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Leibenluft, Ellen; Pine, Daniel S.] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Pollak, Seth D.] Univ Wisconsin, Dept Psychol, Waisman Ctr, Madison, WI 53706 USA. RP Reeb-Sutherland, BC (reprint author), Florida Int Univ, Dept Psychol, 11200 SW 8th St, Miami, FL 33199 USA. EM besuther@fiu.edu OI Perez-Edgar, Koraly/0000-0003-4051-9563 FU NICHD NIH HHS [HD R3717899, R37 HD017899]; NIMH NIH HHS [R01 MH094633, K01 MH073569, MH R01074454, R01 MH074454] NR 34 TC 5 Z9 5 U1 6 U2 39 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0269-9931 EI 1464-0600 J9 COGNITION EMOTION JI Cogn. Emot. PD FEB 17 PY 2015 VL 29 IS 2 BP 372 EP 382 DI 10.1080/02699931.2014.913552 PG 11 WC Psychology, Experimental SC Psychology GA AT3XF UT WOS:000344866900014 PM 24800906 ER PT J AU Klebba, JE Galletta, BJ Nye, J Plevock, KM Buster, DW Hollingsworth, NA Slep, KC Rusan, NM Rogers, GC AF Klebba, Joseph E. Galletta, Brian J. Nye, Jonathan Plevock, Karen M. Buster, Daniel W. Hollingsworth, Natalie A. Slep, Kevin C. Rusan, Nasser M. Rogers, Gregory C. TI Two Polo-like kinase 4 binding domains in Asterless perform distinct roles in regulating kinase stability SO JOURNAL OF CELL BIOLOGY LA English DT Article ID CENTRIOLE DUPLICATION; CENTROSOME; PLK4; CEP152; BIOGENESIS; DROSOPHILA; RECRUITMENT; NUMBER; CELLS; MICROSCOPY AB Plk4 (Polo-like kinase 4) and its binding partner Asterless (Asl) are essential, conserved centriole assembly factors that induce centriole amplification when overexpressed. Previous studies found that Asl acts as a scaffolding protein; its N terminus binds Plk4's tandem Polo box cassette (PB1-PB2) and targets Plk4 to centrioles to initiate centriole duplication. However, how Asl overexpression drives centriole amplification is unknown. In this paper, we investigated the Asl-Plk4 interaction in Drosophila melanogaster cells. Surprisingly, the N-terminal region of Asl is not required for centriole duplication, but a previously unidentified Plk4-binding domain in the C terminus is required. Mechanistic analyses of the different Asl regions revealed that they act uniquely during the cell cycle: the Asl N terminus promotes Plk4 homodimerization and autophosphorylation during interphase, whereas the Asl C terminus stabilizes Plk4 during mitosis. Therefore, Asl affects Plk4 in multiple ways to regulate centriole duplication. Asl not only targets Plk4 to centrioles but also modulates Plk4 stability and activity, explaining the ability of overexpressed Asl to drive centriole amplification. C1 [Klebba, Joseph E.; Nye, Jonathan; Buster, Daniel W.; Hollingsworth, Natalie A.; Rogers, Gregory C.] Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ 85724 USA. [Klebba, Joseph E.; Nye, Jonathan; Buster, Daniel W.; Hollingsworth, Natalie A.; Rogers, Gregory C.] Univ Arizona, Ctr Canc, Tucson, AZ 85724 USA. [Galletta, Brian J.; Plevock, Karen M.; Rusan, Nasser M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Plevock, Karen M.; Slep, Kevin C.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. RP Rusan, NM (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM nasser.rusan@nih.gov; gcrogers@email.arizona.edu RI Rusan, Nasser/P-3511-2016 FU National Institutes of Health [R01GM094415]; March of Dimes [FY11-434]; Division of Intramural Research National Institutes of Health/National Heart, Lung, and Blood Institute [1ZIAHL006104]; National Cancer Institute [30 CA23074]; National Science Foundation [1158151]; Arizona Biomedical Research Commission [1210]; Phoenix Friends FX K.C. Slep is supported by the National Institutes of Health (R01GM094415) and the March of Dimes (FY11-434). N.M. Rusan is supported by the Division of Intramural Research National Institutes of Health/National Heart, Lung, and Blood Institute (1ZIAHL006104). G.C. Rogers is grateful for support from National Cancer Institute (30 CA23074), National Science Foundation (1158151), Arizona Biomedical Research Commission (1210), and the Phoenix Friends. NR 42 TC 9 Z9 9 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD FEB 16 PY 2015 VL 208 IS 4 BP 401 EP 414 DI 10.1083/jcb.201410105 PG 14 WC Cell Biology SC Cell Biology GA CB7YK UT WOS:000349844600005 PM 25688134 ER PT J AU Fennell, A Fernandez-Alvarez, A Tomita, K Cooper, JP AF Fennell, Alex Fernandez-Alvarez, Alfonso Tomita, Kazunori Cooper, Julia Promisel TI Telomeres and centromeres have interchangeable roles in promoting meiotic spindle formation SO JOURNAL OF CELL BIOLOGY LA English DT Article ID OSCILLATORY NUCLEAR-MOVEMENT; FISSION YEAST MEIOSIS; POLE BODY; SCHIZOSACCHAROMYCES-POMBE; CHROMOSOME SEGREGATION; HORSETAIL MOVEMENT; PROTEIN; PROPHASE; HETEROCHROMATIN; DYNAMICS AB Telomeres and centromeres have traditionally been considered to perform distinct roles. During meiotic prophase, in a conserved chromosomal configuration called the bouquet, telomeres gather to the nuclear membrane (NM), often near centrosomes. We found previously that upon disruption of the fission yeast bouquet, centrosomes failed to insert into the NM at meiosis I and nucleate bipolar spindles. Hence, the trans-NM association of telomeres with centrosomes during prophase is crucial for efficient spindle formation. Nonetheless, in approximately half of bouquet-deficient meiocytes, spindles form properly. Here, we show that bouquet-deficient cells can successfully undergo meiosis using centromere-centrosome contact instead of telomere-centrosome contact to generate spindle formation. Accordingly, forced association between centromeres and centrosomes fully rescued the spindle defects incurred by bouquet disruption. Telomeres and centromeres both stimulate focal accumulation of the SUN domain protein Sad1 beneath the centrosome, suggesting a molecular underpinning for their shared spindle-generating ability. Our observations demonstrate an unanticipated level of interchangeability between the two most prominent chromosomal landmarks. C1 [Fennell, Alex; Fernandez-Alvarez, Alfonso; Cooper, Julia Promisel] NCI, Telomere Biol Sect, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. [Fennell, Alex; Fernandez-Alvarez, Alfonso; Cooper, Julia Promisel] London Res Inst, Telomere Biol Lab, Canc Res UK, London WC2A 3LY, England. [Tomita, Kazunori] UCL, UCL Canc Inst, Chromosome Maintenance Grp, London WC1E 6DD, England. RP Cooper, JP (reprint author), NCI, Telomere Biol Sect, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. EM julie.cooper@nih.gov RI Fernandez-Alvarez, Alfonso/N-1249-2016; OI Tomita, Kazunori/0000-0003-1096-6725 FU European Research Council; Cancer Research UK; National Institutes of Health; European Molecular Biology Organization FX This work was supported by the European Research Council, Cancer Research UK, the National Institutes of Health, and a European Molecular Biology Organization long-term fellowship to A. Fernandez-Alvarez. NR 52 TC 11 Z9 11 U1 2 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD FEB 16 PY 2015 VL 208 IS 4 BP 415 EP 428 DI 10.1083/jcb.201409058 PG 14 WC Cell Biology SC Cell Biology GA CB7YK UT WOS:000349844600006 PM 25688135 ER PT J AU Cronin, M Coolbaugh, MJ Nellis, D Zhu, JW Wood, DW Nussinov, R Ma, BY AF Cronin, Melissa Coolbaugh, Michael J. Nellis, David Zhu, Jianwei Wood, David W. Nussinov, Ruth Ma, Buyong TI Dynamics differentiate between active and inactive inteins SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Mini-intein; Protein splicing; Enzyme dynamics; Allostery; Conformational dynamics; Non-linear Arrhenius plot ID MYCOBACTERIUM-TUBERCULOSIS-RECA; C-TERMINAL CLEAVAGE; MOLECULAR-DYNAMICS; CONFORMATIONAL FLEXIBILITY; CONSERVED ASPARTATE; SPLICING INTEINS; PEPTIDE-BOND; PROTEINS; MECHANISM; EVOLUTION AB The balance between stability and dynamics for active enzymes can be somewhat quantified by studies of intein splicing and cleaving reactions. Inteins catalyze the ligation of flanking host exteins while excising themselves. The potential for applications led to engineering of a mini-intein splicing domain, where the homing endonuclease domain of the Mycobacterium tuberculosis RecA (Mtu recA) intein was removed. The remaining domains were linked by several short peptides, but splicing activity in all was substantially lower than the full-length intein. Native splicing activity was restored in some cases by a V67L mutation. Using computations and experiments, we examine the impact of this mutation on the stability and conformational dynamics of the mini-intein splicing domain. Molecular dynamics simulations were used to delineate the factors that determine the active state, including the V67L mini-intein mutant, and peptide linker. We found that (1) the V67L mutation lowers the global fluctuations in all modeled mini-inteins, stabilizing the mini-intein constructs; (2) the connecting linker length affects intein dynamics; and (3) the flexibilities of the linker and intein core are higher in the active structure. We have observed that the interaction of the linker region and a turn region around residues 35-41 provides the pathway for the allostery interaction. Our experiments reveal that intein catalysis is characterized by non-linear Arrhenius plot, confirming the significant contribution of protein conformational dynamics to intein function. We conclude that while the V67L mutation stabilizes the global structure, cooperative dynamics of all intein regions appear more important for intein function than high stability. Our studies suggest that effectively quenching the conformational dynamics of an intein through engineered allosteric interactions could deactivate intein splicing or cleaving. (C) 2014 Elsevier Masson SAS. All rights reserved. C1 [Cronin, Melissa; Nussinov, Ruth; Ma, Buyong] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Coolbaugh, Michael J.; Wood, David W.] Ohio State Univ, Dept Biomol & Chem Engn, Columbus, OH 43210 USA. [Nellis, David] NCI, Biopharmaceut Dev Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Zhu, Jianwei] Shanghai Jiao Tong Univ, Sch Pharm, Shanghai 200240, Peoples R China. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Ma, BY (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. EM mabuyong@mail.nih.gov RI Wood, David/B-2992-2012; Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU Federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E]; startup funds from the Ohio State University FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. M. Cronin thanks student intern program in Frederick National Lab. All simulations were performed using the high-performance computational facilities of the Biowulf PC/Linux cluster at the NIH, Bethesda, MD (http://biowultnih.gov) and ABCC at Frederick National Laboratory. D. Wood was supported by startup funds from the Ohio State University. NR 57 TC 2 Z9 2 U1 1 U2 16 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD FEB 16 PY 2015 VL 91 SI SI BP 51 EP 62 DI 10.1016/j.ejmech.2014.07.094 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CB6LC UT WOS:000349737500006 PM 25087201 ER PT J AU Markossian, S Suresh, S Osmani, AH Osmani, SA AF Markossian, Sarine Suresh, Subbulakshmi Osmani, Aysha H. Osmani, Stephen A. TI Nup2 requires a highly divergent partner, NupA, to fulfill functions at nuclear pore complexes and the mitotic chromatin region SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID SPINDLE-ASSEMBLY CHECKPOINT; CYCLE-DEPENDENT PHOSPHORYLATION; MEDIATED ABSCISSION CHECKPOINT; KINESIN-LIKE PROTEIN; ASPERGILLUS-NIDULANS; RETROTRANSPOSON TF1; NUCLEOPORIN NUP2P; NUP107-160 COMPLEX; YEAST NUCLEOPORIN; STRUCTURAL BASIS AB Chromatin and nuclear pore complexes (NPCs) undergo dramatic changes during mitosis, which in vertebrates and Aspergillus nidulans involves movement of Nup2 from NPCs to the chromatin region to fulfill unknown functions. This transition is shown to require the Cdk1 mitotic kinase and be promoted prematurely by ectopic expression of the NIMA kinase. Nup2 localizes with a copurifying partner termed NupA, a highly divergent yet essential NPC protein. NupA and Nup2 locate throughout the chromatin region during prophase but during anaphase move to surround segregating DNA. NupA function is shown to involve targeting Nup2 to its interphase and mitotic locations. Deletion of either Nup2 or NupA causes identical mitotic defects that initiate a spindle assembly checkpoint ( SAC)-dependent mitotic delay and also cause defects in karyokinesis. These mitotic problems are not caused by overall defects in mitotic NPC disassembly-reassembly or general nuclear import. However, without Nup2 or NupA, although the SAC protein Mad1 locates to its mitotic locations, it fails to locate to NPCs normally in G1 after mitosis. Collectively the study provides new insight into the roles of Nup2 and NupA during mitosis and in a surveillance mechanism that regulates nucleokinesis when mitotic defects occur after SAC fulfillment. C1 [Markossian, Sarine] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Suresh, Subbulakshmi; Osmani, Aysha H.; Osmani, Stephen A.] Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA. RP Osmani, SA (reprint author), Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA. EM osmani.2@osu.edu FU National Institutes of Health [GM042564] FX We thank all members of the Osmani laboratory, particularly Colin P.C. De Souza, for helpful discussions, critical reading of the manuscript, and strains CDS864, CDS578, and CDS831 and Hui-Lin Liu posthumously for strains HA375 and HA377. We thank John R. Davies for help in generating the Nup2 antibody and Jennifer Larson for critical reading of the manuscript. We thank Gregory S. May, University of Texas MD Anderson Cancer Center, for providing the A. fumigatus cDNA library. This work was supported by a grant from the National Institutes of Health (GM042564) to S.A.O. NR 129 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB 15 PY 2015 VL 26 IS 4 BP 605 EP 621 DI 10.1091/mbc.E14-09-1359 PG 17 WC Cell Biology SC Cell Biology GA CE6KJ UT WOS:000351945000003 PM 25540430 ER PT J AU Chen, Z Qi, Y French, S Zhang, GF Garcia, RC Balaban, R Xu, H AF Chen, Zhe Qi, Yun French, Stephanie Zhang, Guofeng Garcia, Raul Covian Balaban, Robert Xu, Hong TI Genetic mosaic analysis of a deleterious mitochondrial DNA mutation in Drosophila reveals novel aspects of mitochondrial regulation and function SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID OXIDATIVE-PHOSPHORYLATION; SYNAPTIC-TRANSMISSION; CELL RESPIRATION; EXPRESSION; CALCIUM; DISEASE; OXIDASE; GENOME; MELANOGASTER; MEMBRANE AB Various human diseases are associated with mitochondrial DNA (mtDNA) mutations, but heteroplasmy-the coexistence of mutant and wild-type mtDNA-complicates their study. We previously isolated a temperature-lethal mtDNA mutation in Drosophila, mt:CoIT300I, which affects the cytochrome c oxidase subunit I (CoI) locus. In the present study, we found that the decrease in cytochrome c oxidase (COX) activity was ascribable to a temperature-dependent destabilization of cytochrome a heme. Consistently, the viability of homoplasmic flies at 29 degrees C was fully restored by expressing an alternative oxidase, which specifically bypasses the cytochrome chains. Heteroplasmic flies are fully viable and were used to explore the age-related and tissue-specific phenotypes of mt: CoIT300I. The proportion of mt: CoIT300I genome remained constant in somatic tissues along the aging process, suggesting a lack of quality control mechanism to remove defective mitochondria containing a deleterious mtDNA mutation. Using a genetic scheme that expresses a mitochondrially targeted restriction enzyme to induce tissue-specific homoplasmy in heteroplasmic flies, we found that mt: CoIT300I homoplasmy in the eye caused severe neurodegeneration at 29 degrees C. Degeneration was suppressed by improving mitochondrial Ca2+ uptake, suggesting that Ca2+ mishandling contributed to mt: CoIT300I pathogenesis. Our results demonstrate a novel approach for Drosophila mtDNA genetics and its application in modeling mtDNA diseases. C1 [Chen, Zhe; Qi, Yun; Xu, Hong] NHLBI, Mol Genet Lab, Bethesda, MD 20892 USA. [French, Stephanie; Garcia, Raul Covian; Balaban, Robert] NHLBI, Cardiac Energet Lab, Bethesda, MD 20892 USA. [Zhang, Guofeng] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Xu, H (reprint author), NHLBI, Mol Genet Lab, Bethesda, MD 20892 USA. EM hong.xu@nih.gov RI Chen, Zhe/E-4278-2015; Chen, Zhe/H-1417-2016; Xu, Hong/H-9997-2016 OI Chen, Zhe/0000-0002-8209-0999; Xu, Hong/0000-0003-1049-1184 FU National Heart, Lung, and Blood Institute Intramural Program FX We thank F. Chanut, K, Delaney, T. Finkel, and P. O'Farrell for their comments and editing of the manuscript and J. Phillips, J. Dows, and the Bloomington Drosophila Stock Center for fly stocks. This work is supported by the National Heart, Lung, and Blood Institute Intramural Program. NR 42 TC 5 Z9 5 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB 15 PY 2015 VL 26 IS 4 BP 674 EP 684 DI 10.1091/mbc.E14-11-1513 PG 11 WC Cell Biology SC Cell Biology GA CE6KJ UT WOS:000351945000008 PM 25501370 ER PT J AU Hui, KL Balagopalan, L Samelson, LE Upadhyaya, A AF Hui, King Lam Balagopalan, Lakshmi Samelson, Lawrence E. Upadhyaya, Arpita TI Cytoskeletal forces during signaling activation in Jurkat T-cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MYOSIN-II FUNCTION; IMMUNOLOGICAL SYNAPSE; TRACTION FORCES; ARP2/3 COMPLEX; RECEPTOR MICROCLUSTERS; ACTIN CYTOSKELETON; RETROGRADE FLOW; SUBSTRATE; RIGIDITY; MOTILITY AB T-cells are critical for the adaptive immune response in the body. The binding of the T-cell receptor (TCR) with antigen on the surface of antigen-presenting cells leads to cell spreading and signaling activation. The underlying mechanism of signaling activation is not completely understood. Although cytoskeletal forces have been implicated in this process, the contribution of different cytoskeletal components and their spatial organization are unknown. Here we use traction force microscopy to measure the forces exerted by Jurkat T-cells during TCR activation. Perturbation experiments reveal that these forces are largely due to actin assembly and dynamics, with myosin contractility contributing to the development of force but not its maintenance. We find that Jurkat T-cells are mechanosensitive, with cytoskeletal forces and signaling dynamics both sensitive to the stiffness of the substrate. Our results delineate the cytoskeletal contributions to interfacial forces exerted by T-cells during activation. C1 [Hui, King Lam; Upadhyaya, Arpita] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Upadhyaya, Arpita] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. [Balagopalan, Lakshmi; Samelson, Lawrence E.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Upadhyaya, A (reprint author), Univ Maryland, Dept Phys, College Pk, MD 20742 USA. EM arpitau@umd.edu FU National Science Foundation [1121710, 1206060]; National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This research was supported by the National Science Foundation (Grants 1121710 and 1206060 to A.U.) and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 64 TC 11 Z9 11 U1 2 U2 9 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB 15 PY 2015 VL 26 IS 4 BP 685 EP 695 DI 10.1091/mbc.E14-03-0830 PG 11 WC Cell Biology SC Cell Biology GA CE6KJ UT WOS:000351945000009 PM 25518938 ER PT J AU Meller, J Rogozin, IB Poliakov, E Meller, N Bedanov-Pack, M Plow, EF Qin, J Podrez, EA Byzova, TV AF Meller, Julia Rogozin, Igor B. Poliakov, Eugenia Meller, Nahum Bedanov-Pack, Mark Plow, Edward F. Qin, Jun Podrez, Eugene A. Byzova, Tatiana V. TI Emergence and subsequent functional specialization of kindlins during evolution of cell adhesiveness SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ADHESION DEFICIENCY-III; LONG-BRANCH ATTRACTION; INTEGRIN ACTIVATION; PROTEIN SEQUENCES; MATRIX ADHESION; FOLLOW-UP; GENE; DOMAIN; MUTATIONS; INVOLVEMENT AB Kindlins are integrin-interacting proteins essential for integrin-mediated cell adhesiveness. In this study, we focused on the evolutionary origin and functional specialization of kindlins as a part of the evolutionary adaptation of cell adhesive machinery. Database searches revealed that many members of the integrin machinery (including talin and integrins) existed before kindlin emergence in evolution. Among the analyzed species, all metazoan lineages-but none of the premetazoans-had at least one kindlin-encoding gene, whereas talin was present in several premetazoan lineages. Kindlin appears to originate from a duplication of the sequence encoding the N-terminal fragment of talin (the talin head domain) with a subsequent insertion of the PH domain of separate origin. Sequence analysis identified a member of the actin filament-associated protein 1 (AFAP1) superfamily as the most likely origin of the kindlin PH domain. The functional divergence between kindlin paralogues was assessed using the sequence swap (chimera) approach. Comparison of kindlin 2 (K2)/kindlin 3 (K3) chimeras revealed that the F2 subdomain, in particular its C-terminal part, is crucial for the differential functional properties of K2 and K3. The presence of this segment enables K2 but not K3 to localize to focal adhesions. Sequence analysis of the C-terminal part of the F2 subdomain of K3 suggests that insertion of a variable glycine-rich sequence in vertebrates contributed to the loss of constitutive K3 targeting to focal adhesions. Thus emergence and subsequent functional specialization of kindlins allowed multicellular organisms to develop additional tissue-specific adaptations of cell adhesiveness. C1 [Meller, Julia; Meller, Nahum; Plow, Edward F.; Qin, Jun; Podrez, Eugene A.; Byzova, Tatiana V.] Cleveland Clin, Lerner Res Inst, Joseph J Jacobs Ctr Thrombosis & Vasc Biol, Dept Mol Cardiol, Cleveland, OH 44195 USA. [Rogozin, Igor B.; Bedanov-Pack, Mark] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Poliakov, Eugenia] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Byzova, TV (reprint author), Cleveland Clin, Lerner Res Inst, Joseph J Jacobs Ctr Thrombosis & Vasc Biol, Dept Mol Cardiol, Cleveland, OH 44195 USA. EM byzovat@ccf.org FU National Institutes of Health Intramural Research Program of the National Heart, Lung, and Blood Institute [HL073311]; National Eye Institute; Intramural Research Program of the National Library of Medicine at the National Institutes of Health (U.S. Department of Health and Human Services) FX This research was supported by the National Institutes of Health Intramural Research Program of the National Heart, Lung, and Blood Institute (grant HL073311) and by National Eye Institute and the Intramural Research Program of the National Library of Medicine at the National Institutes of Health (U.S. Department of Health and Human Services). NR 64 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB 15 PY 2015 VL 26 IS 4 BP 786 EP 796 DI 10.1091/mbc.E14-08-1294 PG 11 WC Cell Biology SC Cell Biology GA CE6KJ UT WOS:000351945000017 PM 25540429 ER PT J AU Zeng, XK Hou, SX AF Zeng, Xiankun Hou, Steven X. TI Enteroendocrine cells are generated from stem cells through a distinct progenitor in the adult Drosophila posterior midgut SO DEVELOPMENT LA English DT Article DE Intestinal stem cell; Secretory enteroendocrine cell; Pre-enteroendocrine cell; Prospero; Drosophila ID INTESTINAL STEM; SELF-RENEWAL; HOMEOSTASIS; RECOMBINASE; EXPRESSION; LINEAGE; TISSUES; LGR5; DIFFERENTIATION; PROLIFERATION AB Functional mature cells are continually replenished by stem cells to maintain tissue homoeostasis. In the adult Drosophila posteriormidgut, both terminally differentiated enterocyte (EC) and enteroendocrine (EE) cells are generated from an intestinal stem cell (ISC). However, it is not clear how the two differentiated cells are generated from the ISC. In this study, we found that only ECs are generated through the Su(H) GBE(+) immature progenitor enteroblasts (EBs), whereas EEs are generated from ISCs through a distinct progenitor pre-EE by a novel lineage-tracing system. EEs can be generated from ISCs in three ways: an ISC becoming an EE, an ISC becoming a new ISC and an EE through asymmetric division, or an ISC becoming two EEs through symmetric division. We further identified that the transcriptional factor Prospero ( Pros) regulates ISC commitment to EEs. Our data provide direct evidence that different differentiated cells are generated by different modes of stem cell lineage specification within the same tissues. C1 [Zeng, Xiankun; Hou, Steven X.] Natl Canc Inst, Ctr Canc Res, Basic Res Lab, Frederick, MD 21701 USA. RP Zeng, XK (reprint author), Natl Canc Inst, Ctr Canc Res, Basic Res Lab, Frederick, MD 21701 USA. EM zengxk@yahoo.com; hous@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. Deposited in PMC for release after 12 months. NR 47 TC 21 Z9 21 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD FEB 15 PY 2015 VL 142 IS 4 BP 644 EP 653 DI 10.1242/dev.113357 PG 10 WC Developmental Biology SC Developmental Biology GA CE3AT UT WOS:000351697100005 PM 25670791 ER PT J AU Canfield, K Li, JQ Wilkins, OM Morrison, MM Ung, M Wells, W Williams, CR Liby, KT Vullhorst, D Buonanno, A Hu, HZ Schiff, R Cook, RS Kurokawa, M AF Canfield, Kaleigh Li, Jiaqi Wilkins, Owen M. Morrison, Meghan M. Ung, Matthew Wells, Wendy Williams, Charlotte R. Liby, Karen T. Vullhorst, Detlef Buonanno, Andres Hu, Huizhong Schiff, Rachel Cook, Rebecca S. Kurokawa, Manabu TI Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells SO CELL CYCLE LA English DT Article DE EGFR; HER2; HER3; HER4; Herceptin ID TRASTUZUMAB RESISTANCE; LAPATINIB MONOTHERAPY; MAMMARY-TUMORS; NEU ONCOGENE; PHASE-II; IN-VITRO; ACTIVATION; GROWTH; PROLIFERATION; DOWNSTREAM AB Approximately 25% of breast cancers overexpress and depend on the receptor tyrosine kinase ERBB2, one of 4 ERBB family members. Targeted therapies directed against ERBB2 have been developed and used clinically, but many patients continue to develop resistance to such therapies. Although much effort has been focused on elucidating the mechanisms of acquired resistance to ERBB2-targeted therapies, the involvement of ERBB4 remains elusive and controversial. We demonstrate that genetic ablation of ERBB4, but not ERBB1-3, led to apoptosis in lapatinib-resistant cells, suggesting that the efficacy of pan-ERBB inhibitors was, at least in part, mediated by the inhibition of ERBB4. Moreover, ERBB4 was upregulated at the protein level in ERBB2+ breast cancer cell lines selected for acquired lapatinib resistance in vitro and in MMTV-Neu mice following prolonged lapatinib treatment. Knockdown of ERBB4 caused a decrease in AKT phosphorylation in resistant cells but not in sensitive cells, suggesting that ERBB4 activated the PI3K/AKT pathway in lapatinib-resistant cells. Importantly, ERBB4 knockdown triggered apoptosis not only in lapatinib-resistant cells but also in trastuzumab-resistant cells. Our results suggest that although ERBB4 is dispensable for naive ERBB2+ breast cancer cells, it may play a key role in the survival of ERBB2+ cancer cells after they develop resistance to ERBB2 inhibitors, lapatinib and trastuzumab. C1 [Canfield, Kaleigh; Li, Jiaqi; Wilkins, Owen M.; Williams, Charlotte R.; Liby, Karen T.; Kurokawa, Manabu] Geisel Sch Med Dartmouth, Dept Pharmacol & Toxicol, Hanover, NH 03755 USA. [Ung, Matthew] Geisel Sch Med Dartmouth, Genet, Hanover, NH USA. [Wells, Wendy] Geisel Sch Med Dartmouth, Pathol, Hanover, NH USA. [Wells, Wendy; Liby, Karen T.; Kurokawa, Manabu] Norris Cotton Canc Ctr, Lebanon, NH USA. [Vullhorst, Detlef; Buonanno, Andres] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Neurobiol, Bethesda, MD USA. [Hu, Huizhong; Schiff, Rachel] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Morrison, Meghan M.; Cook, Rebecca S.] Vanderbilt Univ, Dept Canc Biol, Nashville, TN 37235 USA. RP Kurokawa, M (reprint author), Geisel Sch Med Dartmouth, Dept Pharmacol & Toxicol, Hanover, NH 03755 USA. EM Manabu.Kurokawa@Dartmouth.edu FU NIH [R00CA140948, P30CA23108, P50CA58183, R01CA143126]; Susan G. Komen for the Cure [KG100677] FX This study was supported by NIH grants: R00CA140948 (to MK), P30CA23108 (to the Norris Cotton Cancer Center), P50CA58183 (to RS), and R01CA143126 (to RSC). This work was also supported by Susan G. Komen for the Cure grant KG100677 (to RSC). NR 35 TC 16 Z9 17 U1 0 U2 6 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 FEB 15 PY 2015 VL 14 IS 4 BP 648 EP 655 DI 10.4161/15384101.2014.994966 PG 8 WC Cell Biology SC Cell Biology GA CC1XC UT WOS:000350137700027 PM 25590338 ER PT J AU Matsuda, K Takahashi, A Middlebrooks, CD Obara, W Nasu, Y Inoue, K Tamura, K Yamasaki, I Naya, Y Tanikawa, C Cui, R Figueroa, JD Silverman, DT Rothman, N Namiki, M Tomita, Y Nishiyama, H Kohri, K Deguchi, T Nakagawa, M Yokoyama, M Miki, T Kumon, H Fujioka, T Prokunina-Olsson, L Kubo, M Nakamura, Y Shuin, T AF Matsuda, Koichi Takahashi, Atsushi Middlebrooks, Candace D. Obara, Wataru Nasu, Yasutomo Inoue, Keiji Tamura, Kenji Yamasaki, Ichiro Naya, Yoshio Tanikawa, Chizu Cui, Ri Figueroa, Jonine D. Silverman, Debra T. Rothman, Nathaniel Namiki, Mikio Tomita, Yoshihiko Nishiyama, Hiroyuki Kohri, Kenjiro Deguchi, Takashi Nakagawa, Masayuki Yokoyama, Masayoshi Miki, Tsuneharu Kumon, Hiromi Fujioka, Tomoaki Prokunina-Olsson, Ludmila Kubo, Michiaki Nakamura, Yusuke Shuin, Taro TI Genome-wide association study identified SNP on 15q24 associated with bladder cancer risk in Japanese population SO HUMAN MOLECULAR GENETICS LA English DT Article ID COMMON GENETIC-VARIANTS; SUSCEPTIBILITY LOCI; 5'-FLANKING REGION; HUMAN CYP1A2; LUNG-CANCER; POLYMORPHISM; CARCINOGENESIS; METAANALYSIS; METABOLISM; GENOTYPE AB Through genome-wide association analysis and an independent replication study using a total of 1131 bladder cancer cases and 12 558 non-cancer controls of Japanese populations, we identified a susceptibility locus on chromosome 15q24. SNP rs11543198 was associated with bladder cancer risk with odds ratio (OR) of 1.41 and P-value of 4.03 x 10(-9). Subgroup analysis revealed rs11543198 to have a stronger effect in male smokers with OR of 1.66. SNP rs8041357, which is in complete linkage disequilibrium (r(2) = 1) with rs11543198, was also associated with bladder cancer risk in Europeans (P = 0.045 for an additive and P = 0.025 for a recessive model), despite much lower minor allele frequency in Europeans (3.7%) compared with the Japanese (22.2%). Imputational analysis in this region suggested CYP1A2, which metabolizes tobacco-derived carcinogen, as a causative candidate gene. We also confirmed the association of previously reported loci, namely SLC14A1, APOBEC3A, PSCA and MYC, with bladder cancer. Our finding implies the crucial roles of genetic variations on the chemically associated development of bladder cancer. C1 [Matsuda, Koichi; Tanikawa, Chizu; Cui, Ri] Univ Tokyo, Inst Med Sci, Mol Med Lab, Human Genome Ctr, Tokyo, Japan. [Takahashi, Atsushi; Kubo, Michiaki] Inst Phys & Chem Res RIKEN, Ctr Integrat Med Sci, Sagamihara, Kanagawa, Japan. [Middlebrooks, Candace D.; Figueroa, Jonine D.; Silverman, Debra T.; Rothman, Nathaniel; Prokunina-Olsson, Ludmila] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Obara, Wataru; Fujioka, Tomoaki] Iwate Med Univ, Sch Med, Dept Urol, Morioka, Iwate, Japan. [Nasu, Yasutomo; Kumon, Hiromi] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Urol, Okayama 7008530, Japan. [Inoue, Keiji; Tamura, Kenji; Yamasaki, Ichiro; Shuin, Taro] Kochi Univ, Sch Med, Dept Urol, Kochi 780, Japan. [Naya, Yoshio; Miki, Tsuneharu] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Urol, Kyoto, Japan. [Namiki, Mikio] Kanazawa Univ, Grad Sch Med Sci, Dept Integrat Canc Therapy & Urol, Kanazawa, Ishikawa 9201192, Japan. [Tomita, Yoshihiko] Yamagata Univ, Fac Med, Dept Urol, Yamagata 990, Japan. [Nishiyama, Hiroyuki] Univ Tsukuba, Fac Med, Dept Urol, Ibaraki, Japan. [Kohri, Kenjiro] Nagoya City Univ, Grad Sch Med Sci, Dept Nephrourol, Nagoya, Aichi, Japan. [Deguchi, Takashi] Gifu Univ, Grad Sch Med, Dept Urol, Gifu, Japan. [Nakagawa, Masayuki] Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Urol, Kagoshima 890, Japan. [Yokoyama, Masayoshi] Ehime Univ, Grad Sch Med, Dept Urol, Matsuyama, Ehime 790, Japan. [Nakamura, Yusuke] Univ Chicago, Ctr Personalized Therapeut, Dept Med, Chicago, IL 60637 USA. [Nakamura, Yusuke] Univ Chicago, Ctr Personalized Therapeut, Dept Surg, Chicago, IL 60637 USA. RP Nakamura, Y (reprint author), Univ Chicago, Knapp Ctr Biomed Discovery, Dept Med, Sect Hematol Oncol, Room 6130,MC2115,900 E 57th St, Chicago, IL 60637 USA. EM ynakamura@bsd.uchicago.edu RI cui, ri/P-8507-2014; Kubo, Michiaki/N-7947-2015; OI cui, ri/0000-0001-6202-8779; Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Matsuda, Koichi/0000-0001-7292-2686 FU Ministry of Education, Culture, Sports, Science and Technology of the Japanese government; Intramural Research Program (IRP) of the National Cancer Institute of the US National Institutes of Health FX This work was conducted as a part of the BioBank Japan Project that was supported by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government. The work was supported in part by the Intramural Research Program (IRP) of the National Cancer Institute of the US National Institutes of Health. NR 47 TC 10 Z9 11 U1 1 U2 8 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 FEB 15 PY 2015 VL 24 IS 4 BP 1177 EP 1184 DI 10.1093/hmg/ddu512 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CC1XI UT WOS:000350138300023 PM 25281661 ER PT J AU Baden, LR Liu, JY Li, HL Johnson, JA Walsh, SR Kleinjan, JA Engelson, BA Peter, L Abbink, P Milner, DA Golden, KL Viani, KL Stachler, MD Chen, BJ Pau, MG Weijtens, M Carey, BR Miller, CA Swann, EM Wolff, M Loblein, H Seaman, MS Dolin, R Barouch, DH AF Baden, Lindsey R. Liu, Jinyan Li, Hualin Johnson, Jennifer A. Walsh, Stephen R. Kleinjan, Jane A. Engelson, Brian A. Peter, Lauren Abbink, Peter Milner, Danny A., Jr. Golden, Kevin L. Viani, Kyle L. Stachler, Matthew D. Chen, Benjamin J. Pau, Maria G. Weijtens, Mo Carey, Brittany R. Miller, Caroline A. Swann, Edith M. Wolff, Mark Loblein, Hayley Seaman, Michael S. Dolin, Raphael Barouch, Dan H. TI Induction of HIV-1-Specific Mucosal Immune Responses Following Intramuscular Recombinant Adenovirus Serotype 26 HIV-1 Vaccination of Humans SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; vaccine; adenovirus; mucosal immunity ID LYMPHOCYTES FOLLOWING VACCINATION; T-CELL RESPONSES; RHESUS-MONKEYS; NEUTRALIZING ANTIBODIES; DOUBLE-BLIND; ENV VACCINE; IPCAVD 001; VECTORS; TRIAL; EFFICACY AB Background. Defining mucosal immune responses and inflammation to candidate human immunodeficiency virus type 1 (HIV-1) vaccines represents a current research priority for the HIV-1 vaccine field. In particular, it is unclear whether intramuscular immunization can elicit immune responses at mucosal surfaces in humans. Methods. In this double-blind, randomized, placebo-controlled clinical trial, we evaluated systemic and mucosal immune responses to a candidate adenovirus serotype 26 (Ad26) vectored HIV-1 envelop (Env) vaccine in baseline Ad26-seronegative and Ad26-seropositive healthy volunteers. Systematic mucosal sampling with rectal Weck-Cel sponges and rectal biopsies were performed. Results. Intramuscular immunization elicited both systemic and mucosal Env-specific humoral and cellular immune responses in the majority of subjects. Individuals with preexisting Ad26-specific neutralizing antibodies had vaccine-elicited immune responses comparable to those of subjects who were Ad26 seronegative. We also observed no increase in activated total or vector-specific mucosal CD4(+) T lymphocytes following vaccination by either histopathology or flow cytometry. Conclusions. These data demonstrate that a single intramuscular administration of this Ad26-vectored HIV-1 Env vaccine elicited both systemic and mucosal immune responses in humans. Induction of antigen-specific humoral and cellular mucosal immunity was not accompanied by a detectable increase in mucosal inflammation. C1 [Baden, Lindsey R.; Johnson, Jennifer A.; Walsh, Stephen R.; Kleinjan, Jane A.; Engelson, Brian A.; Milner, Danny A., Jr.; Golden, Kevin L.; Viani, Kyle L.; Stachler, Matthew D.; Chen, Benjamin J.; Dolin, Raphael] Brigham & Womens Hosp, Boston, MA 02115 USA. [Baden, Lindsey R.; Liu, Jinyan; Li, Hualin; Walsh, Stephen R.; Peter, Lauren; Abbink, Peter; Carey, Brittany R.; Miller, Caroline A.; Seaman, Michael S.; Dolin, Raphael; Barouch, Dan H.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Baden, Lindsey R.; Liu, Jinyan; Li, Hualin; Johnson, Jennifer A.; Walsh, Stephen R.; Peter, Lauren; Abbink, Peter; Milner, Danny A., Jr.; Golden, Kevin L.; Viani, Kyle L.; Stachler, Matthew D.; Chen, Benjamin J.; Seaman, Michael S.; Dolin, Raphael; Barouch, Dan H.] Harvard Univ, Sch Med, Boston, MA USA. [Baden, Lindsey R.; Seaman, Michael S.; Dolin, Raphael; Barouch, Dan H.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA USA. [Pau, Maria G.; Weijtens, Mo] Crucell Holland BV, Leiden, Netherlands. [Wolff, Mark; Loblein, Hayley] EMMES Corp, Rockville, MD USA. [Swann, Edith M.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Baden, LR (reprint author), Brigham & Womens Hosp, 15 Francis St, Boston, MA 02115 USA. EM lbaden@partners.org FU NIH [AI060354, AI066305, AI069412, AI078526, AI096040, RR025758]; Ragon Institute of MGH, MIT, and Harvard FX The project was supported in part by the NIH (grant numbers AI060354, AI066305, AI069412, AI078526, AI096040, RR025758); and Ragon Institute of MGH, MIT, and Harvard. NR 29 TC 14 Z9 14 U1 1 U2 3 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 FEB 15 PY 2015 VL 211 IS 4 BP 518 EP 528 DI 10.1093/infdis/jiu485 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC3CJ UT WOS:000350221800004 PM 25165165 ER PT J AU Sarwar, UN Costner, P Enama, ME Berkowitz, N Hu, ZH Hendel, CS Sitar, S Plummer, S Mulangu, S Bailer, RT Koup, RA Mascola, JR Nabel, GJ Sullivan, NJ Graham, BS Ledgerwood, JE AF Sarwar, Uzma N. Costner, Pamela Enama, Mary E. Berkowitz, Nina Hu, Zonghui Hendel, Cynthia S. Sitar, Sandra Plummer, Sarah Mulangu, Sabue Bailer, Robert T. Koup, Richard A. Mascola, John R. Nabel, Gary J. Sullivan, Nancy J. Graham, Barney S. Ledgerwood, Julie E. CA VRC 206 Study Team TI Safety and Immunogenicity of DNA Vaccines Encoding Ebolavirus and Marburgvirus Wild-Type Glycoproteins in a Phase I Clinical Trial SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE filovirus; ebolavirus; marburgvirus; ebola; marburg; DNA; vaccine ID ATTENUATED RECOMBINANT VACCINE; NONHUMAN-PRIMATES; HEALTHY-ADULTS; NEUTRALIZING ANTIBODY; CANDIDATE VACCINE; VIRUS INFECTION; PROTECTION; VECTORS; HUMANS; LIVE AB Background. Ebolavirus and Marburgvirus cause severe hemorrhagic fever with high mortality and are potential bioterrorism agents. There are no available vaccines or therapeutic agents. Previous clinical trials evaluated transmembrane-deleted and point-mutation Ebolavirus glycoproteins (GPs) in candidate vaccines. Constructs evaluated in this trial encode wild-type (WT) GP from Ebolavirus Zaire and Sudan species and the Marburgvirus Angola strain expressed in a DNA vaccine. Methods. The VRC 206 study evaluated the safety and immunogenicity of these DNA vaccines (4 mg administered intramuscularly by Biojector) at weeks 0, 4, and 8, with a homologous boost at or after week 32. Safety evaluations included solicited reactogenicity and coagulation parameters. Primary immune assessment was done by means of GP-specific enzyme-linked immunosorbent assay. Results. The vaccines were well tolerated, with no serious adverse events; 80% of subjects had positive enzyme-linked immunosorbent assay results (>= 30) at week 12. The fourth DNA vaccination boosted the immune responses. Conclusions. The investigational Ebolavirus and Marburgvirus WT GP DNA vaccines were safe, well tolerated, and immunogenic in this phase I study. These results will further inform filovirus vaccine research toward a goal of inducing protective immunity by using WT GP antigens in candidate vaccine regimens. C1 [Sarwar, Uzma N.; Costner, Pamela; Enama, Mary E.; Berkowitz, Nina; Hendel, Cynthia S.; Sitar, Sandra; Plummer, Sarah; Mulangu, Sabue; Bailer, Robert T.; Koup, Richard A.; Mascola, John R.; Nabel, Gary J.; Sullivan, Nancy J.; Graham, Barney S.; Ledgerwood, Julie E.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Hu, Zonghui] NIAID, Biostat Res Branch, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Ledgerwood, JE (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ledgerwood@mail.nih.gov FU NIH Intramural Research Program FX This research was funded by the NIH Intramural Research Program. NR 25 TC 26 Z9 27 U1 1 U2 18 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 FEB 15 PY 2015 VL 211 IS 4 BP 549 EP 557 DI 10.1093/infdis/jiu511 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC3CJ UT WOS:000350221800007 PM 25225676 ER PT J AU Dastgheyb, S Parvizi, J Shapiro, IM Hickok, NJ Otto, M AF Dastgheyb, Sana Parvizi, Javad Shapiro, Irving M. Hickok, Noreen J. Otto, Michael TI Effect of Biofilms on Recalcitrance of Staphylococcal Joint Infection to Antibiotic Treatment SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Staphylococcus aureus; MRSA; antibiotic resistance; joint infection; septic arthritis; biofilm ID AUREUS-INDUCED ARTHRITIS; ANTIMICROBIAL PROPHYLAXIS; VIRULENCE DETERMINANT; SEPTIC ARTHRITIS; FIBRONECTIN; EXPRESSION; CARTILAGE; RSBU AB The pathogenesis of joint infections is not well understood. In particular, we do not know why these infections respond poorly to antibiotic treatment. Here we show that methicillin-resistant Staphylococcus aureus, a major cause of joint infections, forms exceptionally strong biofilmlike aggregates in human synovial fluid ( SF), to an extent significantly exceeding biofilm formation observed in growth medium or serum. Screening a transposon bank identified bacterial fibronectin-and fibrinogen-binding proteins as important for the formation of macroscopic clumps in SF, suggesting an important role of fibrin-containing clots in the formation of bacterial aggregates during joint infection. Pretreatment of SF with plasmin led to a strongly reduced formation of aggregates and increased susceptibility to antibiotics. These results give important insight into the pathogenesis of staphylococcal joint infection and the mechanisms underlying resistance to treatment. Furthermore, they point toward a potential novel approach for treating joint infections. C1 [Dastgheyb, Sana; Otto, Michael] NIAID, NIH, Bethesda, MD 20892 USA. [Dastgheyb, Sana; Shapiro, Irving M.; Hickok, Noreen J.] Thomas Jefferson Univ, Dept Orthoped Surg, Philadelphia, PA 19107 USA. [Parvizi, Javad] Rothman Inst, Philadelphia, PA USA. RP Otto, M (reprint author), NIAID, Lab Human Bacterial Pathogenesis, NIH, Bldg 33 1W10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) [ZIA AI000904-13]; National Institute of Child Health and Human Development [HD06153]; National Institute of Dental and Craniofacial Research [DE019901]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [T32 AR 052273] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) (ZIA AI000904-13, to M. O.), the National Institute of Child Health and Human Development (grant HD06153 to N. J. H.), the National Institute of Dental and Craniofacial Research (grant DE019901 to N. J. H.), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant T32 AR 052273 to I. M. S.). NR 37 TC 18 Z9 18 U1 2 U2 9 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 FEB 15 PY 2015 VL 211 IS 4 BP 641 EP 650 DI 10.1093/infdis/jiu514 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC3CJ UT WOS:000350221800017 PM 25214518 ER PT J AU Mothe, B Hu, XT Llano, A Rosati, M Olvera, A Kulkarni, V Valentin, A Alicea, C Pilkington, GR Sardesai, NY Rocafort, M Crespo, M Carrillo, J Marco, A Mullins, JI Dorrell, L Hanke, T Clotet, B Pavlakis, GN Felber, BK Brander, C AF Mothe, Beatriz Hu, Xintao Llano, Anuska Rosati, Margherita Olvera, Alex Kulkarni, Viraj Valentin, Antonio Alicea, Candido Pilkington, Guy R. Sardesai, Niranjan Y. Rocafort, Muntsa Crespo, Manel Carrillo, Jorge Marco, Andres Mullins, James I. Dorrell, Lucy Hanke, Tomas Clotet, Bonaventura Pavlakis, George N. Felber, Barbara K. Brander, Christian TI A human immune data-informed vaccine concept elicits strong and broad T-cell specificities associated with HIV-1 control in mice and macaques SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE HIV-1 T-cell immunogen; HIV-1 specific CTL; HLA; Immunogenicity; Subdominant; Viral fitness; CTL escape; T-helper epitope; Population coverage ID HUMAN-IMMUNODEFICIENCY-VIRUS; PLACEBO-CONTROLLED TRIAL; HIGHLY PATHOGENIC SIV; THERAPEUTIC IMMUNIZATION; DISCORDANT ASSOCIATIONS; SIVMAC251 CHALLENGE; VIRAL DIVERSITY; NEF PROTEINS; DOUBLE-BLIND; GAG AB Background: None of the HIV T-cell vaccine candidates that have reached advanced clinical testing have been able to induce protective T cell immunity. A major reason for these failures may have been suboptimal T cell immunogen designs. Methods: To overcome this problem, we used a novel immunogen design approach that is based on functional T cell response data from more than 1,000 HIV-1 clade B and C infected individuals and which aims to direct the T cell response to the most vulnerable sites of HIV-1. Results: Our approach identified 16 regions in Gag, Pol, Vif and Nef that were relatively conserved and predominantly targeted by individuals with reduced viral loads. These regions formed the basis of the HIVACAT T-cell Immunogen (HTI) sequence which is 529 amino acids in length, includes more than 50 optimally defined CD4(+) and CD8(+) T-cell epitopes restricted by a wide range of HLA class I and II molecules and covers viral sites where mutations led to a dramatic reduction in viral replicative fitness. In both, C57BL/6 mice and Indian rhesus macaques immunized with an HTI-expressing DNA plasmid (DNA.HTI) induced broad and balanced T-cell responses to several segments within Gag, Pol, and Vif.DNA.HTI induced robust CD4(+) and CD8(+) T cell responses that were increased by a booster vaccination using modified virus Ankara (MVA.HTI), expanding the DNA.HTI induced response to up to 3.2% IFN-gamma T-cells in macaques. HTI-specific T cells showed a central and effector memory phenotype with a significant fraction of the IFN-gamma(+) CD8(+) T cells being Granzyme B+ and able to degranulate (CD107a(+)). Conclusions: These data demonstrate the immunogenicity of a novel HIV-1 T cell vaccine concept that induced broadly balanced responses to vulnerable sites of HIV-1 while avoiding the induction of responses to potential decoy targets that may divert effective T-cell responses towards variable and less protective viral determinants. C1 [Mothe, Beatriz; Llano, Anuska; Olvera, Alex; Rocafort, Muntsa; Carrillo, Jorge; Clotet, Bonaventura; Brander, Christian] Hosp Badalona Germans Trias & Pujol, IrsiCaixa AIDS Res Inst HIVACAT, Badalona 08916, Spain. [Mothe, Beatriz; Clotet, Bonaventura] Hosp Badalona Germans Trias & Pujol, Lluita Sida Fdn, Badalona 08916, Spain. [Mothe, Beatriz; Clotet, Bonaventura] UVic UCC, Vic, Spain. [Hu, Xintao; Kulkarni, Viraj; Alicea, Candido; Pilkington, Guy R.; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Frederick, MD USA. [Rosati, Margherita; Pavlakis, George N.] NCI, Human Retrovirus Sect, Frederick, MD USA. [Sardesai, Niranjan Y.] Inovio Pharmaceut Inc, Blue, PA USA. [Crespo, Manel] Hosp Valle De Hebron, HIV Unit, Barcelona, Spain. [Marco, Andres] Ctr Penitenciaris BCN, Barcelona, Spain. [Mullins, James I.] Univ Washington, Seattle, WA 98195 USA. [Dorrell, Lucy] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Med, Oxford OX3 9DU, England. [Hanke, Tomas] Univ Oxford, Jenner Inst, Oxford, England. [Brander, Christian] Univ Autonoma Barcelona, E-08193 Barcelona, Spain. [Brander, Christian] ICREA, Barcelona, Spain. RP Brander, C (reprint author), Hosp Badalona Germans Trias & Pujol, IrsiCaixa AIDS Res Inst HIVACAT, Crta Canyet S-N, Badalona 08916, Spain. EM cbrander@irsicaixa.es RI Crespo, Manuel/H-8868-2015; OI Crespo, Manuel/0000-0001-9016-0515; Brander, Christian/0000-0002-0548-5778 FU HIVACAT program; Ministerio de Ciencia y Tecnologia, Spain [MTM2008-06747-C02-00]; Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH); NIH [P01AI057005]; European Community (CUT'HIVAC) [EC-FP7-241904]; FIPSE [36-0737-0]; ISCIII [CM08/00020]; ISCIII, Madrid, Spain [JR13/00024] FX This work was supported in part by the HIVACAT program and grants to CB from MTM2008-06747-C02-00 (GG) from the Ministerio de Ciencia y Tecnologia, Spain, FIPSE 36-0737-0, The European Community (CUT'HIVAC, EC-FP7-241904), by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH) (BKF, GNP) and by NIH grant P01AI057005 to JIM. BM was supported by a research fellowship grant from the ISCIII (Rio Hortega, CM08/00020), and is at present time a Joan Rodes investigator from the ISCIII (JR13/00024), Madrid, Spain. CB is ICREA (Institucio Catalana de Recerca I Estudis Avancats) Senior Research Professor. The work was further supported by an unrestricted gift by Rafael Punter, Barcelona and the Barcelona HIV Gala 2013. We thank D. Weiss, J. Treece and staff at Bioqual for their support, J. Bear, B. Chowdhury and R.K. Beach for technical support, and T. Jones for editorial assistance. NR 85 TC 11 Z9 11 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD FEB 15 PY 2015 VL 13 AR 60 DI 10.1186/s12967-015-0392-5 PG 23 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CC6VV UT WOS:000350508000001 PM 25879820 ER PT J AU Dayarian, A Romero, R Wang, ZM Biehl, M Bilal, E Hormoz, S Meyer, P Norel, R Rhrissorrakrai, K Bhanot, G Luo, F Tarca, AL AF Dayarian, Adel Romero, Roberto Wang, Zhiming Biehl, Michael Bilal, Erhan Hormoz, Sahand Meyer, Pablo Norel, Raquel Rhrissorrakrai, Kahn Bhanot, Gyan Luo, Feng Tarca, Adi L. TI Predicting protein phosphorylation from gene expression: top methods from the IMPROVER Species Translation Challenge SO BIOINFORMATICS LA English DT Article AB Motivation: Using gene expression to infer changes in protein phosphorylation levels induced in cells by various stimuli is an outstanding problem. The intra-species protein phosphorylation challenge organized by the IMPROVER consortium provided the framework to identify the best approaches to address this issue. Results: Rat lung epithelial cells were treated with 52 stimuli, and gene expression and phosphorylation levels were measured. Competing teams used gene expression data from 26 stimuli to develop protein phosphorylation prediction models and were ranked based on prediction performance for the remaining 26 stimuli. Three teams were tied in first place in this challenge achieving a balanced accuracy of about 70%, indicating that gene expression is only moderately predictive of protein phosphorylation. In spite of the similar performance, the approaches used by these three teams, described in detail in this article, were different, with the average number of predictor genes per phosphoprotein used by the teams ranging from 3 to 124. However, a significant overlap of gene signatures between teams was observed for the majority of the proteins considered, while Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched in the union of the predictor genes of the three teams for multiple proteins. C1 [Dayarian, Adel; Hormoz, Sahand] Univ Calif Santa Barbara, Kavli Inst Theoret Phys, Santa Barbara, CA 93106 USA. [Romero, Roberto; Tarca, Adi L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Bethesda, MD USA. [Romero, Roberto; Tarca, Adi L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI 48201 USA. [Wang, Zhiming] Hunan Agr Univ, Coll Plant Protect & Coll Sci, Changsha 410128, Hunan, Peoples R China. [Wang, Zhiming; Luo, Feng] Clemson Univ, Sch Comp, Clemson, SC 29634 USA. [Biehl, Michael] Univ Groningen, Johann Bernoulli Inst Math & Comp Sci, NL-9700 AK Groningen, Netherlands. [Bilal, Erhan; Meyer, Pablo; Norel, Raquel; Rhrissorrakrai, Kahn] IBM TJ Watson Res Ctr, Computat Biol Ctr, Yorktown Hts, NY 10003 USA. [Bhanot, Gyan] Rutgers State Univ, Dept Mol Biol & Biochem, Dept Phys, Piscataway, NJ 08854 USA. [Bhanot, Gyan] Rutgers State Univ, BioMaPS Inst, Piscataway, NJ 08854 USA. [Tarca, Adi L.] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. RP Bhanot, G (reprint author), Rutgers State Univ, Dept Mol Biol & Biochem, Dept Phys, Piscataway, NJ 08854 USA. EM gyanbhanot@gmail.com; luofeng@clemson.edu; atarca@med.wayne.edu RI Biehl, Michael/B-5105-2009; OI Biehl, Michael/0000-0001-5148-4568; Norel, Raquel/0000-0001-7737-4172 FU National Science Foundation [NSF PHY-1125915]; Aspen Center for Physics [1066293]; 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); NICHD; NIH [HHSN275201300006C] FX A.D., S.H. and G. B. were supported in part by the National Science Foundation under Grant No. NSF PHY-1125915. G.B. was also supported in part by grant 1066293 from the Aspen Center for Physics, respectively. A.T. and R.R. were 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); and, in part, with Federal funds from NICHD, NIH under Contract No. HHSN275201300006C. NR 16 TC 0 Z9 1 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2015 VL 31 IS 4 BP 462 EP 470 DI 10.1093/bioinformatics/btu490 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA CC0WM UT WOS:000350059600003 PM 25061067 ER PT J AU Appleman, LJ Balasubramaniam, S Parise, RA Bryla, C Redon, CE Nakamura, AJ Bonner, WM Wright, JJ Piekarz, R Kohler, DR Jiang, YX Belani, CP Eiseman, J Chu, E Beumer, JH Bates, SE AF Appleman, Leonard J. Balasubramaniam, Sanjeeve Parise, Robert A. Bryla, Christine Redon, Christophe E. Nakamura, Asako J. Bonner, William M. Wright, John J. Piekarz, Richard Kohler, David R. Jiang, Yixing Belani, Chandra P. Eiseman, Julie Chu, Edward Beumer, Jan H. Bates, Susan E. TI A Phase I Study of DMS612, a Novel Bifunctional Alkylating Agent SO CLINICAL CANCER RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; SULFONATE NSC 281612; ALDEHYDE DEHYDROGENASE; CHEMOTHERAPY; RESISTANCE; PLASMA; BLOOD AB Purpose: DMS612 is a dimethane sulfonate analog with bifunctional alkylating activity and preferential cytotoxicity to human renal cell carcinoma (RCC) in the NCI-60 cell panel. This first-in-human phase I study aimed to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of DMS612 administered by 10-minute intravenous infusion on days 1, 8, and 15 of an every-28-day schedule. Experimental Design: Patients with advanced solid malignancies were eligible. Enrollment followed a 3+3 design. PKs of DMS612 and metabolites were assessed by mass spectroscopy and PD by gamma-H2AX immunofluorescence. Results: A total of 31 patients, including those with colorectal (11), RCC (4), cervical (2), and urothelial (1) cancers, were enrolled. Six dose levels were studied, from 1.5 mg/m(2) to 12 mg/m(2). DLTs of grade 4 neutropenia and prolonged grade 3 thrombocytopenia were observed at 12 mg/m(2). The MTD was determined to be 9 mg/m(2) with a single DLT of grade 4 thrombocytopenia in 1 of 12 patients. Two patients had a confirmed partial response at the 9mg/m(2) dose level, in renal (1) and cervical (1) cancer. DMS612 was rapidly converted into active metabolites. gamma-H2AX immunofluorescence revealed dose-dependent DNA damage in both peripheral blood lymphocytes and scalp hairs. Conclusions: The MTD of DMS12 on days 1, 8, and 15 every 28 days was 9 mg/m(2). DMS612 appears to be an alkylating agent with unique tissue specificities. Dose-dependent PD signals and two partial responses at the MTD support further evaluation of DMS612 in phase II trials. (C) 2014 AACR. C1 [Appleman, Leonard J.; Parise, Robert A.; Eiseman, Julie; Chu, Edward; Beumer, Jan H.] Univ Pittsburgh, Inst Canc, Canc Therapeut Program, Pittsburgh, PA USA. [Appleman, Leonard J.] Univ Pittsburgh, Inst Canc, Prostate Canc Program, Pittsburgh, PA USA. [Appleman, Leonard J.; Chu, Edward] Univ Pittsburgh, Dept Med, Div Hematol & Oncol, Sch Med, Pittsburgh, PA 15213 USA. [Balasubramaniam, Sanjeeve; Bryla, Christine; Redon, Christophe E.; Nakamura, Asako J.; Bonner, William M.; Bates, Susan E.] NCI, Dev Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Wright, John J.; Piekarz, Richard] NCI, Canc Treatment Evaluat Program, Invest Drug Branch, Bethesda, MD 20892 USA. [Kohler, David R.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Jiang, Yixing; Belani, Chandra P.] Penn State Coll Med, Hershey, PA USA. [Eiseman, Julie; Chu, Edward] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Beumer, Jan H.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. RP Bates, SE (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM batess@helix.nih.gov OI Belani, Chandra/0000-0001-5049-5329; Appleman, Leonard/0000-0003-4951-7388; Balasubramaniam, Sanjeeve/0000-0002-0643-2117; Beumer, Jan/0000-0002-8978-9401 FU National Cancer Institute [U01-CA099168, P30-CA47904]; Intramural Research Program of the NIH; National Cancer Institute FX This work was supported, in part, by the National Cancer Institute grants U01-CA099168 (to L.J. Appleman, R.A. Parise, Y. Jiang, C.P. Belani, J. Eiseman, E. Chu, and J. H. Beumer) and P30-CA47904 (to J. H. Beumer and R.A. Parise), and by the Intramural Research Program of the NIH, National Cancer Institute (to S. Balasubramaniam, C. Bryla, W.M. Bonner, C.E. Redon, A.J. Nakamura, J.J. Wright, R.A. Parise, and S.E. Bates). NR 18 TC 2 Z9 2 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 FEB 15 PY 2015 VL 21 IS 4 BP 721 EP 729 DI 10.1158/1078-0432.CCR-14-1333 PG 9 WC Oncology SC Oncology GA CB8AT UT WOS:000349851200010 PM 25467180 ER PT J AU Smith, MA Reynolds, CP Kang, MH Kolb, EA Gorlick, R Carol, H Lock, RB Keir, ST Maris, JM Billups, CA Lyalin, D Kurmasheva, RT Houghton, PJ AF Smith, Malcolm A. Reynolds, C. Patrick Kang, Min H. Kolb, E. Anders Gorlick, Richard Carol, Hernan Lock, Richard B. Keir, Stephen T. Maris, John M. Billups, Catherine A. Lyalin, Dmitry Kurmasheva, Raushan T. Houghton, Peter J. TI Synergistic Activity of PARP Inhibition by Talazoparib (BMN 673) with Temozolomide in Pediatric Cancer Models in the Pediatric Preclinical Testing Program SO CLINICAL CANCER RESEARCH LA English DT Article ID ADVANCED SOLID TUMORS; POLY(ADP-RIBOSE) POLYMERASE; DNA-DAMAGE; PHASE-II; DRUG-SENSITIVITY; EWINGS-SARCOMA; STAGE 1; REPAIR; COMBINATION; CELLS AB Purpose: Inhibitors of PARP, an enzyme involved in base excision repair, have demonstrated single-agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here, we evaluated the stereo-selective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan. Experimental Design: Talazoparib was tested in vitro in combination with temozolomide (0.3-1,000 mmol/L) or topotecan (0.03-100 nmol/L) and in vivo at a dose of 0.1 mg/kg administered twice daily for 5 days combined with temozolomide (30 mg/kg/daily x 5; combination A) or 0.25 mg/kg administered twice daily for 5 days combined with temozolomide (12 mg/kg/daily x 5; combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment. Results: In vitro talazoparib potentiated the toxicity of temozolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30-50-fold). There was less potentiation for topotecan. In vivo, talazoparib potentiated the toxicity of temozolomide, and combination A and combination B represent the MTDs when combined with low-dose or high-dose talazoparib, respectively. Both combinations demonstrated significant synergism against 5 of 10 Ewing sarcoma xenografts. The combination demonstrated modest activity against most other xenograft models. Pharmacodynamic studies showed a treatment-induced complete loss of PARP only in tumor models sensitive to either talazoparib alone or talazoparib plus temozolomide. Conclusions: The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation. (C) 2014 AACR. C1 [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Carol, Hernan; Lock, Richard B.] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Billups, Catherine A.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Lyalin, Dmitry; Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. RP Smith, MA (reprint author), NCI, 9609 Med Ctr Dr,RM 5-W414,MSC 9737, Bethesda, MD 20892 USA. EM Malcolm.Smith@nih.gov RI Lock, Richard/G-4253-2013 FU NCI [NO1-CM-42216, CA21765, CA108786]; BioMarin Pharmaceutical Inc. FX This work was supported by NO1-CM-42216, CA21765, and CA108786 from the NCI and used talazoparib supplied by BioMarin Pharmaceutical Inc. NR 42 TC 21 Z9 21 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2015 VL 21 IS 4 BP 819 EP 832 DI 10.1158/1078-0432.CCR-14-2572 PG 14 WC Oncology SC Oncology GA CB8AT UT WOS:000349851200020 PM 25500058 ER PT J AU Gara, N Abdalla, A Rivera, E Zhao, XC Werner, JM Liang, TJ Hoofnagle, JH Rehermann, B Ghany, MG AF Gara, Naveen Abdalla, Adil Rivera, Elenita Zhao, Xiongce Werner, Jens M. Liang, T. Jake Hoofnagle, Jay H. Rehermann, Barbara Ghany, Marc G. TI Durability of Antibody Response Against Hepatitis B Virus in Healthcare Workers Vaccinated as Adults SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE hepatitis B vaccine; healthcare workers; booster vaccination; chronic hepatitis B ID LONG-TERM IMMUNOGENICITY; FOLLOW-UP; HEPATOCELLULAR-CARCINOMA; HOMOSEXUAL-MEN; UNITED-STATES; IMMUNITY; BOOSTER; PERSISTENCE; PROTECTION; EFFICACY AB Background. Follow-up studies of recipients of hepatitis B vaccine from endemic areas have reported loss of antibody to hepatitis B surface antigen (anti-HBs) in a high proportion of persons vaccinated at birth. In contrast, the long-term durability of antibody in persons vaccinated as adults in nonendemic areas is not well defined. We aimed to assess the durability of anti-HBs among healthcare workers (HCWs) vaccinated as adults and response to a booster among those without protective levels of antibody. Methods. Adult HCWs aged 18-60 at the time of initial vaccination were recruited. All were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and anti-HBs level. HCWs with anti-HBs <12 mIU/mL were offered a booster and levels were measured 1, 7, and 21 days afterward. Results. Anti-HBs levels were <12 mIU/mL in 9 of 50 (18%), 13 of 50 (26%), and 14 of 59 (24%) HCWs 10-15, 16-20, and >20 years postvaccination, respectively, (P = ns). Four HCWs were anti-HBc positive; none had HBsAg. By logistic regression, older age at vaccination was the only predictor of inadequate anti-HBs level (P = .0005). Thirty-four of 36 subjects with inadequate anti-HBs levels received a booster and 32 (94%) developed levels >12 mIU/mL within 3 weeks. Conclusions. Anti-HBs levels decrease after 10-31 years and fall below a level considered protective in approximately 25% of cases. The rapid and robust response to a booster vaccine suggests a long-lasting amnestic response. Hepatitis B vaccination provides long-term protection against hepatitis B and booster vaccination does not appear to be necessary in HCWs. C1 [Gara, Naveen; Abdalla, Adil; Rivera, Elenita; Werner, Jens M.; Liang, T. Jake; Rehermann, Barbara; Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDK, NIH, Bethesda, MD 20892 USA. [Hoofnagle, Jay H.] NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Ghany, MG (reprint author), NIDDK, Liver Dis Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 9B-16, Bethesda, MD 20892 USA. EM marcg@intra.niddk.nih.gov OI Werner, Jens/0000-0001-7156-4370 FU National Institute of Diabetes and Digestive and Kidney Diseases, Intramural Research Program, NIH; Deutsche Forschungsgemeinschaft, Bonn, Germany [We-4675/1-1] FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, Intramural Research Program, NIH. J. M. W. was supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany (We-4675/1-1). NR 35 TC 3 Z9 3 U1 0 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 FEB 15 PY 2015 VL 60 IS 4 BP 505 EP 513 DI 10.1093/cid/ciu867 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CB6VI UT WOS:000349764400002 PM 25389254 ER PT J AU Althoff, KN McGinnis, KA Wyatt, CM Freiberg, MS Gilbert, C Oursler, KK Rimland, D Rodriguez-Barradas, MC Dubrow, R Park, LS Skanderson, M Shiels, MS Gange, SJ Gebo, KA Justice, AC AF Althoff, Keri N. McGinnis, Kathleen A. Wyatt, Christina M. Freiberg, Matthew S. Gilbert, Cynthia Oursler, Krisann K. Rimland, David Rodriguez-Barradas, Maria C. Dubrow, Robert Park, Lesley S. Skanderson, Melissa Shiels, Meredith S. Gange, Stephen J. Gebo, Kelly A. Justice, Amy C. CA VACS TI Comparison of Risk and Age at Diagnosis of Myocardial Infarction, End-Stage Renal Disease, and Non-AIDS-Defining Cancer in HIV-Infected Versus Uninfected Adults SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV infection; aging; myocardial infarction; end-stage renal disease; non-AIDS-defining cancers ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIGH PREVALENCE; UNITED-STATES; VETERANS; INDIVIDUALS; COINFECTION; POPULATION; COHORT; CARE; MEN AB Background. Although it has been shown that human immunodeficiency virus (HIV)-infected adults are at greater risk for aging-associated events, it remains unclear as to whether these events happen at similar, or younger ages, in HIV-infected compared with uninfected adults. The objective of this study was to compare the median age at, and risk of, incident diagnosis of 3 age-associated diseases in HIV-infected and demographically similar uninfected adults. Methods. The study was nested in the clinical prospective Veterans Aging Cohort Study of HIV-infected and demographically matched uninfected veterans, from 1 April 2003 to 31 December 2010. The outcomes were validated diagnoses of myocardial infarction (MI), end-stage renal disease (ESRD), and non-AIDS-defining cancer (NADC). Differences in mean age at, and risk of, diagnosis by HIV status were estimated using multivariate linear regression models and Cox proportional hazards models, respectively. Results. A total of 98 687 (31% HIV-infected and 69% uninfected) adults contributed >450 000 person-years and 689 MI, 1135 ESRD, and 4179 NADC incident diagnoses. Mean age at MI (adjusted mean difference, -0.11; 95% confidence interval [CI], -.59 to .37 years) and NADC (adjusted mean difference, -0.10 [95% CI, -.30 to .10] years) did not differ by HIV status. HIV-infected adults were diagnosed with ESRD at an average age of 5.5 months younger than uninfected adults (adjusted mean difference, -0.46 [95% CI, -.86 to -.07] years). HIV-infected adults had a greater risk of all 3 outcomes compared with uninfected adults after accounting for important confounders. Conclusions. HIV-infected adults had a higher risk of these age-associated events, but they occurred at similar ages than those without HIV. C1 [Althoff, Keri N.; Gange, Stephen J.; Gebo, Kelly A.] Johns Hopkins Univ, Baltimore, MD USA. [McGinnis, Kathleen A.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Wyatt, Christina M.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Freiberg, Matthew S.] Vanderbilt Univ Sch Med, Nashville, TN USA. [Gilbert, Cynthia] Vet Affairs Med Ctr, Washington, DC 20422 USA. [Gilbert, Cynthia] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Oursler, Krisann K.] Salem Vet Affairs Med Ctr, Salem, VA USA. [Oursler, Krisann K.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Rimland, David] Atlanta Vet Affairs Med Ctr, Atlanta, GA USA. [Rimland, David] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Rodriguez-Barradas, Maria C.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Houston, TX 77030 USA. [Dubrow, Robert; Park, Lesley S.; Skanderson, Melissa; Justice, Amy C.] Vet Affairs Connecticut Healthcare Syst, New Haven, CT USA. [Dubrow, Robert; Park, Lesley S.; Skanderson, Melissa; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Dubrow, Robert; Park, Lesley S.; Skanderson, Melissa; Justice, Amy C.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Shiels, Meredith S.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Althoff, KN (reprint author), Johns Hopkins Univ, 615 N Wolfe St,Rm E7142, Baltimore, MD 21231 USA. EM kalthoff@jhu.edu OI Justice, Amy/0000-0003-0139-5502 FU National Institutes of Health: National Institute on Alcohol Abuse and Alcoholism [U24-AA020794, U01-AA020790, U01-AA020795, U01-AA020799, U24-AA022001, U24 AA022007, U10 AA013566-]; National Heart, Lung, and Blood Institute [R01-HL095136, R01-HL090342]; National Institute of Allergy and Infectious Diseases (NIAID) [U01-A1069918]; National Institute of Mental Health [P30-MH062294]; National Institute on Drug Abuse [R01DA035616]; National Cancer Institute (NCI) [R01 CA173754]; Agency for Healthcare Research and Quality [R01-HS018372]; Veterans Health Administration Office of Research and Development [VA REA 08-266]; Office of Academic Affiliations (Medical Informatics Fellowship); NIAID [K01-AI093197]; NCI [F31-CA180775]; National Institute of Diabetes and Digestive and Kidney Diseases [P01-DK056492]; Department of Veterans Affairs, Veterans Health Administration [VA I01 RX000667]; National Cancer Institute FX The Veterans Aging Cohort Study is supported by the National Institutes of Health: National Institute on Alcohol Abuse and Alcoholism (grant numbers U24-AA020794, U01-AA020790, U01-AA020795, U01-AA020799, U24-AA022001, U24 AA022007, U10 AA013566-completed); National Heart, Lung, and Blood Institute (grant numbers R01-HL095136; R01-HL090342); National Institute of Allergy and Infectious Diseases (NIAID) (grant number U01-A1069918); National Institute of Mental Health (grant number P30-MH062294); National Institute on Drug Abuse (grant number R01DA035616); National Cancer Institute (NCI) (grant number R01 CA173754); Agency for Healthcare Research and Quality (grant number R01-HS018372); and the Veterans Health Administration Office of Research and Development (grant number VA REA 08-266, VA IRR Merit Award) and Office of Academic Affiliations (Medical Informatics Fellowship). Additional funding for this work includes K01-AI093197 funded by the NIAID (to K. N. A.), F31-CA180775 funded by the NCI (to L. S. P.), P01-DK056492 funded by the National Institute of Diabetes and Digestive and Kidney Diseases (to C. M. W.), VA I01 RX000667 funded by the Department of Veterans Affairs, Veterans Health Administration (to K. K. O.), and the Intramural Research Program of the National Cancer Institute (to M. S. S.). NR 38 TC 40 Z9 42 U1 1 U2 8 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 FEB 15 PY 2015 VL 60 IS 4 BP 627 EP 638 DI 10.1093/cid/ciu869 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CB6VI UT WOS:000349764400020 PM 25362204 ER PT J AU Soltysik, DA Thomasson, D Rajan, S Biassou, N AF Soltysik, David A. Thomasson, David Rajan, Sunder Biassou, Nadia TI Improving the use of principal component analysis to reduce physiological noise and motion artifacts to increase the sensitivity of task-based fMRI SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE BOLD fMRI; Physiological noise, Principal components analysis ID RESTING STATE NETWORKS; FUNCTIONAL MRI; BRAIN ACTIVATION; BOLD SIGNAL; FLUCTUATIONS; CONNECTIVITY; STRATEGIES; RESPONSES; CORTEX AB Background: Functional magnetic resonance imaging (fMRI) time series are subject to corruption by many noise sources, especially physiological noise and motion. Researchers have developed many methods to reduce physiological noise, including RETROICOR, which retroactively removes cardiac and respiratory waveforms collected during the scan, and CompCor, which applies principal components analysis (PCA) to remove physiological noise components without any physiological monitoring during the scan. New method: We developed four variants of the CompCor method. The optimized CompCor method applies PCA to time series in a noise mask, but orthogonalizes each component to the BOLD response waveform and uses an algorithm to determine a favorable number of components to use as "nuisance regressors." Whole brain component correction (WCompCor) is similar, except that it applies PCA to time-series throughout the whole brain. Low-pass component correction (LCompCor) identifies low-pass filtered components throughout the brain, while high-pass component correction (HCompCor) identifies high-pass filtered components. Comparison with existing method: We compared the new methods with the original CompCor method by examining the resulting functional contrast-to-noise ratio (CNR), sensitivity, and specificity. Results: (1) The optimized CompCor method increased the CNR and sensitivity compared to the original CompCor method and (2) the application of WCompCor yielded the best improvement in the CNR and sensitivity. Conclusions:The sensitivity of the optimized CompCor,WCompCor, and LCompCor methods exceeded that of the original CompCor method. However, regressing noise signals showed a paradoxical consequence of reducing specificity for all noise reduction methods attempted. Published by Elsevier B.V. C1 [Soltysik, David A.; Rajan, Sunder] US FDA, Ctr Devices & Radiol Hlth, Div Biomed Phys, Off Med Prod & Tobacco,Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Thomasson, David] NIAID, Integrated Res Facil, Ft Detrick, MD 21702 USA. [Biassou, Nadia] NIH, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Soltysik, DA (reprint author), US FDA, Ctr Devices & Radiol Hlth, Div Biomed Phys, Off Med Prod & Tobacco,Off Sci & Engn Labs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM davitl.soltysik@fda.hhs.gov OI SOLTYSIK, DAVID/0000-0002-6597-5226 FU Radiology and Imaging Sciences Department of the Warren G. Magnuson Clinical Center at the National Institutes of Health FX This project is supported by the Radiology and Imaging Sciences Department of the Warren G. Magnuson Clinical Center at the National Institutes of Health. NR 46 TC 2 Z9 3 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD FEB 15 PY 2015 VL 241 BP 18 EP 29 DI 10.1016/j.jneumeth.2014.11.015 PG 12 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CC2PW UT WOS:000350188100003 PM 25481542 ER PT J AU Sun, W Kim, HS Lee, S Jung, A Kim, SE Ann, J Yoon, S Choi, S Lee, JH Blumberg, PM Frank-Foltyn, R Bahrenberg, G Schiene, K Stockhausen, H Christoph, T Frormann, S Lee, J AF Sun, Wei Kim, Hyo-Shin Lee, Sunho Jung, Aeran Kim, Sung-Eun Ann, Jihyae Yoon, Suyoung Choi, Sun Lee, Jin Hee Blumberg, Peter M. Frank-Foltyn, Robert Bahrenberg, Gregor Schiene, Klaus Stockhausen, Hannelore Christoph, Thomas Frormann, Sven Lee, Jeewoo TI 6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Vanilloid receptor 1; TRPV1 antagonist; Analgesic; Molecular modeling ID PYRIDINE C-REGION; 2-(3-FLUORO-4-METHYLSULFONYLAMINOPHENYL)PROPANAMIDES; RECEPTOR; ANALOGS; PAIN; DERIVATIVES; ANALGESICS; ACCESS AB A series of N-[{2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)-pyridin-3-yl}methyl] N'-(6,6-fused heterocyclic) ureas have been investigated as hTRPV1 antagonists. Among them, compound 15 showed highly potent TRPV1 antagonism to capsaicin, with K-i(ant) = 0.2 nM, as well as antagonism to other activators, and it was efficacious in a pain model. A docking study of 15 with our hTRPV1 homology model indicates that there is crucial hydrogen bonding between the ring nitrogen and the receptor, contributing to its potency. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Sun, Wei] Shenyang Pharmaceut Univ, Shenyang 110016, Peoples R China. [Sun, Wei; Kim, Hyo-Shin; Lee, Sunho; Jung, Aeran; Kim, Sung-Eun; Ann, Jihyae; Yoon, Suyoung; Lee, Jeewoo] Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Seoul 151742, South Korea. [Choi, Sun; Lee, Jin Hee] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Coll Pharm, Natl Leading Res Lab Mol Modeling & Drug Design, Seoul 120750, South Korea. [Choi, Sun; Lee, Jin Hee] Ewha Womans Univ, Global Top Res Program 5, Seoul 120750, South Korea. [Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Frank-Foltyn, Robert; Bahrenberg, Gregor; Schiene, Klaus; Stockhausen, Hannelore; Christoph, Thomas; Frormann, Sven] Grunenthal GmbH, Grunenthal Innovat, D-52078 Aachen, Germany. RP Lee, J (reprint author), Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Seoul 151742, South Korea. FU Grunenthal; Korea Health Technology RD Project [HI13D2358]; National Research Foundation of Korea [R11-2007-107-02001-0]; National Leading Research Lab Program [2011-0028885]; NIH, Center for Cancer Research, NCI [Z1A BC 005270] FX This research was supported by Grants from Grunenthal, the Korea Health Technology R&D Project (HI13D2358), National Research Foundation of Korea (R11-2007-107-02001-0), the National Leading Research Lab Program (2011-0028885), and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270). NR 22 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 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 15 PY 2015 VL 25 IS 4 BP 803 EP 806 DI 10.1016/j.bmcl.2014.12.086 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA CB6ET UT WOS:000349720400013 PM 25597011 ER PT J AU Han, XS Lin, CC Li, CY de Moor, JS Rodriguez, JL Kent, EE Forsythe, LP AF Han, Xuesong Lin, Chun Chieh Li, Chunyu de Moor, Janet S. Rodriguez, Juan L. Kent, Erin E. Forsythe, Laura P. TI Association Between Serious Psychological Distress and Health Care Use and Expenditures by Cancer History SO CANCER LA English DT Article; Proceedings Paper CT American-Society-of-Clinical-Oncology (ASCO) Quality Care Symposium CY OCT 17-18, 2014 CL Boston, MA SP Amer Soc Clin Oncol DE psychological distress; health care use; medical expenditures; psychosocial care ID LONG-TERM SURVIVORS; PSYCHOSOCIAL CARE; UNITED-STATES; POPULATION; DEPRESSION; SERVICES; ADULTS; INTERVENTIONS; ILLNESS; TRENDS AB BACKGROUNDSerious psychological distress (SPD) is associated with adverse health outcomes such as poor quality of life and shorter survival in cancer survivors, but to the authors' knowledge, the relationship between SPD and health care use and medical expenditures is not clear. METHODSA total of 4326 cancer survivors and 57,109 noncancer participants were identified from the 2008 through 2010 Medical Expenditure Panel Survey, a nationwide population-based survey, and their psychological distress was assessed with the 6-item Kessler Psychological Distress Scale (SPD defined by a score 13). The association between SPD and use and medical expenditures of various types of health care (office-based, outpatient, hospital inpatient, emergency department, dental, and prescriptions) was examined using a 2-part modeling approach that adjusted for demographic, personal, and comorbidity factors. The marginal effects of SPD on health care use and expenditures were calculated for cancer survivors and were compared with those of noncancer participants. RESULTSThe weighted prevalence of SPD in cancer survivors was 8.2% compared with 4.8% in the noncancer participants. SPD was significantly associated with higher use of all care types except dental care in cancer survivors. Cancer survivors with SPD spent $4431 (95% confidence interval, $3419-$5443) more than survivors without SPD on medical services each year, whereas this extra expenditure associated with SPD for participants without cancer was $2685 (95% confidence interval, $2099-$3271). CONCLUSIONSIn a national representative sample of cancer survivors, SPD was found to be associated with higher health care use and medical expenditures. Distress screening and psychosocial care in cancer survivors may help reduce the economic burden of cancer in the United States. Cancer 2015;121:614-622. (c) 2014 American Cancer Society. Serious psychological distress is reported to be associated with adverse health outcomes such as poor quality of life and shorter survival in cancer survivors. In a national representative sample of cancer survivors, serious psychological distress was found to be associated with higher health care use and medical expenditures. C1 [Han, Xuesong; Lin, Chun Chieh] Amer Canc Soc, Surveillance & Hlth Serv Res Program, Atlanta, GA 30303 USA. [Li, Chunyu; Rodriguez, Juan L.] Ctr Dis Control & Prevent, Epidemiol & Appl Res Branch, Div Canc Prevent & Control, Atlanta, GA USA. [de Moor, Janet S.] NCI, Hlth Serv & Econ Branch, NIH, Bethesda, MD 20892 USA. [Kent, Erin E.] NCI, Outcomes Res Branch, NIH, Bethesda, MD 20892 USA. [Forsythe, Laura P.] Patient Ctr Outcomes Res Inst, Res Integrat & Evaluat Program, Washington, DC USA. RP Han, XS (reprint author), Amer Canc Soc, Surveillance & Hlth Serv Res Program, 250 Williams St NW, Atlanta, GA 30303 USA. EM xuesong.han@cancer.org FU Intramural CDC HHS [CC999999] NR 34 TC 11 Z9 11 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD FEB 15 PY 2015 VL 121 IS 4 BP 614 EP 622 DI 10.1002/cncr.29102 PG 9 WC Oncology SC Oncology GA CB1NS UT WOS:000349395200018 PM 25345778 ER PT J AU Mancino, A Termanini, A Barozzi, I Ghisletti, S Ostuni, R Prosperini, E Ozato, K Natoli, G AF Mancino, Alessandra Termanini, Alberto Barozzi, Iros Ghisletti, Serena Ostuni, Renato Prosperini, Elena Ozato, Keiko Natoli, Gioacchino TI A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages SO GENES & DEVELOPMENT LA English DT Article DE IRF8; interferon; chromatin; epigenome; inflammation; macrophages; transcription ID TRANSCRIPTION FACTORS; DENDRITIC CELLS; ENHANCERS; BINDING; DIFFERENTIATION; IDENTIFICATION; ACTIVATION; IDENTITIES; LANDSCAPE; SELECTION AB The transcription factor (TF) interferon regulatory factor 8 (IRF8) controls both developmental and inflammatory stimulus-inducible genes in macrophages, but the mechanisms underlying these two different functions are largely unknown. One possibility is that these different roles are linked to the ability of IRF8 to bind alternative DNA sequences. We found that IRF8 is recruited to distinct sets of DNA consensus sequences before and after lipopolysaccharide (LPS) stimulation. In resting cells, IRF8 was mainly bound to composite sites together with the master regulator of myeloid development PU.1. Basal IRF8-PU.1 binding maintained the expression of a broad panel of genes essential for macrophage functions (such as microbial recognition and response to purines) and contributed to basal expression of many LPS-inducible genes. After LPS stimulation, increased expression of IRF8, other IRFs, and AP-1 family TFs enabled IRF8 binding to thousands of additional regions containing low-affinity multimerized IRF sites and composite IRF-AP-1 sites, which were not premarked by PU. 1 and did not contribute to the basal IRF8 cistrome. While constitutively expressed IRF8-dependent genes contained only sites mediating basal IRF8/PU.1 recruitment, inducible IRF8-dependent genes contained variable combinations of constitutive and inducible sites. Overall, these data show at the genome scale how the same TF can be linked to constitutive and inducible gene regulation via distinct combinations of alternative DNA-binding sites. C1 [Mancino, Alessandra; Termanini, Alberto; Barozzi, Iros; Ghisletti, Serena; Ostuni, Renato; Prosperini, Elena; Natoli, Gioacchino] European Inst Oncol IEO, Dept Expt Oncol, I-20139 Milan, Italy. [Ozato, Keiko] Natl Inst Child Hlth & Human Dev NICHD, Lab Mol Growth Regulat, Genom Differentiat Program, NIH, Bethesda, MD 20892 USA. RP Natoli, G (reprint author), European Inst Oncol IEO, Dept Expt Oncol, I-20139 Milan, Italy. EM gioacchino.natoli@ieo.eu OI Ostuni, Renato/0000-0003-0460-3426 FU European Research Council FX We thank Ido Amit, Philippe Gros, and Silvia Monticelli for critically reading the manuscript. This work was supported by the European Research Council (ERC grant NORM to G.N.). A.M. generated most data sets and the additional experimental data with contributions by S.G., R.O., and E.P.; A.T. computationally analyzed all data sets; I.B. made the SVM analysis; K.O. provided critical reagents; and G.N. designed and supervised the study and wrote the manuscript with input from all coauthors. A.M. and A.T. contributed equally to this work and are listed in alphabetical order. NR 55 TC 18 Z9 18 U1 1 U2 7 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD FEB 15 PY 2015 VL 29 IS 4 BP 394 EP 408 DI 10.1101/gad.257592.114 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA CB7XP UT WOS:000349842300006 PM 25637355 ER PT J AU Bacharova, L Chen, HY Estes, EH Mateasik, A Bluemke, DA Lima, JAC Burke, GL Soliman, EZ AF Bacharova, Ljuba Chen, Haiying Estes, E. Harvey Mateasik, Anton Bluemke, David A. Lima, Joao A. C. Burke, Gregory L. Soliman, Elsayed Z. TI Determinants of Discrepancies in Detection and Comparison of the Prognostic Significance of Left Ventricular Hypertrophy by Electrocardiogram and Cardiac Magnetic Resonance Imaging SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ARTERIAL-HYPERTENSION; ATHEROSCLEROSIS; ETHNICITY; MORTALITY; DIAGNOSIS; DESIGN; HEART; MASS; ASSOCIATION; MYOCARDIUM AB Despite the low sensitivity of the electrocardiogram (ECG) in detecting left ventricular hypertrophy (LVH), ECG-LVH is known to be a strong predictor of cardiovascular risk. Understanding reasons for the discrepancies in detection of LVH by ECG versus imaging could help improve the diagnostic ability of ECG. We examined factors associated with false-positive and false-negative ECG-LVH, using cardiac magnetic resonance imaging (MRI) as the gold standard. We also compared the prognostic significance of ECG-LVH and MRI-LVH as predictors of cardiovascular events. This analysis included 4,748 participants (mean age 61.9 years, 53.5% females, 61.7% nonwhites). Logistic regression with stepwise selection was used to identify factors associated with false-positive (n = 208) and false-negative (n = 387), compared with true-positive (n = 208) and true-negative (n = 4,041) ECG-LVH, respectively. A false-negative ECG-LVH status was associated with increased odds of Hispanic race/ethnicity, current smoking, hypertension, increased systolic blood pressure, prolongation of QRS duration, and higher body mass index and with lower odds of increased ejection fraction (model-generalized R-2 = 0.20). A false-positive ECG-LVH status was associated with lower odds of black race, Hispanic race/ethnicity, minor ST-T abnormalities, increased systolic blood pressure, and presence of any major electrocardiographic abnormalities (model-generalized R-2 = 0.29). Both ECG-LVH and MRI-LVH were associated with an increased risk of cardiovascular disease events (hazard ratio 1.51, 95% confidence interval 1.03 to 2.20 and hazard ratio 1.81, 95% confidence interval 1.33 to 2.46, respectively). In conclusion, discrepancy in LVH detection by ECG and MRI can be relatively improved by considering certain participant characteristics. Discrepancy in diagnostic performance, yet agreement on predictive ability, suggests that LVH by ECG and LVH by imaging are likely to be two distinct but somehow related phenotypes. (C) 2015 Elsevier Inc. All rights reserved. C1 [Bacharova, Ljuba; Mateasik, Anton] Ctr Int Laser, Bratislava, Slovakia. [Chen, Haiying] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Estes, E. Harvey] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Bluemke, David A.] NIH, Clin Ctr, Bethesda, MD 20892 USA. [Bluemke, David A.; Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Burke, Gregory L.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Soliman, Elsayed Z.] Wake Forest Sch Med, Div Publ Health Sci, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC 27157 USA. RP Soliman, EZ (reprint author), Wake Forest Sch Med, Div Publ Health Sci, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC 27157 USA. EM esoliman@wakehealth.edu OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169] FX This research was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. NR 28 TC 17 Z9 18 U1 1 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 2015 VL 115 IS 4 BP 515 EP 522 DI 10.1016/j.amjcard.2014.11.037 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CB5FW UT WOS:000349653900019 PM 25542394 ER PT J AU Voynova, EN Skinner, J Bolland, S AF Voynova, Elisaveta N. Skinner, Jeffrey Bolland, Silvia TI Expansion of an Atypical NK Cell Subset in Mouse Models of Systemic Lupus Erythematosus SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; TOLL-LIKE RECEPTORS; ACTIVATE B-CELLS; DENDRITIC CELLS; ADAPTIVE IMMUNITY; Y-CHROMOSOME; T-CELLS; IN-VIVO; MICE; DIFFERENTIATION AB Chronic inflammatory conditions, such as in autoimmune disease, can disturb immune cell homeostasis and induce the expansion of normally rare cell populations. In our analysis of various murine models of lupus, we detect increased frequency of an uncommon subset identified as NK1.1(+)CD11c(+)CD122(+)MHC class II+. These cells share characteristics with the NK cell lineage and with cells previously described as IFN-producing killer dendritic cells: 1) they depend on IL-15 and express E4BP4; 2) they are cytotoxic and produce type I and type II IFN upon activation; and 3) they are efficient APCs both through MHC class II expression and in cross-presentation to CD8s. These atypical NK cells are responsive to TLR stimulation and thus are most abundant in mice with high copy number of the Tlr7 gene. They are highly proliferative as assessed by in vivo BrdU incorporation. In adoptive transfer experiments they persist in high numbers for months and maintain their surface marker profile, indicating that this population is developmentally stable. Gene expression analyses on both mRNA and microRNAs show a modified cell cycle program in which various miR-15/16 family members are upregulated, presumably as a consequence of the proliferative signal mediated by the increased level of growth factors, Ras and E2F activity. Alternatively, low expression of miR-150, miR-181, and miR-744 in these cells implies a reduction in their differentiation capacity. These results suggest that cells of the NK lineage that undergo TLR stimulation might turn on a proliferative program in detriment of their full differentiation into mature NK cells. C1 [Voynova, Elisaveta N.; Skinner, Jeffrey; Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Bolland, S (reprint author), NIAID, Autoimmun & Funct Genom Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr,Twinbrook 2,Room 217, Rockville, MD 20852 USA. EM SBolland@niaid.nih.gov OI Skinner, Jeff/0000-0001-5697-0442 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 52 TC 4 Z9 5 U1 0 U2 2 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 FEB 15 PY 2015 VL 194 IS 4 BP 1503 EP 1513 DI 10.4049/jimmunol.1402673 PG 11 WC Immunology SC Immunology GA CB2MP UT WOS:000349462000014 PM 25595787 ER PT J AU Manning, ML Mason-Osann, E Onda, M Pastan, I AF Manning, Michael L. Mason-Osann, Emily Onda, Masanori Pastan, Ira TI Bortezomib Reduces Pre-Existing Antibodies to Recombinant Immunotoxins in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID B-CELL EPITOPES; MULTIPLE-MYELOMA; PLASMA-CELLS; PROTEASOME INHIBITION; MURINE HOSTS; PHASE-I; IMMUNOGENICITY; CYCLOPHOSPHAMIDE; LEUKEMIA; PENTOSTATIN AB Recombinant immunotoxin (RIT) therapy is limited in patients by neutralizing Ab responses. Ninety percent of patients with normal immune systems make neutralizing Abs after one cycle of RIT, preventing repeated dosing. Furthermore, some patients have preexisting Abs from environmental exposure to Pseudomonas exotoxin, the component of the RIT that elicits the neutralizing Ab response. Bortezomib is an U. S. Food and Drug Administration-approved proteasome inhibitor that selectively targets and kills plasma cells that are necessary for the neutralizing Ab response. We hypothesized that bortezomib may abrogate neutralizing Ab levels, making dosing of RIT possible in mice already immune to RIT. We immunized BALB/c mice with multiple doses of SS1P, a RIT whose Ab portion targets mesothelin. Mice with elevated Ab levels were separated into groups to receive saline, bortezomib, the pentostatin/cyclophosphamide (PC) regimen, or the bortezomib/PC (BPC) combination regimen. Four weeks after finishing therapy, plasma Ab levels were assayed, and bone marrow was harvested. The bortezomib and PC regimens significantly reduced Ab levels, and we observed fewer plasma cells in the bone marrow of bortezomib-treated mice but not in PC-treated mice. The BPC combination regimen almost completely eliminated Abs and further reduced plasma cells in the bone marrow. This regimen is more effective than individual regimens and may reduce Ab levels in patients with pre-existing neutralizing Abs to Pseudomonas exotoxin, allowing RIT treatment. C1 [Manning, Michael L.; Mason-Osann, Emily; Onda, Masanori; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20894 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, 37 Convent Dr, Bethesda, MD 20894 USA. EM pastani@mail.nih.gov OI Mason-Osann, Emily/0000-0003-0890-6440 FU Intramural Research Program of the Center for Cancer Research; National Cancer Institute; National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 32 TC 3 Z9 3 U1 0 U2 2 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 FEB 15 PY 2015 VL 194 IS 4 BP 1695 EP 1701 DI 10.4049/jimmunol.1402324 PG 7 WC Immunology SC Immunology GA CB2MP UT WOS:000349462000033 PM 25560410 ER PT J AU Gammella, E Diaz, V Recalcati, S Buratti, P Samaja, M Dey, S Noguchi, CT Gassmann, M Cairo, G AF Gammella, Elena Diaz, Victor Recalcati, Stefania Buratti, Paolo Samaja, Michele Dey, Soumyadeep Noguchi, Constance Tom Gassmann, Max Cairo, Gaetano TI Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE iron; ferroportin; erythropoietin receptor; liver; bone morphogenetic protein 6 ID IRON-METABOLISM; DOWN-REGULATION; MICE; HYPOXIA; ANEMIA; INFLAMMATION; CELLS AB Under conditions of accelerated erythropoiesis, elevated erythropoietin (Epo) levels are associated with inhibition of hepcidin synthesis, a response that ultimately increases iron availability to meet the enhanced iron needs of erythropoietic cells. In the search for erythroid regulators of hepcidin, many candidates have been proposed, including Epo itself. We aimed to test whether direct interaction between Epo and the liver is required to regulate hepcidin. We found that prolonged administration of high doses of Epo in mice leads to great inhibition of liver hepcidin mRNA levels, and concomitant induction of the hepcidin inhibitor erythroferrone (ERFE). Epo treatment also resulted in liver iron mobilization, mediated by increased ferroportin activity and accompanied by reduced ferritin levels and increased TfR1 expression. The same inhibitory effect was observed in mice that do not express the homodimeric Epo receptor (EpoR) in liver cells because EpoR expression is restricted to erythroid cells. Similarly, liver signaling pathways involved in hepcidin regulation were not influenced by the presence or absence of hepatic EpoR. Moreover, Epo analogs, possibly interacting with the postulated heterodimeric beta common EpoR, did not affect hepcidin expression. These findings were supported by the lack of inhibition on hepcidin found in hepatoma cells exposed to various concentrations of Epo for different periods of times. Our results demonstrate that hepcidin suppression does not require the direct binding of Epo to its liver receptors and rather suggest that the role of Epo is to stimulate the synthesis of the erythroid regulator ERFE in erythroblasts, which ultimately downregulates hepcidin. C1 [Gammella, Elena; Recalcati, Stefania; Buratti, Paolo; Cairo, Gaetano] Univ Milan, Dept Biomed Sci Hlth, Milan, Italy. [Diaz, Victor; Gassmann, Max] Univ Zurich, Inst Vet Physiol, Vetsuisse Fac, Zurich, Switzerland. [Diaz, Victor; Gassmann, Max] Univ Zurich, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland. [Samaja, Michele] Univ Milan, Dept Hlth Sci, Milan, Italy. [Dey, Soumyadeep; Noguchi, Constance Tom] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Gassmann, Max] Univ Peruana Cayetano Heredia, Lima, Peru. RP Cairo, G (reprint author), Univ Milan, Dept Biomed Sci Hlth, Milan, Italy. EM gaetano.cairo@unimi.it RI Gammella, Elena/M-5037-2016; recalcati, stefania/M-5045-2016; Cairo, Gaetano/M-5104-2016; Buratti, Paolo/A-4449-2017 OI Gammella, Elena/0000-0001-9921-8664; recalcati, stefania/0000-0002-2115-8283; Cairo, Gaetano/0000-0002-8147-4720; Buratti, Paolo/0000-0002-9738-6071 FU Ministero Istruzione, Universita e Ricerca (PRIN Project); World Anti-Doping Agency; Zurich Center for Integrative Human Physiology; Swiss National Science Foundation FX This study was supported by grants from Ministero Istruzione, Universita e Ricerca (PRIN Project) and World Anti-Doping Agency to G. Cairo, and from the Zurich Center for Integrative Human Physiology, the Swiss National Science Foundation to M. Gassmann. NR 23 TC 11 Z9 12 U1 1 U2 15 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 EI 1522-1490 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD FEB 15 PY 2015 VL 308 IS 4 BP R330 EP R335 DI 10.1152/ajpregu.00410.2014 PG 6 WC Physiology SC Physiology GA CB0EW UT WOS:000349299400011 PM 25519735 ER PT J AU Lane, J Yumoto, K Azhar, M Ninomiya-Tsuji, J Inagaki, M Hu, YL Deng, CX Kim, J Mishina, Y Kaartinen, V AF Lane, Jamie Yumoto, Kenji Azhar, Mohamad Ninomiya-Tsuji, Jun Inagaki, Maiko Hu, Yingling Deng, Chu-Xia Kim, Jieun Mishina, Yuji Kaartinen, Vesa TI Tak1, Smad4 and Trim33 redundantly mediate TGF-beta 3 signaling during palate development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE TGF-beta 3 signaling; Palatogenesis; Tak1; Smad4; Trim33 ID TGF-BETA; CLEFT-PALATE; MOLECULAR-MECHANISMS; CONDITIONAL ALLELE; UBIQUITIN LIGASE; EDGE EPITHELIUM; CELL-GROWTH; IN-VITRO; FUSION; MICE AB Transforming growth factor-beta3 (TGF-beta 3) plays a critical role in palatal epithelial cells by inducing palatal epithelial fusion, failure of which results in cleft palate, one of the most common birth defects in humans. Recent studies have shown that Smad-dependent and Smad-independent pathways work redundantly to transduce TGF-beta 3 signaling in palatal epithelial cells. However, detailed mechanisms by which this signaling is mediated still remain to be elucidated. Here we show that TGF-beta activated kinase-1 (Tak1) and Smad4 interact genetically in palatal epithelial fusion. While simultaneous abrogation of both Tak1 and Smad4 in palatal epithelial cells resulted in characteristic defects in the anterior and posterior secondary palate, these phenotypes were less severe than those seen in the corresponding Tgfb3 mutants. Moreover, our results demonstrate that Trim33, a novel chromatin reader and regulator of TGF-beta signaling, cooperates with Smad4 during palatogenesis. Unlike the epithelium-specific Smad4 mutants, epithelium-specific Tak1:Smad4- and Trim33:Smad4-double mutants display reduced expression of Mmp13 in palatal medial edge epithelial cells, suggesting that both of these redundant mechanisms are required for appropriate TGF-beta signal transduction. Moreover, we show that inactivation of Tak1 in Trim33:Smad4 double conditional knockouts leads to the palatal phenotypes which are identical to those seen in epithelium-specific Tgfb3 mutants. To conclude, our data reveal added complexity in TGF-beta signaling during palatogenesis and demonstrate that functionally redundant pathways involving Smad4, Tak1 and Trim33 regulate palatal epithelial fusion. (C) 2014 Elsevier Inc. All rights reserved. C1 [Lane, Jamie; Yumoto, Kenji; Mishina, Yuji; Kaartinen, Vesa] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48019 USA. [Azhar, Mohamad] Indiana Univ, Dept Pediat, Indianapolis, IN USA. [Ninomiya-Tsuji, Jun; Inagaki, Maiko] N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. [Hu, Yingling] Frederick Natl Lab Canc Res, Frederick, MD USA. [Deng, Chu-Xia] Univ Macau, Fac Hlth Sci, Macau, Peoples R China. [Kim, Jieun] Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA. RP Kaartinen, V (reprint author), Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48019 USA. EM vesak@umich.edu RI deng, chuxia/N-6713-2016; OI Kaartinen, Vesa/0000-0002-9432-510X FU NIH RO1 grants [RO1DE020843, RO1GM068812, RO1DE013085] FX We thank Manas K. Ray and Greg Scott for technical assistance, Junichi Iwata for sharing unpublished data, and Ben Allen, Deneen Wellik, Penny Thomas and Rogerio Castilho for helpful discussions. This work was supported by the NIH RO1 grants RO1DE020843 (to YM), RO1GM068812 (JN) and RO1DE013085 (to VK). NR 53 TC 6 Z9 6 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD FEB 15 PY 2015 VL 398 IS 2 BP 231 EP 241 DI 10.1016/j.ydbio.2014.12.006 PG 11 WC Developmental Biology SC Developmental Biology GA CA5VD UT WOS:000348975000009 PM 25523394 ER PT J AU Zhao, HX Zhou, WR Yao, ZJ Wan, Y Cao, JJ Zhang, LL Zhao, JZ Li, HJ Zhou, RJ Li, BJ Wei, G Zhang, ZL French, CA Dekker, JD Yang, YZ Fisher, SE Tucker, HO Guo, XZ AF Zhao, Haixia Zhou, Wenrong Yao, Zhengju Wan, Yong Cao, Jingjing Zhang, Lingling Zhao, Jianzhi Li, Hanjun Zhou, Rujiang Li, Baojie Wei, Gang Zhang, Zhenlin French, Catherine A. Dekker, Joseph D. Yang, Yingzi Fisher, Simon E. Tucker, Haley O. Guo, Xizhi TI Foxp1/2/4 regulate endochondral ossification as a suppresser complex SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Foxp1; Foxp2; Foxp4; Endochondral ossification; Osteoblast; Transcriptional repressor ID OSTEOBLAST DIFFERENTIATION; BONE-FORMATION; CHONDROCYTE DIFFERENTIATION; TRANSCRIPTIONAL CONTROL; SKELETAL DEVELOPMENT; GROWTH-PLATE; DNA-BINDING; EXPRESSION; RUNX2; PROLIFERATION AB Osteoblast induction and differentiation in developing long bones is dynamically controlled by the opposing action of transcriptional activators and repressors. In contrast to the long list of activators that have been discovered over past decades, the network of repressors is not well-defined. Here we identify the expression of Foxp1/2/4 proteins, comprised of Forkhead-box (Fox) transcription factors of the Foxp subfamily, in both perichondrial skeletal progenitors and proliferating chondrocytes during endochondral ossification. Mice carrying loss-of-function and gain-of-function Foxp mutations had gross defects in appendicular skeleton formation. At the cellular level, over-expression of Foxp1/2/4 in chondroctyes abrogated osteoblast formation and chondrocyte hypertrophy. Conversely, single or compound deficiency of Foxp1/2/4 in skeletal progenitors or chondrocytes resulted in premature osteoblast differentiation in the perichondrium, coupled with impaired proliferation, survival, and hypertrophy of chondrocytes in the growth plate. Foxp1/2/4 and Runx2 proteins interacted in vitro and in vivo, and Foxp1/2/4 repressed Runx2 transactivation function in heterologous cells. This study establishes Foxp1/2/4 proteins as coordinators of osteogenesis and chondrocyte hypertrophy in developing long bones and suggests that a novel transcriptional repressor network involving Foxp1/2/4 may regulate Runx2 during endochondral ossification. (C) 2014 Elsevier Inc. All rights reserved. C1 [Zhao, Haixia; Zhou, Wenrong; Yao, Zhengju; Wan, Yong; Cao, Jingjing; Zhang, Lingling; Zhao, Jianzhi; Li, Hanjun; Zhou, Rujiang; Li, Baojie; Guo, Xizhi] Shanghai Jiao Tong Univ, BioX Inst, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Shanghai 200240, Peoples R China. [Wei, Gang] Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai 200032, Peoples R China. [Zhang, Zhenlin] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Orthoped Surg, Shanghai 200240, Peoples R China. [French, Catherine A.] Champalimaud Ctr Unknown, Champalimaud Neurosci Programme, Lisbon, Portugal. [Dekker, Joseph D.; Tucker, Haley O.] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. [Yang, Yingzi] NHGRI, Dev Genet Sect, NIH, Bethesda, MD 20892 USA. [Fisher, Simon E.] Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands. [Fisher, Simon E.] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands. RP Guo, XZ (reprint author), Shanghai Jiao Tong Univ, BioX Inst, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Shanghai 200240, Peoples R China. EM xzguo2005@sjtu.edu.cn RI Fisher, Simon/E-9130-2012; Dekker, Joseph/G-4924-2013; OI Fisher, Simon/0000-0002-3132-1996; Dekker, Joseph/0000-0002-2068-3529; French, Catherine/0000-0003-2072-8413 FU 973 program of China [2014CB942902, 2012CB966903]; NSFC [31171396, 31271553, 81421061, 31100624]; UK Wellcome Trust [080971]; NIH/USA [R01CA31534] FX This work was supported by grants to Xizhi Guo (the 973 program of China 2014CB942902 and 2012CB966903; NSFC 31171396, 31271553, 81421061 and 31100624), to Dr. Simon E. Fisher (UK Wellcome Trust, 080971) and to Dr. Haley Tucker (NIH/USA, R01CA31534). NR 57 TC 11 Z9 11 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD FEB 15 PY 2015 VL 398 IS 2 BP 242 EP 254 DI 10.1016/j.ydbio.2014.12.007 PG 13 WC Developmental Biology SC Developmental Biology GA CA5VD UT WOS:000348975000010 PM 25527076 ER PT J AU Li, X Wolf, ME AF Li, Xuan Wolf, Marina E. TI Multiple faces of BDNF in cocaine addiction SO BEHAVIOURAL BRAIN RESEARCH LA English DT Review DE BDNF; TrkB; Cocaine addiction; AMPA receptor ID AMPA RECEPTOR TRAFFICKING; MESOLIMBIC DOPAMINE SYSTEM; NEUROTROPHIC FACTOR BDNF; VENTRAL TEGMENTAL AREA; CONDITIONED-PLACE PREFERENCE; MEDIAL PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS CORE; LONG-TERM POTENTIATION; SIGNAL-TRANSDUCTION CASCADE; SYNAPTIC PLASTICITY AB Brain-derived neurotrophic factor (BDNF) has been found to play roles in many types of plasticity including drug addiction. Here, we focus on rodent studies over the past two decades that have demonstrated diverse roles of BDNF in models of cocaine addiction. First, we will provide an overview of studies showing that cocaine exposure alters (and generally increases) BDNF levels in reward-related regions including the ventral tegmental area, nucleus accumbens, prefrontal cortex, and amygdala. Then we will review evidence that BDNF contributes to behavioral changes in animal models of cocaine addiction, focusing on conditioned place preference, behavioral sensitization, maintenance and reinstatement of self-administration, and incubation of cocaine craving. Last, we will review the role of BDNF in synaptic plasticity, particularly as it relates to plasticity of AMPA receptor transmission after cocaine exposure. We conclude that BDNF regulates cocaine-induced behaviors in a highly complex manner that varies depending on the brain region (and even among different cell types within the same brain region), the nature of cocaine exposure, and the "addiction phase" examined (e.g., acquisition vs maintenance; early vs late withdrawal). These complexities make BDNF a daunting therapeutic target for treating cocaine addiction. However, recent clinical evidence suggests that the serum BDNF level may serve as a biomarker in cocaine addicts to predict future relapse, providing an alternative direction for exploring BDNF's potential relevance to treating cocaine addiction. (C) 2014 Elsevier B.V. All rights reserved. C1 [Li, Xuan] NIDA, Behav Neurosci Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Wolf, Marina E.] Rosalind Franklin Univ Med & Sci, Dept Neurosci, N Chicago, IL USA. RP Li, X (reprint author), NIDA, Behav Neurosci Res Branch, Intramural Res Program, Suite 08A505-14,251 Bayview Blvd, Baltimore, MD 21224 USA. EM anna.li@nih.gov FU NIH [DA009621, DA015835, DA029099] FX The authors were supported by NIH grants DA009621, DA015835, and DA029099. NR 141 TC 23 Z9 23 U1 1 U2 22 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 FEB 15 PY 2015 VL 279 BP 240 EP 254 DI 10.1016/j.bbr.2014.11.018 PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AZ5IO UT WOS:000348255200030 PM 25449839 ER PT J AU Pepin, KM Leach, CB Marques-Toledo, C Laass, KH Paixao, KS Luis, AD Hayman, DTS Johnson, NG Buhnerkempe, MG Carver, S Grear, DA Tsao, K Eiras, AE Webb, CT AF Pepin, Kim M. Leach, Clint B. Marques-Toledo, Cecilia Laass, Karla H. Paixao, Kelly S. Luis, Angela D. Hayman, David T. S. Johnson, Nels G. Buhnerkempe, Michael G. Carver, Scott Grear, Daniel A. Tsao, Kimberly Eiras, Alvaro E. Webb, Colleen T. TI Utility of mosquito surveillance data for spatial prioritization of vector control against dengue viruses in three Brazilian cities SO PARASITES & VECTORS LA English DT Article DE Vector control; Dengue; Surveillance; Vector density; Mosquito-human interactions; Gravity model; INLA ID RIO-DE-JANEIRO; AEDES-AEGYPTI; HUMAN MOVEMENT; DIPTERA-CULICIDAE; THAI VILLAGES; TRANSMISSION; DYNAMICS; TRAPS; MEASLES; ADULT AB Background: Vector control remains the primary defense against dengue fever. Its success relies on the assumption that vector density is related to disease transmission. Two operational issues include the amount by which mosquito density should be reduced to minimize transmission and the spatio-temporal allotment of resources needed to reduce mosquito density in a cost-effective manner. Recently, a novel technology, MI-Dengue, was implemented city-wide in several Brazilian cities to provide real-time mosquito surveillance data for spatial prioritization of vector control resources. We sought to understand the role of city-wide mosquito density data in predicting disease incidence in order to provide guidance for prioritization of vector control work. Methods: We used hierarchical Bayesian regression modeling to examine the role of city-wide vector surveillance data in predicting human cases of dengue fever in space and time. We used four years of weekly surveillance data from Vitoria city, Brazil, to identify the best model structure. We tested effects of vector density, lagged case data and spatial connectivity. We investigated the generality of the best model using an additional year of data from Vitoria and two years of data from other Brazilian cities: Governador Valadares and Sete Lagoas. Results: We found that city-wide, neighborhood-level averages of household vector density were a poor predictor of dengue-fever cases in the absence of accounting for interactions with human cases. Effects of city-wide spatial patterns were stronger than within-neighborhood or nearest-neighborhood effects. Readily available proxies of spatial relationships between human cases, such as economic status, population density or between-neighborhood roadway distance, did not explain spatial patterns in cases better than unweighted global effects. Conclusions: For spatial prioritization of vector controls, city-wide spatial effects should be given more weight than within-neighborhood or nearest-neighborhood connections, in order to minimize city-wide cases of dengue fever. More research is needed to determine which data could best inform city-wide connectivity. Once these data become available, MI-dengue may be even more effective if vector control is spatially prioritized by considering city-wide connectivity between cases together with information on the location of mosquito density and infected mosquitos. C1 [Pepin, Kim M.; Luis, Angela D.; Webb, Colleen T.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Pepin, Kim M.] USDA, Natl Wildlife Res Ctr, Wildlife Serv, Anim & Plant Hlth Inspect Serv, Ft Collins, CO 80521 USA. [Pepin, Kim M.; Leach, Clint B.; Luis, Angela D.; Hayman, David T. S.; Johnson, Nels G.; Buhnerkempe, Michael G.; Carver, Scott; Grear, Daniel A.; Tsao, Kimberly; Webb, Colleen T.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. [Marques-Toledo, Cecilia] Ecovec SA, Belo Horizonte, MG, Brazil. [Laass, Karla H.; Paixao, Kelly S.; Eiras, Alvaro E.] Univ Fed Minas Gerais, Dept Parasitol, Belo Horizonte, MG, Brazil. [Hayman, David T. S.] Univ Florida, Dept Biol, Gainesville, FL 32611 USA. [Carver, Scott] Univ Tasmania, Sch Biol Sci, Hobart, Tas 7000, Australia. RP Pepin, KM (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM Kim.M.Pepin@aphis.usda.gov; alvaro@icb.ufmg.br RI Carver, Scott/J-7654-2014 OI Carver, Scott/0000-0002-3579-7588 FU RAPIDD program of the Science and Technology Directorate; U.S. Department of Homeland Security; Fogarty International Center, NIH; USDA-APHIS-WS; CNPq [550131/2010-8, 404211/2012-7]; ICNT-Dengue; David H Smith postdoctoral fellowship; University of Tasmania Research Enhancement Grant Scheme [C 20897]; NSF Graduate Research Fellowship Program [DGE-1321845] FX Thanks to the dengue control program managers in the cities of Vitoria, GV and SL, especially to Andre Capezzuto, Jose Batista and Maria Jose Lanza, respectively, for help in obtaining the data for analyses. KMP, ADL, DTSH and CTW were funded by the RAPIDD program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center, NIH. KMP was also funded by USDA-APHIS-WS during the latter part of the study. AEE, CMT, KHL and KSP were funded by CNPq (Pronex-Dengue - grants # 550131/2010-8 and Doenaas Neglenciadas # 404211/2012-7) and ICNT-Dengue. DTSH acknowledges the David H Smith postdoctoral fellowship for funding. SC acknowledges funding from the University of Tasmania Research Enhancement Grant Scheme (grant # C 20897). CBL was supported by the NSF Graduate Research Fellowship Program under grant DGE-1321845. The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of USDA-APHIS-VS, USDA-APHIS-WS, DHS or NIH. NR 36 TC 2 Z9 2 U1 1 U2 5 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 FEB 15 PY 2015 VL 8 AR 98 DI 10.1186/s13071-015-0659 PG 15 WC Parasitology SC Parasitology GA DD3RT UT WOS:000369841000001 PM 25889533 ER PT J AU Wolnicka-Glubisz, A Strickland, FM Wielgus, A Anver, M Merlino, G De Fabo, EC Noonan, FP AF Wolnicka-Glubisz, Agnieszka Strickland, Faith M. Wielgus, Albert Anver, Miriam Merlino, Glenn De Fabo, Edward C. Noonan, Frances P. TI A melanin-independent interaction between Mc1r and Met signaling pathways is required for HGF-dependent melanoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE ultraviolet; melanoma; melanocortin 1 receptor; melanin; HGF/Met ID CUTANEOUS MALIGNANT-MELANOMA; PROTEIN-COUPLED RECEPTORS; MELANOCORTIN 1 RECEPTOR; BRAF-MUTANT MELANOMA; ULTRAVIOLET-RADIATION; HUMAN MELANOCYTES; GROWTH-FACTOR; INFLAMMATORY RESPONSE; UV-RADIATION; DNA-DAMAGE AB Melanocortin 1 receptor (MC1R) signaling stimulates black eumelanin production through a cAMP-dependent pathway. MC1R polymorphisms can impair this process, resulting in a predominance of red phaeomelanin. The red hair, fair skin and UV sensitive phenotype is a well-described melanoma risk factor. MC1R polymorphisms also confer melanoma risk independent of pigment. We investigated the effect of Mc1r deficiency in a mouse model of UV-induced melanoma. C57BL/6-Mc1r(+/+)-HGF transgenic mice have a characteristic hyperpigmented black phenotype with extra-follicular dermal melanocytes located at the dermal/epidermal junction. UVB induces melanoma, independent of melanin pigmentation, but UVA-induced and spontaneous melanomas are dependent on black eumelanin. We crossed these mice with yellow C57BL/6-Mc1r(e/e) animals which have a non-functional Mc1r and produce predominantly yellow phaeomelanin. Yellow C57BL/6-Mc1r(e/e)-HGF mice produced no melanoma in response to UVR or spontaneously even though the HGF transgene and its receptor Met were expressed. Total melanin was less than in C57BL/6-Mc1r(+/+)-HGF mice, hyperpigmentation was not observed and there were few extra-follicular melanocytes. Thus, functional Mc1r was required for expression of the transgenic HGF phenotype. Heterozygous C57BL/6-Mc1r(e/+)-HGF mice were black and hyperpigmented and, although extra-follicular melanocytes and skin melanin content were similar to C57BL/6-Mc1r(+/+)-HGF animals, they developed UV-induced and spontaneous melanomas with significantly less efficiency by all criteria. Thus, heterozygosity for Mc1r was sufficient to restore the transgenic HGF phenotype but insufficient to fully restore melanoma. We conclude that a previously unsuspected melanin-independent interaction between Mc1r and Met signaling pathways is required for HGF-dependent melanoma and postulate that this pathway is involved in human melanoma. What's new? Melanocortin 1 receptor (MC1R), which plays a central role in the production of melanin, is subject to marked genetic variation, with certain variants increasing melanoma risk through fair skin phenotype. Others MCR1 variants, however, influence melanoma risk through pigment-independent alterations. Such variants may include those that affect interactions between Mc1r and hepatocyte growth factor (HGF)/Met signaling, as suggested by this investigation of Mcr1 deficiency in a UV-induced melanoma mouse model. HGF has been implicated in tumor escape from B-RAF inhibitors in human melanoma, and MET is a target for melanoma therapy, suggesting potential therapeutic significance for the findings. C1 [Wolnicka-Glubisz, Agnieszka; De Fabo, Edward C.; Noonan, Frances P.] George Washington Univ, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA. [Wolnicka-Glubisz, Agnieszka] Jagiellonian Univ, Dept Biophys, Fac Biochem Biophys & Biotechnol, Krakow, Poland. [Strickland, Faith M.] Henry Ford Hlth Sci Ctr, Dept Dermatol, Detroit, MI USA. [Wielgus, Albert] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Anver, Miriam] Frederick Natl Lab Canc Res, Pathol Histotechnol Lab, Frederick, MD USA. [Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Noonan, FP (reprint author), George Washington Univ, Dept Microbiol Immunol & Trop Med, 2300 1 St NW, Washington, DC 20037 USA. EM fpn@gwu.edu FU NIH [CA53765, CA92258, AR47951]; US Department of Defense [DAMD17-01-1-1709]; Melanoma Research Foundation; National Cancer Institute; National Institutes of Health [HHSN261200800001E] FX Grant sponsor: NIH; Grant numbers: CA53765, CA92258, AR47951; Grant sponsor: US Department of Defense; Grant number: DAMD17-01-1-1709; Grant sponsors: Melanoma Research Foundation (Established Investigator award); Grant sponsor: National Cancer Institute and National Institutes of Health; Grant number: HHSN261200800001E NR 55 TC 2 Z9 3 U1 7 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2015 VL 136 IS 4 BP 752 EP 760 DI 10.1002/ijc.29050 PG 9 WC Oncology SC Oncology GA AW2AG UT WOS:000346089900023 PM 24975581 ER PT J AU Galeone, C Edefonti, V Parpinel, M Leoncini, E Matsuo, K Talamini, R Olshan, AF Zevallos, JP Winn, DM Jayaprakash, V Moysich, K Zhang, ZF Morgenstern, H Levi, F Bosetti, C Kelsey, K McClean, M Schantz, S Yu, GP Boffetta, P Lee, YCA Hashibe, M La Vecchia, C Boccia, S AF Galeone, Carlotta Edefonti, Valeria Parpinel, Maria Leoncini, Emanuele Matsuo, Keitaro Talamini, Renato Olshan, Andrew F. Zevallos, Jose P. Winn, Deborah M. Jayaprakash, Vijayvel Moysich, Kirsten Zhang, Zuo-Feng Morgenstern, Hal Levi, Fabio Bosetti, Cristina Kelsey, Karl McClean, Michael Schantz, Stimson Yu, Guo-Pei Boffetta, Paolo Lee, Yuan-Chin Amy Hashibe, Mia La Vecchia, Carlo Boccia, Stefania TI Folate intake and the risk of oral cavity and pharyngeal cancer: A pooled analysis within the International Head and Neck Cancer Epidemiology Consortium SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE oral cancer; folate intake; diet; epidemiology; risk factor ID SQUAMOUS-CELL CARCINOMA; METHYLENETETRAHYDROFOLATE REDUCTASE MTHFR; UPPER AERODIGESTIVE TRACT; LUNG-CANCER; FOLIC-ACID; ALCOHOL; POLYMORPHISM; METAANALYSIS; SMOKING; DEFICIENCY AB There are suggestions of an inverse association between folate intake and serum folate levels and the risk of oral cavity and pharyngeal cancers (OPCs), but most studies are limited in sample size, with only few reporting information on the source of dietary folate. Our study aims to investigate the association between folate intake and the risk of OPC within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. We analyzed pooled individual-level data from ten case-control studies participating in the INHANCE consortium, including 5,127 cases and 13,249 controls. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated for the associations between total folate intake (natural, fortification and supplementation) and natural folate only, and OPC risk. We found an inverse association between total folate intake and overall OPC risk (the adjusted OR for the highest vs. the lowest quintile was 0.65, 95% CI: 0.43-0.99), with a stronger association for oral cavity (OR=0.57, 95% CI: 0.43-0.75). A similar inverse association, though somewhat weaker, was observed for folate intake from natural sources only in oral cavity cancer (OR=0.64, 95% CI: 0.45-0.91). The highest OPC risk was observed in heavy alcohol drinkers with low folate intake as compared to never/light drinkers with high folate (OR=4.05, 95% CI: 3.43-4.79); the attributable proportion (AP) owing to interaction was 11.1% (95% CI: 1.4-20.8%). Lastly, we reported an OR of 2.73 (95% CI:2.34-3.19) for those ever tobacco users with low folate intake, compared with nevere tobacco users and high folate intake (AP of interaction =10.6%, 95% CI: 0.41-20.8%). Our project of a large pool of case-control studies supports a protective effect of total folate intake on OPC risk. What's new? Folate is essential to DNA synthesis and repair, suggesting that folate deficiency, in disrupting normal DNA processes, may facilitate the development of certain cancers, including oral and pharyngeal cancer (OPC). The relationship between folate intake and risk of OPC, however, is unclear. In this analysis of data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, high levels of folate intake were found to be inversely associated with overall OPC risk. The association was strongest for cancer of the oral cavity. Risk of OPC was highest among heavy alcohol drinkers with low folate levels. C1 [Galeone, Carlotta; Bosetti, Cristina] IRCCS Ist Ric Farmacol Mario Negri, Dept Epidemiol, Milan, Italy. [Edefonti, Valeria; La Vecchia, Carlo] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Parpinel, Maria] Univ Udine, Dept Med & Biol Sci, Unit Hyg & Epidemiol, I-33100 Udine, Italy. [Leoncini, Emanuele; Boccia, Stefania] Univ Cattolica Sacro Cuore, Dept Publ Hlth, Sect Hyg, Inst Publ Hlth, I-00168 Rome, Italy. [Matsuo, Keitaro] Kyushu Univ, Dept Prevent Med, Fac Med Sci, Kyushu, Japan. [Talamini, Renato] Aviano Canc Ctr, Unit Epidemiol & Biostat, I-33081 Aviano, Italy. [Olshan, Andrew F.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Zevallos, Jose P.] Univ Texas Sch Dent Houston, Bobby R Alford Dept Otolaryngol Head & Neck Surg, Baylor Coll Med, Houston, TX USA. [Winn, Deborah M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Jayaprakash, Vijayvel; Moysich, Kirsten] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Levi, Fabio] Univ Lausanne Hosp, Canc Epidemiol Unit, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland. [Kelsey, Karl] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [McClean, Michael] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Schantz, Stimson] New York Eye & Ear Infirm, Dept Otolaryngol, New York, NY 10003 USA. [Yu, Guo-Pei] Peking Univ, Med Informat Ctr, Beijing 100871, Peoples R China. [Boffetta, Paolo] Icahan Sch Med Mt Sinai, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Icahan Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY USA. [Lee, Yuan-Chin Amy] Univ Utah, Sch Med, Dept Family & Prevent Med, Salt Lake City, UT 84112 USA. [Hashibe, Mia] Univ Utah, Sch Med, Dept Family & Prevent Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Boccia, Stefania] IRCCS San Raffaele Pisana, Area Syst Approaches & Non Communicable Dis, Rome, Italy. RP Boccia, S (reprint author), Univ Cattolica Sacro Cuore, Genet Epidemiol & Publ Hlth Genom Unit, Sect Hyg, Inst Publ Hlth, I-00168 Rome, Italy. EM sboccia@rm.unicatt.it RI McClean, Michael/J-2934-2015; Parpinel, Maria/B-1605-2012; , emanuele/A-5466-2010; OI Matsuo, Keitaro/0000-0003-1761-6314; Parpinel, Maria/0000-0003-1309-4467; , emanuele/0000-0002-7669-8535; La Vecchia, Carlo/0000-0003-1441-897X; EDEFONTI, VALERIA CARLA/0000-0002-1995-1477 FU Los Angeles Study: NIH USA [P50CA090388, R01DA011386, R03CA077954, T32CA009142, U01CA096134, R21ES011667]; The Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; MSKCC study: NIH [R01CA051845]; North Carolina: NIH USA [19941997, R01CA061188]; The National Institute of Environmental Health Sciences [P30ES010126]; US Multicenter study: The Intramural Program of the NCI, NIH, USA; Ministry of Education, Science, Sports, Culture and Technology of Japan [17015052]; The Third-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan [H20-002]; Italian Association for Research on Cancer (AIRC) [10491-2010/2013]; Fondazione Veronesi FX Grant sponsor: Los Angeles Study: NIH USA; Grant numbers: P50CA090388, R01DA011386, R03CA077954, T32CA009142, U01CA096134, R21ES011667; Grant sponsor: The Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; Grant sponsor: MSKCC study: NIH; Grant number: R01CA051845; Grant sponsor: North Carolina (19941997): NIH USA; Grant number: R01CA061188; Grant sponsor: The National Institute of Environmental Health Sciences; Grant number: P30ES010126; Grant sponsor: US Multicenter study: The Intramural Program of the NCI, NIH, USA; Grant sponsor: Japan (2001- 2005): Scientific Research grant from the Ministry of Education, Science, Sports, Culture and Technology of Japan; Grant number: 17015052; Grant sponsor: The Third-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan; Grant number: H20-002; Grant sponsor: Italian Association for Research on Cancer (AIRC); Grant number: 10491-2010/2013; Grant sponsor: Fondazione Veronesi NR 55 TC 7 Z9 7 U1 3 U2 37 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2015 VL 136 IS 4 BP 904 EP 914 DI 10.1002/ijc.29044 PG 11 WC Oncology SC Oncology GA AW2AG UT WOS:000346089900037 PM 24974959 ER PT J AU Mirabello, L Frimer, M Harari, A McAndrew, T Smith, B Chen, ZG Wentzensen, N Wacholder, S Castle, PE Raine-Bennett, T Schiffman, M Burk, RD AF Mirabello, Lisa Frimer, Marina Harari, Ariana McAndrew, Thomas Smith, Benjamin Chen, Zigui Wentzensen, Nicolas Wacholder, Sholom Castle, Philip E. Raine-Bennett, Tina Schiffman, Mark Burk, Robert D. TI HPV16 methyl-haplotypes determined by a novel next-generation sequencing method are associated with cervical precancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE HPV16; methylation; next-generation sequencing; pyrosequencing; cervical precancer ID PAPILLOMAVIRUS TYPE-16 DNA; INTRAEPITHELIAL NEOPLASIA; CARCINOGENIC PROGRESSION; NATURAL-HISTORY; CPG METHYLATION; YOUNG-WOMEN; L1 GENE; CANCER; RISK; INFECTION AB We have developed and evaluated a next-generation bisulfite sequencing (NGS) assay to distinguish HPV16 cervical precancer (CIN2-3; N =59) from HPV16-positive transient infections (N=40). Cervical DNA was isolated and treated with bisulfite and HPV16 methylation was quantified by (i) amplification with barcoded primers and massively parallel single molecule sequencing and (ii) site-specific pyrosequencing. Assays were evaluated for agreement using intraclass correlation coefficients (ICC). Odds ratios (OR) for high methylation vs. low methylation were calculated. Single site pyrosequencing and NGS data were correlated (ICC=0.61) and both indicated hypermethylation was associated with precancer (ORs of 2-37). Concordant NGS and pyrosequencing results yieled ORs that were stronger when compared with using either assay separately. Within the L1 region, the ORs for CIN2-3 were 14.3 and 22.4 using pyrosequencing and NGS assays, respectively; when both methods agreed the OR was 153. NGS assays provide methylation haplotypes, termed methyl-haplotypes from single molecule reads: cases had increased methyl-haplotypes with1 methylated CpG site(s) per fragment compared with controls, particularly in L1 (p=3.0 x 10(-8)). The maximum discrimination of cases from controls for a L1 methyl-haplotype had an AUC of 0.89 corresponding to a sensitivity of 92.5% and a specificity of 73.1%. The strengthening of the OR when the two assays were concordant suggests the true association of CpG methylation with precancer is stronger than with either assay. As cervical cancer prevention moves to DNA testing methods, DNA based biomarkers, such as HPV methylation could serve as a reflex strategy to identify women at high risk for cervix cancer. What's new? Human papillomavirus type 16 (HPV16) is the most prevalent carcinogenic HPV type, but infection progresses to cervical precancer in only a small fraction of cases. Determining whether infections will progress or clear remains an elusive goal, but this study suggests that it may be possible to distinguish between the two with a bisulfite-treated DNA next-generation sequencing (NGS) assay specific to HPV16 DNA methylation. The NGS assay performed similarly to pyrosequencing and has several advantages over traditional methods. Using HPV16 CpG methylation and methyl-haplotype biomarkers, the NGS technique could aid in risk stratification for HPV-positive women. C1 [Mirabello, Lisa; Wentzensen, Nicolas; Wacholder, Sholom; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Frimer, Marina] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Frimer, Marina; McAndrew, Thomas; Burk, Robert D.] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10467 USA. [Harari, Ariana; Burk, Robert D.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Smith, Benjamin; Chen, Zigui; Burk, Robert D.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Castle, Philip E.] Global Canc Initiat, Chestertown, MD USA. [Raine-Bennett, Tina] Kaiser Permanente No Calif, Div Res, Womens Hlth Res Inst, Oakland, CA USA. RP Mirabello, L (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E422, Rockville, MD 20850 USA. EM mirabellol@mail.nih.gov; burk@aecom.yu.edu RI Schiffman, Mark/B-9766-2015; Chen, Zigui/E-8490-2017 FU National Cancer Institute intramural research program of the Division of Cancer Epidemiology and Genetics [UO1-CA78527]; Einstein Cancer Research Center [P30CA013330] FX This work was supported in part by the National Cancer Institute intramural research program of the Division of Cancer Epidemiology and Genetics (UO1-CA78527) to RDB, and Einstein Cancer Research Center (P30CA013330) to RDB. NR 40 TC 6 Z9 6 U1 1 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2015 VL 136 IS 4 BP E146 EP E153 DI 10.1002/ijc.29119 PG 8 WC Oncology SC Oncology GA AW2AG UT WOS:000346089900014 PM 25081507 ER PT J AU Balsam, J Bruck, HA Rasooly, A AF Balsam, Joshua Bruck, Hugh Alan Rasooly, Avraham TI Cell streak imaging cytometry for rare cell detection SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Flow cytometry; Wide-field imaging; Rare cells; Resource-poor settings; Image enhancement; mHealth ID ARRAY BIOSENSOR AB Detection of rare cells, such as circulating tumor cells, have many clinical applications. To measure rare cells with increased sensitivity and improved data managements, we developed an imaging flow cytometer with a streak imaging mode capability. The new streak mode imaging mode utilizes low speed video to capture moving fluorescently labeled cells in a flow cell. Each moving cell is imaged on multiple pixels on each frame, where the cell path is marked as a streak line proportional to the length of the exposure. Finding rare cells (e.g., <1 cell/mL) requires measuring larger sample volumes to achieve higher sensitivity, therefore we combined streak mode imaging with a "wide" high throughput flow cell (e.g. flow rates set to 10 mL/min) in contrast to the conventional "narrow" hydrodynamic focusing cells typically used in cytometry that are inherently limited to low flow rates. The new flow cell is capable of analyzing 20 mL/min of fluorescently labeled cells. To further increase sensitivity, the signal to noise ratio of the images was also enhanced by combining three imaging methods: (1) background subtraction, (2) pixel binning, and (3) CMOS color channel selection. The streaking mode cytometer has been used for the analysis of SYTO-9 labeled THP-1 human monocytes in buffer and in blood. Samples of cells at 1 cell/mL and 0.1 cell/mL were analyzed in 30 mL with flow rates set to 10 mL/min and frame rates of 4 fps (frame per second). For the target of 1 cell/mL, an average concentration of 0.91 cell/mL was measured by cytometry, with a standard error of 0.03 (C-95 = 0.85-0.97). For the target of 0.1 cell/mL, an average concentration of 0.083 cell/mL was measured, with a standard error of 0.01 (C-95 = 0.065-0.102). Whole blood was also spiked with SYTO-9 labeled cells to a concentration of 10 cell/mL, and the average flow cytometry measurement was 8.7 cells/mL (i.e. 0.87 cells/mL in diluted blood) with a 95% CL of 8.1-9.2 cells/mL. This demonstrated the ability to detect rare cells in blood with high accuracy. Such detection approaches for rare cells have many potential clinical applications. Furthermore, the simplicity and low cost of this device may enable expansion of cell-based clinical diagnostics, especially in resource-poor settings. Published by Elsevier B.V. C1 [Balsam, Joshua; Rasooly, Avraham] FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Balsam, Joshua; Bruck, Hugh Alan] Univ Maryland, College Pk, MD 20742 USA. [Rasooly, Avraham] NCI, Off Canc Complementary & Alternat Med, Rockville, MD 20850 USA. RP Rasooly, A (reprint author), NIH NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM rasoolya@mail.nih.gov FU FDA's Center for Devices and Radiological Health, Division of Biology; National Cancer Institute FX This work was supported by the FDA's Center for Devices and Radiological Health, Division of Biology and the National Cancer Institute. The views expressed are those of the authors and do not represent those of the U.S. Government. NR 11 TC 3 Z9 3 U1 4 U2 62 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 EI 1873-4235 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD FEB 15 PY 2015 VL 64 BP 154 EP 160 DI 10.1016/j.bios.2014.08.065 PG 7 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA AT6OQ UT WOS:000345059100024 PM 25212069 ER PT J AU Wu, QJ Xiang, YB Yang, G Li, HL Lan, Q Gao, YT Zheng, W Shu, XO Fowke, JH AF Wu, Qi-Jun Xiang, Yong-Bing Yang, Gong Li, Hong-Lan Lan, Qing Gao, Yu-Tang Zheng, Wei Shu, Xiao-Ou Fowke, Jay H. TI Vitamin E intake and the lung cancer risk among female nonsmokers: A report from the Shanghai Women's Health Study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE diet; dietary supplements; lung neoplasm; prospective study; tocopherols; women ID RANDOMIZED CONTROLLED-TRIAL; BETA-CAROTENE; ALPHA-TOCOPHEROL; GAMMA-TOCOPHEROL; DELTA-TOCOPHEROL; PROSTATE-CANCER; MALE SMOKERS; FOLLOW-UP; SMOKING; COHORT AB Vitamin E includes several tocopherol isoforms, which may reduce lung cancer risk, but past studies evaluating the association between vitamin E intake and lung cancer risk were inconsistent. We prospectively investigated the associations between tocopherol intake from diet and from supplements with lung cancer risk among 72,829 Chinese female nonsmokers aged 40-70 years and participating in the Shanghai Women's Health Study (SWHS). Dietary and supplement tocopherol exposure was assessed by a validated food-frequency questionnaire at baseline and reassessed for change in intake during follow-up. Cox proportional hazards models with time-dependent covariates were used to calculate multivariate-adjusted hazard ratios (HRs) and 95% confidence interval (CIs) for lung cancer. After 12.02 years of follow-up, 481 women were diagnosed with lung cancer. Total dietary tocopherol was inversely associated with lung cancer risk among women meeting dietary guidelines for adequate intake (AI) of tocopherol (14 mg/day or more: HR: 0.78; 95% CI 0.60-0.99; compared with the category less than AI). The protective association between dietary tocopherol intake and lung cancer was restricted to women exposed to side-stream smoke in the home and workplace [HR=0.53 (0.29-0.97), p-trend=0.04]. In contrast, vitamin E supplement use was associated with increased lung cancer risk (HR: 1.33; 95% CI: 1.01-1.73), more so for lung adenocarcinoma risk (HR: 1.79; 95% CI: 1.23-2.60). In summary, dietary tocopherol intake may reduce the risk of lung cancer among female nonsmokers; however, supplements may increase lung adenocarcinoma risk and requires further investigation. What's new? While some studies have suggested that vitamin E may reduce lung-cancer risk among non-smokers, results have been inconsistent. In this large, prospective study, the authors found that increasing vitamin E in the diet was significantly associated with a decreased risk of lung cancer. However, vitamin E from supplements was significantly associated with an increase in lung cancer risk. This suggests that caution is warranted when recommending vitamin E supplementation for lung cancer prevention among non-smoking women. C1 [Wu, Qi-Jun; Xiang, Yong-Bing; Li, Hong-Lan] Shanghai Jiao Tong Univ, Sch Med, Shanghai Canc Inst, State Key Lab Oncogene & Related Genes,Renji Hosp, Shanghai 200030, Peoples R China. [Wu, Qi-Jun; Xiang, Yong-Bing; Li, Hong-Lan; Gao, Yu-Tang] Shanghai Jiao Tong Univ, Sch Med, Shanghai Canc Inst, Dept Epidemiol,Renji Hosp, Shanghai 200030, Peoples R China. [Wu, Qi-Jun; Yang, Gong; Zheng, Wei; Shu, Xiao-Ou; Fowke, Jay H.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Wu, Qi-Jun; Yang, Gong; Zheng, Wei; Shu, Xiao-Ou; Fowke, Jay H.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Lan, Qing] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Fowke, JH (reprint author), Vanderbilt Univ, Med Ctr, Sch Med, Vanderbilt Epidemiol Ctr, 2525 West End Ave,12th Floor,Suite 1200, Nashville, TN 37203 USA. EM Jay.fowke@vanderbilt.edu FU United States National Institutes of Health [R37 CA070867, R01 CA82729, R01 HL095931]; State Key Project Specialized for Infectious Diseases of China [2008ZX10002-015, 2012ZX10002008-002] FX Grant sponsor: United States National Institutes of Health; Grant numbers: R37 CA070867, R01 CA82729 and R01 HL095931; Grant sponsor: State Key Project Specialized for Infectious Diseases of China; Grant numbers: 2008ZX10002-015 and 2012ZX10002008-002 NR 50 TC 7 Z9 7 U1 1 U2 31 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2015 VL 136 IS 3 BP 610 EP 617 DI 10.1002/ijc.29016 PG 8 WC Oncology SC Oncology GA AT2XD UT WOS:000344796700012 PM 24916784 ER PT J AU Pasquali, E Garcia-Borron, JC Fargnoli, MC Gandini, S Maisonneuve, P Bagnardi, V Specchia, C Liu, F Kayser, M Nijsten, T Nagore, E Kumar, R Hansson, J Kanetsky, PA Ghiorzo, P Debniak, T Branicki, W Gruis, NA Han, JL Dwyer, T Blizzard, L Landi, MT Palmieri, G Ribas, G Stratigos, A Council, ML Autier, P Little, J Newton-Bishop, J Sera, F Raimondi, S AF Pasquali, Elena Garcia-Borron, Jose C. Fargnoli, Maria Concetta Gandini, Sara Maisonneuve, Patrick Bagnardi, Vincenzo Specchia, Claudia Liu, Fan Kayser, Manfred Nijsten, Tamar Nagore, Eduardo Kumar, Rajiv Hansson, Johan Kanetsky, Peter A. Ghiorzo, Paola Debniak, Tadeusz Branicki, Wojciech Gruis, Nelleke A. Han, Jiali Dwyer, Terry Blizzard, Leigh Landi, Maria Teresa Palmieri, Giuseppe Ribas, Gloria Stratigos, Alexander Council, M. Laurin Autier, Philippe Little, Julian Newton-Bishop, Julia Sera, Francesco Raimondi, Sara CA M-SKIP Study Grp TI MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: A pooled-analysis from the M-SKIP project SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE melanocortin-1 receptor; melanoma; meta-analysis; genetic epidemiology ID MELANOCORTIN 1 RECEPTOR; ULTRAVIOLET-RADIATION; STIMULATING HORMONE; EUROPEAN POPULATIONS; GENE POLYMORPHISMS; HUMAN MELANOCYTES; HAIR COLOR; METAANALYSIS; ASSOCIATION; PHENOTYPES AB The MC1R gene is a key regulator of skin pigmentation. We aimed to evaluate the association between MC1R variants and the risk of sporadic cutaneous melanoma (CM) within the M-SKIP project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. Data included 5,160 cases and 12,119 controls from 17 studies. We calculated a summary odds ratio (SOR) for the association of each of the nine most studied MC1R variants and of variants combined with CM by using random-effects models. Stratified analysis by phenotypic characteristics were also performed. Melanoma risk increased with presence of any of the main MC1R variants: the SOR for each variant ranged from 1.47 (95%CI: 1.17-1.84) for V60L to 2.74 (1.53-4.89) for D84E. Carriers of any MC1R variant had a 66% higher risk of developing melanoma compared with wild-type subjects (SOR; 95%CI: 1.66; 1.41-1.96) and the risk attributable to MC1R variants was 28%. When taking into account phenotypic characteristics, we found that MC1R-associated melanoma risk increased only for darker-pigmented Caucasians: SOR (95%CI) was 3.14 (2.06-4.80) for subjects with no freckles, no red hair and skin Type III/IV. Our study documents the important role of all the main MC1R variants in sporadic CM and suggests that they have a direct effect on melanoma risk, independently on the phenotypic characteristics of carriers. This is of particular importance for assessing preventive strategies, which may be directed to darker-pigmented Caucasians with MC1R variants as well as to lightly pigmented, fair-skinned subjects. What's new? The MC1R gene regulates production of the protective skin pigment eumelanin in response to sun exposure. In this study, the authors found that carriers of any of nine MC1R variants had a substantially increased risk of developing sporadic CM. Surprisingly, however, this increased risk was significant only for darker-pigmented Caucasians. This information is important for targeted preventive strategies, as fair-skinned people have previously been assumed to be at greatest risk for CM. C1 [Pasquali, Elena; Gandini, Sara; Maisonneuve, Patrick; Bagnardi, Vincenzo; Raimondi, Sara] European Inst Oncol, Div Epidemiol & Biostat, I-20141 Milan, Italy. [Garcia-Borron, Jose C.] Univ Murcia, Dept Biochem Mol Biol & Immunol, E-30001 Murcia, Spain. [Fargnoli, Maria Concetta] Univ Aquila, Dept Dermatol, I-67100 Laquila, Italy. [Bagnardi, Vincenzo] Univ Milano Bicocca, Dept Stat & Quantitat Methods, Milan, Italy. [Specchia, Claudia] Univ Brescia, Dept Mol & Translat Med, I-25121 Brescia, Italy. [Liu, Fan; Kayser, Manfred] Erasmus MC Univ Med Ctr, Dept Forens Mol Biol, Rotterdam, Netherlands. [Nijsten, Tamar] Erasmus MC Univ Med Ctr, Dept Dermatol, Rotterdam, Netherlands. [Nagore, Eduardo] Inst Valenciano Oncol, Dept Dermatol, Valencia, Spain. [Nagore, Eduardo] Univ Catolica Valencia, Valencia, Spain. [Kumar, Rajiv] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany. [Hansson, Johan] Karolinska Inst, Dept Pathol & Oncol, Ctr Canc, Stockholm, Sweden. [Kanetsky, Peter A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Ghiorzo, Paola] Univ Genoa, Dept Internal Med & Med Specialties, I-16126 Genoa, Italy. [Ghiorzo, Paola] IRCCS AOU San Martino IST, Genet Rare Hereditary Cancers, Genoa, Italy. [Debniak, Tadeusz] Pomeranian Med Univ, Dept Genet & Pathol, Polabska, Poland. [Branicki, Wojciech] Inst Forens Res, Krakow, Poland. [Gruis, Nelleke A.] Leiden Univ, Dept Dermatol, Med Ctr, Leiden, Netherlands. [Han, Jiali] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Han, Jiali] Harvard Univ, Sch Med, Boston, MA USA. [Han, Jiali] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Han, Jiali] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Dwyer, Terry] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic, Australia. [Blizzard, Leigh] Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas, Australia. [Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA. [Palmieri, Giuseppe] CNR, Ist Chim Biomol, Unit Canc Genet, Sassari, Italy. [Ribas, Gloria] Fdn Invest Clin Valencia Inst Invest Sanitaria IN, Dept Oncol Med & Hematol, Valencia, Spain. [Stratigos, Alexander] Univ Athens, Dept Dermatol, Andreas Sygros Hosp, Athens, Greece. [Council, M. Laurin] Washington Univ, Sch Med, Div Dermatol, St Louis, MO 63110 USA. [Autier, Philippe] Int Prevent Res Inst, Lyon, France. [Little, Julian] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON K1N 6N5, Canada. [Newton-Bishop, Julia] Univ Leeds, Sect Epidemiol & Biostat, Inst Canc & Pathol, Leeds LS2 9JT, W Yorkshire, England. [Sera, Francesco] UCL Inst Child Hlth, London, England. RP Raimondi, S (reprint author), European Inst Oncol, Div Epidemiol & Biostat, Via Ripamonti 435, I-20141 Milan, Italy. EM sara.raimondi@ieo.it RI Sera, Francesco/C-8176-2011; Garcia-Borron, Jose Carlos/H-2247-2015; Autier, Philippe/A-4402-2014; Raimondi, Sara/J-5236-2016; OI Gandini, Sara/0000-0002-1348-4548; Maisonneuve, Patrick/0000-0002-5309-4704; Garcia-Borron, Jose Carlos/0000-0002-9192-588X; Autier, Philippe/0000-0003-1538-5321; Liu, Fan/0000-0001-9241-8161; Palmieri, Giuseppe/0000-0002-4350-2276; Newton Bishop, Julia/0000-0001-9147-6802; Bowcock, Anne/0000-0001-8691-9090; Raimondi, Sara/0000-0003-4673-9049; Gruis, Nelleke/0000-0002-5210-9150; Kumar, Rajiv/0000-0002-6093-0395; Fargnoli, Maria Concetta/0000-0002-7249-2556 FU Italian Association for Cancer Research [MFAG 11831] FX Grant sponsor: Italian Association for Cancer Research; Grant number: MFAG 11831 NR 50 TC 16 Z9 16 U1 2 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2015 VL 136 IS 3 BP 618 EP 631 DI 10.1002/ijc.29018 PG 14 WC Oncology SC Oncology GA AT2XD UT WOS:000344796700013 PM 24917043 ER PT J AU Kim, C Gao, YT Xiang, YB Barone-Adesi, F Zhang, YW Hosgood, HD Ma, SG Shu, XO Ji, BT Chow, WH Seow, WJ Bassig, B Cai, QY Zheng, W Rothman, N Lan, Q AF Kim, Christopher Gao, Yu-Tang Xiang, Yong-Bing Barone-Adesi, Francesco Zhang, Yawei Hosgood, H. Dean Ma, Shuangge Shu, Xiao-ou Ji, Bu-Tian Chow, Wong-Ho Seow, Wei Jie Bassig, Bryan Cai, Qiuyin Zheng, Wei Rothman, Nathaniel Lan, Qing TI Home kitchen ventilation, cooking fuels, and lung cancer risk in a prospective cohort of never smoking women in Shanghai, China SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE ventilation; coal; lung cancer; never smoking; women; China; Shanghai ID POLYCYCLIC AROMATIC-HYDROCARBONS; ENVIRONMENTAL TOBACCO-SMOKE; INDOOR AIR-POLLUTION; BRONCHIAL EPITHELIAL-CELLS; OIL FUMES; NONSMOKING WOMEN; BIOMASS FUELS; DNA-DAMAGE; HOUSEHOLD; METAANALYSIS AB Indoor air pollution (IAP) caused by cooking has been associated with lung cancer risk in retrospective case-control studies in developing and rural countries. We report the association of cooking conditions, fuel use, oil use, and risk of lung cancer in a developed urban population in a prospective cohort of women in Shanghai. A total of 71,320 never smoking women were followed from 1996 through 2009 and 429 incident lung cancer cases were identified. Questionnaires collected information on household living and cooking practices for the three most recent residences and utilization of cooking fuel and oil, and ventilation conditions. Cox proportional hazards regression estimated the association for kitchen ventilation conditions, cooking fuels, and use of cooking oils for the risk of lung cancer by hazard ratios (HR) with 95% confidence intervals (95% CI). Ever poor kitchen ventilation was associated with a 49% increase in lung cancer risk (HR: 1.49; 95% CI: 1.15-1.95) compared to never poor ventilation. Ever use of coal was not significantly associated. However, ever coal use with poor ventilation (HR: 1.69; 95% CI: 1.22-2.35) and 20 or more years of using coal with poor ventilation (HR: 2.03; 95% CI: 1.35-3.05) was significantly associated compared to no exposure to coal or poor ventilation. Cooking oil use was not significantly associated. These results demonstrate that IAP from poor ventilation of coal combustion increases the risk of lung cancer and is an important public health issue in cities across China where people may have lived in homes with inadequate kitchen ventilation. What's New? Where there's smoke, there's cancer. In households where cooking smoke collects in the kitchen, is there greater risk of lung cancer? These authors collected information from nonsmoking women in Shanghai about their cooking practices, then correlated those data with cases of lung cancer among the population. Inadequate kitchen ventilation, particularly combined with long term use of coal, increased the risk of lung cancer significantly. These findings could have an important impact on public health in urban China. C1 [Kim, Christopher; Ji, Bu-Tian; Seow, Wei Jie; Bassig, Bryan; Rothman, Nathaniel; Lan, Qing] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kim, Christopher; Zhang, Yawei; Ma, Shuangge; Bassig, Bryan] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Barone-Adesi, Francesco] St Georges Univ London, Populat Hlth Res Inst, London, England. [Hosgood, H. Dean] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Shu, Xiao-ou; Cai, Qiuyin; Zheng, Wei] Vanderbilt Univ, Med Ctr, Div Epidemiol, Nashville, TN USA. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. RP Kim, C (reprint author), 9609 Med Ctr Dr,MSC 9771, Bethesda, MD USA. EM Christopher.kim@nih.gov FU NIH intramural research program [N02 CP1101066]; NIH training grant [T32-CA105666]; NIH research grant [R01 CA70867] FX Grant sponsor: NIH intramural research program; Grant number: N02 CP1101066; Grant sponsor: NIH training grant; Grant number: T32-CA105666; Grant sponsor: NIH research grant; Grant number: R01 CA70867. NR 47 TC 8 Z9 8 U1 4 U2 87 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2015 VL 136 IS 3 BP 632 EP 638 DI 10.1002/ijc.29020 PG 7 WC Oncology SC Oncology GA AT2XD UT WOS:000344796700014 PM 24917360 ER PT J AU Tan, ML Miller, BT Te, J Cendagorta, JR Brooks, BR Ichiye, T AF Tan, Ming-Liang Miller, Benjamin T. Te, Jerez Cendagorta, Joseph R. Brooks, Bernard R. Ichiye, Toshiko TI Hydrophobic hydration and the anomalous partial molar volumes in ethanol-water mixtures SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ALCOHOL-WATER; EWALD SUMS; DYNAMICS AB The anomalous behavior in the partial molar volumes of ethanol-water mixtures at low concentrations of ethanol is studied using molecular dynamics simulations. Previous work indicates that the striking minimum in the partial molar volume of ethanol V-E as a function of ethanol mole fraction X-E is determined mainly by water-water interactions. These results were based on simulations that used one water model for the solute-water interactions but two different water models for the water-water interactions. This is confirmed here by using two more water models for the water-water interactions. Furthermore, the previous work indicates that the initial decrease is caused by association of the hydration shells of the hydrocarbon tails, and the minimum occurs at the concentration where all of the hydration shells are touching each other. Thus, the characteristics of the hydration of the tail that cause the decrease and the features of the water models that reproduce this type of hydration are also examined here. The results show that a single-site multipole water model with a charge distribution that mimics the large quadrupole and the p-orbital type electron density out of the molecular plane has "brittle" hydration with hydrogen bonds that break as the tails touch, which reproduces the deep minimum. However, water models with more typical site representations with partial charges lead to flexible hydration that tends to stay intact, which produces a shallow minimum. Thus, brittle hydration may play an essential role in hydrophobic association in water. (C) 2015 AIP Publishing LLC. C1 [Tan, Ming-Liang; Te, Jerez; Cendagorta, Joseph R.; Ichiye, Toshiko] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. [Miller, Benjamin T.; 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. EM ti9@georgetown.edu FU National Science Foundation [CHE-1158267, OCI-1053575]; Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute; Matrix cluster; LoBoS cluster at the Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health FX We are grateful to the National Science Foundation for the support of this work through Grant No. CHE-1158267 (T.I.) and to the McGowan Foundation (T.I.). This research was supported in part by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation Grant No. OCI-1053575; the Matrix cluster, maintained by University Information Services at Georgetown University; and the LoBoS cluster at the Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health. We also thank Alan K. Soper for providing the neutron diffraction data for aqueous solutions of methanol and ethanol. NR 30 TC 4 Z9 4 U1 2 U2 26 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 FEB 14 PY 2015 VL 142 IS 6 AR 064501 DI 10.1063/1.4906750 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA CB7ZH UT WOS:000349847000038 PM 25681917 ER PT J AU Althabe, F Belizan, JM McClure, EM Hemingway-Foday, J Berrueta, M Mazzoni, A Ciganda, A Goudar, SS Kodkany, BS Mahantshetti, NS Dhaded, SM Katageri, GM Metgud, MC Joshi, AM Bellad, MB Honnungar, NV Derman, RJ Saleem, S Pasha, O Ali, S Hasnain, F Goldenberg, RL Esamai, F Nyongesa, P Ayunga, S Liechty, EA Garces, AL Figueroa, L Hambidge, KM Krebs, NF Patel, A Bhandarkar, A Waikar, M Hibberd, PL Chomba, E Carlo, WA Mwiche, A Chiwila, M Manasyan, A Pineda, S Meleth, S Thorsten, V Stolka, K Wallace, DD Koso-Thomas, M Jobe, AH Buekens, PM AF Althabe, Fernando Belizan, Jose M. McClure, Elizabeth M. Hemingway-Foday, Jennifer Berrueta, Mabel Mazzoni, Agustina Ciganda, Alvaro Goudar, Shivaprasad S. Kodkany, Bhalachandra S. Mahantshetti, Niranjana S. Dhaded, Sangappa M. Katageri, Geetanjali M. Metgud, Mrityunjay C. Joshi, Anjali M. Bellad, Mrutyunjaya B. Honnungar, Narayan V. Derman, Richard J. Saleem, Sarah Pasha, Omrana Ali, Sumera Hasnain, Farid Goldenberg, Robert L. Esamai, Fabian Nyongesa, Paul Ayunga, Silas Liechty, Edward A. Garces, Ana L. Figueroa, Lester Hambidge, K. Michael Krebs, Nancy F. Patel, Archana Bhandarkar, Anjali Waikar, Manjushri Hibberd, Patricia L. Chomba, Elwyn Carlo, Waldemar A. Mwiche, Angel Chiwila, Melody Manasyan, Albert Pineda, Sayury Meleth, Sreelatha Thorsten, Vanessa Stolka, Kristen Wallace, Dennis D. Koso-Thomas, Marion Jobe, Alan H. Buekens, Pierre M. TI A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomised trial SO LANCET LA English DT Article ID GESTATIONAL-AGE; GLOBAL-NETWORK; NEWBORN BABIES; SCALE-UP; DEATHS; RISK; INTERVENTIONS; ATTENDANTS; STATEMENT; EXTENSION AB Background Antenatal corticosteroids for pregnant women at risk of preterm birth are among the most effective hospital-based interventions to reduce neonatal mortality. We aimed to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of antenatal corticosteroids at all levels of health care in low-income and middle-income countries. Methods In this 18-month, cluster-randomised trial, we randomly assigned (1:1) rural and semi-urban clusters within six countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) to standard care or a multifaceted intervention including components to improve identification of women at risk of preterm birth and to facilitate appropriate use of antenatal corticosteroids. The primary outcome was 28-day neonatal mortality among infants less than the 5th percentile for birthweight (a proxy for preterm birth) across the clusters. Use of antenatal corticosteroids and suspected maternal infection were additional main outcomes. This trial is registered with ClinicalTrials.gov, number NCT01084096. Findings The ACT trial took place between October, 2011, and March, 2014 (start dates varied by site). 51 intervention clusters with 47 394 livebirths (2520 [5%] less than 5th percentile for birthweight) and 50 control clusters with 50 743 livebirths (2258 [4%] less than 5th percentile) completed follow-up. 1052 (45%) of 2327 women in intervention clusters who delivered less-than-5th-percentile infants received antenatal corticosteroids, compared with 215 (10%) of 2062 in control clusters (p<0.0001). Among the less-than-5th-percentile infants, 28-day neonatal mortality was 225 per 1000 livebirths for the intervention group and 232 per 1000 livebirths for the control group (relative risk [RR] 0.96, 95% CI 0.87-1.06, p=0.65)and suspected maternal infection was reported in 236 (10%) of 2361 women in the intervention group and 133 (6%) of 2094 in the control group (odds ratio [OR] 1.67, 1.33-2.09, p<0.0001). Among the whole population, 28-day neonatal mortality was 27.4 per 1000 livebirths for the intervention group and 23.9 per 1000 livebirths for the control group (RR 1.12, 1.02-1.22, p=0.0127) and suspected maternal infection was reported in 1207 (3%) of 48 219 women in the intervention group and 867 (2%) of 51 523 in the control group (OR 1.45, 1.33-1.58, p<0.0001). Interpretation Despite increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group, and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3.5 neonatal deaths occurred, and the risk of maternal infection seems to have been increased. C1 [Althabe, Fernando; Belizan, Jose M.; Berrueta, Mabel; Mazzoni, Agustina; Ciganda, Alvaro] Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina. [Ciganda, Alvaro] UNICEM, Montevideo, Uruguay. [McClure, Elizabeth M.; Hemingway-Foday, Jennifer; Meleth, Sreelatha; Thorsten, Vanessa; Stolka, Kristen; Wallace, Dennis D.] RTI Int, Durham, NC USA. [Goudar, Shivaprasad S.; Kodkany, Bhalachandra S.; Mahantshetti, Niranjana S.; Dhaded, Sangappa M.; Metgud, Mrityunjay C.; Joshi, Anjali M.; Bellad, Mrutyunjaya B.; Honnungar, Narayan V.] KLE Univ, Jawaharlal Nehru Med Coll, Womens & Childrens Hlth Res Unit, Belgaum, Karnataka, India. [Katageri, Geetanjali M.] S Nijalingappa Med Coll, Bagalkot, Karnataka, India. [Derman, Richard J.] Christiana Care Hlth Syst, Dept Obstet & Gynecol, Newark, DE USA. [Saleem, Sarah; Hasnain, Farid] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Esamai, Fabian; Nyongesa, Paul; Ayunga, Silas] Moi Univ, Sch Med, Eldoret, Kenya. [Liechty, Edward A.] Indiana Univ Sch Med, Indianapolis, IN USA. [Garces, Ana L.; Figueroa, Lester; Pineda, Sayury] Fdn Alimentac Nutr, Ctr Amer & Panama, Guatemala City, Guatemala. [Garces, Ana L.] Francisco Marroquin Univ, Guatemala City, Guatemala. [Hambidge, K. Michael; Krebs, Nancy F.] Univ Colorado, Sch Med, Denver, CO USA. [Patel, Archana; Bhandarkar, Anjali; Waikar, Manjushri] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Patel, Archana] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chomba, Elwyn; Mwiche, Angel] Univ Teaching Hosp, Lusaka, Zambia. [Carlo, Waldemar A.; Manasyan, Albert] Univ Alabama Birmingham, Birmingham, AL USA. [Chiwila, Melody] Ctr Infect Dis Zambia, Lusaka, Zambia. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Jobe, Alan H.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Buekens, Pierre M.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. RP Althabe, F (reprint author), Inst Clin Effectiveness & Hlth Policy IECS, C1414CPV, Buenos Aires, DF, Argentina. EM falthabe@iecs.org.ar OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053; Belizan, Jose/0000-0002-8412-3010 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 37 TC 40 Z9 42 U1 4 U2 16 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 FEB 14 PY 2015 VL 385 IS 9968 BP 629 EP 639 DI 10.1016/S0140-6736(14)61651-2 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CA9AZ UT WOS:000349214000031 PM 25458726 ER PT J AU Tian, YF Gawlak, G Shah, AS Higginbotham, K Tian, XY Kawasaki, Y Akiyama, T Sacks, DB Birukova, AA AF Tian, Yufeng Gawlak, Grzegorz Shah, Alok S. Higginbotham, Katherine Tian, Xinyong Kawasaki, Yoshihiro Akiyama, Tetsu Sacks, David B. Birukova, Anna A. TI Hepatocyte Growth Factor-induced Asef-IQGAP1 Complex Controls Cytoskeletal Remodeling and Endothelial Barrier SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OXIDIZED PHOSPHOLIPIDS; ACTIN-FILAMENTS; SCATTER FACTOR; BETA-CATENIN; RHO GTPASES; C-MET; IQGAP1; RAC; CDC42; PERMEABILITY AB Hepatocyte growth factor (HGF) attenuates agonist-induced endothelial cell (EC) permeability and increases pulmonary endothelial barrier function via Rac-dependent enhancement of the peripheral actin cytoskeleton. However, the precise mechanisms of HGF effects on the peripheral cytoskeleton are not well understood. This study evaluated a role for Rac/Cdc42-specific guanine nucleotide exchange factor Asef and the multifunctional Rac effector, IQGAP1, in the mechanism of HGF-induced EC barrier enhancement. HGF induced Asef and IQGAP1 co-localization at the cell cortical area and stimulated formation of an Asef-IQGAP1 functional protein complex. siRNA-induced knockdown of Asef or IQGAP1 attenuated HGF-induced EC barrier enhancement. Asef knockdown attenuated HGF-induced Rac activation and Rac association with IQGAP1, and it abolished both IQGAP1 accumulation at the cell cortical layer and IQGAP1 interaction with actin cytoskeletal regulators cortactin and Arp3. Asef activation state was essential for Asef interaction with IQGAP1 and protein complex accumulation at the cell periphery. In addition to the previously reported role of the IQGAP1 RasGAP-related domain in the Rac-dependent IQGAP1 activation and interaction with its targets, we show that the IQGAP1 C-terminal domain is essential for HGF-induced IQGAP1/Asef interaction and Asef-Rac-dependent activation leading to IQGAP1 interaction with Arp3 and cortactin as a positive feedback mechanism of IQGAP1 activation. These results demonstrate a novel feedback mechanism of HGF-induced endothelial barrier enhancement via Asef/IQGAP1 interactions, which regulate the level of HGF-induced Rac activation and promote cortical cytoskeletal remodeling via IQGAP1Arp3/cortactin interactions. C1 [Tian, Yufeng; Gawlak, Grzegorz; Shah, Alok S.; Higginbotham, Katherine; Tian, Xinyong; Birukova, Anna A.] Univ Chicago, Dept Med, Sect Pulm & Crit Med, Chicago, IL 60637 USA. [Kawasaki, Yoshihiro; Akiyama, Tetsu] Univ Tokyo, Lab Mol & Genet Informat, Inst Mol & Cellular Biosci, Tokyo 1138654, Japan. [Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Birukova, AA (reprint author), Univ Chicago, Dept Med, Lung Injury Ctr, Sect Pulm & Crit Med, 5841 S Maryland Ave,MC-6026, Chicago, IL 60637 USA. EM abirukov@medicine.bsd.uchicago.edu OI Sacks, David/0000-0003-3100-0735 FU National Institutes of Health from NHLBI [HL89257, HL107920]; Intramural Research Program of the National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grants HL89257 and HL107920 from NHLBI and by the Intramural Research Program of the National Institutes of Health. NR 54 TC 8 Z9 8 U1 2 U2 9 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 FEB 13 PY 2015 VL 290 IS 7 BP 4097 EP 4109 DI 10.1074/jbc.M114.620377 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CB2LH UT WOS:000349458400021 PM 25492863 ER PT J AU Hehl, AB Basso, WU Lippuner, C Ramakrishnan, C Okoniewski, M Walker, RA Grigg, ME Smith, NC Deplazes, P AF Hehl, Adrian B. Basso, Walter U. Lippuner, Christoph Ramakrishnan, Chandra Okoniewski, Michal Walker, Robert A. Grigg, Michael E. Smith, Nicholas C. Deplazes, Peter TI Asexual expansion of Toxoplasma gondii merozoites is distinct from tachyzoites and entails expression of non-overlapping gene families to attach, invade, and replicate within feline enterocytes SO BMC GENOMICS LA English DT Article DE Toxoplasma gondii; Apicomplexa; Coccidia; Cat; Enteroepithelial development; Merozoite; Schizont; Comparative transcriptomics; Surface antigen; Stage-specific gene expression ID DENSE GRANULE PROTEIN; HOST-CELL INVASION; TRANSMEMBRANE MICRONEME PROTEINS; APICAL MEMBRANE ANTIGEN-1; PLASMODIUM-FALCIPARUM; PARASITOPHOROUS VACUOLE; INTESTINAL INFLAMMATION; CYST FORMATION; DNA-BINDING; VIRULENCE AB Background: The apicomplexan parasite Toxoplasma gondii is cosmopolitan in nature, largely as a result of its highly flexible life cycle. Felids are its only definitive hosts and a wide range of mammals and birds serve as intermediate hosts. The latent bradyzoite stage is orally infectious in all warm-blooded vertebrates and establishes chronic, transmissible infections. When bradyzoites are ingested by felids, they transform into merozoites in enterocytes and expand asexually as part of their coccidian life cycle. In all other intermediate hosts, however, bradyzoites differentiate exclusively to tachyzoites, and disseminate extraintestinally to many cell types. Both merozoites and tachyzoites undergo rapid asexual population expansion, yet possess different effector fates with respect to the cells and tissues they develop in and the subsequent stages they differentiate into. Results: To determine whether merozoites utilize distinct suites of genes to attach, invade, and replicate within feline enterocytes, we performed comparative transcriptional profiling on purified tachyzoites and merozoites. We used high-throughput RNA-Seq to compare the merozoite and tachyzoite transcriptomes. 8323 genes were annotated with sequence reads across the two asexually replicating stages of the parasite life cycle. Metabolism was similar between the two replicating stages. However, significant stage-specific expression differences were measured, with 312 transcripts exclusive to merozoites versus 453 exclusive to tachyzoites. Genes coding for 177 predicted secreted proteins and 64 membrane-associated proteins were annotated as merozoite-specific. The vast majority of known dense-granule (GRA), microneme (MIC), and rhoptry (ROP) genes were not expressed in merozoites. In contrast, a large set of surface proteins (SRS) was expressed exclusively in merozoites. Conclusions: The distinct expression profiles of merozoites and tachyzoites reveal significant additional complexity within the T. gondii life cycle, demonstrating that merozoites are distinct asexual dividing stages which are uniquely adapted to their niche and biological purpose. C1 [Hehl, Adrian B.; Basso, Walter U.; Lippuner, Christoph; Ramakrishnan, Chandra; Walker, Robert A.; Deplazes, Peter] Univ Zurich, Inst Parasitol, CH-8057 Zurich, Switzerland. [Okoniewski, Michal] Funct Genom Ctr Zurich, CH-8057 Zurich, Switzerland. [Walker, Robert A.; Smith, Nicholas C.] James Cook Univ, Fac Med Hlth & Mol Sci, Queensland Trop Hlth Alliance Res Lab, Smithfield, Qld 4878, Australia. [Grigg, Michael E.] NIAID, Mol Parasitol Sect, Parasit Dis Lab, NIH, Bethesda, MD USA. RP Hehl, AB (reprint author), Univ Zurich, Inst Parasitol, Winterthurerstr 266a, CH-8057 Zurich, Switzerland. EM adrian.hehl@uzh.ch RI Walker, Robert/C-3202-2013; OI Walker, Robert/0000-0003-0032-9925; Hehl, Adrian/0000-0002-2110-4445; Lippuner, Christoph/0000-0003-2872-9381 FU Functional Genomics Center Zurich; University of Zurich; Intramural Research Program of the NIH; NIAID; Bellberry Foundation; Swiss Government Excellence Scholarship: Postdoctoral Scholarship from the Swiss Confederation FX We are grateful for the excellent technical assistance by Dr. Manuela Schnyder, Therese Michel and Armin Rudemann, and the support by the Functional Genomics Center Zurich. This work was supported by fellowships from the University of Zurich to WUB and CL, and in part by the Intramural Research Program of the NIH and NIAID (MEG). NCS is supported by a grant from the Bellberry Foundation. MEG is a scholar of the Canadian Institute for Advanced Research (CIFAR) Program for Integrated Microbial Biodiversity. RAW was supported by a Swiss Government Excellence Scholarship: Postdoctoral Scholarship from the Swiss Confederation. NR 85 TC 9 Z9 9 U1 2 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD FEB 13 PY 2015 VL 16 AR 66 DI 10.1186/s12864-015-1225-x PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CC2FS UT WOS:000350161200001 PM 25757795 ER EF