FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Nani, RR Shaum, JB Gorka, AP Schnermann, MJ AF Nani, Roger R. Shaum, James B. Gorka, Alexander P. Schnermann, Martin J. TI Electrophile-Integrating Smiles Rearrangement Provides Previously Inaccessible C4 '-O-Alkyl Heptamethine Cyanine Fluorophores SO ORGANIC LETTERS LA English DT Article ID DYES; FLUORESCENCE; CHROMOPHORE; PARADIGM; PROBES; AGENTS AB New synthetic methods to rapidly access useful fluorophores are needed to advance modern molecular imaging techniques. A new variant of the classical Smiles rearrangement is reported that enables the efficient synthesis of previously inaccessible C4'-O-alkyl heptamethine cyanines. The key reaction involves N- to O- transposition with selective electrophile incorporation on nitrogen. A representative fluorophore exhibits excellent resistance to thiol nucleophiles, undergoes productive bioconjugation, and can be used in near-IR fluorescence imaging applications. C1 [Nani, Roger R.; Shaum, James B.; Gorka, Alexander P.; Schnermann, Martin J.] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. RP Schnermann, MJ (reprint author), NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. EM martin.schnermann@nih.gov FU National Institutes of Health, Center for Cancer Research; National Cancer Institute, National Institutes of Health FX We thank Dr. Joseph Barchi (NIH/NCI) for NMR assistance and Dr. James Kelley (NTH/NCI) for mass spectrometric analysis. Dr. Sibaprasad Bhattacharyya (Leidos) is gratefully acknowledged for advice regarding the antibody conjugation reactions. We also acknowledge the Frederick CCR Flow Cytometry Core (Cancer and Inflammation Program, NCI, Frederick) for flow cytometry analysis. This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, and the National Cancer Institute, National Institutes of Health. NR 29 TC 7 Z9 7 U1 4 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 EI 1523-7052 J9 ORG LETT JI Org. Lett. PD JAN 16 PY 2015 VL 17 IS 2 BP 302 EP 305 DI 10.1021/ol503398f PG 4 WC Chemistry, Organic SC Chemistry GA AZ6LR UT WOS:000348331800034 PM 25562683 ER PT J AU Hristovski, D Dinevski, D Kastrin, A Rindflesch, TC AF Hristovski, Dimitar Dinevski, Dejan Kastrin, Andrej Rindflesch, Thomas C. TI Biomedical question answering using semantic relations SO BMC BIOINFORMATICS LA English DT Article ID CLINICAL QUESTIONS; MICROARRAY DATA; TEXT; INFORMATION; KNOWLEDGE; DOCTORS; DISEASE; NEED AB Background: The proliferation of the scientific literature in the field of biomedicine makes it difficult to keep abreast of current knowledge, even for domain experts. While general Web search engines and specialized information retrieval (IR) systems have made important strides in recent decades, the problem of accurate knowledge extraction from the biomedical literature is far from solved. Classical IR systems usually return a list of documents that have to be read by the user to extract relevant information. This tedious and time-consuming work can be lessened with automatic Question Answering (QA) systems, which aim to provide users with direct and precise answers to their questions. In this work we propose a novel methodology for QA based on semantic relations extracted from the biomedical literature. Results: We extracted semantic relations with the SemRep natural language processing system from 122,421,765 sentences, which came from 21,014,382 MEDLINE citations (i.e., the complete MEDLINE distribution up to the end of 2012). A total of 58,879,300 semantic relation instances were extracted and organized in a relational database. The QA process is implemented as a search in this database, which is accessed through a Web-based application, called SemBT (available at http://sembt.mf.uni-lj.si). We conducted an extensive evaluation of the proposed methodology in order to estimate the accuracy of extracting a particular semantic relation from a particular sentence. Evaluation was performed by 80 domain experts. In total 7,510 semantic relation instances belonging to 2,675 distinct relations were evaluated 12,083 times. The instances were evaluated as correct 8,228 times (68%). Conclusions: In this work we propose an innovative methodology for biomedical QA. The system is implemented as a Web-based application that is able to provide precise answers to a wide range of questions. A typical question is answered within a few seconds. The tool has some extensions that make it especially useful for interpretation of DNA microarray results. C1 [Hristovski, Dimitar] Univ Ljubljana, Fac Med, Inst Biostat & Med Informat, SI-1104 Ljubljana, Slovenia. [Kastrin, Andrej] Univ Maribor, Fac Med, SI-2000 Maribor, Slovenia. [Kastrin, Andrej] Fac Informat Studies, Novo Mesto, Slovenia. [Rindflesch, Thomas C.] US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. RP Hristovski, D (reprint author), Univ Ljubljana, Fac Med, Inst Biostat & Med Informat, Vrazov Trg 2, SI-1104 Ljubljana, Slovenia. EM dimitar.hristovski@mf.uni-lj.si OI Hristovski, Dimitar/0000-0001-6908-0246 FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 32 TC 5 Z9 5 U1 2 U2 10 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 JAN 16 PY 2015 VL 16 AR 6 DI 10.1186/s12859-014-0365-3 PG 14 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA AZ8PM UT WOS:000348477400001 PM 25592675 ER PT J AU van Beers, EJ Yang, YQ Raghavachari, N Tian, X Allen, DT Nichols, JS Mendelsohn, L Nekhai, S Gordeuk, VR Taylor, JG Kato, GJ AF van Beers, Eduard J. Yang, Yanqin Raghavachari, Nalini Tian, Xin Allen, Darlene T. Nichols, James S. Mendelsohn, Laurel Nekhai, Sergei Gordeuk, Victor R. Taylor, James G. Kato, Gregory J. TI Iron, Inflammation, and Early Death in Adults With Sickle Cell Disease SO CIRCULATION RESEARCH LA English DT Article DE gene expression; inflammation; iron; mortality; sickle cell disease ID PULMONARY-HYPERTENSION; HEMOLYTIC DISEASES; RISK-FACTORS; HEME; ACTIVATION; MORTALITY; HEMOCHROMATOSIS; MACROPHAGES; RECOGNITION; METABOLISM AB Rationale: Patients with sickle cell disease (SCD) have markers of chronic inflammation, but the mechanism of inflammation and its relevance to patient survival are unknown. Objective: To assess the relationship between iron, inflammation, and early death in SCD. Methods and Results: Using peripheral blood mononuclear cell transcriptome profile hierarchical clustering, we classified 24 patients and 10 controls in clusters with significantly different expression of genes known to be regulated by iron. Subsequent gene set enrichment analysis showed that many genes associated with the high iron cluster were involved in the toll-like receptor system (TLR4, TLR7, and TLR8) and inflammasome complex pathway (NLRP3, NLRC4, and CASP1). Quantitative PCR confirmed this classification and showed that ferritin light chain, TLR4, and interleukin-6 expression were >100-fold higher in patients than in controls (P<0.001). Further linking intracellular iron and inflammation, 14 SCD patients with a ferroportin Q248H variant that causes intracellular iron accumulation had significantly higher levels of interleukin-6 and C-reactive protein compared with 14 matched SCD patients with the wild-type allele (P<0.05). Finally, in a cohort of 412 patients followed for a median period of 47 months (interquartile range, 24-82), C-reactive protein was strongly and independently associated with early death (hazard ratio, 3.0; 95% confidence interval, 1.7-5.2; P<0.001). Conclusions: Gene expression markers of high intracellular iron in patients with SCD are associated with markers of inflammation and mortality. The results support a model in which intracellular iron promotes inflammatory pathways, such as the TLR system and the inflammasome, identifying important new pathways for additional investigation. C1 [van Beers, Eduard J.; Allen, Darlene T.; Nichols, James S.; Mendelsohn, Laurel; Taylor, James G.; Kato, Gregory J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Yang, Yanqin; Raghavachari, Nalini] NHLBI, Genom Core Facil, NIH, Bethesda, MD 20892 USA. [Tian, Xin] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Nekhai, Sergei] Howard Univ, Dept Med, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Gordeuk, Victor R.] Univ Illinois, Ctr Comprehens Sickle Cell, Dept Med, Sect Hematol Oncol, Chicago, IL USA. [Kato, Gregory J.] Univ Pittsburgh, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15260 USA. [Kato, Gregory J.] Univ Pittsburgh, Heart Lung Blood & Vasc Med Inst, Pittsburgh, PA 15260 USA. RP Kato, GJ (reprint author), 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 National Heart, Lung and Blood Institute Division of Intramural Research [1ZIAHL006012-02, 1 ZIA HL006013-03, 1 ZIA HL006023-03]; Novartis FX This research was funded by the National Heart, Lung and Blood Institute Division of Intramural Research (1ZIAHL006012-02, 1 ZIA HL006013-03, and 1 ZIA HL006023-03). E.J. van Beers received financial research support from Novartis to the University of Amsterdam. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication. NR 53 TC 9 Z9 9 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JAN 16 PY 2015 VL 116 IS 2 BP 298 EP U255 DI 10.1161/CIRCRESAHA.116.304577 PG 19 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AZ0MI UT WOS:000347939000015 PM 25378535 ER PT J AU Penaloza-MacMaster, P Barber, DL Wherry, EJ Provine, NM Teigler, JE Parenteau, L Blackmore, S Borducchi, EN Larocca, RA Yates, KB Shen, H Haining, WN Sommerstein, R Pinschewer, DD Ahmed, R Barouch, DH AF Penaloza-MacMaster, Pablo Barber, Daniel L. Wherry, E. John Provine, Nicholas M. Teigler, Jeffrey E. Parenteau, Lily Blackmore, Stephen Borducchi, Erica N. Larocca, Rafael A. Yates, Kathleen B. Shen, Hao Haining, W. Nicholas Sommerstein, Rami Pinschewer, Daniel D. Ahmed, Rafi Barouch, Dan H. TI Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection SO SCIENCE LA English DT Article ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; CHRONIC VIRAL-INFECTION; CD8-T-CELL MEMORY; CD4-T-CELL HELP; CD8(+); RESPONSES; PERSISTENCE; EPITOPE; IDENTIFICATION; ACTIVATION AB CD4 T cells promote innate and adaptive immune responses, but how vaccine-elicited CD4 T cells contribute to immune protection remains unclear. We evaluated whether induction of virus-specific CD4 T cells by vaccination would protect mice against infection with chronic lymphocytic choriomeningitis virus (LCMV). Immunization with vaccines that selectively induced CD4 T cell responses resulted in catastrophic inflammation and mortality after challenge with a persistent strain of LCMV. Immunopathology required antigen-specific CD4 T cells and was associated with a cytokine storm, generalized inflammation, and multi-organ system failure. Virus-specific CD8 T cells or antibodies abrogated the pathology. These data demonstrate that vaccine-elicited CD4 T cells in the absence of effective antiviral immune responses can trigger lethal immunopathology. C1 [Penaloza-MacMaster, Pablo; Provine, Nicholas M.; Teigler, Jeffrey E.; Parenteau, Lily; Blackmore, Stephen; Borducchi, Erica N.; Larocca, Rafael A.; Barouch, Dan H.] Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Barber, Daniel L.] NIAID, Lab Parasit Dis, Bethesda, MD 20892 USA. [Wherry, E. John; Shen, Hao] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Wherry, E. John; Shen, Hao] Univ Penn, Inst Immunol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Yates, Kathleen B.; Haining, W. Nicholas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Sommerstein, Rami; Pinschewer, Daniel D.] Univ Geneva, WHO Collaborating Ctr Vaccine Immunol, Dept Pathol & Immunol, CH-1211 Geneva, Switzerland. [Pinschewer, Daniel D.] Univ Basel, Div Expt Virol, Dept Biomed Haus Peterspl, CH-4009 Basel, Switzerland. [Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Barouch, Dan H.] Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. RP Barouch, DH (reprint author), Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu OI Sommerstein, Rami/0000-0003-1011-6878 FU NIH [AI007245, AI07387, AI078526, AI096040, AI030048]; Bill and Melinda Gates Foundation [OPP1033091]; Swiss National Science Foundation [310030_149340/1]; European Research Council; Ragon Institute; NIAID Intramural Research Program FX We thank A. Wieland, M. Rasheed, A. Kamphorst, K. Araki, S. Crotty, B. Walker, C. Bricault, P. Abbink, and F. Ball for generous advice, assistance, and reagents. The data presented in this manuscript are tabulated in the main paper and the supplementary materials. Supported by NIH grants AI007245 and AI07387 (P.P.M.), AI078526 and AI096040 (D.H.B.), and AI030048 (R.A.); Bill and Melinda Gates Foundation grant OPP1033091 (D.H.B.); Swiss National Science Foundation grant 310030_149340/1 (D.D.P.); the European Research Council (D.D.P.) the Ragon Institute (D.H.B.); and the NIAID Intramural Research Program (D.L.B.). Gene expression data have been uploaded to GEO (accession no. GSE63825). The authors declare no financial conflicts of interest. NR 29 TC 13 Z9 13 U1 0 U2 16 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JAN 16 PY 2015 VL 347 IS 6219 BP 278 EP 283 DI 10.1126/science.aaa2148 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AZ0DA UT WOS:000347915300037 PM 25593185 ER PT J AU Natarajan, P Punta, M Kumar, A Yeh, AP Godzik, A Aravind, L AF Natarajan, Padmaja Punta, Marco Kumar, Abhinav Yeh, Andrew P. Godzik, Adam Aravind, L. TI Structure and sequence analyses of Bacteroides proteins BVU_4064 and BF1687 reveal presence of two novel predominantly-beta domains, predicted to be involved in lipid and cell surface interactions SO BMC BIOINFORMATICS LA English DT Article DE DUF3869; DUF3870; Domain of unknown function; Protein structure; Beta-sandwich; Membrane-associated protein; Transthyretin superfamily; Bacterial pore-forming toxins ID HUMAN MICROBIOME; SIGNAL PEPTIDES; GUT MICROBIOME; DIVERSITY; SERVER; PORE; AEROLYSIN; SOFTWARE; BACTERIA; DISEASE AB Background: N-terminal domains of BVU_4064 and BF1687 proteins from Bacteroides vulgatus and Bacteroides fragilis respectively are members of the Pfam family PF12985 (DUF3869). Proteins containing a domain from this family can be found in most Bacteroides species and, in large numbers, in all human gut microbiome samples. Both BVU_4064 and BF1687 proteins have a consensus lipobox motif implying they are anchored to the membrane, but their functions are otherwise unknown. The C-terminal half of BVU_4064 is assigned to protein family PF12986 (DUF3870); the equivalent part of BF1687 was unclassified. Results: Crystal structures of both BVU_4064 and BF1687 proteins, solved at the JCSG center, show strikingly similar three-dimensional structures. The main difference between the two is that the two domains in the BVU_4064 protein are connected by a short linker, as opposed to a longer insertion made of 4 helices placed linearly along with a strand that is added to the C-terminal domain in the BF1687 protein. The N-terminal domain in both proteins, corresponding to the PF12985 (DUF3869) domain is a beta-sandwich with pre-albumin-like fold, found in many proteins belonging to the Transthyretin clan of Pfam. The structures of C-terminal domains of both proteins, corresponding to the PF12986 (DUF3870) domain in BVU_4064 protein and an unclassified domain in the BF1687 protein, show significant structural similarity to bacterial pore-forming toxins. A helix in this domain is in an analogous position to a loop connecting the second and third strands in the toxin structures, where this loop is implicated to play a role in the toxin insertion into the host cell membrane. The same helix also points to the groove between the N- and C-terminal domains that are loosely held together by hydrophobic and hydrogen bond interactions. The presence of several conserved residues in this region together with these structural determinants could make it a functionally important region in these proteins. Conclusions: Structural analysis of BVU_4064 and BF1687 points to possible roles in mediating multiple interactions on the cell-surface/extracellular matrix. In particular the N-terminal domain could be involved in adhesive interactions, the C-terminal domain and the inter-domain groove in lipid or carbohydrate interactions. C1 [Natarajan, Padmaja; Kumar, Abhinav; Yeh, Andrew P.; Godzik, Adam] Joint Ctr Struct Gen, San Diego, CA USA. [Natarajan, Padmaja; Godzik, Adam] Sanford Burnham Med Res Inst, Program Bioinformat & Syst Biol, La Jolla, CA USA. [Punta, Marco] Wellcome Trust Genome Campus, European Mol Biol Lab, European Bioinformat Inst, Hinxton CB10 1SD, Cambs, England. [Kumar, Abhinav; Yeh, Andrew P.] SLAC Natl Accelerator Lab, Stanford Synchrotron Radiat Lightsource, Menlo Pk, CA 94025 USA. [Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bldg 38A, Bethesda, MD 20894 USA. RP Natarajan, P (reprint author), Joint Ctr Struct Gen, San Diego, CA USA.; Natarajan, P (reprint author), Sanford Burnham Med Res Inst, Program Bioinformat & Syst Biol, La Jolla, CA USA.; Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bldg 38A, Bethesda, MD 20894 USA. EM pnatarajan@sanfordburnham.org; aravind@ncbi.nlm.nih.gov OI Godzik, Adam/0000-0002-2425-852X FU Wellcome Trust [WT077044/Z/05/Z]; Howard Hughes Medical Institute; NIH [U54 GM094586]; National Science Foundation [IIS-0646708, IIS-1153617]; U.S. Department of Energy, Office of Basic Energy Sciences [DE-AC02-76SF00515]; DOE Office of Biological and Environmental Research; National Institutes of Health, National Institute of General Medical Sciences [P41GM103393] FX Wellcome Trust (grant numbers WT077044/Z/05/Z); Howard Hughes Medical Institute (R.D.F.); NIH U54 GM094586; National Science Foundation (IIS-0646708 and IIS-1153617). Funding for open access charge: Wellcome Trust (grant numbers WT077044/Z/05/Z). Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of DOE, NSF, NIGMS, NCRR or NIH. NR 52 TC 1 Z9 1 U1 0 U2 1 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 JAN 16 PY 2015 VL 16 AR 7 DI 10.1186/s12859-014-0434-7 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DD0KF UT WOS:000369608200001 PM 25592227 ER PT J AU Ouyang, M Su, WJ Xiao, L Rao, JN Jiang, LP Li, YW Turner, DJ Gorospe, M Wang, JY AF Ouyang, Miao Su, Weijie Xiao, Lan Rao, Jaladanki N. Jiang, Liping Li, Yanwu Turner, Douglas J. Gorospe, Myriam Wang, Jian-Ying TI Modulation by miR-29b of intestinal epithelium homoeostasis through the repression of menin translation SO BIOCHEMICAL JOURNAL LA English DT Article DE intestinal epithelial cell; intestinal epithelium homoeostasis; menin; microRNA; post-transcriptional regulation ID BINDING PROTEIN HUR; MESSENGER-RNA STABILITY; TUMOR-SUPPRESSOR MENIN; C-MYC EXPRESSION; POLYAMINE DEPLETION; GENE-EXPRESSION; COMPETITIVE-BINDING; CELL-PROLIFERATION; TRANSCRIPTION; APOPTOSIS AB Menin regulates distinct cellular functions by regulating gene transcription through its interaction with partner transcription factors, but the exact mechanisms that controlmenin levels remain largely unknown. In the present study we report that Men1 mRNA, encoding menin, is a novel target of miR-29b and that miR-29b/Men1 mRNA association regulates menin expression post-transcriptionally in rat intestinal epithelial cells (IECs). Overexpression of a miR-29b precursor lowered the levels of Men1 mRNA modestly, but reduced new synthesis of menin robustly; conversely, antagonism of miR-29b enhanced menin protein synthesis and steady-state levels. The repressive effect of miR-29b on menin expression was mediated through a single binding site in the coding region of Men1 mRNA, because point mutation of this site prevented miR-29b-induced repression of menin translation. Increasing cellular polyamines due to overexpression of ornithine decarboxylase (ODC) enhanced menin translation by reducing miR-29b, whereas polyamine depletion by inhibiting ODC increased it, thus suppressing menin expression. Moreover, an increase in menin abundance in an miR-29b-silenced population of IECs led to increased sensitivity to apoptosis, which was prevented by silencing menin. These findings indicate that miR-29b represses translation of Men1 mRNA, in turn affecting intestinal epithelial homoeostasis by altering IEC apoptosis. C1 [Ouyang, Miao; Su, Weijie; Xiao, Lan; Rao, Jaladanki N.; Jiang, Liping; Li, Yanwu; Turner, Douglas J.; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. [Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Ouyang, Miao; Su, Weijie; Xiao, Lan; Rao, Jaladanki N.; Jiang, Liping; Li, Yanwu; Turner, Douglas J.; Wang, Jian-Ying] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Gorospe, Myriam] Natl Inst Aging IRP, Genet Lab, NIH, Baltimore, MD USA. RP Wang, JY (reprint author), Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. EM jwang@smail.umaryland.edu FU US Department of Veterans Affairs; National Institutes of Health [DK57819, DK61972, DK68491]; National Institute on Aging - Intramural Research Program, National Institutes of Health FX This work was supported by Merit Review Awards (to J.-Y.W., J.N.R. and D.J.T.) from the US Department of Veterans Affairs and by grants from National Institutes of Health (DK57819, DK61972 and DK68491 to J.-Y.W.). M.G. is supported by the National Institute on Aging - Intramural Research Program, National Institutes of Health. J-Y.W. is a Senior Research Career Scientist, Biomedical Laboratory Research and Development Service, US Department of Veterans Affairs. NR 58 TC 5 Z9 5 U1 0 U2 2 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD JAN 15 PY 2015 VL 465 BP 315 EP 323 DI 10.1042/BJ20141028 PN 2 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CE2XR UT WOS:000351685700012 PM 25317587 ER PT J AU Schick, UM Auer, PL Bis, JC Lin, HH Wei, P Pankrate, N Lange, LA Brody, J Stitziel, NO Kim, D Carlson, CS Fornage, M Haessler, J Hsu, L Jackson, RD Kooperberg, C Leal, SM Psaty, BM Boerwinkle, E Tracy, R Ardissino, D Shah, S Willer, C Loos, R Melander, O Mcpherson, R Hovingh, K Reilly, M Watkins, H Girelli, D Fontanillas, P Chasman, DI Gabriel, SB Gibbs, R Nickerson, DA Kathiresan, S Peters, U Dupuis, J Wilson, JG Rich, SS Morrison, AC Benjamin, EJ Gross, MD Reiner, AP AF Schick, Ursula M. Auer, Paul L. Bis, Joshua C. Lin, Honghuang Wei, Peng Pankrate, Nathan Lange, Leslie A. Brody, Jennifer Stitziel, Nathan O. S. Kim, Daniel Carlson, Christopher S. Fornage, Myriam Haessler, Jeffery Hsu, Li Jackson, Rebecca D. Kooperberg, Charles Leal, Suzanne M. Psaty, Bruce M. Boerwinkle, Eric Tracy, Russell Ardissino, Diego Shah, Svati Willer, Cristen Loos, Ruth Melander, Olle Mcpherson, Ruth Hovingh, Kees Reilly, Muredach Watkins, Hugh Girelli, Domenico Fontanillas, Pierre Chasman, Daniel I. Gabriel, Stacey B. Gibbs, Richard Nickerson, Deborah A. Kathiresan, Sekar Peters, Ulrike Dupuis, Josee Wilson, James G. Rich, Stephen S. Morrison, Alanna C. Benjamin, Emelia J. Gross, Myron D. Reiner, Alex P. CA Cohorts Heart Aging Res Genomic Ep Natl Heart Lung Blood Inst GO Exom TI Association of exome sequences with plasma C-reactive protein levels in > 9000 participants SO HUMAN MOLECULAR GENETICS LA English DT Article ID CORONARY-HEART-DISEASE; GENOME-WIDE ASSOCIATION; DE-NOVO MUTATIONS; GENETIC-VARIATION; MENDELIAN RANDOMIZATION; CARDIOVASCULAR-DISEASE; LDL-CHOLESTEROL; CRP LEVELS; METABOLIC-SYNDROME; AFRICAN-AMERICANS AB C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in 25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 x 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 x 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-epsilon 2 rs7214 with higher CRP levels. At the exome-wide significance level (P<5.0 x 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P <= 6.8 x 10(-4)) and in retinoic acid receptor-related orphan receptor alpha (RORA) in AAs (P = 1.7 x 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 x 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels. C1 [Schick, Ursula M.; Auer, Paul L.; Carlson, Christopher S.; Haessler, Jeffery; Hsu, Li; Kooperberg, Charles; Peters, Ulrike; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Auer, Paul L.] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Bis, Joshua C.; Brody, Jennifer] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Lin, Honghuang; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Wei, Peng; Fornage, Myriam; Boerwinkle, Eric; Morrison, Alanna C.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Brown Fdn, Houston, TX 77030 USA. [Pankrate, Nathan; Gross, Myron D.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Lange, Leslie A.] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Med, Cardiovasc Div, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63110 USA. [S. Kim, Daniel; Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98105 USA. [Hsu, Li] Univ Washington, Dept Biostat, Seattle, WA 98105 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98105 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA 98105 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98105 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98105 USA. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Leal, Suzanne M.] Baylor Coll Med, Dept Mol & Human Genet, Ctr Stat Genet, Houston, TX 77030 USA. [Boerwinkle, Eric; Gibbs, Richard] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Tracy, Russell] Univ Vermont, Dept Biochem, Burlington, VT 05401 USA. [Tracy, Russell] Univ Vermont, Dept Pathol, Burlington, VT 05401 USA. [Ardissino, Diego] Azienda Osped Univ Parma, Div Cardiol, Parma, Italy. [Shah, Svati] Duke Univ, Dept Med, Div Cardiol, Durham, NC USA. [Shah, Svati] Duke Univ, Ctr Human Genet, Durham, NC USA. [Willer, Cristen] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Willer, Cristen] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Willer, Cristen] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Loos, Ruth] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Loos, Ruth] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Melander, Olle] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Mcpherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON, Canada. [Hovingh, Kees] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Hovingh, Kees] Univ Amsterdam, Acad Med Ctr, Dept Expt Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Reilly, Muredach] Univ Penn, Perleman Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Reilly, Muredach] Univ Penn, Perleman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Cardiovasc Med, Oxford, England. [Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Girelli, Domenico] Univ Verona, Sch Med, Dept Med, I-37100 Verona, Italy. [Fontanillas, Pierre; Gabriel, Stacey B.; Kathiresan, Sekar] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Chasman, Daniel I.] Brigham & Womens Hosp, Div Preventat Med, Ctr Cardiovasc Dis Prevent, Boston, MA 02115 USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Dupuis, Josee; Benjamin, Emelia J.] Boston Univ, NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Rich, Stephen S.] Univ Virginia, Dept Publ Hlth Sci, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. RP Reiner, AP (reprint author), 1100 Fairview Ave N M3-A410, Seattle, WA 98109 USA. EM apreiner@u.washington.edu OI Lin, Honghuang/0000-0003-3043-3942; Stitziel, Nathan/0000-0002-4963-8211; Benjamin, Emelia/0000-0003-4076-2336; Watkins, Hugh/0000-0002-5287-9016 FU NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926]; NIH [5RC2HL 102419, U01DK085526]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268 201100007C, HHSN268201100008C, HHSN268201100009C, HHSN2682011000010C, HHSN2682011000011C, HHSN 2682011000012C]; Boston University [N01-HC-25195]; Affymetrix, Inc. [N02-HL-6-4278]; National Institutes on Aging (NIA) [AG023629]; National Cancer Institute [R25CA094880]; National Heart, Lung, and Blood Institute (NHLBI). [HHSN268201200036C, HHSN268 200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756, R01HL071862]; [R01HL087641]; [R01HL59367]; [R01HL 086694] FX 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). Funding support for 'Building on GWAS for NHLBI-diseases: the US CHARGE consortium' was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL 102419). Data for 'Building on GWAS for NHLBI-diseases: the US CHARGE consortium' were provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study, L. Adrienne Cupples, principal investigator for the Framingham Heart Study, and Bruce Psaty, principal investigator for the Cardiovascular Health Study. Sequencing was carried out at the Baylor Genome Center (U54 HG003273). The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268 201100007C, HHSN268201100008C, HHSN268201100009C, HHSN2682011000010C, HHSN2682011000011C and HHSN 2682011000012C), R01HL087641, R01HL59367 and R01HL 086694. The authors thank the staff and participants of the ARIC study for their important contributions. The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195), and its contract with Affymetrix, Inc., for genome-wide genotyping services (contract no. N02-HL-6-4278), for quality control by Framingham Heart Study investigators using genotypes in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA) computing resources at Boston University Medical Campus. This CHS research was supported by contracts HHSN268201200036C, HHSN268 200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086 and grants HL080295, HL087652, HL105756 from the National Heart, Lung, and Blood Institute (NHLBI) with additional contribution from National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institutes on Aging (NIA). A full list of CHS principal investigators and institutions can be found at CHS-NHLBI.org. Supported in part by grant R25CA094880 from the National Cancer Institute and by R01HL071862 from NHLBI. The Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) project was supported by NIH grant U01DK085526. NR 87 TC 9 Z9 9 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JAN 15 PY 2015 VL 24 IS 2 BP 559 EP 571 DI 10.1093/hmg/ddu450 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CC1WV UT WOS:000350137000021 PM 25187575 ER PT J AU Li, J Lange, LA Duan, Q Lu, YR Singleton, AB Zonderman, AB Evans, MK Li, Y Taylor, HA Willis, MS Nalls, M Wilson, JG Lange, EM AF Li, Jin Lange, Leslie A. Duan, Qing Lu, Yurong Singleton, Andrew B. Zonderman, Alan B. Evans, Michele K. Li, Yun Taylor, Herman A. Willis, Monte S. Nalls, Mike Wilson, James G. Lange, Ethan M. TI Genome-wide admixture and association study of serum iron, ferritin, transferrin saturation and total iron binding capacity in African Americans SO HUMAN MOLECULAR GENETICS LA English DT Article ID CATARACT; POPULATION; HEMOGLOBIN; DEFICIENCY; VARIANTS; MUTATION; TMPRSS6; FAMILY; STORES; DOMAIN AB Iron is an essential component of many important proteins and enzymes, including hemoglobin, which is responsible for carrying oxygen to the cells. African Americans (AAs) have a greater prevalence of iron deficiency compared with European Americans. We conducted genome-wide admixture-mapping and association studies for serum iron, serum ferritin, transferrin saturation (SAT) and total iron binding capacity (TIBC) in 2347 AAs participating in the Jackson Heart Study (JHS). Follow-up replication analyses for JHS iron-trait associated SNPs were conducted in 329 AA participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span study (HANDLS). Higher estimated proportions of global African ancestry were significantly associated with lower levels of iron (P = 2.4 x 10(-5)), SAT (P = 0.0019) and TIBC (P = 0.042). We observed significant associations (P < 5 x 10(-8)) between serum TIBC levels and two independent SNPs around TFon chromosome 3, the first report of a genome-wide significant second independent signal in this region, and SNPs near two novel genes: HDGFL1 on chromosome 6 and MAF on chromosome 16. We also observed significant associations between ferritin levels and SNPs near GAB3 on chromosome X. We replicated our two independent associations at TFand our association at GAB3 in HANDLS. Our study provides evidence for both shared and unique genetic risk factors that are associated with iron-related measures in AAs. The top two variants in TFexplain 11.2% of the total variation in TIBC levels in AAs after accounting forage, gender, body mass index and background ancestry. C1 [Li, Jin; Lange, Leslie A.; Duan, Qing; Lu, Yurong; Li, Yun; Lange, Ethan M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Li, Yun; Lange, Ethan M.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Willis, Monte S.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Singleton, Andrew B.; Nalls, Mike] NIA, Lab Neurogenet, NIH, Bethesda, MD 21225 USA. [Zonderman, Alan B.] NIA, Lab Personal & Cognit, NIH, Bethesda, MD 21225 USA. [Evans, Michele K.] NIA, Hlth Dispar Unit, NIH, Bethesda, MD 21225 USA. [Taylor, Herman A.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Taylor, Herman A.] Jackson State Univ, Sch Hlth Sci, Jackson, MS 39217 USA. [Taylor, Herman A.] Tougaloo Coll, Div Nat Sci, Tougaloo, MS 39174 USA. RP Lange, EM (reprint author), Univ N Carolina, Dept Genet, 5111 Genet Med Bldg, Chapel Hill, NC 27599 USA. EM elange@med.unc.edu RI Singleton, Andrew/C-3010-2009; OI Zonderman, Alan B/0000-0002-6523-4778 FU National Heart, Lung, and Blood Institute; National Institute on Minority Health and Health Disparities; National Institute on Biomedical Imaging and Bioengineering [HHSN268201300046C, HHSN268201300047C, HHSN26820 1300048C, HHSN268201300049C, HHSN268201300050C]; National Institute of Health, National Institute on Aging; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; [R01HG006703] FX JHS is supported by the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities, with additional support from the National Institute on Biomedical Imaging and Bioengineering (grant numbers HHSN268201300046C, HHSN268201300047C, HHSN26820 1300048C, HHSN268201300049C, HHSN268201300050C). HANDLS is supported by the Intramural Research Program of the National Institute of Health, National Institute on Aging and the National Center on Minority Health and Health Disparities (project # Z01-AG000513 and human subjects protocol # 2009-149). E.M.L., Y.L. and Q.D. are partially supported by R01HG006703. NR 36 TC 5 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JAN 15 PY 2015 VL 24 IS 2 BP 572 EP 581 DI 10.1093/hmg/ddu454 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CC1WV UT WOS:000350137000022 PM 25224454 ER PT J AU Kottyan, LC Zoller, EE Bene, J Lu, XM Kelly, JA Rupert, AM Lessard, CJ Vaughn, SE Marion, M Weirauch, MT Namjou, B Adler, A Rasmussen, A Glenn, S Montgomery, CG Hirschfield, GM Xie, G Coltescu, C Amos, C Li, H Ice, JA Nath, SK Mariette, X Bowman, S Rischmueller, M Lester, S Brun, JG Goransson, LG Harboe, E Omdal, R Cunninghame-Graham, DS Vyse, T Miceli-Richard, C Brennan, MT Lessard, JA Wahren-Herlenius, M Kvarnstrom, M Illei, GG Witte, T Jonsson, R Eriksson, P Nordmark, G Ng, WF Anaya, JM Rhodus, NL Sega, BM Merrill, JT James, JA Guthridge, JM Scofield, RH Alarcon-Riquelme, M Bae, SC Boackle, SA Criswell, LA Gilkeson, G Kamen, DL Jacob, CO Kimberly, R Brown, E Edberg, J Alarcon, GS Reveille, JD Vila, LM Petri, M Ramsey-Goldman, R Freedman, BI Niewold, T Stevens, AM Tsao, BP Ying, J Mayes, MD Gorlova, OY Wakeland, W Radstake, T Martin, E Martin, J Siminovitch, K Sivils, KLM Gaffney, PM Langefeld, CD Harley, JB Kaufman, KM AF Kottyan, Leah C. Zoller, Erin E. Bene, Jessica Lu, Xiaoming Kelly, Jennifer A. Rupert, Andrew M. Lessard, Christopher J. Vaughn, Samuel E. Marion, Miranda Weirauch, Matthew T. Namjou, Bahram Adler, Adam Rasmussen, Astrid Glenn, Stuart Montgomery, Courtney G. Hirschfield, Gideon M. Xie, Gang Coltescu, Catalina Amos, Chris Li, He Ice, John A. Nath, Swapan K. Mariette, Xavier Bowman, Simon Rischmueller, Maureen Lester, Sue Brun, Johan G. Goransson, Lasse G. Harboe, Erna Omdal, Roald Cunninghame-Graham, Deborah S. Vyse, Tim Miceli-Richard, Corinne Brennan, Michael T. Lessard, James A. Wahren-Herlenius, Marie Kvarnstrom, Marika Illei, Gabor G. Witte, Torsten Jonsson, Roland Eriksson, Per Nordmark, Gunnel Ng, Wan-Fai Anaya, Juan-Manuel Rhodus, Nelson L. Sega, Barbara M. Merrill, Joan T. James, Judith A. Guthridge, Joel M. Scofield, R. Hal Alarcon-Riquelme, Marta Bae, Sang-Cheol Boackle, Susan A. Criswell, Lindsey A. Gilkeson, Gary Kamen, Diane L. Jacob, Chaim O. Kimberly, Robert Brown, Elizabeth Edberg, Jeffrey Alarcon, Graciela S. Reveille, John D. Vila, Luis M. Petri, Michelle Ramsey-Goldman, Rosalind Freedman, Barry I. Niewold, Timothy Stevens, Anne M. Tsao, Betty P. Ying, Jun Mayes, Maureen D. Gorlova, Olga Y. Wakeland, Ward Radstake, Timothy Martin, Ezequiel Martin, Javier Siminovitch, Katherine Sivils, Kathy L. Moser Gaffney, Patrick M. Langefeld, Carl D. Harley, John B. Kaufman, Kenneth M. CA UK Primary Sjogrens Syndrome Regis TI The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; PRIMARY BILIARY-CIRRHOSIS; INTERFERON REGULATORY FACTOR-5; IRF5 GENE POLYMORPHISMS; PRISTANE-INDUCED LUPUS; STRONG RISK-FACTOR; SUSCEPTIBILITY LOCI; TRANSCRIPTION FACTORS; DISTINCT POPULATIONS; JAPANESE POPULATION AB Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-value(meta) = 6 x 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3(P-values(EU) = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjogren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3. C1 [Kottyan, Leah C.; Zoller, Erin E.; Bene, Jessica; Lu, Xiaoming; Vaughn, Samuel E.; Weirauch, Matthew T.; Namjou, Bahram; Harley, John B.; Kaufman, Kenneth M.] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Div Rheumatol, Cincinnati, OH 45229 USA. [Rupert, Andrew M.; Weirauch, Matthew T.] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 USA. [Kottyan, Leah C.; Weirauch, Matthew T.; Harley, John B.; Kaufman, Kenneth M.] US Dept Vet Affairs Med Ctr, Cincinnati, OH USA. [Kelly, Jennifer A.; Lessard, Christopher J.; Adler, Adam; Rasmussen, Astrid; Glenn, Stuart; Montgomery, Courtney G.; Li, He; Ice, John A.; Nath, Swapan K.; Merrill, Joan T.; James, Judith A.; Guthridge, Joel M.; Scofield, R. Hal; Alarcon-Riquelme, Marta; Sivils, Kathy L. Moser; Gaffney, Patrick M.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Marion, Miranda; Langefeld, Carl D.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Marion, Miranda; Langefeld, Carl D.] Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC USA. [Freedman, Barry I.] Wake Forest Sch Med, Winston Salem, NC USA. [Hirschfield, Gideon M.] Univ Birmingham, NIHR Biomed Res Unit, Birmingham, W Midlands, England. [Xie, Gang; Siminovitch, Katherine] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Coltescu, Catalina] Toronto Western Hosp, Ctr Liver, Toronto, ON M5T 2S8, Canada. [Amos, Chris] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Hanover, NH 03755 USA. [Lessard, Christopher J.; Li, He] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [James, Judith A.; Scofield, R. Hal] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Mariette, Xavier; Miceli-Richard, Corinne] Hop Univ Paris Sud, Dept Rheumatol, INSERM U1012, Le Kremlin Bicetre, France. [Bowman, Simon] Univ Hosp Birmingham, Dept Rheumatol, Birmingham, W Midlands, England. [Rischmueller, Maureen; Lester, Sue] Queen Elizabeth Hosp, Adelaide, SA, Australia. [Lester, Sue] Univ Adelaide, Adelaide, SA, Australia. [Brun, Johan G.] Univ Bergen, Inst Internal Med, Bergen, Norway. [Jonsson, Roland] Univ Bergen, Gade Inst, Broegelmann Res Lab, Bergen, Norway. [Brun, Johan G.; Jonsson, Roland] Haukeland Hosp, Dept Rheumatol, N-5021 Bergen, Norway. [Goransson, Lasse G.; Harboe, Erna; Omdal, Roald] Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway. [Cunninghame-Graham, Deborah S.; Vyse, Tim] Kings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England. [Brennan, Michael T.] Carolinas Med Ctr, Dept Oral Med, Charlotte, NC 28203 USA. [Lessard, James A.] Valley Bone & Joint Clin, Grand Forks, ND USA. [Wahren-Herlenius, Marie; Kvarnstrom, Marika] Karolinska Inst, Dept Med, Stockholm, Sweden. [Illei, Gabor G.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Witte, Torsten] Hannover Med Sch, Hannover, Germany. [Eriksson, Per] Linkoping Univ, Fac Hlth Sci, Dept Rheumatol Clin & Expt Med, Linkoping, Sweden. [Nordmark, Gunnel] Uppsala Univ, Dept Med Sci, Rheumatol, Uppsala, Sweden. [Ng, Wan-Fai] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Anaya, Juan-Manuel] Univ Rosario, Ctr Autoimmune Dis Res CREA, Bogota, Colombia. [Rhodus, Nelson L.] Univ Minnesota, Sch Dent, Dept Oral Surg, Minneapolis, MN 55455 USA. [Sega, Barbara M.] Univ Minnesota, Sch Med, Div Rheumatol, Minneapolis, MN 55455 USA. [Scofield, R. Hal] Div Vet Affairs Med Ctr, Oklahoma City, OK USA. [Alarcon-Riquelme, Marta] Pfizer Univ Granada Junta Andalucia, Genom Invest Oncol GENYO, Granada, Spain. [Bae, Sang-Cheol] Hanyang Univ Hosp Rheumat Dis, Dept Rheumatol, Seoul, South Korea. [Boackle, Susan A.] Univ Colorado, Sch Med, Div Rheumatol, Aurora, CO USA. [Criswell, Lindsey A.] Univ Calif San Francisco, Div Rheumatol, Rosalind Russell Med Res Ctr Arthrit, San Francisco, CA 94143 USA. [Gilkeson, Gary; Kamen, Diane L.] Med Univ S Carolina, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Jacob, Chaim O.] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. [Kimberly, Robert; Brown, Elizabeth; Edberg, Jeffrey; Alarcon, Graciela S.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Div Rheumatol & Clin Immunogenet, Houston, TX 77030 USA. [Vila, Luis M.] Univ Puerto Rico, San Juan, PR 00936 USA. [Petri, Michelle] Johns Hopkins, Div Rheumatol, Baltimore, MD USA. [Ramsey-Goldman, Rosalind] Northwestern Univ, Div Rheumatol, Chicago, IL 60611 USA. [Niewold, Timothy] Mayo Clin, Div Rheumatol & Immunol, Rochester, MN USA. [Stevens, Anne M.] Univ Washington, Seattle, WA 98195 USA. [Stevens, Anne M.] Seattle Childrens Hosp, Seattle, WA USA. [Tsao, Betty P.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Ying, Jun; Mayes, Maureen D.; Gorlova, Olga Y.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Wakeland, Ward] Univ Texas Southwestern Med Sch, Dallas, TX USA. [Radstake, Timothy] Radboud Univ Nijmegen, Med Ctr, Dept Rheumatol, NL-6525 ED Nijmegen, Netherlands. [Martin, Ezequiel; Martin, Javier] Inst Parasitol & Biomed Lopez Neyra Avda, Granada, Spain. [Siminovitch, Katherine] Univ Toronto, Dept Med, Toronto, ON, Canada. RP Kottyan, LC (reprint author), Cincinnati Childrens Hosp, 3333 Burnet Ave,Mail Locat 15012, Cincinnati, OH 45229 USA. EM leah.kottyan@cchmc.org RI Hirschfield, Gideon/M-2143-2015; Witte, Torsten/B-5783-2016; Martin, Javier/B-8141-2008; Siminovitch, Katherine/K-1475-2013; Anaya, Juan-Manuel/J-1960-2016; OI Hirschfield, Gideon/0000-0002-6736-2255; Anaya, Juan-Manuel/0000-0002-6444-1249; Universidad del Rosario, Biblioteca/0000-0003-3491-9392; Kimberly, Robert/0000-0002-5330-3086; Niewold, Timothy/0000-0003-3532-6660; Wahren-Herlenius, Marie/0000-0002-0915-7245 FU National Institutes of Health [AI024717, AR042460, AI031584, DE015223, AR057172, AR043418, AR065626, AR049084, AI082714, AR052300, AR062277, AR060366]; U.S. Department of Defense [PR094002]; U.S. Department of Veterans Affairs [IMMA 9]; General Center Research Center [RR-000079]; Alliance for Lupus Research; Korea Healthcare technology RD Project; Ministry for Health and Welfare, Republic of Korea [HI12C1834]; Swedish Rheumatism Association; American College of Rheumatology Research and Education Foundation/Abbott Healthy Professional Graduate Student Preceptorship Award; Oklahoma Medical Research Foundation; Sjogren's Syndrome Foundation [4434]; Phileona Foundation; French Ministry of Health (PHRC) [2006-AOM06133]; Strategic Research Program at Helse Bergen; Western Norway Regional Health Authority; Broegelmann Foundation [TP03, WI 1031/6-1, KFO 250, Z1]; Medical Research Council (UK) [G0800629]; Northumberland, Tyne Wear CLRN; Canadian Institutes for Health Research [MOP74621]; Ontario Research Fund [REO-061]; PBC Society of Canada; Canadian Institutes of Health Research; Canada Research Chair; Sherman Family Chair in Genomic Medicine; National Institutes of Health. [AI094377, AR062755, AR30692, AR048940, RR026314, RR029882, 1RR025741, TR000165, AR 002138, AI070304, AR43727, AR0608040, AR058959, AR053483, DE018209-02, DE018209, RR020143, AI083194, RR027190, AI101934, GM103510] FX This work has been supported by National Institutes of Health grants and contracts (AI024717, AR042460, AI031584, DE015223, AR057172, AI083194, AR043418, AR065626, AR049084, AI082714, AR052300, AR062277, AR060366, AI094377, GM103510, RR020143, AR062755, AR30692, AR048940, RR027190, RR026314, RR029882, 1RR025741, TR000165, AR 002138, AI070304, AR43727, AR0608040, DE015223, AR058959, AR049084, AR053483 AI082714, DE018209-02, DE018209, RR020143, AI083194, RR027190, AI101934, and GM103510); the U.S. Department of Defense (PR094002); the U.S. Department of Veterans Affairs (IMMA 9); the General Center Research Center (RR-000079); Alliance for Lupus Research; the Korea Healthcare technology R&D Project; Ministry for Health and Welfare, Republic of Korea (HI12C1834); Mary Kirkland Scholar (J.B.H. and L.A.C.); the Swedish Rheumatism Association, American College of Rheumatology Research and Education Foundation/Abbott Healthy Professional Graduate Student Preceptorship Award 2009; Oklahoma Medical Research Foundation, Sjogren's Syndrome Foundation (4434); Phileona Foundation, French Ministry of Health (PHRC No2006-AOM06133); The Strategic Research Program at Helse Bergen, Western Norway Regional Health Authority and The Broegelmann Foundation (KFO 250, TP03, WI 1031/6-1", "KFO 250, Z1); Medical Research Council (UK G0800629); Northumberland, Tyne & Wear CLRN; the Canadian Institutes for Health Research (MOP74621); the Ontario Research Fund (REO-061); the PBC Society of Canada; Canadian Institutes of Health Research; and the Canada Research Chair and the Sherman Family Chair in Genomic Medicine. NR 75 TC 18 Z9 18 U1 2 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JAN 15 PY 2015 VL 24 IS 2 BP 582 EP 596 DI 10.1093/hmg/ddu455 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CC1WV UT WOS:000350137000023 PM 25205108 ER PT J AU Aka, PV Kemp, TJ Rabkin, CS Shiels, MS Polizzotto, MN Lauria, C Vitale, F Pinto, LA Goedert, JJ AF Aka, Peter V. Kemp, Troy J. Rabkin, Charles S. Shiels, Meredith S. Polizzotto, Mark N. Lauria, Carmela Vitale, Francesco Pinto, Ligia A. Goedert, James J. TI A Multiplex Panel of Plasma Markers of Immunity and Inflammation in Classical Kaposi Sarcoma SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE classical Kaposi sarcoma; IP-10; sIL-1RII; human herpesvirus 8 ID RISK-FACTORS AB Kaposi sarcoma (KS) risk is affected by perturbed immunity. Herein, we compared plasma from 15 human immunodeficiency virus (HIV)-negative classic KS cases to plasma from 29 matched controls, using a multiplex panel of immunity markers. Of 70 markers, CXCL10 (IP-10), sIL-1RII, sIL-2RA, and CCL3 (MIP-1A) were strongly and significantly associated with KS, after adjustment for age and smoking status. These and previous observations are consistent with a tumor-promoting role for these cytokines, particularly CXCL10, but the small sample size and case-control design preclude firm conclusions on KS risk or pathogenesis. Larger, well-designed prospective studies are needed to better assess the association of these markers with KS. C1 [Aka, Peter V.; Kemp, Troy J.; Rabkin, Charles S.; Shiels, Meredith S.; Pinto, Ligia A.; Goedert, James J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Polizzotto, Mark N.] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Lauria, Carmela] Lega Italiana Lotta Contro & Tumori Sez Ragusa, Ragusa, Italy. [Vitale, Francesco] Univ Palermo, Dipartimento Sci Promoz Salute & Materno Infantil, I-90133 Palermo, Italy. RP Goedert, JJ (reprint author), NCI, NIH, DCEG, Infect & Immunoepidemiol Branch, 9609 Med Ctr Dr,Rm 6E106 MSC 9704, Bethesda, MD 20892 USA. EM goedertj@mail.nih.gov FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health [Z01-CP-010214] FX This work was supported by the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (intramural research program Z01-CP-010214). NR 15 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2015 VL 211 IS 2 BP 226 EP 229 DI 10.1093/infdis/jiu410 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC3CC UT WOS:000350221000009 PM 25149762 ER PT J AU Ndour, PA Lopera-Mesa, TM Diakite, SAS Chiang, S Mouri, O Roussel, C Jaureguiberry, S Biligui, S Kendjo, E Claessens, A Ciceron, L Mazier, D Thellier, M Diakite, M Fairhurst, RM Buffet, PA AF Ndour, Papa Alioune Lopera-Mesa, Tatiana M. Diakite, Seidina A. S. Chiang, Serena Mouri, Oussama Roussel, Camille Jaureguiberry, Stephane Biligui, Sylvestre Kendjo, Eric Claessens, Antoine Ciceron, Liliane Mazier, Dominique Thellier, Marc Diakite, Mahamadou Fairhurst, Rick M. Buffet, Pierre A. TI Plasmodium falciparum Clearance Is Rapid and Pitting Independent in Immune Malian Children Treated With Artesunate for Malaria SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE malaria; Plasmodium falciparum; parasite clearance; artemisinin; pitting; acquired immunity; spleen ID PARASITE CLEARANCE; INFECTED ERYTHROCYTES; MEROZOITE ANTIGENS; ACQUIRED-IMMUNITY; RANDOMIZED-TRIAL; SURFACE-ANTIGEN; SPLEEN; ANTIBODIES; VACCINE; QUININE AB Background. In Plasmodium falciparum-infected patients treated with artemisinins, parasitemia declines through so-called pitting, an innate splenic process that transforms infected red blood cells (iRBCs) into once-infected RBCs (O-iRBCs). Methods. We measured pitting in 83 French travelers and 42 Malian children treated for malaria with artesunate. Results. In travelers, O-iRBCs peaked at 107.7% initial parasitemia. In Malian children aged 1.5-4 years, O-iRBCs peaked at higher concentrations than in children aged 9-13 years (91.60% vs 31.95%; P = .0097). The parasite clearance time in older children was shorter than in younger children (P = .0001), and the decline in parasitemia in children aged 1.5-4 years often started 6 hours after treatment initiation, a lag phase generally absent in infants and older children. A 6-hour lag phase in artificial pitting of artesunate-exposed iRBCs was also observed in vitro. The proportion of iRBCs recognized by autologous immunoglobulin G(IgG) correlated with the parasite clearance time (r = -0.501; P = .0006) and peak O-iRBC concentration (r = -0.420; P = .0033). Conclusions. Antimalarial immunity correlates with fast artemisinin-induced parasite clearance and low pitting rates. In nonimmune populations, artemisinin-induced P. falciparum clearance is related to pitting and starts after a 6-hour lag phase. In immune populations, passively and naturally acquired immune mechanisms operating faster than pitting may exist. This mechanism may mitigate the emergence of artemisinin-resistant P. falciparum in Africa. C1 [Ndour, Papa Alioune; Roussel, Camille; Biligui, Sylvestre; Kendjo, Eric; Ciceron, Liliane; Mazier, Dominique; Thellier, Marc; Buffet, Pierre A.] UPMC CR7, CIMI PARIS, INSERM U1135, CNRS ERL 8255, F-75651 Paris 13, France. [Ndour, Papa Alioune; Jaureguiberry, Stephane; Biligui, Sylvestre; Kendjo, Eric; Ciceron, Liliane; Mazier, Dominique; Thellier, Marc; Buffet, Pierre A.] Ctr Natl Reference Paludisme Site Pitie Salpetrie, Paris, France. [Ndour, Papa Alioune; Buffet, Pierre A.] Lab Excellence GR Ex, Paris, France. [Mouri, Oussama; Jaureguiberry, Stephane; Mazier, Dominique; Thellier, Marc; Buffet, Pierre A.] Hop La Pitie Salpetriere, AP HP, Serv Parasitol Mycol, Paris, France. [Mouri, Oussama; Jaureguiberry, Stephane; Mazier, Dominique; Thellier, Marc; Buffet, Pierre A.] Serv Malad Infect & Trop, Paris, France. [Lopera-Mesa, Tatiana M.; Chiang, Serena; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Diakite, Seidina A. S.; Diakite, Mahamadou] Univ Bamako, Malaria Res & Training Ctr, Fac Med Pharm & Odontostomatol, Bamako, Mali. [Claessens, Antoine] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh EH8 9YL, Midlothian, Scotland. RP Ndour, PA (reprint author), UPMC CR7, CIMI PARIS, INSERM U1135, CNRS ERL 8255, 47 Blvd Hop, F-75651 Paris 13, France. EM ndourmail@yahoo.fr OI Thellier, Marc/0000-0003-4867-2423; Claessens, Antoine/0000-0002-4277-0914; NDOUR, PAPA ALIOUNE/0000-0001-7203-9754 FU DIM Mal Inf Region Ile de France; Worldwide Antimalarial Resistance Network; National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bill and Melinda Gates Foundation; Follereau Foundation; INSERM-APHP France; University of Oxford FX This work was supported by the DIM Mal Inf Region Ile de France; the Worldwide Antimalarial Resistance Network; the Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health; the Bill and Melinda Gates Foundation (to P. A. N.); the Follereau Foundation (to L. C.); INSERM-APHP France (to S. J.); and the University of Oxford. NR 31 TC 17 Z9 17 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 JAN 15 PY 2015 VL 211 IS 2 BP 290 EP 297 DI 10.1093/infdis/jiu427 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC3CC UT WOS:000350221000017 PM 25183768 ER PT J AU Smiley, ST Singh, A Read, SW Sharma, OK Finzi, D Lane, C Rice, JS AF Smiley, Stephen T. Singh, Anjali Read, Sarah W. Sharma, Opendra K. Finzi, Diana Lane, Clifford Rice, Jeffrey S. TI Progress Toward Curing HIV Infections With Hematopoietic Stem Cell Transplantation SO CLINICAL INFECTIOUS DISEASES LA English DT Review DE HIV; transplantation; latency; reservoirs ID VERSUS-HOST-DISEASE; HUMAN-IMMUNODEFICIENCY-VIRUS; BONE-MARROW-TRANSPLANTATION; ANTIRETROVIRAL THERAPY; T-CELLS; REPLICATION; RESERVOIR; CCR5; CURE; CYCLOPHOSPHAMIDE AB Combination antiretroviral therapy can suppress human immunodeficiency virus (HIV) infection but cannot completely eradicate the virus. A major obstacle in the quest for a cure is the difficulty in targeting and measuring latently infected cells. To date, a single person seems to have been cured of HIV. Hematopoietic stem cell transplantation (HSCT) preceded this cancer patient's long-term sustained HIV remission, but researchers have been unable to replicate this cure, and the mechanisms that led to HIV remission remain to be established. In February 2014, the National Institute of Allergy and Infectious Diseases sponsored a workshop that provided a venue for in-depth discussion of whether HSCT could be exploited to cure HIV in cancer patients requiring such procedures. Participants also discussed how HSCT might be applied to a broader community of HIV-infected persons in whom the risks of HSCT currently outweigh the likelihood and benefits of HIV cure. C1 [Smiley, Stephen T.; Singh, Anjali; Read, Sarah W.; Sharma, Opendra K.; Finzi, Diana] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Lane, Clifford] NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Rice, Jeffrey S.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. RP Smiley, ST (reprint author), NIAID, Div Aids, 5601 Fishers Lane,Room 9E45, Bethesda, MD 20892 USA. EM stephen.smiley@nih.gov NR 40 TC 2 Z9 2 U1 1 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JAN 15 PY 2015 VL 60 IS 2 BP 292 EP 297 DI 10.1093/cid/ciu766 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CB6TR UT WOS:000349760100021 PM 25273081 ER PT J AU Miller, Y Ma, BY Nussinov, R AF Miller, Yifat Ma, Buyong Nussinov, Ruth TI Polymorphism in Self-Assembly of Peptide-Based beta-Hairpin Contributes to Network Morphology and Hydrogel Mechanical Rigidity SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID PARTICLE MESH EWALD; MOLECULAR-DYNAMICS; DESIGNED PEPTIDE; POTENTIAL FUNCTIONS; LIQUID WATER; FLOW-CONTROL; PROTEINS; AGGREGATION; FIBRILS; RELEASE AB Hydrogels are proving to be an excellent class of materials for biomedical applications. The molecular self-assembly of designed MAX1 beta-hairpin peptides into fibrillar networks has emerged as a novel route to form responsive hydrogels. Herein, computational modeling techniques are used to investigate the relative arrangements of individual hairpins within the fibrils that constitute the gel. The modeling provides insight into the morphology of the fibril network, which defines the gels mechanical properties. Our study suggests polymorphic arrangements of the hairpins within the fibrils; however, the relative populations and the relative conformational energies of the polymorphic arrangements show a preference toward an arrangement of hairpins where their turn regions are not capable of forming intermolecular interaction. Repulsive intramolecular electrostatic interactions appear to dictate the formation of fibrils with shorter, rather than longer, persistent lengths. These repulsive intramolecular interactions also disfavor the formation of fibril entanglements. Taken together, the modeling predicts that MAX1 forms a network containing a large number of branch points, a network morphology supported by the formation of short fibril segments. We posit that, under static conditions, the preferred branched structures of the MAX1 peptide assembly result in a cross-linked hydrogel organization. At the same time, the shear stress leads to short fibrillar structures, thus fluidic hydrogel states. C1 [Miller, Yifat] Ben Gurion Univ Negev, Dept Chem, IL-84105 Beer Sheva, Israel. [Miller, Yifat] Ben Gurion Univ Negev, Ilse Katz Inst Nanoscale Sci & Technol, IL-84105 Beer Sheva, Israel. [Ma, Buyong; Nussinov, Ruth] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Miller, Y (reprint author), Ben Gurion Univ Negev, Dept Chem, IL-84105 Beer Sheva, Israel. EM ymiller@bgu.ac.il; NussinoR@hekix.nih.gov RI 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]; Israel Binational Science Foundation [2011128]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Yoav Atsmon-Raz for the RMSD analysis for all models. All simulations have been performed using the high-performance computational facilities of the Miller lab in the BGU HPC computational center and the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). The support of the BGU HPC computational center staff is greatly acknowledged. 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 and by the Israel Binational Science Foundation Grant No. 2011128. 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 42 TC 5 Z9 5 U1 1 U2 32 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JAN 15 PY 2015 VL 119 IS 2 BP 482 EP 490 DI 10.1021/jp511485n PG 9 WC Chemistry, Physical SC Chemistry GA AZ2XX UT WOS:000348093700010 PM 25545881 ER PT J AU Chen, GZ Xu, RF Zhang, SS Wang, YN Wang, PH Edin, ML Zeldin, DC Wang, DW AF Chen, Guangzhi Xu, Renfan Zhang, Shasha Wang, Yinna Wang, Peihua Edin, Matthew L. Zeldin, Darryl C. Wang, Dao Wen TI CYP2J2 overexpression attenuates nonalcoholic fatty liver disease induced by high-fat diet in mice SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE CYP2J2; EETs; nonalcoholic fatty liver disease; palmitic acid; inflammation; oxidative stress ID NF-KAPPA-B; OXIDATIVE STRESS; MURINE STEATOHEPATITIS; INSULIN-RESISTANCE; DIABETES-MELLITUS; ACTIVATION; CELLS; INFLAMMATION; PATHOGENESIS; DYSFUNCTION AB Cytochrome P-450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) exert diverse biological activities, which include potent vasodilatory, anti-inflammatory, antiapoptotic, and antioxidatant effects, and cardiovascular protection. Liver has abundant epoxygenase expression and high levels of EET production; however, the roles of epoxygenases in liver diseases remain to be elucidated. In this study, we investigated the protection against high-fat diet-induced nonalcoholic fatty liver disease (NAFLD) in mice with endothelial-specific CYP2J2 overexpression (Tie2-CYP2J2-Tr). After 24 wk of high-fat diet, Tie2-CYP2J2-Tr mice displayed attenuated NAFLD compared with controls. Tie2-CYP2J2-Tr mice showed significantly decreased plasma triglyceride levels and liver lipid accumulation, improved liver function, reduced inflammatory responses, and less increase in hepatic oxidative stress than wild-type control mice. These effects were associated with inhibition of NF-kappa B/JNK signaling pathway activation and enhancement of the antioxidant defense system in Tie2-CYP2J2-Tr mice in vivo. We also demonstrated that 14,15-EET treatment protected HepG2 cells against palmitic acid-induced inflammation and oxidative stress. 14,15-EET attenuated palmitic acid-induced changes in NF-kappa B/JNK signaling pathways, malondialdehyde generation, glutathione levels, reactive oxygen species production, and NADPH oxidase and antioxidant enzyme expression in HepG2 cells in vitro. Together, these results highlight a new role for CYP epoxygenase-derived EETs in lipotoxicity-related inflammation and oxidative stress and reveal a new molecular mechanism underlying EETs-mediated anti-inflammatory and antioxidant effects that could aid in the design of new therapies for the prevention and treatment of NAFLD. C1 [Chen, Guangzhi; Zhang, Shasha; Wang, Yinna; Wang, Peihua; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Internal Med, Wuhan 430030, Peoples R China. [Chen, Guangzhi; Zhang, Shasha; Wang, Yinna; Wang, Peihua; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Gene Therapy Ctr, Wuhan 430030, Peoples R China. [Xu, Renfan] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Med Ultrasound, Wuhan 430030, Peoples R China. [Edin, Matthew 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 [81400369, 31130031]; National Institutes of Health, National Institute of Environmental Health Sciences [Z01 025034] FX This work was supported by NSFC Grant (nos. 81400369 and 31130031) and in part by the intramural research program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 025034 to D. C. Zeldin). NR 45 TC 11 Z9 11 U1 1 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JAN 15 PY 2015 VL 308 IS 2 BP E97 EP E110 DI 10.1152/ajpendo.00366.2014 PG 14 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA CB0GD UT WOS:000349302900001 PM 25389366 ER PT J AU Li, R Xu, XZ Chen, C Wang, Y Gruzdev, A Zeldin, DC Wang, DW AF Li, Rui Xu, Xizhen Chen, Chen Wang, Yan Gruzdev, Artiom Zeldin, Darryl C. Wang, Dao Wen TI CYP2J2 attenuates metabolic dysfunction in diabetic mice by reducing hepatic inflammation via the PPAR gamma SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE cytochrome P450 epoxygenase 2J2; peroxisome proliferator-activated receptor-gamma ID SOLUBLE EPOXIDE HYDROLASE; IMPROVES INSULIN SENSITIVITY; ACTIVATED PROTEIN-KINASE; DB/DB MICE; CYTOCHROME-P450 2J2; RECEPTOR-GAMMA; CELL GROWTH; FATTY-ACIDS; RESISTANCE; OBESITY AB Epoxyeicosatrienoic acids (EETs) and arachidonic acid-derived cytochrome P450 (CYP) epoxygenase metabolites have diverse biological effects, including anti-inflammatory properties in the vasculature. Increasing evidence suggests that inflammation in type 2 diabetes is a key component in the development of insulin resistance. In this study, we investigated whether CYP epoxygenase expression and exogenous EETs can attenuate insulin resistance in diabetic db/db mice and in cultured hepatic cells (HepG2). In vivo, CYP2J2 expression and the accompanying increase in EETs attenuated insulin resistance, as determined by plasma glucose levels, glucose tolerance test, insulin tolerance test, and hyperinsulinemic euglycemic clamp studies. CYP2J2 expression reduced the production of proinflammatory cytokines in liver, including CRP, IL-6, IL-beta, and TNF alpha, and decreased the infiltration of macrophages in liver. CYP2J2 expression also decreased activation of proinflammatory signaling cascades by decreasing NF-kappa B and MAPK activation in hepatocytes. Interestingly, CYP2J2 expression and exogenous EET treatment increased glucose uptake and activated the insulin-signaling cascade both in vivo and in vitro, suggesting that CYP2J2 metabolites play a role in glucose homeostasis. Furthermore, CYP2J2 expression upregulated PPAR gamma, which has been shown to induce adipogenesis, which attenuates dyslipidemias observed in diabetes. All of the findings suggest that CYP2J2 expression attenuates the diabetic phenotype and insulin resistance via inhibition of NF-kappa B and MAPK signaling pathways and activation of PPAR gamma. C1 [Li, Rui; Xu, Xizhen; Chen, Chen; Wang, Yan; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan 430030, Peoples R China. [Li, Rui; Xu, Xizhen; Chen, Chen; Wang, Yan; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Inst Hypertens, Wuhan 430030, Peoples R China. [Gruzdev, Artiom; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan 430030, Peoples R China. EM dwwang57@263.net.cn FU National Science Foundation of China key projects [30930039, 31130031]; 973 program [2012CB518004]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 025034] FX This work was supported by National Science Foundation of China key projects (nos. 30930039 and 31130031), the 973 program (2012CB518004), and in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 025034 to D. C. Zeldin). NR 63 TC 9 Z9 9 U1 1 U2 12 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JAN 15 PY 2015 VL 308 IS 4 BP E270 EP E282 DI 10.1152/ajpendo.00118.2014 PG 13 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA CB0GL UT WOS:000349303800002 PM 25389363 ER PT J AU Hall, RH Sack, DA AF Hall, Robert H. Sack, David A. TI Introducing cholera vaccination in Asia, Africa and Haiti: A meeting report SO VACCINE LA English DT Article DE Cholera; Cholera vaccination; Oral vaccine; Vaccine demonstration; Vaccine stockpile; Acceptability; Feasibility ID WHOLE-CELL; VIETNAM; IMMUNOGENICITY; KNOWLEDGE; VACCINES; SAFETY; ADULTS; TRIAL; INDIA AB Orally-administered cholera vaccine (OCV) has been increasingly examined as an additional tool to intervene against endemic and epidemic cholera. In 2013, short- and long-term field experience with OCV under nine distinctive field settings was reported from India, Bangladesh, Vietnam, Guinea, Haiti, and Thailand. Lead investigators from each of these projects presented their findings at a symposium chaired by Drs. David A. Sack and Robert H. Hall at the Vaccines for Enteric Diseases (VED) Conference in Bangkok on November 7, 2013. The objective of the symposium was to describe the unique features of each setting and project, share field experience of implementing cholera vaccination, discuss results, and identify constraints to the wider use of OCV. The VED provided a forum where >200 attendees engaged with this exciting and potentially decisive new development in the cholera field. C1 [Hall, Robert H.] NIAID, Bethesda, MD 20892 USA. [Sack, David A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. RP Hall, RH (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM robert.hall@nih.gov FU DOVE project (Delivering Oral Vaccine Effectively); Vaccines for Enteric Diseases Conference held in Bangkok, Thailand, from November 6-8; Bill and Melinda Gates Foundation [OPP1053556] FX The Symposium "Symposium on Implementing Oral Cholera Vaccines" was sponsored in part by the DOVE project (Delivering Oral Vaccine Effectively) and convened during the Vaccines for Enteric Diseases Conference held in Bangkok, Thailand, from November 6-8, 2013. A list of participants and abstracts can be found here. The speakers included Dipika Sur (NICED, Kolkata, India), Firdausi Qadri (icddr,b; Dhaka, Bangladesh), Sah Binod (International Vaccine Institute, Seoul, Republic of Korea), Kashmira Date and Chris Phares (CDC, Atlanta, Georgia, USA), Dang Duc Anh (NIHE, Hanoi, Vietnam), Francisco Luquero (Epicentre/MSF, Paris France), Louise Ivers (Partners in Health, Boston, Massachusetts, USA), and Stephen Martin (WHO, Geneva, Switzerland). The DOVE project is based at the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland USA, and is funded the Bill and Melinda Gates Foundation (OPP1053556). NR 28 TC 1 Z9 1 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JAN 15 PY 2015 VL 33 IS 4 BP 487 EP 492 DI 10.1016/j.vaccine.2014.11.031 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CA8UJ UT WOS:000349196100001 PM 25437100 ER PT J AU Jain, S Farias, GG Bonifacino, JS AF Jain, Shweta Farias, Ginny G. Bonifacino, Juan S. TI Polarized sorting of the copper transporter ATP7B in neurons mediated by recognition of a dileucine signal by AP-1 SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID TRANS-GOLGI NETWORK; CLATHRIN ADAPTER COMPLEX; WILSON DISEASE PROTEIN; P-TYPE ATPASE; HIPPOCAMPAL-NEURONS; INTRACELLULAR-LOCALIZATION; BIOCHEMICAL-CHARACTERIZATION; LIVER-TRANSPLANTATION; REGULATED TRAFFICKING; MEMBRANE TRAFFICKING AB Neurons are highly polarized cells having distinct somatodendritic and axonal domains. Here we report that polarized sorting of the Cu2+ transporter ATP7B and the vesicle-SNARE VAMP4 to the somatodendritic domain of rat hippocampal neurons is mediated by recognition of dileucine-based signals in the cytosolic domains of the proteins by the sigma 1 subunit of the clathrin adaptor AP-1. Under basal Cu2+ conditions, ATP7B was localized to the trans-Golgi network (TGN) and the plasma membrane of the soma and dendrites but not the axon. Mutation of a dileucine-based signal in ATP7B or overexpression of a dominant-negative sigma 1 mutant resulted in nonpolarized distribution of ATP7B between the somatodendritic and axonal domains. Furthermore, addition of high Cu2+ concentrations, previously shown to reduce ATP7B incorporation into AP-1-containing clathrin-coated vesicles, caused loss of TGN localization and somatodendritic polarity of ATP7B. These findings support the notion of AP-1 as an effector of polarized sorting in neurons and suggest that altered polarity of ATP7B in polarized cell types might contribute to abnormal copper metabolism in the MEDNIK syndrome, a neurocutaneous disorder caused by mutations in the sigma 1A subunit isoform of AP-1. C1 [Jain, Shweta; Farias, Ginny G.; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM bonifacinoj@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural Program of the National Institute of Child Health and Human Development, National Institutes of Health [ZIA HD001607-22] FX We thank X. Zhu and N. Tsai for expert technical assistance, X. Ren for help with Figure 4A, S. Lutsenko, M. Krieger, W. Mothes, A. Sharma, and J. Lippincott-Schwartz for kind gifts of reagents, and R. Mattera and S. Kaler for helpful discussions and critical review of the manuscript. This work was funded by the Intramural Program of the National Institute of Child Health and Human Development, National Institutes of Health (ZIA HD001607-22). NR 60 TC 11 Z9 11 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 JAN 15 PY 2015 VL 26 IS 2 BP 218 EP 228 DI 10.1091/mbc.E14-07-1177 PG 11 WC Cell Biology SC Cell Biology GA CA4EO UT WOS:000348857200006 PM 25378584 ER PT J AU Naumiec, GR Cai, LS Pike, VW AF Naumiec, Gregory R. Cai, Lisheng Pike, Victor W. TI New N-aryl-N '-(3-(substituted)phenyl)-N '-methylguanidines as leads to potential PET radioligands for imaging the open NMDA receptor SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE N-Methyl-D-aspartate receptor; Phencyclidine; Positron emission tomography ID IN-VITRO EVALUATION; SYNAPTIC PLASTICITY; CHANNEL; ION; ANTAGONISTS; SUBUNIT; SITE; MICE AB An expansive set of N-aryl-N'-(3-(substituted)phenyl)-N'-methylguanidines was prepared in a search for new leads to prospective PET ligands for imaging of the open channel of the N-methyl-D-aspartate (NMDA) receptor in vivo. The N-aryl rings and their substituents were varied, whereas the N-methyl group was maintained as a site for potential labeling with the positron-emitter, carbon-11 (t(1/2) = 20.4 min). At micromolar concentration, over half of the prepared compounds strongly inhibited the binding of [H-3] TCP to its binding site in the open NMDA receptor in vitro. Four ligands displayed affinities that are similar or superior to those of the promising SPECT radioligand ([I-123]CNS1261). The 30-dimethylamino (19; K-i 36.7 nM), 3'-trifluoromethyl (20; K-i 18.3 nM) and 3'-methylthio (2; K-i 39.8 nM) derivatives of N-1-naphthyl-N'-(phenyl)-N'-methylguanidine were identified as especially attractive leads for PET radioligand development. (C) 2014 Published by Elsevier Ltd. C1 [Naumiec, Gregory R.; Cai, Lisheng; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3 C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH) FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), specifically the National Institute of Mental Health (NIMH). NR 25 TC 3 Z9 3 U1 1 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 JAN 15 PY 2015 VL 25 IS 2 BP 225 EP 228 DI 10.1016/j.bmcl.2014.11.066 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA AY9XQ UT WOS:000347901400014 PM 25499436 ER PT J AU Etemadi, A Kamangar, F Islami, F Poustchi, H Pourshams, A Brennan, P Boffetta, P Malekzadeh, R Dawsey, SM Abnet, CC Emadi, A AF Etemadi, Arash Kamangar, Farin Islami, Farhad Poustchi, Hossein Pourshams, Akram Brennan, Paul Boffetta, Paolo Malekzadeh, Reza Dawsey, Sanford M. Abnet, Christian C. Emadi, Ashkan TI Mortality and cancer in relation to ABO blood group phenotypes in the Golestan Cohort Study SO BMC MEDICINE LA English DT Article DE Blood group; ABO; Rh; Mortality; Cancer; Cardiovascular disease ID VON-WILLEBRAND-FACTOR; CORONARY-ARTERY-DISEASE; CARDIOVASCULAR-DISEASE; ESOPHAGEAL CANCER; GASTRIC-CANCER; HEART-DISEASE; RISK-FACTORS; ASSOCIATION; IRAN; ALLELES AB Background: A few studies have shown an association between blood group alleles and vascular disease, including atherosclerosis, which is thought to be due to the higher level of von Willebrand factor in these individuals and the association of blood group locus variants with plasma lipid levels. No large population-based study has explored this association with overall and cause-specific mortality. Methods: We aimed to study the association between ABO blood groups and overall and cause-specific mortality in the Golestan Cohort Study. In this cohort, 50,045 people 40- to 70-years old were recruited between 2004 and 2008, and followed annually to capture all incident cancers and deaths due to any cause. We used Cox regression models adjusted for age, sex, smoking, socioeconomic status, ethnicity, place of residence, education and opium use. Results: During a total of 346,708 person-years of follow-up (mean duration 6.9 years), 3,623 cohort participants died. Non-O blood groups were associated with significantly increased total mortality (hazard ratio (HR) = 1.09; 95% confidence interval (CI): 1.01 to 1.17) and cardiovascular disease mortality (HR = 1.15; 95% CI: 1.03 to 1.27). Blood group was not significantly associated with overall cancer mortality, but people with group A, group B, and all non-O blood groups combined had increased risk of incident gastric cancer. In a subgroup of cohort participants, we also showed higher plasma total cholesterol and low-density lipoprotein (LDL) in those with blood group A. Conclusions: Non-O blood groups have an increased mortality, particularly due to cardiovascular diseases, which may be due to the effect of blood group alleles on blood biochemistry or their effect on von Willebrand factor and factor VIII levels. C1 [Etemadi, Arash; Islami, Farhad; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Inst, Digest Oncol Res Ctr, Tehran, Iran. [Etemadi, Arash; Dawsey, Sanford M.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Islami, Farhad] Amer Canc Soc, Surveillance & Hlth Serv Res, Atlanta, GA 30329 USA. [Poustchi, Hossein; Pourshams, Akram] Univ Tehran Med Sci, Digest Dis Res Inst, Liver & Pancreatobiliary Res Ctr, Tehran, Iran. [Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Emadi, Ashkan] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Etemadi, A (reprint author), Univ Tehran Med Sci, Digest Dis Res Inst, Digest Oncol Res Ctr, Tehran, Iran. EM arash.etemadi@nih.gov RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016 OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute; Digestive Disease Research Center of Tehran University of Medical Sciences [82-603]; Cancer Research UK [C20/A5860]; International Agency FX This work was supported in part by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute; the Digestive Disease Research Center of Tehran University of Medical Sciences (grant No 82-603); Cancer Research UK (C20/A5860); and by the International Agency for Research on Cancer. NR 35 TC 12 Z9 12 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD JAN 15 PY 2015 VL 13 AR 8 DI 10.1186/s12916-014-0237-8 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AZ7HI UT WOS:000348389800001 PM 25592833 ER PT J AU Crompton, JG Sukumar, M Roychoudhuri, R Clever, D Gros, A Eil, RL Tran, E Hanada, K Yu, ZY Palmer, DC Kerkar, SP Michalek, RD Upham, T Leonardi, A Acquavella, N Wang, E Marincola, FM Gattinoni, L Muranski, P Sundrud, MS Klebanoff, CA Rosenberg, SA Fearon, DT Restifo, NP AF Crompton, Joseph G. Sukumar, Madhusudhanan Roychoudhuri, Rahul Clever, David Gros, Alena Eil, Robert L. Eric Tran Hanada, Ken-ichi Yu, Zhiya Palmer, Douglas C. Kerkar, Sid P. Michalek, Ryan D. Upham, Trevor Leonardi, Anthony Acquavella, Nicolas Wang, Ena Marincola, Francesco M. Gattinoni, Luca Muranski, Pawel Sundrud, Mark S. Klebanoff, Christopher A. Rosenberg, Steven A. Fearon, Douglas T. Restifo, Nicholas P. TI Akt Inhibition Enhances Expansion of Potent Tumor-Specific Lymphocytes with Memory Cell Characteristics SO CANCER RESEARCH LA English DT Article ID CD8(+) T-CELLS; SPARE RESPIRATORY CAPACITY; CANCER IMMUNOSURVEILLANCE; METASTATIC MELANOMA; ADOPTIVE TRANSFER; DIFFERENTIATION; IMMUNOTHERAPY; METABOLISM; EFFECTOR; AUTOIMMUNITY AB Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologicinhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer. (C) 2014 AACR. C1 [Crompton, Joseph G.; Sukumar, Madhusudhanan; Roychoudhuri, Rahul; Clever, David; Gros, Alena; Eil, Robert L.; Eric Tran; Hanada, Ken-ichi; Yu, Zhiya; Palmer, Douglas C.; Kerkar, Sid P.; Upham, Trevor; Leonardi, Anthony; Acquavella, Nicolas; Gattinoni, Luca; Muranski, Pawel; Klebanoff, Christopher A.; Rosenberg, Steven A.; Restifo, Nicholas P.] NCI, NIH, Bethesda, MD 20892 USA. [Crompton, Joseph G.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA USA. [Crompton, Joseph G.; Clever, David; Fearon, Douglas T.] Univ Cambridge, Sch Clin Med, Dept Med, Cambridge, England. [Michalek, Ryan D.] Metabolon Incorp, Durham, NC USA. [Wang, Ena; Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Sundrud, Mark S.] Scripps Res Inst, Dept Canc Biol, Jupiter, FL USA. [Klebanoff, Christopher A.] NCI, Clin Investigator Dev Program, NIH, Bethesda, MD 20892 USA. RP Crompton, JG (reprint author), NCI, NIH, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. EM joe.crompton@nih.gov; sukumarm2@mail.nih.gov; restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Palmer, Douglas/B-9454-2008; Roychoudhuri, Rahul/A-7442-2010; OI Gattinoni, Luca/0000-0003-2239-3282; Palmer, Douglas/0000-0001-5018-5734; Roychoudhuri, Rahul/0000-0002-5392-1853; Restifo, Nicholas P./0000-0003-4229-4580; Gros, Alena/0000-0002-1207-1880 FU Intramural Research Program of the NCI [ZIA BC010763]; Wellcome Trust Translational Medicine and Therapeutics Programme FX The authors were supported by a generous gift from Li Jinyuan and the Tiens Charitable Foundation, the NIH-Center for Regenerative Medicine, the Milstein Family Foundation and by the Intramural Research Program of the NCI (ZIA BC010763), Center for Cancer Research, NIH (Bethesda, MD). This work was done in partial fulfillment of J.G. Crompton's PhD degree from Cambridge University, Cambridge, England and he gratefully acknowledges funding support from the Wellcome Trust Translational Medicine and Therapeutics Programme. NR 39 TC 50 Z9 50 U1 0 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2015 VL 75 IS 2 BP 296 EP 305 DI 10.1158/0008-5472.CAN-14-2277 PG 10 WC Oncology SC Oncology GA AZ0LT UT WOS:000347937600008 PM 25432172 ER PT J AU Boufraqech, M Nilubol, N Zhang, LS Gara, SK Sadowski, SM Mehta, A He, M Davis, S Dreiling, J Copland, JA Smallridge, RC Quezado, MM Kebebew, E AF Boufraqech, Myriem Nilubol, Naris Zhang, Lisa Gara, Sudheer Kumar Sadowski, Samira M. Mehta, Amit He, Mei Davis, Sean Dreiling, Jennifer Copland, John A. Smallridge, Robert C. Quezado, Martha M. Kebebew, Electron TI miR30a Inhibits LOX Expression and Anaplastic Thyroid Cancer Progression SO CANCER RESEARCH LA English DT Article ID LYSYL OXIDASE; DOWN-REGULATION; BETA-AMINOPROPIONITRILE; MESENCHYMAL TRANSITION; MICRORNAS; CARCINOMA; CELLS; METASTASIS; DIFFERENTIATION; MALIGNANCY AB Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies, but its genetic drivers remain little understood. In this study, we report losses in expression of the miRNA miR30a, which is downregulated in ATC compared with differentiated thyroid cancer and normal tissue. miR30a downregulation was associated with advanced differentiated thyroid cancer and higher mortality. Mechanistically, we found miR30a decreased cellular invasion and migration, epithelial-mesenchymal transition marker levels, lysyl oxidase (LOX) expression, and metastatic capacity. LOX was identified as a direct target of miR30a that was overexpressed in ATC and associated with advanced differentiated thyroid cancer and higher mortality rate. Consistent with its role in other cancers, we found that LOX inhibited cell proliferation, cellular invasion, and migration and metastasis in vitro and in vivo. Together, our findings establish a critical functional role for miR30a downregulation in mediating LOX upregulation and thyroid cancer progression, with implications for LOX targeting as a rational therapeutic strategy in ATC. C1 [Boufraqech, Myriem; Nilubol, Naris; Zhang, Lisa; Gara, Sudheer Kumar; Sadowski, Samira M.; Mehta, Amit; He, Mei; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Mehta, Amit] Geisel Sch Med Dartmouth, Hanover, NH USA. [Davis, Sean] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Dreiling, Jennifer; Quezado, Martha M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Copland, John A.; Smallridge, Robert C.] Mayo Clin, Dept Canc Biol, Jacksonville, FL 32224 USA. [Smallridge, Robert C.] Mayo Clin, Div Endocrinol, Dept Internal Med, Jacksonville, FL 32224 USA. RP Kebebew, E (reprint author), NCI, Room 4-5952,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov RI Gara, Sudheer Kumar/E-8084-2016; Boufraqech, Myriem/E-4823-2016; OI Davis, Sean/0000-0002-8991-6458 FU intramural research program of the Center for Cancer Research, NCI, NIH FX This research was supported by the intramural research program of the Center for Cancer Research, NCI, NIH. NR 35 TC 11 Z9 12 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2015 VL 75 IS 2 BP 367 EP 377 DI 10.1158/0008-5472.CAN-14-2304 PG 11 WC Oncology SC Oncology GA AZ0LT UT WOS:000347937600014 PM 25488748 ER PT J AU Iida, J Dorchak, J Clancy, R Slavik, J Ellsworth, R Katagiri, Y Pugacheva, EN van Kuppevelt, TH Mural, RJ Cutler, ML Shriver, CD AF Iida, Joji Dorchak, Jesse Clancy, Rebecca Slavik, Juliana Ellsworth, Rachel Katagiri, Yasuhiro Pugacheva, Elena N. van Kuppevelt, Toin H. Mural, Richard J. Cutler, Mary Lou Shriver, Craig D. TI Role for chondroitin sulfate glycosaminoglycan in NEDD9-mediated breast cancer cell growth SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE NEDD9; Breast cancer; Migration; Growth; Chondroitin sulfate; CD44 ID HUMAN-MELANOMA INVASION; MOLECULAR-INTERACTIONS; HYALURONAN SYNTHESIS; ANTIBODY GD3G7; PROTEOGLYCANS; MATRIX; PROGRESSION; METASTASIS; BINDING; INTEGRIN AB There are lines of evidence demonstrating that NEDD9 (Cas-L, HEF-1) plays a key role in the development, progression, and metastasis of breast cancer cells. We previously reported that NEDD9 plays a critical role for promoting migration and growth of MDA-MB-231. In order to further characterize the mechanisms of NEDD9-mediated cancer migration and growth, stable cells overexpressing NEDD9 were generated using HCC38 as a parental cell line which expresses low level of endogenous NEDD9. Microarray studies demonstrated that core proteins of CD44 and Serglycin were markedly upregulated in HCC38(NEDD9) cells compared to HCC38(Vector) cells, while those of Syndecan-1, Syndecan-2, and Versican were downregulated in HCC38(NEDD9). Importantly, enzymes generating chondroitin sulfate glycosaminoglycans (CS) such as CHST11, CHST15, and CSGALNACT1 were upregulated in HCC38(NEDD9) compared to HCC38(Vector). Immunofluorescence studies using specific antibody, GD3G7, confirmed the enhanced expression of CS-E subunit in HCC38(NEDD9). Immunoprecipitation and western blotting analysis demonstrated that CS-E was attached to CD44 core protein. We demonstrated that removing CS by chondroitinase ABC significantly inhibited anchorage-independent colony formation of HCC38 (NEDD9) in methylcellulose. Importantly, the fact that GD3G7 significantly inhibited colony formation of HCC38(NEDD9) cells suggests that CS-E subunit plays a key role in this process. Furthermore, treatment of HCC38(NEDD9) cells with chondroitinase ABC or GD3G7 significantly inhibited mammosphere formation. Exogenous addition of CS-E enhanced colony formation and mammosphere formation of HCC38 parental and HCC38(Vector) cells. These results suggest that NEDD9 regulates the synthesis and expression of tumor associated glycocalyx structures including CS-E, which plays a key role in promoting and regulating breast cancer progression and metastasis and possibly stem cell phenotypes. (C) 2014 Elsevier Inc. All rights reserved. C1 [Iida, Joji; Dorchak, Jesse; Clancy, Rebecca; Slavik, Juliana; Mural, Richard J.] Windber Res Inst, Dept Cell Biol, Windber, PA 15963 USA. [Ellsworth, Rachel] Henry M Jackson Fdn Adv Mil Med, Clin Breast Care Project, Windber, PA 15963 USA. [Katagiri, Yasuhiro] NHLBI, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Pugacheva, Elena N.] W Virginia Univ, Sch Med, Dept Biochem, Morgantown, WV 26506 USA. [van Kuppevelt, Toin H.] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Biochem, NL-6525 ED Nijmegen, Netherlands. [Cutler, Mary Lou] Univ Hlth Sci, Uniformed Serv, Dept Pathol, Bethesda, MD 20814 USA. [Shriver, Craig D.] Walter Reed Natl Mil Med Ctr, Dept Surg, Bethesda, MD 20814 USA. RP Iida, J (reprint author), Windber Res Inst, Dept Cell Biol, Windber, PA 15963 USA. EM g.iida@wriwindber.org RI Kuppevelt, A.H.M.S.M./L-4463-2015 FU United States Army Medical Research Acquisition Activity (USAMRAA) (Breast Cancer Translational Research) [W81XWH-12-2-0050]; United States Military Cancer Institute (USMCI) [MDA905-02-2-0005] FX During preparation of this manuscript Dr. Richard J Mural passed away after two years of battle with cancer. We greatly appreciate his continuous support and encouragement with dedicating this article to Dr. Richard J Mural. We thank Mrs. Sue Lubert for sequencing DNA and Mrs. Allyson Valente for performing micro-array studies. This research was supported by a grant from the United States Army Medical Research Acquisition Activity (USAMRAA) (Breast Cancer Translational Research: W81XWH-12-2-0050) and the United States Military Cancer Institute (USMCI) (MDA905-02-2-0005). The opinion and assertions contained herein are the private views of the authors and are not to be construed as official or as representing the views of the Department of the Army or the Department of Defense. NR 70 TC 9 Z9 10 U1 1 U2 15 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 EI 1090-2422 J9 EXP CELL RES JI Exp. Cell Res. PD JAN 15 PY 2015 VL 330 IS 2 BP 358 EP 370 DI 10.1016/j.yexcr.2014.11.002 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ5FN UT WOS:000348245900012 PM 25445787 ER PT J AU Ming, M Soltani, K Shea, CR Li, X He, YY AF Ming, M. Soltani, K. Shea, C. R. Li, X. He, Y. Y. TI Dual role of SIRT1 in UVB-induced skin tumorigenesis SO ONCOGENE LA English DT Article DE SIRT1; UVB; skin tumorigenesis; DNA repair; apoptosis ID DNA-DAMAGE RESPONSE; CELL-SURVIVAL; CALORIE RESTRICTION; MAMMALIAN SIRTUINS; CANCER; MICE; P53; DEACETYLASE; PROTEIN; REPAIR AB The protein deacetylase SIRT1 regulates various pathways in metabolism, aging and cancer. However, the role of SIRT1 in skin cancer remains unclear. Here, using mice with targeted deletions of SIRT1 in their epidermis in both resistant B6 and sensitive SKH1 hairless backgrounds, we show that the role of SIRT1 in skin cancer development induced by ultraviolet B (UVB) radiation is dependent on its gene dose. Keratinocyte-specific heterozygous deletion of SIRT1 promotes UVB-induced skin tumorigenesis, whereas homozygous deletion of SIRT1 suppresses skin tumor development but sensitizes the B6 mice to chronic solar injury. In mouse skin, SIRT1 is haploinsufficient for UVB-induced DNA damage repair and expression of xeroderma pigmentosum C (XPC), a protein critical for repairing UVB-induced DNA damage. As compared with normal human skin, downregulation of SIRT1 is in parallel with downregulation of XPC in human cutaneous squamous cell carcinoma at both the protein and mRNA levels. In contrast, homozygous SIRT1 deletion in mouse skin augments p53 acetylation and expression of its transcriptional target Noxa, and sensitizes the epidermis to UVB-induced apoptosis in vivo, while heterozygous SIRT1 deletion has no such effect. The gene dosage-dependent function of SIRT1 in DNA repair and cell survival is consistent with the dual roles of SIRT1 in UVB-induced skin tumorigenesis. Our results reveal the gene dosage-dependent in vivo functions of SIRT1 in skin tumorigenesis and may shed light on the role of SIRT1 in epithelial cancer induced by DNA damage. C1 [Ming, M.; Soltani, K.; Shea, C. R.; He, Y. Y.] Univ Chicago, Dermatol Sect, Dept Med, Chicago, IL 60637 USA. [Li, X.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC USA. RP He, YY (reprint author), Univ Chicago, Dermatol Sect, Dept Med, Chicago, IL 60637 USA. EM yyhe@medicine.bsd.uchicago.edu FU NIH/NIEHS [ES016936]; American Cancer Society (ACS) [RSG-13-078-01]; University of Chicago Cancer Research Center [P30 CA014599]; CTSA [NIH UL1RR024999]; University of Chicago Friends of Dermatology Endowment Fund FX This work was supported by the NIH/NIEHS Grant ES016936 (to YYH), the American Cancer Society (ACS) Grant RSG-13-078-01 (to YYH), the University of Chicago Cancer Research Center (P30 CA014599), the CTSA (NIH UL1RR024999) and the University of Chicago Friends of Dermatology Endowment Fund. We thank Terri Li for Ki67 and TUNEL and XPC immunohistochemical analysis, and Dr Xiaobing Shi for kindly providing the WT and K382R mutant p53 plasmids. NR 45 TC 10 Z9 10 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JAN 15 PY 2015 VL 34 IS 3 BP 281 EP 287 DI 10.1038/onc.2013.583 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AZ3RY UT WOS:000348145500002 PM 24441046 ER PT J AU Sales, KU Friis, S Konkel, JE Godiksen, S Hatakeyama, M Hansen, KK Rogatto, SR Szabo, R Vogel, LK Chen, W Gutkind, JS Bugge, TH AF Sales, K. U. Friis, S. Konkel, J. E. Godiksen, S. Hatakeyama, M. Hansen, K. K. Rogatto, S. R. Szabo, R. Vogel, L. K. Chen, W. Gutkind, J. S. Bugge, T. H. TI Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis SO ONCOGENE LA English DT Article DE epithelial carcinogenesis; inflammation; keratinocyte stem cells; pericellular proteolysis ID PROTEINASE-ACTIVATED RECEPTOR-2; SERINE-PROTEASE MATRIPTASE; TISSUE MICROARRAY ANALYSIS; HUMAN KERATINOCYTES; CLINICOPATHOLOGICAL PARAMETERS; GENE-EXPRESSION; OVARIAN-CANCER; ENDOTHELIAL-CELLS; EPITHELIAL-CELLS; IN-VITRO AB The membrane-anchored serine protease, matriptase, is consistently dysregulated in a range of human carcinomas, and high matriptase activity correlates with poor prognosis. Furthermore, matriptase is unique among tumor-associated proteases in that epithelial stem cell expression of the protease suffices to induce malignant transformation. Here, we use genetic epistasis analysis to identify proteinase-activated receptor (PAR)-2-dependent inflammatory signaling as an essential component of matriptase-mediated oncogenesis. In cell-based assays, matriptase was a potent activator of PAR-2, and PAR-2 activation by matriptase caused robust induction of nuclear factor (NF)kappa B through G alpha i. Importantly, genetic elimination of PAR-2 from mice completely prevented matriptase-induced pre-malignant progression, including inflammatory cytokine production, inflammatory cell recruitment, epidermal hyperplasia and dermal fibrosis. Selective ablation of PAR-2 from bone marrow-derived cells did not prevent matriptase-driven pre-malignant progression, indicating that matriptase activates keratinocyte stem cell PAR-2 to elicit its pro-inflammatory and pro-tumorigenic effects. When combined with previous studies, our data suggest that dual induction of PAR-2-NF kappa B inflammatory signaling and PI3K-Akt-mTor survival/proliferative signaling underlies the transforming potential of matriptase and may contribute to pro-tumorigenic signaling in human epithelial carcinogenesis. C1 [Sales, K. U.; Friis, S.; Konkel, J. E.; Godiksen, S.; Hansen, K. K.; Szabo, R.; Chen, W.; Gutkind, J. S.; Bugge, T. H.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Sales, K. U.] Natl Inst Dent & Craniofacial Res, Clin Res Core, NIH, Bethesda, MD 20892 USA. [Friis, S.; Godiksen, S.; Vogel, L. K.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Cellular & Mol Med, Copenhagen, Denmark. [Godiksen, S.] Univ Copenhagen, Fac Sci, Dept Biol, Copenhagen, Denmark. [Hatakeyama, M.; Rogatto, S. R.] Sao Paulo State Univ UNESP, Fac Med, Dept Urol, Botucatu, SP, Brazil. [Hatakeyama, M.; Rogatto, S. R.] AC Camargo Canc Ctr, Sao Paulo, Brazil. RP Bugge, TH (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Room 211, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov RI Rogatto, Silvia/E-6535-2012 FU NIDCR Intramural Research Program; Augustinus Foundation, Kobmand Kristian Kjaer og hustrus Foundation; Kjaer-Foundation; Dagmar Marshalls Foundation; Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Foundation; Grosserer Valdemar Foersom og Hustru Thyra Foersoms Foundation; Fabrikant Einar Willumsens Mindelegat; Sao Paulo Research Foundation (FAPESP) FX We thank Dr Mary Jo Danton for critically reviewing this manuscript. Histology was performed by Histoserv, Germantown, MD, USA. We thank Dr Allessia Gallo, Shyh-Ing Jang, Colleen Doci, Patricia Pilla, Zhiyong Wang, Canstantinos Mikelis, Ramiro Iglesias-Bartolome and Morgan O'Hare for technical assistance. The study was supported by the NIDCR Intramural Research Program (THB, JSG, WC), the Augustinus Foundation, Kobmand Kristian Kjaer og hustrus Foundation, the Kjaer-Foundation, the Dagmar Marshalls Foundation, the Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Foundation, the Grosserer Valdemar Foersom og Hustru Thyra Foersoms Foundation and Fabrikant Einar Willumsens Mindelegat (SG and LKV), and the Sao Paulo Research Foundation (FAPESP) (MH, SRR). NR 51 TC 10 Z9 11 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JAN 15 PY 2015 VL 34 IS 3 BP 288 EP 298 DI 10.1038/onc.2013.563 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AZ3RY UT WOS:000348145500003 PM 24469043 ER PT J AU Earl, PL Americo, JL Cotter, CA Moss, B AF Earl, Patricia L. Americo, Jeffrey L. Cotter, Catherine A. Moss, Bernard TI Comparative live bioluminescence imaging of monkeypox virus dissemination in a wild-derived inbred mouse (Mus musculus castaneus) and outbred African dormouse (Graphiurus kelleni) SO VIROLOGY LA English DT Article DE Monkeypox virus pathogenesis; Monkeypox virus virulence; Orthopoxviruses; Animal models; Smallpox ID SMALL ANIMAL-MODELS; VACCINIA VIRUS; EXPERIMENTAL-INFECTION; PRAIRIE DOGS; COMPARATIVE PATHOLOGY; SMALLPOX VACCINATION; CYNOMYS-LUDOVICIANUS; STRAINS; DISEASE; PATHOGENESIS AB Monkeypox virus belongs to the orthopoxvirus genus, infects rodents and monkeys in Africa, produces a smallpox-like zoonotic disease in humans, and has the potential for global spread and exploitation for bioterrorism. Several small animal models for studying monkeypox virus pathogenesis have been investigated. The African dormouse is a candidate natural host but is outbred and no immunological reagents exist. Although not a natural host, the CAST/EiJ mouse is inbred and animals and reagents are commercially available. We compared the dissemination of monkeypox virus by bioluminescence imaging in CAST/EiJ mice and dormice. In CAST/EiJ mice, intense replication occurred at the intranasal site of inoculation and virus spread rapidly to lungs and abdominal organs, which had a lower virus burden. Compared to CAST/EiJ mice, dormice exhibited a greater variation of virus spread, a slower time course, less replication in the head and chest, and more replication in abdominal organs prior to death. Published by Elsevier Inc. C1 [Earl, Patricia L.; Americo, Jeffrey L.; Cotter, Catherine A.; Moss, Bernard] NIAID, Viral Dis Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIH, Viral Dis Lab, 33 North Dr, Bethesda, MD 20892 USA. EM bmoss@nih.gov OI Moss, Bernard/0000-0002-2154-8564 FU Division of Intramural Research, NIAID, NIH FX We thank Gary Luker for advice regarding BLI and the NIAID Comparative Medicine Branch for care of animals. The research was supported by the Division of Intramural Research, NIAID, NIH. NR 42 TC 1 Z9 1 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 15 PY 2015 VL 475 BP 150 EP 158 DI 10.1016/j.virol.2014.11.015 PG 9 WC Virology SC Virology GA AZ4FE UT WOS:000348176500015 PM 25462355 ER PT J AU Itzel, T Scholz, P Maass, T Krupp, M Marquardt, JU Strand, S Becker, D Staib, F Binder, H Roessler, S Wang, XW Thorgeirsson, S Muller, M Galle, PR Teufel, A AF Itzel, Timo Scholz, Peter Maass, Thorsten Krupp, Markus Marquardt, Jens U. Strand, Susanne Becker, Diana Staib, Frank Binder, Harald Roessler, Stephanie Wang, Xin Wei Thorgeirsson, Snorri Mueller, Martina Galle, Peter R. Teufel, Andreas TI Translating bioinformatics in oncology: guilt-by-profiling analysis and identification of KIF18B and CDCA3 as novel driver genes in carcinogenesis SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 14th Annual Bioinformatics Open Source Conference (BOSC) CY JUL 19-20, 2013 CL Special Interest Grp, Berlin, GERMANY SP Open Bioinformat Fdn HO Special Interest Grp ID TUMOR-CELL GROWTH; HEPATOCELLULAR-CARCINOMA; MICROARRAY DATA; DATA SETS; CANCER; PREDICTION; ASSOCIATION; DATABASE; SYSTEMS; TRANSFORMATION AB Motivation: Co-regulated genes are not identified in traditional micro-array analyses, but may theoretically be closely functionally linked [guilt-by-association (GBA), guilt-by-profiling]. Thus, bioinformatics procedures for guilt-by-profiling/association analysis have yet to be applied to large-scale cancer biology. We analyzed 2158 full cancer transcriptomes from 163 diverse cancer entities in regard of their similarity of gene expression, using Pearson's correlation coefficient (CC). Subsequently, 428 highly co-regulated genes (vertical bar CC vertical bar >= 0.8) were clustered unsupervised to obtain small co-regulated networks. A major subnetwork containing 61 closely co-regulated genes showed highly significant enrichment of cancer bio-functions. All genes except kinesin family member 18B (KIF18B) and cell division cycle associated 3 (CDCA3) were of confirmed relevance for tumor biology. Therefore, we independently analyzed their differential regulation in multiple tumors and found severe deregulation in liver, breast, lung, ovarian and kidney cancers, thus proving our GBA hypothesis. Overexpression of KIF18B and CDCA3 in hepatoma cells and subsequent microarray analysis revealed significant deregulation of central cell cycle regulatory genes. Consistently, RT-PCR and proliferation assay confirmed the role of both genes in cell cycle progression. Finally, the prognostic significance of the identified KIF18B- and CDCA3-dependent predictors (P = 0.01, P = 0.04) was demonstrated in three independent HCC cohorts and several other tumors. In summary, we proved the efficacy of large-scale guilt-by-profiling/association strategies in oncology. We identified two novel oncogenes and functionally characterized them. The strong prognostic importance of downstream predictors for HCC and many other tumors indicates the clinical relevance of our findings. C1 [Itzel, Timo; Maass, Thorsten; Mueller, Martina; Teufel, Andreas] Univ Regensburg, Dept Med 1, D-93053 Regensburg, Germany. [Scholz, Peter; Krupp, Markus; Marquardt, Jens U.; Strand, Susanne; Becker, Diana; Staib, Frank; Galle, Peter R.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Med 1, D-55131 Mainz, Germany. [Binder, Harald] Johannes Gutenberg Univ Mainz, Univ Med Ctr, IMBEI, D-55131 Mainz, Germany. [Roessler, Stephanie] Heidelberg Univ, Dept Pathol, D-69120 Heidelberg, Germany. [Wang, Xin Wei; Thorgeirsson, Snorri] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. EM andreas.teufel@ukr.de RI Binder, Harald/C-7413-2009; Wang, Xin/B-6162-2009 OI Binder, Harald/0000-0002-5666-8662; FU German Cancer Aid [110989]; Intramural Research Program of the Center for Cancer Research, National Cancer Institute (Bethesda, MD) [Z01 BC 010313] FX TI, HB and AT were supported by the University Medical Center Mainz to establish a bioinformatics core facility. JUM is supported by a grant from the German Cancer Aid (110989). XWW was supported by a grant (Z01 BC 010313) from the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (Bethesda, MD). NR 40 TC 1 Z9 1 U1 2 U2 7 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 JAN 15 PY 2015 VL 31 IS 2 BP 216 EP 224 DI 10.1093/bioinformatics/btu586 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 AY8WU UT WOS:000347832300010 PM 25236463 ER PT J AU Wani, S Das, A Rastogi, A Drahos, J Ricker, W Parsons, R Bansal, A Yen, R Hosford, L Jankowski, M Sharma, P Cook, MB AF Wani, Sachin Das, Ananya Rastogi, Amit Drahos, Jennifer Ricker, Winifred Parsons, Ruth Bansal, Ajay Yen, Roy Hosford, Lindsay Jankowski, Meghan Sharma, Prateek Cook, Michael B. TI Endoscopic Ultrasonography in Esophageal Cancer Leads to Improved Survival Rates: Results From a Population-Based Study SO CANCER LA English DT Article DE endoscopic ultrasonography; endoscopic ultrasound; esophageal cancer; positron emission tomography and computed tomography; staging; survival ID POSITRON-EMISSION-TOMOGRAPHY; CARCINOMA; ULTRASOUND; IMPACT; ADENOCARCINOMA; ENDOSONOGRAPHY; METAANALYSIS; EUS AB BACKGROUNDThe advantages of endoscopic ultrasound (EUS) and computed tomography (CT)-positron emission tomography (PET) with respect to survival for esophageal cancer patients are unclear. This study aimed to assess the effects of EUS, CT-PET, and their combination on overall survival with respect to cases not receiving these procedures. METHODSPatients who were 66 years old when diagnosed with esophageal cancer were identified in the Surveillance, Epidemiology, and End Results-Medicare linked database. Cases were split into 4 analytic groups: EUS only (n=318), CT-PET only (n=853), EUS+CT-PET (n=189), and no EUS or CT-PET (n=2439). Survival times were estimated with the Kaplan-Meier method and were compared with the log-rank test for each group versus the no EUS or CT-PET group. Multivariate Cox proportional hazards models were used to compare 1-, 3-, and 5-year survival rates. RESULTSKaplan-Meier analyses showed that EUS, CT-PET, and EUS+CT-PET patients had improved survival for all stages (with the exception of stage 0 disease) in comparison with patients undergoing no EUS or CT-PET. Receipt of EUS increased the likelihood of receiving endoscopic therapies, esophagectomy, and chemoradiation. Multivariate Cox proportional hazards models showed that receipt of EUS was a significant predictor of improved 1- (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.39-0.59; P<.0001), 3- (HR, 0.57; 95% CI, 0.48-0.66; P<.0001), and 5-year survival (HR, 0.59; 95% CI, 0.50-0.68). Similar results were noted when the results were stratified on the basis of histology and for the CT-PET and EUS+CT-PET groups. CONCLUSIONSReceipt of either EUS or CT-PET alone in esophageal cancer patients was associated with improved 1-, 3-, and 5-year survival. Future studies should identify barriers to the dissemination of these staging modalities. Cancer 2015;121:194-201. (c) 2014 American Cancer Society. Patients undergoing endoscopic ultrasound (EUS), computed tomography (CT)-positron emission tomography (PET), or EUS and CT-PET have improved survival at all stages (with the exception of stage 0 disease) in comparison with patients undergoing no EUS or CT-PET. Receipt of EUS is a significant predictor for improved 1-, 3-, and 5-year survival. Similar results are noted when the results are stratified on the basis of histology and for groups undergoing CT-PET or EUS plus CT-PET. C1 [Wani, Sachin; Yen, Roy; Hosford, Lindsay; Jankowski, Meghan] Univ Colorado, Anschutz Med Ctr, Div Gastroenterol & Hepatol, Aurora, CO 80045 USA. [Wani, Sachin] Vet Affairs Med Ctr, Div Gastroenterol & Hepatol, Denver, CO USA. [Das, Ananya] Arizona Ctr Digest Hlth, Gilbert, AZ USA. [Rastogi, Amit; Bansal, Ajay; Sharma, Prateek] Univ Kansas, Sch Med, Kansas City, MO USA. [Rastogi, Amit; Bansal, Ajay; Sharma, Prateek] Vet Affairs Med Ctr, Kansas City, MO USA. [Drahos, Jennifer; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Ricker, Winifred; Parsons, Ruth] Informat Management Serv Inc, Rockville, MD USA. RP Wani, S (reprint author), Univ Colorado, Anschutz Med Ctr, Div Gastroenterol & Hepatol, Mail Stop F735,1635 Aurora Court,Room 2-031, Aurora, CO 80045 USA. EM sachinwani10@yahoo.com RI Cook, Michael/A-5641-2009 OI Cook, Michael/0000-0002-0533-7302 FU AGA-Takeda Research Scholar Award in Gastroesophageal Reflux Disease and Barrett's Esophagus; National Institutes of Health FX Sachin Wani is supported by the AGA-Takeda Research Scholar Award in Gastroesophageal Reflux Disease and Barrett's Esophagus. Jennifer Drahos and Michael B. Cook are supported by the Intramural Program of the National Institutes of Health. NR 21 TC 10 Z9 11 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JAN 15 PY 2015 VL 121 IS 2 BP 194 EP 201 DI 10.1002/cncr.29043 PG 8 WC Oncology SC Oncology GA AY4IH UT WOS:000347540900006 PM 25236485 ER PT J AU Messinger, YH Stewart, DR Priest, JR Williams, GM Harris, AK Schultz, KAP Yang, JD Doros, L Rosenberg, PS Hill, DA Dehner, LP AF Messinger, Yoav H. Stewart, Douglas R. Priest, John R. Williams, Gretchen M. Harris, Anne K. Schultz, Kris Ann P. Yang, Jiandong Doros, Leslie Rosenberg, Philip S. Hill, D. Ashley Dehner, Louis P. TI Pleuropulmonary Blastoma: A Report on 350 Central Pathology-Confirmed Pleuropulmonary Blastoma Cases by the International Pleuropulmonary Blastoma Registry SO CANCER LA English DT Article DE childhood cancer; DICER1; pleuropulmonary blastoma; rare cancer ID PULMONARY BLASTOMA; PROGNOSTIC-FACTORS; DICER1 MUTATIONS; CHILDHOOD; TUMOR; EXPERIENCE; CHILDREN AB BACKGROUNDPleuropulmonary blastoma (PPB) has 3 subtypes on a tumor progression pathway ranging from type I (cystic) to type II (cystic/solid) and type III (completely solid). A germline mutation in DICER1 is the genetic cause in the majority of PPB cases. METHODSPatients confirmed to have PPB by central pathology review were included, and their clinical characteristics and outcomes were reported. Germline DICER1 mutations were sought with Sanger sequencing. RESULTSThere were 435 cases, and a central review confirmed 350 cases to be PPB; 85 cases (20%) were another entity. Thirty-three percent of the 350 PPB cases were type I or type I regressed (type Ir), 35% were type II, and 32% were type III or type II/III. The median ages at diagnosis for type I, type II, and type III patients were 8, 35, and 41 months, respectively. The 5-year overall survival (OS) rate for type I/Ir patients was 91%; all deaths in this group were due to progression to type II or III. OS was significantly better for type II versus type III (P=.0061); the 5-year OS rates were 71% and 53%, respectively. Disease-free survival (DFS) was also significantly better for type II versus type III (P=.0002); the 5-year DFS rates were 59% and 37%, respectively. The PPB type was the strongest predictor of outcome. Metastatic disease at the diagnosis of types II and III was also an independent unfavorable prognostic factor. Sixty-six percent of the 97 patients tested had a heterozygous germline DICER1 mutation. In this subset, the DICER1 germline mutation status was not related to the outcome. CONCLUSIONSCystic type I/Ir PPB has a better prognosis than type II, and type II has a better outcome than type III. Surveillance of DICER1 carriers may allow the earlier detection of cystic PPB before its progression to type II or III PPB and thereby improve outcomes. Cancer 2015;121:276-85. (c) 2014 American Cancer Society. Three hundred fifty centrally reviewed pleuropulmonary blastoma cases confirm that the outcomes of type I are better than the outcomes of type II and that the outcomes of type II are better than the outcomes of type III. Thus, the early detection of type I pleuropulmonary blastoma before its progression to type II or III may improve outcomes. C1 [Messinger, Yoav H.; Priest, John R.; Williams, Gretchen M.; Harris, Anne K.; Schultz, Kris Ann P.] Childrens Hosp & Clin Minnesota, Int Pleuropulm Blastoma Registry, Minneapolis, MN 55404 USA. [Stewart, Douglas R.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Yang, Jiandong; Hill, D. Ashley] Childrens Natl Med Ctr, Div Pathol, Washington, DC 20010 USA. [Yang, Jiandong; Hill, D. Ashley] George Washington Univ, Sch Med, Dept Integrat Syst Biol, Med Genet Res Ctr, Washington, DC USA. [Doros, Leslie] Childrens Natl Med Ctr, Div Oncol, Washington, DC 20010 USA. [Rosenberg, Philip S.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Dehner, Louis P.] Washington Univ, Lauren V Ackerman Lab Surg Pathol, Barnes Jewish Childrens Hosp, Dept Pathol & Immunol,Med Ctr, St Louis, MO USA. [Dehner, Louis P.] Washington Univ, St Louis Childrens Hosp, Lauren V Ackerman Lab Surg Pathol, Dept Pathol & Immunol,Med Ctr, St Louis, MO 63110 USA. RP Messinger, YH (reprint author), Childrens Hosp & Clin Minnesota, Int Pleuropulm Blastoma Registry, 2545 Chicago Ave South, Minneapolis, MN 55404 USA. EM yoav.messinger@childrensmn.org FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute's Intramural Research Program; Pine Tree Apple Tennis Classic; M. Schutt Foundation; Children's Hospitals of Minnesota Foundation; St. Baldrick's Foundation; Hyundai Hope on Wheels; National Institutes of Health FX This work was supported by the Division of Cancer Epidemiology and Genetics of the National Cancer Institute's Intramural Research Program. Charitable foundation grant support for this research was received from Pine Tree Apple Tennis Classic, the M. Schutt Foundation, and the Children's Hospitals of Minnesota Foundation. Kris Ann P. Schultz reports grants from St. Baldrick's Foundation, Hyundai Hope on Wheels, the National Institutes of Health (loan repayment program) during the conduct of the study. NR 32 TC 20 Z9 22 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JAN 15 PY 2015 VL 121 IS 2 BP 276 EP 285 DI 10.1002/cncr.29032 PG 10 WC Oncology SC Oncology GA AY4IH UT WOS:000347540900015 PM 25209242 ER PT J AU Alderfer, MA Zelley, K Lindell, RB Novokmet, A Mai, PL Garber, JE Nathan, D Scollon, S Chun, NM Patenaude, AF Ford, JM Plon, SE Schiffman, JD Diller, LR Savage, SA Malkin, D Ford, CA Nichols, KE AF Alderfer, Melissa A. Zelley, Kristin Lindell, Robert B. Novokmet, Ana Mai, Phuong L. Garber, Judy E. Nathan, Deepika Scollon, Sarah Chun, Nicolette M. Patenaude, Andrea F. Ford, James M. Plon, Sharon E. Schiffman, Joshua D. Diller, Lisa R. Savage, Sharon A. Malkin, David Ford, Carol A. Nichols, Kim E. TI Parent Decision-Making Around the Genetic Testing of Children for Germline TP53 Mutations SO CANCER LA English DT Article DE genetic testing; Li-Fraumeni syndrome; decision-making; pediatrics; cancer ID LI-FRAUMENI-SYNDROME; CANCER PREDISPOSITION; ISSUES; UPDATE; RISK AB BACKGROUNDLi-Fraumeni syndrome is a rare genetic cancer predisposition syndrome caused by germline TP53 mutations. Up to 20% of mutation carriers develop cancer during childhood. The benefits of TP53 mutation testing of children are a matter of debate and knowledge of parent decision-making around such testing is limited. The current study examined how parents make decisions regarding TP53 testing for their children. METHODSFamilies offered and those pursuing TP53 testing for their children were identified across the study sites. Qualitative interviews with 46 parents (39 families) were analyzed to describe decision-making styles and perceived advantages and disadvantages of testing. RESULTSTP53 mutation testing uptake was high (92%). Three decision-making styles emerged. Automatic decisions (44% of decisions) involved little thought and identified immediate benefit(s) in testing (100% pursued testing). Considered decisions (49%) weighed the risks and benefits but were made easily (77% pursued testing). Deliberated decisions (6%) were difficult and focused on psychosocial concerns (25% pursued testing). Perceived advantages of testing included promoting child health, satisfying a need to know, understanding why cancer(s) occurred, suggesting family member risk, and benefiting research. Disadvantages included psychosocial risks and privacy/discrimination/insurance issues. CONCLUSIONSAlthough empirical evidence regarding the benefits and risks of TP53 testing during childhood are lacking, the majority of parents in the current study decided easily in favor of testing and perceived a range of advantages. The authors conclude that in the context of a clinical diagnosis of Li-Fraumeni syndrome, parents should continue to be offered TP53 testing for their children, counseled regarding potential risks and benefits, and supported in their decision-making process. Cancer 2015;121:286-93. (c) 2014 American Cancer Society. Li-Fraumeni Syndrome (LFS) is a rare genetic cancer predisposition syndrome caused by germline TP53 mutations in which up to 20% of mutation carriers develop cancer during childhood. Although empirical evidence regarding benefits and risks of TP53 testing during childhood are lacking, most parents in our study decided easily in favor of testing and perceived a range of advantages that outweighed risks. C1 [Alderfer, Melissa A.; Zelley, Kristin; Lindell, Robert B.; Nichols, Kim E.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Alderfer, Melissa A.; Ford, Carol A.; Nichols, Kim E.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Novokmet, Ana; Malkin, David] Hosp Sick Children, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada. [Mai, Phuong L.; Savage, Sharon A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Garber, Judy E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA. [Garber, Judy E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Nathan, Deepika; Schiffman, Joshua D.] Univ Utah, Huntsman Canc Inst, High Risk Canc Clin, Salt Lake City, UT USA. [Nathan, Deepika; Schiffman, Joshua D.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Scollon, Sarah; Plon, Sharon E.] Texas Childrens Canc Ctr, Canc Genet & Genom Program, Houston, TX USA. [Scollon, Sarah; Plon, Sharon E.] Texas Childrens Hematol Ctr, Canc Genet & Genom Program, Houston, TX USA. [Chun, Nicolette M.; Ford, James M.] Stanford Univ, Med Ctr, Canc Genet Program, Stanford, CA 94305 USA. [Patenaude, Andrea F.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. [Patenaude, Andrea F.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Ford, James M.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Ford, James M.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Plon, Sharon E.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Plon, Sharon E.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Schiffman, Joshua D.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Diller, Lisa R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Childhood Canc Survivor Program, Boston, MA 02115 USA. [Diller, Lisa R.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Malkin, David] Univ Toronto, Dept Pediat, Toronto, ON, Canada. [Ford, Carol A.] Childrens Hosp Philadelphia, Div Adolescent Med, Philadelphia, PA 19104 USA. RP Alderfer, MA (reprint author), Nemours Alfred I duPont Hosp Children, Ctr Healthcare Delivery Sci, 1600 Rockland Rd, Wilmington, DE 19803 USA. EM melissa.alderfer@nemours.org RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU University of Pennsylvania Center for the Integration of Genetic Healthcare Technologies (Penn-CIGHT); Center for Childhood Cancer Research at The Children's Hospital of Philadelphia; Alex's Lemonade Stand Foundation FX Supported by grants from The University of Pennsylvania Center for the Integration of Genetic Healthcare Technologies (Penn-CIGHT), the Center for Childhood Cancer Research at The Children's Hospital of Philadelphia, and Alex's Lemonade Stand Foundation. NR 14 TC 5 Z9 5 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JAN 15 PY 2015 VL 121 IS 2 BP 286 EP 293 DI 10.1002/cncr.29027 PG 8 WC Oncology SC Oncology GA AY4IH UT WOS:000347540900016 PM 25223899 ER PT J AU Mandl, JN Ahmed, R Barreiro, LB Daszak, P Epstein, JH Virgin, HW Feinberg, MB AF Mandl, Judith N. Ahmed, Rafi Barreiro, Luis B. Daszak, Peter Epstein, Jonathan H. Virgin, Herbert W. Feinberg, Mark B. TI Reservoir Host Immune Responses to Emerging Zoonotic Viruses SO CELL LA English DT Review ID AFRICAN-GREEN MONKEYS; NONPATHOGENIC SIV INFECTION; ACUTE RESPIRATORY SYNDROME; EBOLA HEMORRHAGIC-FEVER; CHRONIC VIRAL-INFECTION; CD4(+) T-CELLS; INFLUENZA-VIRUS; NIPAH VIRUS; PTEROPID BATS; RISK-FACTORS AB Zoonotic viruses, such as HIV, Ebola virus, coronaviruses, influenza A viruses, hantaviruses, or henipaviruses, can result in profound pathology in humans. In contrast, populations of the reservoir hosts of zoonotic pathogens often appear to tolerate these infections with little evidence of disease. Why are viruses more dangerous in one species than another? Immunological studies investigating quantitative and qualitative differences in the host-virus equilibrium in animal reservoirs will be key to answering this question, informing new approaches for treating and preventing zoonotic diseases. Integrating an understanding of host immune responses with epidemiological, ecological, and evolutionary insights into viral emergence will shed light on mechanisms that minimize fitness costs associated with viral infection, facilitate transmission to other hosts, and underlie the association of specific reservoir hosts with multiple emerging viruses. Reservoir host studies provide a rich opportunity for elucidating fundamental immunological processes and their underlying genetic basis, in the context of distinct physiological and metabolic constraints that contribute to host resistance and disease tolerance. C1 [Mandl, Judith N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Barreiro, Luis B.] Univ Montreal, St Justine Hosp Res Ctr, Dept Pediat, Montreal, PQ H3T 1J4, Canada. [Daszak, Peter; Epstein, Jonathan H.] EcoHlth Alliance, New York, NY 10001 USA. [Virgin, Herbert W.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Feinberg, Mark B.] Merck & Co Inc, Merck Vaccines, West Point, PA 19486 USA. RP Mandl, JN (reprint author), McGill Univ, Dept Physiol, Montreal, PQ H3G 0B1, Canada. EM mandlj@niaid.nih.gov RI Barreiro, Luis/I-7772-2015 FU Intramural Research Program of NIAID, NIH FX We would like to thank Nienke Vrisekoop, Roland Regoes, and Ronald Germain for insightful comments, support, and advice during the preparation of this manuscript. We are also extremely grateful to Tony Schountz and our anonymous reviewers for their reading of the manuscript and their very thoughtful feedback. This work was supported, in part, by the Intramural Research Program of NIAID, NIH. NR 124 TC 20 Z9 20 U1 4 U2 89 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JAN 15 PY 2015 VL 160 IS 1-2 BP 20 EP 35 DI 10.1016/j.cell.2014.12.003 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AZ0GD UT WOS:000347923200006 PM 25533784 ER PT J AU Zhang, Y Shen, J AF Zhang, Yan Shen, Jun TI Regional and tissue-specific differences in brain glutamate concentration measured by in vivo single voxel MRS SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Human brain; Glutamate; H-1 MRS; Averaged echo time; Regional difference; Tissue composition; Metabolite quantification ID REGULARIZED LINESHAPE DECONVOLUTION; METABOLITE RELAXATION-TIMES; TE-AVERAGED PRESS; T-2 RELAXATION; WHITE-MATTER; 3 TESLA; SPECTROSCOPY; WATER; DISTRIBUTIONS; QUANTITATION AB Background: There is growing interest in characterizing spatial distribution of glutamate (Glu) in brain disorders. Comparing the differences in Glu concentration using magnetic resonance spectroscopy (MRS) is hampered by the confounding effects of different anatomical regions and tissue composition. New method: Effect of tissue composition on Glu concentrations was studied by selecting closely adjacent voxels within a designated cortical region. Glu regional differences were assessed using voxels comprising essentially the same tissue composition from different cortical regions. Results: Using point-resolved-spectroscopy (PRESS)-based averaged echo time method, Glu concentration in the anterior cingulate cortex (ACC) was found to correlate strongly with tissue gray matter (GM) fraction (r = 0.87, p = 10(-5)). No significant regional difference in Glu concentration was found between frontal and occipital lobes (p = 0.23) when the two measured voxels had essentially the same tissue composition. Comparison with existing methods: The method of the current study is aimed to circumvent the difficulties in differentiating anatomical region from tissue composition, given that both can lead to Glu variations in brain. Glu concentration versus tissue composition was measured in the same anatomical region, while the comparison of regional differences was performed with the two regions that had essentially the same tissue composition. Conclusions: In brain cortices, Glu level is significantly higher in GM than in WM. Glu level difference between frontal lobe and occipital lobe is insignificant. Published by Elsevier B.V. C1 [Zhang, Yan; Shen, Jun] NIMH, MR Spect Core Facil, NIH, Bethesda, MD 20892 USA. [Shen, Jun] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Zhang, Y (reprint author), NIMH, MR Spect Core Facil, Bldg 10 Room 2D50,9000 Rockville Pike, Bethesda, MD 20892 USA. EM zhangya@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [ZIC MH002894-08] FX This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) (grant no. ZIC MH002894-08). The NIMH had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 36 TC 5 Z9 5 U1 0 U2 0 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 JAN 15 PY 2015 VL 239 BP 94 EP 99 DI 10.1016/j.jneumeth.2014.09.021 PG 6 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AY6GE UT WOS:000347664400011 PM 25261738 ER PT J AU Williams, KE Miroshnychenko, O Johansen, EB Niles, RK Sundaram, R Kannan, K Albertolle, M Zhou, Y Prasad, N Drake, PM Giudice, LC Hall, SC Witkowska, HE Louis, GMB Fisher, SJ AF Williams, Katherine E. Miroshnychenko, Olga Johansen, Eric B. Niles, Richard K. Sundaram, Rajeshwari Kannan, Kurunthachalam Albertolle, Matthew Zhou, Yan Prasad, Namrata Drake, Penelope M. Giudice, Linda C. Hall, Steven C. Witkowska, H. Ewa Louis, Germaine M. Buck Fisher, Susan J. TI Urine, peritoneal fluid and omental fat proteomes of reproductive age women: Endometriosis-related changes and associations with endocrine disrupting chemicals SO JOURNAL OF PROTEOMICS LA English DT Article DE Endometriosis; Peritoneal fluid; Urine; Omental fat; Mass spectrometry; Environmental chemicals ID PHTHALATE-ESTERS; ADIPOSE-TISSUE; BISPHENOL-A; BIOMARKERS; PROTEIN; CELLS; CHROMATOGRAPHY; PROGRESSION; DISCOVERY; DIAGNOSIS AB Endometriosis, ectopic growth of the uterine lining (endometrium), which affects 6-11% of reproductive age women, is associated with pelvic pain and infertility. We investigated the peritoneal fluid (PF), urine and omental fat (OF) proteomes of women with endometriosis vs. individuals with no surgically visualized endometriosis. All participants were enrolled in the NICHD-funded ENDO Study. A two-step proteomic study was performed. The first, a broad survey, employed a semi-quantitative gel LC-mass spectrometry (MS) workflow: SDS PAGE fractionation, trypsin digestion and LC MS/MS. The results showed sample integrity but failed to detect any differences between women with and without endometriosis. The second step was a quantitative analysis of OF samples. We employed another sample set (n = 30) from women +/- disease and isobaric mass-tag (iTRAQ) chemistry to label peptides and 2D LC MS/MS for protein identification and quantification. Three proteins matrix metalloproteinase-9, neutrophil elastase, and FAM49B-were significantly lower in abundance in samples from women with endometriosis. Interestingly, neutrophil elastase and FAM49B levels were associated with higher levels of a subset of endocrine disrupting chemicals (EDCs) that were previously measured in the same samples. The results of these experiments showed the feasibility of associating endometriosis with changes in the OF protein repertoire and EDC levels. Biological significance Endometriosis, pathological growth of the uterine lining, is associated with significant morbidities, including pain and infertility. However, the causes of this common condition are poorly understood. This study determined whether endometriosis was associated with changes in the protein composition of peritoneal fluid, urine and/or omental fat. A protein of unknown function (FAM49B) and two proteinases (metalloproteinase-9, neutrophil elastase) were down regulated in OF samples from women with versus without endometriosis. These findings suggested proteinase imbalances at sites that were distant from the endometriotic lesions. Additionally, FAM49B and neutrophil elastase levels were associated with higher levels of a subset of environmental chemicals that were quantified in the same samples, suggesting other possible associations. Thus, this work generated hypotheses that will be tested in further studies. (C) 2014 Elsevier B.V. All rights reserved. C1 [Williams, Katherine E.; Miroshnychenko, Olga; Johansen, Eric B.; Niles, Richard K.; Albertolle, Matthew; Prasad, Namrata; Drake, Penelope M.; Hall, Steven C.; Witkowska, H. Ewa; Fisher, Susan J.] Univ Calif San Francisco, Sandler Moore Mass Spectrometry Core Facil, San Francisco, CA 94143 USA. [Williams, Katherine E.; Prasad, Namrata; Giudice, Linda C.; Hall, Steven C.; Witkowska, H. Ewa; Fisher, Susan J.] Univ Calif San Francisco, Ctr Reprod Sci, San Francisco, CA 94143 USA. [Williams, Katherine E.; Zhou, Yan; Prasad, Namrata; Giudice, Linda C.; Hall, Steven C.; Witkowska, H. Ewa; Fisher, Susan J.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Sundaram, Rajeshwari; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Kannan, Kurunthachalam] New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. [Fisher, Susan J.] Univ Calif San Francisco, Div Maternal Fetal Med, San Francisco, CA 94143 USA. [Zhou, Yan; Fisher, Susan J.] Univ Calif San Francisco, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA. [Fisher, Susan J.] Univ Calif San Francisco, Human Embryon Stem Cell Program, San Francisco, CA 94143 USA. [Fisher, Susan J.] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. RP Fisher, SJ (reprint author), Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. EM sfisher@cgl.ucsf.edu OI Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU NIH/NCI Cancer Center Support Grant [P30 CA082103]; Sandler New Technology Award; Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [NO1-DK-6-3428, NO1-DK-6-3427, 10001406-02] FX Funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contracts NO1-DK-6-3428; NO1-DK-6-3427; 10001406-02). Ethicon Endo-Surgery, LLC, kindly donated the HARMONIC ACE 36P shears and scalpel blades for use in the study through a signed Materials Transfer Agreement with the University of Utah and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The UCSF Sandler-Moore Mass Spectrometry Core Facility acknowledges support from a Sandler New Technology Award, a gift from the Gordon and Betty Moore Foundation, and NIH/NCI Cancer Center Support Grant P30 CA082103. NR 61 TC 3 Z9 4 U1 5 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-3919 EI 1876-7737 J9 J PROTEOMICS JI J. Proteomics PD JAN 15 PY 2015 VL 113 BP 194 EP 205 DI 10.1016/j.jprot.2014.09.015 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AY4ZA UT WOS:000347582200014 PM 25284053 ER PT J AU Gurdasani, D Carstensen, T Tekola-Ayele, F Pagani, L Tachmazidou, I Hatzikotoulas, K Karthikeyan, S Iles, L Pollard, MO Choudhury, A Ritchie, GS Xue, YL Asimit, J Nsubuga, RN Young, EH Pomilla, C Kivinen, K Rockett, K Kamali, A Doumatey, AP Asiki, G Seeley, J Sisay-Joof, F Jallow, M Tollman, S Mekonnen, E Ekong, R Oljira, T Bradman, N Bojang, K Ramsay, M Adeyemo, A Bekele, E Motala, A Norris, SA Pirie, F Kaleebu, P Kwiatkowski, D Tyler-Smith, C Rotimi, C Zeggini, E Sandhu, MS AF Gurdasani, Deepti Carstensen, Tommy Tekola-Ayele, Fasil Pagani, Luca Tachmazidou, Ioanna Hatzikotoulas, Konstantinos Karthikeyan, Savita Iles, Louise Pollard, Martin O. Choudhury, Ananyo Ritchie, GrahamR. S. Xue, Yali Asimit, Jennifer Nsubuga, Rebecca N. Young, Elizabeth H. Pomilla, Cristina Kivinen, Katja Rockett, Kirk Kamali, Anatoli Doumatey, Ayo P. Asiki, Gershim Seeley, Janet Sisay-Joof, Fatoumatta Jallow, Muminatou Tollman, Stephen Mekonnen, Ephrem Ekong, Rosemary Oljira, Tamiru Bradman, Neil Bojang, Kalifa Ramsay, Michele Adeyemo, Adebowale Bekele, Endashaw Motala, Ayesha Norris, Shane A. Pirie, Fraser Kaleebu, Pontiano Kwiatkowski, Dominic Tyler-Smith, Chris Rotimi, Charles Zeggini, Eleftheria Sandhu, Manjinder S. TI The African Genome Variation Project shapes medical genetics in Africa SO NATURE LA English DT Article ID POPULATION-GENETICS; WIDE ASSOCIATION; MALARIA; SELECTION; HYPERTENSION; HISTORY; SUSCEPTIBILITY; REVEALS; DIVERSITY; EVOLUTION AB Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa. C1 [Gurdasani, Deepti; Carstensen, Tommy; Pagani, Luca; Tachmazidou, Ioanna; Hatzikotoulas, Konstantinos; Karthikeyan, Savita; Iles, Louise; Pollard, Martin O.; Ritchie, GrahamR. S.; Xue, Yali; Asimit, Jennifer; Young, Elizabeth H.; Pomilla, Cristina; Kivinen, Katja; Adeyemo, Adebowale; Kwiatkowski, Dominic; Tyler-Smith, Chris; Zeggini, Eleftheria; Sandhu, Manjinder S.] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Gurdasani, Deepti; Carstensen, Tommy; Karthikeyan, Savita; Iles, Louise; Young, Elizabeth H.; Pomilla, Cristina; Sandhu, Manjinder S.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Tekola-Ayele, Fasil; Doumatey, Ayo P.; Adeyemo, Adebowale; Rotimi, Charles] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20891 USA. [Pagani, Luca] Univ Bologna, Dept Biol Geol & Environm Sci, I-40126 Bologna, Italy. [Iles, Louise] Univ York, Dept Archaeol, York YO1 7EP, N Yorkshire, England. [Choudhury, Ananyo; Ramsay, Michele] Univ Witwatersrand, SBIMB, Johannesburg, Gauteng, South Africa. [Ritchie, GrahamR. S.] European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England. [Nsubuga, Rebecca N.; Kamali, Anatoli; Asiki, Gershim; Seeley, Janet; Kaleebu, Pontiano] Uganda Virus Res Inst, MRC, Entebbe, Uganda. [Rockett, Kirk; Kwiatkowski, Dominic] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Sisay-Joof, Fatoumatta; Jallow, Muminatou; Bojang, Kalifa] MRC Unit, Banjul, Gambia. [Tollman, Stephen] MRC, Sch Publ Hlth, Wits Rural Publ Hlth & Hlth Transit Unit, Johannesburg, Gauteng, South Africa. [Tollman, Stephen] INDEPTH Network, Accra, Ghana. [Mekonnen, Ephrem] Univ Addis Ababa, Inst Biotechnol, Addis Ababa, Ethiopia. [Ekong, Rosemary] UCL, Dept Genet Evolut & Environm, London, England. [Oljira, Tamiru] Univ Haramaya, Dept Biol, Dire Dawa, Ethiopia. [Bradman, Neil] Henry Stewart Grp, London WC1A 2HN, England. [Ramsay, Michele] Natl Hlth Lab Serv, Div Human Genet, ZA-2000 Johannesburg, South Africa. [Ramsay, Michele] Univ Witwatersrand, Fac Hlth Sci, Sch Pathol, ZA-2000 Johannesburg, South Africa. [Bekele, Endashaw] Univ Addis Ababa, Coll Nat Sci, Dept Microbial Cellular & Mol Biol, Addis Ababa, Ethiopia. [Motala, Ayesha; Pirie, Fraser] Univ KwaZulu Natal, Dept Endocrinol & Diabet, ZA-4013 Durban, South Africa. [Norris, Shane A.] Univ Witwatersrand, Dept Paediat, Johannesburg, Gauteng, South Africa. RP Sandhu, MS (reprint author), Wellcome Trust Sanger Inst, Genome Campus, Cambridge CB10 1SA, England. EM dg11@sanger.ac.uk; cts@sanger.ac.uk; rotimic@mail.nih.gov; eleftheria@sanger.ac.uk; ms23@sanger.ac.uk RI Pollard, Martin/G-7205-2012; OI Pollard, Martin/0000-0001-8738-0920; Seeley, Janet/0000-0002-0583-5272; Asimit, Jennifer/0000-0002-4857-2249; Pagani, Luca/0000-0002-6639-524X; Adeyemo, Adebowale/0000-0002-3105-3231; Zeggini, Eleftheria/0000-0003-4238-659X; Kivinen, Katja/0000-0002-1135-7625; Kwiatkowski, Dominic/0000-0002-5023-0176; Tekola-Ayele, Fasil/0000-0003-4194-9370 FU Wellcome Trust [WT077383/Z/05/Z]; Wellcome Trust Sanger Institute [WT098051]; Bill and Melinda Gates Foundation; Foundation for the National Institutes of Health [566]; UK Medical Research Council [G0901213-92157, G0801566, G0600718, MR/K013491/1]; South African Sugar Association; Servier South Africa; Victor Daitz Foundation; National Institute on Minority Health and Health Disparities; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Human Genome Research Institute (NHGRI); Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH) [Z01HG200362]; MRC Centre for Genomics and Global Health; Cambridge Commonwealth Scholarship FX This project was funded in part by the Wellcome Trust (grant number WT077383/Z/05/Z), The Wellcome Trust Sanger Institute (grant number WT098051), the Bill and Melinda Gates Foundation, the Foundation for the National Institutes of Health (grant number 566), and the UK Medical Research Council (grant numbers G0901213-92157, G0801566, G0600718 and MR/K013491/1). We also acknowledge the National Institute for Health Research Cambridge Biomedical Research Centre and the Wellcome Trust Cambridge Centre for Global Health Research. We are very grateful to J. Pickrell for sharing human origins data and MALDER code, and for useful input on interpretations of these analyses. We also thank E. Garrison for his suggestions on using Genome in a bottle sets (ftp://ftp-trace.ncbi.nih.gov/giab/ftp/data/NA12878/variant_calls/NIST/R EADME.NIST.v2.18.txt) for validation of whole-genome sequencing data. We also thank the African Partnership for Chronic Disease Research (APCDR)for providing a network to support this study as well as a repository for deposition of curated data. Sample collections from South Africa were funded by The South African Sugar Association, Servier South Africa and The Victor Daitz Foundation. The Kenyan samples were collected by D. Ngare of Moi University, Eldoret, Kenya, as part of the Africa America Diabetes Mellitus (AADM) study and the International HapMap project (D. Ngare, who is now deceased, was a great supporter of genomics in Africa,as exemplified by his leadership in engaging the Luhya and Maasai communities for the HapMap project). The Igbo samples were collected by J. Oli of the University of Nigeria, Enugu, Nigeria. The Ga-Adangbe samples were collected by the laboratories of A. Amoah of the University of Ghana, Accra, Ghana, and J. Acheampong of the University of Science and Technology, Kumasi, Ghana. Support for the AADM study is provided by the National Institute on Minority Health and Health Disparities, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Human Genome Research Institute (NHGRI). The Gambian samples were collected by M. Jallow and colleagues at the MRC Unit, The Gambia and form part of the MalariaGEN Consortial Resource. This research was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH; grant number Z01HG200362) and by the MRC Centre for Genomics and Global Health. D.G. was funded by the Cambridge Commonwealth Scholarship. We thank the 1000 Genomes Project for sharing genotype data that were analysed as part of this project. We also thank all study participants who contributed to this study. NR 50 TC 75 Z9 75 U1 5 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JAN 15 PY 2015 VL 517 IS 7534 BP 327 EP U397 DI 10.1038/nature13997 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY8NK UT WOS:000347810300037 PM 25470054 ER PT J AU Barretto, RPJ Gillis-Smith, S Chandrashekar, J Yarmolinsky, DA Schnitzer, MJ Ryba, NJP Zuker, CS AF Barretto, Robert P. J. Gillis-Smith, Sarah Chandrashekar, Jayaram Yarmolinsky, David A. Schnitzer, Mark J. Ryba, Nicholas J. P. Zuker, Charles S. TI The neural representation of taste quality at the periphery SO NATURE LA English DT Article ID FLUORESCENCE MICROENDOSCOPY; MAMMALIAN BRAIN; CHORDA TYMPANI; UMAMI TASTE; RECEPTORS; STIMULI; SWEET; CELLS; MICE; BUDS AB The mammalian taste system is responsible for sensing and responding to the five basic taste qualities: sweet, sour, bitter, salty and umami. Previously, we showed that each taste is detected by dedicated taste receptor cells (TRCs) on the tongue and palate epithelium(1). To understand how TRCs transmit information to higher neural centres, we examined the tuning properties of large ensembles of neurons in the first neural station of the gustatory system. Here, we generated and characterized a collection of transgenic mice expressing a genetically encoded calcium indicator' in central and peripheral neurons, and used a gradient refractive index microendoscope combined with high-resolution two-photon microscopy to image taste responses from ganglion neurons buried deep at the base of the brain. Our results reveal fine selectivity in the taste preference of ganglion neurons; demonstrate a strong match between TRCs in the tongue and the principal neural afferents relaying taste information to the brain; and expose the highly specific transfer of taste information between taste cells and the central nervous system. C1 [Barretto, Robert P. J.; Gillis-Smith, Sarah; Yarmolinsky, David A.; Zuker, Charles S.] Columbia Univ, Coll Phys & Surg, Howard Hughes Med Inst, New York, NY 10032 USA. [Barretto, Robert P. J.; Gillis-Smith, Sarah; Yarmolinsky, David A.; Zuker, Charles S.] Columbia Univ, Coll Phys & Surg, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Barretto, Robert P. J.; Gillis-Smith, Sarah; Yarmolinsky, David A.; Zuker, Charles S.] Columbia Univ, Coll Phys & Surg, Dept Neurosci, New York, NY 10032 USA. [Chandrashekar, Jayaram; Zuker, Charles S.] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Schnitzer, Mark J.] Stanford Univ, James H Clark Ctr, Stanford, CA 94305 USA. [Ryba, Nicholas J. P.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Zuker, CS (reprint author), Columbia Univ, Coll Phys & Surg, Howard Hughes Med Inst, New York, NY 10032 USA. EM nick.ryba@nih.gov; cz2195@columbia.edu FU NIDCR FX We thank the National Institute of Dental and Craniofacial Research (NIDCR) transgenic-core and C. Guo at Janelia Farms for help in generating the Thy1-GCaMP3 mouse lines, B. Shields for histology support, and Y. Oka and M. Butnaru for nerve recording and pharmacological advice. We also thank members of the Zuker laboratory for helpful comments. This research was supported in part by the intramural research program of NIDCR (N.J.P.R.). C.S.Z. is an investigator of the Howard Hughes Medical Institute and a Senior Fellow at Janelia Farms. NR 30 TC 23 Z9 23 U1 5 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JAN 15 PY 2015 VL 517 IS 7534 BP 373 EP U511 DI 10.1038/nature13873 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY8NK UT WOS:000347810300047 PM 25383521 ER PT J AU Wang, H Ferraris, JD Klein, JD Sands, JM Burg, MB Zhou, XM AF Wang, Hong Ferraris, Joan D. Klein, Janet D. Sands, Jeff M. Burg, Maurice B. Zhou, Xiaoming TI PKC-alpha contributes to high NaCl-induced activation of NFAT5 (TonEBP/OREBP) through MAPK ERK1/2 SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE inner medulla; hypertonicity; Src homology 2 domain-containing phosphatase 1; serine-591-phosphorylated Src homology 2 domain-containing phosphatase 1; urinary concentration; nuclear factor of activated T cells 5; tonicity-responsive enhancer-binding protein; osmotic response element-binding protein ID KINASE-C-ALPHA; TRANSCRIPTION FACTOR TONEBP/OREBP; MEDULLARY COLLECTING DUCTS; PATHOGENIC T(H)17 CELLS; THICK ASCENDING LIMB; TYROSINE-PHOSPHATASE; GENE-EXPRESSION; PROTEIN; HYPERTONICITY; KIDNEY AB High NaCl in the renal medullary interstitial fluid powers the concentration of urine but can damage cells. The transcription factor nuclear factor of activated T cells 5 (NFAT5) activates the expression of osmoprotective genes. We studied whether PKC-alpha contributes to the activation of NFAT5. PKC-alpha protein abundance was greater in the renal medulla than in the cortex. Knockout of PKC-alpha reduced NFAT5 protein abundance and expression of its target genes in the inner medulla. In human embryonic kidney (HEK)-293 cells, high NaCl increased PKC-alpha activity, and small interfering RNA-mediated knockdown of PKC-alpha attenuated high NaCl-induced NFAT5 transcriptional activity. Expression of ERK1/2 protein and phosphorylation of ERK1/2 were higher in the renal inner medulla than in the cortex. Knockout of PKC-alpha decreased ERK1/2 phosphorylation in the inner medulla, as did knockdown of PKC-alpha in HEK-293 cells. Also, knockdown of ERK2 reduced high NaCl-dependent NFAT5 transcriptional activity in HEK-293 cells. Combined knockdown of PKC-alpha and ERK2 had no greater effect than knockdown of either alone. Knockdown of either PKC-alpha or ERK2 reduced the high NaCl-induced increase of NFAT5 transactivating activity. We have previously found that the high NaCl-induced increase of phosphorylation of Ser(591) on Src homology 2 domain-containing phosphatase 1 (SHP-1-S591-P) contributes to the activation of NFAT5 in cell culture, and here we found high levels of SHP-1-S591-P in the inner medulla. PKC-alpha has been previously shown to increase SHP-1-S591-P, which raised the possibility that PKC-alpha might be acting through SHP-1. However, we did not find that knockout of PKC-alpha in the renal medulla or knockdown in HEK-293 cells affected SHP-1-S591-P. We conclude that PKC-alpha contributes to high NaCl-dependent activation of NFAT5 through ERK1/2 but not through SHP-1-S591. C1 [Wang, Hong; Zhou, Xiaoming] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Ferraris, Joan D.; Burg, Maurice B.] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Klein, Janet D.; Sands, Jeff M.] Emory Univ, Sch Med, Div Renal, Atlanta, GA 30322 USA. RP Zhou, XM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM xiaoming.zhou@usuhs.edu FU Uniformed Services University [R083ZY]; National Institutes of Health (NIH) [HL-006134-04, R01-DK-89828] FX This work was funded in part by Uniformed Services University Grant R083ZY (to X. Zhou) and National Institutes of Health (NIH) Grant HL-006134-04 (to M. B. Burg). J. D. Klein and J. M. Sands were supported by NIH Grant R01-DK-89828. NR 51 TC 7 Z9 7 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JAN 15 PY 2015 VL 308 IS 2 BP F140 EP F148 DI 10.1152/ajprenal.00471.2014 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA AY3DC UT WOS:000347463700009 PM 25391900 ER PT J AU Lugrin, J Parapanov, R Rosenblatt-Velin, N Rignault-Clerc, S Feihl, F Waeber, B Muller, O Vergely, C Zeller, M Tardivel, A Schneider, P Pacher, P Liaudet, L AF Lugrin, Jerome Parapanov, Roumen Rosenblatt-Velin, Nathalie Rignault-Clerc, Stephanie Feihl, Francois Waeber, Bernard Mueller, Olivier Vergely, Catherine Zeller, Marianne Tardivel, Aubry Schneider, Pascal Pacher, Pal Liaudet, Lucas TI Cutting Edge: IL-1 alpha Is a Crucial Danger Signal Triggering Acute Myocardial Inflammation during Myocardial Infarction SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NLRP3 INFLAMMASOME; CELLS; INJURY; FIBROBLASTS; REPAIR AB Myocardial infarction (MI) induces a sterile inflammatory response that contributes to adverse cardiac remodeling. The initiating mechanisms of this response remain incompletely defined. We found that necrotic cardiomyocytes released a heat-labile proinflammatory signal activating MAPKs and NF-kappa B in cardiac fibroblasts, with secondary production of cytokines. This response was abolished in Myd88(-/-) fibroblasts but was unaffected in nlrp3-deficient fibroblasts. Despite MyD88 dependency, the response was TLR independent, as explored in TLR reporter cells, pointing to a contribution of the IL-1 pathway. Indeed, necrotic cardiomyocytes released IL-1 alpha, but not IL-1 beta, and the immune activation of cardiac fibroblasts was abrogated by an IL-1R antagonist and an IL-1 alpha-blocking Ab. Moreover, immune responses triggered by necrotic Il1a(-/-) cardiomyocytes were markedly reduced. In vivo, mice exposed to MI released IL-1 alpha in the plasma, and postischemic inflammation was attenuated in Il1a(-/-) mice. Thus, our findings identify IL-1 alpha as a crucial early danger signal triggering post-MI inflammation. C1 [Lugrin, Jerome; Parapanov, Roumen; Liaudet, Lucas] Univ Lausanne, Univ Hosp Med Ctr, Dept Intens Care Med, CH-1011 Lausanne, Switzerland. [Rosenblatt-Velin, Nathalie; Rignault-Clerc, Stephanie; Feihl, Francois; Waeber, Bernard; Liaudet, Lucas] Univ Lausanne, Univ Hosp Med Ctr, Dept Clin Pathophysiol, CH-1011 Lausanne, Switzerland. [Mueller, Olivier] Univ Lausanne, Univ Hosp Med Ctr, Dept Cardiol, CH-1011 Lausanne, Switzerland. [Vergely, Catherine; Zeller, Marianne] Univ Bourgogne, Fac Med & Pharm, INSERM Unite Mixte Rech 866, Lab Physiopathol & Pharmacol Cardiometabol, F-21000 Dijon, France. [Tardivel, Aubry; Schneider, Pascal] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Pacher, Pal] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Liaudet, L (reprint author), Univ Hosp Med Ctr, Fac Biol & Med, Dept Intens Care Med, CH-1010 Lausanne, Switzerland. EM lucas.liaudet@chuv.ch RI Pacher, Pal/B-6378-2008; Vergely, Catherine/L-9534-2015; Lugrin, Jerome/F-8739-2011; Liaudet, Lucas/E-1322-2017 OI Pacher, Pal/0000-0001-7036-8108; Lugrin, Jerome/0000-0002-1178-2752; Liaudet, Lucas/0000-0003-2670-4930 FU Swiss National Foundation for Scientific Research [310030_135394/1, 310030_132491]; Muschamp Foundation; National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism FX This work was supported by the Swiss National Foundation for Scientific Research (Grants 310030_135394/1 to L.L. and 310030_132491 to N.R.-V.), the Muschamp Foundation (to L.L.), and the Intramural Program of the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism (to P.P.). Breeding of Nlrp3-/- mice was supported by the Institute for Arthritis Research at Lausanne University. NR 16 TC 16 Z9 17 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 JAN 15 PY 2015 VL 194 IS 2 BP 499 EP 503 DI 10.4049/jimmunol.1401948 PG 5 WC Immunology SC Immunology GA AX8RR UT WOS:000347176700002 PM 25505286 ER PT J AU Saunders, PM Vivian, JP Baschuk, N Beddoe, T Widjaja, J O'Connor, GM Hitchen, C Pymm, P Andrews, DM Gras, S McVicar, DW Rossjohn, J Brooks, AG AF Saunders, Philippa M. Vivian, Julian P. Baschuk, Nikola Beddoe, Travis Widjaja, Jacqueline O'Connor, Geraldine M. Hitchen, Corinne Pymm, Phillip Andrews, Daniel M. Gras, Stephanie McVicar, Daniel W. Rossjohn, Jamie Brooks, Andrew G. TI The Interaction of KIR3DL1*001 with HLA Class I Molecules Is Dependent upon Molecular Microarchitecture within the Bw4 Epitope SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; MAJOR HISTOCOMPATIBILITY COMPLEX; IMMUNOGLOBULIN-LIKE RECEPTOR; INHIBITORY RECEPTOR; CRYSTAL-STRUCTURE; MEDIATED LYSIS; NK CELLS; T-CELLS; RECOGNITION; KIR3DL1 AB The killer cell Ig-like receptor 3DL1 (KIR3DL1) inhibits activation of NK cells upon interaction with HLA class I molecules such as HLA-B*57:01, which contains the Bw4 epitope spanning residues 77-83 (e.g., NLRIALR), and not with HLA allomorphs that possess the Bw6 motif (e.g., HLA-B*08:01), which differ at residues 77, 80, 81, 82, and 83. Although Bw4 residues Ile(80) and Arg(83) directly interact with KIR3DL1*001, their precise role in determining KIR3DL1-HLA-Bw4 specificity remains unclear. Recognition of HLA-B*57:01 by either KIR3DL1(+) NK cells or the NK cell line YTS transfected with KIR3DL1*001 was impaired by mutation of residues 80 and 83 of HLA-B*57:01 to the corresponding amino acids within the Bw6 motif. Conversely, the simultaneous introduction of three Bw4 residues at positions 80, 82, and 83 into HLA-B*08: 01 conferred an interaction with KIR3DL1*001. Structural analysis of HLA-B*57:01, HLA-B*08:01, and mutants of each bearing substitutions at positions 80 and 83 revealed that Ile(80) and Arg(83) within the Bw4 motif constrain the conformation of Glu(76), primarily through a salt bridge between Arg(83) and Glu(76). This salt bridge was absent in HLA-Bw6 molecules as well as position 83 mutants of HLA-B*57:01. Mutation of the Bw4 residue Ile(80) also disrupted this salt bridge, providing further insight into the role that position 80 plays in mediating KIR3DL1 recognition. Thus, the strict conformation of HLA-Bw4 allotypes, held in place by the Glu(76)-Arg(83) interaction, facilitates KIR3DL1 binding, whereas Bw6 allotypes present a platform on the alpha 1 helix that is less permissive for KIR3DL1 binding. C1 [Saunders, Philippa M.; Widjaja, Jacqueline; Brooks, Andrew G.] Univ Melbourne, Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia. [Vivian, Julian P.; Beddoe, Travis; Hitchen, Corinne; Pymm, Phillip; Gras, Stephanie; Rossjohn, Jamie] Monash Univ, Dept Biochem & Mol Biol, Sch Biomed Sci, Clayton, Vic 3800, Australia. [Vivian, Julian P.; Rossjohn, Jamie] Monash Univ, Australian Res Council, Ctr Excellence Adv Mol Imaging, Clayton, Vic 3800, Australia. [Baschuk, Nikola; Andrews, Daniel M.] Peter McCallum Canc Inst, Canc Immunol Program, Melbourne, Vic 3002, Australia. [O'Connor, Geraldine M.; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Rossjohn, Jamie] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. RP Rossjohn, J (reprint author), Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. EM jamie.rossjohn@monash.edu; agbrooks@unimelb.edu.au RI McVicar, Daniel/G-1970-2015; OI Brooks, Andrew/0000-0002-4085-9683; Rossjohn, Jamie/0000-0002-2020-7522 FU National Health and Medical Research Council; Association for International Cancer Research; Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN26120080001E]; National Health and Medical Research Council Career Development Award FX This work was supported by grants from the National Health and Medical Research Council and the Association for International Cancer Research (to A.G.B. and J.R.), and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, and federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health Contract HHSN26120080001E. J.P.V. is an Australian Research Council Discovery Early Career Researcher Award Fellow; D.M.A. is the recipient of a National Health and Medical Research Council Career Development Award; and J.R. is a National Health and Medical Research Council of Australia Fellow. NR 41 TC 6 Z9 6 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2015 VL 194 IS 2 BP 781 EP 789 DI 10.4049/jimmunol.1402542 PG 9 WC Immunology SC Immunology GA AX8RR UT WOS:000347176700029 PM 25480565 ER PT J AU Kumar, S Sarkar, P Sim, MJW Rajagopalan, S Vogel, SS Long, EO AF Kumar, Santosh Sarkar, Pabak Sim, Malcolm J. W. Rajagopalan, Sumati Vogel, Steven S. Long, Eric O. TI A Single Amino Acid Change in Inhibitory Killer Cell Ig-like Receptor Results in Constitutive Receptor Self-Association and Phosphorylation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BIMOLECULAR FLUORESCENCE COMPLEMENTATION; TARGET-CELLS; DIRECT BINDING; NK CELLS; ACTIVATION; COMPLEX; CYTOTOXICITY; RECOGNITION; LYMPHOCYTES; MOLECULES AB Signaling by immunoreceptors is often initiated by phosphorylation of cytosolic tyrosines, which then recruit effector molecules. In the case of MHC class I-specific inhibitory receptors, phosphorylation of cytosolic tyrosine residues within ITIMs results in recruitment of a protein tyrosine phosphatase that blocks activation signals. Recent work showed that signaling by an HLA-C-specific killer cell Ig-like receptor (KIR) is independent of signaling by activation receptors. It is not known how ITIM phosphorylation is initiated and regulated. In this article, we show that substitution of His-36 in the first Ig domain of KIR2DL1 with alanine (KIR2DL1-H36A) resulted in constitutive KIR2DL1 self-association and phosphorylation, as well as recruitment of tyrosine phosphatase SHP-1. Furthermore, substitution of His-36 with a similar bulky amino acid, phenylalanine, maintained the receptor in its unphosphorylated state, suggesting that steric hindrance by the His-36 side chain prevents constitutive KIR2DL1 self-association and ITIM phosphorylation. The equally strong phosphorylation of KIR2DL1 and KIR2DL1-H36A after inhibition of tyrosine phosphatase by pervanadate suggested that KIR2DL1-H36A is selectively protected from dephosphorylation. We propose that KIR phosphorylation is controlled by the accessibility of ITIM to tyrosine phosphatases and that KIR binding to HLA-C must override the hindrance that His-36 puts on KIR2DL1 self-association. Expression of KIR2DL1-H36A on NK cells led to stronger inhibition of lysis of HLA-C+ target cells than did expression of wild-type KIR2DL1. These results revealed that ITIM phosphorylation is controlled by self-association of KIR and that His-36 serves as a gatekeeper to prevent unregulated signaling through KIR2DL1. C1 [Kumar, Santosh; Sim, Malcolm J. W.; Rajagopalan, Sumati; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Sarkar, Pabak; Vogel, Steven S.] NIAAA, Lab Mol Physiol, NIH, Rockville, MD 20892 USA. [Sim, Malcolm J. W.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Med, Lung Immunol Grp, London W12 0NN, England. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr,Room 201E, Rockville, MD 20852 USA. EM elong@nih.gov OI Vogel, Steven/0000-0002-3005-2667; Sim, Malcolm/0000-0003-3407-9661 FU Intramural Research Program at the National Institutes of Health, National Institute of Allergy and Infectious Diseases; National Institute on Alcohol Abuse and Alcoholism; National Institutes of Health-Wellcome Trust studentship FX This work was supported by the Intramural Research Program at the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute on Alcohol Abuse and Alcoholism. M.J.W.S. is supported by a National Institutes of Health-Wellcome Trust studentship. NR 38 TC 4 Z9 4 U1 0 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2015 VL 194 IS 2 BP 817 EP 826 DI 10.4049/jimmunol.1401830 PG 10 WC Immunology SC Immunology GA AX8RR UT WOS:000347176700033 PM 25505289 ER PT J AU Cannon, TD Chung, Y He, G Sun, DQ Jacobson, A van Erp, TGM McEwen, S Addington, J Bearden, CE Cadenhead, K Cornblatt, B Mathalon, DH McGlashan, T Perkins, D Jeffries, C Seidman, LJ Tsuang, M Walker, E Woods, SW Heinssen, R AF Cannon, Tyrone D. Chung, Yoonho He, George Sun, Daqiang Jacobson, Aron van Erp, Theo G. M. McEwen, Sarah Addington, Jean Bearden, Carrie E. Cadenhead, Kristin Cornblatt, Barbara Mathalon, Daniel H. McGlashan, Thomas Perkins, Diana Jeffries, Clark Seidman, Larry J. Tsuang, Ming Walker, Elaine Woods, Scott W. Heinssen, Robert CA North Amer Prodrome Longitudinal S TI Progressive Reduction in Cortical Thickness as Psychosis Develops: A Multisite Longitudinal Neuroimaging Study of Youth at Elevated Clinical Risk SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Inflammation; MRI; Prefrontal cortex; Prodromal; Psychosis; Schizophrenia ID ULTRA-HIGH-RISK; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; MAGNETIC-RESONANCE; NEUROANATOMICAL ABNORMALITIES; ANTIPSYCHOTIC TREATMENT; HIPPOCAMPAL VOLUME; INDIVIDUALS; SCHIZOPHRENIA; BRAIN AB BACKGROUND: Individuals at clinical high risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with individuals without symptomatic progression and with healthy control subjects. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown. METHODS: In this multisite study, 274 CHR cases, including 35 individuals who converted to psychosis, and 135 healthy comparison subjects were scanned with magnetic resonance imaging at baseline, 12-month follow-up, or the point of conversion for the subjects who developed fully psychotic symptoms. RESULTS: In a traveling subjects substudy, excellent reliability was observed for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR subjects who converted to psychosis showed a steeper rate of gray matter loss in the right superior frontal, middle frontal, and medial orbitofrontal cortical regions as well as a greater rate of expansion of the third ventricle compared with CHR subjects who did not convert to psychosis and healthy control subjects. Differential tissue loss was present in subjects who had not received antipsychotic medications during the interscan interval and was predicted by baseline levels of an aggregate measure of proinflammatory cytokines in plasma. CONCLUSIONS: These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced in subjects with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acuteonset forms of psychosis. C1 [Cannon, Tyrone D.; Chung, Yoonho; He, George; Jacobson, Aron] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Cannon, Tyrone D.; McGlashan, Thomas; Woods, Scott W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Sun, Daqiang; McEwen, Sarah; Bearden, Carrie E.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Sun, Daqiang; McEwen, Sarah; Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [van Erp, Theo G. M.] Univ Calif Irvine, Dept Psychiat, Irvine, CA 92717 USA. [Addington, Jean] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Cadenhead, Kristin; Tsuang, Ming] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Cornblatt, Barbara] Zucker Hillside Hosp, Dept Psychiat, Glen Oaks, NY USA. [Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Perkins, Diana] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Jeffries, Clark] Univ N Carolina, Renaissance Comp Inst, Chapel Hill, NC USA. [Seidman, Larry J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Seidman, Larry J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Walker, Elaine] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Heinssen, Robert] NIMH, Div Treatment & Prevent Res, Rockville, MD 20857 USA. RP Cannon, TD (reprint author), Yale Univ, Dept Psychol, 2 Hillhouse Ave,POB 208205, New Haven, CT 06520 USA. EM tyrone.cannon@yale.edu FU National Institute of Mental Health (NIMH) at the National Institutes of Health [MH081902, MH081857, MH081988, MH081928, MH082004, MH082022, MH081984, MH066160]; NIMH [P50 MH066286, P50 MH080272]; Commonwealth of Massachusetts [SCDMH82101008006] FX This work was supported by a collaborative U01 award from the National Institute of Mental Health (NIMH) at the National Institutes of Health (Grant Nos. MH081902 [TDC], MH081857 [BC], MH081988 [EW], MH081928 [LJS], MH082004 [DP], MH082022 [KC], MH081984 [JA], and MH066160 [SWW]) and NIMH Grant No. P50 MH066286 (CEB), NIMH Grant No. P50 MH080272, and the Commonwealth of Massachusetts (Grant No. SCDMH82101008006 [LJS]). NR 64 TC 74 Z9 74 U1 15 U2 41 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2015 VL 77 IS 2 BP 147 EP 157 DI 10.1016/j.biopsych.2014.05.023 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AW6NQ UT WOS:000346386600010 PM 25034946 ER PT J AU Evans, JW Kundu, P Horovitz, SG Bandettini, PA AF Evans, Jennifer W. Kundu, Prantik Horovitz, Silvina G. Bandettini, Peter A. TI Separating slow BOLD from non-BOLD baseline drifts using multi-echo fMRI SO NEUROIMAGE LA English DT Article DE fMRI; Multi-echo; Denoising; Slow drift; Non-BOLD; BOLD ID EVENT-RELATED FMRI; LOW-FREQUENCY DRIFT; FUNCTIONAL CONNECTIVITY; PERFUSION FMRI; HUMAN BRAIN; CONTRAST SENSITIVITY; EMPIRICAL ANALYSES; NULL-HYPOTHESIS; EPI; CORTEX AB The functional magnetic resonance (fMRI) baseline is known to drift over the course of an experiment and is often attributed to hardware instability. These ultraslow fMRI fluctuations are inseparable from blood oxygenation level dependent (BOLD) changes in standard single echo fMRI and they are therefore typically removed before further analysis in both resting-state and task paradigms. However, some part of these fluctuations may be of neuronal origin, as neural activity can indeed fluctuate at the scale of several minutes or even longer, such as after the administration of drugs or during the ultradian rhythms. Here, we show that it is possible to separate the slow BOLD and non-BOLD drifts automatically using multi-echo fMRI and multi-echo independent components analysis (ME-ICA) denoising by demonstrating the detection of a visual signal evoked from a flickering checkerboard with slowly changing contrast. Published by Elsevier Inc. C1 [Evans, Jennifer W.; Kundu, Prantik; Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, LBC, NIH, Bethesda, MD 20892 USA. [Horovitz, Silvina G.] NINDS, Human Motor Control Sect, MNB, NIH, Bethesda, MD 20892 USA. RP Evans, JW (reprint author), 10 Ctr Dr,Bldg 10,Rm 1D73, Bethesda, MD 20892 USA. EM jennifer.evans@nih.gov OI Kundu, Prantik/0000-0001-9367-3068 FU Intramural NIH HHS [Z99 MH999999] NR 38 TC 9 Z9 9 U1 3 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2015 VL 105 BP 189 EP 197 DI 10.1016/j.neuroimage.2014.10.051 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AW1LG UT WOS:000346050300018 PM 25449746 ER PT J AU Collins, J Huynh, M AF Collins, John Minh Huynh TI Integrative modeling of multi-platform genomic data under the framework of mediation analysis Reply SO STATISTICS IN MEDICINE LA English DT Editorial Material C1 [Collins, John] George Mason Univ, Dept Rehabil Sci, Coll Hlth & Human Serv, Fairfax, VA 22030 USA. [Minh Huynh] NIH, Epidemiol & Biostat Sect, RMD, Mark O Hatfield Clin Res Ctr, Rockville, MD 20852 USA. RP Collins, J (reprint author), George Mason Univ, Dept Rehabil Sci, Coll Hlth & Human Serv, 4400 Univ Dr,2G7, Fairfax, VA 22030 USA. EM jcolli22@gmu.edu; minh.huynh@nih.gov FU Intramural NIH HHS [Z99 CL999999] 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 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JAN 15 PY 2015 VL 34 IS 1 BP 179 EP 180 DI 10.1002/sim.6328 PG 2 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 AW3CI UT WOS:000346162700015 PM 25492618 ER PT J AU Consonni, D De Matteis, S Pesatori, AC Bertazzi, PA Olsson, AC Kromhout, H Peters, S Vermeulen, RCH Pesch, B Bruning, T Kendzia, B Behrens, T Stucker, I Guida, F Wichmann, HE Bruske, I Landi, MT Caporaso, NE Gustavsson, P Plato, N Tse, LA Yu, ITS Jockel, KH Ahrens, W Pohlabeln, H Merletti, F Richiardi, L Simonato, L Forastiere, F Siemiatycki, J Parent, ME Tardon, A Boffetta, P Zaridze, D Chen, Y Field, JK 't Mannetje, A Pearce, N McLaughlin, J Demers, P Lissowska, J Szeszenia-Dabrowska, N Bencko, V Foretova, L Janout, V Rudnai, P Fabianova, E Dumitru, RS Bueno-de-Mesquita, HB Schuz, J Straif, K AF Consonni, Dario De Matteis, Sara Pesatori, Angela C. Bertazzi, Pier Alberto Olsson, Ann C. Kromhout, Hans Peters, Susan Vermeulen, Roel C. H. Pesch, Beate Bruening, Thomas Kendzia, Benjamin Behrens, Thomas Stuecker, Isabelle Guida, Florence Wichmann, Heinz-Erich Brueske, Irene Landi, Maria Teresa Caporaso, Neil E. Gustavsson, Per Plato, Nils Tse, Lap Ah Yu, Ignatius Tak-sun Joeckel, Karl-Heinz Ahrens, Wolfgang Pohlabeln, Hermann Merletti, Franco Richiardi, Lorenzo Simonato, Lorenzo Forastiere, Francesco Siemiatycki, Jack Parent, Marie-Elise Tardon, Adonina Boffetta, Paolo Zaridze, David Chen, Ying Field, John K. 't Mannetje, Andrea Pearce, Neil McLaughlin, John Demers, Paul Lissowska, Jolanta Szeszenia-Dabrowska, Neonila Bencko, Vladimir Foretova, Lenka Janout, Vladimir Rudnai, Peter Fabianova, Eleonora Dumitru, Rodica Stanescu Bueno-de-Mesquita, H. B(as) Schuez, Joachim Straif, Kurt TI Lung cancer risk among bricklayers in a pooled analysis of case-control studies SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE lung neoplasms; case-control studies; bricklayers; occupational health; epidemiology ID CRYSTALLINE SILICA DUST; OCCUPATIONAL-EXPOSURE; CONSTRUCTION-INDUSTRY; NORDIC COUNTRIES; UNITED-STATES; POPULATION; MORTALITY; WORKERS; MEN; CARCINOGENS AB Bricklayers may be exposed to several lung carcinogens, including crystalline silica and asbestos. Previous studies that analyzed lung cancer risk among these workers had several study design limitations. We examined lung cancer risk among bricklayers within SYNERGY, a large international pooled analysis of case-control studies on lung cancer and the joint effects of occupational carcinogens. For men ever employed as bricklayers we estimated odds ratios (OR) and 95% confidence intervals (CI) adjusted for study center, age, lifetime smoking history and employment in occupations with exposures to known or suspected lung carcinogens. Among 15,608 cases and 18,531 controls, there were 695 cases and 469 controls who had ever worked as bricklayers (OR: 1.47; 95% CI: 1.28-1.68). In studies using population controls the OR was 1.55 (95% CI: 1.32-1.81, 540/349 cases/controls), while it was 1.24 (95% CI: 0.93-1.64, 155/120 cases/controls) in hospital-based studies. There was a clear positive trend with length of employment (p<0.001). The relative risk was higher for squamous (OR: 1.68, 95% CI: 1.42-1.98, 309 cases) and small cell carcinomas (OR: 1.78, 95% CI: 1.44-2.20, 140 cases), than for adenocarcinoma (OR: 1.17, 95% CI: 0.95-1.43, 150 cases) (p-homogeneity: 0.0007). ORs were still elevated after additional adjustment for education and in analyses using blue collar workers as referents. This study provided robust evidence of increased lung cancer risk in bricklayers. Although non-causal explanations cannot be completely ruled out, the association is plausible in view of the potential for exposure to several carcinogens, notably crystalline silica and to a lesser extent asbestos. What's new? In their work, bricklayers can be exposed to various airborne carcinogens, including crystalline silica and asbestos. Previous studies of cancer risk have not accounted for full employment history or smoking status, and failed to establish a firm relationship between bricklaying and lung cancer. In this study, the authors used data from the largest collection of case-control studies on lung cancer with complete occupational and smoking history existing today, the SYNERGY project. They found clear evidence that lung cancer risk increases in proportion to the length of time spent working as a bricklayer, paving the way for better protection and compensation for those in this occupation. C1 [Consonni, Dario; Pesatori, Angela C.; Bertazzi, Pier Alberto] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Epidemiol Unit, I-20122 Milan, Italy. [De Matteis, Sara] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [De Matteis, Sara; Pesatori, Angela C.; Bertazzi, Pier Alberto] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Olsson, Ann C.; Schuez, Joachim; Straif, Kurt] Int Agcy Res Canc, F-69372 Lyon, France. [Olsson, Ann C.; Gustavsson, Per; Plato, Nils] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Kromhout, Hans; Peters, Susan; Vermeulen, Roel C. H.] Inst Risk Assessment Sci, Utrecht, Netherlands. [Peters, Susan] Univ Western Australia, Sch Populat Hlth, Perth, WA 6009, Australia. [Pesch, Beate; Bruening, Thomas; Kendzia, Benjamin; Behrens, Thomas] Ruhr Univ Bochum IPA, German Social Accid Insurance Inst, Inst Prevent & Occupat Med, Bochum, Germany. [Stuecker, Isabelle; Guida, Florence] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, U1018, Environm Epidemiol Canc Team, Paris, France. [Stuecker, Isabelle; Guida, Florence] Univ Paris 11, UMRS 1018, Paris, France. [Wichmann, Heinz-Erich; Brueske, Irene] Deutsch Forschungszentrum Gesundheit & Umwelt, Inst Epidemiol 1, Neuherberg, Germany. [Landi, Maria Teresa; Caporaso, Neil E.] NCI, NIH, Bethesda, MD 20892 USA. [Tse, Lap Ah; Yu, Ignatius Tak-sun] Chinese Univ Hong Kong, Sch Publ Hlth & Primary Care, Hong Kong, Hong Kong, Peoples R China. [Joeckel, Karl-Heinz] Univ Duisburg Essen, Univ Hosp, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Ahrens, Wolfgang; Pohlabeln, Hermann] Leibniz Inst Prevent Res & Epidemiol BIPS, Bremen, Germany. [Ahrens, Wolfgang] Univ Bremen, Inst Stat, D-28359 Bremen, Germany. [Merletti, Franco; Richiardi, Lorenzo] Univ Turin, CPO Piemonte, Dept Med Sci, Canc Epidemiol Unit, Turin, Italy. [Simonato, Lorenzo] Univ Padua, Dept Mol Med, Padua, Italy. [Forastiere, Francesco] ASL Roma E, Dept Epidemiol, Rome, Italy. [Siemiatycki, Jack] Univ Montreal, Hosp Res Ctr CRCHUM, Montreal, PQ, Canada. [Siemiatycki, Jack] Sch Publ Hlth, Montreal, PQ, Canada. [Parent, Marie-Elise] INRS Inst Armand Frappier, Epidemiol & Biostat Unit, Laval, PQ, Canada. [Tardon, Adonina] Univ Oviedo, Oviedo, Spain. [Tardon, Adonina] Ciber Epidemiol & Salud Publ CIBERESP, Oviedo, Spain. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Zaridze, David] Russian Canc Res Ctr, Moscow, Russia. [Chen, Ying; Field, John K.] Univ Liverpool, Canc Res Ctr, Dept Mol & Clin Canc Med, Lung Canc Res Programme, Liverpool L69 3BX, Merseyside, England. [Chen, Ying] Keele Univ, Res Inst Primary Care & Hlth Sci, Arthrit Res UK Primary Care Ctr, Keele, Staffs, England. ['t Mannetje, Andrea] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Pearce, Neil] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1, England. [McLaughlin, John] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Demers, Paul] Canc Care Ontario, Occupat Canc Res Ctr, Toronto, ON, Canada. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Szeszenia-Dabrowska, Neonila] Nofer Inst Occupat Med, Lodz, Poland. [Bencko, Vladimir] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Foretova, Lenka] Masaryk Mem Canc Inst, Brno, Czech Republic. [Janout, Vladimir] Palacky Univ, Fac Med, CR-77147 Olomouc, Czech Republic. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Fabianova, Eleonora] Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Dumitru, Rodica Stanescu] Inst Publ Hlth, Bucharest, Romania. [Bueno-de-Mesquita, H. B(as)] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. B(as)] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. B(as)] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. RP Consonni, D (reprint author), Fdn IRCCS Ca Granda Osped Maggiore Policlin, Epidemiol Unit, Via San Barnaba 8, I-20122 Milan, Italy. EM Dario.Consonni@unimi.it RI Janout, Vladimir/M-5133-2014; Chen, Ying/I-4349-2013; Yu, Ignatius Tak Sun/A-9936-2008; Szeszenia-Dabrowska, Neonila/F-7190-2010; Bruning, Thomas/G-8120-2015; Forastiere, Francesco/J-9067-2016; Consonni, Dario/K-7943-2016; Vermeulen, Roel/F-8037-2011; bertazzi, pietro alberto/D-5039-2017 OI richiardi, lorenzo/0000-0003-0316-9402; pesatori, angela/0000-0002-0261-3252; Ahrens, Wolfgang/0000-0003-3777-570X; Field, John/0000-0003-3951-6365; Peters, Susan/0000-0001-5662-1971; Pearce, Neil/0000-0002-9938-7852; Bruning, Thomas/0000-0001-9560-5464; Forastiere, Francesco/0000-0002-9162-5684; Consonni, Dario/0000-0002-8935-3843; Vermeulen, Roel/0000-0003-4082-8163; bertazzi, pietro alberto/0000-0003-3475-2449 FU German Social Accident Insurance (DGUV) [FP 271]; Canadian Institutes for Health Research; Guzzo-SRC Chair in Environment and Cancer; National Cancer Institute of Canada; Canadian Cancer Society; Occupational Cancer Research Centre; Workplace Safety and Insurance Board; Cancer Care Ontario; European Commission's INCO Copernicus program [IC15-CT96-0313]; European Union Nuclear Fission Safety Program [F14P-CT96-0055]; French Agency of Health Security (ANSES); Fondation de France; French National Research Agency (ANR); National Institute of Cancer (INCA); Fondation pour la Recherche Medicale; French Institute for Public Health Surveillance (InVS); Health Ministry (DGS); Organization for the Research on Cancer (ARC); French Ministry of work, solidarity, and public function (DGT); Federal Ministry of Education, Science, Research, and Technology [01 HK 173/0]; Federal Ministry of Science [01 HK 546/8]; Ministry of Labour and Social Affairs [IIIb7-27/13]; Research Grants Council of the Hong Kong Special Administrative Region, China [CUHK4460/03M]; Environmental Epidemiology Program of the Lombardy Region; INAIL; Italian Association for Cancer Research; Region Piedmont; Compagnia di San Paolo; Lazio Region; Health Research Council of New Zealand; New Zealand Department of Labour; Lottery Health Research; Cancer Society of New Zealand; Polish State Committee for Scientific Research [SPUB-M-COPERNICUS/P-05/DZ-30/99/2000]; Instituto Universitario de Oncologia; Universidad de Oviedo; Asturias; Fondo de Investigacion Sanitaria (FIS); Ciber de Epidemiologia y Salud Publica (CIBERESP); Swedish Council for Work Life Research; Swedish Environmental Protection Agency; Dutch Ministry of Health, Welfare and Sports; National Institute of Public Health and the Environment; Europe Against Cancer Program; Roy Castle Foundation; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, Maryland FX Grant sponsor: German Social Accident Insurance (DGUV); Grant number: FP 271; Grant sponsors: Canadian Institutes for Health Research and Guzzo-SRC Chair in Environment and Cancer, National Cancer Institute of Canada, Canadian Cancer Society, Occupational Cancer Research Centre, Workplace Safety and Insurance Board, Canadian Cancer Society, and Cancer Care Ontario; Grant sponsor: European Commission's INCO Copernicus program; Grant number: IC15-CT96-0313; Grant sponsor: European Union Nuclear Fission Safety Program; Grant number: F14P-CT96-0055; Grant sponsors: French Agency of Health Security (ANSES), Fondation de France, French National Research Agency (ANR), National Institute of Cancer (INCA), Fondation pour la Recherche Medicale, French Institute for Public Health Surveillance (InVS), Health Ministry (DGS), Organization for the Research on Cancer (ARC), and French Ministry of work, solidarity, and public function (DGT); Grant sponsor: Federal Ministry of Education, Science, Research, and Technology; Grant number: 01 HK 173/0); Grant sponsor: Federal Ministry of Science; Grant number: 01 HK 546/8; Grant sponsor: Ministry of Labour and Social Affairs; Grant number: IIIb7-27/13; Grant sponsor: Research Grants Council of the Hong Kong Special Administrative Region, China; Grant number: CUHK4460/03M; Grant sponsors: Environmental Epidemiology Program of the Lombardy Region, INAIL, Italian Association for Cancer Research, Region Piedmont, Compagnia di San Paolo, Lazio Region, Health Research Council of New Zealand, New Zealand Department of Labour, Lottery Health Research, Cancer Society of New Zealand; Grant sponsor: Polish State Committee for Scientific Research; Grant number: SPUB-M-COPERNICUS/P-05/DZ-30/99/2000; Grant sponsors: Instituto Universitario de Oncologia, Universidad de Oviedo, Asturias, Fondo de Investigacion Sanitaria (FIS) and Ciber de Epidemiologia y Salud Publica (CIBERESP), Swedish Council for Work Life Research and Swedish Environmental Protection Agency, Dutch Ministry of Health, Welfare and Sports, National Institute of Public Health and the Environment, and Europe Against Cancer Program, Roy Castle Foundation, and Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, Maryland. NR 56 TC 5 Z9 5 U1 2 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2015 VL 136 IS 2 BP 360 EP 371 DI 10.1002/ijc.28986 PG 12 WC Oncology SC Oncology GA AS9ZK UT WOS:000344596600014 PM 24861979 ER PT J AU Silver, J Li, ZY Neuman, K AF Silver, Jonathan Li, Zhenyu Neuman, Keir TI Tethered-bead, immune sandwich assay SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Tethered-bead immunoassay; DNA tethers; Flow-mediated DNA extension; Opto- microfluidics; PSA immunoassay; Single-molecule immunoassay ID SINGLE MOLECULES; RNA-POLYMERASE; DNA; BIOSENSORS; FLOW; MICROSCOPY; ANTIGEN; SURFACE; CELLS; FIELD AB We describe a proof-of-principle, immune sandwich assay in which immune complexes link micron-size beads via DNA tethers to a sensor surface. The number of tethered beads, counted using low-magnification microscopy, provides a measure of the concentration of analyte. The prototype assay was sensitive to pM concentration of analyte. In theory, the assay could be sensitive to sub-fM analyte because beads attached via single-immune complexes and DNA strands form tethers, and tether formation in the absence of analyte is extremely rare. The limiting step at present is binding of streptavidin at the end of DNA to biotin on capture beads. Potential advantages of this type of sensor are discussed. (C) 2014 Elsevier B.V. All rights reserved. C1 [Silver, Jonathan] George Washington Univ, Dept Mech & Aerosp Engn, Washington, DC 20052 USA. [Silver, Jonathan; Neuman, Keir] NHLBI, Biophys Lab, NIH, Bethesda, MD 20902 USA. [Li, Zhenyu] George Washington Univ, Dept Elect & Comp Engn, Washington, DC USA. RP Silver, J (reprint author), George Washington Univ, Dept Mech & Aerosp Engn, Washington, DC 20052 USA. EM jesilver@gwu.edu RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU Intramural Research Program of the National Heart, Lung, and Blood Institute at the National Institutes of Health; Institute of Bioengineering at George Washington University FX We thank Liusongsen Yang for help constructing flow cells and image analysis. This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute at the National Institutes of Health and by a grant from the Institute of Bioengineering at George Washington University to ZL and JS. NR 21 TC 1 Z9 1 U1 1 U2 39 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 JAN 15 PY 2015 VL 63 BP 117 EP 123 DI 10.1016/j.bios.2014.07.011 PG 7 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA AR1HT UT WOS:000343337000017 PM 25064819 ER PT J AU Motta, M Ramadan, A Hillis, AE Gottesman, RF Leigh, R AF Motta, Melissa Ramadan, Amanda Hillis, Argye E. Gottesman, Rebecca F. Leigh, Richard TI Diffusion-perfusion mismatch: an opportunity for improvement in cortical function SO FRONTIERS IN NEUROLOGY LA English DT Article DE diffusion-perfusion mismatch; acute ischemic stroke; penumbra; NIHSS; functional outcome ID POSITRON-EMISSION-TOMOGRAPHY; ACUTE STROKE; ISCHEMIC PENUMBRA; COMPUTED-TOMOGRAPHY; CEREBRAL-ISCHEMIA; TISSUE; MRI; NEGLECT; TIME AB Objective: There has been controversy over whether diffusion-perfusion mismatch provides a biomarker for the ischemic penumbra. In the context of clinical stroke trials, regions of the diffusion-perfusion mismatch that do not progress to infarct in the absence of reperfusion are considered to represent "benign oligemia." However, at least in some cases (particularly large vessel stenosis), some of this hypoperfused tissue may remain dysfunctional for a prolonged period without progressing to infarct and may recover function if eventually reperfused. We hypothesized that patients with persistent diffusion-perfusion mismatch using a hypoperfusion threshold of 4-5.9 s delay on time-to-peak (TTP) maps at least sometimes have persistent cognitive deficits relative to those who show some reperfusion of this hypoperfused tissue. Methods: We tested this hypothesis in 38 patients with acute ischemic stroke who had simple cognitive tests (naming or line cancelation) and MRI with diffusion and perfusion imaging within 24h of onset and again within 10 days, most of whom had large vessel stenosis or occlusion. Results: A persistent perfusion deficit of 4-5.9 s delay in TIP on follow up MRI was associated with a persistent cognitive deficit at that time point (p < 0.001). When we evaluated only patients who did not have infarct growth (n = 14), persistent hypoperfusion (persistent mismatch) was associated with a lack of cognitive improvement compared with those who had reperfused. The initial volume of hypoperfusion did not correlate with the later infarct volume (progression to infarct), but change in volume of hypoperfusion correlated with change in cognitive performance (p = 0.0001). Moreover, multivariable regression showed that the change in volume of hypoperfused tissue of 4-5.9 s delay (p = 0.002), and change in volume of ischemic tissue on diffusion weighted imaging (p = 0.02) were independently associated with change in cognitive function. Conclusion: Our results provide additional evidence that non-infarcted tissue with a TIP delay of 4-5.9 s may be associated with persistent deficits, even if it does not always result in imminent progression to infarct. This tissue may represent the occasional opportunity to intervene to improve function even days after onset of symptoms. C1 [Motta, Melissa] Univ Maryland, Sch Med, R Adams Shock Trauma Ctr, Baltimore, MD 21201 USA. [Ramadan, Amanda] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Hillis, Argye E.; Gottesman, Rebecca F.; Leigh, Richard] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Leigh, R (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, NIH, 10 Ctr Dr,Bldg 10,B1D733 MSC 1063, Bethesda, MD 20892 USA. EM richard.leigh@nih.gov FU National Institutes of Health (National Institute of Deafness and Communication Disorders) [R25NS065729, R01 NS047691, DC05375, R01 DC03681]; National Institutes of Health (National Institute of Neurological Disorders and Stroke) [R25NS065729, R01 NS047691, DC05375, R01 DC03681] FX This research reported in this paper was supported by the National Institutes of Health (National Institute of Deafness and Communication Disorders and National Institute of Neurological Disorders and Stroke) through awards R25NS065729 to authors Melissa Motta and Argye E. Hillis, and R01 NS047691, DC05375, and R01 DC03681 to author Argye E. Hillis. The content is solely the responsibility of the authors and does not necessarily represent the views the National Institutes of Health. NR 20 TC 2 Z9 2 U1 0 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PD JAN 14 PY 2015 VL 5 AR UNSP 280 DI 10.3389/fneur.2014.00280 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CU7WE UT WOS:000363751700001 ER PT J AU Vandekar, SN Shinohara, RT Raznahan, A Roalf, DR Ross, M DeLeo, N Ruparel, K Verma, R Wolf, DH Gur, RC Gur, RE Satterthwaite, TD AF Vandekar, Simon N. Shinohara, Russell T. Raznahan, Armin Roalf, David R. Ross, Michelle DeLeo, Nicholas Ruparel, Kosha Verma, Ragini Wolf, Daniel H. Gur, Ruben C. Gur, Raquel E. Satterthwaite, Theodore D. TI Topologically Dissociable Patterns of Development of the Human Cerebral Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cortex; cortical thickness; development; diffusion imaging; MRI; white matter ID SURFACE-BASED ANALYSIS; WHITE-MATTER VOLUME; MAGNETIC-RESONANCE; DIFFUSION MRI; HUMAN BRAIN; FUNCTIONAL-ORGANIZATION; COGNITIVE-DEVELOPMENT; TANGENTIAL EXPANSION; ONSET SCHIZOPHRENIA; CORTICAL THICKNESS AB Over 90 years ago, anatomists noted the cortex is thinner in sulci than gyri, suggesting that development may occur on a fine scale driven by local topology. However, studies of brain development in youth have focused on describing how cortical thickness varies over large-scale functional and anatomic regions. How the relationship between thickness and local sulcal topology arises in development is still not well understood. Here, we investigated the spatial relationships between cortical thickness, folding, and underlying white matter organization to elucidate the influence of local topology on human brain development. Our approach included using both T1-weighted imaging and diffusion tensor imaging (DTI) in a cross-sectional sample of 932 youths ages 8 - 21 studied as part of the Philadelphia Neurodevelopmental Cohort. Principal components analysis revealed separable development-related processes of regionally specific nonlinear cortical thickening (from ages 8 - 14) and widespread linear cortical thinning that have dissociable relationships with cortical topology. Whereas cortical thinning was most prominent in the depths of the sulci, early cortical thickening was present on the gyri. Furthermore, decline in mean diffusivity calculated from DTI in underlying white matter was correlated with cortical thinning, suggesting that cortical thinning is spatially associated with white matter development. Spatial permutation tests were used to assess the significance of these relationships. Together, these data demonstrate that cortical remodeling during youth occurs on a local topological scale and is associated with changes in white matter beneath the cortical surface. C1 [Vandekar, Simon N.; Roalf, David R.; DeLeo, Nicholas; Ruparel, Kosha; Wolf, Daniel H.; Gur, Ruben C.; Gur, Raquel E.; Satterthwaite, Theodore D.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Vandekar, Simon N.; Shinohara, Russell T.; Ross, Michelle] Univ Penn, Dept Biostat, Philadelphia, PA 19104 USA. [Verma, Ragini; Gur, Ruben C.; Gur, Raquel E.] Univ Penn, Dept Epidemiol, Philadelphia, PA 19104 USA. [Raznahan, Armin] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Gur, Ruben C.] Philadelphia Vet Adm Med Ctr, Philadelphia, PA 19104 USA. RP Satterthwaite, TD (reprint author), Hosp Univ Penn, 10th Floor,Gates Bldg, Philadelphia, PA 19104 USA. EM sattertt@upenn.edu FU National Institute of Mental Health RC2 [MH089983, MH089924]; Center for Biomedical Computing and Image Analysis at the University of Pennsylvania; National Institute of Mental Health [K23MH098130, K01MH102609, R01MH101111, T32MH065218-11]; Marc Rapport Family Investigator grant through the Brain and Behavior Foundation; National Institute of Neurological Disorders and Stroke [R01NS085211]; Sidney R. Baer, Jr. Foundation through the Brain and Behavior Foundation FX This work was supported by National Institute of Mental Health RC2 Grants MH089983 and MH089924. Support for developing statistical analyses (to S.N.V., R.T.S., and T.D.S.) was provided by a seed grant from the Center for Biomedical Computing and Image Analysis at the University of Pennsylvania. T.D.S. was supported by Grant K23MH098130 from the National Institute of Mental Health and the Marc Rapport Family Investigator grant through the Brain and Behavior Foundation. R.T.S. was supported by Grant R01NS085211 from the National Institute of Neurological Disorders and Stroke. D.R.R. was supported by Grant K01MH102609 from the National Institute of Mental Health. D.H.W. was supported by Grant R01MH101111 from the National Institute of Mental Health and the Sidney R. Baer, Jr. Foundation through the Brain and Behavior Foundation. S.N.V. was supported by Grant T32MH065218-11 from the National Institute of Mental Health. We thank Madhura Ingalhalikar and Alex Smith for assistance with data processing. We also thank the acquisition and recruitment team: Jeff Valdez, Raphael Gerraty, Marisa Riley, Jack Keefe, Elliott Yodh, and Rosetta Chiavacci. We thank Chad Jackson for data management. We thank Scott Troyan for assistance with figures. We sincerely thank Fabian Scheipl for help on hypothesis testing in general additive models. We thank Aaron Alexander-Bloch and Phil Reiss for advice on implementation of the general additive model. NR 69 TC 13 Z9 13 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 JAN 14 PY 2015 VL 35 IS 2 BP 599 EP 609 DI 10.1523/JNEUROSCI.3628-14.2015 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CB1SW UT WOS:000349409300016 PM 25589754 ER PT J AU Roberts, AM Ware, JS Herman, DS Schafer, S Baksi, J Bick, AG Buchan, RJ Walsh, R John, S Wilkinson, S Mazzarotto, F Felkin, LE Gong, SS MacArthur, JAL Cunningham, F Flannick, J Gabriel, SB Altshuler, DM Macdonald, PS Heinig, M Keogh, AM Hayward, CS Banner, NR Pennell, DJ O'Regan, DP San, TR De Marvao, A Dawes, TJW Gulati, A Birks, EJ Yacoub, MH Radke, M Gotthardt, M Wilson, JG O'Donnell, CJ Prasad, SK Barton, PJR Fatkin, D Hubner, N Seidman, JG Seidman, CE Cook, SA AF Roberts, Angharad M. Ware, James S. Herman, Daniel S. Schafer, Sebastian Baksi, John Bick, Alexander G. Buchan, Rachel J. Walsh, Roddy John, Shibu Wilkinson, Samuel Mazzarotto, Francesco Felkin, Leanne E. Gong, Sungsam MacArthur, Jacqueline A. L. Cunningham, Fiona Flannick, Jason Gabriel, Stacey B. Altshuler, David M. Macdonald, Peter S. Heinig, Matthias Keogh, Anne M. Hayward, Christopher S. Banner, Nicholas R. Pennell, Dudley J. O'Regan, Declan P. San, Tan Ru De Marvao, Antonio Dawes, Timothy J. W. Gulati, Ankur Birks, Emma J. Yacoub, Magdi H. Radke, Michael Gotthardt, Michael Wilson, James G. O'Donnell, Christopher J. Prasad, Sanjay K. Barton, Paul J. R. Fatkin, Diane Hubner, Norbert Seidman, Jonathan G. Seidman, Christine E. Cook, Stuart A. TI Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID CARDIOVASCULAR MAGNETIC-RESONANCE; FAMILIAL DILATED CARDIOMYOPATHY; HEART-FAILURE; PROGNOSTIC VALUE; RISK-FACTORS; POPULATION; VARIANTS; MUTATIONS; SEQUENCE; GENES AB The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings. C1 [Roberts, Angharad M.; O'Regan, Declan P.; De Marvao, Antonio; Dawes, Timothy J. W.; Cook, Stuart A.] Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Clin Sci, London W12 0NN, England. [Roberts, Angharad M.; Ware, James S.; Baksi, John; Buchan, Rachel J.; Walsh, Roddy; John, Shibu; Wilkinson, Samuel; Mazzarotto, Francesco; Felkin, Leanne E.; Gong, Sungsam; Pennell, Dudley J.; Gulati, Ankur; Prasad, Sanjay K.; Barton, Paul J. R.] Royal Brompton & Harefield Natl Hlth Serv NHS Fdn, Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, London SW3 6NP, England. [Roberts, Angharad M.; Ware, James S.; Baksi, John; Buchan, Rachel J.; Walsh, Roddy; John, Shibu; Wilkinson, Samuel; Mazzarotto, Francesco; Felkin, Leanne E.; Gong, Sungsam; Pennell, Dudley J.; Gulati, Ankur; Prasad, Sanjay K.; Barton, Paul J. R.] Univ London Imperial Coll Sci Technol & Med, London SW3 6NP, England. [Ware, James S.; Mazzarotto, Francesco; Felkin, Leanne E.; Banner, Nicholas R.; Pennell, Dudley J.; Birks, Emma J.; Yacoub, Magdi H.; Barton, Paul J. R.; Cook, Stuart A.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6NP, England. [Ware, James S.; Herman, Daniel S.; Bick, Alexander G.; Seidman, Jonathan G.; Seidman, Christine E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Ware, James S.; Herman, Daniel S.; Bick, Alexander G.; Flannick, Jason; Gabriel, Stacey B.; Altshuler, David M.; Seidman, Christine E.] Broad Inst Harvard, Cambridge, MA 02142 USA. [Ware, James S.; Herman, Daniel S.; Bick, Alexander G.; Flannick, Jason; Gabriel, Stacey B.; Altshuler, David M.; Seidman, Christine E.] MIT, Cambridge, MA 02142 USA. [Herman, Daniel S.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Schafer, Sebastian; Heinig, Matthias] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. [MacArthur, Jacqueline A. L.; Cunningham, Fiona] Wellcome Trust Genome Campus, European Bioinformat Inst, European Mol Biol Lab, Hinxton CB10 1SD, Cambs, England. [Flannick, Jason] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Altshuler, David M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Macdonald, Peter S.; Keogh, Anne M.; Hayward, Christopher S.; Fatkin, Diane] St Vincents Hosp, Dept Cardiol, Darlinghurst, NSW 2010, Australia. [Macdonald, Peter S.; Keogh, Anne M.; Hayward, Christopher S.; Fatkin, Diane] Victor Chang Cardiac Res Inst, Darlinghurst, NSW 2010, Australia. [Macdonald, Peter S.; Keogh, Anne M.; Hayward, Christopher S.; Fatkin, Diane] Univ New S Wales, Fac Med, Kensington, NSW 2052, Australia. [Banner, Nicholas R.] Harefield Hosp, Royal Brompton & Harefield NHS Fdn Trust, Harefield UB9 6JH, Middx, England. [San, Tan Ru; Cook, Stuart A.] Natl Heart Ctr, Singapore 169609, Singapore. [Birks, Emma J.] Univ Louisville, Dept Med, Louisville, KY 40202 USA. [Birks, Emma J.] Jewish Hosp, Louisville, KY 40202 USA. [Radke, Michael; Gotthardt, Michael] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. [Gotthardt, Michael] German Ctr Cardiovasc Res, D-13347 Berlin, Germany. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [O'Donnell, Christopher J.] NHLBI, FraminghamHeart Study, Framingham, MA 01702 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Hubner, Norbert] Charite, D-10117 Berlin, Germany. [Seidman, Christine E.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Seidman, Christine E.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Cook, Stuart A.] Duke Natl Univ Singapore, Singapore 169857, Singapore. RP Cook, SA (reprint author), Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Clin Sci, London W12 0NN, England. EM cseidman@genetics.med.harvard.edu; stuart.cook@nhcs.com.sg RI Mazzarotto, Francesco/E-1843-2017; OI Mazzarotto, Francesco/0000-0002-6159-9980; Felkin, Leanne/0000-0003-1402-8314; Barton, Paul/0000-0002-1165-7767; Schafer, Sebastian/0000-0002-6909-8275; Gotthardt, Michael/0000-0003-1788-3172; Gong, Sungsam/0000-0001-5796-4423; Walsh, Roddy/0000-0001-5092-8825; de Marvao, Antonio/0000-0001-9095-5887; Ware, James/0000-0002-6110-5880 FU NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton & Harefield NHS Foundation Trust; Imperial College London; NIHR Imperial Biomedical Research Centre; British Heart Foundation UK [SP/10/10/28431, PG/12/27/29489]; European Molecular Biology Laboratory; MRC UK; Wellcome Trust UK [087183/Z/08/Z, 092854/Z/10/Z, WT095908]; Fondation Leducq; Tanoto Foundation; Goh Foundation; Academy of Medical Sciences; Arthritis Research UK; Heart Research UK; CORDA; National Medical Research Council (NMRC) Singapore; Rosetrees Trus; European Community's Seventh Framework Programme (FP7 [GEN2PHEN project]) [CardioNeT-ITN-289600, 200754]; National Human Genome Research Institute [U54 HG003067]; NIH [HL080494, 5-T32-GM007748-33]; Howard Hughes Medical Institute; Australian National Health and Medical Research Council; NHLBI [N01-HC-25195, 6R01-NS 17950, N01-HC-95170, N01-HC-95171, N01-HC-95172, HL-102924]; National Institute for Minority Health and Health Disparities; National Institute of Biomedical Imaging and Bioengineering; U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221] FX The research was supported by the NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton & Harefield NHS Foundation Trust and Imperial College London, NIHR Imperial Biomedical Research Centre, British Heart Foundation UK (SP/10/10/28431, PG/12/27/29489), European Molecular Biology Laboratory, MRC UK, Wellcome Trust UK (087183/Z/08/Z, 092854/Z/10/Z, WT095908), Fondation Leducq, Tanoto Foundation, Goh Foundation, Academy of Medical Sciences, Arthritis Research UK, Heart Research UK, CORDA, National Medical Research Council (NMRC) Singapore, Rosetrees Trust, European Community's Seventh Framework Programme (FP7) [CardioNeT-ITN-289600; 200754 - the GEN2PHEN project], National Human Genome Research Institute (U54 HG003067), NIH (HL080494, 5-T32-GM007748-33), Howard Hughes Medical Institute, and the Australian National Health and Medical Research Council. The FHS was supported by the NHLBI (N01-HC-25195, 6R01-NS 17950), and genotyping services from Affymetrix Inc. (N02-HL-6-4278). The JHS is supported by NHLBI (N01-HC-95170, N01-HC-95171, N01-HC-95172), the National Institute for Minority Health and Health Disparities, and the National Institute of Biomedical Imaging and Bioengineering. The WHI Sequencing Project is supported by NHLBI (HL-102924), NIH, and U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. This publication reflects only the author's views, and the funders are not liable for any use that may be made of the information contained herein. NR 67 TC 42 Z9 43 U1 5 U2 19 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JAN 14 PY 2015 VL 7 IS 270 AR 270ra6 DI 10.1126/scitranslmed.3010134 PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AZ6TN UT WOS:000348353400004 PM 25589632 ER PT J AU Rifkind, JM Mohanty, JG Nagababu, E AF Rifkind, Joseph M. Mohanty, Joy G. Nagababu, Enika TI The pathophysiology of extracellular hemoglobin associated with enhanced oxidative reactions SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE extracellular hemoglobin; hemoglobin autoxidation; oxidative reactions; hydrogen peroxide; heme; Fe(IV)hemoglobins; proinflammatory reactions ID RED-BLOOD-CELLS; LOW-DENSITY-LIPOPROTEIN; HYDROGEN-PEROXIDE; HEME DEGRADATION; GLUTATHIONE-PEROXIDASE; ENDOTHELIAL-CELLS; AUTO-TRANSFUSION; HEMOLYTIC-ANEMIA; FENTON REAGENT; DISEASE AB Hemoglobin (Hb) continuously undergoes autoxidation producing superoxide which dismutates into hydrogen peroxide (H2O2) and is a potential source for subsequent oxidative reactions. Autoxidation is most pronounced under hypoxic conditions in the microcirculation and for unstable dimers formed at reduced Hb concentrations. In the red blood cell (RBC), oxidative reactions are inhibited by an extensive antioxidant system. For extracellular Hb, whether from hemolysis of RBCs and/or the infusion of Hb-based blood substitutes, the oxidative reactions are not completely neutralized by the available antioxidant system. Un-neutralized H2O2 oxidizes ferrous and ferric Hbs to Fe(IV)-ferrylHb and OxyferrylHb, respectively. FerrylHb further reacts with H2O2 producing heme degradation products and free iron. OxyferrylHb, in addition to Fe(IV) contains a free radical that can undergo additional oxidative reactions. Fe(III)Hb produced during Hb autoxidation also readily releases heme, an additional source for oxidative stress. These oxidation products are a potential source for oxidative reactions in the plasma, but to a greater extent when the lower molecular weight Hb dimers are taken up into cells and tissues. Heme and oxyferryl have been shown to have a proinflammatory effect further increasing their potential for oxidative stress. These oxidative reactions contribute to a number of pathological situations including atherosclerosis, kidney malfunction, sickle cell disease, and malaria. The toxic effects of extracellular Hb are of particular concern with hemolytic anemia where there is an increase in hemolysis. Hemolysis is further exacerbated in various diseases and their treatments. Blood transfusions are required whenever there is an appreciable decrease in RBCs due to hemolysis or blood loss. It is, therefore, essential that the transfused blood, whether stored RBCs or the blood obtained by an Autologous Blood Recovery System from the patient, do not further increase extracellular Hb. C1 [Rifkind, Joseph M.; Mohanty, Joy G.] NIH, Mol Dynam Sect, Lab Mol Gerontol, Baltimore, MD 21224 USA. [Nagababu, Enika] Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. RP Mohanty, JG (reprint author), NIH, Mol Dynam Sect, Lab Mol Gerontol, NIH,Biomed Res Ctr, 251 Bayview Blvd,Rm 05B0131, Baltimore, MD 21224 USA. EM mohantyj@mail.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging FX This research was supported (in part) by the Intramural Research Program of the NIH, National Institute on Aging. NR 52 TC 3 Z9 4 U1 3 U2 14 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 JAN 14 PY 2015 VL 5 AR 500 DI 10.3389/fphys.2014.00500 PG 7 WC Physiology SC Physiology GA AZ4UP UT WOS:000348219000001 ER PT J AU Fairhurst, RM AF Fairhurst, Rick M. TI PfEMP1' s Magical Embrace of EPCR SO CELL HOST & MICROBE LA English DT Editorial Material ID FALCIPARUM-INFECTED ERYTHROCYTES; MALARIA; RECEPTOR C1 NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Fairhurst, RM (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Room 3E-10A, Rockville, MD 20852 USA. EM rfairhurst@niaid.nih.gov FU Intramural NIH HHS NR 10 TC 0 Z9 0 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD JAN 14 PY 2015 VL 17 IS 1 BP 11 EP 13 DI 10.1016/j.chom.2014.12.010 PG 3 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AZ1YB UT WOS:000348030100005 PM 25590756 ER PT J AU Douglas, AD Baldeviano, GC Lucas, CM Lugo-Roman, LA Crosnier, C Bartholdson, SJ Diouf, A Miura, K Lambert, LE Ventocilla, JA Leiva, KP Milne, KH Illingworth, JJ Spencer, AJ Hjerrild, KA Alanine, DGW Turner, AV Moorhead, JT Edgel, KA Wu, YM Long, CA Wright, GJ Lescano, AG Draper, SJ AF Douglas, Alexander D. Baldeviano, G. Christian Lucas, Carmen M. Lugo-Roman, Luis A. Crosnier, Cecile Bartholdson, S. Josefin Diouf, Ababacar Miura, Kazutoyo Lambert, Lynn E. Ventocilla, Julio A. Leiva, Karina P. Milne, Kathryn H. Illingworth, Joseph J. Spencer, Alexandra J. Hjerrild, Kathryn A. Alanine, Daniel G. W. Turner, Alison V. Moorhead, Jeromy T. Edgel, Kimberly A. Wu, Yimin Long, Carole A. Wright, Gavin J. Lescano, Andres G. Draper, Simon J. TI A PfRH5-Based Vaccine Is Efficacious against Heterologous Strain Blood-Stage Plasmodium falciparum Infection in Aotus Monkeys SO CELL HOST & MICROBE LA English DT Article ID APICAL MEMBRANE ANTIGEN-1; MEROZOITE SURFACE PROTEIN-1; IN-ADJUVANT VACCINES; MALARIA VACCINE; NANCYMAI MONKEYS; PFRH5 POLYMORPHISMS; ANTIBODY TITER; PROTECTION; INVASION; IMMUNIZATION AB Antigenic diversity has posed a critical barrier to vaccine development against the pathogenic blood-stage infection of the human malaria parasite Plasmodium falciparum. To date, only strain-specific protection has been reported by trials of such vaccines in nonhuman primates. We recently showed that P. falciparum reticulocyte binding protein homolog 5 (PfRH5), a merozoite adhesin required for erythrocyte invasion, is highly susceptible to vaccine-inducible strain-transcending parasite-neutralizing antibody. In vivo efficacy of PfRH5-based vaccines has not previously been evaluated. Here, we demonstrate that PfRH5-based vaccines can protect Aotus monkeys against a virulent vaccine-heterologous P. falciparum challenge and show that such protection can be achieved by a human-compatible vaccine formulation. Protection was associated with anti-PfRH5 antibody concentration and in vitro parasite-neutralizing activity, supporting the use of this in vitro assay to predict the in vivo efficacy of future vaccine candidates. These data suggest that PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans. C1 [Douglas, Alexander D.; Milne, Kathryn H.; Illingworth, Joseph J.; Spencer, Alexandra J.; Hjerrild, Kathryn A.; Alanine, Daniel G. W.; Turner, Alison V.; Draper, Simon J.] Univ Oxford, Jenner Inst, Oxford OX3 7DQ, England. [Baldeviano, G. Christian; Lucas, Carmen M.; Lugo-Roman, Luis A.; Ventocilla, Julio A.; Leiva, Karina P.; Moorhead, Jeromy T.; Edgel, Kimberly A.; Lescano, Andres G.] US Naval Med Res Unit 6 NAMRU 6, Lima, Peru. [Crosnier, Cecile; Bartholdson, S. Josefin; Wright, Gavin J.] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England. [Diouf, Ababacar; Miura, Kazutoyo; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Lambert, Lynn E.; Wu, Yimin] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. RP Douglas, AD (reprint author), Univ Oxford, Jenner Inst, Oxford OX3 7DQ, England. EM sandy.douglas@ndm.ox.ac.uk RI Douglas, Alexander/E-7040-2012; Lescano, Andres/B-8479-2008; OI Douglas, Alexander/0000-0002-5410-7562; Lescano, Andres/0000-0001-9779-633X; Spencer, Alexandra/0000-0001-7958-6961; Draper, Simon/0000-0002-9415-1357 FU Wellcome Trust [089455/2/09/z, 092873/z/10/z, 098051]; PATH Malaria Vaccine Initiative; Intramural Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; University Challenge Seed Fund (Isis Innovation, University of Oxford); European Community's Seventh Framework Programme (FP7) [242095 - EVIMalaR]; NIH/FIC by the Fogarty International Center of the US National Institutes of Health [2D43 TW007393]; MRC Career Development Fellowship - UK Medical Research Council [MRC] [G1000527]; MRC Career Development Fellowship - UK Department for International Development [DFID] [G1000527] FX The authors are grateful for the assistance of Adrian Hill, Julie Furze, the Viral Vector Core Facility and Adjuvant Bank (Jenner Institute, University of Oxford); David Staunton (Biophysical Instrument Facility, Department of Biochemistry, University of Oxford); Ly-Mee Yu and Doug Altman (Centre for Statistics in Medicine, University of Oxford); Julian Rayner (Wellcome Trust Sanger Institute, UK); Carmen Franco, Roxana Lescano, Jorge Nunez, Meddly Santolalla, and Lorena Tapia (NAMRU-6, Peru); Olivo Miotto (Mahidol-Oxford Research Unit, Thailand); Yves Durocher for provision of HEK293E cells (CNRC-NRC, Canada); and Alfredo Nicosia (Okairos, Italy) for provision of the ChAd63 vector. A.D.D. held a Wellcome Trust Training Fellowship for Clinicians in Basic Sciences (grant number 089455/2/09/z). J.J.I. is a Wellcome Trust funded student on the Infection, Immunology and Translational Medicine PhD Programme (grant number 092873/z/10/z). C.C., S.J. B., and G.J.W. are supported by the Wellcome Trust (grant number 098051). The GIA work was supported by the PATH Malaria Vaccine Initiative and the Intramural Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. This work was also funded in part by the University Challenge Seed Fund (Isis Innovation, University of Oxford) and by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 242095 - EVIMalaR. A.G.L. is supported by training grant NIH/FIC 2D43 TW007393 awarded to NAMRU-6 by the Fogarty International Center of the US National Institutes of Health. S.J.D. holds a MRC Career Development Fellowship (grant number G1000527; this fellowship is jointly funded by the UK Medical Research Council [MRC] and the UK Department for International Development [DFID] under the MRC/DFID Concordat agreement) and is a Jenner Investigator and Lister Institute Research Prize Fellow. A.D.D., J.J.I., C.C., S.J. B., G.J.W., and S.J.D. are named on patent applications relating to PfRH5 and/or other malaria vaccines. Some of the listed authors are either military service members (K.A.E., L.A.L.-R., J.T.M.) or employees of the US Government (G.C.B., C.M.L., J.A.V., K.P.L., A.G.L.). This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that ''Copyright protection under this title is not available for any work of the United States Government.'' Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the US Government as part of that person's official duties. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government. NR 60 TC 42 Z9 42 U1 2 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD JAN 14 PY 2015 VL 17 IS 1 BP 130 EP 139 DI 10.1016/j.chom.2014.11.017 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AZ1YB UT WOS:000348030100016 PM 25590760 ER PT J AU Kim, DH Xiao, Z Kwon, S Sun, XX Ryerson, D Tkac, D Ma, P Wu, SY Chiang, CM Zhou, E Xu, HE Palvimo, JJ Chen, LF Kemper, B Kemper, JK AF Kim, Dong-Hyun Xiao, Zhen Kwon, Sanghoon Sun, Xiaoxiao Ryerson, Daniel Tkac, David Ma, Ping Wu, Shwu-Yuan Chiang, Cheng-Ming Zhou, Edward Xu, H. Eric Palvimo, Jorma J. Chen, Lin-Feng Kemper, Byron Kemper, Jongsook Kim TI A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity SO EMBO JOURNAL LA English DT Article DE acetylation; NF-B; PIASy; steatosis; SUMO2 ID FARNESOID X RECEPTOR; PPAR-GAMMA; METABOLIC DISEASE; LYSINE ACETYLATION; LIPID-METABOLISM; RESPONSE GENES; LXR-BETA; SIRT1; SUMOYLATION; PATHWAYS AB Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and acetylation-defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-B but blocked that with RXR, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXR target genes. A dysregulated acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders. C1 [Kim, Dong-Hyun; Kwon, Sanghoon; Ryerson, Daniel; Tkac, David; Kemper, Byron; Kemper, Jongsook Kim] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL USA. [Xiao, Zhen] NCI, SAIC Frederick Inc, Adv Technol Program, Lab Proteom & Analyt Technol, Frederick, MD 21701 USA. [Sun, Xiaoxiao; Ma, Ping] Univ Georgia, Dept Stat, Athens, GA 30602 USA. [Wu, Shwu-Yuan; Chiang, Cheng-Ming] Univ Texas Dallas, SW Med Ctr, Dept Biochem, Simmons Comprehens Canc Ctr, Dallas, TX 75235 USA. [Wu, Shwu-Yuan; Chiang, Cheng-Ming] Univ Texas Dallas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75235 USA. [Zhou, Edward; Xu, H. Eric] Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI USA. [Palvimo, Jorma J.] Univ Eastern Finland, Inst Biomed, Kuopio, Finland. [Chen, Lin-Feng] Univ Illinois, Dept Biochem, Urbana, IL 61801 USA. RP Kemper, JK (reprint author), Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL USA. EM jongsook@illinois.edu RI Ma, Ping/M-7746-2015 OI Ma, Ping/0000-0002-5728-3596 FU AHA post-doctoral fellowship [14POST20420006]; NSF [DMS-1440037, DMS-1228288]; NIH [CA103867, DK62777, DK95842]; CPRIT [RP110471, RP140367]; Welch Foundation [I-1805]; Academy of Finland FX We thank Ron Hay at University of Dundee for kindly providing SUMO expression plasmids and Peter Tontonoz at UCLA for (NF-kappa B site)3-tk-luc plasmid. This study was supported by grants from an AHA post-doctoral fellowship to DHK (14POST20420006), NSF grants (DMS-1440037 and DMS-1228288) to PM, NIH (CA103867), CPRIT (RP110471 and RP140367), and Welch Foundation (I-1805) to CMC, the Academy of Finland to JP, and NIH grants (DK62777 and DK95842) to JKK. NR 47 TC 15 Z9 15 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD JAN 14 PY 2015 VL 34 IS 2 BP 184 EP 199 DI 10.15252/embj.201489527 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AY9NY UT WOS:000347878900007 PM 25425577 ER PT J AU Cerbini, T Funahashl, R Luo, YQ Liu, CY Park, K Rao, M Malik, N Zou, JH AF Cerbini, Trevor Funahashl, Ray Luo, Yongquan Liu, Chengyu Park, Kyeyoon Rao, Mahendra Malik, Nasir Zou, Jizhong TI Transcription Activator-Like Effector Nuclease (TALEN)-Mediated CLYBL Targeting Enables Enhanced Transgene Expression and One-Step Generation of Dual Reporter Human Induced Pluripotent Stem Cell (iPSC) and Neural Stem Cell (NSC) Lines SO PLOS ONE LA English DT Article ID GENE CORRECTION; DISEASE; TALEN; SPECIFICITY; MUTATIONS; CLONES; CAS9 AB Targeted genome engineering to robustly express transgenes is an essential methodology for stem cell-based research and therapy. Although designer nucleases have been used to drastically enhance gene editing efficiency, targeted addition and stable expression of transgenes to date is limited at single gene/locus and mostly PPP1R12C/AAVS1 in human stem cells. Here we constructed transcription activator-like effector nucleases (TALENs) targeting the safe-harbor like gene CLYBL to mediate reporter gene integration at 38%-58% efficiency, and used both AAVS1-TALENs and CLYBL-TALENs to simultaneously knock-in multiple reporter genes at dual safe-harbor loci in human induced pluripotent stem cells (iPSCs) and neural stem cells (NSCs). The CLYBL-TALEN engineered cell lines maintained robust reporter expression during self-renewal and differentiation, and revealed that CLYBL targeting resulted in stronger transgene expression and less perturbation on local gene expression than PPP1R12C/AAVS1. TALEN-mediated CLYBL engineering provides improved transgene expression and options for multiple genetic modification in human stem cells. C1 [Cerbini, Trevor; Funahashl, Ray; Luo, Yongquan; Rao, Mahendra; Malik, Nasir; Zou, Jizhong] NIAMSD, NIH, Ctr Regenerat Med, Lab Stem Cell Biol, Bethesda, MD 20892 USA. [Liu, Chengyu; Zou, Jizhong] NHLBI, Ctr Mol Med, Div Intramural Res, Bethesda, MD 20892 USA. [Park, Kyeyoon] NINDS, Stem Cell Unit, Bethesda, MD 20892 USA. RP Zou, JH (reprint author), NIAMSD, NIH, Ctr Regenerat Med, Lab Stem Cell Biol, Bethesda, MD 20892 USA. EM zouj2@mail.nih.gov FU National Institutes of Health Common Fund; National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke FX This research was supported by the National Institutes of Health Common Fund and Intramural Research Programs of the National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 5 Z9 5 U1 1 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 14 PY 2015 VL 10 IS 1 AR e0116032 DI 10.1371/journal.pone.0116032 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AZ0ID UT WOS:000347928300008 PM 25587899 ER PT J AU Costello, RB Lentino, CV Saldanha, L Engler, MM Engler, MB Srinivas, P Sempos, CT AF Costello, Rebecca B. Lentino, Cynthia V. Saldanha, Leila Engler, Marguerite M. Engler, Mary B. Srinivas, Pothur Sempos, Christopher T. TI A select review reporting the quality of studies measuring endothelial dysfunction in randomised diet intervention trials SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Dietary supplements; Dietary ingredients; Vascular function; Flow-mediated dilation; Systematic reviews ID CORONARY-ARTERY-DISEASE; FLOW-MEDIATED DILATION; HEALTHY POSTMENOPAUSAL WOMEN; FLAVANOL-RICH COCOA; CARDIOVASCULAR RISK-FACTORS; PURIFIED EICOSAPENTAENOIC ACID; TYPE-2 DIABETES-MELLITUS; FISH-OIL SUPPLEMENTATION; REDUCES BLOOD-PRESSURE; N-3 FATTY-ACIDS AB A quality assessment of the primary studies reported in the literature carried out using SElect dietary ingredients (DI) purported to affect vascular endothelial function was conducted through a systematic PubMed SEarch from January 2000 to August 2012. A total of SEventy randomiSEd controlled trials with defined DI (folic acid (fifteen), n-3 fatty acids (twenty), cocoa (fifteen) and isoflavones (twenty)) and standardiSEd measures of vascular endothelial function were evaluated. Jadad scores, quality scoring parameters for DI and flow-mediated dilation (FMD) methodology uSEd were ascertained. A total of 3959 randomiSEd subjects, mean age 51 (SE 0.21) years (range 9-79 years), were repreSEnted in the dataSEt. The mean Jadad scores did not differ statistically among the DI studies, with the majority of the studies being of good quality. Higher DI quality scores were achieved by studies using the botanical ingredients cocoa and isoflavones than by thoSE using the nutrient ingredients folic acid and n-3 fatty acids. The mean DI quality scores were 4.13 (SE 0.34), 5.20 (SE 0.47), 6.13 (SE 0.41) and 6.00 (SE 0.59) for the folic acid, n-3 fatty acid, cocoa and isoflavone intervention studies, respectively (and significantly different). The mean Corretti FMD scores were 7.27 (SE 0.56), 7.46 (SE 0.79), 6.29 (SE 0.61) and 7.11 (SE 0.56) for the folic acid, n-3 fatty acid, cocoa and isoflavone intervention studies, respectively (NS). FMD studies failed to adequately describe the equipment uSEd and more than half failed to provide an adequate description of the procedures uSEd for vascular image acquisition and measurement. DI can be utiliSEd for dietary intervention studies; however, the methodology should be clearly reported using the guidelines for assessment for both DI and FMD. C1 [Costello, Rebecca B.; Lentino, Cynthia V.; Saldanha, Leila; Sempos, Christopher T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Engler, Marguerite M.; Engler, Mary B.] NINR, Bethesda, MD 20892 USA. [Srinivas, Pothur] NHLBI, NIH, Bethesda, MD 20892 USA. RP Costello, RB (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Room 3B01,MSC 7517, Bethesda, MD 20892 USA. EM costellb@od.nih.gov FU Office of Dietary Supplements, National Institutes of Health FX The Office of Dietary Supplements, National Institutes of Health, funded and sponsored this work. NR 132 TC 1 Z9 1 U1 0 U2 11 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 EI 1475-2662 J9 BRIT J NUTR JI Br. J. Nutr. PD JAN 14 PY 2015 VL 113 IS 1 BP 89 EP 99 DI 10.1017/S0007114514003353 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AX7OM UT WOS:000347105000009 PM 25374114 ER PT J AU Swoboda, RK Somasundaram, R Caputo-Gross, L Marincola, FM Robbins, P Herlyn, M Herlyn, D AF Swoboda, Rolf K. Somasundaram, Rajasekharan Caputo-Gross, Laura Marincola, Francesco M. Robbins, Paul Herlyn, Meenhard Herlyn, Dorothee TI Antimelanoma CTL recognizes peptides derived from an ORF transcribed from the antisense strand of the 3 ' untranslated region of TRIT1 SO Molecular Therapy-Oncolytics LA English DT Article ID TRANSFER-RNA MODIFICATIONS; CYTOLYTIC T-LYMPHOCYTES; MALIGNANT-MELANOMA; NONCODING RNAS; CANCER; CELLS; GENE; CD4(+); CLONE; IMMUNOTHERAPY AB Noncoding regions of the genome play an important role in tumorigenesis of cancer. Using expression cloning, we have identified a cytotoxic T lymphocyte (CTL)-defined antigen that recognizes a protein sequence derived from an open reading frame transcribed from the reverse strand in the 3' untranslated region of tRNA isopentenyltransferase 1 (TRIT1). A peptide derived from this open reading frame (ORF) sequence and predicted to bind to HLA-B57, sensitized HLA-B57(+) tumor cells to lysis by CTL793. The peptide also induced a CTL response in peripheral blood mononuclear cells (PBMC) of patient 793 and in two other melanoma patients. The CTL lysed peptide-pulsed HLA-B57(+) target cells and melanoma cells with endogenous antigen expression. The recognition of this antigen is not limited to HLA-B57-restricted CTLs. An HLA-A2 peptide derived from the ORF was able to induce CTLs in PBMC of 2 HLA-A2(+) patients. This study describes for the first time a CTL-defined melanoma antigen that is derived from an ORF on the reverse strand of the putative tumor suppressor gene TRIT1. This antigen has potential use as a vaccine or its ability to induce CTLs in vitro could be used as a predictive biomarker. C1 [Swoboda, Rolf K.; Somasundaram, Rajasekharan; Caputo-Gross, Laura; Herlyn, Meenhard; Herlyn, Dorothee] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. [Marincola, Francesco M.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Robbins, Paul] NCI, Surg Branch, NIH, Bethesda, MD USA. [Swoboda, Rolf K.] Abzyme Therapeut, Pottstown, PA USA. [Caputo-Gross, Laura] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. RP Swoboda, RK (reprint author), Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. EM rolf@wistar.org FU [CA60975]; [CA88193]; [CA25874]; [CA10815] FX The research was funded in part by grants CA60975, CA88193, CA25874, and CA10815. We thank Ling Li for supplying melanocytes. The authors declare no conflict of interest. NR 42 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2372-7705 J9 Mol Ther-Oncolytics JI Mol. Ther.-Oncolytics PD JAN 14 PY 2015 VL 2 AR UNSP 14009 DI 10.1038/mto.2014.9 PG 8 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA EE2PX UT WOS:000389427800001 ER PT J AU Tang, BW Raviv, A Esposito, D Flanders, KC Daniel, C Nghiem, BT Garfield, S Lim, L Mannan, P Robles, AI Smith, WI Zimmerberg, J Ravin, R Wakefield, LM AF Tang, Binwu Raviv, Asaf Esposito, Dominic Flanders, Kathleen C. Daniel, Catherine Nghiem, Bao Tram Garfield, Susan Lim, Langston Mannan, Poonam Robles, Ana I. Smith, William I., Jr. Zimmerberg, Joshua Ravin, Rea Wakefield, Lalage M. TI A Flexible Reporter System for Direct Observation and Isolation of Cancer Stem Cells SO STEM CELL REPORTS LA English DT Article ID TUMOR-INITIATING CELLS; PROGENITOR CELLS; GENE-EXPRESSION; ADULT STEM; TGF-BETA; GENERATION; OCT4; PROGRESSION; LINES; DIFFERENTIATION AB Many tumors are hierarchically organized with a minority cell population that has stem-like properties and enhanced ability to initiate tumorigenesis and drive therapeutic relapse. These cancer stem cells (CSCs) are typically identified by complex combinations of cell-surface markers that differ among tumor types. Here, we developed a flexible lentiviral-based reporter system that allows direct visualization of CSCs based on functional properties. The reporter responds to the core stem cell transcription factors OCT4 and SOX2, with further selectivity and kinetic resolution coming from use of a proteasome-targeting degron. Cancer cells marked by this reporter have the expected properties of self-renewal, generation of heterogeneous offspring, high tumor-and metastasis-initiating activity, and resistance to chemotherapeutics. With this approach, the spatial distribution of CSCs can be assessed in settings that retain microenvironmental and structural cues, and CSC plasticity and response to therapeutics can be monitored in real time. C1 [Tang, Binwu; Raviv, Asaf; Flanders, Kathleen C.; Daniel, Catherine; Nghiem, Bao Tram; Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Esposito, Dominic] Frederick Natl Lab Canc Res, Adv Technol Program, Prot Express Lab, Frederick, MD 21701 USA. [Garfield, Susan; Lim, Langston; Mannan, Poonam] NCI, Confocal Microscopy Core, Bethesda, MD 20892 USA. [Robles, Ana I.] NCI, Lab Human Carcinogenesis, Bethesda, MD 20892 USA. [Smith, William I., Jr.] Suburban Hosp, Dept Pathol, Bethesda, MD 20814 USA. [Zimmerberg, Joshua; Ravin, Rea] NICHHD, Program Phys Biol, Bethesda, MD 20892 USA. RP Wakefield, LM (reprint author), NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. EM lw34g@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research [Z01 BC 005785] FX We thank Barbara Taylor, Karen Wolcott, and Suphadra Banerjee of the CCR FACS core facility, Dr. Mario Anzano and Anthony Vieira of the LCBG Animal Core, and Sam Dengler of the LCBG and Jen Mehalko of the Protein Expression Laboratory for their excellent technical assistance. We thank Dr. Brid Ryan for expert guidance with the asymmetric cell division assays. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (grant Z01 BC 005785, to L.M.W.). NR 41 TC 15 Z9 15 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD JAN 13 PY 2015 VL 4 IS 1 BP 155 EP 169 DI 10.1016/j.stemcr.2014.11.002 PG 15 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AZ2AK UT WOS:000348036800014 PM 25497455 ER PT J AU Athwal, RK Walkiewicz, MP Baek, S Fu, S Bui, M Camps, J Ried, T Sung, MH Dalal, Y AF Athwal, Rajbir K. Walkiewicz, Marcin P. Baek, Songjoon Fu, Song Bui, Minh Camps, Jordi Ried, Thomas Sung, Myong-Hee Dalal, Yamini TI CENP-A nucleosomes localize to transcription factor hotspots and subtelomeric sites in human cancer cells SO EPIGENETICS & CHROMATIN LA English DT Article ID CENTROMERE PROTEIN-A; HISTONE H3 VARIANT; I-HYPERSENSITIVE SITES; E3 UBIQUITIN LIGASE; COLORECTAL-CANCER; CRYSTAL-STRUCTURE; BREAST-CANCER; GLUCOCORTICOID-RECEPTOR; GENOME INSTABILITY; CHROMATIN REQUIRES AB Background: The histone H3 variant CENP-A is normally tightly regulated to ensure only one centromere exists per chromosome. Native CENP-A is often found overexpressed in human cancer cells and a range of human tumors. Consequently, CENP-A misregulation is thought to contribute to genome instability in human cancers. However, the consequences of such overexpression have not been directly elucidated in human cancer cells. Results: To investigate native CENP-A overexpression, we sought to uncover CENP-A-associated defects in human cells. We confirm that CENP-A is innately overexpressed in several colorectal cancer cell lines. In such cells, we report that a subset of structurally distinct CENP-A-containing nucleosomes associate with canonical histone H3, and with the transcription-coupled chaperones ATRX and DAXX. Furthermore, such hybrid CENP-A nucleosomes localize to DNase I hypersensitive and transcription factor binding sites, including at promoters of genes across the human genome. A distinct class of CENP-A hotspots also accumulates at subtelomeric chromosomal locations, including at the 8q24/Myc region long-associated with genomic instability. We show this 8q24 accumulation of CENP-A can also be seen in early stage primary colorectal tumors. Conclusions: Our data demonstrate that excess CENP-A accumulates at noncentromeric locations in the human cancer genome. These findings suggest that ectopic CENP-A nucleosomes could alter the state of the chromatin fiber, potentially impacting gene regulation and chromosome fragility. C1 [Athwal, Rajbir K.; Walkiewicz, Marcin P.; Fu, Song; Bui, Minh; Dalal, Yamini] NCI, Ctr Canc Res, Chromatin Struct & Epigenet Mech Unit, NIH, Bethesda, MD 20892 USA. [Athwal, Rajbir K.; Walkiewicz, Marcin P.; Baek, Songjoon; Fu, Song; Bui, Minh; Sung, Myong-Hee] NCI, Ctr Canc Res, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Camps, Jordi; Ried, Thomas] NCI, Ctr Canc Res, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Dalal, Y (reprint author), NCI, Ctr Canc Res, Chromatin Struct & Epigenet Mech Unit, NIH, 41 Ctr Dr, Bethesda, MD 20892 USA. EM dalaly@mail.nih.gov FU National Cancer Institute FX The Intramural Research Program of the National Cancer Institute supported all authors in this study. SF volunteered as a guest researcher for the bulk of this study and was subsequently supported by the NCI post-baccalaureate program. NR 82 TC 13 Z9 13 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8935 J9 EPIGENET CHROMATIN JI Epigenetics Chromatin PD JAN 13 PY 2015 VL 8 AR 2 DI 10.1186/1756-8935-8-2 PG 23 WC Genetics & Heredity SC Genetics & Heredity GA CA6TE UT WOS:000349047900001 PM 25788983 ER PT J AU Posokhova, E Shukla, A Seaman, S Volate, S Hilton, MB Wu, BF Morris, H Swing, DA Zhou, M Zudaire, E Rubin, JS St Croix, B AF Posokhova, Ekaterina Shukla, Animesh Seaman, Steven Volate, Suresh Hilton, Mary Beth Wu, Bofan Morris, Holly Swing, Deborah A. Zhou, Ming Zudaire, Enrique Rubin, Jeffrey S. St Croix, Brad TI GPR124 Functions as a WNT7-Specific Coactivator of Canonical beta-Catenin Signaling SO CELL REPORTS LA English DT Article ID BLOOD-BRAIN-BARRIER; PROTEIN-COUPLED RECEPTOR; MOUSE; LIMB; CNS; ANGIOGENESIS; GENE; POLARITY; MODELS; MARKER AB G protein-coupled receptor 124 (GPR124) is an orphan receptor in the adhesion family of GPCRs, and previous global or endothelial-specific disruption of Gpr124 in mice led to defective CNS angiogenesis and blood-brain barriergenesis. Similar developmental defects were observed following dual deletion of Wnt7a/Wnt7b or deletion of beta-catenin in endothelial cells, suggesting a possible relationship between GPR124 and canonical WNT signaling. Here, we show using in vitro reporter assays, mutation analysis, and genetic interaction studies in vivo that GPR124 functions as a WNT7A/WNT7B-specific costimulator of beta-catenin signaling in brain endothelium. WNT7-stimulated beta-catenin signaling was dependent upon GPR124's intracellular PDZ binding motif and a set of leucine-rich repeats in its extracellular domain. This study reveals a vital role for GPR124 in potentiation of WNT7-induced canonical beta-catenin signaling with important implications for understanding and manipulating CNS-specific angiogenesis and blood-brain barriergenesis. C1 [Posokhova, Ekaterina; Shukla, Animesh; Seaman, Steven; Volate, Suresh; Hilton, Mary Beth; Wu, Bofan; Zudaire, Enrique; St Croix, Brad] NCI, Tumor Angiogenesis Sect, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. [Hilton, Mary Beth] Leidos Inc, Basic Res Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Morris, Holly; Swing, Deborah A.] NCI, Transgen Core Facil, MCGP, Frederick, MD 21702 USA. [Zhou, Ming] Leidos Inc, Lab Prote & Analyt Technol, FNLCR, Frederick, MD 21702 USA. [Rubin, Jeffrey S.] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. RP St Croix, B (reprint author), NCI, Tumor Angiogenesis Sect, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. EM stcroix@ncifcrf.gov FU Center for Cancer Research Intramural Program, NCI, NIH, a part of the U.S. Department of Health and Human Services (DHHS) FX We thank Terry P. Yamaguchi for helpful discussions during our studies and expression vectors for constitutively active beta-catenin and Renilla luciferase. We are grateful to the Open Source WNT project for providing the panel of human WNT plasmids. This work was supported by the Center for Cancer Research Intramural Program, NCI, NIH, a part of the U.S. Department of Health and Human Services (DHHS). The content of this publication does not necessarily reflect the views or policies of the DHHS. NR 24 TC 18 Z9 20 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JAN 13 PY 2015 VL 10 IS 2 BP 123 EP 130 DI 10.1016/j.celrep.2014.12.020 PG 8 WC Cell Biology SC Cell Biology GA AZ2AI UT WOS:000348036600001 PM 25558062 ER PT J AU Collins, FS AF Collins, Francis S. TI Exceptional Opportunities in Medical Science A View From the National Institutes of Health SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Collins, Francis S.] NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NIH, Off Director, 1 Ctr Dr, Bethesda, MD 20892 USA. EM collinsf@mail.nih.gov NR 8 TC 31 Z9 32 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 13 PY 2015 VL 313 IS 2 BP 131 EP 132 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AY6MC UT WOS:000347679300006 PM 25585318 ER PT J AU Ji, Y Wrzesinski, C Yu, ZY Hu, JH Gautam, S Hawk, NV Telford, WG Palmer, DC Franco, Z Sukumar, M Roychoudhuri, R Clever, D Klebanoff, CA Surh, CD Waldmann, TA Restifo, NP Gattinoni, L AF Ji, Yun Wrzesinski, Claudia Yu, Zhiya Hu, Jinhui Gautam, Sanjivan Hawk, Nga V. Telford, William G. Palmer, Douglas C. Franco, Zulmarie Sukumar, Madhusudhanan Roychoudhuri, Rahul Clever, David Klebanoff, Christopher A. Surh, Charles D. Waldmann, Thomas A. Restifo, Nicholas P. Gattinoni, Luca TI miR-155 augments CD8(+) T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic gamma(c) cytokines SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE microRNA-155; adoptive immunotherapy; lymphodepletion; homeostatic cytokines ID INCREASED INTENSITY LYMPHODEPLETION; METASTATIC MELANOMA; ADOPTIVE IMMUNOTHERAPY; IMMUNE-SYSTEM; STEM-CELLS; THERAPY; CANCER; MICRORNA-155; RESPONSES; EFFECTOR AB Lymphodepleting regimens are used before adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic "cytokine sinks." These conditioning modalities, however, are often associated with severe toxicities. We found that microRNA-155 (miR-155) enabled tumor-specific CD8(+) T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T-cell responsiveness to limited amounts of homeostatic gamma c cytokines, resulting in delayed cellular contraction and sustained cytokine production. miR-155 restrained the expression of the inositol 5-phosphatase Ship1, an inhibitor of the serine-threonine protein kinase Akt, and multiple negative regulators of signal transducer and activator of transcription 5 (Stat5), including suppressor of cytokine signaling 1 (Socs1) and the protein tyrosine phosphatase Ptpn2. Expression of constitutively active Stat5a recapitulated the survival advantages conferred by miR-155, whereas constitutive Akt activation promoted sustained effector functions. Our results indicate that overexpression of miR-155 in tumor-specific T cells can be used to increase the effectiveness of adoptive immunotherapies in a cell-intrinsic manner without the need for life-threatening, lymphodepleting maneuvers. C1 [Ji, Yun; Hu, Jinhui; Gautam, Sanjivan; Hawk, Nga V.; Telford, William G.; Gattinoni, Luca] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wrzesinski, Claudia; Yu, Zhiya; Palmer, Douglas C.; Franco, Zulmarie; Sukumar, Madhusudhanan; Roychoudhuri, Rahul; Clever, David; Klebanoff, Christopher A.; Restifo, Nicholas P.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Surh, Charles D.] Acad Immunol & Microbiol, Inst Basic Sci, Pohang 790784, South Korea. [Waldmann, Thomas A.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov; tawald@helix.nih.gov; gattinol@mail.nih.gov RI Gattinoni, Luca/A-2281-2008; Palmer, Douglas/B-9454-2008; Ji, Yun/B-7245-2009; Roychoudhuri, Rahul/A-7442-2010; OI Gattinoni, Luca/0000-0003-2239-3282; Palmer, Douglas/0000-0001-5018-5734; Ji, Yun/0000-0001-6340-7009; Roychoudhuri, Rahul/0000-0002-5392-1853; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health FX We thank A. Mixon and S. Farid for flow cytometry sorting. We thank Dr. Hand for providing the AktCA and Stat5aCA constructs. This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. NR 40 TC 11 Z9 12 U1 0 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 13 PY 2015 VL 112 IS 2 BP 476 EP 481 DI 10.1073/pnas.1422916112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY7HS UT WOS:000347732300056 PM 25548153 ER PT J AU Ong, HL de Souza, LB Zheng, CY Cheng, KT Liu, XB Goldsmith, CM Feske, S Ambudkar, IS AF Ong, Hwei Ling de Souza, Lorena Brito Zheng, Changyu Cheng, Kwong Tai Liu, Xibao Goldsmith, Corinne M. Feske, Stefan Ambudkar, Indu S. TI STIM2 enhances receptor-stimulated Ca2+ signaling by promoting recruitment of STIM1 to the endoplasmic reticulum-plasma membrane junctions SO SCIENCE SIGNALING LA English DT Article ID OPERATED CALCIUM-ENTRY; STORE DEPLETION; CRAC CHANNELS; FLUID SECRETION; DIRECT BINDING; SAM DOMAIN; ACTIVATION; ORAI1; OLIGOMERIZATION; OSCILLATIONS AB A central component of receptor-evoked Ca2+ signaling is store-operated Ca2+ entry (SOCE), which is activated by the assembly of STIM1-Orai1 channels in endoplasmic reticulum (ER) and plasma membrane (PM) (ER-PM) junctions in response to depletion of ER Ca2+. We report that STIM2 enhances agonist-mediated activation of SOCE by promoting STIM1 clustering in ER-PM junctions at low stimulus intensities. Targeted deletion of STIM2 in mouse salivary glands diminished fluid secretion in vivo and SOCE activation in dispersed salivary acinar cells stimulated with low concentrations of muscarinic receptor agonists. STIM2 knockdown in human embryonic kidney (HEK) 293 cells diminished agonist-induced Ca2+ signaling and nuclear translocation of NFAT (nuclear factor of activated T cells). STIM2 lacking five carboxyl-terminal amino acid residues did not promote formation of STIM1 puncta at low concentrations of agonist, whereas coexpression of STIM2 with STIM1 mutant lacking the polybasic region STIM1 Delta K resulted in co-clustering of both proteins. Together, our findings suggest that STIM2 recruits STIM1 to ER-PM junctions at low stimulus intensities when ER Ca2+ stores are mildly depleted, thus increasing the sensitivity of Ca2+ signaling to agonists. C1 [Ong, Hwei Ling; de Souza, Lorena Brito; Liu, Xibao; Ambudkar, Indu S.] NIDCR, Mol Physiol & Therapeut Branch, Secretory Physiol Sect, NIH, Bethesda, MD 20892 USA. [Zheng, Changyu; Goldsmith, Corinne M.] NIDCR, Mol Physiol & Therapeut Branch, Translat Res Core, NIH, Bethesda, MD 20892 USA. [Cheng, Kwong Tai] Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA. [Feske, Stefan] NYU, Langone Med Ctr, Dept Pathol, New York, NY 10016 USA. RP Ambudkar, IS (reprint author), NIDCR, Mol Physiol & Therapeut Branch, Secretory Physiol Sect, NIH, Bethesda, MD 20892 USA. EM indu.ambudkar@nih.gov RI Brito de Souza, Lorena/N-3385-2014; OI Brito de Souza, Lorena/0000-0002-2462-6759; Feske, Stefan/0000-0001-5431-8178 FU NIDCR-Division of Intramural Research; NIH [AI097302] FX We also acknowledge grant support from the NIDCR-Division of Intramural Research for I.S.A. and from NIH (grant no. AI097302) for S.F. NR 42 TC 10 Z9 10 U1 1 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JAN 13 PY 2015 VL 8 IS 359 AR ra3 DI 10.1126/scisignal.2005748 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AZ0EY UT WOS:000347920200002 PM 25587190 ER PT J AU Zhang, X An, X Liu, HX Peng, J Cai, SS Wang, W Lin, DT YupengYang AF Zhang, Xian An, Xu Liu, Hanxiao Peng, Jing Cai, Shanshan Wang, Wei Lin, Da-Ting YupengYang TI The Topographical Arrangement of Cutoff Spatial Frequencies across Lower and Upper Visual Fields in Mouse V1 SO SCIENTIFIC REPORTS LA English DT Article ID RETINAL GANGLION-CELLS; RECEPTIVE-FIELD; FUNCTIONAL SPECIALIZATION; DIRECTION SELECTIVITY; SUPERIOR COLLICULUS; INTRINSIC SIGNAL; VERNIER ACUITY; CORTICAL AREAS; GRATING ACUITY; CORTEX AB The visual response to spatial frequency (SF), a characteristic of spatial structure across position in space, is of particular importance for animal survival. A natural challenge for rodents is to detect predators as early as possible while foraging. Whether neurons in mouse primary visual cortex (V1) are functionally organized to meet this challenge remains unclear. Combining intrinsic signal optical imaging and single-unit recording, we found that the cutoff SF was much greater for neurons whose receptive fields were located above the mouse. Specifically, we discovered that the cutoff SF increased in a gradient that was positively correlated with the elevation in the visual field. This organization was present at eye opening and persisted through adulthood. Dark rearing delayed the maturation of the cutoff SF globally, but had little impact on the topographical organization of the cutoff SF, suggesting that this regional distribution is innately determined. This form of cortical organization of different SFs may benefit the mouse for detection of airborne threats in the natural environment. C1 [Zhang, Xian; An, Xu; Liu, Hanxiao; Peng, Jing; Cai, Shanshan; YupengYang] Univ Sci & Technol China, Sch Life Sci, CAS Key Lab Brain Funct & Dis, Hefei 230027, Peoples R China. [Wang, Wei] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Neurosci, Shanghai 200031, Peoples R China. [Wang, Wei] Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Neurosci, Shanghai 200031, Peoples R China. [Lin, Da-Ting] Natl Inst Drug Abuse, Intramural Res Programme, NIH, Baltimore, MD 21224 USA. RP YupengYang (reprint author), Univ Sci & Technol China, Sch Life Sci, CAS Key Lab Brain Funct & Dis, Hefei 230027, Peoples R China. EM yangyp@ustc.edu.cn FU National '973' Programmes [2009CB941303, 2011CBA00400]; National Natural Science Foundation of China [31371112] FX This work was supported by National '973' Programmes 2009CB941303 and 2011CBA00400, the National Natural Science Foundation of China (Nos. 31371112). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Drs. Nigel Daw, Michael Stryker, Yifeng Zhang, Jianzhong Jin, Ian Andolina and Niall McLoughlin for comments and suggestions on the data analysis and manuscript writing. NR 61 TC 1 Z9 1 U1 9 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 13 PY 2015 VL 5 AR 7734 DI 10.1038/srep07734 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY8WT UT WOS:000347832200003 PM 25583266 ER PT J AU Damsky, W Micevic, G Meeth, K Muthusamy, V Curley, DP Santhanakrishnan, M Erdelyi, I Platt, JT Huang, L Theodosakis, N Zaidi, MR Tighe, S Davies, MA Dankort, D McMahon, M Merlino, G Bardeesy, N Bosenberg, M AF Damsky, William Micevic, Goran Meeth, Katrina Muthusamy, Viswanathan Curley, David P. Santhanakrishnan, Manjula Erdelyi, Ildiko Platt, James T. Huang, Laura Theodosakis, Nicholas Zaidi, M. Raza Tighe, Scott Davies, Michael A. Dankort, David McMahon, Martin Merlino, Glenn Bardeesy, Nabeel Bosenberg, Marcus TI mTORC1 Activation Blocks Braf(V600E)-Induced Growth Arrest but Is Insufficient for Melanoma Formation SO CANCER CELL LA English DT Article ID ONCOGENE-INDUCED SENESCENCE; MALIGNANT MELANOMAS; CUTANEOUS MELANOMA; MELANOCYTIC TUMORS; MOUSE MODEL; COMPLEX 2; PTEN LOSS; EXPRESSION; CANCER; NEVI AB Braf(V600E) induces benign, growth-arrested melanocytic nevus development, but also drives melanoma formation. Cdkn2a loss in Braf(V600E) melanocytes in mice results in rare progression to melanoma, but only after stable growth arrest as nevi. Immediate progression to melanoma is prevented by upregulation of miR-99/100, which downregulates mTOR and IGF1R signaling. mTORC1 activation through Stk11 (Lkb1) loss abrogates growth arrest of Braf(V600E) melanocytic nevi, but is insufficient for complete progression to melanoma. Cdkn2a loss is associated with mTORC2 and Akt activation in human and murine melanocytic neoplasms. Simultaneous Cdkn2a and Lkb1 inactivation in Braf(V600E) melanocytes results in activation of both mTORC1 and mTORC2/Akt, inducing rapid melanoma formation in mice. In this model, activation of both mTORC1/2 is required for Braf-induced melanomagenesis. C1 [Damsky, William; Micevic, Goran; Platt, James T.; Huang, Laura; Bosenberg, Marcus] Yale Univ, Dept Dermatol, New Haven, CT 06510 USA. [Micevic, Goran; Meeth, Katrina; Theodosakis, Nicholas; Bosenberg, Marcus] Yale Univ, Dept Pathol, New Haven, CT 06510 USA. [Muthusamy, Viswanathan] Yale Univ, Dept Chem, New Haven, CT 06510 USA. [Curley, David P.] Brown Univ, Dept Emergency Med, Warren Alpert Med Sch, Providence, RI 02912 USA. [Santhanakrishnan, Manjula] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA. [Erdelyi, Ildiko] Yale Univ, Sch Med, Sect Comparat Med, New Haven, CT 06510 USA. [Zaidi, M. Raza] Temple Univ, Fels Inst Canc Res & Mol Biol, Sch Med, Philadelphia, PA 19140 USA. [Tighe, Scott] Univ Vermont, Coll Med, Vermont Canc Ctr, NextGen Sequencing Facil, Burlington, VT 05405 USA. [Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Dankort, David] McGill Univ, Dept Biol, Montreal, PQ H3A 1B1, Canada. [McMahon, Martin] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA. [McMahon, Martin] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Merlino, Glenn] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Bardeesy, Nabeel] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. RP Damsky, W (reprint author), Yale Univ, Dept Dermatol, New Haven, CT 06510 USA. EM william.damsky@gmail.com; marcus.bosenberg@yale.edu RI Zaidi, M. Raza/H-1386-2016; OI Zaidi, M. Raza/0000-0003-0480-3188; Dankort, David/0000-0002-5862-6829 FU National Cancer Institute [NCI] Cancer Center Support Grant [CCSG] [CA-16672]; NCI [R01 CA112054, P50 CA121974, P01 CA128814]; Hevery Foundation; Joanna M. Nicolay Melanoma Foundation; GlaxoSmithKline; Genentech; Merck; Myriad; AstraZeneca; Sanofi-Aventis FX The authors thank all members of the M.B. lab. We also thank Z. Zhao for FACS sort assistance, the Yale Dermatopathology lab for tissue processing, the University of Vermont Microarray Core Facility for assistance with microarray analyses, and the RPPA Core Facility at MD Anderson Cancer Center for the RPPA analyses (supported by National Cancer Institute [NCI] Cancer Center Support Grant [CCSG] CA-16672). Special thanks to R. Halaban for providing human melanoma cell lines and to D. Stern and his lab for the human melanoma RPPA analyses. This work was supported by grants from the NCI (R01 CA112054, P50 CA121974, and P01 CA128814) and the Hevery and Joanna M. Nicolay Melanoma Foundations. The results in part are based on data generated by the TCGA Research Network. M. A. D. has served on advisory boards for GlaxoSmithKline, Genentech, Novartis, and Sanofi-Aventis and has received research funding from GlaxoSmithKline, Genentech, Merck, Myriad, AstraZeneca, and Sanofi-Aventis. NR 51 TC 18 Z9 19 U1 4 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD JAN 12 PY 2015 VL 27 IS 1 BP 41 EP 56 DI 10.1016/j.ccell.2014.11.014 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AY9ZS UT WOS:000347906900009 PM 25584893 ER PT J AU Arem, H Pfeiffer, RM Engels, EA Alfano, CM Hollenbeck, A Park, Y Matthews, CE AF Arem, Hannah Pfeiffer, Ruth M. Engels, Eric A. Alfano, Catherine M. Hollenbeck, Albert Park, Yikyung Matthews, Charles E. TI Pre- and Postdiagnosis Physical Activity, Television Viewing, and Mortality Among Patients With Colorectal Cancer in the National Institutes of Health-AARP Diet and Health Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GROWTH-FACTOR-I; IGF-BINDING-PROTEINS; BODY-MASS INDEX; QUALITY-OF-LIFE; SEDENTARY BEHAVIOR; ACTIVITY QUESTIONNAIRE; INSULIN-RESISTANCE; FACTOR (IGF)-I; COLON-CANCER; SURVIVAL AB Purpose Physical inactivity has been associated with higher mortality risk among survivors of colorectal cancer (CRC), but the independent effects of pre- versus postdiagnosis activity are unclear, and the association between watching television (TV) and mortality in survivors of CRC is previously undefined. Methods We analyzed the associations between prediagnosis (n = 3,797) and postdiagnosis (n = 1,759) leisure time physical activity (LTPA) and TV watching and overall and disease-specific mortality among patients with CRC. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs, adjusting for known mortality risk factors. Results Comparing survivors of CRC reporting more than 7 hours per week (h/wk) of prediagnosis LTPA with those reporting no LTPA, we found a 20% lower risk of all-cause mortality (HR, 0.80; 95% CI, 0.68 to 0.95; P for trend = .021). Postdiagnosis LTPA of >= 7 h/wk, compared with none, was associated with a 31% lower all-cause mortality risk (HR, 0.69; 95% CI, 0.49 to 0.98; P for trend = .006), independent of prediagnosis activity. Compared with 0 to 2 TV hours per day (h/d) before diagnosis, those reporting >= 5 h/d of TV before diagnosis had a 22% increased all-cause mortality risk (HR, 1.22; 95% CI, 1.06 to 1.41; P trend = .002), and more postdiagnosis TV watching was associated with a nonsignificant 25% increase in all-cause mortality risk (HR, 1.25; 95% CI, 0.93 to 1.67; P for trend = .126). Conclusion LTPA was inversely associated with all-cause mortality, whereas more TV watching was associated with increased mortality risk. For both LTPA and TV watching, postdiagnosis measures independently explained the association with mortality. Clinicians should promote both minimizing TV time and increasing physical activity for longevity among survivors of CRC, regardless of previous behaviors. (C) 2014 by American Society of Clinical Oncology C1 [Arem, Hannah; Pfeiffer, Ruth M.; Engels, Eric A.; Alfano, Catherine M.; Matthews, Charles E.] NCI, Bethesda, MD 20892 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. [Park, Yikyung] Washington Univ Sch Med, St Louis, MO USA. RP Arem, H (reprint author), 9609 Med Ctr Dr,Rm 6E324, Rockville, MD 20892 USA. EM Aremhe2@mail.nih.gov OI Park, Yikyung/0000-0002-6281-489X FU National Institutes of Health, National Cancer Institute (Bethesda, MD) FX Supported, in part, by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (Bethesda, MD). NR 37 TC 19 Z9 19 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2015 VL 33 IS 2 BP 180 EP U87 DI 10.1200/JCO.2014.58.1355 PG 10 WC Oncology SC Oncology GA CF2ZX UT WOS:000352418100012 PM 25488967 ER PT J AU Naghavi, M Wang, HD Lozano, R Davis, A Liang, XF Zhou, MG Vollset, SE Ozgoren, AA Abdalla, S Abd-Allah, F Aziz, MIA Abera, SF Aboyans, V Abraham, B Abraham, JP Abuabara, KE Abubakar, I Abu-Raddad, LJ Abu-Rmeileh, NME Achoki, T Adelekan, A Ademi, ZN Adofo, K Adou, AK Adsuar, JC Aernlov, J Agardh, EE Akena, D Al Khabouri, MJ Alasfoor, D Albittar, M Alegretti, MA Aleman, AV Alemu, ZA Alfonso-Cristancho, R Alhabib, S Ali, MK Ali, R Alla, F Al Lami, F Allebeck, P AlMazroa, MA Salman, RAS Alsharif, U Alvarez, E Alviz-Guzman, N Amankwaa, AA Amare, AT Ameli, O Amini, H Ammar, W Anderson, HR Anderson, BO Antonio, CAT Anwari, P Apfel, H Cunningham, SA Arsenijevic, VSA Al Artaman Asad, MM Asghar, RJ Assadi, R Atkins, LS Atkinson, C Badawi, A Bahit, MC Bakfalouni, T Balakrishnan, K Balalla, S Banerjee, A Barber, RM Barker-Collo, SL Barquera, S Barregard, L Barrero, LH Barrientos-Gutierrez, T Basu, A Basu, S Basulaiman, MO Beardsley, J Bedi, N Beghi, E Bekele, T Bell, ML Benjet, C Bennett, DA Bensenor, IM Benzian, H Bertozzi-Villa, A Beyene, TJ Bhala, N Bhalla, A Bhutta, ZA Bikbov, B Bin Abdulhak, A Biryukov, S Blore, JD Blyth, FM Bohensky, MA Borges, G Bose, D Boufous, S Bourne, RR Boyers, LN Brainin, M Brauer, M Brayne, CEG Brazinova, A Breitborde, N Brenner, H Briggs, ADM Brown, JC Brugha, TS Buckle, GC Bui, LN Bukhman, G Burch, M Nonato, IRC Carabin, H Cardenas, R Carapetis, J Carpenter, DO Caso, V Castaneda-Orjuela, CA Castro, RE Catala-Lopez, F Cavalleri, F Chang, JC Charlson, FC Che, X Chen, HL Chen, YY Chen, JS Chen, ZM Chiang, PPC Chimed-Ochir, O Chowdhury, R Christensen, H Christophi, CA Chuang, TW Chugh, SS Cirillo, M Coates, MM Coffeng, LE Coggeshall, MS Cohen, A Colistro, V Colquhoun, SM Colomar, M Cooper, LT Cooper, C Coppola, LM Cortinovis, M Courville, K Cowie, BC Criqui, MH Crump, JA Cuevas-Nasu, L Leite, IDC Dabhadkar, KC Dandona, L Dandona, R Dansereau, E Dargan, PI Dayama, A De la Cruz-Gongora, V de la Vega, SF De Leo, D Degenhardt, L del Pozo-Cruz, B Dellavalle, RP Deribe, K Jarlais, DCD Dessalegn, M deVeber, GA Dharmaratne, SD Dherani, M Diaz-Ortega, JL Diaz-Torne, C Dicker, D Ding, EL Dokova, K Dorsey, ER Driscoll, TR Duan, LL Duber, HC Durrani, AM Ebel, BE Edmond, KM Ellenbogen, RG Elshrek, Y Ermakov, SP Erskine, HE Eshrati, B Esteghamati, A Estep, K Furst, T Fahimi, S Fahrion, AS Faraon, EJA Farzadfar, F Fay, DFJ Feigl, AB Feigin, VL Felicio, MM Fereshtehnejad, SM Fernandes, JG Ferrari, AJ Fleming, TD Foigt, N Foreman, K Forouzanfar, MH Fowkes, FGR Paleo, UF Franklin, RC Futran, ND Gaffikin, L Gambashidze, K Gankpe, FG Garcia-Guerra, FA Garcia, AC Geleijnse, JM Gessner, BD Gibney, KB Gillum, RF Gilmour, S Abdelmageem, I Ginawi, M Giroud, M Glaser, EL Goenka, S Dantes, HG Gona, P Gonzalez-Medina, D Guinovart, C Gupta, R Gupta, R Gosselin, RA Gotay, CC Goto, A Gowda, HN Graetz, N Greenwell, KF Gugnani, HC Gunnell, D Gutierrez, RA Haagsma, J Hafezi-Nejad, N Hagan, H Hagstromer, M Halasa, YA Hamadeh, RR Hamavid, H Hammami, M Hancock, J Hankey, GJ Hansen, GM Harb, HL Harewood, H Haro, JM Havmoeller, R Hay, RJ Hay, SI Hedayati, MT Pi, IBH Heuton, KR Heydarpour, P Higashi, H Hijar, M Hoek, HW Hoffman, HJ Hornberger, JC Hosgood, HD Hossain, M Hotez, PJ Hoy, DG Hsairi, M Hu, GQ Huang, JJ Huffman, MD Hughes, AJ Husseini, A Huynh, C Iannarone, M Iburg, KM Idrisov, BT Ikeda, N Innos, K Inoue, M Islami, F Ismayilova, S Jacobsen, KH Jassal, S Jayaraman, SP Jensen, PN Jha, V Jiang, GH Jiang, Y Jonas, JB Joseph, J Juel, K Kabagambe, EK Kan, HD Karch, A Karimkhani, C Karthikeyan, G Kassebaum, N Kaul, A Kawakami, N Kazanjan, K Kazi, DS Kemp, AH Kengne, AP Keren, A Kereselidze, M Khader, YS Khalifa, SEAH Khan, EA Khan, G Khang, YH Kieling, C Kinfu, Y Kinge, JM Kim, D Kim, S Kivipelto, M Knibbs, L Knudsen, AK Kokubo, Y Kosen, S Kotagal, M Kravchenko, MA Krishnaswami, S Krueger, H Defo, BK Kuipers, EJ Bicer, BK Kulkarni, C Kulkarni, VS Kumar, K Kumar, RB Kwan, GF Kyu, H Lai, T Balaji, AL Lalloo, R Lallukka, T Lam, H Lan, Q Lansingh, VC Larson, HJ Larsson, A Lavados, PM Lawrynowicz, AEB Leasher, JL Lee, JT Leigh, J Leinsalu, M Leung, R Levitz, C Li, B Li, YC Li, YM Liddell, C Lim, SS de Lima, GMF Lind, ML Lipshultz, SE Liu, SW Liu, Y Lloyd, BK Lofgren, KT Logroscino, G London, SJ Lortet-Tieulent, J Lotufo, PA Lucas, RM Lunevicius, R Lyons, RA Ma, S Machado, VMP MacIntyre, MF Mackay, MT MacLachlan, JH Magis-Rodriguez, C Mahdi, AA Majdan, M Malekzadeh, R Mangalam, S Mapoma, CC Marape, M Marcenes, W Margono, C Marks, GB Marzan, MB Masci, JR Mashal, MTQ Masiye, F Mason-Jones, AJ Matzopolous, R Mayosi, BM Mazorodze, TT McGrath, JJ Mckay, AC Mckee, M McLain, A Meaney, PA Mehndiratta, MM Mejia-Rodriguez, F Melaku, YA Meltzer, M Memish, ZA Mendoza, W Mensah, GA Meretoja, A Mhimbira, FA Miller, TR Mills, EJ Misganaw, A Mishra, SK Mock, CN Moffitt, TE Ibrahim, NM Mohammad, KA Mokdad, AH Mola, GL Monasta, L Monis, JD Hernandez, JCM Montico, M Montine, TJ Mooney, MD Moore, AR Moradi-Lakeh, M Moran, AE Mori, R Moschandreas, J Moturi, WN Moyer, ML Mozaffarian, D Mueller, UO Mukaigawara, M Mullany, EC Murray, J Mustapha, A Naghavi, P Naheed, A Naidoo, KS Naldi, L Nand, D Nangia, V Narayan, KMV Nash, D Nasher, J Nejjari, C Nelson, RG Neuhouser, M Neupane, SP Newcomb, PA Newman, L Newton, CR Ng, M Ngalesoni, FN Nguyen, G Nguyen, NTT Nisar, MI Nolte, S Norheim, OF Norman, RE Norrving, B Nyakarahuka, L Odell, S O'Donnell, M Ohkubo, T Ohno, SL Olusanya, BO Omer, SB Opio, JN Orisakwe, OE Ortblad, KF Ortiz, A Otayza, MLK Pain, AW Pandian, JD Panelo, CI Panniyammakal, J Papachristou, C Caicedo, AJP Patten, SB Patton, GC Paul, VK Pavlin, B Pearce, N Pellegrini, CA Pereira, DM Peresson, SC Perez-Padilla, R Perez-Ruiz, FP Perico, N Pervaiz, A Pesudovs, K Peterson, CB Petzold, M Phillips, BK Phillips, DE Phillips, MR Plass, D Piel, FB Poenaru, D Polinder, S Popova, S Poulton, RG Pourmalek, F Prabhakaran, D Qato, D Quezada, AD Quistberg, DA Rabito, F Rafay, A Rahimi, K Rahimi-Movaghar, V Rahman, SUR Raju, M Rakovac, I Rana, SM Refaat, A Remuzzi, G Ribeiro, AL Ricci, S Riccio, PM Richardson, L Richardus, JH Roberts, B Roberts, DA Robinson, M Roca, A Rodriguez, A Rojas-Rueda, D Ronfani, L Room, R Roth, GA Rothenbacher, D Rothstein, DH Rowley, JT Roy, N Ruhago, GM Rushton, L Sambandam, S Soreide, K Saeedi, MY Saha, S Sahathevan, R Sahraian, MA Sahle, BW Salomon, JA Salvo, D Samonte, GMJ Sampson, U Sanabria, JR Sandar, L Santos, IS Satpathy, M Sawhney, M Saylan, M Scarborough, P Schottker, B Schmidt, JC Schneider, IJC Schumacher, AE Schwebel, DC Scott, JG Sepanlou, SG Servan-Mori, EE Shackelford, K Shaheen, A Shahraz, S Shakh-Nazarova, M Shangguan, S She, J Sheikhbahaei, S Shepard, DS Shibuya, K Shinohara, Y Shishani, K Shiue, I Shivakoti, R Shrime, MG Sigfusdottir, ID Silberberg, DH Silva, AP Simard, EP Sindi, S Singh, JA Singh, L Sioson, E 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Truelsen, Thomas Trujillo, Ulises Trillini, Matias Dimbuene, Zacharie Tsala Tsilimbaris, Miltiadis Tuzcu, E. Murat Ubeda, Clotilde Uchendu, Uche S. Ukwaja, Kingsley N. Undurraga, Eduardo A. Vallely, Andrew J. van de Vijver, Steven van Gool, Coen H. Varakin, Yuri Y. Vasankari, Tommi J. Vasconcelos, Ana Maria Nogales Vavilala, Monica S. Venketasubramanian, N. Vijayakumar, Lakshmi Villalpando, Salvador Violante, Francesco S. Vlassov, Vasiliy Victorovich Wagner, Gregory R. Waller, Stephen G. Wang, JianLi Wang, Linhong Wang, XiaoRong Wang, Yanping Warouw, Tati Suryati Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Wenzhi, Wang Werdecker, Andrea Wessells, K. Ryan R. Westerman, Ronny Whiteford, Harvey A. Wilkinson, James D. Williams, Thomas Neil Woldeyohannes, Solomon Meseret Wolfe, Charles D. A. Wolock, Timothy M. Woolf, Anthony D. Wong, John Q. Wright, Jonathan L. Wulf, Sarah Wurtz, Brittany Xu, Gelin Yang, Yang C. Yano, Yuichiro Yatsuya, Hiroshi Yip, Paul Yonemoto, Naohiro Yoon, Seok-Jun Younis, Mustafa Yu, Chuanhua Jin, Kim Yun Zaki, Maysaa El Sayed Zamakhshary, Mohammed Fouad Zeeb, Hajo Zhang, Yong Zhao, Yong Zheng, Yingfeng Zhu, Jun Zhu, Shankuan Zonies, David Zou, Xiao Nong Zunt, Joseph R. Vos, Theo Lopez, Alan D. Murray, Christopher J. L. CA GBD Mortal 2013 Causes Death Colla TI Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 SO LANCET LA English DT Article ID INFLUENZAE TYPE-B; PNEUMOCOCCAL CONJUGATE VACCINE; PLACEBO-CONTROLLED-TRIAL; 187 COUNTRIES; RISK-FACTORS; ENTERIC MULTICENTER; CHILDREN YOUNGER; CHILDHOOD PNEUMONIA; INTEGRATED APPROACH; POPULATION HEALTH AB Background Up-to-date evidence on levels and trends for age-sex-specifi c all-cause and cause-specifi c mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries. Methods We estimated age-sex-specifi c all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specifi c causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions. Findings Global life expectancy for both sexes increased from 65.3 years (UI 65.0-65.6) in 1990, to 71.5 years (UI 71.0-71.9) in 2013, while the number of deaths increased from 47.5 million (UI 46.8-48.2) to 54.9 million (UI 53.6-56.3) over the same interval. Global progress masked variation by age and sex: for children, average absolute diff erences between countries decreased but relative diff erences increased. For women aged 25-39 years and older than 75 years and for men aged 20-49 years and 65 years and older, both absolute and relative diff erences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10.7%, from 4.3 million deaths in 1990 to 4.8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100 000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions. Interpretation For most countries, the general pattern of reductions in age-sex specifi c mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade. C1 [Naghavi, Mohsen; Wang, Haidong; Lozano, Rafael; Vollset, Stein Emil; Achoki, Tom; Apfel, Henry; Atkinson, Charles; Barber, Ryan M.; Bertozzi-Villa, Amelia; Biryukov, Stan; Brown, Jonathan C.; Catala-Lopez, Ferrn; Coates, Matthew M.; Coffeng, Luc Edgar; Coggeshall, Megan S.; Dandona, Lalit; Dansereau, Emily; Dicker, Daniel; Duber, Herbert C.; Estep, Kara; Fleming, Thomas D.; Forouzanfar, Mohammad H.; Gonzalez-Medina, Diego; Graetz, Nicholas; Haagsma, Juanita; Hamavid, Hannah; Hancock, Jamie; Hansen, Gillian M.; Heuton, Kyle R.; Higashi, Hideki; Huynh, Chantal; Iannarone, Marissa; Joseph, Jonathan; Kassebaum, Nicholas; Kyu, Hmwe; Levitz, Carly; Liddell, Chelsea; Lind, Maggie L.; Lofgren, Katherine T.; MacIntyre, Michael F.; Margono, Christopher; McLain, Abigail; Mokdad, Ali H.; Mooney, Meghan D.; Moradi-Lakeh, Maziar; Moyer, Madeline L.; Mullany, Erin C.; Naghavi, Paria; Ng, Marie; Nguyen, Grant; Odell, Shaun; Ohno, Summer Lockett; Ortblad, Katrina F.; Pain, Amanda W.; Phillips, Bryan K.; Phillips, David E.; Richardson, Lee; Roberts, D. Allen; Robinson, Margaret; Roth, Gregory A.; Sandar, Logan; Schumacher, Austin E.; Shackelford, Katya; Singh, Lavanya; Sioson, Edgar; Stanaway, Jeff Rey D.; Steiner, Caitlyn; Stevens, Antony; Templin, Tara; Thomas, Bernadette A.; Wolock, Timothy M.; Wulf, Sarah; Wurtz, Brittany; Vos, Theo; Murray, Christopher J. L.] Inst Hlth Metr & Evaluat, Seattle, WA USA. [Ellenbogen, Richard G.; Wright, Jonathan L.] Univ Washington, Sch Med, Seattle, WA USA. [Kassebaum, Nicholas] Childrens Hosp, Seattle, WA USA. [Tirschwell, David L.] Dept Neurol, Seattle, WA USA. [Ebel, Beth E.] Univ Washington, Harborview Med Ctr, Harborview Injury Prevent & Res Ctr, Seattle, WA 98104 USA. [Alfonso-Cristancho, Rafael; Anderson, Benjamin O.; Futran, Neal D.; Jensen, Paul N.; Kotagal, Meera; Mock, Charles N.; Montine, Thomas J.; Pellegrini, Carlos A.; Quistberg, D. Alex; Vavilala, Monica S.; Zunt, Joseph R.] Univ Washington, Seattle, WA 98195 USA. 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[Vollset, Stein Emil; Norheim, Ole F.] Univ Bergen, Bergen, Norway. [Ozgoren, Ayse Abbasoglu; Bicer, Burcu Kucuk] Hacettepe Univ, Inst Populat Studies, Ankara, Turkey. [Abdalla, Safa] Sudanese Publ Hlth Consultancy Grp, Solihull, W Midlands, England. [Abd-Allah, Foad] Cairo Univ, Fac Med, Cairo, Egypt. [Aziz, Muna I. Abdel] Inst Publ Hlth, Khartoum, Sudan. [Abera, Semaw Ferede] Coll Hlth Sci, Sch Publ Hlth, Mekelle, Tigray, Ethiopia. [Melaku, Yohannes Adama; Sahle, Berhe Weldearegawi] Mekelle Univ, Mekelle, Tigray, Ethiopia. [Aboyans, Victor] Dupuytren Univ Hosp, Limoges, France. [Abraham, Biju] Oslo & Akershus Univ, Coll Appl Sci HiOA, Oslo, Norway. [Abraham, Jerry P.] Univ Texas San Antonio, Sch Med, San Antonio, TX USA. [Abuabara, Katrina E.; Silberberg, Donald H.] Univ Penn, Philadelphia, PA 19104 USA. [Benzian, Habib] Dept Epidemiol & Publ Hlth, London, England. [Benzian, Habib] UCL, London, England. [Abu-Raddad, Laith J.] Weill Cornell Med Coll Qatar, Doha, Qatar. 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[Al Khabouri, Mazin J.; Alasfoor, Deena] Minist Hlth, Muscat, Oman. [Al Lami, Faris] Baghdad Coll Med, Baghdad, Iraq. [Albittar, Mohammed] Independent, Damascus, Syria. Grp Invest Ciencias Salud & Neurociencias CISNEUR, Cartagena De Indias, Bolivar, Colombia. [Alegretti, Miguel Angel; Aleman, Alicia V.; Cavalleri, Fiorella; Colistro, Valentina] Univ Republica, Fac Med, Dept Prevent & Social Med, Montevideo, Uruguay. [Alemu, Zewdie Aderaw] Debre Markos Univ, Debre Markos, Amhara, Ethiopia. [Alhabib, Samia] Natl Guard Hlth Affairs, Riyadh, Saudi Arabia. [Simard, Edgar P.; Steenland, Kyle] Rollins Sch Publ Hlth, Atlanta, GA USA. [Ali, Mohammed K.; Cunningham, Solveig Argeseanu; Dabhadkar, Kaustubh C.; Liu, Yang; Narayan, K. M. Venkat; Omer, Saad B.; Phillips, Michael R.] Emory Univ, Atlanta, GA 30322 USA. [Ali, Raghib; Bennett, Derrick A.; Briggs, Adam D. M.; Chen, Zhengming; Hay, Simon I.; Piel, Frederic Bernard; Rahimi, Kazem; Scarborough, Peter] Univ Oxford, Oxford, England. [Alla, Francois] Univ Lorraine, Sch Publ Hlth, Nancy, France. [Allebeck, Peter] Dept Publ Hlth Sci, Stockholm, Sweden. [Fereshtehnejad, Seyed-Mohammad] Dept Neurobiol Care Sci & Soc NVS, Stockholm, Sweden. [Kivipelto, Miia] Aging Res Ctr, Stockholm, Sweden. [Weiderpass, Elisabete] Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Hagstromer, Maria; Havmoeller, Rasmus; Sindi, Shireen] Karolinska Inst, Stockholm, Sweden. [AlMazroa, Mohammad A.; Basulaiman, Mohammed Omar; Memish, Ziad A.; Saeedi, Mohammad Yahya] Saudi Minist Hlth, Riyadh, Saudi Arabia. [Salman, Rustam Al-Shahi; Fowkes, F. Gerry R.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Alsharif, Ubai; Nolte, Sandra; Papachristou, Christina] Charite, D-13353 Berlin, Germany. [Alvarez, Elena] Government, Madrid, Spain. [Alviz-Guzman, Nelson; Paternina Caicedo, Angel J.] Univ Cartagena, Cartagena De Indias, Colombia. [Amankwaa, Adansi A.] Albany State Univ, Albany, GA 31705 USA. [Amare, Azmeraw T.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Amare, Azmeraw T.] Bahir Dar Univ, Coll Med & Hlth Sci, Bahir Dar, Ethiopia. [Ameli, Omid] Boston Univ, Boston, MA 02215 USA. [Amini, Hassan] Kurdistan Univ Med Sci, Kurdistan Environm Hlth Res Ctr, Sanandaj, Kurdistan, Iran. [Amini, Hassan] Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland. [Tanner, Marcel] Univ Basel, Basel, Switzerland. [Ammar, Walid] Minist Publ Hlth, Beirut, Lebanon. [Anderson, H. Ross] St Georges Univ London, London, England. [Antonio, Carl Abelardo T.; Faraon, Emerito Jose A.; Panelo, Carlo Irwin] Univ Philippines Manila, Coll Publ Hlth, Manila, Philippines. [Anwari, Palwasha] UNFPA, Kabul, Afghanistan. [Arsenijevic, Valentina S. Arsic] Univ Belgrade, Sch Med, Inst Microbiol & Immunol, Belgrade, Serbia. [Al Artaman] Evidera Inc, Lexington, MA USA. [Asad, Majed Masoud] Minist Hlth, Amman, Jordan. [Asghar, Rana J.] South Asian Publ Hlth Forum, Islamabad, Pakistan. [Assadi, Reza] Mashhad Univ Med Sci, Mashhad, Khorasan Razavi, Iran. [Atkins, Lydia S.] Minist Hlth Wellness Human Serv & Gender Relat, Castries, St Lucia. [Badawi, Alaa] Publ Hlth Agcy Canada, Toronto, ON, Canada. [Bahit, Maria C.] INECO Neurociencias, Santa Fe, NM USA. [Bakfalouni, Talal] Minist Hlth, Damascus, Syria. [Balakrishnan, Kalpana] Sri Ramachandra Univ, Madras, Tamil Nadu, India. [Balalla, Shivanthi; Feigin, Valery L.] Natl Inst Stroke & Appl Neurosciences, Auckland, New Zealand. [Barker-Collo, Suzanne L.] Sch Psychol, Auckland, New Zealand. [del Pozo-Cruz, Borja] Univ Auckland, Auckland 1, New Zealand. [Banerjee, Amitava] Univ Birmingham, Birmingham, W Midlands, England. [Barregard, Lars] Univ Gothenburg, Dept Environm & Occupat Hlth, Gothenburg, Sweden. [Barrero, Lope H.] Pontificia Univ Javeriana, Dept Ind Engn, Bogota, Colombia. [Basu, Arindam] Univ Canterbury, Sch Hlth Sci, Canterbury, New Zealand. 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[Bhalla, Ashish] Postgrad Inst Med Educ & Res, Chandigarh 160012, UT, India. [Bhutta, Zulfiqar A.] Med Ctr, Karachi, Pakistan. [Nisar, Muhammad Imran] Aga Khan Univ, Karachi, Pakistan. [Bikbov, Boris] I Evdokimov Moscow State Univ Med & Dent, Moscow, Russia. [Bin Abdulhak, Aref] Univ Missouri, Kansas City, MO 64110 USA. [Marks, Guy B.] Woolcock Inst Med Res, Sydney, NSW, Australia. [Driscoll, Tim R.] Sydney Sch Publ Hlth, Sydney, NSW, Australia. [Blyth, Fiona M.; Leigh, James] Univ Sydney, Sydney, NSW 2006, Australia. [Borges, Guilherme] Inst Nacl Psiquiatria, Mexico City, DF, Mexico. [Bose, Dipan] World Bank, Washington, DC 20433 USA. [Boufous, Soufiane] Transport & Rd Safety TARS Res, Sydney, NSW, Australia. [Vallely, Andrew J.] Kirby Inst, Sydney, NSW, Australia. [Degenhardt, Louisa; Satpathy, Maheswar] Univ New S Wales, Sydney, NSW, Australia. [Bourne, Rupert R.] Anglia Ruskin Univ, Vis & Eye Res Unit, Cambridge, England. [Boyers, Lindsay N.] Georgetown Univ, Sch Med, Washington, DC USA. [Brainin, Michael] Danube Univ Krems, Krems, Austria. [Krueger, Hans] Sch Populat & Publ Hlth, Vancouver, BC, Canada. [Brauer, Michael; Gotay, Carolyn C.; Pourmalek, Farshad] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Brayne, Carol E. G.] Cambridge Inst Publ Hlth, Cambridge, England. [Brazinova, Alexandra; Majdan, Marek] Trnava Univ, Fac Hlth Sci & Social Work, Trnava, Slovakia. [Breitborde, Nicholas] Univ Arizona, Tucson, AZ USA. [Brenner, Hermann] German Canc Res Ctr, Heidelberg, Germany. [Brugha, Traolach S.] Univ Leicester, Leicester, Leics, England. [Buckle, Geoffrey C.; Gona, Philimon] Univ Massachusetts, Sch Med, Worcester, MA USA. [Bui, Linh Ngoc; Nhung Thi Trang Nguyen] Hanoi Sch Publ Hlth, Hanoi, Vietnam. [Bukhman, Gene] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Ding, Eric L.; Fahimi, Saman; Shangguan, Siyi] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Feigl, Andrea B.; Salomon, Joshua A.; Shrime, Mark G.] Harvard Univ, Cambridge, MA 02138 USA. [Burch, Michael] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Cardenas, Rosario] Univ Autonoma Metropolitana, Mexico City, DF, Mexico. [Carabin, Helesne] Univ Oklahoma, Hlth Sci Ctr, Dept Biostat & Epidemiol, Oklahoma City, OK USA. [Carapetis, Jonathan] Telethon Inst Child Hlth Res, Subiaco, WA, Australia. [Carpenter, David O.] Univ Albany, Rensselaer, NY USA. [Caso, Valeria] Univ Perugia, Stroke Unit, I-06100 Perugia, Italy. [Castaneda-Orjuela, Carlos A.] Colombian Natl Hlth Observ, Inst Nacl Salud, Bogota, Colombia. [Castro, Ruben Estanislao] Univ Diego Portales, Santiago, Chile. [Catala-Lopez, Ferrn] Minist Hlth, Spanish Med & Healthcare Prod Agcy AEMPS, Div Pharmacoepidemiol & Pharmacovigilance, Madrid, Spain. [Chang, Jung-Chen] Natl Taiwan Univ, Taipei 10764, Taiwan. [Hoy, Damian G.] Univ Queensland, Sch Populat Hlth, Herston, Qld, Australia. [Scott, James G.] Univ Queensland, Clin Res Ctr, Herston, Qld, Australia. [Charlson, Fiona C.; Erskine, Holly E.; Ferrari, Alize J.; Knibbs, Luke; McGrath, John J.; Norman, Rosana E.; Whiteford, Harvey A.] Univ Queensland, Brisbane, Qld, Australia. [Che, Xuan] NIH, Bethesda, MD 20892 USA. [She, Jun] Zhongshan Hosp, Shanghai, Peoples R China. [Chen, Yingyao; Kan, Haidong] Fudan Univ, Shanghai 200433, Peoples R China. [Chen, Zhengming] CTSU, Nuffield Dept Populat Hlth, Oxford, England. [Chen, Honglei; London, Stephanie J.] NIEHS, Div Intramural Res, NIH, Dept Hlth & Human Serv,RTP,NC USA, Res Triangle Pk, NC 27709 USA. [Chen, Jian Sheng] Inst Bone & Joint Res, St Laonards, NSW, Australia. [Chimed-Ochir, Odgerel] Univ Occupat & Environm Hlth, Dept Environm Epidemiol, Kitakyushu, Fukuoka 807, Japan. [Chowdhury, Rajiv; Murray, Christopher J. L.] Univ Cambridge, Cambridge, England. [Christensen, Hanne] Bispebjerg Hosp, Copenhagen, Denmark. [Christophi, Costas A.] Cyprus Univ Technol, Limassol, Cyprus. [Chang, Jung-Chen] Taipei Med Univ, Sch Med, Dept Mol Parasitol & Trop Dis, Taipei, Taiwan. [Chuang, Ting-Wu] Taipei Med Univ, Ctr Int Trop Med, Coll Med, Taipei, Taiwan. [Chugh, Sumeet S.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Cirillo, Massimo] Univ Salerno, I-84081 Baronissi, SA, Italy. [Cohen, Aaron] Hlth Effects Inst, Boston, MA USA. [Colomar, Mercedes] UNICEM, Montevideo, Uruguay. [Cooper, Cyrus] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Cooper, Cyrus; Tleyjeh, Imad M.] Mayo Clin, Rochester, MN USA. [Coppola, Luis M.] Hosp Municipal Ramon Santamarina, Buenos Aires, DF, Argentina. [Cowie, Benjamin C.; MacLachlan, Jennifer H.] Victorian Infect Dis Reference Lab, North Melbourne, Vic, Australia. [Criqui, Michael H.; Jassal, Simerjot] Univ Calif San Diego, La Jolla, CA 92093 USA. [Crump, John A.] Dunedin Sch Med, Ctr Int Hlth, Dunedin, Otago, New Zealand. [Poulton, Richie G.] Univ Otago, Dunedin, Otago, New Zealand. [Leite, Iuri da Costa] Natl Sch Publ Hlth ENSP Fiocruz, Rio De Janeiro, Brazil. [Dandona, Lalit; Dandona, Rakhi; Goenka, Shifalika] Publ Hlth Fdn India, New Delhi, India. [Dandona, Rakhi; Goenka, Shifalika] Indian Inst Publ Hlth, New Delhi, India. [Dargan, Paul I.] Guys & St Thomas NHS Fdn Trust, London, England. [Dayama, Anand] Jacobi Med Ctr, Dept Surg, Atlanta, GA USA. [de la Vega, Shelley F.] Univ Philippines, Inst Aging, Manila, Philippines. [Lam, Hilton] Univ Philippines, Natl Inst Hlth, Inst Hlth Policy & Dev Studies, Manila, Philippines. [De Leo, Diego] Griffith Univ, Brisbane, Qld 4111, Australia. [Uchendu, Uche S.] US Dept Vet Affairs, Washington, DC USA. [Dellavalle, Robert P.] Eastern Colorado Healthcare Syst, Denver, CO USA. [Jarlais, Don C. Des] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Dessalegn, Muluken] Africa Med & Res Fdn Ethiopia, Addis Ababa, Ethiopia. [deVeber, Gabrielle A.] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Dharmaratne, Samath D.] Univ Peradeniya, Peradeniya, Sri Lanka. [Dherani, Mukesh] Univ Liverpool, Liverpool L69 3BX, Merseyside, England. [Diaz-Torne, Cesar] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Dokova, Klara] Med Univ Varna, Fac Publ Hlth, Dept Social Med, Varna, Bulgaria. [Dorsey, E. Ray] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Durrani, Adnan M.] NIH, Montgomery, MD USA. [Hankey, Graeme J.] Sch Med & Pharmacol, Perth, WA, Australia. [Kabagambe, Edmond Kato] Univ Western Australia, Perth, WA 6009, Australia. [Elshrek, Yousef] Univ Tripoli, Fac Agr, Dept Food Sci, Tripoli, Libya. [Ermakov, Sergey Petrovich] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Eshrati, Babak] Arak Univ Med Sci & Hlth Affairs, Arak, Markazi, Iran. [Esteghamati, Alireza; Hafezi-Nejad, Nima; Sheikhbahaei, Sara] Endocrinol & Metab Res Ctr, Tehran, Iran. [Farzadfar, Farshad] Noncommunicable Dis Reesearch Ctr, Tehran, Iran. [Malekzadeh, Reza; Sepanlou, Sadaf G.] Digest Dis Res Ctr, Tehran, Iran. [Rahimi-Movaghar, Vafa] Sina Trauma & Surg Res Ctr, Tehran, Iran. [Sahraian, Mohammad Ali] Res Ctr, Tehran, Iran. [Moradi-Lakeh, Maziar] Dept Community Med, Tehran, Iran. [Heydarpour, Pouria] Univ Tehran Med Sci, Tehran, Iran. [Fuerst, Thomas] Ctr Hlth Policy, London, England. [Fuerst, Thomas] Dept Infect Dis Epidemiol, London, England. [Mustapha, Adetoun] MRC PHE Ctr Hlth & Environm, London, England. [Foreman, Kyle; Rodriguez, Alina; Rushton, Lesley; Soljak, Michael; Williams, Thomas Neil] Univ London Imperial Coll Sci Technol & Med, London, England. [Vollset, Stein Emil] Div Informat Evidence Res & Innovat, Copenhagen, Denmark. [Fahrion, Anna S.; Rakovac, Ivo] WHO, Reg Off Europe, DK-2100 Copenhagen, Denmark. [Newman, Lori] WHO, CH-1211 Geneva, Switzerland. [Teixeira, Carolina Maria] ARS Norte, Oporto, Portugal. [Felicio, Manuela Mendonca; de Lima, Graca Maria Ferreira; Machado, Vasco Manuel Pedro] IP Dept Saude Publ, Oporto, Portugal. [Fernandes, Jefferson G.] German Hosp Oswaldo Cruz, Inst Educ & Sci, Sao Paulo, Brazil. [Foigt, Nataliya] Ukraine Acad Med Sci, Inst Gerontol, UA-252655 Kiev, Ukraine. [Franklin, Richard C.] James Cook Univ, Townsville, Qld 4811, Australia. [Gambashidze, Ketevan; Kazanjan, Konstantin; Kereselidze, Maia; Shakh-Nazarova, Marina; Sturua, Lela] Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia. [Gankpe, Fortune Gbetoho] Clin Cooperat Parakou, Parakou, Borgou, Benin. [Garcia, Ana Cristina] Publ Hlth Unit Primary Hlth Care Grp Almada Seixa, Almada, Setubal, Portugal. [Geleijnse, Johanna M.] Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands. [Gessner, Bradford D.] Agence Med Prevent, Paris, France. [Lloyd, Belinda K.] Eastern Hlth Clin Sch, Melbourne, Vic, Australia. [Gibney, Katherine B.; Thrift, Amanda G.] Monash Univ, Melbourne, Vic 3004, Australia. [Gillum, Richard F.] Howard Univ, Washington, DC 20059 USA. [Inoue, Manami] Grad Sch Med, Tokyo, Japan. [Kawakami, Norito] Sch Publ Hlth, Tokyo, Japan. [Gilmour, Stuart; Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Ginawi, Mohamed] Univ Hail, Coll Med, Hail, Saudi Arabia. [Giroud, Maurice] Univ Hosp Dijon, Dijon France, Region Of Burgo, France. [Glaser, Elizabeth L.; Halasa, Yara A.; Idrisov, Bulat T.; Shahraz, Saeid; Shepard, Donald S.; Undurraga, Eduardo A.] Brandeis Univ, Waltham, MA USA. [Gosselin, Richard A.; Kazi, Dhruv S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Goto, Atsushi] Natl Ctr Global Hlth & Med, Dept Diabet Res, Tokyo, Japan. [Gugnani, Harish Chander] St James Sch Med, Kralendijk, Bonaire, Netherlands. [Guinovart, Caterina] PATH, Seattle, WA USA. [Gunnell, David] Univ Bristol, Bristol, Avon, England. [Gupta, Rahul] Fortis Escorts Hosp, Jaipur, Rajasthan, India. [Gupta, Rajeev] Kanawha Charleston Hlth Dept, Charleston, WV USA. [Thurston, George D.] NYU, Nelson Inst Environm Med, Tuxedo Pk, NY USA. [Hagan, Holly] NYU, New York, NY USA. [Hamadeh, Randah Ribhi] Arabian Gulf Univ, Manama, Bahrain. [Hammami, Mouhanad] Wayne Cty Dept Hlth & Human Serv, Detroit, MI USA. [Harewood, Heather] Eunice Gibson Polyclin, Bridgetown, St Michael, Barbados. [Haro, Josep Maria] Univ Barcelona, CIBERSAM, Barcelona, Spain. [Hay, Roderick J.] Int Fdn Dermatol, London, England. [Hedayati, Mohammad T.] Mazandaran Univ Med Sci, Sari, Mazandaran, Iran. [Hijar, Martha] Fdn Entornos AC, Cuernavaca, Morelos, Mexico. [Hoek, Hans W.] Parnassia Psychiat Inst, The Hague, Netherlands. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Hornberger, John C.] Cedar Associates, Menlo Pk, CA USA. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hossain, Mazeda; Larson, Heidi J.; Mckee, Martin; Pearce, Neil; Roberts, Bayard; Stoeckl, Heidi; Tillmann, Taavi] London Sch Hyg & Trop Med, London WC1, England. [Hotez, Peter J.] Baylor Coll Med, Houston, TX 77030 USA. [Hoy, Damian G.] Secretariat Pacific Commun, Publ Hlth Div, Herston, Qld, Australia. [Hsairi, Mohamed] Natl Inst Publ Hlth MOH, Tunis, Tunisia. [Hu, Guoqing] Univ Toronto, Toronto, ON, Canada. [Hu, Guoqing] Cent S Univ, Changsha, Hunan, Peoples R China. [Huffman, Mark D.] Feinberg Sch Med, Chicago, IL USA. [Swaroop, Mamta] Northwestern Univ, Chicago, IL 60611 USA. [Husseini, Abdullatif] Qatar Univ, Publ Hlth Program, Birzeit, Ramallah, Israel. [Iburg, Kim M.] Aarhus Univ, Aarhus, Denmark. [Ikeda, Nayu] Natl Inst Hlth & Nutr, Bunkyo Ku, Tokyo 162, Japan. [Innos, Kaire; Leinsalu, Mall] Natl Inst Hlth Dev, Tallinn, Estonia. [Islami, Farhad] Amer Canc Soc, New York, NY USA. [Ismayilova, Samaya] Self Employed, Baku, Azerbaijan. [Jacobsen, Kathryn H.] George Mason Univ, Fairfax, VA 22030 USA. [Jassal, Simerjot] VA San Diego, San Diego, CA USA. [Jayaraman, Sudha P.] Virginia Commonwealth Univ, Richmond, VA USA. [Jha, Vivekanand] Postgrad Inst Med Educ & Res, Chandigarh 160012, India. [Jiang, Guohong] Tianjin Ctr Dis Control & Prevent, Tianjin, Peoples R China. [Jiang, Ying] Univ Occupat & Environm Hlth, Inst Ind Ecol Sci, Dept Hlth Dev, Dept Environm Epidemiol, Kitakyushu, Fukuoka 807, Japan. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Juel, Knud] Natl Inst Publ Hlth, Copenhagen, Denmark. [Kabagambe, Edmond Kato; Sampson, Uchechukwu] Vanderbilt Univ, Nashville, TN 37235 USA. Univ Balamand, Beirut, Lebanon. [Karch, Andre] Helmholtz Ctr Infect Res, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res DZIF, Braunschweig, Germany. [Karimkhani, Chante] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Moran, Andrew E.] Columbia Univ, New York, NY USA. [Karthikeyan, Ganesan; Paul, Vinod K.] All India Inst Med Sci, New Delhi, India. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Kengne, Andre Pascal; Matzopolous, Richard] South African Med Res Council, Cape Town, Western Cape, South Africa. [Keren, Andre] Hadassah Kerem Univ Hosp, Jerusalem, Israel. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Irbid, Jordan. [Khalifa, Shams Eldin Ali Hassan] Supreme Council Hlth, Doha, Qatar. [Khan, Ejaz Ahmed] Hlth Serv Acad, Islamabad, Punjab, Pakistan. [Khan, Gulfaraz] UAE Univ, Abu Dhabi, U Arab Emirates. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Inst Hlth Policy & Management, Seoul, South Korea. [Kieling, Christian] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Kim, Daniel] Northeastern Univ, Boston, MA 02115 USA. [Kim, Sungroul] Soonchunhyang Univ, Asan, South Korea. [Kinfu, Yohannes] Univ Canberra, Canberra, ACT 2601, Australia. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan. [Kosen, Sowarta] Ctr Community Empowerment Hlth Policy & Humanitie, Jakarta, Indonesia. [Warouw, Tati Suryati] NIHRD, Jakarta, Special Provinc, Indonesia. [Kravchenko, Michael A.; Varakin, Yuri Y.] Res Ctr Neurol, Moscow, Russia. [Krishnaswami, Sanjay] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Krishnaswami, Sanjay] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Defo, Barthelemy Kuate] Univ Montreal, Montreal, PQ, Canada. [Polinder, Suzanne] Dept Publ Hlth, Rotterdam, Netherlands. [Kuipers, Ernst J.; Richardus, Jan Hendrik] Erasmus MC Univ Med Ctr, Rotterdam, Netherlands. [Kulkarni, Chanda] Rajrajeshwari Med Coll & Hosp, Bangalore, Karnataka, India. [Kulkarni, Veena S.] Arkansas State Univ, State Univ, AR 72467 USA. [Kumar, Kaushalendra] Int Inst Populat Sci, Bombay, Maharashtra, India. [Kwan, Gene F.] Boston Med Ctr, Boston, MA USA. [Lai, Taavi] Fourth View Consulting, Tallinn, Estonia. [Lalloo, Ratilal] Australian Res Ctr Populat Oral Hlth, Gold Coast, Qld, Australia. [Lalloo, Ratilal] Univ Adelaide, Sch Dent, Gold Coast, Qld, Australia. [Lallukka, Tea] Finnish Inst Occupat Hlth, Helsinki, Finland. [Lallukka, Tea] Univ Helsinki, Fac Med, Hjelt Inst, FIN-00014 Helsinki, Finland. [Lan, Qing] NCI, Rockville, MD USA. [Lansingh, Van C.] IAPB & Vis 2020 LA, Weston, FL USA. [Lavados, Pablo M.] Univ Desarrollo, Serv Neurol Clin Alemana, Santiago, RM, Chile. [Lawrynowicz, Alicia E. B.; Silva, Andrea P.; Ubeda, Clotilde] Inst Nacl Epidemiol Dr Juan H Jara, Buenos Aires, DF, Argentina. [Leasher, Janet L.] Nova SE Univ, Ft Lauderdale, FL 33314 USA. [Lee, Jong-Tae; Yoon, Seok-Jun] Korea Univ, Seoul, South Korea. [Leung, Ricky] SUNY Albany, Rensselaer, NY USA. [Zhang, Yong] Dept Gerontol, Jinan, Shandong, Peoples R China. [Li, Bin] Jinan Cent Hosp, Jinan, Shandong, Peoples R China. [Li, Yichong] Genentech Inc, San Francisco, CA USA. [Lipshultz, Steven E.] Wayne State Univ, Miami, FL USA. [Lloyd, Belinda K.; Room, Robin] Eastern Hlth, Turning Point Alcohol & Drug Ctr, Fitzroy, Vic, Australia. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. Australian Natl Univ, Canberra, ACT, Australia. [Lunevicius, Raimundas] Aintree Univ Hosp NHS Fdn Trust, NHS Fdn Trust, Liverpool L9 7AL, Merseyside, England. [Lyons, Ronan Anthony] Swansea Univ, swauni, Swansea, W Glam, Wales. [Ma, Stefan] Minist Hlth Singapore, Singapore, Singapore. [Mackay, Mark T.] Royal Childrens Hosp, Melbourne, Vic, Australia. [Magis-Rodriguez, Carlos] Ctr Prevenc & Control VIH SIDA, Mexico City, DF, Mexico. [Mahdi, Abbas A.] King Georges Med Univ, Lucknow, Uttar Pradesh, India. [Mangalam, Srikanth] Tech Stand & Safety Author, Toronto, ON, Canada. [Mapoma, Christopher Chabila; Masiye, Felix] Univ Zambia, Lusaka, Zambia. [Marape, Marape] Botswana Baylor Childrens Clin Ctr Excellence, Gaborone, Botswana. [Marcenes, Wagner] Univ London, London, England. 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Ryan/0000-0002-5485-7144; Khan, Ejaz/0000-0002-7072-8035; Hagstromer, Maria/0000-0002-4607-8677; Bikbov, Boris/0000-0002-1925-7506; MacLachlan, Jennifer/0000-0002-7654-4536; Gibney, Katherine/0000-0001-5851-5339; Stockl, Heidi/0000-0002-0907-8483; Kwan, Gene/0000-0002-0929-6800; Piel, Frederic B./0000-0001-8131-7728; Ukwaja, Kingsley N./0000-0002-1974-8735; Alsharif, Ubai/0000-0002-4024-3950; Amini, Heresh/0000-0002-4825-1322; Lotufo, Paulo/0000-0002-4856-8450; Karch, Andre/0000-0003-3014-8543; Hedayati, Mohammad T./0000-0001-6415-4648; Patten, Scott/0000-0001-9871-4041; Scott, James/0000-0002-0744-0688; Franklin, Richard/0000-0003-1864-4552; Ermakov, Sergey/0000-0003-1072-1162; Pereira, David/0000-0003-0384-7592; Bohensky, Megan/0000-0001-8370-1408; Montico, Marcella/0000-0003-0377-8232; Jacobsen, Kathryn/0000-0002-4198-6246; Lalloo, Ratilal/0000-0001-5822-1269; Tillmann, Taavi/0000-0002-8428-3719; Soshnikov, Sergey/0000-0002-6983-7066; Salomon, Joshua/0000-0003-3929-5515; Beyene, Tariku Jibat/0000-0002-7474-1966; Santos, Itamar/0000-0003-3212-8466; Patton, George/0000-0001-5039-8326; Brenner, Hermann/0000-0002-6129-1572; Nolte, Sandra/0000-0001-6185-9423; Ribeiro, Antonio/0000-0002-2740-0042; Hankey, Graeme /0000-0002-6044-7328; Moffitt, Terrie/0000-0002-8589-6760; Ronfani, Luca/0000-0001-5710-3914; Ameli, Omid/0000-0001-7878-0551; Rakovac, Ivo/0000-0003-3462-2636; Tanne, David/0000-0002-6699-2220; Adsuar, Jose C/0000-0001-7203-3168; Majdan, Marek/0000-0001-8037-742X; NORMAN, ROSANA/0000-0002-9742-1957; Soreide, Kjetil/0000-0001-7594-4354; Chen, Honglei/0000-0003-3446-7779; Perez-Ruiz, Fernando/0000-0002-5268-1894; Catala-Lopez, Ferran/0000-0002-3833-9312; Norheim, Ole F./0000-0002-5748-5956; London, Stephanie/0000-0003-4911-5290; Hay, Simon/0000-0002-0611-7272; Moradi-Lakeh, Maziar/0000-0001-7381-5305; Al-Shahi Salman, Rustam/0000-0002-2108-9222; Prabhakaran, Dorairaj/0000-0002-3172-834X; Deribe, Kebede/0000-0002-8526-6996; Khang, Young-Ho/0000-0002-9585-8266; Ortiz Arduan, Alberto/0000-0002-9805-9523; Kemp, Andrew/0000-0003-1146-3791; Erskine, Holly/0000-0003-3119-9211; Aboyans, Victor/0000-0002-0322-9818; Brauer, Michael/0000-0002-9103-9343; Glaser, Elizabeth/0000-0002-1918-057X; Balakrishnan, Kalpana/0000-0002-5905-1801; Paternina-Caicedo, Angel/0000-0002-6332-5174; Newton, Charles/0000-0002-6999-5507; Cowie, Benjamin/0000-0002-7087-5895; O'Donnell, Martin/0000-0002-7347-7761; O'donnell, Colm/0000-0002-8004-450X; Rodriguez, Alina/0000-0003-1209-8802; Whiteford, Harvey/0000-0003-4667-6623; Charlson, Fiona/0000-0003-2876-5040; LOGROSCINO, GIANCARLO/0000-0003-0423-3242; McGrath, John/0000-0002-4792-6068; wang, YA XING/0000-0003-2749-7793; Naldi, Luigi/0000-0002-3160-2835; Osborne, Nicholas/0000-0002-6700-2284; Thrift, Amanda/0000-0001-8533-4170; Weiderpass, Elisabete/0000-0003-2237-0128; Rahimi, Kazem/0000-0002-4807-4610; Haro, Josep Maria/0000-0002-3984-277X; Degenhardt, Louisa/0000-0002-8513-2218; Monasta, Lorenzo/0000-0001-7774-548X; Sepanlou, Sadaf/0000-0002-3669-5129; Kravchenko, Michael/0000-0001-5187-5518 FU British Heart Foundation [RG/08/014/24067]; Department of Health [CDF-2013-06-012, RP-PG-0407-10184]; Medical Research Council [MC_UP_A620_1014, G9806489, MC_U137686851, MC_U147585819, MC_UU_12011/1, MR/K006525/1, MR/L003120/1]; NCATS NIH HHS [KL2 TR001088]; NIA NIH HHS [P30 AG017253]; NIEHS NIH HHS [P30 ES000260]; Wellcome Trust [089276, 089963, 099876] NR 122 TC 936 Z9 979 U1 232 U2 767 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JAN 10 PY 2015 VL 385 IS 9963 BP 117 EP 171 DI 10.1016/S0140-6736(14)61682-2 PG 55 WC Medicine, General & Internal SC General & Internal Medicine GA AY7BI UT WOS:000347715900024 PM 25530442 ER PT J AU Burleigh, A McKinney, S Brimhall, J Yap, D Eirew, P Poon, S Ng, V Wan, A Prentice, L Annab, L Barrett, JC Caldas, C Eaves, C Aparicio, S AF Burleigh, Angela McKinney, Steven Brimhall, Jazmine Yap, Damian Eirew, Peter Poon, Steven Ng, Viola Wan, Adrian Prentice, Leah Annab, Lois Barrett, J. Carl Caldas, Carlos Eaves, Connie Aparicio, Samuel TI A co-culture genome-wide RNAi screen with mammary epithelial cells reveals transmembrane signals required for growth and differentiation SO BREAST CANCER RESEARCH LA English DT Article ID CHARACTERIZATION IN-VITRO; HUMAN BREAST-TISSUE; ADULT HUMAN BREAST; SERIAL PASSAGE; 3 DIMENSIONS; STEM-CELLS; CANCER; MORPHOGENESIS; GLAND; FIBROBLASTS AB Introduction: The extracellular signals regulating mammary epithelial cell growth are of relevance to understanding the pathophysiology of mammary epithelia, yet they remain poorly characterized. In this study, we applied an unbiased approach to understanding the functional role of signalling molecules in several models of normal physiological growth and translated these results to the biological understanding of breast cancer subtypes. Methods: We developed and utilized a cytogenetically normal clonal line of hTERT immortalized human mammary epithelial cells in a fibroblast-enhanced co-culture assay to conduct a genome-wide small interfering RNA (siRNA) screen for evaluation of the functional effect of silencing each gene. Our selected endpoint was inhibition of growth. In rigorous postscreen validation processes, including quantitative RT-PCR, to ensure on-target silencing, deconvolution of pooled siRNAs and independent confirmation of effects with lentiviral short-hairpin RNA constructs, we identified a subset of genes required for mammary epithelial cell growth. Using three-dimensional Matrigel growth and differentiation assays and primary human mammary epithelial cell colony assays, we confirmed that these growth effects were not limited to the 184-hTERT cell line. We utilized the METABRIC dataset of 1,998 breast cancer patients to evaluate both the differential expression of these genes across breast cancer subtypes and their prognostic significance. Results: We identified 47 genes that are critically important for fibroblast-enhanced mammary epithelial cell growth. This group was enriched for several axonal guidance molecules and G protein-coupled receptors, as well as for the endothelin receptor PROCR. The majority of genes (43 of 47) identified in two dimensions were also required for three-dimensional growth, with HSD17B2, SNN and PROCR showing greater than tenfold reductions in acinar formation. Several genes, including PROCR and the neuronal pathfinding molecules EFNA4 and NTN1, were also required for proper differentiation and polarization in three-dimensional cultures. The 47 genes identified showed a significant nonrandom enrichment for differential expression among 10 molecular subtypes of breast cancer sampled from 1,998 patients. CD79A, SERPINH1, KCNJ5 and TMEM14C exhibited breast cancer subtype-independent overall survival differences. Conclusion: Diverse transmembrane signals are required for mammary epithelial cell growth in two-dimensional and three-dimensional conditions. Strikingly, we define novel roles for axonal pathfinding receptors and ligands and the endothelin receptor in both growth and differentiation. C1 [Burleigh, Angela; McKinney, Steven; Brimhall, Jazmine; Yap, Damian; Eirew, Peter; Poon, Steven; Ng, Viola; Wan, Adrian; Prentice, Leah; Aparicio, Samuel] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1L3, Canada. [Burleigh, Angela; McKinney, Steven; Brimhall, Jazmine; Yap, Damian; Eirew, Peter; Poon, Steven; Ng, Viola; Wan, Adrian; Prentice, Leah; Aparicio, Samuel] British Columbia Canc Agcy, Vancouver, BC V5Z 1L3, Canada. [Prentice, Leah] British Columbia Canc Agcy, Ctr Translat & Appl Genom, Vancouver, BC V5Z 4E6, Canada. [Annab, Lois] Chromatin & Gene Express Sect, Res Triangle Pk, NC 27709 USA. [Barrett, J. Carl] NIEHS, Mol Carcinogenesis Lab, NIH, Durham, NC 27709 USA. [Caldas, Carlos] Univ Cambridge, Li Ka Shin Ctr, Canc Res UK Cambridge Res Inst, Cambridge CB2 0RE, England. [Caldas, Carlos] Univ Cambridge, Li Ka Shin Ctr, Dept Oncol, Cambridge CB2 0RE, England. [Eaves, Connie] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. RP Aparicio, S (reprint author), Univ British Columbia, Dept Pathol & Lab Med, 675 West 10th Ave, Vancouver, BC V5Z 1L3, Canada. EM saparicio@bccrc.ca OI Yap, Damian/0000-0002-5370-4592 NR 70 TC 6 Z9 6 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD JAN 9 PY 2015 VL 17 AR 4 DI 10.1186/s13058-014-0510-y PG 21 WC Oncology SC Oncology GA CE3JR UT WOS:000351723100003 PM 25572802 ER PT J AU Yap, TL Jiang, ZP Heinrich, F Gruschus, JM Pfefferkorn, CM Barros, M Curtis, JE Sidransky, E Lee, JC AF Yap, Thai Leong Jiang, Zhiping Heinrich, Frank Gruschus, James M. Pfefferkorn, Candace M. Barros, Marilia Curtis, Joseph E. Sidransky, Ellen Lee, Jennifer C. TI Structural Features of Membrane-bound Glucocerebrosidase and alpha-Synuclein Probed by Neutron Reflectometry and Fluorescence Spectroscopy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BILAYER-LIPID MEMBRANES; ACID-BETA-GLUCOSIDASE; SAPOSIN-C; PARKINSONS-DISEASE; GAUCHER-DISEASE; LYSOSOMAL DEGRADATION; DEFECTIVE ENZYME; PROTEIN; MUTATIONS; BINDING AB Mutations in glucocerebrosidase (GCase), the enzyme deficient in Gaucher disease, are a common genetic risk factor for the development of Parkinson disease and related disorders, implicating the role of this lysosomal hydrolase in the disease etiology. A specific physical interaction exists between the Parkinson disease-related protein alpha-synuclein (alpha-syn) and GCase both in solution and on the lipid membrane, resulting in efficient enzyme inhibition. Here, neutron reflectometry was employed as a first direct structural characterization of GCase and alpha-syn.GCase complex on a sparsely-tethered lipid bilayer, revealing the orientation of the membrane-bound GCase. GCase binds to and partially inserts into the bilayer with its active site most likely lying just above the membrane-water interface. The interaction was further characterized by intrinsic Trp fluorescence, circular dichroism, and surface plasmon resonance spectroscopy. Both Trp fluorescence and neutron reflectometry results suggest a rearrangement of loops surrounding the catalytic site, where they extend into the hydrocarbon chain region of the outer leaflet. Taking advantage of contrasting neutron scattering length densities, the use of deuterated alpha-syn versus protiated GCase showed a large change in the membrane-bound structure of alpha-syn in the complex. We propose a model of alpha-syn.GCase on the membrane, providing structural insights into inhibition of GCase by alpha-syn. The interaction displaces GCase away from the membrane, possibly impeding substrate access and perturbing the active site. GCase greatly alters membrane-bound alpha-syn, moving helical residues away from the bilayer, which could impact the degradation of alpha-syn in the lysosome where these two proteins interact. C1 [Yap, Thai Leong; Jiang, Zhiping; Gruschus, James M.; Pfefferkorn, Candace M.; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Heinrich, Frank; Barros, Marilia] Carnegie Mellon Univ, Dept Phys, Pittsburgh, PA 15213 USA. [Heinrich, Frank; Curtis, Joseph E.] NIST, Ctr Neutron Res, Gaithersburg, MD 20899 USA. RP Lee, JC (reprint author), NHLBI, Lab Mol Biophys, NIH, 50 South Dr,Bldg 50 Rm 3513, Bethesda, MD 20892 USA. EM leej4@mail.nih.gov RI Heinrich, Frank/A-5339-2010; Lee, Jennifer/E-9658-2015 OI Heinrich, Frank/0000-0002-8579-553X; Lee, Jennifer/0000-0003-0506-8349 FU Intramural Research Program at the National Institutes of Health; NHLBI; NHGRI FX This work was supported by the Intramural Research Program at the National Institutes of Health, NHLBI, and NHGRI. Research was performed in part at the NIST Center for Nanoscale Science and Technology and by the NIST IMS program "Precision Measurements for Integral Membrane Proteins." NR 59 TC 6 Z9 6 U1 3 U2 20 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 9 PY 2015 VL 290 IS 2 BP 744 EP 754 DI 10.1074/jbc.M114.610584 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AY8BA UT WOS:000347778200005 PM 25429104 ER PT J AU Groveman, BR Kraus, A Raymond, LD Dolan, MA Anson, KJ Dorward, DW Caughey, B AF Groveman, Bradley R. Kraus, Allison Raymond, Lynne D. Dolan, Michael A. Anson, Kelsie J. Dorward, David W. Caughey, Byron TI Charge Neutralization of the Central Lysine Cluster in Prion Protein (PrP) Promotes PrPSc-like Folding of Recombinant PrP Amyloids SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID N-TERMINAL TRUNCATION; SCRAPIE PRION; IN-VITRO; MAMMALIAN PRIONS; HYDROGEN/DEUTERIUM EXCHANGE; MOLECULAR-BASIS; NORMAL BRAIN; CONVERSION; FIBRILS; FORM AB The structure of the infectious form of prion protein, PrPSc, remains unclear. Most pure recombinant prion protein (PrP) amyloids generated in vitro are not infectious and lack the extent of the protease-resistant core and solvent exclusion of infectious PrPSc, especially within residues similar to 90-160. Polyanionic cofactors can enhance infectivity and PrPSc-like characteristics of such fibrils, but the mechanism of this enhancement is unknown. In considering structural models of PrPSc multimers, we identified an obstacle to tight packing that might be overcome with polyanionic cofactors, namely, electrostatic repulsion between four closely spaced cationic lysines within a central lysine cluster of residues 101-110. For example, in our parallel in-register intermolecular beta-sheet model of PrPSc, not only would these lysines be clustered within the 101-110 region of the primary sequence, but they would have intermolecular spacings of only similar to 4.8 between stacke beta-strands. We have now performed molecular dynamics simulations predicting that neutralization of the charges on these lysine residues would allow more stable parallel in-register packing in this region. We also show empirically that substitution of these clustered lysine residues with alanines or asparagines results in recombinant PrP amyloid fibrils with extended proteinase-K resistant beta-sheet cores and infrared spectra that are more reminiscent of bona fide PrPSc. These findings indicate that charge neutralization at the central lysine cluster is critical for the folding and tight packing of N-proximal residues within PrP amyloid fibrils. This charge neutralization may be a key aspect of the mechanism by which anionic cofactors promote PrPSc formation. C1 [Groveman, Bradley R.; Kraus, Allison; Raymond, Lynne D.; Anson, Kelsie J.; Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Dorward, David W.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Dolan, Michael A.] NIAID, Computat Biol Sect, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. RP Caughey, B (reprint author), NIAID, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM bcaughey@nih.gov FU Intramural Program of the National Institute of Allergy and Infectious Diseases FX This work was supported, in whole or in part, by the Intramural Program of the National Institute of Allergy and Infectious Diseases. NR 57 TC 13 Z9 14 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 9 PY 2015 VL 290 IS 2 BP 1119 EP 1128 DI 10.1074/jbc.M114.619627 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AY8BA UT WOS:000347778200043 PM 25416779 ER PT J AU Chen, HL Zhao, EJ Zhang, W Lu, Y Liu, R Huang, XM Ciesielski-Jones, AJ Justice, MA Cousins, DS Peddada, S AF Chen, Honglei Zhao, Edward J. Zhang, Wen Lu, Yi Liu, Rui Huang, Xuemei Ciesielski-Jones, Anna J. Justice, Michele A. Cousins, Deborah S. Peddada, Shyamal TI Meta-analyses on prevalence of selected Parkinson's nonmotor symptoms before and after diagnosis SO TRANSLATIONAL NEURODEGENERATION LA English DT Article DE Parkinson's disease; Nonmotor symptoms; Meta-analysis; Prevalence; Natural history ID SLEEP BEHAVIOR DISORDER; BOWEL MOVEMENT FREQUENCY; RISK-FACTORS; IDENTIFICATION TEST; PRODROMAL FEATURES; OLFACTORY FUNCTION; DUAL HIT; DISEASE; CONSTIPATION; LIFE AB Background: Nonmotor symptoms are common among patients with Parkinson's disease (PD) and some may precede disease diagnosis. Methods: We conducted a meta-analysis on the prevalence of selected nonmotor symptoms before and after PD diagnosis, using random-effect models. We searched PubMed (1965 through October/November 2012) for the following symptoms: hyposmia, constipation, rapid eye movement sleep behavior disorder, excessive daytime sleepiness, depression, and anxiety. Eligible studies were publications in English with original data on one or more of these symptoms. Results: The search generated 2,373 non-duplicated publications and 332 met the inclusion criteria, mostly (n = 320) on symptoms after PD diagnosis. For all symptoms, the prevalence was substantially higher in PD cases than in controls, each affecting over a third of the patients. Hyposmia was the most prevalent (75.5% in cases vs. 19.1% in controls), followed by constipation (50% vs. 17.7%), anxiety (39.9% vs. 19.1%), rapid eye movement sleep behavior disorder (37.0% vs. 7.0%), depression (36.6% vs. 14.9%), and excessive daytime sleepiness (33.9% vs. 10.5%). We observed substantial heterogeneities across studies and meta-regression analyses suggested that several factors might have contributed to this. However, the prevalence estimates were fairly robust in several sensitivity analyses. Only 20 studies had data on any symptoms prior to PD diagnosis, but still the analyses revealed higher prevalence in future PD cases than in controls. Conclusion: These symptoms are common among PD patients both before and after diagnosis. Further studies are needed to understand the natural history of nonmotor symptoms in PD and their etiological and clinical implications. C1 [Chen, Honglei; Zhao, Edward J.; Zhang, Wen; Liu, Rui] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Lu, Yi; Ciesielski-Jones, Anna J.; Justice, Michele A.; Cousins, Deborah S.] Social & Sci Syst Inc, Durham, NC USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Radiol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Kinesiol, Hershey, PA 17033 USA. [Peddada, Shyamal] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Chen, HL (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr,POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM chenh2@niehs.nih.gov OI Chen, Honglei/0000-0003-3446-7779 FU NIEHS NIH HHS [Z01 ES101986] NR 39 TC 8 Z9 9 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2047-9158 J9 TRANSL NEURODEGENER JI Transl. Neurodegener. PD JAN 8 PY 2015 VL 4 AR UNSP 1 DI 10.1186/2047-9158-4-1 PG 8 WC Neurosciences SC Neurosciences & Neurology GA CY3MS UT WOS:000366314500001 PM 25671103 ER PT J AU Sauna, ZE Lozier, JN Kasper, CK Yanover, C Nichols, T Howard, TE AF Sauna, Zuben E. Lozier, Jay N. Kasper, Carol K. Yanover, Chen Nichols, Timothy Howard, Tom E. TI The intron-22-inverted F8 locus permits factor VIII synthesis: explanation for low inhibitor risk and a role for pharmacogenomics SO BLOOD LA English DT Article ID SEVERE HEMOPHILIA-A; ENDOGENOUS FACTOR-VIII; MHC CLASS-II; CENTRAL TOLERANCE; GENE; MUTATION; MILD; CELLS; IMMUNOGENICITY; INVERSIONS AB Intron-22-inversion patients express the entire Factor VIII (FVIII)-amino-acid sequence intracellularly as 2 non-secreted polypeptides and have a positive "intracellular (I)-FVIII-CRM" status. Mutations conferring a positive I-FVIII-CRM status are associated with low inhibitor risk and are pharmacogenetically relevant because inhibitor risk may be affected by the nature of the therapeutic FVIII-protein (tFVIII), the affinity of any tFVIII-derived foreign peptide (tFVIII-fp) for anyHLAclass-II isomer (HLA-II) comprising individual major histocompatibility complex (MHC) repertoires, and the stability of any tFVIII-fp/HLA-II complex. We hypothesize that mutations conferring a completely or substantially negative I-FVIII-CRM status are pharmacogenetically irrelevant because inhibitor risk is high with any tFVIII and individual MHC repertoire. C1 [Sauna, Zuben E.] US FDA, Lab Hemostasis, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Lozier, Jay N.] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Kasper, Carol K.] Orthopaed Hemophilia Treatment Ctr, Los Angeles, CA USA. [Kasper, Carol K.] Univ So Calif, Keck Sch Med, Dept Med, Div Hematol, Los Angeles, CA 90033 USA. [Yanover, Chen] IBM Res Lab, Machine Learning Healthcare & Life Sci, Haifa, Israel. [Nichols, Timothy] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Nichols, Timothy] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Howard, Tom E.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Pathol & Lab Med, Los Angeles, CA 90073 USA. [Howard, Tom E.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Howard, Tom E.] Univ So Calif, Keck Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90033 USA. RP Howard, TE (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Dept Pathol & Lab Med, Bldg 500,Room 1258, Los Angeles, CA 90073 USA. EM zuben.sauna@fda.hhs.gov; Tom.Howard@va.gov RI Yanover, Chen/A-3754-2012 OI Yanover, Chen/0000-0003-3663-4286 FU Modernization of Science Program of the Center for Biologics Evaluation and Research, United States Food and Drug Administration; National Heart, Lung and Blood Institute, National Institutes of Health [1RC2-HL101851, HL-71130, HL-72533]; Bayer Healthcare Corporation; Bayer Hemophilia Awards Program; Baxter Healthcare Corporation; Clinical Translational Science Institute at the University of Southern California FX This study was supported by the Modernization of Science Program of the Center for Biologics Evaluation and Research, United States Food and Drug Administration (Z.E.S.); and grants from the National Heart, Lung and Blood Institute, National Institutes of Health (1RC2-HL101851, HL-71130, HL-72533), the Bayer Healthcare Corporation, Bayer Hemophilia Awards Program, Baxter Healthcare Corporation, and the Clinical Translational Science Institute at the University of Southern California (T.E.H.). NR 31 TC 3 Z9 4 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 8 PY 2015 VL 125 IS 2 BP 223 EP 228 DI 10.1182/blood-2013-12-530113 PG 6 WC Hematology SC Hematology GA CD1CA UT WOS:000350810200010 PM 25406352 ER PT J AU Sasaki, H Kurotaki, D Osato, N Sato, H Sasaki, I Koizumi, S Wang, HS Kaneda, C Nishiyama, A Kaisho, T Aburatani, H Morse, HC Ozato, K Tamura, T AF Sasaki, Haruka Kurotaki, Daisuke Osato, Naoki Sato, Hideaki Sasaki, Izumi Koizumi, Shin-ichi Wang, Hongsheng Kaneda, Chika Nishiyama, Akira Kaisho, Tsuneyasu Aburatani, Hiroyuki Morse, Herbert C., III Ozato, Keiko Tamura, Tomohiko TI Transcription factor IRF8 plays a critical role in the development of murine basophils and mast cells SO BLOOD LA English DT Article ID CD8-ALPHA(+) DENDRITIC CELLS; SEQUENCE-BINDING-PROTEIN; IN-VIVO; HEMATOPOIETIC LINEAGES; C/EBP-ALPHA; STEM-CELL; DIFFERENTIATION; ICSBP; PROGENITORS; EXPRESSION AB Basophils and mast cells play critical roles in host defense against pathogens and allergic disorders. However, the molecular mechanism by which these cells are generated is not completely understood. Here we demonstrate that interferon regulatory factor-8 (IRF8), a transcription factor essential for the development of several myeloid lineages, also regulates basophil and mast cell development. irf8(-/-) mice displayed a severe reduction in basophil counts, which was accounted for by the absence of pre-basophil and mast cell progenitors (pre-BMPs). Although Irf8(-/-) mice retained peripheral tissue mast cells, remaining progenitors from mice including granulocyte progenitors (GPs) were unable to efficiently generate either basophils or mast cells, indicating that IRF8 also contributes to the development of mast cells. IRF8 appeared to function at the GP stage, because IRF8 was expressed in GPs, but not in basophils, mast cells, and basophi/mast cell-restricted progenitor cells. Furthermore, we demonstrate that GATA2, a transcription factor known to promote basophil and mast cell differentiation, acts downstream of IRF8. These results shed light on the pathways and mechanism underlying the development of basophils and mast cells. C1 [Sasaki, Haruka; Kurotaki, Daisuke; Sato, Hideaki; Koizumi, Shin-ichi; Kaneda, Chika; Nishiyama, Akira; Tamura, Tomohiko] Yokohama City Univ, Grad Sch Med, Dept Immunol, Yokohama, Kanagawa 2360004, Japan. [Osato, Naoki; Aburatani, Hiroyuki] Univ Tokyo, Adv Sci & Technol Res Ctr, Genome Sci Div, Tokyo, Japan. [Sasaki, Izumi; Kaisho, Tsuneyasu] Osaka Univ, World Premier Int Immunol Frontier Res Ctr, Lab Immune Regulat, Osaka, Japan. [Wang, Hongsheng; Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Lab Immunogenet, NIH, Rockville, MD USA. [Kaisho, Tsuneyasu] RIKEN Res Ctr Allergy & Immunol, Lab Inflammatory Regulat, Yokohama, Kanagawa, Japan. [Ozato, Keiko] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. RP Tamura, T (reprint author), Yokohama City Univ, Grad Sch Med, Dept Immunol, Kanazawa Ku, 3-9 Fukuura, Yokohama, Kanagawa 2360004, Japan. EM tamurat@yokohama-cu.ac.jp FU KAKENHI from the Japan Society for the Promotion of Science [24390246, 24118002, 24790322]; MEXT; Yokohama City University; National Institutes of Health, National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by KAKENHI grants-in-aid (24390246 and 24118002) (T.T.) and (24790322) (D.K.) from the Japan Society for the Promotion of Science, the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from MEXT (T.T.), a grant for Strategic Research Promotion from Yokohama City University (T.T.), and the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (H.W., H.C.M.) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K.O.), and the supercomputing resource was provided by Human Genome Center of the Institute of Medical Science at the University of Tokyo. NR 50 TC 18 Z9 19 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 8 PY 2015 VL 125 IS 2 BP 358 EP 369 DI 10.1182/blood-2014-02-557983 PG 12 WC Hematology SC Hematology GA CD1CA UT WOS:000350810200024 PM 25398936 ER PT J AU Rosenberg, PS Barker, KA Anderson, WF AF Rosenberg, Philip S. Barker, Kimberly A. Anderson, William F. TI Future distribution of multiple myeloma in the United States by sex, age, and race/ethnicity SO BLOOD LA English DT Letter ID SURVIVAL; CANCER; IMPROVEMENT C1 [Rosenberg, Philip S.; Barker, Kimberly A.; Anderson, William F.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Rosenberg, PS (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 7-E-130 MSC 9780, Bethesda, MD 20892 USA. EM rosenbep@mail.nih.gov FU Intramural NIH HHS NR 9 TC 3 Z9 3 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 JAN 8 PY 2015 VL 125 IS 2 BP 410 EP 412 DI 10.1182/blood-2014-10-609461 PG 5 WC Hematology SC Hematology GA CD1CA UT WOS:000350810200030 PM 25573972 ER PT J AU Glubb, DM Maranian, MJ Michailidou, K Pooley, KA Meyer, KB Kar, S Carlebur, S O'Reilly, M Betts, JA Hillman, KM Kaufmann, S Beesley, J Canisius, S Hopper, JL Southey, MC Tsimiklis, H Apicella, C Schmidt, MK Broeks, A Hogervorst, FB van der Schoot, CE Muir, K Lophatananon, A Stewart-Brown, S Siriwanarangsan, P Fasching, PA Ruebner, M Ekici, AB Beckmann, MW Peto, J Dos-Santos-Silva, I Fletcher, O Johnson, N Pharoah, PDP Bolla, MK Wang, Q Dennis, J Sawyer, EJ Tomlinson, I Kerin, MJ Miller, N Burwinkel, B Marme, F Yang, RX Surowy, H Guenel, P Truong, T Menegaux, F Sanchez, M Bojesen, SE Nordestgaard, BG Nielsen, SF Flyger, H Gonzelez-Neira, A Benitez, J Zamora, MP Perez, JIA Anton-Culver, H Neuhausen, SL Brenner, H Dieffenbach, AK Arndt, V Stegmaier, C Meindl, A Schmutzler, RK Brauch, H Ko, YD Bruning, T Nevanlinna, H Muranen, TA Aittomaki, K Blomqvist, C Matsuo, K Ito, H Iwata, H Tanaka, H Dork, T Bogdanova, NV Helbig, S Lindblom, A Margolin, S Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Wu, AH Tseng, CC Van den Berg, D Stram, DO Lambrechts, D Zhao, H Weltens, C van Limbergen, E Chang-Claude, J Flesch-Janys, D Rudolph, A Seibold, P Radice, P Peterlongo, P Barile, M Capra, F Couch, FJ Olson, JE Hallberg, E Vachon, C Giles, GG Milne, RL McLean, C Haiman, CA Henderson, BE Schumacher, F Le Marchand, L Simard, J Goldberg, MS Labreche, F Dumont, M Teo, SH Yip, CH See, MH Cornes, B Cheng, CY Ikram, MK Kristensen, V Zheng, W Halverson, SL Shrubsole, M Long, J Winqvist, R Pylkas, K Jukkola-Vuorinen, A Kauppila, S Andrulis, IL Knight, JA Glendon, G Tchatchou, S Devilee, P Tollenaar, RAEM Seynaeve, C Van Asperen, CJ Garcia-Closas, M Figueroa, J Chanock, SJ Lissowska, J Czene, K Klevebring, D Darabi, H Eriksson, M Hooning, MJ Hollestelle, A Martens, JWM Collee, JM Hall, P Li, JM Humphreys, K Shu, XO Lu, W Gao, YT Cai, H Cox, A Cross, SS Reed, MWR Blot, W Signorello, LB Cai, QY Shah, M Ghoussaini, M Kang, D Choi, JY Park, SK Noh, DY Hartman, M Miao, H Lim, WY Tang, A Hamann, U Torres, D Jakubowska, A Lubinski, J Jaworska, K Durda, K Sangrajrang, S Gaborieau, V Brennan, P McKay, J Olswold, C Slager, S Toland, AE Yannoukakos, D Shen, CY Wu, PE Yu, JC Hou, MF Swerdlow, A Ashworth, A Orr, N Jones, M Pita, G Alonso, MR Alvarez, N Herrero, D Tessier, DC Vincent, D Bacot, F Luccarini, C Baynes, C Ahmed, S Healey, CS Brown, MA Ponder, BAJ Chenevix-Trench, G Thompson, DJ Edwards, SL Easton, DF Dunning, AM French, JD AF Glubb, Dylan M. Maranian, Mel J. Michailidou, Kyriaki Pooley, Karen A. Meyer, Kerstin B. Kar, Siddhartha Carlebur, Saskia O'Reilly, Martin Betts, Joshua A. Hillman, Kristine M. Kaufmann, Susanne Beesley, Jonathan Canisius, Sander Hopper, John L. Southey, Melissa C. Tsimiklis, Helen Apicella, Carmel Schmidt, Marjanka K. Broeks, Annegien Hogervorst, Frans B. van der Schoot, C. Ellen Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Fasching, Peter A. Ruebner, Matthias Ekici, Arif B. Beckmann, Matthias W. Peto, Julian Dos-Santos-Silva, Isabel Fletcher, Olivia Johnson, Nichola Pharoah, Paul D. P. Bolla, Manjeet K. Wang, Qin Dennis, Joe Sawyer, Elinor J. Tomlinson, Ian Kerin, Michael J. Miller, Nicola Burwinkel, Barbara Marme, Frederik Yang, Rongxi Surowy, Harald Guenel, Pascal Truong, Therese Menegaux, Florence Sanchez, Marie Bojesen, Stig E. Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Gonzalez-Neira, Anna Benitez, Javier Pilar Zamora, M. Arias Perez, Jose Ignacio Anton-Culver, Hoda Neuhausen, Susan L. Brenner, Hermann Dieffenbach, Aida Karina Arndt, Volker Stegmaier, Christa Meindl, Alfons Schmutzler, Rita K. Brauch, Hiltrud Ko, Yon-Dschun Bruening, Thomas Nevanlinna, Heli Muranen, Taru A. Aittomaeki, Kristiina Blomqvist, Carl Matsuo, Keitaro Ito, Hidemi Iwata, Hiroji Tanaka, Hideo Doerk, Thilo Bogdanova, Natalia V. Helbig, Sonja Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Wu, Anna H. Tseng, Chiu-chen Van den Berg, David Stram, Daniel O. Lambrechts, Diether Zhao, Hui Weltens, Caroline van Limbergen, Erik Chang-Claude, Jenny Flesch-Janys, Dieter Rudolph, Anja Seibold, Petra Radice, Paolo Peterlongo, Paolo Barile, Monica Capra, Fabio Couch, Fergus J. Olson, Janet E. Hallberg, Emily Vachon, Celine Giles, Graham G. Milne, Roger L. McLean, Catriona Haiman, Christopher A. Henderson, Brian E. Schumacher, Fredrick Le Marchand, Loic Simard, Jacques Goldberg, Mark S. Labreche, France Dumont, Martine Teo, Soo Hwang Yip, Cheng Har See, Mee-Hoong Cornes, Belinda Cheng, Ching-Yu Ikram, M. Kamran Kristensen, Vessela Zheng, Wei Halverson, Sandra L. Shrubsole, Martha Long, Jirong Winqvist, Robert Pylkaes, Katri Jukkola-Vuorinen, Arja Kauppila, Saila Andrulis, Irene L. Knight, Julia A. Glendon, Gord Tchatchou, Sandrine Devilee, Peter Tollenaar, Robert A. E. M. Seynaeve, Caroline Van Asperen, Christi J. Garcia-Closas, Montserrat Figueroa, Jonine Chanock, Stephen J. Lissowska, Jolanta Czene, Kamila Klevebring, Daniel Darabi, Hatef Eriksson, Mikael Hooning, Maartje J. Hollestelle, Antoinette Martens, John W. M. Collee, J. Margriet Hall, Per Li, Jingmei Humphreys, Keith Shu, Xiao-Ou Lu, Wei Gao, Yu-Tang Cai, Hui Cox, Angela Cross, Simon S. Reed, Malcolm W. R. Blot, William Signorello, Lisa B. Cai, Qiuyin Shah, Mitul Ghoussaini, Maya Kang, Daehee Choi, Ji-Yeob Park, Sue K. Noh, Dong-Young Hartman, Mikael Miao, Hui Lim, Wei Yen Tang, Anthony Hamann, Ute Torres, Diana Jakubowska, Anna Lubinski, Jan Jaworska, Katarzyna Durda, Katarzyna Sangrajrang, Suleeporn Gaborieau, Valerie Brennan, Paul McKay, James Olswold, Curtis Slager, Susan Toland, Amanda E. Yannoukakos, Drakoulis Shen, Chen-Yang Wu, Pei-Ei Yu, Jyh-Cherng Hou, Ming-Feng Swerdlow, Anthony Ashworth, Alan Orr, Nick Jones, Michael Pita, Guillermo Rosario Alonso, M. Alvarez, Nuria Herrero, Daniel Tessier, Daniel C. Vincent, Daniel Bacot, Francois Luccarini, Craig Baynes, Caroline Ahmed, Shahana Healey, Catherine S. Brown, Melissa A. Ponder, Bruce A. J. Chenevix-Trench, Georgia Thompson, Deborah J. Edwards, Stacey L. Easton, Douglas F. Dunning, Alison M. French, Juliet D. CA GENICA Network KConFab Investigators Norwegian Breast Canc Study TI Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CYCLIN D1 EXPRESSION; FUNCTIONAL VARIANTS; SUSCEPTIBILITY LOCI; GENES; PROMOTER; ACTIVATION; APOPTOSIS; SUBTYPES; TUMORS AB Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER-: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, p(trend) = 5.7 3 10(-44)) and estrogen-receptor-negative (ER-: OR = 1.10, 95% CI = 1.05-1.15, p(trend) = 3.0 x 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [p(cond) = 1.61 x 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER-: OR = 0.90, 95% CI = 0.87-0.93, p(cond) = 1.4 x 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival. C1 [Glubb, Dylan M.; Betts, Joshua A.; Hillman, Kristine M.; Kaufmann, Susanne; Beesley, Jonathan; Chenevix-Trench, Georgia; Edwards, Stacey L.; French, Juliet D.] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4029, Australia. [Maranian, Mel J.; Pooley, Karen A.; Pharoah, Paul D. P.; Shah, Mitul; Ghoussaini, Maya; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S.; Easton, Douglas F.; Dunning, Alison M.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge CB1 8RN, England. [Michailidou, Kyriaki; Kar, Siddhartha; Pharoah, Paul D. P.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Thompson, Deborah J.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Meyer, Kerstin B.; Carlebur, Saskia; O'Reilly, Martin; Ponder, Bruce A. J.] Univ Cambridge, Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Cambridge CB2 0RE, England. [Meyer, Kerstin B.; Carlebur, Saskia; O'Reilly, Martin; Ponder, Bruce A. J.] Univ Cambridge, Dept Oncol, Li Ka Shing Ctr, Cambridge CB2 0RE, England. [Betts, Joshua A.; Brown, Melissa A.; Edwards, Stacey L.; French, Juliet D.] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia. [Canisius, Sander; Schmidt, Marjanka K.; Broeks, Annegien; Hogervorst, Frans B.; Giles, Graham G.; Milne, Roger L.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands. [Hopper, John L.] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic 3010, Australia. [Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. [van der Schoot, C. Ellen] Sanquin Res, NL-1066 CX Amsterdam, Netherlands. [Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester M13 9PL, Lancs, England. [Siriwanarangsan, Pornthep] Minist Publ Hlth, Nonthaburi 11000, Thailand. [Fasching, Peter A.; Ruebner, Matthias; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Univ Breast Ctr Franconia, Dept Gynecol & Obstet, Univ Hosp Erlangen,Comprehens Canc Ctr Erlangen E, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, D-91054 Erlangen, Germany. [Peto, Julian; Dos-Santos-Silva, Isabel] Univ London London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1E 7HT, England. [Fletcher, Olivia; Johnson, Nichola; Garcia-Closas, Montserrat; Ashworth, Alan; Orr, Nick] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Div Canc Studies, London SE1 9RT, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. 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[Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Sch Med, Inst Clin Med Pathol & Forens Med, Kuopio 70211, Finland. [Kataja, Vesa] Kuopio Univ Hosp, Ctr Canc, Kuopio 70211, Finland. [KConFab Investigators] Peter MacCallum Canc Inst, East Melbourne, Vic 3002, Australia. [Wu, Anna H.; Tseng, Chiu-chen; Van den Berg, David; Stram, Daniel O.; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick] Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Lambrechts, Diether; Zhao, Hui] Univ Leuven, Dept Oncol, Lab Translat Genet, B-3000 Leuven, Belgium. [Lambrechts, Diether; Zhao, Hui] VIB, Vesalius Res Ctr, B-3000 Leuven, Belgium. [Weltens, Caroline; van Limbergen, Erik] Univ Hosp Gashuisberg, B-3000 Leuven, Belgium. [Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. 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[McLean, Catriona] The Alfred, Anat Pathol, Melbourne, Vic 3004, Australia. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96813 USA. [Simard, Jacques; Dumont, Martine] Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada. [Simard, Jacques; Dumont, Martine] Univ Laval, Quebec City, PQ G1V 4G2, Canada. [Goldberg, Mark S.] McGill Univ, Ctr Hlth, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ H3A 1A1, Canada. [Labreche, France] Univ Montreal, Dept Sante Environm & Sante Travail, Dept Med Sociale & Prevent, Montreal, PQ H3A 3C2, Canada. [Teo, Soo Hwang] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya 47500, Malaysia. [Teo, Soo Hwang; Yip, Cheng Har; See, Mee-Hoong] Univ Malaya, Breast Canc Res Unit, Canc Res Inst, Med Ctr, Kuala Lumpur 50603, Malaysia. [Cornes, Belinda; Cheng, Ching-Yu; Ikram, M. Kamran] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 168751, Singapore. [Kristensen, Vessela] Univ Oslo, Inst Clin Med, N-0450 Oslo, Norway. [Kristensen, Vessela] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Dept Clin Mol Biol, N-0450 Oslo, Norway. Univ Bergen, Inst Med, Sect Oncol, N-5020 Bergen, Norway. Univ Hosp North Norway, Norwegian Ctr Integrated Care & Telemedicine, N-9038 Tromso, Norway. Radiumhospitalet, Rikshosp, Natl Resource Ctr Long Term Studies Canc, Canc Clin, N-0310 Oslo, Norway. Radiumhospitalet, Oslo Univ Hosp, Div Canc Med & Radiotherapy, N-0310 Oslo, Norway. Akershus Univ Hosp, Dept Surg, N-1478 Lorenskog, Norway. Radiumhospitalet, Oslo Univ Hosp, Dept Radiol, N-0310 Oslo, Norway. Akershus Univ Hosp, Dept Pathol, N-1478 Lorenskog, Norway. Radiumhospitalet, Oslo Univ Hosp, Dept Oncol, N-0310 Oslo, Norway. Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway. Arctic Univ Norway, Univ Tromso, Fac Hlth Sci, Dept Community Med, N-9019 Tromso, Norway. Univ Oslo, Akershus Univ Hosp, Inst Clin Med, Dept Clin Mol Biol, N-1478 Lorenskog, Norway. [Norwegian Breast Canc Study] Oslo Univ Hosp, Ullevaal Univ Hosp, Inst Clin Med, Dept Breast & Endocrine Surg, N-0450 Oslo, Norway. [Zheng, Wei; Halverson, Sandra L.; Shrubsole, Martha; Long, Jirong; Shu, Xiao-Ou; Cai, Hui; Blot, William; Signorello, Lisa B.; Cai, Qiuyin] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Zheng, Wei; Halverson, Sandra L.; Shrubsole, Martha; Long, Jirong; Shu, Xiao-Ou; Cai, Hui; Blot, William; Signorello, Lisa B.; Cai, Qiuyin] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37203 USA. [Winqvist, Robert; Pylkaes, Katri] Univ Oulu, Lab Canc Genet & Tumor Biol, Dept Clin Chem, NordLab Oulu,Oulu Univ Hosp, Oulu 90210, Finland. [Winqvist, Robert; Pylkaes, Katri] Univ Oulu, Bioctr Oulu, NordLab Oulu, Oulu Univ Hosp, Oulu 90210, Finland. [Jukkola-Vuorinen, Arja] Univ Oulu, Dept Oncol, Oulu Univ Hosp, Oulu 90014, Finland. [Kauppila, Saila] Univ Oulu, Dept Pathol, Oulu Univ Hosp, Oulu 90014, Finland. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON M5T 3M7, Canada. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Glendon, Gord; Tchatchou, Sandrine] Mt Sinai Hosp, Ontario Canc Genet Network, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Devilee, Peter; Tollenaar, Robert A. E. M.] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands. [Devilee, Peter; Tollenaar, Robert A. E. M.] Leiden Univ, Med Ctr, Dept Pathol, NL-2300 RC Leiden, Netherlands. [Seynaeve, Caroline] Netherlands Canc Inst, Family Canc Clin, NL-1066 CX Amsterdam, Netherlands. [Van Asperen, Christi J.] Leiden Univ, Med Ctr, Dept Clin Genet, NL-2300 RC Leiden, Netherlands. [Garcia-Closas, Montserrat; Swerdlow, Anthony; Jones, Michael] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England. [Figueroa, Jonine; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, PL-02781 Warsaw, Poland. [Czene, Kamila; Klevebring, Daniel; Darabi, Hatef; Eriksson, Mikael; Hall, Per; Humphreys, Keith] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W. M.] Erasmus Univ, Med Ctr, Dept Med Oncol, NL-3075 EA Rotterdam, Netherlands. [Collee, J. Margriet] Erasmus Univ, Med Ctr, Dept Clin Genet, NL-3008 AE Rotterdam, Netherlands. [Li, Jingmei] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore. [Lu, Wei] Shanghai Ctr Dis Control & Prevent, Shanghai 200336, Peoples R China. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai 200032, Peoples R China. [Cox, Angela; Reed, Malcolm W. R.] Univ Sheffield, Dept Oncol, Sheffield Canc Res Ctr, Sheffield S10 2RX, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield S10 2RX, S Yorkshire, England. [Blot, William; Signorello, Lisa B.] Int Epidemiol Inst, Rockville, MD 20850 USA. [Kang, Daehee; Park, Sue K.] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea. [Kang, Daehee; Park, Sue K.] Seoul Natl Univ, Canc Res Inst, Seoul 110799, South Korea. [Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul 151742, South Korea. [Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea. [Noh, Dong-Young] Seoul Natl Univ, Bundang Hosp, Dept Surg, Songnam 110744, South Korea. [Hartman, Mikael; Miao, Hui; Lim, Wei Yen] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore. [Hartman, Mikael; Miao, Hui; Lim, Wei Yen] Natl Univ Hlth Syst, Singapore 117597, Singapore. [Hartman, Mikael] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 119228, Singapore. [Hartman, Mikael] Natl Univ Hlth Syst, Singapore 119228, Singapore. [Tang, Anthony] Natl Univ Hlth Syst, Div Gen Surg, Singapore 119228, Singapore. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota 11001000, Colombia. [Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna] Pomeranian Med Univ, Dept Genet & Pathol, PL-70115 Szczecin, Poland. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok 10400, Thailand. [Gaborieau, Valerie; Brennan, Paul; McKay, James] Int Agcy Res Canc, F-69372 Lyon, France. [Toland, Amanda E.] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, Inst Radioisotopes & Radiodiagnost Prod, Athens 15310, Greece. [Shen, Chen-Yang; Wu, Pei-Ei] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung 40402, Taiwan. [Shen, Chen-Yang; Wu, Pei-Ei] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei 115, Taiwan. [Yu, Jyh-Cherng] Tri Serv Gen Hosp, Dept Surg, Taipei 114, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Ctr Canc, Chung Ho Mem Hosp, Kaohsiung 807, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Dept Surg, Chung Ho Mem Hosp, Kaohsiung 807, Taiwan. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, Sutton SM2 5NG, Surrey, England. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois] McGill Univ, Montreal, PQ H3A 0G1, Canada. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada. RP Dunning, AM (reprint author), Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge CB1 8RN, England. EM amd24@medschl.cam.ac.uk; juliet.french@qimrberghofer.edu.au RI Gonzalez-Neira, Anna/C-5791-2015; Hartman, Mikael/B-4324-2011; Yip, Cheng-Har/B-1909-2010; Teo, Soo-hwang/H-2353-2014; Hartikainen, Jaana/E-6256-2015; Li, Jingmei/I-2904-2012; Garcia-Closas, Montserrat /F-3871-2015; Knight, Julia/A-6843-2012; Shrubsole, Martha/K-5052-2015; Dork, Thilo/J-8620-2012; U-ID, Kyushu/C-5291-2016; See, Mee-Hoong, See/P-8440-2014; Bruning, Thomas/G-8120-2015; Andrulis, Irene/E-7267-2013; Edwards, Stacey/A-4980-2011; Tanaka, Hideo/A-8145-2016; Glubb, Dylan/M-7514-2016; Brown, Melissa/F-1451-2010; Brenner, Hermann/B-4627-2017; OI Dunning, Alison Margaret/0000-0001-6651-7166; Ikram, Mohammad Kamran/0000-0003-0173-9571; Giles, Graham/0000-0003-4946-9099; Muranen, Taru/0000-0002-5895-1808; Matsuo, Keitaro/0000-0003-1761-6314; Arndt, Volker/0000-0001-9320-8684; Li, Jingmei/0000-0001-8587-7511; Garcia-Closas, Montserrat /0000-0003-1033-2650; Shrubsole, Martha/0000-0002-5591-7575; See, Mee-Hoong, See/0000-0002-7197-5759; Bruning, Thomas/0000-0001-9560-5464; Glubb, Dylan/0000-0002-2184-7708; Brenner, Hermann/0000-0002-6129-1572; Brown, Melissa/0000-0002-2830-9259; Czene, Kamila/0000-0002-3233-5695; Cross, Simon/0000-0003-2044-1754; Cox, Angela/0000-0002-5138-1099; Yannoukakos, Drakoulis/0000-0001-7509-3510 FU Canadian Institutes of Health Research [CRN-87521]; Cancer Research UK [10124, C1287/A10118, C1287/A10710, C1287/A12014, C490/A10124, C8197/A16565]; Intramural NIH HHS; NCI NIH HHS [R01 CA176785, CA098758, CA116167, CA116201, CA128978, CA132839, CA176785, CA54281, CA63464, N01CN25403, P30 CA015083, P30 CA68485, R01 CA092447, R01 CA77398, R01CA148667, R01CA64277, R37CA70867, U01 CA116167, U19 CA148065, UM1 CA164920] NR 38 TC 16 Z9 16 U1 7 U2 30 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN 8 PY 2015 VL 96 IS 1 BP 5 EP 20 DI 10.1016/j.ajhg.2014.11.009 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA AY6YE UT WOS:000347707800001 PM 25529635 ER PT J AU Zhu, XF Feng, T Tayo, BO Liang, JJ Young, JH Franceschini, N Smith, JA Yanek, LR Sun, YV Edwards, TL Chen, W Nalls, M Fox, E Sale, M Bottinger, E Rotimi, C Liu, YM McKnight, B Liu, K Arnett, DK Chakravati, A Cooper, RS Redline, S AF Zhu, Xiaofeng Feng, Tao Tayo, Bamidele O. Liang, Jingjing Young, J. Hunter Franceschini, Nora Smith, Jennifer A. Yanek, Lisa R. Sun, Yan V. Edwards, Todd L. Chen, Wei Nalls, Mike Fox, Ervin Sale, Michele Bottinger, Erwin Rotimi, Charles Liu, Yongmei McKnight, Barbara Liu, Kiang Arnett, Donna K. Chakravati, Aravinda Cooper, Richard S. Redline, Susan CA COGENT BP Consortium TI Meta-analysis of Correlated Traits via Summary Statistics from GWASs with an Application in Hypertension SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COMBINING DEPENDENT TESTS; BLOOD-PRESSURE TRAITS; PRINCIPAL-COMPONENTS; SUSCEPTIBILITY LOCI; GENETIC ASSOCIATION; PHENOTYPES; VARIANTS; DISEASE; LINKAGE AB Genome-wide association studies (GWASs) have identified many genetic variants underlying complex traits. Many detected genetic loci harbor variants that associate with multiple-even distinct-traits. Most current analysis approaches focus on single traits, even though the final results from multiple traits are evaluated together. Such approaches miss the opportunity to systemically integrate the phenome-wide data available for genetic association analysis. In this study, we propose a general approach that can integrate association evidence from summary statistics of multiple traits, either correlated, independent, continuous, or binary traits, which might come from the same or different studies. We allow for trait heterogeneity effects. Population structure and cryptic relatedness can also be controlled. Our simulations suggest that the proposed method has improved statistical power over single-trait analysis in most of the cases we studied. We applied our method to the Continental Origins and Genetic Epidemiology Network (COGENT) African ancestry samples for three blood pressure traits and identified four loci (CHIC2, HOXA-EVX1, IGFBP1/IGFBP3, and CDH17; p < 5.0 x 10(-8)) associated with hypertension-related traits that were missed by a single-trait analysis in the original report. Six additional loci with suggestive association evidence (p < 5.0 x 10(-7)) were also observed, including CACNA1D and WNT3. Our study strongly suggests that analyzing multiple phenotypes can improve statistical power and that such analysis can be executed with the summary statistics from GWASs. Our method also provides a way to study a cross phenotype (CP) association by using summary statistics from GWASs of multiple phenotypes. C1 [Zhu, Xiaofeng; Feng, Tao; Liang, Jingjing] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Feng, Tao] Heilongjiang Univ, Coll Math Sci, Harbin 150080, Peoples R China. [Tayo, Bamidele O.; Cooper, Richard S.] Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 60153 USA. [Young, J. Hunter; Yanek, Lisa R.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Smith, Jennifer A.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Sun, Yan V.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Edwards, Todd L.] Vanderbilt Univ, Dept Med, Div Epidemiol, Ctr Human Genet Res, Nashville, TN 37212 USA. [Chen, Wei] Tulane Univ, Tulane Ctr Cardiovasc Hlth, New Orleans, LA 70112 USA. [Nalls, Mike] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Fox, Ervin] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39126 USA. [Sale, Michele] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Bottinger, Erwin] Mt Sinai Sch Med, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Rotimi, Charles] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Liu, Yongmei] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27157 USA. [McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Arnett, Donna K.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. [Chakravati, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA. [Redline, Susan] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Redline, Susan] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Zhu, XF (reprint author), Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. EM xiaofeng.zhu@case.edu RI Singleton, Andrew/C-3010-2009; Bovet, Pascal/F-4477-2011; Bochud, Murielle/A-3981-2010; OI Bovet, Pascal/0000-0002-0242-4259; Bochud, Murielle/0000-0002-5727-0218; Adeyemo, Adebowale/0000-0002-3105-3231; Smith, Jennifer/0000-0002-3575-5468 FU NIH from the National Human Genome Research Institute [HG003054]; National Heart, Lung, and Blood Institute [HL086718, HL053353, HL113338, HL123677] FX We are gratefully indebted to Robert C. Elston for his valuable discussions and suggestions that greatly improved the manuscript. The work was supported by the NIH grants HG003054 from the National Human Genome Research Institute and HL086718, HL053353, HL113338, and HL123677 from the National Heart, Lung, and Blood Institute. Funding information for the COGENT BP Consortium is provided in the Supplemental Data. NR 42 TC 22 Z9 23 U1 2 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN 8 PY 2015 VL 96 IS 1 BP 21 EP 36 DI 10.1016/j.ajhg.2014.11.011 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA AY6YE UT WOS:000347707800002 PM 25500260 ER PT J AU Schueler, M Braun, DA Chandrasekar, G Gee, HY Klasson, TD Halbritter, J Bieder, A Porath, JD Airik, R Zhou, WB LoTurco, JJ Che, A Otto, EA Bockenhauer, D Sebire, NJ Honzik, T Harris, PC Koon, SJ Gunay-Aygun, M Saunier, S Zerres, K Bruechle, NO Drenth, JPH Pelletier, L Tapia-Paez, I Lifton, RP Giles, RH Kere, J Hildebrandt, F AF Schueler, Markus Braun, Daniela A. Chandrasekar, Gayathri Gee, Heon Yung Klasson, Timothy D. Halbritter, Jan Bieder, Andrea Porath, Jonathan D. Airik, Rannar Zhou, Weibin LoTurco, Joseph J. Che, Alicia Otto, Edgar A. Boeckenhauer, Detlef Sebire, Neil J. Honzik, Tomas Harris, Peter C. Koon, Sarah J. Gunay-Aygun, Meral Saunier, Sophie Zerres, Klaus Bruechle, Nadina Ortiz Drenth, Joost P. H. Pelletier, Laurence Tapia-Paez, Isabel Lifton, Richard P. Giles, Rachel H. Kere, Juha Hildebrandt, Friedhelm TI DCDC2 Mutations Cause a Renal-Hepatic Ciliopathy by Disrupting Wnt Signaling SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MULTIPOINT LINKAGE ANALYSIS; JOUBERT-SYNDROME; CAUSE NEPHRONOPHTHISIS; CENTROSOMAL PROTEIN; DOMAIN PROTEIN; GENE; CILIARY; DISEASE; INTERACTS; ZEBRAFISH AB Nephronophthisis-related ciliopathies (NPHP-RC) are recessive diseases characterized by renal dysplasia or degeneration. We here identify mutations of DCDC2 as causing a renal-hepatic ciliopathy. DCDC2 localizes to the ciliary axoneme and to mitotic spindle fibers in a cell-cycle-dependent manner. Knockdown of Dcdc2 in IMCD3 cells disrupts ciliogenesis, which is rescued by wild-type (WT) human DCDC2, but not by constructs that reflect human mutations. We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits beta-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors. Mutations detected in human NPHP-RC lack these effects. A Wnt inhibitor likewise restores ciliogenesis in 3D IMCD3 cultures, emphasizing the importance of Wnt signaling for renal tubulogenesis. Knockdown of dcdc2 in zebrafish recapitulates NPHP-RC phenotypes, including renal cysts and hydrocephalus, which is rescued by a Wnt inhibitor and by WT, but not by mutant, DCDC2. We thus demonstrate a central role of Wnt signaling in the pathogenesis of NPHP-RC, suggesting an avenue for potential treatment of NPHP-RC. C1 [Schueler, Markus; Braun, Daniela A.; Gee, Heon Yung; Halbritter, Jan; Porath, Jonathan D.; Airik, Rannar; Hildebrandt, Friedhelm] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Chandrasekar, Gayathri; Bieder, Andrea; Tapia-Paez, Isabel; Kere, Juha] Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden. [Klasson, Timothy D.; Giles, Rachel H.] Univ Med Ctr Utrecht, Dept Hypertens & Nephrol, NL-3584 CX Utrecht, Netherlands. [Zhou, Weibin; Otto, Edgar A.] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [LoTurco, Joseph J.; Che, Alicia] Univ Connecticut, Dept Physiol & Neurobiol, Storrs, CT 06269 USA. [Boeckenhauer, Detlef] UCL, Inst Child Hlth & Pediat Nephrol, Great Ormond St Hosp, London WC1N 3JH, England. [Sebire, Neil J.; Hildebrandt, Friedhelm] Great Ormond St Hosp Sick Children, Dept Histopathol, London WC1N 3JH, England. [Honzik, Tomas] Charles Univ Prague, Fac Med 1, Dept Pediat & Adolescent Med, Prague 12808 2, Czech Republic. [Honzik, Tomas] Gen Univ Hosp, Prague 12808 2, Czech Republic. [Harris, Peter C.; Koon, Sarah J.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN 55905 USA. [Gunay-Aygun, Meral] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Saunier, Sophie] Univ Paris 05, Necker Hosp, Inserm U574, F-75015 Paris, France. [Saunier, Sophie] Univ Paris 05, Necker Hosp, Dept Genet, F-75015 Paris, France. [Zerres, Klaus; Bruechle, Nadina Ortiz] Rhein Westfal TH Aachen, Univ Hosp, Inst Human Genet, D-52074 Aachen, Germany. [Drenth, Joost P. H.] Radboud UMC, Dept Gastroenterol & Hepatol, NL-6500 HB Nijmegen, Netherlands. [Pelletier, Laurence] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Pelletier, Laurence] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Lifton, Richard P.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Lifton, Richard P.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Kere, Juha] Univ Helsinki, Mol Neurol Res Program, Helsinki 00014, Finland. [Kere, Juha] Folkhalsan Inst Genet, Helsinki 00014, Finland. [Kere, Juha] Karolinska Inst, Sci Life Lab, S-17121 Solna, Sweden. RP Kere, J (reprint author), Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden. EM juha.kere@ki.se; friedhelm.hildebrandt@childrens.harvard.edu RI Kere, Juha/A-9179-2008; Drenth, J.P.H./H-8025-2014; OI Kere, Juha/0000-0003-1974-0271; Otto, Edgar/0000-0002-2387-9973; Bieder, Andrea/0000-0002-4566-050X FU Live Cell Imaging unit/Nikon Center of Excellence; Department of Biosciences and Nutrition, Karolinska Institutet; National Institutes of Health [DK1069274, DK1068306, DK064614, DK090728, DK059597, DK099434]; CIHR [MOP130507]; NephCure Foundation; ASN Foundation for Kidney Research; General University Hospital [RVO-VFN 64165/2012]; Knut and Alice Wallenberg Foundation; Swedish Research Council; Centre for Biosciences; Centre for Innovative Medicine; Kungliga Tekniska Hogskolan; Swedish Brain Foundation (Hjarnfonden); Swedish Brain Foundation; European Union [241955, 305608]; Dutch Kidney Foundation [CP11.18 "KOUNCIL"/13A3D103]; Deutsche Forschungs-gemeinschaft [ZE 205/14-1]; Jonasson FX We are grateful to families and study individuals for their contribution. We would like to thank Milan Elleder and Helena Hulkova (Institute for Inherited Metabolic Disorders) for histological preparation of liver biopsy specimen. We thank the zebrafish core facility, Karolinska Institutet for providing zebrafish embryos. We thank Kjell Hultenby, Eva Blomen, and Sally Cheung for technical support. We thank the Live Cell Imaging unit/Nikon Center of Excellence, Department of Biosciences and Nutrition, Karolinska Institutet for their support. This research was supported by grants from the National Institutes of Health to F.H. (DK1069274, DK1068306, DK064614), to P.C.H. (DK090728, DK059597), to R.A. (DK099434), and by the CIHR to L.P. (MOP130507). H.Y.G. is supported by the NephCure Foundation and by the ASN Foundation for Kidney Research. T.H. was supported by General University Hospital program RVO-VFN 64165/2012. This work was in part supported by grants to J.K. from Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Centre for Biosciences, the Centre for Innovative Medicine, and Jonasson donation to the School of Technology and Health, Kungliga Tekniska Hogskolan, Swedish Brain Foundation (Hjarnfonden) and Swedish Brain Foundations postdoc fellowship award to G.C., from the European Union Framework Programmes 241955 "SYSCILIA" and 305608 "EURenOmics" as well as the Dutch Kidney Foundation grants CP11.18 "KOUNCIL"/13A3D103 to R.H.G., and from the Deutsche Forschungs-gemeinschaft to K.Z. (ZE 205/14-1). F.H. is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist, and the Warren E. Grupe Professor. NR 41 TC 14 Z9 19 U1 3 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN 8 PY 2015 VL 96 IS 1 BP 81 EP 92 DI 10.1016/j.ajhg.2014.12.002 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AY6YE UT WOS:000347707800006 PM 25557784 ER PT J AU Neta, G Sanchez, MA Chambers, DA Phillips, SM Leyva, B Cynkin, L Farrell, MM Heurtin-Roberts, S Vinson, C AF Neta, Gila Sanchez, Michael A. Chambers, David A. Phillips, Siobhan M. Leyva, Bryan Cynkin, Laurie Farrell, Margaret M. Heurtin-Roberts, Suzanne Vinson, Cynthia TI Implementation science in cancer prevention and control: a decade of grant funding by the National Cancer Institute and future directions SO IMPLEMENTATION SCIENCE LA English DT Article DE Grants; Review; Implementation science; Study characteristics ID DISSEMINATION; HEALTH; TRANSLATION AB Background: The National Cancer Institute (NCI) has supported implementation science for over a decade. We explore the application of implementation science across the cancer control continuum, including prevention, screening, treatment, and survivorship. Methods: We reviewed funding trends of implementation science grants funded by the NCI between 2000 and 2012. We assessed study characteristics including cancer topic, position on the T2-T4 translational continuum, intended use of frameworks, study design, settings, methods, and replication and cost considerations. Results: We identified 67 NCI grant awards having an implementation science focus. R01 was the most common mechanism, and the total number of all awards increased from four in 2003 to 15 in 2012. Prevention grants were most frequent (49.3%) and cancer treatment least common (4.5%). Diffusion of Innovations and Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) were the most widely reported frameworks, but it is unclear how implementation science models informed planned study measures. Most grants (69%) included mixed methods, and half reported replication and cost considerations (49.3%). Conclusions: Implementation science in cancer research is active and diverse but could be enhanced by greater focus on measures development, assessment of how conceptual frameworks and their constructs lead to improved dissemination and implementation outcomes, and harmonization of measures that are valid, reliable, and practical across multiple settings. C1 [Neta, Gila; Sanchez, Michael A.; Chambers, David A.; Phillips, Siobhan M.; Leyva, Bryan; Cynkin, Laurie; Farrell, Margaret M.; Heurtin-Roberts, Suzanne; Vinson, Cynthia] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. RP Neta, G (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 4E442, Rockville, MD 20852 USA. EM netagil@mail.nih.gov NR 24 TC 9 Z9 9 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD JAN 8 PY 2015 VL 10 AR 4 DI 10.1186/s13012-014-0200-2 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CA8PT UT WOS:000349184100001 PM 25567702 ER PT J AU Ahn, M Han, YH Park, JE Kim, S Lee, WC Lee, SJ Gunasekaran, P Cheong, C Shin, SY Kim, HY Ryu, EK Murugan, RN Kim, NH Bang, JK AF Ahn, Mija Han, Young-Hyun Park, Jung-Eun Kim, Sungmin Lee, Woo Cheol Lee, Soo Jae Gunasekaran, Pethaiah Cheong, Chaejoon Shin, Song Yub, Sr. Kim, Hye-Yeon Ryu, Eun Kyung Murugan, Ravichandran N. Kim, Nam-Hyung Bang, Jeong Kyu TI A New Class of Peptidomimetics Targeting the Polo-Box Domain of Polo-Like Kinase 1 SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID INHIBITORS; BINDING; DESIGN AB Recent progress in the development of peptide-derived Polo-like kinase (Plk1) polo-box domain (PBD) inhibitors has led to the synthesis of multiple peptide ligands with high binding affinity and selectivity. However, few systematic analyses have been conducted to identify key Plk1 residues and characterize their interactions with potent Plk1 peptide inhibitors. We performed systematic deletion analysis using the most potent 4j peptide and studied N-terminal capping of the minimal peptide with diverse organic moieties, leading to the identification of the peptidomimetic 8 (AB-103) series with high binding affinity and selectivity. To evaluate the bioavailability of short peptidomimetic ligands, PEGylated 8 series were synthesized and incubated with HeLa cells to test for cellular uptake, antiproliferative activity, and Plk1 kinase inhibition. Finally, crystallographic studies of the Plk1 PBD in complex with peptidomimetics 8 and 22 (AB-103-5) revealed the presence of two hydrogen bond interactions responsible for their high binding affinity and selectivity. C1 [Ahn, Mija; Kim, Sungmin; Lee, Woo Cheol; Cheong, Chaejoon; Kim, Hye-Yeon; Ryu, Eun Kyung; Murugan, Ravichandran N.; Bang, Jeong Kyu] Korea Basic Sci Inst, Div Magnet Resonance, Chungbuk 363883, Cheongwon, South Korea. [Han, Young-Hyun; Gunasekaran, Pethaiah; Kim, Nam-Hyung] Chungbuk Natl Univ, Dept Anim Sci, Mol Embryol Lab, Cheongju 361763, Chungbuk, South Korea. [Park, Jung-Eun] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, Soo Jae] Chungbuk Natl Univ, Coll Pharm, Cheongju 361763, Chungbuk, South Korea. [Shin, Song Yub, Sr.] Chosun Univ, Grad Sch, Dept Biomat, Kwangju 501759, South Korea. [Shin, Song Yub, Sr.] Chosun Univ, Sch Med, Dept Cellular & Mol Med, Kwangju 501759, South Korea. RP Bang, JK (reprint author), Korea Basic Sci Inst, Div Magnet Resonance, 804-1 Yangcheong Ri, Chungbuk 363883, Cheongwon, South Korea. EM bangjk@kbsi.re.kr FU Korea Basic Science Institute's Research Program [T34418]; Next-Generation BioGreen 21 Program, Rural Development Administration [PJ009594] FX This work was supported by the Korea Basic Science Institute's Research Program grant T34418 (J.K.B.) and the Next-Generation BioGreen 21 Program (no. PJ009594), Rural Development Administration (NHK). NR 20 TC 12 Z9 13 U1 0 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JAN 8 PY 2015 VL 58 IS 1 SI SI BP 294 EP 304 DI 10.1021/jm501147g PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AY7MH UT WOS:000347743700019 PM 25347203 ER PT J AU Marchetti, F Bishop, J Gingerich, J Wyrobek, AJ AF Marchetti, Francesco Bishop, Jack Gingerich, John Wyrobek, Andrew J. TI Meiotic interstrand DNA damage escapes paternal repair and causes chromosomal aberrations in the zygote by maternal misrepair SO SCIENTIFIC REPORTS LA English DT Article ID CROSS-LINK REPAIR; NITROGEN MUSTARDS; TOPOISOMERASE-II; MOUSE ZYGOTES; MUTATIONS; MELPHALAN; ABNORMALITIES; CHROMATIN; CANCER; SPERM AB De novo point mutations and chromosomal structural aberrations (CSA) detected in offspring of unaffected parents show a preferential paternal origin with higher risk for older fathers. Studies in rodents suggest that heritable mutations transmitted from the father can arise from either paternal or maternal misrepair of damaged paternal DNA, and that the entire spermatogenic cycle can be at risk after mutagenic exposure. Understanding the susceptibility and mechanisms of transmission of paternal mutations is important in family planning after chemotherapy and donor selection for assisted reproduction. We report that treatment of male mice with melphalan (MLP), a bifunctional alkylating agent widely used in chemotherapy, induces DNA lesions during male mouse meiosis that persist unrepaired as germ cells progress through DNA repair-competent phases of spermatogenic development. After fertilization, unrepaired sperm DNA lesions are mis-repaired into CSA by the egg's DNA repair machinery producing chromosomally abnormal offspring. These findings highlight the importance of both pre- and post-fertilization DNA repair in assuring the genomic integrity of the conceptus. C1 [Marchetti, Francesco; Gingerich, John] Hlth Canada, Environm Hlth Sci Res Bur, Ottawa, ON K1A 0K9, Canada. [Marchetti, Francesco; Wyrobek, Andrew J.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. [Marchetti, Francesco; Wyrobek, Andrew J.] Lawrence Livermore Natl Lab, Dept Biosci, Livermore, CA 94550 USA. [Bishop, Jack] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Marchetti, F (reprint author), Hlth Canada, Environm Hlth Sci Res Bur, Ottawa, ON K1A 0K9, Canada. EM Francesco.marchetti@hc-sc.gc.ca OI Marchetti, Francesco/0000-0002-9435-4867 FU National Institute of Environmental Health Sciences through a National Institute of Environmental Health Sciences/Department of Energy Interagency Agreement [Y01-ES-102-00]; Canadian Regulatory System for Biotechnology; US Department of Energy by the Lawrence Livermore National Laboratory [W-7405-END-48]; Lawrence Berkeley National Laboratory [DE-AC02-05CH11231] FX This work was funded by the National Institute of Environmental Health Sciences through a National Institute of Environmental Health Sciences/Department of Energy Interagency Agreement (Y01-ES-102-00) and the Canadian Regulatory System for Biotechnology. Work conducted in part under the auspices of the US Department of Energy by the Lawrence Livermore National Laboratory through contract W-7405-END-48 and by the Lawrence Berkeley National Laboratory under contract DE-AC02-05CH11231. We thank Debbie Cabreros for help with the CT8 assay. NR 51 TC 7 Z9 8 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 8 PY 2015 VL 5 AR 7689 DI 10.1038/srep07689 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY8LF UT WOS:000347804300022 PM 25567288 ER PT J AU Zarin, DA Tse, T Sheehan, J AF Zarin, Deborah A. Tse, Tony Sheehan, Jerry TI The Proposed Rule for US Clinical Trial Registration and Results Submission SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PUBLICATION C1 [Zarin, Deborah A.; Tse, Tony; Sheehan, Jerry] NIH, Natl Lib Med, US Dept HHS, Bethesda, MD 20892 USA. RP Zarin, DA (reprint author), NIH, Natl Lib Med, US Dept HHS, Bldg 10, Bethesda, MD 20892 USA. FU Intramural Research Program of the National Library of Medicine, National Institutes of Health FX Supported in part by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. NR 22 TC 23 Z9 24 U1 1 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 8 PY 2015 VL 372 IS 2 BP 174 EP 180 DI 10.1056/NEJMsr1414226 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AY2UA UT WOS:000347443300014 PM 25539444 ER PT J AU Cunningham, LL Tucci, DL AF Cunningham, Lisa L. Tucci, Debara L. TI Restoring Synaptic Connections in the Inner Ear after Noise Damage SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Cunningham, Lisa L.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD 20892 USA. [Tucci, Debara L.] Duke Univ Med Ctr, Dept Otolaryngol Head & Neck Surg, Durham, NC USA. RP Cunningham, LL (reprint author), Natl Inst Deafness & Other Commun Disorders, Bethesda, MD 20892 USA. NR 4 TC 4 Z9 4 U1 2 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 8 PY 2015 VL 372 IS 2 BP 181 EP 182 DI 10.1056/NEJMcibr1413201 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AY2UA UT WOS:000347443300015 PM 25564901 ER PT J AU Pepper, DJ AF Pepper, Dominique J. TI Goal-Directed Resuscitation in Septic Shock SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Pepper, DJ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM dominiquepepper@gmail.com NR 1 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 8 PY 2015 VL 372 IS 2 BP 190 EP 190 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AY2UA UT WOS:000347443300022 PM 25564909 ER PT J AU Lin, A Clasen, L Lee, NR Wallace, GL Lalonde, F Blumenthal, J Giedd, JN Raznahan, A AF Lin, Amy Clasen, Liv Lee, Nancy Raitano Wallace, Gregory L. Lalonde, Francois Blumenthal, Jonathan Giedd, Jay N. Raznahan, Armin TI Mapping the Stability of Human Brain Asymmetry across Five Sex-Chromosome Aneuploidies SO JOURNAL OF NEUROSCIENCE LA English DT Article DE asymmetry; brain; neurodevelopment; sex chromosome ID CORTICAL THICKNESS; CEREBRAL ASYMMETRY; X-CHROMOSOME; GENE-EXPRESSION; HANDEDNESS; CHILDREN; CORTEX; LANGUAGE; SCHIZOPHRENIA; ASSOCIATION AB The human brain displays stereotyped and early emerging patterns of cortical asymmetry in health. It is unclear if these asymmetries are highly sensitive to genetic and environmental variation or fundamental features of the brain that can survive severe developmental perturbations. To address this question, we mapped cortical thickness (CT) asymmetry in a group of genetically defined disorders known to impact CT development. Participants included 137 youth with one of five sex-chromosome aneuploidies [SCAs; XXX (n = 28), XXY (n = 58), XYY(n = 26), XXYY(n = 20), and XXXXY(n = 5)], and 169 age-matched typically developing controls (80 female). In controls, we replicated previously reported rightward inferior frontal and leftward lateral parietal CT asymmetry. These opposing frontoparietal CT asymmetries were broadly preserved in all five SCA groups. However, we also detected foci of shifting CT asymmetry with aneuploidy, which fell almost exclusively within regions of significant CT asymmetry in controls. Specifically, X-chromosome aneuploidy accentuated normative rightward inferior frontal asymmetries, while Y-chromosome aneuploidy reversed normative rightward medial prefrontal and lateral temporal asymmetries. These findings indicate that (1) the stereotyped normative pattern of opposing frontoparietal CT asymmetry arises from developmental mechanisms that can withstand gross chromosomal aneuploidy and (2) X and Y chromosomes can exert focal, nonoverlapping and directionally opposed influences on CT asymmetry within cortical regions of significant asymmetry in health. Our study attests to the resilience of developmental mechanisms that support the global patterning of CT asymmetry in humans, and motivates future research into the molecular bases and functional consequences of sex chromosome dosage effects on CT asymmetry. C1 [Lin, Amy; Clasen, Liv; Lee, Nancy Raitano; Wallace, Gregory L.; Lalonde, Francois; Blumenthal, Jonathan; Giedd, Jay N.; Raznahan, Armin] NIMH, Sect Brain Imaging, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Wallace, Gregory L.] George Washington Univ, Dept Speech & Hearing Sci, Washington, DC 20052 USA. RP Raznahan, A (reprint author), Bldg 10,Room 4C108,10 Ctr Dr, Bethesda, MD 20892 USA. EM raznahana@mail.nih.gov RI Giedd, Jay/J-9644-2015; Lee, Nancy/M-7492-2016; OI Giedd, Jay/0000-0003-2002-8978; Lee, Nancy/0000-0002-6663-0713; Wallace, Gregory/0000-0003-0329-5054 FU National Institutes of Health Intramural Research Program FX This work was funded by the National Institutes of Health Intramural Research Program. We thank the participants and families who took part in this study. We are also grateful to Dr Stephen J. Gotts of the NIH IRP Laboratory of Brain and Cognition for his advice on data modeling methods. NR 45 TC 3 Z9 3 U1 5 U2 21 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 7 PY 2015 VL 35 IS 1 BP 140 EP 145 DI 10.1523/JNEUROSCI.3489-14.2015 PG 6 WC Neurosciences SC Neurosciences & Neurology GA CB1SB UT WOS:000349407200012 PM 25568109 ER PT J AU Scaramuzzino, C Casci, I Parodi, S Lievens, PMJ Polanco, MJ Milioto, C Chivet, M Monaghan, J Mishra, A Badders, N Aggarwal, T Grunseich, C Sambataro, F Basso, M Fackelmayer, FO Taylor, JP Pandey, UB Pennuto, M AF Scaramuzzino, Chiara Casci, Ian Parodi, Sara Lievens, Patricia M. J. Polanco, Maria J. Milioto, Carmelo Chivet, Mathilde Monaghan, John Mishra, Ashutosh Badders, Nisha Aggarwal, Tanya Grunseich, Christopher Sambataro, Fabio Basso, Manuela Fackelmayer, Frank O. Taylor, J. Paul Pandey, Udai Bhan Pennuto, Maria TI Protein Arginine Methyltransferase 6 Enhances Polyglutamine-Expanded Androgen Receptor Function and Toxicity in Spinal and Bulbar Muscular Atrophy SO NEURON LA English DT Article ID TRANSGENIC MOUSE MODEL; IN-VIVO; DROSOPHILA MODEL; NATIVE FUNCTIONS; INDUCED DISEASE; METHYLATION; NEURODEGENERATION; PRMT6; EXPRESSION; COACTIVATOR AB Polyglutamine expansion in androgen receptor (AR) is responsible for spinobulbar muscular atrophy (SBMA) that leads to selective loss of lower motor neurons. Using SBMA as a model, we explored the relationship between protein structure/function and neurodegeneration in polyglutamine diseases. We show here that protein arginine methyltransferase 6 (PRMT6) is a specific co-activator of normal and mutant AR and that the interaction of PRMT6 with AR is significantly enhanced in the AR mutant. AR and PRMT6 interaction occurs through the PRMT6 steroid receptor interaction motif, LXXLL, and the AR activating function 2 surface. AR transactivation requires PRMT6 catalytic activity and involves methylation of arginine residues at Akt consensus site motifs, which is mutually exclusive with serine phosphorylation by Akt. The enhanced interaction of PRMT6 and mutant AR leads to neurodegeneration in cell and fly models of SBMA. These findings demonstrate a direct role of arginine methylation in polyglutamine disease pathogenesis. C1 [Scaramuzzino, Chiara; Parodi, Sara; Lievens, Patricia M. J.; Polanco, Maria J.; Milioto, Carmelo; Aggarwal, Tanya; Pennuto, Maria] Ist Italiano Tecnologia, Dept Neurosci & Brain Technol, I-16163 Genoa, Italy. [Casci, Ian; Monaghan, John; Pandey, Udai Bhan] Univ Pittsburgh, Med Ctr, Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA 15261 USA. [Casci, Ian] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Parodi, Sara; Grunseich, Christopher] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Lievens, Patricia M. J.] Univ Verona, Sect Biol & Genet, Dept Life & Reprod Sci, I-37134 Verona, Italy. [Polanco, Maria J.; Milioto, Carmelo; Chivet, Mathilde; Pennuto, Maria] Univ Trento, Dulbecco Telethon Inst Lab Neurodegenerat Dis, Ctr Integrat Biol CIBIO, I-38123 Trento, Italy. [Mishra, Ashutosh] St Jude Childrens Res Hosp, St Jude Prote Facil, Memphis, TN 38105 USA. [Badders, Nisha; Taylor, J. Paul] St Jude Childrens Res Hosp, Dept Cell & Mol Biol, Memphis, TN 38105 USA. [Sambataro, Fabio] Ist Italiano Tecnol UniPR, Brain Ctr Motor & Social Cognit, I-43100 Parma, Italy. [Basso, Manuela] Univ Trento, Ctr Integrat Biol CIBIO, Lab Transcript Neurobiol, I-38123 Trento, Italy. [Fackelmayer, Frank O.] Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, Dept Biomed Res, Lab Epigenet & Chromosome Biol, Ioannina 45110, Greece. RP Pennuto, M (reprint author), Ist Italiano Tecnologia, Dept Neurosci & Brain Technol, I-16163 Genoa, Italy. EM maria.pennuto@unitn.it RI Sambataro, Fabio/E-3426-2010; OI Sambataro, Fabio/0000-0003-2102-416X; Pennuto, Maria/0000-0001-8634-0767 FU Telethon-Italy [GGP10037, TCP12013]; Marie-Curie Reintegration Grants [FP7-256448, FP7-276981]; Muscular Dystrophy Association [92333]; National Institutes of Health (NIH) [1R01NS081303-01A1]; ALS Association; Robert Packard Center for ALS at Johns Hopkins; NINDS-NIH; EU Cost Action [TD0905]; Boehringer Ingelheim; Marie Curie International Outgoing Fellowships [PIO-GA-2011-300723] FX We thank Dr. Stephane Richard (McGill University) for scientific discussion and comments and Dr. Ernesto Guccione (Institute of Molecular and Cell Biology, Singapore) for providing us with the lentiviral constructs for shRNA against PRMT6. We thank Drs. Massimo Pizzato and Serena Ziglio for assistance with lentivirus production. This work was supported by Telethon-Italy (GGP10037 and TCP12013 to M.P.), Marie-Curie Reintegration Grants (FP7-256448 to M.P. and FP7-276981 to F.S.), Muscular Dystrophy Association (92333 to M.P.), National Institutes of Health (NIH, 1R01NS081303-01A1 to U.B.P.), the ALS Association and the Robert Packard Center for ALS at Johns Hopkins (to U.B.P.), intramural funds from NINDS-NIH, and EU Cost Action TD0905 "Epigenetics: From Bench to Bedside." C.S. was supported by a Boehringer Ingelheim travel grant, and S.P. by Marie Curie International Outgoing Fellowships (PIO-GA-2011-300723). NR 58 TC 20 Z9 20 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JAN 7 PY 2015 VL 85 IS 1 BP 88 EP 100 DI 10.1016/j.neuron.2014.12.031 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AZ5YS UT WOS:000348295100011 PM 25569348 ER PT J AU Del Valle-Pinero, AY Sherwin, LB Anderson, EM Caudle, RM Henderson, WA AF Del Valle-Pinero, Arseima Y. Sherwin, LeeAnne B. Anderson, Ethan M. Caudle, Robert M. Henderson, Wendy A. TI Altered vasoactive intestinal peptides expression in irritable bowel syndrome patients and rats with trinitrobenzene sulfonic acid-induced colitis SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Irritable bowel syndrome; Vasoactive intestinal peptide; Trinitrobenzene sulfonic acid; Gene expression; PCR arrays ID CYCLASE-ACTIVATING POLYPEPTIDE; NOXIOUS VISCERAL STIMULUS; TNBS-INDUCED COLITIS; ULCERATIVE-COLITIS; COLONIC MOTILITY; HYPERSENSITIVITY; DISEASE; IBS; DISORDERS; PAIN AB AIM: To investigate the vasoactive intestinal peptides (VIP) expression in irritable bowel syndrome (IBS) and trinitrobenzene sulfonic acid (TNBS) induced colitis. METHODS: The VIP gene expression and protein plasma levels were measured in adult participants (45.8% male) who met Rome III criteria for IBS for longer than 6 mo and in a rat model of colitis as induced by TNBS. Plasma and colons were collected from naive and inflamed rats. Markers assessing inflammation (i.e., weight changes and myeloperoxidase levels) were assessed on days 2, 7, 14 and 28 and compared to controls. Visceral hypersensitivity of the rats was assessed with colo-rectal distension and mechanical threshold testing on hind paws. IBS patients (n = 12) were age, gender, race, and BMI-matched with healthy controls (n = 12). Peripheral whole blood and plasma from fasting participants was collected and VIP plasma levels were assayed using a VIP peptide-enzyme immunoassay. Human gene expression of VIP was analyzed using a custom PCR array. RESULTS: TNBS induced colitis in the rats was confirmed with weight loss (13.7 +/- 3.2 g) and increased myeloperoxidase activity. Visceral hypersensitivity to colo-rectal distension was increased in TNBS treated rats up to 21 d and resolved by day 28. Somatic hypersensitivity was also increased up to 14 d post TNBS induction of colitis. The expression of an inflammatory marker myeloperoxidase was significantly elevated in the intracellular granules of neutrophils in rat models following TNBS treatment compared to naive rats. This confirmed the induction of inflammation in rats following TNBS treatment. VIP plasma concentration was significantly increased in rats following TNBS treatment as compared to naive animals (P < 0.05). Likewise, the VIP gene expression from peripheral whole blood was significantly upregulated by 2.91-fold in IBS patients when compared to controls (P < 0.00001; 95%CI). VIP plasma protein was not significantly different when compared with controls (P = 0.193). CONCLUSION: Alterations in VIP expression may play a role in IBS. Therefore, a better understanding of the physiology of VIP could lead to new therapeutics. C1 [Del Valle-Pinero, Arseima Y.; Sherwin, LeeAnne B.; Henderson, Wendy A.] NINR, Digest Disorders Unit, Biobehav Branch, Div Intramural Res,NIH,US Dept HHS, Bethesda, MD 20892 USA. [Del Valle-Pinero, Arseima Y.; Anderson, Ethan M.; Caudle, Robert M.] Univ Florida, Coll Med, Dept Neurosci, Gainesville, FL 32610 USA. [Caudle, Robert M.] Univ Florida, Coll Dent, Dept Oral & Maxillofacial Surg, Gainesville, FL 32610 USA. RP Henderson, WA (reprint author), NINR, Digest Disorders Unit, Biobehav Branch, Div Intramural Res,NIH,US Dept HHS, Bethesda, MD 20892 USA. EM hendersw@mail.nih.gov OI Henderson, Wendy/0000-0003-3924-7118 FU National Institutes of Health [NS045614]; National Institute of Diabetes and Digestive and Kidney Diseases [1F31 DK083165-01A1]; Division of Intramural Research, National Institute of Nursing Research [1ZIANR000018-01-05]; Intramural Training Award FX Supported by National Institutes of Health grant, No. NS045614 and the Ruth L. Kirschstein National Research Service Award, No. 1F31 DK083165-01A1 from the National Institute of Diabetes and Digestive and Kidney Diseases; Division of Intramural Research, National Institute of Nursing Research, No. 1ZIANR000018-01-05 to Henderson WA and Intramural Training Award to Del Valle-Pinero AY and Sherwin LB NR 41 TC 2 Z9 2 U1 1 U2 7 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JAN 7 PY 2015 VL 21 IS 1 BP 155 EP 163 DI 10.3748/wjg.v21.i1.155 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AY3CG UT WOS:000347461500014 PM 25574088 ER PT J AU Kubinak, JL Cornwall, DH Hasenkrug, KJ Adler, FR Potts, WK AF Kubinak, Jason L. Cornwall, Douglas H. Hasenkrug, Kim J. Adler, Frederick R. Potts, Wayne K. TI Serial infection of diverse host (Mus) genotypes rapidly impedes pathogen fitness and virulence SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE virulence evolution; endangered species; livestock; sex-against-virulence; genetic diversity; experimental evolution ID EXPERIMENTAL VIRAL EVOLUTION; FOCUS-FORMING VIRUS; GENETIC DIVERSITY; FRIEND-VIRUS; PARASITE INTERACTIONS; MULTILINE CULTIVARS; LABORATORY MOUSE; DISEASE SPREAD; TRADE-OFFS; RESISTANCE AB Reduced genetic variation among hosts may favour the emergence of virulent infectious diseases by enhancing pathogen replication and its associated virulence due to adaptation to a limited set of host genotypes. Here, we test this hypothesis using experimental evolution of a mouse-specific retroviral pathogen, Friend virus (FV) complex. We demonstrate rapid fitness (i.e. viral titre) and virulence increases when FV complex serially infects a series of inbred mice representing the same genotype, but not when infecting a diverse array of inbred mouse strains modelling the diversity in natural host populations. Additionally, a single infection of a different host genotype was sufficient to constrain the emergence of a high fitness/high virulence FV complex phenotype in these experiments. The potent inhibition of viral fitness and virulence was associated with an observed loss of the defective retroviral genome (spleen focus-forming virus), whose presence exacerbates infection and drives disease in susceptible mice. Results from our experiments provide an important first step in understanding how genetic variation among vertebrate hosts influences pathogen evolution and suggests that serial exposure to different genotypes within a single host species may act as a constraint on pathogen adaptation that prohibits the emergence of more virulent infections. From a practical perspective, these results have implications for low-diversity host populations such as endangered species and domestic animals. C1 [Kubinak, Jason L.] Univ Utah, Sch Med, Div Microbiol & Immunol, Dept Pathol, Salt Lake City, UT 84112 USA. [Cornwall, Douglas H.; Adler, Frederick R.; Potts, Wayne K.] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. [Hasenkrug, Kim J.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Adler, Frederick R.] Univ Utah, Dept Math, Salt Lake City, UT 84112 USA. RP Kubinak, JL (reprint author), Univ Utah, Sch Med, Div Microbiol & Immunol, Dept Pathol, 15 North Med Dr East, Salt Lake City, UT 84112 USA. EM jason.kubinak@path.utah.edu FU National Science Foundation [DEB 0918969]; National Institute of Health [R01-GM109500]; National Science Foundation Doctoral Dissertation Improvement grant [DEB 0910052]; National Institute of Allergic and Infectious Diseases [T32AI055434]; National Science Foundation Educational Outreach grant [DGE 08-41233] FX This work was supported by National Science Foundation Grant (DEB 0918969) and a National Institute of Health grant (R01-GM109500) to W. K. P. and F. R. A. J.L.K. was supported by a National Science Foundation Doctoral Dissertation Improvement grant (DEB 0910052) and a National Institute of Allergic and Infectious Diseases training grant (T32AI055434). J.L.K. was also supported by a National Science Foundation Educational Outreach grant (DGE 08-41233). NR 57 TC 0 Z9 0 U1 1 U2 28 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 EI 1471-2954 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD JAN 7 PY 2015 VL 282 IS 1798 AR 20141568 DI 10.1098/rspb.2014.1568 PG 9 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA AS9YT UT WOS:000344595000003 PM 25392466 ER PT J AU Wilky, BA Rudek, MA Ahmed, S Laheru, DA Cosgrove, D Donehower, RC Nelkin, B Ball, D Doyle, LA Chen, H Ye, X Bigley, G Womack, C Azad, NS AF Wilky, B. A. Rudek, M. A. Ahmed, S. Laheru, D. A. Cosgrove, D. Donehower, R. C. Nelkin, B. Ball, D. Doyle, L. A. Chen, H. Ye, X. Bigley, G. Womack, C. Azad, N. S. TI A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours SO BRITISH JOURNAL OF CANCER LA English DT Article DE IGF-1R; MEK; IGF; BRAF; clinical trial ID KINASE KINASE-1/2 INHIBITOR; MUTANT LUNG-CANCER; HEMATOPOIETIC-CELLS; AZD6244 ARRY-142886; OPEN-LABEL; RECEPTOR; GROWTH; RESISTANCE; PATHWAYS; PHOSPHORYLATION AB Background: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). Methods: Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies. Results: Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg(-1) every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of 46 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment. Conclusions: Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition. C1 [Wilky, B. A.; Rudek, M. A.; Ahmed, S.; Laheru, D. A.; Cosgrove, D.; Donehower, R. C.; Nelkin, B.; Ball, D.; Ye, X.; Azad, N. S.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21231 USA. [Doyle, L. A.; Chen, H.] NCI, Bethesda, MD 20892 USA. [Bigley, G.; Womack, C.] AstraZeneca, Oncol iMed, Macclesfield SK10 4TG, Cheshire, England. RP Azad, NS (reprint author), Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, 1650 Orleans St, Baltimore, MD 21231 USA. EM nazad2@jhmi.edu FU NIH [U01 CA070095]; NCI ACTNOW [P30 CA006973]; AstraZeneca FX This work is supported by NIH grants U01 CA070095, with added support from NCI ACTNOW, P30 CA006973, and AstraZeneca. NR 36 TC 14 Z9 15 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 6 PY 2015 VL 112 IS 1 BP 24 EP 31 DI 10.1038/bjc.2014.515 PG 8 WC Oncology SC Oncology GA AZ5SW UT WOS:000348280900006 PM 25268371 ER PT J AU Hauptmann, M Fossa, SD Stovall, M van Leeuwen, FE Johannesen, TB Rajaraman, P Gilbert, ES Smith, SA Weathers, RE Aleman, BMP Andersson, M Curtis, RE Dores, GM Fraumeni, JF Hall, P Holowaty, EJ Joensuu, H Kaijser, M Kleinerman, RA Langmark, F Lynch, CF Pukkala, E Storm, HH Vaalavirta, L van den Belt-Dusebout, AW Travis, LB Morton, LM AF Hauptmann, M. Fossa, S. D. Stovall, M. van Leeuwen, F. E. Johannesen, T. B. Rajaraman, P. Gilbert, E. S. Smith, S. A. Weathers, R. E. Aleman, B. M. P. Andersson, M. Curtis, R. E. Dores, G. M. Fraumeni, J. F. Hall, P. Holowaty, E. J. Joensuu, H. Kaijser, M. Kleinerman, R. A. Langmark, F. Lynch, C. F. Pukkala, E. Storm, H. H. Vaalavirta, L. van den Belt-Dusebout, A. W. Travis, L. B. Morton, L. M. TI Increased stomach cancer risk following radiotherapy for testicular cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE stomach cancer; testicular cancer; radiotherapy; chemotherapy ID LONG-TERM SURVIVORS; 2ND MALIGNANT NEOPLASMS; HODGKINS-DISEASE; GASTROINTESTINAL CANCER; CARDIOVASCULAR-DISEASE; CHILDHOOD-CANCER; SEMINOMA; CHEMOTHERAPY; MORTALITY; AGE AB Background: Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose-response relationship are sparse. Methods: In a cohort of 22 269 5-year TC survivors diagnosed during 1959-1987, doses to stomach subsites were estimated for 92 patients who developed stomach cancer and 180 matched controls. Chemotherapy details were recorded. Odds ratios (ORs) were estimated using logistic regression. Results: Cumulative incidence of second primary stomach cancer was 1.45% at 30 years after TC diagnosis. The TC survivors who received radiotherapy (87 (95%) cases, 151 (84%) controls) had a 5.9-fold (95% confidence interval (CI) 1.7-20.7) increased risk of stomach cancer. Risk increased with increasing stomach dose (P-trend <0.001), with an OR of 20.5 (3.7-114.3) for >= 50.0 Gy compared with <10 Gy. Radiation-related risks remained elevated >= 20 years after exposure (P<0.001). Risk after any chemotherapy was not elevated (OR = 1.1; 95% CI 0.5-2.5; 14 cases and 23 controls). Conclusions: Radiotherapy for TC involving parts of the stomach increased gastric cancer risk for several decades, with the highest risks after stomach doses of >= 30 Gy. Clinicians should be aware of these excesses when previously irradiated TC survivors present with gastrointestinal symptoms and when any radiotherapy is considered in newly diagnosed TC patients. C1 [Hauptmann, M.; van Leeuwen, F. E.; Aleman, B. M. P.; van den Belt-Dusebout, A. W.] Netherlands Canc Inst, Dept Epidemiol & Biostat, NL-1066 CX Amsterdam, Netherlands. [Fossa, S. D.] Oslo Univ Hosp, Dept Oncol, Oslo, Norway. [Fossa, S. D.] Univ Oslo, Oslo, Norway. [Stovall, M.; Smith, S. A.; Weathers, R. E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Johannesen, T. B.; Langmark, F.] Canc Registry Norway, Oslo, Norway. [Rajaraman, P.; Gilbert, E. S.; Curtis, R. E.; Dores, G. M.; Fraumeni, J. F.; Kleinerman, R. A.; Morton, L. M.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Aleman, B. M. P.] Netherlands Canc Inst, Dept Radiat Oncol, Amsterdam, Netherlands. [Andersson, M.] Copenhagen Univ Hosp, Dept Oncol, Copenhagen, Denmark. [Dores, G. M.] Dept Vet Affairs Med Ctr, Oklahoma City, OK USA. [Hall, P.; Kaijser, M.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Hall, P.] Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden. [Holowaty, E. J.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Joensuu, H.; Vaalavirta, L.] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. [Lynch, C. F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Pukkala, E.] Finnish Canc Registry, Inst Stat & Epidemiol Canc Res, FIN-00170 Helsinki, Finland. [Pukkala, E.] Univ Tampere, Sch Hlth Sci, FIN-33101 Tampere, Finland. [Storm, H. H.] Danish Canc Soc, Copenhagen, Denmark. [Travis, L. B.] Univ Rochester, Med Ctr, Dept Radiat Oncol, Rochester, NY 14642 USA. RP Hauptmann, M (reprint author), Netherlands Canc Inst, Dept Epidemiol & Biostat, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. EM m.hauptmann@nki.nl OI Storm, Hans/0000-0001-7223-8198; Kleinerman, Ruth/0000-0001-7415-2478; Joensuu, Heikki/0000-0003-0281-2507 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services and National Cancer Institute [N01-CP-31157]; Danish Cancer Society, Copenhagen, Denmark [N01-CP-31019]; Finnish Cancer Registry, Helsinki, Finland [N01-CP-31154]; Information Management Services, Inc., Silver Spring, USA [N01-CP-31003]; Karolinska Institute, Stockholm, Sweden [N01-CP-31156]; University of Iowa, Iowa City, USA [N01-CP-31155]; University of Texas MD Anderson Cancer Center, Houston, USA [N02-CP-55503]; Westat, Inc., Rockville, USA [N02-CP-31136]; Lance Armstrong Foundation; Dutch Cancer Society [NKI 04-3068]; National Cancer Institute [1R01 CA 157823-01A1] FX We thank Diane Fuchs, Janet Lawler-Heavner and their staff at Westat, Inc. (Rockville, MD, USA) for administrative assistance in conducting the field studies, and Jeremy Miller (Information Management Services, Silver Spring, MD, USA) for computer programming support. This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services and National Cancer Institute contracts to Cancer Care Ontario, Toronto, Canada (N01-CP-31157); Danish Cancer Society, Copenhagen, Denmark (N01-CP-31019); Finnish Cancer Registry, Helsinki, Finland (N01-CP-31154); Information Management Services, Inc., Silver Spring, USA (N01-CP-31003); Karolinska Institute, Stockholm, Sweden (N01-CP-31156); University of Iowa, Iowa City, USA (N01-CP-31155); The University of Texas MD Anderson Cancer Center, Houston, USA (N02-CP-55503); and Westat, Inc., Rockville, USA (N02-CP-31136). The Dutch study was also supported by the Lance Armstrong Foundation and the Dutch Cancer Society (Grant No. NKI 04-3068). Dr Travis was supported by National Cancer Institute 1R01 CA 157823-01A1. NR 49 TC 10 Z9 10 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 JAN 6 PY 2015 VL 112 IS 1 BP 44 EP 51 DI 10.1038/bjc.2014.552 PG 8 WC Oncology SC Oncology GA AZ5SW UT WOS:000348280900009 PM 25349972 ER PT J AU Agarwal, S Hanna, J Sherman, ME Figueroa, J Rimm, DL AF Agarwal, Seema Hanna, J. Sherman, M. E. Figueroa, J. Rimm, D. L. TI Quantitative assessment of miR34a as an independent prognostic marker in breast cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE miR34a; breast cancer; qISH ID IN-SITU HYBRIDIZATION; TUMOR-SUPPRESSOR; TISSUE MICROARRAYS; PROTEIN EXPRESSION; FIXED TISSUES; MICRORNAS; MIR-34A; CELLS; METASTASIS; INVASION AB Background: Aberrant expression of microRNAs (miRNAs) is associated with cancer progression, initiation and metastasis. MiR34a is a miRNA that has been previously described as a tumour suppressor. Herein, we assess the expression of miR34a in three independent breast cancer cohorts using a quantitative in situ hybridisation assay (qISH) and determined its association with disease-specific death in breast cancer. Methods: The qISH method was applied to three independent primary breast cancer cohorts (Cohort 1 with 461, Cohort 2 with 279 and Cohort 3 with 795 patients) using 50 and 30 double DIG-labelled LNA-modified probe against miR34a using the protocol described previously. Level of expression measured as automated quantitative analysis (AQUA) score for miR34a was determined for each patient and assessed for association with risk of disease-specific death. An optimal cutpoint was determined using the X-tile software for disease-specific survival in Cohort 1 and this cutpoint was then applied to the other two cohorts after median normalisation of AQUA scores. Results: Loss of miR34a is associated with poor outcome in three independent breast cancer cohorts (uncorrected log- rank P = 0.0188 for Cohort 1, log-rank P = 0.0024 for Cohort 2 and log-rank P = 0.0455 for Cohort 3). In all three cohorts, loss of miR34a is able to stratify patients with poor disease-specific survival among node-negative patients, but not in node-positive population. Multivariate Cox proportional hazards analysis in Cohort 1 (P = 0.0381) and Cohort 2 (P = 0.0468) revealed that loss of miR34a is associated with poor outcome, independent of age, node status, receptor status and tumour size. Conclusion: Loss of the tumour suppressor, miR34a, identifies a subgroup of breast cancer patients with poor disease-specific survival. This study is consistent with the well-established preclinical observations for miR34a as a tumour suppressor and suggests that miR34a may have future value as a biomarker in breast cancer. C1 [Agarwal, Seema; Hanna, J.; Rimm, D. L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Sherman, M. E.; Figueroa, J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Agarwal, S (reprint author), Georgetown Univ, Dept Pathol, Med Ctr, Washington, DC 20057 USA. EM sa1137@georgetown.edu; david.rimm@yale.edu OI Hanna, Jason/0000-0001-7253-7964 FU Cure Investigator Initiated Research FX This work was supported in part by a Susan G Komen for the Cure Investigator Initiated Research Grant to DLR. We thank Pei Chao and Michael Stagner from Information Management Services (Silver Spring, MD) for data management support; the participants, physicians, pathologists, nurses and interviewers from participating centres in Poland for their efforts during field work; and Drs Montserrat Garcia-Closas, Louise Brinton, Jolanta Lissowska, B Peplonska for their contributions to the PBCS study design. We also thank Stephen Hewitt for TMA construction. NR 43 TC 4 Z9 5 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 6 PY 2015 VL 112 IS 1 BP 61 EP 68 DI 10.1038/bjc.2014.573 PG 8 WC Oncology SC Oncology GA AZ5SW UT WOS:000348280900011 PM 25474246 ER PT J AU Journy, N Rehel, JL Le Pointe, HD Lee, C Brisse, H Chateil, JF Caer-Lorho, S Laurier, D Bernier, MO AF Journy, N. Rehel, J-L Le Pointe, H. Ducou Lee, C. Brisse, H. Chateil, J-F Caer-Lorho, S. Laurier, D. Bernier, M-O TI Are the studies on cancer risk from CT scans biased by indication? Elements of answer from a large-scale cohort study in France SO BRITISH JOURNAL OF CANCER LA English DT Article DE cancer risk; computed tomography; radiation protection; radiology; paediatrics; indication bias; cohort study ID ATOMIC-BOMB SURVIVORS; RADIATION-EXPOSURE; COMPUTED-TOMOGRAPHY; IONIZING-RADIATION; CHILDHOOD-CANCER; SUBSEQUENT RISK; PEDIATRIC CT; BRAIN-TUMORS; CHILDREN; LEUKEMIA AB Background: Recent epidemiological results suggested an increase of cancer risk after receiving computed tomography (CT) scans in childhood or adolescence. Their interpretation is questioned due to the lack of information about the reasons for examination. Our objective was to estimate the cancer risk related to childhood CT scans, and examine how cancer-predisposing factors (PFs) affect assessment of the radiation-related risk. Methods: The cohort included 67 274 children who had a first scan before the age of 10 years from 2000 to 2010 in 23 French departments. Cumulative X-rays doses were estimated from radiology protocols. Cancer incidence was retrieved through the national registry of childhood cancers; PF from discharge diagnoses. Results: During a mean follow-up of 4 years, 27 cases of tumours of the central nervous system, 25 of leukaemia and 21 of lymphoma were diagnosed; 32% of them among children with PF. Specific patterns of CT exposures were observed according to PFs. Adjustment for PF reduced the excess risk estimates related to cumulative doses from CT scans. No significant excess risk was observed in relation to CT exposures. Conclusions: This study suggests that the indication for examinations, whether suspected cancer or PF management, should be considered to avoid overestimation of the cancer risks associated with CT scans. C1 [Journy, N.; Caer-Lorho, S.; Laurier, D.; Bernier, M-O] Inst Radiol Protect & Nucl Safety, Lab Epidemiol, F-92262 Fontenay Aux Roses, France. [Rehel, J-L] Inst Radiol Protect & Nucl Safety, Med Radiat Protect Expertise Unit, F-92262 Fontenay Aux Roses, France. [Le Pointe, H. Ducou] Trousseau Univ Hosp, Dept Paediat Radiol, F-75012 Paris, France. [Lee, C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Brisse, H.] Inst Curie, Dept Radiol, F-75005 Paris, France. [Chateil, J-F] Pellegrin Univ Hosp, Dept Paediat Radiol, F-33000 Bordeaux, France. RP Bernier, MO (reprint author), Inst Radiol Protect & Nucl Safety, Lab Epidemiol, BP 17, F-92262 Fontenay Aux Roses, France. EM marie-odile.bernier@irsn.fr RI Lee, Choonsik/C-9023-2015 OI BRISSE, Herve J./0000-0003-2794-5875; Lee, Choonsik/0000-0003-4289-9870 FU La Ligue contre le cancer [PRE09/MOB]; French National Cancer Institute (INCa) [2011-1-PL-SHS-01-IRSN-1]; European Union's Seventh Programme [269912-EPI-CT] FX We are grateful to the radiologists, clinicians, physicists and administrators working in the participating hospitals who took so much of their time to provide us with the necessary radiology and clinical data: N Andreu, F Clemenceau, D Loisel, B Ory, D Weil (CHU Angers), J-M Garcier, J Guersen, S Mangin (CHU Clermont-Ferrand), S Baron, J Charbonnier, C Gaborit, D Sirinelli (CHU Tours), J-M Chave, E Chirpaz, O Fels, JF Rouanet (CHU La Reunion), N Boutry, A Bruandet, G Potier (CHU Lille), D Defez, Perrot, M Teisseire (CHU Lyon), B Bourliere, P Petit, C Seyler (CHU Marseille), M Saguintaah (CHU Montpellier), M Balde, F Collignon, M-A Galloy, E Pozza, E Schmitt (CHU Nancy), B Dupas, T Lefrancois, M Salaud, N Surer (CHU Nantes), C Barat, C Bertini, M Hajjar (CHU Bordeaux), N Baray, M-A Perrier, H Daubert, L Froment (CHU Rouen), S Dupont, B Giachetto, L Molinier, J Vial (CHU Toulouse), A Bouette, P Chambert (CHU Armand Trousseau-Paris), F Brunelle (CHU Necker-Enfants-Malades-Paris), E Dion (CHU Louis Mourier-Colombes), J Costa, G Sebag (CHU Robert Debre - Paris), G Khalifa (CHU Saint-Vincent de Paul-Paris), J Betout, E Maupu (APHP Siege), D Musset (CHU Antoine Beclere-Clamart), C Adamsbaum, S Franchi, D Pariente (CHU Bicetre), N Sellier (CHU Jean Verdier-Bondy). We also warmly thank E N'Guyen, N Simon, B Lacour and J Clavel (Registre National des Cancers de l'Enfant) for their valuable help in providing data about cancer diagnoses. The research leading to these results has received funding from La Ligue contre le cancer (PRE09/MOB), the French National Cancer Institute (INCa) (2011-1-PL-SHS-01-IRSN-1), and the European Union's Seventh Programme for research, technological development and demonstration under Grant Agreement No 269912-EPI-CT: epidemiological study to quantify risks for paediatric-computerised tomography and to optimise doses. As the methodology for dose assessment applied for the present study differs to this one defined within the Epi-CT project (http://epi-ct.iarc.fr/), this paper does not necessarily reflect the results that will be obtained in the collaborative project from the use of French exposure data. The use of the personal data for this study was approved by the Commission Nationale Informatique et Libertes, responsible for enforcement of data privacy laws in France (approval ID 908354). NR 35 TC 36 Z9 37 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 6 PY 2015 VL 112 IS 1 BP 185 EP 193 DI 10.1038/bjc.2014.526 PG 9 WC Oncology SC Oncology GA AZ5SW UT WOS:000348280900028 PM 25314057 ER PT J AU Bergeron, JRC Worrall, LJ De, S Sgourakis, NG Cheung, AH Lameignere, E Okon, M Wasney, GA Baker, D McIntosh, LP Strynadka, NCJ AF Bergeron, Julien R. C. Worrall, Liam J. De, Soumya Sgourakis, Nikolaos G. Cheung, Adrienne H. Lameignere, Emilie Okon, Mark Wasney, Gregory A. Baker, David McIntosh, Lawrence P. Strynadka, Natalie C. J. TI The Modular Structure of the Inner-Membrane Ring Component PrgK Facilitates Assembly of the Type III Secretion System Basal Body SO STRUCTURE LA English DT Article ID GRAM-NEGATIVE BACTERIA; NEEDLE COMPLEX; SALMONELLA; LIPOPROTEIN; PROTEINS; DISEASE; EXPORT; HOST AB The type III secretion system (T3SS) is a large macromolecular assembly found at the surface of many pathogenic Gram-negative bacteria. Its role is to inject toxic "effector'' proteins into the cells of infected organisms. The molecular details of the assembly of this large, multimembrane-spanning complex remain poorly understood. Here, we report structural, biochemical, and functional analyses of PrgK, an inner-membrane component of the prototypical Salmonella typhimurium T3SS. We have obtained the atomic structures of the two ring building globular domains and show that the C-terminal transmembrane helix is not essential for assembly and secretion. We also demonstrate that structural rearrangement of the two PrgK globular domains, driven by an interconnecting linker region, may promote oligomerization into ring structures. Finally, we used electron microscopy-guided symmetry modeling to propose a structural model for the intimately associated PrgH-PrgK ring interaction within the assembled basal body. C1 [Bergeron, Julien R. C.; Worrall, Liam J.; De, Soumya; Cheung, Adrienne H.; Lameignere, Emilie; Okon, Mark; Wasney, Gregory A.; McIntosh, Lawrence P.; Strynadka, Natalie C. J.] Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V6T 1Z3, Canada. [Bergeron, Julien R. C.; Worrall, Liam J.; Lameignere, Emilie; Wasney, Gregory A.; Strynadka, Natalie C. J.] Univ British Columbia, Ctr Blood Res, Vancouver, BC V6T 1Z3, Canada. [Sgourakis, Nikolaos G.] NIDDK, NIH, Bethesda, MD 20892 USA. [Baker, David] Univ Washington, Dept Genome Sci, Dept Biochem, Seattle, WA 98195 USA. [Baker, David] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. [McIntosh, Lawrence P.] Univ British Columbia, Dept Chem, Vancouver, BC V6T 1Z3, Canada. RP Strynadka, NCJ (reprint author), Univ British Columbia, Dept Biochem & Mol Biol, 2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada. EM ncjs@mail.ubc.ca RI Baker, David/K-8941-2012 OI Baker, David/0000-0001-7896-6217 FU Natural Sciences and Engineering Research Council of Canada; National Research Council Canada; Canadian Institutes of Health Research; Province of Saskatchewan; Western Economic Diversification Canada; University of Saskatchewan; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH; Canadian Institute of Health Research; HHMI International Scholar Program FX We thank Samuel Miller for providing the S. typhimurium prgK- and fliC/prgK-deletion strains. We are also grateful to Kelvin Lau, Bradford Ross, Gerd Prenha, Matthew Solomonson, and Fred Rosell for technical advice. X-ray diffraction data were collected at beamline 08B1-1 at the Canadian Light Source, which is supported by the Natural Sciences and Engineering Research Council of Canada, the National Research Council Canada, the Canadian Institutes of Health Research, the Province of Saskatchewan, Western Economic Diversification Canada, and the University of Saskatchewan. Instrument support was provided by the Canada Foundation for Innovation, the British Columbia Knowledge Development Fund, the UBC Blusson Fund, and the Michael Smith Foundation for Health Research. N.G.S. acknowledges funding by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. J.R.C.B. is a MSFHR postdoctoral fellow. N.C.J.S. is a Canada Research Chair Tier 1 in Antibiotic Discovery. This work was supported by operating grants from the Canadian Institute of Health Research and HHMI International Scholar Program (to N.C.J.S.). NR 37 TC 11 Z9 11 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JAN 6 PY 2015 VL 23 IS 1 BP 161 EP 172 DI 10.1016/j.str.2014.10.021 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AY3FI UT WOS:000347469500020 PM 25533490 ER PT J AU Sgourakis, NG Yau, WM Qiang, W AF Sgourakis, Nikolaos G. Yau, Wai-Ming Qiang, Wei TI Modeling an In-Register, Parallel "Iowa'' A beta Fibril Structure Using Solid-State NMR Data from Labeled Samples with Rosetta SO STRUCTURE LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; AMYLOID PRECURSOR PROTEIN; ASP23-LYS28 SALT-BRIDGE; STRUCTURE-BASED DESIGN; X-RAY-DIFFRACTION; ALZHEIMERS-DISEASE; EXPERIMENTAL CONSTRAINTS; ELECTRON-MICROSCOPY; CHEMICAL-SHIFTS; CORE STRUCTURE AB Determining the structures of amyloid fibrils is an important first step toward understanding the molecular basis of neurodegenerative diseases. For beta-amyloid (A beta) fibrils, conventional solid-state NMR structure determination using uniform labeling is limited by extensive peak overlap. We describe the characterization of a distinct structural polymorph of Ab using solid-state NMR, transmission electron microscopy (TEM), and Rosetta model building. First, the overall fibril arrangement is established using mass-per-length measurements from TEM. Then, the fibril backbone arrangement, stacking registry, and "steric zipper'' core interactions are determined using a number of solid-state NMR techniques on sparsely C-13-labeled samples. Finally, we perform Rosetta structure calculations with an explicitly symmetric representation of the system. We demonstrate the power of the hybrid Rosetta/NMR approach by modeling the in-register, parallel "Iowa'' mutant (D23N) at high resolution (1.2 angstrom backbone rmsd). The final models are validated using an independent set of NMR experiments that confirm key features. C1 [Sgourakis, Nikolaos G.; Yau, Wai-Ming; Qiang, Wei] NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. [Qiang, Wei] SUNY Binghamton, Dept Chem, Binghamton, NY 13902 USA. RP Qiang, W (reprint author), NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. EM wqiang@binghamton.edu FU National Institute of Diabetes, Digestive, and Kidney Disease; National Institute of Allergy and Infectious Diseases; Intramural AIDS-Targeted Antiviral Program of the Office of the Director; NIH; Research Foundation at the State University of New York; National Science Foundation [NSF 0922815] FX This work is supported by the National Institute of Diabetes, Digestive, and Kidney Disease and the National Institute of Allergy and Infectious Diseases Intramural Research Programs; the Intramural AIDS-Targeted Antiviral Program of the Office of the Director; the NIH; and the Research Foundation at the State University of New York. Part of the solid-state NMR measurements was supported by the National Science Foundation Major Instrumentation Program (NSF 0922815). We greatly appreciate the support from Dr. Robert Tycko and Dr. David Baker on materials, instrumentation and computation time, and helpful discussion. We thank Dr. Frank DiMaio for useful discussions. NR 54 TC 13 Z9 13 U1 3 U2 30 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JAN 6 PY 2015 VL 23 IS 1 BP 216 EP 227 DI 10.1016/j.str.2014.10.022 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AY3FI UT WOS:000347469500026 PM 25543257 ER PT J AU Nishiura, H Chowell, G AF Nishiura, Hiroshi Chowell, Gerardo TI Theoretical perspectives on the infectiousness of Ebola virus disease SO THEORETICAL BIOLOGY AND MEDICAL MODELLING LA English DT Review ID REPRODUCTION NUMBER; WEST-AFRICA; TRANSMISSION; EPIDEMIC; OUTBREAK; MODEL AB Background: Ebola virus disease (EVD) has generated a large epidemic in West Africa since December 2013. This mini-review is aimed to clarify and illustrate different theoretical concepts of infectiousness in order to compare the infectiousness across different communicable diseases including EVD. Methods: We employed a transmission model that rests on the renewal process in order to clarify theoretical concepts on infectiousness, namely the basic reproduction number, R-0, which measures the infectiousness per generation of cases, the force of infection (i.e. the hazard rate of infection), the intrinsic growth rate (i.e. infectiousness per unit time) and the per-contact probability of infection (i.e. infectiousness per effective contact). Results: Whereas R-0 of EVD is similar to that of influenza, the growth rate (i.e. the measure of infectiousness per unit time) for EVD was shown to be comparatively lower than that for influenza. Moreover, EVD and influenza differ in mode of transmission whereby the probability of transmission per contact is lower for EVD compared to that of influenza. Conclusions: The slow spread of EVD associated with the need for physical contact with body fluids supports social distancing measures including contact tracing and case isolation. Descriptions and interpretations of different variables quantifying infectiousness need to be used clearly and objectively in the scientific community and for risk communication. C1 [Nishiura, Hiroshi] Univ Tokyo, Grad Sch Med, Bunkyo Ku, Tokyo 1130033, Japan. [Nishiura, Hiroshi] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama 3320012, Japan. [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo] Fogarty Int Ctr, Div Int Epidemiol & Populat Studies, NIH, Bethesda, MD 20892 USA. [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85282 USA. RP Nishiura, H (reprint author), Univ Tokyo, Grad Sch Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. EM nishiurah@m.u-tokyo.ac.jp OI Nishiura, Hiroshi/0000-0003-0941-8537 FU Japan Science and Technology Agency (JST) CREST program; RISTEX program for Science of Science, Technology and Innovation Policy; St Luke's Life Science Institute Research Grant for Clinical Epidemiology Research; NSF, joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases program [1414374]; UK Biotechnology and Biological Sciences Research Council [BB/M008894/1]; Division of International Epidemiology and Population Studies, The Fogarty International Center, US National Institutes of Health FX HN received funding support from the Japan Science and Technology Agency (JST) CREST program, RISTEX program for Science of Science, Technology and Innovation Policy, and St Luke's Life Science Institute Research Grant for Clinical Epidemiology Research 2014. GC acknowledges financial support from the NSF grant 1414374 as part of the joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases program, UK Biotechnology and Biological Sciences Research Council grant BB/M008894/1, and the Division of International Epidemiology and Population Studies, The Fogarty International Center, US National Institutes of Health. NR 27 TC 1 Z9 1 U1 4 U2 31 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4682 J9 THEOR BIOL MED MODEL JI Theor. Biol. Med. Model. PD JAN 6 PY 2015 VL 12 AR UNSP 1 DI 10.1186/1742-4682-12-1 PG 8 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA CA3QJ UT WOS:000348821100001 PM 25566687 ER PT J AU Gopal, T Nagarajan, V Elasri, MO AF Gopal, Tamilselvi Nagarajan, Vijayaraj Elasri, Mohamed O. TI SATRAT: Staphylococcus aureus transcript regulatory network analysis tool SO PEERJ LA English DT Article DE Transcriptome; RNA sequencing; Staphylococcus aureus transcriptome meta-database (SATMD); RNA-Seq; Staphylococcus aureus microarray meta-database (SAMMD); Staphylococcus aureus; Transcript regulatory network; Infectious disease ID COMMUNITY-ONSET PNEUMONIA AB Staphylococcus aureus is a commensal organism that primarily colonizes the nose of healthy individuals. S. aureus causes a spectrum of infections that range from skin and soft-tissue infections to fatal invasive diseases. S. aureus uses a large number of virulence factors that are regulated in a coordinated fashion. The complex regulatory mechanisms have been investigated in numerous high-throughput experiments. Access to this data is critical to studying this pathogen. Previously, we developed a compilation of microarray experimental data to enable researchers to search, browse, compare, and contrast transcript profiles. We have substantially updated this database and have built a novel exploratory tool-SATRAT-the S. aureus transcript regulatory network analysis tool, based on the updated database. This tool is capable of performing deep searches using a query and generating an interactive regulatory network based on associations among the regulators of any query gene. We believe this integrated regulatory network analysis tool would help researchers explore the missing links and identify novel pathways that regulate virulence in S. aureus. Also, the data model and the network generation code used to build this resource is open sourced, enabling researchers to build similar resources for other bacterial systems. C1 [Gopal, Tamilselvi] Informat LLC, Silver Spring, MD 20910 USA. [Nagarajan, Vijayaraj] NIAID, BCBB, OCICB, NIH, Bethesda, MD 20892 USA. [Elasri, Mohamed O.] Univ So Mississippi, Dept Biol Sci, Hattiesburg, MS 39406 USA. RP Gopal, T (reprint author), Informat LLC, Silver Spring, MD 20910 USA. EM informaticsllcmd@gmail.com FU National Institute of Allergy and Infectious Diseases (NIAID/NIH) [1R15AI099922]; Mississippi INBRE; National Institute of General Medical Sciences [P20GM103476] FX This work was funded by the National Institute of Allergy and Infectious Diseases (NIAID/NIH) grant number 1R15AI099922 (to MOE) and by the Mississippi INBRE, an Institutional Development Award from the National Institute of General Medical Sciences under grant number P20GM103476. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 12 TC 0 Z9 0 U1 1 U2 1 PU PEERJ INC PI LONDON PA 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND SN 2167-8359 J9 PEERJ JI PeerJ PD JAN 6 PY 2015 VL 3 AR UNSP e717 DI 10.7717/peerj.717 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY5SK UT WOS:000347631700001 PM 25653902 ER PT J AU Liu, J AF Liu, Jian TI The Ghost in the Machine: Is the Bacterial Chromosome a Phantom Chain? SO BIOPHYSICAL JOURNAL LA English DT News Item ID ESCHERICHIA-COLI; SEGREGATION C1 NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Liu, J (reprint author), NHLBI, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM liuj7@nhlbi.nih.gov NR 10 TC 1 Z9 1 U1 2 U2 5 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 JAN 6 PY 2015 VL 108 IS 1 BP 20 EP 21 DI 10.1016/j.bpj.2014.11.3451 PG 2 WC Biophysics SC Biophysics GA AY3FC UT WOS:000347468900006 PM 25564847 ER PT J AU Khrenova, M Topol, I Collins, J Nemukhin, A AF Khrenova, Maria Topol, Igor Collins, Jack Nemukhin, Alexander TI Estimating Orientation Factors in the FRET Theory of Fluorescent Proteins: The TagRFP-KFP Pair and Beyond SO BIOPHYSICAL JOURNAL LA English DT Article ID TRANSITION DIPOLE-MOMENT; ENERGY-TRANSFER; ABSORPTION; LIFETIME; SPECTRA; SYSTEM; GFP AB The orientation factor kappa(2), one of the key parameters defining Forster resonance energy transfer efficiency, is determined by the transition dipole moment orientations of the donor and acceptor species. Using the results of quantum chemical and quantum mechanical/molecular mechanical calculations for the chromophore-containing pockets in selected colored proteins of the green fluorescent protein family, we derived transition dipole moments corresponding to the S-0,S-min -> S-1 excitation for green fluorescent protein, red fluorescent protein (TagRFP), and kindling fluorescent protein, and the S-1,S-min -> S-0 emission for TagRFP. These data allowed us to estimate kappa(2) values for the TagRFP-linker-kindling fluorescent protein tetrameric complex required for constructing novel sensors. C1 [Khrenova, Maria; Nemukhin, Alexander] Moscow MV Lomonosov State Univ, Dept Chem, Moscow, Russia. [Topol, Igor; Collins, Jack] Leidos Biomed Res Inc, Adv Biomed Comp Ctr, Frederick Natl Lab Canc Res, Informat Syst Program, Frederick, MD 21702 USA. [Nemukhin, Alexander] Emanuel Inst Biochem Phys, Moscow, Russia. RP Topol, I (reprint author), Leidos Biomed Res Inc, Adv Biomed Comp Ctr, Frederick Natl Lab Canc Res, Informat Syst Program, Frederick, MD 21702 USA. EM igor.topol@fnlcr.nih.gov RI Khrenova, Maria/I-4829-2014; Nemukhin, Alexander/P-9662-2015; OI Khrenova, Maria/0000-0001-7117-3089 FU Program on Molecular and Cell Biology from the Russian Academy of Sciences; Russian Foundation for Basic Research [13-03-00207]; Dynasty Foundation fellowship; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Program on Molecular and Cell Biology from the Russian Academy of Sciences and by the Russian Foundation for Basic Research (project 13-03-00207). M.K. acknowledges support from the Dynasty Foundation fellowship. We acknowledge the use of supercomputer resources of the M.V. Lomonosov Moscow State University and of the Joint Supercomputer Center of the Russian Academy of Sciences. We thank the staff and administration of the Advanced Biomedical Computing Center for their support of this project. 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 organization imply endorsement by the U.S. government. NR 38 TC 2 Z9 3 U1 2 U2 18 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 JAN 6 PY 2015 VL 108 IS 1 BP 126 EP 132 DI 10.1016/j.bpj.2014.11.1859 PG 7 WC Biophysics SC Biophysics GA AY3FC UT WOS:000347468900018 PM 25564859 ER PT J AU Greathouse, KL Harris, CC Bultman, SJ AF Greathouse, K. Leigh Harris, Curtis C. Bultman, Scott J. TI Dysfunctional Families: Clostridium scindens and Secondary Bile Acids Inhibit the Growth of Clostridium difficile SO CELL METABOLISM LA English DT Editorial Material C1 [Greathouse, K. Leigh; Harris, Curtis C.] NCI, Lab Human Carcinogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bultman, Scott J.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27516 USA. RP Bultman, SJ (reprint author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27516 USA. EM scott_bultman@med.unc.edu NR 10 TC 1 Z9 1 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD JAN 6 PY 2015 VL 21 IS 1 BP 9 EP 10 DI 10.1016/j.cmet.2014.12.016 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA AY3ER UT WOS:000347467900003 PM 25565200 ER PT J AU Palsson-McDermott, EM Curtis, AM Goel, G Lauterbach, MAR Sheedy, FJ Gleeson, LE van den Bosch, MWM Quinn, SR Domingo-Fernandez, R Johnson, DGW Jiang, JK Israelsen, WJ Keane, J Thomas, C Clish, C Vanden Heiden, M Xavier, RJ O'Neill, LAJ AF Palsson-McDermott, Eva M. Curtis, Anne M. Goel, Gautam Lauterbach, Mario A. R. Sheedy, Frederick J. Gleeson, Laura E. van den Bosch, Mirjam W. M. Quinn, Susan R. Domingo-Fernandez, Raquel Johnson, Daniel G. W. Jiang, Jain-kang Israelsen, William J. Keane, Joseph Thomas, Craig Clish, Clary Vanden Heiden, Matthew Xavier, Ramnik J. O'Neill, Luke A. J. TI Pyruvate Kinase M2 Regulates Hif-1 alpha Activity and IL-1 beta Induction and Is a Critical Determinant of the Warburg Effect in LPS-Activated Macrophages SO CELL METABOLISM LA English DT Article ID TUMOR-GROWTH; MYCOBACTERIUM-TUBERCULOSIS; NUCLEAR TRANSLOCATION; CANCER METABOLISM; PKM2; ISOFORM; PROMOTES; GLUCOSE; GENE; FRUCTOSE-1,6-BISPHOSPHATE AB Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1 alpha and IL-1 beta, as well as the expression of a range of other Hif-1 alpha-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1 alpha, which can directly bind to the IL-1b promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1 beta production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response. C1 [Palsson-McDermott, Eva M.; Curtis, Anne M.; Lauterbach, Mario A. R.; van den Bosch, Mirjam W. M.; Quinn, Susan R.; Domingo-Fernandez, Raquel; Johnson, Daniel G. W.; O'Neill, Luke A. J.] Univ Dublin Trinity Coll, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin 2, Ireland. [Goel, Gautam; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Goel, Gautam; Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Goel, Gautam; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Goel, Gautam; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Goel, Gautam; Clish, Clary; Xavier, Ramnik J.] Broad Inst Harvard Univ & Massachusetts Inst Tec, Cambridge, MA 02142 USA. [Sheedy, Frederick J.; Gleeson, Laura E.; Keane, Joseph] Univ Dublin Trinity Coll, Dept Clin Med, Sch Med, Dublin 2, Ireland. [Israelsen, William J.; Vanden Heiden, Matthew] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Jiang, Jain-kang; Thomas, Craig] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Vanden Heiden, Matthew] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. RP O'Neill, LAJ (reprint author), Univ Dublin Trinity Coll, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin 2, Ireland. EM laoneill@tcd.ie OI Keane, Joseph/0000-0001-5313-385X FU Science Foundation Ireland; European Research Council; Health Research Board; European Community [HEALTH-14-2011-281608]; Wellcome Trust; Baggot St Hospital Trust; National Institutes of Health FX We thank Science Foundation Ireland, the European Research Council, the Health Research Board, European Community Seventh Framework Programme (FP7-2007-2013) under grant agreement No. HEALTH-14-2011-281608 'TIMER', Wellcome Trust, Baggot St Hospital Trust, and National Institutes of Health for funding. NR 36 TC 70 Z9 71 U1 12 U2 40 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD JAN 6 PY 2015 VL 21 IS 1 BP 65 EP 80 DI 10.1016/j.cmet.2014.12.005 PG 16 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA AY3ER UT WOS:000347467900011 PM 25565206 ER PT J AU Sorlie, PD Sholinsky, PD Lauer, MS AF Sorlie, Paul D. Sholinsky, Phyliss D. Lauer, Michael S. TI Reinvestment in Government-Funded Research A Great Way to Share SO CIRCULATION LA English DT Editorial Material ID BIOMEDICAL-RESEARCH C1 [Sorlie, Paul D.; Sholinsky, Phyliss D.; Lauer, Michael S.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov NR 11 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JAN 6 PY 2015 VL 131 IS 1 BP 17 EP 18 DI 10.1161/CIRCULATIONAHA.114.014204 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AY0PW UT WOS:000347299900012 PM 25411156 ER PT J AU Pfeffer, MA Claggett, B Assmann, SF Boineau, R Anand, IS Clausell, N Desai, AS Diaz, R Fleg, JL Gordeev, I Heitner, JF Lewis, EF O'Meara, E Rouleau, JL Probstfield, JL Shaburishvili, T Shah, SJ Solomon, SD Sweitzer, NK McKinlay, SM Pitt, B AF Pfeffer, Marc A. Claggett, Brian Assmann, Susan F. Boineau, Robin Anand, Inder S. Clausell, Nadine Desai, Akshay S. Diaz, Rafael Fleg, Jerome L. Gordeev, Ivan Heitner, John F. Lewis, Eldrin F. O'Meara, Eileen Rouleau, Jean-Lucien Probstfield, Jeffrey L. Shaburishvili, Tamaz Shah, Sanjiv J. Solomon, Scott D. Sweitzer, Nancy K. McKinlay, Sonja M. Pitt, Bertram TI Regional Variation in Patients and Outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) Trial SO CIRCULATION LA English DT Article DE heart failure; randomized controlled trials; spironolactone ID ACUTE MYOCARDIAL-INFARCTION; VENTRICULAR EJECTION FRACTION; CLINICAL-TRIALS; SUBGROUP ANALYSES; INTERNATIONAL DIFFERENCES; SUBSEQUENT MORTALITY; TASK-FORCE; HOSPITALIZATION; HYPERKALEMIA; PREVALENCE AB Background-Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) patients with heart failure and preserved left ventricular ejection fraction assigned to spironolactone did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for management of heart failure) compared with patients receiving placebo. In a post hoc analysis, an approximate to 4-fold difference was identified in this composite event rate between the 1678 patients randomized from Russia and Georgia compared with the 1767 enrolled from the United States, Canada, Brazil, and Argentina (the Americas). Methods and Results-To better understand this regional difference in clinical outcomes, demographic characteristics of these populations and their responses to spironolactone were explored. Patients from Russia/Georgia were younger, had less atrial fibrillation and diabetes mellitus, but were more likely to have had prior myocardial infarction or a hospitalization for heart failure. Russia/Georgia patients also had lower left ventricular ejection fraction and creatinine but higher diastolic blood pressure (all P<0.001). Hyperkalemia and doubling of creatinine were more likely and hypokalemia was less likely in patients receiving spironolactone in the Americas with no significant treatment effects in Russia/Georgia. All clinical event rates were markedly lower in Russia/Georgia, and there was no detectable impact of spironolactone on any outcomes. In contrast, in the Americas, the rates of the primary outcome, cardiovascular death, and hospitalization for heart failure were significantly reduced by spironolactone. Conclusions-This post hoc analysis demonstrated greater potassium and creatinine changes and possible clinical benefits with spironolactone in patients with heart failure and preserved ejection fraction from the Americas. C1 [Pfeffer, Marc A.; Claggett, Brian; Desai, Akshay S.; Lewis, Eldrin F.; Solomon, Scott D.] Brigham & Womens Hosp, Cardiovasc Div, Boston, MA 02115 USA. [Assmann, Susan F.; McKinlay, Sonja M.] New England Res Inst Inc, Watertown, MA USA. [Boineau, Robin; Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Anand, Inder S.] VA Med Ctr, Minneapolis, MN USA. [Anand, Inder S.] Univ Minnesota, Minneapolis, MN USA. [Clausell, Nadine] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Diaz, Rafael] Estudios Clin Latinoamer, Rosario, Santa Fe, Argentina. [Gordeev, Ivan] Pirogov Russian Natl Res Med Univ, Moscow, Russia. [Heitner, John F.] New York Methodist Hosp, Brooklyn, NY USA. [O'Meara, Eileen; Rouleau, Jean-Lucien] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Probstfield, Jeffrey L.] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [Shaburishvili, Tamaz] Diagnost Serv Clin, Tbilisi, Rep of Georgia. [Shah, Sanjiv J.] Northwestern Univ, Chicago, IL 60611 USA. [Sweitzer, Nancy K.] Univ Wisconsin, Madison, WI 53706 USA. [Pitt, Bertram] Univ Michigan, Sch Med, Ann Arbor, MI USA. RP Pfeffer, MA (reprint author), Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA. EM mpfeffer@rics.bwh.harvard.edu RI Clausell, Nadine /C-7813-2016 OI Clausell, Nadine /0000-0003-4207-3809 FU National Heart, Lung, and Blood Institute, National Institutes of Health [HHSN268200425207C] FX This work was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, contract HHSN268200425207C. The content of this article does not necessarily represent the views of the National Heart, Lung, and Blood Institute or of the Department of Health and Human Services. NR 48 TC 82 Z9 82 U1 3 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JAN 6 PY 2015 VL 131 IS 1 BP 34 EP + DI 10.1161/CIRCULATIONAHA.114.013255 PG 23 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AY0PW UT WOS:000347299900015 PM 25406305 ER PT J AU Greco, G Shi, W Michler, RE Meltzer, DO Ailawadi, G Hohmann, SF Thourani, VH Argenziano, M Alexander, JH Sankovic, K Gupta, L Blackstone, EH Acker, MA Russo, MJ Lee, A Burks, SG Gelijns, AC Bagiella, E Moskowitz, AJ Gardner, TJ AF Greco, Giampaolo Shi, Wei Michler, Robert E. Meltzer, David O. Ailawadi, Gorav Hohmann, Samuel F. Thourani, Vinod H. Argenziano, Michael Alexander, John H. Sankovic, Kathy Gupta, Lopa Blackstone, Eugene H. Acker, Michael A. Russo, Mark J. Lee, Albert Burks, Sandra G. Gelijns, Annetine C. Bagiella, Emilia Moskowitz, Alan J. Gardner, Timothy J. TI Costs Associated With Health Care-Associated Infections in Cardiac Surgery SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE health care-associated infection; hospital costs; length of stay ID SURGICAL-SITE INFECTIONS; VENTILATOR-ASSOCIATED PNEUMONIA; BLOOD-STREAM INFECTIONS; BYPASS GRAFT-SURGERY; LENGTH-OF-STAY; QUALITY IMPROVEMENT; ACQUIRED INFECTION; IMPACT; COMPLICATIONS; READMISSION AB BACKGROUND Health care-associated infections (HAIs) are the most common noncardiac complications after cardiac surgery and are associated with increased morbidity and mortality. Current information about their economic burden is limited. OBJECTIVES This research was designed to determine the cost associated with major types of HAIs during the first 2 months after cardiac surgery. METHODS Prospectively collected data from a multicenter, observational study of the Cardiothoracic Surgery Clinical Trials Network, in which patients were monitored for infections for 65 days after surgery, were merged with related financial data routinely collected by the University HealthSystem Consortium. Incremental length of stay (LOS) and cost associated with HAIs were estimated using generalized linear models, with adjustments for patient demographics, clinical history, baseline laboratory values, and surgery type. RESULTS Among 4,320 cardiac surgery patients (mean age: 64 +/- 13 years), 119 (2.8%) experienced a major HAI during the index hospitalization. The most common HAIs were pneumonia (48%), sepsis (20%), and Clostridium difficile colitis (18%). On average, the estimated incremental cost associated with a major HAI was nearly $38,000, of which 47% was related to intensive care unit services. The incremental LOS was 14 days. Overall, there were 849 readmissions; among these, 8.7% were attributed to major HAIs. The cost of readmissions due to major HAIs was, on average, nearly threefold that of readmissions not related to HAIs. CONCLUSIONS Hospital cost, LOS, and readmissions are strongly associated with HAIs. These associations suggest the potential for large reductions in costs if HAIs following cardiac surgery can be reduced. (Management Practices and the Risk of Infections Following Cardiac Surgery; NCT01089712) (C) 2015 by the American College of Cardiology Foundation. C1 [Greco, Giampaolo; Shi, Wei; Gelijns, Annetine C.; Bagiella, Emilia; Moskowitz, Alan J.] Icahn Sch Med Mt Sinai, Icahn Sch Med, Dept Populat Sci & Policy, InCHOIR, New York, NY 10029 USA. [Michler, Robert E.] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Cardiothorac Surg, New York, NY USA. [Meltzer, David O.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Ailawadi, Gorav] Univ Virginia, Sch Med, Div Thorac & Cardiovasc Surg, Charlottesville, VA 22908 USA. [Hohmann, Samuel F.] Univ HealthSyst Consortium, Chicago, IL USA. [Thourani, Vinod H.] Emory Univ, Sch Med, Div Cardiothorac Surg, Clin Res Unit, Atlanta, GA 30322 USA. [Argenziano, Michael] Columbia Univ, Coll Phys & Surg, Dept Surg, Div Cardiothorac Surg, New York, NY USA. [Alexander, John H.] Duke Univ, Med Ctr, Dept Surg, Div Cardiovasc & Thorac Surg, Durham, NC 27710 USA. [Sankovic, Kathy] Cleveland Clin Fdn, Dept Thorac & Cardiovasc Surg, Cleveland, OH 44195 USA. [Acker, Michael A.] Univ Penn, Sch Med, Div Cardiovasc Surg, Dept Surg, Philadelphia, PA 19104 USA. [Russo, Mark J.] Barnabas Heart Hosp, Newark, NJ USA. [Lee, Albert] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Gardner, Timothy J.] Christiana Care Hlth Syst, Ctr Heart & Vasc Hlth, Newark, DE USA. RP Greco, G (reprint author), Icahn Sch Med Mt Sinai, One Gustave L Levy Pl,Box 1077, New York, NY 10029 USA. EM giampaolo.greco@mountsinai.org RI Meltzer, David/C-2926-2009; OI Meltzer, David/0000-0003-2790-7393; Moskowitz, Alan/0000-0002-4412-9450 FU Canadian Institutes of Health Research; NCATS NIH HHS [UL1 TR000430]; NHLBI NIH HHS [7U01 HL088942, U01 HL088942] NR 47 TC 12 Z9 12 U1 2 U2 7 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 JAN 6 PY 2015 VL 65 IS 1 BP 15 EP 23 DI 10.1016/j.jacc.2014.09.079 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AY2GI UT WOS:000347406400003 PM 25572505 ER PT J AU Mock, JY Chartron, JW Zaslaver, M Xu, Y Ye, YH Clemons, WM AF Mock, Jee-Young Chartron, Justin William Zaslaver, Ma'ayan Xu, Yue Ye, Yihong Clemons, William Melvon, Jr. TI Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE GET pathway; Scythe; Bat3; X-ray crystallography; tail-anchored proteins ID UBIQUITIN-LIKE DOMAIN; RETICULUM-ASSOCIATED DEGRADATION; MEMBRANE-PROTEIN INSERTION; ENDOPLASMIC-RETICULUM; INDUCED APOPTOSIS; CHAPERONE ACTIVITY; GET4/GET5 COMPLEX; CRYSTAL-STRUCTURE; MAMMALIAN-CELLS; BCL-2 FAMILY AB BCL2-associated athanogene cochaperone 6 (Bag6) plays a central role in cellular homeostasis in a diverse array of processes and is part of the heterotrimeric Bag6 complex, which also includes ubiquitin-like 4A (Ubl4A) and transmembrane domain recognition complex 35 (TRC35). This complex recently has been shown to be important in the TRC pathway, the mislocalized protein degradation pathway, and the endoplasmic reticulum-associated degradation pathway. Here we define the architecture of the Bag6 complex, demonstrating that both TRC35 and Ubl4A have distinct C-terminal binding sites on Bag6 defining a minimal Bag6 complex. A crystal structure of the Bag6-Ubl4A dimer demonstrates that Bag6-BAG is not a canonical BAG domain, and this finding is substantiated biochemically. Remarkably, the minimal Bag6 complex defined here facilitates tail-anchored substrate transfer from small glutamine-rich tetratricopeptide repeat-containing protein a to TRC40. These findings provide structural insight into the complex network of proteins coordinated by Bag6. C1 [Mock, Jee-Young; Chartron, Justin William; Zaslaver, Ma'ayan; Clemons, William Melvon, Jr.] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA. [Xu, Yue; Ye, Yihong] Natl Inst Diabet & Digest & Kidney Dis, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Clemons, WM (reprint author), CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA. EM clemons@caltech.edu RI Xu, Yue/F-8188-2015; OI Mock, Jee-Young/0000-0002-4656-3357; Clemons, William/0000-0002-0021-889X FU National Institutes of Health [R01GM097572] FX We thank Daniel Lin and Jens Kaiser for help with data processing; Yoko Shibata and Richard Morimoto (Northwestern University) for plasmids; Michael Rome and Meera Rao for critical reading of the manuscript; members of the W.M.C. laboratory for support and useful discussions; the staff at the Advanced Light Source for assistance with synchrotron data collection; and Gordon and Betty Moore for support of the Molecular Observatory at California Institute of Technology. W.M.C. is supported by National Institutes of Health Grant R01GM097572. NR 54 TC 12 Z9 12 U1 0 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 6 PY 2015 VL 112 IS 1 BP 106 EP 111 DI 10.1073/pnas.1402745112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY2WN UT WOS:000347447100037 PM 25535373 ER PT J AU Tian, HY Zhou, S Dong, L Van Boeckel, TP Cui, YJ Wu, YR Cazelles, B Huang, SQ Yang, RF Grenfell, BT Xu, B AF Tian, Huaiyu Zhou, Sen Dong, Lu Van Boeckel, Thomas P. Cui, Yujun Wu, Yarong Cazelles, Bernard Huang, Shanqian Yang, Ruifu Grenfell, Bryan T. Xu, Bing TI Avian influenza H5N1 viral and bird migration networks in Asia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bird migration; HPAI H5N1; viral migration; network; satellite tracking ID WILD BIRDS; A VIRUS; SPREAD; EVOLUTION; DYNAMICS; IDENTIFICATION; SURVEILLANCE; WATERFOWL; DISTANCE; AFRICA AB The spatial spread of the highly pathogenic avian influenza virus H5N1 and its long-term persistence in Asia have resulted in avian influenza panzootics and enormous economic losses in the poultry sector. However, an understanding of the regional long-distance transmission and seasonal patterns of the virus is still lacking. In this study, we present a phylogeographic approach to reconstruct the viral migration network. We show that within each wild fowl migratory flyway, the timing of H5N1 outbreaks and viral migrations are closely associated, but little viral transmission was observed between the flyways. The bird migration network is shown to better reflect the observed viral gene sequence data than other networks and contributes to seasonal H5N1 epidemics in local regions and its large-scale transmission along flyways. These findings have potentially far-reaching consequences, improving our understanding of how bird migration drives the periodic reemergence of H5N1 in Asia. C1 [Tian, Huaiyu; Huang, Shanqian; Xu, Bing] Beijing Normal Univ, Coll Global Change & Earth Syst Sci, State Key Lab Remote Sensing Sci, Beijing 100875, Peoples R China. [Zhou, Sen; Xu, Bing] Tsinghua Univ, Ctr Earth Syst Sci, Key Lab Earth Syst Modelling, Minist Educ, Beijing 100084, Peoples R China. [Zhou, Sen; Xu, Bing] Tsinghua Univ, Sch Environm, Beijing 100084, Peoples R China. [Dong, Lu] Beijing Normal Univ, Coll Life Sci, Key Lab Biodivers & Ecol Engn, Minist Educ, Beijing 100875, Peoples R China. [Van Boeckel, Thomas P.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Cui, Yujun; Wu, Yarong; Yang, Ruifu] Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Beijing 100071, Peoples R China. [Cazelles, Bernard] Univ Paris 06, CNRS, UMR 7625, F-75230 Paris 05, France. [Cazelles, Bernard] Ecole Normale Super, F-75230 Paris 05, France. [Cazelles, Bernard] Inst Rech Dev, Unite Modelisat Mathemat & Informat Syst Complexe, Unite Mixte Int 209, F-93142 Bondy, France. [Cazelles, Bernard] Univ Paris 06, F-93142 Bondy, France. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Xu, Bing] Univ Utah, Dept Geog, Salt Lake City, UT 84112 USA. RP Grenfell, BT (reprint author), Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. EM grenfell@princeton.edu; bingxu@tsinghua.edu.cn RI Xu, Bing/C-5769-2015; Xu, Bing/C-7732-2015; Cazelles, Bernard/B-1572-2013; Tian, Huaiyu/G-1934-2016 OI Cazelles, Bernard/0000-0002-7972-361X; FU Ministry of Science and Technology, China, National Research Program [2010CB530300, 2012CB955501, 2012AA12A407]; National Natural Science Foundation of China [41271099]; Science and Technology Directorate, US Department of Homeland Security [HSHQDC-12-C-00058]; Bill and Melinda Gates Foundation; Fogarty International Center, National Institutes of Health FX We thank the US Geological Survey, Western Ecological Research Center, Patuxent Wildlife Research Center, and Avian Influenza Program. This research was supported by the Ministry of Science and Technology, China, National Research Program (2010CB530300, 2012CB955501, and 2012AA12A407), and the National Natural Science Foundation of China (41271099). B.T.G. was supported by the Science and Technology Directorate, US Department of Homeland Security (Contract HSHQDC-12-C-00058 and the Research and Policy for Infectious Disease Dynamics program), the Bill and Melinda Gates Foundation, and the Fogarty International Center, National Institutes of Health. NR 53 TC 29 Z9 32 U1 6 U2 76 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 6 PY 2015 VL 112 IS 1 BP 172 EP 177 DI 10.1073/pnas.1405216112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY2WN UT WOS:000347447100048 PM 25535385 ER PT J AU Wang, Y Lang, LX Huang, P Wang, Z Jacobson, O Kiesewetter, DO Ali, IU Teng, GJ Niu, G Chen, XY AF Wang, Yu Lang, Lixin Huang, Peng Wang, Zhe Jacobson, Orit Kiesewetter, Dale O. Ali, Iqbal U. Teng, Gaojun Niu, Gang Chen, Xiaoyuan TI In vivo albumin labeling and lymphatic imaging SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE PET; lymph node; optical imaging; albumin; Evans blue ID BREAST-CANCER PATIENTS; SENTINEL-NODE BIOPSY; BLUE-DYE; MOLECULAR-MECHANISMS; SERUM-ALBUMIN; SURGERY; PET; DIFFERENTIATION; METASTASIS; NAVIGATION AB The ability to accurately and easily locate sentinel lymph nodes (LNs) with noninvasive imaging methods would assist in tumor staging and patient management. For this purpose, we developed a lymphatic imaging agent by mixing fluorine-18 aluminum fluoride-labeled NOTA (1,4,7-triazacyclononane-N, N',N''-triaceticacid)-conjugated truncated Evans blue (F-18-AlF-NEB) and Evans blue (EB) dye. After local injection, both 18F-AlF-NEB and EB form complexes with endogenous albumin in the interstitial fluid and allow for visualizing the lymphatic system. Positron emission tomography (PET) and/or optical imaging of LNs was performed in three different animal models including a hind limb inflammation model, an orthotropic breast cancer model, and a metastatic breast cancer model. In all three models, the LNs can be distinguished clearly by the apparent blue color and strong fluorescence signal from EB as well as a high-intensity PET signal from F-18-AlF-NEB. The lymphatic vessels between the LNs can also be optically visualized. The easy preparation, excellent PET and optical imaging quality, and biosafety suggest that this combination of F-18-AlF-NEB and EB has great potential for clinical application to map sentinel LNs and provide intraoperative guidance. C1 [Wang, Yu; Teng, Gaojun] Southeast Univ, Sch Med, Zhongda Hosp, Dept Radiol,Jiangsu Key Lab Mol Imaging & Funct I, Nanjing 210009, Jiangsu, Peoples R China. [Wang, Yu; Lang, Lixin; Huang, Peng; Wang, Zhe; Jacobson, Orit; Kiesewetter, Dale O.; Ali, Iqbal U.; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM gjteng@vip.sina.com; niug@mail.nih.gov; shawn.chen@nih.gov RI Huang, Peng/H-9985-2013; Ali, Imran/F-7710-2010; Huang, Peng/R-2480-2016 OI Ali, Imran/0000-0001-6511-8374; Huang, Peng/0000-0003-3651-7813 FU Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, NIH FX This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, NIH. NR 36 TC 10 Z9 10 U1 10 U2 36 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 6 PY 2015 VL 112 IS 1 BP 208 EP 213 DI 10.1073/pnas.1414821112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY2WN UT WOS:000347447100054 PM 25535368 ER PT J AU Bowles, NP Karatsoreos, IN Li, XS Vemuri, VK Wood, JA Li, ZY Tamashiro, KLK Schwartz, GJ Makriyannis, AM Kunos, G Hillard, CJ McEwen, BS Hill, MN AF Bowles, Nicole P. Karatsoreos, Ilia N. Li, Xiaosong Vemuri, V. Kiran Wood, Jodi-Anne Li, Zhiying Tamashiro, Kellie L. K. Schwartz, Gary J. Makriyannis, Alexandros M. Kunos, George Hillard, Cecilia J. McEwen, Bruce S. Hill, Matthew N. TI A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE corticosterone; 2-AG; anandamide; obesity; liver ID DIET-INDUCED OBESITY; INDUCED INSULIN-RESISTANCE; STRESS-INDUCED OBESITY; ADIPOSE-TISSUE; FOOD-INTAKE; CARDIOMETABOLIC RISK; ENERGY-BALANCE; CB1 RECEPTOR; LEPTIN; MICE AB Glucocorticoids are known to promote the development of metabolic syndrome through the modulation of both feeding pathways and metabolic processes; however, the precise mechanisms of these effects are not well-understood. Recent evidence shows that glucocorticoids possess the ability to increase endocannabinoid signaling, which is known to regulate appetite, energy balance, and metabolic processes through both central and peripheral pathways. The aim of this study was to determine the role of endocannabinoid signaling in glucocorticoid-mediated obesity and metabolic syndrome. Using a mouse model of excess corticosterone exposure, we found that the ability of glucocorticoids to increase adiposity, weight gain, hormonal dysregulation, hepatic steatosis, and dyslipidemia was reduced or reversed in mice lacking the cannabinoid CB1 receptor as well as mice treated with the global CB1 receptor antagonist AM251. Similarly, a neutral, peripherally restricted CB1 receptor antagonist (AM6545) was able to attenuate the metabolic phenotype caused by chronic corticosterone, suggesting a peripheral mechanism for these effects. Biochemical analyses showed that chronic excess glucocorticoid exposure produced a significant increase in hepatic and circulating levels of the endocannabinoid anandamide, whereas no effect was observed in the hypothalamus. To test the role of the liver, specific and exclusive deletion of hepatic CB1 receptor resulted in a rescue of the dyslipidemic effects of glucocorticoid exposure, while not affecting the obesity phenotype or the elevations in insulin and leptin. Together, these data indicate that glucocorticoids recruit peripheral endocannabinoid signaling to promote metabolic dysregulation, with hepatic endocannabinoid signaling being especially important for changes in lipid metabolism. C1 [Bowles, Nicole P.; Karatsoreos, Ilia N.; McEwen, Bruce S.; Hill, Matthew N.] Rockefeller Univ, Neuroendocrinol Lab, New York, NY 10065 USA. [Li, Zhiying] Rockefeller Univ, Mol Genet Lab, New York, NY 10065 USA. [Karatsoreos, Ilia N.] Washington State Univ, Dept Integrat Physiol & Neurosci, Pullman, WA 99164 USA. [Li, Xiaosong; Schwartz, Gary J.] Yeshiva Univ Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. [Li, Xiaosong; Schwartz, Gary J.] Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA. [Vemuri, V. Kiran; Wood, Jodi-Anne; Makriyannis, Alexandros M.] Northeastern Univ, Dept Pharmaceut Sci, Ctr Drug Discovery, Boston, MA 02115 USA. [Vemuri, V. Kiran; Wood, Jodi-Anne; Makriyannis, Alexandros M.] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Tamashiro, Kellie L. K.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Kunos, George] NIAAA, NIH, Bethesda, MD 20892 USA. [Hillard, Cecilia J.] Med Coll Wisconsin, Dept Pharmacol & Toxicol, Milwaukee, WI 53226 USA. [Hillard, Cecilia J.] Med Coll Wisconsin, Neurosci Res Ctr, Milwaukee, WI 53226 USA. [Hill, Matthew N.] Univ Calgary, Hotchkiss Brain Inst, Dept Cell Biol & Anat, Calgary, AB T2N 4N1, Canada. [Hill, Matthew N.] Univ Calgary, Hotchkiss Brain Inst, Dept Psychiat, Calgary, AB T2N 4N1, Canada. RP Bowles, NP (reprint author), Rockefeller Univ, Neuroendocrinol Lab, New York, NY 10065 USA. EM nbowles@mail.rockefeller.edu; mcewen@mail.rockefeller.edu; mnhill@ucalgary.ca FU Hope for Depression Research Foundation; Johnson and Johnson Pharmaceuticals; NIH Einstein DRTC Animal Physiology Core [DK 020541, DA9158, DA23142, DA026996]; Research and Education Component of the Advancing a Healthier Wisconsin Endowment; National Institute on Alcohol Abuse and Alcoholism, NIH; Ford Foundation Fellowship; Tier II Canada Research Chair; Natural Sciences and Engineering Research Council of Canada FX We thank Sarah Bhagat for her technical assistance at the early stage of this study. This research was supported, in part, by an operating grant from the Hope for Depression Research Foundation and an unrestricted operating grant from Johnson and Johnson Pharmaceuticals (to B.S.M.). NIH Grants DK 020541 Einstein DRTC Animal Physiology Core (to G.J.S.), DA9158 (to A.M.M.), DA23142 (to A.M.M.), and DA026996 (to C.J.H.); the Research and Education Component of the Advancing a Healthier Wisconsin Endowment to the Medical College of Wisconsin; and intramural funds from the National Institute on Alcohol Abuse and Alcoholism, NIH (G.K.) also supported this research. N.P.B. was a recipient of a predoctoral Ford Foundation Fellowship. M.N.H. is the recipient of a Tier II Canada Research Chair, and this research was supported by an operating grant from the Natural Sciences and Engineering Research Council of Canada. NR 61 TC 14 Z9 14 U1 2 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 6 PY 2015 VL 112 IS 1 BP 285 EP 290 DI 10.1073/pnas.1421420112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY2WN UT WOS:000347447100067 PM 25535367 ER PT J AU Stringer, TP Guerrieri, D Vivar, C van Praag, H AF Stringer, T. P. Guerrieri, D. Vivar, C. van Praag, H. TI Plant-derived flavanol (-)epicatechin mitigates anxiety in association with elevated hippocampal monoamine and BDNF levels, but does not influence pattern separation in mice SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID NITRIC-OXIDE SYNTHASE; SPATIAL MEMORY; OXIDATIVE STRESS; TEA POLYPHENOL; ELECTROCONVULSIVE SEIZURE; VAL66MET POLYMORPHISM; PARKINSONS-DISEASE; SIGNALING PATHWAYS; ADULT HIPPOCAMPUS; DENTATE GYRUS AB Flavanols found in natural products such as cocoa and green tea elicit structural and biochemical changes in the hippocampus, a brain area important for mood and cognition. Here, we evaluated the outcome of daily consumption of the flavanol (-)epicatechin (4 mg per day in water) by adult male C57BL/6 mice on measures of anxiety in the elevated plus maze (EPM) and open field (OF). Furthermore, pattern separation, the ability to distinguish between closely spaced identical stimuli, considered to be mediated by the hippocampal dentate gyrus (DG), was tested using the touchscreen. To investigate mechanisms through which (-)epicatechin may exert its effects, mice were injected with bromodeoxyuridine (50 mg kg(-1)) to evaluate adult hippocampal neurogenesis. In addition, monoaminergic and neurotrophin signaling pathway proteins were measured in tissue derived from subject cortices and hippocampi. Flavanol consumption reduced anxiety in the OF and EPM. Elevated hippocampal and cortical tyrosine hydroxylase, downregulated cortical monoamine oxidase-A levels, as well as increased hippocampal brain-derived neurotrophic factor (BDNF) and pro-BDNF support the flavanol's anxiolytic effects. In addition, elevated pAkt in hippocampus and cortex was observed. (-)Epicatechin ingestion did not facilitate touchscreen performance or DG neurogenesis, suggesting a non-neurogenic mechanism. The concurrent modulation of complementary neurotrophic and monoaminergic signaling pathways may contribute to beneficial mood-modulating effects of this flavanol. C1 [Stringer, T. P.; Guerrieri, D.; Vivar, C.; van Praag, H.] NIA, Neuroplast & Behav Unit, Lab Neurosci, Intramural Res Program,NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. RP van Praag, H (reprint author), NIA, Neuroplast & Behav Unit, Lab Neurosci, Intramural Res Program,NIH,Biomed Res Ctr, 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 work was supported by the Intramural Research Program of the National Institute on Aging. We thank Sarah Collica for technical assistance and Linda Kitabayashi for preparation of the photomicrograph. NR 85 TC 10 Z9 11 U1 8 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JAN 6 PY 2015 VL 5 AR e493 DI 10.1038/tp.2014.135 PG 9 WC Psychiatry SC Psychiatry GA DA2TU UT WOS:000367650100003 PM 25562843 ER PT J AU Caudron, Q Mahmud, AS Metcalf, CJE Gottfredsson, M Viboud, C Cliff, AD Grenfell, BT AF Caudron, Q. Mahmud, A. S. Metcalf, C. J. E. Gottfredsson, M. Viboud, C. Cliff, A. D. Grenfell, B. T. TI Predictability in a highly stochastic system: final size of measles epidemics in small populations SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE measles; dynamics; epidemiology; small populations ID COMMUNITY SIZE; DYNAMICS; PERSISTENCE; DISEASES; RATES; MODEL AB A standard assumption in the modelling of epidemic dynamics is that the population of interest is well mixed, and that no clusters of metapopulations exist. The well-known and oft-used SIR model, arguably the most important compartmental model in theoretical epidemiology, assumes that the disease being modelled is strongly immunizing, directly transmitted and has a well-defined period of infection, in addition to these population mixing assumptions. Childhood infections, such as measles, are prime examples of diseases that fit the SIR-like mechanism. These infections have been well studied for many systems with large, well-mixed populations with endemic infection. Here, we consider a setting where populations are small and isolated. The dynamics of infection are driven by stochastic extinction-recolonization events, producing large, sudden and short-lived epidemics before rapidly dying out from a lack of susceptible hosts. Using a TSIR model, we fit prevaccination measles incidence and demographic data in Bornholm, the Faroe Islands and four districts of Iceland, between 1901 and 1965. The datasets for each of these countries suffer from different levels of data heterogeneity and sparsity. We explore the potential for prediction of this model: given historical incidence data and up-to-date demographic information, and knowing that a new epidemic has just begun, can we predict how large it will be? We show that, despite a lack of significant seasonality in the incidence of measles cases, and potentially severe heterogeneity at the population level, we are able to estimate the size of upcoming epidemics, conditioned on the first time step, to within reasonable confidence. Our results have potential implications for possible control measures for the early stages of new epidemics in small populations. C1 [Caudron, Q.; Metcalf, C. J. E.; Grenfell, B. T.] Princeton Univ, Woodrow Wilson Sch Publ & Int Affairs, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Mahmud, A. S.] Princeton Univ, Woodrow Wilson Sch Publ & Int Affairs, Off Populat Res, Princeton, NJ 08544 USA. [Metcalf, C. J. E.; Gottfredsson, M.; Viboud, C.; Grenfell, B. T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Gottfredsson, M.] Landspitali Univ Hosp, Dept Med, Reykjavik, Iceland. [Gottfredsson, M.] Univ Iceland, Sch Hlth Sci, Fac Med, Reykjavik, Iceland. [Cliff, A. D.] Univ Cambridge, Dept Geog, Cambridge CB2 3EN, England. RP Caudron, Q (reprint author), Princeton Univ, Woodrow Wilson Sch Publ & Int Affairs, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM qcaudron@princeton.edu OI CAUDRON, Quentin/0000-0002-0132-5005; Gottfredsson, Magnus/0000-0003-2465-0422 FU US Department of Homeland Security [HSHQDC-12-C-00058]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [5R24HD047879]; National Institutes of Health [5T32HD007163]; Bill and Melinda Gates Foundation; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX Q.C., C.J.E.M. and B.T.G. were supported by funding from the US Department of Homeland Security contract HSHQDC-12-C-00058. A.S.M. acknowledges funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant no. 5R24HD047879) and from the National Institutes of Health (training grant no. 5T32HD007163). B.T.G. acknowledges support from the Bill and Melinda Gates Foundation. C.J.E.M. and B.T.G. were funded by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 21 TC 2 Z9 2 U1 1 U2 21 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 EI 1742-5662 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD JAN 6 PY 2015 VL 12 IS 102 AR 20141125 DI 10.1098/rsif.2014.1125 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU3GI UT WOS:000345500000031 PM 25411411 ER PT J AU Harly, C Peigne, CM Scotet, E AF Harly, Christelle Peigne, Cassie-Marie Scotet, Emmanuel TI Molecules and mechanisms implicated in the peculiar antigenic activation process of human V gamma 9V delta 2T cells SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE human gamma delta T lymphocytes; functions; antigenic activation; phosphoantigens; butyrophilin ID DELTA-T-CELLS; NONPEPTIDIC MYCOBACTERIAL LIGANDS; PRENYL PYROPHOSPHATE ANTIGENS; BURKITTS-LYMPHOMA CELLS; TCR-GAMMA-DELTA; DENDRITIC-CELLS; ISOPRENOID BIOSYNTHESIS; TUMOR-CELLS; PHOSPHORYLATED ANTIGENS; V-GAMMA-2V-DELTA-2 TCR AB In human beings, as well as in most non-human primates, the major peripheral gamma delta T cell subset, which accounts several percent of the whole lymphoid cells pool in adults, carries an heterodimeric TCR composed of V gamma 9 and V delta 2 chains. V gamma 9V delta 2 T cells are specifically and strongly activated by small organic pyrophosphate molecules termed phosphoantigens (phosphoAg). These low molecular weight compounds are metabolites that are produced by either microbes or endogenously, as intermediates of the mammalian mevalonate pathway, and can accumulate intracellularly during cell stress like transformation or infection. Despite the characterization of numerous natural and synthetic phosphoAg, the mechanism(s) underlying the unique and specific antigenic activation process induced by these compounds remains poorly understood. Activation is both TCR-and cell-to-cell contact-dependent, and results of previous studies have also strongly suggested a key contribution of membrane-associated molecules of primate origin expressed on target cells. The recent identification of B7-related butyrophilin (BIN) molecules CD277/BTN3A, and more precisely their BTN3A1 isoforms, as mandatory molecules in the phosphoAginduced recognition of target cells by V gamma 9V delta 2 T cells opens important opportunities for research and applications in this field. Here, we review the unusual and complex antigenic reactivity of human V gamma 9V delta 2 T cells. We highlight the recent advances in our understanding of this process, and propose a model that integrates the type I glycoprotein BTN3A1 and its intracellular B30.2 domain as a physical intermediate implicated in the detection of dysregulated intracellular levels of phosphoAg and the sensing of cell stress by V gamma 9V delta 2T cells. A better understanding of this mechanism will help optimize novel immunotherapeutical approaches that utilize the unique functional potential of this major gamma delta T cell subset. C1 [Harly, Christelle] NCI, Lab Genome Integr, Ctr Canc Res, Bethesda, MD 20892 USA. [Harly, Christelle] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA. [Peigne, Cassie-Marie; Scotet, Emmanuel] Ctr Rech Cancerol Nantes Angers, INSERM, Unite Mixte Rech 892, Nantes, France. [Peigne, Cassie-Marie; Scotet, Emmanuel] Univ Nantes, Nantes, France. [Peigne, Cassie-Marie; Scotet, Emmanuel] CNRS, Unite Mixte Rech 6299, Nantes, France. RP Scotet, E (reprint author), IRS UN, Ctr Rech Cancerol Nantes Angers, INSERM UMR 892, 8 Quai Moncousu, F-44007 Nantes, France. EM emmanuel.scotet@inserm.fr RI SCOTET, Emmanuel/L-2576-2015 FU INSERM; Universite de Nantes; Association pour la Recherche contre le Cancer; Institut National du Cancer; Agence Nationale de la Recherche; Ligue Nationale contre le Cancer; Investissements d'Avenir; US National Institute of Health [AI059621] FX The authors thank Ulrich tarry for help preparing this manuscript. This work was supported by INSERM, Universite de Nantes, Association pour la Recherche contre le Cancer, Institut National du Cancer, Agence Nationale de la Recherche (#GDSTRESS), Ligue Nationale contre le Cancer and Investissements d'Avenir (Agence Nationale de la Recherche-Programme Laboratoires d'Excellence Immunotherapy Graft Oncology), and the US National Institute of Health (AI059621). NR 97 TC 4 Z9 4 U1 2 U2 7 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD JAN 5 PY 2015 VL 5 AR 657 DI 10.3389/fimmu.2014.00657 PG 13 WC Immunology SC Immunology GA CI2SS UT WOS:000354597900001 ER PT J AU Liu, MT Wang, J Wu, XG Wang, E Abergel, RJ Shuh, DK Raymond, KN Liu, P AF Liu, Mingtao Wang, Jennie Wu, Xiaogang Wang, Euphemia Abergel, Rebecca J. Shuh, David K. Raymond, Kenneth N. Liu, Paul TI Characterization, HPLC method development and impurity identification for 3,4,3-LI(1,2-HOPO), a potent actinide chelator for radionuclide decorporation SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE 3,4,3-LI(1,2-HOPO); NSC 749716; HPLC method development and validation; Metal chelation; Speciation; Impurity and degradation product characterization ID LIQUID-CHROMATOGRAPHY; AGENTS; 5-LIO(ME-3,2-HOPO); COMPLEXES; EFFICACY; EDTA AB 3,4,3-LI(1,2-HOPO), 1,5,10,14-tetra(1-hydroxy-2-pyridon-6-oyl)-1,5,10,14-tetraazatetradecane), is a potent octadentate chelator of actinides. It is being developed as a decorporation treatment for internal contamination with radionuclides. Conventional HPLC methods exhibited speciation peaks and bridging, likely attributable to the agent's complexation with residual metallic ions in the HPLC system. Derivatization of the target ligand in situ with Fe(III) chloride, however, provided a single homogeneous iron-complex that can readily be detected and analyzed by HPLC. The HPLC method used an Agilent Eclipse XDB-C18 column (150 mm x 4.6 mm, 5 mu m) at 25 degrees C with UV detection at 280 nm. A gradient elution, with acetonitrile (11% to 100%)/buffer mobile phase, was developed for impurity profiling. The buffer consisted of 0.02% formic acid and 10 mM ammonium formate at pH 4.6. An Agilent 1200 LC-6530 Q-TOF/MS system was employed to characterize the [Fe(III)-3,4,3-LI(1,2-HOPO)] derivative and impurities. The proposed HPLC method was validated for specificity, linearity (concentration range 0.13-0.35 mg/mL, r = 0.9999), accuracy (recovery 98.3-103.3%), precision (RSD <= 1.6%) and sensitivity (LOD 0.08 mu g/mL). The LC/HRMS revealed that the derivative was a complex consisting of one 3,4,3-LI(1,2-HOPO) molecule, one hydroxide ligand, and two iron atoms. Impurities were also identified with LC/HRMS. The validated HPLC method was used in shelf-life evaluation studies which showed that the API remained unchanged for one year at 25 degrees C/60% RH. (C) 2014 Elsevier B.V. All rights reserved. C1 [Liu, Mingtao; Wang, Jennie; Wu, Xiaogang; Wang, Euphemia] SRI Int, Pharmaceut Dev Dept, Biosci Div, Menlo Pk, CA 94025 USA. [Abergel, Rebecca J.; Shuh, David K.; Raymond, Kenneth N.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Chem Sci, Berkeley, CA 94720 USA. [Raymond, Kenneth N.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Liu, Paul] NCI, Pharmaceut Resources Branch, DCTD, NIH, Bethesda, MD 20892 USA. RP Wang, J (reprint author), SRI Int, Pharmaceut Dev Dept, Biosci Div, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM jennie.wang@sri.com FU NIH Common Fund; NIAID through Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, U.S. National Institutes of Health [HHSN261200722003C, HHSN261201200028C] FX This work was supported by the NIH Common Fund and NIAID through Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, U.S. National Institutes of Health under Contract No. HHSN261200722003C and Contract No. HHSN261201200028C. NR 15 TC 3 Z9 3 U1 3 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JAN 5 PY 2015 VL 102 BP 443 EP 449 DI 10.1016/j.jpba.2014.10.015 PG 7 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA AY0HH UT WOS:000347277500054 PM 25459944 ER PT J AU Weidlich, IE Pevzner, Y Miller, BT Filippov, IV Woodcock, HL Brooks, BR AF Weidlich, Iwona E. Pevzner, Yuri Miller, Benjamin T. Filippov, Igor V. Woodcock, H. Lee Brooks, Bernard R. TI Development and Implementation of (Q)SAR Modeling Within the CHARMMing Web-User Interface SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE CHARMMing; SAR; QSAR; machine learning; random forest ID DRUG DISCOVERY; NEAREST-NEIGHBOR; CHEMICAL SPACE; PUBCHEM; QSAR; VALIDATION; GENERATION; SAR AB Recent availability of large publicly accessible databases of chemical compounds and their biological activities (PubChem, ChEMBL) has inspired us to develop a web-based tool for structure activity relationship and quantitative structure activity relationship modeling to add to the services provided by CHARMMing (). This new module implements some of the most recent advances in modern machine learning algorithmsRandom Forest, Support Vector Machine, Stochastic Gradient Descent, Gradient Tree Boosting, so forth. A user can import training data from Pubchem Bioassay data collections directly from our interface or upload his or her own SD files which contain structures and activity information to create new models (either categorical or numerical). A user can then track the model generation process and run models on new data to predict activity. (c) 2014 Wiley Periodicals, Inc. C1 [Weidlich, Iwona E.] Computat Drug Design Syst CODDES LLC, Rockville, MD 20852 USA. [Weidlich, Iwona E.; Miller, Benjamin T.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Rockville, MD 20852 USA. [Pevzner, Yuri; Woodcock, H. Lee] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. [Filippov, Igor V.] VIF Innovat LLC, Rockville, MD 20852 USA. RP Weidlich, IE (reprint author), Computat Drug Design Syst CODDES LLC, Rockville, MD 20852 USA. EM iweidlic@coddes.com OI Miller, Benjamin/0000-0003-1647-0122 FU Intramural Research Program of the National Heart, Lung and Blood Institute of the National Institutes of Health; NIH [1K22HL088341-01A1]; University of South Florida FX Contract grant sponsor: Intramural Research Program of the National Heart, Lung and Blood Institute of the National Institutes of Health; Contract grant sponsor: NIH; Contract grant number: 1K22HL088341-01A1; Contract grant sponsor: University of South Florida NR 52 TC 3 Z9 3 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 EI 1096-987X J9 J COMPUT CHEM JI J. Comput. Chem. PD JAN 5 PY 2015 VL 36 IS 1 BP 62 EP 67 DI 10.1002/jcc.23765 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA AU3KC UT WOS:000345510800007 PM 25362883 ER PT J AU Bogoch, II Creatore, MI Cetron, MS Brownstein, JS Pesik, N Miniota, J Tam, T Hu, W Nicolucci, A Ahmed, S Yoon, JW Berry, I Hay, SI Anema, A Tatem, AJ MacFadden, D German, M Khan, K AF Bogoch, Isaac I. Creatore, Maria I. Cetron, Martin S. Brownstein, John S. Pesik, Nicki Miniota, Jennifer Tam, Theresa Hu, Wei Nicolucci, Adriano Ahmed, Saad Yoon, James W. Berry, Isha Hay, Simon I. Anema, Aranka Tatem, Andrew J. MacFadden, Derek German, Matthew Khan, Kamran TI Assessment of the potential for international dissemination of Ebola virus via commercial air travel during the 2014 west African outbreak SO LANCET LA English DT Article ID HEALTH REGULATIONS AB Background The WHO declared the 2014 west African Ebola epidemic a public health emergency of international concern in view of its potential for further international spread. Decision makers worldwide are in need of empirical data to inform and implement emergency response measures. Our aim was to assess the potential for Ebola virus to spread across international borders via commercial air travel and assess the relative efficiency of exit versus entry screening of travellers at commercial airports. Methods We analysed International Air Transport Association data for worldwide flight schedules between Sept 1, 2014, and Dec 31, 2014, and historic traveller flight itinerary data from 2013 to describe expected global population movements via commercial air travel out of Guinea, Liberia, and Sierra Leone. Coupled with Ebola virus surveillance data, we modelled the expected number of internationally exported Ebola virus infections, the potential effect of air travel restrictions, and the efficiency of airport-based traveller screening at international ports of entry and exit. We deemed individuals initiating travel from any domestic or international airport within these three countries to have possible exposure to Ebola virus. We deemed all other travellers to have no significant risk of exposure to Ebola virus. Findings Based on epidemic conditions and international flight restrictions to and from Guinea, Liberia, and Sierra Leone as of Sept 1, 2014 (reductions in passenger seats by 51% for Liberia, 66% for Guinea, and 85% for Sierra Leone), our model projects 2.8 travellers infected with Ebola virus departing the above three countries via commercial flights, on average, every month. 91 547 (64%) of all air travellers departing Guinea, Liberia, and Sierra Leone had expected destinations in low-income and lower-middle-income countries. Screening international travellers departing three airports would enable health assessments of all travellers at highest risk of exposure to Ebola virus infection. C1 [Bogoch, Isaac I.; MacFadden, Derek; Khan, Kamran] Univ Toronto, Dept Med, Div Infect Dis, Toronto, ON, Canada. [Bogoch, Isaac I.] Univ Hlth Network, Div Internal Med, Toronto, ON, Canada. [Bogoch, Isaac I.] Univ Hlth Network, Div Infect Dis, Toronto, ON, Canada. [Creatore, Maria I.; Miniota, Jennifer; Hu, Wei; Nicolucci, Adriano; Yoon, James W.; Berry, Isha; German, Matthew; Khan, Kamran] St Michaels Hosp, Li Ka Shing Knowledge Inst, Ctr Res Inner City Hlth, Toronto, ON M5B 1W8, Canada. [Cetron, Martin S.] Ctr Dis Control & Prevent, Div Global Migrat & Quarantine, Atlanta, GA USA. [Brownstein, John S.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA USA. [Brownstein, John S.; Anema, Aranka] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA USA. [Pesik, Nicki] Ctr Dis Control & Prevent, Quarantine & Border Hlth Serv Branch, Div Global Migrat & Quarantine, Atlanta, GA USA. [Tam, Theresa] Publ Hlth Agcy Canada, Hlth Secur Infrastruct Branch, Ottawa, ON, Canada. [Ahmed, Saad] Univ Western Ontario, Schulich Sch Med & Dent, London, ON, Canada. [Hay, Simon I.; Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Anema, Aranka] Univ British Columbia, Fac Med, Dept Med, Vancouver, BC, Canada. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden. RP Khan, K (reprint author), St Michaels Hosp, 30 Bond St, Toronto, ON M5B 1W8, Canada. EM khank@smh.ca RI Hay, Simon/F-8967-2015 OI Hay, Simon/0000-0002-0611-7272 FU Canadian Institutes of Health Research FX Canadian Institutes of Health Research. NR 18 TC 40 Z9 41 U1 3 U2 75 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JAN 3 PY 2015 VL 385 IS 9962 BP 29 EP 35 DI 10.1016/S0140-6736(14)61828-6 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AX8IW UT WOS:000347154200025 PM 25458732 ER PT J AU Malinovsky, Y Albert, PS AF Malinovsky, Yaakov Albert, Paul S. TI A Note on the Minimax Solution for the Two-Stage Group Testing Problem SO AMERICAN STATISTICIAN LA English DT Article DE Loss function; Optimal design; Optimization problem ID COST; PRIORS; HIV; DISTRIBUTIONS; INFECTIONS; DEFECTIVES AB Group testing is an active area of current research and has important applications in medicine, biotechnology, genetics, and product testing. There have been recent advances in design and estimation, but the simple Dorfman procedure introduced by R. Dorfman in 1943 is widely used in practice. In many practical situations, the exact value of the probability p of being affected is unknown. We present both minimax and Bayesian solutions for the group size problem when p is unknown. For unbounded p, we show that the minimax solution for group size is 8, while using a Bayesian strategy with Jeffreys' prior results in a group size of 13. We also present solutions when p is bounded from above. For the practitioner, we propose strong justification for using a group size of between 8 and 13 when a constraint on p is not incorporated and provide useable code for computing the minimax group size under a constrained p. C1 [Malinovsky, Yaakov] Univ Maryland, Dept Math & Stat, Baltimore, MD 21250 USA. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. RP Malinovsky, Y (reprint author), Univ Maryland, Dept Math & Stat, Baltimore, MD 21250 USA. EM yaakovm@umbc.edu; albertp@mail.nih.gov FU UMBC Summer Faculty Fellowship; Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural program FX The work was partially supported by a 2013 UMBC Summer Faculty Fellowship grant and the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural program. The authors thank an editor, associate editor, and two referees for their thoughtful and constructive comments and suggestions that resulted in very significant improvements in the article. The authors also thank Sara Joslyn for editing the article and Abram Kagan and Yosef Rinott for discussions on the topic and comments on the article. NR 32 TC 1 Z9 1 U1 0 U2 1 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0003-1305 EI 1537-2731 J9 AM STAT JI Am. Stat. PD JAN 2 PY 2015 VL 69 IS 1 BP 45 EP 52 DI 10.1080/00031305.2014.983545 PG 8 WC Statistics & Probability SC Mathematics GA CE3ZC UT WOS:000351767700009 PM 28042146 ER PT J AU Hobson, JA AF Hobson, J. Allan TI Dreams and Consciousness: Response to Colace and Boag SO CONTEMPORARY PSYCHOANALYSIS LA English DT Article C1 [Hobson, J. Allan] Harvard Univ, Sch Med, Psychiat, Boston, MA USA. [Hobson, J. Allan] Bellevue Hosp, Med, New York, NY USA. [Hobson, J. Allan] Massachusetts Mental Hlth Ctr, Psychiat, Boston, MA 02115 USA. [Hobson, J. Allan] NIMH, New York, NY USA. [Hobson, J. Allan] Univ Lyon, Natl Inst Mental Hlth, Dept Physiol, Lyon, France. RP Hobson, JA (reprint author), 322 Shore Dr, Salem, NH 03079 USA. EM allan_hobson@hms.harvard.edu NR 11 TC 1 Z9 1 U1 0 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0010-7530 EI 2330-9091 J9 CONTEMP PSYCHOANAL JI Contemp. Psychoanal. PD JAN 2 PY 2015 VL 51 IS 1 BP 126 EP 131 DI 10.1080/00107530.2014.958048 PG 6 WC Psychiatry; Psychology, Psychoanalysis SC Psychiatry; Psychology GA CD5WQ UT WOS:000351159800006 ER PT J AU Colon-Ramos, U Rutten, LJF Moser, RP Colon-Lopez, V Ortiz, AP Yaroch, AL AF Colon-Ramos, Uriyoan Rutten, Lila J. Finney Moser, Richard P. Colon-Lopez, Vivian Ortiz, Ana P. Yaroch, Amy Lazarus TI The Association Between Fruit and Vegetable Intake, Knowledge of the Recommendations, and Health Information Seeking Within Adults in the U.S. Mainland and in Puerto Rico SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID FACTOR SURVEILLANCE SYSTEM; NATIONAL TRENDS SURVEY; INTERVIEW SURVEY; MEDICAL ENCOUNTER; CONSUMPTION; DISPARITIES; SUBGROUPS; LITERACY AB Health information correlates of fruit and vegetable intake and of knowledge of the fruit and vegetable recommendations were examined using bivariate and multivariate regressions with data from the 2007-2008 U.S. National Cancer Institute's Health Information National Trends Survey in the United States and in Puerto Rico. Residents from Puerto Rico had the lowest reported fruit and vegetable intake and the lowest knowledge of the recommended servings of fruits and vegetables to maintain good health, compared with U.S. Hispanics, non-Hispanic Whites, and Blacks. Sixty-seven percent of Puerto Rican residents and 62% of U.S. Hispanics reported never seeking information on health or medical topics. In multivariate analysis, those who never sought information on health or medical topics reported significantly lower fruit and vegetable intake (coefficient=-0.24; 95% CI [-0.38, -0.09]), and were less likely to know the fruit and vegetable recommendations (OR=0.32; 95% CI [0.20, 0.52]), compared with those who obtained information from their health care providers. Health promotion initiatives in the United States and Puerto Rico have invested in mass media campaigns to increase consumption of and knowledge about fruit and vegetables, but populations with the lowest intake are less likely to seek information. Strategies must be multipronged to address institutional, economic, and behavioral constraints of populations who do not seek out health information from any sources. C1 [Colon-Ramos, Uriyoan] George Washington Univ, Dept Global Hlth, Sch Publ Hlth & Hlth Serv, Washington, DC 20052 USA. [Rutten, Lila J. Finney] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Rutten, Lila J. Finney] Mayo Clin, Populat Hlth Sci Program, Ctr Sci Hlth Care Delivery, Rochester, MN USA. [Moser, Richard P.] NCI, Behav Res Program, Bethesda, MD 20892 USA. [Colon-Lopez, Vivian] Univ Puerto Rico, Grad Sch Publ Hlth, Dept Hlth Serv Adm, San Juan, PR 00936 USA. [Ortiz, Ana P.] Univ Puerto Rico, Grad Sch Publ Hlth, Dept Biostat & Epidemiol, San Juan, PR 00936 USA. [Yaroch, Amy Lazarus] Gretchen Swanson Ctr Nutr, Omaha, NE USA. RP Colon-Ramos, U (reprint author), George Washington Univ, Dept Global Hlth, Milken Inst Sch Publ Hlth, 950 New Hampshire Ave 410, Washington, DC 20052 USA. EM uriyoan@gwu.edu NR 35 TC 1 Z9 1 U1 1 U2 10 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD JAN 2 PY 2015 VL 20 IS 1 BP 105 EP 111 DI 10.1080/10810730.2014.914607 PG 7 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA CB0LD UT WOS:000349316500011 PM 25204843 ER PT J AU Schutt, RC Trachtenberg, BH Cooke, JP Traverse, JH Henry, TD Pepine, CJ Willerson, JT Perin, EC Ellis, SG Zhao, DXM Bhatnagar, A Johnstone, BH Lai, DJ Resende, M Ebert, RF Wu, JC Sayre, SL Orozco, A Zierold, C Simari, RD Moye, L Cogle, CR Taylor, DA AF Schutt, Robert C. Trachtenberg, Barry H. Cooke, John P. Traverse, Jay H. Henry, Timothy D. Pepine, Carl J. Willerson, James T. Perin, Emerson C. Ellis, Stephen G. Zhao, David X. M. Bhatnagar, Aruni Johnstone, Brian H. Lai, Dejian Resende, Micheline Ebert, Ray F. Wu, Joseph C. Sayre, Shelly L. Orozco, Aaron Zierold, Claudia Simari, Robert D. Moye, Lem Cogle, Christopher R. Taylor, Doris A. CA CCTRN TI Bone Marrow Characteristics Associated With Changes in Infarct Size After STEMI A Biorepository Evaluation From the CCTRN TIME Trial SO CIRCULATION RESEARCH LA English DT Article DE acute myocardial infarction; adult stem cell; coronary circulation; regeneration ID ENDOTHELIAL PROGENITOR CELLS; ACUTE MYOCARDIAL-INFARCTION; CARDIOVASCULAR RISK; RANDOMIZED-TRIAL; THERAPY; NEOVASCULARIZATION; TRANSPLANTATION; ANGIOGENESIS; POPULATION; COLONIES AB Rationale: Despite significant interest in bone marrow mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have resulted in only modest benefits. However, selected patients have shown improvements after autologous BMC therapy, but the contributing factors are unclear. Objective: The purpose of this study was to identify BMC characteristics associated with a reduction in infarct size after ST-segment-elevation-myocardial infarction. Methods and Results: This prospective study comprised patients consecutively enrolled in the CCTRN TIME (Cardiovascular Cell Therapy Research Network Timing in Myocardial Infarction Evaluation) trial who agreed to have their BMCs stored and analyzed at the CCTRN Biorepository. Change in infarct size between baseline (3 days after percutaneous coronary intervention) and 6-month follow-up was measured by cardiac MRI. Infarct-size measurements and BMC phenotype and function data were obtained for 101 patients (mean age, 56.5 years; mean screening ejection fraction, 37%; mean baseline cardiac MRI ejection fraction, 45%). At 6 months, 75 patients (74.3%) showed a reduction in infarct size (mean change, -21.0+/-17.6%). Multiple regression analysis indicated that infarct size reduction was greater in patients who had a larger percentage of CD31(+) BMCs (P=0.046) and in those with faster BMC growth rates in colony-forming unit Hill and endothelial-colony forming cell functional assays (P=0.033 and P=0.032, respectively). Conclusions: This study identified BMC characteristics associated with a better clinical outcome in patients with segment-elevation-myocardial infarction and highlighted the importance of endothelial precursor activity in regenerating infarcted myocardium. Furthermore, it suggests that for these patients with segment-elevation-myocardial infarction, myocardial repair was more dependent on baseline BMC characteristics than on whether the patient underwent intracoronary BMC transplantation. C1 [Schutt, Robert C.; Trachtenberg, Barry H.; Cooke, John P.] Houston Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA. [Schutt, Robert C.; Trachtenberg, Barry H.; Cooke, John P.] Houston Methodist Res Inst, Houston, TX USA. [Traverse, Jay H.] Minneapolis Heart Inst Fdn, Abbott Northwestern Hosp, Minneapolis, MN USA. [Henry, Timothy D.] Cedars Sinai Heart Inst, Los Angeles, CA USA. [Pepine, Carl J.; Cogle, Christopher R.] Univ Florida, Coll Med, Gainesville, FL USA. [Willerson, James T.; Perin, Emerson C.; Resende, Micheline; Orozco, Aaron; Taylor, Doris A.] CHI St Lukes Hlth, Texas Heart Inst, Houston, TX USA. [Zierold, Claudia] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Ellis, Stephen G.] Cleveland Clin Fdn, Cleveland, OH USA. [Zhao, David X. M.] Sch Med, Winston Salem, NC USA. [Bhatnagar, Aruni] Univ Louisville, Sch Med, Louisville, KY 40292 USA. [Johnstone, Brian H.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Lai, Dejian; Sayre, Shelly L.; Moye, Lem] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Ebert, Ray F.] NHLBI, Bethesda, MD 20892 USA. [Wu, Joseph C.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Simari, Robert D.] Univ Kansas, Med Ctr, Sch Med, Lawrence, KS 66045 USA. RP Moye, L (reprint author), 1200 Pressler St E1009, Houston, TX 77030 USA. EM Lemmoye@msn.com RI Cogle, Christopher/H-1746-2016; OI Cogle, Christopher/0000-0001-5422-6863; Cooke, John/0000-0003-0033-9138 FU University of Florida [R01 HL091005, UM1 HL087318] FX This study was funded by UM1 HL087318 (Cardiovascular Cell Therapy Research Network) and R01 HL091005 (Ancillary Studies), University of Florida. NR 42 TC 13 Z9 13 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JAN 2 PY 2015 VL 116 IS 1 BP 99 EP U240 DI 10.1161/CIRCRESAHA.116.304710 PG 17 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AX6TA UT WOS:000347052800017 PM 25406300 ER PT J AU Gupta, SD Gable, K Alexaki, A Chandris, P Proia, RL Dunn, TM Harmon, JM AF Gupta, Sita D. Gable, Kenneth Alexaki, Aikaterini Chandris, Panagiotis Proia, Richard L. Dunn, Teresa M. Harmon, Jeffrey M. TI Expression of the ORMDLS, Modulators of Serine Palmitoyltransferase, Is Regulated by Sphingolipids in Mammalian Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Enzyme; Lipid Metabolism; Metabolic Regulation; Serine Palmitoyltransferase; Sphingolipid ID PROTEINS MEDIATE; HOMEOSTASIS; ASTHMA; BIOSYNTHESIS; GENE; ORM2; ACCUMULATION; INHIBITION; SUBUNITS; STRESS AB Background: In contrast to their yeast orthologues, the mechanism by which mammalian ORMDLs regulate serine palmitoyltransferase is not understood. Results: Overexpression of serine palmitoyltransferase in HEK293 cells results in increased long-chain base synthesis and an activity-dependent increase in ORMDL expression. Conclusion: A product of ceramide synthase mediates regulation of ORMDL expression and inhibition of serine palmitoyltransferase. Significance: Serine palmitoyltransferase activity indirectly regulates ORMDL expression. The relationship between serine palmitoyltransferase (SPT) activity and ORMDL regulation of sphingolipid biosynthesis was investigated in mammalian HEK293 cells. Each of the three human ORMDLs reduced the increase in long-chain base synthesis seen after overexpression of wild-type SPT or SPT containing the C133W mutation in hLCB1, which produces the non-catabolizable sphingoid base, 1-deoxySa. ORMDL-dependent repression of sphingoid base synthesis occurred whether SPT was expressed as individual subunits or as a heterotrimeric single-chain SPT fusion protein. Overexpression of the single-chain SPT fusion protein under the control of a tetracycline-inducible promoter in stably transfected cells resulted in increased endogenous ORMDL expression. This increase was not transcriptional; there was no significant increase in any of the ORMDL mRNAs. Increased ORMDL protein expression required SPT activity since overexpression of a catalytically inactive SPT with a mutation in hLCB2a had little effect. Significantly, increased ORMDL expression was also blocked by myriocin inhibition of SPT as well as fumonisin inhibition of the ceramide synthases, suggesting that increased expression is a response to a metabolic signal. Moreover, blocking ORMDL induction with fumonisin treatment resulted in significantly greater increases in in vivo SPT activity than was seen when ORMDLs were allowed to increase, demonstrating the physiological significance of this response. C1 [Gupta, Sita D.; Gable, Kenneth; Dunn, Teresa M.] Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. [Harmon, Jeffrey M.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. [Alexaki, Aikaterini; Chandris, Panagiotis; Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Harmon, JM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pharmacol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM jeffrey.harmon@usuhs.edu OI Harmon, Jeffrey/0000-0001-7833-931X FU Uniformed Services University [R071KD, CO75PI]; National Institutes of Health [R01NS072446, R21HD080181]; Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by Uniformed Services University Grants R071KD and CO75PI, by National Institutes of Health Grants R01NS072446 and R21HD080181, and by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 29 TC 9 Z9 9 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 2 PY 2015 VL 290 IS 1 BP 90 EP 98 DI 10.1074/jbc.M114.588236 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AX9OG UT WOS:000347231200009 PM 25395622 ER PT J AU Neafsey, DE Waterhouse, RM Abai, MR Aganezov, SS Alekseyev, MA Allen, JE Amon, J Arca, B Arensburger, P Artemov, G Assour, LA Basseri, H Berlin, A Birren, BW Blandin, SA Brockman, AI Burkot, TR Burt, A Chan, CS Chauve, C Chiu, JC Christensen, M Costantini, C Davidson, VLM Deligianni, E Dottorini, T Dritsou, V Gabriel, SB Guelbeogo, WM Hall, AB Han, MV Hlaing, T Hughes, DST Jenkins, AM Jiang, XF Jungreis, I Kakani, EG Kamali, M Kemppainen, P Kennedy, RC Kirmitzoglou, IK Koekemoer, LL Laban, N Langridge, N Lawniczak, MKN Lirakis, M Lobo, NF Lowy, E MacCallum, RM Mao, CH Maslen, G Mbogo, C McCarthy, J Michel, K Mitchell, SN Moore, W Murphy, KA Naumenko, AN Nolan, T Novoa, EM O'Loughlin, S Oringanje, C Oshaghi, MA Pakpour, N Papathanos, PA Peery, AN Povelones, M Prakash, A Price, DP Rajaraman, A Reimer, LJ Rinker, DC Rokas, A Russell, TL Sagnon, N Sharakhova, MV Shea, T Simao, FA Simard, F Slotman, MA Somboon, P Stegniy, V Struchiner, CJ Thomas, GWC Tojo, M Topalis, P Tubio, JMC Unger, MF Vontas, J Walton, C Wilding, CS Willis, JH Wu, YC Yan, GY Zdobnov, EM Zhou, XF Catteruccia, F Christophides, GK Collins, FH Cornman, RS Crisanti, A Donnelly, MJ Emrich, SJ Fontaine, MC Gelbart, W Hahn, MW Hansen, IA Howell, PI Kafatos, FC Kellis, M Lawson, D Louis, C Luckhart, S Muskavitch, MAT Ribeiro, JM Riehle, MA Sharakhov, IV Tu, ZJ Zwiebel, LJ Besansky, NJ AF Neafsey, Daniel E. Waterhouse, Robert M. Abai, Mohammad R. Aganezov, Sergey S. Alekseyev, Max A. Allen, James E. Amon, James Arca, Bruno Arensburger, Peter Artemov, Gleb Assour, Lauren A. Basseri, Hamidreza Berlin, Aaron Birren, Bruce W. Blandin, Stephanie A. Brockman, Andrew I. Burkot, Thomas R. Burt, Austin Chan, Clara S. Chauve, Cedric Chiu, Joanna C. Christensen, Mikkel Costantini, Carlo Davidson, Victoria L. M. Deligianni, Elena Dottorini, Tania Dritsou, Vicky Gabriel, Stacey B. Guelbeogo, Wamdaogo M. Hall, Andrew B. Han, Mira V. Hlaing, Thaung Hughes, Daniel S. T. Jenkins, Adam M. Jiang, Xiaofang Jungreis, Irwin Kakani, Evdoxia G. Kamali, Maryam Kemppainen, Petri Kennedy, Ryan C. Kirmitzoglou, Ioannis K. Koekemoer, Lizette L. Laban, Njoroge Langridge, Nicholas Lawniczak, Mara K. N. Lirakis, Manolis Lobo, Neil F. Lowy, Ernesto MacCallum, Robert M. Mao, Chunhong Maslen, Gareth Mbogo, Charles McCarthy, Jenny Michel, Kristin Mitchell, Sara N. Moore, Wendy Murphy, Katherine A. Naumenko, Anastasia N. Nolan, Tony Novoa, Eva M. O'Loughlin, Samantha Oringanje, Chioma Oshaghi, Mohammad A. Pakpour, Nazzy Papathanos, Philippos A. Peery, Ashley N. Povelones, Michael Prakash, Anil Price, David P. Rajaraman, Ashok Reimer, Lisa J. Rinker, David C. Rokas, Antonis Russell, Tanya L. Sagnon, N'Fale Sharakhova, Maria V. Shea, Terrance Simao, Felipe A. Simard, Frederic Slotman, Michel A. Somboon, Pradya Stegniy, Vladimir Struchiner, Claudio J. Thomas, Gregg W. C. Tojo, Marta Topalis, Pantelis Tubio, Jose M. C. Unger, Maria F. Vontas, John Walton, Catherine Wilding, Craig S. Willis, Judith H. Wu, Yi-Chieh Yan, Guiyun Zdobnov, Evgeny M. Zhou, Xiaofan Catteruccia, Flaminia Christophides, George K. Collins, Frank H. Cornman, Robert S. Crisanti, Andrea Donnelly, Martin J. Emrich, Scott J. Fontaine, Michael C. Gelbart, William Hahn, Matthew W. Hansen, Immo A. Howell, Paul I. Kafatos, Fotis C. Kellis, Manolis Lawson, Daniel Louis, Christos Luckhart, Shirley Muskavitch, Marc A. T. Ribeiro, Jose M. Riehle, Michael A. Sharakhov, Igor V. Tu, Zhijian Zwiebel, Laurence J. Besansky, Nora J. TI Highly evolvable malaria vectors: The genomes of 16 Anopheles mosquitoes SO SCIENCE LA English DT Article ID ANTENNAL TRANSCRIPTOME PROFILES; SEX-CHROMOSOME EVOLUTION; CUTICULAR PROTEIN GENES; AEDES-AEGYPTI; R CONSENSUS; GAMBIAE; DROSOPHILA; EXPRESSION; ANNOTATION; FAMILY AB Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning similar to 100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts. C1 [Neafsey, Daniel E.; Berlin, Aaron; Birren, Bruce W.; Shea, Terrance] Broad Inst, Genome Sequencing & Anal Program, Cambridge, MA 02142 USA. [Waterhouse, Robert M.; Chan, Clara S.; Jungreis, Irwin; Novoa, Eva M.; Wu, Yi-Chieh; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Waterhouse, Robert M.; Chan, Clara S.; Jungreis, Irwin; Novoa, Eva M.; Wu, Yi-Chieh; Kellis, Manolis] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA 02142 USA. [Waterhouse, Robert M.; Simao, Felipe A.; Zdobnov, Evgeny M.] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland. [Waterhouse, Robert M.; Simao, Felipe A.; Zdobnov, Evgeny M.] Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland. [Abai, Mohammad R.; Basseri, Hamidreza; Oshaghi, Mohammad A.] Univ Tehran Med Sci, Dept Med Entomol & Vector Control, Sch Publ Hlth, Tehran, Iran. [Abai, Mohammad R.; Basseri, Hamidreza; Oshaghi, Mohammad A.] Univ Tehran Med Sci, Inst Hlth Res, Tehran, Iran. [Aganezov, Sergey S.; Alekseyev, Max A.] George Washington Univ, Dept Math, Ashburn, VA 20147 USA. [Aganezov, Sergey S.; Alekseyev, Max A.] George Washington Univ, Computat Biol Inst, Ashburn, VA 20147 USA. [Allen, James E.; Christensen, Mikkel; Hughes, Daniel S. T.; Langridge, Nicholas; Lowy, Ernesto; Maslen, Gareth; Lawson, Daniel] EMBL EBI, Cambridge CB10 1SD, England. [Amon, James] Minist Hlth, Natl Vector Borne Dis Control Programme, Port Vila, Tafea Province, Vanuatu. [Arca, Bruno] Univ Roma La Sapienza, Div Parasitol, Dept Publ Hlth & Infect Dis, I-00185 Rome, Italy. [Arensburger, Peter; McCarthy, Jenny] Calif State Polytech Pomona, Dept Biol Sci, Pomona, CA 91768 USA. [Artemov, Gleb; Stegniy, Vladimir] Tomsk State Univ, Tomsk 634050, Russia. [Assour, Lauren A.; Emrich, Scott J.] Univ Notre Dame, Eck Inst Global Hlth, Dept Comp Sci & Engn, Notre Dame, IN 46556 USA. [Blandin, Stephanie A.] INSERM, U963, F-67084 Strasbourg, France. [Blandin, Stephanie A.] CNRS, UPR9022, IBMC, F-67084 Strasbourg, France. [Brockman, Andrew I.; Dottorini, Tania; Kirmitzoglou, Ioannis K.; Lawniczak, Mara K. N.; MacCallum, Robert M.; Nolan, Tony; Papathanos, Philippos A.; Christophides, George K.; Crisanti, Andrea; Kafatos, Fotis C.] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, London SW7 2AZ, England. [Burkot, Thomas R.; Russell, Tanya L.] James Cook Univ, Australian Inst Trop Hlth Med, Fac Med Hlth & Mol Sci, Cairns 4870, Australia. [Burt, Austin; O'Loughlin, Samantha] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, Ascot SL5 7PY, Berks, England. [Chauve, Cedric; Rajaraman, Ashok] Simon Fraser Univ, Dept Math, Burnaby, BC V5A 1S6, Canada. [Chiu, Joanna C.; Murphy, Katherine A.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Costantini, Carlo; Simard, Frederic] Inst Rech Dev, Unites Mixtes Rech Malad Infect & Vecteurs Ecol G, F-64501 Montpellier, France. [Davidson, Victoria L. M.; Michel, Kristin] Kansas State Univ, Div Biol, Manhattan, KS 66506 USA. [Deligianni, Elena; Topalis, Pantelis; Louis, Christos] Fdn Res & Technol, Inst Mol Biol & Biotechnol, GR-70013 Iraklion, Crete, Greece. [Dritsou, Vicky; Papathanos, Philippos A.; Crisanti, Andrea; Louis, Christos] Univ Perugia, Ctr Funct Genom, I-06100 Perugia, Italy. [Gabriel, Stacey B.] Broad Inst, Cambridge, MA 02142 USA. [Guelbeogo, Wamdaogo M.; Sagnon, N'Fale] Ctr Natl Rech & Format Paludisme, Ouagadougou, Burkina Faso. [Hall, Andrew B.; Jiang, Xiaofang; Sharakhov, Igor V.; Tu, Zhijian] Virginia Polytech Inst & State Univ, Program Genet Bioinformat & Computat Biol, Blacksburg, VA 24061 USA. [Han, Mira V.] Univ Nevada, Sch Life Sci, Las Vegas, NV 89154 USA. [Hlaing, Thaung] Dept Med Res, Dagon Township 11191, Yangon, Myanmar. [Hughes, Daniel S. T.] Baylor Coll Med, Houston, TX 77030 USA. [Jenkins, Adam M.; Muskavitch, Marc A. T.] Boston Coll, Chestnut Hill, MA 02467 USA. [Jiang, Xiaofang; Tu, Zhijian] Virginia Polytech Inst & State Univ, Dept Biochem, Blacksburg, VA 24061 USA. [Kakani, Evdoxia G.; Mitchell, Sara N.; Catteruccia, Flaminia] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Kakani, Evdoxia G.; Catteruccia, Flaminia] Univ Perugia, Dipartimento Med Sperimentale & Sci Biochim, Perugia, Italy. [Kamali, Maryam; Naumenko, Anastasia N.; Peery, Ashley N.; Sharakhova, Maria V.; Sharakhov, Igor V.] Virginia Polytech Inst & State Univ, Dept Entomol, Blacksburg, VA 24061 USA. [Kemppainen, Petri; Walton, Catherine] Univ Manchester, Fac Life Sci, Computat Evolutionary Biol Grp, Oxford M13 9PT, England. [Kennedy, Ryan C.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Kirmitzoglou, Ioannis K.] Univ Cyprus, Dept Biol Sci, Bioinformat Res Lab, CY-1678 Nicosia, Cyprus. [Koekemoer, Lizette L.] Natl Hlth Lab Serv, Natl Inst Communicable Dis, Wits Res Inst Malaria, Fac Hlth Sci, ZA-2131 Johannesburg, South Africa. [Koekemoer, Lizette L.] Natl Hlth Lab Serv, Natl Inst Communicable Dis, Vector Control Reference Unit, ZA-2131 Johannesburg, South Africa. [Laban, Njoroge] Natl Museums Kenya, Nairobi, Kenya. [Lirakis, Manolis; Vontas, John; Louis, Christos] Univ Crete, Dept Biol, GR-70013 Iraklion, Greece. [Lobo, Neil F.; Unger, Maria F.; Collins, Frank H.; Fontaine, Michael C.; Besansky, Nora J.] Univ Notre Dame, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Lobo, Neil F.; Unger, Maria F.; Collins, Frank H.; Fontaine, Michael C.; Besansky, Nora J.] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. [Mao, Chunhong] Virginia Polytech Inst & State Univ, Virginia Bioinformat Inst, Blacksburg, VA 24061 USA. [Mbogo, Charles] Ctr Geog Med Res, Kenya Med Res Inst, Wellcome Trust Res Programme, Kilifi, Kenya. [Moore, Wendy; Oringanje, Chioma; Riehle, Michael A.] Univ Arizona, Dept Entomol, Tucson, AZ 85721 USA. [Pakpour, Nazzy; Luckhart, Shirley] Univ Calif Davis, Sch Med, Dept Med Microbiol & Immunol, Davis, CA 95616 USA. [Povelones, Michael] Univ Penn, Sch Vet Med, Dept Pathol, Philadelphia, PA 19104 USA. [Prakash, Anil] Indian Council Med Res, Reg Med Res Ctr NE, Dibrugarh 786001, Assam, India. [Price, David P.; Hansen, Immo A.] New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. [Price, David P.; Hansen, Immo A.] New Mexico State Univ, Mol Biol Program, Las Cruces, NM 88003 USA. [Reimer, Lisa J.; Donnelly, Martin J.] Univ Liverpool Liverpool Sch Trop Med, Dept Vector Biol, Liverpool L3 5QA, Merseyside, England. [Rinker, David C.; Rokas, Antonis] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN 37235 USA. [Rokas, Antonis; Zhou, Xiaofan] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37235 USA. [Slotman, Michel A.] Texas A&M Univ, Dept Entomol, College Stn, TX 77807 USA. [Somboon, Pradya] Chiang Mai Univ, Fac Med, Dept Parasitol, Chiang Mai 50200, Thailand. [Struchiner, Claudio J.] Fundacao Oswaldo Cruz, Rio De Janeiro, RJ, Brazil. [Struchiner, Claudio J.] Univ Estado Rio de Janeiro, Inst Social Med, BR-20550011 Rio De Janeiro, Brazil. [Thomas, Gregg W. C.; Hahn, Matthew W.] Indiana Univ, Sch Informat & Comp, Bloomington, IN 47405 USA. [Tojo, Marta] Univ Santiago de Compostela, Inst Invest Sanitarias, Ctr Res Mol Med & Chron Dis, Sch Med,Dept Physiol, La Coruna, Spain. [Tubio, Jose M. C.] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, Cambs, England. [Wilding, Craig S.] Liverpool John Moores Univ, Sch Nat Sci & Psychol, Liverpool L3 3AF, Merseyside, England. [Willis, Judith H.; Cornman, Robert S.] Univ Georgia, Dept Cellular Biol, Athens, GA 30602 USA. [Wu, Yi-Chieh] Harvey Mudd Coll, Dept Comp Sci, Claremont, CA 91711 USA. [Yan, Guiyun] Univ Calif Irvine, Coll Hlth Sci, Program Publ Hlth, Irvine, CA 92697 USA. [Donnelly, Martin J.] Wellcome Trust Sanger Inst, Malaria Programme, Cambridge CB10 1SJ, England. [Fontaine, Michael C.] Univ Groningen, Ctr Evolutionary & Ecol Studies, Marine Evolut & Conservat Grp, NL-9747 AG Groningen, Netherlands. [Gelbart, William] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Hahn, Matthew W.] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Howell, Paul I.] Ctr Dis Control & Prevent, Atlanta, GA 30329 USA. [Muskavitch, Marc A. T.] Biogen Idec Inc, Cambridge, MA 02142 USA. [Ribeiro, Jose M.] NIAID, Lab Malaria & Vector Res, Rockville, MD 20852 USA. [Zwiebel, Laurence J.] Vanderbilt Univ & Med Ctr, Dept Biol Sci, Inst Chem Biol, Nashville, TN 37235 USA. [Zwiebel, Laurence J.] Vanderbilt Univ & Med Ctr, Dept Pharmacol, Inst Genet & Global Hlth, Nashville, TN 37235 USA. RP Neafsey, DE (reprint author), Broad Inst, Genome Sequencing & Anal Program, 415 Main St, Cambridge, MA 02142 USA. EM neafsey@broadinstitute.org; nbesansk@nd.edu RI Novoa, Eva Maria/B-1004-2015; Stegniy, Vladimir/N-7656-2014; Tubio, Jose/H-5076-2015; Ribeiro, Jose/J-7011-2015; Wilding, Craig/C-5500-2012; Rokas, Antonis/A-9775-2008; Alekseyev, Max/D-9362-2016; Waterhouse, Robert/A-1858-2010; Artemov, Gleb/N-7651-2014; Blandin, Stephanie/I-2786-2016; SIMARD, Frederic/J-9489-2016; Zdobnov, Evgeny/K-1133-2012 OI Hahn, Matthew/0000-0002-5731-8808; Ribeiro, Jose/0000-0002-9107-0818; Arca, Bruno/0000-0002-4029-0984; Novoa, Eva Maria/0000-0001-5567-1299; Tubio, Jose/0000-0003-3540-2459; Wilding, Craig/0000-0001-5818-2706; Rokas, Antonis/0000-0002-7248-6551; Alekseyev, Max/0000-0002-5140-8095; Waterhouse, Robert/0000-0003-4199-9052; SIMARD, Frederic/0000-0002-2871-5329; FU National Center for Biotechnology Information [PRJNA67511] FX All sequencing reads and genome assemblies have been submitted to the National Center for Biotechnology Information (umbrella BioProject ID, PRJNA67511). Genome and transcriptome assemblies are also available from VectorBase (https://vectorbase.org) and the Broad Institute (https://olive.broadinstitute.org/collections/anopheles.4). The authors acknowledge the NIH Eukaryotic Pathogen and Disease Vector Sequencing Project Working Group for guidance and development of this project. Sequence data generation was supported at the Broad Institute by the National Human Genome Research Institute (U54 HG003067). We thank the many members of the Broad Institute Genomics Platform and Genome Sequencing and Analysis Program who contributed to sequencing data generation and analysis. NR 53 TC 92 Z9 97 U1 30 U2 171 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JAN 2 PY 2015 VL 347 IS 6217 AR UNSP 1258522 DI 10.1126/science.1258522 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AX7NK UT WOS:000347102300042 PM 25554792 ER PT J AU Li, KG Seo, DC Torabi, MR AF Li, Kaigang Seo, Dong-Chul Torabi, Mohammad R. TI Measuring Outcome Expectancy Value of Leisure-Time Physical Activity for African Americans SO BEHAVIORAL MEDICINE LA English DT Article DE cross-validation; African Americans; leisure-time physical activity; confirmatory factor analysis; outcome expectancy value ID SOCIAL-COGNITIVE THEORY; SELF-EFFICACY; HEALTH-PROMOTION; ADOLESCENT GIRLS; US ADULTS; DETERMINANTS; PREVENTION; BARRIERS; DISEASE; OBESITY AB A scale was adapted from existing scales to measure the outcome expectancy value (EV) as one of contributory factors to leisure-time physical activity (LTPA) and was administered to 649 African American adults. The eligible participants (N = 569) for the analysis were split into three subsamples (rate = 0.5 : 0.25 : 0.25) respectively for Exploratory Factor Analysis (N = 285) and cross-validation (N = 142 for the calibration group and N = 142 for the validation group) to evaluate the psychometric properties of the scale. Item analysis of the scale provided adequate psychometric properties. The 2-factor solution with positive and negative outcome EV subscales was supported based on the exploratory factor analysis and the multiple-group confirmatory factor analysis for both the calibration and validation samples. The results support the factorial construct validity and criterion validity of the outcome EV scale applied to assess LTPA in a sample of church-going African Americans. C1 [Li, Kaigang] NICHHD, Bethesda, MD 20852 USA. [Seo, Dong-Chul] Ewha Womans Univ, Coll Hlth Sci, Seoul, South Korea. [Torabi, Mohammad R.] Indiana Univ Sch Publ Hlth Bloomington, Bloomington, IN USA. RP Li, KG (reprint author), NICHHD, Hlth Behav Branch, 6100 Execut Blvd 7B13B, Bethesda, MD 20852 USA. EM likaigang@gmail.com RI Seo, Dong-Chul/A-6935-2009 OI Seo, Dong-Chul/0000-0002-1972-6237 NR 46 TC 0 Z9 0 U1 3 U2 14 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0896-4289 EI 1940-4026 J9 BEHAV MED JI Behav. Med. PD JAN 2 PY 2015 VL 41 IS 1 BP 33 EP 39 DI 10.1080/08964289.2014.881775 PG 7 WC Behavioral Sciences; Psychiatry SC Behavioral Sciences; Psychiatry GA AW6BB UT WOS:000346353400005 PM 24438219 ER PT J AU Somsouk, M Estes, JD Deleage, C Dunham, RM Albright, R Inadomi, JM Martin, JN Deeks, SG McCune, JM Hunt, PW AF Somsouk, Ma Estes, Jacob D. Deleage, Claire Dunham, Richard M. Albright, Rebecca Inadomi, John M. Martin, Jeffrey N. Deeks, Steven G. McCune, Joseph M. Hunt, Peter W. TI Gut epithelial barrier and systemic inflammation during chronic HIV infection SO AIDS LA English DT Article DE epithelial proliferation; HIV; immune activation; inflammation; microbial translocation ID IMMUNODEFICIENCY-VIRUS-INFECTION; COMBINATION ANTIRETROVIRAL THERAPY; T-CELL-ACTIVATION; IMMUNE ACTIVATION; MICROBIAL TRANSLOCATION; MUCOSAL; MORTALITY; APOPTOSIS; DYSFUNCTION; DEPLETION AB Objective: Microbial translocation and innate immune action characterize HIV infection. Continued gut mucosal dysfunction during treatment and its relationship to CD4(+) T-cell recovery has not been well described. Design: A cross-sectional study was performed of antiretroviral therapy (ART)-suppressed (immunologic responders with CD4(+) > 500 cells/mu l and immunologic nonresponders with CD4(+) < 350 cells/mu l), untreated HIV-infected, and seronegative participants consenting to gut biopsies and a blood draw. Methods: Neutrophil infiltration as a surrogate response to epithelial breach, colorectal epithelial proliferation as a measure of repair, and mucosal apoptosis by immunohistochemistry were determined in gut biopsies. Plasma markers of monocyte activation (sCD14), immune activation (interleukin-6), and indoleamine 2,3-dioxygenase-1 activity (plasma kynurenine/tryptophanratio) were concurrently measured. Results: Each HIV-infected group had greater neutrophil infiltration than controls. Similarly, untreated HIV-infected participants and ART-suppressed immunologic responders had increased epithelial proliferation compared with controls, but immunologic nonresponders had no appreciable increase in epithelial proliferation despite elevated neutrophil infiltration. The CD4(+) T-cell count was positively correlated with epithelial proliferation and was modestly negatively correlated with neutrophil infiltration in ART-suppressed patients. Epithelial proliferation was inversely correlated with mucosal apoptosis, and apoptosis was linked to plasma sCD14 and modestly to kynurenine/tryptophan ratio. Conclusions: Neutrophil infiltration and mucosal apoptosis remain abnormally high despite ART. Epithelial proliferation increases in HIV, but may be impaired in immunologic nonresponders. Whether mucosal apoptosis is a cause or consequence of epithelial proliferative defects is unclear, but appears to be associated with systemic inflammation. The impact of ART and interventions targeting the gut epithelial barrier in treated HIV infection warrant further investigation. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Somsouk, Ma] Univ Calif San Francisco, Dept Med, Div Gastroenterol, San Francisco, CA USA. [Estes, Jacob D.; Deleage, Claire] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Dunham, Richard M.; Albright, Rebecca; McCune, Joseph M.] Univ Calif San Francisco, Dept Med, Div Expt Med, San Francisco, CA USA. [Inadomi, John M.] Univ Washington, Dept Med, Div Gastroenterol, Washington, DC USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Deeks, Steven G.; Hunt, Peter W.] Univ Calif San Francisco, Dept Med, Div HIV AIDS, San Francisco, CA USA. RP Somsouk, M (reprint author), 1001 Potrero Ave, San Francisco, CA 94110 USA. EM somsoukma@medsfgh.ucsf.edu FU National Cancer Institute [K23 CA157929]; National Institute of Allergy and Infectious Disease [P30 AI27763]; NIH [R24 AI067039]; federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Funding: This work was supported by the National Cancer Institute (K23 CA157929 to M.S.), the National Institute of Allergy and Infectious Disease (P30 AI27763), NIH grant number: R24 AI067039 and in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 29 Z9 30 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JAN 2 PY 2015 VL 29 IS 1 BP 43 EP 51 DI 10.1097/QAD.0000000000000511 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AU4NB UT WOS:000345586900006 PM 25387317 ER PT J AU Lipshultz, SE Williams, PL Zeldow, B Wilkinson, JD Rich, KC van Dyke, RB Seage, GR Dooley, LB Kaltman, JR Siberry, GK Mofenson, LM Shearer, WT Colan, SD AF Lipshultz, Steven E. Williams, Paige L. Zeldow, Bret Wilkinson, James D. Rich, Kenneth C. van Dyke, Russell B. Seage, George R., III Dooley, Laurie B. Kaltman, Jonathan R. Siberry, George K. Mofenson, Lynne M. Shearer, William T. Colan, Steven D. CA Pediat HIV AIDS Cohort Study PHACS TI Cardiac effects of in-utero exposure to antiretroviral therapy in HIV-uninfected children born to HIV-infected mothers SO AIDS LA English DT Article DE antiretroviral drugs; cardiac; HIV; pediatrics; toxicity ID POSSIBLE MITOCHONDRIAL DYSFUNCTION; IDIOPATHIC DILATED CARDIOMYOPATHY; ZIDOVUDINE; TRANSMISSION; MYOCARDITIS; PREVENTION; TOXICITY; ALCOHOL; INFANTS; DESIGN AB Objectives: We evaluated the potential cardiac effects of in-utero exposures to antiretroviral drugs in HIV-exposed but uninfected (HEU) children. Design and methods: We compared echocardiographic parameters of left ventricular function (ejection fraction, fractional shortening, and stress-velocity index) and structure (left ventricular dimension, posterior wall/septal thickness, mass, thickness-to-dimension ratio, and wall stress) (expressed as Z-scores to account for age and body surface area) between HEU and HIV-unexposed cohorts from the Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring for ART Toxicities study. Within the HEU group, we investigated the associations between the echocardiographic Z-scores and in-utero exposures to maternal antiretroviral drugs. Results: There were no significant differences in echocardiographic Z-scores between 417 HEU and 98 HIV-unexposed children aged 2-7 years. Restricting the analysis to HEU children, first-trimester exposures to combination antiretroviral therapy (a regimen including at least three antiretroviral drugs) and to certain specific antiretroviral drugs were associated with significantly lower stress-velocity Z-scores (mean decreases of 0.22-0.40 SDs). Exposure to combination antiretroviral therapy was also associated with lower left ventricular dimension Z-scores (mean decrease of 0.44 SD). First-trimester exposure to combination antiretroviral therapy was associated with higher mean left ventricular posterior wall thickness and lower mean left ventricular wall stress Z-scores. Conclusion: There was no evidence of significant cardiac toxicity of perinatal combination antiretroviral therapy exposure in HEU children. Subclinical differences in left ventricular structure and function with specific in-utero antiretroviral exposures indicate the need for a longitudinal cardiac study in HEU children to assess long-term cardiac risk and cardiac monitoring recommendations. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Lipshultz, Steven E.; Wilkinson, James D.] Wayne State Univ, Sch Med, Detroit, MI 48201 USA. [Lipshultz, Steven E.; Wilkinson, James D.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Lipshultz, Steven E.] Univ Miami, Leonard M Miller Sch Med, Miami, FL USA. [Williams, Paige L.; Zeldow, Bret; Seage, George R., III] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Rich, Kenneth C.] Univ Illinois, Chicago, IL USA. [van Dyke, Russell B.] Tulane Univ, Hlth Sci Ctr, New Orleans, LA 70118 USA. [Dooley, Laurie B.] Frontier Sci Technol & Res Fdn, Amherst, NY USA. [Kaltman, Jonathan R.] NHLBI, Bethesda, MD 20892 USA. [Siberry, George K.; Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Shearer, William T.] Baylor Coll Med, Houston, TX 77030 USA. [Shearer, William T.] Texas Childrens Hosp, Houston, TX 77030 USA. [Colan, Steven D.] Boston Childrens Hosp, Boston, MA USA. RP Lipshultz, SE (reprint author), Wayne State Univ, Sch Med, Dept Pediat, 3901 Beaubien Blvd,1K40, Detroit, MI 48201 USA. EM slipshultz@med.wayne.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]; Tulane University School of Medicine [HD052104]; National Institutes of Health [HD052102, HD052104] FX Funding/support: 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) and the Tulane University School of Medicine (HD052104). Data management services were provided by Frontier Science and Technology Research Foundation, and regulatory services and logistical support were provided by Westat, Inc.; Sources of funding: National Institutes of Health (HD052102; HD052104). NR 37 TC 9 Z9 9 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JAN 2 PY 2015 VL 29 IS 1 BP 91 EP 100 DI 10.1097/QAD.0000000000000499 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AU4NB UT WOS:000345586900012 PM 25562493 ER PT J AU Brunoni, AR Machado-Vieira, R Zarate, CA Vieira, ELM Valiengo, L Bensenor, IM Lotufo, PA Gattaz, WF Teixeira, AL AF Brunoni, Andre R. Machado-Vieira, Rodrigo Zarate, Carlos A., Jr. Vieira, Erica L. M. Valiengo, Leandro Bensenor, Isabela M. Lotufo, Paulo A. Gattaz, Wagner F. Teixeira, Antonio L. TI Assessment of non-BDNF neurotrophins and GDNF levels after depression treatment with sertraline and transcranial direct current stimulation in a factorial, randomized, sham-controlled trial (SELECT-TDCS): An exploratory analysis SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Article DE GDNF; Major depressive disorder; Neurotrophins; Sertraline; Transcranial direct current stimulation ID ELECTRICAL-CURRENT THERAPY; LATE-LIFE DEPRESSION; NERVE GROWTH-FACTOR; MAJOR DEPRESSION; ANTIDEPRESSANT TREATMENT; MOOD DISORDERS; INDUCED NEUROPLASTICITY; BRAIN-STIMULATION; DC STIMULATION; PLASMA-LEVELS AB The neurotrophic hypothesis of depression states that the major depressive episode is associated with lower neurotrophic factors levels, which increase with amelioration of depressive symptoms. However, this hypothesis has not been extended to investigate neurotrophic factors other than the brain-derived neurotrophic factor (BDNF). We therefore explored whether plasma levels of neurotrophins 3 (NT-3) and 4 (NT-4), nerve growth factor (NGF) and glial cell line derived neurotrophic factor (GDNF) changed after antidepressant treatment and correlated with treatment response. Seventy-three patients with moderate-to-severe, antidepressant-free unipolar depression were assigned to a pharmacological (sertraline) and a non-pharmacological (transcranial direct current stimulation, tDCS) intervention in a randomized, 2 x 2, placebo-controlled design. The plasma levels of NT-3, NT-4, NGF and GDNF were determined by enzyme-linked immunosorbent assay before and after a 6-week treatment course and analyzed according to clinical response and allocation group. We found that tDCS and sertraline (separately and combined) produced significant improvement in depressive symptoms. Plasma levels of all neurotrophic factors were similar across groups at baseline and remained significantly unchanged regardless of the intervention and of clinical response. Also, baseline plasma levels were not associated with clinical response. To conclude, in this 6-week placebo-controlled trial, NT-3, NT-4, NGF and GDNF plasma levels did not significantly change with sertraline or tDCS. These data suggest that these neurotrophic factors are not surrogate biomarkers of treatment response or involved in the antidepressant mechanisms of tDCS. (C) 2014 Elsevier Inc. All rights reserved. C1 [Brunoni, Andre R.; Valiengo, Leandro; Bensenor, Isabela M.; Lotufo, Paulo A.] Univ Sao Paulo, Univ Hosp, Ctr Clin & Epidemiol Res, BR-05508000 Sao Paulo, Brazil. [Brunoni, Andre R.; Valiengo, Leandro; Bensenor, Isabela M.; Lotufo, Paulo A.] Univ Sao Paulo, Univ Hosp, Interdisciplinary Ctr Appl Neuromodulat CINA, BR-05508000 Sao Paulo, Brazil. [Brunoni, Andre R.; Valiengo, Leandro] Univ Sao Paulo, Fac Med, Dept & Inst Psychiat, SIN, BR-05508000 Sao Paulo, Brazil. [Brunoni, Andre R.; Machado-Vieira, Rodrigo; Valiengo, Leandro; Gattaz, Wagner F.] Univ Sao Paulo, Dept & Inst Psychiat, Lab Neurosci LIM27, BR-05508000 Sao Paulo, Brazil. [Machado-Vieira, Rodrigo; Zarate, Carlos A., Jr.] NIMH, Intramural Res Program, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Vieira, Erica L. M.; Teixeira, Antonio L.] Fac Med Minas Gerais, Interdisciplinary Lab Med Invest, Belo Horizonte, MG, Brazil. RP Brunoni, AR (reprint author), Univ Sao Paulo, Univ Hosp, Ctr Clin & Epidemiol Res, Av Prof Lineu Prestes 2565,3o Andar, BR-05508000 Sao Paulo, Brazil. EM brunoni@usp.br RI Lotufo, Paulo/A-9843-2008; Brunoni, Andre/H-8394-2012; Vieira, Erica/A-1976-2013; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI Lotufo, Paulo/0000-0002-4856-8450; Brunoni, Andre/0000-0002-6310-3571; Vieira, Erica/0000-0002-4147-5614; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU FAPESP (Sao Paulo Research Foundation [2009/05728-7]; FAPEMIG; CNPq; NARSAD Young Investigator from the Brain & Behavior Research Foundation [20493]; FAPESP Young Researcher from the Sao Paulo State Foundation [20911-5]; National Council for Scientific and Technological Development (CNPq) [470904]; Associacao Beneficente Alzira Denise da Silva (ABADHS) FX This study was partially funded by FAPESP (Sao Paulo Research Foundation, Grant Number: 2009/05728-7), FAPEMIG and CNPq. The sponsors played no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, and preparation, review or approval of the manuscript. A.R.B. is supported by the following grants: 2013 NARSAD Young Investigator from the Brain & Behavior Research Foundation (Grant Number 20493), 2013 FAPESP Young Researcher from the Sao Paulo State Foundation (Grant Number 20911-5) and National Council for Scientific and Technological Development (CNPq, Grant Number 470904). C.A.Z. is listed as a coinventor on a patent application for the use of ketamine and its metabolites in major depression. C.A.Z. has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government. The Laboratory of Neuroscience receives financial support from the Associacao Beneficente Alzira Denise da Silva (ABADHS). NR 59 TC 8 Z9 8 U1 2 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD JAN 2 PY 2015 VL 56 BP 91 EP 96 DI 10.1016/j.pnpbp.2014.08.009 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AU3PR UT WOS:000345526400012 PM 25172025 ER PT J AU Loch, AA Zanetti, MV de Sousa, RT Chaim, TM Serpa, MH Gattaz, WF Teixeira, AL Machado-Vieira, R AF Loch, Alexandre A. Zanetti, Marcus V. de Sousa, Rafael T. Chaim, Tiffany M. Serpa, Mauricio H. Gattaz, Wagner F. Teixeira, Antonio L. Machado-Vieira, Rodrigo TI Elevated neurotrophin-3 and neurotrophin 4/5 levels in unmedicated bipolar depression and the effects of lithium SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Article DE Biomarkers; Bipolar disorder; Lithium; Neurotrophic; Treatment ID OXIDATIVE STRESS; MOOD DISORDERS; IN-VIVO; NEURONS; EPISODES; SERUM; BDNF; HIPPOCAMPAL; EXPRESSION; NT-3 AB Background: Bipolar disorder (BD) has been associated with diverse abnormalities in neural plasticity and cellular resilience. Neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) support synaptic neuronal survival and differentiation. NT-3 and NT-4/5 levels were found to be altered in BD, potentially representing a physiological response against cellular stress. However, the use of psychopharmacological agents and heterogeneous mood states may constitute important biases in such studies. Thus, we aimed to assess NT-3 and NT-4/5 levels in medication-free BD type I or II individuals in a current depressive episode, before and after 6weeks of lithium monotherapy and matched with healthy controls. Methods: Twenty-three patients with BD type I or II during a depressive episode and 28 healthy controls were studied. Patients were required to have a 21-item Hamilton Depression Rating Scale score >= 18 and had not undergone any psychopharmacological treatment for at least 6 weeks prior to study entry. Patients were treated with lithium for 6 weeks and plasma NT-3 and NT-4/5 levels were determined at baseline and end point using ELISA method. Results: Baseline plasma levels of both NT-3 and NT-4/5 were significantly increased in acutely depressed BD subjects in comparison to healthy controls (p = 0.040 and 0.039, respectively). The NT-3 and NT-4/5 levels did not significantly change after lithium treatment. NT-3 and NT-4/5 levels were positively correlated to illness duration in BD (p = 0.032 and 0.034, respectively). Conclusion: Our findings suggest that NT-3 and NT-4/5 levels are increased in the depressive phase of BD, which seems directly associated with illness duration. The increased levels of NT-3 and NT-4/5 may underlie a biological response to cellular stress associated with the course of BD. (C) 2014 Elsevier Inc. All rights reserved. C1 [Loch, Alexandre A.; Zanetti, Marcus V.; de Sousa, Rafael T.; Gattaz, Wagner F.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Dept & Inst Psychiat, Lab Neurosci, LIM 27, Sao Paulo, Brazil. [Zanetti, Marcus V.; Gattaz, Wagner F.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo, Brazil. [Zanetti, Marcus V.; Chaim, Tiffany M.; Serpa, Mauricio H.] Univ Sao Paulo, Dept & Inst Psychiat, Lab Psychiat Neuroimaging, LIM 21, Sao Paulo, Brazil. [Machado-Vieira, Rodrigo] NIMH, ETPB, NIH, Bethesda, MD USA. [Teixeira, Antonio L.] Fac Med Minas Gerais, Interdisciplinary Lab Med Invest, Belo Horizonte, MG, Brazil. RP Machado-Vieira, R (reprint author), Univ Sao Paulo, Dept & Inst Psychiat, Lab Neurosci LIM27, Rua Dr Ovidio Pires Campos 785, Sao Paulo, Brazil. EM machadovieirar@gmail.com RI Loch, Alexandre/C-8526-2011; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI Loch, Alexandre/0000-0002-0006-8107; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Sao Paulo Research Foundation (FAPESP, Brazil) [2009/14891-9, 2013/03905-4]; CNPq; Fapemig FX This study was sponsored by Sao Paulo Research Foundation (FAPESP, Brazil) (2009/14891-9, RM-V), CNPq, and Fapemig. Dr. Marcus V. Zanetti is funded by FAPESP, Brazil (process no. 2013/03905-4). NR 32 TC 1 Z9 1 U1 1 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD JAN 2 PY 2015 VL 56 BP 243 EP 246 DI 10.1016/j.pnpbp.2014.09.014 PG 4 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AU3PR UT WOS:000345526400034 PM 25290636 ER PT J AU Pecoraro, A Mimiaga, M O'Cleirigh, C Safren, SA Blokhina, E Verbitskaya, E Yaroslavtseva, T Ustinov, A Lioznov, DA Zvartau, E Krupitsky, E Woody, GE AF Pecoraro, Anna Mimiaga, Matthew O'Cleirigh, Conall Safren, Steven A. Blokhina, Elena Verbitskaya, Elena Yaroslavtseva, Tatiana Ustinov, Andrey Lioznov, Dmitry A. Zvartau, Edwin Krupitsky, Evgeny Woody, George E. TI Depression, substance use, viral load, and CD4+ count among patients who continued or left antiretroviral therapy for HIV in St. Petersburg, Russian Federation SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE attrition; retention; Russian Federation; AIDS; HIV ID PREVENTING RELAPSE; RELEASE NALTREXONE; OPIOID DEPENDENCE; LENINGRAD REGION; RANDOMIZED-TRIAL; ADHERENCE; DRUG; FACILITATORS; MEDICATION; BARRIERS AB Antiretroviral therapy (ART) became more widely available in the Russian Federation in 2006 when the Global Fund made a contribution to purchase ART with a mandate to increase numbers of patients receiving it. Funds were distributed to AIDS Centers and selected hospitals, and numbers quickly increased. Though ART is highly effective for adherent patients, dropout has been a problem; thus understanding characteristics of patients who remain on ART vs. those who leave treatment may provide information to facilitate engagement. We retrospectively assessed depression, hopelessness, substance use, viral load, and CD4+ counts of 120 patients who dropped out of ART for >= 12 months (Lost-to-Care, LTCs) and 120 who continued for >= 12 months (Engaged-in-Care, EICs). As expected, LTCs had higher viral loads and depression, lower CD4+ counts, more alcohol, heroin, and injection drug use in the past 30 days. A binary logistic regression with Center for Epidemiologic Studies Depression score, Beck Hopelessness score, whether drugs/alcohol had ever prevented them from taking ART, and past 30 days' alcohol use [chi(2)(4) = 64.27, p = .0.000] correctly classified 74.5% of participants as LTC or EIC, suggesting that integrated treatment for substance use, psychiatric, and HIV could reduce dropout and improve outcomes. C1 [Pecoraro, Anna; Woody, George E.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Pecoraro, Anna; Woody, George E.] NIDA Clin Trials Network, Philadelphia, PA USA. [Mimiaga, Matthew] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Mimiaga, Matthew; O'Cleirigh, Conall; Safren, Steven A.] Harvard Univ, Sch Med, Boston, MA USA. [O'Cleirigh, Conall; Safren, Steven A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Blokhina, Elena; Verbitskaya, Elena; Yaroslavtseva, Tatiana; Ustinov, Andrey; Lioznov, Dmitry A.; Zvartau, Edwin; Krupitsky, Evgeny] First Pavlov State Med Univ, Valdman Inst Pharmacol, St Petersburg, Russia. [Krupitsky, Evgeny] Bekhterev Res Psychoneurol Inst, St Petersburg, Russia. RP Pecoraro, A (reprint author), Univ Penn, Sch Med, Philadelphia, PA 19104 USA. EM annp@mail.med.upenn.edu RI Verbitskaya, Elena/N-3867-2015; Lioznov, Dmitry/J-2539-2013 OI Verbitskaya, Elena/0000-0003-3770-993X; Lioznov, Dmitry/0000-0003-3643-7354 FU NIDA NIH HHS [R01 DA026336]; PEPFAR NR 25 TC 8 Z9 8 U1 0 U2 9 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD JAN 2 PY 2015 VL 27 IS 1 BP 86 EP 92 DI 10.1080/09540121.2014.959464 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA AS6UL UT WOS:000344397500015 PM 25264710 ER PT J AU Walsh, KS Paltin, I Gioia, GA Isquith, P Kadan-Lottick, NS Neglia, JP Brouwers, P AF Walsh, Karin S. Paltin, Iris Gioia, Gerard A. Isquith, Peter Kadan-Lottick, Nina S. Neglia, Joseph P. Brouwers, Pim TI Everyday executive function in standard-risk acute lymphoblastic leukemia survivors SO CHILD NEUROPSYCHOLOGY LA English DT Article DE Central nervous system; Neuropsychology; Leukemia; Neurobehavioral manifestations; Survivors ID TRAUMATIC BRAIN-INJURY; ACUTE LYMPHOCYTIC-LEUKEMIA; LONG-TERM SURVIVORS; CHILDHOOD LEUKEMIA; COGNITIVE IMPAIRMENT; CRANIAL IRRADIATION; CHILDREN; CHEMOTHERAPY; PERFORMANCE; ATTENTION AB We aimed to evaluate parent-rated executive function (EF) in pediatric standard risk acute lymphoblastic leukemia (SR-ALL) survivors compared to a healthy comparison (HC) group. We hypothesized that SR-ALL survivors would have greater reported executive dysfunction compared to HC, and that those younger at the time of treatment would demonstrate greater EF difficulties. A sample of 256 SR-ALL survivors evaluated an average nine years after treatment were compared to HC matched for gender, assessment age, and maternal education. Profile analysis was used to compare the groups across EF scales on the BRIEF. The prevalence of clinical elevations in the groups was compared via chi square, and odds ratios were calculated. Regression models were applied to examine the role of age at diagnosis and age at assessment in reported EF. Results indicated that SR-ALL survivors' mean scores of EF are similar to HC, except for flexibility and initiation. Survivors were rated as having clinical impairments with flexibility, initiation, working memory, and emotional control at rates two to three times that of HC. The risk of working memory and self-monitoring deficits was greater in survivors who were older when assessed. There was no relationship between age at diagnosis or treatment regimen on EF. These findings suggest sparing of extensive and severe EF deficits in SR-ALL survivors overall. However, a subset of survivors displays clinically significant executive dysfunction. There appears to be a heightened susceptibility to disrupted metacognitive functions as survivors age. This has implications for how we monitor neurocognitive development and functioning of SR-ALL survivors, and highlights opportunities for cognitive interventions. C1 [Walsh, Karin S.; Gioia, Gerard A.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Walsh, Karin S.; Gioia, Gerard A.] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Paltin, Iris] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. [Paltin, Iris] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Isquith, Peter] Geisel Sch Med Dartmouth, Norwich, VT USA. [Kadan-Lottick, Nina S.] Yale Univ, Sch Med, New Haven, CT USA. [Kadan-Lottick, Nina S.] Yale Sect Pediat Hematol Oncol, New Haven, CT USA. [Neglia, Joseph P.] Univ Minnesota, Amplatz Childrens Hosp, Minneapolis, MN USA. [Brouwers, Pim] Baylor Coll Med, Houston, TX 77030 USA. [Brouwers, Pim] NIMH, Div AIDS Res, NIH, Rockville, MD 20857 USA. RP Walsh, KS (reprint author), Childrens Natl Med Ctr, 111 Michigan Ave, Washington, DC 20010 USA. EM kwalsh@childrensnational.org OI Walsh, Karin/0000-0001-9637-2164 FU American Cancer Society; St. Baldrick's Foundation FX This study was supported by research funding by the American Cancer Society to Joseph Neglia and Nina Kadan-Lottick. Dr. Kadan-Lottick's effort was additionally funded as a St. Baldrick's Foundation Scholar. NR 38 TC 6 Z9 6 U1 1 U2 20 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0929-7049 EI 1744-4136 J9 CHILD NEUROPSYCHOL JI Child Neuropsychol. PD JAN 2 PY 2015 VL 21 IS 1 BP 78 EP 89 DI 10.1080/09297049.2013.876491 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA AS6TC UT WOS:000344394100005 PM 24428397 ER PT J AU Resnik, DB Neal, T Raymond, A Kissling, GE AF Resnik, David B. Neal, Talicia Raymond, Austin Kissling, Grace E. TI Research Misconduct Definitions Adopted by U.S. Research Institutions SO ACCOUNTABILITY IN RESEARCH-POLICIES AND QUALITY ASSURANCE LA English DT Article DE research misconduct; policies; ethics; integrity; definitions AB In 2000, the U.S. federal government adopted a uniform definition of research misconduct as fabrication, falsification, or plagiarism (FFP), which became effective in 2001. Institutions must apply this definition of misconduct to federally-funded research to receive funding. While institutions are free to adopt definitions of misconduct that go beyond the federal standard, it is not known how many do. We analyzed misconduct policies from 183 U.S. research institutions and coded them according to thirteen different types of behavior mentioned in the misconduct definition. We also obtained data on the institution's total research funding and public vs. private status, and the year it adopted the definition. We found that more than half (59%) of the institutions in our sample had misconduct policies that went beyond the federal standard. Other than FFP, the most common behaviors included in definitions were "other serious deviations" (45.4%), "significant or material violations of regulations" (23.0%), "misuse of confidential information" (15.8%), "misconduct related to misconduct" (14.8%), "unethical authorship other than plagiarism" (14.2%), "other deception involving data manipulation" (13.1%), and "misappropriation of property/theft" (10.4%). Significantly more definitions adopted in 2001 or later went beyond the federal standard than those adopted before 2001 (73.2% vs. 26.8%), and significantly more definitions adopted by institutions in the lower quartile of total research funding went beyond the federal standard than those adopted by institutions in the upper quartiles. Public vs. private status was not significantly associated with going beyond the federal standard. C1 [Resnik, David B.; Kissling, Grace E.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Neal, Talicia] Charlotte Sch Law, Charlotte, NC USA. [Raymond, Austin] Elon Law Sch, Greensboro, NC 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 ES102646-01] NR 9 TC 5 Z9 6 U1 2 U2 32 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0898-9621 EI 1545-5815 J9 ACCOUNT RES JI Account. Res. PD JAN 2 PY 2015 VL 22 IS 1 BP 14 EP 21 DI 10.1080/08989621.2014.891943 PG 8 WC Medical Ethics SC Medical Ethics GA AS4KS UT WOS:000344245200002 PM 25275621 ER PT J AU Matsunaga, F Gao, L Huang, XP Saven, JG Roth, BL Liu, RY AF Matsunaga, Felipe Gao, Lu Huang, Xi-Ping Saven, Jeffery G. Roth, Bryan L. Liu, Renyu TI Molecular interactions between general anesthetics and the 5HT(2B) receptor SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Article DE propofol; anesthetics; serotonin receptor; isoflurane ID PROTEIN-COUPLED RECEPTORS; 5-HT3 RECEPTORS; CARDIOVASCULAR-SYSTEM; VOLATILE ANESTHETICS; ENDOTHELIAL-CELLS; XENOPUS OOCYTES; NITRIC-OXIDE; PROPOFOL; SEROTONIN; BINDING AB Background: Serotonin modulates many processes through a family of seven serotonin receptors. However, no studies have screened for interactions between general anesthetics currently in clinical use and serotonergic G-protein-coupled receptors (GPCRs). Given that both intravenous and inhalational anesthetics have been shown to target other classes of GPCRs, we hypothesized that general anesthetics might interact directly with some serotonin receptors and thus modify their function. Methods: Radioligand binding assays were performed to screen serotonin receptors for interactions with propofol and isoflurane as well as for affinity determinations. Docking calculations using the crystal structure of 5-HT2B were performed to computationally confirm the binding assay results and locate anesthetic binding sites. Results: The 5-HT2B class of receptors interacted significantly with both propofol and isoflurane in the primary screen. The affinities for isoflurane and propofol were determined to be 7.78 and .95 mu M, respectively, which were at or below the clinical concentrations for both anesthetics. The estimated free energy derived from docking calculations for propofol (-6.70 kcal/mol) and isoflurane (-5.10 kcal/mol) correlated with affinities from the binding assay. The anesthetics were predicted to dock at a pharmacologically relevant binding site of 5HT(2B). Conclusions: The molecular interactions between propofol and isoflurane with the 5-HT2B class of receptors were discovered and characterized. This finding implicates the serotonergic GPCRs as potential anesthetic targets. C1 [Matsunaga, Felipe; Liu, Renyu] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Gao, Lu; Saven, Jeffery G.] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC USA. RP Liu, RY (reprint author), Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, 336 John Morgan Bldg,3620 Hamilton Walk, Philadelphia, PA 19104 USA. EM liur@uphs.upenn.edu RI Roth, Bryan/F-3928-2010 FU Department of Anesthesiology and Critical Care at University of Pennsylvania; Foundation for Anesthesia Education and Research; NIH [K08-GM-093115-01, P01GM055876]; NSF [DMR-1120901]; National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C] FX This research was supported by departmental funding from the Department of Anesthesiology and Critical Care at University of Pennsylvania (PI RL), funding from the Foundation for Anesthesia Education and Research (PI, RL), NIH [grant number K08-GM-093115-01] (PI: RL). Jeffery G. Saven acknowledges support from NIH [grant number P01GM055876] and NSF [grant number DMR-1120901]. This work is also supported by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2008-00025-C (NIMH PDSP), which is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. NR 55 TC 2 Z9 2 U1 3 U2 27 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0739-1102 EI 1538-0254 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD JAN 2 PY 2015 VL 33 IS 1 BP 211 EP 218 DI 10.1080/07391102.2013.869483 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AR9QP UT WOS:000343910000017 PM 24365264 ER PT J AU Gu, DY Yang, Y Xin, XL Aisa, HA Ito, Y AF Gu, Dongyu Yang, Yi Xin, Xuelei Aisa, Haji Akber Ito, Yoichiro TI Novel Design for Centrifugal Counter-Current Chromatography: VI. Ellipsoid Column SO JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES LA English DT Article DE rotary-seal-free centrifuge; hydrostatic counter-current chromatographic system; centrifugal counter-current chromatography; retention of the stationary phase; protein separation; peak resolution; ellipsoid column ID LARGE-SCALE SEPARATION; ALKALOIDS AB A novel ellipsoid column was designed for centrifugal counter-current chromatography. Performance of the ellipsoid column with a capacity of 3.4mL was examined with three different solvent systems composed of 1-butanol-acetic acid-water (4:1:5, v/v/v) (BAW), hexane-ethyl acetate-methanol-0.1M HCl (1:1:1:1, v/v/v/v) (HEMH), and 12.5% (w/w) PEG1000 and 12.5% (w/w) dibasic potassium phosphate in water (PEG-DPP) each with suitable test samples. In dipeptide separation with BAW system, both stationary phase retention (Sf) and peak resolution (Rs) of the ellipsoid column were much higher at 0 degrees column angle (column axis parallel to the centrifugal force) than at 90 degrees column angle (column axis perpendicular to the centrifugal force), where elution with the lower phase at a low flow rate produced the best separation yielding Rs at 2.02 with 27.8% Sf at a flow rate of 0.07mL/min. In the DNP-amino acid separation with HEMW system, the best results were obtained at a flow rate of 0.05ml/min with 31.6% Sf yielding high Rs values at 2.16 between DNP-DL-glu and DNP-beta-ala peaks and 1.81 between DNP-beta-ala and DNP-L-ala peaks. In protein separation with PEG-DPP system, lysozyme and myolobin were resolved at Rs of 1.08 at a flow rate of 0.03mL/min with 38.9% Sf. Most of those Rs values exceed those obtained from the figure-8 column under similar experimental conditions previously reported. C1 [Gu, Dongyu; Yang, Yi; Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Gu, Dongyu; Yang, Yi; Xin, Xuelei; Aisa, Haji Akber] Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Key Lab Xinjiang Indigenous Med Plants Resource U, Urumqi, Peoples R China. [Gu, Dongyu] Dalian Ocean Univ, Sch Marine Sci & Environm Engn, Dalian, Peoples R China. RP Ito, Y (reprint author), NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, 10 Ctr Dr,Bldg 10,Room 8N230, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov FU China National Funds for Distinguished Young Scientists [30925045]; West Light Foundation of The Chinese Academy of Sciences [XBBS201011]; Major State Basic Research Development Program [2011CB512013] FX This work was funded by the China National Funds for Distinguished Young Scientists (Grant No. 30925045), the West Light Foundation of The Chinese Academy of Sciences (No. XBBS201011), and the Major State Basic Research Development Program (Grant No. 2011CB512013). NR 20 TC 2 Z9 2 U1 1 U2 12 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 JAN 2 PY 2015 VL 38 IS 1 BP 68 EP 73 DI 10.1080/10826076.2014.883533 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AS6NZ UT WOS:000344381300010 PM 25309116 ER PT B AU Ernst, M Hale, EA Balderston, N Torrisi, S AF Ernst, Monique Hale, Elizabeth A. Balderston, Nicholas Torrisi, Salvatore BE Ewing, SWF Witkiewitz, K Filbey, FM TI Introduction to Functional Brain Connectivity: Potential Contributions to Understanding Adolescent Vulnerability to Substance Abuse SO Neuroimaging and Psychosocial Addiction Treatment: An Integrative Guide for Researchers and Clinicians LA English DT Editorial Material; Book Chapter ID RESTING STATE FMRI; INDEPENDENT COMPONENT ANALYSIS; INHIBITORY CONTROL; LIFE-SPAN; NETWORKS; ARCHITECTURE; MRI; NEURODEVELOPMENT; CHILDHOOD; ASYMMETRY C1 [Ernst, Monique] NIMH, Dept Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. [Hale, Elizabeth A.; Balderston, Nicholas; Torrisi, Salvatore] NIMH, NIH, Bethesda, MD 20892 USA. RP Ernst, M (reprint author), NIMH, Dept Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. NR 69 TC 0 Z9 0 U1 0 U2 0 PU PALGRAVE PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, ENGLAND BN 978-1-137-36265-0; 978-1-137-36264-3 PY 2015 BP 181 EP 199 D2 10.1057/9781137362650 PG 19 WC Substance Abuse; Neuroimaging SC Substance Abuse; Neurosciences & Neurology GA BG4NC UT WOS:000389017700013 ER PT J AU Bornstein, MH AF Bornstein, Marc H. BE Elliot, AJ Fairchild, MD Franklin, A TI Emergence and early development of color vision and color perception SO HANDBOOK OF COLOR PSYCHOLOGY LA English DT Article; Book Chapter ID YOUNG HUMAN INFANTS; MODULATION-SENSITIVE MECHANISM; 2-MONTH-OLD HUMAN INFANTS; WALLACHS RATIO RULE; SHORT-TERM-MEMORY; SPECTRAL SENSITIVITY; CONTRAST SENSITIVITY; 4-MONTH-OLD INFANTS; CATEGORICAL PERCEPTION; CHROMATIC DISCRIMINATION C1 [Bornstein, Marc H.] NICHHD, Child & Family Res, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), NICHHD, Child & Family Res, Bethesda, MD 20892 USA. NR 211 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-107-04323-7 PY 2015 BP 149 EP 179 D2 10.1017/CBO9781107337930 PG 31 WC Neurosciences; Psychology; Psychology, Multidisciplinary SC Neurosciences & Neurology; Psychology GA BG4EL UT WOS:000388685900008 ER PT J AU Azoury, SC Crompton, JG Straughan, DM Klemen, ND Reardon, ES Beresnev, TH Hughes, MS AF Azoury, Said C. Crompton, Joseph G. Straughan, David M. Klemen, Nicholas D. Reardon, Emily S. Beresnev, Tatiana H. Hughes, Marybeth S. TI Unknown primary nasopharyngeal melanoma presenting as severe recurrent epistaxis and hearing loss following treatment and remission of metastatic disease: A case report and literature review SO INTERNATIONAL JOURNAL OF SURGERY CASE REPORTS LA English DT Review DE Nasopharyngeal; Head and neck; Mucosal; Melanoma; Metastasis ID MUCOSAL MELANOMA; MALIGNANT-MELANOMA; SINONASAL MELANOMA; NASAL CAVITY; HEAD; NECK; EPIDEMIOLOGY; RADIATION AB INTRODUCTION: Primary nasopharyngeal melanoma is an exceedingly rare pathology with unclear etiology and oftentimes obscure clinical presentation. Despite improved diagnostic capabilities, these lesions are often diagnosed at an advanced stage and associated prognosis is poor, partly due to high rates of recurrences and metastasis. PRESENTATION OF CASE: A 74-year-old woman was diagnosed with metastatic melanoma to the liver, of unknown primary. Just prior to the time of diagnosis, she experienced several episodes of severe epistaxis which she managed conservatively. Her symptoms eventually subsided without further medical evaluation. The patient was initially treated with interleukin-2 (IL-2) for her advanced disease, but her cancer progressed. She was then enrolled in a protocol for percutaneous hepatic perfusion (PHP) with melphalan and had complete radiographic resolution of disease, yet her nosebleeds recurred and persisted despite conservative measures. Six years after her initial diagnosis, a nasopharyngoscopy demonstrated a pigmented lesion in the posterior nasopharynx. Surgical resection was performed (pathology consistent with mucosal melanoma) followed by radiation therapy. She has since had complete resolution of bleeding and shows no evidence of cancer. DISCUSSION: To our knowledge, this is the first report of a diagnosis of primary nasopharyngeal melanoma 6-years following complete remission of metastatic disease. Surgery remains the primary treatment for disease and symptom control in this setting. CONCLUSION: Timely diagnosis of nasopharyngeal melanomas remains challenging. Thorough clinical evaluations should be performed in such patients, and attention should be paid to recurrent and persistent symptoms, such as epistaxis and hearing loss. This may allow for earlier detection of primary disease. Published by Elsevier Ltd. on behalf of Surgical Associates Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Azoury, Said C.; Crompton, Joseph G.; Straughan, David M.; Klemen, Nicholas D.; Reardon, Emily S.; Beresnev, Tatiana H.; Hughes, Marybeth S.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Azoury, Said C.] Johns Hopkins Univ, Sch Med, Dept Surg, Johns Hopkins Hosp, Baltimore, MD 21218 USA. [Beresnev, Tatiana H.] Leidos Biomed Res Inc, Clin Monitoring Res Program, Frederick, MD USA. RP Azoury, SC (reprint author), NCI, NIH, Baltimore, MD 21287 USA. EM sazoury1@jhmi.edu NR 20 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2210-2612 J9 INT J SURG CASE REP JI Int. J. Surg. Case Rep. PY 2015 VL 10 BP 232 EP 235 DI 10.1016/j.ijscr.2015.03.053 PG 4 WC Surgery SC Surgery GA ED3FL UT WOS:000388734800063 PM 25898283 ER PT J AU Neychev, V Borruso, J AF Neychev, Vladimir Borruso, John TI Bowel ischemia and necrosis in anorexia nervosa: A case report and review of the literature SO INTERNATIONAL JOURNAL OF SURGERY CASE REPORTS LA English DT Review ID NECROTIZING COLITIS; EATING-DISORDERS; COMPLICATIONS; POPULATION AB INTRODUCTION: Bowel ischemia and necrosis is an uncommon complication of anorexia nervosa (AN), which may pose significant diagnostic and therapeutic challenges. The review of the existing literature shows that the mortality rate of this condition reaches 80%. CASE: We present a case of a 30 year old woman with long-standing AN complicated by ischemia and necrosis of the entire small bowel and the right hemicolon. CONCLUSION: A high index of suspicion of bowel ischemia is necessary when patients with AN present with abdominal symptoms. Timely diagnosis and treatment may prevent bowel necrosis and death. Published by Elsevier Ltd. on behalf of Surgical Associates Ltd. C1 [Neychev, Vladimir] NCI, Endocrine Oncol Branch, NIH, 10 Ctr Dr,CRC 3-5840, Bethesda, MD 20892 USA. [Borruso, John] Danbury Hosp, Dept Surg, Danbury, CT 06810 USA. RP Neychev, V (reprint author), NCI, Endocrine Oncol Branch, NIH, 10 Ctr Dr,CRC 3-5840, Bethesda, MD 20892 USA. EM vladimir.neychev@nih.gov NR 11 TC 3 Z9 3 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2210-2612 J9 INT J SURG CASE REP JI Int. J. Surg. Case Rep. PY 2015 VL 8 BP 141 EP 143 DI 10.1016/j.ijscr.2015.01.035 PG 3 WC Surgery SC Surgery GA ED3ET UT WOS:000388732900040 PM 25681813 ER PT B AU O'Toole, D Tang, LH Jensen, RT Falconi, M Pape, UF Kwekkeboom, D AF O'Toole, Dermot Tang, Laura H. Jensen, Robert T. Falconi, Massimo Pape, U. -F. Kwekkeboom, Dik BE OSullivan, B Brierley, JD DCruz, AK Fey, MF Pollock, R Vermorken, JB Huang, SH TI Neuroendocrine tumours SO UICC MANUAL OF CLINICAL ONCOLOGY, 9TH EDITION LA English DT Article; Book Chapter ID ENETS CONSENSUS GUIDELINES; MANAGEMENT; NEOPLASMS; METASTASES; FOREGUT; SYSTEM C1 [O'Toole, Dermot] St James Hosp, Trinity Ctr Hlth Sci, Dept Clin Med & Gastroenterol, Dublin, Ireland. [O'Toole, Dermot] Trinity Coll Dublin, Dublin, Ireland. [O'Toole, Dermot] St Vincents Univ Hosp, Dept Neuroendocrine Tumours, Dublin, Ireland. [Tang, Laura H.] Mem Sloan Kettering Canc, Dept Pathol, New York, NY USA. [Jensen, Robert T.] NIDDK, Cell Biol Sect, Digest Dis Branch, NIH, Bethesda, MD USA. [Falconi, Massimo] Salute & Vita Univ, Hosp San Raffaele, Pancreat Surg Unit, Milan, Italy. [Pape, U. -F.] Campus Virchow Klinikum, Dept Internal Med, Div Hepatol & Gastroenterol, Berlin, Germany. [Kwekkeboom, Dik] Erasmus MC, Dept Nucl Med, Rotterdam, Netherlands. RP O'Toole, D (reprint author), St James Hosp, Trinity Ctr Hlth Sci, Dept Clin Med & Gastroenterol, Dublin, Ireland. NR 20 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, WEST SUSSEX, ENGLAND BN 978-1-119-01313-6; 978-1-4443-3244-5 PY 2015 BP 656 EP 673 D2 10.1002/9781119013143 PG 18 WC Oncology SC Oncology GA BG1BQ UT WOS:000386636800054 ER PT S AU Shin, HC Lu, L Kim, L Seff, A Yao, JH Summers, RM AF Shin, Hoo-Chang Lu, Le Kim, Lauren Seff, Ari Yao, Jianhua Summers, Ronald M. GP IEEE TI Interleaved Text/Image Deep Mining on a Large-Scale Radiology Database SO 2015 IEEE CONFERENCE ON COMPUTER VISION AND PATTERN RECOGNITION (CVPR) SE IEEE Conference on Computer Vision and Pattern Recognition LA English DT Proceedings Paper CT IEEE Conference on Computer Vision and Pattern Recognition (CVPR) CY JUN 07-12, 2015 CL Boston, MA SP IEEE AB Despite tremendous progress in computer vision, effective learning on very large-scale (> 100K patients) medical image databases has been vastly hindered. We present an interleaved text/image deep learning system to extract and mine the semantic interactions of radiology images and reports from a national research hospital's picture archiving and communication system. Instead of using full 3D medical volumes, we focus on a collection of representative similar to 216K 2D key images/slices (selected by clinicians for diagnostic reference) with text-driven scalar and vector labels. Our system interleaves between unsupervised learning (e.g., latent Dirichlet allocation, recurrent neural net language models) on document-and sentence-level texts to generate semantic labels and supervised learning via deep convolutional neural networks (CNNs) to map from images to label spaces. Disease-related key words can be predicted for radiology images in a retrieval manner. We have demonstrated promising quantitative and qualitative results. The large-scale datasets of extracted key images and their categorization, embedded vector labels and sentence descriptions can be harnessed to alleviate the deep learning "datahungry" obstacle in the medical domain. C1 [Shin, Hoo-Chang; Lu, Le; Kim, Lauren; Seff, Ari; Yao, Jianhua; Summers, Ronald M.] Natl Inst Hlth Clin Ctr, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Shin, HC (reprint author), Natl Inst Hlth Clin Ctr, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci, Bethesda, MD 20892 USA. EM hoochang.shin@nih.gov; le.lu@nih.gov; lauren.kim2@nih.gov; ari.seff@nih.gov; jyao@cc.nih.gov; rms@nih.gov NR 46 TC 1 Z9 1 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1063-6919 BN 978-1-4673-6964-0 J9 PROC CVPR IEEE PY 2015 BP 1090 EP 1099 PG 10 WC Computer Science, Artificial Intelligence SC Computer Science GA BG3KA UT WOS:000387959201012 ER PT B AU Bennett, JE AF Bennett, John E. BE Hospenthal, DR Rinaldi, MG TI Diagnostic Histopathology SO DIAGNOSIS AND TREATMENT OF FUNGAL INFECTIONS, SECOND EDITION SE Infectious Disease-Series LA English DT Article; Book Chapter C1 [Bennett, John E.] NIH, Lab Clin Infect Dis, Ctr Clin, Clin Ctr Room 12C103B,9000 Rockville Pike, Bethesda, MD USA. RP Bennett, JE (reprint author), NIH, Lab Clin Infect Dis, Ctr Clin, Clin Ctr Room 12C103B,9000 Rockville Pike, Bethesda, MD USA. EM jbennett@niaid.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND BN 978-3-319-13090-3; 978-3-319-13089-7 J9 INFECT DIS-SER PY 2015 BP 37 EP 43 DI 10.1007/978-3-319-13090-3_4 D2 10.1007/978-3-319-13090-3 PG 7 WC Infectious Diseases SC Infectious Diseases GA BF9SL UT WOS:000385855800005 ER PT B AU von Geldern, G Nath, A AF von Geldern, Gloria Nath, Avindra BE Demaerschalk, BM Wingerchuk, DM TI Central nervous system infections SO EVIDENCE-BASED NEUROLOGY: MANAGEMENT OF NEUROLOGICAL DISORDERS, 2ND EDITION LA English DT Article; Book Chapter ID HERPES-SIMPLEX ENCEPHALITIS; POLYMERASE-CHAIN-REACTION; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; ACTIVE ANTIRETROVIRAL THERAPY; ACUTE BACTERIAL-MENINGITIS; RECONSTITUTION INFLAMMATORY SYNDROME; CHILDHOOD TUBERCULOUS MENINGITIS; PLACEBO-CONTROLLED TRIAL; CRYPTOCOCCAL MENINGITIS; AMPHOTERICIN-B C1 [von Geldern, Gloria; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bldg 10-7C-103,10 Ctr Dr, Bethesda, MD 20892 USA. RP von Geldern, G (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bldg 10-7C-103,10 Ctr Dr, Bethesda, MD 20892 USA. NR 118 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, WEST SUSSEX, ENGLAND BN 978-1-119-06732-0; 978-0-470-65778-2 PY 2015 BP 131 EP 142 D2 10.1002/9781119067344 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA BF7RF UT WOS:000384349500015 ER PT B AU Rueda, C Fernandez, MA Barragan, S Peddada, SD AF Rueda, Cristina Fernandez, Miguel A. Barragan, Sandra Peddada, Shyamal D. BE Dryden, IL Kent, JT TI Some advances in constrained inference for ordered circular parameters in oscillatory systems SO GEOMETRY DRIVEN STATISTICS LA English DT Article; Book Chapter ID CYCLE-REGULATED GENES; CELL-CYCLE; FISSION YEAST; CIRCUMPLEX MODEL; CANCER TRIAL; EXPRESSION; REGRESSION; IDENTIFICATION; CLASSIFICATION; COORDINATION C1 [Rueda, Cristina; Fernandez, Miguel A.; Barragan, Sandra] Univ Valladolid, Dept Stat & OR, Valladolid, Spain. [Peddada, Shyamal D.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Rueda, C (reprint author), Univ Valladolid, Dept Stat & OR, Valladolid, Spain. NR 53 TC 0 Z9 0 U1 2 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, WEST SUSSEX, ENGLAND BN 978-1-118-86661-0; 978-1-118-86657-3 PY 2015 BP 97 EP 114 D2 10.1002/9781118866641 PG 18 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA BF8SL UT WOS:000385227600004 ER PT S AU Newman, DJ Cragg, GM AF Newman, David J. Cragg, Gordon M. BE Levin, JI TI Bioactive Macrocycles from Nature SO MACROCYCLES IN DRUG DISCOVERY SE RSC Drug Discovery Series LA English DT Article; Book Chapter ID HISTONE DEACETYLASE INHIBITOR; BRYOSTATIN ANTITUMOR MACROLIDES; MICROTUBULE-STABILIZING AGENTS; AZUMAMIDES-A-E; RAPAMYCIN AY-22,989; DRUG DISCOVERY; IN-VITRO; MYXOCOCCUS-XANTHUS; CANCER CELLS; HETEROLOGOUS EXPRESSION C1 [Newman, David J.; Cragg, Gordon M.] NCI, Nat Prod Branch, Dev Therapeut Program, DCTD,Frederick Natl Lab, POB B, Frederick, MD 21702 USA. RP Newman, DJ (reprint author), NCI, Nat Prod Branch, Dev Therapeut Program, DCTD,Frederick Natl Lab, POB B, Frederick, MD 21702 USA. EM dn22a@nih.gov NR 182 TC 4 Z9 4 U1 2 U2 2 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, CAMBRIDGE CB4 4WF, CAMBS, ENGLAND SN 2041-3203 BN 978-1-78262-311-3; 978-1-84973-701-2 J9 RSC DRUG DISCOV JI RSC Drug Discov. PY 2015 VL 40 BP 1 EP 36 PG 36 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BG3NU UT WOS:000388091100003 ER PT B AU Breggin, PR AF Breggin, Peter R. BE Kirkcaldy, B TI Understanding and Overcoming Guilt, Shame, and Anxiety: Based on the Theory of Negative Legacy Emotions SO PROMOTING PSYCHOLOGICAL WELL-BEING IN CHILDREN AND FAMILIES LA English DT Article; Book Chapter C1 [Breggin, Peter R.] Ctr Study Empath Therapy, Ithaca, NY 14850 USA. [Breggin, Peter R.] NIMH, Bethesda, MD 20892 USA. RP Breggin, PR (reprint author), Ctr Study Empath Therapy, Ithaca, NY 14850 USA. NR 22 TC 0 Z9 0 U1 0 U2 0 PU PALGRAVE PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, ENGLAND BN 978-1-137-47996-9; 978-1-137-47995-2 PY 2015 BP 68 EP 80 D2 10.1057/9781137479969 PG 13 WC Family Studies; Psychology, Multidisciplinary SC Family Studies; Psychology GA BG1GY UT WOS:000386737000005 ER PT B AU Scholmerich, A Agache, A Leyendecker, B AF Schoelmerich, Axel Agache, Alexandra Leyendecker, Birgit BE Kirkcaldy, B TI Child Well-Being: Indicators and. Measurement SO PROMOTING PSYCHOLOGICAL WELL-BEING IN CHILDREN AND FAMILIES LA English DT Article; Book Chapter ID INDEX; CULTURE; SELF C1 [Schoelmerich, Axel; Leyendecker, Birgit] Ruhr Univ Bochum, Dev Psychol, Bochum, Germany. [Schoelmerich, Axel] NICHHD, Bethesda, MD 20892 USA. [Schoelmerich, Axel] Univ Halle Wittenberg, Flunitan Dev, Halle, Germany. [Agache, Alexandra] Ruhr Univ Bochum, Fac Psychol, Bochum, Germany. RP Scholmerich, A (reprint author), Ruhr Univ Bochum, Dev Psychol, Bochum, Germany. NR 20 TC 0 Z9 0 U1 1 U2 1 PU PALGRAVE PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, ENGLAND BN 978-1-137-47996-9; 978-1-137-47995-2 PY 2015 BP 123 EP 134 D2 10.1057/9781137479969 PG 12 WC Family Studies; Psychology, Multidisciplinary SC Family Studies; Psychology GA BG1GY UT WOS:000386737000008 ER PT B AU Antoniou, AS Mitsopoulou, E Chrousos, GP AF Antoniou, Alexander-Stamatios Mitsopoulou, Eftychia Chrousos, George P. BE Kirkcaldy, B TI Psychosocial Factors and Suicidal Behaviour in Adolescents SO PROMOTING PSYCHOLOGICAL WELL-BEING IN CHILDREN AND FAMILIES LA English DT Article; Book Chapter ID NESTED CASE-CONTROL; RISK-FACTORS; SELF-HARM; MENTAL-HEALTH; YOUNG-PEOPLE; DEPRESSION; YOUTH; INTERVENTIONS; ASSOCIATIONS; PREVALENCE C1 [Antoniou, Alexander-Stamatios] Univ Athens, Psychol, GR-10679 Athens, Greece. [Antoniou, Alexander-Stamatios] Minist Justice, Inst Epanodos, Athens, Greece. [Antoniou, Alexander-Stamatios] Natl Council Radio Televis ESR, Athens, Greece. [Antoniou, Alexander-Stamatios] Hellen Psychol Soc, Div Org Psychol, Thessaloniki, Greece. [Mitsopoulou, Eftychia] 2nd Model Expt Jr lhgh Sch Athens, Athens, Greece. [Mitsopoulou, Eftychia] Univ Athens, Fac Primary Educ, Athens, Greece. [Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, Athens, Greece. [Chrousos, George P.] NICHD, Pediat & Reprod Endocrinol Branch, Bethesda, MD USA. [Chrousos, George P.] NIH, Bethesda, MD 20892 USA. [Chrousos, George P.] Lib Congress, Technol & Soc, Washington, DC 20540 USA. [Chrousos, George P.] European Soc Clin Invest, Utrecht, Netherlands. RP Antoniou, AS (reprint author), Univ Athens, Psychol, GR-10679 Athens, Greece. NR 82 TC 0 Z9 0 U1 1 U2 1 PU PALGRAVE PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, ENGLAND BN 978-1-137-47996-9; 978-1-137-47995-2 PY 2015 BP 154 EP 171 D2 10.1057/9781137479969 PG 18 WC Family Studies; Psychology, Multidisciplinary SC Family Studies; Psychology GA BG1GY UT WOS:000386737000010 ER PT S AU Nicastro, HL Dunn, BK AF Nicastro, Holly L. Dunn, Barbara K. BE Preedy, VR TI The Selenium and Vitamin E Cancer Prevention Trial (SELECT): Prevention of Prostate Cancer Using Selenium and/or Vitamin E in the SELECT Cancer Prevention Trial SO SELENIUM: CHEMISTRY, ANALYSIS, FUNCTION AND EFFECTS SE Food and Nutritional Components in Focus LA English DT Article; Book Chapter ID NUTRITION INTERVENTION TRIALS; DISEASE-SPECIFIC MORTALITY; ALPHA-TOCOPHEROL; MINERAL SUPPLEMENTATION; RISK; CARCINOGENESIS; SURVIVAL; LINXIAN; COHORT; CHINA C1 [Nicastro, Holly L.] NCI, Canc Prevent Fellowship Program, Nutr Sci Res Grp, Canc Prevent Div,NIH, 9609 Med Ctr Dr 5E-572, Bethesda, MD 20852 USA. [Dunn, Barbara K.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20852 USA. RP Nicastro, HL (reprint author), NCI, Canc Prevent Fellowship Program, Nutr Sci Res Grp, Canc Prevent Div,NIH, 9609 Med Ctr Dr 5E-572, Bethesda, MD 20852 USA. EM dunnb@mail.nih.gov NR 33 TC 0 Z9 0 U1 0 U2 0 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, CAMBRIDGE CB4 4WF, CAMBS, ENGLAND SN 2045-1695 BN 978-1-78262-221-5; 978-1-84973-891-0 J9 FOOD NUTR COMPON FOC PY 2015 IS 9 BP 428 EP 457 D2 10.1039/9781782622215 PG 30 WC Chemistry, Analytical; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA BG3LC UT WOS:000387992800026 ER PT B AU Aravind, L Zhang, DP Iyer, LM AF Aravind, L. Zhang, Dapeng Iyer, Lakshminarayan M. BE Hausinger, RP Schofield, CJ TI The TET/JBP Family of Nucleic Acid Base-Modifying 2-Oxoglutarate and Iron-Dependent Dioxygenases SO 2-OXOGLUTARATE-DEPENDENT OXYGENASES LA English DT Article; Book Chapter ID EMBRYONIC STEM-CELLS; MOUSE GERM-LINE; DNA DEMETHYLATION; DEOXYRIBONUCLEIC-ACID; COMPLEX MODIFICATIONS; POSTNATAL-DEVELOPMENT; PATERNAL GENOME; MAMMALIAN DNA; 5-HYDROXYMETHYLCYTOSINE; TET2 C1 [Aravind, L.; Zhang, Dapeng; Iyer, Lakshminarayan M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov NR 82 TC 0 Z9 0 U1 0 U2 0 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, CAMBRIDGE CB4 4WF, CAMBS, ENGLAND BN 978-1-78262-195-9; 978-1-84973-950-4 PY 2015 BP 289 EP 308 D2 10.1039/9781782621959 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BG2DI UT WOS:000387272100012 ER PT B AU Wheeler, DC Siangphoe, U AF Wheeler, David C. Siangphoe, Umaporn BE Kanaroglou, P Delmelle, E Paez, A TI Modeling Spatial Variation in Disease Risk in Epidemiologic Studies SO SPATIAL ANALYSIS IN HEALTH GEOGRAPHY SE Geographies of Health LA English DT Article; Book Chapter ID NON-HODGKIN-LYMPHOMA; UNITED-STATES; TEMPORAL ANALYSIS; CANCER-MORTALITY; BREAST-CANCER; CHILDHOOD LEUKEMIA; CLUSTER DETECTION; BIRTH COHORT; LIFE-COURSE; SMALL-AREA C1 [Wheeler, David C.] Virginia Commonwealth Univ, Sch Med, Dept Biostat, Richmond, VA 23284 USA. [Wheeler, David C.] NCI, Bethesda, MD 20892 USA. [Siangphoe, Umaporn] Virginia Commonwealth Univ, Biostat, Richmond, VA 23284 USA. RP Wheeler, DC (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biostat, Richmond, VA 23284 USA. NR 56 TC 0 Z9 0 U1 0 U2 0 PU ASHGATE PUBLISHING LTD PI ALDERSHOT PA GOWER HOUSE, CROFT ROAD, ALDERSHOT GU11 3HR, ENGLAND BN 978-1-47-241620-9; 978-1-47-241619-3 J9 GEOGR HEALTH PY 2015 BP 121 EP 137 PG 17 WC Geography; Public, Environmental & Occupational Health SC Geography; Public, Environmental & Occupational Health GA BG0RI UT WOS:000386481100008 ER PT J AU Ramirez, DF Zambrano, R Cochran, E Brown, R AF Ramirez, Felipe D. Zambrano, R. Cochran, E. Brown, R. TI Metreleptin Use in Children with Congenital Generalized Lipodystrophy SO HORMONE RESEARCH IN PAEDIATRICS LA English DT Meeting Abstract C1 [Ramirez, Felipe D.; Zambrano, R.] LSU Hlth Sci Ctr, New Orleans, LA USA. [Cochran, E.; Brown, R.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1663-2818 EI 1663-2826 J9 HORM RES PAEDIAT JI Horm. Res. Paediatr. PY 2015 VL 84 SU 2 MA O24 BP 30 EP 30 PG 1 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA DX1UO UT WOS:000384152700056 ER PT S AU Van Waes, C AF Van Waes, Carter BE Miller, J LePrell, CG Rybak, L TI Role of Free Radicals in Head and Neck Cancer SO FREE RADICALS IN ENT PATHOLOGY SE Oxidative Stress in Applied Basic Research and Clinical Practice LA English DT Article; Book Chapter ID NF-KAPPA-B; SQUAMOUS-CELL CARCINOMA; FANCONI-ANEMIA; LUNG CARCINOGENESIS; OXIDATIVE STRESS; TUMOR-GROWTH; IN-VIVO; EXPRESSION; ACTIVATION; PATHWAY C1 [Van Waes, Carter] NIDCD, Head & Neck Surg Branch, NIH, CRC Rm 4-2732,10 Ctr Dr, Bethesda, MD 20892 USA. RP Van Waes, C (reprint author), NIDCD, Head & Neck Surg Branch, NIH, CRC Rm 4-2732,10 Ctr Dr, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov NR 48 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2197-7224 BN 978-3-319-13473-4; 978-3-319-13472-7 J9 OXID STRESS APPL BAS JI Oxid. Stress Appl. Basic Res. Clin. Pract. PY 2015 BP 457 EP 466 DI 10.1007/978-3-319-13473-4_22 D2 10.1007/978-3-319-13473-4 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Medicine, Research & Experimental; Otorhinolaryngology SC Biochemistry & Molecular Biology; Research & Experimental Medicine; Otorhinolaryngology GA BF9WT UT WOS:000386013700022 ER PT J AU Gupta, R Gupta, S AF Gupta, Ramji Gupta, Sarthak TI Topical Adapalene in the Treatment of Plantar Warts; Randomized Comparative Open Trial in Comparison with Cryo-Therapy SO INDIAN JOURNAL OF DERMATOLOGY LA English DT Article DE Adapalene; cryo-therapy; occlusion; plantar wart ID IMIQUIMOD 5-PERCENT CREAM; CUTANEOUS WARTS; VIRAL WARTS; DIFFERENTIATION; MANAGEMENT; EFFICACY; ACNE AB Background: Various therapeutic modalities, which are available for treating plantar wart, have not been successful every time. Aims: To evaluate topical adapalene under occlusion in the treatment of plantar warts and compare it with cryo-therapy. Materials and Methods: 50 patients with 424 plantar warts were included in this single center, two arm, prospective, randomized, control, open study. Patients were allocated randomly into two groups consisting of 25 patients each. Group A patients having 299 plantar warts were treated using adapalene gel 0.1% under occlusion while Group B patients having 125 warts were treated using cryo-therapy. All the patients were evaluated weekly till the clearance of all the warts and the results compared. Result: All the warts of 25 patients of Group A that were treated using adapalene gel 0.1% cleared in 36.71 +/- 19.24 (55.95-17.47) days except those in one patient. In Group B, warts in all except one treated by cryo-therapy cleared in 52.17 +/- 30.06 (82.23-22.11) days. There were no side effects like scar formation, irritation, erythema, or infections with adapalene group while in the cryo group scar was seen in 2 patients, pain in 24, erythema in 10, and infection in 3 patients. Conclusion: Adapalene gel 0.1% under occlusion is an effective, safe and easy to use treatment for plantar warts and may help clear lesions faster than cryo-therapy. C1 [Gupta, Ramji] Indraprastha Apollo Hosp, Dept Dermatol, New Delhi, India. [Gupta, Sarthak] NIAMSD, Dept Rheumatol, NIH, Bethesda, MD 20892 USA. RP Gupta, R (reprint author), M-54,Jal Vihar Rd,Lajpat Nagar 2, New Delhi 110024, India. EM drramjigupta@yahoo.co.in NR 19 TC 2 Z9 2 U1 0 U2 1 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0019-5154 EI 1998-3611 J9 INDIAN J DERMATOL JI Indian J. Dermatol. PD JAN-FEB PY 2015 VL 60 IS 1 DI 10.4103/0019-5154.147835 PG 4 WC Dermatology SC Dermatology GA DY3IY UT WOS:000384986700029 PM 25657417 ER PT J AU Denniston, RW AF Denniston, Robert W. TI Commentary: The land of insurmountable opportunities SO INTERNATIONAL JOURNAL OF ALCOHOL AND DRUG RESEARCH LA English DT Editorial Material DE Alcohol policy; alcohol industry; evidence-based prevention; environmental approaches ID PUBLIC-HEALTH AB Much is known about how to change alcohol policy to reduce harm, but despite the evidence little action has been taken at the national level in the United States. Government officials have shown little interest in putting prevention research results to work. The influence of the alcohol industry on policy-makers combined with free market ideology has thwarted change despite the efforts of advocacy groups working to reduce harm. The role of the alcohol industry at the national and international level serves as a powerful deterrent to policy change. C1 [Denniston, Robert W.] NIAAA, Rockville, MD 20852 USA. [Denniston, Robert W.] Subst Abuse & Mental Hlth Serv Adm, Rockville, MD USA. [Denniston, Robert W.] Off Natl Drug Control Policy, Rockville, MD USA. RP Denniston, RW (reprint author), NIAAA, Rockville, MD 20852 USA. EM justdoitbob@hotmail.com NR 9 TC 0 Z9 0 U1 0 U2 0 PU OHIO STATE UNIV, COLL SOCIAL WORK PI COLUMBUS PA 1947 COLLEGE RD, COLUMBUS, OH 43210 USA SN 1925-7066 J9 INT J ALCOHOL DRUG R JI Int. J. Alcohol Drug Res. PY 2015 VL 4 IS 2 SI SI BP 97 EP 99 DI 10.7895/ijadr.v4i2.207 PG 3 WC Behavioral Sciences SC Behavioral Sciences GA DY8HP UT WOS:000385370400002 ER PT S AU Miller, DS AF Miller, David S. BE Schuetz, JD Ishikawa, T TI Regulation of ABC Transporters Blood-Brain Barrier: The Good, the Bad, and the Ugly SO ABC TRANSPORTERS AND CANCER SE Advances in Cancer Research LA English DT Review; Book Chapter ID P-GLYCOPROTEIN EXPRESSION; CANCER RESISTANCE PROTEIN; XENOBIOTIC EFFLUX TRANSPORTERS; MEDIATED UP-REGULATION; NECROSIS-FACTOR-ALPHA; SPINAL CORD BARRIERS; DISEASE MOUSE MODEL; ALZHEIMERS-DISEASE; DRUG-DELIVERY; AMYLOID-BETA AB The brain capillary endothelial cells that constitute the blood-brain barrier express multiple ABC transport proteins on the luminal, blood-facing, plasma membrane. These transporters function as ATP-driven efflux pumps for xenobiotics and endogenous metabolites. High expression of these ABC transporters at the barrier is a major obstacle to the delivery of therapeutics, including chemotherapeutics, to the CNS. Here, I review the signals that alter ABC transporter expression and transport function with an emphasis on P-glycoprotein, Mrp2, and breast cancer resistance protein (BCRP), the efflux transporters for which we have the most detailed picture of regulation. Recent work shows that transporter protein expression can be upregulated in response to inflammatory and oxidative stress, therapeutic drugs, diet, and persistent environmental pollutants; as a consequence, drug delivery to the brain is reduced (potentially bad and ugly). In contrast, basal transport activity of P-glycoprotein and BCRP can be reduced through complex signaling pathways that involve events in and on the brain capillary endothelial cells. Targeting these signaling events provides opportunities to rapidly and reversibly increase brain accumulation of drugs that are substrates for the transporters ( potentially good). The clinical usefulness of targeting signaling to reduce efflux transporter activity and improve drug delivery to the CNS remains to be established. C1 [Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Miller, DS (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov NR 69 TC 15 Z9 16 U1 8 U2 15 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-230X BN 978-0-12-801361-8; 978-0-12-801251-2 J9 ADV CANCER RES JI Adv.Cancer Res. PY 2015 VL 125 BP 43 EP 70 DI 10.1016/bs.acr.2014.10.002 PG 28 WC Oncology SC Oncology GA BF8GH UT WOS:000385012300003 PM 25640266 ER PT S AU Chufan, EE Sim, HM Ambudkar, SV AF Chufan, Eduardo E. Sim, Hong-May Ambudkar, Suresh V. BE Schuetz, JD Ishikawa, T TI Molecular Basis of the Polyspecificity of P-Glycoprotein (ABCB1): Recent Biochemical and Structural Studies SO ABC TRANSPORTERS AND CANCER SE Advances in Cancer Research LA English DT Review; Book Chapter ID DRUG-BINDING SITE; MULTIDRUG-RESISTANCE; ATP HYDROLYSIS; CAENORHABDITIS-ELEGANS; CATALYTIC CYCLE; TRANSMEMBRANE SEGMENTS; PHARMACOPHORE MODEL; ALTERNATING ACCESS; BOUND STATES; EFFLUX PUMP AB ABCB1 (P-glycoprotein/P-gp) is an ATP-binding cassette transporter well known for its association with multidrug resistance in cancer cells. Powered by the hydrolysis of ATP, it effluxes structurally diverse compounds. In this chapter, we discuss current views on the molecular basis of the substrate polyspecificity of P-gp. One of the features that accounts for this property is the structural flexibility observed in P-gp. Several X-ray crystal structures of mouse P-gp have been published recently in the absence of nucleotide, with and without bound inhibitors. All the structures are in an inward-facing conformation exhibiting different degrees of domain separation, thus revealing a highly flexible protein. Biochemical and biophysical studies also demonstrate this flexibility in mouse as well as human P-gp. Site-directed mutagenesis has revealed the existence of multiple transport-active binding sites in P-gp for a single substrate. Thus, drugs can bind at either primary or secondary sites. Biochemical, molecular modeling, and structure-activity relationship studies suggest a large, common drug-binding pocket with overlapping sites for different substrates. We propose that in addition to the structural flexibility, the molecular or chemical flexibility also contributes to the binding of substrates to multiple sites forming the basis of polyspecificity. C1 [Chufan, Eduardo E.; Sim, Hong-May; Ambudkar, Suresh V.] NCI, Ctr Canc Res, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ambudkar, SV (reprint author), NCI, Ctr Canc Res, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov FU Intramural NIH HHS NR 79 TC 15 Z9 17 U1 3 U2 12 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-230X BN 978-0-12-801361-8; 978-0-12-801251-2 J9 ADV CANCER RES JI Adv.Cancer Res. PY 2015 VL 125 BP 71 EP 96 DI 10.1016/bs.acr.2014.10.003 PG 26 WC Oncology SC Oncology GA BF8GH UT WOS:000385012300004 PM 25640267 ER PT S AU Wu, YM Sinden, RE Churcher, TS Tsuboi, T Yusibov, V AF Wu, Yimin Sinden, Robert E. Churcher, Thomas S. Tsuboi, Takafumi Yusibov, Vidadi BE Rollinson, D Stothard, JR TI Development of Malaria Transmission-Blocking Vaccines: From Concept to Product SO ADVANCES IN PARASITOLOGY, VOL 89 SE Advances in Parasitology LA English DT Review; Book Chapter ID PLASMODIUM-FALCIPARUM MALARIA; OOKINETE-SURFACE PROTEIN; MEMBRANE-FEEDING ASSAY; SEXUAL STAGE ANTIGENS; MONTANIDE ISA 720; AERUGINOSA EXOPROTEIN-A; DOMAIN-RELATED PROTEIN; PAPUA-NEW-GUINEA; PHASE-I TRIAL; MOSQUITO-MIDGUT AB Despite decades of effort battling against malaria, the disease is still a major cause of morbidity and mortality. Transmission- blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination. In the 1950s, Huff et al. first demonstrated the induction of transmission-blocking immunity in chickens by repeated immunizations with Plasmodium gallinaceum-infected red blood cells. Since then, significant progress has been made in identification of parasite antigens responsible for transmission-blocking activity. Recombinant technologies accelerated evaluation of these antigens as vaccine candidates, and it is possible to induce effective transmission-blocking immunity in humans both by natural infection and now by immunization with recombinant vaccines. This chapter reviews the efforts to produce TBVs, summarizes the current status and advances and discusses the remaining challenges and approaches. C1 [Wu, Yimin] NIAID, Lab Malaria Immunol & Vaccinol, Rockville, MD USA. [Sinden, Robert E.] Jenner Inst, Oxford, England. [Churcher, Thomas S.] Imperial Coll London, MRC, Ctr Outbreak Anal & Modelling, Dept Infect Dis Epidemiol,Sch Publ Hlth, London, England. [Tsuboi, Takafumi] Ehime Univ, Div Malaria Res, Matsuyama, Ehime, Japan. [Yusibov, Vidadi] Fraunhofer USA Ctr Mol Biotechnol, Newark, DE USA. RP Wu, YM (reprint author), PATH Malaria Vaccine Initiat, Washington, DC 20001 USA. EM ywu@path.org OI Churcher, Thomas/0000-0002-8442-0525 FU Intramural NIH HHS; Medical Research Council [MR/K010174/1] NR 205 TC 14 Z9 15 U1 3 U2 5 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-308X BN 978-0-12-803334-0; 978-0-12-803301-2 J9 ADV PARASIT JI Adv.Parasitol. PY 2015 VL 89 BP 109 EP 152 DI 10.1016/bs.apar.2015.04.001 PG 44 WC Infectious Diseases; Parasitology SC Infectious Diseases; Parasitology GA BF8KY UT WOS:000385154500003 PM 26003037 ER PT S AU Pierson, TC Diamond, MS AF Pierson, Theodore C. Diamond, Michael S. BE Klasse, PJ TI A Game of Numbers: The Stoichiometry of Antibody-Mediated Neutralization of Flavivirus Infection SO MOLECULAR BASIS OF VIRAL INFECTION SE Progress in Molecular Biology and Translational Science LA English DT Review; Book Chapter ID WEST-NILE-VIRUS; TICK-BORNE ENCEPHALITIS; YELLOW-FEVER VACCINE; PROTEIN DOMAIN-III; DENGUE VIRUS; ENVELOPE PROTEIN; DEPENDENT ENHANCEMENT; MONOCLONAL-ANTIBODY; JAPANESE ENCEPHALITIS; IN-VIVO AB The humoral response contributes to the protection against viral pathogens. Although antibodies have the potential to inhibit viral infections via several mechanisms, an ability to neutralize viruses directly may be particularly important. Neutralizing antibody titers are commonly used as predictors of protection from infection, especially in the context of vaccine responses and immunity. Despite the simplicity of the concept, how antibody binding results in virus inactivation is incompletely understood despite decades of research. Flaviviruses have been an attractive system in which to seek a structural and quantitative understanding of how antibody interactions with virions modulate infection because of the contribution of antibodies to both protection and pathogenesis. This review will present a stoichiometric model of antibody-mediated neutralization of flaviviruses and discuss how these concepts can inform the development of vaccines and antibody-based therapeutics. C1 [Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Immunol, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO 63110 USA. RP Pierson, TC (reprint author), NIAID, Viral Pathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM piersontc@niaid.nih.gov; diamond@borcim.wustl.edu FU NIAID NIH HHS [R01 AI073755, R01 AI089591, R01AI073755]; PHS HHS [R01A1089591] NR 123 TC 3 Z9 3 U1 2 U2 3 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 1877-1173 BN 978-0-12-802587-1; 978-0-12-802461-4 J9 PROG MOL BIOL TRANSL JI Prog. Molec. Biol. Transl. Sci. PY 2015 VL 129 BP 141 EP 166 DI 10.1016/bs.pmbts.2014.10.005 PG 26 WC Biochemistry & Molecular Biology; Infectious Diseases; Virology SC Biochemistry & Molecular Biology; Infectious Diseases; Virology GA BF8GQ UT WOS:000385020000006 PM 25595803 ER PT S AU Tedbury, PR Freed, EO AF Tedbury, Philip R. Freed, Eric O. BE Klasse, PJ TI The Cytoplasmic Tail of Retroviral Envelope Glycoproteins SO MOLECULAR BASIS OF VIRAL INFECTION SE Progress in Molecular Biology and Translational Science LA English DT Review; Book Chapter ID HUMAN-IMMUNODEFICIENCY-VIRUS; JAAGSIEKTE SHEEP RETROVIRUS; MURINE-LEUKEMIA-VIRUS; POLARIZED EPITHELIAL-CELLS; ROUS-SARCOMA-VIRUS; MEMBRANE-SPANNING DOMAIN; AMINO-ACID SUBSTITUTIONS; INFECTIOUS-ANEMIA VIRUS; VIRAL PARTICLE RELEASE; N-LINKED GLYCOSYLATION AB Retroviruses comprise a large, diverse group that infects a broad range of host organisms. Pathogenicity varies widely; the human immunodeficiency virus is the causative agent of acquired immunodeficiency syndrome, one of the world's leading infectious causes of death, while many nonhuman retroviruses cause cancer in the host. Retroviruses have been studied intensively, and great strides have been made in understanding aspects of retroviral biology. While the principal functions of the viral structural proteins are well understood, there remain many incompletely characterized domains. One of these is the cytoplasmic tail (CT) of the envelope glycoprotein. Several functions of the CT are highly conserved, whereas other properties are unique to a specific retrovirus. For example, the lentiviruses encode envelope glycoproteins with particularly large cytoplasmic domains. The functions of the long lentiviral envelope CT are still being deciphered. The reported functions of retroviral envelope CTs are discussed in this chapter. C1 [Tedbury, Philip R.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21701 USA. EM efreed@nih.gov OI Tedbury, Philip/0000-0001-8151-4967 FU Intramural NIH HHS NR 196 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 1877-1173 BN 978-0-12-802587-1; 978-0-12-802461-4 J9 PROG MOL BIOL TRANSL JI Prog. Molec. Biol. Transl. Sci. PY 2015 VL 129 BP 253 EP 284 DI 10.1016/bs.pmbts.2014.10.009 PG 32 WC Biochemistry & Molecular Biology; Infectious Diseases; Virology SC Biochemistry & Molecular Biology; Infectious Diseases; Virology GA BF8GQ UT WOS:000385020000010 PM 25595807 ER PT S AU Evans, PR Dudek, SM Hepler, JR AF Evans, Paul R. Dudek, Serena M. Hepler, John R. BE Fisher, RA TI Regulator of G Protein Signaling 14: A Molecular Brake on Synaptic Plasticity Linked to Learning and Memory SO RGS PROTEIN PHYSIOLOGY AND PATHOPHYSIOLOGY SE Progress in Molecular Biology and Translational Science LA English DT Review; Book Chapter ID HETEROTRIMERIC G-PROTEINS; VASOPRESSIN 1B RECEPTOR; LONG-TERM POTENTIATION; HIPPOCAMPAL AREA CA2; CENTRAL-NERVOUS-SYSTEM; GUANINE-NUCLEOTIDE EXCHANGE; MEDIAL ENTORHINAL CORTEX; G-ALPHA-I; RGS PROTEINS; SUPRAMAMMILLARY NUCLEUS AB The regulators of G protein signaling (RGS) proteins are a diverse family of proteins that function as central components of G protein and other signaling pathways. In the brain, regulator of G protein signaling 14 (RGS14) is enriched in neurons in the hippocampus where the mRNA and protein are highly expressed. This brain region plays a major role in processing learning and forming new memories. RGS14 is an unusual RGS protein that acts as a multifunctional scaffolding protein to integrate signaling events and pathways essential for synaptic plasticity, including conventional and unconventional G protein signaling, mitogen-activated protein kinase, and, possibly, calcium signaling pathways. Within the hippocampus of primates and rodents, RGS14 is predominantly found in the enigmatic CA2 subfield. Principal neurons within the CA2 subfield differ from neighboring hippocampal regions in that they lack a capacity for long-term potentiation (LTP) of synaptic transmission, which is widely viewed as the cellular substrate of learning and memory formation. RGS14 was recently identified as a natural suppressor of LTP in hippocampal CA2 neurons as well as forms of learning and memory that depend on the hippocampus. Although CA2 has only recently been studied, compelling recent evidence implicates area CA2 as a critical component of hippocampus circuitry with functional roles in mediating certain types of learning and memory. This review will highlight the known functions of RGS14 in cell signaling and hippocampus physiology, and discuss potential roles for RGS14 in human cognition and disease. C1 [Evans, Paul R.; Hepler, John R.] Emory Univ, Sch Med, Dept Pharmacol, Rollins Res Ctr, Atlanta, GA 30322 USA. [Dudek, Serena M.] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hepler, JR (reprint author), Emory Univ, Sch Med, Dept Pharmacol, Rollins Res Ctr, Atlanta, GA 30322 USA. EM jhepler@emory.edu OI Dudek, Serena M./0000-0003-4094-8368 FU Intramural NIH HHS; NIEHS NIH HHS [Z01-ES-100221]; NINDS NIH HHS [1F31NS086174, F31 NS086174, 5R01 NS37112, 1R21NS074975] NR 123 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 1877-1173 BN 978-0-12-802954-1; 978-0-12-802938-1 J9 PROG MOL BIOL TRANSL JI Prog. Molec. Biol. Transl. Sci. PY 2015 VL 133 BP 169 EP 206 DI 10.1016/bs.pmbts.2015.03.006 PG 38 WC Biochemistry & Molecular Biology; Physiology SC Biochemistry & Molecular Biology; Physiology GA BF8GO UT WOS:000385016400010 PM 26123307 ER PT J AU Zhao, YD Polley, EC Li, MC Lih, CJ Palmisano, A Sims, DJ Rubinstein, LV Conley, BA Chen, AP Williams, PM Kummar, S Doroshow, JH Simon, RM AF Zhao, Yingdong Polley, Eric C. Li, Ming-Chung Lih, Chih-Jian Palmisano, Alida Sims, David J. Rubinstein, Lawrence V. Conley, Barbara A. Chen, Alice P. Williams, P. Mickey Kummar, Shivaani Doroshow, James H. Simon, Richard M. TI GeneMed: An Informatics Hub for the Coordination of Next-Generation Sequencing Studies that Support Precision Oncology Clinical Trials SO CANCER INFORMATICS LA English DT Article DE GeneMed; MPACT; next-generation sequencing; precision medicine; informatics system; clinical trial ID GENOME AB We have developed an informatics system, GeneMed, for the National Cancer Institute (NCI) molecular profiling-based assignment of cancer therapy (MPACT) clinical trial (NCT01827384) being conducted in the National Institutes of Health (NIH) Clinical Center. This trial is one of the first to use a randomized design to examine whether assigning treatment based on genomic tumor screening can improve the rate and duration of response in patients with advanced solid tumors. An analytically validated next-generation sequencing (NGS) assay is applied to DNA from patients' tumors to identify mutations in a panel of genes that are thought likely to affect the utility of targeted therapies available for use in the clinical trial. The patients are randomized to a treatment selected to target a somatic mutation in the tumor or with a control treatment. The GeneMed system streamlines the workflow of the clinical trial and serves as a communications hub among the sequencing lab, the treatment selection team, and clinical personnel. It automates the annotation of the genomic variants identified by sequencing, predicts the functional impact of mutations, identifies the actionable mutations, and facilitates quality control by the molecular characterization lab in the review of variants. The GeneMed system collects baseline information about the patients from the clinic team to determine eligibility for the panel of drugs available. The system performs randomized treatment assignments under the oversight of a supervising treatment selection team and generates a patient report containing detected genomic alterations. NCI is planning to expand the MPACT trial to multiple cancer centers soon. In summary, the GeneMed system has been proven to be an efficient and successful informatics hub for coordinating the reliable application of NGS to precision medicine studies. C1 [Zhao, Yingdong; Polley, Eric C.; Li, Ming-Chung; Palmisano, Alida; Rubinstein, Lawrence V.; Simon, Richard M.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Rockville, MD 20850 USA. [Lih, Chih-Jian; Sims, David J.; Williams, P. Mickey] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Mol Characterizat & Clin Assay Dev Lab, Frederick, MD USA. [Conley, Barbara A.] NCI, Canc Diag Program, Div Canc Treatment & Diag, Rockville, MD USA. [Chen, Alice P.; Kummar, Shivaani; Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD USA. RP Simon, RM (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, Rockville, MD 20850 USA. EM rsimon@nih.gov RI Palmisano, Alida/C-2254-2015 OI Palmisano, Alida/0000-0002-1859-3719 NR 16 TC 8 Z9 8 U1 0 U2 1 PU LIBERTAS ACAD PI AUCKLAND PA PO BOX 300-874, ALBANY 0752, AUCKLAND, 00000, NEW ZEALAND SN 1176-9351 J9 CANCER INFORM JI Cancer Inform. PY 2015 VL 14 SU 2 BP 45 EP 55 DI 10.4137/CIN.S17282 PG 11 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DW9FH UT WOS:000383960900006 PM 25861217 ER PT J AU Isokpehi, RD Valero, KCW Graham, BE Pacurari, M Sims, JN Udensi, UK Ndebele, K AF Isokpehi, Raphael D. Valero, Katharina C. Wollenberg Graham, Barbara E. Pacurari, Maricica Sims, Jennifer N. Udensi, Udensi K. Ndebele, Kenneth TI Secondary Data Analytics of Aquaporin Expression Levels in Glioblastoma Stem-Like Cells SO CANCER INFORMATICS LA English DT Article DE aquaporins; aquaporin-1; aquaporin-4; brain; cancer; gliomas; glioblastoma; hypoxia; neurospheres; visual analytics ID VISUAL ANALYTICS; GLIOMA AB Glioblastoma is the most common brain tumor in adults in which recurrence has been attributed to the presence of cancer stem cells in a hypoxic microenvironment. On the basis of tumor formation in vivo and growth type in vitro, two published microarray gene expression profiling studies grouped nine glioblastoma stem-like (GS) cell lines into one of two groups: full (GSf) or restricted (GSr) stem-like phenotypes. Aquaporin-1 (AQP1) and aquaporin-4 (AQP4) are water transport proteins that are highly expressed in primary glial-derived tumors. However, the expression levels of AQP1 and AQP4 have not been previously described in a panel of 92 glioma samples. Therefore, we designed secondary data analytics methods to determine the expression levels of AQP1 and AQP4 in GS cell lines and glioblastoma neurospheres. Our investigation also included a total of 2,566 expression levels from 28 Affymetrix microarray probe sets encoding 13 human aquaporins (AQP0-AQP12); CXCR4 (the receptor for stromal cell derived factor-1 [SDF-1], a potential glioma stem cell therapeutic target]); and PROM1 (gene encoding CD133, the widely used glioma stem cell marker). Interactive visual representation designs for integrating phenotypic features and expression levels revealed that inverse expression levels of AQP1 and AQP4 correlate with distinct phenotypes in a set of cell lines grouped into full and restricted stem-like phenotypes. Discriminant function analysis further revealed that AQP1 and AQP4 expression are better predictors for tumor formation and growth types in glioblastoma stem-like cells than are CXCR4 and PROM1. Future investigations are needed to characterize the molecular mechanisms for inverse expression levels of AQP1 and AQP4 in the glioblastoma stem-like neurospheres. C1 [Isokpehi, Raphael D.; Valero, Katharina C. Wollenberg] Bethune Cookman Univ, Coll Sci Engn & Math, Daytona Beach, FL 32114 USA. [Graham, Barbara E.; Sims, Jennifer N.; Ndebele, Kenneth] Jackson State Univ, Lab Canc Immunol Target Identificat & Validat, Dept Biol, Jackson, MS USA. [Graham, Barbara E.; Udensi, Udensi K.; Ndebele, Kenneth] Jackson State Univ, NIH RCMI Ctr Environm Hlth, Coll Sci Engn & Technol, Jackson, MS USA. [Pacurari, Maricica] Jackson State Univ, Dept Biol, Jackson, MS USA. [Ndebele, Kenneth] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA USA. RP Isokpehi, RD (reprint author), Bethune Cookman Univ, Coll Sci Engn & Math, Daytona Beach, FL 32114 USA. EM isokpehir@cookman.edu OI Wollenberg Valero, Katharina/0000-0001-8858-1804 FU NIGMS NIH HHS [T36 GM095335]; NIMHD NIH HHS [G12 MD007581, P20 MD006899] NR 21 TC 0 Z9 0 U1 0 U2 0 PU LIBERTAS ACAD PI AUCKLAND PA PO BOX 300-874, ALBANY 0752, AUCKLAND, 00000, NEW ZEALAND SN 1176-9351 J9 CANCER INFORM JI Cancer Inform. PY 2015 VL 14 BP 95 EP 103 DI 10.4137/CIN.S22058 PG 9 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DW9EG UT WOS:000383958200001 PM 26279619 ER PT J AU Finney, RP Chen, QR Nguyen, CV Hsu, CH Yan, CH Hu, Y Abawi, M Bian, XP Meerzaman, DM AF Finney, Richard P. Chen, Qing-Rong Nguyen, Cu V. Hsu, Chih Hao Yan, Chunhua Hu, Ying Abawi, Massih Bian, Xiaopeng Meerzaman, Daoud M. TI Alview: Portable Software for Viewing Sequence Reads in BAM Formatted Files SO CANCER INFORMATICS LA English DT Article DE genomics; short read; alignment; visualization; BAM; open source AB The name Alview is a contraction of the term Alignment Viewer. Alview is a compiled to native architecture software tool for visualizing the alignment of sequencing data. Inputs are files of short-read sequences aligned to a reference genome in the SAM/BAM format and files containing reference genome data. Outputs are visualizations of these aligned short reads. Alview is written in portable C with optional graphical user interface (GUI) code written in C, C++, and Objective-C. The application can run in three different ways: as a web server, as a command line tool, or as a native, GUI program. Alview is compatible with Microsoft Windows, Linux, and Apple OS X. It is available as a web demo at https://cgwb.nci.nih.gov/cgi-bin/alview. The source code and Windows/Mac/Linux executables are available via https://github.com/NCIP/alview. C1 [Finney, Richard P.; Chen, Qing-Rong; Nguyen, Cu V.; Hsu, Chih Hao; Yan, Chunhua; Hu, Ying; Abawi, Massih; Bian, Xiaopeng; Meerzaman, Daoud M.] NCI, Computat Genom Res Grp, Ctr Bioinformat & Informat Technol, Bethesda, MD 20892 USA. RP Finney, RP (reprint author), NCI, Computat Genom Res Grp, Ctr Bioinformat & Informat Technol, Bethesda, MD 20892 USA. EM finneyr@mail.nih.gov NR 9 TC 1 Z9 1 U1 1 U2 1 PU LIBERTAS ACAD PI AUCKLAND PA PO BOX 300-874, ALBANY 0752, AUCKLAND, 00000, NEW ZEALAND SN 1176-9351 J9 CANCER INFORM JI Cancer Inform. PY 2015 VL 14 BP 105 EP 107 DI 10.4137/CIN.S26470 PG 3 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DW9EI UT WOS:000383958400001 PM 26417198 ER PT S AU Xu, ZY Bagci, U Udupa, JK Mollura, DJ AF Xu, Ziyue Bagci, Ulas Udupa, Jayaram K. Mollura, Daniel J. BE Gao, F Shi, K Li, S TI Fuzzy Connectedness Image Co-segmentation for Hybrid PET/MRI and PET/CT Scans SO COMPUTATIONAL METHODS FOR MOLECULAR IMAGING SE Lecture Notes in Computational Vision and Biomechanics LA English DT Article; Book Chapter DE Co-segmentation; Fuzzy connectedness; PET/MRI; PET/CT; Image segmentation ID DELINEATION; DEFINITION AB In this paper, we presented a 3-D computer-aided co-segmentation tool for tumor/lesion detection and quantification from hybrid PET/MRI and PET/CT scans. The proposed method was designed with a novel modality-specific visibility weighting scheme built upon a fuzzy connectedness (FC) image segmentation algorithm. In order to improve the determination of lesion margin, it is necessary to combine the complementary information of tissues from both anatomical and functional domains. Therefore, a robust image segmentation method that simultaneously segments tumors/lesions in each domain is required. However, this task, named co-segmentation, is a challenging problem due to (1) unique challenges brought by each imaging modality, and (2) a lack of one-to-one region and boundary correspondences of lesions in different imaging modalities. Owing to these hurdles, the algorithm is desired to have a sufficient flexibility to utilize the strength of each modality. In this work, seed points were first selected from high uptake regions within PET images. Then, lesion boundaries were delineated using a hybrid approach based on novel affinity function design within the FC framework. Further, an advanced extension of FC algorithm called iterative relative FC (IRFC) was used with automatically identified background seeds. The segmentation results were compared to the reference truths provided by radiologists. Experimental results showed that the proposed method effectively utilized multi-modality information for co-segmentation, with a high accuracy (mean DSC of 85%) and can be a viable alternative to the state-of-the art joint segmentation method of random walk (RW) with higher efficiency. C1 [Bagci, Ulas] Univ Cent Florida, CRCV, Comp Sci, HEC 221, Orlando, FL 32816 USA. [Xu, Ziyue; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Udupa, Jayaram K.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Bagci, U (reprint author), Univ Cent Florida, CRCV, Comp Sci, HEC 221, Orlando, FL 32816 USA. EM bagci@crcv.ucf.edu OI Bagci, Ulas/0000-0001-7379-6829 NR 8 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2212-9391 BN 978-3-319-18431-9; 978-3-319-18430-2 J9 L N COMPUT VIS BIOME PY 2015 VL 22 BP 15 EP 24 DI 10.1007/978-3-319-18431-9_2 D2 10.1007/978-3-319-18431-9 PG 10 WC Biophysics; Computer Science, Artificial Intelligence; Engineering, Biomedical SC Biophysics; Computer Science; Engineering GA BF6NS UT WOS:000383355200002 ER PT J AU Kaplan, RM Smith, WB AF Kaplan, Robert M. Smith, Wendy B. BE Jeste, DV Palmer, BW TI What Is Well-Being? SO POSITIVE PSYCHIATRY: A CLINICAL HANDBOOK LA English DT Article; Book Chapter ID QUALITY-OF-LIFE; HEALTH; TECHNOLOGY; PREVALENCE; PREVENTION; VALIDITY; OUTCOMES; INDEXES; DISEASE; SF-36 C1 [Kaplan, Robert M.] US Dept HHS, Agcy Healthcare Res & Qual, Rockville, MD 20852 USA. [Smith, Wendy B.] NIH, Res Dev & Outreach, Off Behav & Social Sci Res, Off Director, Bethesda, MD 20892 USA. RP Kaplan, RM (reprint author), US Dept HHS, Agcy Healthcare Res & Qual, Rockville, MD 20852 USA. NR 29 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209 USA BN 978-1-58562-495-9 PY 2015 BP 111 EP 125 D2 10.1176/appi.books.9781615370818 PG 15 WC Psychiatry SC Psychiatry GA BF6IU UT WOS:000383142600007 ER PT J AU Sharmin, M Raij, A Epstien, D Nahum-Shani, I Beck, JG Vhaduri, S Preston, K Kumar, S AF Sharmin, Moushumi Raij, Andrew Epstien, David Nahum-Shani, Inbal Beck, J. Gayle Vhaduri, Sudip Preston, Kenzie Kumar, Santosh GP ACM TI Visualization of Time-Series Sensor Data to Inform the Design of Just-In-Time Adaptive Stress Interventions SO PROCEEDINGS OF THE 2015 ACM INTERNATIONAL JOINT CONFERENCE ON PERVASIVE AND UBIQUITOUS COMPUTING (UBICOMP 2015) LA English DT Proceedings Paper CT ACM International Joint Conference on Pervasive and Ubiquitous Computing (UbiComp) CY SEP 07-11, 2015 CL Osaka, JAPAN SP Assoc Comp Machinery, ACM SIGCHI, ACM SIGMOBILE, Panasonic, Bell Labs, Microsoft, Google, Yahoo Japan, KDDI, FXPAL, Rakuten Inst Technol, ISTC PC, NTT DOCOMO, Telefonica Investigac & Desarrollo DE Stress; Stress Management; Visualization; Just-in-time Adaptive Interventions (JITAIs) AB We investigate needs, challenges, and opportunities in visualizing time-series sensor data on stress to inform the design of just-in-time adaptive interventions (JITAIs). We identify seven key challenges: massive volume and variety of data, complexity in identifying stressors, scalability of space, multifaceted relationship between stress and time, a need for representation at multiple granularities, interperson variability, and limited understanding of JITAI design requirements due to its novelty. We propose four new visualizations based on one million minutes of sensor data (n = 70). We evaluate our visualizations with stress researchers (n = 6) to gain first insights into its usability and usefulness in JITAI design. Our results indicate that spatiotemporal visualizations help identify and explain between-and within-person variability in stress patterns and contextual visualizations enable decisions regarding the timing, content, and modality of intervention. Interestingly, a granular representation is considered informative but noise-prone; an abstract representation is the preferred starting point for designing JITAIs. C1 [Sharmin, Moushumi; Beck, J. Gayle; Kumar, Santosh] Univ Memphis, Memphis, TN 38152 USA. [Raij, Andrew] Univ Cent Florida, Orlando, FL 32816 USA. [Epstien, David; Preston, Kenzie] NIDA IRP, Baltimore, MD USA. [Nahum-Shani, Inbal] Univ Michigan, Ann Arbor, MI 48109 USA. [Vhaduri, Sudip] Univ Notre Dame, Notre Dame, IN 46556 USA. RP Sharmin, M (reprint author), Univ Memphis, Memphis, TN 38152 USA. EM msharmin@memphis.edu; raij@ucf.edu; depstein@intra.nida.nih.gov; inbal@umich.edu; jgbeck@memphis.edu; svhaduri@nd.edu; kpreston@intra.nida.nih.gov; skumar4@memphis.edu NR 40 TC 0 Z9 0 U1 0 U2 0 PU ASSOC COMPUTING MACHINERY PI NEW YORK PA 1515 BROADWAY, NEW YORK, NY 10036-9998 USA BN 978-1-4503-3574-4 PY 2015 BP 505 EP 516 DI 10.1145/2750858.2807537 PG 12 WC Computer Science, Theory & Methods; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BF6WQ UT WOS:000383742200046 ER PT B AU Ku, S Klaessig, F AF Ku, Sharon Klaessig, Frederick BE Schlaudt, O Huber, L TI A MATTER OF SIZE DOES NOT MATTER: MATERIAL AND INSTITUTIONAL AGENCIES IN NANOTECHNOLOGY STANDARDIZATION SO STANDARDIZATION IN MEASUREMENT: PHILOSOPHICAL, HISTORICAL AND SOCIOLOGICAL ISSUES SE History and Philosophy of Technoscience LA English DT Article; Book Chapter C1 [Ku, Sharon] Drexel Univ, Dept Hist & Polit, Philadelphia, PA 19104 USA. [Ku, Sharon] NIH, Off Hist, Bethesda, MD 20892 USA. [Klaessig, Frederick] Evonik Degussa GmbH, Aerosil Business Line, Essen, Germany. RP Ku, S (reprint author), Drexel Univ, Dept Hist & Polit, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE PI ABINGDON PA 2 PARK SQ, MILTON PARK, ABINGDON OX14 4RN, OXFORD, ENGLAND BN 978-1-317-31669-5; 978-1-84893-571-6 J9 HIST PHILOS TECHNOSC PY 2015 VL 7 BP 189 EP 206 PG 18 WC History & Philosophy Of Science SC History & Philosophy of Science GA BF6FQ UT WOS:000383032900015 ER PT J AU Kim, IC Thoma, GR AF Kim, In Cheol Thoma, George R. GP IEEE TI Automated Classification of Author's Sentiments in Citation Using Machine Learning Techniques: A Preliminary Study SO 2015 IEEE CONFERENCE ON COMPUTATIONAL INTELLIGENCE IN BIOINFORMATICS AND COMPUTATIONAL BIOLOGY (CIBCB) LA English DT Proceedings Paper CT IEEE Conference on Computational Intelligence in Bioinformatics and Computational Biology CIBCB CY AUG 12-15, 2015 CL Honolulu, HI DE Citation analysis; author's sentiments; "Comment-on"; support vector machine; n-grams word statistics; MEDLINE ID TEXT CATEGORIZATION AB Scientific papers generally include citations to external sources such as journal articles, books, or Web links to refer to works that are related in an important way to the research. The reason for the citation appears within the sentences surrounding the citation tag in the body text, and represents the relationship between the citation and cited works as supportive, contrastive, corrective, etc. This could be an important clue for researchers seeking relevant previous work or approaches for a certain research purpose. We propose to develop an automated method to identify the citing author's sentiments toward the cited external sources expressed in citation sentences using machine-learning techniques and linguistic cues. As a preliminary study, this paper presents a support vector machine (SVM)-based text categorization technique to classify the author's sentiments specifically toward Comment-on (CON) articles. CON, a MEDLINE citation field, indicates previously published articles commented on by authors of a given article expressing possibly complimentary or contradictory opinions. An SVM with a radial basis kernel function (RBF) is implemented, and Input feature vectors for the SVM are created based on n-grams word statistics representing the distribution of words in CON sentences. Experiments conducted on a set of CON sentences collected from 414 different online biomedical journal titles show that the SVM with a RBF yields the best result for an input feature vector combining uni-gram and bi-gram word statistics. C1 [Kim, In Cheol; Thoma, George R.] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, 8600 Rockville Pike, Bethesda, MD 20894 USA. RP Kim, IC (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4799-6926-5 PY 2015 BP 488 EP 494 PG 7 WC Computer Science, Information Systems; Mathematical & Computational Biology SC Computer Science; Mathematical & Computational Biology GA BF1SY UT WOS:000380434200049 ER PT S AU Cavalcante, FR Carvalho, AB Santos, WS Lee, C AF Cavalcante, F. R. Carvalho Junior, A. B. Santos, W. S. Lee, Choonsik BE Jaffray, DA TI Monte Carlo simulation of interventional cardiac scenarios using a newborn hybrid phantom and MCNPX code SO WORLD CONGRESS ON MEDICAL PHYSICS AND BIOMEDICAL ENGINEERING, 2015, VOLS 1 AND 2 SE IFMBE Proceedings LA English DT Proceedings Paper CT World Congress on Medical Physics and Biomedical Engineering CY JUN 07-12, 2015 CL Toronto, CANADA DE Dose conversion coefficients; interventional procedure; NURBS phantom; MCNPX code AB We developed exposure scenarios of pediatric interventional cardiology using a newborn hybrid phantom and the radiation transport code MCNPX. Six angiographic projections (AP, PA, LAO45, RAO45, LAO90 and RAO90) were simulated considering three X-ray energy spectra (60, 70 and 80 kVp), focus-skin distance (FSD) not less than 45 cm and a 7 x 7 cm(2) field size. The equivalent and effective doses were computed and normalized by the kerma-area product (KAP) resulting the conversion coefficients HT/KAP and E/KAP. The results showed highest HT/KAP values in AP projection (80 kVp). Increasing photon energy, average E/KAP values presented relative differences of 18% (60 to 70 kVp) and 15% (70 to 80 kVp). E/KAP values were compared with those published for mathematical newborn phantom. Results showed relative differences of 14% for AP projection (70 kVp) and 60% for lateral projections (60 kVp). C1 [Cavalcante, F. R.; Carvalho Junior, A. B.] Univ Fed Sergipe, Dept Fis, Sao Cristovao, Brazil. [Santos, W. S.] Comissao Nacl Energia Nucl, Inst Pesquisas Energet & Nucl, Sao Paulo, Brazil. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. RP Cavalcante, FR (reprint author), Univ Fed Sergipe, Dept Fis, Sao Cristovao, Brazil. NR 8 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1680-0737 BN 978-3-319-19387-8; 978-3-319-19386-1 J9 IFMBE PROC PY 2015 VL 51 BP 173 EP 176 DI 10.1007/978-3-319-19387-8_42 PG 4 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA BF5AQ UT WOS:000381813000042 ER PT S AU Oldfield, R Jalilian, I Song, MJ Tate, MK AF Oldfield, Richard Jalilian, Iman Song, Min Jae Tate, Melissa Knothe BE Jaffray, DA TI Mapping the Stem Cell's Mechanome Using Paired Live Cell Multiplexed Imaging and Modeling SO WORLD CONGRESS ON MEDICAL PHYSICS AND BIOMEDICAL ENGINEERING, 2015, VOLS 1 AND 2 SE IFMBE Proceedings LA English DT Proceedings Paper CT World Congress on Medical Physics and Biomedical Engineering CY JUN 07-12, 2015 CL Toronto, CANADA ID MECHANICAL MODULATION; TISSUE; FATE; SHAPE C1 [Oldfield, Richard; Jalilian, Iman; Tate, Melissa Knothe] Univ New South Wales, Grad Sch Biomed Engn, Sydney, NSW 2052, Australia. [Song, Min Jae] NIH, Bethesda, MD 20892 USA. RP Oldfield, R (reprint author), Univ New South Wales, Grad Sch Biomed Engn, Sydney, NSW 2052, Australia. EM m.knothetate@unsw.edu.au NR 10 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1680-0737 BN 978-3-319-19387-8; 978-3-319-19386-1 J9 IFMBE PROC PY 2015 VL 51 BP 275 EP 275 PG 1 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA BF5AQ UT WOS:000381813000067 ER PT J AU Hafftka, A Celik, H Cloninger, A Czaja, W Spencer, RG AF Hafftka, Ariel Celik, Hasan Cloninger, Alexander Czaja, Wojciech Spencer, Richard G. GP IEEE TI 2D Sparse Sampling Algorithm for N D Fredholm Equations with Applications to NMR Relaxometry SO 2015 INTERNATIONAL CONFERENCE ON SAMPLING THEORY AND APPLICATIONS (SAMPTA) LA English DT Proceedings Paper CT International Conference on Sampling Theory and Applications (SampTA) CY MAY 25-29, 2015 CL Washington, DC SP Univ Maryland, Army Res Lab ID MATRIX COMPLETION AB In [1], Cloninger, Czaja, Bai, and Basser developed an algorithm for compressive sampling based data acquisition for the solution of 2 D Fredholm equations. We extend the algorithm to N dimensional data, by randomly sampling in 2 dimensions and fully sampling in the remaining N - 2 dimensions. This new algorithm has direct applications to 3-dimensional nuclear magnetic resonance relaxometry and related experiments, such as T-1 - D - T-2 or T-1 - T-1,rho - T-2. In these experiments, the first two parameters are time-consuming to acquire, so sparse sampling in the first two parameters can provide significant experimental time savings, while compressive sampling is unnecessary in the third parameter. C1 [Hafftka, Ariel] Univ Maryland, Appl Math & Sci Computat, College Pk, MD 20742 USA. [Celik, Hasan; Spencer, Richard G.] NIA, Lab Clin Invest, NIH, Bethesda, MD 20892 USA. [Cloninger, Alexander] Yale Univ, Appl Math, New Haven, CT 06520 USA. [Czaja, Wojciech] Univ Maryland, Dept Math, College Pk, MD 20742 USA. RP Hafftka, A (reprint author), Univ Maryland, Appl Math & Sci Computat, College Pk, MD 20742 USA. EM ahafftka@math.umd.edu; hasan.celik@nih.gov; alexander.cloninger@yale.edu; wojtek@math.umd.edu; spencerri@mail.nih.gov NR 22 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4673-7353-1 PY 2015 BP 367 EP 371 PG 5 WC Engineering, Electrical & Electronic; Mathematics, Interdisciplinary Applications SC Engineering; Mathematics GA BF2UI UT WOS:000380500800077 ER PT J AU Shamputa, IC Cho, SN Lebron, J Via, LE AF Shamputa, Isdore C. Cho, Sang Nae Lebron, Janette Via, Laura E. BE Mukundan, H Chambers, MA Waters, WR Larsen, MH TI Introduction and Epidemiology of Mycobacterium tuberculosis Complex in Humans SO TUBERCULOSIS, LEPROSY AND MYCOBACTERIAL DISEASES OF MAN AND ANIMALS: THE MANY HOSTS OF MYCOBACTERIA LA English DT Editorial Material; Book Chapter ID ANTITUBERCULOSIS-DRUG-RESISTANCE; HUMAN-IMMUNODEFICIENCY-VIRUS; PULMONARY TUBERCULOSIS; CONGENITAL TUBERCULOSIS; GENETIC SUSCEPTIBILITY; LATENT TUBERCULOSIS; CHINESE POPULATION; UPDATED ANALYSIS; PROPHIT SURVEY; GLOBAL TRENDS C1 [Shamputa, Isdore C.] NIH, TB Res Sect, Lab Clin Infect Dis, Bldg 10, Bethesda, MD 20892 USA. [Lebron, Janette] NIH, Bldg 10, Bethesda, MD 20892 USA. [Via, Laura E.] NIAID, TB Res Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Cho, Sang Nae] Yonsei Univ, Coll Med, Dept Microbiol, Seoul, South Korea. RP Via, LE (reprint author), NIAID, TB Res Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM icshamputa@itg.be; raycho@yonsei.ac.kr; jlebron1@jhmi.edu; lvia@niaid.nih.gov NR 118 TC 0 Z9 0 U1 0 U2 0 PU CABI PUBLISHING-C A B INT PI WALLINGFORD PA CABI PUBLISHING, WALLINGFORD 0X10 8DE, OXON, ENGLAND BN 978-1-78064-396-0 PY 2015 BP 1 EP 16 D2 10.1079/9781780643960.0000 PG 16 WC Infectious Diseases; Veterinary Sciences SC Infectious Diseases; Veterinary Sciences GA BF5FO UT WOS:000381942700002 ER PT J AU Sizemore, C Lacourciere, K Parker, T AF Sizemore, Christine Lacourciere, Karen Parker, Tina BE Mukundan, H Chambers, MA Waters, WR Larsen, MH TI Introduction - The Many Hosts of Mycobacteria: An Interdisciplinary Approach to Understanding Mycobacterial Diseases SO TUBERCULOSIS, LEPROSY AND MYCOBACTERIAL DISEASES OF MAN AND ANIMALS: THE MANY HOSTS OF MYCOBACTERIA LA English DT Editorial Material; Book Chapter C1 [Sizemore, Christine; Lacourciere, Karen; Parker, Tina] NIAID, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Sizemore, C (reprint author), NIAID, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM csizemore@niaid.nih.gov; lacourcierek@niaid.nih.gov; parkerti@niaid.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 0 PU CABI PUBLISHING-C A B INT PI WALLINGFORD PA CABI PUBLISHING, WALLINGFORD 0X10 8DE, OXON, ENGLAND BN 978-1-78064-396-0 PY 2015 BP XV EP XVII D2 10.1079/9781780643960.0000 PG 3 WC Infectious Diseases; Veterinary Sciences SC Infectious Diseases; Veterinary Sciences GA BF5FO UT WOS:000381942700001 ER PT J AU Barry, CE AF Barry, Clifton E., III BE Mukundan, H Chambers, MA Waters, WR Larsen, MH TI The Continuing Co-evolution of Mycobacterium tuberculosis and Homo sapiens SO TUBERCULOSIS, LEPROSY AND MYCOBACTERIAL DISEASES OF MAN AND ANIMALS: THE MANY HOSTS OF MYCOBACTERIA LA English DT Article; Book Chapter ID TUMOR-NECROSIS-FACTOR; RHEUMATOID-ARTHRITIS; BEIJING GENOTYPE; IMMUNE-RESPONSE; RNA-POLYMERASE; PA-824; RESISTANCE; COMPLEX; STRAINS; OBESITY C1 [Barry, Clifton E., III] NIAID, TB Res Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Barry, CE (reprint author), NIAID, TB Res Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM cbarry@niaid.nih.gov NR 64 TC 0 Z9 0 U1 0 U2 0 PU CABI PUBLISHING-C A B INT PI WALLINGFORD PA CABI PUBLISHING, WALLINGFORD 0X10 8DE, OXON, ENGLAND BN 978-1-78064-396-0 PY 2015 BP 112 EP 123 D2 10.1079/9781780643960.0000 PG 12 WC Infectious Diseases; Veterinary Sciences SC Infectious Diseases; Veterinary Sciences GA BF5FO UT WOS:000381942700007 ER PT J AU Sharpe, S Via, LE Verreck, FAW Lin, PL AF Sharpe, Sally Via, Laura E. Verreck, Frank A. W. Lin, P. Ling BE Mukundan, H Chambers, MA Waters, WR Larsen, MH TI Non-human Primate Laboratory Models of Tuberculosis SO TUBERCULOSIS, LEPROSY AND MYCOBACTERIAL DISEASES OF MAN AND ANIMALS: THE MANY HOSTS OF MYCOBACTERIA LA English DT Article; Book Chapter ID MARMOSET CALLITHRIX-JACCHUS; MACAQUES MACACA-MULATTA; BACILLUS-CALMETTE-GUERIN; SIMIAN IMMUNODEFICIENCY VIRUS; INDIAN RHESUS MACAQUES; VIRULENT MYCOBACTERIUM-TUBERCULOSIS; MONKEYS SAIMIRI-SCIUREUS; PLASMA ANTIBODY PROFILES; NECROSIS-FACTOR-ALPHA; T-CELL DEPLETION C1 [Sharpe, Sally] Publ Hlth England, Porton Down, England. [Via, Laura E.] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. [Verreck, Frank A. W.] Biomed Primate Res Ctr, Dept Parasitol, Rijswijk, Netherlands. [Lin, P. Ling] Univ Pittsburgh, Dept Pediat, Childrens Hosp Pittsburgh, UPMC, Pittsburgh, PA 15260 USA. RP Lin, PL (reprint author), Univ Pittsburgh, Dept Pediat, Childrens Hosp Pittsburgh, UPMC, Pittsburgh, PA 15260 USA. EM sally.sharpe@phe.gov; lvia@niaid.nih.gov; verreck@bprc.nl; philana.lin@chp.edu NR 146 TC 1 Z9 1 U1 0 U2 1 PU CABI PUBLISHING-C A B INT PI WALLINGFORD PA CABI PUBLISHING, WALLINGFORD 0X10 8DE, OXON, ENGLAND BN 978-1-78064-396-0 PY 2015 BP 451 EP 469 D2 10.1079/9781780643960.0000 PG 19 WC Infectious Diseases; Veterinary Sciences SC Infectious Diseases; Veterinary Sciences GA BF5FO UT WOS:000381942700026 ER PT S AU Briggman, KL Kristan, WB Gonzalez, JE Kleinfeld, D Tsien, RY AF Briggman, Kevin L. Kristan, William B. Gonzalez, Jesus E. Kleinfeld, David Tsien, Roger Y. BE Canepari, M Zecevic, D Bernus, O TI Monitoring Integrated Activity of Individual Neurons Using FRET-Based Voltage-Sensitive Dyes SO MEMBRANE POTENTIAL IMAGING IN THE NERVOUS SYSTEM AND HEART SE Advances in Experimental Medicine and Biology LA English DT Article; Book Chapter DE Fluorescence resonance energy transfer (FRET); Voltage-sensitive dyes; Invertebrate ganglia; Invertebrate neurons; Genetically encoded probes; Functional connectivity ID RESONANCE ENERGY-TRANSFER; FLUORESCENT PROTEIN; ELECTRICAL-ACTIVITY; OPTICAL RECORDINGS; BEHAVIORAL CIRCUIT; ACTION-POTENTIALS; MEMBRANE VOLTAGE; NEURAL CIRCUITS; CHANNEL; LEECH AB Pairs of membrane-associated molecules exhibiting fluorescence resonance energy transfer (FRET) provide a sensitive technique to measure changes in a cell's membrane potential. One of the FRET pair binds to one surface of the membrane and the other is a mobile ion that dissolves in the lipid bilayer. The voltage-related signal can be measured as a change in the fluorescence of either the donor or acceptor molecules, but measuring their ratio provides the largest and most noise-free signal. This technology has been used in a variety of ways; three are documented in this chapter: (1) high throughput drug screening, (2) monitoring the activity of many neurons simultaneously during a behavior, and (3) finding synaptic targets of a stimulated neuron. In addition, we provide protocols for using the dyes on both cultured neurons and leech ganglia. We also give an updated description of the mathematical basis for measuring the coherence between electrical and optical signals. Future improvements of this technique include faster and more sensitive dyes that bleach more slowly, and the expression of one of the FRET pair genetically. C1 [Briggman, Kevin L.] NINDS, Circuit Dynam & Connect Unit, NIH, Bethesda, MD 20892 USA. [Kristan, William B.] Univ Calif San Diego, Neurobiol Sect, Div Biol Sci, 9500 Gilman Dr, La Jolla, CA 92093 USA. [Gonzalez, Jesus E.] Avelas Biosci, La Jolla, CA 92037 USA. [Kleinfeld, David] Univ Calif San Diego, Dept Phys, La Jolla, CA 92093 USA. [Tsien, Roger Y.] Univ Calif San Diego, Dept Pharmacol, Howard Hughes Med Inst, George Palade Labs 310, La Jolla, CA 92093 USA. RP Kristan, WB (reprint author), Univ Calif San Diego, Neurobiol Sect, Div Biol Sci, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM kevin.briggman@nih.gov; wkristan@ucsd.edu; txsandpiper@sbcglobal.net FU NINDS NIH HHS [R01 NS027177] NR 55 TC 0 Z9 0 U1 2 U2 5 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 0065-2598 BN 978-3-319-17641-3; 978-3-319-17640-6 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2015 VL 859 BP 149 EP 169 DI 10.1007/978-3-319-17641-3_6 D2 10.1007/978-3-319-17641-3 PG 21 WC Cell Biology; Medicine, Research & Experimental; Physiology SC Cell Biology; Research & Experimental Medicine; Physiology GA BF4JM UT WOS:000381082700007 PM 26238052 ER PT S AU Roth, HR Lee, CT Shin, HC Seff, A Kim, L Yao, J Lu, L Summers, RM AF Roth, Holger R. Lee, Christopher T. Shin, Hoo-Chang Seff, Ari Kim, Lauren Yao, Jianhua Lu, Le Summers, Ronald M. GP IEEE TI ANATOMY-SPECIFIC CLASSIFICATION OF MEDICAL IMAGES USING DEEP CONVOLUTIONAL NETS SO 2015 IEEE 12th International Symposium on Biomedical Imaging (ISBI) SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT IEEE 12th International Symposium on Biomedical Imaging CY APR 16-19, 2015 CL New York, NY SP NIBIB, NATL INST, IEEE, EMB DE Image Classification; Computed tomography (CT); Convolutional Networks; Deep Learning ID NEURAL-NETWORKS; ANNOTATION AB Automated classification of human anatomy is an important prerequisite for many computer-aided diagnosis systems. The spatial complexity and variability of anatomy throughout the human body makes classification difficult. "Deep learning" methods such as convolutional networks (ConvNets) outperform other state-of-the-art methods in image classification tasks. In this work, we present a method for organ-or body-part-specific anatomical classification of medical images acquired using computed tomography (CT) with ConvNets. We train a ConvNet, using 4,298 separate axial 2D key-images to learn 5 anatomical classes. Key-images were mined from a hospital PACS archive, using a set of 1,675 patients. We show that a data augmentation approach can help to enrich the data set and improve classification performance. Using ConvNets and data augmentation, we achieve anatomy-specific classification error of 5.9 % and area-under-the-curve (AUC) values of an average of 0.998 in testing. We demonstrate that deep learning can be used to train very reliable and accurate classifiers that could initialize further computer-aided diagnosis. C1 [Roth, Holger R.; Lee, Christopher T.; Shin, Hoo-Chang; Seff, Ari; Kim, Lauren; Yao, Jianhua; Lu, Le; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Roth, HR (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM holger.roth@nih.gov; rms@nih.gov NR 16 TC 3 Z9 3 U1 3 U2 3 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4799-2374-8 J9 I S BIOMED IMAGING PY 2015 BP 101 EP 104 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BF3IK UT WOS:000380546000025 ER PT S AU Ozarslan, E Memic, M Avram, AV Afzali, M Basser, PJ Westin, CF AF Ozarslan, E. Memic, M. Avram, A. V. Afzali, M. Basser, P. J. Westin, C. -F. GP IEEE TI ROTATING FIELD GRADIENT (RFG) MR OFFERS IMPROVED ORIENTATIONAL SENSITIVITY SO 2015 IEEE 12th International Symposium on Biomedical Imaging (ISBI) SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT IEEE 12th International Symposium on Biomedical Imaging CY APR 16-19, 2015 CL New York, NY SP NIBIB, NATL INST, IEEE, EMB DE MRI; diffusion; anisotropy; connectome; connectivity; tractography; orientation; RFG; rotating; microstructure; white-matter ID DIFFUSION; RESOLUTION; ANGLE; NMR AB Rotating field gradients (RFGs), generated by simultaneously applying sine-and cosine-modulated gradient waveforms along two perpendicular directions, provide an alternative diffusion sensitization mechanism for magnetic resonance imaging and spectroscopy. Two RFGs with a 90-degree phase shift between them are applied around the 180-degree RF pulse in a spin echo sequence to measure the diffusion orientation distribution function (dODF) directly. The technique obviates transforming the data from a space reciprocal to the displacement space. Here, we compare RFG results with those obtained by two pulsed field gradient (PFG) techniques: q-ball imaging (QBI) and its extension to constant solid angles (CSA). Our results indicate that RFG provides more accuracy than QBI, while the spurious peaks encountered with the QBI-CSA approach are absent when the RFG-based technique is used. These observations suggest the superior performance of RFG-based methods for mapping the anatomical connections within the nervous system. C1 [Ozarslan, E.; Memic, M.] Bogazici Univ, Dept Phys, Istanbul, Turkey. [Ozarslan, E.; Westin, C. -F.] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Boston, MA USA. [Avram, A. V.; Basser, P. J.] NICHD, Sect Tissue Biophys & Biomimet, PPITS, NIH, Bethesda, MD USA. [Afzali, M.] Sharif Univ Technol, Dept Elect Engn, Tehran, Iran. RP Ozarslan, E (reprint author), Bogazici Univ, Dept Phys, Istanbul, Turkey. NR 17 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4799-2374-8 J9 I S BIOMED IMAGING PY 2015 BP 955 EP 958 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BF3IK UT WOS:000380546000228 ER PT S AU Liu, JM Narayanan, D Chang, K Kim, L Turkbey, E Lu, L Yao, JH Summers, RM AF Liu, Jiamin Narayanan, Divya Chang, Kevin Kim, Lauren Turkbey, Evrim Lu, Le Yao, Jianhua Summers, Ronald M. GP IEEE TI AUTOMATED SEGMENTATION OF THE THYROID GLAND ON CT USING MULTI-ATLAS LABEL FUSION AND RANDOM FOREST SO 2015 IEEE 12th International Symposium on Biomedical Imaging (ISBI) SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT IEEE 12th International Symposium on Biomedical Imaging CY APR 16-19, 2015 CL New York, NY SP NIBIB, NATL INST, IEEE, EMB DE thyroid gland segmentation; multi-atlas label fusion; random forest AB The thyroid gland is an important endocrine organ. For a variety of clinical applications, a system for automated segmentation of the thyroid is desirable. Thyroid segmentation is challenging due to the inhomogeneous nature of the thyroid and the surrounding structures which have similar intensities. In this paper, we propose a fully automated method for thyroid detection and segmentation on CT scans. The thyroid gland is initially estimated by a multi-atlas segmentation with joint label fusion algorithm. The segmentation is then corrected by supervised statistical learning-based voxel labeling with a random forest algorithm. Multi-atlas label fusion transfers expert-labeled thyroids from atlases to a target image using deformable registration. Errors produced by label transfer are reduced by label fusion that combines the results produced by all atlases into a consensus solution. Then, random forest employs an ensemble of decision trees that are trained on labeled thyroids to recognize various features. The trained forest classifier is then applied to the estimated thyroid by voxel scanning to assign the class-conditional probability. Voxels from the expert-labeled thyroids in CT volumes are treated as positive classes and background non-thyroid voxels as negatives. We applied our method to 73 patients using 5 as atlases. The system achieved an overall 0.70 Dice Similarity Coefficient ( DSC) if using the multi-atlas label fusion only and was improved to 0.75 DSC after the random forest correction. C1 [Liu, Jiamin; Narayanan, Divya; Chang, Kevin; Kim, Lauren; Turkbey, Evrim; Lu, Le; Yao, Jianhua; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci, Ctr Clin, Bldg 10 Room 1C224 MSC 1182, Bethesda, MD 20892 USA. RP Liu, JM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci, Ctr Clin, Bldg 10 Room 1C224 MSC 1182, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4799-2374-8 J9 I S BIOMED IMAGING PY 2015 BP 1114 EP 1117 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BF3IK UT WOS:000380546000266 ER PT S AU Xu, ZY Bagci, U Gao, MC Mollura, DJ AF Xu, Ziyue Bagci, Ulas Gao, Mingchen Mollura, Daniel J. GP IEEE TI HIGHLY PRECISE PARTIAL VOLUME CORRECTION FOR PET IMAGES: AN ITERATIVE APPROACH VIA SHAPE CONSISTENCY SO 2015 IEEE 12th International Symposium on Biomedical Imaging (ISBI) SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT IEEE 12th International Symposium on Biomedical Imaging CY APR 16-19, 2015 CL New York, NY SP NIBIB, NATL INST, IEEE, EMB DE Positron Emission Tomography; Partial Volume Correction; Shape Consistency; Regional Means; Affinity Propagation ID SEGMENTATION AB Positron emission tomography ( PET) is capable of capturing the functional information. A major limitation for PET imaging is the low spatial resolution, leading to partial volume effects ( PVE). PVE introduces significant bias to the image quantification, causing compromised measurement for uptake regions, especially smaller ones. For quantitative PET, accurate uptake values are critical for diagnostic evaluation and treatment planning. Therefore, a partial volume correction ( PVC) technique is highly desirable in order to avoid size-dependent underestimation for true activities. In this paper, we present a new iterative PVC approach for PET images. The proposed method uses the state-of-the-art simultaneous delineation and noise removal algorithm to estimate the local uptake regions. The delineation is further utilized for weighted PVC with regard to a shape consistency measurement. The process is performed iteratively until delineation convergence. Qualitative and quantitative results demonstrate that the proposed framework successfully corrects the PVE and preserves local structures. C1 [Xu, Ziyue; Bagci, Ulas; Gao, Mingchen; Mollura, Daniel J.] NIH, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. [Bagci, Ulas] Univ Cent Florida, CRCV, Orlando, FL 32816 USA. RP Bagci, U (reprint author), NIH, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. EM bagci@crcv.ucf.edu OI Bagci, Ulas/0000-0001-7379-6829 NR 11 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4799-2374-8 J9 I S BIOMED IMAGING PY 2015 BP 1196 EP 1199 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BF3IK UT WOS:000380546000286 ER PT S AU Jacobs, M Gorbachev, M Benovoy, M Chang, LC Arai, AE Hsu, LY AF Jacobs, Matthew Gorbachev, Mikhail Benovoy, Mitchel Chang, Lin-Ching Arai, Andrew E. Hsu, Li-Yueh GP IEEE TI AUTOMATED MEASUREMENT OF ARTERIAL INPUT FUNCTION IN FIRST-PASS MYOCARDIAL PERFUSION MAGNETIC RESONANCE IMAGES USING INDEPENDENT COMPONENT ANALYSIS SO 2015 IEEE 12th International Symposium on Biomedical Imaging (ISBI) SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT IEEE 12th International Symposium on Biomedical Imaging CY APR 16-19, 2015 CL New York, NY SP NIBIB, NATL INST, IEEE, EMB DE cardiovascular magnetic resonance; myocardial perfusion imaging; arterial input function ID CORONARY-ANGIOGRAPHY AB Quantitative assessment of first-pass cardiac magnetic resonance (CMR) perfusion imaging is useful for detecting coronary artery disease, but it requires the measurement of the arterial input function (AIF) from the left ventricle. This is usually done manually, which is time consuming and subjective. This study presents an automated method for measuring the AIF from the first-pass CMR perfusion images. It was tested on 194 clinical perfusion studies and compared with manual reference measurements. Our results show the proposed method successfully measured 98.79% of the perfusion series, with manual and automated measurements strongly correlating. Temporal statistics were similar for both measurements, showing agreement between the automated and manual AIFs. The automated method, however, more accurately selected the brightest left ventricle pixels and excluded papillary muscles. These improvements may help make AIF measurement and quantitative CMR myocardial perfusion analysis more accurate and readily available. C1 [Jacobs, Matthew; Gorbachev, Mikhail; Benovoy, Mitchel; Arai, Andrew E.; Hsu, Li-Yueh] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Jacobs, Matthew; Gorbachev, Mikhail; Chang, Lin-Ching] Catholic Univ Amer, Dept Elect Engn & Comp Sci, Washington, DC 20064 USA. [Benovoy, Mitchel] Ecole Polytech Montreal, Montreal, PQ, Canada. RP Jacobs, M (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 14 TC 1 Z9 1 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4799-2374-8 J9 I S BIOMED IMAGING PY 2015 BP 1332 EP 1335 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BF3IK UT WOS:000380546000320 ER PT S AU Nandy, K Gulda, PR Chellappa, R Lockett, SJ AF Nandy, Kaustav Gulda, Prabhkar R. Chellappa, Rama Lockett, Stephen J. GP IEEE TI PROBABILISTIC EDGE DETECTION IN 3D OPTICAL MICROSCOPY IMAGES OF TISSUE SAMPLES SO 2015 IEEE 12th International Symposium on Biomedical Imaging (ISBI) SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT IEEE 12th International Symposium on Biomedical Imaging CY APR 16-19, 2015 CL New York, NY SP NIBIB, NATL INST, IEEE, EMB DE Probabilistic edge detection; fluorescence microscopy; 3D image analysis; tissue sample; acinus AB Inspired by a state of the art 2D algorithm for edge detection in natural images, in this work we report the development of an accurate 3D probabilistic edge detector for fluorescence optical microscopy images of tissue samples. The method utilizes multi-orientation and multi-scale brightness, textural and spectral properties of the data to compute a probabilistic edge map. To demonstrate the strengths and accuracy of the proposed algorithm, comparisons of the edge maps produced by our algorithm and several other popular edge detectors on simulated and real 3D microscopic volumes are provided. C1 [Nandy, Kaustav; Gulda, Prabhkar R.; Lockett, Stephen J.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Opt Microscopy & Anal Lab, Frederick, MD 21702 USA. [Chellappa, Rama] Univ Maryland, Dept Elect & Comp Engn, College Pk, MD 20742 USA. RP Nandy, K (reprint author), Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Opt Microscopy & Anal Lab, Frederick, MD 21702 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4799-2374-8 J9 I S BIOMED IMAGING PY 2015 BP 1462 EP 1465 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BF3IK UT WOS:000380546000351 ER PT S AU Huang, S Gao, MC Yang, D Huang, XL Elgammal, A Zhang, XH AF Huang, Sheng Gao, Mingchen Yang, Dan Huang, Xiaolei Elgammal, Ahmed Zhang, Xiaohong GP IEEE TI UNBALANCED GRAPH-BASED TRANSDUCTION ON SUPERPIXELS FOR AUTOMATIC CERVIGRAM IMAGE SEGMENTATION SO 2015 IEEE 12th International Symposium on Biomedical Imaging (ISBI) SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT IEEE 12th International Symposium on Biomedical Imaging CY APR 16-19, 2015 CL New York, NY SP NIBIB, NATL INST, IEEE, EMB DE Image Segmentation; Transductive Learning; Unbalanced Classification; Graph Learning; Semi supervised Learning AB We propose a novel medical image segmentation algorithm by transductively inferring the labels. In this approach, super pixels are first generated to incorporate the local spatial information and also to speed up the segmentation. The segmentation task can be deemed as an unbalanced superpixels labeling problem due to the fact that the region of interest is only a small fraction compared to the whole image. We present a new transductive learning-based algorithm called Class Averaging Graph -based Transduction (CAGT) to avoid the biased labeling caused by the imbalance. The proposed algorithm was applied to the automatic cervigram image segmentation to demonstrate it effectiveness. C1 [Huang, Sheng; Yang, Dan; Zhang, Xiaohong] Chongqing Univ, Minist Educ, Key Lab Dependable Serv Comp Cyber Phys Soc, Chongqing 400044, Peoples R China. [Gao, Mingchen] NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Elgammal, Ahmed] Rutgers State Univ, Piscataway, NJ 08854 USA. [Huang, Xiaolei] Lehigh Univ, Bethlehem, PA 18015 USA. RP Huang, S (reprint author), Chongqing Univ, Minist Educ, Key Lab Dependable Serv Comp Cyber Phys Soc, Chongqing 400044, Peoples R China. NR 10 TC 0 Z9 0 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4799-2374-8 J9 I S BIOMED IMAGING PY 2015 BP 1556 EP 1559 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BF3IK UT WOS:000380546000374 ER PT S AU Benovoy, M Jacobs, M Cheriet, F Dahdah, N Arai, AE Hsu, LY AF Benovoy, Mitchel Jacobs, Matthew Cheriet, Farida Dahdah, Nagib Arai, Andrew E. Hsu, Li-Yueh GP IEEE TI AUTOMATIC NONRIGID MOTION CORRECTION FOR QUANTITATIVE FIRST-PASS CARDIAC MR PERFUSION IMAGING SO 2015 IEEE 12th International Symposium on Biomedical Imaging (ISBI) SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT IEEE 12th International Symposium on Biomedical Imaging CY APR 16-19, 2015 CL New York, NY SP NIBIB, NATL INST, IEEE, EMB DE cardiac magnetic resonance; perfusion; nonrigid; motion correction AB First-pass dynamic contrast-enhanced cardiac magnetic resonance imaging is an increasingly important diagnostic tool for coronary artery disease. It is typically performed with breath holding and electrocardiogram gating to minimize motion, but movement caused by residual respiration, cardiac arrhythmia, or missed gating triggers during image acquisition will induce nonrigid deformations of the myocardium that can hamper interpretation and perfusion quantification. We propose an automatic nonrigid image registration framework to correct motion in a series of cardiac magnetic resonance perfusion images. Our method employs reference frame detection combined with robust flow field estimation using a large displacement optical flow formulation coupled with post -hoc image warping and flow field distortion correction. This framework is multi-threadable and can be applied to standard myocardial series, arterial input function series, and proton density weighted images to facilitate perfusion quantification. C1 [Benovoy, Mitchel; Jacobs, Matthew; Arai, Andrew E.; Hsu, Li-Yueh] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Benovoy, Mitchel; Cheriet, Farida] Ecole Polytech Montreal, Dept Biomed Engn, Montreal, PQ, Canada. [Jacobs, Matthew] Catholic Univ Amer, Dept Elect Engn & Comp Sci, Washington, DC 20064 USA. [Dahdah, Nagib] Ste Justine Univ Hosp Res Ctr, Montreal, PQ, Canada. RP Benovoy, M (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 13 TC 1 Z9 1 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4799-2374-8 J9 I S BIOMED IMAGING PY 2015 BP 1588 EP 1591 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BF3IK UT WOS:000380546000382 ER PT J AU Rossi, E Fontelo, P Ackerman, MJ Pozzi, G Marceglia, S AF Rossi, Elena Fontelo, Paul Ackerman, Michael J. Pozzi, Giuseppe Marceglia, Sara BE Balakrishnan, P Srivatsava, J Fu, WT Harabagiu, S Wang, F TI A prototype of mobile app/EHR communication through standards for home treatment of transcranial Direct Current Stimulation SO 2015 IEEE INTERNATIONAL CONFERENCE ON HEALTHCARE INFORMATICS (ICHI 2015) LA English DT Proceedings Paper CT International Conference on Healthcare Informatics (ICHI) CY OCT 21-23, 2015 CL Dallas, TX SP IEEE, IEEE comp soc, UT DALLAS DE Electric Stimulation Therapy; Electronic Health Record; Mobile Health App; Transcranial Direct Current Stimulation ID ELECTRONIC HEALTH RECORDS; CARE AB Daily management of neurodegenerative diseases by electrical neuromodulation techniques requires an integrated health care system for the continuous assistance to the patient. In this scenario, a direct bi-directional exchange of information between the patient's electronic health record (EHR) and patient's personal mobile health apps (mHealth) can boost the active contribution of patients and caregivers to safe homecare management. Grounding on a recently proposed standards-based architecture, we describe here a prototype implementing the mHealth App/EHR bi-directional health information exchange for supporting homecare transcranial Direct Current Stimulation (tDCS) therapy. We first modeled the tDCS case study using the Unified Modeling Language (UML) and, then, we developed the mHealth app for the patient side in order to implement the exchange architecture. We then connected the app to an EHR system developed using a web-based platform (WebBioBank) based on a framework for EHR management. The neurologist, using the EHR system, can configure the patient's homecare plan sent to the mHealth App, and can see the patient's monitoring reports sent from the mHealth App to the EHR. The integration architecture is implemented by CDA-2 compliant XML encrypted files. The current prototype proves that direct information exchange between mHealth Apps and EHR systems is possible by a standards-based architecture and can be effectively used to improve patient-neurologist communication as well as to support tDCS home therapy. C1 [Rossi, Elena; Pozzi, Giuseppe] Politecn Milan, Dipartimento Elettron Informaz & Bioingn, Milan, Italy. [Fontelo, Paul; Ackerman, Michael J.] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bethesda, MD 20892 USA. [Marceglia, Sara] Univ Trieste, Dipartimento Ingn & Architettura, Trieste, Italy. RP Rossi, E (reprint author), Politecn Milan, Dipartimento Elettron Informaz & Bioingn, Milan, Italy. EM elena.rossi@polimi.it; pfontelo@mail.nih.gov; mackerman@mail.nih.gov; giuseppe.pozzi@polimi.it; sara.marceglia@units.it NR 20 TC 0 Z9 0 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4673-9548-9 PY 2015 BP 310 EP 315 DI 10.1109/ICHI.2015.44 PG 6 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BF1IC UT WOS:000380399000038 ER PT S AU Wolcott, HN Fouch, MJ Hsu, E Bernaciak, C Corrigan, J Williams, D AF Wolcott, Holly N. Fouch, Matthew J. Hsu, Elizabeth Bernaciak, Catherine Corrigan, James Williams, Duane BE Salah, AA Tonta, Y Salah, AAA Sugimoto, C Al, U TI Modeling Time-dependent and -independent Indicators to Facilitate Identification of Breakthrough Research Papers SO PROCEEDINGS OF ISSI 2015 ISTANBUL: 15TH INTERNATIONAL SOCIETY OF SCIENTOMETRICS AND INFORMETRICS CONFERENCE SE Proceedings of the International Conference on Scientometrics and Informetrics LA English DT Proceedings Paper CT 15th International Conference of the International-Society-for-Scientometrics-and-Informetrics (ISSI) on Scientometrics and Informetrics CY JUN 29-JUL 04, 2015 CL Bogazici Univ, Istanbul, TURKEY SP Int Soc Scientometr & Informetr, Hacettepe Univ, Sci & Technol Res Council Turkey, Turkish Acad Network & Informat Ctr HO Bogazici Univ AB Research funding organizations invest substantial resources to stay current with important research findings within their mission areas to identify and support promising new lines of inquiry. To that end, we continue to pursue the development of tools to identify research publications that have a strong likelihood of driving new avenues of research. This research-in-progress paper describes our work incorporating multiple time-dependent and-independent features of publications into a model that aims to identify candidate breakthrough papers as early as possible following publication. We used multiple Random Forest models to assess the ability of indicators to reliably distinguish a gold standard set of breakthrough publications as identified by subject matter experts from among a comparison group of similar Thomson Reuters Web of Science (TM) publications. These indicators will be selected for inclusion in a multi-variate model to test their predictive value. Prospective use of these indicators and models is planned to further establish their reliability. C1 [Wolcott, Holly N.; Fouch, Matthew J.; Bernaciak, Catherine; Williams, Duane] Thomson Reuters, Intellectual Property & Sci, Rockville, MD 20850 USA. [Hsu, Elizabeth; Corrigan, James] NCI, Off Sci Planning & Assessment, Bethesda, MD 20892 USA. RP Wolcott, HN (reprint author), Thomson Reuters, Intellectual Property & Sci, Rockville, MD 20850 USA. EM holly.wolcott@thomsonreuters.com; corrigan@mail.nih.gov NR 16 TC 1 Z9 1 U1 3 U2 3 PU INT SOC SCIENTOMETRICS & INFORMETRICS-ISSI PI LEUVEN PA KATHOLIEKE UNIV LEUVEN, FACULTEIT E T E W, DEKENSTRAAT 2, LEUVEN, B-3000, BELGIUM SN 2175-1935 BN 978-975-518-381-7 J9 PRO INT CONF SCI INF PY 2015 BP 403 EP 408 PG 6 WC Computer Science, Interdisciplinary Applications SC Computer Science GA BF2TX UT WOS:000380499700056 ER PT J AU Marchell, R Locatis, C Ackerman, M AF Marchell, Richard Locatis, Craig Ackerman, Michael BE Smari, WW McQuay, W Nygard, M Natarian, J TI High Definition Live Interactive and Store and Forward Teledermatology: Initial Qualitative Observations SO PROCEEDINGS OF THE 2015 INTERNATIONAL CONFERENCE ON COLLABORATION TECHNOLOGIES AND SYSTEMS LA English DT Proceedings Paper CT Proceedings of the 2015 International Conference on Collaboration Technologies and Systems CY JUN 01-05, 2015 CL Atlanta, GA SP Honeywell Int Inc, Knowledge Based Systems, Inc. (KBSI), Ball Aerospace and Technologies Corp, ClearFunnel, Inc, Intel Corp, LexisNexis Corp, Microsoft Res, PayPal, Inc., Springer Verlag DE collaboration enabling technologies; information infrastructure for collaboration; tele and collaboration technologies in healthcare ID MANAGEMENT; DIAGNOSIS; TELEMEDICINE AB Initial qualitative findings from a study of uncompressed and compressed high definition live interactive video, and store and forward teledermatology (photographs and written histories for later review) are presented. Quantitative data collected in the study are still being compiled and analyzed comparing diagnostic concordance and confidence with in-person exams. The early qualitative findings suggest bifurcated patient and physician preferences for the different remote exam methods. C1 [Marchell, Richard] Med Univ S Carolina, Dept Dermatol, Charleston, SC 29425 USA. [Locatis, Craig; Ackerman, Michael] Natl Lib Med, NIH, Bethesda, MD USA. RP Marchell, R (reprint author), Med Univ S Carolina, Dept Dermatol, Charleston, SC 29425 USA. EM marchell@musc.edu; locatis@nlm.nih.gov; ackerman@nlm.nih.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4673-7648-8 PY 2015 BP 446 EP 449 PG 4 WC Computer Science, Information Systems; Computer Science, Theory & Methods SC Computer Science GA BF2HZ UT WOS:000380469300075 ER PT J AU de Maturana, EL Picornell, A Masson-Lecomte, A Kogevinas, M Marquez, M Carrato, A Tardon, A Lloreta, J Garcia-Closas, M Silverman, D Rothman, N Chanock, S Real, F Goddard, M Malats, N AF Lopez de Maturana, E. Picornell, A. Masson-Lecomte, A. Kogevinas, M. Marquez, M. Carrato, A. Tardon, A. Lloreta, J. Garcia-Closas, M. Silverman, D. Rothman, N. Chanock, S. Real, F. Goddard, M. Malats, N. CA SBC EPICURO Investigators TI A Bayesian Lasso Genome-Wide Multimarker Approach to Predict Prognosis: An Application to Bladder Cancer Progression SO HUMAN HEREDITY LA English DT Meeting Abstract CT 44th European Mathematical Genetics Meeting (EMGM) CY MAY 11-12, 2016 CL Newcastle upon Tyne, ENGLAND C1 [Lopez de Maturana, E.; Picornell, A.; Masson-Lecomte, A.; Marquez, M.; Real, F.; Malats, N.] Spanish Natl Canc Res Ctr CNIO, Madrid, Spain. [Kogevinas, M.] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Carrato, A.] Hosp Univ Ramon y Cajal, Madrid, Spain. [Tardon, A.] Univ Oviedo, Oviedo, Spain. [Garcia-Closas, M.] Inst Canc Res, London, England. [Silverman, D.; Rothman, N.; Chanock, S.] NCI, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Goddard, M.] Univ Melbourne, Melbourne, Vic, Australia. RI Kogevinas, Manolis/C-3918-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0001-5652 EI 1423-0062 J9 HUM HERED JI Hum. Hered. PY 2015 VL 80 IS 3 MA 38 BP 117 EP 117 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA DR8IA UT WOS:000380140400039 ER PT J AU Wang, SL Chen, F Gu, JC Fang, JW AF Wang, Shulin Chen, Fang Gu, Jinchao Fang, Jianwen GP IEEE TI Cancer Classification Using Collaborative Representation Classifier Based on Non-convex Lp-norm and Novel Decision Rule SO 2015 SEVENTH INTERNATIONAL CONFERENCE ON ADVANCED COMPUTATIONAL INTELLIGENCE (ICACI) LA English DT Proceedings Paper CT International Conference on Advanced Computational Intelligence CY MAR 27-29, 2015 CL Fujian, PEOPLES R CHINA ID ROBUST FACE RECOGNITION; GENE-EXPRESSION PROFILE; SPARSE REPRESENTATION; TUMOR CLASSIFICATION; L(1)-MINIMIZATION; PREDICTION; ALGORITHMS; LEUKEMIA AB Sparse representation classification (SRC) and collaborative representation classification (CRC) are the most promising classifiers for classifying high dimensional data. However, they may suffer from outliers and noises, as l(2)-norm on signal fidelity is not effective enough to represent the test sample in that case. Recent studies show that non-convex l(p)-norm minimization can boost the performance of classifiers compared with l(1)- and l(2)-norm minimization in classification. In this paper, we present an improved collaborative representation classification method for the accurate identification of cancer subtype. We improve CRC method by adopting non-convex lp-norm on the signal fidelity term and introducing a new classification decision rule. We compute the coding coefficients over training samples for test sample via generalized iterated shrinkage algorithm (GISA) and classify the test sample into the subclass which has the maximum sum of coefficient (SoC). Extensive experiments on eight publicly available gene expression profde (GEP) datasets demonstrate the superiority of our proposed method. C1 [Wang, Shulin; Chen, Fang; Gu, Jinchao] Hunan Univ, Coll Comp Sci & Elect Engn, Changsha 410082, Hunan, Peoples R China. [Fang, Jianwen] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Rockville, MD 20850 USA. RP Wang, SL (reprint author), Hunan Univ, Coll Comp Sci & Elect Engn, Changsha 410082, Hunan, Peoples R China. EM smartforesting@gmail.com; keepmoving90@qq.com; gu0802@126.com; jianwen.fang@nih.gov NR 26 TC 0 Z9 0 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4799-7259-3 PY 2015 BP 189 EP 194 PG 6 WC Computer Science, Theory & Methods; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BF2MC UT WOS:000380479600063 ER PT S AU Moakher, M Basser, PJ AF Moakher, Maher Basser, Peter J. BE Hotz, I Schultz, T TI Fiber Orientation Distribution Functions and Orientation Tensors for Different Material Symmetries SO VISUALIZATION AND PROCESSING OF HIGHER ORDER DESCRIPTORS FOR MULTI-VALUED DATA SE Mathematics and Visualization LA English DT Proceedings Paper CT Workshop on the Visualization and Processing of Higher Order Descriptors for Multi-Valued Data CY FEB, 2014 CL Dagstuhl, GERMANY ID DENSITY-FUNCTION; DIRECTIONAL-DATA; FABRIC TENSORS; DIFFUSION; DECOMPOSITION; COMPOSITES; TRANSFORM; KERNEL AB In this paper we give closed-form expressions of the orientation tensors up to the order four associated with some axially-symmetric orientation distribution functions (ODF), including the well-known von Mises-Fisher, Watson, and de la Vallee Poussin ODFs. Each is characterized by a mean direction and a concentration parameter. Then, we use these elementary ODFs as building blocks to construct new ones with a specified material symmetry and derive the corresponding orientation tensors. For a general ODF we present a systematic way of calculating the corresponding orientation tensors from certain coefficients of the expansion of the ODF in spherical harmonics. C1 [Moakher, Maher] Univ Tunis El Manar, ENIT LAMSIN, Lab Math & Numer Modeling Engn Sci, Natl Engn Sch Tunis, BP 37, Tunis 1002, Tunisia. [Basser, Peter J.] NICHD, Sect Tissue Biophys & Biomimet, PPITS, NIH, Bethesda, MD 20892 USA. RP Moakher, M (reprint author), Univ Tunis El Manar, ENIT LAMSIN, Lab Math & Numer Modeling Engn Sci, Natl Engn Sch Tunis, BP 37, Tunis 1002, Tunisia. EM maher.moakher@gmail.com; pjbasser@helix.nih.gov RI Moakher, Maher/A-6315-2010 OI Moakher, Maher/0000-0002-9432-0456 NR 35 TC 2 Z9 2 U1 1 U2 2 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 1612-3786 BN 978-3-319-15090-1; 978-3-319-15089-5 J9 MATH VIS PY 2015 BP 37 EP 71 DI 10.1007/978-3-319-15090-1_3 PG 35 WC Computer Science, Artificial Intelligence; Mathematics, Applied; Imaging Science & Photographic Technology SC Computer Science; Mathematics; Imaging Science & Photographic Technology GA BF2ER UT WOS:000380461100003 ER PT B AU Richmond, BJ AF Richmond, Barry J. BE Liljenstrom, H TI An Interaction Between Orbitofrontal and Rhinal Cortices Contributing to Reward Seeking Behavior SO ADVANCES IN COGNITIVE NEURODYNAMICS (IV) LA English DT Proceedings Paper CT 4th International Conference on Cognitive Neurodynamics (ICCN) CY JUN 23-27, 2013 CL Sigtuna, SWEDEN SP Agora Biosystems, Sigtunastiftelsen, Vetenskapsradet, Springer, Uppsala Univ, Swedish Univ Agr Sci DE Reward value; Orbitofrontal cortex; Rhinal cortex; Disconnection; Monkey ID MEDIAL TEMPORAL-LOBE; CORTEX; SCHEDULES; NEURONS; MEMORY AB Monkeys given a disconnection of rhinal cortex from orbitofrontal cortex do not distinguish among different reward sizes, in a manner similar to that seen in monkeys with a bilateral rhinal cortex removal. Thus, it seems that reacting to differences among rewards requires communication between rhinal and orbitofrontal cortices. We suggest that the orbitofrontal cortex assesses value and rhinal is important for remembering the relations among the different reward sizes. This interaction provides a platform for studying information exchange across brain regions. C1 [Richmond, Barry J.] NIMH, Neuropsychol Lab, NIH, Bldg 49,Rm 1B80, Bethesda, MD 20892 USA. RP Richmond, BJ (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Rm 1B80, Bethesda, MD 20892 USA. EM bjr@ln.nimh.nih.gov NR 12 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 978-94-017-9548-7; 978-94-017-9547-0 PY 2015 BP 89 EP 92 DI 10.1007/978-94-017-9548-7_12 PG 4 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA BF1CJ UT WOS:000380362800012 ER PT B AU Belic, JJ Klaus, A Plenz, D Kotaleski, JH AF Belic, Jovana J. Klaus, Andreas Plenz, Dietmar Kotaleski, Jeanette Hellgren BE Liljenstrom, H TI Mapping of Cortical Avalanches to the Striatum SO ADVANCES IN COGNITIVE NEURODYNAMICS (IV) LA English DT Proceedings Paper CT 4th International Conference on Cognitive Neurodynamics (ICCN) CY JUN 23-27, 2013 CL Sigtuna, SWEDEN SP Agora Biosystems, Sigtunastiftelsen, Vetenskapsradet, Springer, Uppsala Univ, Swedish Univ Agr Sci DE Neuronal avalanches; Striatum; Cortico-striatal network; Cortex; Basal ganglia ID NEURONAL AVALANCHES; NETWORKS AB Neuronal avalanches are found in the resting state activity of the mammalian cortex. Here we studied whether and how cortical avalanches are mapped onto the striatal circuitry, the first stage of the basal ganglia. We first demonstrate using organotypic cortex-striatum-substantia nigra cultures from rat that indeed striatal neurons respond to cortical avalanches originating in superficial layers. We simultaneously recorded spontaneous local field potentials (LFPs) in the cortical and striatal tissue using high-density microelectrode arrays. In the cortex, spontaneous neuronal avalanches were characterized by intermittent spatiotemporal activity clusters with a cluster size distribution that followed a power law with exponent -1.5. In the striatum, intermittent spatiotemporal activity was found to correlate with cortical avalanches. However, striatal negative LFP peaks (nLFPs) did not show avalanche signatures, but formed a cluster size distribution that had a much steeper drop-off, i. e., lacked large spatial clusters that are commonly expected for avalanche dynamics. The underlying de-correlation of striatal activity could have its origin in the striatum through local inhibition and/ or could result from a particular mapping in the corticostriatal pathway. Here we show, usingmodeling, that highly convergent corticostriatal projections can map spatially extended cortical activity into spatially restricted striatal regimes. C1 [Belic, Jovana J.; Kotaleski, Jeanette Hellgren] KTH Royal Inst Technol, Sch Comp Sci & Commun, S-10044 Stockholm, Sweden. [Belic, Jovana J.] Univ Freiburg, Bernstein Ctr Freiburg, D-79104 Freiburg, Germany. [Klaus, Andreas; Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Bethesda, MD 20892 USA. RP Belic, JJ (reprint author), KTH Royal Inst Technol, Sch Comp Sci & Commun, S-10044 Stockholm, Sweden. EM belic@kth.se NR 14 TC 2 Z9 2 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 978-94-017-9548-7; 978-94-017-9547-0 PY 2015 BP 291 EP 297 DI 10.1007/978-94-017-9548-7_41 PG 7 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA BF1CJ UT WOS:000380362800041 ER PT B AU Kish, LB Granqvist, CG Bezrukov, SM Horvath, T AF Kish, Laszlo B. Granqvist, Claes G. Bezrukov, Sergey M. Horvath, Tamas BE Liljenstrom, H TI Brain: Biological Noise-Based Logic SO ADVANCES IN COGNITIVE NEURODYNAMICS (IV) LA English DT Proceedings Paper CT 4th International Conference on Cognitive Neurodynamics (ICCN) CY JUN 23-27, 2013 CL Sigtuna, SWEDEN SP Agora Biosystems, Sigtunastiftelsen, Vetenskapsradet, Springer, Uppsala Univ, Swedish Univ Agr Sci DE Neural logic; Deterministic logic; Logic variable; Neural spikes; Stochastic signal AB Neural spikes in the brain form stochastic sequences, i.e., belong to the class of pulse noises. This stochasticity is a counterintuitive feature because extracting information-such as the commonly supposed neural information of mean spike frequency-requires long times for reasonably low error probability. The mystery could be solved by noise-based logic, wherein randomness has an important function and allows large speed enhancements for special-purpose tasks, and the same mechanism is at work for the brain logic version of this concept. C1 [Kish, Laszlo B.] Texas A&M Univ, Dept Elect Engn, College Stn, TX 77843 USA. [Granqvist, Claes G.] Uppsala Univ, Dept Engn Sci, Angstrom Lab, SE-75121 Uppsala, Sweden. [Bezrukov, Sergey M.] NICHD, Lab Phys & Struct Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Horvath, Tamas] Schloss Birlinghoven, Fraunhofer IAIS, Div Knowledge Discovery, D-53754 St Augustin, Germany. [Horvath, Tamas] Univ Bonn, Dept Comp Sci, Bonn, Germany. RP Kish, LB (reprint author), Texas A&M Univ, Dept Elect Engn, College Stn, TX 77843 USA. EM Laszlokish@tamu.edu NR 3 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 978-94-017-9548-7; 978-94-017-9547-0 PY 2015 BP 319 EP 322 DI 10.1007/978-94-017-9548-7_45 PG 4 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA BF1CJ UT WOS:000380362800045 ER PT S AU Bourne, PE AF Bourne, Philip E. BE Huan, J Miyano, S Shehu, A Hu, X Ma, B Rajasekaran, S Gombar, VK Schapranow, IM Yoo, IH Zhou, JY Chen, B Pai, V Pierce, B TI Big Data in Biomedicine - An NIH Perspective SO PROCEEDINGS 2015 IEEE INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND BIOMEDICINE SE IEEE International Conference on Bioinformatics and Biomedicine-BIBM LA English DT Proceedings Paper CT IEEE International Conference on Bioinformatics and Biomedicine CY NOV 09-12, 2015 CL Washington, DC SP IEEE, IEEE Comp Soc, Natl Sci Fdn AB Biomedical research is becoming increasingly data driven, analytical and hence digital. In recognition of this evolution NIH has established the Office for Data Science with trans NIH responsibility for maximizing the value of this digital enterprise. This effort brings together communities, policy changes and new infrastructure to be applied to existing and new areas of research such as precision medicine. We will review these changes from the perspective of research advances that are underway and highlight how this community can further engage in these activities. C1 [Bourne, Philip E.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Bourne, PE (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2156-1125 BN 978-1-4673-6798-1 J9 IEEE INT C BIOINFORM PY 2015 BP 1 EP 1 PG 1 WC Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology SC Computer Science; Mathematical & Computational Biology GA BE9EI UT WOS:000377335600001 ER PT S AU Xue, ZY Candemir, S Antani, S Long, LR Jaeger, S Demner-Fushman, D Thoma, GR AF Xue, Zhiyun Candemir, Serna Antani, Sameer Long, L. Rodney Jaeger, Stefan Demner-Fushman, Dina Thoma, George R. BE Huan, J Miyano, S Shehu, A Hu, X Ma, B Rajasekaran, S Gombar, VK Schapranow, IM Yoo, IH Zhou, JY Chen, B Pai, V Pierce, B TI Foreign Object Detection in Chest X-rays SO PROCEEDINGS 2015 IEEE INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND BIOMEDICINE SE IEEE International Conference on Bioinformatics and Biomedicine-BIBM LA English DT Proceedings Paper CT IEEE International Conference on Bioinformatics and Biomedicine CY NOV 09-12, 2015 CL Washington, DC SP IEEE, IEEE Comp Soc, Natl Sci Fdn DE chest X-ray; object detection; computer aided diagnosis; lung segmentation ID RADIOGRAPHS; SEGMENTATION; DATABASE AB Automatic analysis of chest X-ray images is one important approach for screening/identifying pulmonary diseases. The existence of foreign objects in the images hinders the performance of such processing. In this paper, we focus on one type of foreign objects that is often shown in the images of a large dataset of chest X-rays we are working on-the buttons on the gown that the patient is wearing. The method we propose involves four major steps: intensity normalization, low contrast image identification and enhancement, segmentation of lung regions, and button object extraction. Based on the characteristics of the button objects, we applied two methods for the step of button object extraction. One was based on the circular Hough transform; the other was based on the Viola-Jones algorithm. We tested and compared both methods using a ground truth dataset containing 505 button objects. The results demonstrate the effectiveness of the proposed method. C1 [Xue, Zhiyun; Candemir, Serna; Antani, Sameer; Long, L. Rodney; Jaeger, Stefan; Demner-Fushman, Dina; Thoma, George R.] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. RP Xue, ZY (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. EM xuez@mail.nih.gov; candemirs@mail.nih.gov; santani@mail.nih.gov; rlong@mail.nih.gov; jaegersr@mail.nih.gov; ddemner@mail.nih.gov; gthoma@mail.nih.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2156-1125 BN 978-1-4673-6798-1 J9 IEEE INT C BIOINFORM PY 2015 BP 956 EP 961 PG 6 WC Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology SC Computer Science; Mathematical & Computational Biology GA BE9EI UT WOS:000377335600169 ER PT S AU Sung, H Sorant, AJM Sabourin, JA Schwantes-An, TH Justice, CM Bailey-Wilson, JE Wilson, AF AF Sung, Heejong Sorant, Alexa J. M. Sabourin, Jeremy A. Schwantes-An, Tae-Hwi Justice, Cristina M. Bailey-Wilson, Joan E. Wilson, Alexander F. BE Huan, J Miyano, S Shehu, A Hu, X Ma, B Rajasekaran, S Gombar, VK Schapranow, IM Yoo, IH Zhou, JY Chen, B Pai, V Pierce, B TI Tiled regression reduces type I error rates in tests of association of rare single nucleotide variants with non-normally distributed traits, compared with simple linear regression SO PROCEEDINGS 2015 IEEE INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND BIOMEDICINE SE IEEE International Conference on Bioinformatics and Biomedicine-BIBM LA English DT Proceedings Paper CT IEEE International Conference on Bioinformatics and Biomedicine CY NOV 09-12, 2015 CL Washington, DC SP IEEE, IEEE Comp Soc, Natl Sci Fdn DE type I error rate; tiled regression; minor allele frequency; non-normality AB The effects of the minor allele frequency of single nucleotide variants and the degree of departure from normality of a quantitative trait on type I error rates were evaluated using Genetic Analysis Workshop 17 mini-exome sequence data. Four simulated traits were generated: standard normal and gamma distributed traits and two transformations of the gamma distributed trait by log(10) and rank-based inverse normal functions. Tiled regression was compared with simple linear regression. Average type I error rates were obtained for minor allele frequency classes. The distribution of the type I error rate for tiled regression analysis followed a pattern similar to that of simple linear regression analysis, but with much lower type I error. C1 [Sung, Heejong; Sorant, Alexa J. M.; Sabourin, Jeremy A.; Schwantes-An, Tae-Hwi; Justice, Cristina M.; Bailey-Wilson, Joan E.; Wilson, Alexander F.] NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD USA. RP Sung, H (reprint author), NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD USA. EM sunghe@mail.nih.gov; ajms@mail.nih.gov; sabourinja@mail.nih.gov; ant2@mail.nih.gov; cmj@mail.nih.gov; jebw@mail.nih.gov; afw@mail.nih.gov NR 5 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2156-1125 BN 978-1-4673-6798-1 J9 IEEE INT C BIOINFORM PY 2015 BP 1336 EP 1340 PG 5 WC Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology SC Computer Science; Mathematical & Computational Biology GA BE9EI UT WOS:000377335600229 ER PT S AU Du, W Cheung, H Johnson, CA Goldberg, I Thambisetty, M Becker, K AF Du, Wei Cheung, Huey Johnson, Calvin A. Goldberg, Ilya Thambisetty, Madhav Becker, Kevin BE Huan, J Miyano, S Shehu, A Hu, X Ma, B Rajasekaran, S Gombar, VK Schapranow, IM Yoo, IH Zhou, JY Chen, B Pai, V Pierce, B TI A Longitudinal Support Vector Regression for Prediction of ALS Score SO PROCEEDINGS 2015 IEEE INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND BIOMEDICINE SE IEEE International Conference on Bioinformatics and Biomedicine-BIBM LA English DT Proceedings Paper CT IEEE International Conference on Bioinformatics and Biomedicine CY NOV 09-12, 2015 CL Washington, DC SP IEEE, IEEE Comp Soc, Natl Sci Fdn DE longitudinal data; support vector regression; ALS; machine learning AB Longitudinal studies play a key role in various fields, including epidemiology, clinical research, and genomic analysis. Currently, the most popular methods in longitudinal data analysis are model-driven regression approaches, which impose strong prior assumptions and are unable to scale to large problems in the manner of machine learning algorithms. In this work, we propose a novel longitudinal support vector regression (LSVR) algorithm that not only takes the advantage of one of the most popular machine learning methods, but also is able to model the temporal nature of longitudinal data by taking into account observational dependence within subjects. We test LSVR on publicly available data from the DREAM-Phil Bowen ALS Prediction Prize4Life challenge. Results suggest that LSVR is at a minimum competitive with favored machine learning methods and is able to outperform those methods in predicting ALS score one month in advance. C1 [Du, Wei; Cheung, Huey; Johnson, Calvin A.] NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Goldberg, Ilya; Thambisetty, Madhav; Becker, Kevin] NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Du, W (reprint author), NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM johnson@mail.nih.gov OI Goldberg, Ilya/0000-0001-8514-6110 NR 11 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2156-1125 BN 978-1-4673-6798-1 J9 IEEE INT C BIOINFORM PY 2015 BP 1586 EP 1590 PG 5 WC Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology SC Computer Science; Mathematical & Computational Biology GA BE9EI UT WOS:000377335600269 ER PT S AU Park, HS Chae, SH Yoon, JW Kim, J Sudduth, A Stanley, C AF Park, Hyung-Soon Chae, Sang Hoon Yoon, Jung Won Kim, Jonghyun Sudduth, Amanda Stanley, Christopher GP IEEE TI Implementing Overground Turning on a Linear Treadmill SO 2015 12TH INTERNATIONAL CONFERENCE ON UBIQUITOUS ROBOTS AND AMBIENT INTELLIGENCE (URAI) SE International Conference on Ubiquitous Robots and Ambient Intelligence LA English DT Proceedings Paper CT 12th International Conference on Ubiquitous Robots and Ambient Intelligence (URAI) CY OCT 28-30, 2015 CL Goyang, SOUTH KOREA SP Korean Robot Soc, IEEE, Inst Control Robot & Syst, MySET, Robot Soc Japan DE Gait Rehabilitation; Turning; User-driven Treadmill; Virtual Reality ID WALKING AB The purpose of treadmill-based locomotor training is to transfer walking skills obtained from training to real world walking (overground: OG). For optimal skill transfer, treadmill-based training should simulate OG as closely as possible. The constant speed of a standard treadmill encourages automaticity rather than engagement and fails to simulate the variable speeds encountered during OG walking. Our effort to overcome this limitation has focused on developing user-driven treadmill (UDT) velocity control schemes that allow the user to freely change walking speed and feel the same inertial force that they feel during OG walking. In this study, we have combined the user driven treadmill control with the virtual reality (VR) display to simulate realistic turning in a safe environment. C1 [Park, Hyung-Soon; Chae, Sang Hoon] Korea Adv Inst Sci & Technol, Dept Mech Engn, Daejeon, South Korea. [Yoon, Jung Won] Gyeongsang Natl Univ, Dept Mech Engn, Jinju, South Korea. [Kim, Jonghyun] DGIST, Dept Robot Engn, Daegu, South Korea. [Sudduth, Amanda; Stanley, Christopher] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Park, HS (reprint author), Korea Adv Inst Sci & Technol, Dept Mech Engn, Daejeon, South Korea. EM hyungspark@kaist.ac.kr; jwyoon@gnu.ac.kr; jhkim@dgist.ac.kr; stanleycl@cc.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2325-033X BN 978-1-4673-7971-7 J9 INT CONF UBIQ ROBOT PY 2015 BP 390 EP 391 PG 2 WC Computer Science, Artificial Intelligence; Robotics SC Computer Science; Robotics GA BF0PD UT WOS:000379215900111 ER PT S AU De Castro, M Zand, DJ Lichter-Konecki, U Kirmse, B AF De Castro, Mauricio Zand, Dina J. Lichter-Konecki, Uta Kirmse, Brian BE Zschocke, J Baumgartner, M Morava, E Patterson, M Rahman, S Peters, V TI Severe Neonatal Holocarboxylase Synthetase Deficiency in West African Siblings SO JIMD REPORTS, VOL 20 SE JIMD Reports LA English DT Article; Book Chapter ID MULTIPLE CARBOXYLASE DEFICIENCY; MOLECULAR ANALYSIS; JAPANESE PATIENTS; DIAGNOSIS; GENE AB In multiple carboxylase deficiency (MCD), the biotin-dependent carboxylases have decreased activity due to either biotinidase deficiency or holocarboxylase synthetase (HS) deficiency. We report the case of two siblings from Ghana, the first of which presented shortly after birth with profound lactic acidosis and a urine organic acid profile consistent with MCD. In the first sibling, treatment with pulverized biotin tablets (20 mg) was begun immediately, but the patient died at 10 days of age from cardiac arrest secondary to refractory metabolic acidosis. Autopsy revealed a biotin bezoar. Sequencing of HCLS showed homozygosity for a novel missense variant (p.G241W). The second sibling had a similar presentation at birth: severe metabolic acidosis and respiratory distress. A urine organic acid profile was consistent with HS deficiency; he was treated with biotin powder (20 mg), and after 24 h, the lactate decreased significantly; by day 5 of life, the patient was tolerating 40 mg of biotin, feeding by mouth and off all other medications and support. This is the first report of the p.G241W mutation. To our knowledge, this is also the first mutation described in West African patients with HS deficiency and the cases demonstrate that it is biotin responsive. Additionally, our experience suggests that the powdered form of biotin supplementation may be more digestible than tablets for the treatment of severe neonatal HS deficiency. C1 [De Castro, Mauricio] NHGRI, Med Genet Branch, US Dept HHS, NIH, 35 Convent Dr,MSC 3717,Room 1B207, Bethesda, MD 20892 USA. [Zand, Dina J.; Lichter-Konecki, Uta; Kirmse, Brian] Childrens Natl Hlth Syst, Genet & Metab, Washington, DC USA. RP De Castro, M (reprint author), NHGRI, Med Genet Branch, US Dept HHS, NIH, 35 Convent Dr,MSC 3717,Room 1B207, Bethesda, MD 20892 USA. EM mauricio.decastro-pretelt@nih.gov NR 16 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 2192-8304 BN 978-3-662-46700-8; 978-3-662-46699-5 J9 JIMD REP PY 2015 VL 20 BP 1 EP 4 DI 10.1007/8904_2014_367 D2 10.1007/978-3-662-46700-8 PG 4 WC Endocrinology & Metabolism; Genetics & Heredity SC Endocrinology & Metabolism; Genetics & Heredity GA BE8SM UT WOS:000376984500001 PM 25690727 ER PT S AU Choi, EY Patel, K Haddad, MR Yi, L Holmes, C Goldstein, DS Dutra, A Pak, E Kaler, SG AF Choi, Eun-Young Patel, Keyur Haddad, Marie Reine Yi, Ling Holmes, Courtney Goldstein, David S. Dutra, Amalia Pak, Evgenia Kaler, Stephen G. BE Zschocke, J Baumgartner, M Morava, E Patterson, M Rahman, S Peters, V TI Tandem Duplication of Exons 1-7 Neither Impairs ATP7A Expression Nor Causes a Menkes Disease Phenotype SO JIMD REPORTS, VOL 20 SE JIMD Reports LA English DT Article; Book Chapter ID COPPER TRANSPORT; MUTATIONS; LOCALIZATION; DIAGNOSIS; PLASMA; GENE AB ATP7A duplications are estimated to represent the molecular cause of Menkes disease in 4-10% of affected patients. We identified a novel duplication of ATP7A exons 1-7 discovered in the context of a challenging prenatal diagnostic situation. All other reported ATP7A duplications (n - 24) involved intragenic tandem duplications, predicted to disrupt the normal translational reading frame and produce nonfunctional ATP7A proteins. In contrast, the exon 1-7 duplication occurred at the 50 end of the ATP7A gene rather than within the gene and did not correspond to any known copy number variants. We hypothesized that, if the exon 1-7 duplication was in tandem, functional ATP7A molecules could be generated depending on promoter selection, mRNA splicing, and the proximal and distal duplication breakpoints and that Menkes disease would be averted. Here, we present detailed molecular characterization of this novel duplication, as well as 2-year postnatal clinical and biochemical correlations. The case highlights the ongoing need for cautious interpretation of prenatal genetic test results. C1 [Choi, Eun-Young; Patel, Keyur; Haddad, Marie Reine; Yi, Ling; Kaler, Stephen G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Translat Neurosci,Mol Med Program, Porter Neurosci Res Ctr 2, NIH, Bldg 35,Room 2D-971,35A Convent Dr,MSC 3754, Bethesda, MD 20892 USA. [Holmes, Courtney; Goldstein, David S.] NINDS, Clin Neurocardiol Sect, Bethesda, MD 20892 USA. [Dutra, Amalia; Pak, Evgenia] NHGRI, Cytogenet & Microscopy Core, NIH, Bethesda, MD 20892 USA. RP Kaler, SG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Translat Neurosci,Mol Med Program, Porter Neurosci Res Ctr 2, NIH, Bldg 35,Room 2D-971,35A Convent Dr,MSC 3754, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov NR 17 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 2192-8304 BN 978-3-662-46700-8; 978-3-662-46699-5 J9 JIMD REP PY 2015 VL 20 BP 57 EP 63 DI 10.1007/8904_2014_391 D2 10.1007/978-3-662-46700-8 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity SC Endocrinology & Metabolism; Genetics & Heredity GA BE8SM UT WOS:000376984500009 PM 25638460 ER PT J AU Conforto, AB Anjos, SM Menezes, I Siqueira, IL Machado, AG Conti, J Peckham, PH Mello, EA Cohen, LG AF Conforto, A. B. Anjos, S. M. Menezes, I. Siqueira, I. L. Machado, A. G. Conti, J. Peckham, P. H. Mello, E. A. Cohen, L. G. TI Central and peripheral stimulation to enhance effects of motor training in patients with stroke - preliminary results SO CEREBROVASCULAR DISEASES LA English DT Meeting Abstract CT 24th European Stroke Conference CY MAY 13-15, 2015 CL Vienna, AUSTRIA C1 [Conforto, A. B.; Anjos, S. M.; Menezes, I.; Siqueira, I. L.; Conti, J.; Mello, E. A.] Univ Sao Paulo, Hosp Clin, BR-05508 Sao Paulo, Brazil. [Conforto, A. B.] Hosp Israelita Albert Einstein, Sao Paulo, Brazil. [Machado, A. G.] Cleveland Clin, Cleveland, Brazil. [Peckham, P. H.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Cohen, L. G.] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 4 U2 4 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1015-9770 EI 1421-9786 J9 CEREBROVASC DIS JI Cerebrovasc. Dis. PY 2015 VL 39 SU 2 BP 264 EP 264 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DM0HD UT WOS:000376023400404 ER PT J AU de Vlieger, JSB Muhlebach, S Shah, VP McNeil, SE Borchard, G Weinstein, V Fluhmann, B Neervannan, S Crommelin, DJA AF de Vlieger, Jon S. B. Muhlebach, Stefan Shah, Vinod P. McNeil, Scott E. Borchard, Gerrit Weinstein, Vera Fluhmann, Beat Neervannan, Sesha Crommelin, Daan J. A. TI Non-biological complex drugs (NBCDs) and their follow-on versions: time for an editorial section SO GABI JOURNAL-GENERICS AND BIOSIMILARS INITIATIVE JOURNAL LA English DT Article DE Glatiramoids; iron-carbohydrate complexes; liposomes; nanomedicines; Non-Biological Complex Drug (NBCD) products; therapeutic equivalence ID INTRAVENOUS IRON SUCROSE; NANOMEDICINES AB This paper discusses the group of non-biological complex drug (NBCD) products and presents the reasons why NBCDs should be assigned a special position in our arsenal of medicines as well as why from now on a special section will be devoted to report on these NBCD products in the GaBI Journal. C1 [de Vlieger, Jon S. B.] Dutch Top Inst Pharma, POB 142, NL-2300 AC Leiden, Netherlands. [Muhlebach, Stefan] Vifor Pharma Ltd, CH-8152 Glattbrugg, Switzerland. [Muhlebach, Stefan] Univ Basel, Dept Pharmaceut Sci, Pharmactr, CH-4056 Basel, Switzerland. [McNeil, Scott E.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Frederick, MD 21702 USA. [Borchard, Gerrit] Univ Lausanne 30, Univ Geneva, Sch Pharmaceut Sci, Biopharmaceut Sci, CH-1211 Geneva 4, Switzerland. [Weinstein, Vera] Teva Pharmaceut Ind Ltd, Discovery & Prod Dev, Global Res & Dev, Netanya, Israel. [Fluhmann, Beat] Vifor Fresenius Med Care Renal Pharma Ltd, CH-9001 St Gallen, Switzerland. [Neervannan, Sesha] Allergan Plc, Pharmaceut Dev Brands R&D, Irvine, CA 92612 USA. [Crommelin, Daan J. A.] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Pharmaceut Sci, NL-3508 TC Utrecht, Netherlands. RP de Vlieger, JSB (reprint author), Dutch Top Inst Pharma, POB 142, NL-2300 AC Leiden, Netherlands. NR 30 TC 0 Z9 0 U1 0 U2 0 PU PRO PHARMA COMMUNICATIONS INT PI MOL PA POSTBUS 10001, MOL, 2400, BELGIUM SN 2033-6403 EI 2033-6772 J9 GABI J JI GaBI J. PY 2015 VL 4 IS 4 BP 167 EP 170 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DP3JN UT WOS:000378389400004 ER PT S AU Kleinerman, RA Morton, LM Wong, JR Tucker, MA AF Kleinerman, Ruth A. Morton, Lindsay M. Wong, Jeannette R. Tucker, Margaret A. BE Francis, JH Abramson, DH TI Second Tumors in Retinoblastoma Survivors SO RECENT ADVANCES IN RETINOBLASTOMA TREATMENT SE Essentials in Ophthalmology LA English DT Article; Book Chapter ID LONG-TERM SURVIVORS; HEREDITARY RETINOBLASTOMA; CHILDHOOD-CANCER; HERITABLE RETINOBLASTOMA; BREAST-CANCER; FOLLOW-UP; RISK; RADIOTHERAPY; CHEMOTHERAPY; GENE C1 [Kleinerman, Ruth A.; Morton, Lindsay M.; Wong, Jeannette R.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Tucker, Margaret A.] NCI, Human Genet Program, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Kleinerman, RA (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. EM kleinerr@mail.nih.gov NR 40 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 1612-3212 BN 978-3-319-19467-7; 978-3-319-19466-0 J9 ESSENT OPHTHALMOL PY 2015 BP 105 EP 112 DI 10.1007/978-3-319-19467-7_10 D2 10.1007/978-3-319-19467-7 PG 8 WC Ophthalmology SC Ophthalmology GA BE8LP UT WOS:000376577700011 ER PT S AU Watkins, PV Doolittle, LM Krusienski, DJ Anderson, NR AF Watkins, Paul V. Doolittle, Luke M. Krusienski, Dean J. Anderson, Nicholas R. GP IEEE TI A theoretical limit and simulation of time-domain event detection in the EEG SO 2015 7TH INTERNATIONAL IEEE/EMBS CONFERENCE ON NEURAL ENGINEERING (NER) SE International IEEE EMBS Conference on Neural Engineering LA English DT Proceedings Paper CT 7th Annual International IEEE EMBS Conference on Neural Engineering (NER) CY APR 22-24, 2015 CL Montpellier, FRANCE SP IEEE, EMBS ID AUTOMATIC RECOGNITION; FREQUENCY-BANDS AB Scalp recordings of cortical activations, Electroencephalography (EEG), are commonly used clinically to detect diseases or injuries to the underlying cortical physiology. Unfortunately, the EEG signal is also artifact prone and these artifacts can exhibit a similar temporal and spectral profile as that caused by the potential disease. We have created a model of simulated (synthetic) EEG and artifacts to explore their interplay and the theoretical limits of detection when artifacts may not be separable from clinical events of interest. A theoretical limit of separation without an EEG signal is derived and then simulated upper bounds for time-domain event detection are created using simulated EEG data. C1 [Watkins, Paul V.] NINDS, NIH, Bethesda, MD 20892 USA. [Doolittle, Luke M.] Natus Med, Madison, WI 53562 USA. [Krusienski, Dean J.] Old Dominion Univ, Dept Elect & Comp Engn, Norfolk, VA 23529 USA. [Anderson, Nicholas R.] Cortech Solut, Wilmington, NC 28403 USA. RP Anderson, NR (reprint author), Cortech Solut, Wilmington, NC 28403 USA. EM pwatkins@gmail.com; luke.doolittle@gmail.com; dkrusien@odu.edu; nickr.anderson@gmail.com NR 15 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1948-3546 BN 978-1-4673-6389-1 J9 I IEEE EMBS C NEUR E PY 2015 BP 1020 EP 1023 PG 4 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA BE9FT UT WOS:000377414600256 ER PT J AU Adjemian, J Olivier, KN Prevots, DR AF Adjemian, J. Olivier, K. N. Prevots, D. R. TI Predictors Of Prolonged Nontuberculous Mycobacterial Infections In Patients With Cystic Fibrosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Adjemian, J.; Prevots, D. R.] NIAID, Bethesda, MD 20892 USA. [Olivier, K. N.] NHLBI, Bethesda, MD 20892 USA. EM jennifer.adjemian@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A5255 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582807075 ER PT J AU Akrami, K Pondo, J Nunes, E Sousa, J Figueiredo, I Cossa, A Teixiera, J Hassane, A AF Akrami, K. Pondo, J. Nunes, E. Sousa, J. Figueiredo, I. Cossa, A. Teixiera, J. Hassane, A. TI Pleurodesis: A Comparison Of Two Sclerosing Agents For Pleural Effusions In A Resource Poor Area SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Akrami, K.] NIH, Bethesda, MD 20892 USA. [Pondo, J.; Nunes, E.; Sousa, J.; Figueiredo, I.; Cossa, A.; Teixiera, J.; Hassane, A.] Maputo Cent Hosp, Maputo, Mozambique. EM kevan.akrami@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A1119 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582800120 ER PT J AU Al-Naamani, N Chirinos, JA Finkelman, M Zamani, P Paulus, JK Roberts, KE Barr, RG Lima, JAC Bluemke, DA Kronmal, R Kawut, SM AF Al-Naamani, N. Chirinos, J. A. Finkelman, M. Zamani, P. Paulus, J. K. Roberts, K. E. Barr, R. G. Lima, J. A. C. Bluemke, D. A. Kronmal, R. Kawut, S. M. CA MESA-Right Ventricle Study TI Systemic Vascular Changes Are Associated With Right Ventricular Mass: The MESA-Right Ventricle Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Al-Naamani, N.; Roberts, K. E.] Tufts Med Ctr, Boston, MA USA. [Chirinos, J. A.; Zamani, P.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Chirinos, J. A.; Zamani, P.] Vet Adm Med Ctr, Philadelphia, PA 19104 USA. [Finkelman, M.; Paulus, J. K.] Tufts Clin & Translat Sci Inst, Boston, MA USA. [Barr, R. G.] Columbia Univ, Med Ctr, New York, NY USA. [Lima, J. A. C.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Bluemke, D. A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. [Kronmal, R.] Univ Washington, Seattle, WA 98195 USA. [Kawut, S. M.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. EM nalnaamani@tuftsmedicalcenter.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A5534 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582807395 ER PT J AU An, S Tang, WY Ahn, K Mitzner, W Huang, J Kumar, S Biswal, S Panettieri, RA Solway, J Liggett, SB AF An, S. Tang, W. -Y. Ahn, K. Mitzner, W. Huang, J. Kumar, S. Biswal, S. Panettieri, R. A. Solway, J. Liggett, S. B. TI Inflammation-Independent Regulation Of Airway Smooth Muscle Mechanical Properties In Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [An, S.; Tang, W. -Y.; Mitzner, W.; Huang, J.; Kumar, S.; Biswal, S.] Johns Hopkins Univ, Baltimore, MD USA. [Ahn, K.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Panettieri, R. A.] Univ Penn, Philadelphia, PA 19104 USA. [Solway, J.] Univ Chicago, Chicago, IL 60637 USA. [Liggett, S. B.] Univ S Florida, Tampa, MD USA. EM san3@jhu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2466 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582802320 ER PT J AU Antkowiak, MC Burg, E Ubags, N Fessler, MB Poynter, ME Suratt, BT AF Antkowiak, M. C. Burg, E. Ubags, N. Fessler, M. B. Poynter, M. E. Suratt, B. T. TI Low Density Lipoprotein Activates Neutrophils Via Tlr4 And The Map Kinase And Nfkb Pathways SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Antkowiak, M. C.; Burg, E.; Ubags, N.; Suratt, B. T.] Univ Vermont, Burlington, VT USA. [Antkowiak, M. C.; Fessler, M. B.] Natl Inst Environm Hlth, Res Triangle Pk, NC USA. [Poynter, M. E.] Univ Vermont, Coll Med, Burlington, VT USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A4351 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582805410 ER PT J AU Barochia, AV Kaler, M Cuento, RA Mushaben, E Weir, N Sampson, ML Fontana, JR MacDonald, SD Moss, J Mangianello, V Remaley, AT Levine, SJ AF Barochia, A. V. Kaler, M. Cuento, R. A. Mushaben, E. Weir, N. Sampson, M. L. Fontana, J. R. MacDonald, S. D. Moss, J. Mangianello, V. Remaley, A. T. Levine, S. J. TI Serum Apolipoprotein A-I And Large High-Density Lipoprotein (hdl) Particles Are Positively Correlated With Fev1 In Atopic Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Barochia, A. V.; Kaler, M.; Cuento, R. A.; Mushaben, E.; Weir, N.; Sampson, M. L.; Fontana, J. R.; MacDonald, S. D.; Moss, J.; Mangianello, V.; Remaley, A. T.; Levine, S. J.] NIH, Bethesda, MD 20892 USA. EM barochiaav@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A4331 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582805390 ER PT J AU Biller, JA Eagle, G McGinnis, JP Micioni, L Daley, CL Winthrop, KL Ruoss, SJ Addrizzo-Harris, DJ Flume, PA Dorgan, DJ Salathe, M Brown-Elliott, BA Wallace, RJ Griffith, DE Olivier, KN AF Biller, J. A. Eagle, G. McGinnis, J. P. Micioni, L. Daley, C. L. Winthrop, K. L. Ruoss, S. J. Addrizzo-Harris, D. J. Flume, P. A. Dorgan, D. J. Salathe, M. Brown-Elliott, B. A. Wallace, R. J. Griffith, D. E. Olivier, K. N. TI Efficacy Of Liposomal Amikacin For Inhalation (lai) In Achieving Nontuberculous Mycobacteria (ntm) Culture Negativity In Patients Whose Lung Infection Is Refractory To Guideline-Based Therapy SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Biller, J. A.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Eagle, G.; McGinnis, J. P.; Micioni, L.] Insmed Inc, Bridgewater, NJ USA. [Daley, C. L.] Natl Jewish Hlth, Denver, CO USA. [Winthrop, K. L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Ruoss, S. J.] Stanford Univ, Stanford, CA 94305 USA. [Addrizzo-Harris, D. J.] NYU, Sch Med, New York, NY USA. [Flume, P. A.] Med Univ S Carolina, Charleston, SC 29425 USA. [Dorgan, D. J.] Univ Penn, Philadelphia, PA 19104 USA. [Salathe, M.] Univ Miami, Miami, FL USA. [Brown-Elliott, B. A.] Univ Texas Hlth Sci Ctr Tyler, Tyler, TX USA. [Wallace, R. J.] Univ Texas Hlth Sci Ctr, Tyler, TX USA. [Griffith, D. E.] Univ Texas Hlth Ctr Tyler, Tyler, TX USA. [Olivier, K. N.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A6295 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582808530 ER PT J AU Burkart, KM Stilp, AM Sofer, T London, S Davis, S Celedon, JC Barr, RG AF Burkart, K. M. Stilp, A. M. Sofer, T. London, S. Davis, S. Celedon, J. C. Barr, R. G. TI Genome-Wide Association Study (gwas) Of Lung Function Among Hispanic/latino Individuals Of Diverse Backgrounds. The Hispanic Community Health Study/study Of LatINOS (hchs/sol) SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Burkart, K. M.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Burkart, K. M.; Stilp, A. M.] Univ Washington, Seattle, WA 98195 USA. [Sofer, T.] Univ Washington, Seattle, WA 98195 USA. [London, S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Davis, S.] Univ N Carolina, Chapel Hill, NC USA. [Celedon, J. C.] Univ Pittsburgh, Childrens Hosp Pittsburgh UPMC, Pittsburgh, PA USA. [Barr, R. G.] Columbia Univ, Presbyterian Hosp, New York, NY USA. EM kb2319@columbia.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A1069 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582800070 ER PT J AU Chang, H Adjemian, J Dell, SDM Ferkol, TW Leigh, MW Milla, CE Rosenfeld, M Sagel, SD Knowles, MR Olivier, KN AF Chang, H. Adjemian, J. Dell, S. D. M. Ferkol, T. W. Leigh, M. W. Milla, C. E. Rosenfeld, M. Sagel, S. D. Knowles, M. R. Olivier, K. N. TI Prevalence Of Airway Microbial Flora In Primary Ciliary Dyskinesia SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Chang, H.] NIAID, Bethesda, MD 20892 USA. [Adjemian, J.] NIAID, NIH, Bethesda, MD 20892 USA. [Dell, S. D. M.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Ferkol, T. W.] Washington Univ, St Louis, MO USA. [Leigh, M. W.] Univ N Carolina, Chapel Hill, NC USA. [Milla, C. E.] Stanford Univ, Palo Alto, CA 94304 USA. [Rosenfeld, M.] Childrens Hosp Reg Med Ctr, Seattle, WA USA. [Sagel, S. D.] Univ Colorado Denver, Childrens Hosp, Aurora, CO USA. [Knowles, M. R.] Univ N Carolina, Chapel Hill, NC USA. [Olivier, K. N.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM kenneth.olivier@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A1798 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582801197 ER PT J AU Chen, MY Yao, J Schuzer, J Haughey, ME Jones, AM Julien-Williams, P Moss, J AF Chen, M. Y. Yao, J. Schuzer, J. Haughey, M. E. Jones, A. M. Julien-Williams, P. Moss, J. TI Iterative Reconstruction Enables Nearly 75% Radiation Dose Reduction For Automated Quantitative Assessment Of Lymphangioleiomyomatosis Cyst Score SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Chen, M. Y.; Haughey, M. E.; Jones, A. M.; Julien-Williams, P.; Moss, J.] NHLBI, NIH, Bethesda, MD 20892 USA. [Yao, J.] NIH, Bethesda, MD 20892 USA. [Schuzer, J.] Toshiba Med Res Inst, Vernon Hills, IL USA. EM marcus.chen@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A1398 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582800397 ER PT J AU Cui, Y Ma, D Nwokeji, A Maynard, D Cullinane, A George, G D'Agostino, E Gochuico, BR Handin, R El-Chemaly, S AF Cui, Y. Ma, D. Nwokeji, A. Maynard, D. Cullinane, A. George, G. D'Agostino, E. Gochuico, B. R. Handin, R. El-Chemaly, S. TI Dysregulated Angiotensin Ii Receptor Type-1 And Myosin Iib-Mediated Migration Of Hermansky-Pudlak Syndrome Fibroblasts SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Cui, Y.; Ma, D.; Nwokeji, A.; George, G.; D'Agostino, E.; Handin, R.; El-Chemaly, S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Maynard, D.; Cullinane, A.; Gochuico, B. R.] NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A4947 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582806381 ER PT J AU Duncan, EA Ortega, H Gleich, G Price, R Yancey, S Klion, A AF Duncan, E. A. Ortega, H. Gleich, G. Price, R. Yancey, S. Klion, A. TI Observational Experience Describing The Use Of Mepolizumab In Patients With Hypereosinophilic Syndrome SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Duncan, E. A.; Ortega, H.; Yancey, S.] GSK, Res Triangle Pk, NC USA. [Gleich, G.] Univ Utah, Salt Lake City, UT USA. [Price, R.] GSK, Uxbridge, Middx, England. [Klion, A.] NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A1365 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582800364 ER PT J AU Ferrada, M Decker, B Mennow, R Munro, N Kent, T O'Grady, NP Palmore, T AF Ferrada, M. Decker, B. Mennow, R. Munro, N. Kent, T. O'Grady, N. P. Palmore, T. TI Empiric Use Of Empiric Antimicrobial Drugs In Neutropenic Icu Patients SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Ferrada, M.; Decker, B.; Mennow, R.; Munro, N.; Kent, T.; O'Grady, N. P.; Palmore, T.] NIH, Bethesda, MD 20892 USA. EM marcela.ferrada@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A4536 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582805595 ER PT J AU Gesthalter, YB Kusko, RL Holland, WP Allen-Ziegler, K Limburg, PJ Aubry, MC Mandrekar, SJ Lenburg, M Wigle, D Szabo, E Spira, A Beane, J AF Gesthalter, Y. B. Kusko, R. L. Holland, W. P. Allen-Ziegler, K. Limburg, P. J. Aubry, M. C. Mandrekar, S. J. Lenburg, M. Wigle, D. Szabo, E. Spira, A. Beane, J. TI Pioglitazone Reverses Oncogenic Pathways In Airway Epithelium Of Lung Cancer Patients SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Gesthalter, Y. B.; Beane, J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Kusko, R. L.; Lenburg, M.; Spira, A.] Boston Univ, Boston, MA 02215 USA. [Holland, W. P.; Allen-Ziegler, K.; Limburg, P. J.; Aubry, M. C.; Mandrekar, S. J.; Wigle, D.] Mayo Clin, Rochester, MN 55905 USA. [Szabo, E.] NCI, Bethesda, MD 20892 USA. EM ygesty@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2428 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582802222 ER PT J AU Gowdy, KM Madenspacher, JH Thomas, SY Nakano, H Cook, DN Fessler, MB AF Gowdy, K. M. Madenspacher, J. H. Thomas, S. Y. Nakano, H. Cook, D. N. Fessler, M. B. TI Novel Role For Scavenger Receptor B-I In Neutrophilic Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Gowdy, K. M.] E Carolina Univ, Greenville, NC USA. [Madenspacher, J. H.; Thomas, S. Y.; Nakano, H.; Cook, D. N.; Fessler, M. B.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2501 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582802355 ER PT J AU Henkle, E Daley, CL Griffith, DE Walsh, JW Leitman, P Malanga, E Aksamit, TR O'Donnell, AE Thomashow, B Olivier, KN Knowles, MR Barker, AF Metersky, ML Tino, G Eden, E Salathe, M Johnson, M Wilkins, T Prieto, D Winthrop, KL AF Henkle, E. Daley, C. L. Griffith, D. E. Walsh, J. W. Leitman, P. Malanga, E. Aksamit, T. R. O'Donnell, A. E. Thomashow, B. Olivier, K. N. Knowles, M. R. Barker, A. F. Metersky, M. L. Tino, G. Eden, E. Salathe, M. Johnson, M. Wilkins, T. Prieto, D. Winthrop, K. L. CA Bronchiectasis Res Registry TI Patterns Of Pharmacotherapy For Non-Cystic Fibrosis Bronchiectasis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Henkle, E.; Barker, A. F.; Winthrop, K. L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Daley, C. L.] Natl Jewish Hlth, Denver, CO USA. [Griffith, D. E.] Univ Texas Hlth Ctr Tyler, Tyler, TX USA. [Walsh, J. W.] COPD Fdn, Miami, FL USA. [Leitman, P.] NTM Info & Res, Coral Gables, FL USA. [Malanga, E.; Prieto, D.] COPD Fdn, Washington, DC USA. [Aksamit, T. R.] Mayo Clin, Rochester, MN USA. [O'Donnell, A. E.] Georgetown Univ Hosp, Washington, DC 20007 USA. [Thomashow, B.] Columbia Univ, New York, NY USA. [Olivier, K. N.] NHLBI, Bethesda, MD 20892 USA. [Knowles, M. R.; Wilkins, T.] Univ N Carolina, Chapel Hill, NC USA. [Metersky, M. L.] Univ Connecticut, Sch Med, Farmington, CT USA. [Tino, G.] Hosp Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Eden, E.] Columbia Univ St Lukes, New York, NY USA. [Salathe, M.] Univ Miami, Miami, FL USA. [Johnson, M.] Mayo Clin Florida, Jacksonville, FL USA. EM henkle@ohsu.edu NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2445 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582802299 ER PT J AU Hoppin, J Umbach, D Long, S London, S Henneberger, PK Blair, A Freeman, LB Sandler, DP AF Hoppin, J. Umbach, D. Long, S. London, S. Henneberger, P. K. Blair, A. Freeman, L. Beane Sandler, D. P. TI Pesticides Are Associated With Allergic And Non-Allergic Wheeze Among Male Farmers SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Hoppin, J.] N Carolina State Univ, Raleigh, NC 27695 USA. [Umbach, D.] NIEHS, Res Triangle Pk, NC USA. [Long, S.] Westat Corp, Durham, NC USA. [London, S.; Sandler, D. P.] NIEHS, Res Triangle Pk, NC 27709 USA. [Henneberger, P. K.] NIOSH, CDC, Morgantown, WV USA. [Blair, A.; Freeman, L. Beane] NCI, Rockville, MD USA. EM jahoppin@ncsu.edu RI Beane Freeman, Laura/C-4468-2015 OI Beane Freeman, Laura/0000-0003-1294-4124 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A6263 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582808498 ER PT J AU Hussain, S Bushel, P Gerrish, K Garantziotis, S AF Hussain, S. Bushel, P. Gerrish, K. Garantziotis, S. TI Human Bronchial Epithelia From Healthy And Asthmatic Subjects Show Differential Sensitivity Towards Toxic Effects Of Multi-Walled Carbon Nanotubes SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Hussain, S.; Bushel, P.; Gerrish, K.; Garantziotis, S.] NIEHS, Res Triangle Pk, NC 27709 USA. EM salik.hussain@nih.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A3227 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582803502 ER PT J AU Jaswal, DS Remy, KE Cui, X Puch, IC Solomon, S Sun, J Eichacker, PQ AF Jaswal, D. S. Remy, K. E. Cui, X. Puch, I. Cortes Solomon, S. Sun, J. Eichacker, P. Q. TI The Effect Of Anthrax Immunoglobulin (aig) On Survival In A Canine Model Of B. Anthracis Lethal And Edema Toxin Associated Shock SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Jaswal, D. S.; Remy, K. E.; Cui, X.; Puch, I. Cortes; Solomon, S.; Sun, J.; Eichacker, P. Q.] NIH, Bethesda, MD 20892 USA. EM dharmvir.jaswal@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2550 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582802404 ER PT J AU Jaswal, DS Namagerdi, LO Sampath-Kumar, H Fitz, Y Li, Y Cui, X Eichacker, PQ AF Jaswal, D. S. Namagerdi, L. Ohanjanian Sampath-Kumar, H. Fitz, Y. Li, Y. Cui, X. Eichacker, P. Q. TI The Development And Implementation Of An Isolated Perfused Rat Kidney Model To Study Renal Tubular Function SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Jaswal, D. S.; Namagerdi, L. Ohanjanian; Sampath-Kumar, H.; Fitz, Y.; Li, Y.; Cui, X.; Eichacker, P. Q.] NIH, Bethesda, MD 20892 USA. EM dharmvir.jaswal@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2552 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582802406 ER PT J AU Jaswal, DS Sampath-Kumar, H Namagerdi, LO Fitz, Y Li, Y Cui, X Eichacker, PQ AF Jaswal, D. S. Sampath-Kumar, H. Namagerdi, L. Ohanjanian Fitz, Y. Li, Y. Cui, X. Eichacker, P. Q. TI B. Anthracis Edema Toxin Increases Fractional Free Water Reabsorption In An Isolated Perfused Rat Kidney Model SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Jaswal, D. S.; Sampath-Kumar, H.; Namagerdi, L. Ohanjanian; Fitz, Y.; Li, Y.; Cui, X.; Eichacker, P. Q.] NIH, Bethesda, MD 20892 USA. EM dharmvir.jaswal@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2551 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582802405 ER PT J AU Laslett, DB Kawut, SM Praestgaard, A Barr, G Bluemke, DM Kronmal, RA Lima, J Ventetuolo, CE AF Laslett, D. B. Kawut, S. M. Praestgaard, A. Barr, G. Bluemke, D. M. Kronmal, R. A. Lima, J. Ventetuolo, C. E. TI Association Of Non-Steroidal Anti-Inflammatory Drug (nsaid) Use With Right Ventricular (rv) Morphology: The MESA-Right Ventricle Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Laslett, D. B.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Kawut, S. M.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Praestgaard, A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Bluemke, D. M.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Kronmal, R. A.] Univ Washington, Seattle, WA 98195 USA. [Lima, J.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Ventetuolo, C. E.] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Providence, RI 02903 USA. EM DAVID.LASLETT@uphs.upenn.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A6452 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582807225 ER PT J AU Li, Y Namagerdi, LO Sampath-Kumar, H Cui, X Fitz, Y Eichacker, PQ AF Li, Y. Namagerdi, L. Ohanjanian Sampath-Kumar, H. Cui, X. Fitz, Y. Eichacker, P. Q. TI Nitric Oxide Synthase Inhibition Improves Hemodynamics And Survival In B. Anthracis Edema Toxin Challenged Rats SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Li, Y.; Namagerdi, L. Ohanjanian; Sampath-Kumar, H.; Cui, X.; Fitz, Y.; Eichacker, P. Q.] NIH, Ctr Clin, Bethesda, MD 20892 USA. EM yli@mail.cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2549 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582802403 ER PT J AU Marzec, JM Ciencewicki, J Serra, ME Gerek, M Polack, F Kleeberger, SR AF Marzec, J. M. Ciencewicki, J. Serra, M. E. Gerek, M. Polack, F. Kleeberger, S. R. TI Macrophage Associated Receptor With Collagenous Structure (marco) Variant Modulates Susceptibility To Respiratory Syncytial Virus (rsv) SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Marzec, J. M.; Ciencewicki, J.; Kleeberger, S. R.] NIEHS, Res Triangle Pk, NC 27709 USA. [Serra, M. E.; Gerek, M.] Fundacian Infant, Buenos Aires, DF, Argentina. [Polack, F.] Vanderbilt Univ, Nashville, TN 37235 USA. EM marzec@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A3239 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582803514 ER PT J AU Mathias, RA Johnston, HR Torgerson, D Levin, AM Lange, LA Ortega, VE Hu, Y Caraballo, L Foreman, MG Hartert, T Herrera-Paz, E Knight-Madden, JM Kumar, R Mayorga, A Olopade, C Ware, LB Marrugo, J Oliveira, RR Yazdanbakhsh, M Wilson, JG Williams, L Watson, H Faruque, MU Rotimi, C Ober, C Meyers, D Bleecker, ER Burchard, EG Qin, Z Taub, M Beaty, TH Ruczinski, I Barnes, KC AF Mathias, R. A. Johnston, H. R. Torgerson, D. Levin, A. M. Lange, L. A. Ortega, V. E. Hu, Y. Caraballo, L. Foreman, M. G. Hartert, T. Herrera-Paz, E. Knight-Madden, J. M. Kumar, R. Mayorga, A. Olopade, C. Ware, L. B. Marrugo, J. Oliveira, R. R. Yazdanbakhsh, M. Wilson, J. G. Williams, L. Watson, H. Faruque, M. U. Rotimi, C. Ober, C. Meyers, D. Bleecker, E. R. Burchard, E. G. Qin, Z. Taub, M. Beaty, T. H. Ruczinski, I. Barnes, K. C. TI The Value Of Whole Genome Sequencing In Identifying Genetic Determinants Of Asthma In Populations Of African Ancestry SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Mathias, R. A.] Johns Hopkins Med, Baltimore, MD USA. [Johnston, H. R.; Hu, Y.; Qin, Z.] Emory Univ, Atlanta, GA 30322 USA. [Torgerson, D.; Burchard, E. G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Levin, A. M.; Williams, L.] Henry Ford Hlth Syst, Detroit, MI USA. [Lange, L. A.; Meyers, D.; Bleecker, E. R.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Ortega, V. E.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Caraballo, L.; Marrugo, J.] Univ Cartagena, Cartagena, Colombia. [Foreman, M. G.] Morehouse Sch Med, Atlanta, GA 30310 USA. [Hartert, T.; Ware, L. B.] Vanderbilt Univ, Nashville, TN 37235 USA. [Herrera-Paz, E.] Univ Catol Honduras, San Pedro Sula, Honduras. [Knight-Madden, J. M.] Univ W Indies, Kingston 7, Jamaica. [Kumar, R.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Mayorga, A.] Ctr Neumol & Alergias, San Pedro Sula, Honduras. [Olopade, C.; Ober, C.] Univ Chicago, Chicago, IL 60637 USA. [Oliveira, R. R.] Ctr Pesquisas Goncalo Moniz, Salvador, BA, Brazil. [Yazdanbakhsh, M.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Wilson, J. G.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Watson, H.] Univ W Indies, St Michael, Barbados. [Faruque, M. U.] Howard Univ, Washington, DC 20059 USA. [Rotimi, C.] NHGRI, Bethesda, MD 20892 USA. [Taub, M.; Ruczinski, I.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Beaty, T. H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Barnes, K. C.] Johns Hopkins Univ, Baltimore, MD USA. EM kbarnes@jhmi.edu NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A1063 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582800064 ER PT J AU Mushaben, E Dai, C Yao, X Nugent, G Keeran, K Yu, Z Aponte, A Gucek, M Levine, SJ AF Mushaben, E. Dai, C. Yao, X. Nugent, G. Keeran, K. Yu, Z. Aponte, A. Gucek, M. Levine, S. J. TI The Macrophage Scavenger Receptor Cd163 Binds The German Cockroach Protein, Vitellogenin, And Attenuates Allergic Sensitization And Airway Hyperreactivity In A Murine Model Of Experimental Cockroach-Induced Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Mushaben, E.; Dai, C.; Yao, X.; Nugent, G.; Keeran, K.; Yu, Z.; Aponte, A.; Gucek, M.; Levine, S. J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A5661 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582807522 ER PT J AU Nick, JA Caceres, SM Kret, JE Poch, KR Strand, M Faino, A Nichols, D Saavedra, M Taylor-Cousar, JL Coldren, CD Geraci, M Burnham, EL Suratt, BT Fessler, M Abraham, E Moss, M Malcolm, KC AF Nick, J. A. Caceres, S. M. Kret, J. E. Poch, K. R. Strand, M. Faino, A. Nichols, D. Saavedra, M. Taylor-Cousar, J. L. Coldren, C. D. Geraci, M. Burnham, E. L. Suratt, B. T. Fessler, M. Abraham, E. Moss, M. Malcolm, K. C. TI Association Of Interferon-Stimulated Gene Expression With Worse Outcomes In The Acute Respiratory Distress Syndrome SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Nick, J. A.; Caceres, S. M.; Poch, K. R.; Strand, M.; Faino, A.; Nichols, D.; Saavedra, M.; Taylor-Cousar, J. L.; Malcolm, K. C.] Natl Jewish Hlth, Denver, CO USA. [Kret, J. E.] Dist Columbia Dept Hlth, Washington, DC USA. [Faino, A.; Coldren, C. D.; Geraci, M.; Burnham, E. L.; Moss, M.] Univ Colorado Denver, Aurora, CO USA. [Suratt, B. T.] Univ Vermont, Coll Med, Burlington, VT USA. [Fessler, M.] NIEHS, Res Triangle Pk, NC 27709 USA. [Abraham, E.] Wake Forest, Winston Salem, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2376 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582802170 ER PT J AU Obeidat, M Nie, Y Hao, K Bosse, Y Laviolette, M Nickle, D Postma, DS Timens, W Gharib, S Tobin, M Hall, I London, S Sin, D Pare, P AF Obeidat, M. Nie, Y. Hao, K. Bosse, Y. Laviolette, M. Nickle, D. Postma, D. S. Timens, W. Gharib, S. Tobin, M. Hall, I. London, S. Sin, D. Pare, P. CA T SpiroMeta-Consortium T CHARGE-Consortium SpiroMeta-CHARGE Consortia TI Systems Genetics Approach Identifies Nicotine Receptor Antagonist As A Potential Therapeutic Target In COPD SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Obeidat, M.; Nie, Y.; Sin, D.; Pare, P.] Univ British Columbia, Ctr Heart Lung Innovat, St Pauls Hosp, Vancouver, BC V5Z 1M9, Canada. [Hao, K.] Mt Sinai Sch Med, New York, NY USA. [Bosse, Y.; Laviolette, M.] Univ Laval, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada. [Nickle, D.] Merck Res Labs, Boston, MA USA. [Postma, D. S.; Timens, W.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Tobin, M.] Univ Leicester, Leicester, Leics, England. [T SpiroMeta-Consortium] Univ Nottingham, Nottingham NG7 2RD, England. [T CHARGE-Consortium] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Gharib, S.] Univ Washington, Dept Med, Seattle, MA USA. [Hall, I.] Univ Nottingham Hosp, Nottingham NG7 2UH, England. [London, S.] NIEHS, Res Triangle Pk, NC 27709 USA. EM maen.obeidat@hli.ubc.ca NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2202 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582801594 ER PT J AU Park, I Olivier, KN Holland, SM Sampaio, EP Zelazny, AM AF Park, I. Olivier, K. N. Holland, S. M. Sampaio, E. P. Zelazny, A. M. TI The Shift In Lipid Metabolism In Mycobacterium Abscessus During Early Stage Of Human Lung Infection May Set The Stage For Its Persistence SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Park, I.; Holland, S. M.; Sampaio, E. P.] NIAID, NIH, Bethesda, MD 20892 USA. [Olivier, K. N.] NHLBI, Bethesda, MD 20892 USA. [Zelazny, A. M.] NIAID, Bethesda, MD USA. EM inkwon.park@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2182 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582801574 ER PT J AU Patlolla, H Miller, AC AF Patlolla, H. Miller, A. C. TI Pulmonary Mycobacterium Tuberculosis Associated Immune Thrombocytopenia Purpura SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Patlolla, H.] Mt Sinai Hosp, Chicago, IL USA. [Miller, A. C.] NIH, Bethesda, MD 20892 USA. EM harish.patlolla@sinai.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A3256 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582803531 ER PT J AU Pepper, DJ Danner, RL Suffredini, AF AF Pepper, D. J. Danner, R. L. Suffredini, A. F. TI High Dose Phenylephrine Causing Atypical Takotsubo-Like Cardiac Dysfunction SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc ID CARDIOMYOPATHY C1 [Pepper, D. J.; Danner, R. L.; Suffredini, A. F.] NIH, Bethesda, MD 20892 USA. EM dominique.pepper@nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A4525 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582805584 ER PT J AU Pepper, DJ Harris, AL AF Pepper, D. J. Harris, A. L. TI Lemierre Syndrome: The Forgotten Disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Pepper, D. J.] NIH, Bethesda, MD 20892 USA. [Pepper, D. J.; Harris, A. L.] Univ MS, Med Ctr, GV Sonny Montgomery VAMC, Jackson, MS USA. EM dominique.pepper@nih.gov NR 2 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A1828 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582801227 ER PT J AU Remy, KE Cortes-Puch, I Solomon, SB Sun, J Lertora, JJ Gladwin, MT Kim-Shapiro, DB Klein, HG Natanson, C AF Remy, K. E. Cortes-Puch, I. Solomon, S. B. Sun, J. Lertora, J. J. Gladwin, M. T. Kim-Shapiro, D. B. Klein, H. G. Natanson, C. TI Haptoglobin Administration Improves Lung Injury And Survival In Canines Challenged With S. Aureus Pneumonia And Exchange Transfused Fresh But Not Older Stored Blood SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Remy, K. E.; Cortes-Puch, I.; Solomon, S. B.; Sun, J.; Lertora, J. J.; Klein, H. G.; Natanson, C.] NIH, Bethesda, MD 20892 USA. [Remy, K. E.; Gladwin, M. T.] Univ Pittsburgh, Pittsburgh, PA USA. [Kim-Shapiro, D. B.] Wake Forest Univ, Winston Salem, NC 27109 USA. EM kenneth.remy@nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2556 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582802410 ER PT J AU Ruoss, SJ Eagle, G McGinnis, JP Micioni, L Daley, CL Winthrop, KL Addrizzo-Harris, DJ Flume, PA Dorgan, DJ Salathe, M Griffith, DE Olivier, KN AF Ruoss, S. J. Eagle, G. McGinnis, J. P. Micioni, L. Daley, C. L. Winthrop, K. L. Addrizzo-Harris, D. J. Flume, P. A. Dorgan, D. J. Salathe, M. Griffith, D. E. Olivier, K. N. TI Analysis Of Functional Exercise Capacity (via The Six-Minute Walk Test [6mwt]) And Culture Negativity In Patients With Nontuberculous Mycobacteria (ntm) Lung Infection Refractory To Guideline-Based Therapy Treated With Liposomal Amikacin For Inhalation (lai) SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Ruoss, S. J.] Stanford Univ, Stanford, CA 94305 USA. [Eagle, G.; McGinnis, J. P.; Micioni, L.] Insmed Inc, Bridgewater, NJ USA. [Daley, C. L.] Natl Jewish Hlth, Denver, CO USA. [Winthrop, K. L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Addrizzo-Harris, D. J.] NYU, Sch Med, New York, NY USA. [Flume, P. A.] Med Univ S Carolina, Charleston, SC 29425 USA. [Dorgan, D. J.] Univ Penn, Philadelphia, PA 19104 USA. [Salathe, M.] Univ Miami, Miami, FL USA. [Griffith, D. E.] Univ Texas Hlth Ctr Tyler, Tyler, TX USA. [Olivier, K. N.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A6296 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582808531 ER PT J AU Sato, T Shibata, Y Yamamoto, M Kudo, M Kaneko, T Ishigatsubo, Y Klinman, D AF Sato, T. Shibata, Y. Yamamoto, M. Kudo, M. Kaneko, T. Ishigatsubo, Y. Klinman, D. TI Effect Of Intratracheal Immunostimulatory-Oligonucleotides With Biodegradable Polyketal Nanoparticles On Murine Lung Cancer SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Sato, T.; Shibata, Y.; Yamamoto, M.; Kudo, M.; Kaneko, T.; Ishigatsubo, Y.] Yokohama City Univ, Grad Sch Med, Yokohama, Kanagawa 232, Japan. [Klinman, D.] NCI, Frederick, MD 21701 USA. EM takashisato1220@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2426 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582802220 ER PT J AU Snyder, RJ Hussain, S Rice, AB Miller-DeGraff, L Randell, SH Garantziotis, S AF Snyder, R. J. Hussain, S. Rice, A. B. Miller-DeGraff, L. Randell, S. H. Garantziotis, S. TI Exposure To Multi-Walled Carbon Nanotubes May Impair Mucociliary Differentiation Of Human Bronchial Epithelia In Air Liquid Interface Culture SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Snyder, R. J.; Randell, S. H.] Univ N Carolina, Chapel Hill, NC USA. [Hussain, S.; Rice, A. B.; Miller-DeGraff, L.; Garantziotis, S.] NIEHS, Durham, NC USA. EM rjsnyder@email.unc.edu RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A3228 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582803503 ER PT J AU Strollo, SE Adjemian, J Prevots, DR AF Strollo, S. E. Adjemian, J. Prevots, D. R. TI The Burden Of Pulmonary Nontuberculous Mycobacterial Disease In The United States: State-Specific Case Estimates And Associated Cost SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Strollo, S. E.; Adjemian, J.; Prevots, D. R.] NIAID, NIH, Bethesda, MD 20892 USA. EM sara.strollo@nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A5260 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582807079 ER PT J AU Taveira-DaSilva, AM Julien-Williams, PA Jones, AM Moss, J AF Taveira-DaSilva, A. M. Julien-Williams, P. A. Jones, A. M. Moss, J. TI Prevalence Of Pneumothoraces In Lymphangioleiomyomatosis Patients Undergoing Pulmonary Function And Exercise Testing SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Taveira-DaSilva, A. M.; Julien-Williams, P. A.; Jones, A. M.; Moss, J.] NHLBI, NIH, Bethesda, MD 20892 USA. EM dasilvaa@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A1395 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582800394 ER PT J AU Taveira-DaSilva, AM Jones, A Julien-Williams, P Moss, J AF Taveira-DaSilva, A. M. Jones, A. Julien-Williams, P. Moss, J. TI Long-Term Effect Of Sirolimus Treatment On Serum Levels Of VEGF-D In Lymphangioleiomyomatosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Taveira-DaSilva, A. M.; Jones, A.; Julien-Williams, P.; Moss, J.] NHLBI, NIH, Bethesda, MD 20892 USA. EM dasilvaa@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A1394 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582800393 ER PT J AU Thomas, SY Whitehead, GS Gowdy, KM Ward, JM Nakano, K Malhotra, AF Nakano, H Cook, DN AF Thomas, S. Y. Whitehead, G. S. Gowdy, K. M. Ward, J. M. Nakano, K. Malhotra, A. F. Nakano, H. Cook, D. N. TI Myd88-Dependent Epithelial And Dendritic Cell Signaling And Crosstalk Trigger Distinct Types Of Allergic Inflammatory Responses In The Lung SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Thomas, S. Y.; Whitehead, G. S.; Ward, J. M.; Nakano, K.; Malhotra, A. F.; Nakano, H.; Cook, D. N.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Gowdy, K. M.] E Carolina Univ, Greenville, NC USA. EM seddon.thomas@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A6432 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582807205 ER PT J AU Ventetuolo, CE Mitra, N Wan, F Manichaikul, A Barr, RG Johnson, C Bluemke, D Lima, J Tandri, H Ouyang, P Kawut, SM AF Ventetuolo, C. E. Mitra, N. Wan, F. Manichaikul, A. Barr, R. G. Johnson, C. Bluemke, D. Lima, J. Tandri, H. Ouyang, P. Kawut, S. M. TI Genetic Variation In Sex Hormone Pathways And Right Ventricular Structure And Function: The Multi-Ethnic Study Of Atherosclerosis-Right Ventricle Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Ventetuolo, C. E.] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Providence, RI 02903 USA. [Ventetuolo, C. E.; Mitra, N.; Wan, F.] Univ Penn, Philadelphia, PA 19104 USA. [Manichaikul, A.] Univ Virginia, Charlottesville, VA USA. [Barr, R. G.] Columbia Univ, Med Ctr, New York, NY USA. [Johnson, C.] Univ Washington, Seattle, WA 98195 USA. [Bluemke, D.] NIH, Bethesda, MD 20892 USA. [Lima, J.; Tandri, H.; Ouyang, P.] Johns Hopkins Univ, Baltimore, MD USA. [Kawut, S. M.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A1042 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582800043 ER PT J AU Ventetuolo, CE Baird, G Barr, RG Bluemke, D Fritz, JS Hill, NS Klinger, JR Krishnan, I Lima, J Ouyang, P Palevsky, HI Palmisciano, A Pinder, D Preston, IR Roberts, KE Kawut, SM AF Ventetuolo, C. E. Baird, G. Barr, R. G. Bluemke, D. Fritz, J. S. Hill, N. S. Klinger, J. R. Krishnan, I. Lima, J. Ouyang, P. Palevsky, H. I. Palmisciano, A. Pinder, D. Preston, I. R. Roberts, K. E. Kawut, S. M. TI Sex Hormones In Men With Pulmonary Arterial Hypertension: A Case-Control Study Using The Multi-Ethnic Study Of Atherosclerosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Ventetuolo, C. E.; Klinger, J. R.; Krishnan, I.; Palmisciano, A.] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Providence, RI 02903 USA. [Baird, G.] Rhode Isl Hosp, Providence, RI USA. [Barr, R. G.] Columbia Univ, Med Ctr, New York, NY USA. [Bluemke, D.] NIH, Bethesda, MD 20892 USA. [Fritz, J. S.; Palevsky, H. I.; Pinder, D.; Kawut, S. M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Hill, N. S.; Preston, I. R.; Roberts, K. E.] Tufts Med Ctr, Boston, MA USA. [Lima, J.; Ouyang, P.] Johns Hopkins, Baltimore, MD USA. EM corey_ventetuolo@brown.edu NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A4093 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582805152 ER PT J AU Wenger, DS Ding, J Barr, RG Bluemke, DA Hough, CL Kronmal, R Lima, J Tracy, RP Kawut, SM Leary, PJ AF Wenger, D. S. Ding, J. Barr, R. G. Bluemke, D. A. Hough, C. L. Kronmal, R. Lima, J. Tracy, R. P. Kawut, S. M. Leary, P. J. TI Relationship Of Pericardial Fat With Right Ventricular Structure And Function: The Multi-Ethnic Study Of Atherosclerosis- Right Ventricle Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Wenger, D. S.; Kronmal, R.; Kawut, S. M.; Leary, P. J.] Univ Washington, Seattle, WA 98195 USA. [Ding, J.] Wake Forest Sch Med, Winston Salem, NC USA. [Barr, R. G.] Columbia Univ, Med Ctr, New York, NY USA. [Bluemke, D. A.] NIH, Bethsda, MD USA. [Hough, C. L.] Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. [Lima, J.] Johns Hopkins Sch Med, Baltimore, MD USA. [Tracy, R. P.] Univ Vermont, Burlington, VT USA. [Kawut, S. M.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A4855 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582806289 ER PT J AU Wills, A Adjemian, J Manganiello, VC Fontanta, JR Prevots, DR AF Wills, A. Adjemian, J. Manganiello, V. C. Fontanta, J. R. Prevots, D. R. TI Prevalence Of Sarcoidosis Among U.s. Medicare Part B Beneficiaries Aged >= 65 Years, 2000-2007 SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Wills, A.; Adjemian, J.; Prevots, D. R.] NIAID, Epidemiol Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Wills, A.; Manganiello, V. C.; Fontanta, J. R.] NHLBI, NIH, Bethesda, MD 20892 USA. EM aprielle.wills@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A3751 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582804393 ER PT J AU Winthrop, KL Eagle, G McGinnis, JP Micioni, L Daley, CL Ruoss, SJ Addrizzo-Harris, DJ Flume, PA Dorgan, DJ Salathe, M Brown-Elliott, BA Wallace, RJ Griffith, DE Olivier, KN AF Winthrop, K. L. Eagle, G. McGinnis, J. P. Micioni, L. Daley, C. L. Ruoss, S. J. Addrizzo-Harris, D. J. Flume, P. A. Dorgan, D. J. Salathe, M. Brown-Elliott, B. A. Wallace, R. J. Griffith, D. E. Olivier, K. N. TI Subgroup Analyses Of Baseline Demographics And Efficacy In Patients With Refractory Nontuberculous Mycobacteria (ntm) Lung Infection Treated With Liposomal Amikacin For Inhalation (lai) SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Winthrop, K. L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Eagle, G.; McGinnis, J. P.; Micioni, L.] Insmed Inc, Bridgewater, NJ USA. [Daley, C. L.] Natl Jewish Hlth, Denver, CO USA. [Ruoss, S. J.] Stanford Univ, Stanford, CA 94305 USA. [Addrizzo-Harris, D. J.] NYU, Sch Med, New York, NY USA. [Flume, P. A.] Med Univ S Carolina, Charleston, SC 29425 USA. [Dorgan, D. J.] Univ Penn, Philadelphia, PA 19104 USA. [Salathe, M.] Univ Miami, Miami, FL USA. [Brown-Elliott, B. A.] Univ Texas Hlth Sci Ctr Tyler, Tyler, TX USA. [Wallace, R. J.] Univ Texas Hlth Sci Ctr, Tyler, TX USA. [Griffith, D. E.] Univ Texas Hlth Ctr Tyler, Tyler, TX USA. [Olivier, K. N.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A6294 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582808529 ER PT J AU Wyss, AB House, JS Hoppin, JA Henneberger, PK London, S AF Wyss, A. B. House, J. S. Hoppin, J. A. Henneberger, P. K. London, S. CA Agr Lung Hlth Study TI Raw Milk Consumption And Pulmonary Function In Adults In The Agricultural Lung Health Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Wyss, A. B.; House, J. S.; London, S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Wyss, A. B.; Hoppin, J. A.] N Carolina State Univ, Raleigh, NC 27695 USA. [Henneberger, P. K.] NIOSH, Morgantown, WV USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A4675 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582806110 ER PT J AU Yan, X Chu, JH Gomez, JL Koenigs, M Holm, C He, X Perez, MF Zhao, H Mane, S Martinez, FD Ober, C Nicolae, DL Barnes, KC London, SJ Gilliland, FD Weiss, ST Raby, BA Cohn, LE Chupp, GL AF Yan, X. Chu, J. -H. Gomez, J. L. Koenigs, M. Holm, C. He, X. Perez, M. F. Zhao, H. Mane, S. Martinez, F. D. Ober, C. Nicolae, D. L. Barnes, K. C. London, S. J. Gilliland, F. D. Weiss, S. T. Raby, B. A. Cohn, L. E. Chupp, G. L. TI Non-Invasive Analysis Of The Airway Transcriptome Discriminates Clinical Phenotypes Of Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Yan, X.; Gomez, J. L.; Holm, C.; He, X.; Perez, M. F.; Mane, S.; Cohn, L. E.; Chupp, G. L.] Yale Univ, Sch Med, New Haven, CT USA. [Yan, X.; Chu, J. -H.; Weiss, S. T.; Raby, B. A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Koenigs, M.] Ohio State Univ, Columbus, OH 43210 USA. [Zhao, H.] Yale Univ, Sch Epidemiol & Publ Hlth, New Haven, CT USA. [Martinez, F. D.] Univ Arizona, Tucson, AZ USA. [Ober, C.] Unviers Chicago, Chicago, IL USA. [Nicolae, D. L.] Univ Chicago, Chicago, IL 60637 USA. [Barnes, K. C.] Johns Hopkins, Baltimore, MD USA. [London, S. J.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Gilliland, F. D.] Univ So Calif, Los Angeles, CA USA. EM xiting.yan@yale.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A6056 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582808305 ER PT J AU Yang, IV Pedersen, BS Liu, A O'Connor, GT Teach, SJ Kattan, M Misiak, RT Gruchalla, R Steinbach, SF Szefler, SJ Gill, MA Calatroni, A David, G Hennessy, CE Davidson, EJ Gergen, P Togias, A Busse, WW Schwartz, DA AF Yang, I. V. Pedersen, B. S. Liu, A. O'Connor, G. T. Teach, S. J. Kattan, M. Misiak, R. T. Gruchalla, R. Steinbach, S. F. Szefler, S. J. Gill, M. A. Calatroni, A. David, G. Hennessy, C. E. Davidson, E. J. Gergen, P. Togias, A. Busse, W. W. Schwartz, D. A. TI Dna Methylation Changes In Nasal Epithelia Assoicated With Allergic Asthma In The Inner City SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Yang, I. V.; Hennessy, C. E.; Davidson, E. J.] Univ Colorado, Aurora, CO USA. [Pedersen, B. S.; Schwartz, D. A.] Univ Colorado, Denver, CO 80202 USA. [Liu, A.; Szefler, S. J.] Natl Jewish Hlth, Denver, CO USA. [O'Connor, G. T.; Steinbach, S. F.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Teach, S. J.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Kattan, M.] Columbia Univ, Med Ctr, New York, NY USA. [Misiak, R. T.] Henry Ford Hosp, Detroit, MI 48202 USA. [Gruchalla, R.] Univ Texas Southwestern Med Sch, Dallas, TX USA. [Gill, M. A.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Calatroni, A.; David, G.] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Gergen, P.; Togias, A.] NIAID, Bethesda, MD 20892 USA. [Busse, W. W.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A5379 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582807247 ER PT J AU Yang, JX Parikh, M Carr, J Gomes, A Habibi, M Hueper, K Hoffman, EA Lima, J Kawut, SM Prince, M Smith, B Swift, AJ Sun, Y Vogel-Claussen, J Wild, JM Bluemke, DM Barr, RG AF Yang, J. X. Parikh, M. Carr, J. Gomes, A. Habibi, M. Hueper, K. Hoffman, E. A. Lima, J. Kawut, S. M. Prince, M. Smith, B. Swift, A. J. Sun, Y. Vogel-Claussen, J. Wild, J. M. Bluemke, D. M. Barr, R. G. TI Cardiac Hemodynamics In COPD And Emphysema Estimated By Magnetic Resonance Imaging SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Yang, J. X.; Prince, M.; Sun, Y.; Barr, R. G.] Columbia Univ, Med Ctr, New York, NY USA. [Parikh, M.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Carr, J.] Northwestern Univ, Chicago, IL 60611 USA. [Gomes, A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Habibi, M.; Hueper, K.] Johns Hopkins Univ, Baltimore, MD USA. [Hoffman, E. A.] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Lima, J.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Kawut, S. M.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Swift, A. J.; Wild, J. M.] Univ Sheffield, Sheffield, S Yorkshire, England. [Vogel-Claussen, J.] Hannover Med Sch, Hannover, Germany. [Bluemke, D. M.] NIH, Bethesda, MD 20892 USA. EM jxy2002@columbia.edu NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A6380 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582803349 ER PT S AU Berezovskaya, FS Karev, GP AF Berezovskaya, Faina S. Karev, Georgiy P. BE Cojocaru, MG Kotsireas, IS Makarov, RN Melnik, RVN Shodiev, H TI Stabilizing Role of Predators in Niche Construction Modeling SO INTERDISCIPLINARY TOPICS IN APPLIED MATHEMATICS, MODELING AND COMPUTATIONAL SCIENCE SE Springer Proceedings in Mathematics & Statistics LA English DT Proceedings Paper CT Interdisciplinary International Conference on Applied Mathematics, Modelling and Computational Science (AMMCS) CY AUG 26-30, 2013 CL Wilfrid Laurier Univ, Waterloo Campus, Waterloo, CANADA HO Wilfrid Laurier Univ, Waterloo Campus AB In this chapter a question of "how much over-consumption a renewable resource can tolerate" is addressed using a mathematical model, where a consumer population competes for the common resource, can contribute to resource restoration, and is subject to attacks of predators. The bifurcation analysis of the system shows that well-adapted predators can keep the system in a stable equilibrium even for "strong" prey over-consumption, when the initial system of resource-consumer goes to extinct. Thus, predators may extend the domain of total model system coexistence in niche. C1 [Berezovskaya, Faina S.] Howard Univ, Dept Math, Washington, DC 20059 USA. [Karev, Georgiy P.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Berezovskaya, FS (reprint author), Howard Univ, Dept Math, Washington, DC 20059 USA. EM fberezovskaya@howard.edu; karev@ncbi.nlm.nih.gov NR 6 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 2194-1009 BN 978-3-319-12307-3; 978-3-319-12306-6 J9 SPRINGER P MATH STAT PY 2015 VL 117 BP 73 EP 79 DI 10.1007/978-3-319-12307-3_11 PG 7 WC Mathematics, Applied; Mathematics; Statistics & Probability SC Mathematics GA BE9FG UT WOS:000377391500011 ER PT J AU Drgonova, J Walther, D Wang, KJ Hartstein, GL Lochte, B Troncoso, J Uetani, N Iwakura, Y Uhl, GR AF Drgonova, Jana Walther, Donna Wang, Katherine J. Hartstein, G. Luke Lochte, Bryson Troncoso, Juan Uetani, Noriko Iwakura, Yoichiro Uhl, George R. TI Mouse Model for Protein Tyrosine Phosphatase D (PTPRD) Associations with Restless Leg Syndrome or Willis-Ekbom Disease and Addiction: Reduced Expression Alters Locomotion, Sleep Behaviors and Cocaine-Conditioned Place Preference SO MOLECULAR MEDICINE LA English DT Article ID GENOME-WIDE ASSOCIATION; SMOKING-CESSATION SUCCESS; MOLECULAR-GENETICS; NICOTINE REPLACEMENT; ALCOHOL DEPENDENCE; MICE; DELTA; TRIAL; PARTICIPANTS; KNOCKOUT AB The receptor type protein tyrosine phosphatase D (PTPRD) gene encodes a cell adhesion molecule likely to influence development and connections of addiction-, locomotion-and sleep-related brain circuits in which it is expressed. The PTPRD gene harbors genome-wide association signals in studies of restless leg syndrome (Willis-Ekbom disease [WED]/restless leg syndrome [RLS]; p < 10(-8)) and addiction-related phenotypes (clusters of nearby single nucleotide polymorphisms [SNPs] with 10(-2) > p > 10(-8) associations in several reports). We now report work that seeks (a) association between PTPRD genotypes and expression of its mRNA in postmortem human brains and (b) RLS-related, addiction-related and comparison behavioral phenotypes in hetero-and homozygous PTPRD knockout mice. We identify associations between PTPRD SNPs and levels of PTPRD mRNA in human brain samples that support validity of mouse models with altered PTPRD expression. Knockouts display less behaviorally defined sleep at the end of their active periods. Heterozygotes move more despite motor weakness/impersistence. Heterozygotes display shifted dose-response relationships for cocaine reward. They display greater preference for places paired with 5 mg/kg cocaine and less preference for places paired with 10 or 20 mg/kg. The combined data provide support for roles for common, level-of-expression PTPRD variation in locomotor, sleep and drug reward phenotypes relevant to RLS and addiction. Taken together, mouse and human results identify PTPRD as a novel therapeutic target for RLS and addiction phenotypes. C1 [Drgonova, Jana; Walther, Donna; Wang, Katherine J.; Hartstein, G. Luke; Lochte, Bryson; Uhl, George R.] NIDA, Mol Neurobiol Branch, NIH, Intramural Res Program, Baltimore, MD USA. [Troncoso, Juan] Johns Hopkins Sch Med, Div Neuropathol, Baltimore, MD USA. [Uetani, Noriko] McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ, Canada. [Iwakura, Yoichiro] Univ Tokyo, Ctr Med Expt, Tokyo, Japan. [Uhl, George R.] New Mexico VA Hlth Care Syst, Res, Albuquerque, NM USA. RP Uhl, GR (reprint author), NMVAHCS, Res, Albuquerque, NM 87108 USA. EM guhl@intra.nida.nih.gov RI Iwakura, Yoichiro/E-5457-2011 OI Iwakura, Yoichiro/0000-0002-9934-5775 FU NIH-IRP; NIDA; U.S. Department of Health and Human Services (HHS); New Mexico VA Health Care System (NMVAHCS) FX This work was supported by the NIH-IRP, NIDA, U.S. Department of Health and Human Services (HHS) (GR Uhl) and by New Mexico VA Health Care System (NMVAHCS) (GR Uhl). We are grateful for help from C Johnson, D Arking, D Naimen, J Bader and J Schroder; for access to brain samples from the University of Maryland Brain Tissue Bank; and for access to data for PTPRD from A Hart and A Palmer. All human and/or animal studies were approved by the appropriate institutional committees. NR 38 TC 1 Z9 1 U1 5 U2 5 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 EI 1528-3658 J9 MOL MED JI Mol. Med. PY 2015 VL 21 BP 717 EP 725 DI 10.2119/molmed.2015.00017 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DN7QE UT WOS:000377271200004 ER PT J AU Djoumerska-Alexieva, I Roumenina, L Pashov, A Dimitrov, J Hadzhieva, M Lindig, S Voynova, E Dimitrova, P Ivanovska, N Bockmeyer, C Stefanova, Z Fitting, C Blass, M Claus, R von Gunten, S Kaveri, S Cavaillon, JM Bauer, M Vassilev, T AF Djoumerska-Alexieva, Iglika Roumenina, Lubka Pashov, Anastas Dimitrov, Jordan Hadzhieva, Maya Lindig, Sandro Voynova, Elisaveta Dimitrova, Petya Ivanovska, Nina Bockmeyer, Clemens Stefanova, Zvetanka Fitting, Catherine Blaess, Markus Claus, Ralf von Gunten, Stephan Kaveri, Srini Cavaillon, Jean-Marc Bauer, Michael Vassilev, Tchavdar TI Intravenous Immunoglobulin with Enhanced Polyspecificity Improves Survival in Experimental Sepsis and Aseptic Systemic Inflammatory Response Syndromes SO MOLECULAR MEDICINE LA English DT Article ID SEPTIC SHOCK; IVIG PREPARATIONS; IMMUNE GLOBULIN; COMPLEMENT; METAANALYSIS; ACTIVATION; MECHANISMS; ANTIBODIES; DISEASES; BINDING AB Sepsis is a major cause for death worldwide. Numerous interventional trials with agents neutralizing single proinflammatory mediators have failed to improve survival in sepsis and aseptic systemic inflammatory response syndromes. This failure could be explained by the widespread gene expression dysregulation known as "genomic storm" in these patients. A multifunctional polyspecific therapeutic agent might be needed to thwart the effects of this storm. Licensed pooled intravenous immunoglobulin preparations seemed to be a promising candidate, but they have also failed in their present form to prevent sepsis-related death. We report here the protective effect of a single dose of intravenous immunoglobulin preparations with additionally enhanced polyspecificity in three models of sepsis and aseptic systemic inflammation. The modification of the pooled immunoglobulin G molecules by exposure to ferrous ions resulted in their newly acquired ability to bind some proinflammatory molecules, complement components and endogenous "danger" signals. The improved survival in endotoxemia was associated with serum levels of proinflammatory cytokines, diminished complement consumption and normalization of the coagulation time. We suggest that intravenous immunoglobulin preparations with additionally enhanced polyspecificity have a clinical potential in sepsis and related systemic inflammatory syndromes. C1 [Djoumerska-Alexieva, Iglika; Pashov, Anastas; Dimitrov, Jordan; Hadzhieva, Maya; Dimitrova, Petya; Ivanovska, Nina; Stefanova, Zvetanka; Vassilev, Tchavdar] Bulgarian Acad Sci, Dept Immunol, Stefan Angelov Inst Microbiol, 26 Acad Georgi Bonchev St, Sofia 1113, Bulgaria. [Roumenina, Lubka; Dimitrov, Jordan; Kaveri, Srini] INSERM UMRS 1138, Ctr Rech Cordeliers, Paris, France. [Lindig, Sandro; Blaess, Markus; Claus, Ralf; Bauer, Michael; Vassilev, Tchavdar] Univ Jena, Univ Hosp, Ctr Sepsis Control & Care, Jena, Germany. [Voynova, Elisaveta] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Bockmeyer, Clemens] Hannover Med Sch, Inst Pathol, Hannover, Germany. [Fitting, Catherine; Cavaillon, Jean-Marc] Inst Pasteur, Cytokines & Inflammat Unit, Paris, France. [von Gunten, Stephan] Univ Bern, Inst Pharmacol, Bern, Switzerland. RP Vassilev, T (reprint author), Bulgarian Acad Sci, Dept Immunol, Stefan Angelov Inst Microbiol, 26 Acad Georgi Bonchev St, Sofia 1113, Bulgaria. EM vassilev@microbio.bas.bg RI Dimitrov, Jordan/N-2141-2014 FU Bulgarian-Swiss Research Programme [BSRP IZEBZO_142967]; Bulgarian National Science Fund [DFNI B02/29]; Pasteur Institute [ACIP A07-2012]; NATO Science for Peace Program [SfP 982158]; German Federal Ministry of Education and Research (BMBF) [01EO1002, 03Z2J521] FX This work was supported by grants from the Bulgarian-Swiss Research Programme (BSRP IZEBZO_142967), the Bulgarian National Science Fund (DFNI B02/29), the Pasteur Institute (ACIP A07-2012), the NATO Science for Peace Program (SfP 982158), and the German Federal Ministry of Education and Research (BMBF; grant 01EO1002) and grant 03Z2J521 (Meta-ZIK), both to the Centre for Sepsis Control and Care. We thank D Himsel for technical assistance. NR 38 TC 2 Z9 2 U1 2 U2 2 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 EI 1528-3658 J9 MOL MED JI Mol. Med. PY 2015 VL 21 BP 1002 EP 1010 DI 10.2119/molmed.2014.00224 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DN7QE UT WOS:000377271200031 ER PT J AU Etemadi, A Abnet, C Kamangar, F Wacholder, S Islami, F Brennan, P Boffetta, P Malekzadeh, R Dawsey, S AF Etemadi, A. Abnet, C. Kamangar, F. Wacholder, S. Islami, F. Brennan, P. Boffetta, P. Malekzadeh, R. Dawsey, S. TI Impact of Body Size and Physical Activity during Adolescence and Adult Life on Overall and Cause-specific Mortality in a Large Cohort Study from Iran SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th IEA World Congress of Epidemiology (WCE) CY AUG 17-21, 2014 CL Anchorage, AK SP Int Epidemiol Assoc C1 [Etemadi, A.; Abnet, C.; Wacholder, S.; Dawsey, S.] NCI, Bethesda, MD 20892 USA. [Etemadi, A.; Islami, F.; Malekzadeh, R.] Univ Tehran Med Sci, Tehran, Iran. [Kamangar, F.] Morgan State Univ, Baltimore, MD 21239 USA. [Brennan, P.] Int Agcy Res Canc, Lyon, MD USA. [Boffetta, P.] Mt Sinai Sch Med, New York, NY USA. RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PY 2015 VL 44 SU 1 MA 2480 BP 79 EP 79 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DM9BV UT WOS:000376659900178 ER PT J AU Alvarez-Hernandez, G Murillo-Benitez, C Candia-Plata, MC Moro, M AF Alvarez-Hernandez, G. Murillo-Benitez, C. Candia-Plata, M. C. Moro, M. TI Rocky Mountain Spotted Fever Reemergence in children from Sonora, Mexico. 2004-12. SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th IEA World Congress of Epidemiology (WCE) CY AUG 17-21, 2014 CL Anchorage, AK SP Int Epidemiol Assoc C1 [Alvarez-Hernandez, G.; Candia-Plata, M. C.] Univ Sonora, Hermosillo 83000, Sonora, Mexico. [Murillo-Benitez, C.] Inst Tecnolo & Estudios Super Monterrey, Monterrey, Mexico. [Moro, M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PY 2015 VL 44 SU 1 MA 3030 BP 243 EP 243 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DM9BV UT WOS:000376659900631 ER PT J AU Hoffman, HJ Li, CM Bainbridge, KE Losonczy, KG Chiu, MS Rice, ML AF Hoffman, H. J. Li, C. M. Bainbridge, K. E. Losonczy, K. G. Chiu, M. S. Rice, M. L. TI Voice, Speech, and Language Problems in the US Pediatric Population: The 2012 National Health Interview Survey (NHIS). SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th IEA World Congress of Epidemiology (WCE) CY AUG 17-21, 2014 CL Anchorage, AK SP Int Epidemiol Assoc C1 [Hoffman, H. J.; Li, C. M.; Bainbridge, K. E.; Losonczy, K. G.; Chiu, M. S.] NIDCD, NIH, Bethesda, MD USA. [Rice, M. L.] Univ Kansas, Lawrence, KS 66045 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PY 2015 VL 44 SU 1 MA 3852 BP 260 EP 260 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DM9BV UT WOS:000376659900680 ER PT S AU Demner-Fushman, D Shooshan, SE Rodriguez, L Antani, S Thoma, GR AF Demner-Fushman, Dina Shooshan, Sonya E. Rodriguez, Laritza Antani, Sameer Thoma, George R. BE Muller, H DelToro, OAJ Hanbury, A Langs, G Rodriguez, AF TI Annotation of Chest Radiology Reports for Indexing and Retrieval SO MULTIMODAL RETRIEVAL IN THE MEDICAL DOMAIN, MRMD 2015 SE Lecture Notes in Computer Science LA English DT Proceedings Paper CT 1st International Workshop on Multimodal Retrieval in the Medical Domain (MRMD) CY MAR 29, 2015 CL Vienna, AUSTRIA DE Information storage and retrieval; Vocabulary; controlled; Radiology ID DISEASES AB Annotation of MEDLINE citations with controlled vocabulary terms improves the quality of retrieval results. Due to variety in descriptions of similar clinical phenomena and abundance of negation and uncertainty, annotation of clinical radiology reports for subsequent indexing and retrieval with a search engine is even more important. Provided with an opportunity to add about 4,000 radiology reports to collections indexed with NLM image retrieval engine Open-i, we needed to assure good retrieval quality. To accomplish this, we explored automatic and manual approaches to annotation, as well as developed a small controlled vocabulary of chest x-ray indexing terms and guidelines for manual annotation. Manual annotation captured the most salient findings in the reports and normalized the sparse distinct descriptions of similar findings to one controlled vocabulary term. This paper presents the vocabulary and the manual annotation process, as well as an evaluation of the automatic annotation of the reports. C1 [Demner-Fushman, Dina; Shooshan, Sonya E.; Rodriguez, Laritza; Antani, Sameer; Thoma, George R.] US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. RP Demner-Fushman, D (reprint author), US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. EM ddemner@mail.nih.gov; sshooshan@mail.nih.gov; rodriguezlm2@mail.nih.gov; santani@mail.nih.gov; gthoma@mail.nih.gov NR 22 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 0302-9743 BN 978-3-319-24471-6; 978-3-319-24470-9 J9 LECT NOTES COMPUT SC PY 2015 VL 9059 BP 99 EP 111 DI 10.1007/978-3-319-24471-6_9 PG 13 WC Computer Science, Artificial Intelligence; Computer Science, Information Systems; Computer Science, Theory & Methods; Medical Informatics SC Computer Science; Medical Informatics GA BE7EI UT WOS:000375149600009 ER PT S AU Cruz-Chan, JV Valenzuela, J Dumonteil, E AF Vladimir Cruz-Chan, Julio Valenzuela, Jesus Dumonteil, Eric BE FrancoParedes, C SantosPreciado, JI TI Leishmaniasis in the Americas SO NEGLECTED TROPICAL DISEASES - LATIN AMERICA AND THE CARIBBEAN SE Neglected Tropical Diseases LA English DT Article; Book Chapter DE Leishmania; Sand fly; Lutzomyia; Visceral leishmaniasis; Cutaneous leishmaniasis; New world ID VISCERAL-LEISHMANIASIS; CUTANEOUS LEISHMANIASIS; CANINE LEISHMANIASIS; NEW-WORLD; TEGUMENTARY LEISHMANIASIS; CHICLEROS ULCER; SAND FLIES; MOLECULAR EPIDEMIOLOGY; MUCOSAL LEISHMANIASIS; LUTZOMYIA-LONGIPALPIS AB Leishmaniasis is a neglected tropical disease caused by kinetoplastid protozoan parasites belonging to the Leishmania genus. Infection causes a wide diversity of clinical manifestations, ranging in severity from asymptomatic infections, self-healing cutaneous lesions (cutaneous leishmaniasis (CL)), mucocutaneous lesions (mucocutaneous leishmaniasis (MCL)), diffuse leishmaniasis, and visceral leishmaniasis (VL) which can be lethal when untreated. Leishmania parasites are transmitted to vertebrate hosts through the bite of female sandflies of the genus Lutzomyia in the New World. We review here some of the key aspects of leishmaniasis in Latin America and highlight some of the specificities of the disease in the American continent. The diversity of vector and parasite species poses additional challenges compared to the situation in the Old World. Indeed, this diversity implies that most tools for disease surveillance and control, including diagnostics, vector control interventions, therapeutic treatments, and vaccines, need to be adapted to ensure their efficacy. Further research is thus needed to optimize leishmaniasis control and surveillance in the Americas. C1 [Vladimir Cruz-Chan, Julio; Dumonteil, Eric] Univ Autonoma Yucatan, Ctr Invest Reg Dr Hideyo Noguchi, Lab Parasitol, Ave Itzaes 490 X 59, Merida 97000, Yucatan, Mexico. [Valenzuela, Jesus] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Dumonteil, Eric] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Trop Med, New Orleans, LA 70118 USA. RP Dumonteil, E (reprint author), Univ Autonoma Yucatan, Ctr Invest Reg Dr Hideyo Noguchi, Lab Parasitol, Ave Itzaes 490 X 59, Merida 97000, Yucatan, Mexico. EM oliver@uady.mx NR 79 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 2194-8275 BN 978-3-7091-1422-3; 978-3-7091-1421-6 J9 NEGLECT TROP DIS PY 2015 BP 113 EP 128 DI 10.1007/978-3-7091-1422-3_6 D2 10.1007/978-3-7091-1422-3 PG 16 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA BE6QN UT WOS:000374638500007 ER PT S AU Varshney, GK Sood, R Burgess, SM AF Varshney, Gaurav K. Sood, Raman Burgess, Shawn M. BE Friedmann, T Dunlap, JC Goodwin, SF TI Understanding and Editing the Zebrafish Genome SO ADVANCES IN GENETICS, VOL 92 SE Advances in Genetics LA English DT Review; Book Chapter ID ZINC-FINGER NUCLEASES; DEVELOPMENTAL GENE-EXPRESSION; ENU-INDUCED MUTATIONS; TARGETED MUTAGENESIS; IN-VIVO; INSERTIONAL MUTAGENESIS; CRISPR/CAS9 SYSTEM; TAL EFFECTORS; HUMAN-DISEASE; DNA-CLEAVAGE AB In the last two decades, zebrafish has become one of the fastest growing model organisms in terms of publications, however it has been plagued with the absence of a key tool in the genetics toolbox: the ability to systematically make targeted mutations in the genome. That all changed with the recent emergence of custom-built, sequence-specific nucleases, i.e., zinc finger nucleases (ZFNs), TAL-effector nucleases (TALENs), or clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas9. Here, we provide a comprehensive review of the application of these genome-editing tools to generate targeted knockout and knock-in mutants in zebrafish. These technologies have allowed us to transition from targeted knockouts in zebrafish being a difficult, resource intensive undertaking, to something that can be done in virtually any lab with modest molecular biology experience. Furthermore, this review provides a comprehensive listing of genetic and genomic resources and online tools that zebrafish researchers can use to help find a desired mutation or design effective ZFNs, TALENs, or CRISPR guide RNAs for their targeting experiments. C1 [Varshney, Gaurav K.; Sood, Raman; Burgess, Shawn M.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. RP Burgess, SM (reprint author), NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov OI Varshney, Gaurav K./0000-0002-0429-1904 FU Intramural NIH HHS NR 190 TC 8 Z9 8 U1 6 U2 12 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-2660 BN 978-0-12-804079-9; 978-0-12-804014-0 J9 ADV GENET JI Adv. Genet. PY 2015 VL 92 BP 1 EP 52 DI 10.1016/bs.adgen.2015.09.002 PG 52 WC Genetics & Heredity SC Genetics & Heredity GA BE8AJ UT WOS:000376148000001 PM 26639914 ER PT S AU Le Roy, A Wang, K Schaack, B Schuck, P Breyton, C Ebel, C AF Le Roy, Aline Wang, Kai Schaack, Beatrice Schuck, Peter Breyton, Cecile Ebel, Christine BE Cole, JL TI AUC and Small-Angle Scattering for Membrane Proteins SO ANALYTICAL ULTRACENTRIFUGATION SE Methods in Enzymology LA English DT Review; Book Chapter ID VELOCITY ANALYTICAL ULTRACENTRIFUGATION; DETECTED SEDIMENTATION-VELOCITY; DETERGENT-SOLUBILIZED STATE; SIZE-DISTRIBUTION ANALYSIS; RECEPTOR-BINDING PROTEIN; NEUTRON-SCATTERING; X-RAY; MOLECULAR-WEIGHT; STRUCTURAL-CHARACTERIZATION; SAXS DATA AB Analytical ultracentrifugation is a key tool to assess homogeneity of membrane protein samples, to determine protein association state and detergent concentration, and to characterize protein-protein equilibrium. Combining absorbance and interference detections gives information on the amount of the detergent and lipid bound to proteins. Changing the solvent density affects specifically the buoyancy of each of the different components, and can also be used to gain information on particle composition and interaction. We will present the related tools, recently implemented in the softwares Sedphat (sedfitsedphat.nibib.nih.gov/software) and Gussi (http://biophysics.swmed.edu/MBR/software.html), which help to measure the amount of detergent bound to the protein, and ascertain the protein association state within the protein-detergent complex. In addition, fluorescence detection allows focusing specifically on a labeled component within a complex mixture. We present two examples of sedimentation velocity experiments, allowing on one hand to evidence complex formation between an unpurified GFP-labeled protein and a membrane protein, and on the other hand to characterize fluorescent lipid vesicles. Small-angle X-ray and neutron scattering are techniques that give insights into the structure and conformation of macromolecules in solution. However, the detergents used to purify membrane protein are often imperfectly masked due to their amphipathic character. Particular strategies addressing membrane proteins were recently proposed, which are shortly presented. C1 [Le Roy, Aline; Wang, Kai; Schaack, Beatrice; Breyton, Cecile; Ebel, Christine] Univ Grenoble Alpes, IBS, Grenoble, France. [Le Roy, Aline; Wang, Kai; Schaack, Beatrice; Breyton, Cecile; Ebel, Christine] CNRS, IBS, Grenoble, France. [Le Roy, Aline; Wang, Kai; Schaack, Beatrice; Breyton, Cecile; Ebel, Christine] CEA, IBS, Grenoble, France. [Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. RP Ebel, C (reprint author), Univ Grenoble Alpes, IBS, Grenoble, France. EM christine.ebel@ibs.fr OI Schuck, Peter/0000-0002-8859-6966 FU Intramural NIH HHS NR 59 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 BN 978-0-12-802909-1; 978-0-12-802908-4 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2015 VL 562 BP 257 EP 286 DI 10.1016/bs.mie.2015.06.010 PG 30 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BE8AP UT WOS:000376153000013 PM 26412656 ER PT S AU Sastry, M Bewley, CA Kwong, PD AF Sastry, Mallika Bewley, Carole A. Kwong, Peter D. BE Kelman, Z TI Effective Isotope Labeling of Proteins in a Mammalian Expression System SO ISOTOPE LABELING OF BIOMOLECULES - LABELING METHODS SE Methods in Enzymology LA English DT Review; Book Chapter ID DICTYOSTELIUM-DISCOIDEUM; NMR-SPECTROSCOPY; HUMAN CD2; RESONANCE ASSIGNMENTS; ADHESION DOMAIN; MESSENGER-RNAS; HSQC-SPECTRA; CELL-LINES; ADENOVIRUS; VECTORS AB Isotope labeling of biologically interesting proteins is a prerequisite for structural and dynamics studies by NMR spectroscopy. Many of these proteins require mammalian cofactors, chaperons, or posttranslational modifications such as myristoylation, glypiation, disulfide bond formation, or N- or O-linked glycosylation; and mammalian cells have the necessary machinery to produce them in their functional forms. Here, we describe recent advances in mammalian expression, including an efficient adenoviral vector-based system, for the production of isotopically labeled proteins. This system enables expression of mammalian proteins and their complexes, including proteins that require posttranslational modifications. We describe a roadmap to produce isotopically labeled N-15 and C-13 posttranslationally modified proteins, such as the outer domain of HIV-1 gp120, which has four disulfide bonds and 15 potential sites of N-linked glycosylation. These methods should allow NMR spectroscopic analysis of the structure and function of posttranslationally modified and secreted, cytoplasmic, or membrane-bound proteins. C1 [Sastry, Mallika; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bewley, Carole A.] Natl Inst Diabet & Digest & Kidney Dis, Bioorgan Chem Lab, NIH, Bethesda, MD USA. RP Sastry, M (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sastrym@niaid.nih.gov; CaroleB@mail.nih.gov; pdkwong@nih.gov NR 68 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 BN 978-0-12-803080-6; 978-0-12-803048-6 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2015 VL 565 BP 289 EP 307 DI 10.1016/bs.mie.2015.09.021 PG 19 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BE8AO UT WOS:000376152000013 PM 26577736 ER PT S AU Kumari, G Sen, R AF Kumari, Gita Sen, Ranjan BE Murre, C TI Chromatin Interactions in the Control of Immunoglobulin Heavy Chain Gene Assembly SO MOLECULAR MECHANISMS THAT ORCHESTRATE THE ASSEMBLY OF ANTIGEN RECEPTOR LOCI SE Advances in Immunology LA English DT Review; Book Chapter ID HISTONE LYSINE METHYLATION; CLASS-SWITCH RECOMBINATION; B-CELL-DEVELOPMENT; ANTISENSE INTERGENIC TRANSCRIPTION; NUCLEAR LAMINA INTERACTIONS; 3' REGULATORY REGION; CIS-ACTING ELEMENTS; V(D)J RECOMBINATION; IGH LOCUS; INTRONIC ENHANCER AB Expression of antibody heavy chain occurs via precisely timed developmental activation of the immunoglobulin heavy chain (IgH) gene locus during B cell development. IgH locus activation permits coordinated gene rearrangements that assemble variable (V-H), diversity (D-H), and joining (J(H)) gene segments into functional genes. Chromosomal conformation changes and epigenetic mechanisms play critical roles in ensuring rearrangement fidelity while minimizing hazardous consequences of broken DNA ends generated during recombination. In this review, we summarize the current status of regulatory mechanisms that underpin effective IgH gene assembly. For this, the germline locus is divided into two parts: a 2.4 Mb 50 part that contains all V-H gene segments and a 300 kb 30 domain that contains D-H and J(H) gene segments, as well as exons that encode IgH isotypes. Structural features of each part are discussed individually, followed by consideration of how the two parts come together to complete IgH recombination. Throughout we emphasize current insights, propose plausible mechanisms, and highlight key questions for future studies. C1 [Kumari, Gita; Sen, Ranjan] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. RP Sen, R (reprint author), NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. EM senranja@grc.nia.nih.gov FU Intramural NIH HHS NR 199 TC 3 Z9 3 U1 3 U2 3 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-2776 BN 978-0-12-803330-2; 978-0-12-803296-1 J9 ADV IMMUNOL JI Adv.Immunol. PY 2015 VL 128 BP 41 EP 92 DI 10.1016/bs.ai.2015.08.001 PG 52 WC Immunology SC Immunology GA BE8AN UT WOS:000376151400003 PM 26477365 ER PT S AU Zhang, JW Ferre-D'Amare, AR AF Zhang, Jinwei Ferre-D'Amare, Adrian R. BE Ponchon, L TI Post-crystallization Improvement of RNA Crystal Diffraction Quality SO RNA SCAFFOLDS: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE X-ray crystallography; Crystal dehydration; Ion replacement; Riboswitch; T-box RNA; tRNA ID ANGSTROM RESOLUTION; SECONDARY STRUCTURE; DEHYDRATION; RIBOSWITCH; RIBOZYME; MOTIF; ANTITERMINATION; COMPLEX; ELEMENT; TURNS AB The crystallization and structural determination of large RNAs and their complexes remain major bottle-necks in the mechanistic analysis of cellular and viral RNAs. Here, we describe a protocol that combines post-crystallization dehydration and ion replacement that dramatically improved the diffraction quality of crystals of a large gene-regulatory tRNA-mRNA complex. Through this method, the resolution limit of X-ray data extended from 8.5 to 3.2 angstrom, enabling structure determination. Although this protocol was developed for a particular RNA complex, the general importance of solvent and counterions in nucleic acid structure may render it generally useful for crystallographic analysis of other RNAs. C1 [Zhang, Jinwei; Ferre-D'Amare, Adrian R.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Zhang, JW (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS [, Z99 HL999999, ZIA HL006102-04]; NIGMS NIH HHS [P41 GM103403] NR 30 TC 0 Z9 0 U1 1 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2730-2; 978-1-4939-2729-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2015 VL 1316 BP 13 EP 24 DI 10.1007/978-1-4939-2730-2_2 D2 10.1007/978-1-4939-2730-2 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BE6YK UT WOS:000374927600003 PM 25967049 ER PT J AU Imai, CM Halldorsson, TI Eiriksdottir, G Cotch, MF Stein-Grimsdottir, L Thorsdottir, I Launer, LJ Harris, T Gudnason, V Gunnarsdottir, I AF Imai, Cindy Mari Halldorsson, Thorhallur Ingi Eiriksdottir, Gudny Cotch, Mary Frances Stein-Grimsdottir, Laufey Thorsdottir, Inga Launer, Lenore J. Harris, Tamara Gudnason, Vilmundur Gunnarsdottir, Ingibjorg TI Depression and serum 25-hydroxyvitamin D in older adults living at northern latitudes-AGES-Reykjavik Study SO ANNALS OF NUTRITION AND METABOLISM LA English DT Meeting Abstract DE vitamin D; depression; older adults; nutrition epidemiology C1 [Imai, Cindy Mari] Univ Iceland, Unit Nutr Res, Reykjavik, Iceland. [Halldorsson, Thorhallur Ingi; Stein-Grimsdottir, Laufey; Thorsdottir, Inga; Gunnarsdottir, Ingibjorg] Landspitali, Unit Nutr Res, Reykjavik, Iceland. [Halldorsson, Thorhallur Ingi; Stein-Grimsdottir, Laufey; Thorsdottir, Inga; Gunnarsdottir, Ingibjorg] Univ Iceland, Fac Food Sci & Nutr, Sch Hlth Sci, Reykjavik, Iceland. [Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Launer, Lenore J.; Harris, Tamara] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0250-6807 EI 1421-9697 J9 ANN NUTR METAB JI Ann. Nutr. Metab. PY 2015 VL 67 SU 1 MA 149/73 BP 306 EP 306 PG 1 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA DK5VM UT WOS:000374988801238 ER PT J AU Vermeulen, E Stronks, K Visser, M Brouwer, I Schene, A Mocking, R Colpo, M Bandinelli, S Ferrucci, L Nicolaou, M AF Vermeulen, Esther Stronks, Karien Visser, Marjolein Brouwer, Ingeborg Schene, Aart Mocking, Roel Colpo, Marco Bandinelli, Stefania Ferrucci, Luigi Nicolaou, Mary TI Diet in Tuscan population associated with lower depressive symptoms over time SO ANNALS OF NUTRITION AND METABOLISM LA English DT Meeting Abstract DE diet; dietary pattern; depression; depressive symptoms; Reduced Rank Regression C1 [Vermeulen, Esther; Nicolaou, Mary] Acad Med Ctr, Dept Publ Hlth, Nutr, Amsterdam, Netherlands. [Stronks, Karien] Acad Med Ctr, Social Med, Amsterdam, Netherlands. [Visser, Marjolein] Vrije Univ Amsterdam, Dept Hlth Sci, Hlth Aging, Amsterdam, Netherlands. [Brouwer, Ingeborg] Vrije Univ Amsterdam, Inst Hlth Sci, Amsterdam, Netherlands. [Schene, Aart] Amsterdam Med Ctr, Dept Psychiat, Psychiat, Amsterdam, Netherlands. [Mocking, Roel] Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Colpo, Marco] Azienda Sanit Firenze, InCHIANTI Study Grp, Stat, Florence, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, InCHIANTI Study Grp, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0250-6807 EI 1421-9697 J9 ANN NUTR METAB JI Ann. Nutr. Metab. PY 2015 VL 67 SU 1 MA 149/152 BP 315 EP 316 PG 2 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA DK5VM UT WOS:000374988801260 ER PT J AU Kim, YM Chaemsaithong, P Romero, R Shaman, M Kim, CJ Kim, JS Qureshi, F Jacques, SM Ahmed, AI Chaiworapongsa, T Hassan, SS Yeo, L Korzeniewski, SJ AF Kim, Yeon Mee Chaemsaithong, Piya Romero, Roberto Shaman, Majid Kim, Chong Jai Kim, Jung-Sun Qureshi, Faisal Jacques, Suzanne M. Ahmed, Ahmed I. Chaiworapongsa, Tinnakorn Hassan, Sonia S. Yeo, Lami Korzeniewski, Steven J. TI The frequency of acute atherosis in normal pregnancy and preterm labor, preeclampsia, small-for-gestational age, fetal death and midtrimester spontaneous abortion SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Atherosclerosis; CD68; fibrinoid; foam cells; macrophage; spiral artery ID C-REACTIVE-PROTEIN; INTRAUTERINE GROWTH-RETARDATION; TUMOR-NECROSIS-FACTOR; SYSTEMIC-LUPUS-ERYTHEMATOSUS; CIRCULATING IMMUNE-COMPLEXES; PRO-INFLAMMATORY CYTOKINES; MATERNAL VASCULAR-LESIONS; LATE-ONSET PREECLAMPSIA; CORONARY-HEART-DISEASE; BED SPIRAL ARTERIES AB Objective: Acute atherosis is characterized by subendothelial lipid-filled foam cells, fibrinoid necrosis and perivascular lymphocytic infiltration. This lesion is generally confined to non-transformed spiral arteries and is frequently observed in patients with preeclampsia. However, the frequency of acute atherosis in the great obstetrical syndromes is unknown. The purpose of this study was to determine the frequency and topographic distribution of acute atherosis in placentas and placental bed biopsy samples obtained from women with normal pregnancy and those affected by the "great obstetrical syndromes''. We also examined the relationship between acute atherosis and pregnancy outcome in patients with preeclampsia. Material and methods: A retrospective cohort study of pregnant women who delivered between July 1998 and July 2014 at Hutzel Women's Hospital/Detroit Medical Center was conducted to examine 16 345 placentas. Patients were classified into the following groups: (1) uncomplicated pregnancy; (2) spontaneous preterm labor (sPTL) and preterm prelabor rupture of membranes (PPROM); (3) preeclampsia; (4) gestational hypertension; (5) small-for-gestational age (SGA); (6) chronic hypertension; (5) fetal death; (6) spontaneous abortion and (7) others. A subset of patients had placental bed biopsy. The incidence of acute atherosis was compared among the different groups. Results: (1) The prevalence of acute atherosis in uncomplicated pregnancies was 0.4% (29/6961) based upon examination of nearly 7000 placentas; (2) the frequency of acute atherosis was 10.2% (181/1779) in preeclampsia, 9% (26/292) in fetal death, 2.5% (3/120) in midtrimester spontaneous abortion, 1.7% (22/1,298) in SGA neonates and 1.2% (23/1,841) in sPTL and PPROM; (3) among patients with preeclampsia, those with acute atherosis than in those without the lesion had significantly more severe disease, earlier onset, and a greater frequency of SGA neonates (p<0.05 all) and (4) the lesion was more frequently observed in the decidua (parietalis or basalis) than in the decidual segment of the spiral arteries in patients with placental bed biopsies. Conclusions: Acute atherosis is rare in normal pregnancy, and occurs more frequently in patients with pregnancy complications, including preeclampsia, sPTL, preterm PROM, midtrimester spontaneous abortion, fetal death and SGA. C1 [Kim, Yeon Mee] Inje Univ, Coll Med, Haeundae Paik Hosp, Dept Pathol, Busan, South Korea. [Chaemsaithong, Piya; Romero, Roberto; Shaman, Majid; Kim, Chong Jai; Kim, Jung-Sun; Qureshi, Faisal; Jacques, Suzanne M.; Ahmed, Ahmed I.; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Yeo, Lami; Korzeniewski, Steven J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Chaemsaithong, Piya; Romero, Roberto; Shaman, Majid; Kim, Chong Jai; Kim, Jung-Sun; Qureshi, Faisal; Jacques, Suzanne M.; Ahmed, Ahmed I.; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Yeo, Lami; Korzeniewski, Steven J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Chaemsaithong, Piya; Shaman, Majid; Ahmed, Ahmed I.; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Yeo, Lami; Korzeniewski, Steven J.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto; Korzeniewski, Steven J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI USA. [Kim, Chong Jai] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul, South Korea. [Kim, Jung-Sun] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol, Seoul, South Korea. [Qureshi, Faisal; Jacques, Suzanne M.] Harper Univ Hosp, Dept Pathol, Detroit, MI USA. [Qureshi, Faisal; Jacques, Suzanne M.] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM ykim.haeundae@gmail.com; romeror@mail.nih.gov FU Intramural NIH HHS [ZIA HD002400-23]; NICHD NIH HHS [HHSN275201300006C]; PHS HHS [HHSN275201300006C] NR 143 TC 7 Z9 7 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PY 2015 VL 28 IS 17 BP 2001 EP 2009 DI 10.3109/14767058.2014.976198 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DK2OP UT WOS:000374754600001 PM 25308204 ER PT S AU Hollingsworth, JW Nadadur, SS AF Hollingsworth, John W. Nadadur, Srikanth S. BE Nadadur, SS Hollingsworth, JW TI Air Pollution and Health Effects Preface SO AIR POLLUTION AND HEALTH EFFECTS SE Molecular and Integrative Toxicology LA English DT Editorial Material; Book Chapter ID AMERICAN-HEART-ASSOCIATION; CARDIOVASCULAR-DISEASE; STATEMENT C1 [Hollingsworth, John W.] Ohio State Univ, Dept Internal Med, Div Pulm Allergy Crit Care & Sleep Med, Columbus, OH 43210 USA. [Nadadur, Srikanth S.] Natl Inst Environm Hlth Sci, Div Extramural Res & Training, Res Triangle Pk, NC USA. RP Hollingsworth, JW (reprint author), Ohio State Univ, Dept Internal Med, Div Pulm Allergy Crit Care & Sleep Med, Columbus, OH 43210 USA. NR 5 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER-VERLAG LONDON LTD PI GODALMING PA SWEETAPPLE HOUSE CATTESHALL RD FARNCOMBE, GODALMING GU7 1NH, SURREY, ENGLAND SN 2168-4219 BN 978-1-4471-6669-6; 978-1-4471-6668-9 J9 MOLEC INTEGR TOXICOL PY 2015 BP V EP VII D2 10.1007/978-1-4471-6669-6 PG 3 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BE5XX UT WOS:000373624200001 ER PT S AU Chae, JJ Kastner, DL AF Chae, Jae Jin Kastner, Daniel L. BE Gattorno, M TI Pathogenesis SO FAMILIAL MEDITERRANEAN FEVER SE Rare Diseases of the Immune System LA English DT Article; Book Chapter ID FAMILIAL MEDITERRANEAN FEVER; DEATH-DOMAIN-FOLD; NF-KAPPA-B; COLD AUTOINFLAMMATORY SYNDROME; MUCKLE-WELLS-SYNDROME; PYRIN DOMAIN; COLCHICINE-RESISTANT; INFLAMMASOME ACTIVATION; NLRP3 INFLAMMASOME; EXPANDING FAMILY C1 [Chae, Jae Jin; Kastner, Daniel L.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Chae, JJ (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM chaej@exchange.nih.gov; kastnerd@mail.nih.gov NR 77 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2282-6505 BN 978-3-319-14615-7; 978-3-319-14614-0 J9 RARE DIS IMMUNE SYST PY 2015 VL 3 BP 13 EP 30 DI 10.1007/978-3-319-14615-7_2 D2 10.1007/978-3-319-14615-7 PG 18 WC Immunology; Pathology SC Immunology; Pathology GA BE5ZS UT WOS:000373700500003 ER PT J AU Rekik, I Allassonniere, S Luby, M Carpenter, TK Wardlaw, JM AF Rekik, Islem Allassonniere, Stephanie Luby, Marie Carpenter, Trevor K. Wardlaw, Joanna M. TI Phase-based metamorphosis of diffusion lesion in relation to perfusion values in acute ischemic stroke SO NEUROIMAGE-CLINICAL LA English DT Article DE Metamorphosis; Ischemic stroke; Lesion evolution; Diffusion imaging; Perfusion imaging; Magnetic resonance imaging ID MAGNETIC-RESONANCE; IMAGE-ANALYSIS; HETEROGENEITY; PREDICTION; INSIGHTS; OUTCOMES; VOLUME; MRI AB Examining the dynamics of stroke ischemia is limited by the standard use of 2D-volume or voxel-based analysis techniques. Recently developed spatiotemporal models such as the 4D metamorphosis model showed promise for capturing ischemia dynamics. We used a 4D metamorphosis model to evaluate acute ischemic stroke lesion morphology from the acute diffusion-weighted imaging (DWI) to final T2-weighted imaging (T2-w). In 20 representative patients, we metamorphosed the acute lesion to subacute lesion to final infarct. From the DWI lesion deformation maps we identified dynamic lesion areas and examined their association with perfusion values inside and around the lesion edges, blinded to reperfusion status. We then tested the model in ten independent patients from the STroke Imaging Repository (STIR). Perfusion values varied widely between and within patients, and were similar in contracting and expanding DWI areas in many patients in both datasets. In 25% of patients, the perfusion values were higher in DWI-contracting than DWI-expanding areas. A similar wide range of perfusion values and ongoing expansion and contraction of the DWI lesion were seen subacutely. There was more DWI contraction and less expansion in patients who received thrombolysis, although with widely ranging perfusion values that did not differ. 4D metamorphosis modeling shows promise as a method to improve use of multimodal imaging to understand the evolution of acute ischemic tissue towards its fate. (C) 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). C1 [Rekik, Islem; Carpenter, Trevor K.; Wardlaw, Joanna M.] Univ Edinburgh, Brain Res Imaging Ctr, Div Neuroimaging Sci, Edinburgh EH8 9YL, Midlothian, Scotland. [Rekik, Islem; Carpenter, Trevor K.; Wardlaw, Joanna M.] SINAPSE Collaborat, Brain Res Imaging Ctr, London, England. [Rekik, Islem; Allassonniere, Stephanie] Ecole Polytech, CMAP, F-91128 Palaiseau, France. [Luby, Marie] NINDS, NIH, Bethesda, MD 20892 USA. [Luby, Marie] UT Southwestern Med Ctr, Dept Neurol & Neurotherapeut, Seton UT Southwestern Clin Res Inst Austin, Austin, TX USA. RP Rekik, I (reprint author), Univ Edinburgh, Brain Res Imaging Ctr, Div Neuroimaging Sci, Edinburgh EH8 9YL, Midlothian, Scotland. EM islem.rekik@gmail.com; stephanie.allassonniere@polytechnique.edu; LubyM@ninds.nih.gov; trevor.carpenter@ed.ac.uk; joanna.wardlaw@ed.ac.uk FU Scottish Funding Council through the Scottish Imaging Network; Platform for Scientific Excellence (SINAPSE) Collaboration; Centre for Clinical Brain Sciences; Tony Watson Bequest and a Scottish Overseas Research Award from the University of Edinburgh; Scottish Funding Council SINAPSE Collaboration; Cohen Charitable Trust; Chief Scientist Office of the Scottish Government; Seton/UT Southwestern Clinical Research Institute of Austin; Department of Neurology and Neurotherapeutics; UT Southwestern Medical Center, Austin, TX, USA; National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health (NIH), Bethesda, MD, USA FX This study was funded by the Scottish Funding Council through the Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration (http://www.sinapse.ac.uk/), the Centre for Clinical Brain Sciences, the Tony Watson Bequest and a Scottish Overseas Research Award from the University of Edinburgh (PhD for Islem Rekik), the Scottish Funding Council SINAPSE Collaboration (to Prof. Joanna Wardlaw), the Cohen Charitable Trust (to Dr. Trevor Carpenter and Dr Islem Rekik), and the Chief Scientist Office of the Scottish Government.; This work was also supported by the Seton/UT Southwestern Clinical Research Institute of Austin, the Department of Neurology and Neurotherapeutics, the UT Southwestern Medical Center, Austin, TX, USA, the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institutes of Health (NIH), Bethesda, MD, USA. NR 16 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1582 J9 NEUROIMAGE-CLIN JI NeuroImage-Clin. PY 2015 VL 9 BP 44 EP 49 DI 10.1016/j.nicl.2015.07.007 PG 6 WC Neuroimaging SC Neurosciences & Neurology GA DI0LR UT WOS:000373188400006 PM 26288755 ER PT J AU Maestu, F Pena, JM Garces, P Gonzalez, S Bajo, R Bagic, A Cuesta, P Funke, M Makela, JP Menasalvas, E Nakamura, A Parkkonen, L Lopez, ME del Pozo, F Sudre, G Zamrini, E Pekkonen, E Henson, RN Becker, JT AF Maestu, Fernando Pena, Jose-Maria Garces, Pilar Gonzalez, Santiago Bajo, Ricardo Bagic, Anto Cuesta, Pablo Funke, Michael Makela, Jyrki P. Menasalvas, Ernestina Nakamura, Akinori Parkkonen, Lauri Lopez, Maria E. del Pozo, Francisco Sudre, Gustavo Zamrini, Edward Pekkonen, Eero Henson, Richard N. Becker, James T. CA Magnetoencephalography Int TI A multicenter study of the early detection of synaptic dysfunction in Mild Cognitive Impairment using Magnetoencephalography-derived functional connectivity SO NEUROIMAGE-CLINICAL LA English DT Article DE Magnetoencephalography; Mild Cognitive Impairment; Functional connectivity; Data mining; Machine learning; Synaptic dysfunction; Multicenter study ID SIGNAL SPACE SEPARATION; RESTING-STATE FMRI; ALZHEIMERS-DISEASE; NEURODEGENERATION; CLASSIFICATION; VALIDATION; NETWORK AB Synaptic disruption is an early pathological sign of the neurodegeneration of Dementia of the Alzheimer's type (DAT). The changes in network synchronization are evident in patients with Mild Cognitive Impairment (MCI) at the group level, but there are very few Magnetoencephalography (MEG) studies regarding discrimination at the individual level. In an international multicenter study, we used MEG and functional connectivity metrics to discriminate MCI from normal aging at the individual person level. A labeled sample of features (links) that distinguished MCI patients from controls in a training dataset was used to classify MCI subjects in two testing datasets from four other MEG centers. We identified a pattern of neuronal hypersynchronization in MCI, in which the features that best discriminated MCI were fronto-parietal and interhemispheric links. The hypersynchronization pattern found in the MCI patients was stable across the five different centers, and may be considered an early sign of synaptic disruption and a possible preclinical biomarker for MCI/DAT. (C) 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/). C1 [Maestu, Fernando; Pena, Jose-Maria; Garces, Pilar; Gonzalez, Santiago; Bajo, Ricardo; Cuesta, Pablo; Menasalvas, Ernestina; Lopez, Maria E.; del Pozo, Francisco] Univ Complutense Madrid, Ctr Biomed Technol, Lab Cognit & Computat Neurosci, Madrid, Spain. [Maestu, Fernando; Pena, Jose-Maria; Garces, Pilar; Gonzalez, Santiago; Bajo, Ricardo; Cuesta, Pablo; Menasalvas, Ernestina; Lopez, Maria E.; del Pozo, Francisco] Tech Univ Madrid, Madrid, Spain. [Bagic, Anto; Becker, James T.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Funke, Michael] Univ Texas Hlth Sci Ctr Houston, Dept Pediat, Houston, TX 77030 USA. [Makela, Jyrki P.] Univ Helsinki, Cent Hosp, HUS Med Imaging Ctr, BioMag Lab, Helsinki, Finland. [Nakamura, Akinori] Natl Ctr Geriatr & Gerontol, Dept Clin & Expt Neuroimaging, Obu, Japan. [Parkkonen, Lauri] Aalto Univ, Sch Sci, Dept Biomed Engn & Computat Sci, Espoo, Finland. [Parkkonen, Lauri] Elekta Oy, Helsinki, Finland. [Sudre, Gustavo] NIH, Human Genome Res Inst, Bethesda, MD 20892 USA. [Zamrini, Edward] Univ Utah, Dept Neurol, Salt Lake City, UT USA. [Pekkonen, Eero] Univ Helsinki, Dept Neurol, FIN-00014 Helsinki, Finland. [Henson, Richard N.] Med Res Council Cognit & Brain Sci Unit, Cambridge, England. [Becker, James T.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Becker, James T.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. RP Maestu, F (reprint author), Ctr Biomed Technol, Lab Cognit & Computat Neurosci, Campus Montegancedo, Madrid 28223, Spain. RI Maestu, Fernando/E-3213-2012; Lopez, Maria Eugenia/E-9311-2016; Parkkonen, Lauri/G-6755-2012; OI Maestu, Fernando/0000-0002-3195-0071; Lopez, Maria Eugenia/0000-0002-3928-2629; Parkkonen, Lauri/0000-0002-0130-0801; Cuesta Prieto, Pablo/0000-0002-8459-3354; Henson, Richard/0000-0002-0712-2639 FU National Institutes of Health [P01AG05133, R21MH098745]; Spanish Ministry of Innovation and Science [PSI2009-14415-C03-01, PSI2012-38375-C03-01]; SalWe Research Program for Mind and Body [1104/10]; UK Medical Research Council [MC_A060_5PR10]; JSPS KAKENHI [24590908] FX This research was supported in part by funds from the National Institutes of Health (P01AG05133, R21MH098745), the Spanish Ministry of Innovation and Science (PSI2009-14415-C03-01 and PSI2012-38375-C03-01), SalWe Research Program for Mind and Body (grant number: 1104/10), the UK Medical Research Council (MC_A060_5PR10), and JSPS KAKENHI grant number 24590908. Thanks to Lisa Brindley and Elisa Cooper for helping to collect the Cambridge MEG data, and Peter Nestor for referring the Cambridge patients. We are also grateful to Melissa Fabrizio and Wiltrud Fassbinder for collecting the Pittsburgh MEG data. NR 36 TC 4 Z9 4 U1 3 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1582 J9 NEUROIMAGE-CLIN JI NeuroImage-Clin. PY 2015 VL 9 BP 103 EP 109 DI 10.1016/j.nicl.2015.07.011 PG 7 WC Neuroimaging SC Neurosciences & Neurology GA DI0LR UT WOS:000373188400013 PM 26448910 ER PT J AU Hwang, S White, SF Nolan, ZT Williams, WC Sinclair, S Blair, RJR AF Hwang, Soonjo White, Stuart F. Nolan, Zachary T. Williams, W. Craig Sinclair, Stephen Blair, R. J. R. TI Executive attention control and emotional responding in attention-deficit/hyperactivity disorder - A functional MRI study SO NEUROIMAGE-CLINICAL LA English DT Article DE Attention-deficit/hyperactivity disorder; Affective Stroop; Executive attention; Emotion regulation; fMRI ID DEFICIT HYPERACTIVITY DISORDER; PEDIATRIC BIPOLAR DISORDER; PSYCHIATRIC-DISORDERS; STIMULANT-MEDICATION; COGNITIVE CONTROL; WORKING-MEMORY; ADHD; CHILDREN; FMRI; AMYGDALA AB Background: There are suggestions that patients with attention-deficit/hyperactivity disorder (ADHD) show impairment in executive attention control and emotion regulation. This study investigated emotion regulation as a function of the recruitment of executive attention in patients with ADHD. Methods: Thirty-five healthy children/adolescents (mean age = 13.91) and twenty-six children/adolescents with ADHD (mean age = 14.53) participated in this fMRI study. They completed the affective Stroop paradigm viewing positive, neutral and negative images under varying cognitive loads. A 3-way ANOVA (diagnosis-by-condition-by-emotion) was conducted on the BOLD response data. Following this, 2 3-way ANOVAs (diagnosis-by-condition-by-emotion) were applied to context-dependent psychophysiological interaction (gPPI) analyses generated from a dorsomedial frontal cortex and an amygdala seed (identified from the BOLD response ANOVA main effects of condition and emotion respectively). Results: A diagnosis-by-condition interaction within dorsomedial frontal cortex revealed reduced recruitment of dorsomedial frontal cortex as a function of increased task demands in the children/adolescents with ADHD relative to healthy children/adolescents. The level of reduction in recruitment of dorsomedial frontal cortex was significantly correlated with symptom severity (total and hyperactivity) measured by Conner's Parent Report Scale in the children/adolescents with ADHD. In addition, analysis of gPPI data from a dorsomedial frontal cortex seed revealed significant diagnosis-by-condition interactions within lateral frontal cortex; connectivity between dorsomedial frontal cortex and lateral frontal cortex was reduced in the patients with ADHD relative to comparison youth during congruent and incongruent task trials relative to view trials. There were no interactions of group, or main effect of group, within the amygdala in the BOLD response ANOVA (though children/adolescents with ADHD showed increased responses to positive images within temporal cortical regions during task trials; identified by the diagnosis-by-condition-by-emotion interaction). However, analysis of gPPI data from an amygdala seed revealed decreased connectivity between amygdala and lentiform nucleus in the presence of emotional stimuli in children/adolescents with ADHD (diagnosis-by-emotion interaction). Conclusion: The current study demonstrated disrupted recruitment of regions implicated in executive function and impaired connectivity within those regions in children/adolescents with ADHD. There were also indications of heightened representation of emotional stimuli in patients with ADHD. However, as the findings were specific for positive stimuli, the suggestion of a general failure in emotion regulation in ADHD was not supported. Published by Elsevier Inc. C1 [Hwang, Soonjo; White, Stuart F.; Sinclair, Stephen; Blair, R. J. R.] NIMH, Sect Affect Cognit Neurosci, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Nolan, Zachary T.] Penn State Univ, Coll Med, Hershey, PA USA. [Williams, W. Craig] Stanford Univ, Dept Psychol, Stanford, CA USA. RP Hwang, S (reprint author), 9000 Rockville Pike,Bldg 15 K,Room 204, Bethesda, MD 20892 USA. EM soonjo.hwang@nih.gov FU National Institute of Mental Health, National Institutes of Health [1-ZIA-MH002860-08] FX This work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health under grant number 1-ZIA-MH002860-08 to Dr. Blair. Ethics approval for this study was granted by the NIH Combined Neuroscience Institutional Review Board under protocol number 05-M-0105. NR 64 TC 0 Z9 0 U1 6 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1582 J9 NEUROIMAGE-CLIN JI NeuroImage-Clin. PY 2015 VL 9 BP 545 EP 554 DI 10.1016/j.nicl.2015.10.005 PG 10 WC Neuroimaging SC Neurosciences & Neurology GA DI0LR UT WOS:000373188400058 PM 26640766 ER PT J AU White, SF Costanzo, ME Blair, JR Roy, MJ AF White, Stuart F. Costanzo, Michelle E. Blair, James R. Roy, Michael J. TI PTSD symptom severity is associated with increased recruitment of top-down attentional control in a trauma-exposed sample SO NEUROIMAGE-CLINICAL LA English DT Article DE Post-traumatic stress disorder; Emotion attention; Amygdala; Top down attention ID POSTTRAUMATIC-STRESS-DISORDER; GENERALIZED ANXIETY DISORDER; COGNITIVE CONTROL; VISUAL-ATTENTION; EMOTION; AMYGDALA; FACES; INDIVIDUALS; MODULATION; MECHANISMS AB Background: Recent neuroimaging work suggests that increased amygdala responses to emotional stimuli and dysfunction within regions mediating top down attentional control (dorsomedial frontal, lateral frontal and parietal cortices) may be associated with the emergence of anxiety disorders, including posttraumatic stress disorder (PTSD). This report examines amygdala responsiveness to emotional stimuli and the recruitment of top down attention systems as a function of task demands in a population of U.S. military service members who had recently returned from combat deployment in Afghanistan/Iraq. Given current interest in dimensional aspects of pathophysiology, it is worthwhile examining patients who, while not meeting full PTSD criteria, show clinically significant functional impairment. Methods: Fifty-seven participants with sub-threshold levels of PTSD symptoms completed the affective Stroop task while undergoing fMRI. Participants with PTSD or depression at baseline were excluded. Results: Greater PTSD symptom severity scores were associated with increased amygdala activation to emotional, particularly positive, stimuli relative to neutral stimuli. Furthermore, greater PTSD symptom severity was associated with increased superior/middle frontal cortex response during task conditions relative to passive viewing conditions. In addition, greater PTSD symptom severity scores were associated with: (i) increased activation in the dorsolateral prefrontal, lateral frontal, inferior parietal cortices and dorsomedial frontal cortex/dorsal anterior cingulate cortex (dmFC/dACC) in response to emotional relative to neutral stimuli; and (ii) increased functional connectivity during emotional trials, particularly positive trials, relative to neutral trials between the right amygdala and dmFC/dACC, left caudate/anterior insula cortex, right lentiform nucleus/caudate, bilateral inferior parietal cortex and left middle temporal cortex. Conclusions: We suggest that these data may reflect two phenomena associated with increased PTSD symptomatology in combat-exposed, but PTSD negative, armed services members. First, these data indicate increased emotional responsiveness by: (i) the positive relationship between PTSD symptom severity and amygdala responsiveness to emotional relative to neutral stimuli; (ii) greater BOLD response as a function of PTSD symptom severity in regions implicated in emotion (striatum) and representation (occipital and temporal cortices) during emotional relative to neutral conditions; and (iii) increased connectivity between the amygdala and regions implicated in emotion (insula/caudate) and representation (middle temporal cortex) as a function of PTSD symptom severity during emotional relative to neutral trials. Second, these data indicate a greater need for the recruitment of regions implicated in top down attention as indicated by (i) greater BOLD response in superior/middle frontal gyrus as a function of PTSD symptom severity in task relative to view conditions; (ii) greater BOLD response in dmFC/dACC, lateral frontal and inferior parietal cortices as a function of PTSD symptom severity in emotional relative to neutral conditions and (iii) greater functional connectivity between the amygdala and inferior parietal cortex as a function of PTSD symptom severity during emotional relative to neutral conditions. Published by Elsevier Inc. C1 [White, Stuart F.; Blair, James R.] NIMH, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Costanzo, Michelle E.; Roy, Michael J.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Costanzo, Michelle E.; Roy, Michael J.] Walter Reed Natl Mil Ctr, Bethesda, MD 20814 USA. [Costanzo, Michelle E.] Henry M Jackson Fdn, Bethesda, MD USA. RP White, SF (reprint author), NIMH, 9000 Rockville Pike,Bldg 15k,Room 205,MSC 2670, Bethesda, MD 20892 USA. EM stuart.white@nih.gov; stuart.white@nih.gov FU National Institute of Mental Health, National Institutes of Health [1-ZIA-MH002860]; Center for Neuroscience and Regenerative Medicine [300601 8.01 60855510005] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health under grant number 1-ZIA-MH002860 to James Blair and the Center for Neuroscience and Regenerative Medicine under grant number 300601 8.01 60855510005 to Michael Roy. This work was approved under the Uniformed Services University of the Health Sciences Institutional Review Board protocol 11N-0090. NCT number: NCT01296126. NR 41 TC 9 Z9 9 U1 2 U2 14 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1582 J9 NEUROIMAGE-CLIN JI NeuroImage-Clin. PY 2015 VL 7 BP 19 EP 27 DI 10.1016/j.nicl.2014.11.012 PG 9 WC Neuroimaging SC Neurosciences & Neurology GA DI0GE UT WOS:000373172600004 PM 25610763 ER PT J AU Meoded, A Morrissette, AE Katipally, R Schanz, O Gotts, SJ Floeter, MK AF Meoded, Avner Morrissette, Arthur E. Katipally, Rohan Schanz, Olivia Gotts, Stephen J. Floeter, Mary Kay TI Cerebro-cerebellar connectivity is increased in primary lateral sclerosis SO NEUROIMAGE-CLINICAL LA English DT Article DE Motor neuron disease; Resting state functional MRI; Connectivity; Cerebellum; Primary lateral sclerosis ID STATE FUNCTIONAL CONNECTIVITY; DIFFUSION-TENSOR MRI; STRUCTURAL CONNECTIVITY; ALZHEIMERS-DISEASE; HUMAN BRAIN; FRONTOTEMPORAL DEMENTIA; DIAGNOSTIC-CRITERIA; MOTOR NETWORK; TRACT DAMAGE; ALS AB Increased functional connectivity in resting state networks was found in several studies of patients with motor neuron disorders, although diffusion tensor imaging studies consistently show loss of white matter integrity. To understand the relationship between structural connectivity and functional connectivity, we examined the structural connections between regions with altered functional connectivity in patients with primary lateral sclerosis (PLS), a long-lived motor neuron disease. Conneclivily matrices were constructed from resting stale fMRI in 16 PLS patients lo identify areas of differing connectivity between patients and healthy controls. Probabilistic fiber tracking was used lo examine structural connections between regions of differing connecLivily.PLS patients had 12 regions with increased functional connectivity compared Lo controls, with a predominance of cerebrocerebellar connections. Increased functional connectivily was strongest between the cerebellum and cortical motor areas and between the cerebellum and frontal and temporal cortex. Fiber Lracking defected no difference in connections between regions with increased functional connectivity. We conclude that functional connectivity changes are not strongly based in structural connectivity. Increased functional connectivity may be caused by common inputs, or by reduced selectivity of cortical activation, which could result from loss of intracortical inhibition when cortical afferents are intact. Published by Elsevier Inc. C1 [Meoded, Avner; Morrissette, Arthur E.; Katipally, Rohan; Schanz, Olivia; Floeter, Mary Kay] NINDS, NIH, Bethesda, MD 20892 USA. [Gotts, Stephen J.] NIMH, NIH, Bethesda, MD 20892 USA. RP Floeter, MK (reprint author), Room 7-5680,10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. EM floeterm@ninds.nih.gov OI Gotts, Stephen/0000-0002-7903-1832 FU National Institutes of Health, NINDS [Z01 NS002976]; National Institutes of Health, NIMH [Z01 MH002920] FX The research was supported by the intramural programs of the National Institutes of Health, NINDS (Z01 NS002976) and NIMH (Z01 MH002920). The assistance of Laura Danielian with image acquisition and processing is gratefully acknowledged. NR 63 TC 4 Z9 5 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1582 J9 NEUROIMAGE-CLIN JI NeuroImage-Clin. PY 2015 VL 7 BP 288 EP 296 DI 10.1016/j.nicl.2014.12.009 PG 9 WC Neuroimaging SC Neurosciences & Neurology GA DI0GE UT WOS:000373172600033 PM 25610792 ER PT J AU Plitt, M Barnes, KA Martin, A AF Plitt, Mark Barnes, Kelly Anne Martin, Alex TI Functional connectivity classification of autism identifies highly predictive brain features but falls short of biomarker standards SO NEUROIMAGE-CLINICAL LA English DT Article DE Autism; Bioimarkers; Machine learning classification; Social brain ID SPECTRUM DISORDERS; CHILDREN; FMRI AB Objectives: Autism spectrum disorders (ASD) are diagnosed based on early-manifesting clinical symptoms, including markedly impaired social communication. We assessed the viability of resting-state functional MR1 (rs-IMRI) connectivity measures as diagnostic biomarkers for ASD and investigated which connectivity features are predictive of a diagnosis. Methods: Rs-fMRI scans from 59 high functioning males with ASD and 59 age- and IQ-matched typically developing (TD) males were used to build a series of machine learning classifiers. Classification features were obtained using 3 sets of brain regions. Another set of classifiers was built from participants' scores on behavioral metrics. An additional age and IQ-matched cohort of 178 individuals (89 ASD; 89 TD) from the Autism Brain Imaging Data Exchange (ABIDE) open-access dataset (http://fcon_1000.projects.nitrcorg/incli/abidc/) were included for replication. Results: High classification accuracy was achieved through several rs-IMRI methods (peak accuracy 76.67%). However, classification via behavioral measures consistently surpassed rs-fMRI classifiers (peak accuracy 95.19%). The class probability estimates, P(ASDIfMRI data), from brain-based classifiers significantly correlated with scores on a measure of social functioning, the Social Responsiveness Scale (SRS), as did the most informative features from 2 of the 3 sets of brain-based features. The most informative connections predominantly originated from regions strongly associated with social functioning. Conclusions: While individuals can be classified as having ASD with statistically significant accuracy from their rs-fMRI scans alone, this method falls short of biomarker standards. Classification methods provided further evidence that ASD functional connectivity is characterized by dysfunction of large-scale functional networks, particularly those involved in social information processing. Published by Elsevier Inc. C1 [Plitt, Mark; Barnes, Kelly Anne; Martin, Alex] NIMH, Sect Cognit Neuropsychol, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Plitt, M (reprint author), 10 Ctr Dr,MSC 1366,Bldg 10,4C214, Bethesda, MD 20892 USA. EM mark.plitt@nih.gov FU NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation; Intramural Research Program at NIMH FX Thanks go to Steve Gotts, PhD for helpful discussion regarding methods and statistics. The authors declare no competing interests. This work was supported by a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (KAB) and by the Intramural Research Program at NIMH (AM). Ethics approval for this study was granted by the NIH Combined Neuroscience Institutional Review Board under protocol number 10-M-0027. The clinical trial number (clinicaltrials.gov) for this protocol is NCT01031407. NR 40 TC 11 Z9 11 U1 3 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1582 J9 NEUROIMAGE-CLIN JI NeuroImage-Clin. PY 2015 VL 7 BP 359 EP 366 DI 10.1016/j.nicl.2014.12.013 PG 8 WC Neuroimaging SC Neurosciences & Neurology GA DI0GE UT WOS:000373172600040 PM 25685703 ER PT J AU Li, XZ van Gelderen, P Sati, P de Zwart, JA Reich, DS Duyn, JH AF Li, Xiaozhen van Gelderen, Peter Sati, Pascal de Zwart, Jacco A. Reich, Daniel S. Duyn, Jeff H. TI Detection of demyelination in multiple sclerosis by analysis of T-2* relaxation at 7 T SO NEUROIMAGE-CLINICAL LA English DT Article DE T-2* relaxation; Water compartment; Multiple sclerosis; Demyelination ID MYELIN WATER FRACTION; HIGH-FIELD MRI; WHITE-MATTER; MAGNETIZATION-TRANSFER; BRAIN; FREQUENCY; RESONANCE; MICROSTRUCTURE; HISTOPATHOLOGY; ORIENTATION AB Multiple sclerosis (MS) is a relatively common cause of inflammatory demyelinating lesions of the central nervous system. In an attempt to detect and characterize ongoing demyelination in MS patient brains, we used a novel magnetic resonance imaging (MRI) technique, involving the fitting of a three-component model to the T-2* relaxation behavior at high-field (7 T). This model allowed estimation of the amount of myelin water (and thus indirectly myelin content), axonal water, and interstitial water. In this study, 25 relapsing-remitting MS patients underwent a 7 T MRI from which 12 gadolinium-enhancing lesions, 61 non-enhancing lesions, and their corresponding contralateral normal appearing white matter (NAWM) regions were analyzed. In both enhancing and non-enhancing lesions, the amplitude of myelin water was significantly decreased, and interstitial and axonal water were increased relative to the contralateral NAWM. Longer relaxation time T-2* of interstitial and axonal water, and lower frequency shift of axonal water, were also observed in both enhancing and non-enhancing lesions when compared to the contralateral NAWM. No significant difference was found between enhancing lesions and non-enhancing lesions. These findings suggest that the fitting of a three-component model to the T-2* decay curve in MS lesions may help to quantify myelin loss. Published by Elsevier Inc. C1 [Li, Xiaozhen; van Gelderen, Peter; de Zwart, Jacco A.; Duyn, Jeff H.] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Li, Xiaozhen] Karolinska Inst, Ctr Alzheimer Dis Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, SE-14157 Stockholm, Sweden. [Sati, Pascal; Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Div Neuroimmunol & Neurovirol, NIH, Bethesda, MD 20892 USA. RP Li, XZ (reprint author), Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Novum 5th Floor,Blickagangen 6, S-14157 Huddinge, Sweden. EM xiaozhen.li@nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU NINDS FX We thank the National Institute of Neurological Disorders and Stroke (NINDS) Neuroimmunology Clinic for coordinating the recruitment of human subjects. We acknowledge the NINDS Intramural Research Program for support, as well as the National Institutes of Health - Karolinska Institutet Graduate Programme for International PhDs. NR 26 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1582 J9 NEUROIMAGE-CLIN JI NeuroImage-Clin. PY 2015 VL 7 BP 709 EP 714 DI 10.1016/j.nicl.2015.02.021 PG 6 WC Neuroimaging SC Neurosciences & Neurology GA DI0GE UT WOS:000373172600076 PM 26594617 ER PT J AU Shinohara, RT Sweeney, EM Goldsmith, J Shiee, N Mateen, FJ Calabresi, PA Jarso, S Pham, DL Reich, DS Crainiceanu, CM AF Shinohara, Russell T. Sweeney, Elizabeth M. Goldsmith, Jeff Shiee, Navid Mateen, Farrah J. Calabresi, Peter A. Jarso, Samson Pham, Dzung L. Reich, Daniel S. Crainiceanu, Ciprian M. CA Australian Imaging Biomarkers Alzheimer's Dis Neuroimaging TI Statistical normalization techniques for magnetic resonance imaging (vol 6, pg 9, 2014) SO NEUROIMAGE-CLINICAL LA English DT Correction C1 [Shinohara, Russell T.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Sweeney, Elizabeth M.; Reich, Daniel S.] NINDS, Translat Neurol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Sweeney, Elizabeth M.; Reich, Daniel S.; Crainiceanu, Ciprian M.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Goldsmith, Jeff] Columbia Univ, Dept Biostat, New York, NY 10032 USA. [Shiee, Navid; Pham, Dzung L.] Henry M Jackson Fdn, Ctr Neurosci & Regenerat Med, Bethesda, MD 20892 USA. [Mateen, Farrah J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Mateen, Farrah J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Calabresi, Peter A.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. [Jarso, Samson; Reich, Daniel S.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21287 USA. RP Shinohara, RT (reprint author), Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, 210 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM rshi@upenn.edu RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 1 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1582 J9 NEUROIMAGE-CLIN JI NeuroImage-Clin. PY 2015 VL 7 BP 848 EP 848 DI 10.1016/j.nicl.2015.02.011 PG 1 WC Neuroimaging SC Neurosciences & Neurology GA DI0GE UT WOS:000373172600093 PM 26082894 ER PT J AU Wang, JC Cao, HB Liao, YH Liu, WQ Tan, LW Tang, YQ Chen, JD Xu, XF Li, HJ Luo, CR Liu, CY Merikangas, KR Calhoun, V Tang, JS Shugart, YY Chen, XG AF Wang, Jicai Cao, Hongbao Liao, Yanhui Liu, Weiqing Tan, Liwen Tang, Yanqing Chen, Jindong Xu, Xiufeng Li, Haijun Luo, Chunrong Liu, Chunyu Merikangas, Kathleen Ries Calhoun, Vince Tang, Jinsong Shugart, Yin Yao Chen, Xiaogang TI Three dysconnectivity patterns in treatment-resistant schizophrenia patients and their unaffected siblings SO NEUROIMAGE-CLINICAL LA English DT Article DE Schizophrenia; TRS; Brain plasticity; Functional connectivity; Sibling controls ID FUNCTIONAL NETWORK CONNECTIVITY; RESTING-STATE FMRI; 1ST-DEGREE RELATIVES; PREFRONTAL CORTEX; NONPSYCHOTIC SIBLINGS; COGNITIVE DEFICITS; TIME-SERIES; BRAIN; ABNORMALITIES; HEALTHY AB Among individuals diagnosed with schizophrenia, approximately 20%-33% are recognized as treatment-resistant schizophrenia (TRS) patients. These TRS patients suffer more severely from the disease but struggle to benefit from existing antipsychotic treatments. A few recent studies suggested that schizophreniamay be caused by impaired synaptic plasticity that manifests as functional dysconnectivity in the brain, however, few of those studies focused on the functional connectivity changes in the brains of TRS groups. In this study, we compared the whole brain connectivity variations in TRS patients, their unaffected siblings, and healthy controls. Connectivity network features between and within the 116 automated anatomical labeling (AAL) brain regions were calculated and compared using maps created with three contrasts: patient vs. control, patient vs. sibling, and sibling vs. control. To evaluate the predictive power of the selected features, we performed a multivariate classification approach. We also evaluated the influence of six important clinical measures (e.g. age, education level) on the connectivity features. This study identified abnormal significant connectivity changes of three patterns in TRS patients and their unaffected siblings: 1) 69 patient-specific connectivity (PCN); 2) 102 shared connectivity (SCN); and 3) 457 unshared connectivity (UCN). While the first two patterns were widely reported by previous non-TRS specific studies, we were among the first to report widespread significant connectivity differences between TRS patient groups and their healthy sibling groups. Observations of this study may provide new insights for the understanding of the neurophysiological mechanisms of TRS. (C) 2015 The Authors. Published by Elsevier Inc. C1 [Wang, Jicai; Liao, Yanhui; Liu, Weiqing; Tan, Liwen; Chen, Jindong; Tang, Jinsong; Chen, Xiaogang] Cent S Univ, Xiangya Hosp 2, Inst Mental Hlth, Changsha 410011, Hunan, Peoples R China. [Cao, Hongbao; Tang, Jinsong; Shugart, Yin Yao] NIMH, Unit Stat Genom, NIH, Bethesda, MD 20892 USA. [Wang, Jicai; Liu, Weiqing; Xu, Xiufeng] Kunming Med Univ, Affiliated Hosp 1, Dept Psychiat, Kunming 650032, Yunnan, Peoples R China. [Tang, Yanqing] China Med Univ, Affiliated Hosp 1, Dept Psychiat, Shenyang 110001, Liaoning, Peoples R China. [Liu, Chunyu; Chen, Xiaogang] Cent S Univ, State Key Lab Med Genet, Changsha 410078, Hunan, Peoples R China. [Merikangas, Kathleen Ries] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Calhoun, Vince] Mind Res Network, Albuquerque, NM 87131 USA. [Calhoun, Vince] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87106 USA. [Chen, Xiaogang] Cent S Univ, Natl Technol Inst Psychiat, Changsha 410011, Hunan, Peoples R China. [Li, Haijun; Luo, Chunrong] First Peoples Hosp Kunming, Dept Radiol, Kunming 650011, Yunnan, Peoples R China. RP Tang, JS (reprint author), Cent S Univ, Xiangya Hosp 2, Inst Mental Hlth, Changsha 410011, Hunan, Peoples R China. EM tangjinsonghn@gmail.com; kay1yao@mail.nih.gov; chenxghn@gmail.com RI Liao, Yanhui/L-1590-2016 OI Liao, Yanhui/0000-0003-4735-3252 FU Natural Science Foundation of China [30900486, 81371480, 81100996, 81471361, 81271484, 81071099, 81271499]; National Key Basic Research and Development Program (973) [2012CB517904]; Sheng-Hua Yuying project of Central South University; Sheng-Hua Lieying project of Central South University; program of China Scholarships Council; Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP, NIMH, NIH) [MH002930-03]; [NIBIB2R01EB000840]; [COBRE5P20RR021938/P20GM103472] FX This work was supported by the Natural Science Foundation of China (grant nos. 30900486 and 81371480 to JT, 81100996 to YL, 81471361 and 81271484 to XC, 81071099, and 81271499 to YT) and the National Key Basic Research and Development Program (973) (grant no. 2012CB517904 to XC). JT was supported by the Sheng-Hua Yuying project of Central South University; YL was supported by the Sheng-Hua Lieying project of Central South University; Financial support from the program of China Scholarships Council to JT; Drs. Cao and Shugart gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP, NIMH, NIH) (project number MH002930-03). This work was also in part supported by grants NIBIB2R01EB000840 and COBRE5P20RR021938/P20GM103472 (to Dr. Calhoun). The authors have no conflicts of interest to disclose, financial or otherwise. NR 54 TC 1 Z9 2 U1 7 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1582 J9 NEUROIMAGE-CLIN JI NeuroImage-Clin. PY 2015 VL 8 BP 95 EP 103 DI 10.1016/j.nicl.2015.03.017 PG 9 WC Neuroimaging SC Neurosciences & Neurology GA DI0LE UT WOS:000373187100009 PM 26106532 ER PT J AU Hanley, AP Blumenthal, JD Lee, NR Baker, EH Clasen, LS Giedd, JN AF Hanley, Alli P. Blumenthal, Jonathan D. Lee, Nancy Raitano Baker, Eva H. Clasen, Liv S. Giedd, Jay N. TI Brain and behavior in 48, XXYY syndrome SO NEUROIMAGE-CLINICAL LA English DT Article DE Sex chromosomes aneuploidy; 48,XXYY; Brain anatomy; White matter lesions ID KLINEFELTERS-SYNDROME; SEX-CHROMOSOMES; X-CHROMOSOME; MRI DATA; HYPERINTENSITIES; NEUROANATOMY; ORIGIN AB The phenotype of 48, XXYY syndrome (referred to as XXYY) is associated with characteristic but variable developmental, cognitive, behavioral and physical abnormalities. To discern the neuroanatomical phenotype of the syndrome, we conducted quantitative and qualitative analyses on MRI brain scans from 25 males with XXYY and 92 age and SES matched typically developing XY males. Quantitatively, males in the XXYY group had smaller gray and white matter volumes of the frontal and temporal lobes. Conversely, both gray and white matter volumes of the parietal lobe as well as lateral ventricular volume were larger in the XXYY group. Qualitatively, males in the XXYY group had a higher incidence of colpocephaly (84% vs. 34%, p <= 0.001), white matter lesions (25% vs. 5%, p = 0.007), and thin posterior body of the corpus callosum (28% vs. 3%, p = 0.001). The specificity of these findings may shed light on the role of the X and Y chromosomes in typical and atypical brain development and help provide direction for future studies of brain-behavior relationships in males with XXYY syndrome. Published by Elsevier Inc. C1 [Hanley, Alli P.; Blumenthal, Jonathan D.; Clasen, Liv S.] NIMH, Child Psychiat Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Lee, Nancy Raitano] Drexel Univ, Dept Psychol, Philadelphia, PA 19104 USA. [Baker, Eva H.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, DHHS, Bethesda, MD USA. [Giedd, Jay N.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. RP Blumenthal, JD (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Room 4C110,10 Ctr Dr, Bethesda, MD 20892 USA. EM jb364e@nih.gov RI Giedd, Jay/J-9644-2015; Lee, Nancy/M-7492-2016 OI Giedd, Jay/0000-0003-2002-8978; Lee, Nancy/0000-0002-6663-0713 FU Intramural Research Program of the NIMH FX The Intramural Research Program of the NIMH supported this research. The authors were solely responsible for the study design; collection, analysis and interpretation of data; the writing of the report; and the decision to submit for publication. We thank the families who participated in this research, and the Association of X and Y Chromosome Variations for their assistance with recruitment of participants. NR 43 TC 1 Z9 2 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1582 J9 NEUROIMAGE-CLIN JI NeuroImage-Clin. PY 2015 VL 8 BP 133 EP 139 DI 10.1016/j.nicl.2015.04.009 PG 7 WC Neuroimaging SC Neurosciences & Neurology GA DI0LE UT WOS:000373187100014 PM 26106537 ER PT J AU Chu, RKO Braun, AR Meltzer, JA AF Chu, Ron K. O. Braun, Allen R. Meltzer, Jed A. TI MEG-based detection and localization of perilesional dysfunction in chronic stroke SO NEUROIMAGE-CLINICAL LA English DT Article DE Magnetoencephalography; Beamformer source reconstruction; Time-frequency analysis; Chronic stroke ID LOW-FREQUENCY RTMS; MULTISCALE ENTROPY ANALYSIS; CHRONIC NONFLUENT APHASIA; INTENSIVE SPEECH-THERAPY; POSTSTROKE APHASIA; BRAIN PLASTICITY; ISCHEMIC-STROKE; SAMPLE ENTROPY; APPROXIMATE ENTROPY; LANGUAGE RECOVERY AB Post-stroke impairment is associated not only with structural lesions, but also with dysfunction in surviving perilesional tissue. Previous studies using equivalent current dipole source localization of MEG/EEG signals have demonstrated a preponderance of slow-wave activity localized to perilesional areas. Recent studies have also demonstrated the utility of nonlinear analyses such as multiscale entropy (MSE) for quantifying neuronal dysfunction in a wide range of pathologies. The current study utilized beamformer-based reconstruction of signals in source space to compare spectral and nonlinear measures of electrical activity in perilesional and healthy cortices. Data were collected from chronic stroke patients and healthy controls, both young and elderly. We assessed relative power in the delta (1-4 Hz), theta (4-7 Hz), alpha (8-12 Hz) and beta (15-30 Hz) frequency bands, and also measured the nonlinear complexity of electrical activity using MSE. Perilesional tissue exhibited a general slowing of the power spectrum(increased delta/theta, decreased beta) as well as a reduction in MSE. All measures tested were similarly sensitive to changes in the posterior perilesional regions, but anterior perilesional dysfunction was detected better by MSE and beta power. The findings also suggest that MSE is specifically sensitive to electrophysiological dysfunction in perilesional tissue, while spectral measures were additionally affected by an increase in rolandic beta power with advanced age. Furthermore, perilesional electrophysiological abnormalities in the left hemisphere were correlated with the degree of language task-induced activation in the right hemisphere. Finally, we demonstrate that single subject spectral and nonlinear analyses can identify dysfunctional perilesional regions within individual patients that may be ideal targets for interventions with non-invasive brain stimulation. (C) 2015 The Authors. Published by Elsevier Inc. C1 [Chu, Ron K. O.; Meltzer, Jed A.] Univ Toronto, Dept Psychol, 100 St George St,4th Floor,Smith Hall, Sidney, ON M5S 3G3, Canada. [Meltzer, Jed A.] Univ Toronto, Dept Speech Language Pathol, Toronto, ON M5G 1V7, Canada. [Chu, Ron K. O.; Meltzer, Jed A.] Baycrest Ctr Geriatr Care, Rotman Res Inst, Toronto, ON M6A 2E1, Canada. [Meltzer, Jed A.] Heart & Stroke Fdn Canadian Partnership Stroke Re, Ottawa, ON K1G 5Z3, Canada. [Braun, Allen R.] Natl Inst Deafness & Other Commun Disorders, Language Sect, NIH, Bethesda, MD USA. RP Chu, RKO (reprint author), 3560 Bathurst St, Toronto, ON, Canada. EM ron.chu@utoronto.ca OI Meltzer, Jed/0000-0002-4301-1901 FU Intramural Research Program of the National Institute on Deafness and Other Communication Disorders; Heart and Stroke Foundation Canadian Partnership for Stroke Recovery; Alzheimer's Association FX We thank the participating patients and their families. Data collection was funded by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders. Later analyses were supported by grants from the Heart and Stroke Foundation Canadian Partnership for Stroke Recovery and the Alzheimer's Association. NR 73 TC 2 Z9 2 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1582 J9 NEUROIMAGE-CLIN JI NeuroImage-Clin. PY 2015 VL 8 BP 157 EP 169 DI 10.1016/j.nicl.2015.03.019 PG 13 WC Neuroimaging SC Neurosciences & Neurology GA DI0LE UT WOS:000373187100017 PM 26106540 ER PT J AU Kutch, JJ Yani, MS Asavasopon, S Kirages, DJ Rana, M Cosand, L Labus, JS Kilpatrick, LA Ashe-McNalley, C Farmer, MA Johnson, KA Ness, TJ Deutsch, G Harris, RE Apkarian, AV Clauw, DJ Mackey, SC Mullins, C Mayer, EA AF Kutch, Jason J. Yani, Moheb S. Asavasopon, Skulpan Kirages, Daniel J. Rana, Manku Cosand, Louise Labus, Jennifer S. Kilpatrick, Lisa A. Ashe-McNalley, Cody Farmer, Melissa A. Johnson, Kevin A. Ness, Timothy J. Deutsch, Georg Harris, Richard E. Apkarian, A. Vania Clauw, Daniel J. Mackey, Sean C. Mullins, Chris Mayer, Emeran A. TI Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP Research Network Neuroimaging Study SO NEUROIMAGE-CLINICAL LA English DT Article ID LOW-BACK-PAIN; ANTERIOR CINGULATE CORTEX; FUNCTIONAL CONNECTIVITY; MOTOR CORTEX; FLOOR; HEALTHY; INSULA AB Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N=28), as well as group of age-matched healthy male controls (N=27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing. (C) 2015 The Authors. Published by Elsevier Inc. C1 [Kutch, Jason J.; Yani, Moheb S.; Kirages, Daniel J.; Rana, Manku] Univ So Calif, Div Biokinesiol & Phys Therapy, Los Angeles, CA USA. [Asavasopon, Skulpan] Loma Linda Univ, Phys Therapy Dept, Loma Linda, CA 92350 USA. [Cosand, Louise] Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. [Labus, Jennifer S.; Kilpatrick, Lisa A.; Ashe-McNalley, Cody; Mayer, Emeran A.] Univ Calif Los Angeles, David Geffen Sch Med, PAIN, Oppenheimer Ctr Neurobiol Stress, Los Angeles, CA 90095 USA. [Farmer, Melissa A.; Apkarian, A. Vania] Northwestern Univ, Feinberg Sch Med, Dept Physiol, Chicago, IL 60611 USA. [Johnson, Kevin A.; Mackey, Sean C.] Stanford Univ, Med Ctr, Dept Anesthesiol Perioperat & Pain Med, Div Pain Med, Stanford, CA 94305 USA. [Ness, Timothy J.; Deutsch, Georg] Univ Alabama Birmingham, Dept Radiol, Birmingham Med Ctr, Birmingham, AL USA. [Ness, Timothy J.; Deutsch, Georg] Univ Alabama Birmingham, Dept Anesthesiol, Birmingham Med Ctr, Birmingham, AL USA. [Harris, Richard E.; Clauw, Daniel J.] Univ Michigan, Dept Anesthesiol, Chron Pain & Fatigue Res Ctr, Ann Arbor, MI 48109 USA. [Mullins, Chris] NIDDK, NIH, Bethesda, MD 20892 USA. RP Kutch, JJ (reprint author), Univ So Calif, 1540 E Alcazar St,CHP 155, Los Angeles, CA 90033 USA. EM kutch@usc.edu RI Kirages, Daniel/J-7974-2016; OI Apkarian, A. Vania/0000-0002-9788-7458 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) [DK82370, DK82342, DK82315, DK82344, DK82325, DK82345, DK82333, DK82316]; USC Division of Biokinesiology and Physical Therapy [USCBKN/PT-2013A]; Loma Linda University Physical Therapy Department [LLU-647525-2007]; National Center for Medical Rehabilitation Research of the National Institutes of Health [T32 HD064578] FX We thank all of the volunteers who participated in the study. We would like to thank Nina Bradley, Bruce Naliboff, and Kirsten Tillisch for helpful discussions. Funding for the MAPP Research Network was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (DK82370, DK82342, DK82315, DK82344, DK82325, DK82345, DK82333, and DK82316). This work was also supported, in part, by the USC Division of Biokinesiology and Physical Therapy under award number USCBKN/PT-2013A, the Loma Linda University Physical Therapy Department under award number LLU-647525-2007, and National Center for Medical Rehabilitation Research of the National Institutes of Health under award number T32 HD064578. We declare the following interests: financial interest and/or other relationship with Pfizer, Cerephex, Lilly, Merck, Nuvo, Furest, Tonix, Purdue, Therauance and Johnson & Johnson (DJC), financial interest and/or other relationship with National Institutes of Health and Medtronic (TJN), financial interest and/or other relationship with National Institutes of Health (CM). NR 50 TC 10 Z9 11 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1582 J9 NEUROIMAGE-CLIN JI NeuroImage-Clin. PY 2015 VL 8 BP 493 EP 502 DI 10.1016/j.nicl.2015.05.013 PG 10 WC Neuroimaging SC Neurosciences & Neurology GA DI0LE UT WOS:000373187100053 PM 26106574 ER PT S AU Candia, J Banavar, JR Losert, W AF Candia, Julian Banavar, Jayanth R. Losert, Wolfgang BE Wang, X TI Uncovering Phenotypes with Supercells: Applications to Single-Cell Sequencing SO SINGLE CELL SEQUENCING AND SYSTEMS IMMUNOLOGY SE Translational Bioinformatics LA English DT Article; Book Chapter DE Single-cell biology; Single-cell genomics; Cell heterogeneity; Machine learning; Supercells ID TUMOR HETEROGENEITY; STEM-CELLS; HEMATOPOIETIC STEM; HUMAN BRAIN; CANCER; RETROTRANSPOSITION; PLASTICITY; GENOMES; SEQ AB The so-called "Supercell paradigm" is a method for phenotyping based on single-cell multidimensional data, which has been recently proposed by the authors of this Chapter and collaborators within the larger context of single-cell biology. Supercells are multidimensional objects that represent the collective behavior of groups of cells and carry a distinct phenotype, which is often obscured at the single-cell level due to high cell-to-cell variability. The Supercell framework provides a quantitative assessment of the critical sample size and the number of simultaneous single-cell measurements needed to build a phenotype, which is a key piece of information given the fact that, in many single-cell applications, the number of measured cells and the number of measurements per cell are severely limited due to a variety of constraints, such as experimental costs, technological capabilities, specimen collection procedures, the availability of specialized personnel, and others. In this Chapter, we review the Supercell method and explore the potential for its application to single-cell sequencing datasets. C1 [Candia, Julian] NIH, Ctr Human Immunol, 10 7N115,9000 Rockville Pike, Bethesda, MD 20892 USA. [Banavar, Jayanth R.; Losert, Wolfgang] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. RP Candia, J (reprint author), NIH, Ctr Human Immunol, 10 7N115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM julian.candia@nih.gov OI Candia, Julian/0000-0001-5793-8989 NR 35 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 2213-2783 BN 978-94-017-9753-5; 978-94-017-9752-8 J9 TRANSL BIOINFORM PY 2015 BP 11 EP 30 DI 10.1007/978-94-017-9753-5_2 D2 10.1007/978-94-017-9753-5 PG 20 WC Mathematical & Computational Biology; Immunology SC Mathematical & Computational Biology; Immunology GA BE5PI UT WOS:000373182700003 ER PT S AU Wenger, C Salvador, R Basser, PJ Miranda, PC AF Wenger, Cornelia Salvador, Ricardo Basser, Peter J. Miranda, Pedro C. GP IEEE TI Modeling Tumor Treating Fields (TTFields) application within a realistic human head model SO 2015 37TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) CY AUG 25-29, 2015 CL Milan, ITALY ID ALTERNATING ELECTRIC-FIELDS; WHITE-MATTER; ANISOTROPIC CONDUCTIVITY; GLIOBLASTOMA; BRAIN AB Tumor Treating Fields (TTFields) are an antimitotic treatment against brain and other tumors. They are applied regionally and non-invasively by inducing intermediate frequency (100-300 kHz) alternating electric field of intensities between 1 to 3 V/cm through transducer arrays placed on the patient's skin close to the tumor. All TTFields studies predicted variability in treatment response among patients, whereas in vitro experiments indicate that the magnitude and direction of the electric field in the tumor might be crucial determinants of efficacy. Differences in the field might arise from varying tumor positions or array placement. By investigating different scenarios within a realistic human head model we hope to advance our understanding of TTFields therapy in clinical practice. We constructed a model from MRI data to calculate the electric field distribution in the brain using the Finite Element Method. An anisotropic electrical conductivity tensor was estimated using diffusion tensor imaging data. The head model contained different tissue types: scalp, skull, cerebrospinal fluid, gray and white matter. Additionally a virtual spherical tumor was included, two positions for the tumor were considered. Transducer arrays were placed on the scalp to model the commonly used device for TTFields delivery. One additional setup of the two transducer pairs was specifically adapted to the second tumor position. The results predict that the electric field strength exceeds the assumed therapeutic threshold value of 1 V/cm in both tumors for both active array pairs. For the second tumor the adapted transducer layout improved field delivery. The average field strength in the tumor further depends on tumor electrical properties. Yet a cystic and a solid tumor experience the same average field strength when treated with TTFields. As a next step towards personalized TTFields therapy, we will explore possible benefits of individualized treatment planning. C1 [Wenger, Cornelia; Salvador, Ricardo; Miranda, Pedro C.] Univ Lisbon, Fac Ciencias, Inst Biophys & Biomed Engn, P-1749016 Lisbon, Portugal. [Basser, Peter J.] NICHD, NIH, Bethesda, MD 20892 USA. RP Wenger, C (reprint author), Univ Lisbon, Fac Ciencias, Inst Biophys & Biomed Engn, P-1749016 Lisbon, Portugal. EM cwenger@fc.ul.pt; rnsalvador@fc.ul.pt; pjbasser@helix.nih.gov; pcmiranda@fc.ul.pt RI Miranda, Pedro/A-5643-2013; OI Miranda, Pedro/0000-0002-6793-8111; Wenger, Cornelia/0000-0001-7889-9093 NR 18 TC 0 Z9 0 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-9270-1 J9 IEEE ENG MED BIO PY 2015 BP 2555 EP 2558 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BE4HD UT WOS:000371717202207 ER PT S AU Wenger, C Giladi, M Bomzon, Z Salvador, R Basser, PJ Miranda, PC AF Wenger, Cornelia Giladi, Moshe Bomzon, Ze'ev Salvador, Ricardo Basser, Peter J. Miranda, Pedro C. GP IEEE TI Modeling Tumor Treating Fields (TTFields) application in single cells during metaphase and telophase SO 2015 37TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) CY AUG 25-29, 2015 CL Milan, ITALY ID ALTERNATING ELECTRIC-FIELDS; DIELECTROPHORESIS; ELECTROROTATION; DISRUPTION; MEMBRANES; MITOSIS; VOLUME AB Effects of electric fields on biological cells have been extensively studied but primarily in the low and high frequency regimes. Low frequency AC fields have been investigated for applications to nerve and muscle stimulation or to examine possible environmental effects of 60 Hz excitation. High frequency fields have been studied to understand tissue heating and tumor ablation. Biological effects at intermediate frequencies (in the 100-500 kHz regime) have only recently been discovered and are now being used clinically to disrupt cell division, primarily for the treatment of recurrent glioblastoma multiforme. In this study, we develop a computational framework to investigate the mechanisms of action of these Tumor Treating Fields (TTFields) and to understand in vitro findings observed in cell culture. Using Finite Element Method models of isolated cells we show that the intermediate frequency range is unique because it constitutes a transition region in which the intracellular electric field, shielded at low frequencies, increases significantly. We also show that the threshold at which this increase occurs depends on the dielectric properties of the cell membrane. Furthermore, our models of different stages of the cell cycle and of the morphological changes associated with cytokinesis show that peak dielectrophoretic forces develop within dividing cells exposed to TTFields. These findings are in agreement with in vitro observations, and enhance our understanding of how TTFields disrupt cellular function. C1 [Wenger, Cornelia; Salvador, Ricardo; Miranda, Pedro C.] Univ Lisbon, Fac Ciencias, Inst Biophys & Biomed Engn, P-1749016 Lisbon, Portugal. [Giladi, Moshe; Bomzon, Ze'ev] Novocure, Root, Switzerland. [Basser, Peter J.] NICHD, NIH, Bethesda, MD 20892 USA. RP Wenger, C (reprint author), Univ Lisbon, Fac Ciencias, Inst Biophys & Biomed Engn, P-1749016 Lisbon, Portugal. EM cwenger@fc.ul.pt; mosheg@novocure.com; zbomzon@novocure.com; rnsalvador@fc.ul.pt; pjbasser@helix.niv.gov; pcmiranda@fc.ul.pt RI Miranda, Pedro/A-5643-2013; OI Miranda, Pedro/0000-0002-6793-8111; Wenger, Cornelia/0000-0001-7889-9093 NR 24 TC 2 Z9 2 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-9270-1 J9 IEEE ENG MED BIO PY 2015 BP 6892 EP 6895 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BE4HD UT WOS:000371717207042 ER PT S AU Wessel, AW Hanson, EP AF Wessel, Alex W. Hanson, Eric P. BE May, MJ TI A Method for the Quantitative Analysis of Stimulation-Induced Nuclear Translocation of the p65 Subunit of NF-kappa B from Patient-Derived Dermal Fibroblasts SO NF-KAPPA B: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE NF-kappa B; p65; Nuclear translocation; Fibroblasts; IL-1R; TNFR; TLR; RLR; Microscopy ID MUTATION; MODULATOR AB Developmental and immune-mediated disease has been linked to genetic mutation of key signaling components involved in NF-kappa B activation that leads to impaired activation or regulation of the canonical IKK complex. We identify patients with suspected or known defects of the NF-kappa B signaling pathway through clinical phenotyping and genetic sequencing. To help understand how mutations cause disease, we quantitate the kinetics and dose-response of NF-kappa B activation signaling events in their cells. Following activation of the canonical IKK complex, phosphorylation of the inhibitor of NF-kappa B proteins (I kappa B) leads to their degradation and the subsequent translocation of NF-kappa B family members from the cell cytoplasm to the nucleus. Here, we provide a method to obtain patient-derived dermal fibroblasts and quantitatively assess the integrity of the signal transduction pathway from receptor activation to nuclear p65 translocation. C1 [Wessel, Alex W.; Hanson, Eric P.] NIH, Immunodeficiency & Inflammat Unit, Arthrit & Rheumatism Branch, Bldg 10, Bethesda, MD 20892 USA. RP Wessel, AW (reprint author), NIH, Immunodeficiency & Inflammat Unit, Arthrit & Rheumatism Branch, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2422-6; 978-1-4939-2421-9 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2015 VL 1280 BP 413 EP 426 DI 10.1007/978-1-4939-2422-6_25 D2 10.1007/978-1-4939-2422-6 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BE5GD UT WOS:000372806300026 PM 25736764 ER PT J AU Hristovski, D Kastrin, A Rindflesch, TC AF Hristovski, Dimitar Kastrin, Andrej Rindflesch, Thomas C. BE Pei, J Silvestri, F Tang, J TI Semantics-Based Cross-domain Collaboration Recommendation in the Life Sciences: Preliminary Results SO PROCEEDINGS OF THE 2015 IEEE/ACM INTERNATIONAL CONFERENCE ON ADVANCES IN SOCIAL NETWORKS ANALYSIS AND MINING (ASONAM 2015) LA English DT Proceedings Paper CT IEEE/ACM International Conference on Advances in Social Networks Analysis and Mining (ASONAM) CY AUG 25-28, 2015 CL Paris, FRANCE SP IEEE, Assoc Comp Machinery, ACM SIGKDD, IEEE Comp Soc, IEEE TCDE, Springer, Cisco, Telecom ParisTech DE Research collaboration; Recommendation system; Literature-based discovery; Semantic MEDLINE ID KNOWLEDGE AB In this work we propose a novel approach for semantics-based cross-domain recommendation for research collaboration. First, we construct a large network representing authors, their expertize, current collaborations, and biomedical knowledge in general. We constructed the network from the bibliographic database MEDLINE and from semantic relations extracted from MEDLINE with the SemRep natural language processing system. Then, by using the literature-based discovery paradigm, we recommend novel collaborations, which include not only pairs of authors, but also novel topics for collaboration and an explanation why the collaboration makes sense. C1 [Hristovski, Dimitar] Univ Ljubljana, Fac Med, Ljubljana, Slovenia. [Kastrin, Andrej] Fac Informat Studies, Novo Mesto, Slovenia. [Rindflesch, Thomas C.] Natl Lib Med, Bethesda, MD USA. RP Hristovski, D (reprint author), Univ Ljubljana, Fac Med, Ljubljana, Slovenia. EM dimitar.hristovski@gmail.com; andrej.kastrin@guest.arnes.si; trindflesch@mail.nih.gov NR 8 TC 0 Z9 0 U1 4 U2 4 PU ASSOC COMPUTING MACHINERY PI NEW YORK PA 1515 BROADWAY, NEW YORK, NY 10036-9998 USA BN 978-1-4503-3854-7 PY 2015 BP 805 EP 806 DI 10.1145/2808797.2809300 PG 2 WC Computer Science, Artificial Intelligence; Computer Science, Information Systems SC Computer Science GA BE4JN UT WOS:000371793500122 ER PT S AU Wang, SL Chen, F Fang, JW AF Wang, Shulin Chen, Fang Fang, Jianwen GP IEEE TI Spectral Clustering of High-dimensional Data via Nonnegative Matrix Factorization SO 2015 INTERNATIONAL JOINT CONFERENCE ON NEURAL NETWORKS (IJCNN) SE IEEE International Joint Conference on Neural Networks (IJCNN) LA English DT Proceedings Paper CT International Joint Conference on Neural Networks (IJCNN) CY JUL 12-17, 2015 CL Killarney, IRELAND DE Nonnegative Matrix Factorization; affinity matrix; spectral clustering; cosine similarity; high-dimensional data ID EXPRESSION; CLASSIFICATION; PREDICTION; DISCOVERY; LEUKEMIA AB Spectral clustering has become a popular subspace clustering algorithm in machine learning and data mining, which aims at finding a low-dimensional representation by utilizing the spectrum of a Laplacian matrix. It is a key to construct a discriminative and reliable affinity matrix for spectral clustering to achieve impressive clustering quality. As the real word data increase with higher dimension of features and larger number of data samples, it is a challenge to construct a good affinity matrix. Recently, sparse representation based spectral clustering (SRSC) has proven its efficiency for clustering and lead to promising clustering results in high-dimensional data. SRSC constructs affinity matrix by using sparse representation coefficient vectors. However, it is very time consuming. Additionally, the dimension of the sparse coefficient vector is equal to the number of samples, which may make the affinity matrix not discriminative enough. Therefore, it is inefficient to apply SRSC in clustering large scale datasets. To remedy these issues, we propose a new spectral clustering algorithm which constructs affinity matrix via Nonnegative Matrix Factorization (NMF) coefficient vectors. We call our algorithm as NMF based spectral clustering (NMFSC). The dimension of NMF coefficient vector is independent on the number of the samples and significantly smaller than that of sparse coefficient vector. Therefore, the affinity matrix can be constructed via NMF coefficient vector with much lower computational cost. The experimental results on several public gene expression profiling (GEP) datasets demonstrate the advantage of NMF coefficient over sparse representation coefficient and suggest that NMFSC is promising in clustering high-dimensional data. C1 [Wang, Shulin; Chen, Fang] Hunan Univ, Coll Comp Sci & Elect Engn, Changsha 410082, Hunan, Peoples R China. [Fang, Jianwen] NCI, Div Canc Treatment & Diag, Rockville, MD USA. RP Wang, SL (reprint author), Hunan Univ, Coll Comp Sci & Elect Engn, Changsha 410082, Hunan, Peoples R China. EM smartforesting@gmail.com; jianwen.fang@nih.gov NR 30 TC 0 Z9 0 U1 3 U2 3 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2161-4393 BN 978-1-4799-1959-8 J9 IEEE IJCNN PY 2015 PG 8 WC Computer Science, Artificial Intelligence; Computer Science, Hardware & Architecture; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BE3HR UT WOS:000370730601036 ER PT S AU Chadwick, RS Cartagena-Rivera, AX AF Chadwick, Richard S. Cartagena-Rivera, Alexander X. BE Karavitaki, KD Corey, DP TI Using Noncontact AFM Frequency Shifts to Determine Stereocilia Bundle Stiffness and Tension in the Developing Cochlear Sensory Epithelium SO MECHANICS OF HEARING: PROTEIN TO PERCEPTION SE AIP Conference Proceedings LA English DT Proceedings Paper CT 12th International Workshop on the Mechanics of Hearing CY JUN 23-29, 2014 CL Cape Sounio, GREECE ID ATOMIC-FORCE MICROSCOPY; HAIR BUNDLES; CELLS AB Measurement of frequency shifts of cantilevers having an attached microsphere oscillating at acoustic frequencies can be used to assess mechanical properties of cochlear structures. The method has already been reported for measuring elastic and viscous properties of the tectorial membrane. We describe here how the method can be used to examine other cochlear structures. Theory and formulas for relating hair bundle stiffness and tension in the developing cochlear sensory epithelium to measured frequency shifts are given to estimate the expected frequency shifts and show feasibility of the measurements. We show through a molecular model of myosin II located along the edges of confluent hexagons that myosin contractile forces are balanced by isotropic tension in the developing confluent sheet of cells. C1 [Chadwick, Richard S.; Cartagena-Rivera, Alexander X.] Natl Inst Deafness & Other Commun Disorders, Sect Auditory Mech, Lab Cellular Biol, NIH, Bethesda, MD USA. RP Chadwick, RS (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Auditory Mech, Lab Cellular Biol, NIH, Bethesda, MD USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 978-0-7354-1350-4 J9 AIP CONF PROC PY 2015 VL 1703 AR 030012 DI 10.1063/1.4939327 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Otorhinolaryngology SC Biochemistry & Molecular Biology; Biophysics; Otorhinolaryngology GA BE4PY UT WOS:000372065400014 ER PT S AU Iwasa, KH Ricci, AJ AF Iwasa, Kuni H. Ricci, Anthony J. BE Karavitaki, KD Corey, DP TI The Avian Tectorial Membrane: Why is it Tapered? SO MECHANICS OF HEARING: PROTEIN TO PERCEPTION SE AIP Conference Proceedings LA English DT Proceedings Paper CT 12th International Workshop on the Mechanics of Hearing CY JUN 23-29, 2014 CL Cape Sounio, GREECE ID BASILAR PAPILLA; HAIR-BUNDLE; AMPLIFICATION; MORPHOLOGY; MOTION; CHICK; CELLS AB While the mammalian-and the avian inner ears have well defined tonotopic organizations as well as hair cells specialized for motile and sensing roles, the structural organization of the avian ear is different from its mammalian cochlear counterpart. Presumably this difference stems from the difference in the way motile hair cells function. Short hair cells, whose role is considered analogous to mammalian outer hair cells, presumably depends on their hair bundles, and not motility of their cell body, in providing the motile elements of the cochlear amplifier. This report focuses on the role of the avian tectorial membrane, specifically by addressing the question, "Why is the avian tectorial membrane tapered from the neural to the abneural direction?" C1 [Iwasa, Kuni H.; Ricci, Anthony J.] Stanford Univ, Otolaryngol Head & Neck Surg, Stanford, CA 94305 USA. [Iwasa, Kuni H.] NIDCD, NIH, Bethesda, MD USA. [Ricci, Anthony J.] Stanford Univ, Mol & Cellular Physiol, Stanford, CA 94305 USA. RP Iwasa, KH (reprint author), Stanford Univ, Otolaryngol Head & Neck Surg, Stanford, CA 94305 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 978-0-7354-1350-4 J9 AIP CONF PROC PY 2015 VL 1703 AR 080005 DI 10.1063/1.4939396 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Otorhinolaryngology SC Biochemistry & Molecular Biology; Biophysics; Otorhinolaryngology GA BE4PY UT WOS:000372065400083 ER PT J AU Althabe, F Moore, JL Gibbons, L Berrueta, M Goudar, SS Chomba, E Derman, RJ Patel, A Saleem, S Pasha, O Esamai, F Garces, A Liechty, EA Hambidge, KM Krebs, NF Hibberd, PL Goldenberg, RL Koso-Thomas, M Carlo, WA Cafferata, ML Buekens, P McClure, EM AF Althabe, Fernando Moore, Janet L. Gibbons, Luz Berrueta, Mabel Goudar, Shivaprasad S. Chomba, Elwyn Derman, Richard J. Patel, Archana Saleem, Sarah Pasha, Omrana Esamai, Fabian Garces, Ana Liechty, Edward A. Hambidge, K. Michael Krebs, Nancy F. Hibberd, Patricia L. Goldenberg, Robert L. Koso-Thomas, Marion Carlo, Waldemar A. Cafferata, Maria L. Buekens, Pierre McClure, Elizabeth M. TI Adverse maternal and perinatal outcomes in adolescent pregnancies: The Global Network's Maternal Newborn Health Registry study SO REPRODUCTIVE HEALTH LA English DT Article ID TEENAGE PREGNANCY; AGE; POPULATION; BIRTHS AB Background: Adolescent girls between 15 and 19 years give birth to around 16 million babies each year, around 11% of births worldwide. We sought to determine whether adolescent mothers are at higher risk of maternal and perinatal adverse outcomes compared with mothers aged 20-24 years in a prospective, population-based observational study of newborn outcomes in low resource settings. Methods: We undertook a prospective, population-based multi-country research study of all pregnant women in defined geographic areas across 7 sites in six low-middle income countries (Kenya, Zambia, India, Pakistan, Guatemala and Argentina). The study population for this analysis was restricted to women aged 24 years or less, who gave birth to infants of at least 20 weeks' gestation and 500g or more. We compared adverse pregnancy maternal and perinatal outcomes among pregnant adolescents 15-19 years, < 15 years, and adults 20-24 years. Results: A total of 269,273 women were enrolled from January 2010 to December 2013. Of all pregnancies 11.9% (32,097/269,273) were in adolescents 15-19 years, while 0.14% (370/269,273) occurred among girls < 15 years. Pregnancy among adolescents 15-19 years ranged from 2% in Pakistan to 26% in Argentina, and adolescent pregnancies < 15 year were only observed in sub-Saharan Africa and Latin America. Compared to adults, adolescents did not show increased risk of maternal adverse outcomes. Risks of preterm birth and LBW were significantly higher among both early and older adolescents, with the highest risks observed in the < 15 years group. Neonatal and perinatal mortality followed a similar trend in sub-Saharan Africa and Latin America, with the highest risk in early adolescents, although the differences in this age group were not significant. However, in South Asia the risks of neonatal and perinatal death were not different among adolescents 15-19 years compared to adults. Conclusions: This study suggests that pregnancy among adolescents is not associated with worse maternal outcomes, but is associated with worse perinatal outcomes, particularly in younger adolescents. However, this may not be the case in regions like South Asia where there are decreasing rates of adolescent pregnancies, concentrated among older adolescents. The increased risks observed among adolescents seems more likely to be associated with biological immaturity, than with socio-economic factors, inadequate antenatal or delivery care. C1 [Althabe, Fernando; Gibbons, Luz; Berrueta, Mabel] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Moore, Janet L.; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Goudar, Shivaprasad S.] KLE Univ, Jawaharlal Nehru Med Coll, Belgaum, India. [Chomba, Elwyn] Univ Zambia, Univ Teaching Hosp, Lusaka, Zambia. [Derman, Richard J.] Christiana Care, Newark, DE USA. [Patel, Archana] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Saleem, Sarah; Pasha, Omrana] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Esamai, Fabian] Moi Univ, Sch Med, Eldoret, Kenya. [Garces, Ana] FANCAP, Guatemala City, Guatemala. [Liechty, Edward A.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Hambidge, K. Michael] Univ Colorado, Sch Med, Denver, CO USA. [Krebs, Nancy F.; Hibberd, Patricia L.] Massachusetts Gen Hosp Children, Boston, MA USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet Gynecol, New York, NY USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Cafferata, Maria L.] UNICEM, Buenos Aires, DF, Argentina. [Buekens, Pierre] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. RP Althabe, F (reprint author), Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. EM althabe@gmail.com FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 17 TC 9 Z9 10 U1 3 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S8 DI 10.1186/1742-4755-12-S2-S8 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400008 PM 26063350 ER PT J AU Bauserman, M Lokangaka, A Thorsten, V Tshefu, A Goudar, SS Esamai, F Garces, A Saleem, S Pasha, O Patel, A Manasyan, A Berrueta, M Kodkany, B Chomba, E Liechty, EA Hambidge, KM Krebs, NF Derman, RJ Hibberd, PL Althabe, F Carlo, WA Koso-Thomas, M Goldenberg, RL Wallace, DD McClure, EM Bose, CL AF Bauserman, Melissa Lokangaka, Adrien Thorsten, Vanessa Tshefu, Antoinette Goudar, Shivaprasad S. Esamai, Fabian Garces, Ana Saleem, Sarah Pasha, Omrana Patel, Archana Manasyan, Albert Berrueta, Mabel Kodkany, Bhala Chomba, Elwyn Liechty, Edward A. Hambidge, K. Michael Krebs, Nancy F. Derman, Richard J. Hibberd, Patricia L. Althabe, Fernando Carlo, Waldemar A. Koso-Thomas, Marion Goldenberg, Robert L. Wallace, Dennis D. McClure, Elizabeth M. Bose, Carl L. TI Risk factors for maternal death and trends in maternal mortality in low- and middle-income countries: a prospective longitudinal cohort analysis SO REPRODUCTIVE HEALTH LA English DT Article ID SYSTEMATIC ANALYSIS; NEWBORN; SURVEILLANCE; HEALTH; CARE AB Background: Because large, prospective, population-based data sets describing maternal outcomes are typically not available in low-and middle-income countries, it is difficult to monitor maternal mortality rates over time and to identify factors associated with maternal mortality. Early identification of risk factors is essential to develop comprehensive intervention strategies preventing pregnancy-related complications. Our objective was to describe maternal mortality rates in a large, multi-country dataset and to determine maternal, pregnancy-related, delivery and postpartum characteristics that are associated with maternal mortality. Methods: We collected data describing all pregnancies from 2010 to 2013 among women enrolled in the multinational Global Network for Women's and Children's Health Research Maternal and Neonatal Health Registry (MNHR). We reported the proportion of mothers who died per pregnancy and the maternal mortality ratio (MMR). Generalized linear models were used to evaluate the relationship of potential medical and social factors and maternal mortality and to develop point and interval estimates of relative risk associated with these factors. Generalized estimating equations were used to account for the correlation of outcomes within cluster to develop appropriate confidence intervals. Results: We recorded 277,736 pregnancies and 402 maternal deaths for an MMR of 153/100,000 live births. We observed an improvement in the total MMR from 166 in 2010 to 126 in 2013. The MMR in Latin American sites (91) was lower than the MMR in Asian (178) and African sites (125). When adjusted for study site and the other variables, no formal education (RR 3.2 [1.5, 6.9]), primary education only (RR 3.4 [1.6, 7.5]), secondary education only (RR 2.5 [1.1, 5.7]), lack of antenatal care (RR 1.8 [1.2, 2.5]), caesarean section delivery (RR 1.9 [1.3, 2.8]), hemorrhage (RR 3.3 [2.2, 5.1]), and hypertensive disorders (RR 7.4 [5.2, 10.4]) were associated with higher risks of death. Conclusions: The MNHR identified preventable causes of maternal mortality in diverse settings in low-and middle-income countries. The MNHR can be used to monitor public health strategies and determine their association with reducing maternal mortality. C1 [Bauserman, Melissa; Bose, Carl L.] Univ N Carolina, Sch Med, Dept Pediat, Div Neonatal Perinatal Med, Chapel Hill, NC USA. [Lokangaka, Adrien; Tshefu, Antoinette] Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO. [Thorsten, Vanessa; Wallace, Dennis D.; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Goudar, Shivaprasad S.; Kodkany, Bhala] KLE Univ, Jawaharlal Nehru Med Coll, Belgaum, India. [Esamai, Fabian] Moi Univ, Sch Med, Eldoret, Kenya. [Garces, Ana] Fdn Alimentac & Nutr, Ctr Amer & Panama, Guatemala City, Guatemala. [Saleem, Sarah; Pasha, Omrana] Aga Khan Univ, Karachi, Pakistan. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Manasyan, Albert; Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Berrueta, Mabel; Althabe, Fernando] Univ Buenos Aires, Inst Clin Effectiveness & Hlth Policy, RA-1053 Buenos Aires, DF, Argentina. [Liechty, Edward A.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Hambidge, K. Michael; Krebs, Nancy F.] Univ Colorado, Sch Med, Boulder, CO 80309 USA. [Derman, Richard J.] Christiana Hlth Care, Newark, DE USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Goldenberg, Robert L.] Columbia Univ, Sch Med, Dept Obstet & Gynecol, New York, NY 10027 USA. RP Bauserman, M (reprint author), Univ N Carolina, Sch Med, Dept Pediat, Div Neonatal Perinatal Med, Chapel Hill, NC USA. EM Melissa_bauserman@med.unc.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health [U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, U10HD076474] FX The project was funded by grants (U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, and U10HD076474) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health. NR 19 TC 3 Z9 3 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S5 DI 10.1186/1742-4755-12-S2-S5 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400005 PM 26062992 ER PT J AU Bose, CL Bauserman, M Goldenberg, RL Goudar, SS McClure, EM Pasha, O Carlo, WA Garces, A Moore, JL Miodovnik, M Koso-Thomas, M AF Bose, Carl L. Bauserman, Melissa Goldenberg, Robert L. Goudar, Shivaprasad S. McClure, Elizabeth M. Pasha, Omrana Carlo, Waldemar A. Garces, Ana Moore, Janet L. Miodovnik, Menachem Koso-Thomas, Marion TI The Global Network Maternal Newborn Health Registry: a multi-national, community-based registry of pregnancy outcomes SO REPRODUCTIVE HEALTH LA English DT Article ID COUNTRIES; MORTALITY AB Background: The Global Network for Women's and Children's Health Research (Global Network) supports and conducts clinical trials in resource-limited countries by pairing foreign and U.S. investigators, with the goal of evaluating low-cost, sustainable interventions to improve the health of women and children. Accurate reporting of births, stillbirths, neonatal deaths, maternal mortality, and measures of obstetric and neonatal care is critical to efforts to discover strategies for improving pregnancy outcomes in resource-limited settings. Because most of the sites in the Global Network have weak registration within their health care systems, the Global Network developed the Maternal Newborn Health Registry (MNHR), a prospective, population-based registry of pregnancies at the Global Network sites to provide precise data on health outcomes and measures of care. Methods: Pregnant women are enrolled in the MNHR if they reside in or receive healthcare in designated groups of communities within sites in the Global Network. For each woman, demographic, health characteristics and major outcomes of pregnancy are recorded. Data are recorded at enrollment, the time of delivery and at 42 days postpartum. Results: From 2010 through 2013 Global Network sites were located in Argentina, Guatemala, Belgaum and Nagpur, India, Pakistan, Kenya, and Zambia. During this period, 283,496 pregnant women were enrolled in the MNHR; this number represented 98.8% of all eligible women. Delivery data were collected for 98.8% of women and 42-day follow-up data for 98.4% of those enrolled. In this supplement, there are a series of manuscripts that use data gathered through the MNHR to report outcomes of these pregnancies. Conclusions: Developing public policy and improving public health in countries with poor perinatal outcomes is, in part, dependent upon understanding the outcome of every pregnancy. Because the worst pregnancy outcomes typically occur in countries with limited health registration systems and vital records, alternative registration systems may prove to be highly valuable in providing data. The MNHR, an international, multicenter, population-based registry, assesses pregnancy outcomes over time in support of efforts to develop improved perinatal healthcare in resource-limited areas. C1 [Bose, Carl L.; Bauserman, Melissa] Univ N Carolina, Sch Med, Dept Pediat, Div Neonatal Perinatal Med, Chapel Hill, NC USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Goudar, Shivaprasad S.] KLE Univ Jawaharlal Nehru Med Coll, Womens & Childrens Hlth Res Unit, Belgaum, India. [McClure, Elizabeth M.; Moore, Janet L.] RTI Int, Durham, NC USA. [Pasha, Omrana] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Carlo, Waldemar A.] Univ Alabama Birmingham, Sch Med, Dept Pediat, Div Neonatol, Birmingham, AL USA. [Garces, Ana] San Carlos Univ, Sch Med, Dept Pediat, Guatemala City, Guatemala. [Miodovnik, Menachem; Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Ctr Res Mothers & Children, Bethesda, MD USA. RP Bose, CL (reprint author), Univ N Carolina, Sch Med, Dept Pediat, Div Neonatal Perinatal Med, Chapel Hill, NC USA. EM carl_bose@med.unc.edu FU NICHD NIH HHS [U10HD076474, U10HD076461, U10 HD078438, U10 HD076474, U10HD078439, U01HD040636, U10HD076465, U10HD078437, U10HD076457, U01 HD040607, U10 HD076465, U10HD078438] NR 24 TC 6 Z9 6 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S1 DI 10.1186/1742-4755-12-S2-S1 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400001 PM 26063166 ER PT J AU Bucher, S Marete, I Tenge, C Liechty, EA Esamai, F Patel, A Goudar, SS Kodkany, B Garces, A Chomba, E Althabe, F Barreuta, M Pasha, O Hibberd, P Derman, RJ Otieno, K Hambidge, KM Krebs, NF Carlo, WA Chemweno, C Goldenberg, RL McClure, EM Moore, JL Wallace, DD Saleem, S Koso-Thomas, M AF Bucher, Sherri Marete, Irene Tenge, Constance Liechty, Edward A. Esamai, Fabian Patel, Archana Goudar, Shivaprasad S. Kodkany, Bhalchandra Garces, Ana Chomba, Elwyn Althabe, Fernando Barreuta, Mabel Pasha, Omrana Hibberd, Patricia Derman, Richard J. Otieno, Kevin Hambidge, K. Michael Krebs, Nancy F. Carlo, Waldemar A. Chemweno, Carolyne Goldenberg, Robert L. McClure, Elizabeth M. Moore, Janet L. Wallace, Dennis D. Saleem, Sarah Koso-Thomas, Marion TI A prospective observational description of frequency and timing of antenatal care attendance and coverage of selected interventions from sites in Argentina, Guatemala, India, Kenya, Pakistan and Zambia SO REPRODUCTIVE HEALTH LA English DT Article ID MIDDLE-INCOME COUNTRIES; PREGNANT-WOMEN; WESTERN KENYA; BIRTH PREPAREDNESS; MATERNAL HEALTH; RISK-FACTORS; STILLBIRTHS; DELIVERY; MALARIA; ANEMIA AB Background: The Global Network for Women's and Children's Health Research is one of the largest international networks for testing and generating evidence-based recommendations for improvement of maternal-child health in resource-limited settings. Since 2009, Global Network sites in six low and middle-income countries have collected information on antenatal care practices, which are important as indicators of care and have implications for programs to improve maternal and child health. We sought to: (1) describe the quantity of antenatal care attendance over a four-year period; and (2) explore the quality of coverage for selected preventative, screening, and birth preparedness components. Methods: The Maternal Newborn Health Registry (MNHR) is a prospective, population-based birth and pregnancy outcomes registry in Global Network sites, including: Argentina, Guatemala, India (Belgaum and Nagpur), Kenya, Pakistan, and Zambia. MNHR data from these sites were prospectively collected from January 1, 2010 -December 31, 2013 and analyzed for indicators related to quantity and patterns of ANC and coverage of key elements of recommended focused antenatal care. Descriptive statistics were generated overall by global region (Africa, Asia, and Latin America), and for each individual site. Results: Overall, 96% of women reported at least one antenatal care visit. Indian sites demonstrated the highest percentage of women who initiated antenatal care during the first trimester. Women from the Latin American and Indian sites reported the highest number of at least 4 visits. Overall, 88% of women received tetanus toxoid. Only about half of all women reported having been screened for syphilis (49%) or anemia (50%). Rates of HIV testing were above 95% in the Argentina, African, and Indian sites. The Pakistan site demonstrated relatively high rates for birth preparation, but for most other preventative and screening interventions, posted lower coverage rates as compared to other Global Network sites. Conclusions: Results from our large, prospective, population-based observational study contribute important insight into regional and site-specific patterns for antenatal care access and coverage. Our findings indicate a quality and coverage gap in antenatal care services, particularly in regards to syphilis and hemoglobin screening. We have identified site-specific gaps in access to, and delivery of, antenatal care services that can be targeted for improvement in future research and implementation efforts. C1 [Bucher, Sherri; Liechty, Edward A.; Chemweno, Carolyne] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Marete, Irene; Tenge, Constance; Esamai, Fabian; Otieno, Kevin] Moi Univ, Sch Med, Child Hlth & Paediat, Eldoret, Kenya. [Patel, Archana] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Goudar, Shivaprasad S.; Kodkany, Bhalchandra] KLE Univ Jawaharlal Nehru Med Coll, Belgaum, India. [Garces, Ana] Fdn Alimentac & Nutr Ctr Amer & Panama, Guatemala City, Guatemala. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Althabe, Fernando; Barreuta, Mabel] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Pasha, Omrana; Saleem, Sarah] Aga Khan Univ, Karachi, Pakistan. [Hibberd, Patricia] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Derman, Richard J.] Christiana Care Hlth Syst, Newark, DE USA. [Hambidge, K. Michael; Krebs, Nancy F.] Univ Denver, Sch Med, Denver, CO USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet Gynecol, New York, NY USA. [McClure, Elizabeth M.; Moore, Janet L.; Wallace, Dennis D.] RTI Int, Durham, NC USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Bucher, S (reprint author), Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. EM shbucher@iu.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health [U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, U10HD076474] FX The project was funded by grants (U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, and U10HD076474) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health. NR 68 TC 3 Z9 3 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S12 DI 10.1186/1742-4755-12-S2-S12 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400012 PM 26063483 ER PT J AU Dhaded, SM Somannavar, MS Vernekar, SS Goudar, SS Mwenche, M Derman, R Moore, JL Patel, A Pasha, O Esamai, F Garces, A Althabe, F Chomba, E Liechty, EA Hambidge, KM Krebs, NF Berrueta, M Ciganda, A Hibberd, PL Goldenberg, RL McClure, EM Koso-Thomas, M Manasyan, A Carlo, WA AF Dhaded, Sangappa M. Somannavar, Manjunath S. Vernekar, Sunil S. Goudar, Shivaprasad S. Mwenche, Musaku Derman, Richard Moore, Janet L. Patel, Archana Pasha, Omrana Esamai, Fabian Garces, Ana Althabe, Fernando Chomba, Elwyn Liechty, Edward A. Hambidge, K. Michael Krebs, Nancy F. Berrueta, Mabel Ciganda, Alvaro Hibberd, Patricia L. Goldenberg, Robert L. McClure, Elizabeth M. Koso-Thomas, Marion Manasyan, Albert Carlo, Waldemar A. TI Neonatal mortality and coverage of essential newborn interventions 2010-2013: a prospective, population-based study from low-middle income countries SO REPRODUCTIVE HEALTH LA English DT Article ID BORN TOO SOON; GLOBAL-NETWORK; RISK-FACTORS; DEATHS; BABIES; SURVIVAL; COHORT; CARE AB Background: Approximately 3 million neonatal deaths occur each year worldwide. Simple interventions have been tested and found to be effective in reducing the neonatal mortality. In order to effectively implement public health interventions, it is important to know the rates of neonatal mortality and understand the contributing risk factors. Hence, this prospective, population-based, observational study was carried out to inform these needs. Methods: The Global Network's Maternal Newborn Health Registry was initiated in the seven sites in 2008. Registry administrators (RAs) attempt to identify and enroll all eligible women by 20 weeks gestation and collect basic health data, and outcomes after delivery and at 6 weeks post-partum. All study data were collected, reviewed, and edited by staff at each study site. The study was reviewed and approved by each sites' ethics review committee. Results: Overall, the 7-day neonatal mortality rate (NMR) was 20.6 per 1000 live births and the 28-day NMR was 25.7 per 1000 live births. Higher neonatal mortality was associated with maternal age > 35 and < 20 years relative to women 20-35 years of age. Preterm births were at increased risk of both early and 28-day neonatal mortality (RR 8.1, 95% CI 7.5-8.8 and 7.5, 95% CI 6.9-8.1) compared to term as were those with low birth weight (< 2500g). Neonatal resuscitation rates were 4.8% for hospital deliveries compared to 0.9% for home births. In the hospital, 26.5% of deliveries were by cesarean section with an overall cesarean section rate of 12.5%. Neonatal mortality rates were highest in the Pakistan site and lowest in Argentina. Conclusions: Using prospectively collected data with high follow up rates (99%), we documented characteristics associated with neonatal mortality. Low birth weight and prematurity are among the strongest predictors of neonatal mortality. Other risk factors for neonatal deaths included male gender, multiple gestation and major congenital anomalies. Breech presentation/transverse lie, and no antenatal care were also significant risk factors for neonatal death. Coverage of interventions varied by setting of delivery, with the overall population rate of most evidence-based interventions low. This study informs about risk factors for neonatal mortality which can serve to design strategies/interventions to reduce risk of neonatal mortality. C1 [Dhaded, Sangappa M.; Somannavar, Manjunath S.; Vernekar, Sunil S.; Goudar, Shivaprasad S.] KLE Univ Jawaharlal Nehru Med Coll, Womens & Childrens Hlth Res Unit, Belgaum, Karnataka, India. [Mwenche, Musaku; Chomba, Elwyn] Univ Zambia, Univ Teaching Hosp, Lusaka, Zambia. [Derman, Richard] Christiana Care Hlth Syst, Newark, DE USA. [Moore, Janet L.; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Patel, Archana] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Pasha, Omrana] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Esamai, Fabian] Moi Univ, Sch Med, Eldoret, Kenya. [Garces, Ana] FANCAP, Guatemala City, Guatemala. [Althabe, Fernando; Berrueta, Mabel; Ciganda, Alvaro] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Liechty, Edward A.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Hambidge, K. Michael; Krebs, Nancy F.] Univ Colorado, Sch Med, Denver, CO USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp Children, Boston, MA USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet Gynecol, New York, NY USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Manasyan, Albert; Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. RP Dhaded, SM (reprint author), KLE Univ Jawaharlal Nehru Med Coll, Womens & Childrens Hlth Res Unit, Belgaum, Karnataka, India. EM drdhadedsm@gmail.com OI Somannavar, Manjunath/0000-0002-8871-5072 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, U10HD076474] FX The study was funded by grants (U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, and U10HD076474) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 23 TC 5 Z9 5 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S6 DI 10.1186/1742-4755-12-S2-S6 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400006 PM 26063125 ER PT J AU Goudar, SS Goco, N Somannavar, MS Vernekar, SS Mallapur, AA Moore, JL Wallace, DD Sloan, NL Patel, A Hibberd, PL Koso-Thomas, M McClure, EM Goldenberg, RL AF Goudar, Shivaprasad S. Goco, Norman Somannavar, Manjunath S. Vernekar, Sunil S. Mallapur, Ashalata A. Moore, Janet L. Wallace, Dennis D. Sloan, Nancy L. Patel, Archana Hibberd, Patricia L. Koso-Thomas, Marion McClure, Elizabeth M. Goldenberg, Robert L. TI Institutional deliveries and perinatal and neonatal mortality in Southern and Central India SO REPRODUCTIVE HEALTH LA English DT Article ID JANANI-SURAKSHA-YOJANA; LOW-RESOURCE SETTINGS; DEVELOPING-COUNTRIES; MATERNAL MORTALITY; GLOBAL-NETWORK; OBSTETRIC CARE; STILLBIRTH; INTRAPARTUM; KARNATAKA; IMPACT AB Background: Skilled birth attendance and institutional delivery have been advocated for reducing maternal, perinatal and neonatal mortality (PMR and NMR). India has successfully implemented various strategies to promote skilled attendance and incentivize institutional deliveries in the last 5 years. Objectives: The study evaluates the trends in institutional delivery, PMR, NMR, and their risk factors in two Eunice Kennedy Shriver NICHD Global Network for Women's and Children's Health Research sites, in Belgaum and Nagpur, India, between January 2010 and December 2013. Design/methods: Descriptive data stratified by level of delivery care and key risk factors were analyzed for 36 geographic clusters providing 48 months of data from a prospective, population-based surveillance system that registers all pregnant permanent residents in the study area, and their pregnancy outcomes irrespective of where they deliver. Log binomial models with generalized estimating equations to control for correlation of clustered observations were used to test the trends significance Results: 64,803 deliveries were recorded in Belgaum and 39,081 in Nagpur. Institutional deliveries increased from 92.6% to 96.1% in Belgaum and from 89.5% to 98.6% in Nagpur (both p< 0.0001); hospital rates increased from 63.4% to 71.0% (p= 0.002) and from 63.1% to 72.0% (p< 0.0001), respectively. PMR declined from 41.3 to 34.6 (p= 0.008) deaths per 1,000 births in Belgaum and from 47.4 to 40.8 (p= 0.09) in Nagpur. Stillbirths also declined, from 22.5 to 16.3 per 1,000 births in Belgaum and from 29.3 to 21.1 in Nagpur (both p= 0.002). NMR remained unchanged. Conclusions: Significant increases in institutional deliveries, particularly in hospitals, were accompanied by reductions in stillbirths and PMR, but not by NMR. C1 [Goudar, Shivaprasad S.; Somannavar, Manjunath S.; Vernekar, Sunil S.] KLE Univ Jawaharlal Nehru Med Coll, Womens & Childrens Hlth Res Unit, Belgaum, Karnataka, India. [Goco, Norman; Moore, Janet L.; Wallace, Dennis D.; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Mallapur, Ashalata A.] S Nijalingappa Med Coll, Bagalkot, Karnataka, India. [Sloan, Nancy L.] Christiana Care Hlth Syst, Newark, DE USA. [Patel, Archana] Latta Med Res Fdn, Nagpur, Maharashtra, India. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Goldenberg, Robert L.] Columbia Univ, Sch Med, Dept Obstet & Gynecol, New York, NY USA. RP Goudar, SS (reprint author), KLE Univ Jawaharlal Nehru Med Coll, Womens & Childrens Hlth Res Unit, Belgaum, Karnataka, India. EM sgoudar@jnmc.edu OI Somannavar, Manjunath/0000-0002-8871-5072 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD040477, U01 HD043475, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01HD040636, U01 HD040574, U01 HD40636] FX The study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01 HD040477, U01 HD043475, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01HD040636, U01 HD040574, U01 HD40636). NR 29 TC 3 Z9 3 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S13 DI 10.1186/1742-4755-12-S2-S13 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400013 PM 26063586 ER PT J AU Goudar, SS Stolka, KB Koso-Thomas, M Honnungar, NV Mastiholi, SC Ramadurg, UY Dhaded, SM Pasha, O Patel, A Esamai, F Chomba, E Garces, A Althabe, F Carlo, WA Goldenberg, RL Hibberd, PL Liechty, EA Krebs, NF Hambidge, MK Moore, JL Wallace, DD Derman, RJ Bhalachandra, KS Bose, CL AF Goudar, Shivaprasad S. Stolka, Kristen B. Koso-Thomas, Marion Honnungar, Narayan V. Mastiholi, Shivanand C. Ramadurg, Umesh Y. Dhaded, Sangappa M. Pasha, Omrana Patel, Archana Esamai, Fabian Chomba, Elwyn Garces, Ana Althabe, Fernando Carlo, Waldemar A. Goldenberg, Robert L. Hibberd, Patricia L. Liechty, Edward A. Krebs, Nancy F. Hambidge, Michael K. Moore, Janet L. Wallace, Dennis D. Derman, Richard J. Bhalachandra, Kodkany S. Bose, Carl L. TI Data quality monitoring and performance metrics of a prospective, population-based observational study of maternal and newborn health in low resource settings SO REPRODUCTIVE HEALTH LA English DT Article ID BIRTH REGISTRY; IMPLEMENTATION; SYSTEMS; NORWAY AB Background: To describe quantitative data quality monitoring and performance metrics adopted by the Global Network's (GN) Maternal Newborn Health Registry (MNHR), a maternal and perinatal population-based registry (MPPBR) based in low and middle income countries (LMICs). Methods: Ongoing prospective, population-based data on all pregnancy outcomes within defined geographical locations participating in the GN have been collected since 2008. Data quality metrics were defined and are implemented at the cluster, site and the central level to ensure data quality. Quantitative performance metrics are described for data collected between 2010 and 2013. Results: Delivery outcome rates over 95% illustrate that all sites are successful in following patients from pregnancy through delivery. Examples of specific performance metric reports illustrate how both the metrics and reporting process are used to identify cluster-level and site-level quality issues and illustrate how those metrics track over time. Other summary reports (e. g. the increasing proportion of measured birth weight compared to estimated and missing birth weight) illustrate how a site has improved quality over time. Conclusion: High quality MPPBRs such as the MNHR provide key information on pregnancy outcomes to local and international health officials where civil registration systems are lacking. The MNHR has measures in place to monitor data collection procedures and improve the quality of data collected. Sites have increasingly achieved acceptable values of performance metrics over time, indicating improvements in data quality, but the quality control program must continue to evolve to optimize the use of the MNHR to assess the impact of community interventions in research protocols in pregnancy and perinatal health. C1 [Goudar, Shivaprasad S.; Honnungar, Narayan V.; Mastiholi, Shivanand C.; Dhaded, Sangappa M.; Bhalachandra, Kodkany S.] KLE Univ, Jawaharlal Nehru Med Coll, Womens & Childrens Hlth Res Unit, Belgaum, Karnataka, India. [Stolka, Kristen B.; Moore, Janet L.; Wallace, Dennis D.] RTI Int, Durham, NC USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Ctr Res Mothers & Children, Bethesda, MD USA. [Ramadurg, Umesh Y.] S Nijalingappa Med Coll, Belgaum, Karnataka, India. [Pasha, Omrana] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Patel, Archana] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Esamai, Fabian] Univ Sch Med, Eldoret, Kenya. [Chomba, Elwyn] Univ Zambia, Univ Teaching Hosp, Lusaka, Zambia. [Garces, Ana] San Carlos Univ, Sch Med, Dept Pediat, Guatemala City, Guatemala. [Althabe, Fernando] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Carlo, Waldemar A.] Univ Alabama Birmingham, Sch Med, Dept Pediat, Div Neonatol, Birmingham, AL USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp Children, Boston, MA USA. [Liechty, Edward A.] Indiana Univ Sch Med, Indianapolis, IA USA. [Krebs, Nancy F.; Hambidge, Michael K.] Univ Colorado, Sch Med, Denver, CO USA. [Bose, Carl L.] Univ N Carolina, Sch Med, Dept Pediat, Div Neonatal Perinatal Med, Chapel Hill, NC USA. [Derman, Richard J.] Christiana Care Hlth Syst, Newark, DE USA. RP Stolka, KB (reprint author), RTI Int, Durham, NC USA. EM kstolka@rti.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health [U01 HD040477, U01 HD043475, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01HD040636, U01 HD040574, U01 HD40636] FX The project was funded by grants (U01 HD040477, U01 HD043475, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01HD040636, U01 HD040574, U01 HD40636) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health. NR 25 TC 3 Z9 3 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S2 DI 10.1186/1742-4755-12-S2-S2 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400002 PM 26062714 ER PT J AU Harrison, MS Ali, S Pasha, O Saleem, S Althabe, F Berrueta, M Mazzoni, A Chomba, E Carlo, WA Garces, A Krebs, NF Hambidge, KM Goudar, SS Dhaded, SM Kodkany, B Derman, RJ Patel, A Hibberd, PL Esamai, F Liechty, EA Moore, JL Koso-Thomas, M McClure, EM Goldenberg, RL AF Harrison, Margo S. Ali, Sumera Pasha, Omrana Saleem, Sarah Althabe, Fernando Berrueta, Mabel Mazzoni, Agustina Chomba, Elwyn Carlo, Waldemar A. Garces, Ana Krebs, Nancy F. Hambidge, K. Michael Goudar, Shivaprasad S. Dhaded, S. M. Kodkany, Bhala Derman, Richard J. Patel, Archana Hibberd, Patricia L. Esamai, Fabian Liechty, Edward A. Moore, Janet L. Koso-Thomas, Marion McClure, Elizabeth M. Goldenberg, Robert L. TI A prospective population-based study of maternal, fetal, and neonatal outcomes in the setting of prolonged labor, obstructed labor and failure to progress in low- and middle-income countries SO REPRODUCTIVE HEALTH LA English DT Article AB Background: This population-based study sought to quantify maternal, fetal, and neonatal morbidity and mortality in low-and middle-income countries associated with obstructed labor, prolonged labor and failure to progress (OL/PL/FTP). Methods: A prospective, population-based observational study of pregnancy outcomes was performed at seven sites in Argentina, Guatemala, India (2 sites, Belgaum and Nagpur), Kenya, Pakistan and Zambia. Women were enrolled in pregnancy and delivery and 6-week follow-up obtained to evaluate rates of OL/PL/FTP and outcomes resulting from OL/PL/FTP, including: maternal and delivery characteristics, maternal and neonatal morbidity and mortality and stillbirth. Results: Between 2010 and 2013, 266,723 of 267,270 records (99.8%) included data on OL/PL/FTP with an overall rate of 110.4/1000 deliveries that ranged from 41.6 in Zambia to 200.1 in Pakistan. OL/PL/FTP was more common in women aged < 20, nulliparous women, more educated women, women with infants > 3500g, and women with a BMI > 25 (RR 1.4, 95% CI 1.3 -1.5), with the suggestion of OL/PL/FTP being less common in preterm deliveries. Protective characteristics included parity of = 3, having an infant < 1500g, and having a BMI < 18. Women with OL/ PL/FTP were more likely to die within 42 days (RR 1.9, 95% CI 1.4 -2.4), be infected (RR 1.8, 95% CI 1.5 -2.2), and have hemorrhage antepartum (RR 2.8, 95% CI 2.1 -3.7) or postpartum (RR 2.4, 95% CI 1.8 -3.3). They were also more likely to have a stillbirth (RR 1.6, 95% CI 1.3 -1.9), a neonatal demise at < 28 days (RR 1.9, 95% CI 1.6 -2.1), or a neonatal infection (RR 1.2, 95% CI 1.1 -1.3). As compared to operative vaginal delivery and cesarean section (CS), women experiencing OL/PL/FTP who gave birth vaginally were more likely to become infected, to have an infected neonate, to hemorrhage in the antepartum and postpartum period, and to die, have a stillbirth, or have a neonatal demise. Women with OL/PL/FTP were far more likely to deliver in a facility and be attended by a physician or other skilled provider than women without this diagnosis. Conclusions: Women with OL/PL/FTP in the communities studied were more likely to be primiparous, younger than age 20, overweight, and of higher education, with an infant with birthweight of > 3500g. Women with this diagnosis were more likely to experience a maternal, fetal, or neonatal death, antepartum and postpartum hemorrhage, and maternal and neonatal infection. They were also more likely to deliver in a facility with a skilled provider. CS may decrease the risk of poor outcomes (as in the case of antepartum hemorrhage), but unassisted vaginal delivery exacerbates all of the maternal, fetal, and neonatal outcomes evaluated in the setting of OL/PL/FTP. C1 [Harrison, Margo S.; Goldenberg, Robert L.] Columbia Univ, Dept Obstet Gynecol, New York, NY USA. [Ali, Sumera; Pasha, Omrana; Saleem, Sarah] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Althabe, Fernando; Berrueta, Mabel] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Mazzoni, Agustina] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Chomba, Elwyn] Univ Zambia, Univ Teaching Hosp, Lusaka, Zambia. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Garces, Ana] FANCAP, Guatemala City, Guatemala. [Krebs, Nancy F.; Hambidge, K. Michael] Univ Colorado, Sch Med, Denver, CO USA. [Goudar, Shivaprasad S.; Dhaded, S. M.; Kodkany, Bhala] KLE Univ Jawaharlal Nehru Med Coll, Belgaum, India. [Derman, Richard J.] Christiana Care Hlth Syst, Newark, DE USA. [Patel, Archana] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Hibberd, Patricia L.] Massachusetts Gen Hosp Children, Boston, MA USA. [Esamai, Fabian] Moi Univ, Sch Med, Eldoret, Kenya. [Liechty, Edward A.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Moore, Janet L.; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Harrison, MS (reprint author), Columbia Univ, Dept Obstet Gynecol, New York, NY USA. EM msh2154@cumc.columbia.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, U10HD076474] FX The study was funded by grants (U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, and U10HD076474) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 11 TC 7 Z9 8 U1 3 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S9 DI 10.1186/1742-4755-12-S2-S9 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400009 PM 26063492 ER PT J AU Marete, I Tenge, C Chemweno, C Bucher, S Pasha, O Ramadurg, UY Mastiholi, SC Chiwila, M Patel, A Althabe, F Garces, A Moore, JL Liechty, EA Derman, RJ Hibberd, PL Hambidge, KM Goldenberg, RL Carlo, WA Koso-Thomas, M McClure, EM Esamai, F AF Marete, Irene Tenge, Constance Chemweno, Carolyne Bucher, Sherri Pasha, Omrana Ramadurg, Umesh Y. Mastiholi, Shivanand C. Chiwila, Melody Patel, Archana Althabe, Fernando Garces, Ana Moore, Janet L. Liechty, Edward A. Derman, Richard J. Hibberd, Patricia L. Hambidge, K. Michael Goldenberg, Robert L. Carlo, Waldemar A. Koso-Thomas, Marion McClure, Elizabeth M. Esamai, Fabian TI Lost to follow-up among pregnant women in a multi-site community based maternal and newborn health registry: a prospective study SO REPRODUCTIVE HEALTH LA English DT Article ID CARE; SERVICES; KENYA; HIV AB Background: It is important when conducting epidemiologic studies to closely monitor lost to follow up (LTFU) rates. A high LTFU rate may lead to incomplete study results which in turn can introduce bias to the trial or study, threatening the validity of the findings. There is scarce information on LTFU in prospective community-based perinatal epidemiological studies. This paper reports the rates of LTFU, describes socio-demographic characteristics, and pregnancy/delivery outcomes of mothers LTFU in a large community-based pregnancy registry study. Methods: Data were from a prospective, population-based observational study of the Global Network for Women's and Children's Health Research Maternal Newborn Health Registry (MNHR). This is a multi-centre, international study in which pregnant women were enrolled in mid-pregnancy, followed through parturition and 42 days post-delivery. Risk for LTFU was calculated within a 95% CI. Results: A total of 282,626 subjects were enrolled in this study, of which 4,893 were lost to follow-up. Overall, there was a 1.7% LTFU to follow up rate. Factors associated with a higher LTFU included mothers who did not know their last menstrual period (RR 2.2, 95% CI 1.1, 4.4), maternal age of < 20 years (RR 1.2, 95% CI 1.1, 1.3), women with no formal education (RR 1.2, 95% CI 1.1, 1.4), and attending a government clinic for antenatal care (RR 2.0, 95% CI 1.4, 2.8). Post-natal factors associated with a higher LTFU rate included a newborn with feeding problems (RR 1.6, 94% CI 1.2, 2.2). Conclusions: The LTFU rate in this community-based registry was low (1.7%). Maternal age, maternal level of education, pregnancy status at enrollment and using a government facility for ANC are factors associated with being LTFU. Strategies to ensure representation and high retention in community studies are important to informing progress toward public health goals. C1 [Marete, Irene; Tenge, Constance; Chemweno, Carolyne; Esamai, Fabian] Moi Univ, Dept Child Hlth & Paediat, Sch Med, Eldoret, Kenya. [Bucher, Sherri; Liechty, Edward A.] Indiana Univ, Riley Hosp, Dept Paediat, Indianapolis, IN 46204 USA. [Pasha, Omrana] Aga Khan Univ, Dept Community Hlth Serv, Karachi, Pakistan. [Ramadurg, Umesh Y.] S Nijalingappa Med Coll, Bagalkot, Karnataka, India. [Mastiholi, Shivanand C.] KLE Univ, Jawaharlal Nehru Med Coll, Belgaum, Karnataka, India. [Chiwila, Melody] Univ Teaching Hosp, Lusaka, Zambia. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Althabe, Fernando] Inst Clin Effectiveness, Buenos Aires, DF, Argentina. [Garces, Ana] Francisco Marroquin Univ, Multidisciplinary Hlth Inst, Guatemala City, Guatemala. [Moore, Janet L.; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Derman, Richard J.] Christiana Care Hlth Syst, Wilmington, DC USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Div Global Hlth, Boston, MA 02114 USA. [Hambidge, K. Michael] Univ Colorado, Dept Paediat, Denver, CO 80202 USA. [Goldenberg, Robert L.] Columbia Univ, New York, NY USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Paediat, Birmingham, AL USA. [Koso-Thomas, Marion] NICHHD, Bethesda, MD 20892 USA. RP Marete, I (reprint author), Moi Univ, Dept Child Hlth & Paediat, Sch Med, Eldoret, Kenya. EM mareteirene07@yahoo.com FU Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health United State of America [U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, U10HD076474] FX We acknowledge the work of all the Registry Administrators in the seven Global Network sites. This work was supported by grants (U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, and U10HD076474) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health United State of America. NR 17 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S4 DI 10.1186/1742-4755-12-S2-S4 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400004 PM 26062899 ER PT J AU McClure, EM Saleem, S Goudar, SS Moore, JL Garces, A Esamai, F Patel, A Chomba, E Althabe, F Pasha, O Kodkany, BS Bose, CL Berreuta, M Liechty, EA Hambidge, KM Krebs, NF Derman, RJ Hibberd, PL Buekens, P Manasyan, A Carlo, WA Wallace, DD Koso-Thomas, M Goldenberg, RL AF McClure, Elizabeth M. Saleem, Sarah Goudar, Shivaprasad S. Moore, Janet L. Garces, Ana Esamai, Fabian Patel, Archana Chomba, Elwyn Althabe, Fernando Pasha, Omrana Kodkany, Bhalachandra S. Bose, Carl L. Berreuta, Mabel Liechty, Edward A. Hambidge, K. Michael Krebs, Nancy F. Derman, Richard J. Hibberd, Patricia L. Buekens, Pierre Manasyan, Albert Carlo, Waldemar A. Wallace, Dennis D. Koso-Thomas, Marion Goldenberg, Robert L. TI Stillbirth rates in low-middle income countries 2010-2013: a population-based, multi-country study from the Global Network SO REPRODUCTIVE HEALTH LA English DT Article ID LOW-RESOURCE SETTINGS; PERINATAL-MORTALITY; CESAREAN DELIVERY; OBSTETRIC CARE; PREGNANCY OUTCOMES; NEONATAL DEATHS; NEWBORN HEALTH; INTRAPARTUM; DETERMINANTS; BANGLADESH AB Background: Stillbirth rates remain nearly ten times higher in low-middle income countries (LMIC) than high income countries. In LMIC, where nearly 98% of stillbirths worldwide occur, few population-based studies have documented characteristics or care for mothers with stillbirths. Non-macerated stillbirths, those occurring around delivery, are generally considered preventable with appropriate obstetric care. Methods: We undertook a prospective, population-based observational study of all pregnant women in defined geographic areas across 7 sites in low-resource settings (Kenya, Zambia, India, Pakistan, Guatemala and Argentina). Staff collected demographic and health care characteristics with outcomes obtained at delivery. Results: From 2010 through 2013, 269,614 enrolled women had 272,089 births, including 7,865 stillbirths. The overall stillbirth rate was 28.9/1000 births, ranging from 13.6/1000 births in Argentina to 56.5/1000 births in Pakistan. Stillbirth rates were stable or declined in 6 of the 7 sites from 2010-2013, only increasing in Pakistan. Less educated, older and women with less access to antenatal care were at increased risk of stillbirth. Furthermore, women not delivered by a skilled attendant were more likely to have a stillbirth (RR 2.8, 95% CI 2.2, 3.5). Compared to live births, stillbirths were more likely to be preterm (RR 12.4, 95% CI 11.2, 13.6). Infants with major congenital anomalies were at increased risk of stillbirth (RR 9.1, 95% CI 7.3, 11.4), as were multiple gestations (RR 2.8, 95% CI 2.4, 3.2) and breech (RR 3.0, 95% CI 2.6, 3.5). Altogether, 67.4% of the stillbirths were non-macerated. 7.6% of women with stillbirths had cesarean sections, with obstructed labor the primary indication (36.9%). Conclusions: Stillbirth rates were high, but with reductions in most sites during the study period. Disadvantaged women, those with less antenatal care and those delivered without a skilled birth attendant were at increased risk of delivering a stillbirth. More than two-thirds of all stillbirths were non-macerated, suggesting potentially preventable stillbirth. Additionally, 8% of women with stillbirths were delivered by cesarean section. The relatively high rate of cesarean section among those with stillbirths suggested that this care was too late or not of quality to prevent the stillbirth; however, further research is needed to evaluate the quality of obstetric care, including cesarean section, on stillbirth in these low resource settings. C1 [McClure, Elizabeth M.; Moore, Janet L.] RTI Int, Durham, NC USA. [Saleem, Sarah; Pasha, Omrana] Aga Khan Univ, Karachi, Pakistan. [Goudar, Shivaprasad S.; Kodkany, Bhalachandra S.] KLE Univ, Jawaharlal Nehru Med Coll, Belgaum, India. [Garces, Ana] Fdn Alimentac Nutr, Ctr Amer & Panama, Guatemala City, Guatemala. [Esamai, Fabian] Moi Univ, Sch Med, Eldoret, Kenya. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Althabe, Fernando; Berreuta, Mabel] Univ Buenos Aires, Inst Clin Effectiveness & Hlth Policy, RA-1053 Buenos Aires, DF, Argentina. [Bose, Carl L.] Univ N Carolina, Chapel Hill, NC USA. [Liechty, Edward A.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Hambidge, K. Michael; Krebs, Nancy F.] Univ Denver, Sch Med, Denver, CO USA. [Derman, Richard J.] Christiana Care Hlth Syst, Newark, DE USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Buekens, Pierre] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Manasyan, Albert; Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Goldenberg, Robert L.] Columbia Univ, Sch Med, Dept Obstet & Gynecol, New York, NY USA. RP McClure, EM (reprint author), RTI Int, Durham, NC USA. EM mcclure@rti.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, U10HD076474] FX The study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, and U10HD076474). NR 31 TC 11 Z9 11 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S7 DI 10.1186/1742-4755-12-S2-S7 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400007 PM 26063292 ER PT J AU Pasha, O Goudar, SS Patel, A Garces, A Esamai, F Chomba, E Moore, JL Kodkany, BS Saleem, S Derman, RJ Liechty, EA Hibberd, PL Hambidge, KM Krebs, NF Carlo, WA McClure, EM Koso-Thomas, M Goldenberg, RL AF Pasha, Omrana Goudar, Shivaprasad S. Patel, Archana Garces, Ana Esamai, Fabian Chomba, Elwyn Moore, Janet L. Kodkany, Bhalchandra S. Saleem, Sarah Derman, Richard J. Liechty, Edward A. Hibberd, Patricia L. Hambidge, K. Michael Krebs, Nancy F. Carlo, Waldemar A. McClure, Elizabeth M. Koso-Thomas, Marion Goldenberg, Robert L. TI Postpartum contraceptive use and unmet need for family planning in five low-income countries SO REPRODUCTIVE HEALTH LA English DT Article ID SHORT INTERPREGNANCY INTERVALS; PERINATAL OUTCOMES; BIRTH OUTCOMES; WOMEN; RISK; PREGNANCY; HEALTH; DEATH; DISCONTINUATION; QUALITY AB Background: During the post-partum period, most women wish to delay or prevent future pregnancies. Despite this, the unmet need for family planning up to a year after delivery is higher than at any other time. This study aims to assess fertility intention, contraceptive usage and unmet need for family planning amongst women who are six weeks postpartum, as well as to identify those at greatest risk of having an unmet need for family planning during this period. Methods: Using the NICHD Global Network for Women's and Children's Health Research's multi-site, prospective, ongoing, active surveillance system to track pregnancies and births in 100 rural geographic clusters in 5 countries (India, Pakistan, Zambia, Kenya and Guatemala), we assessed fertility intention and contraceptive usage at day 42 post-partum. Results: We gathered data on 36,687 women in the post-partum period. Less than 5% of these women wished to have another pregnancy within the year. Despite this, rates of modern contraceptive usage varied widely and unmet need ranged from 25% to 96%. Even amongst users of modern contraceptives, the uptake of the most effective long-acting reversible contraceptives (intrauterine devices) was low. Women of age less than 20 years, parity of two or less, limited education and those who deliver at home were at highest risk for having unmet need. Conclusions: Six weeks postpartum, almost all women wish to delay or prevent a future pregnancy. Even in sites where early contraceptive adoption is common, there is substantial unmet need for family planning. This is consistently highest amongst women below the age of 20 years. Interventions aimed at increasing the adoption of effective contraceptive methods are urgently needed in the majority of sites in order to reduce unmet need and to improve both maternal and infant outcomes, especially amongst young women. C1 [Pasha, Omrana; Saleem, Sarah] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Goudar, Shivaprasad S.; Kodkany, Bhalchandra S.] KLE Univ Jawaharlal Nehru Med Coll, Belgaum, Karnataka, India. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Garces, Ana] FANCAP, Guatemala City, Guatemala. [Esamai, Fabian] Moi Univ, Dept Pediat, Eldoret, Kenya. [Chomba, Elwyn] Univ Zambia, Dept Pediat, Lusaka, Zambia. [Moore, Janet L.] Social Stat & Environm Sci Res Triangle Inst, Durham, NC USA. [Derman, Richard J.; McClure, Elizabeth M.] Christiana Care Hlth Syst, Dept Obstet & Gynecol, Newark, DE USA. [Liechty, Edward A.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp Children, Dept Pediat, Boston, MA USA. [Hambidge, K. Michael; Krebs, Nancy F.] Univ Colorado, Hlth Sci Ctr, Dept Pediat, Denver, CO 80262 USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Koso-Thomas, Marion] NICHD, Bethesda, MD USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. RP Pasha, O (reprint author), Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. EM Omrana.pasha@aku.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, U10HD076474] FX This study was supported through grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, and U10HD076474). NR 36 TC 5 Z9 5 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S11 DI 10.1186/1742-4755-12-S2-S11 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400011 PM 26063346 ER PT J AU Pasha, O Saleem, S Ali, S Goudar, SS Garces, A Esamai, F Patel, A Chomba, E Althabe, F Moore, JL Harrison, M Berrueta, MB Hambidge, KM Krebs, NF Hibberd, PL Carlo, WA Kodkany, B Derman, RJ Liechty, EA Koso-Thomas, M McClure, EM Goldenberg, RL AF Pasha, Omrana Saleem, Sarah Ali, Sumera Goudar, Shivaprasad S. Garces, Ana Esamai, Fabian Patel, Archana Chomba, Elwyn Althabe, Fernando Moore, Janet L. Harrison, Margo Berrueta, Mabel B. Hambidge, K. Michael Krebs, Nancy F. Hibberd, Patricia L. Carlo, Waldemar A. Kodkany, Bhala Derman, Richard J. Liechty, Edward A. Koso-Thomas, Marion McClure, Elizabeth M. Goldenberg, Robert L. TI Maternal and newborn outcomes in Pakistan compared to other low and middle income countries in the Global Network's Maternal Newborn Health Registry: an active, community-based, pregnancy surveillance mechanism SO REPRODUCTIVE HEALTH LA English DT Article ID NEONATAL-MORTALITY; OBSTETRIC CARE; CHILD HEALTH; INTERVENTIONS; STILLBIRTHS; DEATHS; RISK AB Background: Despite global improvements in maternal and newborn health (MNH), maternal, fetal and newborn mortality rates in Pakistan remain stagnant. Using data from the Global Network's Maternal Newborn Health Registry (MNHR) the objective of this study is to compare the rates of maternal mortality, stillbirth and newborn mortality and levels of putative risk factors between the Pakistani site and those in other countries. Methods: Using data collected through a multi-site, prospective, ongoing, active surveillance system to track pregnancies and births in communities in discrete geographical areas in seven sites across six countries including Pakistan, India, Kenya, Zambia, Guatemala and Argentina from 2010 to 2013, the study compared MNH outcomes and risk factors. The MNHR captures more than 60,000 deliveries annually across all sites with over 10,000 of them in Thatta, Pakistan. Results: The Pakistan site had a maternal mortality ratio almost three times that of the other sites (313/100,000 vs 116/100,000). Stillbirth (56.5 vs 22.9/1000 births), neonatal mortality (50.0 vs 20.7/1000 livebirths) and perinatal mortality rates (95.2/1000 vs 39.0/1000 births) in Thatta, Pakistan were more than twice those of the other sites. The Pakistani site is the only one in the Global Network where maternal mortality increased (from 231/100,000 to 353/100,000) over the study period and fetal and neonatal outcomes remained stagnant. The Pakistan site lags behind other sites in maternal education, high parity, and appropriate antenatal and postnatal care. However, facility delivery and skilled birth attendance rates were less prominently different between the Pakistani site and other sites, with the exception of India. The difference in the fetal and neonatal outcomes between the Pakistani site and the other sites was most pronounced amongst normal birth weight babies. Conclusions: The increase in maternal mortality and the stagnation of fetal and neonatal outcomes from 2010 to 2013 indicates that current levels of antenatal and newborn care interventions in Thatta, Pakistan are insufficient to protect against poor maternal and neonatal outcomes. Delivery care in the Pakistani site, while appearing quantitatively equivalent to the care in sites in Africa, is less effective in saving the lives of women and their newborns. By the metrics available from this study, the quality of obstetric and neonatal care in the site in Pakistan is poor. C1 [Pasha, Omrana; Saleem, Sarah; Ali, Sumera] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Goudar, Shivaprasad S.; Kodkany, Bhala] KLE Univ Jawaharlal Nehru Med Coll, Belgaum, India. [Garces, Ana] FANCAP, Guatemala City, Guatemala. [Esamai, Fabian] Moi Univ, Sch Med, Eldoret, Kenya. [Patel, Archana] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Chomba, Elwyn] Univ Zambia, Univ Teaching Hosp, Lusaka, Zambia. [Althabe, Fernando; Berrueta, Mabel B.] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Moore, Janet L.; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Harrison, Margo; Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Hambidge, K. Michael; Krebs, Nancy F.] Univ Colorado, Sch Med, Denver, CO USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp Children, Boston, MA USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Derman, Richard J.] Christiana Care Hlth Syst, Newark, DE USA. [Liechty, Edward A.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Pasha, O (reprint author), Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. EM omrana.pasha@aku.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 32 TC 2 Z9 2 U1 2 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S15 DI 10.1186/1742-4755-12-S2-S15 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400015 PM 26062610 ER PT J AU Patel, A Bucher, S Pusdekar, Y Esamai, F Krebs, NF Goudar, SS Chomba, E Garces, A Pasha, O Saleem, S Kodkany, BS Liechty, EA Kodkany, B Derman, RJ Carlo, WA Hambidge, KM Goldenberg, RL Althabe, F Berrueta, M Moore, JL McClure, EM Koso-Thomas, M Hibberd, PL AF Patel, Archana Bucher, Sherri Pusdekar, Yamini Esamai, Fabian Krebs, Nancy F. Goudar, Shivaprasad S. Chomba, Elwyn Garces, Ana Pasha, Omrana Saleem, Sarah Kodkany, Bhalachandra S. Liechty, Edward A. Kodkany, Bhala Derman, Richard J. Carlo, Waldemar A. Hambidge, K. Michael Goldenberg, Robert L. Althabe, Fernando Berrueta, Mabel Moore, Janet L. McClure, Elizabeth M. Koso-Thomas, Marion Hibberd, Patricia L. TI Rates and determinants of early initiation of breastfeeding and exclusive breast feeding at 42 days postnatal in six low and middle-income countries: A prospective cohort study SO REPRODUCTIVE HEALTH LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; SECONDARY DATA-ANALYSIS; NEONATAL-MORTALITY; NEWBORN-CARE; PERINATAL-MORTALITY; BIRTH ATTENDANTS; GLOBAL-NETWORK; RURAL GHANA; HEALTH; INFANT AB Background: Early initiation of breastfeeding after birth and exclusive breastfeeding through six months of age confers many health benefits for infants; both are crucial high impact, low-cost interventions. However, determining accurate global rates of these crucial activities has been challenging. We use population-based data to describe: (1) rates of early initiation of breastfeeding (defined as within 1 hour of birth) and of exclusive breastfeeding at 42 days post-partum; and (2) factors associated with failure to initiate early breastfeeding and exclusive breastfeeding at 42 days post-partum. Methods: Prospectively collected data from women and their live-born infants enrolled in the Global Network's Maternal and Newborn Health Registry between January 1, 2010-December 31, 2013 included women-infant dyads in 106 geographic areas (clusters) at 7 research sites in 6 countries (Kenya, Zambia, India [2 sites], Pakistan, Argentina and Guatemala). Rates and risk factors for failure to initiate early breastfeeding were investigated for the entire cohort and rates and risk factors for failure to maintain exclusive breastfeeding was assessed in a sub-sample studied at 42 days post-partum. Result: A total of 255,495 live-born women-infant dyads were included in the study. Rates and determinants for the exclusive breastfeeding sub-study at 42 days post-partum were assessed from among a sub-sample of 105,563 subjects. Although there was heterogeneity by site, and early initiation of breastfeeding after delivery was high, the Pakistan site had the lowest rates of early initiation of breastfeeding. The Pakistan site also had the highest rate of lack of exclusive breastfeeding at 42 days post-partum. Across all regions, factors associated with failure to initiate early breastfeeding included nulliparity, caesarean section, low birth weight, resuscitation with bag and mask, and failure to place baby on the mother's chest after delivery. Factors associated with failure to achieve exclusive breastfeeding at 42 days varied across the sites. The only factor significant in all sites was multiple gestation. Conclusions: In this large, prospective, population-based, observational study, rates of both early initiation of breastfeeding and exclusive breastfeeding at 42 days post-partum were high, except in Pakistan. Factors associated with these key breastfeeding indicators should assist with more effective strategies to scale-up these crucial public health interventions. C1 [Patel, Archana; Pusdekar, Yamini; Althabe, Fernando] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Patel, Archana; Pusdekar, Yamini; Althabe, Fernando] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Bucher, Sherri; Liechty, Edward A.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Esamai, Fabian] Moi Univ, Eldoret, Kenya. [Krebs, Nancy F.; Hambidge, K. Michael] Univ Colorado, Sch Med, Denver, CO USA. [Goudar, Shivaprasad S.; Kodkany, Bhalachandra S.; Kodkany, Bhala] KLE Univ Jawaharlal Nehru Med Coll, Belgaum, India. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Garces, Ana] FANCAP, Guatemala City, Guatemala. [Pasha, Omrana; Saleem, Sarah] Aga Khan Univ, Karachi, Pakistan. [Derman, Richard J.] Christiana Care Hlth Syst, Newark, DE USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Goldenberg, Robert L.] Columbia Univ, New York, NY USA. [Berrueta, Mabel] IECS, Buenos Aires, DF, Argentina. [Moore, Janet L.; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, US Natl Inst Hlth, Bethesda, MD USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp Children, Boston, MA USA. RP Patel, A (reprint author), Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. EM dr_apatel@yahoo.com FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, U10HD076474] FX This project was funded by grants (U01 HD040477, U01HD040636, U10HD078437, U10HD076461, U10HD076465, U10HD076457, U10HD078439, U10HD078438, and U10HD076474) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 61 TC 3 Z9 5 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PY 2015 VL 12 SU 2 AR S10 DI 10.1186/1742-4755-12-S2-S10 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG8LU UT WOS:000372336400010 PM 26063291 ER PT B AU Hanson, RL Malhotra, A AF Hanson, Robert L. Malhotra, Alka BE Duggirala, R Almasy, L WilliamsBlangero, S Paul, SFD Kole, C TI Association Studies to Map Genes for Disease-Related Traits in Humans SO GENOME MAPPING AND GENOMICS IN HUMAN AND NON-HUMAN PRIMATES SE Genome Mapping and Genomics in Animals LA English DT Article; Book Chapter ID GENOME-WIDE ASSOCIATION; LINKAGE DISEQUILIBRIUM; SUSCEPTIBILITY LOCI; SAMPLE-SIZE; CANCER SUSCEPTIBILITY; IMPUTATION ACCURACY; GENOTYPE-IMPUTATION; DIABETES-MELLITUS; RESEQUENCING DATA; AMERICAN-INDIANS C1 [Hanson, Robert L.; Malhotra, Alka] NIDDK, Diabet Epidemiol & Clin Res Sect, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RP Hanson, RL (reprint author), NIDDK, Diabet Epidemiol & Clin Res Sect, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM rhanson@phx.niddk.nih.gov; alka@niddk.nih.gov NR 70 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY BN 978-3-662-46306-2; 978-3-662-46305-5 J9 GENOME MAPP GENOMICS JI Genome Mapp. Genomics Anim. PY 2015 VL 5 BP 53 EP 66 DI 10.1007/978-3-662-46306-2_4 D2 10.1007/978-3-662-46306-2 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA BE4MT UT WOS:000371927800005 ER PT B AU Mitchell, BD Schaffer, AA Pollin, TI Streeten, EA Horenstein, RB Steinle, NI Yerges-Armstrong, L Shuldiner, AR O'Connell, JR AF Mitchell, Braxton D. Schaeffer, Alejandro A. Pollin, Toni I. Streeten, Elizabeth A. Horenstein, Richard B. Steinle, Nanette I. Yerges-Armstrong, Laura Shuldiner, Alan R. O'Connell, Jeffrey R. BE Duggirala, R Almasy, L WilliamsBlangero, S Paul, SFD Kole, C TI Mapping Genes in Isolated Populations: Lessons from the Old Order Amish SO GENOME MAPPING AND GENOMICS IN HUMAN AND NON-HUMAN PRIMATES SE Genome Mapping and Genomics in Animals LA English DT Article; Book Chapter ID APOLIPOPROTEIN-C-III; A-I; PREMATURE ATHEROSCLEROSIS; DIETARY-CHOLESTEROL; LANCASTER COUNTY; LINKAGE ANALYSIS; CORONARY EVENTS; PLANT STEROLS; DISEASE; SITOSTEROLEMIA C1 [Mitchell, Braxton D.; Pollin, Toni I.; Streeten, Elizabeth A.; Horenstein, Richard B.; Steinle, Nanette I.; Yerges-Armstrong, Laura; Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Dept Med, 22 S Greene St, Baltimore, MD 21201 USA. [Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, DHHS, 8600 Rockville Pike, Bethesda, MD 20894 USA. [Streeten, Elizabeth A.; Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21201 USA. [Steinle, Nanette I.] Vet Adm Med Ctr, Diabet & Endocrinol Sect, Baltimore, MD 21201 USA. RP Mitchell, BD (reprint author), Univ Maryland, Sch Med, Dept Med, 22 S Greene St, Baltimore, MD 21201 USA. EM bmitchel@medicine.umaryland.edu; aschaffe@helix.nih.gov; tpollin@medicine.umaryland.edu; estreete@medicine.umaryland.edu; rhorenst@medicine.umaryland.edu; nsteinle@medicine.umaryland.edu; lyerges@medicine.umaryland.edu; ashuldin@medicine.umaryland.edu; joconnel@medicine.umaryland.edu OI Mitchell, Braxton/0000-0003-4920-4744 NR 53 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY BN 978-3-662-46306-2; 978-3-662-46305-5 J9 GENOME MAPP GENOMICS JI Genome Mapp. Genomics Anim. PY 2015 VL 5 BP 141 EP 153 DI 10.1007/978-3-662-46306-2_10 D2 10.1007/978-3-662-46306-2 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA BE4MT UT WOS:000371927800011 ER PT S AU Rostovtseva, TK Bezrukov, SM AF Rostovtseva, Tatiana K. Bezrukov, Sergey M. BE Delcour, AH TI Function and Regulation of Mitochondrial Voltage-Dependent Anion Channel SO ELECTROPHYSIOLOGY OF UNCONVENTIONAL CHANNELS AND PORES SE Springer Series in Biophysics LA English DT Article; Book Chapter DE VDAC; Tubulin; Voltage gating; ATP transport; Lipid membranes; Beta-barrel channels ID ISCHEMIA-REPERFUSION INJURY; TUBULIN-BLOCKED STATE; VDAC1 N-TERMINUS; OUTER-MEMBRANE; PHOSPHOLIPID-VESICLES; LIPID-COMPOSITION; ATP TRANSPORT; CYTOCHROME-C; SUCCINIC ANHYDRIDE; SELECTIVE CHANNEL AB The voltage-dependent anion channel (VDAC) is the major protein of the mitochondrial outer membrane (MOM). It is now generally accepted that this channel is responsible for most of the metabolite flux in and out of mitochondria. Small ions, adenine nucleotides such as ATP and ADP, and other water soluble mitochondrial respiratory substrates cross the MOM through VDAC. Therefore, any restriction to metabolite exchange through VDAC is able to lead to an essential disturbance of mitochondrial energetic functions and cell metabolism. This review discusses the mechanisms of regulation of these fluxes by VDAC through its ability to "gate" or adopt different conducting states. The focus of the first part is on the biophysical properties of this evolutionary conserved beta-barrel channel reconstituted into its "native" lipid environment and especially on the mechanisms of modification of VDAC gating by electrical field, medium pH, and membrane lipid composition. The second part of this review addresses the novel mechanism of VDAC regulation by dimeric tubulin, an abundant cytosolic protein, and the physiological implications of the uncovered VDAC-tubulin interaction. One of the intriguing consequences of VDAC regulation by tubulin is its coupling with the Warburg-type aerobic glycolysis characteristic of many tumor cells where the VDAC-tubulin complex may play a role of "glycolytic switch" moving cells between aerobic glycolysis and oxidative phosphorylation. The discussed biophysical insights of VDAC blockage by tubulin, obtained from experiments at the single-molecule level, could be also important for understanding the molecular mechanisms of functional interactions between water soluble and membrane proteins in general. C1 [Rostovtseva, Tatiana K.; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. RP Rostovtseva, TK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. EM rostovtt@mail.nih.gov NR 113 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 0932-2353 BN 978-3-319-20149-8; 978-3-319-20148-1 J9 SPRINGER SER BIOPHYS JI Springer Ser. Biophys. PY 2015 VL 18 BP 3 EP 31 DI 10.1007/978-3-319-20149-8_1 D2 10.1007/978-3-319-20149-8 PG 29 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA BE4BQ UT WOS:000371485200002 ER PT J AU Freeman, ML Mudd, JC Younes, SA Panigrahi, S Lee, SA Hunt, PW Gianella, S Lederman, MM AF Freeman, M. L. Mudd, J. C. Younes, S. A. Panigrahi, S. Lee, S. A. Hunt, P. W. Gianella, S. Lederman, M. M. TI CD8 T-cells expressing the fractalkine (endothelial homing) receptor CX3CR1 in treated HIV infection are promoted by CMV co-infection and functionally impaired by platelet interactions SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 17th International Workshop on Co-Morbidities and Adverse Drug Reaction in HIV CY OCT 20-22, 2015 CL Barcelona, SPAIN C1 [Freeman, M. L.; Mudd, J. C.; Younes, S. A.; Panigrahi, S.; Lederman, M. M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Mudd, J. C.] NIAID, NIH, Bethesda, MD 20892 USA. [Lee, S. A.; Hunt, P. W.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Gianella, S.] Univ Calif San Diego, La Jolla, CA 92093 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2015 VL 20 SU 1 MA O07 BP A8 EP A8 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA DE8VV UT WOS:000370915700008 ER PT J AU Funderburg, NT Xu, D Playford, M Andrade, A Kuritzkes, D Lederman, MM Mehta, NN AF Funderburg, N. T. Xu, D. Playford, M. Andrade, A. Kuritzkes, D. Lederman, M. M. Mehta, N. N. TI Treatment of HIV disease with a raltegravir-based regimen increases LDL levels, but improves HDL composition and function SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 17th International Workshop on Co-Morbidities and Adverse Drug Reaction in HIV CY OCT 20-22, 2015 CL Barcelona, SPAIN C1 [Funderburg, N. T.] Ohio State Univ, Columbus, OH 43210 USA. [Xu, D.; Playford, M.; Mehta, N. N.] NHLBI, Bethesda, MD 20892 USA. [Andrade, A.] Johns Hopkins Univ, Baltimore, MD USA. [Kuritzkes, D.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Lederman, M. M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. RI Funderburg, Nicholas/L-8022-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2015 VL 20 SU 1 MA P02 BP A30 EP A30 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA DE8VV UT WOS:000370915700033 ER PT J AU Mulligan, K Rutledge, B Kapogiannis, BG Siberry, GK Anderson, PL Landowitz, RJ Rudy, B Liu, N Havens, PL Wilson, CM Hosek, S AF Mulligan, K. Rutledge, B. Kapogiannis, B. G. Siberry, G. K. Anderson, P. L. Landowitz, R. J. Rudy, B. Liu, N. Havens, P. L. Wilson, C. M. Hosek, S. CA Adolescent Trial Network ATN HIV A TI Bone changes in young men ages 18-22 enrolled in a pre-exposure prophylaxis (PrEP) safety and demonstration study using tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 17th International Workshop on Co-Morbidities and Adverse Drug Reaction in HIV CY OCT 20-22, 2015 CL Barcelona, SPAIN C1 [Mulligan, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Rutledge, B.; Liu, N.] WESTAT Corp, Rockville, MD 20850 USA. [Kapogiannis, B. G.; Siberry, G. K.] NICHHD, Natl Inst Hlth, Bethesda, MD 20892 USA. [Anderson, P. L.] Univ Colorado, Denver, CO 80202 USA. [Landowitz, R. J.] Univ Calif Los Angeles, Los Angeles, CA USA. [Rudy, B.] NYU Med Ctr, New York, NY 10016 USA. [Havens, P. L.] Med Coll Wisconsin, Milwaukee, WI USA. [Wilson, C. M.] Univ Alabama Birmingham, Birmingham, AL USA. [Hosek, S.] John H Stroger Jr Hosp Cook Cty, Chicago, IL USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2015 VL 20 SU 1 MA O26 BP A21 EP A22 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA DE8VV UT WOS:000370915700027 ER PT J AU Younes, SA Freeman, ML Mudd, JC Shive, CL Reynaldi, A Panigrahi, S Estes, JD Deleage, C Lucero, C Anderson, J Schacker, TW Davenport, MP McCune, JM Hunt, PW Lee, SA Serano-Villar, S Canaday, DH Sekaly, RP Rodriguez, B Sieg, SF Lederman, MM AF Younes, S-A Freeman, M. L. Mudd, J. C. Shive, C. L. Reynaldi, A. Panigrahi, S. Estes, J. D. Deleage, C. Lucero, C. Anderson, J. Schacker, T. W. Davenport, M. P. McCune, J. M. Hunt, P. W. Lee, S. A. Serano-Villar, S. Canaday, D. H. Sekaly, R-P Rodriguez, B. Sieg, S. F. Lederman, M. M. TI IL-15 and CMV co-infection drive CD8 T-cell expansion in HIV-1 infection SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 17th International Workshop on Co-Morbidities and Adverse Drug Reaction in HIV CY OCT 20-22, 2015 CL Barcelona, SPAIN C1 [Younes, S-A; Freeman, M. L.; Mudd, J. C.; Shive, C. L.; Panigrahi, S.; Canaday, D. H.; Sekaly, R-P; Rodriguez, B.; Sieg, S. F.; Lederman, M. M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Younes, S-A; Freeman, M. L.; Mudd, J. C.; Shive, C. L.; Panigrahi, S.; Canaday, D. H.; Sekaly, R-P; Rodriguez, B.; Sieg, S. F.; Lederman, M. M.] Univ Hosp, Cleveland, OH USA. [Reynaldi, A.; Davenport, M. P.] Univ New S Wales, Sydney, NSW, Australia. [Estes, J. D.; Deleage, C.; Lucero, C.] Frederick Natl Lab Canc Res, Frederick, MD USA. [Anderson, J.; Schacker, T. W.] Univ Minnesota, Minneapolis, MN USA. [McCune, J. M.; Hunt, P. W.; Lee, S. A.] Univ Calif Irvine, Irvine, CA USA. [Serano-Villar, S.] Univ Hosp Ramon & Cajal, Madrid, Spain. NR 0 TC 1 Z9 1 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2015 VL 20 SU 1 MA O08 BP A8 EP A9 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA DE8VV UT WOS:000370915700009 ER PT S AU Vecchiarelli, AG Taylor, JA Mizuuchi, K AF Vecchiarelli, Anthony G. Taylor, James A. Mizuuchi, Kiyoshi BE Ross, J Marshall, WF TI Reconstituting ParA/ParB-mediated transport of DNA cargo SO BUILDING A CELL FROM ITS COMPONENT PARTS SE Methods in Cell Biology LA English DT Review; Book Chapter ID DIFFUSION-RATCHET MECHANISM; F-PLASMID; PATTERN-FORMATION; PARTITION; PROTEIN; ATPASE; SOPA; SEGREGATION AB Protein gradients play key roles in subcellular spatial organization. In bacteria, ParA adenosine triphosphatases, or ATPases, form dynamic gradients on the nucleoid surface, which imparts positional information for the segregation, transport, and positioning of chromosomes, plasmids, and large protein assemblies. Despite the apparent simplicity of these minimal and self-organizing systems, the mechanism remains unclear. The small size of bacteria along with the number of physical and biochemical processes involved in subcellular organization makes it difficult to study these systems under controlled conditions in vivo. We developed a cell-free reconstitution technique that allows for the visualization of ParA-mediated cargo transport on a DNA carpet, which acts as a biomimetic of the nucleoid surface. Here, we present methods to express, purify, and visualize the dynamic properties of the SopABC system from F plasmid, considered a paradigm for the study of ParA-type systems. We hope similar cell-free studies will be used to address the biochemical and biophysical underpinnings of this ubiquitous transport scheme in bacteria. C1 [Vecchiarelli, Anthony G.; Taylor, James A.; Mizuuchi, Kiyoshi] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Vecchiarelli, AG (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM vecchiarelliag@mail.nih.gov FU Intramural NIH HHS NR 21 TC 2 Z9 2 U1 1 U2 8 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-679X BN 978-0-12-802450-8 J9 METHOD CELL BIOL JI Methods Cell Biol. PY 2015 VL 128 BP 243 EP 269 DI 10.1016/bs.mcb.2015.01.021 PG 27 WC Cell Biology SC Cell Biology GA BE3BW UT WOS:000370490800014 PM 25997351 ER PT J AU Maragh, S Veltri, RW Lund, SP Mangold, L Isharwal, S Christudass, CS Partin, AW Humphreys, EB Sorbara, L Srivastava, S Wagner, PD AF Maragh, Samantha Veltri, Robert W. Lund, Steven P. Mangold, Leslie Isharwal, Sumit Christudass, Christhunesa S. Partin, Alan W. Humphreys, Elizabeth B. Sorbara, Lynn Srivastava, Sudhir Wagner, Paul D. TI Evaluation of two mitochondrial DNA biomarkers for prostate cancer detection SO CANCER BIOMARKERS LA English DT Article DE Prostate; cancer; biomarker; mitochondrial DNA; 3.4kb deletion; urine; serum; FFPE; NIST; EDRN ID DETECTION RESEARCH NETWORK; BIOPSY SPECIMENS; HEALTH INDEX; COPY NUMBER; ANTIGEN; MUTATIONS; SERUM; MEN; REPRODUCIBILITY; PERCENT-P2PSA AB BACKGROUND: A 3.4kb deletion (3.4kb.) in mitochondrial DNA (mtDNA) found in histologically normal prostate biopsy specimens has been reported to be a biomarker for the increased probability of prostate cancer. Increased m