FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Feo, P Di Gioia, S Carloni, E Vitiello, B Tozzi, AE Vicari, S AF Feo, Paolo Di Gioia, Simona Carloni, Emanuela Vitiello, Benedetto Tozzi, Alberto Eugenio Vicari, Stefano TI Prevalence of psychiatric symptoms in children and adolescents one year after the 2009 L'Aquila earthquake SO BMC PSYCHIATRY LA English DT Article DE Abruzzo; Child and adolescent; Mental health; CBCL; Post traumatic stress disorder ID POSTTRAUMATIC-STRESS-DISORDER; POST TRAUMATIC STRESS; MENTAL-HEALTH STATUS; HURRICANE KATRINA; FAMILY CONTEXT; TRAIT ANXIETY; FOLLOW-UP; DISASTERS; YOUTH; SURVIVORS AB Background: In 2009, an earthquake devastated the Abruzzo region in Italy. Despite the occurrence of several disasters in this country, no study on mental health of Italian children has ever been conducted in complex emergencies. Objective of the study was to assess the prevalence of psychiatric symptoms among children in the affected area 12 to 17 months after the event. Methods: A community sample of 1839 3-14 years children was identified from the general population assigned to 37 paediatricians of the National Health System, including children living in the earthquake epicentre, the surrounding earthquake zone, and the adjacent non-affected areas. Psychiatric symptoms were assessed with the Child Behavior Checklist (CBCL) and the Youth Self Report (YSR), completed by 452 children aged 11-14 years. The association between symptoms and sociodemographic, health, family, and earthquake-related factors was examined. Results: The prevalence of CBCL-defined cases was 14.9% in the epicentre, 13.0% in the remainder earthquake zone, 13.9% in the unaffected area (p = .876). No differences among areas were found when comparing the YSR results. Prevalence of CBCL-defined post-traumatic stress (PTS) cases was 8.4% in the epicentre, 4.0% in the remainder earthquake zone, 2.2% in the unaffected area (p = .002). PTS and anxiety were significantly more frequent in the epicentre than in other areas only in the 6-10 year-old children group (respectively p = .009 and p = .014). In multivariate logistic analyses, factors associated with PTS were living in the epicentre (OR = 3.6) and child or maternal history of mental health care prior to the earthquake (respectively OR = 7.1 and OR = 4.5). Conclusions: Children living in the epicentre, particularly those 6-10 years old, had the highest prevalence of CBCL-defined cases, and of PTS and anxiety symptoms one year after the earthquake. No signs of increased psychopathology were detected in younger (3-5 years) or older children (11-14 years). Family and health related factors showed stronger association with psychiatric outcomes than earthquake-related factors. The identification of populations at higher risk of developing psychiatric symptoms has implications for public health interventions in complex emergencies. C1 [Feo, Paolo; Di Gioia, Simona; Vicari, Stefano] IRCCS, Bambino Gesu Childrens Hosp, Child & Adolescent Neuropsychiat Unit, Dept Neurosci, I-00165 Rome, Italy. [Carloni, Emanuela; Tozzi, Alberto Eugenio] IRCCS, Bambino Gesu Childrens Hosp, I-00165 Rome, Italy. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. RP Vicari, S (reprint author), IRCCS, Bambino Gesu Childrens Hosp, Child & Adolescent Neuropsychiat Unit, Dept Neurosci, Piazza SantOnofrio 4, I-00165 Rome, Italy. EM stefano.vicari@opbg.net RI Tozzi, Alberto Eugenio/F-9494-2012 OI Tozzi, Alberto Eugenio/0000-0002-6884-984X FU Ministers of the Infirm - Camillians; Caritas Italiana FX The study was supported by the Ministers of the Infirm - Camillians - and Caritas Italiana, which are gratefully acknowledged, and was conducted thanks to the collaboration of the Italian Federation of Paediatricians (FIMP) and Abruzzo Family Paediatricians of the National Health System: C Albano, PMC Battistella, MT Bontempo, G Caravelli, MF Chiarieri, G Ciarelli, V Curti, N D'Amario, G De Felice, P De Gregorio, E Del Vomano, F Di Croce, T Di Giampietro, A Di Marzio, P Di Saverio, M Ferretti, T Galante, G Giampaolo, V Ippoliti, A Lamborghini, M Lanci, G Lanciaprima, M Lepido, MG Libertini, MR Lombari, A Magnelli, L Marchione, DM Molina Meli, M Napoleone, R Nardi, G Olivieri, M Passali, R Rosati, RA Sacco, A Santilli, MR Sisto, ML Zaino. We thank the children and parents who participated, for their precious help. NR 68 TC 3 Z9 3 U1 3 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-244X J9 BMC PSYCHIATRY JI BMC Psychiatry PD SEP 24 PY 2014 VL 14 AR 270 DI 10.1186/s12888-014-0270-3 PG 12 WC Psychiatry SC Psychiatry GA AP9EA UT WOS:000342380200001 PM 25248437 ER PT J AU Kraft, MB Poudel, YB Kedei, N Lewin, NE Peach, ML Blumberg, PM Keck, GE AF Kraft, Matthew B. Poudel, Yam B. Kedei, Noemi Lewin, Nancy E. Peach, Megan L. Blumberg, Peter M. Keck, Gary E. TI Synthesis of a des-B-Ring Bryostatin Analogue Leads to an Unexpected Ring Expansion of the Bryolactone Core SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CANDIDATUS ENDOBUGULA SERTULA; BRYOZOAN BUGULA-NERITINA; PROTEIN-KINASE-C; INITIAL BIOLOGICAL EVALUATION; PHORBOL ESTER RECEPTOR; A-RING; ALZHEIMERS-DISEASE; PYRAN ANNULATION; ANTINEOPLASTIC AGENTS; NATURAL-PRODUCTS AB A convergent synthesis of a des-B-ring bryostatin analogue is described. This analogue was found to undergo an unexpected ring expansion of the bryolactone core to generate the corresponding 21-membered macrocycle. The parent analogue and the ring-expanded product both displayed nanomolar binding affinity for PKC. Despite containing A-ring substitution identical to that of bryostatin 1 and displaying bryostatin-like biological function, the des-B-ring analogues displayed a phorbol-like biological function in cells. These studies shed new light on the role of the bryostatin B-ring in conferring bryo-like biological function to bryostatin analogues. C1 [Kraft, Matthew B.; Poudel, Yam B.; Keck, Gary E.] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. [Kedei, Noemi; Lewin, Nancy E.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Peach, Megan L.] Leidos Biomed Res Inc, Basic Sci Program, Biol Chem Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Keck, GE (reprint author), Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. EM keck@chem.utah.edu FU NIH [GM28961]; Intramural Research Program, CCR, NCI, NIH [Z1A BC 005270]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank Prof. Michael Krische for informing us of his results with analogue WN-1 prior to publication and to graciously agreeing to submit our manuscripts together. Financial support was provided by the NIH through Grant GM28961 and through the Intramural Research Program, CCR, NCI, NIH (Project Z1A BC 005270). This project was also funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. NR 65 TC 13 Z9 13 U1 1 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 24 PY 2014 VL 136 IS 38 BP 13202 EP 13208 DI 10.1021/ja5078188 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA AP8KP UT WOS:000342328200033 PM 25207434 ER PT J AU Andrews, IP Ketcham, JM Blumberg, PM Kedei, N Lewin, NE Peach, ML Krische, MJ AF Andrews, Ian P. Ketcham, John M. Blumberg, Peter M. Kedei, Noemi Lewin, Nancy E. Peach, Megan L. Krische, Michael J. TI Synthesis of seco-B-Ring Bryostatin Analogue WN-1 via C-C Bond-Forming Hydrogenation: Critical Contribution of the B-Ring in Determining Bryostatin-like and Phorbol 12-Myristate 13-Acetate-like Properties SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PROTEIN-KINASE-C; PERIODATE-PERMANGANATE OXIDATIONS; DISEASE TRANSGENIC MICE; BIOLOGICAL EVALUATION; ALZHEIMERS-DISEASE; LEUKEMIA-CELLS; A-RING; ANTITUMOR MACROLIDES; ASYMMETRIC-SYNTHESIS; BUGULA-NERITINA AB The seco-B-ring bryostatin analogue, macrodiolide WN-1, was prepared in 17 steps (longest linear sequence) and 30 total steps with three bonds formed via hydrogen-mediated C C coupling. This synthetic route features a palladium-catalyzed alkoxycarbonylation of a C-2-symmetric diol to form the C9-deoxygenated bryostatin A-ring. WN-1 binds to PKC alpha (K-i = 16.1 nM) and inhibits the growth of multiple leukemia cell lines. Although structural features of the WN-1 A-ring and C-ring are shared by analogues that display bryostatin-like behavior, WN-1 displays PMA-like behavior in U937 cell attachment and proliferation assays, as well as in K562 and MV-4-11 proliferation assays. Molecular modeling studies suggest the pattern of internal hydrogen bonds evident in bryostatin 1 is preserved in WN-1, and that upon docking WN-1 into the crystal structure of the C1b domain of PKC delta, the binding mode of bryostatin 1 is reproduced. The collective data emphasize the critical contribution of the B-ring to the function of the upper portion of the molecule in conferring a bryostatin-like pattern of biological activity. C1 [Andrews, Ian P.; Ketcham, John M.; Krische, Michael J.] Univ Texas Austin, Dept Chem & Biochem, Austin, TX 78712 USA. [Blumberg, Peter M.; Kedei, Noemi; Lewin, Nancy E.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Peach, Megan L.] Leidos Biomed Res Inc, Basic Sci Program, Biol Chem Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Blumberg, PM (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov; mkrische@mail.utexas.edu FU Robert A. Welch Foundation [F-0038]; NIH-NIGMS [RO1-GM093905]; Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z1A BC 005270]; Cancer Prevention Research Institute of Texas [RP101501]; Federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The Robert A. Welch Foundation (F-0038) and the NIH-NIGMS (RO1-GM093905) are acknowledged for partial support of this research. Partial support was also provided by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Z1A BC 005270). The Cancer Prevention Research Institute of Texas (RP101501) is acknowledged for Postdoctoral Fellowship support (I.P.A.). Skilled technical assistance was provided by Kim Wasik. This project was funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. NR 85 TC 11 Z9 11 U1 0 U2 38 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 24 PY 2014 VL 136 IS 38 BP 13209 EP 13216 DI 10.1021/ja507825s PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA AP8KP UT WOS:000342328200034 PM 25207655 ER PT J AU Burger, JD Doughty, E Khare, R Wei, CH Mishra, R Aberdeen, J Tresner-Kirsch, D Wellner, B Kann, MG Lu, ZY Hirschman, L AF Burger, John D. Doughty, Emily Khare, Ritu Wei, Chih-Hsuan Mishra, Rajashree Aberdeen, John Tresner-Kirsch, David Wellner, Ben Kann, Maricel G. Lu, Zhiyong Hirschman, Lynette TI Hybrid curation of gene-mutation relations combining automated extraction and crowdsourcing SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID BIOMEDICAL LITERATURE; BIOCREATIVE III; DATABASE; NORMALIZATION; VARIANTS; TASK; TEXT; ASSOCIATION; MEDICINE AB Background: This article describes capture of biological information using a hybrid approach that combines natural language processing to extract biological entities and crowdsourcing with annotators recruited via Amazon Mechanical Turk to judge correctness of candidate biological relations. These techniques were applied to extract gene-mutation relations from biomedical abstracts with the goal of supporting production scale capture of gene-mutation-disease findings as an open source resource for personalized medicine. Results: The hybrid system could be configured to provide good performance for gene-mutation extraction (precision similar to 82%; recall similar to 70% against an expert-generated gold standard) at a cost of $0.76 per abstract. This demonstrates that crowd labor platforms such as Amazon Mechanical Turk can be used to recruit quality annotators, even in an application requiring subject matter expertise; aggregated Turker judgments for gene-mutation relations exceeded 90% accuracy. Over half of the precision errors were due to mismatches against the gold standard hidden from annotator view (e. g. incorrect EntrezGene identifier or incorrect mutation position extracted), or incomplete task instructions (e. g. the need to exclude nonhuman mutations). Conclusions: The hybrid curation model provides a readily scalable cost-effective approach to curation, particularly if coupled with expert human review to filter precision errors. We plan to generalize the framework and make it available as open source software. C1 [Burger, John D.; Aberdeen, John; Tresner-Kirsch, David; Wellner, Ben; Hirschman, Lynette] Mitre Corp, Bedford, MA 01730 USA. [Doughty, Emily] Stanford Univ, Biomed Informat Program, Stanford, CA 94305 USA. [Khare, Ritu; Wei, Chih-Hsuan; Lu, Zhiyong] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Mishra, Rajashree; Kann, Maricel G.] Univ Maryland Baltimore Cty, Baltimore, MD 21250 USA. RP Burger, JD (reprint author), Mitre Corp, Burlington Rd, Bedford, MA 01730 USA. EM john@mitre.org; lynette@mitre.org FU Intramural Research Program of NIH, National Library of Medicine; National Institutes of Health (NIH) [1K22CA143148]; American Cancer Society, ACS-IRG; MITRE Corporation FX This research has been partially funded by the Intramural Research Program of NIH, National Library of Medicine and by The National Institutes of Health (NIH) grant 1K22CA143148 to M. G. K. (PI) and the American Cancer Society, ACS-IRG grant to M. G. K. (PI). The curation results reported in Supplementary Appendix A (Returking of Random HITS) was performed at University of Maryland, Baltimore County, under the supervision of M. G. K. by Urooj Aqeel, Veer Gariwala, Mitsu Shah, Nikhil Yesupriya and Ye Sol Yun. Funding for open access charge: The MITRE Corporation. NR 39 TC 9 Z9 9 U1 2 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD SEP 24 PY 2014 AR bau094 DI 10.1093/database/bau094 PG 13 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AP4MT UT WOS:000342051800001 ER PT J AU Leitl, MD Potter, DN Cheng, KJ Rice, KC Carlezon, WA Negus, SS AF Leitl, Michael D. Potter, David N. Cheng, Kejun Rice, Kenner C. Carlezon, William A., Jr. Negus, S. Stevens TI Sustained pain-related depression of behavior: effects of intraplantar formalin and complete freund's adjuvant on intracranial self-stimulation (ICSS) and endogenous kappa opioid biomarkers in rats SO MOLECULAR PAIN LA English DT Article DE Complete Freund's adjuvant; Formalin; Pain/analgesics; Depression; Intracranial self-stimulation; Kappa opioid ID ANTERIOR CINGULATE CORTEX; LONG-TERM HYPERALGESIA; INFLAMMATORY PAIN; FACIAL EXPRESSIONS; SPINAL-CORD; GUINEA-PIG; HIND PAW; RELEASE; STRESS; ACTIVATION AB Background: Intraplantar administration of complete Freund's adjuvant (CFA) and formalin are two noxious stimuli commonly used to produce sustained pain-related behaviors in rodents for research on neurobiology and treatment of pain. One clinically relevant manifestation of pain is depression of behavior and mood. This study compared effects of intraplantar CFA and formalin on depression of positively reinforced operant behavior in an assay of intracranial self-stimulation (ICSS) in rats. Effects of CFA and formalin on other physiological and behavioral measures, and opioid effects on formalin-induced depression of ICSS, were also examined. Results: There were four main findings. First, consistent with previous studies, both CFA and formalin produced similar paw swelling and mechanical hypersensitivity. Second, CFA produced weak and transient depression of ICSS, whereas formalin produced a more robust and sustained depression of ICSS that lasted at least 14 days. Third, formalin-induced depression of ICSS was reversed by morphine doses that did not significantly alter ICSS in saline-treated rats, suggesting that formalin effects on ICSS can be interpreted as an example of pain-related and analgesic-reversible depression of behavior. Finally, formalin-induced depression of ICSS was not associated with changes in central biomarkers for activation of endogenous kappa opioid systems, which have been implicated in depressive-like states in rodents, nor was it blocked by the kappa antagonist norbinaltorphimine. Conclusions: These results suggest differential efficacy of sustained pain stimuli to depress brain reward function in rats as assessed with ICSS. Formalin-induced depression of ICSS does not appear to engage brain kappa opioid systems. C1 [Leitl, Michael D.; Negus, S. Stevens] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23284 USA. [Potter, David N.; Carlezon, William A., Jr.] Harvard Univ, McLean Hosp, Sch Med, Behav Genet Lab, Belmont, MA USA. [Cheng, Kejun; Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, NIH, Bethesda, MD USA. RP Negus, SS (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, 410 N 12th St,POB 980613, Richmond, VA 23284 USA. EM ssnegus@vcu.edu FU NIH; National Institute on Neurological Disorders and Stroke; National Institute on Drug Abuse of the National Institutes of Health [R01 NS070715, R01 DA030404]; Intramural Research Programs of the National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism; [T32 DA007027] FX Dr Carlezon declares that his research has been funded by NIH. He has a US patent covering the use of k -antagonists in the treatment of depressive disorders (Assignee: McLean Hospital). In the past 3 years, Dr Carlezon has received compensation for professional services from The American College of Neuropsychopharmacology and Concert Pharmaceuticals. Dr Negus declares that his research has been funded by NIH. During the past 3 years, he has received compensation as a consultant for or collaborator with the pharmaceutical companies Alkermes and Grunenthal for projects related to abuse liability assessment. Research reported in this publication was supported by the National Institute on Neurological Disorders and Stroke and the National Institute on Drug Abuse of the National Institutes of Health under Award Numbers R01 NS070715 and R01 DA030404. In addition, Mr. Leitl was supported in part by T32 DA007027. A portion of this work was also supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. NR 54 TC 16 Z9 16 U1 3 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD SEP 23 PY 2014 VL 10 AR 62 DI 10.1186/1744-8069-10-62 PG 11 WC Neurosciences SC Neurosciences & Neurology GA AS9KJ UT WOS:000344561400001 PM 25245060 ER PT J AU Tapia-Pizarro, A Figueroa, P Brito, J Marin, JC Munroe, DJ Croxatto, HB AF Tapia-Pizarro, Alejandro Figueroa, Paula Brito, Julio Carlos Marin, Juan Munroe, David J. Croxatto, Horacio B. TI Endometrial gene expression reveals compromised progesterone signaling in women refractory to embryo implantation SO REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY LA English DT Article DE Endometrium; Gene expression; PROGINS; Implantation failure ID UNEXPLAINED INFERTILITY; TRANSCRIPTION FACTORS; MENSTRUAL-CYCLE; CANDIDATE GENES; RECEPTIVITY; GLYCODELIN; MIFEPRISTONE; CELLS; RESISTANCE; FAILURE AB Background: Endometrial function is essential for embryo implantation. The aim of this study was to analyze gene expression profiles from individual endometrial samples obtained from women with repeated implantation failure after IVF in oocyte donation programs. Methods: Seventeen volunteers were recruited: women who had previously participated as recipients in oocyte donation cycles and repeatedly exhibited implantation failure (Group A, study group, n = 5) or had at least one successful cycle (Group B, control group, n = 6) and spontaneously fertile women (Group C, normal fertility group, n = 6). An endometrial cycle was induced with exogenous estradiol (E2) and progesterone (P) and an endometrial sample was collected on the seventh day of P treatment. Results: Transcriptome analysis showed 82 genes with consistent differential gene expression when comparing A vs. B and A vs. C. One hundred transcripts differentially expressed in group A vs. B have been shown to be regulated by P, suggesting compromised P signaling in the endometrium. The P receptor (PR) mutation PROGINS was not detected in women from group A. Semi-quantitation of immunoreactive PRA/B, PRB and Sp1 (a transcription factor related to P signaling) in paraffin-embedded endometrial sections, did not show statistically significant differences amongst groups. However immunostaining glycodelin was significantly decreased in endometrial samples from group A Conclusions: We conclude that some cases of repeated implantation failure could be associated with an aberrant gene expression profile. Compromised P signaling might be the underlying mechanism for such endometrial gene expression deregulation in women with repeated implantation failure. C1 [Tapia-Pizarro, Alejandro] Univ Chile, Fac Med, Inst Invest Materno Infantil, Santiago 7, Chile. [Figueroa, Paula; Brito, Julio] Univ Mayor, Fac Med, Santiago, Chile. [Carlos Marin, Juan] Univ Bio Bio, Fac Ciencias, Chillan, Chile. [Munroe, David J.] NCI, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Croxatto, Horacio B.] Univ Andres Bello, Ctr Integrat Med & Innovat Sci, Santiago, Chile. RP Tapia-Pizarro, A (reprint author), Univ Chile, Fac Med, Inst Invest Materno Infantil, Santiago 7, Chile. EM atapiap@gmail.com FU FONDECYT [11100443, 1140614]; FONDAP [15010006] FX This work was supported by FONDECYT 11100443 / 1140614 and FONDAP 15010006. NR 58 TC 5 Z9 6 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7827 J9 REPROD BIOL ENDOCRIN JI Reprod. Biol. Endocrinol. PD SEP 23 PY 2014 VL 12 AR 92 DI 10.1186/1477-7827-12-92 PG 15 WC Endocrinology & Metabolism; Reproductive Biology SC Endocrinology & Metabolism; Reproductive Biology GA AS2MX UT WOS:000344115400001 PM 25248672 ER PT J AU Prasad, V Goldstein, JA AF Prasad, Vinay Goldstein, Jeffrey A. TI US News and World Report Cancer Hospital Rankings: Do They Reflect Measures of Research Productivity? SO PLOS ONE LA English DT Article ID U.S. NEWS; REPUTATION; AMERICA AB Context: Prior research has faulted the US News and World Report hospital specialty rankings for excessive reliance on reputation, a subjective measure of a hospital's performance. Objective: To determine whether and to what extent reputation correlates with objective measures of research productivity among cancer hospitals. Design: A retrospective observational study. Setting: Automated search of NIH Reporter, BioEntrez, BioMedline and Clinicaltrials.gov databases. Participants: The 50 highest ranked cancer hospitals in 2013's US News and World Report Rankings. Exposure: We ascertained the number of NCI funded grants, and the cumulative funds received by each cancer center. Additionally, we identified the number of phase I, phase II, and phase III studies published and indexed in MEDLINE, and registered at clinicaltrials.gov. All counts were over the preceding 5 years. For published articles, we summed the impact factor of the journals in which they appeared. Trials were attributed to centers on the basis of the affiliation of the lead author or study principal investigator. Main Outcome: Correlation coefficients from simple and multiple linear regressions for measures of research productivity and a center's reputation. Results: All measures of research productivity demonstrated robust correlation with reputation (meanr-squared = 0.65, median r-squared = 0.68, minimum r-squared = .41, maximum r-squared = 0.80). A multivariable model showed that 93% of the variation in reputation is explained by objective measures. Conclusion: Contrary to prior criticism, the majority of reputation, used in US News and World Rankings, can be explained by objective measures of research productivity among cancer hospitals. C1 [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Goldstein, Jeffrey A.] Univ Chicago, Prtizker Sch Med, Chicago, IL 60637 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov OI Prasad, Vinay/0000-0002-6110-8221 NR 8 TC 9 Z9 9 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 23 PY 2014 VL 9 IS 9 AR e107803 DI 10.1371/journal.pone.0107803 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP8TL UT WOS:000342351800040 PM 25247921 ER PT J AU Rietveld, CA Esko, T Davies, G Pers, TH Turley, P Benyamin, B Chabris, CF Emilsson, V Johnson, AD Lee, JJ de Leeuw, C Marioni, RE Medland, SE Miller, MB Rostapshova, O van der Lee, SJ Vinkhuyzen, AAE Amin, N Conley, D Derringer, J van Duijn, CM Fehrmann, R Franke, L Glaeser, EL Hansell, NK Hayward, C Iacono, WG Ibrahim-Verbaas, C Jaddoe, V Karjalainen, J Laibson, D Lichtenstein, P Liewald, DC Magnusson, PKE Martin, NG Mcgue, M McMahon, G Pedersen, NL Pinker, S Porteous, DJ Posthuma, D Rivadeneira, F Smith, BH Starr, JM Tiemeier, H Timpson, NJ Trzaskowski, M Uitterlinden, AG Verhulst, FC Ward, ME Wright, MJ Smith, GD Deary, IJ Johannesson, M Plomin, R Visscher, PM Benjamin, DJ Cesarini, D Koellinger, PD AF Rietveld, Cornelius A. Esko, Tonu Davies, Gail Pers, Tune H. Turley, Patrick Benyamin, Beben Chabris, Christopher F. Emilsson, Valur Johnson, Andrew D. Lee, James J. de Leeuw, Christiaan Marioni, Riccardo E. Medland, Sarah E. Miller, Michael B. Rostapshova, Olga van der Lee, Sven J. Vinkhuyzen, Anna A. E. Amin, Najaf Conley, Dalton Derringer, Jaime van Duijn, Cornelia M. Fehrmann, Rudolf Franke, Lude Glaeser, Edward L. Hansell, Narelle K. Hayward, Caroline Iacono, William G. Ibrahim-Verbaas, Carla Jaddoe, Vincent Karjalainen, Juha Laibson, David Lichtenstein, Paul Liewald, David C. Magnusson, Patrik K. E. Martin, Nicholas G. McGue, Matt McMahon, George Pedersen, Nancy L. Pinker, Steven Porteous, David J. Posthuma, Danielle Rivadeneira, Fernando Smith, Blair H. Starr, John M. Tiemeier, Henning Timpson, Nicholas J. Trzaskowski, Maciej Uitterlinden, Andre G. Verhulst, Frank C. Ward, Mary E. Wright, Margaret J. Smith, George Davey Deary, Ian J. Johannesson, Magnus Plomin, Robert Visscher, Peter M. Benjamin, Daniel J. Cesarini, David Koellinger, Philipp D. TI Common genetic variants associated with cognitive performance identified using the proxy-phenotype method SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GENOME-WIDE ASSOCIATION; ACADEMIC-ACHIEVEMENT; INTELLIGENCE; LOCI; COMPONENTS; GWAS AB We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. C1 [Rietveld, Cornelius A.; Koellinger, Philipp D.] Erasmus Univ, Erasmus Sch Econ, Dept Appl Econ, NL-3000 DR Rotterdam, Netherlands. [Rietveld, Cornelius A.; Jaddoe, Vincent; Rivadeneira, Fernando; Tiemeier, Henning; Uitterlinden, Andre G.; Koellinger, Philipp D.] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Ibrahim-Verbaas, Carla] Erasmus MC, Dept Neurol, NL-3000 CA Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [van der Lee, Sven J.; Amin, Najaf; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol & Biostat, Genet Epidemiol Unit, NL-3000 CA Rotterdam, Netherlands. [Jaddoe, Vincent] Erasmus MC, Generat Study Grp R, NL-3000 CA Rotterdam, Netherlands. [Esko, Tonu; Pers, Tune H.] Boston Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA. [Esko, Tonu; Pers, Tune H.] Broad Inst Massachusetts Inst Technol & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Esko, Tonu] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Esko, Tonu] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Davies, Gail; Marioni, Riccardo E.; Liewald, David C.; Porteous, David J.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Davies, Gail; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Turley, Patrick; Glaeser, Edward L.; Laibson, David; Lichtenstein, Paul] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Lee, James J.; Pinker, Steven] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Benyamin, Beben; Marioni, Riccardo E.; Vinkhuyzen, Anna A. E.; Visscher, Peter M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Chabris, Christopher F.] Union Coll, Dept Psychol, Schenectady, NY 12308 USA. [Emilsson, Valur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Emilsson, Valur] Univ Iceland, Fac Pharmaceut Sci, IS-107 Reykjavik, Iceland. [Johnson, Andrew D.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Lee, James J.; Miller, Michael B.; Iacono, William G.; McGue, Matt] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [de Leeuw, Christiaan; Posthuma, Danielle] Vrije Univ Amsterdam, Dept Complex Trait Genet, NL-1081 HV Amsterdam, Netherlands. [de Leeuw, Christiaan; Posthuma, Danielle] Vrije Univ Amsterdam Med Ctr, NL-1081 HV Amsterdam, Netherlands. [de Leeuw, Christiaan] Radboud Univ Nijmegen, Fac Sci, Inst Comp & Informat Sci, Machine Learning Grp, NL-6500 GL Nijmegen, Netherlands. [Marioni, Riccardo E.; Hayward, Caroline; Porteous, David J.] Univ Edinburgh, Ctr Genom & Expt Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Hayward, Caroline] Univ Edinburgh, Inst Genet & Mol Med, Human Genet Unit, MRC, Edinburgh EH4 2XU, Midlothian, Scotland. [Medland, Sarah E.] QIMR Berghofer Med Res Inst, Quantitat Genet Lab, Brisbane, Qld 4029, Australia. [Martin, Nicholas G.] QIMR Berghofer Med Res Inst, Genet Epidemiol Lab, Brisbane, Qld 4029, Australia. [Rostapshova, Olga; Ibrahim-Verbaas, Carla] Harvard Univ, Kennedy Sch, Cambridge, MA 02139 USA. [Conley, Dalton] NYU, Dept Sociol, New York, NY 10012 USA. [Cesarini, David] NYU, Dept Econ, Ctr Expt Social Sci, New York, NY 10012 USA. [Derringer, Jaime] Univ Illinois, Dept Psychol, Urbana, IL 61820 USA. [van Duijn, Cornelia M.] Leiden Univ, Med Ctr, Ctr Med Syst Biol, NL-2300 RC Leiden, Netherlands. [Fehrmann, Rudolf; Franke, Lude; Karjalainen, Juha] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands. [Hansell, Narelle K.; Wright, Margaret J.] QIMR Berghofer Med Res Inst, Neuroimaging Genet Grp, Brisbane, Qld 4029, Australia. [Magnusson, Patrik K. E.; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [McMahon, George; Ward, Mary E.] Univ Bristol, Sch Social & Community Med, Bristol BS8 2PR, Avon, England. [Posthuma, Danielle; Tiemeier, Henning; Verhulst, Frank C.] Erasmus MC, Dept Child & Adolescent Psychiat, NL-3000 CB Rotterdam, Netherlands. [Posthuma, Danielle] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, NL-1081 BT Amsterdam, Netherlands. [Smith, Blair H.] Univ Dundee, Med Res Inst, Dundee DD2 4RB, Scotland. [Timpson, Nicholas J.; Smith, George Davey] Univ Bristol, MRC, Integrat Epidemiol Unit, Bristol BS8 2PR, Avon, England. [Trzaskowski, Maciej; Plomin, Robert] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, MRC, London SE5 8AF, England. [Johannesson, Magnus] Stockholm Sch Econ, Dept Econ, S-11383 Stockholm, Sweden. [Visscher, Peter M.] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld 4102, Australia. [Benjamin, Daniel J.] Cornell Univ, Dept Econ, Ithaca, NY 14853 USA. [Cesarini, David] NYU, Inst Interdisciplinary Study Decis Making, New York, NY 10012 USA. [Koellinger, Philipp D.] Univ Amsterdam, Fac Econ & Business, NL-1012 WX Amsterdam, Netherlands. RP Benjamin, DJ (reprint author), Cornell Univ, Dept Econ, Ithaca, NY 14853 USA. EM daniel.benjamin@gmail.com; p.d.koellinger@uva.nl RI Magnusson, Patrik/C-4458-2017; Medland, Sarah/C-7630-2013; Fehrmann, Rudolf/E-2551-2011; Johannesson, Magnus/E-9680-2011; Rivadeneira, Fernando/O-5385-2015; Hansell, Narelle/A-4553-2016; Wright, Margaret/A-4560-2016; Fox, Laura /C-6249-2016; Johnson, Andrew/G-6520-2013; Franke, Lude/P-7036-2016; Karjalainen, Juha/P-8624-2016; Davey Smith, George/A-7407-2013 OI Vinkhuyzen, Anna/0000-0003-3352-0603; Visscher, Peter/0000-0002-2143-8760; Smith, Blair/0000-0002-5362-9430; Benyamin, Beben/0000-0001-5608-2293; Martin, Nicholas/0000-0003-4069-8020; Koellinger, Philipp/0000-0001-7413-0412; Cesarini, David/0000-0002-0043-009X; Tiemeier, Henning/0000-0002-4395-1397; Esko, Tonu/0000-0003-1982-6569; lichtenstein, paul/0000-0003-3037-5287; Plomin, Robert/0000-0002-0756-3629; Timpson, Nicholas/0000-0002-7141-9189; Medland, Sarah/0000-0003-1382-380X; Fehrmann, Rudolf/0000-0002-7516-315X; Johannesson, Magnus/0000-0001-8759-6393; Rivadeneira, Fernando/0000-0001-9435-9441; Hansell, Narelle/0000-0002-8229-9741; Wright, Margaret/0000-0001-7133-4970; Franke, Lude/0000-0002-5159-8802; Davey Smith, George/0000-0002-1407-8314 FU Social Science Genetic Association Consortium (SSGAC); National Science Foundation; National Institutes of Health (NIH)/Office of Behavioral and Social Science Research (OBSSR) [SES-1064089]; Ragnar Soderberg Foundation [E9/11]; Swedish Research Council [412-2013-1061]; National Institute on Aging/NIH [P01AG005842, P01AG005842-20S2, P30AG012810, T32AG000186-23] FX This research was carried out under the auspices of the Social Science Genetic Association Consortium (SSGAC), a cooperative enterprise among medical researchers and social scientists that coordinates genetic association studies for social science variables. Data for our analyses come from many studies and organizations, some of which are subject to a Material Transfer Agreement (SI Appendix). Results from the meta-analysis, the complete biological annotation, and a frequently asked questions document describing the findings of this paper are available at the website of the consortium: www.ssgac.org. The formation of the SSGAC was made possible by a National Science Foundation EArly-concept Grant for Exploratory Research (EAGER) grant and National Institutes of Health (NIH)/Office of Behavioral and Social Science Research (OBSSR) Supplemental Grant SES-1064089. This research was funded, in part, by Ragnar Soderberg Foundation Grant E9/11, Swedish Research Council Grant 412-2013-1061, and National Institute on Aging/NIH Grants P01AG005842, P01AG005842-20S2, P30AG012810, and T32AG000186-23. A full list of acknowledgments is in SI Appendix. NR 24 TC 48 Z9 48 U1 3 U2 45 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 SEP 23 PY 2014 VL 111 IS 38 BP 13790 EP 13794 DI 10.1073/pnas.1404623111 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP3PC UT WOS:000341988200038 PM 25201988 ER PT J AU Ma, CA Pusso, A Wu, LM Zhao, YG Hoffmann, V Notarangelo, LD Fowlkes, BJ Jain, A AF Ma, Chi A. Pusso, Antonia Wu, Liming Zhao, Yongge Hoffmann, Victoria Notarangelo, Luigi D. Fowlkes, B. J. Jain, Ashish TI Novel INHAT Repressor (NIR) is required for early lymphocyte development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell cycle; apoptosis; transcription ID CENTER B-CELLS; V(D)J RECOMBINATION; AURORA-B; ALPHA-BETA; T-CELLS; P53; MICE; SURVIVAL; PHOSPHORYLATION; ACTIVATION AB Novel inhibitor of histone acetyltransferase repressor (NIR) is a transcriptional corepressor with inhibitor of histone acetyltransferase activity and is a potent suppressor of p53. Although NIR deficiency in mice leads to early embryonic lethality, lymphoid-restricted deletion resulted in the absence of double-positive CD4(+)CD8(+) thymocytes, whereas bone-marrow-derived B cells were arrested at the B220(+)CD19(-)pro-B-cell stage. V(D) J recombination was preserved in NIR-deficient DN3 double-negative thymocytes, suggesting that NIR does not affect p53 function in response to physiologic DNA breaks. Nevertheless, the combined deficiency of NIR and p53 provided rescue of DN3L double-negative thymocytes and their further differentiation to double-and single-positive thymocytes, whereas B cells in the marrow further developed to the B220(+)CD19(+) pro-B-cell stage. Our results show that NIR cooperate with p53 to impose checkpoint for the generation of mature B and T lymphocytes. C1 [Ma, Chi A.; Pusso, Antonia; Wu, Liming; Zhao, Yongge; Jain, Ashish] NIAID, Clin Immunol Unit, Lab Host Defenses, Bethesda, MD 20892 USA. [Fowlkes, B. J.] NIAID, Immunol Lab, Bethesda, MD 20892 USA. [Hoffmann, Victoria] NIH, Diagnost & Res Serv Branch, Bethesda, MD 20892 USA. [Notarangelo, Luigi D.] Harvard Univ, Sch Med, Childrens Hosp, Dept Med, Boston, MA 02115 USA. RP Jain, A (reprint author), NIAID, Clin Immunol Unit, Lab Host Defenses, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ashish.jain1@merck.com RI Notarangelo, Luigi/F-9718-2016 OI Notarangelo, Luigi/0000-0002-8335-0262 FU National Institute of Allergy and Infectious Diseases/National Institutes of Health FX We thank Warren Strober, R my Bosselut, David Allman, and Ronald Germain for their input and suggestions; Joshua Milner for support; Donna Butcher, Miriam Anver, Angela Thornton, Mathew Sebastian, Andrea Carpenter, Atsushi Kitani, and Ivan Fuss for technical assistance; and Mary Derry for editorial assistance. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases/National Institutes of Health. NR 35 TC 0 Z9 0 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 23 PY 2014 VL 111 IS 38 BP 13930 EP 13935 DI 10.1073/pnas.1310118111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP3PC UT WOS:000341988200061 PM 25201955 ER PT J AU Lee, WY Sanz, MJ Wong, CHY Hardy, PO Salman-Dilgimen, A Moriarty, TJ Chaconas, G Marques, A Krawetz, R Mody, CH Kubes, P AF Lee, Woo-Yong Sanz, Maria-Jesus Wong, Connie H. Y. Hardy, Pierre-Olivier Salman-Dilgimen, Aydan Moriarty, Tara J. Chaconas, George Marques, Adriana Krawetz, Roman Mody, Christopher H. Kubes, Paul TI Invariant natural killer T cells act as an extravascular cytotoxic barrier for joint-invading Lyme Borrelia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE joint iNKT cells; granzyme B; Lyme arthritis ID NKT CELLS; BLOOD-VESSELS; BURGDORFERI; ACTIVATION; ARTHRITIS; ANTIGENS; INFLAMMATION; COMPLEMENT; EVOLUTION; MONOCYTES AB CXCR6-GFP(+) cells, which encompass 70% invariant natural killer T cells (iNKT cells), have been found primarily patrolling inside blood vessels in the liver. Although the iNKT cells fail to interact with live pathogens, they do respond to bacterial glycolipids presented by CD1d on liver macrophage that have caught the microbe. In contrast, in this study using dual laser multichannel spinning-disk intravital microscopy of joints, the CXCR6-GFP, which also made up 60-70% iNKT cells, were not found in the vasculature but rather closely apposed to and surrounding the outside of blood vessels, and to a lesser extent throughout the extravascular space. These iNKT cells also differed in behavior, responding rapidly and directly to joint-homing pathogens like Borrelia burgdorferi, which causes Lyme disease. These iNKT cells interacted with B. burgdorferi at the vessel wall and disrupted dissemination attempts by these microbes into joints. Successful penetrance of B. burgdorferi out of the vasculature and into the joint tissue was met by a lethal attack by extravascular iNKT cells through a granzyme-dependent pathway, an observation also made in vitro for iNKT cells from joint but not liver or spleen. These results suggest a novel, critical extravascular iNKT cell immune surveillance in joints that functions as a cytotoxic barrier and explains a large increase in pathogen burden of B. burgdorferi in the joint of iNKT cell-deficient mice, and perhaps the greater susceptibility of humans to this pathogen because of fewer iNKT cells in human joints. C1 [Lee, Woo-Yong; Wong, Connie H. Y.; Kubes, Paul] Univ Calgary, Dept Physiol & Pharmacol, Calgary, AB T2N 4N1, Canada. [Hardy, Pierre-Olivier; Chaconas, George; Mody, Christopher H.] Univ Calgary, Dept Microbiol & Infect Dis, Calgary, AB T2N 4N1, Canada. [Salman-Dilgimen, Aydan; Moriarty, Tara J.; Chaconas, George] Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada. [Krawetz, Roman] Univ Calgary, Dept Surg, Calgary, AB T2N 4N1, Canada. [Krawetz, Roman] Univ Calgary, Dept Cell Biol & Anat, Calgary, AB T2N 4N1, Canada. [Mody, Christopher H.] Univ Calgary, Dept Internal Med, Calgary, AB T2N 4N1, Canada. [Lee, Woo-Yong; Wong, Connie H. Y.; Hardy, Pierre-Olivier; Salman-Dilgimen, Aydan; Moriarty, Tara J.; Chaconas, George; Mody, Christopher H.; Kubes, Paul] Univ Calgary, Calvin Phoebe & Joan Snyder Inst Chron Dis, Calgary, AB T2N 4N1, Canada. [Sanz, Maria-Jesus] Univ Valencia, Fac Med, Dept Pharmacol, E-46010 Valencia, Spain. [Sanz, Maria-Jesus] Univ Valencia, INCLIVA, Inst Hlth Res, E-46010 Valencia, Spain. [Marques, Adriana] NIAID, Clin Studies Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Kubes, P (reprint author), Univ Calgary, Calvin Phoebe & Joan Snyder Inst Chron Dis, Calgary, AB T2N 4N1, Canada. EM pkubes@ucalgary.ca RI Moriarty, Tara/K-1684-2016; OI Moriarty, Tara/0000-0002-1751-5145; Mody, Christopher H./0000-0001-7264-3679; Wong, Connie/0000-0002-9020-1847 FU Canadian Institutes for Health Research; Canadian Foundation for Innovation; Spanish Ministry of Education [PR2010-0477]; Canada Research Chair in the Molecular Biology of Lyme borreliosis; Alberta Heritage Foundation for Medical Research; Canadian Institutes of Health Research [MOP-53086] FX We thank the Live Cell Imaging Facility for training/assistance related to microscopy (P. Colarusso and K. Stevens); the Flow Cytometry Facility for their assistance (L. Kennedy and Y. Liu); and T. Nussbaumer for excellent technical support. Work in the authors' laboratory is supported by Canadian Institutes for Health Research operating grants and group grant, as well as the Canadian Foundation for Innovation; P. K. is an Alberta Innovates Health Solutions Scientist and the Snyder Chair in Critical Care Medicine; M.-J.S. is supported by a grant from the Spanish Ministry of Education (PR2010-0477); G. C. received salary support as the Canada Research Chair in the Molecular Biology of Lyme borreliosis and in the form of a Scientist Award from the Alberta Heritage Foundation for Medical Research, as well as operating grant support from the Canadian Institutes of Health Research (MOP-53086). NR 34 TC 12 Z9 12 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 23 PY 2014 VL 111 IS 38 BP 13936 EP 13941 DI 10.1073/pnas.1404769111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP3PC UT WOS:000341988200062 PM 25205813 ER PT J AU Ichii, O Otsuka-Kanazawa, S Nakamura, T Ueno, M Kon, Y Chen, WP Rosenberg, AZ Kopp, JB AF Ichii, Osamu Otsuka-Kanazawa, Saori Nakamura, Teppei Ueno, Masaaki Kon, Yasuhiro Chen, Weiping Rosenberg, Avi Z. Kopp, Jeffrey B. TI Podocyte Injury Caused by Indoxyl Sulfate, a Uremic Toxin and Aryl-Hydrocarbon Receptor Ligand SO PLOS ONE LA English DT Article ID NF-KAPPA-B; REGULATES RENAL EXPRESSION; GENE-EXPRESSION; 3-INDOXYL SULFATE; OXIDATIVE STRESS; TUBULAR CELLS; UP-REGULATION; ACTIVATION; MOUSE; RATS AB Indoxyl sulfate is a uremic toxin and a ligand of the aryl-hydrocarbon receptor (AhR), a transcriptional regulator. Elevated serum indoxyl sulfate levels may contribute to progressive kidney disease and associated vascular disease. We asked whether indoxyl sulfate injures podocytes in vivo and in vitro. Mice exposed to indoxyl sulfate for 8 w exhibited prominent tubulointerstitial lesions with vascular damage. Indoxyl sulfate-exposed mice with microalbuminuria showed ischemic changes, while more severely affected mice showed increased mesangial matrix, segmental solidification, and mesangiolysis. In normal mouse kidneys, AhR was predominantly localized to the podocyte nuclei. In mice exposed to indoxyl sulfate for 2 h, isolated glomeruli manifested increased Cyp1a1 expression, indicating AhR activation. After 8 w of indoxyl sulfate, podocytes showed foot process effacement, cytoplasmic vacuoles, and a focal granular and wrinkled pattern of podocin and synaptopodin expression. Furthermore, vimentin and AhR expression in the glomerulus was increased in the indoxyl sulfate-exposed glomeruli compared to controls. Glomerular expression of characteristic podocyte mRNAs was decreased, including Actn4, Cd2ap, Myh9, Nphs1, Nphs2, Podxl, Synpo, and Wt1. In vitro, immortalized-mouse podocytes exhibited AhR nuclear translocation beginning 30 min after 1 mM indoxyl sulfate exposure, and there was increased phospho-Rac1/Cdc42 at 2 h. After exposure to indoxyl sulfate for 24 h, mouse podocytes exhibited a pro-inflammatory phenotype, perturbed actin cytoskeleton, decreased expression of podocyte-specific genes, and decreased cell viability. In immortalized human podocytes, indoxyl sulfate treatment caused cell injury, decreased mRNA expression of podocyte-specific proteins, as well as integrins, collagens, cytoskeletal proteins, and bone morphogenetic proteins, and increased cytokine and chemokine expression. We propose that basal levels of AhR activity regulate podocyte function under normal conditions, and that increased activation of podocyte AhR by indoxyl sulfate contributes to progressive glomerular injury. C1 [Ichii, Osamu; Otsuka-Kanazawa, Saori; Nakamura, Teppei; Kon, Yasuhiro] Hokkaido Univ, Grad Sch Vet Med, Dept Biomed Sci, Anat Lab, Sapporo, Hokkaido 060, Japan. [Ichii, Osamu; Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. [Nakamura, Teppei; Ueno, Masaaki] Japan Food Res Labs, Chitose Lab, Sect Biol Safety Res, Chitose, Japan. [Chen, Weiping] NIDDK, Microarray Core Facil, NIH, Bethesda, MD USA. [Rosenberg, Avi Z.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Ichii, O (reprint author), Hokkaido Univ, Grad Sch Vet Med, Dept Biomed Sci, Anat Lab, Sapporo, Hokkaido 060, Japan. EM ichi-o@vetmed.hokudai.ac.jp OI Kopp, Jeffrey/0000-0001-9052-186X; Rosenberg, Avi/0000-0003-2356-950X FU Japan Society for the Promotion of Science; Ministry of Education, Culture, Sports, Science, and Technology of Japan [24688033]; Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) FX This work was partially supported by grants from the Institutional Program for Young Researcher Overseas Visits from the Japan Society for the Promotion of Science, a Grant-in-Aid for Young Scientists (A) (No. 24688033, Dr. Ichii) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by the Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (Dr. Kopp). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 11 Z9 12 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2014 VL 9 IS 9 AR e108448 DI 10.1371/journal.pone.0108448 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6FX UT WOS:000343679800089 PM 25244654 ER PT J AU Vsevolozhskaya, OA Zaykin, DV Greenwood, MC Wei, CS Lu, Q AF Vsevolozhskaya, Olga A. Zaykin, Dmitri V. Greenwood, Mark C. Wei, Changshuai Lu, Qing TI Functional Analysis of Variance for Association Studies SO PLOS ONE LA English DT Article ID LINEAR-MODELS; MISSING HERITABILITY; MULTIPLE-REGRESSION; QUANTITATIVE TRAIT; PERMUTATION TESTS; COMMON VARIANTS; HUMAN-DISEASES; RARE VARIANTS; LOCI; ANOVA AB While progress has been made in identifying common genetic variants associated with human diseases, for most of common complex diseases, the identified genetic variants only account for a small proportion of heritability. Challenges remain in finding additional unknown genetic variants predisposing to complex diseases. With the advance in next-generation sequencing technologies, sequencing studies have become commonplace in genetic research. The ongoing exome-sequencing and whole-genome-sequencing studies generate a massive amount of sequencing variants and allow researchers to comprehensively investigate their role in human diseases. The discovery of new disease-associated variants can be enhanced by utilizing powerful and computationally efficient statistical methods. In this paper, we propose a functional analysis of variance (FANOVA) method for testing an association of sequence variants in a genomic region with a qualitative trait. The FANOVA has a number of advantages: (1) it tests for a joint effect of gene variants, including both common and rare; (2) it fully utilizes linkage disequilibrium and genetic position information; and (3) allows for either protective or risk-increasing causal variants. Through simulations, we show that FANOVA outperform two popularly used methods - SKAT and a previously proposed method based on functional linear models (FLM), - especially if a sample size of a study is small and/or sequence variants have low to moderate effects. We conduct an empirical study by applying three methods (FANOVA, SKAT and FLM) to sequencing data from Dallas Heart Study. While SKAT and FLM respectively detected ANGPTL 4 and ANGPTL 3 associated with obesity, FANOVA was able to identify both genes associated with obesity. C1 [Vsevolozhskaya, Olga A.; Wei, Changshuai; Lu, Qing] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Zaykin, Dmitri V.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Greenwood, Mark C.] Montana State Univ, Dept Math Sci, Bozeman, MT 59717 USA. RP Vsevolozhskaya, OA (reprint author), Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. EM vsevoloz@msu.edu; qlu@msu.edu RI Wei, Changshuai/A-7750-2015 OI Wei, Changshuai/0000-0003-0148-6797 FU National Institute on Drug Abuse [T32DA021129]; National Institutes of Health, National Institute of Environmental Health Sciences; NIDA [K01DA033346] FX This work was supported by a National Institute on Drug Abuse T32 research training program grant award (T32DA021129), QL's NIDA Mentored Research Scientist Development Award (K01DA033346), and by DVZ's Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The content is the sole responsibility of the authors and does not necessarily represent the official views of Michigan State University, the National Institute on Drug Abuse, the National Institute of Environmental Health Sciences or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 9 Z9 9 U1 1 U2 9 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 SEP 22 PY 2014 VL 9 IS 9 AR e105074 DI 10.1371/journal.pone.0105074 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6FX UT WOS:000343679800002 PM 25244256 ER PT J AU Fawzi, NL Libich, DS Ying, JF Tugarinov, V Clore, GM AF Fawzi, Nicolas L. Libich, David S. Ying, Jinfa Tugarinov, Vitali Clore, G. Marius TI Characterizing Methyl-Bearing Side Chain Contacts and Dynamics Mediating Amyloid beta Protofibril Interactions Using C-13(methyl)-DEST and Lifetime Line Broadening SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE amyloid beta; high-molecular-weight assemblies; NMR spectroscopy; protein-protein interactions ID SLOWLY EXCHANGING PROTEIN; SOLUTION NMR; CONFORMATIONAL DIFFERENCES; ALZHEIMERS-DISEASE; STATE NMR; OLIGOMERS; SYSTEMS; PEPTIDES; FIBRILS AB Many details pertaining to the formation and interactions of protein aggregates associated with neurodegenerative diseases are invisible to conventional biophysical techniques. We recently introduced N-15 dark-state exchange saturation transfer (DEST) and N-15 lifetime line-broadening to study solution backbone dynamics and position-specific binding probabilities for amyloid beta (A beta) monomers in exchange with large (2-80 MDa) protofibrillar A beta aggregates. Here we use C-13(methyl) DEST and lifetime line-broadening to probe the interactions and dynamics of methyl-bearing side chains in the A beta-protofibril-bound state. We show that all methyl groups of A beta 40 populate direct-contact bound states with a very fast effective transverse relaxation rate, indicative of side-chain-mediated direct binding to the protofibril surface. The data are consistent with position-specific enhancements of C-13(methyl)-R-2(tethered) values in tethered states, providing further insights into the structural ensemble of the protofibril-bound state. C1 [Fawzi, Nicolas L.] Brown Univ, Dept Mol Pharmacol Physiol & Biotechnol, Providence, RI 02912 USA. [Libich, David S.; Ying, Jinfa; Tugarinov, Vitali; Clore, G. Marius] NIDDK, NIH, Bethesda, MD 20892 USA. RP Fawzi, NL (reprint author), Brown Univ, Dept Mol Pharmacol Physiol & Biotechnol, Providence, RI 02912 USA. EM nicolas_fawzi@brown.edu; mariusc@mail.nih.gov FU NIDDK; AIDS Targeted Antiviral Program of the NIH; NIGMS [P20 GM103430-13, P20 GM104937-07] FX We thank Drs. Garrett and Baber for technical assistance, and Dr. Torchia for very valuable discussions. This work was supported by the intramural program of NIDDK and the AIDS Targeted Antiviral Program of the NIH Director (to G. M. C.), and by pilot project awards (to N.L.F.) as part of Institutional Development Awards (IDeA) from NIGMS under grant numbers P20 GM103430-13 and P20 GM104937-07. NR 23 TC 10 Z9 10 U1 3 U2 16 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD SEP 22 PY 2014 VL 53 IS 39 BP 10345 EP 10349 DI 10.1002/anie.201405180 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA AQ4JA UT WOS:000342760700009 PM 25130489 ER PT J AU Liu, Z Thacker, SG Fernandez-Castillejo, S Neufeld, EB Remaley, AT Bittman, R AF Liu, Zheng Thacker, Seth G. Fernandez-Castillejo, Sara Neufeld, Edward B. Remaley, Alan T. Bittman, Robert TI Synthesis of Cholesterol Analogues Bearing BODIPY Fluorophores by Suzuki or Liebeskind-Srogl Cross-Coupling and Evaluation of Their Potential for Visualization of Cholesterol Pools SO CHEMBIOCHEM LA English DT Article DE BODIPY-cholesterol; confocal microscopy; fluorescence imaging; Liebeskind-Srogl coupling; Suzuki coupling ID DYES; CELLS; TRAFFICKING; DIFFUSION; REVEALS AB We report a synthetic route to BODIPY-cholesterol conjugates in which the key steps were Suzuki or Liebeskind-Srogl cross-coupling of cholesterol phenyl moieties with structurally diverse BODIPY scaffolds. All conjugates feature single-bonded and hydrophobic linkages between the fluorophore and sterol that are devoid of heteroatoms. Using HeLa cells, we show that these BODIPY-cholesterol analogues can be used simultaneously with the parent BODIPY-cholesterol for cell imaging and flow cytometry. The BODIPY-cholesterol analogues exhibit similar cellular localization in HeLa cells and show similar cholesterol efflux properties from THP-1 cells to HDL acceptors. These results demonstrate that the red-shifted BODIPY-cholesterol analogues behave in a manner similar to unlabeled cholesterol and are useful probes for simultaneous visualization of intracellular cholesterol pools and for monitoring cholesterol efflux from cells to extracellular acceptors. C1 [Liu, Zheng; Bittman, Robert] CUNY Queens Coll, Dept Chem & Biochem, Flushing, NY 11367 USA. [Thacker, Seth G.; Fernandez-Castillejo, Sara; Neufeld, Edward B.; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bethesda, MD 20892 USA. RP Bittman, R (reprint author), CUNY Queens Coll, Dept Chem & Biochem, Flushing, NY 11367 USA. EM robert.bittman@qc.cuny.edu FU National Institutes of Health [HL-083187] FX This work was supported in part by National Institutes of Health grant HL-083187. We thank Alyssa Reimer for the synthesis of 9 on a large scale. Confocal microscopy was performed in the NHLBI light microscopy core facility, and we thank Daniela Malide for assistance with the co-localization analysis. NR 36 TC 3 Z9 3 U1 1 U2 31 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1439-4227 EI 1439-7633 J9 CHEMBIOCHEM JI ChemBioChem PD SEP 22 PY 2014 VL 15 IS 14 BP 2087 EP 2096 DI 10.1002/cbic.201402042 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA AQ4YI UT WOS:000342807100012 PM 25154602 ER PT J AU Sisirak, V Ganguly, D Lewis, KL Couillault, C Tanaka, L Bolland, S D'Agati, V Elkon, KB Reizis, B AF Sisirak, Vanja Ganguly, Dipyaman Lewis, Kanako L. Couillault, Coline Tanaka, Lena Bolland, Silvia D'Agati, Vivette Elkon, Keith B. Reizis, Boris TI Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TRANSCRIPTION FACTOR E2-2; I INTERFERON; LYMPHOCYTE DEVELOPMENT; VIRAL-INFECTION; NUCLEIC-ACIDS; DISEASE; EXPRESSION; TLR7; DIFFERENTIATION; PATHOGENESIS AB Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of antibodies to self-nucleic acids, immune complex deposition, and tissue inflammation such as glomerulonephritis. Innate recognition of self-DNA and -RNA and the ensuing production of cytokines such as type I interferons (IFNs) contribute to SLE development. Plasmacytoid dendritic cells (pDCs) have been proposed as a source of pathogenic IFN in SLE; however, their net contribution to the disease remains unclear. We addressed this question by reducing gene dosage of the pDC-specific transcription factor E2-2 (Tcf4), which causes a specific impairment of pDC function in otherwise normal animals. We report that global or DC-specific Tcf4 haplodeficiency ameliorated SLE-like disease caused by the overexpression of the endosomal RNA sensor Tlr7. Furthermore, Tcf4 haplodeficiency in the B6.Sle1.Sle3 multigenic model of SLE nearly abolished key disease manifestations including anti-DNA antibody production and glomerulonephritis. Tcf4-haplodeficient SLE-prone animals showed a reduction of the spontaneous germinal center reaction and its associated gene expression signature. These results provide genetic evidence that pDCs are critically involved in SLE pathogenesis and autoantibody production, confirming their potential utility as therapeutic targets in the disease. C1 [Sisirak, Vanja; Ganguly, Dipyaman; Lewis, Kanako L.; Couillault, Coline; Reizis, Boris] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. [D'Agati, Vivette] Columbia Univ, Med Ctr, Dept Pathol, New York, NY 10032 USA. [Tanaka, Lena; Elkon, Keith B.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Bolland, Silvia] NIAID, Immunogenet Lab, Rockville, MD 20852 USA. RP Reizis, B (reprint author), Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. EM bvr2101@columbia.edu RI Sisirak, Vanja/O-9393-2016; OI Sisirak, Vanja/0000-0003-3070-6533; Ganguly, Dipyaman/0000-0002-7786-1795; Reizis, Boris/0000-0003-1140-7853 FU National Institutes of Health [AI072571]; Lupus Research Institute; S.L.E. Lupus Research Foundation; Cancer Research Institute FX This research was supported by the National Institutes of Health grant AI072571 and the Lupus Research Institute (B. Reizis), the S.L.E. Lupus Research Foundation (D. Ganguly), and the Cancer Research Institute (V. Sisirak). NR 43 TC 48 Z9 49 U1 1 U2 8 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD SEP 22 PY 2014 VL 211 IS 10 BP 1969 EP 1976 DI 10.1084/jem.20132522 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AQ4EC UT WOS:000342744800007 PM 25180061 ER PT J AU Shingai, M Donau, OK Plishka, RJ Buckler-White, A Mascola, JR Nabel, GJ Nason, MC Montefiori, D Moldt, B Poignard, P Diskin, R Bjorkman, PJ Eckhaus, MA Klein, F Mouquet, H Lorenzi, JCC Gazumyan, A Burton, DR Nussenzweig, MC Martin, MA Nishimura, Y AF Shingai, Masashi Donau, Olivia K. Plishka, Ronald J. Buckler-White, Alicia Mascola, John R. Nabel, Gary J. Nason, Martha C. Montefiori, David Moldt, Brian Poignard, Pascal Diskin, Ron Bjorkman, Pamela J. Eckhaus, Michael A. Klein, Florian Mouquet, Hugo Lorenzi, Julio Cesar Cetrulo Gazumyan, Anna Burton, Dennis R. Nussenzweig, Michel C. Martin, Malcolm A. Nishimura, Yoshiaki TI Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RHESUS-MONKEYS; ENVELOPE GLYCOPROTEIN; RATIONAL DESIGN; ENV TRIMERS; IN-VITRO; CHALLENGE; MUCOSAL; PROTECTION; VACCINE AB It is widely appreciated that effective human vaccines directed against viral pathogens elicit neutralizing antibodies (NAbs). The passive transfer of anti-HIV-1 NAbs conferring sterilizing immunity to macaques has been used to determine the plasma neutralization titers, which must be present at the time of exposure, to prevent acquisition of SIV/HIV chimeric virus (SHIV) infections. We administered five recently isolated potent and broadly acting anti-HIV neutralizing monoclonal antibodies (mAbs) to rhesus macaques and challenged them intrarectally 24 h later with either of two different R5-tropic SHIVs. By combining the results obtained from 60 challenged animals, we determined that the protective neutralization titer in plasma preventing virus infection in 50% of the exposed monkeys was relatively modest (similar to 1:100) and potentially achievable by vaccination. C1 [Shingai, Masashi; Donau, Olivia K.; Plishka, Ronald J.; Buckler-White, Alicia; Martin, Malcolm A.; Nishimura, Yoshiaki] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Mascola, John R.; Nabel, Gary J.] NIAID, Virol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Montefiori, David] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Moldt, Brian; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Moldt, Brian; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Moldt, Brian; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Diskin, Ron] Weizmann Inst Sci, Dept Biol Struct, IL-7610001 Rehovot, Israel. [Bjorkman, Pamela J.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Bjorkman, Pamela J.; Nussenzweig, Michel C.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Eckhaus, Michael A.] NIH, Diagnost & Res Serv Branch, Off Director, Bethesda, MD 20892 USA. [Klein, Florian; Lorenzi, Julio Cesar Cetrulo; Gazumyan, Anna; Nussenzweig, Michel C.] Rockefeller Univ,New, Lab Mol Immunol, New York, NY 10065 USA. [Mouquet, Hugo] Inst Pasteur, Dept Immunol, Lab Humoral Response Pathogens, F-75724 Paris, France. [Burton, Dennis R.] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM malm@nih.gov; ynishimura@niaid.nih.gov RI Cetrulo Lorenzi, Julio Cesar/B-5264-2008; poignard, pascal/N-6678-2013 OI Cetrulo Lorenzi, Julio Cesar/0000-0003-2492-3961; FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 62 TC 83 Z9 84 U1 2 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD SEP 22 PY 2014 VL 211 IS 10 BP 2061 EP 2074 DI 10.1084/jem.20132494 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AQ4EC UT WOS:000342744800013 PM 25155019 ER PT J AU Conti, HR Peterson, AC Brane, L Huppler, AR Hernandez-Santos, N Whibley, N Garg, AV Simpson-Abelson, MR Gibson, GA Mamo, AJ Osborne, LC Bishu, S Ghilardi, N Siebenlist, U Watkins, SC Artis, D McGeachy, MJ Gaffen, SL AF Conti, Heather R. Peterson, Alanna C. Brane, Lucas Huppler, Anna R. Hernandez-Santos, Nydiaris Whibley, Natasha Garg, Abhishek V. Simpson-Abelson, Michelle R. Gibson, Gregory A. Mamo, Anna J. Osborne, Lisa C. Bishu, Shrinivas Ghilardi, Nico Siebenlist, Ulrich Watkins, Simon C. Artis, David McGeachy, Mandy J. Gaffen, Sarah L. TI Oral-resident natural Th17 cells and gamma delta T cells control opportunistic Candida albicans infections SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; INNATE LYMPHOID-CELLS; HOST-DEFENSE; OROPHARYNGEAL CANDIDIASIS; MUCOSAL CANDIDIASIS; FUNGAL-INFECTION; RESPONSES; IMMUNITY; RECEPTOR; IL-17 AB Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection caused by Candida albicans. OPC is frequent in HIV/AIDS, implicating adaptive immunity. Mice are naive to Candida, yet IL-17 is induced within 24 h of infection, and susceptibility is strongly dependent on IL-17R signaling. We sought to identify the source of IL-17 during the early innate response to candidiasis. We show that innate responses to Candida require an intact TCR, as SCID, IL-7R alpha(-/-), and Rag1(-/-) mice were susceptible to OPC, and blockade of TCR signaling by cyclosporine induced susceptibility. Using fate-tracking IL-17 reporter mice, we found that IL-17 is produced within 1-2 d by tongue-resident populations of gamma delta T cells and CD3(+)CD4(+)CD44(hi)TCR beta(+)CCR6(+) natural Th17 (nTh17) cells, but not by TCR-deficient innate lymphoid cells (ILCs) or NK cells. These cells function redundantly, as TCR-beta(-/-) and TCR-delta(-/-) mice were both resistant to OPC. Whereas.. T cells were previously shown to produce IL-17 during dermal candidiasis and are known to mediate host defense at mucosal surfaces, nTh17 cells are poorly understood. The oral nTh17 population expanded rapidly after OPC, exhibited high TCR-beta clonal diversity, and was absent in Rag1(-/-), IL-7R alpha(-/-), and germ-free mice. These findings indicate that nTh17 and gamma delta T cells, but not ILCs, are key mucosal sentinels that control oral pathogens. C1 [Conti, Heather R.; Peterson, Alanna C.; Brane, Lucas; Hernandez-Santos, Nydiaris; Whibley, Natasha; Garg, Abhishek V.; Simpson-Abelson, Michelle R.; Mamo, Anna J.; McGeachy, Mandy J.; Gaffen, Sarah L.] Univ Pittsburgh, Div Clin Immunol & Rheumatol, Pittsburgh, PA 15261 USA. [Bishu, Shrinivas] Univ Pittsburgh, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15261 USA. [McGeachy, Mandy J.; Gaffen, Sarah L.] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA 15261 USA. [Gibson, Gregory A.; Watkins, Simon C.] Univ Pittsburgh, Ctr Biol Imaging, Pittsburgh, PA 15261 USA. [Huppler, Anna R.] Childrens Hosp Pittsburgh, Dept Infect Dis, Pittsburgh, PA 15224 USA. [Osborne, Lisa C.; Artis, David] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Ghilardi, Nico] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA. [Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20852 USA. RP Gaffen, SL (reprint author), Univ Pittsburgh, Div Clin Immunol & Rheumatol, Pittsburgh, PA 15261 USA. EM sig65@pitt.edu RI Osborne, Lisa/K-3027-2015 OI Osborne, Lisa/0000-0002-7170-3235 FU National Institutes of Health (NIH) [DE022550, AI107825, DE023815]; Children's Hospital of Pittsburgh of UPMC; Pediatric Infectious Disease Society Award; Stanley Plotkin Sanofi Pasteur Fellowship Award; Edmond J. Safra Foundation/Cancer Research Institute Irvington Fellowship; Intramural Research Program of the NIAID, NIH; Novartis; Eli Lilly; Janssen; Amgen; [AI095466]; [AI097333]; [AI106697]; [AI1110822]; [F32-DE023293]; [F32-AI098243]; [T32-DK063922] FX S.L. Gaffen was supported by National Institutes of Health (NIH) grants DE022550, AI107825, and DE023815. D. Artis was supported by AI095466, AI097333, and AI106697, and M.J. McGeachy by AI1110822. H.R. Conti was supported by F32-DE023293, M.R. Simpson-Abelson by F32-AI098243, S.Bishu by T32-DK063922, and A.R. Huppler by the Children's Hospital of Pittsburgh of UPMC and a Pediatric Infectious Disease Society Award (funded by the Stanley Plotkin Sanofi Pasteur Fellowship Award). L. Osborne was supported by the Edmond J. Safra Foundation/Cancer Research Institute Irvington Fellowship. U. Siebenlist was supported by the Intramural Research Program of the NIAID, NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; S.L. Gaffen has received a research grant from Novartis, and consulting fees, travel reimbursements, or honoraria from Novartis, Eli Lilly, Janssen, and Amgen. N. Ghilardi is an employee of Genentech. The authors declare no additional competing financial interests. NR 55 TC 43 Z9 44 U1 4 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD SEP 22 PY 2014 VL 211 IS 10 BP 2075 EP 2084 DI 10.1084/jem.20130877 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AQ4EC UT WOS:000342744800014 PM 25200028 ER PT J AU Cui, F Chen, L LoVerso, PR Zhurkin, VB AF Cui, Feng Chen, Linlin LoVerso, Peter R. Zhurkin, Victor B. TI Prediction of nucleosome rotational positioning in yeast and human genomes based on sequence-dependent DNA anisotropy SO BMC BIOINFORMATICS LA English DT Article DE Nucleosomes; Rotational positioning; Sequence-dependent DNA anisotropy; Prediction of nucleosome positioning ID HYDROXYL RADICAL CLEAVAGE; HIGH-RESOLUTION; IN-VITRO; SACCHAROMYCES-CEREVISIAE; MICROCOCCAL NUCLEASE; PAIR RESOLUTION; MINOR-GROOVE; OCCUPANCY; CHROMATIN; HISTONE AB Background: An organism's DNA sequence is one of the key factors guiding the positioning of nucleosomes within a cell's nucleus. Sequence-dependent bending anisotropy dictates how DNA is wrapped around a histone octamer. One of the best established sequence patterns consistent with this anisotropy is the periodic occurrence of AT-containing dinucleotides (WW) and GC-containing dinucleotides (SS) in the nucleosomal locations where DNA is bent in the minor and major grooves, respectively. Although this simple pattern has been observed in nucleosomes across eukaryotic genomes, its use for prediction of nucleosome positioning was not systematically tested. Results: We present a simple computational model, termed the W/S scheme, implementing this pattern, without using any training data. This model accurately predicts the rotational positioning of nucleosomes both in vitro and in vivo, in yeast and human genomes. About 65 - 75% of the experimentally observed nucleosome positions are predicted with the precision of one to two base pairs. The program is freely available at http://people.rit.edu/fxcsbi/WS_scheme/. We also introduce a simple and efficient way to compare the performance of different models predicting the rotational positioning of nucleosomes. Conclusions: This paper presents the W/S scheme to achieve accurate prediction of rotational positioning of nucleosomes, solely based on the sequence-dependent anisotropic bending of nucleosomal DNA. This method successfully captures DNA features critical for the rotational positioning of nucleosomes, and can be further improved by incorporating additional terms related to the translational positioning of nucleosomes in a species-specific manner. C1 [Cui, Feng; LoVerso, Peter R.] Rochester Inst Technol, Thomas H Gosnell Sch Life Sci, Rochester, NY 14623 USA. [Chen, Linlin] Rochester Inst Technol, Sch Math Sci, Rochester, NY 14623 USA. [Zhurkin, Victor B.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Zhurkin, VB (reprint author), Rochester Inst Technol, Thomas H Gosnell Sch Life Sci, Rochester, NY 14623 USA. EM fxcsbi@rit.edu; zhurkin@nih.gov FU Rochester Institute of Technology; National Cancer Institute FX The authors are grateful to George Leiman for text editing. FC is supported by the start-up funds, Faculty of Development (FEAD) funds and Dean's Research Initiation Grant (D-RIG) funds of Rochester Institute of Technology. VBZ is supported by the Intramural Research Program of National Cancer Institute. NR 57 TC 3 Z9 3 U1 3 U2 13 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 SEP 22 PY 2014 VL 15 AR 313 DI 10.1186/1471-2105-15-313 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA AQ3NI UT WOS:000342700300001 PM 25244936 ER PT J AU Li, XL Fang, EF Scheibye-Knudsen, M Cui, HH Qiu, L Li, J He, YP Huang, J Bohr, VA Ng, TB Guo, HW AF Li, Xiaolin Fang, Evandro Fei Scheibye-Knudsen, Morten Cui, Honghua Qiu, Lu Li, Jian He, Yuping Huang, Jing Bohr, Vilhelm A. Ng, Tzi Bun Guo, Hongwei TI Di-(2-ethylhexyl) phthalate inhibits DNA replication leading to hyperPARylation, SIRT1 attenuation, and mitochondrial dysfunction in the testis SO SCIENTIFIC REPORTS LA English DT Article ID GERM-CELL APOPTOSIS; HUMAN SPERM; IN-UTERO; EXPOSURE; DEHP; DAMAGE; HEALTH; INFERTILITY; METABOLISM; SENESCENCE AB Di-(2-ethylhexyl)-phthalate (DEHP) is a ubiquitously used endocrine disruptor. There is widespread exposure to DEHP in the general population which has raised substantial public concern due to its potential detrimental health effects. It is particularly pertinent to investigate the molecular mechanisms of its testicular toxicity which are largely unknown. By feeding male rats DEHP for 2 weeks, rat spermatogenesis became disrupted, resulting in a decreased number of spermatocytes and spermatids. Since rapidly dividing tissues appeared to be particularly vulnerable to DEHP toxicity we investigated the effect of DEHP on DNA replication. Intriguingly, DEHP appeared to inhibit DNA replication as evidenced by results of fiber tract analysis. This led to induction of the mitochondrial apoptotic pathways and increased ROS production. Furthermore, the toxicity of DEHP led to respiratory chain defects and attenuation of ATP level probably brought about by hyperPARylation and undermined SIRT1 activity. Our findings reveal a previously unknown mitochondrial dysfunction in DEHP-induced testicular toxicity and highlight the importance of SIRT1 in male reproduction. C1 [Li, Xiaolin; Guo, Hongwei] Fudan Univ, Sch Publ Hlth, Shanghai 200032, Peoples R China. [Li, Xiaolin; Qiu, Lu; Li, Jian; He, Yuping] Shanghai Entry Exit Inspect & Quarantine Bur, Shanghai 200135, Peoples R China. [Fang, Evandro Fei; Scheibye-Knudsen, Morten; Huang, Jing; Bohr, Vilhelm A.] Natl Inst Ageing, Lab Mol Gerontol, NIH, Baltimore, MD USA. [Fang, Evandro Fei; Ng, Tzi Bun] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Cui, Honghua] Shanghai Stomatol Dis Ctr, Shanghai 200001, Peoples R China. RP Ng, TB (reprint author), Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. EM b021770@mailserv.cuhk.edu.hk; hwguo@shmu.edu.cn OI Scheibye-Knudsen, Morten/0000-0002-6637-1280 FU Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee [13140901000]; Ministry of Science and Technology of China [2013BAD12B06]; NIH, National Institute on Ageing, USA [Z01 AG000723 02] FX This research was supported by Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee (No. 13140901000, 2013), and National Key Technology Research and Development Programme of the Ministry of Science and Technology of China (No. 2013BAD12B06, 2013). E.F.F., M.S.K., H.J. and V.B. were supported by the Intramural Research Programme of the NIH, National Institute on Ageing (Z01 AG000723 02), USA. We thank Drs. Peter Sykora and Joseph Hsu at NIA, NIH for reading of the manuscript. This article was written in a personal capacity (E.F.F., M.S.K., H.J. and V.B.) and does not represent the opinions of the US Food and Drug Administration, the US Department of Health and Human Services, or the US Federal Government. NR 50 TC 2 Z9 2 U1 2 U2 18 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 SEP 22 PY 2014 VL 4 AR 6434 DI 10.1038/srep06434 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP5IG UT WOS:000342112300003 PM 25242624 ER PT J AU Geyer, AM O'Reilly, S Lee, C Long, DJ Bolch, WE AF Geyer, Amy M. O'Reilly, Shannon Lee, Choonsik Long, Daniel J. Bolch, Wesley E. TI The UF/NCI family of hybrid computational phantoms representing the current US population of male and female children, adolescents, and adults-application to CT dosimetry SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop on Computational Phantoms for Radiation Protection, Imaging, and Radiotherapy CY MAY 20-22, 2013 CL Zurich, SWITZERLAND DE computational phantom; patient-dependent phantom; obesity; computed tomography ID TOTAL-BODY FAT; MONTE-CARLO; DISTRIBUTIONS AB Substantial increases in pediatric and adult obesity in the US have prompted a major revision to the current UF/NCI (University of Florida/National Cancer Institute) family of hybrid computational phantoms to more accurately reflect current trends in larger body morphometry. A decision was made to construct the new library in a gridded fashion by height/weight without further reference to age-dependent weight/height percentiles as these become quickly outdated. At each height/weight combination, circumferential parameters were defined and used for phantom construction. All morphometric data for the new library were taken from the CDC NHANES survey data over the time period 1999-2006, the most recent reported survey period. A subset of the phantom library was then used in a CT organ dose sensitivity study to examine the degree to which body morphometry influences the magnitude of organ doses for patients that are underweight to morbidly obese in body size. Using primary and secondary morphometric parameters, grids containing 100 adult male height/weight bins, 93 adult female height/weight bins, 85 pediatric male height/weight bins and 73 pediatric female height/weight bins were constructed. These grids served as the blueprints for construction of a comprehensive library of patient-dependent phantoms containing 351 computational phantoms. At a given phantom standing height, normalized CT organ doses were shown to linearly decrease with increasing phantom BMI for pediatric males, while curvilinear decreases in organ dose were shown with increasing phantom BMI for adult females. These results suggest that one very useful application of the phantom library would be the construction of a pre-computed dose library for CT imaging as needed for patient dose-tracking. C1 [Geyer, Amy M.; O'Reilly, Shannon; Long, Daniel J.; Bolch, Wesley E.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA. [Lee, Choonsik] NCI, NIH, Bethesda, MD 20892 USA. RP Geyer, AM (reprint author), Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA. EM wbolch@ufl.edu RI Lee, Choonsik/C-9023-2015 OI Lee, Choonsik/0000-0003-4289-9870 FU Radiation Epidemiology Branch of the National Cancer Institute [HHS-N2612-0090-0098P, HHS-N2612-0100-0692P]; Biomedical Research and Education Foundation FX This work was supported by contracts nos. HHS-N2612-0090-0098P and HHS-N2612-0100-0692P with the Radiation Epidemiology Branch of the National Cancer Institute, and by a grant from the Biomedical Research and Education Foundation. NR 16 TC 11 Z9 11 U1 0 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD SEP 21 PY 2014 VL 59 IS 18 SI SI BP 5225 EP 5242 DI 10.1088/0031-9155/59/18/5225 PG 18 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AO5JW UT WOS:000341381900004 PM 25144322 ER PT J AU Winter, PW York, AG Nogare, DD Ingaramo, M Christensen, R Chitnis, A Patterson, GH Shroff, H AF Winter, Peter W. York, Andrew G. Nogare, Damian Dalle Ingaramo, Maria Christensen, Ryan Chitnis, Ajay Patterson, George H. Shroff, Hari TI Two-photon instant structured illumination microscopy improves the depth penetration of super-resolution imaging in thick scattering samples SO OPTICA LA English DT Article ID FLUORESCENCE MICROSCOPY; ADAPTIVE OPTICS; MOUSE-BRAIN; RESOLUTION; LIVE; 3D; CELLS; NANOSCALE AB Fluorescence imaging methods that achieve spatial resolution beyond the diffraction limit (super-resolution) are of great interest in biology. We describe a super-resolution method that combines two-photon excitation with structured illumination microscopy (SIM), enabling three-dimensional interrogation of live organisms with similar to 150 nm lateral and similar to 400 nm axial resolution, at frame rates of similar to 1 Hz. By performing optical rather than digital processing operations to improve resolution, our microscope permits super-resolution imaging with no additional cost in acquisition time or phototoxicity relative to the pointscanning two-photon microscope upon which it is based. Our method provides better depth penetration and inherent optical sectioning than all previously reported super-resolution SIM implementations, enabling super-resolution imaging at depths exceeding 100 mu m from the coverslip surface. The capability of our system for interrogating thick live specimens at high resolution is demonstrated by imaging whole nematode embryos and larvae, and tissues and organs inside zebrafish embryos. C1 [Winter, Peter W.; York, Andrew G.; Christensen, Ryan; Shroff, Hari] Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD 20892 USA. [Nogare, Damian Dalle; Chitnis, Ajay] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neural Dev Dynam, NIH, Bethesda, MD 20892 USA. [Ingaramo, Maria; Patterson, George H.] Natl Inst Biomed Imaging & Bioengn, Sect Biophoton, NIH, Bethesda, MD 20892 USA. RP Winter, PW (reprint author), Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD 20892 USA. EM peter.winter@nih.gov RI Shroff, Hari/E-7247-2016 OI Shroff, Hari/0000-0003-3613-8215 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB) [EB000074]; National Institute of Child Health and Human Development (NICHD) FX National Institute of Biomedical Imaging and Bioengineering (NIBIB) (EB000074); National Institute of Child Health and Human Development (NICHD). NR 31 TC 15 Z9 15 U1 2 U2 10 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2334-2536 J9 OPTICA JI Optica PD SEP 20 PY 2014 VL 1 IS 3 BP 181 EP 191 DI 10.1364/OPTICA.1.000181 PG 11 WC Optics SC Optics GA CI6IY UT WOS:000354863600010 PM 25485291 ER PT J AU Gopal, S Achenbach, CJ Yanik, EL Dittmer, DP Eron, JJ Engels, EA AF Gopal, Satish Achenbach, Chad J. Yanik, Elizabeth L. Dittmer, Dirk P. Eron, Joseph J. Engels, Eric A. TI Reply to P. De Paoli et al SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID HIV-INFECTED PATIENTS C1 [Gopal, Satish; Dittmer, Dirk P.; Eron, Joseph J.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Achenbach, Chad J.] Northwestern Univ, Chicago, IL 60611 USA. [Yanik, Elizabeth L.; Engels, Eric A.] NCI, Bethesda, MD 20892 USA. RP Gopal, S (reprint author), Univ N Carolina, Chapel Hill, NC 27599 USA. OI Achenbach, Chad/0000-0003-4847-7249 FU FIC NIH HHS [K01 TW009488] NR 4 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2014 VL 32 IS 27 BP 3079 EP 3079 DI 10.1200/JCO.2014.57.0309 PG 1 WC Oncology SC Oncology GA AP4QE UT WOS:000342062200026 PM 25002715 ER PT J AU Walitza, S Marinova, Z Grunblatt, E Lazic, SE Remschmidt, H Vloet, TD Wendland, JR AF Walitza, Susanne Marinova, Zoya Gruenblatt, Edna Lazic, Stanley E. Remschmidt, Helmut Vloet, Timo D. Wendland, Jens R. TI Trio study and meta-analysis support the association of genetic variation at the serotonin transporter with early-onset obsessive-compulsive disorder SO NEUROSCIENCE LETTERS LA English DT Article DE Obsessive-compulsive disorder; Serotonin transporter; 5-HTTLPR; Transmission disequilibrium test; Meta-analysis ID LA-TOURETTE SYNDROME; PUBLICATION BIAS; SLC6A4; DISEQUILIBRIUM; POLYMORPHISMS; ADOLESCENTS; POPULATION; VARIANTS; CHILDREN; SUBTYPES AB Despite compelling evidence for major genetic contributions to the etiology of obsessive-compulsive disorder (OCD), few genetic variants have been consistently associated with this debilitating illness. Molecular genetic studies in children and adolescents with OCD are of particular interest, since early onset of the disease has been observed to be associated with increased familiality. We replicate here for the first time in early-onset OCD patients, a previously reported association of OCD with the common gain-of-function L-A allele at the serotonin transporter linked polymorphic region known as 5-HTTLPR in a collection of parent-offspring trios. The present meta-analysis of this recently refined serotonin transporter gene variant revealed further support for the L-A allele conferring increased genetic susceptibility to OCD. We conclude that the 5-HTTLPR is currently the single best supported risk variant for OCD, in regards of early-onset OCD, albeit of modest effect size and the possibility that the conferred risk might not be specific to OCD. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Walitza, Susanne; Marinova, Zoya; Gruenblatt, Edna] Univ Zurich, Univ Clin Child & Adolescent Psychiat, CH-8032 Zurich, Switzerland. [Walitza, Susanne] Univ Wurzburg, Dept Child & Adolescent Psychiat & Psychotherapy, Wurzburg, Germany. [Walitza, Susanne; Gruenblatt, Edna] Univ Zurich, Neurosci Ctr Zurich, CH-8032 Zurich, Switzerland. [Walitza, Susanne; Gruenblatt, Edna] Swiss Fed Inst Technol, Zurich, Switzerland. [Gruenblatt, Edna] Univ Hosp Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany. [Lazic, Stanley E.] Novartis Inst Biomed Res, Silica Lead Discovery, Basel, Switzerland. [Remschmidt, Helmut] Philipps Univ, Dept Child & Adolescent Psychiat Psychosomat & Ps, Marburg, Germany. [Vloet, Timo D.] Rhein Westfal TH Aachen, Dept Child & Adolescent Psychiat & Psychotherapy, Aachen, Germany. [Wendland, Jens R.] NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. RP Walitza, S (reprint author), Univ Zurich, Univ Clin Child & Adolescent Psychiat, Neumunsterallee 9, CH-8032 Zurich, Switzerland. EM Susanne.Walitza@kjpdzh.ch; zoya.marinova@kjpdzh.ch RI Grunblatt, Edna/A-6762-2016; OI Grunblatt, Edna/0000-0001-8505-7265; Walitza, Susanne/0000-0002-8161-8683 FU Intramural Research Program of the NIH, National Institute of Mental Health [MH000336-30]; Swiss National Science Foundation [130237] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Mental Health (contract MH000336-30) and by the Swiss National Science Foundation (project number 130237). We would like to thank Prof. Steven Taylor for his help with the meta-analysis. NR 30 TC 7 Z9 8 U1 2 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 19 PY 2014 VL 580 BP 100 EP 103 DI 10.1016/j.neulet.2014.07.038 PG 4 WC Neurosciences SC Neurosciences & Neurology GA AQ0NC UT WOS:000342479000020 PM 25093702 ER PT J AU Aghazadeh, Y Ye, XY Blonder, J Papadopoulos, V AF Aghazadeh, Yasaman Ye, Xiaoying Blonder, Josip Papadopoulos, Vassilios TI Protein Modifications Regulate the Role of 14-3-3 gamma Adaptor Protein in cAMP-induced Steroidogenesis in MA-10 Leydig Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STEROID-BIOSYNTHESIS; FUNCTIONAL SPECIFICITY; CHOLESTEROL TRANSPORT; CRYSTAL-STRUCTURE; LIGAND-BINDING; IN-VIVO; PHOSPHORYLATION; ISOFORM; 14-3-3-PROTEINS; ACTIVATION AB The 14-3-3 protein family comprises adaptors and scaffolds that regulate intracellular signaling pathways. The 14-3-3 gamma isoform is a negative regulator of steroidogenesis that is hormonally induced and transiently functions at the initiation of steroidogenesis by delaying maximal steroidogenesis in MA-10 mouse tumor Leydig cells. Treatment of MA-10 cells with the cAMP analog 8-bromo-cAMP (8-Br-cAMP), which stimulates steroidogenesis, triggers the interaction of 14-3-3 gamma with the steroidogenic acute regulatory protein (STAR) in the cytosol, limiting STAR activity to basal levels. Over time, this interaction ceases, allowing for a 2-fold induction in STAR activity and maximal increase in the rate of steroid formation. The 14-3-3 gamma/ STAR pattern of interaction was found to be opposite that of the 14-3-3 gamma homodimerization pattern. Phosphorylation and acetylation of 14-3-3 gamma showed similar patterns to homodimerization and STAR binding, respectively. 14-3-3 gamma Ser(58) phosphorylation and 14-3-3 gamma Lys(49) acetylation were blocked using trans-activator of HIV transcription factor 1 peptides coupled to 14-3-3 gamma sequences containing Ser(58) or Lys(49). Blocking either one of these modifications further induced 8-Br-cAMP-induced steroidogenesis while reducing lipid storage, suggesting that the stored cholesterol is used for steroid formation. Taken together, these results indicate that Ser(58) phosphorylation and Lys(49) acetylation of 14-3-3 gamma occur in a coordinated time-dependent manner to regulate 14-3-3 gamma homodimerization. 14-3-3 gamma Ser(58) phosphorylation is required for STAR interactions under control conditions, and 14-3-3 gamma Lys(49) acetylation is important for the cAMP-dependent induction of these interactions. C1 [Aghazadeh, Yasaman; Papadopoulos, Vassilios] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ H3G 1A4, Canada. [Aghazadeh, Yasaman; Papadopoulos, Vassilios] McGill Univ, Dept Med, Montreal, PQ H3G 1A4, Canada. [Papadopoulos, Vassilios] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1A4, Canada. [Papadopoulos, Vassilios] McGill Univ, Dept Biochem, Montreal, PQ H3G 1A4, Canada. [Ye, Xiaoying; Blonder, Josip] NCI, Prot Characterizat Lab, Canc Res Technol Program, Leidos Biomed Res Inc,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Papadopoulos, V (reprint author), McGill Univ, Ctr Hlth, Res Inst, 1650 Cedar Ave,C10-148, Montreal, PQ H3G 1A4, Canada. EM vassilios.papadopoulos@mcgill.ca FU Le Fonds de la recherche du Quebec-Sante FX We thank Dr. Mario Ascoli (University of Iowa, Iowa City, IA) for supplying the MA-10 cell line and Dr. Buck Hales (Southern Illinois University) for supplying the STAR antibody. The Research Institute of McGill University Health Centre was supported by a center grant from Le Fonds de la recherche du Quebec-Sante. NR 49 TC 5 Z9 5 U1 0 U2 6 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 SEP 19 PY 2014 VL 289 IS 38 BP 26542 EP 26553 DI 10.1074/jbc.M114.569079 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP5OP UT WOS:000342128800045 PM 25086053 ER PT J AU Mehla, J Ernst, R Moore, R Wakschlag, A Marquis, MK Ambudkar, SV Golin, J AF Mehla, Jitender Ernst, Robert Moore, Rachel Wakschlag, Adina Marquis, Mary Kate Ambudkar, Suresh V. Golin, John TI Evidence for a Molecular Diode-based Mechanism in a Multispecific ATP-binding cassette (ABC) Exporter SER-1368 AS A GATEKEEPING RESIDUE IN THE YEAST MULTIDRUG TRANSPORTER Pdr5 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MULTIDRUG TRANSPORTER PDR5; P-GLYCOPROTEIN; MALTOSE TRANSPORTER; CRYSTAL-STRUCTURE; SACCHAROMYCES-CEREVISIAE; DRUG-RESISTANCE; HYDROLYSIS; EFFLUX; INTERMEDIATE; INTERFACE AB ATP-binding cassette multidrug efflux pumps transport a wide range of substrates. Current models suggest that a drug binds relatively tightly to a transport site in the transmembrane domains when the protein is in the closed inward facing conformation. Upon binding of ATP, the transporter can switch to an outward facing (drug off or drug releasing) structure of lower affinity. ATP hydrolysis is critically important for remodeling the drug-binding site to facilitate drug release and to reset the transporter for a new transport cycle. We characterized the novel phenotype of an S1368A mutant that lies in the putative drug-binding pocket of the yeast multidrug transporter Pdr5. This substitution created broad, severe drug hypersensitivity, although drug binding, ATP hydrolysis, and intradomain signaling were indistinguishable from the wild-type control. Several different rhodamine 6G efflux and accumulation assays yielded evidence consistent with the possibility that Ser-1368 prevents reentry of the excluded drug. C1 [Golin, John] Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. [Ernst, Robert] Goethe Univ Frankfurt, Inst Biochem, Bioctr, D-60438 Frankfurt, Germany. [Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Golin, J (reprint author), Catholic Univ Amer, Dept Biol, 620 Michigan Ave NE, Washington, DC 20064 USA. EM golin@cua.edu RI Mehla, Jitender/M-6165-2016; Fachbereich14, Dekanat/C-8553-2015 OI Mehla, Jitender/0000-0002-7829-557X; FU National Institutes of Health, NCI, Intramural Research Program, Center for Cancer Research; National Science Foundation [MCB1048838] FX work was supported, in whole or in part, by the National Institutes of Health, NCI, Intramural Research Program, Center for Cancer Research (to S. V. A.). This work was also supported by National Science Foundation Grant MCB1048838 (to J. G.). NR 26 TC 4 Z9 4 U1 0 U2 6 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 SEP 19 PY 2014 VL 289 IS 38 BP 26597 EP 26606 DI 10.1074/jbc.M114.586032 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP5OP UT WOS:000342128800050 PM 25112867 ER PT J AU Ritchie, MD Verma, SS Hall, MA Goodloe, RJ Berg, RL Carrell, DS Carlson, CS Chen, L Crosslin, DR Denny, JC Jarvik, G Li, RL Linneman, JG Pathak, J Peissig, P Rasmussen, LV Ramirez, AH Wang, XM Wilke, RA Wolf, WA Torstenson, ES Turner, SD McCarty, CA AF Ritchie, Marylyn D. Verma, Shefali S. Hall, Molly A. Goodloe, Robert J. Berg, Richard L. Carrell, Dave S. Carlson, Christopher S. Chen, Lin Crosslin, David R. Denny, Joshua C. Jarvik, Gail Li, Rongling Linneman, James G. Pathak, Jyoti Peissig, Peggy Rasmussen, Luke V. Ramirez, Andrea H. Wang, Xiaoming Wilke, Russell A. Wolf, Wendy A. Torstenson, Eric S. Turner, Stephen D. McCarty, Catherine A. TI Electronic medical records and genomics (eMERGE) network exploration in cataract: Several new potential susceptibility loci SO MOLECULAR VISION LA English DT Article ID AGE-RELATED CATARACT; BODY-MASS INDEX; S-TRANSFERASE M1; BEAVER DAM EYE; CORTICAL CATARACT; LENS OPACITIES; FAMILIAL AGGREGATION; VISUAL IMPAIRMENT; ENVIRONMENTAL-FACTORS; MOLECULAR-GENETICS AB Purpose: Cataract is the leading cause of blindness in the world, and in the United States accounts for approximately 60% of Medicare costs related to vision. The purpose of this study was to identify genetic markers for age-related cataract through a genome-wide association study (GWAS). Methods: In the electronic medical records and genomics (eMERGE) network, we ran an electronic phenotyping algorithm on individuals in each of five sites with electronic medical records linked to DNA biobanks. We performed a GWAS using 530,101 SNPs from the Illumina 660W-Quad in a total of 7,397 individuals (5,503 cases and 1,894 controls). We also performed an age-at-diagnosis case-only analysis. Results: We identified several statistically significant associations with age-related cataract (45 SNPs) as well as age at diagnosis (44 SNPs). The 45 SNPs associated with cataract at p<1x10(-5) are in several interesting genes, including ALDOB, MAP3K1, and MEF2C. All have potential biologic relationships with cataracts. Conclusions: This is the first genome-wide association study of age-related cataract, and several regions of interest have been identified. The eMERGE network has pioneered the exploration of genomic associations in biobanks linked to electronic health records, and this study is another example of the utility of such resources. Explorations of age-related cataract including validation and replication of the association results identified herein are needed in future studies. C1 [Ritchie, Marylyn D.; Verma, Shefali S.; Hall, Molly A.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Goodloe, Robert J.; Torstenson, Eric S.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Berg, Richard L.; Linneman, James G.; Peissig, Peggy] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA. [Carrell, Dave S.] Grp Hlth Res Inst, Seattle, WA USA. [Carlson, Christopher S.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Chen, Lin] Marshfield Clin Res Fdn, Marshfield, WI USA. [Crosslin, David R.; Jarvik, Gail] Univ Washington, Div Med Genet, Seattle, WA 98195 USA. [Crosslin, David R.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Denny, Joshua C.; Wang, Xiaoming; Wilke, Russell A.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37235 USA. [Denny, Joshua C.; Ramirez, Andrea H.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Jarvik, Gail] Univ Washington, Dept Med, Seattle, WA USA. [Jarvik, Gail] Univ Washington, Dept Genome Sci, Seattle, WA USA. [Li, Rongling] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Pathak, Jyoti] Mayo Clin, Coll Med, Dept Biomed Informat, Rochester, MN USA. [Rasmussen, Luke V.] Northwestern Univ, Dept Prevent Med, Div Hlth & Biomed Informat, Chicago, IL 60611 USA. [Wilke, Russell A.] IMAGENETICS, Sanford Med Ctr, Fargo, ND USA. [Wilke, Russell A.] Univ N Dakota, Dept Internal Med, Fargo, ND USA. [Wolf, Wendy A.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA. [Wolf, Wendy A.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Turner, Stephen D.] Univ Virginia, Charlottesville, VA USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN USA. RP Ritchie, MD (reprint author), Penn State Univ, Ctr Syst Genom, Huck Inst Life Sci, Dept Biochem & Mol Biol, 512 Wartik Lab, University Pk, PA 16802 USA. EM marylyn.ritchie@psu.edu RI Jarvik, Gail/N-6476-2014; OI Jarvik, Gail/0000-0002-6710-8708; Rasmussen, Luke/0000-0002-4497-8049 FU NHGRI; NIGMS (Group Health Cooperative) [U01HG004610]; State of Washington Life Sciences Discovery Fund award; NIGMS (Marshfield Clinic) [U01HG004608]; NIGMS (Mayo Clinic) [U01HG04599]; NIGMS (Northwestern University) [U01HG004609]; NIGMS (Vanderbilt University) [U01HG04603]; NIGMS (Essentia Institute of Rural Health) [U01HG006389] FX The eMERGE Network was initiated and funded by NHGRI, with additional funding from NIGMS through the following grants: U01HG004610 (Group Health Cooperative); U01HG004608 (Marshfield Clinic); U01HG04599 (Mayo Clinic); U01HG004609 (Northwestern University); U01HG04603 (Vanderbilt University, also serving as the Coordinating Center); U01HG006389 (Essentia Institute of Rural Health). The Northwest Institute of Medical Genetics is also supported by a State of Washington Life Sciences Discovery Fund award. NR 62 TC 6 Z9 6 U1 1 U2 7 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD SEP 19 PY 2014 VL 20 BP 1281 EP 1295 PG 15 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA AP3LG UT WOS:000341976900003 PM 25352737 ER PT J AU Tong, SQ Shen, MM Cheng, DP Zhang, YM Ito, Y Yan, JZ AF Tong, Shengqiang Shen, Mangmang Cheng, Dongping Zhang, Yamei Ito, Yoichiro Yan, Jizhong TI Chiral ligand exchange high-speed countercurrent chromatography: mechanism and application in enantioseparation of aromatic alpha-hydroxyl acids SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Chiral ligand exchange; High-speed countercurrent chromatography; Enantioseparation; Aromatic alpha-hydroxyl acids; Separation mechanism ID CENTRIFUGAL PARTITION CHROMATOGRAPHY; COIL PLANET CENTRIFUGE; AMINO-ACIDS; LIQUID-CHROMATOGRAPHY; OPTICAL ISOMERS; SEPARATION; RESOLUTION; PHASES AB This work concentrates on the separation mechanism and application of chiral ligand exchange high-speed countercurrent chromatography in enantioseparation of ten racemic aromatic a-hydroxyl acids, including mandelic acid, 2-chloromandelic acid, 4-methoxymandelic acid, 4-hydroxymandelic acid, alpha-methylmandelic acid, 4-hydroxy-3-methoxy-mandelic acid, 3-chloromandelic acid, 4-bromomandelic acid, alpha-cyclopentylmandelic acid and alpha-cyclohexylmandelic acid, in which five of the racemates were successfully enantioseparated by analytical apparatus with an optimized solvent system. The two-phase solvent system was composed of butanol-water (1:1, v/v) or hexane-n-butanol-water (0.5:0.5:1, v/v), to which N-n-dodecyl-L-proline was added in the organic phase as chiral ligand and cupric acetate was added in the aqueous phase as a transition metal ion. Various influence factors in high-speed counter-current chromatography were optimized by enantioselective liquid-liquid extraction. The separation mechanism for chiral ligand exchange high-speed countercurrent chromatography was proposed based on the results of present studies. Successful enantioseparations of 72 mg of mandelic acid, 76 mg of 2-chloromandelic acid and 74 mg of 4-methoxymandelic acid were achieved individually with high resolution by preparative high-speed countercurrent chromatography. The HPLC purity of all enantiomers was over 96% with the recovery in the range of 82-90% from the collected fractions. (C) 2014 Elsevier B.V. All rights reserved. C1 [Tong, Shengqiang; Shen, Mangmang; Cheng, Dongping; Zhang, Yamei; Yan, Jizhong] Zhejiang Univ Technol, Coll Pharmaceut Sci, Hangzhou 310032, Zhejiang, Peoples R China. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Ito, Y (reprint author), NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM itoy@nhlbi.nih.gov; zyx@zjut.edu.cn OI ito, yoichiro/0000-0001-9018-295X FU Natural Science Foundation of P. R. China [21105090]; Department of Education of Zhejiang Province of China [pd2013031] FX This work was financially supported by Natural Science Foundation of P. R. China (21105090) and Department of Education of Zhejiang Province of China (pd2013031). S.Q. Tong also thanks Personnel Department of Zhejiang University of Technology for providing the visiting scholar program (2011). NR 24 TC 5 Z9 9 U1 2 U2 41 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD SEP 19 PY 2014 VL 1360 BP 110 EP 118 DI 10.1016/j.chroma.2014.07.057 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AO6NS UT WOS:000341469400013 PM 25087742 ER PT J AU Arnaoutov, A Dasso, M AF Arnaoutov, Alexei Dasso, Mary TI IRBIT is a novel regulator of ribonucleotide reductase in higher eukaryotes SO SCIENCE LA English DT Article ID ALLOSTERIC REGULATION; INDUCED OLIGOMERIZATION; COMPREHENSIVE MODEL; STRUCTURAL BASIS; BINDING; CONSEQUENCES; INHIBITOR; RECEPTOR; SML1 AB Ribonucleotide reductase (RNR) supplies the balanced pools of deoxynucleotide triphosphates (dNTPs) necessary for DNA replication and maintenance of genomic integrity. RNR is subject to allosteric regulatory mechanisms in all eukaryotes, as well as to control by small protein inhibitors Sml1p and Spd1p in budding and fission yeast, respectively. Here, we show that the metazoan protein IRBIT forms a deoxyadenosine triphosphate (dATP)-dependent complex with RNR, which stabilizes dATP in the activity site of RNR and thus inhibits the enzyme. Formation of the RNR-IRBIT complex is regulated through phosphorylation of IRBIT, and ablation of IRBIT expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression. We demonstrate a mechanism for RNR regulation in higher eukaryotes that acts by enhancing allosteric RNR inhibition by dATP. C1 [Arnaoutov, Alexei; Dasso, Mary] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Arnaoutov, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM arnaouta@mail.nih.gov OI Dasso, Mary/0000-0002-5410-1371 NR 19 TC 13 Z9 14 U1 2 U2 14 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 SEP 19 PY 2014 VL 345 IS 6203 BP 1512 EP 1515 DI 10.1126/science.1251550 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP0LM UT WOS:000341752900044 PM 25237103 ER PT J AU Eicher, T Seeger, MA Anselmi, C Zhou, WC Brandstatter, L Verrey, F Diederichs, K Faraldo-Gomez, JD Pos, KM AF Eicher, Thomas Seeger, Markus A. Anselmi, Claudio Zhou, Wenchang Brandstaetter, Lorenz Verrey, Francois Diederichs, Kay Faraldo-Gomez, Jose D. Pos, Klaas M. TI Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump AcrB SO ELIFE LA English DT Article ID ESCHERICHIA-COLI; MOLECULAR-DYNAMICS; CRYSTAL-STRUCTURE; PSEUDOMONAS-AERUGINOSA; ROTATING MECHANISM; BINDING POCKET; DRUG TRANSPORT; PROTEIN; TOLC; SIMULATIONS AB Membrane transporters of the RND superfamily confer multidrug resistance to pathogenic bacteria, and are essential for cholesterol metabolism and embryonic development in humans. We use high-resolution X-ray crystallography and computational methods to delineate the mechanism of the homotrimeric RND-type proton/drug antiporter AcrB, the active component of the major efflux system AcrAB-TolC in Escherichia coli, and one most complex and intriguing membrane transporters known to date. Analysis of wildtype AcrB and four functionally-inactive variants reveals an unprecedented mechanism that involves two remote alternating-access conformational cycles within each protomer, namely one for protons in the transmembrane region and another for drugs in the periplasmic domain, 50 angstrom apart. Each of these cycles entails two distinct types of collective motions of two structural repeats, coupled by flanking a-helices that project from the membrane. Moreover, we rationalize how the cross-talk among protomers across the trimerization interface might lead to a more kinetically efficient efflux system. C1 [Eicher, Thomas; Brandstaetter, Lorenz; Pos, Klaas M.] Goethe Univ, Inst Biochem, Frankfurt, Germany. [Eicher, Thomas; Brandstaetter, Lorenz; Pos, Klaas M.] Goethe Univ, Cluster Excellence Frankfurt, Frankfurt, Germany. [Eicher, Thomas; Seeger, Markus A.; Brandstaetter, Lorenz; Verrey, Francois] Univ Zurich, Inst Physiol, Zurich, Switzerland. [Eicher, Thomas; Seeger, Markus A.; Brandstaetter, Lorenz; Verrey, Francois] Univ Zurich, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland. [Seeger, Markus A.] Univ Zurich, Inst Med Microbiol, Zurich, Switzerland. [Anselmi, Claudio; Zhou, Wenchang; Faraldo-Gomez, Jose D.] NHLBI, Theoret Mol Biophys Sect, NIH, Bethesda, MD 20892 USA. [Zhou, Wenchang; Diederichs, Kay] Univ Konstanz, Dept Biol, Constance, Germany. RP Faraldo-Gomez, JD (reprint author), NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jose.faraldo@nih.gov; pos@em.uni-frankfurt.de RI Anselmi, Claudio/D-6244-2012; Faraldo-Gomez, Jose/H-7127-2016; Fachbereich14, Dekanat/C-8553-2015; OI Anselmi, Claudio/0000-0002-3017-5085; Verrey, Francois/0000-0003-3250-9824 FU Deutsche Forschungsgemeinschaft [DFG-EXEC115]; Swiss National Science Foundation [31003A_118402, PP00P3_144823]; German Research Foundation Collaborative Research Centre [DFG-SFB807_TP18]; Innovative Medicines Initiative Joint Undertaking Project Translocation [GA_115525]; National Heart, Lung, and Blood Institute; University of Zurich; University of Konstanz; Chinese Scholarship Council [CSC2008101067] FX Deutsche Forschungsgemeinschaft Cluster of Excellence DFG-EXEC115 Klaas M Pos, Jose D Faraldo-Gomez; Swiss National Science Foundation 31003A_118402 Klaas M Pos; German Research Foundation Collaborative Research Centre DFG-SFB807_TP18 Klaas M Pos; Innovative Medicines Initiative Joint Undertaking Project Translocation GA_115525 Klaas M Pos; National Heart, Lung, and Blood Institute Division of Intramural research Jose D Faraldo-Gomez; University of Zurich Lorenz Brandstatter; University of Konstanz Wenchang Zhou; Chinese Scholarship Council CSC2008101067 Wenchang Zhou; Swiss National Science Foundation Swiss National Science Foundation Professorship PP00P3_144823 Markus A Seeger; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 53 TC 34 Z9 34 U1 0 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD SEP 19 PY 2014 VL 3 AR e03145 DI 10.7554/eLife.03145 PG 26 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AP4ZJ UT WOS:000342089200002 ER PT J AU Connelly, JP Kwon, EM Gao, YX Trivedi, NS Elkahloun, AG Horwitz, MS Cheng, LZ Liu, PP AF Connelly, Jon P. Kwon, Erika M. Gao, Yongxing Trivedi, Niraj S. Elkahloun, Abdel G. Horwitz, Marshall S. Cheng, Linzhao Liu, P. Paul TI Targeted correction of RUNX1 mutation in FPD patient-specific induced pluripotent stem cells rescues megakaryopoietic defects SO BLOOD LA English DT Article ID FAMILIAL PLATELET DISORDER; ACUTE MYELOGENOUS LEUKEMIA; ADULT HEMATOPOIESIS; AML1; EXPRESSION; HAPLOINSUFFICIENCY; DIFFERENTIATION; PREDISPOSITION; IIIA AB Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) is an autosomal dominant disease of the hematopoietic system that is caused by heterozygous mutations in RUNX1. FPD/AML patients have a bleeding disorder characterized by thrombocytopenia with reduced platelet numbers and functions, and a tendency to develop AML. No suitable animal models exist for FPD/AML, as Runx1(+/-) mice and zebra fish do not develop bleeding disorders or leukemia. Here we derived induced pluripotent stem cells (iPSCs) from 2 patients in a family with FPD/AML, and found that the FPD iPSCs display defects in megakaryocytic differentiation in vitro. We corrected the RUNX1 mutation in 1 FPD iPSC line through gene targeting, which led to normalization of megakaryopoiesis of the iPSCs in culture. Our results demonstrate successful in vitro modeling of FPD with patient-specific iPSCs and confirm that RUNX1 mutations are responsible for megakaryopoietic defects in FPD patients. C1 [Connelly, Jon P.; Kwon, Erika M.; Liu, P. Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Gao, Yongxing; Cheng, Linzhao] Johns Hopkins Univ, Stem Cell Program, Inst Cell Engn, Baltimore, MD USA. [Gao, Yongxing; Cheng, Linzhao] Johns Hopkins Univ, Div Hematol, Baltimore, MD USA. [Trivedi, Niraj S.] NHGRI, Bioinformat & Sci Programming Core, NIH, Bethesda, MD 20892 USA. [Elkahloun, Abdel G.] NHGRI, Microarray Core, NIH, Bethesda, MD 20892 USA. [Horwitz, Marshall S.] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. RP Liu, PP (reprint author), 49 Convent Dr,Bldg 49,Room 3A26, Bethesda, MD 20892 USA. EM pliu@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health, National Institutes of Health [U01-HL107446, 2R01-HL073781, 2R01-DK-78340] FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, National Institutes of Health grants U01-HL107446 and 2R01-HL073781 (L. C.) and 2R01-DK-78340 (M.S.H.). NR 25 TC 12 Z9 13 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD SEP 18 PY 2014 VL 124 IS 12 BP 1926 EP 1930 DI 10.1182/blood-2014-01550525 PG 5 WC Hematology SC Hematology GA AQ4JT UT WOS:000342762800014 PM 25114263 ER PT J AU Capitini, CM Nasholm, NM Chien, CD Larabee, SM Qin, HY Song, YK Klover, PJ Hennighausen, L Khan, J Fry, TJ AF Capitini, Christian M. Nasholm, Nicole M. Chien, Christopher D. Larabee, Shannon M. Qin, Haiying Song, Young K. Klover, Peter J. Hennighausen, Lothar Khan, Javed Fry, Terry J. TI Absence of STAT1 in donor-derived plasmacytoid dendritic cells results in increased STAT3 and attenuates murine GVHD SO BLOOD LA English DT Article ID GRAFT-VERSUS-HOST; BONE-MARROW-TRANSPLANTATION; ANTIGEN-PRESENTING CELLS; REGULATORY T-CELLS; IFN-GAMMA; INTERFERON RESPONSES; DISEASE; ACTIVATION; DIFFERENTIATION; MACROPHAGES AB Selective targeting of non-T cells, including antigen-presenting cells (APCs), is a potential strategy to prevent graft-versus-host-disease (GVHD) but to maintain graft-versus-tumor (GVT) effects. Because type I and II interferons signal through signal transducer and activator of transcription-1 (STAT1), and contribute to activation of APCs after allogeneic bone marrow transplant (alloBMT), we examined whether the absence of STAT1 in donor APCs could prevent GVHD while preserving immune competence. Transplantation of STAT1(-/-) bone marrow (BM) prevented GVHD induced by STAT1(+/+) T cells, leading to expansion of B220(+) cells and regulatory T cells. STAT1(-/-) BM also preserved GVT activity and enhanced overall survival of tumor-challenged mice in the setting of GVHD. Furthermore, recipients of allogeneic STAT1(-/-) BM demonstrated increased CD9(-) Siglec H hi plasmacytoid dendritic cells (pDCs), and depletion of pDCs after STAT1(-/-) BM transplantation prevented GVHD resistance. STAT1(-/-) pDCs were found to produce decreased free radicals, IFN alpha, and interleukin (IL)-12, and increased IL-10. Additionally, STAT1(-/-) pDCs that were isolated after alloBMT showed increased gene expression of S100A8 and S100A9, and transplantation of S100A9(-/-) BM reduced GVHD-free survival. Finally, elevated STAT3 was found in STAT1(-/-) pDCs isolated after alloBMT. We conclude that interfering with interferon signaling in APCs such as pDCs provides a novel approach to regulate the GVHD/GVT axis. C1 [Capitini, Christian M.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pediat, Madison, WI 53705 USA. [Capitini, Christian M.] Univ Wisconsin, Sch Med & Publ Hlth, Carbone Canc Ctr, Madison, WI 53705 USA. [Nasholm, Nicole M.; Chien, Christopher D.; Larabee, Shannon M.; Qin, Haiying; Song, Young K.; Khan, Javed; Fry, Terry J.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Klover, Peter J.; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Capitini, CM (reprint author), Univ Wisconsin, 1111 Highland Ave,WIMR 4137, Madison, WI 53705 USA. EM ccapitini@pediatrics.wisc.edu OI Capitini, Christian/0000-0002-2276-6731 FU National Institutes of Health/NCI [K08 CA174750]; Hyundai Hope on Wheels; Midwest Athletes Against Childhood Cancer Fund; Lisa's Heart Kids Cancer Research Fund; Children's Cancer Foundation; National Institutes of Health FX This work was supported by grants from the National Institutes of Health/NCI K08 CA174750, Hyundai Hope on Wheels, the Midwest Athletes Against Childhood Cancer Fund, Lisa's Heart Kids Cancer Research Fund (C. M. C.), the Children's Cancer Foundation (T.J.F.), and the Intramural Research Program at the National Institutes of Health (J.K., L. H., T.J.F.). NR 52 TC 7 Z9 7 U1 1 U2 6 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 SEP 18 PY 2014 VL 124 IS 12 BP 1976 EP 1986 DI 10.1182/blood-2013-05-500876 PG 11 WC Hematology SC Hematology GA AQ4JT UT WOS:000342762800020 PM 25079358 ER PT J AU Eloyan, A Shou, HC Shinohara, RT Sweeney, EM Nebel, MB Cuzzocreo, JL Calabresi, PA Reich, DS Lindquist, MA Crainiceanu, CM AF Eloyan, Ani Shou, Haochang Shinohara, Russell T. Sweeney, Elizabeth M. Nebel, Mary Beth Cuzzocreo, Jennifer L. Calabresi, Peter A. Reich, Daniel S. Lindquist, Martin A. Crainiceanu, Ciprian M. TI Health Effects of Lesion Localization in Multiple Sclerosis: Spatial Registration and Confounding Adjustment SO PLOS ONE LA English DT Article ID GRAY-MATTER ATROPHY; IMAGE REGISTRATION; LOCATION; MRI; DISABILITY; ALGORITHMS; CONVERSION AB Brain lesion localization in multiple sclerosis (MS) is thought to be associated with the type and severity of adverse health effects. However, several factors hinder statistical analyses of such associations using large MRI datasets: 1) spatial registration algorithms developed for healthy individuals may be less effective on diseased brains and lead to different spatial distributions of lesions; 2) interpretation of results requires the careful selection of confounders; and 3) most approaches have focused on voxel-wise regression approaches. In this paper, we evaluated the performance of five registration algorithms and observed that conclusions regarding lesion localization can vary substantially with the choice of registration algorithm. Methods for dealing with confounding factors due to differences in disease duration and local lesion volume are introduced. Voxel-wise regression is then extended by the introduction of a metric that measures the distance between a patient-specific lesion mask and the population prevalence map. C1 [Eloyan, Ani; Sweeney, Elizabeth M.; Reich, Daniel S.; Lindquist, Martin A.; Crainiceanu, Ciprian M.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Shou, Haochang; Shinohara, Russell T.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Sweeney, Elizabeth M.; Reich, Daniel S.] NINDS, Translat Neurol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Nebel, Mary Beth] Kennedy Krieger Inst, Lab Neurocognit & Imaging Res, Baltimore, MD USA. [Nebel, Mary Beth; Calabresi, Peter A.; Reich, Daniel S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Cuzzocreo, Jennifer L.; Reich, Daniel S.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. RP Eloyan, A (reprint author), Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. EM aeloyan1@jhu.edu RI Reich, Daniel/E-5701-2010; Nebel, Mary Beth/D-3305-2015 OI Reich, Daniel/0000-0002-2628-4334; Nebel, Mary Beth/0000-0003-0185-3382 FU National Institute of Biomedical Imaging And Bioengineering [R01EB012547]; National Institute of Neurological Disorders and Stroke (NINDS) [R01NS060910, RO1 NS08521]; National Institute of Mental Health [RO1 MH095836]; Intramural Research Program of NINDS FX The project described was supported by R01EB012547 from the National Institute of Biomedical Imaging And Bioengineering, R01NS060910 and RO1 NS08521 from the National Institute of Neurological Disorders and Stroke (NINDS), and RO1 MH095836 from the National Institute of Mental Health. Dr. Reich's research is supported by the Intramural Research Program of NINDS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 4 Z9 4 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 18 PY 2014 VL 9 IS 9 AR e107263 DI 10.1371/journal.pone.0107263 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ6KR UT WOS:000342921200020 PM 25233361 ER PT J AU Morisaki, T McNally, JG AF Morisaki, Tatsuya McNally, James G. TI Photoswitching-Free FRAP Analysis with a Genetically Encoded Fluorescent Tag SO PLOS ONE LA English DT Article ID CHROMATIN PROTEINS; LIVING CELLS; DNA-DAMAGE; IN-VIVO; RECOVERY; BINDING; MICROSCOPY; DIFFUSION; DYNAMICS; MOBILITY AB Fluorescence recovery after photobleaching (FRAP) is a widely used imaging technique for measuring protein dynamics in live cells that has provided many important biological insights. Although FRAP presumes that the conversion of a fluorophore from a bright to a dark state is irreversible, GFP as well as other genetically encoded fluorescent proteins now in common use can also exhibit a reversible conversion known as photoswitching. Various studies have shown how photoswitching can cause at least four different artifacts in FRAP, leading to false conclusions about various biological phenomena, including the erroneous identification of anomalous diffusion or the overestimation of the freely diffusible fraction of a cellular protein. Unfortunately, identifying and then correcting these artifacts is difficult. Here we report a new characteristic of an organic fluorophore tetramethylrhodamine bound to the HaloTag protein (TMR-HaloTag), which like GFP can be genetically encoded, but which directly and simply overcomes the artifacts caused by photoswitching in FRAP. We show that TMR exhibits virtually no photoswitching in live cells under typical imaging conditions for FRAP. We also demonstrate that TMR eliminates all of the four reported photoswitching artifacts in FRAP. Finally, we apply this photoswitching-free FRAP with TMR to show that the chromatin decondensation following UV irradiation does not involve loss of nucleosomes from the damaged DNA. In sum, we demonstrate that the TMR Halo label provides a genetically encoded fluorescent tag very well suited for accurate FRAP experiments. C1 [Morisaki, Tatsuya; McNally, James G.] NCI, Fluorescence Imaging Grp, NIH, Bethesda, MD 20892 USA. RP McNally, JG (reprint author), Helmholtz Ctr Berlin, Inst Soft Matter & Funct Mat, Berlin, Germany. EM james.mcnally@helmholtz-berlin.de FU intramural program of the Center for Cancer Research, National Cancer Institute, US National Institutes of Health; Japan Society for the Promotion of Science; Helmholtz-Zentrum Berlin FX TM and JGM were supported by the intramural program of the Center for Cancer Research, National Cancer Institute, US National Institutes of Health. TM was supported by the Japan Society for the Promotion of Science. JGM was supported by the Helmholtz-Zentrum Berlin. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 4 Z9 4 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 18 PY 2014 VL 9 IS 9 AR e107730 DI 10.1371/journal.pone.0107730 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ6KR UT WOS:000342921200048 PM 25233348 ER PT J AU Simpson, CL Wojciechowski, R Oexle, K Murgia, F Portas, L Li, XH Verhoeven, VJM Vitart, V Schache, M Hosseini, SM Hysi, PG Raffel, LJ Cotch, MF Chew, E Klein, BEK Klein, R Wong, TY Van Duijn, CM Mitchell, P Saw, SM Fossarello, M Wang, JJ Polasek, O Campbell, H Rudan, I Oostra, BA Uitterlinden, AG Hofman, A Rivadeneira, F Amin, N Karssen, LC Vingerling, JR Doering, A Bettecken, T Bencic, G Gieger, C Wichmann, HE Wilson, JF Venturini, C Fleck, B Cumberland, PM Rahi, JS Hammond, CJ Hayward, C Wright, AF Paterson, AD Baird, PN Klaver, CCW Rotter, JI Pirastu, M Meitinger, T Bailey-Wilson, JE Stambolian, D AF Simpson, Claire L. Wojciechowski, Robert Oexle, Konrad Murgia, Federico Portas, Laura Li, Xiaohui Verhoeven, Virginie J. M. Vitart, Veronique Schache, Maria Hosseini, S. Mohsen Hysi, Pirro G. Raffel, Leslie J. Cotch, Mary Frances Chew, Emily Klein, Barbara E. K. Klein, Ronald Wong, Tien Yin Van Duijn, Cornelia M. Mitchell, Paul Saw, Seang Mei Fossarello, Maurizio Wang, Jie Jin Polasek, Ozren Campbell, Harry Rudan, Igor Oostra, Ben A. Uitterlinden, Andre G. Hofman, Albert Rivadeneira, Fernando Amin, Najaf Karssen, Lennart C. Vingerling, Johannes R. Doering, Angela Bettecken, Thomas Bencic, Goran Gieger, Christian Wichmann, H. -Erich Wilson, James F. Venturini, Cristina Fleck, Brian Cumberland, Phillippa M. Rahi, Jugnoo S. Hammond, Chris J. Hayward, Caroline Wright, Alan F. Paterson, Andrew D. Baird, Paul N. Klaver, Caroline C. W. Rotter, Jerome I. Pirastu, Mario Meitinger, Thomas Bailey-Wilson, Joan E. Stambolian, Dwight CA DCCT EDIC Res Grp TI Genome-Wide Meta-Analysis of Myopia and Hyperopia Provides Evidence for Replication of 11 Loci SO PLOS ONE LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; AUSTRALIAN SCHOOL-CHILDREN; REFRACTIVE ERROR; LINKAGE-DISEQUILIBRIUM; FAMILIAL AGGREGATION; ASSOCIATION SCANS; OUTDOOR ACTIVITY; COMMON VARIANTS; MULTIPLE; GENE AB Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25x10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11x10(-11)) and 8q12 (minimum p value 1.82x10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage-disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level'' association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution. C1 [Simpson, Claire L.; Wojciechowski, Robert; Bailey-Wilson, Joan E.] NHGRI, NIH, Baltimore, MD 21224 USA. [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Oexle, Konrad; Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Murgia, Federico; Portas, Laura; Pirastu, Mario] Natl Res Council Italy, Inst Populat Genet, Sassari, Italy. [Li, Xiaohui; Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles BioMed Res Inst, Torrance, CA 90509 USA. [Verhoeven, Virginie J. M.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Verhoeven, Virginie J. M.; Van Duijn, Cornelia M.; Uitterlinden, Andre G.; Hofman, Albert; Rivadeneira, Fernando; Amin, Najaf; Karssen, Lennart C.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Vitart, Veronique; Hayward, Caroline; Wright, Alan F.] Univ Edinburgh, MRC Human Genet Unit, IGMM, Edinburgh, Midlothian, Scotland. [Schache, Maria; Wong, Tien Yin; Wang, Jie Jin; Baird, Paul N.] Univ Melbourne, Ctr Eye Res Australia, Royal Victorian Eye & Ear Hosp, Melbourne, Vic, Australia. [Hosseini, S. Mohsen; Paterson, Andrew D.] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. [Hosseini, S. Mohsen; Paterson, Andrew D.] George Washington Univ, Biostat Ctr, Diabet Control & Complicat Trial & Follow Up Stud, DCCT EDIC Res Grp, Rockville, MD USA. [Hysi, Pirro G.; Venturini, Cristina; Hammond, Chris J.] UCL, St Thomas Hosp, Dept Twin Res & Genet Epidemiol, London, England. [Raffel, Leslie J.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Cotch, Mary Frances; Chew, Emily] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Klein, Barbara E. K.; Klein, Ronald] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, Madison, WI USA. [Wong, Tien Yin] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Mitchell, Paul; Wang, Jie Jin] Univ Sydney, Dept Ophthalmol, Ctr Vis Res, Sydney, NSW 2006, Australia. [Mitchell, Paul; Wang, Jie Jin] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Saw, Seang Mei] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Epidemiol & Publ Hlth, Singapore 117595, Singapore. [Fossarello, Maurizio] Clin Oculist Univ Cagliari, Dipartimento Sci Chirurg, Cagliari, Italy. [DCCT EDIC Res Grp] George Washington Univ, Biostat Ctr, Diabet Control & Complicat Trial & Follow Up Stud, Rockville, MD USA. [Polasek, Ozren] Univ Split, Croatian Ctr Global Hlth, Sch Med, Split, Croatia. [Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Uitterlinden, Andre G.; Hofman, Albert; Rivadeneira, Fernando] Netherlands Genom Initiat, Netherlands Consortium Healthy Ageing, The Hague, Netherlands. [Doering, Angela; Wichmann, H. -Erich] Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Bettecken, Thomas; Meitinger, Thomas] Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Bencic, Goran] Hosp Sestre Milosrdnice, Dept Ophthalmol, Zagreb, Croatia. [Gieger, Christian] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Fleck, Brian] Princess Alexandra Eye Pavil, Edinburgh, Midlothian, Scotland. [Cumberland, Phillippa M.; Rahi, Jugnoo S.] UCL, Inst Child Hlth, MRC Ctr Epidemiol Child Hlth, London, England. [Rahi, Jugnoo S.] UCL, Inst Ophthalmol, London, England. [Rahi, Jugnoo S.] UCL, Ulverscroft Vis Res Grp, Inst Child Hlth, London, England. [Stambolian, Dwight] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. RP Bailey-Wilson, JE (reprint author), NHGRI, NIH, Baltimore, MD 21224 USA. EM jebw@mail.nih.gov RI Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; van der Geest, Rob/J-8193-2015; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Paterson, Andrew/A-4088-2011; Rudan, Igor/I-1467-2012; OI Wojciechowski, Robert/0000-0002-9593-4652; Baird, Paul/0000-0002-1305-3502; Cotch, Mary Frances/0000-0002-2046-4350; Gieger, Christian/0000-0001-6986-9554; Fossarello, Maurizio/0000-0003-1520-7760; Hammond, Christopher/0000-0002-3227-2620; Karssen, Lennart C./0000-0002-1959-342X; Wang, Jie Jin/0000-0001-9491-4898; van der Geest, Rob/0000-0002-9084-5597; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Rivadeneira, Fernando/0000-0001-9435-9441; Paterson, Andrew/0000-0002-9169-118X; Rudan, Igor/0000-0001-6993-6884; Bailey-Wilson, Joan/0000-0002-9153-2920; Hosseini, Mohsen/0000-0003-3626-9928 FU Intramural Research Program of the National Human Genome Research Institute; National Eye Institute; National Institutes of Health; NIH [R01EY020483, R01EY016379]; Helmholtz Center Munich; German Federal Ministry of Education and Research (BMBF); National Heart, Lung, and Blood Institute (NHLBI); NHLBI [N02-HL-6-4278]; Intramural Research Program of the National Eye Institute [ZIAEY000403]; National Center for Research Resources [UL1RR033176]; National Center for Advancing Translational Sciences [UL1TR000124]; Australian National Health & Medical Research Council (NHMRC) [974159, 991407, 211069, 457349]; Centre for Clinical Research Excellence (CCRE) in Translational Clinical Research in Eye Diseases, CCRE in TCR-Eye [529923]; Australian NHMRC project grants [512423, 475604, 529912, 590204]; Wellcome Trust, United Kingdom; Wellcome Trust Case Control Consortium 2 [085475/B/08/Z, 085475/08/Z]; NHMRC fellowship scheme [631096, 1028444, 358702, 632909]; Italian Ministry of Education, University and Research (MIUR) [5571/DSPAR/2002, 718/Ric/2005]; National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [N01-DK-6-2204, R01-DK-077510]; Netherlands Organisation of Scientific Research (NWO) [Vidi 91796357]; Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Netherlands Organization for Health Research and Development (ZonMw); UitZicht; Research Institute for Diseases in the Elderly; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; the European Commission (DG XII); Municipality of Rotterdam; Netherlands Genomics Initiative/NWO; Center for Medical Systems Biology of NGI; Lijf en Leven; M. D. Fonds; Henkes Stichting; Stichting Nederlands Oogheelkundig Onderzoek; Swart van Essen; Bevordering van Volkskracht; Blindenhulp; Landelijke Stichting voor Blinden en Slechtzienden; Rotterdamse Vereniging voor Blindenbelangen; OOG; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; Rotterdam Eye Hospital Research Foundation; Topcon Europe; Medical Research Council (United Kingdom), from the Republic of Croatia Ministry of Science, Education and Sports [108-1080315-0302]; EU [LSHG-CT-2006-018947]; Chief Scientist Office of the Scottish Government; Royal Society; Medical Research Council Human Genetics Unit; European Union [LSHG-CT-2006-018947]; Wellcome Trust; NIHR Biomedical Research Centre in Child Health; NIHR Biomedical Research Centre in Ophthalmology; [N01 HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [RR-024156] FX This work was funded in part by the Intramural Research Program of the National Human Genome Research Institute (JEBW, RW, CLS) and the National Eye Institute (MFC, EC), National Institutes of Health, and NIH R01EY020483 (DS, TM, JEBW). The KORA Study is supported by funds from Helmholtz Center Munich and the German Federal Ministry of Education and Research (BMBF). The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA SNP Health Association Resource (SHARe) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and RR-024156. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. Funding for the collection of refractive error data was supported by the Intramural Research Program of the National Eye Institute (ZIAEY000403). Support was also provided by the National Center for Research Resources, Grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000124. The Blue Mountains Eye Study was supported by the Australian National Health & Medical Research Council (NHMRC) project grants (IDs 974159, 991407, 211069 and 457349) and Centre for Clinical Research Excellence (CCRE) in Translational Clinical Research in Eye Diseases, CCRE in TCR-Eye (ID 529923). The Blue Mountains Eye Study GWAS and genotyping costs were supported by Australian NHMRC project grants (IDs 512423, 475604, 529912 and 590204), and the Wellcome Trust, United Kingdom, as part of Wellcome Trust Case Control Consortium 2 (grant IDs 085475/B/08/Z and 085475/08/Z). EGH (631096), PNB (1028444) and JJW (358702 and 632909) are supported by the NHMRC fellowship scheme. The Centre for Eye Research Australia receives Operational Infrastructure Support from the Victorian government. OGP-Talana was supported by grants from the Italian Ministry of Education, University and Research (MIUR) no. 5571/DSPAR/2002 and (FIRB) D. M no. 718/Ric/2005. The DCCT Research Group is sponsored through research contracts from the National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, N01-DK-6-2204, R01-DK-077510) and the National Institutes of Health. ADP holds a Canada Research Chair in the Genetics of Complex Diseases. The Rotterdam Study and ERF were supported by the Netherlands Organisation of Scientific Research (NWO) (Vidi 91796357); Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Netherlands Organization for Health Research and Development (ZonMw); UitZicht; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); the Municipality of Rotterdam; the Netherlands Genomics Initiative/NWO; Center for Medical Systems Biology of NGI; Lijf en Leven; M. D. Fonds; Henkes Stichting; Stichting Nederlands Oogheelkundig Onderzoek; Swart van Essen; Bevordering van Volkskracht; Blindenhulp; Landelijke Stichting voor Blinden en Slechtzienden; Rotterdamse Vereniging voor Blindenbelangen; OOG; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; the Rotterdam Eye Hospital Research Foundation; and Topcon Europe.; The Croatian studies were funded by grants from the Medical Research Council (United Kingdom), from the Republic of Croatia Ministry of Science, Education and Sports (108-1080315-0302). The authors acknowledge the Wellcome Trust Clinical facility (Edinburgh) for the genotyping of the CROATIA-Vis study, an EU framework 6 project EUROSPAN (contract no LSHG-CT-2006-018947) for the genotyping of the CROATIA-Korcula study that was performed at the Helmholtz Zentrum Munchen (Munich, Germany). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the Medical Research Council Human Genetics Unit and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). The authors acknowledge the Wellcome Trust Clinical facility (Edinburgh) for DNA extraction for the ORCADES study and Peter Lichner and the Helmholtz Zentrum Munchen genotyping staff (Munich, Germany) for genotyping. The GWAS of the 1958 British birth cohort was funded by the Wellcome Trust. This work was carried out at the UCL Institutes of Child Health and Institutes of Ophthalmology which also receive funding from the NIHR Biomedical Research Centres in Child Health and Ophthalmology respectively. The Wisconsin Epidemiologic Study of Diabetic Retinopathy was funded by NIH grant R01EY016379. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 5 Z9 6 U1 1 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 18 PY 2014 VL 9 IS 9 AR e107110 DI 10.1371/journal.pone.0107110 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ6KR UT WOS:000342921200013 PM 25233373 ER PT J AU Ueyama, K Mori, K Shoji, T Omata, H Gehlbach, PL Brough, DE Wei, LL Yoneya, S AF Ueyama, Kazuhiro Mori, Keisuke Shoji, Takuhei Omata, Hidekazu Gehlbach, Peter L. Brough, Douglas E. Wei, Lisa L. Yoneya, Shin TI Ocular Localization and Transduction by Adenoviral Vectors Are Serotype-Dependent and Can Be Modified by Inclusion of RGD Fiber Modifications SO PLOS ONE LA English DT Article ID MEDIATED GENE-TRANSFER; EPITHELIUM-DERIVED FACTOR; HEPATOCYTES IN-VIVO; TRANSGENE EXPRESSION; INTEGRIN ALPHA(V)BETA(3); COMPLEMENT ACTIVATION; MACULAR DEGENERATION; IMMUNE-RESPONSES; PROTEIN CD46; CELL-LINE AB Purpose: To evaluate localization and transgene expression from adenoviral vector of serotypes 5, 35, and 28, +/- an RGD motif in the fiber following intravitreal or subretinal administration. Methods: Ocular transduction by adenoviral vector serotypes +/- RGD was studied in the eyes of mice receiving an intravitreous or subretinal injection. Each serotype expressed a CMV-GFP expression cassette and histological sections of eyes were examined. Transgene expression levels were examined using luciferase (Luc) regulated by the CMV promoter. Results: GFP localization studies revealed that serotypes 5 and 28 given intravitreously transduced corneal endothelial, trabecular, and iris cells. Intravitreous delivery of the unmodified Ad35 serotype transduced only trabecular meshwork cells, but, the modification of the RGD motif into the fiber of the Ad35 viral vector base expanded transduction to corneal endothelial and iris cells. Incorporation of the RGD motif into the fiber knob with deletion of RGD from the penton base did not affect the transduction ability of the Ad5 vector base. Subretinal studies showed that RGD in the Ad5 knob shifted transduction from RPE cells to photoreceptor cells. Using a CMV-Luc expression cassette, intravitreous delivery of all the tested vectors, such as Ad5-, Ad35- and Ad28- resulted in an initial rapid induction of luciferase activity that thereafter declined. Subretinal administration of vectors showed a marked difference in transgene activity. Ad35-Luc gene expression peaked at 7 days and remained elevated for 6 months. Ad28-Luc expression was high after 1 day and remained sustained for one month. Conclusions: Different adenoviral vector serotypes 6 modifications transduce different cells within the eye. Transgene expression can be brief or extended and is serotype and delivery route dependent. Thus, adenoviral vectors provide a versatile platform for the delivery of therapeutic agents for ocular diseases. C1 [Ueyama, Kazuhiro; Mori, Keisuke; Shoji, Takuhei; Omata, Hidekazu; Yoneya, Shin] Saitama Med Univ, Dept Ophthalmol, Iruma, Saitama, Japan. [Gehlbach, Peter L.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Brough, Douglas E.; Wei, Lisa L.] GenVec Inc, Gaithersburg, MD USA. [Wei, Lisa L.] NEI, Bethesda, MD 20892 USA. RP Ueyama, K (reprint author), Saitama Med Univ, Dept Ophthalmol, Iruma, Saitama, Japan. EM thecollectors20060211@yahoo.co.jp OI Shoji, Takuhei/0000-0002-5464-2573 NR 40 TC 3 Z9 3 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 18 PY 2014 VL 9 IS 9 AR e108071 DI 10.1371/journal.pone.0108071 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ6KR UT WOS:000342921200078 PM 25232844 ER PT J AU Nishiura, H Chowell, G AF Nishiura, H. Chowell, G. TI Authors' reply: Feedback from modelling to surveillance of Ebola virus disease SO EUROSURVEILLANCE LA English DT Letter C1 [Nishiura, H.] Univ Tokyo, Grad Sch Med, Tokyo, Japan. [Chowell, G.] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ USA. [Chowell, G.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Nishiura, H (reprint author), Univ Tokyo, Grad Sch Med, Tokyo, Japan. EM nishiurah@m.u-tokyo.ac.jp NR 6 TC 0 Z9 0 U1 2 U2 5 PU EUR CENTRE DIS PREVENTION & CONTROL PI STOCKHOLM PA TOMTEBODAVAGEN 11A, STOCKHOLM, 171 83, SWEDEN SN 1560-7917 J9 EUROSURVEILLANCE JI Eurosurveillance PD SEP 18 PY 2014 VL 19 IS 37 BP 24 EP 25 AR 20908 PG 2 WC Infectious Diseases SC Infectious Diseases GA AQ1TX UT WOS:000342565500007 ER PT J AU Calantone, N Wu, F Klase, Z Deleage, C Perkins, M Matsuda, K Thompson, EA Ortiz, AM Vinton, CL Ourmanov, I Lore, K Douek, DC Estes, JD Hirsch, VM Brenchley, JM AF Calantone, Nina Wu, Fan Klase, Zachary Deleage, Claire Perkins, Molly Matsuda, Kenta Thompson, Elizabeth A. Ortiz, Alexandra M. Vinton, Carol L. Ourmanov, Ilnour Lore, Karin Douek, Daniel C. Estes, Jacob D. Hirsch, Vanessa M. Brenchley, Jason M. TI Tissue Myeloid Cells in SIV-Infected Primates Acquire Viral DNA through Phagocytosis of Infected T Cells SO IMMUNITY LA English DT Article ID RESTRICTION FACTOR SAMHD1; GASTROINTESTINAL-TRACT; HIV-1 INFECTION; RHESUS MACAQUES; VIRUS; MACROPHAGES; VPX; DEPLETION; RESERVOIRS; DISEASE AB The viral accessory protein Vpx, expressed by certain simian and human immunodeficiency viruses (SIVs and HIVs), is thought to improve viral infectivity of myeloid cells. We infected 35 Asian macaques and African green monkeys with viruses that do or do not express Vpx and examined viral targeting of cells in vivo. While lack of Vpx expression affected viral dynamics in vivo, with decreased viral loads and infection of CD4(+) T cells, Vpx expression had no detectable effect on infectivity of myeloid cells. Moreover, viral DNA was observed only within myeloid cells in tissues not massively depleted of CD4(+) T cells. Myeloid cells containing viral DNA also showed evidence of T cell phagocytosis in vivo, suggesting that their viral DNA may be attributed to phagocytosis of SIV-infected T cells. These data suggest that myeloid cells are not a major source of SIV in vivo, irrespective of Vpx expression. C1 [Calantone, Nina; Wu, Fan; Klase, Zachary; Perkins, Molly; Matsuda, Kenta; Ortiz, Alexandra M.; Vinton, Carol L.; Ourmanov, Ilnour; Hirsch, Vanessa M.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Deleage, Claire; Estes, Jacob D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Ft Detrick, MD 21702 USA. [Thompson, Elizabeth A.; Lore, Karin; Douek, Daniel C.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Thompson, Elizabeth A.; Lore, Karin] Karolinska Inst, Dept Med, S-171 Stockholm, Sweden. RP Brenchley, JM (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM jbrenchl@mail.nih.gov FU Division of Intramural Research/NIAID/NIH FX We would like to acknowledge H. Cronise, J. Swerczek, R. Herbert, and all the veterinary staff at the NIH animal center. We would like to thank CLIC/BBC for advice and helpful discussions. Funding for this study was provided in part by the Division of Intramural Research/NIAID/NIH. The content of this publication does not necessarily reflect the views or policies of DHHS, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 48 TC 20 Z9 20 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD SEP 18 PY 2014 VL 41 IS 3 BP 493 EP 502 DI 10.1016/j.immuni.2014.08.014 PG 10 WC Immunology SC Immunology GA AQ2ON UT WOS:000342626500018 PM 25238099 ER PT J AU Tang, S Huang, G Fan, W Chen, Y Ward, JM Xu, XJ Xu, Q Kang, A McBurney, MW Fargo, DC Hu, G Baumgart-Vogt, E Zhao, YM Li, XL AF Tang, Shuang Huang, Gang Fan, Wei Chen, Yue Ward, James M. Xu, Xiaojiang Xu, Qing Kang, Ashley McBurney, Michael W. Fargo, David C. Hu, Guang Baumgart-Vogt, Eveline Zhao, Yingming Li, Xiaoling TI SIRT1-Mediated Deacetylation of CRABPII Regulates Cellular Retinoic Acid Signaling and Modulates Embryonic Stem Cell Differentiation SO MOLECULAR CELL LA English DT Article ID BINDING PROTEIN-II; MUTANT MICE; NUCLEAR RECEPTORS; SIRT1; EXPRESSION; RESTRICTION; METABOLISM; SURVIVAL; ROLES; CDX1 AB Retinoid homeostasis is critical for normal embryonic development. Both the deficiency and excess of these compounds are associated with congenital malformations. Here we demonstrate that SIRT1, the most conserved mammalian NAD(+)-dependent protein deacetylase, contributes to homeostatic retinoic acid (RA) signaling and modulates mouse embryonic stem cell (mESC) differentiation in part through deacetylation of cellular retinoic acid binding protein II (CRABPII). We show that RA-mediated acetylation of CRABPII at K102 is essential for its nuclear accumulation and subsequent activation of RA signaling. SIRT1 interacts with and deacetylates CRABPII, regulating its subcellular localization. Consequently, SIRT1 deficiency induces hyperacetylation and nuclear accumulation of CRABPII, enhancing RA signaling and accelerating mESC differentiation in response to RA. Consistently, SIRT1 deficiency is associated with elevated RA signaling and development defects in mice. Our findings reveal a molecular mechanism that regulates RA signaling and highlight the importance of SIRT1 in regulation of ESC pluripotency and embryogenesis. C1 [Tang, Shuang; Huang, Gang] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Dept Nucl Med, Shanghai 200127, Peoples R China. [Tang, Shuang; Xu, Qing; Kang, Ashley; Li, Xiaoling] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Fan, Wei; Baumgart-Vogt, Eveline] Univ Giessen, Div Med Cell Biol, Inst Anat & Cell Biol 2, D-35385 Giessen, Germany. [Chen, Yue; Zhao, Yingming] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA. [Ward, James M.; Xu, Xiaojiang; Fargo, David C.] NIEHS, Res Triangle Pk, NC 27709 USA. [Kang, Ashley] NIEHS, Scholars Connect Program, Res Triangle Pk, NC 27709 USA. [McBurney, Michael W.] Ottawa Gen Hosp, Res Inst, Program Canc Therapeut, Ottawa, ON K1H 8L6, Canada. [Hu, Guang] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Huang, G (reprint author), Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Dept Nucl Med, Shanghai 200127, Peoples R China. EM huang2802@163.com; lix3@niehs.nih.gov RI Hu, Guang/E-7474-2016; OI Hu, Guang/0000-0003-0437-4723; Baumgart-Vogt, Eveline/0000-0002-8265-3763; Tang, Shuang/0000-0002-3501-7836 FU Intramural Research Program of National Institute of Environmental Health Sciences of the NIH [Z01 ES102205]; NIH [GM105933, CA160036]; Shanghai Jiao Tong University; New Drug Discovery Project [2012ZX09506-001-005] FX We thank Drs. Paul Wade and Raja Jothi and members of the Li laboratory for critical reading of the manuscript. We would also like to thank Dr. Sue Edelstein from the NIEHS Photography & Graphics Service Center for the cartoon graph of Figure S7A and the graphical abstract; Ms. Julie Foley from the NIEHS Cellular & Molecular Pathology Branch for histological analyses of mouse embryos; and Mr. C. Jeff Tucker and Dr. Agnes Janoshazi from NIEHS Fluorescence Microscopy and Imaging Center for quantification of confocal images. This research was supported by the Intramural Research Program of National Institute of Environmental Health Sciences of the NIH to X. L. (Z01 ES102205) and by NIH grants to Y.Z. (GM105933 and CA160036). S. T. was supported by a predoctoral fellowship from Shanghai Jiao Tong University and by a research grant to G. H. (New Drug Discovery Project, 2012ZX09506-001-005). NR 48 TC 9 Z9 9 U1 3 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD SEP 18 PY 2014 VL 55 IS 6 BP 843 EP 855 DI 10.1016/j.molcel.2014.07.011 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AQ2MA UT WOS:000342619200006 PM 25155613 ER PT J AU Fauci, AS AF Fauci, Anthony S. TI Ebola - Underscoring the Global Disparities in Health Care Resources SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 74 Z9 79 U1 3 U2 70 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 SEP 18 PY 2014 VL 371 IS 12 BP 1084 EP 1086 DI 10.1056/NEJMp1409494 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AO9PI UT WOS:000341687300002 PM 25119491 ER PT J AU Biesecker, LG Green, RC AF Biesecker, Leslie G. Green, Robert C. TI Diagnostic Clinical Genome and Exome Sequencing SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Biesecker, Leslie G.] NHGRI, Bethesda, MD 20892 USA. [Green, Robert C.] Harvard Univ, Sch Med, Boston, MA USA. RP Biesecker, LG (reprint author), NHGRI, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov NR 1 TC 33 Z9 35 U1 1 U2 7 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 SEP 18 PY 2014 VL 371 IS 12 BP 1170 EP 1170 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AO9PI UT WOS:000341687300032 PM 25229935 ER PT J AU Zhang, B Wang, J Wang, X Zhu, J Liu, Q Shi, Z Chambers, MC Zimmerman, LJ Shaddox, KF Kim, S Davies, SR Wang, S Wang, P Kinsinger, CR Rivers, RC Rodriguez, H Townsend, RR Ellis, MJC Carr, SA Tabb, DL Coffey, RJ Slebos, RJC Liebler, DC AF Zhang, Bing Wang, Jing Wang, Xiaojing Zhu, Jing Liu, Qi Shi, Zhiao Chambers, Matthew C. Zimmerman, Lisa J. Shaddox, Kent F. Kim, Sangtae Davies, Sherri R. Wang, Sean Wang, Pei Kinsinger, Christopher R. Rivers, Robert C. Rodriguez, Henry Townsend, R. Reid Ellis, Matthew J. C. Carr, Steven A. Tabb, David L. Coffey, Robert J. Slebos, Robbert J. C. Liebler, Daniel C. CA NCI CPTAC TI Proteogenomic characterization of human colon and rectal cancer SO NATURE LA English DT Article ID RNA-SEQ DATA; COMPREHENSIVE GENOMIC CHARACTERIZATION; HEPATOCYTE NUCLEAR FACTOR-4-ALPHA; HUMAN BREAST-TUMORS; SHOTGUN PROTEOMICS; COLORECTAL-CANCER; GENE-EXPRESSION; PROTEIN EXPRESSION; PEPTIDE IDENTIFICATION; MOLECULAR PORTRAITS AB Extensive genomic characterization of human cancers presents the problem of inference from genomic abnormalities to cancer phenotypes. To address this problem, we analysed proteomes of colon and rectal tumours characterized previously by The Cancer Genome Atlas (TCGA) and perform integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. Messenger RNA transcript abundance did not reliably predict protein abundance differences between tumours. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA 'microsatellite instability/CpG island methylation phenotype' transcriptomic subtype, but had distinct mutation, methylation and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis- and trans-effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates, including HNF4A(hepatocyte nuclear factor 4, alpha), TOMM34 (translocase of outer mitochondrial membrane 34) and SRC (SRC proto-oncogene, non-receptor tyrosine kinase). Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology. C1 [Zhang, Bing; Wang, Jing; Wang, Xiaojing; Zhu, Jing; Liu, Qi; Chambers, Matthew C.; Tabb, David L.] Vanderbilt Univ Sch Med, Dept Biomed Informat, Nashville, TN 37232 USA. [Zhang, Bing; Slebos, Robbert J. C.] Vanderbilt Univ Sch Med, Dept Canc Biol, Nashville, TN 37232 USA. [Shi, Zhiao] Vanderbilt Univ, Adv Comp Ctr Res & Educ, Nashville, TN 37232 USA. [Shi, Zhiao] Vanderbilt Univ, Dept Elect Engn & Comp Sci, Nashville, TN 37232 USA. [Zimmerman, Lisa J.; Liebler, Daniel C.] Vanderbilt Univ Sch Med, Dept Biochem, Nashville, TN 37232 USA. [Zimmerman, Lisa J.; Shaddox, Kent F.; Slebos, Robbert J. C.; Liebler, Daniel C.] Vanderbilt Ingram Canc Ctr, Jim Ayers Inst Precanc Detect & Diag, Nashville, TN 37232 USA. [Kim, Sangtae] Pacific NW Natl Lab, Directorate Fundamental & Computat Sci, Richland, WA 99352 USA. [Davies, Sherri R.; Townsend, R. Reid; Ellis, Matthew J. C.] Washington Univ Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Wang, Sean] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Wang, Pei] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA. [Kinsinger, Christopher R.; Rivers, Robert C.; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, Bethesda, MD 20892 USA. [Carr, Steven A.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Coffey, Robert J.] Vanderbilt Univ Sch Med, Dept Med, Nashville, TN 37232 USA. RP Liebler, DC (reprint author), Vanderbilt Univ Sch Med, Dept Biochem, Nashville, TN 37232 USA. EM daniel.liebler@vanderbilt.edu OI Payne, Samuel/0000-0002-8351-1994; Liebler, Daniel/0000-0002-7873-3031; Fenyo, David/0000-0001-5049-3825 FU National Cancer Institute (NCI) CPTAC awards [U24CA159988, U24CA160035, U24CA160034]; NCI SPORE award [P50CA095103]; NCI Cancer Center Support Grant [P30CA068485]; National Institutes of Health [GM088822]; Leidos Biomedical Research, Inc. [13XS029] FX This work was supported by National Cancer Institute (NCI) CPTAC awards U24CA159988, U24CA160035, and U24CA160034; by NCI SPORE award P50CA095103 and NCI Cancer Center Support Grant P30CA068485; by National Institutes of Health grant GM088822; and by contract 13XS029 from Leidos Biomedical Research, Inc. Genomics data for this study were generated by The Cancer Genome Atlas pilot project established by the NCI and the National Human Genome Research Institute. Information about TCGA and the investigators and institutions comprising the TCGA research network can be found at http://cancergenome.nih.gov/. NR 83 TC 231 Z9 237 U1 25 U2 136 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 SEP 18 PY 2014 VL 513 IS 7518 BP 382 EP + DI 10.1038/nature13438 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP1GD UT WOS:000341814900052 PM 25043054 ER PT J AU Lazaridis, I Patterson, N Mittnik, A Renaud, G Mallick, S Kirsanow, K Sudmant, PH Schraiber, JG Castellano, S Lipson, M Berger, B Economou, C Bollongino, R Fu, QM Bos, KI Nordenfelt, S Li, H de Filippo, C Prufer, K Sawyer, S Posth, C Haak, W Hallgren, F Fornander, E Rohland, N Delsate, D Francken, M Guinet, JM Wahl, J Ayodo, G Babiker, HA Bailliet, G Balanovska, E Balanovsky, O Barrantes, R Bedoya, G Ben-Ami, H Bene, J Berrada, F Bravi, CM Brisighelli, F Busby, GBJ Cali, F Churnosov, M Cole, DEC Corach, D Damba, L van Driem, G Dryomov, S Dugoujon, JM Fedorova, SA Romero, IG Gubina, M Hammer, M Henn, BM Hervig, T Hodoglugil, U Jha, AR Karachanak-Yankova, S Khusainova, R Khusnutdinova, E Kittles, R Kivisild, T Klitz, W Kucinskas, V Kushniarevich, A Laredj, L Litvinov, S Loukidis, T Mahley, RW Melegh, B Metspalu, E Molina, J Mountain, J Nakkalajarvi, K Nesheva, D Nyambo, T Osipova, L Parik, J Platonov, F Posukh, O Romano, V Rothhammer, F Rudan, I Ruizbakiev, R Sahakyan, H Sajantila, A Salas, A Starikovskaya, EB Tarekegn, A Toncheva, D Turdikulova, S Uktveryte, I Utevska, O Vasquez, R Villena, M Voevoda, M Winkler, CA Yepiskoposyan, L Zalloua, P Zemunik, T Cooper, A Capelli, C Thomas, MG Ruiz-Linares, A Tishkoff, SA Singh, L Thangaraj, K Villems, R Comas, D Sukernik, R Metspalu, M Meyer, M Eichler, EE Burger, J Slatkin, M Paabo, S Kelso, J Reich, D Krause, J AF Lazaridis, Iosif Patterson, Nick Mittnik, Alissa Renaud, Gabriel Mallick, Swapan Kirsanow, Karola Sudmant, Peter H. Schraiber, Joshua G. Castellano, Sergi Lipson, Mark Berger, Bonnie Economou, Christos Bollongino, Ruth Fu, Qiaomei Bos, Kirsten I. Nordenfelt, Susanne Li, Heng de Filippo, Cesare Pruefer, Kay Sawyer, Susanna Posth, Cosimo Haak, Wolfgang Hallgren, Fredrik Fornander, Elin Rohland, Nadin Delsate, Dominique Francken, Michael Guinet, Jean-Michel Wahl, Joachim Ayodo, George Babiker, Hamza A. Bailliet, Graciela Balanovska, Elena Balanovsky, Oleg Barrantes, Ramiro Bedoya, Gabriel Ben-Ami, Haim Bene, Judit Berrada, Fouad Bravi, Claudio M. Brisighelli, Francesca Busby, George B. J. Cali, Francesco Churnosov, Mikhail Cole, David E. C. Corach, Daniel Damba, Larissa van Driem, George Dryomov, Stanislav Dugoujon, Jean-Michel Fedorova, Sardana A. Romero, Irene Gallego Gubina, Marina Hammer, Michael Henn, Brenna M. Hervig, Tor Hodoglugil, Ugur Jha, Aashish R. Karachanak-Yankova, Sena Khusainova, Rita Khusnutdinova, Elza Kittles, Rick Kivisild, Toomas Klitz, William Kucinskas, Vaidutis Kushniarevich, Alena Laredj, Leila Litvinov, Sergey Loukidis, Theologos Mahley, Robert W. Melegh, Bela Metspalu, Ene Molina, Julio Mountain, Joanna Nakkalajarvi, Klemetti Nesheva, Desislava Nyambo, Thomas Osipova, Ludmila Parik, Jueri Platonov, Fedor Posukh, Olga Romano, Valentino Rothhammer, Francisco Rudan, Igor Ruizbakiev, Ruslan Sahakyan, Hovhannes Sajantila, Antti Salas, Antonio Starikovskaya, Elena B. Tarekegn, Ayele Toncheva, Draga Turdikulova, Shahlo Uktveryte, Ingrida Utevska, Olga Vasquez, Rene Villena, Mercedes Voevoda, Mikhail Winkler, Cheryl A. Yepiskoposyan, Levon Zalloua, Pierre Zemunik, Tatijana Cooper, Alan Capelli, Cristian Thomas, Mark G. Ruiz-Linares, Andres Tishkoff, Sarah A. Singh, Lalji Thangaraj, Kumarasamy Villems, Richard Comas, David Sukernik, Rem Metspalu, Mait Meyer, Matthias Eichler, Evan E. Burger, Joachim Slatkin, Montgomery Paeaebo, Svante Kelso, Janet Reich, David Krause, Johannes TI Ancient human genomes suggest three ancestral populations for present-day Europeans SO NATURE LA English DT Article ID DNA-SEQUENCING DATA; GENETIC DIVERSITY; HUNTER-GATHERERS; WIDE ASSOCIATION; HISTORY; ADMIXTURE; NEANDERTHAL; FARMERS; AFRICA; CAVE AB We sequenced the genomes of a similar to 7,000-year-old farmer from Germany and eight similar to 8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes(1-4) with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians(3), who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations' deep relationships and show that early European farmers had similar to 44% ancestry from a 'basal Eurasian' population that split before the diversification of other non-African lineages. C1 [Lazaridis, Iosif; Mallick, Swapan; Fu, Qiaomei; Nordenfelt, Susanne; Li, Heng; Rohland, Nadin; Reich, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Lazaridis, Iosif; Patterson, Nick; Mallick, Swapan; Berger, Bonnie; Nordenfelt, Susanne; Li, Heng; Rohland, Nadin; Reich, David] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Mittnik, Alissa; Bos, Kirsten I.; Posth, Cosimo; Krause, Johannes] Univ Tubingen, Inst Archaeol Sci, D-72074 Tubingen, Germany. [Renaud, Gabriel; Castellano, Sergi; Fu, Qiaomei; de Filippo, Cesare; Pruefer, Kay; Sawyer, Susanna; Meyer, Matthias; Paeaebo, Svante; Kelso, Janet] Max Planck Inst Evolutionare Anthropol, D-04103 Leipzig, Germany. [Kirsanow, Karola; Bollongino, Ruth; Burger, Joachim] Johannes Gutenberg Univ Mainz, Inst Anthropol, D-55128 Mainz, Germany. [Sudmant, Peter H.; Schraiber, Joshua G.; Eichler, Evan E.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Schraiber, Joshua G.; Klitz, William; Slatkin, Montgomery] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Lipson, Mark; Berger, Bonnie] MIT, Dept Math & Comp Sci, Cambridge, MA 02139 USA. [Lipson, Mark; Berger, Bonnie] MIT, Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Economou, Christos] Stockholm Univ, Archaeol Res Lab, S-11418 Stockholm, Sweden. [Fu, Qiaomei] Chinese Acad Sci, IVPP, Key Lab Vertebrate Evolut & Human Origins, Beijing 100049, Peoples R China. [Haak, Wolfgang; Cooper, Alan] Univ Adelaide, Sch Earth & Environm Sci, Australian Ctr Ancient DNA & Environm Inst, Adelaide, SA 5005, Australia. [Hallgren, Fredrik; Fornander, Elin] Cultural Heritage Fdn, S-72212 Vasteras, Sweden. [Delsate, Dominique; Guinet, Jean-Michel] Natl Museum Nat Hist, L-2160 Luxembourg, Luxembourg. [Delsate, Dominique] Natl Museum Nat Hist, Natl Ctr Archaeol Res, L-2160 Luxembourg, Luxembourg. [Francken, Michael] Univ Tubingen, Senckenberg Ctr Human Evolut & Paleoenvironm, Dept Paleoanthropol, D-72070 Tubingen, Germany. [Wahl, Joachim] State Off Cultural Heritage Management Baden Wurt, D-78467 Constance, Germany. [Ayodo, George] Ctr Global Hlth & Child Dev, Kisumu 40100, Kenya. [Babiker, Hamza A.] Univ Edinburgh, Sch Biol Sci, Inst Evolut Res, Edinburgh EH9 3JT, Midlothian, Scotland. [Babiker, Hamza A.] Univ Edinburgh, Sch Biol Sci, Inst Immunol Res, Edinburgh EH9 3JT, Midlothian, Scotland. [Babiker, Hamza A.] Univ Edinburgh, Sch Biol Sci, Inst Infect Res, Edinburgh EH9 3JT, Midlothian, Scotland. [Babiker, Hamza A.] Sultan Qaboos Univ, Fac Med, Dept Biochem, Muscat 123, Oman. [Bailliet, Graciela; Bravi, Claudio M.] Consejo Nacl Invest Cient & Tecn, CCT, Inst Multidisciplinario Biol Celular IMBICE, Lab Genet Mol Poblac, La Plata, Buenos Aires, Argentina. [Bailliet, Graciela; Bravi, Claudio M.] CICPBA, La Plata, Buenos Aires, Argentina. [Balanovska, Elena; Balanovsky, Oleg] Russian Acad Med Sci, Med Genet Res Ctr, Moscow 115478, Russia. [Balanovsky, Oleg] NI Vavilov Gen Genet Res Inst, Moscow 119991, Russia. [Barrantes, Ramiro] Univ Costa Rica, Escuela Biol, San Jose 2060, Costa Rica. [Bedoya, Gabriel] Univ Antioquia, Res Grp GENMOL, Inst Biol, Medellin, Colombia. [Ben-Ami, Haim] Rambam Hlth Care Campus, IL-31096 Haifa, Israel. [Bene, Judit; Melegh, Bela] Univ Pecs, Dept Med Genet, H-7624 Pecs, Hungary. [Bene, Judit; Melegh, Bela] Univ Pecs, Szentagothai Res Ctr, H-7624 Pecs, Hungary. [Berrada, Fouad] Al Akhawayn Univ Ifrane AUI, Sch Sci & Engn, Ifrane 53000, Morocco. [Brisighelli, Francesca] Univ Cattolica Sacro Cuore, Inst Legal Med, Forens Genet Lab, I-00168 Rome, Italy. [Busby, George B. J.; Capelli, Cristian] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Busby, George B. J.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Cali, Francesco] IRCCS Assoc Oasi Maria SS, Genet Mol Lab, I-94018 Troina, Italy. [Churnosov, Mikhail] Belgorod State Univ, Belgorod 308015, Russia. [Cole, David E. C.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5G 1L5, Canada. [Corach, Daniel] Univ Buenos Aires, Sch Pharm & Biochem, Serv Huellas Digitales Genet, RA-1113 Caba, Argentina. [Damba, Larissa; Gubina, Marina; Osipova, Ludmila; Posukh, Olga; Voevoda, Mikhail] Russian Acad Sci, Inst Cytol & Genet, Siberian Branch, Novosibirsk 630090, Russia. [van Driem, George] Univ Bern, Inst Linguist, CH-3012 Bern, Switzerland. [Dryomov, Stanislav; Starikovskaya, Elena B.; Sukernik, Rem] Russian Acad Sci, Inst Mol & Cellular Biol, Siberian Branch, Lab Human Mol Genet, Novosibirsk 630090, Russia. [Dugoujon, Jean-Michel] Univ Toulouse 3, CNRS UMR 5288, F-31000 Toulouse, France. [Fedorova, Sardana A.] North Eastern Fed Univ, Yakutsk 677013, Russia. [Fedorova, Sardana A.] Yakut Res Ctr Complex Med Problems, Yakutsk 677013, Russia. [Romero, Irene Gallego; Jha, Aashish R.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Hammer, Michael] Univ Arizona, ARL Div Biotechnol, Tucson, AZ 85721 USA. [Henn, Brenna M.] SUNY Stony Brook, Dept Ecol & Evolut, Stony Brook, NY 11794 USA. [Hervig, Tor] Univ Bergen, Dept Clin Sci, N-5021 Bergen, Norway. [Hodoglugil, Ugur] Illumina, NextBio, Santa Clara, CA 95050 USA. [Karachanak-Yankova, Sena; Nesheva, Desislava; Toncheva, Draga] Med Univ Sofia, Natl Human Genome Ctr, Dept Med Genet, Sofia 1431, Bulgaria. [Khusainova, Rita; Khusnutdinova, Elza; Litvinov, Sergey] Russian Acad Sci, Ufa Res Ctr, Inst Biochem & Genet, Ufa 450054, Russia. [Khusainova, Rita; Khusnutdinova, Elza; Litvinov, Sergey] Bashkir State Univ, Dept Genet & Fundamental Med, Ufa 450074, Russia. [Kittles, Rick] Univ Arizona, Coll Med, Tucson, AZ 85724 USA. [Kivisild, Toomas] Univ Cambridge, Div Biol Anthropol, Cambridge CB2 1QH, England. [Kucinskas, Vaidutis; Uktveryte, Ingrida] Vilnius State Univ, Dept Human & Med Genet, LT-08661 Vilnius, Lithuania. [Kushniarevich, Alena; Litvinov, Sergey; Sahakyan, Hovhannes; Villems, Richard; Metspalu, Mait] Estonian Bioctr, Evolutionary Biol Grp, EE-51010 Tartu, Estonia. [Laredj, Leila] Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France. [Loukidis, Theologos; Thomas, Mark G.; Ruiz-Linares, Andres] UCL, Dept Genet Evolut & Environm, London WC1E 6BT, England. [Mahley, Robert W.] Gladstone Inst, San Francisco, CA 94158 USA. [Metspalu, Ene; Parik, Jueri; Villems, Richard] Univ Tartu, Dept Evolutionary Biol, EE-51010 Tartu, Estonia. [Molina, Julio] Ctr Invest Biomed Guatemala, Guatemala City, Guatemala. [Mountain, Joanna] 23andMe, Res Dept, Mountain View, CA 94043 USA. [Nakkalajarvi, Klemetti] Univ Oulu, Cultural Anthropol Program, Oulu 90014, Finland. [Nyambo, Thomas] Muhimbili Univ Hlth & Allied Sci, Dept Biochem, Dar Es Salaam 65001, Tanzania. [Platonov, Fedor] North Eastern Fed Univ, Res Inst Hlth, Yakutsk 677000, Russia. [Romano, Valentino] Univ Palermo, Dipartimento Fis & Chim, I-90128 Palermo, Italy. [Rothhammer, Francisco] Univ Tarapaca, Inst Alta Invest, Arica 1000000, Chile. [Rothhammer, Francisco] Univ Chile, Fac Med, Programa Genet Humana, ICBM, Santiago 8320000, Chile. [Rothhammer, Francisco] Ctr Invest Hombre Desierto, Arica 1000000, Chile. [Rudan, Igor] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Ruizbakiev, Ruslan] Uzbek Acad Sci, Inst Immunol, Tashkent 70000, Uzbekistan. [Sahakyan, Hovhannes; Yepiskoposyan, Levon] Natl Acad Sci Armenia, Inst Mol Biol, Lab Ethnogenom, Yerevan 0014, Armenia. [Sajantila, Antti] Univ Helsinki, Dept Forens Med, Hjelt Inst, Helsinki 00014, Finland. [Sajantila, Antti] Univ North Texas Hlth Sci Ctr, Dept Mol & Med Genet, Inst Appl Genet, Ft Worth, TX 76107 USA. [Salas, Antonio] Univ Santiago de Compostela, Fac Med, GMX, Dept Anat Patol & Ciencias Forenses,Unidade Xenet, Galcia 15872, Spain. [Salas, Antonio] Univ Santiago de Compostela, Fac Med, GMX, Inst Ciencias Forenses, Galcia 15872, Spain. [Tarekegn, Ayele] Henry Stewart Grp, London WC1A 2HN, England. [Turdikulova, Shahlo] Acad Sci Uzbek, Inst Bioorgan Chem, Tashkent 100125, Uzbekistan. [Utevska, Olga] Kharkov Natl Univ, Dept Genet & Cytol, UA-61077 Kharkov, Ukraine. [Vasquez, Rene; Villena, Mercedes] Univ Mayor San Andres, Inst Boliviano Biol Altura, La Paz 5912, Bolivia. [Vasquez, Rene; Villena, Mercedes] Univ Autonoma Tomas Frias, Potosi, Bolivia. [Voevoda, Mikhail] Russian Acad Med Sci, Siberian Branch, Inst Internal Med, Novosibirsk 630089, Russia. [Voevoda, Mikhail] Novosibirsk State Univ, Novosibirsk 630090, Russia. [Winkler, Cheryl A.] NCI, Basic Res Lab, NIH, Frederick Natl Lab,Leidos Biomed, Frederick, MD 21702 USA. [Zalloua, Pierre] Lebanese Amer Univ, Sch Med, Beirut 135053, Lebanon. [Zalloua, Pierre] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Zemunik, Tatijana] Univ Split, Sch Med, Dept Med Biol, Split 21000, Croatia. [Tishkoff, Sarah A.] Univ Penn, Dept Biol & Genet, Philadelphia, PA 19104 USA. [Singh, Lalji; Thangaraj, Kumarasamy] CSIR Ctr Cellular & Mol Biol, Hyderabad 500007, Andhra Pradesh, India. [Villems, Richard] Estonian Acad Sci, EE-10130 Tallinn, Estonia. [Comas, David] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Inst Biol Evolut CSIC UPF, Barcelona 08003, Spain. [Eichler, Evan E.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Reich, David] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Krause, Johannes] Univ Tubingen, Senckenberg Ctr Human Evolut & Palaeoenvironm, D-72070 Tubingen, Germany. [Krause, Johannes] Max Planck Inst Geschichte & Nat Wissensch, D-07745 Jena, Germany. RP Reich, D (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM reich@genetics.med.harvard.edu; johannes.krause@uni-tuebingen.de RI Dryomov, Stanislav/N-5476-2015; Posukh, Olga/Q-6065-2016; Cali, Francesco/D-9178-2017; Thomas, Mark/A-2219-2012; Osipova, Ludmila/O-6480-2014; Li, Heng/D-9344-2011; Haak, Wolfgang/C-2362-2014; Metspalu, Mait/G-8671-2015; Krause, Johannes/E-6640-2015; Salas, Antonio/E-3977-2012; Starikovskaya, Elena/N-5636-2015; Sukernik, Rem/N-6990-2015; Castellano, Sergi/A-7437-2016; Litvinov, Sergey/L-1738-2013; Rudan, Igor/I-1467-2012; Khusnutdinova, Elza/A-4810-2013 OI Thangaraj, Kumarasamy/0000-0002-0075-0106; zalloua, pierre/0000-0002-8494-5081; Romano, Valentino/0000-0003-3238-5702; Scavuzzo, Cataldo/0000-0002-3905-4191; Busby, George/0000-0003-4148-6222; Posukh, Olga/0000-0003-1352-3591; Cali, Francesco/0000-0001-8667-8223; Sahakyan, Hovhannes/0000-0003-1596-2838; Sudmant, Peter/0000-0002-9573-8248; Gallego Romero, Irene/0000-0003-1613-8998; Utevska, Olga/0000-0002-5787-0467; Turdikulova, Shahlo/0000-0003-0764-2332; Thomas, Mark/0000-0002-2452-981X; Osipova, Ludmila/0000-0001-7602-1156; Li, Heng/0000-0003-4874-2874; Haak, Wolfgang/0000-0003-2475-2007; Metspalu, Mait/0000-0003-3099-9161; Krause, Johannes/0000-0001-5475-4690; Salas, Antonio/0000-0002-2336-702X; Castellano, Sergi/0000-0002-5819-4210; Rudan, Igor/0000-0001-6993-6884; FU DFG [KR 4015/1-1]; Carl-Zeiss Foundation; Baden Wurttemberg Foundation; Max Planck Society; NSERC; NSF [OCI-1053575]; RFBR [13-06-00670, 13-04-01711, 13-04-90420]; Molecular and Cell Biology Program of the Presidium, Russian Academy of Sciences; OTKA [73430, 103983]; Finnish Professorpool (Paulo Foundation) Grant; LITGEN project - European Social Fund under Global Grant Measure [VP1-3.1-SMM-07-K-01-013]; Ukrainian SFFS grant [F53.4/071]; NIH [8DP1ES022577-04, GM40282, HG004120, HG002385, GM100233]; NSF HOMINID [BCS-0827436, BCS-1032255]; Indian CSIR Network Project [BSC0121]; Indian CSIR Bhatnagar Fellowship; European Union Regional Development Fund through Centre of Excellence in Genomics; University of Tartu; Estonian Basic Research grant [SF0270177As08]; Estonian Science Foundation [8973]; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; NIH, National Cancer Institute, Center for Cancer Research; [SAF2011-26983]; [EM2012/045] FX We thank the 1,615 volunteers from 147 diverse populations who donated DNA samples and whose genetic data are newly reported in this study. We are grateful to C. Beall, N. Bradman, A. Gebremedhin, D. Labuda, M. Nelis and A. Di Rienzo for sharing DNA samples; to D. Weigel, C. Lanz, V. Schunemann, P. Bauer and O. Riess for support and access to DNA sequencing facilities; to P. Johnson for advice on contamination estimation; to G. Hellenthal for help with the ChromoPainter software; and to P. Skoglund for sharing graphics software. We thank K. Nordtvedt for alerting us to newly discovered Y-chromosome SNPs. We downloaded the POPRES data from dbGaP at (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs 000145.v4.p2) through dbGaP accession number phs000145.v1.p2. We thank all the volunteers who donated DNA. We thank the staff of the Unita Operativa Complessa di Medicina Trasfusionale, Azienda Ospedaliera Umberto I, Siracusa, Italy for assistance in sample collection; and The National Laboratory for the Genetics of Israeli Populations for facilitating access to DNA. We thank colleagues at the Applied Genomics at the Children's Hospital of Philadelphia, especially H. Hakonarson, C. Kim, K. Thomas, and C. Hou, for genotyping samples on the Human Origins array. J.Kr., A. M. and C. P. are grateful for support from DFG grant number KR 4015/1-1, the Carl-Zeiss Foundation and the Baden Wurttemberg Foundation. S. P., G. R., Q. F., C. F., K. P., S. C. and J.Ke. acknowledge support from the Presidential Innovation Fund of the Max Planck Society. G. R. was supported by an NSERC fellowship. J.G.S. acknowledges use of the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by NSF grant number OCI-1053575. E. B. and O. B. were supported by RFBR grants 13-06-00670, 13-04-01711, 13-04-90420 and by the Molecular and Cell Biology Program of the Presidium, Russian Academy of Sciences. B. M. was supported by grants OTKA 73430 and 103983. A.Saj. was supported by a Finnish Professorpool (Paulo Foundation) Grant. The Lithuanian sampling was supported by the LITGEN project (VP1-3.1-SMM-07-K-01-013), funded by the European Social Fund under the Global Grant Measure. A. S. was supported by Spanish grants SAF2011-26983 and EM2012/045. O. U. was supported by Ukrainian SFFS grant F53.4/071. S. A. T. was supported by NIH Pioneer Award 8DP1ES022577-04 and NSF HOMINID award BCS-0827436. K. T. was supported by an Indian CSIR Network Project (GENESIS: BSC0121). L. S. was supported by an Indian CSIR Bhatnagar Fellowship. R. V., M. M., J.P. and E. M. were supported by the European Union Regional Development Fund through the Centre of Excellence in Genomics to the Estonian Biocentre and University of Tartu and by an Estonian Basic Research grant SF0270177As08. M. M. was additionally supported by Estonian Science Foundation grant number 8973. J.G.S. and M. S. were supported by NIH grant GM40282. P. H. S. and E. E. E. were supported by NIH grants HG004120 and HG002385. D. R. and N.P. were supported by NSF HOMINID award BCS-1032255 and NIH grant GM100233. D. R. and E. E. E. are Howard Hughes Medical Institute investigators. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.; This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 69 TC 169 Z9 169 U1 25 U2 285 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 SEP 18 PY 2014 VL 513 IS 7518 BP 409 EP + DI 10.1038/nature13673 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP1GD UT WOS:000341814900058 PM 25230663 ER PT J AU Ma, YY Lee, BR Wang, XS Guo, CY Liu, L Cui, RJ Lan, Y Balcita-Pedicino, JJ Wolf, ME Sesack, SR Shaham, Y Schluter, OM Huang, YHH Dong, Y AF Ma, Yao-Ying Lee, Brian R. Wang, Xiusong Guo, Changyong Liu, Lei Cui, Ranji Lan, Yan Balcita-Pedicino, Judith J. Wolf, Marina E. Sesack, Susan R. Shaham, Yavin Schlueter, Oliver M. Huang, Yanhua H. Dong, Yan TI Bidirectional Modulation of Incubation of Cocaine Craving by Silent Synapse-Based Remodeling of Prefrontal Cortex to Accumbens Projections SO NEURON LA English DT Article ID NUCLEUS-ACCUMBENS; SEEKING BEHAVIOR; INDUCED REINSTATEMENT; AMPA RECEPTORS; DRUG-SEEKING; ADDICTION; NEURONS; RELAPSE; RAT; SENSITIZATION AB Glutamatergic projections from the medial prefrontal cortex (mPFC) to nucleus accumbens (NAc) contribute to cocaine relapse. Here we show that silent synapse-based remodeling of the two major mPFC-to-NAc projections differentially regulated the progressive increase in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving). Specifically, cocaine self-administration in rats generated AMPA receptor-silent glutamatergic synapses within both infralimbic (IL) and prelimbic mPFC (PrL) to NAc projections, measured after 1 day of withdrawal. After 45 days of withdrawal, IL-to-NAc silent synapses became unsilenced/matured by recruiting calcium-permeable (CP) AMPARs, whereas PrL-to-NAc silent synapses matured by recruiting non-CP-AMPARs, resulting in differential remodeling of these projections. Optogenetic reversal of silent synapse-based remodeling of IL-to-NAc and PrL-to-NAc projections potentiated and inhibited, respectively, incubation of cocaine craving on withdrawal day 45. Thus, pro-and antirelapse circuitry remodeling is induced in parallel after cocaine self-administration. These results may provide substrates for utilizing endogenous antirelapse mechanisms to reduce cocaine relapse. C1 [Ma, Yao-Ying; Guo, Changyong; Lan, Yan; Balcita-Pedicino, Judith J.; Sesack, Susan R.; Dong, Yan] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA 15260 USA. [Wang, Xiusong; Sesack, Susan R.; Huang, Yanhua H.; Dong, Yan] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. [Lee, Brian R.] Allen Inst Brain Sci, Seattle, WA 98103 USA. [Liu, Lei; Cui, Ranji] NE Normal Univ, Sch Life Sci, Changchun, Jilin, Peoples R China. [Wolf, Marina E.] Rosalind Franklin Univ Med & Sci, Dept Neurosci, N Chicago, IL 60064 USA. [Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Schlueter, Oliver M.] European Neurosci Inst, Mol Neurobiol & Cluster Excellence Nanoscale Micr, D-37077 Gottingen, Germany. RP Huang, YHH (reprint author), Univ Pittsburgh, Dept Psychiat, 3811 Ohara St, Pittsburgh, PA 15260 USA. EM huangy3@upmc.edu; yandong@pitt.edu RI dong, yan/J-2859-2014; Dong, Yan/A-4154-2016; Huang, Yanhua/P-1583-2015 OI Dong, Yan/0000-0003-0016-9028; Huang, Yanhua/0000-0003-1770-0196 FU NIH [DA028020, DA009621, DA015835, DA029565, DA035805, MH101147, DA023206, DA030379, DA034856]; Pennsylvania Department of Health Commonwealth Universal Research Enhancement; NSFC [81328011]; Deutsche Forschungsgemeinschaft through Cluster of Excellence "Nanoscale Microscopy and Molecular Physiology of the Brain"; Max-Planck Society; University Medicine Gottingen; Drug Supply Program of NIH NIDA FX We thank Drs. Peter Kalivas and Peter Neumann for helpful comments on the manuscript. The reported work was supported by NIH intramural funds (Y.S.) and extramural funds DA028020 (B. R. L.), DA009621 (M. E. W.), DA015835 (M. E. W.), DA029565 (Y.H.H.), DA035805 (Y.H.H.), MH101147 (Y.H.H.), DA023206 (Y.D.), DA030379 (M. E. W. and Y.D.), DA034856 (Y.D.), the Pennsylvania Department of Health Commonwealth Universal Research Enhancement (Y.H.H.), NSFC 81328011 (R. C.), and the Deutsche Forschungsgemeinschaft through the Cluster of Excellence "Nanoscale Microscopy and Molecular Physiology of the Brain" (O.M.S.). The European Neuroscience Institute-Gottingen is jointly funded by the Max-Planck Society and University Medicine Gottingen. Cocaine was supplied by the Drug Supply Program of NIH NIDA. NR 55 TC 58 Z9 59 U1 2 U2 21 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 SEP 17 PY 2014 VL 83 IS 6 BP 1453 EP 1467 DI 10.1016/j.neuron.2014.08.023 PG 15 WC Neurosciences SC Neurosciences & Neurology GA AQ0WC UT WOS:000342502400028 PM 25199705 ER PT J AU Conlan, S Thomas, PJ Deming, C Park, M Lau, AF Dekker, JP Snitkin, ES Clark, TA Luong, K Song, Y Tsai, YC Boitano, M Dayal, J Brooks, SY Schmidt, B Young, AC Thomas, JW Bouffard, GG Blakesley, RW Mullikin, JC Korlach, J Henderson, DK Frank, KM Palmore, TN Segre, JA AF Conlan, Sean Thomas, Pamela J. Deming, Clayton Park, Morgan Lau, Anna F. Dekker, John P. Snitkin, Evan S. Clark, Tyson A. Khai Luong Song, Yi Tsai, Yu-Chih Boitano, Matthew Dayal, Jyoti Brooks, Shelise Y. Schmidt, Brian Young, Alice C. Thomas, James W. Bouffard, Gerard G. Blakesley, Robert W. Mullikin, James C. Korlach, Jonas Henderson, David K. Frank, Karen M. Palmore, Tara N. Segre, Julia A. CA NISC Comparative Sequencing TI Single-molecule sequencing to track plasmid diversity of hospital-associated carbapenemase-producing Enterobacteriaceae SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID GRAM-NEGATIVE BACILLI; CARE-UNIT PATIENTS; HANDWASHING SINKS; GENOME ASSEMBLIES; NEW-YORK; OUTBREAK; TIME; TRANSMISSION; RESISTANCE; INFECTIONS AB Public health officials have raised concerns that plasmid transfer between Enterobacteriaceae species may spread resistance to carbapenems, an antibiotic class of last resort, thereby rendering common health care-associated infections nearly impossible to treat. To determine the diversity of carbapenemase-encoding plasmids and assess their mobility among bacterial species, we performed comprehensive surveillance and genomic sequencing of carbapenem-resistant Enterobacteriaceae in the National Institutes of Health (NIH) Clinical Center patient population and hospital environment. We isolated a repertoire of carbapenemase-encoding Enterobacteriaceae, including multiple strains of Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Enterobacter cloacae, Citrobacter freundii, and Pantoea species. Long-read genome sequencing with full end-to-end assembly revealed that these organisms carry the carbapenem resistance genes on a wide array of plasmids. K. pneumoniae and E. cloacae isolated simultaneously from a single patient harbored two different carbapenemase-encoding plasmids, indicating that plasmid transfer between organisms was unlikely within this patient. We did, however, find evidence of horizontal transfer of carbapenemase-encoding plasmids between K. pneumoniae, E. cloacae, and C. freundii in the hospital environment. Our data, including full plasmid identification, challenge assumptions about horizontal gene transfer events within patients and identify possible connections between patients and the hospital environment. In addition, we identified a new carbapenemase-encoding plasmid of potentially high clinical impact carried by K. pneumoniae, E. coli, E. cloacae, and Pantoea species, in unrelated patients and in the hospital environment. C1 [Conlan, Sean; Deming, Clayton; Snitkin, Evan S.; Segre, Julia A.] NHGRI, Bethesda, MD 20892 USA. [Thomas, Pamela J.; Park, Morgan; Dayal, Jyoti; Brooks, Shelise Y.; Schmidt, Brian; Young, Alice C.; Thomas, James W.; Bouffard, Gerard G.; Blakesley, Robert W.; Mullikin, James C.; NISC Comparative Sequencing] NIH, Intramural Sequencing Ctr NISC, Bethesda, MD 20852 USA. [Lau, Anna F.; Dekker, John P.; Henderson, David K.; Frank, Karen M.; Palmore, Tara N.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Clark, Tyson A.; Khai Luong; Song, Yi; Tsai, Yu-Chih; Boitano, Matthew; Korlach, Jonas] Pacific Biosci, Menlo Pk, CA 94025 USA. RP Frank, KM (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM karen.frank@nih.gov; tpalmore@mail.nih.gov; jsegre@nhgri.nih.gov FU National Human Genome Research Institute; NIH Clinical Center Intramural Research Programs; NIH; Pharmacology Research Associate Training Fellowship, National Institute of General Medical Sciences FX Funding: Supported by the National Human Genome Research Institute and NIH Clinical Center Intramural Research Programs and by an NIH Director's Challenge Award. E.S.S. is supported by a Pharmacology Research Associate Training Fellowship, National Institute of General Medical Sciences. NR 48 TC 71 Z9 71 U1 3 U2 20 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 SEP 17 PY 2014 VL 6 IS 254 AR 254ra126 DI 10.1126/scitranslmed.3009845 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AQ0JJ UT WOS:000342469000010 PM 25232178 ER PT J AU An, LY Wang, YF Zhang, N Yan, SH Bax, A Yao, LS AF An, Liaoyuan Wang, Yefei Zhang, Ning Yan, Shihai Bax, Ad Yao, Lishan TI Protein Apparent Dielectric Constant and Its Temperature Dependence from Remote Chemical Shift Effects SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; ELECTRIC-FIELDS; ACTIVE-SITE; SHIELDING POLARIZABILITIES; NMR-SPECTROSCOPY; BINDING DOMAIN; WATER; PEPTIDES; POLAR; SENSITIVITY AB A NMR protocol is introduced that permits accurate measurement of minute, remote chemical shift perturbations (CSPs), caused by a mutation-induced change in the electric field. Using protein GB3 as a model system, H-1(N) CSPs in K19A and K19E mutants can be fitted to small changes in the electric field at distal sites in the protein using the Buckingham equation, yielding an apparent dielectric constant epsilon(a) of 8.6 +/- 0.8 at 298 K. These CSPs, and their derived epsilon(a) value, scale strongly with temperature. For example, CSPs at 313 K are about similar to 30% smaller than those at 278 K, corresponding to an effective epsilon(a) value of about 7.3 at 278 K and 10.5 at 313 K. Molecular dynamics simulations in explicit solvent indicate that solvent water makes a significant contribution to epsilon(a). C1 [An, Liaoyuan; Wang, Yefei; Zhang, Ning; Yao, Lishan] Chinese Acad Sci, Qingdao Inst Bioenergy & Bioproc Technol, Lab Biofuels, Qingdao 266101, Peoples R China. [Yan, Shihai] Qingdao Agr Univ, Coll Chem & Pharmaceut Sci, Qingdao 266109, Peoples R China. [Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Yao, LS (reprint author), Chinese Acad Sci, Qingdao Inst Bioenergy & Bioproc Technol, Lab Biofuels, Qingdao 266101, Peoples R China. EM yaols@qibebt.ac.cn RI yao, lishan/H-3662-2012 OI yao, lishan/0000-0003-1797-922X FU 100 Talent Project of Chinese Academy of Sciences; National Nature Science Foundation of China [21173247, 31270785]; Foundation for Outstanding Young Scientist in Shandong Province [JQ201104, ZR2011BQ008]; Intramural Research Program of the NIDDK, National Institutes of Health (NIH) FX This work was supported in part by the 100 Talent Project of Chinese Academy of Sciences, National Nature Science Foundation of China (Grant No. 21173247 and 31270785 to L.Y.) and the Foundation for Outstanding Young Scientist in Shandong Province (Grant No. JQ201104 to L.Y. and ZR2011BQ008 to Y.W.). A.B. is supported by the Intramural Research Program of the NIDDK, National Institutes of Health (NIH). NR 39 TC 3 Z9 3 U1 2 U2 30 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 17 PY 2014 VL 136 IS 37 BP 12816 EP 12819 DI 10.1021/ja505852b PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA AP5LC UT WOS:000342119700004 PM 25192058 ER PT J AU Zhang, F Pararnasivam, M Ca, Q Dai, XX Wang, PC Lin, K Song, JK Seidman, MM Wang, YS AF Zhang, Fan Pararnasivam, Manikandan Ca, Qian Dai, Xiaoxia Wang, Pengcheng Lin, Krystal Song, Jikui Seidman, Michael M. Wang, Yinsheng TI Arsenite Binds to the RING Finger Domains of RNF20-RNF40 Histone E3 Ubiquitin Ligase and Inhibits DNA Double-Strand Break Repair SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PROTEINS; H2B; CELLS; METABOLITES; PROMOTES; AFFINITY; WATER AB Arsenic is a widespread environmental contaminant. However, the exact molecular mechanisms underlying the carcinogenic effects of arsenic remain incompletely understood. Core histones can be ubiquitinated by RING finger E3 ubiquitin ligases, among which the RNF20-RNF40 heterodimer catalyzes the ubiquitination of histone H2B at lysine 120. This ubiquitination event is important for the formation of open and biochemically accessible chromatin fiber that is conducive for DNA repair. Herein, we found that arsenite could bind directly to the RING finger domains of RNF20 and RNF40 in vitro and in cells, and treatment with arsenite resulted in substantially impaired H2B ubiquitination in multiple cell lines. Exposure to arsenite also diminished the recruitment of BRCA1 and RAD51 to laser-induced DNA double-strand break (DSB) sites, compromised DNA DSB repair in human cells, and rendered cells sensitive toward a radiomimetic agent, neocarzinostatin. Together, the results from the present study revealed, for the first time, that arsenite may exert its carcinogenic effect by targeting cysteine residues in the RING finger domains of histone E3 ubiquitin ligase, thereby altering histone epigenetic mark and compromising DNA DSB repair. Our results also suggest arsenite as a general inhibitor for RING finger E3 ubiquitin ligases. C1 [Zhang, Fan; Dai, Xiaoxia; Wang, Yinsheng] Univ Calif Riverside, Dept Chem, Riverside, CA 92521 USA. [Ca, Qian; Wang, Pengcheng; Wang, Yinsheng] Univ Calif Riverside, Environm Toxicol Grad Program, Riverside, CA 92521 USA. [Lin, Krystal; Song, Jikui] Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA. [Pararnasivam, Manikandan; Seidman, Michael M.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Wang, YS (reprint author), Univ Calif Riverside, Dept Chem, Riverside, CA 92521 USA. EM Yinsheng.Wang@ucr.edu RI CAI, QIAN/E-2352-2017 OI CAI, QIAN/0000-0002-7865-5993 FU National Institutes of Health [R01 ES019873]; Intramural Research Program of the NIH, National Institute on Aging [AG000746-02] FX This research was supported in part by the National Institutes of Health (R01 ES019873 to Y.W.) and the Intramural Research Program of the NIH, National Institute on Aging (AG000746-02). The authors would like to thank Profs. Jeremy M. Stark, Jiri Lukas, Gerd P. Pfeifer, Yossi Shiloh, and Alan R. Lehmann for generously providing cells and plasmids. NR 28 TC 6 Z9 7 U1 2 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 17 PY 2014 VL 136 IS 37 BP 12884 EP 12887 DI 10.1021/ja507863d PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA AP5LC UT WOS:000342119700021 PM 25170678 ER PT J AU Stroncek, DF Fellowes, V Pham, C Khuu, H Fowler, DH Wood, LV Sabatino, M AF Stroncek, David F. Fellowes, Vicki Pham, Chauha Khuu, Hanh Fowler, Daniel H. Wood, Lauren V. Sabatino, Marianna TI Counter-flow elutriation of clinical peripheral blood mononuclear cell concentrates for the production of dendritic and T cell therapies SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Cellular therapy; Cell processing; Counter-flow elutriation; Dendritic cells; Adoptive cell therapy ID MONOCYTE ENRICHMENT; CD14(+) MONOCYTES; CLINIMACS SYSTEM; SCALE; GENERATION; TRANSPLANTATION; CRYOPRESERVATION; IMMUNOTHERAPY; LEUKAPHERESIS; PURIFICATION AB Introduction: Peripheral blood mononuclear cells (PBMC) concentrates collected by apheresis are frequently used as starting material for cellular therapies, but the cell of interest must often be isolated prior to initiating manufacturing. Study design and methods: The results of enriching 59 clinical PBMC concentrates for monocytes or lymphocytes from patients with solid tumors or multiple myeloma using a commercial closed system semi-automated counter-flow elutriation instrument (Elutra, Terumo BCT) were evaluated for quality and consistency. Elutriated monocytes (n = 35) were used to manufacture autologous dendritic cells and elutriated lymphocytes (n = 24) were used manufacture autologous T cell therapies. Elutriated monocytes with >10% neutrophils were subjected to density gradient sedimentation to reduce neutrophil contamination and elutriated lymphocytes to RBC lysis. Results: Elutriation separated the PBMC concentrates into 5 fractions. Almost all of the lymphocytes, platelets and red cells were found in fractions 1 and 2; in contrast, most of the monocytes, 88.6 +/- 43.0%, and neutrophils, 74.8 +/- 64.3%, were in fraction 5. In addition, elutriation of 6 PBMCs resulted in relatively large quantities of monocytes in fractions 1 or 2. These 6 PBMCs contained greater quantities of monocytes than the other 53 PBMCs. Among fraction 5 isolates 38 of 59 contained >10% neutrophils. High neutrophil content of fraction 5 was associated with greater quantities of neutrophils in the PBMC concentrate. Following density gradient separation the neutrophil counts fell to 3.6 +/- 3.4% (all products contained <10% neutrophils). Following red cell lysis of the elutriated lymphocyte fraction the lymphocyte recovery was 86.7 +/- 24.0% and 34.3 +/- 37.4% of red blood cells remained. Conclusions: Elutriation was consistent and effective for isolating monocytes and lymphocytes from PBMC concentrates for manufacturing clinical cell therapies, but further processing is often required. C1 [Stroncek, David F.; Pham, Chauha; Khuu, Hanh; Sabatino, Marianna] NIH, Dept Transfus Med, Cell Proc Sect, Ctr Clin, Bethesda, MD 20892 USA. [Fellowes, Vicki; Fowler, Daniel H.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Wood, Lauren V.] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Cell Proc Sect, Ctr Clin, 10 Ctr Drive MSC 1184,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU intramural programs of the NIH Clinical Center; National Cancer Institute, NIH, Bethesda, Maryland, USA FX The authors thank that staff of the Cell Processing Section, Department of Transfusion Medicine, Clinical Center, NIH for preforming the elutriation procedures. These studies were supported by funds from the intramural programs of the NIH Clinical Center and National Cancer Institute, NIH, Bethesda, Maryland, USA. NR 26 TC 4 Z9 4 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD SEP 17 PY 2014 VL 12 AR 241 DI 10.1186/s12967-014-0241-y PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AP6FV UT WOS:000342173900001 PM 25223845 ER PT J AU Yang, AI Vanegas, N Lungu, C Zaghloul, KA AF Yang, Andrew I. Vanegas, Nora Lungu, Codrin Zaghloul, Kareem A. TI Beta-Coupled High-Frequency Activity and Beta-Locked Neuronal Spiking in the Subthalamic Nucleus of Parkinson's Disease SO JOURNAL OF NEUROSCIENCE LA English DT Article DE beta oscillations; cross-frequency interactions; high-frequency oscillations; Parkinson's disease; spike-field interactions; subthalamic nucleus ID DEEP BRAIN-STIMULATION; PRIMARY MOTOR CORTEX; LOCAL-FIELD POTENTIALS; BASAL GANGLIA; OSCILLATORY ACTIVITY; PATHOLOGICAL SYNCHRONIZATION; EPILEPTIC HIPPOCAMPUS; GAMMA OSCILLATIONS; ENTORHINAL CORTEX; FAST RIPPLES AB Beta frequency (13-30 Hz) oscillatory activity in the subthalamic nucleus (STN) of Parkinson's disease (PD) has been shown to influence the temporal dynamics of high-frequency oscillations (HFOs; 200-500 Hz) and single neurons, potentially compromising the functional flexibility of the motor circuit. We examined these interactions by simultaneously recording both local field potential and single-unit activity from the basal ganglia of 15 patients with PD during deep brain stimulation (DBS) surgery of the bilateral STN. Phase-amplitude coupling (PAC) in the STN was specific to beta phase and HFO amplitude, and this coupling was strongest at the dorsal STN border. We found higher beta-HFO PAC near DBS lead contacts that were clinically effective compared with the remaining non-effective contacts, indicating that PAC may be predictive of response to STN DBS. Neuronal spiking was locked to the phase of 8-30 Hz oscillations, and the spatial topography of spike-phase locking (SPL) was similar to that of PAC. Comparisons of PAC and SPL showed a lack of spatiotemporal correlations. Beta-coupled HFOs and field-locked neurons had different preferred phase angles and did not co-occur within the same cycle of the modulating oscillation. Our findings provide additional support that beta-HFO PAC may be central to the pathophysiology of PD and suggest that field-locked neurons alone are not sufficient for the emergence of beta-coupled HFOs. C1 [Yang, Andrew I.; Zaghloul, Kareem A.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Vanegas, Nora; Lungu, Codrin] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Vanegas, Nora] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Zaghloul, KA (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 3D20,10 Ctr Dr, Bethesda, MD 20892 USA. EM kareem.zaghloul@nih.gov NR 58 TC 23 Z9 23 U1 1 U2 23 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 SEP 17 PY 2014 VL 34 IS 38 BP 12816 EP 12827 DI 10.1523/JNEUROSCI.1895-14.2014 PG 12 WC Neurosciences SC Neurosciences & Neurology GA AP0QO UT WOS:000341767800018 PM 25232117 ER PT J AU Chefer, S Reba, RC Leyson, CZ Seidel, J Johnson, RF Blaney, JE Jahrling, PB Dyall, J AF Chefer, Svetlana Reba, Richard C. Leyson, Christopher Z. Seidel, Jurgen Johnson, Reed F. Blaney, Joseph E. Jahrling, Peter B. Dyall, Julie TI The effect of volume of interest definition on quantification of lymph node immune response to a monkeypox virus infection assessed by F-18-FDG-PET SO EJNMMI RESEARCH LA English DT Article DE PET; Immune response quantitation; Animal model; SUV; Monkeypox; Intravenous inoculation ID STANDARDIZED UPTAKE VALUE; CELL LUNG-CANCER; INTEROBSERVER VARIABILITY; ROI DEFINITION; UPTAKE VALUES; TUMORS; SUV; PET; RESOLUTION; ACCURACY AB Background: 2-deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography (F-18-FDG-PET) is applied in the clinic for infection assessment and is under consideration for investigating the inflammatory/immune response in lymphoid tissue in animal models of viral infection. Assessing changes in F-18-FDG uptake of lymph nodes (LNs), primary lymphoid tissues targeted during viral infection, requires suitable methods for image analysis. Similar to tumor evaluation, reliable quantitation of the LN function via multiple F-18-FDG-PET sessions will depend how the volume of interest is defined. Volume of interest definition has a direct effect on statistical outcome. The current study objective is to compare for the first time agreement between conventional and modified VOI metrics to determine which method(s) provide(s) reproducible standardized uptake values (SUVs) for F-18-FDG uptake in the LN of rhesus macaques. Methods: Multiple F-18-FDG-PET images of LNs in macaques were acquired prior to and after monkeypox virus intravenous inoculation. We compared five image analysis approaches, SUVmax, SUVmean, SUVthreshold, modified SUVthreshold, and SUVfixed (volume), to investigate the impact of these approaches on quantification of the changes in LN metabolic activity denoting the immune response during viral infection progression. Results: The lowest data repeatability was observed with SUVmax. The best correspondence was between SUVfixed volume and conventional and modified SUVthreshold. A statistically significant difference in the LN F-18-FDG uptake between surviving and moribund animals was shown using modified SUVthreshold and SUVfixed volume (adjusted p = 0.0037 and p = 0.0001, respectively). Conclusions: Quantification of the LN F-18-FDG uptake is highly sensitive to the method applied for PET image analysis. SUVfixed volume and modified SUVthreshold demonstrate better reproducibility for SUV estimates than SUVmax, SUVmean, and SUVthreshold. SUVfixed volume and modified SUVthreshold are capable of distinguishing between groups with different disease outcomes. Therefore, these methods are the preferred approaches for evaluating the LN function during viral infection by F-18-FDG-PET. Validation of multiple approaches is necessary to choose a suitable method to monitor changes in LN metabolic activity during progression of viral infection. C1 [Chefer, Svetlana; Leyson, Christopher Z.; Seidel, Jurgen; Dyall, Julie] NIAID, Div Clin Res, Integrated Res Facil, NIH, Frederick, MD 21702 USA. [Reba, Richard C.] NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Johnson, Reed F.; Blaney, Joseph E.; Jahrling, Peter B.] NIAID, Div Intramural Res, Emerging Viral Pathogens Sect, NIH, Frederick, MD 21702 USA. RP Chefer, S (reprint author), NIAID, Div Clin Res, Integrated Res Facil, NIH, 8200 Res Plaza, Frederick, MD 21702 USA. EM schefer@mail.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID); Integrated Research Facility (NIAID, Division of Clinical Research); Battelle Memorial Institute; NIAID [HHS N272200700016I] FX We thank Jennifer Hufton from the imaging team, Russell Byrum from the NIAID Comparative Medicine Branch, and Comparative Medicine veterinarians for successful implementation of PET-CT scanning protocols in the biosafety level 3 suite. In addition, we acknowledge Shen Kui for help with statistical analysis. We thank Laura Bollinger and Jiro Wada for outstanding assistance in technical writing and figure preparation of this manuscript on behalf of the Battelle Memorial Institute. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), Integrated Research Facility (NIAID, Division of Clinical Research), and Battelle Memorial Institute's prime contract with NIAID (Contract number HHS N272200700016I). NR 24 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2191-219X J9 EJNMMI RES JI EJNMMI Res. PD SEP 16 PY 2014 VL 4 BP 1 EP 12 AR 49 DI 10.1186/s13550-014-0049-z PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN0RW UT WOS:000358122100001 PM 26116113 ER PT J AU Rose, S Stansky, E Dagur, PK Samsel, L Weiner, E Jahanshad, A Doveikis, J Naik, HB Playford, MP McCoy, JP Mehta, NN AF Rose, Shawn Stansky, Elena Dagur, Pradeep K. Samsel, Leigh Weiner, Elizabeth Jahanshad, Amir Doveikis, Julia Naik, Haley B. Playford, Martin P. McCoy, J. Philip Mehta, Nehal N. TI Characterization of immune cells in psoriatic adipose tissue SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Adipose tissue; Immunophenotyping; Imaging flow cytometry; Psoriasis ID LOW-DENSITY-LIPOPROTEIN; REGULATORY T-CELLS; ACUTE CORONARY SYNDROMES; INSULIN-RESISTANCE; METABOLIC SYNDROME; OXIDIZED LDL; SCAVENGER RECEPTORS; OBESE-PATIENTS; RISK-FACTORS; NK CELLS AB Background: Adipose tissue normally contains immune cells that regulate adipocyte function and contribute to metabolic disorders including obesity and diabetes mellitus. Psoriasis is associated with increased risk for metabolic disease, which may in part be due to adipose dysfunction, which has not been investigated in psoriasis. There is currently no standardized method for immunophenotyping human adipose tissue. In prior studies, characteristic phenotypic markers of immune cell populations identified in animal models or in other human tissues have been applied in a similar manner to human adipose tissue. Rarely have these populations been verified with confirmatory methodologies or functional studies. Thus, we performed a comprehensive phenotypic and functional analysis of immune cell populations in psoriatic adipose tissue. Methods: Conventional and imaging flow cytometry were used to define immune cell populations in biopsy specimens of psoriatic adipose tissue (n = 30) including T cells, B cells, NK cells, NKT cells, neutrophils, and macrophages. Relationships between adipose immune cell types and body mass index were determined using Spearman regression analysis, and multivariate linear regression analysis was performed to adjust for cardiometabolic disease risk factors. Results: These analyses revealed a wide range of cell surface receptors on adipose tissue macrophages, which may serve a dual purpose in immunity and metabolism. Further, both CD16+CD56(Lo) and CD16-CD56(Hi) NK cells were found to correlate inversely with body mass index. The relationship between the predominant CD16+CD56(Lo) NK cell population and body mass index persisted after adjusting for age, sex, diabetes, and tobacco use. Conclusions: Together, these studies enhance our understanding of adipose immune cell phenotype and function, and demonstrate that examination of adipose tissue may provide greater insight into cardiometabolic pathophysiology in psoriasis. C1 [Rose, Shawn; Weiner, Elizabeth; Jahanshad, Amir; Doveikis, Julia; Playford, Martin P.; Mehta, Nehal N.] NHLBI, Sect Inflammat & Cardiometab Dis, NIH, Bethesda, MD 20892 USA. [Rose, Shawn] NIAMSD, NIH, Bethesda, MD 20892 USA. [Stansky, Elena; Dagur, Pradeep K.; Samsel, Leigh; McCoy, J. Philip] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. [Stansky, Elena; Dagur, Pradeep K.; Samsel, Leigh; McCoy, J. Philip] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Naik, Haley B.] NCI, NIH, Bethesda, MD 20892 USA. [Mehta, Nehal N.] NHLBI, Cardiovasc & Pulm Branch, CRC, Bethesda, MD 20892 USA. RP Mehta, NN (reprint author), NHLBI, Sect Inflammat & Cardiometab Dis, NIH, Bldg 10, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov FU National Heart Lung and Blood Institute (NHLBI DIR grant) [HL006193-01]; National Institute of Arthritis and Skin and Musculoskeletal Diseases; National Cancer Institute FX This work was funded using intramural funds from the National Heart Lung and Blood Institute (NHLBI DIR grant HL006193-01), the National Institute of Arthritis and Skin and Musculoskeletal Diseases, and the National Cancer Institute. NR 58 TC 5 Z9 5 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD SEP 16 PY 2014 VL 12 AR 258 DI 10.1186/s12967-014-0258-2 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AT8EN UT WOS:000345166900001 PM 25224267 ER PT J AU Mark, DB Knight, JD Velazquez, EJ Wasilewski, J Howlett, JG Smith, PK Spertus, JA Rajda, M Yadav, R Hamman, BL Malinowski, M Naik, A Rankin, G Harding, TM Drew, LA Desvigne-Nickens, P Anstrom, KJ AF Mark, Daniel B. Knight, J. David Velazquez, Eric J. Wasilewski, Jaroslaw Howlett, Jonathan G. Smith, Peter K. Spertus, John A. Rajda, Miroslaw Yadav, Rakesh Hamman, Baron L. Malinowski, Marcin Naik, Ajay Rankin, Gena Harding, Tina M. Drew, Laura A. Desvigne-Nickens, Patrice Anstrom, Kevin J. TI Quality-of-Life Outcomes With Coronary Artery Bypass Graft Surgery in Ischemic Left Ventricular Dysfunction A Randomized Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID HEART-FAILURE; FUNCTIONAL STATUS; MEDICAL THERAPY; TASK-FORCE; DISEASE; GUIDELINES; CARDIOMYOPATHY; QUESTIONNAIRE; ASSOCIATION; ANGINA AB Background: The STICH (Surgical Treatment for Ischemic Heart Failure) trial compared a strategy of routine coronary artery bypass grafting (CABG) with guideline-based medical therapy for patients with ischemic left ventricular dysfunction. Objective: To describe treatment-related quality-of-life (QOL) outcomes, a major prespecified secondary end point in the STICH trial. Design: Randomized trial. (ClinicalTrials.gov: NCT00023595) Setting: 99 clinical sites in 22 countries. Patients: 1212 patients with a left ventricular ejection fraction of 0.35 or less and coronary artery disease. Intervention: Random assignment to medical therapy alone (602 patients) or medical therapy plus CABG (610 patients). Measurements: A battery of QOL instruments at baseline (98.9% complete) and 4, 12, 24, and 36 months after randomization (collection rates were 80% to 89% of those eligible). The principal prespecified QOL measure was the Kansas City Cardiomyopathy Questionnaire, which assesses the effect of heart failure on patients' symptoms, physical function, social limitations, and QOL. Results: The Kansas City Cardiomyopathy Questionnaire overall summary score was consistently higher (more favorable) in the CABG group than in the medical therapy group by 4.4 points (95% CI, 1.8 to 7.0 points) at 4 months, 5.8 points (CI, 3.1 to 8.6 points) at 12 months, 4.1 points (CI, 1.2 to 7.1 points) at 24 months, and 3.2 points (CI, 0.2 to 6.3 points) at 36 months. Sensitivity analyses to account for the effect of mortality on follow-up QOL measurement were consistent with the primary findings. Limitation: Therapy was not masked. Conclusion: In this cohort of symptomatic high-risk patients with ischemic left ventricular dysfunction and multivessel coronary artery disease, CABG plus medical therapy produced clinically important improvements in quality of life compared with medical therapy alone over 36 months. C1 Duke Univ, Med Ctr, Outcomes Res Grp, Duke Clin Res Inst, Durham, NC 27710 USA. Med Univ Silesia, PL-40635 Katowice, Poland. Dalhousie Univ, Queen Elizabeth II Hlth Sci Ctr, Halifax, NS, Canada. Univ Missouri, St Lukes Mid Amer Heart Inst, Kansas City, MO 64111 USA. All India Inst Med Sci, Delhi, India. Baylor Soltero Cardiovasc Res Ctr, Dallas, TX 75226 USA. SAL Hosp, Ahmadabad, Gujarat, India. NHLBI, Bethesda, MD 20892 USA. RP Mark, DB (reprint author), Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. EM daniel.mark@duke.edu OI Mark, Daniel/0000-0001-6340-8087 FU National Heart, Lung, and Blood Institute; National Institutes of Health [U01 HL69011] FX By the National Heart, Lung, and Blood Institute and the National Institutes of Health (grant U01 HL69011; Dr. Mark). NR 27 TC 9 Z9 9 U1 1 U2 6 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 16 PY 2014 VL 161 IS 6 BP 392 EP U47 DI 10.7326/M13-1380 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AR9LF UT WOS:000343894400014 PM 25222386 ER PT J AU Kottilil, S Wright, M Polis, MA Masur, H AF Kottilil, Shyam Wright, Mary Polis, Michael A. Masur, Henry TI Treatment of Hepatitis C Virus Infection: Is It Time for the Internist to Take the Reins? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID CARE; SOFOSBUVIR C1 NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Masur, H (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 10 TC 10 Z9 10 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 16 PY 2014 VL 161 IS 6 BP 443 EP U104 DI 10.7326/M14-0741 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AR9LF UT WOS:000343894400020 PM 25222390 ER PT J AU Zhao, HY Ma, J Ingaramo, M Andrade, E MacDonald, J Ramsay, G Piszczek, G Patterson, GH Schuck, P AF Zhao, Huaying Ma, Jia Ingaramo, Maria Andrade, Eric MacDonald, Jeff Ramsay, Glen Piszczek, Grzegorz Patterson, George H. Schuck, Peter TI Accounting for Photophysical Processes and Specific Signal Intensity Changes in Fluorescence-Detected Sedimentation Velocity SO ANALYTICAL CHEMISTRY LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; SIZE-DISTRIBUTION ANALYSIS; ANALYTICAL ULTRACENTRIFUGATION; LAMM EQUATION; NUMERICAL-SOLUTIONS; DETECTION SYSTEM; OLIGOMERIZATION; COMPLEX; BINDING; MACROMOLECULES AB Fluorescence detected sedimentation velocity (FDS-SV) has emerged as a powerful technique for the study of high-affinity protein interactions, with hydrodynamic resolution exceeding that of diffusion-based techniques, and with sufficient sensitivity for binding studies at low picomolar concentrations. For the detailed quantitative analysis of the observed sedimentation boundaries, it is necessary to adjust the conventional sedimentation models to the FDS data structure. A key consideration is the change in the macromolecular fluorescence intensity during the course of the experiment, caused by slow drifts of the excitation laser power, and/or by photophysical processes. In the present work, we demonstrate that FDS-SV data have inherently a reference for the time-dependent macromolecular signal intensity, resting on a geometric link between radial boundary migration and plateau signal. We show how this new time-domain can be exploited to study molecules exhibiting photobleaching and photoactivation. This expands the application of FDS-SV to proteins tagged with photoswitchable fluorescent proteins, organic dyes, or nanoparticles, such as those recently introduced for subdiffraction microscopy and enables FDS-SV studies of their interactions and size distributions. At the same time, we find that conventional fluorophores undergo minimal photobleaching under standard illumination in the FDS. These findings support the application of a high laser power density for the detection, which we demonstrate can further increase the signal quality. C1 [Zhao, Huaying; Ma, Jia; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Ingaramo, Maria; Andrade, Eric; Patterson, George H.] Natl Inst Biomed Imaging & Bioengn, Sect Biophoton, NIH, Bethesda, MD 20892 USA. [MacDonald, Jeff; Ramsay, Glen] Aviv Biomed Inc, Lakewood, NJ 08701 USA. [Piszczek, Grzegorz] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. EM schuckp@mail.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX We thank Stefan Jakobs for the gift of the plasmid containing the histidine tagged Padron. This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 65 TC 4 Z9 4 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD SEP 16 PY 2014 VL 86 IS 18 BP 9286 EP 9292 DI 10.1021/ac502478a PG 7 WC Chemistry, Analytical SC Chemistry GA AP1BK UT WOS:000341801200054 PM 25136929 ER PT J AU Wang, J Sohn, H Sun, GP Milner, JD Pierce, SK AF Wang, Jing Sohn, Haewon Sun, Guangping Milner, Joshua D. Pierce, Susan K. TI The autoinhibitory C-terminal SH2 domain of phospholipase C-gamma 2 stabilizes B cell receptor signalosome assembly SO SCIENCE SIGNALING LA English DT Article ID PHOSPHORYLATION-INDUCED ACTIVATION; BRUTONS TYROSINE KINASE; GAMMA ISOZYMES; CUTTING EDGE; ANTIGEN; SYK; BLNK; CBL; PROTEIN; IMMUNODEFICIENCY AB The binding of antigen to the B cell receptor (BCR) stimulates the assembly of a signaling complex (signalosome) composed initially of the kinases Lyn, spleen tyrosine kinase (Syk), and Bruton's tyrosine kinase (Btk), as well as the adaptor protein B cell linker (BLNK). Together, these proteins recruit and activate phospholipase C-gamma 2 (PLC-gamma 2), a critical effector that stimulates increases in intracellular Ca2+ and activates various signaling pathways downstream of the BCR. Individuals with one copy of a mutant PLCG2 gene, which encodes a variant PLC-gamma 2 that lacks the autoinhibitory C-terminal Src homology 2 (cSH2) domain, exhibit PLC-gamma 2-associated antibody deficiency and immune dysregulation (PLAID). Paradoxically, although COS-7 cells expressing the variant PLC-gamma 2 show enhanced basal and stimulated PLC-gamma 2 activity, B cells from PLAID patients show defective intracellular Ca2+ responses upon cross-linking of the BCR. We found that the cSH2 domain of PLC-gamma 2 played a critical role in stabilizing the early signaling complex that is stimulated by BCR cross-linking. In the presence of the variant PLC-gamma 2, Syk, Btk, and BLNK were only weakly phosphorylated and failed to stably associate with the BCR. Thus, BCRs could not form stable clusters, resulting in dysregulation of downstream signaling and trafficking of the BCR. Thus, the cSH2 domain functions not only to inhibit the active site of PLC-gamma 2 but also to directly or indirectly stabilize the early BCR signaling complex. C1 [Wang, Jing; Sohn, Haewon; Pierce, Susan K.] NIAID, Lab Immunogenet, NIH, Rockville, MD 20852 USA. [Sun, Guangping; Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Pierce, SK (reprint author), NIAID, Lab Immunogenet, NIH, Rockville, MD 20852 USA. EM spierce@nih.gov FU National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 49 TC 7 Z9 7 U1 0 U2 6 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 SEP 16 PY 2014 VL 7 IS 343 AR ra89 DI 10.1126/scisignal.2005392 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AP8YU UT WOS:000342366100003 PM 25227611 ER PT J AU Hu, HT Eller, MA Zafar, S Zhou, Y Gu, MN Wei, Z Currier, JR Marovich, MA Kibuuka, HN Bailer, RT Koup, RA Robb, ML Michael, NL Kim, JH Ratto-Kim, S AF Hu, Haitao Eller, Michael A. Zafar, Shah Zhou, Yu Gu, Mengnan Wei, Zhi Currier, Jeffrey R. Marovich, Mary A. Kibuuka, Hannah N. Bailer, Robert T. Koup, Richard A. Robb, Merlin L. Michael, Nelson L. Kim, Jerome H. Ratto-Kim, Silvia TI Preferential infection of human Ad5-specific CD4 T cells by HIV in Ad5 naturally exposed and recombinant Ad5-HIV vaccinated individuals SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE AIDS; antigen-specific CD4 T cells; viral vectors ID ADENOVIRUS VACCINE; ENVELOPE PROTEIN; CCR5 LIGANDS; DOUBLE-BLIND; TRIAL; REPLICATION; RESPONSES; EFFICACY; STEP; SIV AB Efficacy trials of adenovirus 5-vectored candidate HIV vaccines [ recombinant Ad5 ( rAd5)-HIV] were halted for futility due to lack of vaccine efficacy and unexpected excess HIV infections in the vaccine recipients. The potential immunologic basis for these observations is unclear. We comparatively evaluated the HIV susceptibility and phenotypes of human CD4 T cells specific to Ad5 and CMV, two viruses that have been used as HIV vaccine vectors. We show that Ad5- specific CD4 T cells, either induced by natural Ad5 exposure or expanded by rAd5 vaccination, are highly susceptible to HIV in vitro and are preferentially lost in HIV-infected individuals compared with CMV-specific CD4 T cells. Further investigation demonstrated that Ad5- specific CD4 T cells selectively display a proinflammatory Th17-like phenotype and express macrophage inflammatory protein 3 alpha and alpha 4 beta 7 integrin, suggestive of gut mucosa homing potential of these cells. Analysis of HIV p24 and cytokine coexpression using flow cytometry revealed preferential infection of IL- 17- and IL-2-producing, Ad5-specific CD4 T cells by HIV in vitro. Our data suggest a potential mechanism explaining the excess HIV infections in vaccine recipients after rAd5-HIV vaccination and highlight the importance of testing the HIV susceptibility of vaccine-generated, vector and insert-specific CD4 T cells in future HIV vaccine studies. C1 [Hu, Haitao; Eller, Michael A.; Zafar, Shah; Robb, Merlin L.; Michael, Nelson L.; Kim, Jerome H.; Ratto-Kim, Silvia] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. [Currier, Jeffrey R.] Walter Reed Army Inst Res, Viral Dis Branch, Silver Spring, MD 20910 USA. [Hu, Haitao; Eller, Michael A.; Zafar, Shah; Robb, Merlin L.; Ratto-Kim, Silvia] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD 20817 USA. [Zhou, Yu] Temple Univ, Dept Pathol & Lab Med, Sch Med, Philadelphia, PA 19140 USA. [Gu, Mengnan; Wei, Zhi] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA. [Marovich, Mary A.] NIAID, Div AIDS, NIH, Bethesda, MD 20817 USA. [Kibuuka, Hannah N.] Makerere Univ Walter Reed Project, Kampala, Uganda. [Bailer, Robert T.; Koup, Richard A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Hu, HT (reprint author), Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. EM hhu@hivresearch.org FU Robert Mapplethorpe Foundation HIV/AIDS grant; National Institutes of Health [1R21AI110214]; Henry M. Jackson Foundation [W81XWH-07-2-0067]; US Department of Defense [W81XWH-07-2-0067] FX We thank all the PBMC donors for their contributions to this study. The work was supported by a Robert Mapplethorpe Foundation HIV/AIDS grant (to H. H.), National Institutes of Health Grant 1R21AI110214 (to H. H.), and by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation and the US Department of Defense. NR 30 TC 14 Z9 16 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 16 PY 2014 VL 111 IS 37 BP 13439 EP 13444 DI 10.1073/pnas.1400446111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO8UH UT WOS:000341630000052 PM 25197078 ER PT J AU Guerreiro, R Bras, J Hardy, J Singleton, A AF Guerreiro, Rita Bras, Jose Hardy, John Singleton, Andrew TI Next generation sequencing techniques in neurological diseases: redefining clinical and molecular associations SO HUMAN MOLECULAR GENETICS LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; GENOME-WIDE ASSOCIATION; FRONTOTEMPORAL LOBAR DEGENERATION; NEURONAL CEROID-LIPOFUSCINOSIS; PARKINSONS-DISEASE; GLUCOCEREBROSIDASE MUTATIONS; SUSCEPTIBILITY LOCI; REPEAT EXPANSION; SQSTM1 MUTATIONS; RISK LOCI AB The development of next-generation sequencing technologies has allowed for the identification of several new genes and genetic factors in human genetics. Common results from the application of these technologies have revealed unexpected presentations for mutations in known disease genes. In this review, we summarize the major contributions of exome sequencing to the study of neurodegenerative disorders and other neurological conditions and discuss the interface between Mendelian and complex neurological diseases with a particular focus on pleiotropic events. C1 [Guerreiro, Rita; Bras, Jose; Hardy, John] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 1PJ, England. [Guerreiro, Rita; Bras, Jose; Hardy, John] UCL Inst Neurol, Reta Lila Weston Labs, London WC1N 1PJ, England. [Guerreiro, Rita; Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Guerreiro, R (reprint author), UCL Inst Neurol, Reta Lila Weston Res Labs, 1 Wakefield St, London WC1N 1PJ, England. EM r.guerreiro@ucl.ac.uk RI Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009; OI Bras, Jose/0000-0001-8186-0333 FU Alzheimer's Research UK; Wellcome Trust/MRC Joint Call in Neurodegeneration award [WT089698]; Wellcome Trust/MRC FX The authors' work is supported by the Alzheimer's Research UK and by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (UKPDC) whose members are from the UCL/Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust/MRC. NR 85 TC 20 Z9 20 U1 0 U2 5 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 SEP 15 PY 2014 VL 23 SI 1 BP R47 EP R53 DI 10.1093/hmg/ddu203 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CB7RS UT WOS:000349825700007 PM 24794858 ER PT J AU Santos, MA John, S Nussenzweig, A AF Santos, Margarida A. John, Sam Nussenzweig, Andre TI Tumor promoting role of the DNA damage response SO CELL CYCLE LA English DT Editorial Material ID DIFFERENTIATION; RENEWAL C1 [Santos, Margarida A.; John, Sam; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. RP Nussenzweig, A (reprint author), NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov NR 5 TC 2 Z9 2 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD SEP 15 PY 2014 VL 13 IS 18 BP 2807 EP 2808 DI 10.4161/15384101.2014.959855 PG 2 WC Cell Biology SC Cell Biology GA AZ6JI UT WOS:000348325800005 PM 25486465 ER PT J AU Nussinov, R Jang, HB Tsai, CJ AF Nussinov, Ruth Jang, Hyunbum Tsai, Chung-Jung TI The structural basis for cancer treatment decisions SO ONCOTARGET LA English DT Article DE Cancer treatment decisions; driver mutations; driver genes; redundant pathways; parallel pathways; computational biology; protein structure; cellular network; oncogenic mutations ID PROTEIN-PROTEIN INTERACTIONS; RECEPTOR TYROSINE KINASE; RAF INHIBITOR RESISTANCE; GROWTH-FACTOR RECEPTOR; FREE-ENERGY LANDSCAPE; TUMOR-SUPPRESSOR; EGFR KINASE; FUNCTIONAL CONSEQUENCES; ONCOGENIC ACTIVATION; PRECISION MEDICINE AB Cancer treatment decisions rely on genetics, large data screens and clinical pharmacology. Here we point out that genetic analysis and treatment decisions may overlook critical elements in cancer development, progression and drug resistance. Two critical structural elements are missing in genetics-based decision-making: the mechanisms of oncogenic mutations and the cellular network which is rewired in cancer. These lay the foundation for the structural basis for cancer treatment decisions, which is rooted in the physical principles of the molecular conformational behavior of single molecules and their interactions. Improved tumor mutational analysis platforms and knowledge of the redundant pathways which can take over in cancer, may not only supplement known actionable findings, but forecast possible cancer progression and resistance. Such forward-looking can be powerful, endowing the oncologist with mechanistic insight and cancer prognosis, and consequently more informed treatment options. Examples include redundant pathways taking over after inhibition of EGFR constitutive activation, mutations in PIK3CA p110a and p85, and the non-hotspot AKT1 mutants conferring constitutive membrane localization. C1 [Nussinov, Ruth; Jang, Hyunbum; Tsai, Chung-Jung] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Dept Human Genet & Mol Med, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM NussinoR@helix.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. 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 178 TC 12 Z9 12 U1 1 U2 9 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 15 PY 2014 VL 5 IS 17 BP 7285 EP 7302 PG 18 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ1XY UT WOS:000348029800007 PM 25277176 ER PT J AU Zuo, ZH Che, X Wang, YL Li, BW Li, JX Dai, W Lin, CP Huang, CS AF Zuo, Zhenghong Che, Xun Wang, Yulei Li, Bowen Li, Jingxia Dai, Wei Lin, Charles P. Huang, Chuanshu TI High mobility group Box-1 inhibits cancer cell motility and metastasis by suppressing activation of transcription factor CREB and nWASP expression SO ONCOTARGET LA English DT Article DE HMGB1; metastasis; CREB; nWASP ID GLYCATION END-PRODUCTS; NUCLEAR-PROTEIN HMGB1; ACTIN-BASED MOTILITY; N-WASP; TUMOR-CELLS; RECEPTOR; FILAMENTS; INVASION; RELEASE; RAGE AB The ability to metastasize is a hallmark of malignant tumors, and metastasis is the principal cause of death of cancer patients. The High Mobility Group Box-1 (HMGB1) is a multifunction protein that serves as both a chromatin protein and an extracellular signaling molecule. Our current study demonstrated a novel mechanism of HMGB1 in the regulation of cancer cell actin polymerization, cell skeleton formation, cancer cell motility and metastasis. We found that knockdown of HMGB1 in human lung cancer A549 cells significantly increased cell beta-actin polymerization, cell skeleton formation, cancer cell migration and invasion in vitro, as well as metastasis in vivo. And this increase could be inhibited by treatment of HMGB1 knockdown cells with recombinant human HMGB1. Further studies discovered that HMGB1 suppressed phosphorylation, nuclear translocation, and activation of CREB, by inhibiting nuclear translocation of PKA catalytic subunit. This reduces nWASP mRNA transcription and expression, further impairing cancer cell motility. Our findings on the novel mechanism underlying the HMGB1 anti-metastatic effect on cancer provides significant insight into the understanding of the nature of HMGB1 in cancer invasion and metastasis, further serving as key information for utilization of HMGB1 and its regulated downstream components as new targets for cancer therapy. C1 [Zuo, Zhenghong; Che, Xun; Wang, Yulei; Li, Jingxia; Dai, Wei; Huang, Chuanshu] NYU, Sch Med, Nelson Inst Environm Med, Tuxedo Pk, NY 10987 USA. [Zuo, Zhenghong; Li, Bowen] Xiamen Univ, State Key Lab Cellular Stress Biol, Sch Life Sci, Xiamen, Peoples R China. [Lin, Charles P.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Huang, CS (reprint author), NYU, Sch Med, Nelson Inst Environm Med, Tuxedo Pk, NY 10987 USA. EM chuanshu.huang@nyumc.org RI Zuo, Zhenghong/G-4615-2010 FU [NIH/NCI CA165980]; [CA177665]; [CA112557] FX This work was partially supported by grants from NIH/NCI CA165980, CA177665 and CA112557. NR 49 TC 11 Z9 11 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 15 PY 2014 VL 5 IS 17 BP 7458 EP 7470 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ1XY UT WOS:000348029800020 PM 25277185 ER PT J AU Lv, P Wang, Y Ma, J Wang, Z Li, JL Hong, CS Zhuang, ZP Zeng, YX AF Lv, Peng Wang, Yue Ma, Jie Wang, Zheng Li, Jing-Li Hong, Christopher S. Zhuang, Zhengping Zeng, Yi-Xin TI Inhibition of protein phosphatase 2A with a small molecule LB100 radiosensitizes nasopharyngeal carcinoma xenografts by inducing mitotic catastrophe and blocking DNA damage repair SO ONCOTARGET LA English DT Article DE LB100; Radiosensitization; Protein phosphatase 2A; Nasopharyngeal Carcinoma ID STRAND BREAK REPAIR; IONIZING-RADIATION; CANCER-CHEMOTHERAPY; TUMOR-SUPPRESSOR; DRUG DISCOVERY; MICROCYSTIN-LR; CELL-DEATH; IN-VIVO; PP2A; P53 AB Nasopharyngeal carcinoma (NPC), while uncommon worldwide, is a major health problem in China. Although local radiation and surgery provide good control of NPC, better treatments that permit reductions in radiation dosing are needed. Inhibition of protein phosphatase 2A (PP2A), a ubiquitous multifunctional enzyme with critical roles in cell cycle regulation and DNA-damage response, reportedly sensitizes cancer cells to radiation and chemotherapy. We studied PP2A inhibition with LB100, a small molecule currently in a Phase I clinical trial, on radiosensitization of two human nasopharyngeal cell lines: CNE1, which is reportedly radioresistant, and CNE2. In both cell lines, LB100 exposure increased intracellular p-Plk1, TCTP, and Cdk1 and decreased p53, changes associated with cell cycle arrest, mitotic catastrophe and radio-inhibition of cell proliferation. Mice bearing subcutaneous xenografts of either cell line were administered 1.5 mg/kg LB100 daily for three days and a single dose of 20 Gy radiation (day 3), which produced marked and prolonged tumor mass regression (dose enhancement factors of 2.98 and 2.27 for CNE1 and CNE2 xenografts, respectively). Treatment with either LB100 or radiation alone only transiently inhibited xenograft growth. Our results support further exploration of PP2A inhibition as part of radiotherapy regimens for NPC and potentially other solid tumors. C1 [Lv, Peng; Ma, Jie; Wang, Zheng; Zeng, Yi-Xin] Chinese Acad Med Sci CAMS, Canc Inst & Hosp, Beijing, Peoples R China. [Lv, Peng] Capital Med Univ, Beijing Neurosurg Inst, Beijing, Peoples R China. [Wang, Yue; Li, Jing-Li] Natl Inst Food & Drug Control, Inst Med Device Standardizat Adm, Beijing, Peoples R China. [Hong, Christopher S.; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Zeng, Yi-Xin] Sun Yat Sen Univ, Ctr Canc, Dept Expt Res, Guangzhou 510275, Guangdong, Peoples R China. [Zeng, Yi-Xin] State Key Lab Oncol Southern China, Guangzhou, Guangdong, Peoples R China. RP Zhuang, ZP (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM zhuangp@ninds.nih.gov; zengyix@mail.sysu.edu.cn FU National Natural Science Foundation of China (NSFC) [81302370]; National Basic Research Program of China (973 Plan) [2011CB504302, 2013CB910304] FX We thank professors Yexiong Li, WeiZhi Yang, Bo Chen, Shunan Qi, Department of Radiation Oncology; Changming An, Department of Head and Neck Surgical Oncology, Cancer Hospital & Institute, Chinese Academy of Medicine Sciences (CAMS) & Peking Union Medical College (PUMC) for their valuable help on the manuscript and Dr. J. S. Kovach, Lixte Biotechnology Holdings, Inc. (East Setauket, NY) for providing the LB100 compound. This work was funded by National Natural Science Foundation of China (NSFC; 81302370) and National Basic Research Program of China (973 Plan; 2011CB504302, 2013CB910304). NR 59 TC 16 Z9 18 U1 0 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 15 PY 2014 VL 5 IS 17 BP 7512 EP 7524 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ1XY UT WOS:000348029800024 PM 25245035 ER PT J AU Hara, T Jones, MF Subramanian, M Li, XL Ou, O Zhu, YL Yang, Y Wakefield, LM Hussain, SP Gaedcke, J Ried, T Luo, J Caplen, NJ Lal, A AF Hara, Toshifumi Jones, Matthew F. Subramanian, Murugan Li, Xiao Ling Ou, Oliver Zhu, Yuelin Yang, Yuan Wakefield, Lalage M. Hussain, S. Perwez Gaedcke, Jochen Ried, Thomas Luo, Ji Caplen, Natasha J. Lal, Ashish TI Selective targeting of KRAS-Mutant cells by miR-126 through repression of multiple genes essential for the survival of KRAS-Mutant cells SO ONCOTARGET LA English DT Article DE Colorectal Cancer; miRNA; miR-126; KRAS; KRAS mutant ID MESSENGER-RNA; CANCER-CELLS; TUMOR-SUPPRESSOR; CODING REGIONS; RAS ONCOGENES; LUNG-CANCER; COLORECTAL-CANCER; MICRORNAS; EXPRESSION; BINDING AB MicroRNAs (miRNAs) regulate the expression of hundreds of genes. However, identifying the critical targets within a miRNA-regulated gene network is challenging. One approach is to identify miRNAs that exert a context-dependent effect, followed by expression profiling to determine how specific targets contribute to this selective effect. In this study, we performed miRNA mimic screens in isogenic KRAS-Wild-type (WT) and KRAS-Mutant colorectal cancer (CRC) cell lines to identify miRNAs selectively targeting KRAS-Mutant cells. One of the miRNAs we identified as a selective inhibitor of the survival of multiple KRAS-Mutant CRC lines was miR-126. In KRAS-Mutant cells, miR-126 over-expression increased the G1 compartment, inhibited clonogenicity and tumorigenicity, while exerting no effect on KRAS-WT cells. Unexpectedly, the miR-126-regulated transcriptome of KRAS-WT and KRAS-Mutant cells showed no significant differences. However, by analyzing the overlap between miR-126 targets with the synthetic lethal genes identified by RNAi in KRAS-Mutant cells, we identified and validated a subset of miR-126-regulated genes selectively required for the survival and clonogenicity of KRAS-Mutant cells. Our strategy therefore identified critical target genes within the miR-126-regulated gene network. We propose that the selective effect of miR-126 on KRAS-Mutant cells could be utilized for the development of targeted therapy for KRAS mutant tumors. C1 [Hara, Toshifumi; Jones, Matthew F.; Subramanian, Murugan; Li, Xiao Ling; Lal, Ashish] NCI, Regulatory RNAs & Canc Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Ou, Oliver; Caplen, Natasha J.] NCI, Gene Silencing Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Zhu, Yuelin] NCI, Mol Genet Sect, Genet Branch, NIH, Bethesda, MD 20892 USA. [Yang, Yuan; Wakefield, Lalage M.] NCI, Canc Biol TGF Beta Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Hussain, S. Perwez] NCI, Pancreat Canc Unit, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Gaedcke, Jochen] Univ Med Gottingen, Dept Gen & Visceral Surg, Gottingen, Germany. [Ried, Thomas] NCI, Canc Genom Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Luo, Ji] NCI, Canc Syst Biol Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Lal, A (reprint author), NCI, Regulatory RNAs & Canc Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM ashish.lal@nih.gov RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We thank B. Vogelstein (Johns Hopkins University, USA) for the isogenic HCT116 cell lines and Z. Mourelatos (University of Pennsylvania, USA) for the Ago2 (2A8) antibody. NR 71 TC 8 Z9 10 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 15 PY 2014 VL 5 IS 17 BP 7635 EP 7650 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ1XY UT WOS:000348029800034 PM 25245095 ER PT J AU Liu, CQ Lin, C Gao, C May-Simera, H Swaroop, A Li, TS AF Liu, Chunqiao Lin, Chen Gao, Chun May-Simera, Helen Swaroop, Anand Li, Tiansen TI Null and hypomorph Prickle1 alleles in mice phenocopy human Robinow syndrome and disrupt signaling downstream of Wnt5a SO BIOLOGY OPEN LA English DT Article DE Planar cell polarity; Development; Morphogenesis; Organogenesis; Conditional mouse mutants ID PLANAR CELL POLARITY; NEURAL-TUBE CLOSURE; BRACHYDACTYLY TYPE-B; INNER-EAR; EMBRYONIC-DEVELOPMENT; CONVERGENT EXTENSION; HAIR-CELLS; LOOP-TAIL; MOUSE; GENE AB Planar cell polarity (PCP) signaling plays a critical role in tissue morphogenesis. In mammals, disruption of three of the six "core PCP" components results in polarity-dependent defects with rotated cochlear hair cell stereocilia and open neural tube. We recently demonstrated a role of Prickle1, a core PCP molecule in Drosophila, in mammalian neuronal development. To examine Prickle1 function along a broader developmental window, we generated three mutant alleles in mice. We show that the complete loss of Prickle1 leads to systemic tissue outgrowth defects, aberrant cell organization and disruption of polarity machinery. Curiously, Prickle1 mutants recapitulate the characteristic features of human Robinow syndrome and phenocopy mouse mutants with Wnt5a or Ror2 gene defects, prompting us to explore an association of Prickle1 with the Wnt pathway. We show that Prickle1 is a proteasomal target of Wnt5a signaling and that Dvl2, a target of Wnt5a signaling, is misregulated in Prickle1 mutants. Our studies implicate Prickle1 as a key component of the Wnt-signaling pathway and suggest that Prickle1 mediates some of the WNT5A-associated genetic defects in Robinow syndrome. C1 [Liu, Chunqiao; Lin, Chen; May-Simera, Helen; Swaroop, Anand; Li, Tiansen] Neurobiol Neurodegenerat & Repair Lab N NRL, Bethesda, MD 20892 USA. [Gao, Chun] NEI, Imaging Core Facil, Bethesda, MD 20892 USA. RP Liu, CQ (reprint author), Neurobiol Neurodegenerat & Repair Lab N NRL, MSC0610,6 Ctr Dr, Bethesda, MD 20892 USA. EM cqliu99@gmail.com; swaroopa@nei.nih.gov; Tiansen.Li@nih.gov OI Swaroop, Anand/0000-0002-1975-1141 FU NIH FX This research is partly or wholly funded by the NIH. NR 57 TC 5 Z9 5 U1 0 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 2046-6390 J9 BIOL OPEN JI Biol. Open PD SEP 15 PY 2014 VL 3 IS 9 BP 861 EP 870 DI 10.1242/bio.20148375 PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AZ2ZJ UT WOS:000348097400009 PM 25190059 ER PT J AU Viboud, C Eisenstein, J Reid, AH Janczewski, TA Morens, DM Taubenberger, JK AF Viboud, Cecile Eisenstein, Jana Reid, Ann H. Janczewski, Thomas A. Morens, David M. Taubenberger, Jeffery K. TI Age-Specific Mortality During the 1918-19 Influenza Pandemic and Possible Relationship to the 1889-92 Influenza Pandemic Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID PNEUMONIA C1 [Viboud, Cecile] Fogarty Int Ctr, Bethesda, MD USA. [Eisenstein, Jana] NCI, Bethesda, MD 20892 USA. [Morens, David M.; Taubenberger, Jeffery K.] NIAID, NIH, Bethesda, MD 20892 USA. [Reid, Ann H.; Janczewski, Thomas A.] Armed Forces Inst Pathol, Washington, DC 20306 USA. RP Viboud, C (reprint author), NIH, 16 Ctr Dr, Bethesda, MD 20892 USA. EM viboudc@mail.nih.gov NR 9 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2014 VL 210 IS 6 BP 995 EP 997 DI 10.1093/infdis/jiu192 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0DW UT WOS:000344608300021 PM 24676205 ER PT J AU Takeda, Y Kang, HS Lih, FB Jiang, HF Blaner, WS Jetten, AM AF Takeda, Yukimasa Kang, Hong Soon Lih, Fred B. Jiang, Hongfeng Blaner, William S. Jetten, Anton M. TI Retinoid acid-related orphan receptor gamma, ROR gamma, participates in diurnal transcriptional regulation of lipid metabolic genes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID LIVER-X-RECEPTOR; INSULIN SENSITIVITY; NUCLEAR RECEPTORS; CIRCADIAN CLOCK; REV-ERB; IN-VIVO; ALPHA; EXPRESSION; IDENTIFICATION; INTEGRATION AB The hepatic circadian clock plays a pivotal role in regulating major aspects of energy homeostasis and lipid metabolism. In this study, we show that ROR gamma robustly regulates the rhythmic expression of several lipid metabolic genes, including the insulin-induced gene 2a, Insig2a, elongation of very long chain fatty acids-like 3, Elovl3 and sterol 12 alpha-hydroxylase, Cyp8b1, by enhancing their expression at ZT20-4. The time-dependent increase in their expression correlates with the rhythmic expression pattern of ROR gamma. The enhanced recruitment of ROR gamma to ROREs in their promoter region, increased histone acetylation, and reporter and mutation analysis support the concept that ROR gamma regulates the transcription of several lipid metabolic genes directly by binding ROREs in their promoter regulatory region. Consistent with the disrupted expression of a number of lipid metabolic genes, loss of ROR gamma reduced the level of several lipids in liver and blood in a ZT-preferred manner. Particularly the whole-body bile acid pool size was considerably reduced in ROR gamma(-/-)mice in part through its regulation of severalCyp genes. Similar observations were made in liver-specific ROR gamma-deficient mice. Altogether, our study indicates that ROR gamma functions as an important link between the circadian clock and the transcriptional regulation of several metabolic genes. C1 [Takeda, Yukimasa; Kang, Hong Soon; Jetten, Anton M.] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Lih, Fred B.] NIEHS, Collaborat Mass Spectrometry Grp, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Jiang, Hongfeng; Blaner, William S.] Colombia Univ, Dept Med, New York, NY 10032 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Div Intramural Res, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS); National Institutes of Health (NIH) [Z01-ES-101586, Z01-ES-050167]; Japanese Society for the Promotion of Science; NIEHS; NIH FX Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS); National Institutes of Health (NIH) [Z01-ES-101586, Z01-ES-050167]; Japanese Society for the Promotion of Science. Funding for open access charge: NIEHS; NIH. NR 45 TC 6 Z9 6 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 15 PY 2014 VL 42 IS 16 BP 10448 EP 10459 DI 10.1093/nar/gku766 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT0TM UT WOS:000344647700026 PM 25143535 ER PT J AU Jha, JK Ghirlando, R Chattoraj, DK AF Jha, Jyoti K. Ghirlando, Rodolfo Chattoraj, Dhruba K. TI Initiator protein dimerization plays a key role in replication control of Vibrio cholerae chromosome 2 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID P1 PLASMID REPLICATION; PREVENTING RE-REPLICATION; DNA-REPLICATION; SEDIMENTATION-VELOCITY; TRANSCRIPTION FACTORS; BACILLUS-SUBTILIS; STRUCTURAL BASIS; BINDING PROTEIN; IN-VITRO; ORIGIN AB RctB, the initiator of replication of Vibrio cholerae chromosome 2 (chr2), binds to the origin of replication to specific 12-mer sites both as a monomer and a dimer. Binding to 12-mers is essential for initiation. The monomers also bind to a second kind of site, 39-mers, which inhibits initiation. Mutations in rctB that reduce dimer binding increase monomer binding to 12-mers but decrease monomer binding to 39-mers. The mechanism of this paradoxical binding behavior has been unclear. Using deletion and alanine substitution mutants of RctB, we have now localized to a 71 amino acid region residues important for binding to the two kinds of DNA sites and for RctB dimerization. We find that the dimerization domain overlaps with both the DNA binding domains, explaining how changes in the dimerization domain can alter both kinds of DNA binding. Moreover, dimerization-defective mutants could be initiation-defective without apparent DNA binding defect. These results suggest that dimerization might be important for initiation beyond its role in controlling DNA binding. The finding that determinants of crucial initiator functions reside in a small region makes the region an attractive target for anti-V. cholerae drugs. C1 [Jha, Jyoti K.; Chattoraj, Dhruba K.] NCI, Biochem & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Chattoraj, DK (reprint author), NCI, Biochem & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM chattoraj@nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; Intramural Research Program; Center for Cancer Research; National Cancer Institute; National Institutes of Health FX Intramural Research Program of the Center for Cancer Research, National Cancer Institute, and of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Funding for open access charge: Intramural Research Program; Center for Cancer Research; National Cancer Institute; National Institutes of Health. NR 51 TC 3 Z9 3 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 15 PY 2014 VL 42 IS 16 BP 10538 EP 10549 DI 10.1093/nar/gku771 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT0TM UT WOS:000344647700033 PM 25159619 ER PT J AU Fauci, AS Folkers, GK Marston, HD AF Fauci, Anthony S. Folkers, Gregory K. Marston, Hilary D. TI Ending the Global HIV/AIDS Pandemic: The Critical Role of an HIV Vaccine SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE human immunodeficiency virus (HIV); HIV prevention; HIV vaccine. ID IMMUNODEFICIENCY-VIRUS; MALE CIRCUMCISION; INFECTION; PREVENTION; THAILAND; TRIAL AB While the human immunodeficiency virus (HIV)/AIDS pandemic continues, the incidence of HIV infections has fallen because of the deployment of antiretroviral drugs and multiple prevention modalities. To achieve a durable end to the pandemic, a vaccine remains essential. Recent advances in vaccinology offer new promise for an effective HIV vaccine. C1 [Fauci, Anthony S.; Folkers, Gregory K.; Marston, Hilary D.] NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, Bldg 31,Rm 7A-03, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov FU Department of Medicine of the Johns Hopkins School of Medicine FX Supplement sponsorship. This article was published as part of a supplement titled "The John Bartlett Festschrift: Celebrating a Career in Medicine," sponsored solely by the Department of Medicine of the Johns Hopkins School of Medicine in recognition of John Bartlett's contributions to medicine. NR 25 TC 11 Z9 11 U1 2 U2 9 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 SEP 15 PY 2014 VL 59 SU 2 BP S80 EP S84 DI 10.1093/cid/ciu420 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AR2KT UT WOS:000343415000006 PM 25151483 ER PT J AU Bricceno, KV Martinez, T Leikina, E Duguez, S Partridge, TA Chernomordik, LV Fischbeck, KH Sumner, CJ Burnett, BG AF Bricceno, Katherine V. Martinez, Tara Leikina, Evgenia Duguez, Stephanie Partridge, Terence A. Chernomordik, Leonid V. Fischbeck, Kenneth H. Sumner, Charlotte J. Burnett, Barrington G. TI Survival motor neuron protein deficiency impairs myotube formation by altering myogenic gene expression and focal adhesion dynamics SO HUMAN MOLECULAR GENETICS LA English DT Article ID SPINAL MUSCULAR-ATROPHY; SKELETAL-MUSCLE; MYOBLAST FUSION; SATELLITE CELLS; NEUROMUSCULAR-JUNCTIONS; SMN EXPRESSION; MOUSE MODELS; VINCULIN; MICE; DEFECTS AB While spinal muscular atrophy (SMA) is characterized by motor neuron degeneration, it is unclear whether and how much survival motor neuron (SMN) protein deficiency in muscle contributes to the pathophysiology of the disease. There is increasing evidence from patients and SMA model organisms that SMN deficiency causes intrinsic muscle defects. Here we investigated the role of SMN in muscle development using muscle cell lines and primary myoblasts. Formation of multinucleate myotubes by SMN-deficient muscle cells is inhibited at a stage preceding plasma membrane fusion. We found increased expression and reduced induction of key muscle development factors, such as MyoD and myogenin, with differentiation of SMN-deficient cells. In addition, SMN-deficient muscle cells had impaired cell migration and altered organization of focal adhesions and the actin cytoskeleton. Partially restoring SMN inhibited the premature expression of muscle differentiation markers, corrected the cytoskeletal abnormalities and improved myoblast fusion. These findings are consistent with a role for SMN in myotube formation through effects on muscle differentiation and cell motility. C1 [Bricceno, Katherine V.; Fischbeck, Kenneth H.; Burnett, Barrington G.] NINDS, Neurogenet Branch, Bethesda, MD 20892 USA. [Leikina, Evgenia; Chernomordik, Leonid V.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Program Phys Biol, NIH, Bethesda, MD USA. [Bricceno, Katherine V.] George Washington Univ, Inst Biomed Sci, Washington, DC USA. [Martinez, Tara; Sumner, Charlotte J.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Sumner, Charlotte J.] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21218 USA. [Duguez, Stephanie; Partridge, Terence A.] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. [Burnett, Barrington G.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. RP Burnett, BG (reprint author), 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM bburnett@usuhs.edu RI Duguez, Stephanie/J-1904-2016 OI Duguez, Stephanie/0000-0001-6510-5426 FU intramural NINDS research funds; Families of SMA; NINDS [R01NS062869]; Spinal Muscular Atrophy Foundation; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by intramural NINDS research funds. B. G. B. was supported by Families of SMA. C.J.S. was supported by NINDS grant R01NS062869 and funds from the Spinal Muscular Atrophy Foundation. L. V. C. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 46 TC 14 Z9 15 U1 1 U2 10 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 SEP 15 PY 2014 VL 23 IS 18 BP 4745 EP 4757 DI 10.1093/hmg/ddu189 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AQ9OF UT WOS:000343184400001 PM 24760765 ER PT J AU Di Narzo, AF Kozlenkov, A Roussos, P Hao, K Hurd, Y Lewis, DA Sibille, E Siever, LJ Koonin, E Dracheva, S AF Di Narzo, Antonio Fabio Kozlenkov, Alexey Roussos, Panos Hao, Ke Hurd, Yasmin Lewis, David A. Sibille, Etienne Siever, Larry J. Koonin, Eugene Dracheva, Stella TI A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide SO HUMAN MOLECULAR GENETICS LA English DT Article ID PRE-MESSENGER-RNA; MAJOR DEPRESSIVE DISORDER; DNA METHYLATION; 5-HT2C RECEPTORS; HUMAN BRAIN; CONSTITUTIVE ACTIVITY; NEURONAL CLASSES; TRANSCRIPTOME; MECHANISMS; ORGANIZATION AB Editing of the pre-mRNA for the serotonin receptor 2C (5-HT2CR) by site-specific adenosine deamination (A-to-I pre-mRNA editing) substantially increases the functional plasticity of this key neurotransmitter receptor and is thought to contribute to homeostatic mechanisms in neurons. 5-HT2CR mRNA editing generates up to 24 different receptor isoforms. The extent of editing correlates with 5-HT2CR functional activity: more highly edited isoforms exhibit the least function. Altered 5-HT2CR editing has been reported in postmortem brains of suicide victims. We report a comparative analysis of the connections among 5-HT2CR editing, genome-wide gene expression and DNA methylation in suicide victims, individuals with major depressive disorder and non-psychiatric controls. The results confirm previous findings of an overrepresentation of highly edited mRNA variants (which encode hypoactive 5-HT2CR receptors) in the brains of suicide victims. A large set of genes for which the expression level is associated with editing was detected. This signature set of editing-associated genes is significantly enriched for genes that are involved in synaptic transmission, genes that are preferentially expressed in neurons, and genes whose expression is correlated with the level of DNA methylation. Notably, we report that the link between 5-HT2CR editing and gene expression is disrupted in suicide victims. The results suggest that the postulated homeostatic function of 5-HT2CR editing is dysregulated in individuals who committed suicide. C1 [Di Narzo, Antonio Fabio; Roussos, Panos; Hao, Ke] Icahn Sch Med Mt Sinai, Friedman Brain Inst, Dept Genet & Genom Sci, New York, NY 10029 USA. [Kozlenkov, Alexey; Roussos, Panos; Hurd, Yasmin; Siever, Larry J.; Dracheva, Stella] Icahn Sch Med Mt Sinai, Friedman Brain Inst, Dept Psychiat, New York, NY 10029 USA. [Kozlenkov, Alexey; Roussos, Panos; Siever, Larry J.; Dracheva, Stella] James J Peters VA Med Ctr, Bronx, NY 10468 USA. [Lewis, David A.; Sibille, Etienne] Univ Pittsburgh, Dept Psychiat, Ctr Neurosci, Pittsburgh, PA USA. [Koonin, Eugene] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Dracheva, S (reprint author), James J Peters VA Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM stella.dracheva@mssm.edu RI Roussos, Panos/J-7090-2013 OI Roussos, Panos/0000-0002-4640-6239 FU VISN3 Mental Illness Research and Education Clinical Center (MIRECC), VA Merit Review Award [BX001829]; National Institute of Health [R21MH090352, R21DA031557, R01DA01 5446]; Hope for Depression Research Foundation grant; intramural funds of the US Department of Health and Human Services FX This work was funded by VISN3 Mental Illness Research and Education Clinical Center (MIRECC), VA Merit Review Award (BX001829 to S. D.); National Institute of Health (R21MH090352 and R21DA031557 to S. D.; and R01DA01 5446 to Y. H.); and Hope for Depression Research Foundation grant to S. D. E. V. K. is supported by intramural funds of the US Department of Health and Human Services to National Library of Medicine. NR 74 TC 7 Z9 7 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 SEP 15 PY 2014 VL 23 IS 18 BP 4801 EP 4813 DI 10.1093/hmg/ddu195 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AQ9OF UT WOS:000343184400005 PM 24781207 ER PT J AU Lokanga, RA Zhao, XN Entezam, A Usdin, K AF Lokanga, Rachel Adihe Zhao, Xiao-Nan Entezam, Ali Usdin, Karen TI X inactivation plays a major role in the gender bias in somatic expansion in a mouse model of the fragile X-related disorders: implications for the mechanism of repeat expansion SO HUMAN MOLECULAR GENETICS LA English DT Article ID PREMATURE OVARIAN FAILURE; OXIDATIVE STRESS; TREMOR/ATAXIA SYNDROME; MISMATCH REPAIR; MESSENGER-RNA; HUMAN-CELLS; TRANSCRIPTION; INSTABILITY; PROTEIN; MICE AB The Fragile X-related disorders are X-linked disorders resulting from the inheritance of FMR1 alleles with >54 CGG/CCG repeats in their 5' UTR. The repeats expand both somatically and on intergenerational transmission and increased repeat numbers are associated with increased risk of disease and increased risk of further expansion. The mechanism responsible for expansion is unknown. Here, we show in a knockin mouse model of these disorders that somatic expansion is much less common in females than in males. We show that this is due in large part to the fact that expansions occur only when the repeat is on the active X chromosome. However, even when this is taken into account, expansions in females are still less common than expected. This additional gender effect is not due to a protective effect of estrogen, a deleterious effect of testosterone or to differences in the expression of the Fmr1 gene or a variety of X-linked and autosomal DNA repair genes. However, our data do suggest that a higher level of expression of genes that protect against oxidative damage in females may contribute to their lower levels of expansion. Whatever the basis, our data suggest that the risk for somatic expansion may be lower in women than it is in men. This could help explain the reduced penetrance of some aspects of disease pathology in women. The fact that expansion only occurs when the Fmr1 allele is on the active X chromosome has important implications for the mechanism of repeat expansion. C1 [Lokanga, Rachel Adihe; Zhao, Xiao-Nan; Entezam, Ali; Usdin, Karen] NIDDK, Sect Gene Struct & Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Lokanga, Rachel Adihe] Univ Cape Town, Dept Med Biochem, ZA-7925 Cape Town, South Africa. RP Usdin, K (reprint author), NIH, Bldg 8,Room 2A19,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. EM ku@helix.nih.gov RI Zhao, Xiaonan/S-3139-2016 FU Intramural Program of the NIDDK [DK057808-07] FX The work described in this article was funded by a grant from the Intramural Program of the NIDDK to K. U. (DK057808-07). NR 44 TC 6 Z9 6 U1 1 U2 6 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 SEP 15 PY 2014 VL 23 IS 18 BP 4985 EP 4994 DI 10.1093/hmg/ddu213 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AQ9OF UT WOS:000343184400019 ER PT J AU Kuhs, KAL Porras, C Schiller, JT Rodriguez, AC Schiffman, M Gonzalez, P Wacholder, S Ghosh, A Li, Y Lowy, DR Kreimer, AR Poncelet, S Schussler, J Quint, W van Doorn, LJ Sherman, ME Sidawy, M Herrero, R Hildesheim, A Safaeian, M AF Kuhs, Krystle A. Lang Porras, Carolina Schiller, John T. Cecilia Rodriguez, Ana Schiffman, Mark Gonzalez, Paula Wacholder, Sholom Ghosh, Arpita Li, Yan Lowy, Douglas R. Kreimer, Aimee R. Poncelet, Sylviane Schussler, John Quint, Wim van Doorn, Leen-Jan Sherman, Mark E. Sidawy, Mary Herrero, Rolando Hildesheim, Allan Safaeian, Mahboobeh CA Costa Rica Vaccine Trial Grp TI Effect of Different Human Papillomavirus Serological and DNA Criteria on Vaccine Efficacy Estimates SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE human papillomavirus; methodological differences; naive population; vaccine efficacy ID RANDOMIZED CONTROLLED-TRIAL; YOUNG-WOMEN; PARTICLE VACCINE; DOUBLE-BLIND; QUADRIVALENT VACCINE; INFECTION; ASSAY; DISEASES; TYPE-18 AB Two trials of clinically approved human papillomavirus (HPV) vaccines, Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE I/II) and the Papilloma Trial Against Cancer in Young Adults (PATRICIA), reported a 22% difference in vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 2 or worse in HPV-naive subcohorts; however, serological testing methods and the HPV DNA criteria used to define HPV-unexposed women differed between the studies. We applied previously described methods to simulate these HPV-naive subcohorts within the Costa Rica HPV16/18 Vaccine Trial and assessed how these criteria affect the estimation of VE. We applied 2 enzyme-linked immunosorbent assay (ELISA) thresholds for HPV16 and HPV18 seropositivity (8 and 7 ELISA units/mL, respectively, for PATRICIA; 54 and 65 ELISA units/mL, respectively, for FUTURE I/II (to approximate the competitive Luminex immunoassay)) and 2 criteria for HPV DNA positivity (12 oncogenic HPV types, plus HPV66 and 68/73 for PATRICIA; or plus HPV6 and 11 for FUTURE I/II). VE was computed in the 2 naive subcohorts. Using the FUTURE I/II and PATRICIA criteria, VE estimates against cervical intraepithelial neoplasia grade 2 or worse, regardless of HPV type, were 69.0% (95% confidence interval: 40.3%, 84.9%) and 80.8% (95% confidence interval: 52.6%, 93.5%), respectively (P = 0.1). Although the application of FUTURE I/II criteria to our cohort resulted in the inclusion of more sexually experienced women, methodological differences did not fully explain the VE differences. C1 [Kuhs, Krystle A. Lang; Schiller, John T.; Schiffman, Mark; Wacholder, Sholom; Lowy, Douglas R.; Kreimer, Aimee R.; Sherman, Mark E.; Hildesheim, Allan; Safaeian, Mahboobeh] NCI, NIH, Bethesda, MD 20892 USA. [Porras, Carolina; Cecilia Rodriguez, Ana; Gonzalez, Paula; Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Gonzalez, Paula; Herrero, Rolando] Int Agcy Res Canc, Prevent & Implementat Grp, F-69372 Lyon, France. [Ghosh, Arpita] Publ Hlth Fdn India, New Delhi, India. [Li, Yan] Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. [Poncelet, Sylviane] GlaxoSmithKline GSK Vaccines, Rixensart, Belgium. [Schussler, John] Informat Management Serv Inc, Calverton, MD USA. [Quint, Wim; van Doorn, Leen-Jan] DDL Diagnost Lab, Rijswijk, Netherlands. [Sidawy, Mary] Georgetown Univ, Washington, DC USA. RP Kuhs, KAL (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,RM 6-E210, Bethesda, MD 20892 USA. EM krystle.kuhs@nih.gov RI Hildesheim, Allan/B-9760-2015; Kreimer, Aimee/H-1687-2015 OI Hildesheim, Allan/0000-0003-0257-2363; FU NCI [N01-CP-11005]; NIH Office of Research on Women's Health; GSK Biologicals SA under US Food and Drug Administration (FDA) [FDA BB-IND 7920] FX This trial is sponsored and funded by the NCI (contract N01-CP-11005), with funding support from the NIH Office of Research on Women's Health. GSK Biologicals SA provided vaccine and support for aspects of the trial associated with regulatory submission needs of the company under a US Food and Drug Administration (FDA) clinical trials agreement (FDA BB-IND 7920) during the 4-year, randomized, blinded phase of our study. Vaccine was provided for our trial by GSK Vaccines under a clinical trials agreement with the NCI. GSK Vaccines also provided support for aspects of the trial associated with regulatory submission needs of the company. The authors received no financial support or other form of compensation related to the development of the manuscript. The trial is registered with clinicaltrials.gov (NCT00128661). The protocol is available at http://proyectoguanacaste.org. NR 17 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2014 VL 180 IS 6 BP 599 EP 607 DI 10.1093/aje/kwu168 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AQ7XK UT WOS:000343033400007 ER PT J AU George, SM Ballard-Barbash, R Manson, JE Reedy, J Shikany, JM Subar, AF Tinker, LF Vitolins, M Neuhouser, ML AF George, Stephanie M. Ballard-Barbash, Rachel Manson, JoAnn E. Reedy, Jill Shikany, James M. Subar, Amy F. Tinker, Lesley F. Vitolins, Mara Neuhouser, Marian L. TI Comparing Indices of Diet Quality With Chronic Disease Mortality Risk in Postmenopausal Women in the Women's Health Initiative Observational Study: Evidence to Inform National Dietary Guidance SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE diet; diet quality indices; mortality risk; postmenopausal women; prospective cohort study ID BREAST-CANCER; MEDITERRANEAN DIET; PHYSICAL-ACTIVITY; EATING INDEX; CARDIOVASCULAR-DISEASE; PROCESSED MEAT; CLINICAL-TRIAL; BLOOD-PRESSURE; ALL-CAUSE; SURVIVAL AB Poor diet quality is thought to be a leading risk factor for years of life lost. We examined how scores on 4 commonly used diet quality indices-the Healthy Eating Index 2010 (HEI), the Alternative Healthy Eating Index 2010 (AHEI), the Alternate Mediterranean Diet (aMED), and the Dietary Approaches to Stop Hypertension (DASH)-are related to the risks of death from all causes, cardiovascular disease (CVD), and cancer among postmenopausal women. Our prospective cohort study included 63,805 participants in the Women's Health Initiative Observational Study (from 1993-2010) who completed a food frequency questionnaire at enrollment. Cox proportional hazards models were fit using person-years as the underlying time metric. We estimated multivariate hazard ratios and 95% confidence intervals for death associated with increasing quintiles of diet quality index scores. During 12.9 years of follow-up, 5,692 deaths occurred, including 1,483 from CVD and 2,384 from cancer. Across indices and after adjustment for multiple covariates, having better diet quality (as assessed by HEI, AHEI, aMED, and DASH scores) was associated with statistically significant 18%-26% lower all-cause and CVD mortality risk. Higher HEI, aMED, and DASH (but not AHEI) scores were associated with a statistically significant 20%-23% lower risk of cancer death. These results suggest that postmenopausal women consuming a diet in line with a priori diet quality indices have a lower risk of death from chronic disease. C1 [George, Stephanie M.; Ballard-Barbash, Rachel; Reedy, Jill; Subar, Amy F.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Dept Med, Sch Med, Cambridge, MA 02138 USA. [Shikany, James M.] Univ Alabama Birmingham, Sch Med, Div Prevent Med, Birmingham, AL USA. [Tinker, Lesley F.; Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Vitolins, Mara] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. RP George, SM (reprint author), 9609 Med Ctr Dr,Room 3E408,MSC 9762, Bethesda, MD 20892 USA. EM stephanie.george@nih.gov FU Applied Research Program of the National Cancer Institute; National Heart, Lung, and Blood Institute [HHSN268201100046C, HHSN 268201100001C, HHSN268201100002C, HHSN2682011 00003C, HHSN26820110004C, HHSN271201100004C] FX This study was supported by the Applied Research Program of the National Cancer Institute. The Women's Health Initiative is funded by the National Heart, Lung, and Blood Institute (grants HHSN268201100046C, HHSN 268201100001C, HHSN268201100002C, HHSN2682011 00003C, HHSN26820110004C, and HHSN271201100004C). NR 52 TC 40 Z9 40 U1 5 U2 19 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2014 VL 180 IS 6 BP 616 EP 625 DI 10.1093/aje/kwu173 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AQ7XK UT WOS:000343033400009 PM 25035143 ER PT J AU Salami, SS Vira, MA Turkbey, B Fakhoury, M Yaskiv, O Villani, R Ben-Levi, E Rastinehad, AR AF Salami, Simpa S. Vira, Manish A. Turkbey, Baris Fakhoury, Mathew Yaskiv, Oksana Villani, Robert Ben-Levi, Eran Rastinehad, Ardeshir R. TI Multiparametric Magnetic Resonance Imaging Outperforms the Prostate Cancer Prevention Trial Risk Calculator in Predicting Clinically Significant Prostate Cancer SO CANCER LA English DT Article DE prostate imaging; prostate fusion biopsy; prostate cancer screening; risk calculator; nomogram ID TRANSRECTAL ULTRASOUND BIOPSY; COMPLICATIONS; PERFORMANCE; ANTIGEN; MEN AB BACKGROUND: The Prostate Cancer Prevention Trial risk calculator for high-grade (PCPTHG) prostate cancer (CaP) was developed to improve the detection of clinically significant CaP. In this study, the authors compared the performance of the PCPTHG against multiparametric magnetic resonance imaging (MP-MRI) in predicting men at risk of CaP. METHODS: Men with an abnormal prostate-specific antigen (PSA) level or digital rectal examination (DRE) and a suspicious lesion on a 3-Tesla MP-MRI were enrolled prospectively. Three radiologists reviewed and graded all lesions on a 5-point Likert scale. Biopsy of suspicious lesion(s) was performed using a proprietary MRI/transrectal ultrasound fusion-guided prostate biopsy system, after which 12-core biopsy was performed. A genitourinary pathologist reviewed all pathology slides. The performance of PCPTHG was compared with that of MP-MRI in predicting clinically significant CaP. RESULTS: Of 175 men who were eligible for analysis, 64.6% (113 of 175 men) were diagnosed with CaP, including 93 of 113 men (82.3%) who had clinically significant disease. Age, abnormal DRE, PSA, PSA density, prostate size, extraprostatic extension on MRI, apparent diffusion coefficient value, and MRI lesion size were identified as significant predictors of high-grade CaP (all P<.05). The area under the receiver operating characteristic curve of PCPTHG for predicting high-grade CaP was 0.676 (95% confidence interval [CI], 0.592-0.751). By using a risk cutoff of >= 15% for biopsy as, proposed previously for high-grade CaP, sensitivity was 96.4%, specificity was 7.6%, and the false-positive rate was 51.1%. In contrast, the area under the receiver operating characteristic curve of MP-MRI for high-grade CaP was 0.769 (95% CI, 0.703-0.834), and it was 0.812 (95% CI, 0.754-0.869) for clinically significant CaP. CONCLUSIONS: MP-MRI outperforms PCPTHG in predicting clinically significant CaP, and its application may help select patients who will benefit from CaP diagnosis and treatment. (C) 2014 American Cancer Society. C1 [Salami, Simpa S.; Vira, Manish A.; Fakhoury, Mathew; Rastinehad, Ardeshir R.] Hofstra North Shore LIJ Sch Med, Arthur Smith Inst Urol, New Hyde Pk, NY 11040 USA. Hofstra North Shore LIJ Sch Med, Dept Pathol, New Hyde Pk, NY 11040 USA. [Turkbey, Baris; Yaskiv, Oksana] NIH, Mol Imaging Program, Bethesda, MD 20892 USA. [Villani, Robert; Ben-Levi, Eran; Rastinehad, Ardeshir R.] Hofstra North Shore LIJ Sch Med, Dept Diagnost & Intervent Radiol, New Hyde Pk, NY 11040 USA. RP Salami, SS (reprint author), Hofstra North Shore LIJ Sch Med, Arthur Smith Inst Urol, 450 Lakeville Rd,Suite M-41, New Hyde Pk, NY 11040 USA. EM ssalami@nshs.edu FU provision of research equipment from InVivo FX This work was supported by the provision of research equipment from InVivo to Dr. Rastinchad. NR 22 TC 24 Z9 24 U1 0 U2 2 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 SEP 15 PY 2014 VL 120 IS 18 BP 2876 EP 2882 DI 10.1002/cncr.28790 PG 7 WC Oncology SC Oncology GA AQ2PM UT WOS:000342629700015 PM 24917122 ER PT J AU Lewis, DR Check, DP Caporaso, NE Travis, WD Devesa, SS AF Lewis, Denise Riedel Check, David P. Caporaso, Neil E. Travis, William D. Devesa, Susan S. TI US Lung Cancer Trends by Histologic Type SO CANCER LA English DT Article DE lung cancer incidence; histology; epidemiology; trends; gender; race; ethnicity; cigarette smoking ID UNITED-STATES; CIGARETTE-SMOKING; NEVER-SMOKERS; RISK-FACTORS; MORTALITY; WOMEN; RATES; ADENOCARCINOMA; CLASSIFICATION; EPIDEMIOLOGY AB BACKGROUND: Lung cancer incidence rates overall are declining in the United States. This study investigated the trends by histologic type and demographic characteristics. METHODS: Surveillance, Epidemiology, and End Results ( SEER) program rates of microscopically confirmed lung cancer overall and squamous cell, small cell, adenocarcinoma, large cell, other, and unspecified carcinomas among US whites and blacks diagnosed from 1977 to 2010 and white non-Hispanics, Asian/Pacific Islanders, and white Hispanics diagnosed from 1992 to 2010 were analyzed by sex and age. RESULTS: Squamous and small cell carcinoma rates declined since the 1990s, although less rapidly among females than males. Adenocarcinoma rates decreased among males and only through 2005, after which they then rose during 2006 to 2010 among every racial/ethnic/sex group; rates for unspecified type declined. Male/female rate ratios declined among whites and blacks more than among other groups. Recent rates among young females were higher than among males for adenocarcinoma among all racial/ethnic groups and for other specified carcinomas among whites. CONCLUSIONS: US lung cancer trends vary by sex, histologic type, racial/ethnic group, and age, reflecting historical cigarette smoking rates, duration, cessation, cigarette composition, and exposure to other carcinogens. Substantial excesses among males have diminished and higher rates of adenocarcinoma among young females have emerged as rates among males declined more rapidly. The recognition of EGFR mutation and ALK rearrangements that occur primarily in adenocarcinomas are the primary basis for the molecular revolution that has transformed lung cancer diagnosis and treatment over the past decade, and these changes have affected recent type-specific trends. (C) 2014 American Cancer Society. C1 [Lewis, Denise Riedel] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Check, David P.; Caporaso, Neil E.; Devesa, Susan S.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Travis, William D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Lewis, DR (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM lewisde@mail.nih.gov RI Check, David/J-7184-2015 OI Check, David/0000-0003-3887-0493 FU Intramural NIH HHS [Z99 CA999999] NR 37 TC 36 Z9 36 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD SEP 15 PY 2014 VL 120 IS 18 BP 2883 EP 2892 DI 10.1002/cncr.28749 PG 10 WC Oncology SC Oncology GA AQ2PM UT WOS:000342629700016 PM 25113306 ER PT J AU Miskimon, M Han, S Lee, JJ Ringkamp, M Wilson, MA Petralia, RS Dong, X Worley, PF Baraban, JM Reti, IM AF Miskimon, M. Han, S. Lee, J. J. Ringkamp, M. Wilson, M. A. Petralia, R. S. Dong, X. Worley, P. F. Baraban, J. M. Reti, I. M. TI Selective expression of Narp in primary nociceptive neurons: Role in microglia/macrophage activation following nerve injury SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Pain; AMPA; Dorsal root ganglion; CGRP; Pentraxin; Inflammation ID RAT SPINAL-CORD; ACTIVITY REGULATED PENTRAXIN; NEUROPATHIC PAIN; THERMAL NOCICEPTION; INNATE IMMUNITY; DORSAL-HORN; MICROGLIA; RECEPTORS; TRANSECTION; PATHWAYS AB Neuronal activity regulated pentraxin (Narp) is a secreted protein implicated in regulating synaptic plasticity via its association with the extracellular surface of AMPA receptors. We found robust Narp immunostaining in dorsal root ganglia (DRG) that is largely restricted to small diameter neurons, and in the superficial layers of the dorsal horn of the spinal cord. In double staining studies of DRG, we found that Narp is expressed in both IB4- and CGRP-positive neurons, markers of distinct populations of nociceptive neurons. Although a panel of standard pain behavioral assays were unaffected by Narp deletion, we found that Narp knockout mice displayed an exaggerated microglia/macrophage response in the dorsal horn of the spinal cord to sciatic nerve transection 3 days after surgery compared with wild type mice. As other members of the pentraxin family have been implicated in regulating innate immunity, these findings suggest that Narp, and perhaps other neuronal pentraxins, also regulate inflammation in the nervous system. (C) 2014 Elsevier B.V. All rights reserved. C1 [Miskimon, M.; Wilson, M. A.; Dong, X.; Worley, P. F.; Baraban, J. M.; Reti, I. M.] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA. [Han, S.; Lee, J. J.; Baraban, J. M.; Reti, I. M.] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD 21205 USA. [Ringkamp, M.] Johns Hopkins Univ, Dept Neurosurg, Baltimore, MD 21205 USA. [Petralia, R. S.] Johns Hopkins Univ, NIDCD, NIH, Baltimore, MD 21205 USA. [Reti, I. M.] Lab Origin, Tampa, FL USA. RP Reti, IM (reprint author), Johns Hopkins Univ, 600 N Wolfe St,Meyer 3-181, Baltimore, MD 21205 USA. EM imreti@jhmi.edu OI Baraban, Jay/0000-0002-8165-2638 FU NIDCD Intramural Research Program; [RO1DA016303] FX This work was supported by RO1DA016303. RSP was supported by the NIDCD Intramural Research Program. We thank Dr. Ya-Xian Wang for the help with the immunogold studies. NR 37 TC 1 Z9 1 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 EI 1872-8421 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD SEP 15 PY 2014 VL 274 IS 1-2 BP 86 EP 95 DI 10.1016/j.jneuroim.2014.06.016 PG 10 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA AQ5TN UT WOS:000342871600011 PM 25005116 ER PT J AU Solanki, S Dube, PR Tano, JY Birnbaumer, L Vazquez, G AF Solanki, Sumeet Dube, Prabhatchandra R. Tano, Jean-Yves Birnbaumer, Lutz Vazquez, Guillermo TI Reduced endoplasmic reticulum stress-induced apoptosis and impaired unfolded protein response in TRPC3-deficient M1 macrophages SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE TRPC channels; macrophage apoptosis; endoplasmic reticulum stress ID CHANNELS; ATHEROSCLEROSIS; EXPRESSION; SURVIVAL; MOUSE; INVOLVEMENT; PRIMERBANK; ACTIVATION; MECHANISMS; DEATH AB Endoplasmic reticulum (ER) stress is a prominent mechanism of macrophage apoptosis in advanced atherosclerotic lesions. Recent studies from our laboratory showed that advanced atherosclerotic plaques in Apoe(-/-) mice with bone marrow deficiency of the calcium-permeable channel Transient Receptor Potential Canonical 3 (TRPC3) are characterized by reduced areas of necrosis and fewer apoptotic macrophages than animals transplanted with Trpc3(+/+) bone marrow. In vitro, proinflammatory M1 but not anti-inflammatory M2 macrophages derived from Trpc3(-/-) Apoe(-/-) animals exhibited reduced ER stress-induced apoptosis. However, whether this was due to a specific effect of TRPC3 deficiency on macrophage ER stress signaling remained to be determined. In the present work we used polarized macrophages derived from mice with macrophage-specific deficiency of TRPC3 to examine the expression level of ER stress markers and the activation status of some typical mediators of macrophage apoptosis. We found that the reduced susceptibility of TRPC3-deficient M1 macrophages to ER stress-induced apoptosis correlates with an impaired unfolded protein response (UPR), reduced mitochondrion-dependent apoptosis, and reduced activation of the proapoptotic molecules calmodulin-dependent protein kinase II and signal transducer and activator of transcription 1. Notably, none of these pathways was altered in TRPC3-deficient M2 macrophages. These findings show for the first time an obligatory requirement for a member of the TRPC family of cation channels in ER stress-induced apoptosis in macrophages, underscoring a rather selective role of the TRPC3 channel on mechanisms related to the UPR signaling in M1 macrophages. C1 [Solanki, Sumeet; Dube, Prabhatchandra R.; Tano, Jean-Yves; Vazquez, Guillermo] Univ Toledo, Dept Physiol & Pharmacol, Toledo, OH 43606 USA. [Solanki, Sumeet; Dube, Prabhatchandra R.; Tano, Jean-Yves; Vazquez, Guillermo] Univ Toledo, Ctr Diabet & Endocrine Res, Toledo, OH 43606 USA. [Birnbaumer, Lutz] NIEHS, Lab Membrane Signaling, Dept Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Vazquez, G (reprint author), 3000 Transverse Dr,Mail Stop 1008, Toledo, OH 43614 USA. EM guillermo.vazquez@utoledo.edu FU National Institutes of Health (NIH) [R01 HL-111877-01]; Intramural Research Program of the NIH [Z01-ES-101864]; University of Toledo College of Medicine FX This work was supported by National Institutes of Health (NIH) Grant R01 HL-111877-01 (to G. Vazquez), the Intramural Research Program of the NIH Project Z01-ES-101864 (to L. Birnbaumer), and the University of Toledo College of Medicine. NR 28 TC 8 Z9 9 U1 1 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 EI 1522-1563 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD SEP 15 PY 2014 VL 307 IS 6 BP C521 EP C531 DI 10.1152/ajpcell.00369.2013 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA AP9AA UT WOS:000342369400004 PM 25031020 ER PT J AU Rahma, OE Gammoh, E Simon, RM Khleif, SN AF Rahma, Osama E. Gammoh, Emily Simon, Richard M. Khleif, Samir N. TI Is the "3+3" Dose-Escalation Phase I Clinical Trial Design Suitable for Therapeutic Cancer Vaccine Development? A Recommendation for Alternative Design SO CLINICAL CANCER RESEARCH LA English DT Article ID DRUG DEVELOPMENT; PEPTIDE VACCINE; CARCINOEMBRYONIC ANTIGEN; IMMUNE-RESPONSES; OVARIAN-CANCER; ONCOLOGY; MELANOMA; IMMUNOTHERAPY; IMMUNOGENICITY; INJECTION AB Purpose: Phase I clinical trials are generally conducted to identify the maximum tolerated dose (MTD) or the biologically active dose (BAD) using a traditional dose-escalation design. This design may not be applied to cancer vaccines, given their unique mechanism of action. The FDA recently published "Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines." However, many questions about the design of cancer vaccine studies remain unanswered. Experimental Design: We analyzed the toxicity profile in 239 phase I therapeutic cancer vaccine trials. We addressed the ability of dose escalation to determine the MTD or the BAD in trials that used a dose-escalation design. Results: The rate of grade 3/4 vaccine-related systemic toxicities was 1.25 adverse events per 100 patients and 2 per 1,000 vaccines. Only two of the 127 dose-escalation trials reported vaccine-related dose limiting toxicities, both of which used bacterial vector vaccines. Out of the 116 trials analyzed for the dose-immune response relationship, we found a statistically significant dose-immune response correlation only when the immune response was measured by antibodies (P < 0.001) or delayed type hypersensitivity (P < 0.05). However, the increase in cellular immune response did not appear further sustainable with the continued increase in dose. Conclusions: Our analysis suggests that the risks of serious toxicities with therapeutic cancer vaccines are extremely low and that toxicities do not correlate with dose levels. Accordingly, the conventional dose-escalation design is not suitable for cancer vaccines with few exceptions. Here, we propose an alternative design for therapeutic cancer vaccine development. (C)2014 AACR. C1 [Rahma, Osama E.; Gammoh, Emily; Khleif, Samir N.] NCI, Vaccine Branch, Bethesda, MD 20892 USA. [Rahma, Osama E.] Univ Virginia, Div Hematol Oncol, Charlottesville, VA USA. [Simon, Richard M.] NCI, Biometr Res Branch, Rockville, MD USA. [Khleif, Samir N.] Georgia Hlth Sci Canc Ctr, Augusta, GA USA. RP Khleif, SN (reprint author), Georgia Regent Univ, Ctr Canc, 1411 Laney Walker Blvd, Augusta, GA 30912 USA. EM skhleif@gru.edu FU NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 42 TC 10 Z9 10 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2014 VL 20 IS 18 BP 4758 EP 4767 DI 10.1158/1078-0432.CCR-13-2671 PG 10 WC Oncology SC Oncology GA AP8VX UT WOS:000342358500005 PM 25037736 ER PT J AU Schwandt, A Harris, PJ Hunsberger, S Deleporte, A Smith, GL Vulih, D Anderson, BD Ivy, SP AF Schwandt, A. Harris, P. J. Hunsberger, S. Deleporte, A. Smith, G. L. Vulih, D. Anderson, B. D. Ivy, S. P. TI The Role of Age on Dose-Limiting Toxicities in Phase I Dose-Escalation Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID CANCER CLINICAL-TRIALS; CENTER EXPERIENCE; ONCOLOGY TRIALS; BREAST-CANCER; OLDER-ADULTS; PROGNOSTIC-FACTORS; PATIENT; PARTICIPATION; BARRIERS; SURVIVAL AB Purpose: Elderly oncology patients are not enrolled in early-phase trials in proportion to the numbers of geriatric patients with cancer. There may be concern that elderly patients will not tolerate investigational agents as well as younger patients, resulting in a disproportionate number of dose-limiting toxicities (DLT). Recent single-institution studies provide conflicting data on the relationship between age and DLT. Experimental Design: We retrospectively reviewed data about patients treated on single-agent, dose-escalation, phase I clinical trials sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute. Patients' dose levels were described as a percentage of maximum tolerated dose, the highest dose level at which <33% of patients had a DLT, or recommended phase II dose (RP2D). Mixed-effect logistic regression models were used to analyze relationships between the probability of a DLT and age and other explanatory variables. Results: Increasing dose, increasing age, and worsening performance status (PS) were significantly related to an increased probability of a DLT in this model (P < 0.05). There was no association between dose level administered and age (P = 0.57). Conclusions: This analysis of phase I dose-escalation trials, involving more than 500 patients older than 70 years of age, is the largest reported. As age and dose level increased and PS worsened, the probability of a DLT increased. Although increasing age was associated with occurrence of DLT, this risk remained within accepted thresholds of risk for phase I trials. There was no evidence of age bias on enrollment of patients on low or high dose levels. (C)2014 AACR. C1 [Schwandt, A.] Case Western Reserve Sch Med, Cleveland, OH USA. [Harris, P. J.; Hunsberger, S.; Smith, G. L.; Ivy, S. P.] NCI, Bethesda, MD 20850 USA. [Deleporte, A.] Inst Jules Bordet, B-1000 Brussels, Belgium. [Vulih, D.; Anderson, B. D.] Theradex Syst Inc, Princeton, NJ USA. RP Ivy, SP (reprint author), NCI, Invest Drug Branch, Therapy Evaluat Program, 9609 Med Ctr Dr,Room 5-W458, Bethesda, MD 20850 USA. EM ivyp@ctep.nci.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 36 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2014 VL 20 IS 18 BP 4768 EP 4775 DI 10.1158/1078-0432.CCR-14-0866 PG 8 WC Oncology SC Oncology GA AP8VX UT WOS:000342358500006 PM 25028396 ER PT J AU Saito, M Shiraishi, K Matsumoto, K Schetter, AJ Ogata-Kawata, H Tsuchiya, N Kunitoh, H Nokihara, H Watanabe, SI Tsuta, K Kumamoto, K Takenoshita, S Yokota, J Harris, CC Kohno, T AF Saito, Motonobu Shiraishi, Kouya Matsumoto, Kenji Schetter, Aaron J. Ogata-Kawata, Hiroko Tsuchiya, Naoto Kunitoh, Hideo Nokihara, Hiroshi Watanabe, Shun-ichi Tsuta, Koji Kumamoto, Kensuke Takenoshita, Seiichi Yokota, Jun Harris, Curtis C. Kohno, Takashi TI A Three-microRNA Signature Predicts Responses to Platinum-Based Doublet Chemotherapy in Patients with Lung Adenocarcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; MICRORNA EXPRESSION; GENE-EXPRESSION; CANCER CELLS; ADJUVANT CHEMOTHERAPY; PROGNOSTIC CLASSIFIER; PHASE-III; ALK; SURVIVAL; FUSIONS AB Purpose: To examine the clinical utility of intratumor microRNAs (miRNA) as a biomarker for predicting responses to platinum-based doublet chemotherapy in patients with recurring lung adenocarcinoma (LADC). Experimental Design: The expression of miRNAs was examined in LADC tissues surgically resected from patients treated with platinum-based doublet chemotherapy at the time of LADC recurrence. Microarray-based screening of 904 miRNAs followed by quantitative reverse transcription-PCR-based verification in 40 test cohort samples, including 16 (40.0%) responders, was performed to identify miRNAs that are differentially expressed in chemotherapy responders and nonresponders. Differential expression was confirmed in a validation cohort (n = 63 samples), including 18 (28.6%) responders. An miRNA signature that predicted responses to platinum-based doublet chemotherapy was identified and its accuracy was examined by principal component and support vector machine analyses. Genotype data for the TP53-Arg72Pro polymorphism, which is associated with responses to platinum-based doublet chemotherapy, were subsequently incorporated into the prediction analysis. Results: A signature comprising three miRNAs (miR1290, miR196b, and miR135a*) enabled the prediction of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in both the test and validation cohorts (82.5% and 77.8%). Examination of the latter was performed using miRNAs extracted from archived formalin-fixed paraffin-embedded tissues. Combining this miRNA signature with the TP53-Arg72Pro polymorphism genotype marginally improved the predictive power. Conclusion: The three-miRNA signature in surgically resected primary LADC tissues may by clinically useful for predicting responsiveness to platinum-based doublet chemotherapy in patients with LADC recurrence. (C)2014 AACR. C1 [Saito, Motonobu; Shiraishi, Kouya; Ogata-Kawata, Hiroko; Tsuchiya, Naoto; Yokota, Jun; Kohno, Takashi] Natl Canc Ctr, Res Inst, Div Genome Biol, Tokyo 1040045, Japan. [Saito, Motonobu; Kumamoto, Kensuke; Takenoshita, Seiichi] Fukushima Med Univ, Sch Med, Dept Organ Regulatory Surg, Fukushima, Japan. [Matsumoto, Kenji] Natl Res Inst Child Hlth & Dev, Dept Allergy & Immunol, Setagaya Ku, Tokyo, Japan. [Schetter, Aaron J.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kunitoh, Hideo] Natl Canc Ctr, Japanese Red Cross Med Ctr, Dept Med Oncol, Tokyo, Japan. [Nokihara, Hiroshi] Natl Canc Ctr, Div Thorac Oncol, Tokyo, Japan. [Watanabe, Shun-ichi] Natl Canc Ctr, Div Thorac Surg, Tokyo, Japan. [Tsuta, Koji] Natl Canc Ctr, Div Pathol & Clin Labs, Tokyo, Japan. [Yokota, Jun] Inst Predict & Personalized Med Canc, Barcelona, Spain. RP Kohno, T (reprint author), Natl Canc Ctr, Res Inst, Div Genome Biol, Chuo Ku, 1-1 Tsukiji 5 Chome, Tokyo 1040045, Japan. EM tkkohno@ncc.go.jp FU Advanced Research for Medical Products Mining Program of the National Institute of Biomedical Innovation (NIBIO); Ministry of Health, Labor, and Welfare; Japan Society for the Promotion of Science (JSPS) [24790340]; Third-Term Comprehensive Control Research for Cancer [H25-Young Scientists-009] FX This work was supported in part by the Advanced Research for Medical Products Mining Program of the National Institute of Biomedical Innovation (NIBIO), Grants-in-Aid from the Ministry of Health, Labor, and Welfare for the Third Term Comprehensive 10 year Strategy for Cancer Control, and Grant-in-Aid from Japan Society for the Promotion of Science (JSPS) for Scientific Research (B). Grant-in-Aid for Young Scientists (B; 24790340) and Third-Term Comprehensive Control Research for Cancer (H25-Young Scientists-009). NR 42 TC 6 Z9 6 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2014 VL 20 IS 18 BP 4784 EP 4793 DI 10.1158/1078-0432.CCR-14-1096 PG 10 WC Oncology SC Oncology GA AP8VX UT WOS:000342358500008 PM 25142144 ER PT J AU Khiati, S Rosa, ID Sourbier, C Ma, XF Rao, VA Neckers, LM Zhang, HL Pommier, Y AF Khiati, Salim Rosa, Ilaria Dalla Sourbier, Carole Ma, Xuefei Rao, V. Ashutosh Neckers, Leonard M. Zhang, Hongliang Pommier, Yves TI Mitochondrial Topoisomerase I (Top1mt) Is a Novel Limiting Factor of Doxorubicin Cardiotoxicity SO CLINICAL CANCER RESEARCH LA English DT Article ID CYTOCHROME-C-OXIDASE; ANTHRACYCLINE CARDIOTOXICITY; MOLECULAR-BASIS; HEART-FAILURE; MTDNA LESIONS; DNA DAMAGE; ADRIAMYCIN; CARDIOMYOPATHY; CHEMOTHERAPY; CANCER AB Purpose: Doxorubicin is one of the most effective chemotherapeutic agents. However, up to 30% of the patients treated with doxorubicin suffer from congestive heart failure. The mechanism of doxorubicin cardiotoxicity is likely multifactorial and most importantly, the genetic factors predisposing to doxorubicin cardiotoxicity are unknown. On the basis of the fact that mtDNA lesions and mitochondrial dysfunctions have been found in human hearts exposed to doxorubicin and that mitochondrial topoisomerase 1 (Top1mt) specifically controls mtDNA homeostasis, we hypothesized that Top1mt knockout (KO) mice might exhibit hypersensitivity to doxorubicin. Experimental Design: Wild-type (WT) and KO Top1mt mice were treated once a week with 4 mg/kg doxorubicin for 8 weeks. Heart tissues were analyzed one week after the last treatment. Results: Genetic inactivation of Top1mt in mice accentuates mtDNA copy number loss and mtDNA damage in heart tissue following doxorubicin treatment. Top1mt KO mice also fail to maintain respiratory chain protein production and mitochondrial cristae ultrastructure organization. These mitochondrial defects result in decreased O-2 consumption, increased reactive oxygen species production, and enhanced heart muscle damage in animals treated with doxorubicin. Accordingly, Top1mt KO mice die within 45 days after the last doxorubicin injection, whereas the WT mice survive. Conclusions: Our results provide evidence that Top1mt, which is conserved across vertebrates, is critical for cardiac tolerance to doxorubicin and adaptive response to doxorubicin cardiotoxicity. They also suggest the potential of Top1mt single-nucleotide polymorphisms testing to investigate patient susceptibility to doxorubicin-induced cardiotoxicity. (C) 2014 AACR. C1 [Khiati, Salim; Rosa, Ilaria Dalla; Zhang, Hongliang; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Khiati, Salim; Rosa, Ilaria Dalla; Zhang, Hongliang; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Sourbier, Carole; Neckers, Leonard M.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Ma, Xuefei] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Rao, V. Ashutosh] US FDA, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. RP Pommier, Y (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov FU NIH through the Intramural Program of the NCI, Center for Cancer Research [Z01 BC 006161] FX This work was supported by the NIH through the Intramural Program of the NCI, Center for Cancer Research (Z01 BC 006161). NR 50 TC 19 Z9 19 U1 0 U2 15 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2014 VL 20 IS 18 BP 4873 EP 4881 DI 10.1158/1078-0432.CCR-13-3373 PG 9 WC Oncology SC Oncology GA AP8VX UT WOS:000342358500016 PM 24714774 ER PT J AU Nickerson, ML Dancik, GM Im, KM Edwards, MG Turan, S Brown, J Ruiz-Rodriguez, C Owens, C Costello, JC Guo, GW Tsang, SX Li, YR Zhou, Q Cai, ZM Moore, LE Lucia, MS Dean, M Theodorescu, D AF Nickerson, Michael L. Dancik, Garrett M. Im, Kate M. Edwards, Michael G. Turan, Sevilay Brown, Joseph Ruiz-Rodriguez, Christina Owens, Charles Costello, James C. Guo, Guangwu Tsang, Shirley X. Li, Yingrui Zhou, Quan Cai, Zhiming Moore, Lee E. Lucia, M. Scott Dean, Michael Theodorescu, Dan TI Concurrent Alterations in TERT, KDM6A, and the BRCA Pathway in Bladder Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID TRANSITIONAL-CELL CARCINOMA; RESISTANT PROSTATE-CANCER; PROMOTER MUTATIONS; GENE; BAP1; GENOME; TUMORS; DEMETHYLATION; PREDISPOSE; EXPRESSION AB Purpose: Genetic analysis of bladder cancer has revealed a number of frequently altered genes, including frequent alterations of the telomerase (TERT) gene promoter, although few altered genes have been functionally evaluated. Our objective is to characterize alterations observed by exome sequencing and sequencing of the TERT promoter, and to examine the functional relevance of histone lysine (K)-specific demethylase 6A (KDM6A/UTX), a frequently mutated histone demethylase, in bladder cancer. Experimental Design: We analyzed bladder cancer samples from 54 U.S. patients by exome and targeted sequencing and confirmed somatic variants using normal tissue from the same patient. We examined the biologic function of KDM6A using in vivo and in vitro assays. Results: We observed frequent somatic alterations in BRCA1 associated protein-1 (BAP1) in 15% of tumors, including deleterious alterations to the deubiquitinase active site and the nuclear localization signal. BAP1 mutations contribute to a high frequency of tumors with breast cancer (BRCA) DNA repair pathway alterations and were significantly associated with papillary histologic features in tumors. BAP1 and KDM6A mutations significantly co-occurred in tumors. Somatic variants altering the TERT promoter were found in 69% of tumors but were not correlated with alterations in other bladder cancer genes. We examined the function of KDM6A, altered in 24% of tumors, and show depletion in human bladder cancer cells, enhanced in vitro proliferation, in vivo tumor growth, and cell migration. Conclusions: This study is the first to identify frequent BAP1 and BRCA pathway alterations in bladder cancer, show TERT promoter alterations are independent of other bladder cancer gene alterations, and show KDM6A loss is a driver of the bladder cancer phenotype. (C) 2014 AACR. C1 [Nickerson, Michael L.; Im, Kate M.; Turan, Sevilay; Ruiz-Rodriguez, Christina; Dean, Michael] NCI, Canc & Inflammat Program, NIH, Frederick, MD 21701 USA. [Dancik, Garrett M.; Owens, Charles; Theodorescu, Dan] Univ Colorado, Dept Surg, Aurora, CO 80045 USA. [Edwards, Michael G.] Univ Colorado, Dept Med, Div Pulm Sci & Crit Care, Denver, CO USA. [Brown, Joseph] Ingenuity, Redwood City, CA USA. [Costello, James C.; Theodorescu, Dan] Univ Colorado, Dept Pharmacol, Aurora, CO 80045 USA. [Guo, Guangwu; Tsang, Shirley X.; Li, Yingrui; Zhou, Quan] BGI Shenzhen, Shenzhen, Peoples R China. [Cai, Zhiming] Shenzhen Second Peoples Hosp, Shenzhen, Peoples R China. [Moore, Lee E.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Lucia, M. Scott] Univ Colorado, Dept Pathol, Aurora, CO 80045 USA. [Theodorescu, Dan] Univ Colorado, Ctr Comprehens Canc, Aurora, CO 80045 USA. RP Theodorescu, D (reprint author), Univ Colorado, Ctr Comprehens Canc, MS F-434,13001 East 17th Pl, Aurora, CO 80045 USA. EM dan.theodorescu@ucdenver.edu RI Dean, Michael/G-8172-2012; Li, Yingrui/K-1064-2015 OI Dean, Michael/0000-0003-2234-0631; FU NIH [CA075115, CA104106]; NIH, the National Cancer Institute, Center for Cancer Research FX This work is supported in part by NIH grants CA075115 and CA104106 (D. Theodorescu) and by the Intramural Research Program of the NIH, the National Cancer Institute, Center for Cancer Research (M. L. Nickerson, M. Dean). 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 16 Z9 17 U1 3 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2014 VL 20 IS 18 BP 4935 EP 4948 DI 10.1158/1078-0432.CCR-14-0330 PG 14 WC Oncology SC Oncology GA AP8VX UT WOS:000342358500022 PM 25225064 ER PT J AU Lee, S Pant, HC Shea, TB AF Lee, Sangmook Pant, Harish C. Shea, Thomas B. TI Divergent and convergent roles for kinases and phosphatases in neurofilament dynamics SO JOURNAL OF CELL SCIENCE LA English DT Article DE Neurofilament; Kinase; Phosphatase; Axonal stability; Cytoskeleton ID GLYCOGEN-SYNTHASE KINASE-3; CYCLIN-DEPENDENT KINASE-5; REGULATES AXONAL-TRANSPORT; INTERMEDIATE-FILAMENTS; BETA-CATENIN; TAIL DOMAIN; CELLULAR PHOSPHORYLATION; CDK5 ACTIVITY; UP-REGULATION; IN-VIVO AB C-terminal neurofilament phosphorylation mediates cation-dependent self-association leading to neurofilament incorporation into the stationary axonal cytoskeleton. Multiple kinases phosphorylate the C-terminal domains of the heavy neurofilament subunit (NF-H), including cyclin-dependent protein kinase 5 (CDK5), mitogen-activated protein kinases (MAPKs), casein kinase 1 and 2 (CK1 and CK2) and glycogen synthase kinase 3 beta (GSK3 beta). The respective contributions of these kinases have been confounded because they phosphorylate multiple substrates in addition to neurofilaments and display extensive interaction. Herein, differentiated NB2a/d1 cells were transfected with constructs expressing GFP-tagged NF-H, isolated NF-H sidearms and NF-H lacking the distal-most 187 amino acids. Cultures were treated with roscovitine, PD98059, Li+, D4476, tetrabromobenzotriazole and calyculin, which are active against CDK5, MKK1 (also known as MAP2K1), GSK3 beta, CK1, CK2 and protein phosphatase 1 (PP1), respectively. Sequential phosphorylation by CDK5 and GSK3 beta mediated the neurofilament-neurofilament associations. The MAPK pathway (i.e. MKK1 to ERK1/2) was found to downregulate GSK3 beta, and CK1 activated PP1, both of which promoted axonal transport and restricted neurofilament-neurofilament associations to axonal neurites. The MAPK pathway and CDK5, but not CK1 and GSK3 beta, inhibited neurofilament proteolysis. These findings indicate that phosphorylation of neurofilaments by the proline-directed MAPK pathway and CDK5 counterbalance the impact of phosphorylation of neurofilaments by the non-proline-directed CK1 and GSK3 beta. C1 [Lee, Sangmook; Shea, Thomas B.] Univ Massachusetts Lowell, Dept Biol Sci, Ctr Cellular Neurobiol & Neurodegenerat Res, Lowell, MA 01854 USA. [Pant, Harish C.] NINDS, Cytoskeletal Prot Regulat Sect, NIH, Bethesda, MD 20892 USA. RP Lee, S (reprint author), Univ Massachusetts Lowell, Dept Biol Sci, Ctr Cellular Neurobiol & Neurodegenerat Res, Lowell, MA 01854 USA. EM sangmook_lee@uml.edu; PantH@ninds.nih.gov; thomas_shea@uml.edu FU National Science Federation FX This work was supported by the National Science Federation. NR 87 TC 8 Z9 8 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD SEP 15 PY 2014 VL 127 IS 18 BP 4064 EP 4077 DI 10.1242/jcs.153346 PG 14 WC Cell Biology SC Cell Biology GA AP8VR UT WOS:000342357900017 PM 25015294 ER PT J AU Wahlang, B Song, M Beier, JI Falkner, KC Al-Eryani, L Clair, HB Prough, RA Osborne, TS Malarkey, DE States, JC Cave, MC AF Wahlang, Banrida Song, Ming Beier, Juliane I. Falkner, K. Cameron Al-Eryani, Laila Clair, Heather B. Prough, Russell A. Osborne, Tanasa S. Malarkey, David E. States, J. Christopher Cave, Matthew C. TI Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Aroclor 1260; PCBs; NAFLD; CAR; PXR; AhR ID PREGNANE-X-RECEPTOR; CONSTITUTIVE ANDROSTANE RECEPTOR; POLYCHLORINATED-BIPHENYLS; DRUG-METABOLISM; GENE-EXPRESSION; CROSS-TALK; INSULIN-RESISTANCE; ENERGY-METABOLISM; HEPATIC STEATOSIS; MICE AB Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD) in epidemiologic studies. The purpose of this study was to evaluate the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity (DIO). Male C57Bl/6J mice were fed control diet or 42% high fat diet (HFD) and exposed to Aroclor 1260 (20 mg/kg or 200 mg/kg in corn oil) for 12 weeks. A glucose tolerance test was performed; plasma/tissues were obtained at necropsy for measurements of adipocytokine levels, histology, and gene expression. Aroclor 1260 exposure was associated with decreased body fat in HFD-fed mice but had no effect on blood glucose/lipid levels. Paradoxically, Aroclor 1260 + HFD co-exposed mice demonstrated increased hepatic inflammatory foci at both doses while the degree of steatosis did not change. Serum cytokines, ALT levels and hepatic expression of IL-6 and TNF alpha were increased only at 20 mg/kg, suggesting an inhibition of pro-inflammatory cytokine production at the 200 mg/kg exposure. Aroclor 1260 induced hepatic expression of cytochrome P450s including Cyp3a11 (Pregnane-Xenobiotic Receptor target) and Cyp2b10 (constitutive androstane receptor target) but Cyp2b10 inducibility was diminished with HFD-feeding. Cyp1a2 (aryl hydrocarbon Receptor target) was induced only at 200 mg/kg. In summary, Aroclor 1260 worsened hepatic and systemic inflammation in DIO. The results indicated a bimodal response of PCB-diet interactions in the context of inflammation which could potentially be explained by xenobiotic receptor activation. Thus, PCB exposure may be a relevant "second hit" in the transformation of steatosis to steatohepatitis. (C) 2014 Published by Elsevier Inc. C1 [Wahlang, Banrida; Beier, Juliane I.; Al-Eryani, Laila; States, J. Christopher; Cave, Matthew C.] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40202 USA. [Song, Ming; Falkner, K. Cameron; Cave, Matthew C.] Univ Louisville, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Louisville, KY 40202 USA. [Clair, Heather B.; Prough, Russell A.] Univ Louisville, Sch Med, Dept Biochem & Mol Biol, Louisville, KY 40202 USA. [Osborne, Tanasa S.; Malarkey, David E.] NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Cave, Matthew C.] Robley Rex Vet Affairs Med Ctr, Louisville, KY 40206 USA. RP Cave, MC (reprint author), Univ Louisville, Dept Med, Dept Pharmacol & Toxicol, Div Gastroenterol Hepatol & Nutr, 505 South Hancock St, Louisville, KY 40202 USA. EM matt.cave@louisville.edu FU National Institute of Environmental Health Sciences (NIEHS) [1RO1ES021375, T35ES14559]; National Institutes of Health (NIH) [K23AA018399]; Division of the National Toxicology Program of the NIH, NIEHS FX This work was supported by the National Institute of Environmental Health Sciences (NIEHS) [Grant 1RO1ES021375 and T35ES14559] and the National Institutes of Health (NIH) [Grant K23AA018399]. This research was also supported [in part] by the Division of the National Toxicology Program of the NIH, NIEHS. NR 43 TC 10 Z9 10 U1 3 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 15 PY 2014 VL 279 IS 3 BP 380 EP 390 DI 10.1016/j.taap.2014.06.019 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AP7SW UT WOS:000342278000014 PM 24998970 ER PT J AU Sieckmann, DG Jaffe, H Golech, S Cai, DC Hallenbeck, JM McCarron, RM AF Sieckmann, Donna G. Jaffe, Howard Golech, Susanne Cai, DeCheng Hallenbeck, John M. McCarron, Richard M. TI Anti-lymphoproliferative activity of alpha-2-macroglobulin in the plasma of hibernating 13-lined ground squirrels and woodchucks SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE Hibernation; 13-Lined ground squirrel; Woodchuck; Lymphocyte proliferation; Alpha-2-macroglobulin; Serine proteinase inhibitors ID PREGNANCY ZONE PROTEIN; ACUTE-PHASE RESPONSE; IMMUNE-SYSTEM; IMMUNOSUPPRESSIVE PROPERTIES; MAMMALIAN HIBERNATION; GENE-EXPRESSION; GROWTH-FACTORS; IN-VITRO; ALPHA(2)-MACROGLOBULIN; BINDING AB Plasma from hibernating (HIB) woodchucks (Marmota mottax) or 13-lined ground squirrels (Ictidomys tridecemlineatus) suppressed H-3-thymidine uptake in mouse spleen cell cultures stimulated with Concanavalin A (ConA); plasma from non-hibernating animals were only slightly inhibitory. Maximum inhibition occurred when HIB plasma was added to the cultures prior to ConA. After HPLC size exclusion chromatography of the HIB ground squirrel plasma, a single fraction (fraction-14) demonstrated inhibitory activity. Assay of fraction-14 from 8 HIB squirrels showed inhibition ranging from 13 to 95%; inhibition was correlated to the time the squirrels were exposed to cold prior to hibernation. Western blot analysis showed the factor to be a large molecular weight protein (>300 kDa), and mass spectrometry identified sequences that were 100% homologous with alpha-2-macroglobulin from humans and other species. These findings indicate a hibernation-related protein that may be responsible for immune system down regulation. (C) 2014 Published by Elsevier B.V. C1 [Sieckmann, Donna G.; Golech, Susanne; McCarron, Richard M.] Naval Med Res Ctr, Silver Spring, MD 20910 USA. [Jaffe, Howard] NINDS, LNC NINDS Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. [Cai, DeCheng; Hallenbeck, John M.] NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. [McCarron, Richard M.] Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. RP Sieckmann, DG (reprint author), Naval Med Res Ctr, Neurotrauma Dept, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM donna.sieckmann@med.navy.mil; richard.mccarron@med.navy.mil FU Office of Naval Research [62233N.333.120.A0102] FX Helpful discussions with Drs. Ken Storey, Chien-Chung Chao, and Craig P. Dufresne, are gratefully acknowledged. The authors wish to thank Craig Morrisette and Meng Shi for expert assistance with statistical evaluations. The authors also thank Aletha Holser and Wendy Candela for assistance in editing the manuscript. The excellent technical assistance of Lindsey Jones and Noa Hammer are gratefully acknowledged. This work was supported by the Office of Naval Research, Work Unit No. 62233N.333.120.A0102. The opinions expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, the Department of Defense, or the U.S. Government. D.G.S. was an employee of the U.S. Government. This work was prepared as part of her 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 U.S. Government as part of that person's official duties. NR 44 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 EI 1873-2534 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD SEP 15 PY 2014 VL 161 IS 1-2 BP 1 EP 11 DI 10.1016/j.vetimm.2014.05.006 PG 11 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA AP7KY UT WOS:000342257400001 PM 25113962 ER PT J AU Turanov, AA Shchedrina, VA Everley, RA Lobanov, AV Yim, SH Marino, SM Gygi, SP Hatfield, DL Gladyshev, VN AF Turanov, Anton A. Shchedrina, Valentina A. Everley, Robert A. Lobanov, Alexei V. Yim, Sun Hee Marino, Stefano M. Gygi, Steven P. Hatfield, Dolph L. Gladyshev, Vadim N. TI Selenoprotein S is involved in maintenance and transport of multiprotein complexes SO BIOCHEMICAL JOURNAL LA English DT Article DE coiled-coil domain; multiprotein complex; protein-protein interaction; selenocysteine; selenoprotein S ID ENDOPLASMIC-RETICULUM MEMBRANE; MISFOLDED PROTEINS; MASS-SPECTROMETRY; SELENIUM; DISLOCATION; EXPRESSION; CELLS; GENE; ER; RETROTRANSLOCATION AB SelS (Selenoprotein S) is a selenocysteine-containing protein with roles in ER (endoplasmic reticulum) function and inflammation. It has been implicated in ERAD (ER-associated protein degradation), and clinical studies revealed an association of its promoter polymorphism with cytokine levels and human diseases. However, the pathways and interacting proteins that could shed light on pathogenesis of Se1S-associated diseases have not been studied systematically. We performed a large-scale affinity isolation of human SelS and its mutant forms and analysed the proteins that interact with them. All previously known SelS targets and nearly two hundred additional proteins were identified that were remarkably enriched for various multiprotein complexes. Subsequent chemical cross-linking experiments identified the specific interacting sites in SelS and its several targets. Most of these interactions involved coiled-coil domains. The data suggest that SelS participates in intracellular membrane transport and maintenance of protein complexes by anchoring them to the ER membrane. C1 [Turanov, Anton A.; Shchedrina, Valentina A.; Lobanov, Alexei V.; Yim, Sun Hee; Gladyshev, Vadim N.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Turanov, Anton A.; Shchedrina, Valentina A.; Lobanov, Alexei V.; Yim, Sun Hee; Gladyshev, Vadim N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Everley, Robert A.; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Marino, Stefano M.] Akdeniz Univ, Dept Agr Biotechnol, TR-07058 Antalya, Turkey. [Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Mouse Canc Genet Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. EM vgladyshev@rics.bwh.harvard.edu FU National Institute of Health (NIH) [GM061603] FX This work was supported by the National Institute of Health (NIH) [grant number GM061603 (to V.N.G.)]. NR 37 TC 12 Z9 12 U1 2 U2 15 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 SEP 15 PY 2014 VL 462 BP 555 EP 565 DI 10.1042/BJ20140076 PN 3 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP1BT UT WOS:000341802100016 PM 24897171 ER PT J AU Romagnoli, R Baraldi, PG Lopez-Cara, C Salvador, MK Preti, D Tabrizi, MA Balzarini, J Nussbaumer, P Bassetto, M Brancale, A Fu, XH Yang-Gao Li, J Zhang, SZ Hamel, E Bortolozzi, R Basso, G Viola, G AF Romagnoli, Romeo Baraldi, Pier Giovanni Lopez-Cara, Carlota Salvador, Maria Kimatrai Preti, Delia Tabrizi, Mojgan Aghazadeh Balzarini, Jan Nussbaumer, Peter Bassetto, Marcella Brancale, Andrea Fu, Xian-Hua Yang-Gao Li, Jun Zhang, Su-Zhan Hamel, Ernest Bortolozzi, Roberta Basso, Giuseppe Viola, Giampietro TI Design, synthesis and biological evaluation of 3,5-disubstituted 2-amino thiophene derivatives as a novel class of antitumor agents SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Tubulin; Thiophene; Anticancer agents; Colchicine site; Apoptosis ID CELL-DEATH; ANTIMITOTIC AGENTS; MESSENGER-RNA; LAVENDUSTIN-A; IN-VIVO; TUBULIN; APOPTOSIS; POLYMERIZATION; MICROTUBULES; SIMULATION AB In search of new compounds with strong antiproliferative activity and simple molecular structure, we designed a novel series of agents based on the 2-amino-3-alkoxycarbonyl/ cyano-5-arylethylthiophene scaffold. The presence of the ethyl spacer between the 2',5'-dimethoxyphenyl and the 5-position of the thiophene ring, as well as the number and location of methoxy substitutents on the phenyl ring, played a profound role in affecting the antiproliferative activity. Among the synthesized compounds, we identified the 2-amino-3-cyano-[2-(2,5-dimethoxyphenyl)ethyl] thiophene 2c as the most promising derivative against a wide panel of cancer cell lines (IC50 = 17-130 nM). The antiproliferative activity of this compound appears to correlate well with its ability to inhibit tubulin assembly and the binding of colchicine to tubulin. Moreover 2c, as determined by flow cytometry, strongly induced arrest in the G2/M phase of the cell cycle, and annexin-V and propidium iodide staining indicate that cell death proceeds through an apoptotic mechanism that follows the intrinsic mitochondrial pathway. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Lopez-Cara, Carlota; Salvador, Maria Kimatrai; Preti, Delia; Tabrizi, Mojgan Aghazadeh] Univ Ferrara, Dipartimento Sci Farmaceut, I-44121 Ferrara, Italy. [Balzarini, Jan] Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Leuven, Belgium. [Nussbaumer, Peter] Lead Discovery Ctr Gmbh, Dortmund, Germany. [Bassetto, Marcella; Brancale, Andrea] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales. [Fu, Xian-Hua; Yang-Gao; Li, Jun; Zhang, Su-Zhan] Zhejiang Univ, China Natl Minist Educ, Key Lab Canc Prevent & Intervent, Canc Inst,Affiliated Hosp 2,Sch Med, Hangzhou 310009, Zhejiang, Peoples R China. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Ft Detrick, MD 21702 USA. [Bortolozzi, Roberta; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Dipartimento Salute Donna & Bambino, Lab Oncoematol, I-35131 Padua, Italy. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, Via Fossato Mortara 17-19, I-44121 Ferrara, Italy. EM rmr@unife.it; pgb@unife.it; giampietro.viola1@unipd.it RI Brancale, Andrea/N-9445-2014; Viola, Giampietro/I-4095-2012; Bortolozzi, Roberta/D-4950-2015; Romagnoli, Romeo/G-9887-2015; preti, delia/G-9916-2015; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Baraldi, Pier Giovanni/B-7933-2017; OI Brancale, Andrea/0000-0002-9728-3419; Viola, Giampietro/0000-0001-9329-165X; Bortolozzi, Roberta/0000-0002-3357-4815; preti, delia/0000-0002-1075-3781; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; Bassetto, Marcella/0000-0002-2491-5868; BASSO, GIUSEPPE/0000-0002-2634-9302 FU Intramural NIH HHS [Z99 CA999999] NR 40 TC 8 Z9 8 U1 1 U2 23 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD SEP 15 PY 2014 VL 22 IS 18 BP 5097 EP 5109 DI 10.1016/j.bmc.2013.12.030 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA AP2DD UT WOS:000341881800007 PM 24398384 ER PT J AU Galletta, BJ Guillen, RX Fagerstrom, CJ Brownlee, CW Lerit, DA Megraw, TL Rogers, GC Rusan, NM AF Galletta, Brian J. Guillen, Rodrigo X. Fagerstrom, Carey J. Brownlee, Chris W. Lerit, Dorothy A. Megraw, Timothy L. Rogers, Gregory C. Rusan, Nasser M. TI Drosophila pericentrin requires interaction with calmodulin for its function at centrosomes and neuronal basal bodies but not at sperm basal bodies SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID TUBULIN RING COMPLEX; SPINDLE POLE BODY; GAMMA-TUBULIN; INTRAFLAGELLAR TRANSPORT; MICROTUBULE NUCLEATION; CENTRIOLE DUPLICATION; PRIMORDIAL DWARFISM; SHARES HOMOLOGY; SENSORY CILIA; STEM-CELLS AB Pericentrin is a critical centrosomal protein required for organizing pericentriolar material (PCM) in mitosis. Mutations in pericentrin cause the human genetic disorder Majewski/microcephalic osteodysplastic primordial dwarfism type II, making a detailed understanding of its regulation extremely important. Germaine to pericentrin's function in organizing PCM is its ability to localize to the centrosome through the conserved C-terminal PACT domain. Here we use Drosophila pericentrin-like-protein (PLP) to understand how the PACT domain is regulated. We show that the interaction of PLP with calmodulin (CaM) at two highly conserved CaM-binding sites in the PACT domain controls the proper targeting of PLP to the centrosome. Disrupting the PLP-CaM interaction with single point mutations renders PLP inefficient in localizing to centrioles in cultured S2 cells and Drosophila neuroblasts. Although levels of PCM are unaffected, it is highly disorganized. We also demonstrate that basal body formation in the male testes and the production of functional sperm does not rely on the PLP-CaM interaction, whereas production of functional mechanosensory neurons does. C1 [Galletta, Brian J.; Guillen, Rodrigo X.; Fagerstrom, Carey J.; Lerit, Dorothy A.; Rusan, Nasser M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Brownlee, Chris W.; Rogers, Gregory C.] Univ Arizona, Ctr Canc, Dept Cellular & Mol Med, Tucson, AZ 85724 USA. [Megraw, Timothy L.] Florida State Univ, Coll Med, Dept Biomed Sci, Tallahassee, FL 32304 USA. RP Rusan, NM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Nasser@nih.gov RI Rusan, Nasser/P-3511-2016 FU Division of Intramural Research at the National Heart, Lung, and Blood Institute/National Institutes of Health [1ZIAHL006126]; National Cancer Institute/National Institutes of Health [P30CA23074]; GI SPORE (National Cancer Institute/National Institutes of Health) [P50CA95060]; National Science Foundation [1158151]; Arizona Biomedical Research Commission [1210]; National Institute of General Medical Sciences/National Institutes of Health [R01GM068756] FX We thank Jeremy Smyth for his comments and suggestions. N.M.R. is supported by the Division of Intramural Research at the National Heart, Lung, and Blood Institute/National Institutes of Health (1ZIAHL006126). G.C.R. is supported by National Cancer Institute/National Institutes of Health (P30CA23074) and GI SPORE (National Cancer Institute/National Institutes of Health, P50CA95060), the National Science Foundation (1158151), and the Arizona Biomedical Research Commission (1210). T.L.M. is supported by the National Institute of General Medical Sciences/National Institutes of Health (R01GM068756). NR 58 TC 10 Z9 11 U1 1 U2 5 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 SEP 15 PY 2014 VL 25 IS 18 BP 2682 EP 2694 DI 10.1091/mbc.E13-10-0617 PG 13 WC Cell Biology SC Cell Biology GA AP4WA UT WOS:000342078800002 PM 25031429 ER PT J AU Henderson, MJ Wires, ES Trychta, KA Richie, CT Harvey, BK AF Henderson, Mark J. Wires, Emily S. Trychta, Kathleen A. Richie, Christopher T. Harvey, Brandon K. TI SERCaMP: a carboxy-terminal protein modification that enables monitoring of ER calcium homeostasis SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; SARCOPLASMIC-RETICULUM; IN-VITRO; RYANODINE RECEPTOR; SECRETORY PATHWAY; KDEL RECEPTORS; CA2+ ATPASE; INHIBITOR; CELECOXIB; VIVO AB Endoplasmic reticulum (ER) calcium homeostasis is disrupted in diverse pathologies, including neurodegeneration, cardiovascular diseases, and diabetes. Temporally defining calcium dysregulation during disease progression, however, has been challenging. Here we describe secreted ER calcium-monitoring proteins (SERCaMPs), which allow for longitudinal monitoring of ER calcium homeostasis. We identified a carboxy-terminal modification that is sufficient to confer release of a protein specifically in response to ER calcium depletion. A Gaussia luciferase (GLuc)-based SERCaMP provides a simple and sensitive method to monitor ER calcium homeostasis in vitro or in vivo by analyzing culture medium or blood. GLuc-SERCaMPs revealed ER calcium depletion in rat primary neurons exposed to various ER stressors. In vivo, ER calcium disruption in rat liver was monitored over several days by repeated sampling of blood. Our results suggest that SERCaMPs will have broad applications for the long-term monitoring of ER calcium homeostasis and the development of therapeutic approaches to counteract ER calcium dysregulation. C1 [Henderson, Mark J.; Wires, Emily S.; Trychta, Kathleen A.; Richie, Christopher T.; Harvey, Brandon K.] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. RP Harvey, BK (reprint author), NIDA, Intramural Res Program, Baltimore, MD 21224 USA. EM BHarvey@intra.nida.nih.gov FU Intramural Research Program, National Institute on Drug Abuse FX We thank Doug Howard, Lowella Fortuno, Josh Hinkle, Ray Rogers, Rodden Reyes, and Jennifer Bossert for technical assistance. We also thank Tsung-Ping Su, Bruce Hope, Marc Halterman, Mart Saarma, and Mikko Airavaara for critical reading of the manuscript and Deon Harvey for assistance with figure preparation. This work was supported by the Intramural Research Program, National Institute on Drug Abuse. NR 44 TC 6 Z9 6 U1 1 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP 15 PY 2014 VL 25 IS 18 BP 2828 EP 2839 DI 10.1091/mbc.E14-06-1141 PG 12 WC Cell Biology SC Cell Biology GA AP4WA UT WOS:000342078800014 PM 25031430 ER PT J AU Miedema, MD Maziarz, M Biggs, ML Zieman, SJ Kizer, JR Ix, JH Mozaffarian, D Tracy, RP Psaty, BM Siscovick, DS Mukamal, KJ Djousse, L AF Miedema, Michael D. Maziarz, Marlena Biggs, Mary L. Zieman, Susan J. Kizer, Jorge R. Ix, Joachim H. Mozaffarian, Dariush Tracy, Russell P. Psaty, Bruce M. Siscovick, David S. Mukamal, Kenneth J. Djousse, Luc TI Plasma-Free Fatty Acids, Fatty Acid-Binding Protein 4, and Mortality in Older Adults (from the Cardiovascular Health Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; RISK; PATHOGENESIS; INSULIN; OBESITY AB Plasma-free fatty acids (FFAs) are largely derived from adipose tissue. Elevated levels of FFA and fatty acid binding protein 4 (FABP4), a key cytoplasmic chaperone of fatty acids, have been associated with adverse cardiovascular outcomes, but limited data are available on the relation of these biomarkers with cardiovascular and total mortality. We studied 4,707 participants with a mean age of 75 years who had plasma FFA and FABP4 measured in 1992 to 1993 as part of the Cardiovascular Health Study, an observational cohort of community-dwelling older adults. Over a median follow-up of 11.8 years, 3,555 participants died. Cox proportional hazard regression was used to determine the association between FFA, FABP4, and mortality. In fully adjusted models, FFA were associated with dose-dependent significantly higher total mortality (hazard ratio [HR] per SD: 1.14, 95% confidence interval [CI] 1.09 to 1.18), but FABP4 levels were not (HR 1.04, 95% CI 0.98 to 1.09). In a cause-specific mortality analysis, higher concentrations of FFA were associated with significantly higher risk of death because of cardiovascular disease, dementia, infection, and respiratory causes but not cancer or trauma. We did not find evidence of an interaction between FFA and FABP4 (p = 0.45), but FABP4 appeared to be associated with total mortality differentially in men and women (HR 1.17, 95% CI 1.08 to 1.26 for men; HR 1.02, 95% CI 0.96 to 1.07 for women, interaction p value <0.001). In conclusion, in a cohort of community-dwelling older subjects, elevated plasma concentrations of FFA, but not FABP4, were associated with cardiovascular and noncardiovascular mortality. (C) 2014 Elsevier Inc. All rights reserved. C1 [Miedema, Michael D.; Djousse, Luc] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Aging, Boston, MA 02115 USA. [Miedema, Michael D.; Djousse, Luc] Boston Vet Affairs Healthcare Syst, Boston, MA USA. [Miedema, Michael D.] Minneapolis Heart Inst, Minneapolis, MN USA. [Miedema, Michael D.] Minneapolis Heart Inst Fdn, Minneapolis, MN USA. [Maziarz, Marlena; Biggs, Mary L.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Zieman, Susan J.] NIA, NIH, Bethesda, MD 20892 USA. [Kizer, Jorge R.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Prevent Med, San Diego, CA 92103 USA. [Mozaffarian, Dariush] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol, Colchester Res Facil, Colchester, VA USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Miedema, MD (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Aging, Boston, MA 02115 USA. EM mdm307@mail.harvard.edu RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute [HHSN 268201200036 C, HHSN268200800007 C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL0945565]; National Institute on Aging [AG023629] FX This research was supported by contracts HHSN 268201200036 C, HHSN268200800007 C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants HL080295 and HL0945565 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by AG023629 from the National Institute on Aging. Funding agencies did not have any role in the design and conduct of the study and collection, management, analysis, and interpretation of the data. The authors have no conflicts of interest to disclose. NR 30 TC 6 Z9 6 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 15 PY 2014 VL 114 IS 6 BP 843 EP 848 DI 10.1016/j.amjcard.2014.06.012 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP0JF UT WOS:000341746900006 PM 25073566 ER PT J AU Sanghi, A Zaringhalam, M Corcoran, CC Saeed, F Hoffert, JD Sandoval, P Pisitkun, T Knepper, MA AF Sanghi, Akshay Zaringhalam, Matthew Corcoran, Callan C. Saeed, Fahad Hoffert, Jason D. Sandoval, Pablo Pisitkun, Trairak Knepper, Mark A. TI A knowledge base of vasopressin actions in the kidney SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aquaporin-2; database; ENaC; urea channel ID MEDULLARY COLLECTING DUCT; AQUAPORIN-2 TRAFFICKING; RENAL-CELLS; RAT-KIDNEY; MYOSIN-II; KINASE; PHOSPHORYLATION; BIOLOGY; TRANSLOCATION; AQP2 AB Biological information is growing at a rapid pace, making it difficult for individual investigators to be familiar with all information that is relevant to their own research. Computers are beginning to be used to extract and curate biological information; however, the complexity of human language used in research papers continues to be a critical barrier to full automation of knowledge extraction. Here, we report a manually curated knowledge base of vasopressin actions in renal epithelial cells that is designed to be readable either by humans or by computer programs using natural language processing algorithms. The knowledge base consists of three related databases accessible at https://helixweb.nih.gov/ESBL/TinyUrls/Vaso_portal.html. One of the component databases reports vasopressin actions on individual proteins expressed in renal epithelia, including effects on phosphorylation, protein abundances, protein translocation from one subcellular compartment to another, protein-protein binding interactions, etc. The second database reports vasopressin actions on physiological measures in renal epithelia, and the third reports specific mRNA species whose abundances change in response to vasopressin. We illustrate the application of the knowledge base by using it to generate a protein kinase network that connects vasopressin binding in collecting duct cells to physiological effects to regulate the water channel protein aquaporin-2. C1 [Sanghi, Akshay; Zaringhalam, Matthew; Corcoran, Callan C.; Hoffert, Jason D.; Sandoval, Pablo; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. [Pisitkun, Trairak] Chulalongkorn Univ, Fac Med, Bangkok 10330, Thailand. [Saeed, Fahad] Western Michigan Univ, Dept Elect & Comp Engn, Kalamazoo, MI 49008 USA. [Saeed, Fahad] Western Michigan Univ, Dept Comp Sci, Kalamazoo, MI 49008 USA. RP Knepper, MA (reprint author), NIH, 10 Ctr Dr,Bldg 10,Rm 6N260, Bethesda, MD 20892 USA. EM knep@helix.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute [ZO1-HL001285, ZO1-HL 006129]; CU Research Cluster: Ratchadapisek Sompoch Endowment Fund (Chulalongkorn University); National Institutes of Health (NIH) FX This work was funded by the operating budget of the Division of Intramural Research, National Heart, Lung, and Blood Institute (projects ZO1-HL001285 and ZO1-HL 006129 to M. A. Knepper). T. Pisitkun is currently supported by CU Research Cluster: 2014 Ratchadapisek Sompoch Endowment Fund (Chulalongkorn University). A. Sanghi (Johns Hopkins University) and C. Corcoran (Duke University) were undergraduate students supported by the National Institutes of Health (NIH) Summer Internship Program. M. Zaringhalam was an undergraduate student supported by the Colgate University Off-Campus Study Program at the NIH. NR 40 TC 5 Z9 5 U1 1 U2 8 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 SEP 15 PY 2014 VL 307 IS 6 BP F747 EP F755 DI 10.1152/ajprenal.00012.2014 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA AO9UT UT WOS:000341704300014 PM 25056354 ER PT J AU Krasavin, M Sosnov, AV Karapetian, R Konstantinov, I Soldatkina, O Godovykh, E Zubkov, F Bai, RL Hamel, E Gakh, AA AF Krasavin, Mikhail Sosnov, Andrey V. Karapetian, Ruben Konstantinov, Igor Soldatkina, Olga Godovykh, Elena Zubkov, Fedor Bai, Ruoli Hamel, Ernest Gakh, Andrei A. TI Antiproliferative 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides, a new tubulin inhibitor chemotype SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Prostate cancer; DU-145; Screening; Chemotherapeutic agents; Rational single-molecule polypharmacy; Tubulin inhibitor ID POTENTIAL THERAPEUTIC AGENTS; PROSTATE-CANCER; ANTIMITOTIC AGENT; IDENTIFICATION; ANALOGS; 1,2,4-OXADIAZOLES; COLCHICINE; DISCOVERY; GROWTH; SERIES AB We discovered a new chemical class of antiproliferative agents, 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides. SAR-guided optimization of the two distinct terminal fragments yielded a compound with 120 nM potency in an antiproliferative assay. Biological activity profile studies (COMPARE analysis) demonstrated that 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides act as tubulin inhibitors, and this conclusion was confirmed via biochemical assays with pure tubulin and demonstration of increased numbers of mitotic cells following treatment of a leukemia cell line. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Krasavin, Mikhail] St Petersburg State Univ, Dept Chem, Peterhof 198504, Russia. [Sosnov, Andrey V.] Russian Acad Sci, Inst Physiol Act Cpds, ORCHIMED, Chernogolovka 142432, Moscow Region, Russia. [Karapetian, Ruben; Konstantinov, Igor; Soldatkina, Olga; Godovykh, Elena] Chem Div Res Inst, Chimki 114401, Moscow Region, Russia. [Zubkov, Fedor] Peoples Friendship Univ Russia, Moscow 117198, Russia. [Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Gakh, Andrei A.] Oak Ridge Natl Lab, Oak Ridge, TN 37831 USA. [Gakh, Andrei A.] Univ Virginia, Charlottesville, VA 22908 USA. [Gakh, Andrei A.] Discovery Chem Project, Bethesda, MD 20824 USA. RP Gakh, AA (reprint author), Oak Ridge Natl Lab, Oak Ridge, TN 37831 USA. RI Krasavin, Mikhail/F-2343-2011; OI Krasavin, Mikhail/0000-0002-0200-4772 FU U.S. Department of Energy [DE-AC05-00OR22725]; National Cancer Institute FX This Letter is a contribution from the Discovery Chemistry Project funded in part by the U.S. Department of Energy in collaboration with the National Cancer Institute. Oak Ridge National Laboratory is managed and operated by UT-Battelle, LLC, under contract DE-AC05-00OR22725 for the U.S. Department of Energy. NR 32 TC 2 Z9 2 U1 0 U2 10 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 SEP 15 PY 2014 VL 24 IS 18 BP 4477 EP 4481 DI 10.1016/j.bmcl.2014.07.089 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA AO6CC UT WOS:000341435000024 PM 25155551 ER PT J AU Alexander-Bloch, AF Reiss, PT Rapoport, J McAdams, H Giedd, JN Bullmore, ET Gogtay, N AF Alexander-Bloch, Aaron F. Reiss, Philip T. Rapoport, Judith McAdams, Harry Giedd, Jay N. Bullmore, Ed T. Gogtay, Nitin TI Abnormal Cortical Growth in Schizophrenia Targets Normative Modules of Synchronized Development SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Neuroimaging; penalized splines; psychosis; system; topology ID HUMAN CEREBRAL-CORTEX; SMOOTHING PARAMETER-ESTIMATION; CHILDHOOD-ONSET SCHIZOPHRENIA; BRAIN FUNCTIONAL NETWORKS; METAANALYSIS; REGRESSION; HANDEDNESS; THICKNESS; MODELS; MRI AB Background: Schizophrenia is a disorder of brain connectivity and altered neurodevelopmental processes. Cross-sectional case-control studies in different age groups have suggested that deficits in cortical thickness in childhood-onset schizophrenia may normalize over time, suggesting a disorder-related difference in cortical growth trajectories. Methods: We acquired magnetic resonance imaging scans repeated over several years for each subject, in a sample of 106 patients with childhood-onset schizophrenia and 102 age-matched healthy volunteers. Using semiparametric regression, we modeled the effect of schizophrenia on the growth curve of cortical thickness in similar to 80,000 locations across the cortex, in the age range 8 to 30 years. In addition, we derived normative developmental modules composed of cortical regions with similar maturational trajectories for cortical thickness in typical brain development. Results: We found abnormal nonlinear growth processes in prefrontal and temporal areas that have previously been implicated in schizophrenia, distinguishing for the first time between cortical areas with age-constant deficits in cortical thickness and areas whose maturational trajectories are altered in schizophrenia. In addition, we showed that when the brain is divided into five normative developmental modules, the areas with abnormal cortical growth overlap significantly only with the cingulo-fronto-temporal module. Conclusions: These findings suggest that abnormal cortical development in schizophrenia may be modularized or constrained by the normal community structure of developmental modules of the human brain connectome. C1 [Alexander-Bloch, Aaron F.; Rapoport, Judith; McAdams, Harry; Giedd, Jay N.; Gogtay, Nitin] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Alexander-Bloch, Aaron F.; Bullmore, Ed T.] Univ Cambridge, Behav & Clin Neurosci Inst, Brain Mapping Unit, Cambridge, England. [Alexander-Bloch, Aaron F.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Reiss, Philip T.] NYU, Sch Med, New York, NY USA. [Reiss, Philip T.] Nathan S Kline Inst Psychiat Res, New York, NY USA. [Bullmore, Ed T.] Cambridgeshire & Peterborough Natl Hlth Serv Fdn, Cambridge, England. [Bullmore, Ed T.] GlaxoSmithKline, Alternat Discovery & Dev, Stevenage, Herts, England. RP Alexander-Bloch, AF (reprint author), NIMH, Child Psychiat Branch, 10 Ctr Dr,Bldg 10,Room 3N202, Bethesda, MD 20892 USA. EM aalexanderbloch@gmail.com RI Gogtay, Nitin/A-3035-2008; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-2002-8978; Alexander-Bloch, Aaron/0000-0001-6554-1893; Reiss, Philip/0000-0002-8491-7080; Bullmore, Edward/0000-0002-8955-8283 FU National Institutes of Health (NIH) Intramural Research Program; NIH-Cambridge Graduate Partnership PhD program; Wellcome Trust; Medical Research Council United Kingdom FX This study was supported by the National Institutes of Health (NIH) Intramural Research Program. AFA-B was supported by the NIH-Cambridge Graduate Partnership PhD program. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at NIH (http://biowulf.nih.gov). The Behavioural and Clinical Neuroscience Institute is supported by the Wellcome Trust and the Medical Research Council United Kingdom. NR 78 TC 22 Z9 22 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2014 VL 76 IS 6 BP 438 EP 446 DI 10.1016/j.biopsych.2014.02.010 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AN8WT UT WOS:000340887100007 PM 24690112 ER PT J AU Hsu, WL Chien, YC Chiang, CJ Yang, HI Lou, PJ Wang, CP Yu, KJ You, SL Wang, LY Chen, SY Yang, CS Chen, CJ AF Hsu, Wan-Lun Chien, Yin-Chu Chiang, Chun-Ju Yang, Hwai-I Lou, Pei-Jen Wang, Cheng-Ping Yu, Kelly J. You, San-Lin Wang, Li-Yu Chen, Shu-Yuan Yang, Czau-Siung Chen, Chien-Jen TI Lifetime risk of distinct upper aerodigestive tract cancers and consumption of alcohol, betel and cigarette SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE betel quid chewing; cigarette smoking; alcohol drinking; cumulative lifetime incidence; UADT cancers ID NASOPHARYNGEAL CARCINOMA; ORAL-CANCER; NECK-CANCER; QUID USE; SMOKING; TOBACCO; TAIWAN; SITE; MEN; CARCINOGENESIS AB The cancer of upper aerodigestive tract (UADT) is a common cancers in the world. However, its lifetime risk by consumption of alcohol, betel and cigarettes remain to be elucidated. This study aimed to estimate lifetime risk of distinct UADT cancers and assess their associations with alcohol, betel and cigarette consumption. Three cohorts of 25,611 men were enrolled in 1982-1992 in Taiwan. The history of alcohol, betel and cigarette consumption was enquired through questionnaire interview. Newly developed UADT cancers were ascertained through computerized linkage with national cancer registry profile. Lifetime (30-80 years old) risk and multivariate-adjusted hazard ratio (HRadj) of distinct UADT cancers by alcohol, betel and cigarette consumption were estimated. A total of 269 pathologically confirmed cases of UADT cancers were newly-diagnosed during 472,096 person-years of follow-up. The lifetime risk of UADT cancer was 9.42 and 1.65% for betel chewers and nonchewers, 3.22 and 1.21% for cigarette smokers and nonsmokers and 4.77 and 1.85% for alcohol drinkers and nondrinkers. The HRadj (95% confidence interval) of developing UADT cancer was 3.36 (2.51-4.49), 2.02 (1.43-2.84), 1.90 (1.46-2.49), respectively, for the consumption of betel, cigarette and alcohol. Alcohol, betel and cigarette had different effect on cancers at various anatomical sites of UADT. The cancer risk from the mouth, pharynx, esophagus to larynx increased for alcohol and cigarette consumption, but decreased for betel consumption. Alcohol, betel and cigarette consumption are independent risk predictors for distinct UADT cancers. C1 [Hsu, Wan-Lun; Yang, Hwai-I; You, San-Lin; Chen, Chien-Jen] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan. [Chien, Yin-Chu; Yang, Hwai-I] China Med Univ Hosp, Mol & Genom Epidemiol Ctr, Taichung, Taiwan. [Chiang, Chun-Ju; Chen, Chien-Jen] Natl Taiwan Univ, Coll Publ Hlth, Grad Inst Epidemiol & Prevent Med, Taipei 10764, Taiwan. [Lou, Pei-Jen; Wang, Cheng-Ping] Natl Taiwan Univ Hosp, Dept Otolaryngol, Taipei, Taiwan. [Lou, Pei-Jen; Wang, Cheng-Ping] Natl Taiwan Univ, Coll Med, Dept Otolaryngol, Taipei 10764, Taiwan. [Yu, Kelly J.] NCI, Canc Prevent Div, NIH, DHHS, Bethesda, MD 20892 USA. [You, San-Lin] Yuanpei Univ, Dept Healthcare Management, Hsinchu, Taiwan. [Wang, Li-Yu] Mackay Med Coll, Dept Med, New Taipei City, Taiwan. [Chen, Shu-Yuan] Tzu Chi Univ, Dept Publ Hlth, Hualien, Taiwan. [Yang, Czau-Siung] Natl Taiwan Univ, Coll Med, Grad Inst Microbiol, Taipei 10764, Taiwan. RP Chen, CJ (reprint author), Acad Sinica, Genom Res Ctr, 128 Acad Rd,Sect 2, Taipei 115, Taiwan. EM chencj@gate.sinica.edu.tw RI Chen, Chien-Jen/C-6976-2008; OI WANG, CHENG-PING/0000-0001-7872-1463; LOU, PEI-JEN/0000-0002-3383-8593 FU Department of Health, Executive Yuan, Republic of China, Taiwan; Academia Sinica, Taiwan FX Grant sponsor: Department of Health, Executive Yuan, Republic of China, Taiwan; Academia Sinica, Taiwan NR 29 TC 5 Z9 6 U1 0 U2 15 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 SEP 15 PY 2014 VL 135 IS 6 BP 1480 EP 1486 DI 10.1002/ijc.28791 PG 7 WC Oncology SC Oncology GA AL6US UT WOS:000339269100021 PM 24535776 ER PT J AU Leiguarda, R Clarens, F Amengual, A Drucaroff, L Hallett, M AF Leiguarda, Ramon Clarens, Florencia Amengual, Alejandra Drucaroff, Lucas Hallett, Mark TI Short apraxia screening test SO JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY LA English DT Article DE Specificity; Sensitivity; Screening test; Apraxia evaluation ID STROKE PATIENTS; REHABILITATION AB Background: Limb apraxia comprises many different and common disorders, which are largely unrecognized essentially because there is no easy-to-use screening test sensitive enough to identify all types of limb praxis deficits. Method: We evaluated 70 right-handed patients with limb apraxia due to a single focal lesion of the left hemisphere and 40 normal controls, using a new apraxia screening test. The test covered 12 items including: intransitive gestures, transitive gestures elicited under verbal, visual, and tactile modalities, imitation of meaningful and meaningless postures and movements, and a multiple object test. Results: Interrater reliability was maximum for a cutoff of >2 positive items identifying apraxia on the short battery (Cohen's kappa .918, p < .0001), and somewhat less for >3 items (Cohen's kappa .768, p < .0001). Although both results were statistically significant, >2 was higher, indicating greater apraxia diagnosis agreement between raters at this cutoff value. Conclusions: The screening test proved to have high specificity and sensitivity to diagnose every type of upper limb praxis deficit, thus showing advantages over previously published tests. C1 [Leiguarda, Ramon; Clarens, Florencia; Amengual, Alejandra; Drucaroff, Lucas] FLENI, Neurol Res Inst, Dept Cognit Neurol & Neuropsychiat, Buenos Aires, DF, Argentina. [Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Leiguarda, R (reprint author), Montaneses 2325,C1428AQK, Buenos Aires, DF, Argentina. EM rleiguarda@fleni.org.ar FU Office of Rare Diseases; National Institute of Neurological Disorders and Stroke at the National Institutes of Health; Movement Disorder Society FX This article is the final and definitive version of our work. We authorize Taylor & Francis to host our manuscript, and we assign the copyright including abstract, text, bibliography, and all accompanying tables, illustrations, data, and video. Also authors do not have any potential conflict of interest in the publication of the manuscript. The Short Apraxia Screening Test (SAST) we have validated is a modification of a battery outlined during the International Workshop on Ideomotor Apraxia, held in Bethesda, Maryland, on September 2004, sponsored by the Office of Rare Diseases and the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, and by the Movement Disorder Society. The authors thank the following individuals for their participation and contribution in the elaboration of the battery: Richard Andersen, Stephan Bohlhalter, Laurel Buxbaum, Leonardo Cohen, Jose L. Contreras-Vidal, Hans Joachim Freund, Scott Grafton, Leslie J. G. Rothi, Michael Graziano, Kathleen Haaland, Brenda Hanna-Pladdy, Edward B. Healton, Kenneth Heilman, Anthony E. Lang, Jay P. Mohr, Hiroshi Shibasaki, Angela Sirigu, Alan Sunderland, Ivan Toni, Louis Wheaton, and Steven Wise. NR 30 TC 0 Z9 0 U1 0 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1380-3395 EI 1744-411X J9 J CLIN EXP NEUROPSYC JI J. Clin. Exp. Neuropsychol. PD SEP 14 PY 2014 VL 36 IS 8 BP 867 EP 874 DI 10.1080/13803395.2014.951315 PG 8 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA AS9EO UT WOS:000344546100008 PM 25360559 ER PT J AU Risso, D Tofanelli, S Morini, G Luiselli, D Drayna, D AF Risso, Davide Tofanelli, Sergio Morini, Gabriella Luiselli, Donata Drayna, Dennis TI Genetic variation in taste receptor pseudogenes provides evidence for a dynamic role in human evolution SO BMC EVOLUTIONARY BIOLOGY LA English DT Article DE Bitter taste; Evolution; Genetic polymorphisms; Pseudogenization; TAS2Rs ID SUBDIVIDED POPULATION; POSITIVE SELECTION; DNA POLYMORPHISM; HUMAN GENOME; BITTER; SENSITIVITY; VERTEBRATES; CHIMPANZEES; PRIMATES; DATABASE AB Background: Human bitter taste receptors are encoded by a gene family consisting of 25 functional TAS2R loci. In addition, humans carry 11 TAS2R pseudogenes, some of which display evidence for substantial diversification among species, showing lineage-specific loss of function. Since bitter taste is thought to help prevent the intake of toxic substances, diversity at TAS2R genes could reflect the action of natural selection on the ability to recognize some bitter compounds rather than others. Whether species-specific variation in TAS2R pseudogenes is solely the result of genetic drift or whether it may have been influenced by selection due to different feeding behaviors has been an open question. Results: In this study, we analyzed patterns of variation at human TAS2R pseudogenes in both African and non-African populations, and compared them to those observable in nonhuman primates and archaic human species. Our results showed a similar worldwide distribution of allelic variation for most of the pseudogenes, with the exception of the TAS2R6P and TAS2R18P loci, both of which presented an unexpected higher frequency of derived alleles outside Africa. At the TAS2R6P locus, two SNPs were found in strong linkage disequilibrium (r(2) > 0.9) with variants in the functional TAS2R5 gene, which showed signatures of selection. The human TAS2R18P carried a species-specific stop-codon upstream of four polymorphic insertions in the reading frame. SNPs at this locus showed significant positive values in a number of neutrality statistics, and age estimates indicated that they arose after the homo-chimp divergence. Conclusions: The similar distribution of variation of many human bitter receptor pseudogenes among human populations suggests that they arose from the ancestral forms by a unidirectional loss of function. However we explain the higher frequency of TAS2R6P derived alleles outside Africa as the effect of the balancing selection acting on the closely linked TAS2R5 gene. In contrast, TAS2R18P displayed a more complex history, suggesting an acquired function followed by a recent pseudogenization that predated the divergence of human modern and archaic species, which we hypothesize was associated with adaptions to dietary changes. C1 [Risso, Davide; Drayna, Dennis] NIDCD, NIH, Bethesda, MD 20892 USA. [Risso, Davide; Luiselli, Donata] Univ Bologna, Lab Mol Anthropol, Dept BiGeA, I-40126 Bologna, Italy. [Risso, Davide; Luiselli, Donata] Univ Bologna, Ctr Genome Biol, I-40126 Bologna, Italy. [Tofanelli, Sergio] Univ Pisa, Dept Biol, I-56126 Pisa, Italy. [Morini, Gabriella] Univ Gastron Sci, I-12042 Pollenzo, CN, Italy. RP Drayna, D (reprint author), NIDCD, NIH, Bethesda, MD 20892 USA. EM drayna@nidcd.nih.gov RI Risso, Davide/J-6841-2015 OI Risso, Davide/0000-0001-9848-8996 FU National Institute on Deafness and Other Communication Disorders Intramural grant [Z1A-000046-14] FX This research was supported by the National Institute on Deafness and Other Communication Disorders Intramural grant number Z1A-000046-14. We would like to thank Dr. Marco Sazzini for help in preparing the manuscript and Drs. Igor Rogozin and Rob Morell for their helpful suggestions. NR 45 TC 2 Z9 2 U1 1 U2 43 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD SEP 13 PY 2014 VL 14 AR 198 DI 10.1186/s12862-014-0198-8 PG 9 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA AQ2BP UT WOS:000342590600001 PM 25216916 ER PT J AU Wang, HD Liddell, CA Coates, MM Mooney, MD Levitz, CE Schumacher, AE Apfel, H Iannarone, M Phillips, B Lofgren, KT Sandar, L Dorrington, RE Rakovac, I Jacobs, TA Liang, XF Zhou, MG Zhu, J Yang, GH Wang, YP Liu, SW Li, YC Ozgoren, AA Abera, SF Abubakar, I Achoki, T Adelekan, A Ademi, Z Alemu, ZA Allen, PJ AlMazroa, MA Alvarez, E Amankwaa, AA Amare, AT Ammar, W Anwari, P Cunningham, SA Asad, MM Assadi, R Banerjee, A Basu, S Bedi, N Bekele, T Bell, ML Bhutta, ZQ Blore, JD Basara, BB Boufous, S Breitborde, N Bruce, NG Bui, LN Carapetis, JR Cardenas, R Carpenter, DO Caso, V Castro, RE Catala-Lopez, F Cavlin, A Che, X Chiang, PPC Chowdhury, R Christophi, CA Chuang, TW Cirillo, M Leite, ID Courville, KJ Dandona, L Dandona, R Davis, A Dayama, A Deribe, K Dharmaratne, SD Dherani, MK Dilmen, U Ding, EL Edmond, KM Ermakov, SP Farzadfar, F Fereshtehnejad, SM Fijabi, DO Foigt, N Forouzanfar, MH Garcia, AC Geleijnse, JM Gessner, BD Goginashvili, K Gona, P Goto, A Gouda, HN Green, MA Greenwell, KF Gugnani, HC Gupta, R Hamadeh, RR Hammami, M Harb, HL Hay, S Hedayati, MT Hosgood, HD Hoy, DG Idrisov, BT Islami, F Ismayilova, S Jha, V Jiang, GH Jonas, JB Juel, K Kabagambe, EK Kazi, DS Kengne, AP Kereselidze, M Khader, YS Khalifa, SEAH Khang, YH Kim, D Kinfu, Y Kinge, JM Kokubo, Y Kosen, S Defo, BK Kumar, GA Kumar, K Kumar, RB Lai, T Lan, Q Larsson, A Lee, JT Leinsalu, M Lim, SS Lipshultz, SE Logroscino, G Lotufo, PA Lunevicius, R Lyons, RA Ma, S Mahdi, AA Marzan, MB Mashal, MTQ Mazorodze, TT McGrath, JJ Memish, ZA Mendoza, W Mensah, GA Meretoja, A Miller, TR Mills, EJ Mohammad, KA Mokdad, AH Monasta, L Montico, M Moore, AR Moschandreas, J Msemburi, WT Mueller, UO Muszynska, MM Naghavi, M Naidoo, KS Narayan, KMV Nejjari, C Ng, M Ngirabega, JD Nieuwenhuijsen, MJ Nyakarahuka, L Ohkubo, T Omer, SB Caicedo, AJP Pillay-van Wyk, V Pope, D Pourmalek, F Prabhakaran, D Rahman, SUR Rana, SM Reilly, RQ Rojas-Rueda, D Ronfani, L Rushton, L Saeedi, MY Salomon, JA Sampson, U Santos, IS Sawhney, M Schmidt, JC Shakh-Nazarova, M She, J Sheikhbahaei, S Shibuya, K Shin, HH Shishani, K Shiue, I Sigfusdottir, ID Singh, JA Skirbekk, V Sliwa, K Soshnikov, SS Sposato, LA Stathopoulou, VK Stroumpoulis, K Tabb, KM Talongwa, RT Teixeira, CM Terkawi, AS Thomson, AJ Thorne-Lyman, AL Toyoshima, H Dimbuene, ZT Uwaliraye, P Uzun, SB Vasankari, TJ Vasconcelos, AMN Vlassov, VV Vollset, SE Waller, S Wan, X Weichenthal, S Weiderpass, E Weintraub, RG Westerman, R Wilkinson, JD Williams, HC Yang, YC Yentur, GK Yip, P Yonemoto, N Younis, M Yu, C Jin, KY Zaki, ME Zhu, SK Vos, T Lopez, AD Murray, CJL AF Wang, Haidong Liddell, Chelsea A. Coates, Matthew M. Mooney, Meghan D. Levitz, Carly E. Schumacher, Austin E. Apfel, Henry Iannarone, Marissa Phillips, Bryan Lofgren, Katherine T. Sandar, Logan Dorrington, Rob E. Rakovac, Ivo Jacobs, Troy A. Liang, Xiaofeng Zhou, Maigeng Zhu, Jun Yang, Gonghuan Wang, Yanping Liu, Shiwei Li, Yichong Ozgoren, Ayse Abbasoglu Abera, Semaw Ferede Abubakar, Ibrahim Achoki, Tom Adelekan, Ademola Ademi, Zanfina Alemu, Zewdie Aderaw Allen, Peter J. AlMazroa, Mohammad AbdulAziz Alvarez, Elena Amankwaa, Adansi A. Amare, Azmeraw T. Ammar, Walid Anwari, Palwasha Cunningham, Solveig Argeseanu Asad, Majed Masoud Assadi, Reza Banerjee, Amitava Basu, Sanjay Bedi, Neeraj Bekele, Tolesa Bell, Michelle L. Bhutta, Zulfi Qar Blore, Jed D. Basara, Berrak Bora Boufous, Soufiane Breitborde, Nicholas Bruce, Nigel G. Linh Ngoc Bui Carapetis, Jonathan R. Cardenas, Rosario Carpenter, David O. Caso, Valeria Estanislao Castro, Ruben Catala-Lopez, Ferran Cavlin, Alanur Che, Xuan Chiang, Peggy Pei-Chia Chowdhury, Rajiv Christophi, Costas A. Chuang, Ting-Wu Cirillo, Massimo Leite, Iuri da Costa Courville, Karen J. Dandona, Lalit Dandona, Rakhi Davis, Adrian Dayama, Anand Deribe, Kebede Dharmaratne, Samath D. Dherani, Mukesh K. Dilmen, Ugur Ding, Eric L. Edmond, Karen M. Ermakov, Sergei Petrovich Farzadfar, Farshad Fereshtehnejad, Seyed-Mohammad Fijabi, Daniel Obadare Foigt, Nataliya Forouzanfar, Mohammad H. Garcia, Ana C. Geleijnse, Johanna M. Gessner, Bradford D. Goginashvili, Ketevan Gona, Philimon Goto, Atsushi Gouda, Hebe N. Green, Mark A. Greenwell, Karen Fern Gugnani, Harish Chander Gupta, Rahul Hamadeh, Randah Ribhi Hammami, Mouhanad Harb, Hilda L. Hay, Simon Hedayati, Mohammad T. Hosgood, H. Dean Hoy, Damian G. Idrisov, Bulat T. Islami, Farhad Ismayilova, Samaya Jha, Vivekanand Jiang, Guohong Jonas, Jost B. Juel, Knud Kabagambe, Edmond Kato Kazi, Dhruv S. Kengne, Andre Pascal Kereselidze, Maia Khader, Yousef Saleh Khalifa, Shams Eldin Ali Hassan Khang, Young-Ho Kim, Daniel Kinfu, Yohannes Kinge, Jonas M. Kokubo, Yoshihiro Kosen, Soewarta Defo, Barthelemy Kuate Kumar, G. Anil Kumar, Kaushalendra Kumar, Ravi B. Lai, Taavi Lan, Qing Larsson, Anders Lee, Jong-Tae Leinsalu, Mall Lim, Stephen S. Lipshultz, Steven E. Logroscino, Giancarlo Lotufo, Paulo A. Lunevicius, Raimundas Lyons, Ronan Anthony Ma, Stefan Mahdi, Abbas Ali Marzan, Melvin Barrientos Mashal, Mohammad Taufi Q. Mazorodze, Tasara T. McGrath, John J. Memish, Ziad A. Mendoza, Walter Mensah, George A. Meretoja, Atte Miller, Ted R. Mills, Edward J. Mohammad, Karzan Abdulmuhsin Mokdad, Ali H. Monasta, Lorenzo Montico, Marcella Moore, Ami R. Moschandreas, Joanna Msemburi, William T. Mueller, Ulrich O. Muszynska, Magdalena M. Naghavi, Mohsen Naidoo, Kovin S. Narayan, K. M. Venkat Nejjari, Chakib Ng, Marie de Dieu Ngirabega, Jean Nieuwenhuijsen, Mark J. Nyakarahuka, Luke Ohkubo, Takayoshi Omer, Saad B. Paternina Caicedo, Angel J. Pillay-van Wyk, Victoria Pope, Dan Pourmalek, Farshad Prabhakaran, Dorairaj Rahman, Sajjad U. R. Rana, Saleem M. Reilly, Robert Quentin Rojas-Rueda, David Ronfani, Luca Rushton, Lesley Saeedi, Mohammad Yahya Salomon, Joshua A. Sampson, Uchechukwu Santos, Itamar S. Sawhney, Monika Schmidt, Juergen C. Shakh-Nazarova, Marina She, Jun Sheikhbahaei, Sara Shibuya, Kenji Shin, Hwashin Hyun Shishani, Kawkab Shiue, Ivy Sigfusdottir, Inga Dora Singh, Jasvinder A. Skirbekk, Vegard Sliwa, Karen Soshnikov, Sergey S. Sposato, Luciano A. Stathopoulou, Vasiliki Kalliopi Stroumpoulis, Konstantinos Tabb, Karen M. Talongwa, Roberto Tchio Teixeira, Carolina Maria Terkawi, Abdullah Sulieman Thomson, Alan J. Thorne-Lyman, Andrew L. Toyoshima, Hideaki Dimbuene, Zacharie Tsala Uwaliraye, Parfait Uzun, Selen Beguem Vasankari, Tommi J. Nogales Vasconcelos, Ana Maria Vlassov, Vasiliy Victorovich Vollset, Stein Emil Waller, Stephen Wan, Xia Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Westerman, Ronny Wilkinson, James D. Williams, Hywel C. Yang, Yang C. Yentur, Gokalp Kadri Yip, Paul Yonemoto, Naohiro Younis, Mustafa Yu, Chuanhua Jin, Kim Yun Zaki, Maysaa El Sayed Zhu, Shankuan Vos, Theo Lopez, Alan D. Murray, Christopher J. L. TI Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 SO LANCET LA English DT Article ID MILLENNIUM DEVELOPMENT GOALS; CHILD-MORTALITY; MATERNAL EDUCATION; DEVELOPING-COUNTRIES; INCOME COUNTRIES; HEALTH; DEMOCRACY; COVERAGE; SURVIVAL; TRENDS AB Background Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success. Methods We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29 000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030. Findings We estimated that 6.3 million (95% UI 6.0-6.6) children under-5 died in 2013, a 64% reduction from 17.6 million (17.1-18.1) in 1970. In 2013, child mortality rates ranged from 152.5 per 1000 livebirths (130.6-177.4) in Guinea-Bissau to 2.3 (1.8-2.9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from 6.8% to 0.1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41.6% of under-5 deaths compared with 37.4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1.4 million more child deaths, and rising income per person and maternal education led to 0.9 million and 2.2 million fewer deaths, respectively. Changes in secular trends led to 4.2 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone. Interpretation Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030. C1 [Wang, Haidong; Liddell, Chelsea A.; Coates, Matthew M.; Mooney, Meghan D.; Levitz, Carly E.; Schumacher, Austin E.; Apfel, Henry; Iannarone, Marissa; Phillips, Bryan; Lofgren, Katherine T.; Sandar, Logan; Achoki, Tom; Dandona, Lalit; Forouzanfar, Mohammad H.; Lim, Stephen S.; Mokdad, Ali H.; Naghavi, Mohsen; Vos, Theo; Murray, Christopher J. L.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. [Sliwa, Karen] Univ Cape Town, Fac Hlth Sci, Hatter Inst Cardiovasc Res Africa, ZA-7925 Cape Town, South Africa. [Dorrington, Rob E.] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Rakovac, Ivo] WHO, Reg Off Europe, DK-2100 Copenhagen, Denmark. [Jacobs, Troy A.] USAID, HIDN, MCH Div, Global Hlth Bur, Washington, DC USA. [Liang, Xiaofeng; Zhou, Maigeng; Liu, Shiwei] Chinese Ctr Dis Control & Prevent, Natl Ctr Chron & Noncommunicable Dis Control & Pr, Beijing, Peoples R China. [Zhu, Jun; Wang, Yanping] Natl Off Maternal & Childs Hlth Surveillance, Chengdu, Peoples R China. [Jiang, Guohong] Tianjin Ctr Dis Control & Prevent, Tianjin, Peoples R China. [Yang, Gonghuan] Peking Union Med Coll, Beijing 100021, Peoples R China. [Ozgoren, Ayse Abbasoglu; Cavlin, Alanur] Hacettepe Univ, Inst Populat Studies, Ankara, Turkey. [Abera, Semaw Ferede] Mekelle Univ, Tigray, Ethiopia. [Abubakar, Ibrahim] UCL, London, England. [Achoki, Tom] Minist Hlth, Gaborone, Botswana. [Adelekan, Ademola] Publ Hlth Promot Alliance, Osogpb, Nigeria. [Chiang, Peggy Pei-Chia] Univ Melbourne, Gen Practice & Primary Hlth Care Acad Ctr, Melbourne, Vic, Australia. [Ademi, Zanfina; Blore, Jed D.; Meretoja, Atte; Weintraub, Robert G.; Lopez, Alan D.] Univ Melbourne, Melbourne, Vic, Australia. [Alemu, Zewdie Aderaw] Markos Univ, Debre Markos, Ethiopia. [Allen, Peter J.] Minist Hlth, Belmopan, Cayo, Belize. [AlMazroa, Mohammad AbdulAziz; Memish, Ziad A.; Saeedi, Mohammad Yahya] Saudi Minist Hlth, Riyadh, Saudi Arabia. [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. [Ammar, Walid; Harb, Hilda L.] Minist Publ Hlth, Beirut, Lebanon. [Anwari, Palwasha] UNFPA, Kabul, Afghanistan. [Dayama, Anand] Emory Univ, Sch Med, Atlanta, GA USA. [Cunningham, Solveig Argeseanu; Narayan, K. M. Venkat; Omer, Saad B.] Emory Univ, Atlanta, GA USA. [Asad, Majed Masoud] Minist Hlth, Amman, Jordan. [Assadi, Reza] Mashhad Univ Med Sci, Mashhad, Khorasan, Iran. [Banerjee, Amitava] Univ Birmingham, Birmingham, W Midlands, England. [Basu, Sanjay] Stanford Univ, Stanford, CA 94305 USA. [Bedi, Neeraj] Coll Publ Hlth & Trop Med, Jazan, Saudi Arabia. [Bekele, Tolesa] Madawalabu Univ, Bale Goba, Oromia, Ethiopia. [Bell, Michelle L.] Yale Univ, New Haven, CT USA. [Bhutta, Zulfi Qar] Aga Khan Univ, Med Ctr, Karachi, Pakistan. [Basara, Berrak Bora; Dilmen, Ugur; Uzun, Selen Beguem; Yentur, Gokalp Kadri] Minist Hlth, Gen Directorate Hlth Res, Ankara, Turkey. [Boufous, Soufiane] Univ New S Wales, Sydney, NSW, Australia. [Breitborde, Nicholas] Univ Arizona, Tucson, AZ USA. [Bruce, Nigel G.; Dherani, Mukesh K.; Pope, Dan] Univ Liverpool, Liverpool L69 3BX, Merseyside, England. [Linh Ngoc Bui] Hanoi Sch Publ Hlth, Hanoi, Vietnam. [Carapetis, Jonathan R.] Telethon Inst Child Hlth Res, Subiaco, WA, Australia. [Cardenas, Rosario] Univ Autonoma Metropolitana, Mexico City, DF, Mexico. [Carpenter, David O.] Univ Albany, Rensselaer, NY USA. [Caso, Valeria] Univ Perugia, Stroke Unit, I-06100 Perugia, Italy. [Estanislao Castro, Ruben] Univ Diego Port, Santiago, Chile. [Catala-Lopez, Ferran] Minist Hlth, Spanish Med & Healthcare Prod Agcy AEMPS, Div Pharmacol & Pharmacovigilance, Madrid, Spain. [Mensah, George A.] NHLBI, CTRIS, Bethesda, MD 20892 USA. [Lan, Qing] NCI, Bethesda, MD 20892 USA. [Che, Xuan] NIH, Bethesda, MD 20892 USA. [Chowdhury, Rajiv] Univ Cambridge, Cambridge, England. [Christophi, Costas A.] Cyprus Univ Technol, Limassol, Cyprus. [Chuang, Ting-Wu] Taipei Med Univ, Taipei, Taiwan. [Cirillo, Massimo] Univ Salerno, I-84081 Baronissi, SA, Italy. [Leite, Iuri da Costa] Fiocruz MS, ENSP, Natl Sch Publ Hlth, BR-21045900 Rio De Janeiro, Brazil. [Courville, Karen J.] Hosp Dr Gustavo N Collado, Chitre, Herrera, Panama. [Dandona, Lalit; Dandona, Rakhi; Kumar, G. Anil; Kumar, Ravi B.] Publ Hlth Fdn India, New Delhi, India. [Davis, Adrian; Schmidt, Juergen C.] Publ Hlth England, London, England. [Deribe, Kebede] Univ Addis Ababa, Addis Ababa, Ethiopia. [Dharmaratne, Samath D.] Univ Peradeniya, Peradeniya, Sri Lanka. [Ding, Eric L.; Salomon, Joshua A.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Edmond, Karen M.] Univ Western Australia, Perth, WA 6009, Australia. [Ermakov, Sergei Petrovich] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Forouzanfar, Mohammad H.; Sheikhbahaei, Sara] Univ Tehran Med Sci, Noncommunicable Dis Res Ctr, Endocrine & Metab Res Inst, Tehran, Iran. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Fereshtehnejad, Seyed-Mohammad] Karolinska Inst, Stockholm, Sweden. [Idrisov, Bulat T.] Brandeis Univ, Heller Grad Sch, Waltham, MA USA. [Foigt, Nataliya] Ukraine Acad Med Sci, Inst Gerontol, UA-252655 Kiev, Ukraine. [Garcia, Ana C.] Primary Hlth Care Grp Almada Seixal Reg Lisbon, Publ Hlth Unit, Almada, Portugal. [Geleijnse, Johanna M.] Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands. [Gessner, Bradford D.] Agence Med Prevent, Paris, France. [Goginashvili, Ketevan] Minist Labour Hlth & Social Aff airs, Tbilisi, Rep of Georgia. [Gona, Philimon] Univ Massachusetts, Sch Med, Worcester, MA USA. [Goto, Atsushi] Natl Ctr Global Hlth & Med, Dept Diabet Res, Tokyo, Japan. [Hoy, Damian G.] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. [Gouda, Hebe N.; McGrath, John J.] Univ Queensland, Brisbane, Qld, Australia. [Green, Mark A.] Univ Sheffield, Sheffield, S Yorkshire, England. [Greenwell, Karen Fern] Stattis LLC, Kishinev, Moldova. [Gugnani, Harish Chander] St James Sch Med, Kralendijk, Kralendijk, Bonaire, Netherlands. [Gupta, Rahul] Kanawha Charleston Hlth Dept, Charleston, WV USA. [Hamadeh, Randah Ribhi] Arabian Gulf Univ, Manama, Bahrain. [Hammami, Mouhanad] Wayne Cty Dept Hlth & Human Serv, Detroit, MI USA. [Hay, Simon] Univ Oxford, Oxford, England. [Hedayati, Mohammad T.] Mazandaran Univ Med Sci, Sari, Mazandaran, Iran. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hoy, Damian G.] Secretariat Pacific Community, Publ Hlth Div, Noumea, New Caledonia. [Islami, Farhad] Amer Canc Soc, New York, NY USA. [Jha, Vivekanand] Postgrad Inst Med Educ & Res, Chandigarh, India. [Jonas, Jost B.] Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Juel, Knud] Natl Inst Publ Hlth, Copenhagen, Denmark. [Kabagambe, Edmond Kato] Vanderbilt Univ, Nashville, TN 37235 USA. [Kazi, Dhruv S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kengne, Andre Pascal; Msemburi, William T.; Pillay-van Wyk, Victoria] South African Med Res Council, Cape Town, Western Cape, South Africa. [Kereselidze, Maia; Shakh-Nazarova, Marina] Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, AlRamtha, Irbid, Jordan. [Khalifa, Shams Eldin Ali Hassan] Supreme Council Hlth, Doha, Qatar. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Inst Hlth Policy & Management, Seoul, South Korea. [Kim, Daniel] Northeastern Univ, Boston, MA 02115 USA. [Kinfu, Yohannes] Univ Canberra, Canberra, ACT 2601, Australia. [Kinge, Jonas M.; Skirbekk, Vegard; Vollset, Stein Emil] Norwegian Inst Publ Hlth, Oslo, Norway. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Med & Epidemiol Informat, Dept Prevent Cardiol, Suita, Osaka, Japan. [Kosen, Soewarta] NIHRD, Ctr Community Empowerment Hlth Policy & Humanitie, Jakarta, Indonesia. [Defo, Barthelemy Kuate] Univ Montreal, Montreal, PQ, Canada. [Kumar, Kaushalendra] Int Inst Populat Sci, Mumbai, Maharashtra, India. [Lai, Taavi] Fourth View Consulting, Tallinn, Estonia. [Larsson, Anders] Uppsala Univ, Uppsala, Sweden. [Lee, Jong-Tae] Korea Univ, Seoul, South Korea. [Leinsalu, Mall] Natl Inst Hlth Dev, Tallinn, Estonia. [Lipshultz, Steven E.] Wayne State Univ, Miami, FL USA. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. [Lotufo, Paulo A.; Santos, Itamar S.] Univ Sao Paulo, Sao Paulo, Brazil. [Lunevicius, Raimundas] Aintree Univ Hosp NHS Fdn Trust, NHS Fdn Trust, Liverpool L9 7AL, Merseyside, England. [Lyons, Ronan Anthony] Swansea Univ, Swansea, W Glam, Wales. [Ma, Stefan] Minist Hlth Singapore, Singapore, Singapore. [Mahdi, Abbas Ali] King Georges Med Univ, Lucknow, Uttar Pradesh, India. [Mashal, Mohammad Taufi Q.] Minist Publ Hlth, Kabul, Afghanistan. [Marzan, Melvin Barrientos] Univ East Ramon Magsaysay, Med Ctr, Quezon City, Metro Manila, Philippines. [Mazorodze, Tasara T.] AIDC EC, Port Elizabeth, Eastern Cape, South Africa. [Mendoza, Walter] UNFPA, Lima, Peru. [Miller, Ted R.] Pacific Inst Res & Evaluat, Calverton, MD USA. [Mills, Edward J.] Univ Ottawa, Ottawa, ON, Canada. [Mohammad, Karzan Abdulmuhsin] Univ Salahaddin, Erbil, Iraq. [Monasta, Lorenzo; Montico, Marcella; Ronfani, Luca] Inst Maternal & Child Hlth IRCCS Burlo Garofolo, Trieste, Italy. [Moore, Ami R.] Univ N Texas, Denton, TX 76203 USA. [Moschandreas, Joanna] Univ Crete, Iraklion, Greece. [Mueller, Ulrich O.] Univ Marburg, Marburg, Germany. [Muszynska, Magdalena M.] Warsaw Sch Econ, Warsaw, Poland. [Naidoo, Kovin S.] Univ KwaZulu Natal, Durban, KwaZulu Natal, South Africa. [Nejjari, Chakib] Univ Sidi Mohamed Ben Abdellah, Fac Med & Pharm, Dept Epidemiol & Publ Hlth, Fes, Morocco. [de Dieu Ngirabega, Jean] Rwanda Biomed Ctr, Kigali, Rwanda. [Nyakarahuka, Luke] Makerere Univ, Kampala, Uganda. [Ohkubo, Takayoshi] Teikyo Univ, Sch Med, Tokyo 173, Japan. [Paternina Caicedo, Angel J.] Univ Cartagena, Cartagena, Bolivar, Colombia. [Pourmalek, Farshad] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Prabhakaran, Dorairaj] Ctr Chron Dis Control, New Delhi, India. [Rahman, Sajjad U. R.] Hamad Med Corp, Doha, Qatar. [Rana, Saleem M.] Univ Punjab, Dept Publ Hlth, Lahore, Punjab, Pakistan. [Rushton, Lesley] Univ London Imperial Coll Sci Technol & Med, London, England. [Sawhney, Monika] Marshall Univ, Huntington, WV USA. [She, Jun] Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Shin, Hwashin Hyun; Weichenthal, Scott] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Shishani, Kawkab] Washington State Univ, Spokane, WA USA. [Shiue, Ivy] Heriot Watt Univ, Edinburgh, Midlothian, Scotland. [Sigfusdottir, Inga Dora] Reykjavik Univ, Reykjavik, Iceland. [Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Soshnikov, Sergey S.] Fed Res Inst Hlth Org, Moscow, Russia. [Soshnikov, Sergey S.] Informat Minist Hlth Russian Federat, Moscow, Russia. [Sposato, Luciano A.] Univ Western Ontario, Dept Clin Neurol Sci, London, ON, Canada. [Stathopoulou, Vasiliki Kalliopi] Ctr Hosp Nord Deux Sevres, Bressuire, France. [Stroumpoulis, Konstantinos] Alexandra Gen Hosp Athens, Ctr Dis Control, KEELPNO, Athens, Greece. [Tabb, Karen M.] Univ Illinois, Champaign, IL 61820 USA. [Talongwa, Roberto Tchio] Minist Hlth, Yaounde, Cameroon. [Teixeira, Carolina Maria] ARS Norte, Oporto, Portugal. [Terkawi, Abdullah Sulieman] Univ Virginia, Dept Anesthesiol, Charlottesville, VA USA. [Terkawi, Abdullah Sulieman] King Fahad Med City, Dept Anesthesiol, Riyadh, Saudi Arabia. [Thorne-Lyman, Andrew L.] Columbia Univ, New York, NY USA. [Thorne-Lyman, Andrew L.] Earth Inst, New York, NY USA. [Toyoshima, Hideaki] Hlth Care Ctr Anjo Kosei Hosp, Anjo, Aichi, Japan. [Dimbuene, Zacharie Tsala] Univ Kinshasa, Fac Econ & Management, Dept Populat Sci & Dev, Kinshasa, Zaire. [Uwaliraye, Parfait] Minist Hlth, Kigali City, Rwanda. [Vasankari, Tommi J.] UKK Inst Hlth Promot Res, Tampere, Finland. [Nogales Vasconcelos, Ana Maria] Univ Brasilia, Brasilia, DF, Brazil. [Vlassov, Vasiliy Victorovich] Natl Res Univ, Higher Sch Econ, Moscow, Russia. [Waller, Stephen] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Wan, Xia] Chinese Acad Med Sci, Inst Basic Med Sci, Beijing 100730, Peoples R China. [Weintraub, Robert G.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Wilkinson, James D.] Univ Miami, Miami, FL USA. [Williams, Hywel C.] Univ Nottingham, Nottingham NG7 2RD, England. [Yang, Gonghuan] Peking Union Med Coll, Beijing 100021, Peoples R China. [Yang, Yang C.] Univ N Carolina, Chapel Hill, NC USA. [Yip, Paul] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Yonemoto, Naohiro] Natl Ctr Neurol & Psychiat, Kodira, Tokyo, Japan. [Younis, Mustafa] Jackson State Univ, Jackson, MS USA. [Yu, Chuanhua] Wuhan Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Wuhan 430072, Hubei, Peoples R China. [Yu, Chuanhua] Wuhan Univ, Global Hlth Inst, Wuhan 430072, Hubei, Peoples R China. [Jin, Kim Yun] TCM MED TK SDN BHD, Nusajaya, Johor Bahru, Malaysia. [Zaki, Maysaa El Sayed] Mansoura Fac Med, Mansoura, Egypt. [Zhu, Shankuan] Zhejiang Univ, Sch Publ Hlth, Hangzhou 310003, Zhejiang, Peoples R China. RP Wang, HD (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. EM haidong@uw.edu RI Montico, Marcella/B-5290-2013; Salomon, Joshua/D-3898-2009; Nieuwenhuijsen, Mark/C-3914-2017; Lotufo, Paulo/A-9843-2008; Hedayati, Mohammad T./E-2304-2017; Ermakov, Sergey/G-1709-2016; Davis, Adrian/E-6022-2015; Meretoja, Atte/G-7381-2014; Rakovac, Ivo/A-7678-2013; Paternina-Caicedo, Angel/N-4496-2015; El Sayed Zaki, Maysaa/C-1522-2013; Monasta, Lorenzo/B-1388-2012; LOGROSCINO, GIANCARLO/K-5148-2016; wang, YA XING/K-9671-2016; Hay, Simon/F-8967-2015; Weiderpass, Elisabete/M-4029-2016; Ronfani, Luca/B-6668-2013; Cunningham, Solveig/K-6760-2012; McGrath, John/G-5493-2010; Banerjee, Amitava/D-4381-2014 OI Soshnikov, Sergey/0000-0002-6983-7066; assadi, reza/0000-0002-5016-2994; Vlassov, Vasiliy/0000-0001-5203-549X; Santos, Itamar/0000-0003-3212-8466; Pourmalek, Farshad/0000-0002-2134-0771; Miller, Ted/0000-0002-0958-2639; Prabhakaran, Dorairaj/0000-0002-3172-834X; Deribe, Kebede/0000-0002-8526-6996; Khang, Young-Ho/0000-0002-9585-8266; Gouda, Hebe/0000-0002-5709-4509; Abubakar, Ibrahim/0000-0002-0370-1430; Ding, Eric/0000-0002-5881-8097; Tabb Dina, Karen/0000-0002-4722-9502; Goto, Atsushi/0000-0003-0669-654X; Catala-Lopez, Ferran/0000-0002-3833-9312; Montico, Marcella/0000-0003-0377-8232; Salomon, Joshua/0000-0003-3929-5515; Nieuwenhuijsen, Mark/0000-0001-9461-7981; Lotufo, Paulo/0000-0002-4856-8450; Hedayati, Mohammad T./0000-0001-6415-4648; Ermakov, Sergey/0000-0003-1072-1162; Davis, Adrian/0000-0001-7134-7528; Meretoja, Atte/0000-0001-6433-1931; Che, Xuan/0000-0001-7981-6456; Rakovac, Ivo/0000-0003-3462-2636; Paternina-Caicedo, Angel/0000-0002-6332-5174; El Sayed Zaki, Maysaa/0000-0001-5431-0248; Monasta, Lorenzo/0000-0001-7774-548X; LOGROSCINO, GIANCARLO/0000-0003-0423-3242; wang, YA XING/0000-0003-2749-7793; Hay, Simon/0000-0002-0611-7272; Weiderpass, Elisabete/0000-0003-2237-0128; Ronfani, Luca/0000-0001-5710-3914; Cunningham, Solveig/0000-0002-2354-1526; McGrath, John/0000-0002-4792-6068; Banerjee, Amitava/0000-0001-8741-3411 FU Bill & Melinda Gates Foundation; US Agency for International Development FX We thank the countless individuals who have contributed to the Global Burden of Disease Study 2013 in various capacities. We would also like to acknowledge the extensive support from all staff members at the Institute for Health Metrics and Evaluation and specifically thank:; Michael F MacIntyre, Peter Speyer, and Summer Lockett Ohno for their management of the Global Burden of Disease Study 2013; Rafael Lozano for his expert input on results; Peter Speyer, James Bullard, Serkan Yalcin, Edgar Sioson, Andrew Ernst, and Bill Britt for their tireless support of the computational infrastructure required to produce the results;; Linda Ettinger for her expert administrative support; Peter Speyer, Abigail McLain, Eden Stork, Brent Bell, Noelle Nightingale, Jamie Hancock, Lyla E Medeiros, Rachel Woodbrook, Natalie Stephens, Elissa Thomas, Erica Leigh Nelson, Stephanie R Atkinson, and Matthew Israelson for their persistent and invaluable work to gain access to and catalogue as much data as possible to inform the estimates; Timothy M Wolock, Ryan M Barber, Emily A Dansereau, D Allen Roberts, Katrina Ortblad, Herbert C Duber, Megan S Coggeshall, Elizabeth K Johnson, and Jonathan C Brown for their extensive efforts to develop and improve the HIV modeling process;; Madeline L Moyer, Katya A Shackelford, Maggie Lind, and Lavanya Singh for their work extracting essential data; Erin C Mullany and Gillian Hansen for their systematic efforts organising correspondence with co-authors; and Katya A Shackelford, Madeline L Moyer, Megan S Coggeshall, Gillian Hansen, Farah Daoud, and Christopher Margono for their work fact-checking and proofing the final report. No individuals acknowledged received additional compensation for their efforts. This study was funded by the Bill & Melinda Gates Foundation and the US Agency for International Development. NR 86 TC 187 Z9 191 U1 18 U2 141 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 SEP 13 PY 2014 VL 384 IS 9947 BP 957 EP 979 DI 10.1016/S0140-6736(14)60497-9 PG 23 WC Medicine, General & Internal SC General & Internal Medicine GA AO9ML UT WOS:000341679700030 PM 24797572 ER PT J AU Kassebaum, NJ Bertozzi-Villa, A Coggeshall, MS Shackelford, KA Steiner, C Heuton, KR Gonzalez-Medina, D Barber, R Huynh, C Dicker, D Templin, T Wolock, TM Ozgoren, AA Abd-Allah, F Abera, SF Abubakar, I Achoki, T Adelekan, A Ademi, Z Adou, AK Adsuar, JC Agardh, EE Akena, D Alasfoor, D Alemu, ZA Alfonso-Cristancho, R Alhabib, S Ali, R Al Kahbouri, MJ Alla, F Allen, PJ AlMazroa, MA Alsharif, U Alvarez, E Alvis-Guzman, N Amankwaa, AA Amare, AT Amini, H Ammar, W Antonio, CAT Anwari, P Arnlov, J Arsenijevic, VSA Artaman, A Asad, MM Asghar, RJ Assadi, R Atkins, LS Badawi, A Balakrishnan, K Basu, A Basu, S Beardsley, J Bedi, N Bekele, T Bell, ML Bernabe, E Beyene, TJ Bhutta, Z Bin Abdulhak, A Blore, JD Basara, BB Bose, D Breitborde, N Cardenas, R Castaneda-Orjuela, CA Castro, RE Catala-Lopez, F Cavlin, A Chang, JC Che, X Christophi, CA Chugh, SS Cirillo, M Colquhoun, SM Cooper, LT Cooper, C Leite, ID Dandona, L Dandona, R Davis, A Dayama, A Degenhardt, L De Leo, D del Pozo-Cruz, B Deribe, K Dessalegn, M deVeber, GA Dharmaratne, SD Dilmen, U Ding, EL Dorrington, RE Driscoll, TR Ermakov, SP Esteghamati, A Faraon, EJA Farzadfar, F Felicio, MM Fereshtehnejad, SM de Lima, GMF Forouzanfar, MH Franca, EB Gaffikin, L Gambashidze, K Gankpe, FG Garcia, AC Geleijnse, JM Gibney, KB Giroud, M Glaser, EL Goginashvili, K Gona, P Gonzalez-Castell, D Goto, A Gouda, HN Gugnani, HC Gupta, R Gupta, R Hafezi-Nejad, N Hamadeh, RR Hammami, M Hankey, GJ Harb, HL Havmoeller, R Hay, SI Pi, IBH Hoek, HW Hosgood, HD Hoy, DG Husseini, A Idrisov, BT Innos, K Inoue, M Jacobsen, KH Jahangir, E Jee, SH Jensen, PN Jha, V Jiang, GH Jonas, JB Juel, K Kabagambe, EK Kan, HD Karam, NE Karch, A Karema, CK Kaul, A Kawakami, N Kazanjan, K Kazi, DS Kemp, AH Kengne, AP Kereselidze, M Khader, YS Khalifa, SEAH Khan, EA Khang, YH Knibbs, L Kokubo, Y Kosen, S Defo, BK Kulkarni, C Kulkarni, VS Kumar, GA Kumar, K Kumar, RB Kwan, G Lai, T Lalloo, R Lam, H Lansingh, VC Larsson, A Lee, JT Leigh, J Leinsalu, M Leung, R Li, XH Li, YC Li, YM Liang, J Liang, XF Lim, SS Lin, HH Lipshultz, SE Liu, SW Liu, Y Lloyd, BK London, SJ Lotufo, PA Ma, JX Ma, S Machado, VMP Mainoo, NK Majdan, M Mapoma, CC Marcenes, W Marzan, MB Mason-Jones, AJ Mehndiratta, MM Mejia-Rodriguez, F Memish, ZA Mendoza, W Miller, TR Mills, EJ Mokdad, AH Mola, GL Monasta, L Monis, JD Hernandez, JCM Moore, AR Moradi-Lakeh, M Mori, R Mueller, UO Mukaigawara, M Naheed, A Naidoo, KS Nand, D Nangia, V Nash, D Nejjari, C Nelson, RG Neupane, SP Newton, CR Ng, M Nieuwenhuijsen, MJ Nisar, MI Nolte, S Norheim, OF Nyakarahuka, L Oh, IH Ohkubo, T Olusanya, BO Omer, SB Opio, JN Orisakwe, OE Pandian, JD Papachristou, C Park, JH Caicedo, AJP Patten, SB Paul, VK Pavlin, BI Pearce, N Pereira, DM Pesudovs, K Petzold, M Poenaru, D Polanczyk, GV Polinder, S Pope, D Pourmalek, F Qato, D Quistberg, DA Rafay, A Rahimi, K Rahimi-Movaghar, V ur Rahman, S Raju, M Rana, SM Refaat, A Ronfani, L Roy, N Pimienta, TGS Sahraian, MA Salomon, JA Sampson, U Santos, IS Sawhney, M Sayinzoga, F Schneider, IJC Schumacher, A Schwebel, DC Seedat, S Sepanlou, SG Servan-Mori, EE Shakh-Nazarova, M Sheikhbahaei, S Shibuya, K Shin, HH Shiue, I Sigfusdottir, ID Silberberg, DH Silva, AP Singh, JA Skirbekk, V Sliwa, K Soshnikov, SS Sposato, LA Sreeramareddy, CT Stroumpoulis, K Sturua, L Sykes, BL Tabb, KM Talongwa, RT Tan, F Teixeira, CM Tenkorang, EY Terkawi, AS Thorne-Lyman, AL Tirschwell, DL Towbin, JA Tran, BX Tsilimbaris, M Uchendu, US Ukwaja, KN Undurraga, EA Uzun, SB Vallely, AJ van Gool, CH Vasankari, TJ Vavilala, MS Venketasubramanian, N Villalpando, S Violante, FS Vlassov, VV Vos, T Waller, S Wang, HD Wang, LH Wang, XR Wang, YP Weichenthal, S Weiderpass, E Weintraub, RG Westerman, R Wilkinson, JD Woldeyohannes, SM Wong, JQ Wordofa, MA Xu, GL Yang, YC Yano, Y Yentur, GK Yip, P Yonemoto, N Yoon, SJ Younis, MZ Yu, CH Jin, KY Zaki, ME Zhao, Y Zheng, YF Zhou, MG Zhu, J Zou, XN Lopez, AD Naghavi, M Murray, CJL Lozano, R AF Kassebaum, Nicholas J. Bertozzi-Villa, Amelia Coggeshall, Megan S. Shackelford, Katya A. Steiner, Caitlyn Heuton, Kyle R. Gonzalez-Medina, Diego Barber, Ryan Huynh, Chantal Dicker, Daniel Templin, Tara Wolock, Timothy M. Ozgoren, Ayse Abbasoglu Abd-Allah, Foad Abera, Semaw Ferede Abubakar, Ibrahim Achoki, Tom Adelekan, Ademola Ademi, Zanfina Adou, Arsene Kouablan Adsuar, Jose C. Agardh, Emilie E. Akena, Dickens Alasfoor, Deena Alemu, Zewdie Aderaw Alfonso-Cristancho, Rafael Alhabib, Samia Ali, Raghib Al Kahbouri, Mazin J. Alla, Francois Allen, Peter J. AlMazroa, Mohammad A. Alsharif, Ubai Alvarez, Elena Alvis-Guzman, Nelson Amankwaa, Adansi A. Amare, Azmeraw T. Amini, Hassan Ammar, Walid Antonio, Carl A. T. Anwari, Palwasha Arnlov, Johan Arsic Arsenijevic, Valentina S. Artaman, Ali Asad, Majed Masoud Asghar, Rana J. Assadi, Reza Atkins, Lydia S. Badawi, Alaa Balakrishnan, Kalpana Basu, Arindam Basu, Sanjay Beardsley, Justin Bedi, Neeraj Bekele, Tolesa Bell, Michelle L. Bernabe, Eduardo Beyene, Tariku J. Bhutta, Zulfiqar Bin Abdulhak, Aref Blore, Jed D. Basara, Berrak Bora Bose, Dipan Breitborde, Nicholas Cardenas, Rosario Castaneda-Orjuela, Carlos A. Castro, Ruben Estanislao Catala-Lopez, Ferran Cavlin, Alanur Chang, Jung-Chen Che, Xuan Christophi, Costas A. Chugh, Sumeet S. Cirillo, Massimo Colquhoun, Samantha M. Cooper, Leslie Trumbull Cooper, Cyrus Leite, Iuri da Costa Dandona, Lalit Dandona, Rakhi Davis, Adrian Dayama, Anand Degenhardt, Louisa De Leo, Diego del Pozo-Cruz, Borja Deribe, Kebede Dessalegn, Muluken deVeber, Gabrielle A. Dharmaratne, Samath D. Dilmen, Ugur Ding, Eric L. Dorrington, Rob E. Driscoll, Tim R. Ermakov, Sergei Petrovich Esteghamati, Alireza Faraon, Emerito Jose A. Farzadfar, Farshad Felicio, Manuela Mendonca Fereshtehnejad, Seyed-Mohammad Ferreira de Lima, Graca Maria Forouzanfar, Mohammad H. Franca, Elisabeth B. Gaffikin, Lynne Gambashidze, Ketevan Gankpe, Fortune Gbetoho Garcia, Ana C. Geleijnse, Johanna M. Gibney, Katherine B. Giroud, Maurice Glaser, Elizabeth L. Goginashvili, Ketevan Gona, Philimon Gonzalez-Castell, Dinorah Goto, Atsushi Gouda, Hebe N. Gugnani, Harish Chander Gupta, Rahul Gupta, Rajeev Hafezi-Nejad, Nima Hamadeh, Randah Ribhi Hammami, Mouhanad Hankey, Graeme J. Harb, Hilda L. Havmoeller, Rasmus Hay, Simon I. Heredia Pi, Ileana B. Hoek, Hans W. Hosgood, H. Dean Hoy, Damian G. Husseini, Abdullatif Idrisov, Bulat T. Innos, Kaire Inoue, Manami Jacobsen, Kathryn H. Jahangir, Eiman Jee, Sun Ha Jensen, Paul N. Jha, Vivekanand Jiang, Guohong Jonas, Jost B. Juel, Knud Kabagambe, Edmond Kato Kan, Haidong Karam, Nadim E. Karch, Andre Karema, Corine Kakizi Kaul, Anil Kawakami, Norito Kazanjan, Konstantin Kazi, Dhruv S. Kemp, Andrew H. Kengne, Andre Pascal Kereselidze, Maia Khader, Yousef Saleh Khalifa, Shams Eldin Ali Hassan Khan, Ejaz Ahmed Khang, Young-Ho Knibbs, Luke Kokubo, Yoshihiro Kosen, Soewarta Defo, Barthelemy Kuate Kulkarni, Chanda Kulkarni, Veena S. Kumar, G. Anil Kumar, Kaushalendra Kumar, Ravi B. Kwan, Gene Lai, Taavi Lalloo, Ratilal Lam, Hilton Lansingh, Van C. Larsson, Anders Lee, Jong-Tae Leigh, James Leinsalu, Mall Leung, Ricky Li, Xiaohong Li, Yichong Li, Yongmei Liang, Juan Liang, Xiaofeng Lim, Stephen S. Lin, Hsien-Ho Lipshultz, Steven E. Liu, Shiwei Liu, Yang Lloyd, Belinda K. London, Stephanie J. Lotufo, Paulo A. Ma, Jixiang Ma, Stefan Pedro Machado, Vasco Manuel Mainoo, Nana Kwaku Majdan, Marek Mapoma, Christopher Chabila Marcenes, Wagner Barrientos Marzan, Melvin Mason-Jones, Amanda J. Mehndiratta, Man Mohan Mejia-Rodriguez, Fabiola Memish, Ziad A. Mendoza, Walter Miller, Ted R. Mills, Edward J. Mokdad, Ali H. Mola, Glen Liddell Monasta, Lorenzo de la Cruz Monis, Jonathan Montanez Hernandez, Julio Cesar Moore, Ami R. Moradi-Lakeh, Maziar Mori, Rintaro Mueller, Ulrich O. Mukaigawara, Mitsuru Naheed, Aliya Naidoo, Kovin S. Nand, Devina Nangia, Vinay Nash, Denis Nejjari, Chakib Nelson, Robert G. Neupane, Sudan Prasad Newton, Charles R. Ng, Marie Nieuwenhuijsen, Mark J. Nisar, Muhammad Imran Nolte, Sandra Norheim, Ole F. Nyakarahuka, Luke Oh, In-Hwan Ohkubo, Takayoshi Olusanya, Bolajoko O. Omer, Saad B. Opio, John Nelson Orisakwe, Orish Ebere Pandian, Jeyaraj D. Papachristou, Christina Park, Jae-Hyun Paternina Caicedo, Angel J. Patten, Scott B. Paul, Vinod K. Pavlin, Boris Igor Pearce, Neil Pereira, David M. Pesudovs, Konrad Petzold, Max Poenaru, Dan Polanczyk, Guilherme V. Polinder, Suzanne Pope, Dan Pourmalek, Farshad Qato, Dima Quistberg, D. Alex Rafay, Anwar Rahimi, Kazem Rahimi-Movaghar, Vafa ur Rahman, Sajjad Raju, Murugesan Rana, Saleem M. Refaat, Amany Ronfani, Luca Roy, Nobhojit Sanchez Pimienta, Tania Georgina Sahraian, Mohammad Ali Salomon, Joshua A. Sampson, Uchechukwu Santos, Itamar S. Sawhney, Monika Sayinzoga, Felix Schneider, Ione J. C. Schumacher, Austin Schwebel, David C. Seedat, Soraya Sepanlou, Sadaf G. Servan-Mori, Edson E. Shakh-Nazarova, Marina Sheikhbahaei, Sara Shibuya, Kenji Shin, Hwashin Hyun Shiue, Ivy Sigfusdottir, Inga Dora Silberberg, Donald H. Silva, Andrea P. Singh, Jasvinder A. Skirbekk, Vegard Sliwa, Karen Soshnikov, Sergey S. Sposato, Luciano A. Sreeramareddy, Chandrashekhar T. Stroumpoulis, Konstantinos Sturua, Lela Sykes, Bryan L. Tabb, Karen M. Talongwa, Roberto Tchio Tan, Feng Teixeira, Carolina Maria Tenkorang, Eric Yeboah Terkawi, Abdullah Sulieman Thorne-Lyman, Andrew L. Tirschwell, David L. Towbin, Jeffrey A. Tran, Bach X. Tsilimbaris, Miltiadis Uchendu, Uche S. Ukwaja, Kingsley N. Undurraga, Eduardo A. Uzun, Selen Begum Vallely, Andrew J. van Gool, Coen H. Vasankari, Tommi J. Vavilala, Monica S. Venketasubramanian, N. Villalpando, Salvador Violante, Francesco S. Vlassov, Vasiliy Victorovich Vos, Theo Waller, Stephen Wang, Haidong Wang, Linhong Wang, XiaoRong Wang, Yanping Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Westerman, Ronny Wilkinson, James D. Woldeyohannes, Solomon Meseret Wong, John Q. Wordofa, Muluemebet Abera Xu, Gelin Yang, Yang C. Yano, Yuichiro Yentur, Gokalp Kadri Yip, Paul Yonemoto, Naohiro Yoon, Seok-Jun Younis, Mustafa Z. Yu, Chuanhua Jin, Kim Yun Zaki, Maysaa El Sayed Zhao, Yong Zheng, Yingfeng Zhou, Maigeng Zhu, Jun Zou, Xiao Nong Lopez, Alan D. Naghavi, Mohsen Murray, Christopher J. L. Lozano, Rafael TI Global, regional, and national levels and causes of maternal mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 SO LANCET LA English DT Article ID IMMUNODEFICIENCY VIRUS-1 INFECTION; PREGNANCY-RELATED MORTALITY; HIV-INFECTION; PERIPARTUM CARDIOMYOPATHY; HEALTH INITIATIVES; ADULT MORTALITY; CHILD SURVIVAL; SOUTH-AFRICA; WOMEN; DEATHS AB Background The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100 000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery. Methods We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values. Findings 292 982 (95% UI 261017-327792) maternal deaths occurred in 2013, compared with 376 034 (343483-407574) in 1990. The global annual rate of change in the MMR was -0.3% (-1.1 to 0.6) from 1990 to 2003, and -2.7% (-3.9 to -1.5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0.4% (-0.2-0.6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956.8 (685.1-1262.8) in South Sudan to 2.4 (1.6-3.6) in Iceland. Interpretation Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa. C1 [Kassebaum, Nicholas J.; Bertozzi-Villa, Amelia; Coggeshall, Megan S.; Shackelford, Katya A.; Steiner, Caitlyn; Heuton, Kyle R.; Gonzalez-Medina, Diego; Barber, Ryan; Huynh, Chantal; Dicker, Daniel; Templin, Tara; Wolock, Timothy M.; Dandona, Lalit; Forouzanfar, Mohammad H.; Lim, Stephen S.; Mokdad, Ali H.; Moradi-Lakeh, Maziar; Ng, Marie; Schumacher, Austin; Vos, Theo; Wang, Haidong; Naghavi, Mohsen; Murray, Christopher J. L.; Lozano, Rafael] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. [Tirschwell, David L.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Kassebaum, Nicholas J.] Univ Washington, Sch Med, Seattle Childrens Hosp, Dept Pediat Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Alfonso-Cristancho, Rafael; Jensen, Paul N.; Quistberg, D. Alex; Vavilala, Monica S.] Univ Washington, Seattle, WA 98195 USA. [Ozgoren, Ayse Abbasoglu; Cavlin, Alanur] Hacettepe Univ, Inst Populat Studies, Ankara, Turkey. [Abd-Allah, Foad] Cairo Univ, Fac Med, Cairo, Egypt. [Abera, Semaw Ferede] Mekelle Univ, Coll Hlth Sci, Sch Publ Hlth, Mekelle, Tigray, Ethiopia. [Abubakar, Ibrahim] UCL, London, England. [Achoki, Tom] Minist Hlth, Gaborone, Botswana. [Adelekan, Ademola] Publ Hlth Promot Alliance, Osogbp, Nigeria. [Colquhoun, Samantha M.] Univ Melbourne, Ctr Int Child Hlth, Melbourne, Vic, Australia. [Ademi, Zanfina; Blore, Jed D.; Weintraub, Robert G.; Lopez, Alan D.] Univ Melbourne, Melbourne, Vic, Australia. [Adou, Arsene Kouablan] Assoc Ivoirienne Bien Etre Familial, Abidjan, Cote Ivoire. [Adsuar, Jose C.] Univ Extremadura, Caceres, Spain. [Agardh, Emilie E.] Inst Publ Hlth Sci, Stockholm, Sweden. [Akena, Dickens; Nyakarahuka, Luke] Makerere Univ, Kampala, Uganda. [Alasfoor, Deena; Al Kahbouri, Mazin J.] Minist Hlth, Muscat, Oman. [Alemu, Zewdie Aderaw] Debre Markos Univ, Debre Markos, Amhara, Ethiopia. [Alhabib, Samia] Natl Guard Hlth Affairs, Riyadh, Saudi Arabia. [Ali, Raghib; Hay, Simon I.; Rahimi, Kazem] Univ Oxford, Oxford, England. [Alla, Francois] Univ Lorraine, Sch Publ Hlth, Nancy, France. [Allen, Peter J.] Minist Hlth, Belmopan, Cayo, Belize. [AlMazroa, Mohammad A.; Memish, Ziad A.] Saudi Minist Hlth, Riyadh, Saudi Arabia. [Alsharif, Ubai; Nolte, Sandra; Papachristou, Christina] Charite, D-13353 Berlin, Germany. [Alvarez, Elena] Govt Delegat Natl Plan Drugs, Spanish Observ Drugs, Madrid, Spain. [Catala-Lopez, Ferran] Spanish Med & Healthcare Prod Agcy, Div Pharmacoepidemiol & Pharmacovigilance, Madrid, Spain. [Alvarez, Elena] Minist Hlth Social Serv & Equal, Madrid, Spain. [Alvis-Guzman, Nelson] 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. [Amini, Hassan] Kurdistan Univ Med Sci, Kurdistan Environm Hlth Res Ctr, Sanandaj, Kurdistan, Iran. [Ammar, Walid; Harb, Hilda L.] Minist Publ Hlth, Beirut, Lebanon. [Antonio, Carl A. T.; Faraon, Emerito Jose A.] Univ Philippines, Coll Publ Hlth, Manila, Philippines. [Anwari, Palwasha] UN Populat Fund, Kabul, Afghanistan. [Arnlov, Johan; Larsson, Anders] Uppsala Univ, Uppsala, Sweden. [Arsic Arsenijevic, Valentina S.] Univ Belgrade, Sch Med, Inst Microbiol & Immunol, Belgrade, Serbia. [Artaman, Ali] Median, Windsor, ON, Canada. [Asad, Majed Masoud] Minist Hlth, Amman, Jordan. [Asghar, Rana J.] Field Epidemiol & Lab Training Program, Islamabad, Pakistan. [Assadi, Reza] Mashhad Univ Med Sci, Mashhad, Iran. [Atkins, Lydia S.] Minist Hlth Wellness Human Serv & Gender Relat, Sans Souci, Castries, St Lucia. [Badawi, Alaa] Publ Hlth Agcy Canada, Toronto, ON, Canada. [Balakrishnan, Kalpana] Sri Ramachandra Univ, Madras, Tamil Nadu, India. [Basu, Arindam] Univ Canterbury, Sch Hlth Sci, Christchurch 1, New Zealand. [Gaffikin, Lynne] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Basu, Sanjay] Stanford Univ, Stanford, CA 94305 USA. [Beardsley, Justin] Univ Oxford, Ho Chi Minh City, Vietnam. [Bedi, Neeraj] Coll Publ Hlth & Trop Med, Jazan, Saudi Arabia. [Bekele, Tolesa] Madawalabu Univ, Bale Goba, Oromia, Ethiopia. [Bell, Michelle L.] Yale Univ, New Haven, CT USA. [Bernabe, Eduardo] Kings Coll London, London WC2R 2LS, England. [Beyene, Tariku J.; Deribe, Kebede] Univ Addis Ababa, Debre Zeit, Ethiopia. [Bhutta, Zulfiqar] Aga Khan Univ, Med Ctr, Karachi, Pakistan. [Nisar, Muhammad Imran] Aga Khan Univ, Karachi, Pakistan. [Bin Abdulhak, Aref] Univ Missouri, Kansas City, MO 64110 USA. [Basara, Berrak Bora; Dilmen, Ugur; Yentur, Gokalp Kadri] Gen Directorate Hlth Res, Ankara, Turkey. [Uzun, Selen Begum] Minist Hlth, Ankara, Turkey. [Bose, Dipan] World Bank, Washington, DC 20433 USA. [Breitborde, Nicholas] Univ Arizona, Tucson, AZ USA. [Cardenas, Rosario] Univ Autonoma Metropolitana, Mexico City, DF, Mexico. [Castaneda-Orjuela, Carlos A.] Inst Nacl Salud, Colombian Natl Hlth Observ, Bogota, Colombia. [Castro, Ruben Estanislao] Univ Diego Portales, Santiago, Chile. [Lin, Hsien-Ho] Natl Taiwan Univ, Coll Publ Hlth, Taipei 10764, Taiwan. [Chang, Jung-Chen] Natl Taiwan Univ, Taipei 10764, Taiwan. [Che, Xuan] NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Christophi, Costas A.] Cyprus Univ Technol, Limassol, Cyprus. [Chugh, Sumeet S.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Cirillo, Massimo] Univ Salerno, I-84081 Baronissi, Italy. [Cooper, Leslie Trumbull] Mayo Clin, Rochester, MN USA. [Cooper, Cyrus] Univ Southampton, Med Res Council Lifecourse Epidemiol Unit, Southampton, Hants, England. [Leite, Iuri da Costa] Natl Sch Publ Hlth, ENSP Fiocruz, Rio De Janeiro, Brazil. [Dandona, Lalit; Dandona, Rakhi; Kumar, G. Anil; Kumar, Ravi B.] Publ Hlth Fdn India, New Delhi, India. [Davis, Adrian] Publ Hlth England, London, England. [Dayama, Anand] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Liu, Yang; Omer, Saad B.] Emory Univ, Atlanta, GA 30322 USA. [Vallely, Andrew J.] Univ New S Wales, Kirby Inst, Sydney, NSW, Australia. [Degenhardt, Louisa] Univ New S Wales, Sydney, NSW, Australia. [De Leo, Diego] Griffith Univ, Brisbane, Qld 4111, Australia. [del Pozo-Cruz, Borja] Univ Auckland, Auckland 1, New Zealand. [Dessalegn, Muluken] 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. [Ding, Eric L.] Harvard Univ, Harvard Sch Publ Hlth, Boston, MA 02115 USA. [Salomon, Joshua A.] Harvard Univ, Boston, MA 02115 USA. [Sliwa, Karen] Univ Cape Town, Fac Hlth Sci, Hatter Inst Cardiovasc Res Africa, ZA-7925 Cape Town, South Africa. [Dorrington, Rob E.] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Driscoll, Tim R.] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Leigh, James] Univ Sydney, Sydney, NSW 2006, Australia. [Ermakov, Sergei Petrovich] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Farzadfar, Farshad] Univ Tehran Med Sci, Noncommunicable Dis Res Ctr, Tehran, Iran. [Esteghamati, Alireza; Hafezi-Nejad, Nima; Sheikhbahaei, Sara] Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Tehran, Iran. [Sepanlou, Sadaf G.] Univ Tehran Med Sci, Digest Dis Res Inst, Tehran, Iran. [Sahraian, Mohammad Ali] Univ Tehran Med Sci, MS Res Ctr, Tehran, Iran. [Rahimi-Movaghar, Vafa] Univ Tehran Med Sci, Sina Trauma & Surg Res Ctr, Tehran, Iran. [Felicio, Manuela Mendonca; Teixeira, Carolina Maria] ARS Norte IP, Dept Saude Publ, Oporto, Portugal. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Fereshtehnejad, Seyed-Mohammad; Havmoeller, Rasmus] Karolinska Inst, Stockholm, Sweden. [Pedro Machado, Vasco Manuel] Northern Reg Hlth Adm, Oporto, Portugal. [Ferreira de Lima, Graca Maria] Dept Publ Hlth, Unidade Local Saude Matosinhos, Oporto, Portugal. [Franca, Elisabeth B.] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Gambashidze, Ketevan; Kazanjan, Konstantin; Kereselidze, Maia; Shakh-Nazarova, Marina; Sturua, Lela] Natl Ctr Dis Control & Publ Hlth Georgia, Tbilisi, Rep of Georgia. [Gankpe, Fortune Gbetoho] Clin Cooperat Parakou, Parakou, Borgou, Benin. [Garcia, Ana C.] Grp Almada Seixal, Unit Primary Hlth Care, Almada, Setubal, Portugal. [Geleijnse, Johanna M.] Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands. [Gibney, Katherine B.; Lloyd, Belinda K.] Monash Univ, Melbourne, Vic 3004, Australia. [Giroud, Maurice] Univ Hosp Dijon, Dijon, France. [Glaser, Elizabeth L.] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA USA. [Idrisov, Bulat T.; Undurraga, Eduardo A.] Brandeis Univ, Waltham, MA USA. [Goginashvili, Ketevan] Minist Labour Hlth & Social Affairs, Tbilisi, Rep of Georgia. [Gona, Philimon] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Gonzalez-Castell, Dinorah; Heredia Pi, Ileana B.; Mejia-Rodriguez, Fabiola; Montanez Hernandez, Julio Cesar; Sanchez Pimienta, Tania Georgina; Servan-Mori, Edson E.; Villalpando, Salvador; Lozano, Rafael] Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [Goto, Atsushi] Natl Ctr Global Hlth & Med, Dept Diabet Res, Tokyo, Japan. [Hoy, Damian G.] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. [Gouda, Hebe N.; Knibbs, Luke] Univ Queensland, Brisbane, Qld, Australia. [Gugnani, Harish Chander] St James Sch Med, Kralendijk, Bonaire, Netherlands. [Gupta, Rahul] Kanawha Charleston Hlth Dept, Charleston, WV USA. [Gupta, Rajeev] Fortis Escorts Hosp, Jaipur, Rajasthan, India. [Hamadeh, Randah Ribhi] Arabian Gulf Univ, Manama, Bahrain. [Hammami, Mouhanad] Wayne Cty Dept Hlth & Human Serv, Detroit, MI USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Hoek, Hans W.] Parnassia Psychiat Inst, The Hague, Netherlands. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hoy, Damian G.] Secretariat Pacific Community, Publ Hlth Div, Noumea, New Caledonia. [Husseini, Abdullatif] Birzeit Univ, Birzeit, Ramallah, Israel. [Innos, Kaire; Leinsalu, Mall] Natl Inst Hlth Dev, Tallinn, Estonia. [Kawakami, Norito] Univ Tokyo, Sch Publ Hlth, Tokyo, Japan. [Inoue, Manami] Univ Tokyo, Grad Sch Med, Tokyo, Japan. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Jacobsen, Kathryn H.] George Mason Univ, Fairfax, VA 22030 USA. [Jahangir, Eiman] Ochsner Med Ctr, New Orleans, LA USA. [Jee, Sun Ha] Yonsei Univ, Grad Sch Publ Hlth, Seoul 120749, South Korea. [Jha, Vivekanand] Postgrad Inst Med Educ & Res, Chandigarh, India. [Jiang, Guohong] Tianjin Ctr Dis Control & Prevent, Tianjin, Peoples R China. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Heidelberg, Germany. [Juel, Knud] Natl Inst Publ Hlth, Copenhagen, Denmark. [Kabagambe, Edmond Kato; Sampson, Uchechukwu] Vanderbilt Univ, Nashville, TN 37235 USA. [Kan, Haidong] Fudan Univ, Shanghai 200433, Peoples R China. [Karam, Nadim E.] Univ Balamand, Beirut, Lebanon. [Karch, Andre] Helmholtz Ctr Infect Res, Braunschweig, Germany. [Karema, Corine Kakizi] Minist Hlth, Malaria & Other Parasit Div, Kigali, Rwanda. [Sayinzoga, Felix] Minist Hlth, Kigali, Rwanda. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Kazi, Dhruv S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kemp, Andrew H.; Lotufo, Paulo A.; Polanczyk, Guilherme V.; Santos, Itamar S.] Univ Sao Paulo, Sao Paulo, Brazil. [Kengne, Andre Pascal] South African Med Res Council, Cape Town, South Africa. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Al Ramtha, Jordan. [Khalifa, Shams Eldin Ali Hassan] Supreme Council Hlth, Doha, Qatar. [Khan, Ejaz Ahmed] Hlth Serv Acad, Islamabad, Pakistan. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Inst Hlth Policy & Management, Seoul, South Korea. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Med & Epidemiol Informat, Dept Prevent Cardiol, Suita, Osaka, Japan. [Kosen, Soewarta] Natl Inst Hlth Res & Dev, Ctr Community Empowerment Hlth Policy & Humanitie, Jakarta, Indonesia. [Defo, Barthelemy Kuate] Univ Montreal, Montreal, PQ, Canada. [Kulkarni, Chanda] Rajrajeshwari Med Coll & Hosp, Bangalore, Karnataka, India. [Kulkarni, Veena S.] Arkansas State Univ, Jonesboro, AR USA. [Kumar, Kaushalendra] Int Inst Populat Sci, Mumbai, Maharashtra, India. [Kumar, Ravi B.] Publ Hlth Fdn India, Indian Inst Publ Hlth, Gurgaon, India. [Kwan, Gene] Boston Med Ctr, Boston, MA USA. [Lai, Taavi] Fourth View Consulting, Tallinn, Estonia. [Lalloo, Ratilal] Univ Adelaide, ARCPOH, Sch Dent, Adelaide, SA, Australia. [Lam, Hilton] Natl Inst Hlth, Inst Hlth Policy & Dev Studies, Manila, Philippines. [Lansingh, Van C.] Int Agcy Prevent Blindness & Vis 2020, Weston, FL USA. [Lee, Jong-Tae; Yoon, Seok-Jun] Korea Univ, Seoul, South Korea. [Leung, Ricky] SUNY Albany, Rensselaer, NY USA. [Li, Xiaohong] Natl Ctr Birth Defects Monitoring China, Chengdu, Peoples R China. [Li, Yichong; Liu, Shiwei; Ma, Jixiang; Wang, Linhong; Zhou, Maigeng] Natl Ctr Chron & Noncommunicable Dis Control & Pr, Beijing, Peoples R China. [Tan, Feng] Natl Inst Occupat Hlth & Poison Control, Beijing, Peoples R China. [Liang, Xiaofeng] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. [Li, Yongmei] Genentech Inc, San Francisco, CA USA. [Liang, Juan; Wang, Yanping; Zhu, Jun] Sichuan Univ, West China Univ Hosp 2, Natl Off Maternal & Child Hlth Surveillance, Chengdu 610064, Peoples R China. [Lipshultz, Steven E.] Wayne State Univ, Miami, FL USA. [London, Stephanie J.] NIEHS, Res Triangle Pk, NC 27709 USA. [Ma, Stefan] Minist Hlth Singapore, Singapore, Singapore. [Mainoo, Nana Kwaku] Xpharmconsult, Kumasi, Ghana. [Majdan, Marek] Trnava Univ, Fac Hlth Sci & Social Work, Dept Publ Hlth, Trnava, Slovakia. [Mapoma, Christopher Chabila] Univ Zambia, Lusaka, Zambia. [Marcenes, Wagner] Univ London, London, England. [Barrientos Marzan, Melvin] Univ East Ramon Magsaysay, Mem Med Ctr, Quezon City, Philippines. [Mason-Jones, Amanda J.] Univ York, York YO10 5DD, N Yorkshire, England. [Mehndiratta, Man Mohan] Janakpuri Super Specialty Hosp, New Delhi, India. [Mendoza, Walter] UN Populat Fund, Lima, Peru. [Miller, Ted R.] Pacific Inst Res & Evaluat, Calverton, MD USA. [Mills, Edward J.] Univ Ottawa, Ottawa, ON, Canada. [Mola, Glen Liddell] Univ Papua New Guinea, Port Moresby, Papua N Guinea. [Monasta, Lorenzo; Ronfani, Luca] Ist Ricovero & Cura Carattere Sci Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [de la Cruz Monis, Jonathan] Bur Int Hlth Cooperat, Manila City, Philippines. [Moore, Ami R.] Univ N Texas, Denton, TX 76203 USA. [Moradi-Lakeh, Maziar] Univ Med Sci, Dept Community Med, Tehran, Iran. [Mori, Rintaro] Natl Ctr Child Hlth & Dev, Tokyo, Japan. [Mueller, Ulrich O.; Westerman, Ronny] Univ Marburg, Marburg, Germany. [Mukaigawara, Mitsuru] Med & Dent Univ, Tokyo, Japan. [Naheed, Aliya] Int Ctr Diarrhoea Dis Res, Dhaka, Bangladesh. [Naidoo, Kovin S.] Univ KwaZulu Natal, Durban, South Africa. [Nand, Devina] Minist Hlth Fiji, Suva, Fiji. [Nangia, Vinay] Suraj Eye Inst, Nagpur, Maharashtra, India. [Nash, Denis] CUNY, Sch Publ Hlth, New York, NY 10021 USA. [Nejjari, Chakib] Fac Med, Fes, Morocco. [Nelson, Robert G.] NIDDK, Phoenix, AZ USA. [Neupane, Sudan Prasad] Univ Oslo, Norwegian Ctr Addict Res SERAF, Oslo, Norway. [Newton, Charles R.] Kenya Med Res Inst Wellcome Trust Programme, Kilifi, Kenya. [Nieuwenhuijsen, Mark J.] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Norheim, Ole F.] Univ Bergen, Bergen, Norway. [Oh, In-Hwan] Kyung Hee Unvers, Seoul, South Korea. [Ohkubo, Takayoshi] Teikyo Univ, Sch Med, Tokyo 173, Japan. [Olusanya, Bolajoko O.] Ctr Healthy Start Initiat, Lagos, Nigeria. [Opio, John Nelson] Lira Dist Local Govt, Lira Municipal Council, Lira, Uganda. [Orisakwe, Orish Ebere] Univ Port Harcourt, Fac Pharm, Toxicol Unit, Port Harcourt, Nigeria. [Pandian, Jeyaraj D.] Christian Med Coll Ludhiana, Ludhiana, Punjab, India. [Park, Jae-Hyun] Sungkyunkwan Univ, Sch Med, Suwon, South Korea. [Paternina Caicedo, Angel J.] Univ Cartagena, Cartagena, Colombia. [Patten, Scott B.] Univ Calgary, Calgary, AB, Canada. [Paul, Vinod K.] AIIMS, New Delhi, India. [Pavlin, Boris Igor] WHO, Waigani, Papua N Guinea. [Pearce, Neil] London Sch Hyg & Trop Med, London WC1, England. [Pereira, David M.] Univ Minho, Headquarters European Inst Excellence Tissue Engn, 3Bs Res Grp Biomat Biodegradables & Biomimet, Braga, Portugal. [Pereira, David M.] ICVS 3Bs PT Govt Associate Lab, Braga, Portugal. [Pesudovs, Konrad] Flinders Univ S Australia, Adelaide, SA, Australia. [Petzold, Max] Gothenburg Univ, Sahlgrenska Acad, Ctr Appl Biostat, S-41124 Gothenburg, Sweden. [Poenaru, Dan] McMaster Univ, Hamilton, ON, Canada. [Polinder, Suzanne] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Pope, Dan] Univ Liverpool, Liverpool L69 3BX, Merseyside, England. [Pourmalek, Farshad] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Qato, Dima] Univ Illinois, Coll Pharm, Chicago, IL USA. [Tabb, Karen M.] Univ Illinois, Chicago, IL USA. [Rafay, Anwar] Contech Int, Lahore, Pakistan. [ur Rahman, Sajjad] Hamad Med Corp, Doha, Qatar. [Raju, Murugesan] Univ Missouri, Columbia, MO USA. [Rana, Saleem M.] Univ Punjab, Dept Publ Hlth, Lahore, Pakistan. [Refaat, Amany] Walden Univ, Minneapolis, MN USA. [Roy, Nobhojit] Bhaba Atom Res Ctr Hosp, Mumbai, Maharashtra, India. [Sawhney, Monika] Marshall Univ, Huntington, WV USA. [Schneider, Ione J. C.] Univ Fed Santa Catarina, Florianopolis, SC, Brazil. [Schwebel, David C.; Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Seedat, Soraya] Univ Stellenbosch, Cape Town, South Africa. [Shin, Hwashin Hyun; Weichenthal, Scott] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Shiue, Ivy] Heriot Watt Univ, Edinburgh, Midlothian, Scotland. [Sigfusdottir, Inga Dora] Reykjavik Univ, Reykjavik, Iceland. [Silberberg, Donald H.] Univ Penn, Philadelphia, PA 19104 USA. [Silva, Andrea P.] Inst Nacl Epidemiol DrJuan H Jara, Mar Del Plata, Argentina. [Skirbekk, Vegard] Norwegian Inst Publ Hlth, Oslo, Norway. [Soshnikov, Sergey S.] Fed Res Inst Hlth Org, Moscow, Russia. [Soshnikov, Sergey S.] Informat Minist Hlth Russian Federat, Moscow, Russia. [Sposato, Luciano A.] Western Univ, Dept Clin Neurol Sci, London, ON, Canada. [Sreeramareddy, Chandrashekhar T.] Univ Tunku Abdul Rahman, Kajang, Malaysia. [Stroumpoulis, Konstantinos] Hellen Ctr Dis Control & Prevent KEELPNO Greece, Athens, Greece. [Sykes, Bryan L.] Univ Calif Irvine, Dept Criminol Law & Soc & Sociol, Irvine, CA USA. [Talongwa, Roberto Tchio] Minist Publ Hlth, Yaounde, Cameroon. [Tenkorang, Eric Yeboah] Mem Univ, St John, NF, Canada. [Terkawi, Abdullah Sulieman] Univ Virginia, Dept Anesthesiol, Charlottesville, VA USA. [Terkawi, Abdullah Sulieman] King Fahad Med City, Dept Anesthesiol, Riyadh, Saudi Arabia. [Thorne-Lyman, Andrew L.] Columbia Univ, Earth Inst, New York, NY USA. [Towbin, Jeffrey A.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Tran, Bach X.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Tsilimbaris, Miltiadis] Univ Crete, Dept Med, Iraklion, Greece. [Uchendu, Uche S.] Dept Vet Affairs, Washington, DC USA. [Ukwaja, Kingsley N.] Fed Teaching Hosp Abakaliki, Dept Internal Med, Abakaliki, Nigeria. [van Gool, Coen H.] Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. [Vasankari, Tommi J.] UKK Inst Hlth Promot Res, Tampere, Finland. [Venketasubramanian, N.] Raffles Hosp, Ctr Neurosci, Singapore, Singapore. [Violante, Francesco S.] Univ Bologna, Bologna, Italy. [Vlassov, Vasiliy Victorovich] Higher Sch Econ, Moscow, Russia. [Waller, Stephen] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Wang, XiaoRong] Shandong Univ, Affiliated Jinan Central Hosp, Jinan 250100, Peoples R China. [Weintraub, Robert G.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Wilkinson, James D.] Univ Miami, Miami, FL USA. [Woldeyohannes, Solomon Meseret] Univ Gondar, Inst Publ Hlth, Gondar, Ethiopia. [Wong, John Q.] Ateneo Sch Med & Publ Hlth, Manila, Philippines. [Wordofa, Muluemebet Abera] Jimma Univ, Jimma, Ethiopia. [Xu, Gelin] Nanjing Univ, Jinling Hosp, Sch Med, Nanjing 210008, Jiangsu, Peoples R China. [Yang, Yang C.] Univ N Carolina, Chapel Hill, NC USA. [Yano, Yuichiro] Jichi Med Univ, Sch Med, Div Cardiovasc Med, Shimotsuke, Japan. [Yip, Paul] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Yonemoto, Naohiro] Natl Ctr Neurol & Psychiat, Kodaira, Tokyo, Japan. [Younis, Mustafa Z.] Jackson State Univ, Jackson, MS USA. [Yu, Chuanhua] Wuhan Univ, Sch Publ Hlth, Global Hlth Inst, Dept Epidemiol & Biostat, Wuhan 430072, Peoples R China. [Jin, Kim Yun] TCM MedicalTk, Nusajaya, Johor Bahru, Malaysia. [Zaki, Maysaa El Sayed] Mansoura Fac Med, Mansoura, Egypt. [Zhao, Yong] Chongqing Med Univ, Chongqing, Peoples R China. [Zheng, Yingfeng] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510275, Guangdong, Peoples R China. [Zou, Xiao Nong] Chinese Acad Med Sci, Canc Inst & Hosp, Beijing 100730, Peoples R China. RP Kassebaum, NJ (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, 2301 Fifth Ave,Suite 600, Seattle, WA 98121 USA. EM nickjk@uw.edu RI Undurraga, Eduardo/I-3739-2014; Karch, Andre/D-6973-2017; Ermakov, Sergey/G-1709-2016; Balakrishnan, Kalpana/B-6653-2015; Davis, Adrian/E-6022-2015; El Sayed Zaki, Maysaa/C-1522-2013; Monasta, Lorenzo/B-1388-2012; Sepanlou, Sadaf/H-9343-2016; Jahangir, Eiman/P-1053-2015; Jacobsen, Kathryn/B-5857-2008; wang, YA XING/K-9671-2016; Hay, Simon/F-8967-2015; Weiderpass, Elisabete/M-4029-2016; Salomon, Joshua/D-3898-2009; Nieuwenhuijsen, Mark/C-3914-2017; Alsharif, Ubai/C-6527-2017; Amini, Heresh/B-3076-2010; Lotufo, Paulo/A-9843-2008; Hankey, Graeme /H-4968-2014; Ronfani, Luca/B-6668-2013; Degenhardt, Louisa/D-4515-2012; Nolte, Sandra/B-7498-2008; Lalloo, Ratilal/O-5624-2014; Adsuar, Jose C/C-6558-2008; Majdan, Marek/K-5017-2012; Castro, Ruben/J-1948-2015; Rahimi, Kazem/Q-1279-2015; Pereira, David/M-9286-2013; Kaul, Anil/B-2075-2016; Patten, Scott/B-4434-2011 OI Bernabe, Eduardo/0000-0002-1858-3713; Norheim, Ole F./0000-0002-5748-5956; London, Stephanie/0000-0003-4911-5290; Hoek, Hans/0000-0001-6353-5465; Moradi-Lakeh, Maziar/0000-0001-7381-5305; Castaneda-Orjuela, Carlos/0000-0002-8735-6223; Neupane, Sudan Prasad/0000-0002-7389-4178; Deribe, Kebede/0000-0002-8526-6996; Khang, Young-Ho/0000-0002-9585-8266; Kemp, Andrew/0000-0003-1146-3791; Gouda, Hebe/0000-0002-5709-4509; Glaser, Elizabeth/0000-0002-1918-057X; Catala-Lopez, Ferran/0000-0002-3833-9312; Villalpando, Salvador/0000-0001-6429-3816; Quistberg, Alex/0000-0001-9730-2686; Pourmalek, Farshad/0000-0002-2134-0771; Miller, Ted/0000-0002-0958-2639; Leung, Ricky/0000-0002-2852-6771; Liu, Zhi-Hong/0000-0001-6093-0726; Pesudovs, Konrad/0000-0002-6322-9369; Husseini, Abdullatif/0000-0001-8767-5956; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Xu, Gelin/0000-0002-6194-0341; Goto, Atsushi/0000-0003-0669-654X; Soshnikov, Sergey/0000-0002-6983-7066; Newton, Charles/0000-0002-6999-5507; assadi, reza/0000-0002-5016-2994; Vlassov, Vasiliy/0000-0001-5203-549X; Santos, Itamar/0000-0003-3212-8466; Che, Xuan/0000-0001-7981-6456; Abubakar, Ibrahim/0000-0002-0370-1430; Ukwaja, Kingsley N./0000-0002-1974-8735; Undurraga, Eduardo/0000-0002-4425-1253; Paternina-Caicedo, Angel/0000-0002-6332-5174; Beyene, Tariku Jibat/0000-0002-7474-1966; LIN, HSIEN-HO/0000-0002-7481-6016; Olusanya, Bolajoko/0000-0002-3826-0583; Tabb Dina, Karen/0000-0002-4722-9502; Heredia-Pi, Ileana Beatriz/0000-0002-9998-9239; Vallely, Andrew/0000-0003-1558-4822; Karch, Andre/0000-0003-3014-8543; Ermakov, Sergey/0000-0003-1072-1162; Ding, Eric/0000-0002-5881-8097; Khan, Ejaz/0000-0002-7072-8035; Balakrishnan, Kalpana/0000-0002-5905-1801; Gibney, Katherine/0000-0001-5851-5339; Davis, Adrian/0000-0001-7134-7528; El Sayed Zaki, Maysaa/0000-0001-5431-0248; Monasta, Lorenzo/0000-0001-7774-548X; Sepanlou, Sadaf/0000-0002-3669-5129; Jahangir, Eiman/0000-0001-6944-5321; Jacobsen, Kathryn/0000-0002-4198-6246; wang, YA XING/0000-0003-2749-7793; Hay, Simon/0000-0002-0611-7272; Weiderpass, Elisabete/0000-0003-2237-0128; Salomon, Joshua/0000-0003-3929-5515; Nieuwenhuijsen, Mark/0000-0001-9461-7981; Alsharif, Ubai/0000-0002-4024-3950; Amini, Heresh/0000-0002-4825-1322; Lotufo, Paulo/0000-0002-4856-8450; Hankey, Graeme /0000-0002-6044-7328; Ronfani, Luca/0000-0001-5710-3914; Degenhardt, Louisa/0000-0002-8513-2218; Nolte, Sandra/0000-0001-6185-9423; Lalloo, Ratilal/0000-0001-5822-1269; Adsuar, Jose C/0000-0001-7203-3168; Majdan, Marek/0000-0001-8037-742X; Rahimi, Kazem/0000-0002-4807-4610; Pereira, David/0000-0003-0384-7592; Patten, Scott/0000-0001-9871-4041 FU Amgen; GlaxoSmithKline; Alliance for Better Bone Health; Merck Sharp and Dohme; Eli Lilly; Pfizer; Novartis; Servier; Medtronic; Roche; CSL; Meiji; Otsuka; LAP Consulting; Fujitsu Software Technologies; Japan Productivity Center; Occupational Health Foundation; Japan Housing Finance Agency; Aishin-Seiki; Japan Dental Association; Sekisui Chemicals; Junpukai Health Care Center; Osaka Chamber of Commerce and Industry; Igaku-Shoin; Taisha-kan; Nanko-do; Nanzan-do; PHP Publication; Japanese Ministry of Education, Science, and Technology; Japanese Ministry of Health, Labor and Welfare; Softbank; Japan Management Association; National Council for Scientific and Technological Development; Sdo Paulo Research Foundation; University of Sdo Paulo; Shire; Editora Manole; Takeda; Savient; Regeneron; Allergan FX Cyrus Cooper has received consultancy fees, lecture fees, and honoraria from Amgen, GlaxoSmithKline, Alliance for Better Bone Health, Merck Sharp and Dohme, Eli Lilly, Pfizer, Novartis, Servier, Medtronic, and Roche. Katherine B Gibney received the National Health and Medical Research Council Gustav Nossal scholarship sponsored by CSL in 2012; this award is peer-reviewed through the standard National Health and Medical Research Countil peer-review process, and CSL does not play any part in selection of the awardee. Norito Kawakami has received fees from Meiji, Otsuka, LAP Consulting, Fujitsu Software Technologies, Japan Productivity Center, Occupational Health Foundation, Japan Housing Finance Agency, Aishin-Seiki, and the Japan Dental Association; consultancy fees from Sekisui Chemicals, Junpukai Health Care Center, and Osaka Chamber of Commerce and Industry; and royalties from Igaku-Shoin, Taisha-kan, Nanko-do, Nanzan-do, PHP Publication, and Fujitsu Software Technologies. Norito Kawakami has also received research grants from the Japanese Ministry of Education, Science, and Technology; the Japanese Ministry of Health, Labor and Welfare; Fujitsu Software Technologies; Softbank; and Japan Management Association. Guilherme V Polanczyk has received grants or research support from the National Council for Scientific and Technological Development, the Sdo Paulo Research Foundation, and the University of Sdo Paulo; has served as a paid consultant to Shire; has served on the speakers' bureau of Shire; and has received royalties from Editora Manole. Jasvinder A Singh has received research grants from Takeda and Savient; has received consultant fees from Savient, Takeda, Regeneron, and Allergan; is a member of the executive of OMERACT, an organisation that develops outcome measures in rheumatology and receives arms-length funding from 36 companies; is a member of the American College of Rheumatology's Guidelines Subcommittee of the Quality of Care Committee; and is a member of the Veterans Affairs Rheumatology Field Advisory Committee. The other authors declare no competing interests. NR 74 TC 274 Z9 281 U1 35 U2 226 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 SEP 13 PY 2014 VL 384 IS 9947 BP 980 EP 1004 DI 10.1016/S0140-6736(14)60696-6 PG 25 WC Medicine, General & Internal SC General & Internal Medicine GA AO9ML UT WOS:000341679700031 PM 24797575 ER PT J AU Murray, CJL Ortblad, KF Guinovart, C Lim, SS Wolock, TM Roberts, DA Dansereau, EA Graetz, N Barber, RM Brown, JC Wang, HD Duber, HC Naghavi, M Dicker, D Dandona, L Salomon, JA Heuton, KR Foreman, K Phillips, DE Fleming, TD Flaxman, AD Phillips, BK Johnson, EK Coggeshall, MS Abd-Allah, F Abera, SF Abraham, JP Abubakar, I Abu-Raddad, LJ Abu-Rmeileh, NM Achoki, T Adeyemo, AO Adou, AK Adsuar, JC Agardh, EE Akena, D Al Kahbouri, MJ Alasfoor, D Albittar, MI Alcala-Cerra, G Alegretti, MA Alemu, ZA Alfonso-Cristancho, R Alhabib, S Ali, R Alla, F Allen, PJ Alsharif, U Alvarez, E Alvis-Guzman, N Amankwaa, AA Amare, AT Amini, H Ammar, W Anderson, BO Antonio, CAT Anwari, P Arnlov, J Arsenijevic, VSA Artaman, A Asghar, RJ Assadi, R Atkins, LS Badawi, A Balakrishnan, K Banerjee, A Basu, S Beardsley, J Bekele, T Bell, ML Bernabe, E Beyene, TJ Bhala, N Bhalla, A Bhutta, ZA Bin Abdulhak, A Binagwaho, A Blore, JD Basara, BB Bose, D Brainin, M Breitborde, N Castaneda-Orjuela, CA Catala-Lopez, F Chadha, VK Chang, JC Chiang, PPC Chuang, TW Colomar, M Cooper, LT Cooper, C Courville, KJ Cowie, BC Criqui, MH Dandona, R Dayama, A De Leo, D Degenhardt, L Del Pozo-Cruz, B Deribe, K Des Jarlais, DC Dessalegn, M Dharmaratne, SD Dilmen, U Ding, EL Driscoll, TR Durrani, AM Ellenbogen, RG Ermakov, SP Esteghamati, A Faraon, EJA Farzadfar, F Fereshtehnejad, SM Fijabi, DO Forouzanfar, MH Paleo, UF Gaffikin, L Gamkrelidze, A Gankpe, FG Geleijnse, JM Gessner, BD Gibney, KB Ginawi, IAM Glaser, EL Gona, P Goto, A Gouda, HN Gugnani, HC Gupta, R Gupta, R Hafezi-Nejad, N Hamadeh, RR Hammami, M Hankey, GJ Harb, HL Haro, JM Havmoeller, R Hay, SI Hedayati, MT Pi, IBH Hoek, HW Hornberger, JC Hosgood, HD Hotez, PJ Hoy, DG Huang, JJ Iburg, KM Idrisov, BT Innos, K Jacobsen, KH Jeemon, P Jensen, PN Jha, V Jiang, GH Jonas, JB Juel, K Kan, HD Kankindi, I Karam, NE Karch, A Karema, CK Kaul, A Kawakami, N Kazi, DS Kemp, AH Kengne, AP Keren, A Kereselidze, M Khader, YS Khalifa, SEAH Khan, EA Khang, YH Khonelidze, I Kinfu, Y Kinge, JM Knibbs, L Kokubo, Y Kosen, S Defo, BK Kulkarni, VS Kulkarni, C Kumar, K Kumar, RB Kumar, GA Kwan, GF Lai, T Balaji, AL Lam, H Lan, Q Lansingh, VC Larson, HJ Larsson, A Lee, JT Leigh, J Leinsalu, M Leung, R Li, YC Li, YM De Lima, GMF Lin, HH Lipshultz, SE Liu, SW Liu, Y Lloyd, BK Lotufo, PA Machado, VMP Maclachlan, JH Magis-Rodriguez, C Majdan, M Mapoma, CC Marcenes, W Marzan, MB Masci, JR Mashal, MT Mason-Jones, AJ Mayosi, BM Mazorodze, TT Mckay, AC Meaney, PA Mehndiratta, MM Mejia-Rodriguez, F Melaku, YA Memish, ZA Mendoza, W Miller, TR Mills, EJ Mohammad, KA Mokdad, AH Mola, GL Monasta, L Montico, M Moore, AR Mori, R Moturi, WN Mukaigawara, M Murthy, KS Naheed, A Naidoo, KS Naldi, L Nangia, V Narayan, KMV Nash, D Nejjari, C Nelson, RG Neupane, SP Newton, CR Ng, M Nisar, MI Nolte, S Norheim, OF Nowaseb, V Nyakarahuka, L Oh, IH Ohkubo, T Olusanya, BO Omer, SB Opio, JN Orisakwe, OE Pandian, JD Papachristou, C Caicedo, AJP Patten, SB Paul, VK Pavlin, BI Pearce, N Pereira, DM Pervaiz, A Pesudovs, K Petzold, M Pourmalek, F Qato, D Quezada, AD Quistberg, DA Rafay, A Rahimi, K Rahimi-Movaghar, V Rahman, SU Raju, M Rana, SM Razavi, H Reilly, RQ Remuzzi, G Richardus, JH Ronfani, L Roy, N Sabin, N Saeedi, MY Sahraian, MA Samonte, GMJ Sawhney, M Schneider, IJC Schwebel, DC Seedat, S Sepanlou, SG Servan-Mori, EE Sheikhbahaei, S Shibuya, K Shin, HH Shiue, I Shivakoti, R Sigfusdottir, ID Silberberg, DH Silva, AP Simard, EP Singh, JA Skirbekk, V Sliwa, K Soneji, S Soshnikov, SS Sreeramareddy, CT Stathopoulou, VK Stroumpoulis, K Swaminathan, S Sykes, BL Tabb, KM Talongwa, RT Tenkorang, EY Terkawi, AS Thomson, AJ Thorne-Lyman, AL Towbin, JA Traebert, J Tran, BX Dimbuene, ZT Tsilimbaris, M Uchendu, US Ukwaja, KN Uzun, SB Vallely, AJ Vasankari, TJ Venketasubramanian, N Violante, FS Vlassov, VV Vollset, SE Waller, S Wallin, MT Wang, LH Wang, XR Wang, YP Weichenthal, S Weiderpass, E Weintraub, RG Westerman, R White, RA Wilkinson, JD Williams, TN Woldeyohannes, SM Wong, JQ Xu, GL Yang, YC Yano, Y Yentur, GK Yip, P Yonemoto, N Yoon, SJ Younis, M Yu, CH Jin, KY Zaki, ME Zhao, Y Zheng, YF Zhou, MG Zhu, J Zou, XN Lopez, AD Vos, T AF Murray, Christopher J. L. Ortblad, Katrina F. Guinovart, Caterina Lim, Stephen S. Wolock, Timothy M. Roberts, D. Allen Dansereau, Emily A. Graetz, Nicholas Barber, Ryan M. Brown, Jonathan C. Wang, Haidong Duber, Herbert C. Naghavi, Mohsen Dicker, Daniel Dandona, Lalit Salomon, Joshua A. Heuton, Kyle R. Foreman, Kyle Phillips, David E. Fleming, Thomas D. Flaxman, Abraham D. Phillips, Bryan K. Johnson, Elizabeth K. Coggeshall, Megan S. Abd-Allah, Foad Abera, Semaw Ferede Abraham, Jerry P. Abubakar, Ibrahim Abu-Raddad, Laith J. Abu-Rmeileh, Niveen Me Achoki, Tom Adeyemo, Austine Olufemi Adou, Arsene Kouablan Adsuar, Jose C. Agardh, Emilie Elisabet Akena, Dickens Al Kahbouri, Mazin J. Alasfoor, Deena Albittar, Mohammed I. Alcala-Cerra, Gabriel Angel Alegretti, Miguel Alemu, Zewdie Aderaw Alfonso-Cristancho, Rafael Alhabib, Samia Ali, Raghib Alla, Francois Allen, Peter J. Alsharif, Ubai Alvarez, Elena Alvis-Guzman, Nelson Amankwaa, Adansi A. Amare, Azmeraw T. Amini, Hassan Ammar, Walid Anderson, Benjamin O. Antonio, Carl Abelardo T. Anwari, Palwasha Arnlov, Johan Arsenijevic, Valentina S. Arsic Artaman, Ali Asghar, Rana J. Assadi, Reza Atkins, Lydia S. Badawi, Alaa Balakrishnan, Kalpana Banerjee, Amitava Basu, Sanjay Beardsley, Justin Bekele, Tolesa Bell, Michelle L. Bernabe, Eduardo Beyene, Tariku Jibat Bhala, Neeraj Bhalla, Ashish Bhutta, Zulfiqar A. Bin Abdulhak, Aref Binagwaho, Agnes Blore, Jed D. Basara, Berrak Bora Bose, Dipan Brainin, Michael Breitborde, Nicholas Castaneda-Orjuela, Carlos A. Catala-Lopez, Ferran Chadha, Vineet K. Chang, Jung-Chen Chiang, Peggy Pei-Chia Chuang, Ting-Wu Colomar, Mercedes Cooper, Leslie Trumbull Cooper, Cyrus Courville, Karen J. Cowie, Benjamin C. Criqui, Michael H. Dandona, Rakhi Dayama, Anand De Leo, Diego Degenhardt, Louisa Del Pozo-Cruz, Borja Deribe, Kebede Des Jarlais, Don C. Dessalegn, Muluken Dharmaratne, Samath D. Dilmen, Ugur Ding, Eric L. Driscoll, Tim R. Durrani, Adnan M. Ellenbogen, Richard G. Ermakov, Sergey Petrovich Esteghamati, Alireza Faraon, Emerito Jose A. Farzadfar, Farshad Fereshtehnejad, Seyed-Mohammad Fijabi, Daniel Obadare Forouzanfar, Mohammad H. Paleo, Urbano Fra Gaffikin, Lynne Gamkrelidze, Amiran Gankpe, Fortune Gbetoho Geleijnse, Johanna M. Gessner, Bradford D. Gibney, Katherine B. Ginawi, Ibrahim Abdelmageem Mohamed Glaser, Elizabeth L. Gona, Philimon Goto, Atsushi Gouda, Hebe N. Gugnani, Harish Chander Gupta, Rajeev Gupta, Rahul Hafezi-Nejad, Nima Hamadeh, Randah Ribhi Hammami, Mouhanad Hankey, Graeme J. Harb, Hilda L. Maria Haro, Josep Havmoeller, Rasmus Hay, Simon I. Hedayati, Mohammad T. Heredia Pi, Ileana B. Hoek, Hans W. Hornberger, John C. Hosgood, H. Dean Hotez, Peter J. Hoy, Damian G. Huang, John J. Iburg, Kim M. Idrisov, Bulat T. Innos, Kaire Jacobsen, Kathryn H. Jeemon, Panniyammakal Jensen, Paul N. Jha, Vivekanand Jiang, Guohong Jonas, Jost B. Juel, Knud Kan, Haidong Kankindi, Ida Karam, Nadim E. Karch, Andre Karema, Corine Kakizi Kaul, Anil Kawakami, Norito Kazi, Dhruv S. Kemp, Andrew H. Kengne, Andre Pascal Keren, Andre Kereselidze, Maia Khader, Yousef Saleh Khalifa, Shams Eldin Ali Hassan Khan, Ejaz Ahmed Khang, Young-Ho Khonelidze, Irma Kinfu, Yohannes Kinge, Jonas M. Knibbs, Luke Kokubo, Yoshihiro Kosen, S. Defo, Barthelemy Kuate Kulkarni, Veena S. Kulkarni, Chanda Kumar, Kaushalendra Kumar, Ravi B. Kumar, G. Anil Kwan, Gene F. Lai, Taavi Balaji, Arjun Lakshmana Lam, Hilton Lan, Qing Lansingh, Van C. Larson, Heidi J. Larsson, Anders Lee, Jong-Tae Leigh, James Leinsalu, Mall Leung, Ricky Li, Yichong Li, Yongmei Ferreira De Lima, Graca Maria Lin, Hsien-Ho Lipshultz, Steven E. Liu, Shiwei Liu, Yang Lloyd, Belinda K. Lotufo, Paulo A. Pedro Machado, Vasco Manuel Maclachlan, Jennifer H. Magis-Rodriguez, Carlos Majdan, Marek Mapoma, Christopher Chabila Marcenes, Wagner Barrieotos Marzan, Melvin Masci, Joseph R. Mashal, Mohammad Taufiq Mason-Jones, Amanda J. Mayosi, Bongani M. Mazorodze, Tasara T. Mckay, Abigail Cecilia Meaney, Peter A. Mehndiratta, Man Mohan Mejia-Rodriguez, Fabiola Melaku, Yohannes Adama Memish, Ziad A. Mendoza, Walter Miller, Ted R. Mills, Edward J. Mohammad, Karzan Abdulmuhsin Mokdad, Ali H. Mola, Glen Liddell Monasta, Lorenzo Montico, Marcella Moore, Ami R. Mori, Rintaro Moturi, Wilkister Nyaora Mukaigawara, Mitsuru Murthy, Kinnari S. Naheed, Aliya Naidoo, Kovin S. Naldi, Luigi Nangia, Vinay Narayan, K. M. Venkat Nash, Denis Nejjari, Chakib Nelson, Robert G. Neupane, Sudan Prasad Newton, Charles R. Ng, Marie Nisar, Muhammad Imran Nolte, Sandra Norheim, Ole F. Nowaseb, Vincent Nyakarahuka, Luke Oh, In-Hwan Ohkubo, Takayoshi Olusanya, Bolajoko O. Omer, Saad B. Opio, John Nelson Orisakwe, Orish Ebere Pandian, Jeyaraj D. Papachristou, Christina Paternina Caicedo, Angel J. Patten, Scott B. Paul, Vinod K. Pavlin, Boris Igor Pearce, Neil Pereira, David M. Pervaiz, Aslam Pesudovs, Konrad Petzold, Max Pourmalek, Farshad Qato, Dima Quezada, Amado D. Quistberg, D. Alex Rafay, Anwar Rahimi, Kazem Rahimi-Movaghar, Vafa Rahman, Sajjad Ur Raju, Murugesan Rana, Saleem M. Razavi, Homie Reilly, Robert Quentin Remuzzi, Giuseppe Richardus, Jan Hendrik Ronfani, Luca Roy, Nobhojit Sabin, Nsanzimana Saeedi, Mohammad Yahya Sahraian, Mohammad Ali Samonte, Genesis May J. Sawhney, Monika Schneider, Ione J. C. Schwebel, David C. Seedat, Soraya Sepanlou, Sadaf G. Servan-Mori, Edson E. Sheikhbahaei, Sara Shibuya, Kenji Shin, Hwashin Hyun Shiue, Ivy Shivakoti, Rupak Sigfusdottir, Inga Dora Silberberg, Donald H. Silva, Andrea P. Simard, Edgar P. Singh, Jasvinder A. Skirbekk, Vegard Sliwa, Karen Soneji, Samir Soshnikov, Sergey S. Sreeramareddy, Chandrashekhar T. Stathopoulou, Vasiliki Kalliopi Stroumpoulis, Konstantinos Swaminathan, Soumya Sykes, Bryan L. Tabb, Karen M. Talongwa, Roberto Tchio Tenkorang, Eric Yeboah Terkawi, Abdullah Sulieman Thomson, Alan J. Thorne-Lyman, Andrew L. Towbin, Jeffrey A. Traebert, Jefferson Tran, Bach X. Dimbuene, Zacharie Tsala Tsilimbaris, Miltiadis Uchendu, Uche S. Ukwaja, Kingsley N. Uzun, Selen Begum Vallely, Andrew J. Vasankari, Tommi J. Venketasubramanian, N. Violante, Francesco S. Vlassov, Vasiliy Victorovich Vollset, Stein Emil Waller, Stephen Wallin, Mitchell T. Wang, Linhong Wang, XiaoRong Wang, Yanping Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Westerman, Ronny White, Richard A. Wilkinson, James D. Williams, Thomas Neil Woldeyohannes, Solomon Meseret Wong, John Q. Xu, Gelin Yang, Yong C. Yano, Yuichiro Yentur, Gokalp Kadri Yip, Paul Yonemoto, Naohiro Yoon, Seok-Jun Younis, Mustafa Yu, Chuanhua Jin, Kim Yun Zaki, Maysaa El Sayed Zhao, Yong Zheng, Yingfeng Zhou, Maigeng Zhu, Jun Zou, Xiao Nong Lopez, Alan D. Vos, Theo TI Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 SO LANCET LA English DT Article ID MIDDLE-INCOME COUNTRIES; FEMALE SEX WORKERS; PLASMODIUM-FALCIPARUM MALARIA; ACTIVE ANTIRETROVIRAL THERAPY; MILLENNIUM DEVELOPMENT GOALS; SEVERE FEBRILE ILLNESS; PROSPECTIVE COHORT; VERBAL AUTOPSY; PROJECTION PACKAGE; COST-EFFECTIVENESS AB Background The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration. Methods To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets. Findings Globally in 2013, there were 1.8 million new HIV infections (95% uncertainty interval 1.7 million to 2.1 million), 29.2 million prevalent HIV cases (28.1 to 31.7), and 1.3 million HIV deaths (1.3 to 1.5). At the peak of the epidemic in 2005, HIV caused 1.7 million deaths (1.6 million to 1.9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19.1 million life-years (16.6 million to 21.5 million) have been saved, 70.3% (65.4 to 76.1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7.5 million (7.4 million to 7.7 million), prevalence was 11.9 million (11.6 million to 12.2 million), and number of deaths was 1.4 million (1.3 million to 1.5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7.1 million (6.9 million to 7.3 million), prevalence was 11.2 million (10.8 million to 11.6 million), and number of deaths was 1.3 million (1.2 million to 1.4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64.0% of cases (63.6 to 64.3) and 64.7% of deaths (60.8 to 70.3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1.2 million deaths (1.1 million to 1.4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31.5% (15.7 to 44.1). Outside of Africa, malaria mortality has been steadily decreasing since 1990. Interpretation Our estimates of the number of people living with HIV are 18.7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action. C1 [Murray, Christopher J. L.; Ortblad, Katrina F.; Guinovart, Caterina; Wolock, Timothy M.; Roberts, D. Allen; Dansereau, Emily A.; Graetz, Nicholas; Barber, Ryan M.; Brown, Jonathan C.; Wang, Haidong; Duber, Herbert C.; Naghavi, Mohsen; Dicker, Daniel; Dandona, Lalit; Heuton, Kyle R.; Phillips, David E.; Fleming, Thomas D.; Flaxman, Abraham D.; Phillips, Bryan K.; Johnson, Elizabeth K.; Coggeshall, Megan S.; Forouzanfar, Mohammad H.; Mokdad, Ali H.; Ng, Marie; Vos, Theo] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Ellenbogen, Richard G.] Harborview, Seattle, WA USA. [Ellenbogen, Richard G.] Univ Washington Med, Seattle, WA USA. [Alfonso-Cristancho, Rafael; Anderson, Benjamin O.; Jensen, Paul N.; Quistberg, D. Alex] Univ Washington, Seattle, WA 98195 USA. [Dandona, Lalit; Dandona, Rakhi; Kumar, G. Anil; Murthy, Kinnari S.] Publ Hlth Fdn India, New Delhi, India. [Foreman, Kyle; Williams, Thomas Neil] Univ London Imperial Coll Sci Technol & Med, London, England. [Ding, Eric L.] Harvard Univ, Harvard Sch Publ Hlth, Cambridge, MA 02138 USA. [Salomon, Joshua A.] Harvard Univ, Cambridge, MA 02138 USA. [Abd-Allah, Foad] Cairo Univ, Fac Med, Cairo, Egypt. [Abera, Semaw Ferede] Mekelle Univ, Coll Hlth Sci, Sch Publ Hlth, Mekelle, Ethiopia. [Melaku, Yohannes Adama] Mekelle Univ, Mekelle, Ethiopia. [Abraham, Jerry P.] Univ Texas San Antonio, Sch Med, San Antonio, TX USA. [Abubakar, Ibrahim] UCL, London, England. [Abu-Raddad, Laith J.] Weill Cornell Med Coll Qatar, Doha, Qatar. [Abu-Rmeileh, Niveen Me] Birzeti Univ, Inst Community & Publ Hlth, Ramallah, West Bank, Palestinian Ter. [Achoki, Tom] Minist Hlth, Gaborone, Botswana. [Adeyemo, Austine Olufemi] Evidence Act MamaYe, Freetown, Western Area, Sierra Leone. [Adou, Arsene Kouablan] Assoc Ivoirienne Bien Etre Familial, Abidjan, Cote Ivoire. [Adsuar, Jose C.; Paleo, Urbano Fra] Univ Extremadura, Caceres, Spain. [Agardh, Emilie Elisabet] Inst Publ Hlth Sci, Stockholm, Sweden. [Akena, Dickens; Nyakarahuka, Luke] Makerere Univ, Kampala, Uganda. [Al Kahbouri, Mazin J.; Alasfoor, Deena] Minist Hlth, Muscat, Oman. [Albittar, Mohammed I.] Independent, Damascus, Syria. [Alcala-Cerra, Gabriel] Grp Invest Ciencias Salud & Neurociencias CISNEUR, Cartagena de Indias, Colombia. [Angel Alegretti, Miguel] Univ Republica, Fac Med, Dept Prevent & Social Med, Montevideo, Uruguay. [Alemu, Zewdie Aderaw] Debre Markos Univ, Debre Markos, Ethiopia. [Alhabib, Samia] Natl Guard Hlth Affairs, Riyadh, Saudi Arabia. [Ali, Raghib; Hay, Simon I.; Rahimi, Kazem] Univ Oxford, Oxford, England. [Alla, Francois] Univ Lorraine, Sch Publ Hlth, Nancy, France. [Allen, Peter J.] Minist Hlth, Belmopan, Cayo, Belize. [Alsharif, Ubai; Nolte, Sandra; Papachristou, Christina] Charite, D-13353 Berlin, Germany. [Alvarez, Elena] Govt, Madrid, Spain. [Alvis-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. [Amini, Hassan] Kurdistan Univ Med Sci, Kurdistan Environm Hlth Res Ctr, Sanandaj, Kurdistan, Iran. [Ammar, Walid; Harb, Hilda L.] Minist Publ Hlth, Beirut, Lebanon. [Antonio, Carl Abelardo T.; Faraon, Emerito Jose A.] Univ Philippines, Coll Publ Hlth, Manila, Philippines. [Anwari, Palwasha] UNFPA, Kabul, Afghanistan. [Arnlov, Johan; Larsson, Anders] Uppsala Univ, Uppsala, Sweden. [Karema, Corine Kakizi] Malaria & Other Parasit Dis Div, Kigali, Rwanda. [Binagwaho, Agnes; Kankindi, Ida] Minist Hlth, Kigali, Rwanda. [Arsenijevic, Valentina S. Arsic] Univ Belgrade, Sch Med, Inst Microbiol & Immunol, Belgrade, Serbia. [Artaman, Ali] Median Inc, Windsor, ON, Canada. [Asghar, Rana J.] Asian Publ Hlth Forum, Islamabad, Pakistan. [Assadi, Reza] Mashhad Univ Med Sci, Mashhad, Iran. [Atkins, Lydia S.] Minist Hlth Wellness Human Serv & Gender Relat, Castries, St Lucia. [Badawi, Alaa] Publ Hlth Agcy Canada, Toronto, ON, Canada. [Balakrishnan, Kalpana] Sri Ramachandra Univ, Chennai, Tamil Nadu, India. [Banerjee, Amitava] Univ Birmingham, Birmingham, W Midlands, England. [Gaffikin, Lynne] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Basu, Sanjay] Stanford Univ, Stanford, CA 94305 USA. [Beardsley, Justin] Univ Oxford, Ho Chi Minh City, Vietnam. [Bekele, Tolesa] Madawalabu Univ, Bale, Goba, Ethiopia. [Bell, Michelle L.; Huang, John J.] Yale Univ, New Haven, CT USA. [Bernabe, Eduardo] Kings Coll London, London WC2R 2LS, England. [Beyene, Tariku Jibat; Deribe, Kebede] Univ Addis Ababa, Addis Ababa, Ethiopia. [Bhala, Neeraj] Wellington Hosp, Wellington, New Zealand. [Bhalla, Ashish; Jha, Vivekanand] Postgrad Inst Med Educ & Res, Chandigarh, India. [Bhutta, Zulfiqar A.] Aga Khan Univ, Med Ctr, Nairobi, Kenya. [Bin Abdulhak, Aref] Univ Missouri, Kansas City, MO 64110 USA. [Chiang, Peggy Pei-Chia] Univ Melbourne, Gen Practice & Primary Hlth Care Acad Ctr, Melbourne, Vic, Australia. [Blore, Jed D.; Balaji, Arjun Lakshmana; Weintraub, Robert G.; Lopez, Alan D.] Univ Melbourne, Melbourne, Vic, Australia. [Weintraub, Robert G.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Basara, Berrak Bora; Yentur, Gokalp Kadri] Gen Directorate Hlth Res, Ankara, Turkey. [Dilmen, Ugur; Uzun, Selen Begum] Minist Hlth, Ankara, Turkey. [Bose, Dipan] World Bank, Washington, DC 20433 USA. [Brainin, Michael] Danube Univ Krems, Krems, Austria. [Breitborde, Nicholas] Univ Arizona, Tucson, AZ USA. [Castaneda-Orjuela, Carlos A.] Inst Nacl Salud, Colombian Natl Hlth Observ, Bogota, Colombia. [Catala-Lopez, Ferran] Spanish Med & Healthcare Prod Agcy AEMPS, Div Pharmacoepidemiol & Pharmacovigilance, Minist Hlth, Madrid, Spain. [Chadha, Vineet K.] Natl TB Inst, Bangalore, Karnataka, India. [Lin, Hsien-Ho] Natl Taiwan Univ, Inst Epidemiol & Prevent Med, Taipei 10764, Taiwan. [Chang, Jung-Chen] Natl Taiwan Univ, Taipei 10764, Taiwan. [Chuang, Ting-Wu] Taipei Med Univ, Coll Med, Dept Parasitol, Taipei, Taiwan. [Chuang, Ting-Wu] Taipei Med Univ, Coll Med, Ctr Int Trop Med, Taipei, Taiwan. [Colomar, Mercedes] UNICEM, Montevideo, Uruguay. [Cooper, Leslie Trumbull] Mayo Clin, Rochester, MN USA. [Cooper, Cyrus] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Courville, Karen J.] Hosp Dr Gustavo N Collado, Chitre, Herrera, Panama. [Cowie, Benjamin C.; Maclachlan, Jennifer H.] Victorian Infect Dis Reference Lab, North Melbourne, Vic, Australia. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Dayama, Anand] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Liu, Yang; Narayan, K. M. Venkat; Omer, Saad B.] Emory Univ, Atlanta, GA 30322 USA. [De Leo, Diego] Griffith Univ, Brisbane, Qld 4111, Australia. [Vallely, Andrew J.] Univ New S Wales, Kirby Inst, Sydney, NSW, Australia. [Degenhardt, Louisa] Univ New S Wales, Sydney, NSW, Australia. [Del Pozo-Cruz, Borja] Univ Auckland, Auckland 1, New Zealand. [Des Jarlais, Don C.] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Dessalegn, Muluken] Africa Med & Res Fdn Ethiopia, Addis Ababa, Ethiopia. [Dharmaratne, Samath D.] Univ Peradeniya, Peradeniya, Sri Lanka. [Driscoll, Tim R.] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Leigh, James] Univ Sydney, Sydney, NSW 2006, Australia. [Durrani, Adnan M.] NIH, Montgomery, MD USA. [Ermakov, Sergey Petrovich] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Farzadfar, Farshad] Univ Tehran Med Sci, Noncommunicable Dis Res Ctr, Tehran, Iran. [Esteghamati, Alireza; Hafezi-Nejad, Nima; Sheikhbahaei, Sara] Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Tehran, Iran. [Rahimi-Movaghar, Vafa] Univ Tehran Med Sci, Sina Trauma & Surg Res Ctr, Tehran, Iran. [Sahraian, Mohammad Ali] Univ Tehran Med Sci, MS Res Ctr, Tehran, Iran. [Sepanlou, Sadaf G.] Univ Tehran Med Sci, Digest Dis Res Inst, Tehran, Iran. [Fereshtehnejad, Seyed-Mohammad] Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Stockholm, Sweden. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Havmoeller, Rasmus] Karolinska Inst, Stockholm, Sweden. [Fijabi, Daniel Obadare] Brandeis Univ, Heller Grad Sch, Waltham, MA USA. [Glaser, Elizabeth L.] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA USA. [Idrisov, Bulat T.] Brandeis Univ, Waltham, MA USA. [Gamkrelidze, Amiran; Kereselidze, Maia; Khonelidze, Irma] Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia. [Gankpe, Fortune Gbetoho] Clin Cooperat Parakou, Parakou, Borgou, Benin. [Geleijnse, Johanna M.] Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands. [Gessner, Bradford D.] Agence Med Prevent, Paris, France. [Lloyd, Belinda K.] Monash Univ, Eastern Hlth Clin Sch, Melbourne, Vic 3004, Australia. [Gibney, Katherine B.] Monash Univ, Melbourne, Vic 3004, Australia. [Lloyd, Belinda K.] Eastern Hlth, Turning Point, Fitzroy, Vic, Australia. [Ginawi, Ibrahim Abdelmageem Mohamed] Univ Hail, Coll Med, Hail, Saudi Arabia. [Gona, Philimon] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Goto, Atsushi] Natl Ctr Global Hlth & Med, Dept Diabet Res, Tokyo, Japan. [Hoy, Damian G.] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. [Gouda, Hebe N.; Knibbs, Luke] Univ Queensland, Brisbane, Qld, Australia. [Hoy, Damian G.] Secretariat Pacific Community, Publ Hlth Div, Noumea, New Caledonia. [Gugnani, Harish Chander] St James Sch Med, Kralendijk, Bonaire, Neth Antilles. [Gupta, Rajeev] Fortis Escorts Hosp, Jaipur, Rajasthan, India. [Gupta, Rahul] Kanawha Charleston Hlth Dept, Charleston, WV USA. [Hamadeh, Randah Ribhi] Arabian Gulf Univ, Manama, Bahrain. [Hammami, Mouhanad] Wayne Cty Dept Hlth & Human Serv, Detroit, MI USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Maria Haro, Josep] Univ Barcelona, CIBERSAM, Parc Sanitari Sant Joan de Deu, Barcelona, Spain. [Hedayati, Mohammad T.] Mazandaran Univ Med Sci, Sari, Mazandaran, Iran. [Heredia Pi, Ileana B.; Mejia-Rodriguez, Fabiola; Quezada, Amado D.; Servan-Mori, Edson E.] Natl Inst Publ Hlth Mexico, Cuernavaca, Morelos, Mexico. [Hoek, Hans W.] Parnassia Psychiat Inst, The Hague, Netherlands. [Hornberger, John C.] Cedar Associates, Menlo Pk, CA USA. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hotez, Peter J.] Baylor Coll Med, Houston, TX 77030 USA. [Iburg, Kim M.] Aarhus Univ, Aarhus, Denmark. [Innos, Kaire; Leinsalu, Mall] Natl Inst Hlth Dev, Tallinn, Estonia. [Jacobsen, Kathryn H.] George Mason Univ, Fairfax, VA 22030 USA. [Jeemon, Panniyammakal] Ctr Chron Dis Control, New Delhi, India. [Jiang, Guohong] Tianjin Ctr Dis Control & Prevent, Tianjin, Peoples R China. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Juel, Knud] Natl Inst Publ Hlth, Copenhagen, Denmark. [Kan, Haidong] Fudan Univ, Shanghai 200433, Peoples R China. [Karam, Nadim E.] Univ Balamand, Beirut, Lebanon. [Karch, Andre] Helmholtz Ctr Infect Res, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res DZIF, Hannover, Germany. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Kawakami, Norito] Univ Tokyo, Sch Publ Hlth, Tokyo, Japan. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Kazi, Dhruv S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kemp, Andrew H.; Lotufo, Paulo A.] Univ Sao Paulo, Sao Paulo, Brazil. [Kengne, Andre Pascal] South African Med Res Council, Cape Town, Western Cape, South Africa. [Keren, Andre] Hadassah Ein Kerem Univ Hosp, Jerusalem, Israel. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Al Ramtha, Jordan. [Khalifa, Shams Eldin Ali Hassan] Supreme Council Hlth, Doha, Qatar. [Khan, Ejaz Ahmed] Hlth Serv Acad, Islamabad, Punjab, Pakistan. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Inst Hlth Policy & Management, Seoul, South Korea. [Kinfu, Yohannes] Univ Canberra, Canberra, ACT 2601, Australia. [White, Richard A.] Norwegian Inst Publ Hlth, Dept Infect Dis Epidemiol, Div Infect Dis Control, Oslo, Norway. [White, Richard A.] Norwegian Inst Publ Hlth, Dept Hlth Stat, Div Epidemiol, Oslo, Norway. [Kinge, Jonas M.; Skirbekk, Vegard; Vollset, Stein Emil] Norwegian Inst Publ Hlth, Oslo, Norway. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Med & Epidemiol Informat, Dept Prevent Cardiol, Suita, Osaka, Japan. [Kosen, S.] NIHRD, Ctr Community Empowerment Hlth Policy & Humanitie, Jakarta, Indonesia. [Defo, Barthelemy Kuate] Univ Montreal, Montreal, PQ, Canada. [Kulkarni, Veena S.] Arkansas State Univ, Jonesboro, AR USA. [Kulkarni, Chanda] Rajrajeshwari Med Coll & Hosp, Bangalore, Karnataka, India. [Kumar, Kaushalendra] Int Inst Populat Sci, Mumbai, Maharashtra, India. [Kumar, Ravi B.] Publ Hlth Fdn India, Indian Inst Publ Hlth, Gurgaon, Haryana, India. [Kwan, Gene F.] Boston Med Ctr, Boston, MA USA. [Lai, Taavi] Fourth View Consulting, Tallinn, Estonia. [Lam, Hilton] Natl Inst Hlth, Inst Hlth Policy & Dev Studies, Manila, Philippines. [Lan, Qing] Natl Canc Inst, Rockville, MD USA. [Lansingh, Van C.] IAPB & Vis 2020 LA, Weston, FL USA. [Larson, Heidi J.; Pearce, Neil] London Sch Hyg & Trop Med, Bloomsbury, England. [Lee, Jong-Tae; Yoon, Seok-Jun] Korea Univ, Seoul, South Korea. [Leung, Ricky] SUNY Albany, Rensselaer, NY 12222 USA. [Li, Yichong; Liu, Shiwei; Wang, Linhong; Zhou, Maigeng] Chinese Ctr Dis Control & Prevent, Natl Ctr Chron & Noncommunicable Dis Control & Pr, Beijing, Peoples R China. [Li, Yongmei] Genentech Inc, San Francisco, CA USA. [Ferreira De Lima, Graca Maria] Dept Publ Hlth, Unidade Local Saude Matosinhos, Oporto, Portugal. [Pedro Machado, Vasco Manuel] Dept Publ Hlth, Northern Reg Hlth Adm, Oporto, Portugal. [Lipshultz, Steven E.] Wayne State Univ, Miami, FL USA. [Magis-Rodriguez, Carlos] Ctr Nacl Prevenc & Control VIH SIDA, Mexico City, DF, Mexico. [Majdan, Marek] Trnava Univ, Fac Hlth Sci & Social Work, Dept Publ Hlth, Trnava, Slovakia. [Mapoma, Christopher Chabila] Univ Zambia, Lusaka, Zambia. [Marcenes, Wagner] Univ London, London, England. [Barrieotos Marzan, Melvin] Univ East Ramon, Magsaysay Med Ctr, Quezon City, Philippines. [Masci, Joseph R.] Elmhurst Hosp Ctr, Mt Sinai Serv, Elmhurst, NY USA. [Mashal, Mohammad Taufiq] Minist Publ Hlth, Kabul, Afghanistan. [Mason-Jones, Amanda J.] Univ York, York YO10 5DD, N Yorkshire, England. [Sliwa, Karen] Univ Cape Town, Fac Hlth Sci, Hatter Inst Cardiovasc Res Africa, ZA-7925 Cape Town, Western Cape, South Africa. [Mayosi, Bongani M.] Univ Cape Town, ZA-7925 Cape Town, Western Cape, South Africa. [Mazorodze, Tasara T.] AIDC EC, Port Elizabeth, South Africa. [Mckay, Abigail Cecilia] EmergentCorp, Belize City, Belize. [Meaney, Peter A.] Univ Penn, Pereleman Sch Med, Philadelphia, PA 19104 USA. [Silberberg, Donald H.] Univ Penn, Philadelphia, PA 19104 USA. [Mehndiratta, Man Mohan] Janakpuri Superspecialty Hosp, New Delhi, India. [Memish, Ziad A.; Saeedi, Mohammad Yahya] Minist Hlth, Riyadh, Saudi Arabia. [Mendoza, Walter] UNFPA, Lima, Peru. [Miller, Ted R.] Pacific Inst Res & Evaluat, Calverton, MD USA. [Miller, Ted R.] Curtin Univ, Ctr Populat Hlth Res, Perth, WA 6845, Australia. [Mills, Edward J.] Univ Ottawa, Ottawa, ON, Canada. [Mohammad, Karzan Abdulmuhsin] Univ Salahaddin, Erbil, Iraq. [Mola, Glen Liddell] Univ Papua New Guinea, Port Moresby, NCD, Papua N Guinea. [Monasta, Lorenzo; Montico, Marcella; Ronfani, Luca] Inst Maternal & Child Hlth IRCCS Burlo Garofolo, Trieste, Italy. [Moore, Ami R.] Univ N Texas, Denton, TX 76203 USA. [Mori, Rintaro] Natl Ctr Child Hlth & Dev, Tokyo, Tokyo, Japan. [Moturi, Wilkister Nyaora] Egerton Univ, Egerton, Rift Valley, Kenya. [Mukaigawara, Mitsuru] Tokyo Med & Dent Univ, Bunkyo Ku, Tokyo, Japan. [Naheed, Aliya] Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh. [Naidoo, Kovin S.] Univ KwaZulu Natal, Durban, KwaZulu Natal, South Africa. [Naldi, Luigi] Azienda Osped Papa Giovanni XXIII, Bergamo, Italy. [Nangia, Vinay] Suraj Eye Inst, Nagpur, Maharashtra, India. [Nash, Denis] CUNY, Sch Publ Hlth, New York, NY 10021 USA. [Nejjari, Chakib] Fac Med, Fes, Morocco. [Nelson, Robert G.] NIDDK, Phoenix, AZ USA. [Neupane, Sudan Prasad] Univ Oslo, Norwegian Ctr Addict Res SERAF, Oslo, Norway. [Newton, Charles R.] Kenya Med Res Inst Wellcome Trust Programme, Kilifi, Kenya. [Nisar, Muhammad Imran] Aga Khan Univ, Karachi, Pakistan. [Norheim, Ole F.; Vollset, Stein Emil] Univ Bergen, Bergen, Norway. [Nowaseb, Vincent] Polytech Namibia, Windhoek, Namibia. [Oh, In-Hwan] Kyung Hee Univ, Seoul, South Korea. [Ohkubo, Takayoshi] Teikyo Univ, Sch Med, Tokyo 173, Japan. [Olusanya, Bolajoko O.] Ctr Hlth Start Initiat, Lagos, Nigeria. [Opio, John Nelson] Lira Dist Local Govt, Lira Municipal Council, Northern Uganda, Uganda. [Orisakwe, Orish Ebere] Univ Port Harcourt, Fac Pharm, Toxicol Unit, Port Harcourt, Rivers State, Nigeria. [Pandian, Jeyaraj D.] Christian Med Coll Ludhiana, Ludhiana, Punjab, India. [Patten, Scott B.] Univ Calgary, Calgary, AB, Canada. [Paul, Vinod K.] AIIMS, New Delhi, India. [Pavlin, Boris Igor] Independent, Waigani, NCD, Papua N Guinea. [Pereira, David M.] Univ Minho, Headquarters European Inst Excellence Tissue Engn, 3Bs Res Grp Biomat Biodegradables & Biomimet, Braga, Portugal. [Pereira, David M.] ICVS 3Bs PT Govt Associate Lab, Braga, Portugal. [Pervaiz, Aslam] Postgrad Med Inst, Lahore, Punjab, Pakistan. [Pesudovs, Konrad] Flinders Univ S Australia, Adelaide, SA, Australia. [Petzold, Max] Univ Gothenburg, Sahlgrenska Acad, Ctr Appl Biostat, Gothenburg, Sweden. [Pourmalek, Farshad] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Qato, Dima] Univ Illinois, Coll Pharm, Chicago, IL USA. [Rafay, Anwar] Contech Intl, Lahore, Punjab, Pakistan. [Rahman, Sajjad Ur] Hamad Med Corp, Doha, Qatar. [Raju, Murugesan] Univ Missouri, Columbia, MO USA. [Rana, Saleem M.] Univ Punjab, Dept Publ Hlth, Lahore, Punjab, Pakistan. [Razavi, Homie] Ctr Dis Anal, Louisville, CO USA. [Reilly, Robert Quentin] Private Consultant, Cairns, Qld, Australia. [Remuzzi, Giuseppe] Ctr Anna Maria Astori, IRCCS Mario Negri Inst Pharmacol Res, Bergamo, Italy. [Richardus, Jan Hendrik] Univ Med Ctr Rotterdam, Erasmus MC, Rotterdam, Netherlands. [Roy, Nobhojit] BARC Hosp, Mumbai, Maharashtra, India. [Sabin, Nsanzimana] Rwanda Biomed Ctr, Kigali, Rwanda. [Samonte, Genesis May J.] Natl Epidemiol Ctr, Dept Hlth, Natl HIV AIDS & STI Surveillance & Strateg Inform, Manila, National Capita, Philippines. [Sawhney, Monika] Marshall Univ, Huntington, WV USA. [Schneider, Ione J. C.] Univ Fed Santa Catarina, Florianopolis, SC, Brazil. [Schwebel, David C.; Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Seedat, Soraya] Univ Stellenbosch, Cape Town, South Africa. [Shin, Hwashin Hyun; Weichenthal, Scott] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Shiue, Ivy] Heriot Watt Univ, Edinburgh, Midlothian, Scotland. [Shivakoti, Rupak] Johns Hopkins Univ, Ctr Clin Global Hlth Educ, Baltimore, MD USA. [Tran, Bach X.] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Sigfusdottir, Inga Dora] Reykjavik Univ, Reykjavik, Iceland. [Silva, Andrea P.] Inst Nacl Epidemiol Dr Juan H Jara, Mar Del Plata, Buenos Aires, Argentina. [Simard, Edgar P.] Surveillance & Hlth Serv Res Program Amer Canc So, Atlanta, GA USA. [Soneji, Samir] Dartmouth Coll, Lebanon, NH 03756 USA. [Soshnikov, Sergey S.] Fed Res Inst Hlth Org, Moscow, Russia. [Soshnikov, Sergey S.] Informat Minist Hlth Russian Federat, Moscow, Russia. [Sreeramareddy, Chandrashekhar T.] Univ Tunku Abdul Rahman, Fac Med & Hlth Sci, Kajang, Selangor, Malaysia. [Stathopoulou, Vasiliki Kalliopi] Ctr Hosp Nord Deux Sevres, Bressuire, France. [Stroumpoulis, Konstantinos] Alexandra Gen Hosp Athens, KEELPNO Ctr Dis Control, Athens, Greece. [Swaminathan, Soumya] Natl Inst Res TB, Chennai, Tamil Nadu, India. [Sykes, Bryan L.] Univ Calif Irvine, Dept Criminol Law & Soc, Chicago, IL USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Sociol, Chicago, IL USA. [Tabb, Karen M.] Univ Illinois, Champaign, IL 61820 USA. [Talongwa, Roberto Tchio] Minist Hlth MINSANTE, Yaounde, Cameroon. [Tenkorang, Eric Yeboah] Mem Univ, St John, NF, Canada. [Terkawi, Abdullah Sulieman] Univ Virginia, Dept Anesthesiol, Charlottesville, VA USA. [Terkawi, Abdullah Sulieman] King Fahad Med City, Dept Anesthesiol, Riyadh, Saudi Arabia. [Thomson, Alan J.] Adapt Knowledge Management, Victoria, BC, Canada. [Thorne-Lyman, Andrew L.] Columbia Univ, Earth Inst, New York, NY USA. [Towbin, Jeffrey A.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Traebert, Jefferson] Univ Southern Santa Catarina, Palhoca, SC, Brazil. [Dimbuene, Zacharie Tsala] Univ Kinshasa, Fac Econ & Management, Dept Populat Sci & Dev, Kinshasa, Congo. [Tsilimbaris, Miltiadis] Univ Crete, Dept Med, Iraklion, Greece. [Uchendu, Uche S.] Dept Vet Affairs, Washington, DC USA. [Ukwaja, Kingsley N.] Fed Teaching Hosp Abakaliki, Dept Internal Med, Abakailiki, Ebonyi State, Nigeria. [Vasankari, Tommi J.] UKK Inst Hlth Promot Res, Tampere, Finland. [Venketasubramanian, N.] Raffles Hosp, Ctr Neurosci, Singapore, Singapore. [Violante, Francesco S.] Univ Bologna, Bologna, Italy. [Vlassov, Vasiliy Victorovich] Higher Sch Econ, Moscow, Russia. [Waller, Stephen] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Wallin, Mitchell T.] VA Med Ctr, Washington, DC USA. [Wallin, Mitchell T.] Georgetown Univ, Dept Neurol, Washington, DC USA. [Wang, XiaoRong] Shandong Univ, Jinan Cent Hosp, Jinan 250100, Peoples R China. [Wang, Yanping; Zhu, Jun] Natl Off Maternal & Child Hlth Surveillance, Chengdu, Peoples R China. [Westerman, Ronny] Univ Marburg, Marburg, Germany. [Wilkinson, James D.] Univ Miami, Miami, FL USA. [Woldeyohannes, Solomon Meseret] Univ Gondar, Inst Publ Hlth, Gondar, Ethiopia. [Wong, John Q.] Ateneo Sch Med & Publ Hlth, Pasig, Metro Manila, Philippines. [Xu, Gelin] Nanjing Univ, Jinling Hosp, Sch Med, Nanjing 210008, Jiangsu, Peoples R China. [Yang, Yong C.] Univ N Carolina, Chapel Hill, NC USA. [Yano, Yuichiro] Jichi Med Univ, Sch Med, Div Cardiovasc Med, Shimotsuke, Tochigi, Japan. [Yip, Paul] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Yonemoto, Naohiro] Natl Ctr Neurol & Psychiat, Tokyo, Japan. [Younis, Mustafa] Jackson State Univ, Jackson, MS USA. [Yu, Chuanhua] Wuhan Univ, Sch Publ Hlth & Global Hlth Inst, Dept Epidemiol & Biostat, Wuhan, Peoples R China. [Jin, Kim Yun] TCM MEDICAL TK SDN BHD, Nusajaya, Johor Bahru, Malaysia. [Zaki, Maysaa El Sayed] Mansoura Fac Med, Mansoura, Egypt. [Zhao, Yong] Chongqing Med Univ, Chongqing, Peoples R China. [Zheng, Yingfeng] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510275, Guangdong, Peoples R China. [Zou, Xiao Nong] Chinese Acad Med Sci, Canc Inst Hosp, Beijing 100730, Peoples R China. RP Murray, CJL (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. RI Balakrishnan, Kalpana/B-6653-2015; Beyene, Tariku Jibat/A-6875-2017; Alsharif, Ubai/C-6527-2017; Amini, Heresh/B-3076-2010; Lotufo, Paulo/A-9843-2008; Karch, Andre/D-6973-2017; Hedayati, Mohammad T./E-2304-2017; Ermakov, Sergey/G-1709-2016; Haro, Josep Maria/D-1423-2011; Kaul, Anil/B-2075-2016; Patten, Scott/B-4434-2011; El Sayed Zaki, Maysaa/C-1522-2013; Monasta, Lorenzo/B-1388-2012; Sepanlou, Sadaf/H-9343-2016; Jacobsen, Kathryn/B-5857-2008; wang, YA XING/K-9671-2016; Hay, Simon/F-8967-2015; Naldi, Luigi/K-6343-2016; Weiderpass, Elisabete/M-4029-2016; Montico, Marcella/B-5290-2013; Salomon, Joshua/D-3898-2009; Hankey, Graeme /H-4968-2014; Ronfani, Luca/B-6668-2013; Degenhardt, Louisa/D-4515-2012; Nolte, Sandra/B-7498-2008; Banerjee, Amitava/D-4381-2014; Kemp, Andrew/C-7984-2012; Adsuar, Jose C/C-6558-2008; Majdan, Marek/K-5017-2012; Paternina-Caicedo, Angel/N-4496-2015; Rahimi, Kazem/Q-1279-2015; Pereira, David/M-9286-2013; OI Pourmalek, Farshad/0000-0002-2134-0771; Miller, Ted/0000-0002-0958-2639; Leung, Ricky/0000-0002-2852-6771; Liu, Zhi-Hong/0000-0001-6093-0726; Pesudovs, Konrad/0000-0002-6322-9369; Neupane, Sudan Prasad/0000-0002-7389-4178; Deribe, Kebede/0000-0002-8526-6996; Khang, Young-Ho/0000-0002-9585-8266; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Xu, Gelin/0000-0002-6194-0341; Goto, Atsushi/0000-0003-0669-654X; Soshnikov, Sergey/0000-0002-6983-7066; Newton, Charles/0000-0002-6999-5507; assadi, reza/0000-0002-5016-2994; Vlassov, Vasiliy/0000-0001-5203-549X; Quistberg, Alex/0000-0001-9730-2686; LIN, HSIEN-HO/0000-0002-7481-6016; Abu-Raddad, Laith/0000-0003-0790-0506; Olusanya, Bolajoko/0000-0002-3826-0583; Tabb Dina, Karen/0000-0002-4722-9502; Heredia-Pi, Ileana Beatriz/0000-0002-9998-9239; Vallely, Andrew/0000-0003-1558-4822; Cowie, Benjamin/0000-0002-7087-5895; Gibney, Katherine/0000-0001-5851-5339; Hotez, Peter/0000-0001-8770-1042; Abubakar, Ibrahim/0000-0002-0370-1430; Ukwaja, Kingsley N./0000-0002-1974-8735; Ding, Eric/0000-0002-5881-8097; Balakrishnan, Kalpana/0000-0002-5905-1801; Beyene, Tariku Jibat/0000-0002-7474-1966; 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; Ermakov, Sergey/0000-0003-1072-1162; Bhala, Neeraj/0000-0003-2502-1177; MacLachlan, Jennifer/0000-0002-7654-4536; Kwan, Gene/0000-0002-0929-6800; Haro, Josep Maria/0000-0002-3984-277X; Patten, Scott/0000-0001-9871-4041; El Sayed Zaki, Maysaa/0000-0001-5431-0248; Monasta, Lorenzo/0000-0001-7774-548X; Sepanlou, Sadaf/0000-0002-3669-5129; Jacobsen, Kathryn/0000-0002-4198-6246; wang, YA XING/0000-0003-2749-7793; Hay, Simon/0000-0002-0611-7272; Naldi, Luigi/0000-0002-3160-2835; Weiderpass, Elisabete/0000-0003-2237-0128; Montico, Marcella/0000-0003-0377-8232; Salomon, Joshua/0000-0003-3929-5515; Hankey, Graeme /0000-0002-6044-7328; Ronfani, Luca/0000-0001-5710-3914; Degenhardt, Louisa/0000-0002-8513-2218; Nolte, Sandra/0000-0001-6185-9423; Banerjee, Amitava/0000-0001-8741-3411; Kemp, Andrew/0000-0003-1146-3791; Adsuar, Jose C/0000-0001-7203-3168; Majdan, Marek/0000-0001-8037-742X; Paternina-Caicedo, Angel/0000-0002-6332-5174; Rahimi, Kazem/0000-0002-4807-4610; Pereira, David/0000-0003-0384-7592; Glaser, Elizabeth/0000-0002-1918-057X; Catala-Lopez, Ferran/0000-0002-3833-9312; Bernabe, Eduardo/0000-0002-1858-3713; Norheim, Ole F./0000-0002-5748-5956; Hoek, Hans/0000-0001-6353-5465; Castaneda-Orjuela, Carlos/0000-0002-8735-6223 FU UK National Institute for Health Research; MRC; Qatar National Research Fund [NPRP 04-924-3-251]; Health Sciences and Neurosciences (CI SNEURO) Research Group; Australian National Health and Medical Research Council Principal Research Fellowship [1041742]; NIH [DA R01 003574]; Welcome Trust Fellowship in Public Health and Tropical Medicine [099876]; International Society of Nephrology (ISN); Agency for Health Quality and Research Center for Education and Research on Therapeutics (AHRQ CERTs) [U19 HS021110]; National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) [P50 AR060772, U34 AR062891]; National Institute of Aging (NIA) [U01 AG018947]; National Cancer Institute (NCI) [U10 CA149950]; Patient Centered Outcomes Research Institute (PCORI) [CE-1304-6631]; VA Medical Center at Birmingham, Alabama, USA; National Center for Advancing Translational Sciences [KL2TR001088]; National Health and Medical Research Council (NHMRC), Australia; Nature Science Foundation of China (NSFC) [81070922] FX We thank the countless individuals who have contributed to the Global Burden of Disease Study 2013 in various capacities. We would like to acknowledge the extensive support from all staff members at the Institute for Health Metrics and Evaluation and specifically thank: Michael F MacIntyre, Peter Speyer, and Summer Lockett Ohno for their management of the Global Burden of Disease Study 2013; Kelsey Pierce for her valuable assistance; Peter Speyer, James Bullard, Serkan Yalcin, Edgar Sioson, Evan Laurie, Charles Atkinson, and Andrew Ernst for their tireless support of the computational infrastructure necessary to produce the results; Linda A Ettinger for her expert administrative support; Peter Speyer, Abigail McLain, James Hancock, Marissa Iannarone, and Eden Stork for their persistent and invaluable work to gain access to and catalogue as much data as possible to inform the estimates; Stan Biryukov for his assistance with the tuberculosis database; Henry Apfel and Madeline Moyer for data extraction and processing; Christopher Margono, Michelle Subart, Lavanya Singh and Margaret Lind for assistance with galleys; Matthew M Coates, Carly E Levitz, Chelsea A Lidell, Meghan D Mooney, and Austin E Schumaker for production of all-cause mortality estimates; Amelia Bertozzi-Villa for review of Python coding of the Spectrum model. We would also like to acknowledge Mary Mahy, Keith Sabin and John Stover for sharing the UNAIDS EPP files with us and especially John Stover for responding to multiple queries regarding Spectrum. Additionally, Ibrahim Abubakar would like to acknowledge the UK National Institute for Health Research and MRC for funding. Laith J Abu-Raddad would like to acknowledge the support of Qatar National Research Fund (NPRP 04-924-3-251) who provided the main funding for generating the data provided to the GBD-IH ME effort. Gabriel Alcala-Cerra would like to acknowledge institutional support from Health Sciences and Neurosciences (CI SNEURO) Research Group. Louisa Degenhardt is supported by an Australian National Health and Medical Research Council Principal Research Fellowship (#1041742). Dr. Des Jarlais would like to acknowledge funding from NIH Grant DA R01 003574. KD is supported by a Welcome Trust Fellowship in Public Health and Tropical Medicine [grant number 099876]. Prof. Giuseppe Remuzzi would like to acknowledge the International Society of Nephrology (ISN) for their support of his involvement in the GBD 2013. JAS is supported by grants from the Agency for Health Quality and Research Center for Education and Research on Therapeutics (AHRQ CERTs) U19 HS021110, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) P50 AR060772 and U34 AR062891, National Institute of Aging (NIA) U01 AG018947, National Cancer Institute (NCI) U10 CA149950, and research contract CE-1304-6631 from the Patient Centered Outcomes Research Institute (PCORI). JAS is also supported by the resources and the use of facilities at the VA Medical Center at Birmingham, Alabama, USA. Dr. Soneji was supported by the National Center for Advancing Translational Sciences grant number KL2TR001088. Karen M Tabb would like to acknowledge her current support: Lemann Institute Faculty Research Grant, University of Illinois. Andrew J Vallely is supported by a Training Fellowship from the National Health and Medical Research Council (NHMRC), Australia. Gelin Xu is currently funded by the Nature Science Foundation of China (NSFC, 81070922). No individuals acknowledged received additional compensation for their efforts. NR 158 TC 240 Z9 249 U1 34 U2 263 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 SEP 13 PY 2014 VL 384 IS 9947 BP 1005 EP 1070 DI 10.1016/S0140-6736(14)60844-8 PG 66 WC Medicine, General & Internal SC General & Internal Medicine GA AO9ML UT WOS:000341679700032 PM 25059949 ER PT J AU Tallon, LJ Liu, XY Bennuru, S Chibucos, MC Godinez, A Ott, S Zhao, X Sadzewicz, L Fraser, CM Nutman, TB Hotopp, JCD AF Tallon, Luke J. Liu, Xinyue Bennuru, Sasisekhar Chibucos, Marcus C. Godinez, Alvaro Ott, Sandra Zhao, Xuechu Sadzewicz, Lisa Fraser, Claire M. Nutman, Thomas B. Hotopp, Julie C. Dunning TI Single molecule sequencing and genome assembly of a clinical specimen of Loa loa, the causative agent of loiasis SO BMC GENOMICS LA English DT Article ID LATERAL GENE-TRANSFER; READ ALIGNMENT; BRUGIA-MALAYI; RNA GENES; ANNOTATION; TOOL; GENERATION; NEMATODE; OUTBREAK; PARASITE AB Background: More than 20% of the world's population is at risk for infection by filarial nematodes and >180 million people worldwide are already infected. Along with infection comes significant morbidity that has a socioeconomic impact. The eight filarial nematodes that infect humans are Wuchereria bancrofti, Brugia malayi, Brugia timori, Onchocerca volvulus, Loa loa, Mansonella perstans, Mansonella streptocerca, and Mansonella ozzardi, of which three have published draft genome sequences. Since all have humans as the definitive host, standard avenues of research that rely on culturing and genetics have often not been possible. Therefore, genome sequencing provides an important window into understanding the biology of these parasites. The need for large amounts of high quality genomic DNA from homozygous, inbred lines; the availability of only short sequence reads from next-generation sequencing platforms at a reasonable expense; and the lack of random large insert libraries has limited our ability to generate high quality genome sequences for these parasites. However, the Pacific Biosciences single molecule, real-time sequencing platform holds great promise in reducing input amounts and generating sufficiently long sequences that bypass the need for large insert paired libraries. Results: Here, we report on efforts to generate a more complete genome assembly for L. loa using genetically heterogeneous DNA isolated from a single clinical sample and sequenced on the Pacific Biosciences platform. To obtain the best assembly, numerous assemblers and sequencing datasets were analyzed, combined, and compared. Quiver-informed trimming of an assembly of only Pacific Biosciences reads by HGAP2 was selected as the final assembly of 96.4 Mbp in 2,250 contigs. This results in similar to 9% more of the genome in similar to 85% fewer contigs from similar to 80% less starting material at a fraction of the cost of previous Roche 454-based sequencing efforts. Conclusions: The result is the most complete filarial nematode assembly produced thus far and demonstrates the utility of single molecule sequencing on the Pacific Biosciences platform for genetically heterogeneous metazoan genomes. C1 [Tallon, Luke J.; Liu, Xinyue; Chibucos, Marcus C.; Godinez, Alvaro; Ott, Sandra; Zhao, Xuechu; Sadzewicz, Lisa; Fraser, Claire M.; Hotopp, Julie C. Dunning] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Bennuru, Sasisekhar; Nutman, Thomas B.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Chibucos, Marcus C.; Hotopp, Julie C. Dunning] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Hotopp, JCD (reprint author), Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. EM jdhotopp@som.umaryland.edu OI Fraser, Claire/0000-0003-1462-2428; Chibucos, Marcus/0000-0001-9586-0780 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900009C, U19AI110820]; NIH Director's New Innovator Award Program [1-DP2-OD007372]; Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases FX We would like to thank Sergey Koren and Adam Phillippy from the National Biodefense Analysis and Countermeasures Center (NBACC) for their advice on CA assembly. This project has been funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under contract number HHSN272200900009C and grant U19AI110820. As JCDH also received funding from the NIH Director's New Innovator Award Program (1-DP2-OD007372) and SB and TN received funding from the Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases. NR 42 TC 5 Z9 5 U1 1 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD SEP 12 PY 2014 VL 15 AR 788 DI 10.1186/1471-2164-15-788 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AP5CG UT WOS:000342096700002 PM 25217238 ER PT J AU Kaltman, JR Evans, FJ Danthi, NS Wu, CO DiMichele, DM Lauer, MS AF Kaltman, Jonathan R. Evans, Frank J. Danthi, Narasimhan S. Wu, Colin O. DiMichele, Donna M. Lauer, Michael S. TI Prior Publication Productivity, Grant Percentile Ranking, and Topic-Normalized Citation Impact of NHLBI Cardiovascular R01 Grants SO CIRCULATION RESEARCH LA English DT Article DE bibliometrics; National Heart, Lung, and Blood Institute (US) AB Rationale: We previously demonstrated absence of association between peer-review-derived percentile ranking and raw citation impact in a large cohort of National Heart, Lung, and Blood Institute cardiovascular R01 grants, but we did not consider pregrant investigator publication productivity. We also did not normalize citation counts for scientific field, type of article, and year of publication. Objective: To determine whether measures of investigator prior productivity predict a grant's subsequent scientific impact as measured by normalized citation metrics. Methods and Results: We identified 1492 investigator-initiated de novo National Heart, Lung, and Blood Institute R01 grant applications funded between 2001 and 2008 and linked the publications from these grants to their InCites (Thompson Reuters) citation record. InCites provides a normalized citation count for each publication stratifying by year of publication, type of publication, and field of science. The coprimary end points for this analysis were the normalized citation impact per million dollars allocated and the number of publications per grant that has normalized citation rate in the top decile per million dollars allocated (top 10% articles). Prior productivity measures included the number of National Heart, Lung, and Blood Institute-supported publications each principal investigator published in the 5 years before grant review and the corresponding prior normalized citation impact score. After accounting for potential confounders, there was no association between peer-review percentile ranking and bibliometric end points (all adjusted P>0.5). However, prior productivity was predictive (P<0.0001). Conclusions: Even after normalizing citation counts, we confirmed a lack of association between peer-review grant percentile ranking and grant citation impact. However, prior investigator publication productivity was predictive of grant-specific citation impact. C1 [Kaltman, Jonathan R.; Evans, Frank J.] NHLBI, Heart Dev & Struct Dis Branch, Div Cardiovasc Sci, Bethesda, MD 20817 USA. [Danthi, Narasimhan S.] NHLBI, Adv Technol & Surg Branch, Div Cardiovasc Sci, Bethesda, MD 20817 USA. [Wu, Colin O.] NHLBI, Off Biostat Res, Div Cardiovasc Sci, Bethesda, MD 20817 USA. [Lauer, Michael S.] NHLBI, Off Director, Div Cardiovasc Sci, Bethesda, MD 20817 USA. [DiMichele, Donna M.] NHLBI, Off Director, Div Blood Dis & Resources, Bethesda, MD 20817 USA. RP Lauer, MS (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8128, Bethesda, MD 20817 USA. EM lauerm@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 12 TC 17 Z9 17 U1 3 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD SEP 12 PY 2014 VL 115 IS 7 BP 617 EP 624 DI 10.1161/CIRCRESAHA.115.304766 PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AP4VI UT WOS:000342076700009 PM 25214575 ER PT J AU Meng, E Mitra, A Tripathi, K Finan, MA Scalici, J McClellan, S da Silva, LM Reed, E Shevde, LA Palle, K Rocconi, RP AF Meng, Erhong Mitra, Aparna Tripathi, Kaushlendra Finan, Michael A. Scalici, Jennifer McClellan, Steve da Silva, Luciana Madeira Reed, Eddie Shevde, Lalita A. Palle, Komaraiah Rocconi, Rodney P. TI ALDH1A1 Maintains Ovarian Cancer Stem Cell-Like Properties by Altered Regulation of Cell Cycle Checkpoint and DNA Repair Network Signaling SO PLOS ONE LA English DT Article ID ALDEHYDE DEHYDROGENASE; BREAST-CANCER; CISPLATIN; RESISTANCE; CARCINOMA; MARKER; SUSCEPTIBILITY; IDENTIFICATION; COMBINATION; TRANSITION AB Objective: Aldehyde dehydrogenase (ALDH) expressing cells have been characterized as possessing stem cell-like properties. We evaluated ALDH+ ovarian cancer stem cell-like properties and their role in platinum resistance. Methods: Isogenic ovarian cancer cell lines for platinum sensitivity (A2780) and platinum resistant (A2780/CP70) as well as ascites from ovarian cancer patients were analyzed for ALDH+ by flow cytometry to determine its association to platinum resistance, recurrence and survival. A stable shRNA knockdown model for ALDH1A1 was utilized to determine its effect on cancer stem cell-like properties, cell cycle checkpoints, and DNA repair mediators. Results: ALDH status directly correlated to platinum resistance in primary ovarian cancer samples obtained from ascites. Patients with ALDH(HIGH) displayed significantly lower progression free survival than the patients with ALDH(LOW) cells (9 vs. 3 months, respectively p<0.01). ALDH1A1-knockdown significantly attenuated clonogenic potential, PARP-1 protein levels, and reversed inherent platinum resistance. ALDH1A1-knockdown resulted in dramatic decrease of KLF4 and p21 protein levels thereby leading to S and G2 phase accumulation of cells. Increases in S and G2 cells demonstrated increased expression of replication stress associated Fanconi Anemia DNA repair proteins (FANCD2, FANCJ) and replication checkpoint (pS317 Chk1) were affected. ALDH1A1-knockdown induced DNA damage, evidenced by robust induction of gamma-H2AX and BAX mediated apoptosis, with significant increases in BRCA1 expression, suggesting ALDH1A1-dependent regulation of cell cycle checkpoints and DNA repair networks in ovarian cancer stem-like cells. Conclusion: This data suggests that ovarian cancer cells expressing ALDH1A1 may maintain platinum resistance by altered regulation of cell cycle checkpoint and DNA repair network signaling. C1 [Meng, Erhong; Mitra, Aparna; Tripathi, Kaushlendra; Finan, Michael A.; Scalici, Jennifer; McClellan, Steve; da Silva, Luciana Madeira; Palle, Komaraiah; Rocconi, Rodney P.] Univ S Alabama, Mitchell Canc Inst, Mobile, AL 36688 USA. [Reed, Eddie] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. [Shevde, Lalita A.] Univ Alabama Birmingham, Birmingham, AL USA. RP Palle, K (reprint author), Univ S Alabama, Mitchell Canc Inst, Mobile, AL 36688 USA. EM kpalle@health.southalabama.edu; rocconi@health.southalabama.edu RI tripathi, kaushlendra /O-3022-2013 OI tripathi, kaushlendra /0000-0002-3578-2917 FU Gynecologic Cancer Foundation Sherri's From a Whisper to a Roar; Women's Motorcycle Foundation Ovarian Cancer Research Award; Eleanor Ruth Frenkel Fund for Ovarian Cancer Research; NIH [R01GM098956]; Abraham Mitchell Endowment grant FX This work was supported by the Gynecologic Cancer Foundation Sherri's From a Whisper to a Roar, Women's Motorcycle Foundation Ovarian Cancer Research Award and The Eleanor Ruth Frenkel Fund for Ovarian Cancer Research (R.P.R); NIH grant R01GM098956, and Abraham Mitchell Endowment grant (K.P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 23 Z9 23 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 12 PY 2014 VL 9 IS 9 AR e107142 DI 10.1371/journal.pone.0107142 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP0SM UT WOS:000341774300045 PM 25216266 ER PT J AU Taylor, AJ McClure, CD Shipkowski, KA Thompson, EA Hussain, S Garantziotis, S Parsons, GN Bonner, JC AF Taylor, Alexia J. McClure, Christina D. Shipkowski, Kelly A. Thompson, Elizabeth A. Hussain, Salik Garantziotis, Stavros Parsons, Gregory N. Bonner, James C. TI Atomic Layer Deposition Coating of Carbon Nanotubes with Aluminum Oxide Alters Pro-Fibrogenic Cytokine Expression by Human Mononuclear Phagocytes In Vitro and Reduces Lung Fibrosis in Mice In Vivo SO PLOS ONE LA English DT Article ID CERIUM DIOXIDE NANOPARTICLES; INFLAMMATORY RESPONSES; PULMONARY-FIBROSIS; MURINE MODEL; OSTEOPONTIN; TOXICITY; EXPOSURE; INHALATION; DISEASE; CELLS AB Background: Multi-walled carbon nanotubes (MWCNTs) pose a possible human health risk for lung disease as a result of inhalation exposure. Mice exposed to MWCNTs develop pulmonary fibrosis. Lung macrophages engulf MWCNTs and produce pro-fibrogenic cytokines including interleukin (IL)-1 beta, IL-6, tumor necrosis factor (TNF)-alpha, and osteopontin (OPN). Atomic layer deposition (ALD) is a novel process used to enhance functional properties of MWCNTs, yet the consequence of ALD-modified MWCNTs on macrophage biology and fibrosis is unknown. Methods: The purpose of this study was to determine whether ALD coating with aluminum oxide (Al2O3) would alter the fibrogenic response to MWCNTs and whether cytokine expression in human macrophage/monocytes exposed to MWCNTs in vitro would predict the severity of lung fibrosis in mice. Uncoated (U)-MWCNTs or ALD-coated (A)-MWCNTs were incubated with THP-1 macrophages or human peripheral blood mononuclear cells (PBMC) and cell supernatants assayed for cytokines by ELISA. C57BL6 mice were exposed to a single dose of A- or U-MWCNTs by oropharyngeal aspiration (4 mg/kg) followed by evaluation of histopathology, lung inflammatory cell counts, and cytokine levels at day 1 and 28 post-exposure. Results: ALD coating of MWCNTs with Al2O3 enhanced IL-1 beta secretion by THP-1 and PBMC in vitro, yet reduced protein levels of IL-6, TNF-alpha, and OPN production by THP-1 cells. Moreover, Al2O3 nanoparticles, but not carbon black NPs, increased IL-1 beta but decreased OPN and IL-6 in THP-1 and PBMC. Mice exposed to U-MWCNT had increased levels of all four cytokines assayed and developed pulmonary fibrosis by 28 days, whereas ALD-coating significantly reduced fibrosis and cytokine levels at the mRNA or protein level. Conclusion: These findings indicate that ALD thin film coating of MWCNTs with Al2O3 reduces fibrosis in mice and that in vitro phagocyte expression of IL-6, TNF-alpha, and OPN, but not IL-1 beta, predict MWCNT-induced fibrosis in the lungs of mice in vivo. C1 [Taylor, Alexia J.; Shipkowski, Kelly A.; Thompson, Elizabeth A.; Bonner, James C.] N Carolina State Univ, Dept Biol Sci, Environm & Mol Toxicol Program, Raleigh, NC 27695 USA. [McClure, Christina D.; Parsons, Gregory N.] N Carolina State Univ, Dept Chem & Biomol Engn, Raleigh, NC 27695 USA. [Hussain, Salik; Garantziotis, Stavros] NIEHS, Clin Res Unit, Res Triangle Pk, NC USA. RP Bonner, JC (reprint author), N Carolina State Univ, Dept Biol Sci, Environm & Mol Toxicol Program, Raleigh, NC 27695 USA. EM james_bonner@ncsu.edu RI Parsons, Gregory/O-9762-2014; Hussain, Salik/O-1687-2016; Garantziotis, Stavros/A-6903-2009 OI Parsons, Gregory/0000-0002-0048-5859; Garantziotis, Stavros/0000-0003-4007-375X FU U.S. Public Health Service Grants; National Institute of Environmental Health Sciences (NIEHS) [R01ES020897, NIEHS RC2-ES018772]; Intramural Research Program of the NIEHS FX This work was supported by U.S. Public Health Service Grants, National Institute of Environmental Health Sciences (NIEHS) R01ES020897 and NIEHS RC2-ES018772 (awarded to JCB), and in part by the Intramural Research Program of the NIEHS (SH, SG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 13 Z9 13 U1 5 U2 31 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 SEP 12 PY 2014 VL 9 IS 9 AR e106870 DI 10.1371/journal.pone.0106870 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP0SM UT WOS:000341774300028 PM 25216247 ER PT J AU Porcu, E Sipos, A Basso, G Hamel, E Bai, RL Stempfer, V Udvardy, A Benyei, AC Schmidhammer, H Antus, S Viola, G AF Porcu, Elena Sipos, Attila Basso, Giuseppe Hamel, Ernest Bai, Ruoli Stempfer, Verena Udvardy, Antal Benyei, Attila Cs Schmidhammer, Helmut Antus, Sandor Viola, Giampietro TI Novel 9 '-substituted-noscapines: Synthesis with Suzuki cross-coupling, structure elucidation and biological evaluation SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Noscapine; Antimicrotubule agents; Apoptosis; Cell cycle arrest; Suzuki reaction ID MICROTUBULE-INTERFERING AGENTS; SUBSTITUTED NOSCAPINE ANALOGS; PHTHALIDEISOQUINOLINE ALKALOIDS; ANTICANCER ACTIVITY; ANTIMITOTIC AGENTS; ALPHA-NOSCAPINE; CANCER CELLS; TUBULIN; APOPTOSIS; COLCHICINE AB Tubulin is a major molecular target for anticancer drugs. The dynamic process of microtubule assembly and disassembly can be blocked by various agents that bind to distinct sites on tubulin, usually its beta-subunit. Among the antimitotic agents that perturb microtubule dynamics, noscapinoids represent an emerging class of agents. In particular, 9'-bromonoscapine (EM011) has been identified as a potent noscapine analog. Here we present high yielding, efficient synthetic methods based on Suzuki coupling of 9'-alkyl and 9'-arylnoscapines and an evaluation of their antiproliferative properties. Our results showed that 9'-alkyl and 9'-aryl derivatives inhibit proliferation of human cancer cells. The most active compounds were the 9'-methyl and the 9'-phenyl derivatives, which showed similar cytotoxic potency in comparison to the 9'-brominated derivative. Interestingly these newly synthesized derivatives did not induce cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. All of these derivatives, except 9'-(2-methoxyphenyl)-noscapine, efficiently induced a cell cycle arrest in the G2/M phase of the cell cycle in HeLa and Jurkat cells. Furthermore, we showed that the most active compounds in HeLa cells induced apoptosis following the mitochondrial pathway with the activation of both caspase-9 and caspase-3. In addition, these compounds significantly reduced the expression of the anti-apoptotic proteins Mcl-1 and Bcl-2. (C) 2014 Elsevier Masson SAS. All rights reserved. C1 [Porcu, Elena; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Dept Womans & Childs Hlth, Lab Oncohematol, I-35128 Padua, Italy. [Hamel, Ernest; Bai, Ruoli] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Stempfer, Verena; Schmidhammer, Helmut] Univ Innsbruck, Inst Pharm, Dept Pharmaceut Chem, A-6020 Innsbruck, Austria. [Stempfer, Verena; Schmidhammer, Helmut] Univ Innsbruck, Ctr Mol Biosci Innsbruck, A-6020 Innsbruck, Austria. [Udvardy, Antal; Benyei, Attila Cs] Univ Debrecen, Dept Phys Chem, Debrecen, Hungary. [Sipos, Attila; Benyei, Attila Cs] Univ Debrecen, Med & Hlth Sci Ctr, Dept Pharmaceut Chem, Debrecen, Hungary. [Antus, Sandor] Univ Debrecen, Dept Organ Chem, Debrecen, Hungary. RP Viola, G (reprint author), Univ Padua, Dept Womans & Childs Hlth, Lab Oncohematol, Via Giustiniani 2, I-35128 Padua, Italy. EM Giampietro.viola.1@unipd.it RI Viola, Giampietro/I-4095-2012; OI Viola, Giampietro/0000-0001-9329-165X; BASSO, GIUSEPPE/0000-0002-2634-9302; , Sipos/0000-0003-0613-0845 FU European Union; State of Hungary (OTKA) [101372]; European Social Fund [TAMOP 4.2.4. A/2-11.-1-2012-0001] FX This research was supported by the European Union and the State of Hungary (OTKA Grant No. 101372), co-financed by the European Social Fund in the framework of TAMOP 4.2.4. A/2-11.-1-2012-0001 'National Excellence Program'. NR 59 TC 6 Z9 6 U1 0 U2 16 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD SEP 12 PY 2014 VL 84 BP 476 EP 490 DI 10.1016/j.ejmech.2014.07.050 PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AO6LV UT WOS:000341464500044 PM 25050880 ER PT J AU Pajevic, S Basser, PJ Fields, RD AF Pajevic, S. Basser, P. J. Fields, R. D. TI ROLE OF MYELIN PLASTICITY IN OSCILLATIONS AND SYNCHRONY OF NEURONAL ACTIVITY SO NEUROSCIENCE LA English DT Article DE activity-dependent myelination; white matter plasticity; synchronization; oscillations; conduction velocity and delays; coupled oscillators ID INTERAURAL TIME DIFFERENCES; LIMIT-CYCLE OSCILLATORS; BRAINS WHITE-MATTER; PHASE SYNCHRONIZATION; COUPLED OSCILLATORS; CONDUCTION-VELOCITY; SOUND LOCALIZATION; PREFRONTAL CORTEX; ACTION-POTENTIALS; VISUAL-CORTEX AB Conduction time is typically ignored in computational models of neural network function. Here we consider the effects of conduction delays on the synchrony of neuronal activity and neural oscillators, and evaluate the consequences of allowing conduction velocity (CV) to be regulated adaptively. We propose that CV variation, mediated by myelin, could provide an important mechanism of activity-dependent nervous system plasticity. Even small changes in CV, resulting from small changes in myelin thickness or nodal structure, could have profound effects on neuronal network function in terms of spike-time arrival, oscillation frequency, oscillator coupling, and propagation of brain waves. For example, a conduction delay of 5 ms could change interactions of two coupled oscillators at the upper end of the gamma frequency range (similar to 100 Hz) from constructive to destructive interference; delays smaller than 1 ms could change the phase by 30, significantly affecting signal amplitude. Myelin plasticity, as another form of activity-dependent plasticity, is relevant not only to nervous system development but also to complex information processing tasks that involve coupling and synchrony among different brain rhythms. We use coupled oscillator models with time delays to explore the importance of adaptive time delays and adaptive synaptic strengths. The impairment of activity-dependent myelination and the loss of adaptive time delays may contribute to disorders where hyper- and hypo-synchrony of neuronal firing leads to dysfunction (e.g., dyslexia, schizophrenia, epilepsy). This article is part of a Special Issue entitled: The CNS White Matter. Published by Elsevier Ltd. on behalf of IBRO. C1 [Pajevic, S.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technology, Bethesda, MD 20892 USA. [Basser, P. J.] NICHD, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, Bethesda, MD USA. [Fields, R. D.] NICHHD, Nervous Syst Dev & Plast Sect, NIH, Bethesda, MD USA. RP Fields, RD (reprint author), NIH, Bldg 35,Room 2A211,MSC 3713, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov FU Intramural NIH HHS [ZIA HD000713-19] NR 90 TC 45 Z9 45 U1 3 U2 26 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD SEP 12 PY 2014 VL 276 BP 135 EP 147 DI 10.1016/j.neuroscience.2013.11.007 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AO4UT UT WOS:000341337600012 PM 24291730 ER PT J AU Gire, SK Goba, A Andersen, KG Sealfon, RSG Park, DJ Kanneh, L Jalloh, S Momoh, M Fullah, M Dudas, G Wohl, S Moses, LM Yozwiak, NL Winnicki, S Matranga, CB Malboeuf, CM Qu, J Gladden, AD Schaffner, SF Yang, X Jiang, PP Nekoui, M Colubri, A Coomber, MR Fonnie, M Moigboi, A Gbakie, M Kamara, FK Tucker, V Konuwa, E Saffa, S Sellu, J Jalloh, AA Kovoma, A Koninga, J Mustapha, I Kargbo, K Foday, M Yillah, M Kanneh, F Robert, W Massally, JLB Chapman, SB Bochicchio, J Murphy, C Nusbaum, C Young, S Birren, B Grant, DS Scheiffelin, JS Lander, ES Happi, C Gevao, SM Gnirke, A Rambaut, A Garry, RF Khan, SH Sabeti, PC AF Gire, Stephen K. Goba, Augustine Andersen, Kristian G. Sealfon, Rachel S. G. Park, Daniel J. Kanneh, Lansana Jalloh, Simbirie Momoh, Mambu Fullah, Mohamed Dudas, Gytis Wohl, Shirlee Moses, Lina M. Yozwiak, Nathan L. Winnicki, Sarah Matranga, Christian B. Malboeuf, Christine M. Qu, James Gladden, Adrianne D. Schaffner, Stephen F. Yang, Xiao Jiang, Pan-Pan Nekoui, Mahan Colubri, Andres Coomber, Moinya Ruth Fonnie, Mbalu Moigboi, Alex Gbakie, Michael Kamara, Fatima K. Tucker, Veronica Konuwa, Edwin Saffa, Sidiki Sellu, Josephine Jalloh, Abdul Azziz Kovoma, Alice Koninga, James Mustapha, Ibrahim Kargbo, Kandeh Foday, Momoh Yillah, Mohamed Kanneh, Franklyn Robert, Willie Massally, James L. B. Chapman, Sinead B. Bochicchio, James Murphy, Cheryl Nusbaum, Chad Young, Sarah Birren, BruceW. Grant, Donald S. Scheiffelin, John S. Lander, Eric S. Happi, Christian Gevao, Sahr M. Gnirke, Andreas Rambaut, Andrew Garry, Robert F. Khan, S. Humarr Sabeti, Pardis C. TI Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak SO SCIENCE LA English DT Article ID PURIFYING SELECTION; HEMORRHAGIC-FEVER; DENGUE VIRUS; POLYMERASE; RNA AB In its largest outbreak, Ebola virus disease is spreading through Guinea, Liberia, Sierra Leone, and Nigeria. We sequenced 99 Ebola virus genomes from 78 patients in Sierra Leone to similar to 2000x coverage. We observed a rapid accumulation of interhost and intrahost genetic variation, allowing us to characterize patterns of viral transmission over the initial weeks of the epidemic. This West African variant likely diverged from central African lineages around 2004, crossed from Guinea to Sierra Leone in May 2014, and has exhibited sustained human-to-human transmission subsequently, with no evidence of additional zoonotic sources. Because many of the mutations alter protein sequences and other biologically meaningful targets, they should be monitored for impact on diagnostics, vaccines, and therapies critical to outbreak response. C1 [Gire, Stephen K.; Andersen, Kristian G.; Wohl, Shirlee; Yozwiak, Nathan L.; Winnicki, Sarah; Schaffner, Stephen F.; Jiang, Pan-Pan; Nekoui, Mahan; Colubri, Andres; Sabeti, Pardis C.] Harvard Univ, Dept Organism & Evolutionary Biol, Ctr Syst Biol, Cambridge, MA 02138 USA. [Gire, Stephen K.; Andersen, Kristian G.; Sealfon, Rachel S. G.; Park, Daniel J.; Wohl, Shirlee; Yozwiak, Nathan L.; Winnicki, Sarah; Matranga, Christian B.; Malboeuf, Christine M.; Qu, James; Gladden, Adrianne D.; Schaffner, Stephen F.; Yang, Xiao; Jiang, Pan-Pan; Nekoui, Mahan; Chapman, Sinead B.; Bochicchio, James; Murphy, Cheryl; Nusbaum, Chad; Young, Sarah; Birren, BruceW.; Lander, Eric S.; Gnirke, Andreas; Sabeti, Pardis C.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Gire, Stephen K.; Kanneh, Lansana; Jalloh, Simbirie; Momoh, Mambu; Fullah, Mohamed; Coomber, Moinya Ruth; Fonnie, Mbalu; Moigboi, Alex; Gbakie, Michael; Kamara, Fatima K.; Tucker, Veronica; Konuwa, Edwin; Saffa, Sidiki; Sellu, Josephine; Jalloh, Abdul Azziz; Kovoma, Alice; Koninga, James; Mustapha, Ibrahim; Kargbo, Kandeh; Foday, Momoh; Yillah, Mohamed; Kanneh, Franklyn; Robert, Willie; Massally, James L. B.; Grant, Donald S.; Khan, S. Humarr] Kenema Govt Hosp, Kenema, Sierra Leone. [Sealfon, Rachel S. G.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Momoh, Mambu; Fullah, Mohamed] Eastern Polytech Coll, Kenema, Sierra Leone. [Dudas, Gytis; Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3JT, Midlothian, Scotland. [Wohl, Shirlee; Lander, Eric S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Moses, Lina M.; Scheiffelin, John S.; Garry, Robert F.] Tulane Univ, Med Ctr, New Orleans, LA 70112 USA. [Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Happi, Christian] Redeemers Univ, Redemption, Ogun State, Nigeria. [Gevao, Sahr M.] Univ Sierra Leone, Freetown, Sierra Leone. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Rambaut, Andrew] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh EH9 3JT, Midlothian, Scotland. RP Goba, A (reprint author), Kenema Govt Hosp, Kenema, Sierra Leone. EM augstgoba@yahoo.com; andersen@broadinstitute.org; psabeti@oeb.harvard.edu RI Schaffner, Stephen/D-1189-2011; OI Rambaut, Andrew/0000-0003-4337-3707; Dudas, Gytis/0000-0002-0227-4158 FU NSF Graduate Research Fellowship Program; NIH grant [GM080177, 1DP2OD006514-01]; NIH [1U01HG007480-01]; World Bank; European Union [FP7/2007-2013 278433-PREDEMICS]; European Research Council [260864]; Natural Environment Research Council grant [D76739X]; National Institute of Allergy and Infectious Diseases grant [HHSN272200900049C] FX We thank the Office of the President of Sierra Leone (President E. Koroma, M. Jones, S. Blyden), the Sierra Leone Ministry of Health and Sanitation (Minister M. Kargbo, B. Kargbo, M. A. Vandi, A. Jambai), the Kenema District Health Management Team, and the Lassa fever program for their efforts in outbreak response. We thank P. Cingolani, Y.-C. Wu, M. Lipsitch, S. Gunther, S. Baize, N. Wauquier, J. Bangura, V. Lungay, L. Hensley, J. Johnson, M. Voorhees, A. O'Hearn, R. Schoepp, L. Gaffney, J. Kuhn, S. C. Sealfon, J. B. Shapiro, C. Edwards, and Sabeti lab members for technical support and feedback. Supported by the NSF Graduate Research Fellowship Program (R. S. G. S.), NIH grant GM080177 (S. Wohl), NIH grant 1U01HG007480-01 and the World Bank (C. H.), European Union grant FP7/2007-2013 278433-PREDEMICS and European Research Council grant 260864 (A. R.), Natural Environment Research Council grant D76739X (G. D.), NIH grant 1DP2OD006514-01, and National Institute of Allergy and Infectious Diseases grant HHSN272200900049C. Sequence data are available at NCBI (NCBI BioGroup: PRJNA257197). Sharing of RNA samples used in this study requires approval from the Sierra Leone Ministry of Health and Sanitation. NR 16 TC 369 Z9 394 U1 39 U2 462 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 SEP 12 PY 2014 VL 345 IS 6202 BP 1369 EP 1372 DI 10.1126/science.1259657 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO6TG UT WOS:000341483800071 PM 25214632 ER PT J AU Bass, AJ Thorsson, V Shmulevich, I Reynolds, SM Miller, M Bernard, B Hinoue, T Laird, PW Curtis, C Shen, H Weisenberger, DJ Schultz, N Shen, RL Weinhold, N Keiser, DP Bowlby, R Sipahimalani, P Cherniack, AD Getz, G Liu, YC Noble, MS Pedamallu, C Sougnez, C Taylor-Weiner, A Akbani, R Lee, JS Liu, WB Mills, GB Yang, D Zhang, W Pantazi, A Parfenov, M Gulley, M Piazuelo, MB Schneider, BG Kim, J Boussioutas, A Sheth, M Demchok, JA Rabkin, CS Willis, JE Ng, S Garman, K Beer, DG Pennathur, A Raphael, BJ Wu, HT Odze, R Kim, HK Bowen, J Leraas, KM Lichtenberg, TM Weaver, L McLellan, M Wiznerowicz, M Sakai, R Getz, G Sougnez, C Lawrence, MS Cibulskis, K Lichtenstein, L Fisher, S Gabriel, SB Lander, ES Ding, L Niu, BF Ally, A Balasundaram, M Birol, I Bowlby, R Brooks, D Butterfield, YSN Carlsen, R Chu, A Chu, J Chuah, E Chun, HJE Clarke, A Dhalla, N Guin, R Holt, RA Jones, SJM Kasaian, K Lee, D Li, HYA Lim, E Ma, Y Marra, MA Mayo, M Moore, RA Mungall, AJ Mungall, KL Nip, KM Robertson, AG Schein, JE Sipahimalani, P Tam, A Thiessen, N Beroukhim, R Carter, SL Cherniack, AD Cho, J Cibulskis, K DiCara, D Frazer, S Fisher, S Gabriel, SB Gehlenborg, N Heiman, DI Jung, J Kim, J Lander, ES Lawrence, MS Lichtenstein, L Lin, P Meyerson, M Ojesina, AI Pedamallu, CS Saksena, G Schumacher, SE Sougnez, C Stojanov, P Tabak, B Taylor-Weiner, A Voet, D Rosenberg, M Zack, TI Zhang, HL Zou, LH Protopopov, A Santoso, N Parfenov, M Lee, S Zhang, J Mahadeshwar, HS Tang, JB Ren, XJ Seth, S Yang, LX Xu, AW Song, XZ Pantazi, A Xi, RB Bristow, CA Hadjipanayis, A Seidman, J Chin, L Park, PJ Kucherlapati, R Akbani, R Ling, SY Liu, WB Rao, A Weinstein, JN Kim, SB Lee, JS Lu, YL Mills, G Hinoue, T Weisenberger, DJ Bootwalla, MS Lai, PH Shen, H Triche, T Van Den Berg, DJ Baylin, SB Herman, JG Getz, G Chin, L Liu, YC Murray, BA Noble, MS Askoy, BA Ciriello, G Dresdner, G Gao, JJ Gross, B Jacobsen, A Lee, W Ramirez, R Sander, C Schultz, N Senbabaoglu, Y Sinha, R Sumer, SO Sun, YC Weinhold, N Thorsson, V Bernard, B Iype, L Kramer, RW Kreisberg, R Miller, M Reynolds, SM Rovira, H Tasman, N Shmulevich, I Ng, S Haussler, D Stuart, JM Akbani, R Ling, SY Liu, WB Rao, A Weinstein, JN Verhaak, RGW Mills, GB Leiserson, MDM Raphael, BJ Wu, HT Taylor, BS Black, AD Bowen, J Carney, JA Gastier-Foster, JM Helsel, C Leraas, KM Lichtenberg, TM McAllister, C Ramirez, NC Tabler, TR Wise, L Zmuda, E Penny, R Crain, D Gardner, J Lau, K Curely, E Mallery, D Morris, S Paulauskis, J Shelton, T Shelton, C Sherman, M Benz, C Lee, JH Fedosenko, K Manikhas, G Voronina, O Belyaev, D Dolzhansky, O Rathmell, WK Brzezinski, J Ibbs, M Korski, K Kycler, W Lazniak, R Leporowska, E Mackiewicz, A Murawa, D Murawa, P Spychala, A Suchorska, WM Tatka, H Teresiak, M Wiznerowicz, M Abdel-Misih, R Bennett, J Brown, J Iacocca, M Rabeno, B Kwon, SY Penny, R Gardner, J Kemkes, A Mallery, D Morris, S Shelton, T Shelton, C Curley, E Alexopoulou, I Engel, J Bartlett, J Albert, M Park, DY Dhir, R Luketich, J Landreneau, R Janjigian, YY Kelsen, DP Cho, E Ladanyi, M Tang, L McCall, SJ Park, YS Cheong, JH Ajani, J Camargo, MC Alonso, S Ayala, B Jensen, MA Pihl, T Raman, R Walton, J Wan, YH Demchok, JA Eley, G Shaw, KRM Sheth, M Tarnuzzer, R Wang, ZN Yang, LM Zenklusen, JC Davidsen, T Hutter, CM Sofia, HJ Burton, R Chudamani, S Liu, J AF Bass, Adam J. Thorsson, Vesteinn Shmulevich, Ilya Reynolds, Sheila M. Miller, Michael Bernard, Brady Hinoue, Toshinori Laird, Peter W. Curtis, Christina Shen, Hui Weisenberger, Daniel J. Schultz, Nikolaus Shen, Ronglai Weinhold, Nils Keiser, David P. Bowlby, Reanne Sipahimalani, Payal Cherniack, Andrew D. Getz, Gad Liu, Yingchun Noble, Michael S. Pedamallu, Chandra Sougnez, Carrie Taylor-Weiner, Amaro Akbani, Rehan Lee, Ju-Seog Liu, Wenbin Mills, Gordon B. Yang, Da Zhang, Wei Pantazi, Angeliki Parfenov, Michael Gulley, Margaret Piazuelo, M. Blanca Schneider, Barbara G. Kim, Jihun Boussioutas, Alex Sheth, Margi Demchok, John A. Rabkin, Charles S. Willis, Joseph E. Ng, Sam Garman, Katherine Beer, David G. Pennathur, Arjun Raphael, Benjamin J. Wu, Hsin-Ta Odze, Robert Kim, Hark K. Bowen, Jay Leraas, Kristen M. Lichtenberg, Tara M. Weaver, Lichtenberg McLellan, Michael Wiznerowicz, Maciej Sakai, Ryo Getz, Gad Sougnez, Carrie Lawrence, Michael S. Cibulskis, Kristian Lichtenstein, Lee Fisher, Sheila Gabriel, Stacey B. Lander, Eric S. Ding, Li Niu, Beifang Ally, Adrian Balasundaram, Miruna Birol, Inanc Bowlby, Reanne Brooks, Denise Butterfield, Yaron S. N. Carlsen, Rebecca Chu, Andy Chu, Justin Chuah, Eric Chun, Hye-Jung E. Clarke, Amanda Dhalla, Noreen Guin, Ranabir Holt, Robert A. Jones, Steven J. M. Kasaian, Katayoon Lee, Darlene Li, Haiyan A. Lim, Emilia Ma, Yussanne Marra, Marco A. Mayo, Michael Moore, Richard A. Mungall, Andrew J. Mungall, Karen L. Nip, Ka Ming Robertson, A. Gordon Schein, Jacqueline E. Sipahimalani, Payal Tam, Angela Thiessen, Nina Beroukhim, Rameen Carter, Scott L. Cherniack, Andrew D. Cho, Juok Cibulskis, Kristian DiCara, Daniel Frazer, Scott Fisher, Sheila Gabriel, Stacey B. Gehlenborg, Nils Heiman, David I. Jung, Joonil Kim, Jaegil Lander, Eric S. Lawrence, Michael S. Lichtenstein, Lee Lin, Pei Meyerson, Matthew Ojesina, Akinyemi I. Pedamallu, Chandra Sekhar Saksena, Gordon Schumacher, Steven E. Sougnez, Carrie Stojanov, Petar Tabak, Barbara Taylor-Weiner, Amaro Voet, Doug Rosenberg, Mara Zack, Travis I. Zhang, Hailei Zou, Lihua Protopopov, Alexei Santoso, Netty Parfenov, Michael Lee, Semin Zhang, Jianhua Mahadeshwar, Harshad S. Tang, Jiabin Ren, Xiaojia Seth, Sahil Yang, Lixing Xu, Andrew W. Song, Xingzhi Pantazi, Angeliki Xi, Ruibin Bristow, Christopher A. Hadjipanayis, Angela Seidman, Jonathan Chin, Lynda Park, Peter J. Kucherlapati, Raju Akbani, Rehan Ling, Shiyun Liu, Wenbin Rao, Arvind Weinstein, John N. Kim, Sang-Bae Lee, Ju-Seog Lu, Yiling Mills, Gordon Hinoue, Toshinori Weisenberger, Daniel J. Bootwalla, Moiz S. Lai, Phillip H. Shen, Hui Triche, Timothy, Jr. Van Den Berg, David J. Baylin, Stephen B. Herman, James G. Getz, Gad Chin, Lynda Liu, Yingchun Murray, Bradley A. Noble, Michael S. Askoy, B. Arman Ciriello, Giovanni Dresdner, Gideon Gao, Jianjiong Gross, Benjamin Jacobsen, Anders Lee, William Ramirez, Ricardo Sander, Chris Schultz, Nikolaus Senbabaoglu, Yasin Sinha, Rileen Sumer, S. Onur Sun, Yichao Weinhold, Nils Thorsson, Vesteinn Bernard, Brady Iype, Lisa Kramer, Roger W. Kreisberg, Richard Miller, Michael Reynolds, Sheila M. Rovira, Hector Tasman, Natalie Shmulevich, Ilya Ng, Sam Haussler, David Stuart, Josh M. Akbani, Rehan Ling, Shiyun Liu, Wenbin Rao, Arvind Weinstein, John N. Verhaak, Roeland G. W. Mills, Gordon B. Leiserson, Mark D. M. Raphael, Benjamin J. Wu, Hsin-Ta Taylor, Barry S. Black, Aaron D. Bowen, Jay Carney, Julie Ann Gastier-Foster, Julie M. Helsel, Carmen Leraas, Kristen M. Lichtenberg, Tara M. McAllister, Cynthia Ramirez, Nilsa C. Tabler, Teresa R. Wise, Lisa Zmuda, Erik Penny, Robert Crain, Daniel Gardner, Johanna Lau, Kevin Curely, Erin Mallery, David Morris, Scott Paulauskis, Joseph Shelton, Troy Shelton, Candace Sherman, Mark Benz, Christopher Lee, Jae-Hyuk Fedosenko, Konstantin Manikhas, Georgy Voronina, Olga Belyaev, Dmitry Dolzhansky, Oleg Rathmell, W. Kimryn Brzezinski, Jakub Ibbs, Matthew Korski, Konstanty Kycler, Witold Lazniak, Radoslaw Leporowska, Ewa Mackiewicz, Andrzej Murawa, Dawid Murawa, Pawel Spychala, Arkadiusz Suchorska, Wiktoria M. Tatka, Honorata Teresiak, Marek Wiznerowicz, Maciej Abdel-Misih, Raafat Bennett, Joseph Brown, Jennifer Iacocca, Mary Rabeno, Brenda Kwon, Sun-Young Penny, Robert Gardner, Johanna Kemkes, Ariane Mallery, David Morris, Scott Shelton, Troy Shelton, Candace Curley, Erin Alexopoulou, Iakovina Engel, Jay Bartlett, John Albert, Monique Park, Do-Youn Dhir, Rajiv Luketich, James Landreneau, Rodney Janjigian, Yelena Y. Kelsen, David P. Cho, Eunjung Ladanyi, Marc Tang, Laura McCall, Shannon J. Park, Young S. Cheong, Jae-Ho Ajani, Jaffer Camargo, M. Constanza Alonso, Shelley Ayala, Brenda Jensen, Mark A. Pihl, Todd Raman, Rohini Walton, Jessica Wan, Yunhu Demchok, John A. Eley, Greg Shaw, Kenna R. Mills Sheth, Margi Tarnuzzer, Roy Wang, Zhining Yang, Liming Zenklusen, Jean Claude Davidsen, Tanja Hutter, Carolyn M. Sofia, Heidi J. Burton, Robert Chudamani, Sudha Liu, Jia CA Canc Genome Atlas Res Network TI Comprehensive molecular characterization of gastric adenocarcinoma SO NATURE LA English DT Article ID SOMATIC MUTATIONS; GENE-EXPRESSION; CELL LYMPHOMAS; EBV-INFECTION; CANCER; EXOME; METHYLATION; SUBTYPES; KINASE; CLASSIFICATION AB Gastric cancer is a leading cause of cancer deaths, but analysis of molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roalmap for patient stratification and trials of targeted therapies. C1 [Bass, Adam J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Bass, Adam J.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. [Thorsson, Vesteinn; Shmulevich, Ilya; Reynolds, Sheila M.; Miller, Michael; Bernard, Brady; Iype, Lisa; Kramer, Roger W.; Kreisberg, Richard; Rovira, Hector; Tasman, Natalie] Inst Syst Biol, Seattle, WA 98109 USA. [Hinoue, Toshinori; Laird, Peter W.; Shen, Hui; Weisenberger, Daniel J.; Bootwalla, Moiz S.; Lai, Phillip H.; Triche, Timothy, Jr.; Van Den Berg, David J.] Univ So Calif, USC Epigenome Ctr, Los Angeles, CA 90033 USA. [Curtis, Christina] Univ So Calif, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Schultz, Nikolaus; Weinhold, Nils; Askoy, B. Arman; Ciriello, Giovanni; Dresdner, Gideon; Gao, Jianjiong; Gross, Benjamin; Jacobsen, Anders; Lee, William; Ramirez, Ricardo; Sander, Chris; Senbabaoglu, Yasin; Sinha, Rileen; Sumer, S. Onur; Sun, Yichao] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Shen, Ronglai] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Keiser, David P.; Janjigian, Yelena Y.; Kelsen, David P.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Bowlby, Reanne; Sipahimalani, Payal; Ally, Adrian; Balasundaram, Miruna; Birol, Inanc; Brooks, Denise; Butterfield, Yaron S. N.; Carlsen, Rebecca; Chu, Andy; Chu, Justin; Chuah, Eric; Chun, Hye-Jung E.; Clarke, Amanda; Dhalla, Noreen; Guin, Ranabir; Holt, Robert A.; Jones, Steven J. M.; Kasaian, Katayoon; Lee, Darlene; Li, Haiyan A.; Lim, Emilia; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Mungall, Karen L.; Nip, Ka Ming; Robertson, A. Gordon; Schein, Jacqueline E.; Tam, Angela; Thiessen, Nina] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Cherniack, Andrew D.; Getz, Gad; Liu, Yingchun; Noble, Michael S.; Pedamallu, Chandra; Sougnez, Carrie; Taylor-Weiner, Amaro; Lawrence, Michael S.; Cibulskis, Kristian; Lichtenstein, Lee; Fisher, Sheila; Gabriel, Stacey B.; Lander, Eric S.; Beroukhim, Rameen; Carter, Scott L.; Cho, Juok; DiCara, Daniel; Frazer, Scott; Gehlenborg, Nils; Heiman, David I.; Jung, Joonil; Kim, Jaegil; Lin, Pei; Meyerson, Matthew; Ojesina, Akinyemi I.; Pedamallu, Chandra Sekhar; Saksena, Gordon; Schumacher, Steven E.; Stojanov, Petar; Tabak, Barbara; Voet, Doug; Rosenberg, Mara; Zack, Travis I.; Zhang, Hailei; Zou, Lihua; Murray, Bradley A.] Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Akbani, Rehan; Lee, Ju-Seog; Liu, Wenbin; Ling, Shiyun; Rao, Arvind; Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Mills, Gordon B.; Kim, Sang-Bae; Lee, Ju-Seog; Lu, Yiling; Mills, Gordon] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Yang, Da; Zhang, Wei] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Pantazi, Angeliki; Parfenov, Michael; Santoso, Netty; Ren, Xiaojia; Hadjipanayis, Angela; Seidman, Jonathan; Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Gulley, Margaret] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Piazuelo, M. Blanca; Schneider, Barbara G.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. [Kim, Jihun; Park, Young S.] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 138736, South Korea. [Boussioutas, Alex] Univ Melbourne, Sir Peter MacCallum Canc Dept Oncol, East Melbourne 3002, Australia. [Sheth, Margi; Demchok, John A.; Eley, Greg; Shaw, Kenna R. Mills; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean Claude] NCI, Bethesda, MD 20892 USA. [Rabkin, Charles S.; Camargo, M. Constanza] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Willis, Joseph E.] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Ng, Sam; Haussler, David; Stuart, Josh M.] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Haussler, David; Stuart, Josh M.] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Garman, Katherine] Duke Univ, Dept Med, Div Gastroenterol, Durham, NC 27710 USA. [Beer, David G.] Univ Michigan, Ctr Canc, Dept Thorac Surg, Ann Arbor, MI 48109 USA. [Pennathur, Arjun; Dhir, Rajiv; Luketich, James; Landreneau, Rodney] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Raphael, Benjamin J.; Wu, Hsin-Ta; Leiserson, Mark D. M.] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA. [Wu, Hsin-Ta; Leiserson, Mark D. M.] Brown Univ, Ctr Computat Mol Biol, Providence, RI 02912 USA. [Odze, Robert] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kim, Hark K.] Natl Canc Ctr, Goyang 410769, South Korea. [Bowen, Jay; Leraas, Kristen M.; Lichtenberg, Tara M.; Weaver, Lichtenberg; Black, Aaron D.; Carney, Julie Ann; Gastier-Foster, Julie M.; Helsel, Carmen; McAllister, Cynthia; Ramirez, Nilsa C.; Tabler, Teresa R.; Wise, Lisa; Zmuda, Erik] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA. [McLellan, Michael; Ding, Li; Niu, Beifang] Washington Univ, Genome Inst, St Louis, MO 63108 USA. [Wiznerowicz, Maciej; Brzezinski, Jakub; Ibbs, Matthew; Korski, Konstanty; Kycler, Witold; Lazniak, Radoslaw; Leporowska, Ewa; Mackiewicz, Andrzej; Murawa, Dawid; Murawa, Pawel; Spychala, Arkadiusz; Suchorska, Wiktoria M.; Tatka, Honorata; Teresiak, Marek] Greater Poland Canc Ctr, PL-61866 Poznan, Poland. [Sakai, Ryo] Katholieke Univ Leuven, Dept Elect Engn ESAT STADIUS, Leuven, Belgium. [Protopopov, Alexei; Zhang, Jianhua; Mahadeshwar, Harshad S.; Tang, Jiabin; Seth, Sahil; Song, Xingzhi; Bristow, Christopher A.; Chin, Lynda; Verhaak, Roeland G. W.] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Dept Genom Med, Houston, TX 77054 USA. [Lee, Semin; Yang, Lixing; Xu, Andrew W.; Xi, Ruibin; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Baylin, Stephen B.; Herman, James G.] Johns Hopkins Univ, Canc Biol Div, Baltimore, MD 21231 USA. [Taylor, Barry S.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Penny, Robert; Crain, Daniel; Gardner, Johanna; Lau, Kevin; Curely, Erin; Mallery, David; Morris, Scott; Paulauskis, Joseph; Shelton, Troy; Shelton, Candace; Sherman, Mark; Kemkes, Ariane] Int Genom Consortium, Phoenix, AZ 85004 USA. [Benz, Christopher] Buck Inst Res Aging, Novato, CA 94945 USA. [Lee, Jae-Hyuk] Chonnam Natl Univ, Sch Med, Kwangju 501746, South Korea. [Fedosenko, Konstantin; Manikhas, Georgy] City Clin Oncol Dispensary, St Petersburg 198255, Russia. [Voronina, Olga; Belyaev, Dmitry; Dolzhansky, Oleg] Cureline Inc, San Francisco, CA 94080 USA. [Rathmell, W. Kimryn] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Rathmell, W. Kimryn] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Abdel-Misih, Raafat; Bennett, Joseph; Brown, Jennifer; Iacocca, Mary; Rabeno, Brenda] Christiana Care Hlth Syst, Helen Graham Canc Ctr & Res Inst, Newark, DE 19713 USA. [Kwon, Sun-Young] Keimyung Univ, Sch Med, Taegu 700712, South Korea. [Alexopoulou, Iakovina] St Josephs Healthcare Hamilton, Ontario Tumour Bank, Hamilton, ON L8N 3Z5, Canada. [Engel, Jay] Kingston Gen Hosp, Ontario Tumour Bank, Kingston, ON K7L 5H6, Canada. [Bartlett, John; Albert, Monique] Ontario Inst Canc Res, Ontario Tumour Bank, Toronto, ON M5G 0A3, Canada. [Park, Do-Youn] Pusan Natl Univ Hosp, Pusan 602739, South Korea. [Cho, Eunjung; Ladanyi, Marc; Tang, Laura] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [McCall, Shannon J.] Duke Univ, Dept Pathol, Durham, NC 27710 USA. [Cheong, Jae-Ho] Yonsei Univ, Coll Med, Dept Surg, Seoul 120752, South Korea. [Ajani, Jaffer] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Alonso, Shelley; Ayala, Brenda; Jensen, Mark A.; Pihl, Todd; Raman, Rohini; Walton, Jessica; Wan, Yunhu] SRA Int, Fairfax, VA 22033 USA. [Davidsen, Tanja] NCI, Ctr Biomed Informat & Informat Technol, Rockville, MD 20850 USA. [Hutter, Carolyn M.; Sofia, Heidi J.] NHGRI, Bethesda, MD 20892 USA. [Burton, Robert; Chudamani, Sudha; Liu, Jia] SAIC Frederick Inc, Frederick, MD 21702 USA. RP Bass, AJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM adam_bass@dfci.harvard.edu RI Senbabaoglu, Yasin/I-4922-2013; Laird, Peter/G-8683-2012; Jacobsen, Anders/K-1081-2013; Ling, Shiyun/P-2242-2014; Schein, Jacquie/G-3674-2015; Holt, Robert/C-3303-2009; Jones, Steven/C-3621-2009; Camargo, M. Constanza/R-9891-2016; Lee, Semin/S-2629-2016; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011; OI Senbabaoglu, Yasin/0000-0003-0958-958X; Seth, Sahil/0000-0003-4579-3959; Sinha, Rileen/0000-0001-5497-5055; Yang, Da/0000-0002-8336-9457; Boussioutas, Alex/0000-0002-8109-6897; Gehlenborg, Nils/0000-0003-0327-8297; McCall, Shannon/0000-0003-3957-061X; Jacobsen, Anders/0000-0001-6847-4980; Lee, Semin/0000-0002-9015-6046; Birol, Inanc/0000-0003-0950-7839; Schultz, Nikolaus/0000-0002-0131-4904; Ojesina, Akinyemi/0000-0003-0755-3639; Ibbs, Matthew/0000-0003-2510-3447; Schneider, Barbara/0000-0003-4421-1355 FU Intramural Research Program; United States National Institutes of Health [5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273, P30CA16672] FX We are grateful to all the patients and families who contributed to this study and to C. Gunter and J. Weinstein for scientific editing, to M. Sheth for administrative support and to L. Omberg for support with the Sage Bionetworks Synapse platform. This work was supported by the Intramural Research Program and the following grants from the United States National Institutes of Health: 5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273 and P30CA16672. NR 40 TC 373 Z9 393 U1 32 U2 147 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 SEP 11 PY 2014 VL 513 IS 7517 BP 202 EP 209 DI 10.1038/nature13480 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5DP UT WOS:000341362800044 ER PT J AU Evans, SL Dal Monte, O Noble, P Averbeck, BB AF Evans, Simon L. Dal Monte, Olga Noble, Pamela Averbeck, Bruno B. TI Intranasal oxytocin effects on social cognition: A critique SO BRAIN RESEARCH LA English DT Article DE Oxytocin; Intranasal administration; CSF; Social stimuli; Pro-social neuropeptide; Anxiety; Social cognition ID AUTISM SPECTRUM DISORDERS; MALE PRAIRIE VOLES; CEREBROSPINAL-FLUID; PLASMA OXYTOCIN; PSYCHOSOCIAL STRESS; PARTNER PREFERENCE; INCREASES TRUST; BRAIN RESPONSES; RHESUS MACAQUES; MACACA-MULATTA AB The last decade has seen a large number of published findings supporting the hypothesis that intranasally delivered oxytocin (OT) can enhance the processing of social stimuli and regulate social emotion-related behaviors such as trust, memory, fidelity, and anxiety. The use of nasal spray for administering OT in behavioral research has become a standard method, but many questions still exist regarding its action. OT is a peptide that cannot cross the blood-brain barrier, and it has yet to be shown that it does indeed reach the brain when delivered intranasally. Given the evidence, it seems highly likely that OT does affect behavior when delivered as a nasal spray. These effects may be driven by at least three possible mechanisms. First, the intranasally delivered OT may diffuse directly into the CNS where it directly engages OT receptors. Second, the intranasally delivered OT may trigger increased central release via an indirect peripheral mechanism. And third, the indirect peripheral effects may directly lead to behavioral effects via some mechanism other than increased central release. Although intranasally delivered OT likely affects behavior, there are conflicting reports as to the exact nature of those behavioral changes: some studies suggest that OT effects are not always "pro-social" and others suggest effects on social behaviors are due to a more general anxiolytic effect. In this critique, we draw from work in healthy human populations and the animal literature to review the mechanistic aspects of intranasal OT delivery, and to discuss intranasal OT effects on social cognition and behavior. We conclude that future work should control carefully for anxiolytic and gender effects, which could underlie inconsistencies in the existing literature. This article is part of a Special Issue entitled Oxytocin and Social Behav. Published by Elsevier B.V. C1 [Evans, Simon L.] Univ Sussex, Sch Psychol, Brighton BN1 9QG, E Sussex, England. [Dal Monte, Olga; Noble, Pamela; Averbeck, Bruno B.] NIMH, Lab Neuropsychol, NIH, Bethesda, MD USA. [Dal Monte, Olga] Univ Turin, Dept Neuropsychol, Turin, Italy. RP Averbeck, BB (reprint author), Univ Sussex, Sch Psychol, Brighton BN1 9QG, E Sussex, England. EM bruno.averbeck@nih.gov OI dal monte, olga/0000-0002-7823-4769 FU National Institute of Mental Health, NIMH FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, NIMH. NR 104 TC 16 Z9 16 U1 4 U2 43 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD SEP 11 PY 2014 VL 1580 SI SI BP 69 EP 77 DI 10.1016/j.brainres.2013.11.008 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AQ1MS UT WOS:000342546100005 PM 24239931 ER PT J AU Simbiri, KO Biddle, J Kinyera, T Were, PA Tenge, C Kawira, E Masalu, N Sumba, PO Lawler-Heavner, J Stefan, CD Buonaguro, FM Robinson, D Newton, R Harford, J Bhatia, K Mbulaiteye, SM AF Simbiri, Kenneth O. Biddle, Joshua Kinyera, Tobias Were, Pamela Akinyi Tenge, Constance Kawira, Esther Masalu, Nestory Sumba, Peter Odada Lawler-Heavner, Janet Stefan, Cristina D. Buonaguro, Franco M. Robinson, Detra Newton, Robert Harford, Joe Bhatia, Kishor Mbulaiteye, Sam M. TI Burkitt lymphoma research in East Africa: highlights from the 9th African organization for research and training in cancer conference held in Durban, South Africa in 2013 SO INFECTIOUS AGENTS AND CANCER LA English DT Article ID SICKLE-CELL TRAIT; MALARIA RESISTANCE; VIRUS; MALIGNANCIES; SETTINGS; ONCOLOGY; CHILDREN AB A one-day workshop on Burkitt lymphoma (BL) was held at the 9th African Organization for Research and Training in Cancer (AORTIC) conference in 2013 in Durban, South Africa. The workshop featured 15 plenary talks by delegates representing 13 institutions that either fund or implement research on BL targeting AORTIC delegates primarily interested in pediatric oncology. The main outcomes of the meeting were improved sharing of knowledge and experience about ongoing epidemiologic BL research, BL treatment in different settings, the role of cancer registries in cancer research, and opportunities for African scientists to publish in scientific journals. The idea of forming a consortium of BL to improve coordination, information sharing, accelerate discovery, dissemination, and translation of knowledge and to build capacity, while reducing redundant efforts was discussed. Here, we summarize the presentations and discussions from the workshop. C1 [Simbiri, Kenneth O.] SUNY Upstate Med Univ, New York, NY USA. [Biddle, Joshua] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kinyera, Tobias] St Marys Hosp, EMBLEM Study, Lacor, Uganda. [Were, Pamela Akinyi] Moi Teaching & Referral Hosp, EMBLEM Study, Eldoret, Kenya. [Tenge, Constance] Moi Univ, EMBLEM Study, Eldoret, Kenya. [Kawira, Esther] SHED Fdn, EMBLEM Study, Shirati, Tanzania. [Masalu, Nestory] Bugando Med Ctr, Mwanza, Tanzania. [Sumba, Peter Odada] Kenya Govt Med Res Ctr, Kisumu, Kenya. [Lawler-Heavner, Janet; Robinson, Detra] Westat Corp, Rockville, MD USA. [Stefan, Cristina D.] Univ Stellenbosch, Cape Town, South Africa. [Buonaguro, Franco M.] Inst Nazl Tumori, Naples, Italy. [Newton, Robert] Univ York Heslington, York, N Yorkshire, England. [Newton, Robert] Int Agcy Res Canc, MRC, F-69372 Lyon, France. [Harford, Joe; Bhatia, Kishor; Mbulaiteye, Sam M.] NCI, NIH, DCEG, Bethesda, MD 20892 USA. RP Mbulaiteye, SM (reprint author), NCI, NIH, DCEG, 9609 Med Ctr Dr,Rm 6E118,MSC 9704, Bethesda, MD 20892 USA. EM mbulaits@mail.nih.gov FU AORTIC Secretariat; MICROGEM, Napoli, Italy FX The authors would like to thank the AORTIC Secretariat and MICROGEM, Napoli, Italy for supporting the workshop. NR 48 TC 2 Z9 2 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-9378 J9 INFECT AGENTS CANCER JI Infect. Agents Cancer PD SEP 11 PY 2014 VL 9 AR 32 DI 10.1186/1750-9378-9-32 PG 8 WC Oncology; Immunology SC Oncology; Immunology GA AP4KW UT WOS:000342046600002 PM 25686906 ER PT J AU Srinivasrao, G Park, JE Kim, S Ahn, M Cheong, C Nam, KY Gunasekaran, P Hwang, E Kim, NH Shin, SY Lee, KS Ryu, E Bang, JK AF Srinivasrao, Ganipisetti Park, Jung-Eun Kim, Sungmin Ahn, Mija Cheong, Chaejoon Nam, Ky-Youb Gunasekaran, Pethaiah Hwang, Eunha Kim, Nam-Hyung Shin, Song Yub Lee, Kyung S. Ryu, Eunkyung Bang, Jeong Kyu TI Design and Synthesis of a Cell-Permeable, Drug-Like Small Molecule Inhibitor Targeting the Polo-Box Domain of Polo-Like Kinase 1 SO PLOS ONE LA English DT Article ID PLK1; PEPTIDE; POLO-LIKE-KINASE-1; LOCALIZATION; RECOGNITION; DIVISION; POSITION; AFFINITY; MITOSIS; CANCER AB Background: Polo-like kinase-1 (Plk1) plays a crucial role in cell proliferation and the inhibition of Plk1 has been considered as a potential target for specific inhibitory drugs in anti-cancer therapy. Several research groups have identified peptide-based inhibitors that target the polo-box domain (PBD) of Plk1 and bind to the protein with high affinity in in vitro assays. However, inadequate proteolytic resistance and cell permeability of the peptides hinder the development of these peptide-based inhibitors into novel therapeutic compounds. Methodology/Principal Findings: In order to overcome the shortcomings of peptide-based inhibitors, we designed and synthesized small molecule inhibitors. Among these molecules, bg-34 exhibited a high binding affinity for Plk1-PBD and it could cross the cell membrane in its unmodified form. Furthermore, bg-34-dependent inhibition of Plk1-PBD was sufficient for inducing apoptosis in HeLa cells. Moreover, modeling studies performed on Plk1-PBD in complex with bg-34 revealed that bg-34 can interact effectively with Plk1-PBD. Conclusion/Significance: We demonstrated that the molecule bg-34 is a potential drug candidate that exhibits anti-Plk1-PBD activity and possesses the favorable characteristics of high cell permeability and stability. We also determined that bg-34 induced apoptotic cell death by inhibiting Plk1-PBD in HeLa cells at the same concentration as PEGylated 4j peptide, which can inhibit Plk1-PBD activity 1000 times more effectively than bg-34 can in in vitro assays. This study may help to design and develop drug-like small molecule as Plk1-PBD inhibitor for better therapeutic activity. C1 [Srinivasrao, Ganipisetti; Kim, Sungmin; Ahn, Mija; Cheong, Chaejoon; Hwang, Eunha; Ryu, Eunkyung; Bang, Jeong Kyu] Korea Basic Sci Inst, Div Magnet Resonance, Ochang, Chung Buk, South Korea. [Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Nam, Ky-Youb] Asan Med Ctr, Inst Innovat Canc Res, Seoul, South Korea. [Nam, Ky-Youb] Asan Med Ctr, Dept Convergence Med, Seoul, South Korea. [Gunasekaran, Pethaiah; Kim, Nam-Hyung] Chungbuk Natl Univ, Dept Anim Sci, Mol Embryol Lab, Cheongju, Chung Buk, South Korea. [Shin, Song Yub] Chosun Univ, Grad Sch, Dept Biomat, Kwangju, South Korea. [Shin, Song Yub] Chosun Univ, Sch Med, Dept Cellular & Mol Med, Kwangju, South Korea. RP Ryu, E (reprint author), Korea Basic Sci Inst, Div Magnet Resonance, Ochang, Chung Buk, South Korea. EM ekryu@kbsi.re.kr; bangjk@kbsi.re.kr FU Korea Basic Science Institute's Research Program grant [T34418]; Next-Generation BioGreen 21 Program, RuralDevelopment Administration [PJ009594] FX This work was supported by the Korea Basic Science Institute's Research Program grant T34418 (JKB) and the Next-Generation BioGreen 21 Program (#PJ009594), RuralDevelopment Administration (NHK). K.-Y. Nam would like to thank Professor Kyoung Tai No (Yonsei Univ.) for allowing to access the computational resources in his group. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 9 Z9 9 U1 2 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 11 PY 2014 VL 9 IS 9 AR UNSP e107432 DI 10.1371/journal.pone.0107432 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP1UA UT WOS:000341855900072 PM 25211362 ER PT J AU Nishiura, H Chowell, G AF Nishiura, H. Chowell, G. TI Early transmission dynamics of Ebola virus disease (EVD), West Africa, March to August 2014 SO EUROSURVEILLANCE LA English DT Article ID REPRODUCTIVE NUMBER; HEMORRHAGIC-FEVER; SERIAL INTERVAL; UGANDA; EPIDEMIC AB The effective reproduction number, R-t, of Ebola virus disease was estimated using country-specific data reported from Guinea, Liberia and Sierra Leone to the World Health Organization from March to August, 2014. R-t for the three countries lies consistently above 1.0 since June 2014. Country-specific R-t for Liberia and Sierra Leone have lied between 1.0 and 2.0. R-t<2 indicate that control could be attained by preventing over half of the secondary transmissions per primary case. C1 [Nishiura, H.] Univ Tokyo, Grad Sch Med, Tokyo, Japan. [Chowell, G.] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ USA. [Chowell, G.] NIH, Fogarty Int Ctr, Div Int Epidemiol & Populat Studies, Bethesda, MD 20892 USA. RP Nishiura, H (reprint author), Univ Tokyo, Grad Sch Med, Tokyo, Japan. EM nishiurah@m.u-tokyo.ac.jp OI Nishiura, Hiroshi/0000-0003-0941-8537 FU Japanese Society for the Promotion of Science (JSPS) KAKENHI Grant [26700028]; St Luke's Life Science Institute Research Grant for Clinical Epidemiology Research; Commissioned Research program of the Ministry of Health, Labour and Welfare, Japan [H26-ShinkoJitsuyoka- General-016]; NSF grant as part of the joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases program [1414374]; Fogarty International Center, US National Institutes of Health; Visiting Foreign Scholar program of the Heiwa Nakajima Foundation at the University of Tokyo; UK Biotechnology and Biological Sciences Research Council [BB/M008894/1] FX HN received funding support from the Japanese Society for the Promotion of Science (JSPS) KAKENHI Grant Number 26700028, St Luke's Life Science Institute Research Grant for Clinical Epidemiology Research 2014 and the Commissioned Research program of the Ministry of Health, Labour and Welfare, Japan (H26-ShinkoJitsuyoka- General-016). 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, the Fogarty International Center, US National Institutes of Health and the Visiting Foreign Scholar program of the Heiwa Nakajima Foundation for supporting a sabbatical research visit at the University of Tokyo. NR 21 TC 26 Z9 26 U1 3 U2 58 PU EUR CENTRE DIS PREVENTION & CONTROL PI STOCKHOLM PA TOMTEBODAVAGEN 11A, STOCKHOLM, 171 83, SWEDEN SN 1560-7917 J9 EUROSURVEILLANCE JI Eurosurveillance PD SEP 11 PY 2014 VL 19 IS 36 BP 5 EP 10 AR 20894 PG 6 WC Infectious Diseases SC Infectious Diseases GA AO8RW UT WOS:000341622900002 ER PT J AU Atkins, KM Thomas, LL Barroso-Gonzalez, J Thomas, L Auclair, S Yin, J Kang, H Chung, JH Dikeakos, JD Thomas, G AF Atkins, Katelyn M. Thomas, Laura L. Barroso-Gonzalez, Jonathan Thomas, Laurel Auclair, Sylvain Yin, Jun Kang, Hyeog Chung, Jay H. Dikeakos, Jimmy D. Thomas, Gary TI The Multifunctional Sorting Protein PACS-2 Regulates SIRT1-Mediated Deacetylation of p53 to Modulate p21-Dependent Cell-Cycle Arrest SO CELL REPORTS LA English DT Article ID TRAIL-INDUCED APOPTOSIS; DNA-DAMAGE; STEM-CELLS; GASTROINTESTINAL-SYNDROME; INCREASED SENSITIVITY; SIRT1 DEACETYLASE; IN-VIVO; MHC-I; ACETYLATION; BINDING AB SIRT1 regulates the DNA damage response by deacetylating p53, thereby repressing p53 transcriptional output. Here, we demonstrate that the sorting protein PACS-2 regulates SIRT1-mediated deacetylation of p53 to modulate the DNA damage response. PACS-2 knockdown cells failed to efficiently undergo p53-induced cell-cycle arrest in response to DNA damage. Accordingly, p53 acetylation was reduced both in PACS-2 knockdown cells and thymocytes from Pacs-2(- /-) mice, thereby blunting induction of the cyclin-dependent kinase inhibitor p21 (CDKN1A). The SIRT1 inhibitor EX-527 or SIRT1 knockdown restored p53 acetylation and p21 induction as well as p21-dependent cell-cycle arrest in PACS-2 knockdown cells. Trafficking studies revealed that cytoplasmic PACS-2 shuttled to the nucleus, where it interacted with SIRT1 and repressed SIRT1-mediated p53 deacetylation. Correspondingly, in vitro assays demonstrated that PACS-2 directly inhibited SIRT1-catalyzed p53 deacetylation. Together, these findings identify PACS-2 as an in vivo mediator of the SIRT1-p53-p21 axis that modulates the DNA damage response. C1 [Atkins, Katelyn M.] Oregon Hlth & Sci Univ, Dept Cell & Dev Biol, Portland, OR 97239 USA. [Thomas, Laura L.; Barroso-Gonzalez, Jonathan; Thomas, Laurel; Auclair, Sylvain; Yin, Jun; Thomas, Gary] Univ Pittsburgh, Sch Med, Dept Mol Genet & Microbiol, Pittsburgh, PA 15219 USA. [Kang, Hyeog; Chung, Jay H.] NHLBI, Lab Obes & Aging Res, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [Dikeakos, Jimmy D.] Univ Western Ontario, Schulich Sch Med & Dent, London, ON N6A 5C1, Canada. RP Thomas, G (reprint author), Univ Pittsburgh, Sch Med, Dept Mol Genet & Microbiol, Pittsburgh, PA 15219 USA. EM thomasg@pitt.edu FU NIH [R01 CA151564]; Knight Cancer Institute; University of Pittsburgh; RSNA [RMS1112]; N.L. Tartar Foundation FX The authors thank B. Vogelstein, L. Zhang, J.Yu, D. Sieburth, G. V. Thomas, P. Stork, and J. Denu for reagents and J. Yu, M. Dai, V. Procaccia, T. Smithgall, J.A. Tanyi, and J. Moroco for advice and assistance with experiments. This work was supported by NIH R01 CA151564 and awards from the Knight Cancer Institute and the University of Pittsburgh (to G.T). K.M.A. is a Rubinstein Radiation Research Scholar and was supported by RSNA RMS1112 and the N.L. Tartar Foundation. NR 62 TC 10 Z9 10 U1 0 U2 6 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 SEP 11 PY 2014 VL 8 IS 5 BP 1545 EP 1557 DI 10.1016/j.celrep.2014.07.049 PG 13 WC Cell Biology SC Cell Biology GA AO8AO UT WOS:000341574800029 PM 25159152 ER PT J AU White, SF Adalio, C Nolan, ZT Yang, JJ Martin, A Blair, JR AF White, Stuart F. Adalio, Christopher Nolan, Zachary T. Yang, Jiongjiong Martin, Alex Blair, James R. TI The amygdala's response to face and emotional information and potential category-specific modulation of temporal cortex as a function of emotion SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE amygdala; animate; emotion; fusiform gyrus; temporal cortex ID MANIPULATABLE OBJECTS; BRAIN; HABITUATION; PERCEPTION; ANIMATE; FMRI; REPRESENTATION; EXPERIENCE; MOVEMENTS; KNOWLEDGE AB The amygdala has been implicated in the processing of emotion and animacy information and to be responsive to novelty. However, the way in which these functions interact is poorly understood. Subjects (N = 30) viewed threatening or neutral images that could be either animate (facial expressions) or inanimate (objects) in the context of a dot probe task. The amygdala showed responses to both emotional and animacy information, but no emotion by stimulus-type interaction; i.e., emotional face and object stimuli, when matched for arousal and valence, generate comparable amygdala activity relative to neutral face and object stimuli. Additionally, a habituation effect was not seen in amygdala; however, increased amygdala activity was observed for incongruent relative to congruent negative trials in second vs. first exposures. Furthermore, medial fusiform gyrus showed increased response to inanimate stimuli, while superior temporal sulcus showed increased response to animate stimuli. Greater functional connectivity between bilateral amygdala and medial fusiform gyrus was observed to negative vs. neutral objects, but not to fearful vs. neutral faces. The current data suggest that the amygdala is responsive to animate and emotional stimuli. Additionally, these data suggest that the interaction between the various functions of the amygdala may need to be considered simultaneously to fully understand how they interact. Moreover, they suggest category-specific modulation of medial fusiform cortex as a function of emotion. C1 [White, Stuart F.; Nolan, Zachary T.; Blair, James R.] NIMH, Sect Affect Cognit Neurosci, Bethesda, MD 20892 USA. [Adalio, Christopher] Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. [Yang, Jiongjiong] Peking Univ, Dept Psychol, Beijing 100871, Peoples R China. [Martin, Alex] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP White, SF (reprint author), NIMH, 9000 Rockville Pike,Bldg 15k,Room 205,MSC2670, Bethesda, MD 20892 USA. EM whitesf@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health [1-ZIA-MH002860] 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. NR 46 TC 1 Z9 1 U1 1 U2 14 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD SEP 11 PY 2014 VL 8 AR 714 DI 10.3389/fnhum.2014.00714 PG 9 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AO5WB UT WOS:000341415800002 PM 25309390 ER PT J AU Roberts, KG Li, Y Payne-Turner, D Harvey, RC Yang, YL Pei, D McCastlain, K Ding, L Lu, C Song, G Ma, J Becksfort, J Rusch, M Chen, SC Easton, J Cheng, J Boggs, K Santiago-Morales, N Iacobucci, I Fulton, RS Wen, J Valentine, M Cheng, C Paugh, SW Devidas, M Chen, IM Reshmi, S Smith, A Hedlund, E Gupta, P Nagahawatte, P Wu, G Chen, X Yergeau, D Vadodaria, B Mulder, H Winick, NJ Larsen, EC Carroll, WL Heerema, NA Carroll, AJ Grayson, G Tasian, SK Moore, AS Keller, F Frei-Jones, M Whitlock, JA Raetz, EA White, DL Hughes, TP Auvil, JMG Smith, MA Marcucci, G Bloomfield, CD Mrozek, K Kohlschmidt, J Stock, W Kornblau, SM Konopleva, M Paietta, E Pui, CH Jeha, S Relling, MV Evans, WE Gerhard, DS Gastier-Foster, JM Mardis, E Wilson, RK Loh, ML Downing, JR Hunger, SP Willman, CL Zhang, J Mullighan, CG AF Roberts, K. G. Li, Y. Payne-Turner, D. Harvey, R. C. Yang, Y-L. Pei, D. McCastlain, K. Ding, L. Lu, C. Song, G. Ma, J. Becksfort, J. Rusch, M. Chen, S-C. Easton, J. Cheng, J. Boggs, K. Santiago-Morales, N. Iacobucci, I. Fulton, R. S. Wen, J. Valentine, M. Cheng, C. Paugh, S. W. Devidas, M. Chen, I-M. Reshmi, S. Smith, A. Hedlund, E. Gupta, P. Nagahawatte, P. Wu, G. Chen, X. Yergeau, D. Vadodaria, B. Mulder, H. Winick, N. J. Larsen, E. C. Carroll, W. L. Heerema, N. A. Carroll, A. J. Grayson, G. Tasian, S. K. Moore, A. S. Keller, F. Frei-Jones, M. Whitlock, J. A. Raetz, E. A. White, D. L. Hughes, T. P. Auvil, J. M. Guidry Smith, M. A. Marcucci, G. Bloomfield, C. D. Mrozek, K. Kohlschmidt, J. Stock, W. Kornblau, S. M. Konopleva, M. Paietta, E. Pui, C-H. Jeha, S. Relling, M. V. Evans, W. E. Gerhard, D. S. Gastier-Foster, J. M. Mardis, E. Wilson, R. K. Loh, M. L. Downing, J. R. Hunger, S. P. Willman, C. L. Zhang, J. Mullighan, C. G. TI Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID B-CELL PRECURSOR; ETV6-NTRK3 FUSION TRANSCRIPTS; PEDIATRIC ACUTE LEUKEMIAS; INHIBITOR THERAPY; GENE FUSION; CRLF2; EXPRESSION; IMATINIB; DELETION; MODELS AB BACKGROUND Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. C1 [Roberts, K. G.; Payne-Turner, D.; Yang, Y-L.; McCastlain, K.; Song, G.; Ma, J.; Chen, S-C.; Cheng, J.; Santiago-Morales, N.; Iacobucci, I.; Wen, J.; Downing, J. R.; Mullighan, C. G.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [Li, Y.; Becksfort, J.; Rusch, M.; Hedlund, E.; Gupta, P.; Nagahawatte, P.; Wu, G.; Chen, X.; Zhang, J.] St Jude Childrens Res Hosp, Dept Computat Biol & Bioinformat, Memphis, TN 38105 USA. [Pei, D.; Cheng, C.] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA. [Paugh, S. W.; Relling, M. V.; Evans, W. E.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Pui, C-H.; Jeha, S.] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Li, Y.; Ding, L.; Lu, C.; Rusch, M.; Easton, J.; Cheng, J.; Boggs, K.; Fulton, R. S.; Hedlund, E.; Gupta, P.; Nagahawatte, P.; Wu, G.; Chen, X.; Yergeau, D.; Vadodaria, B.; Mulder, H.; Relling, M. V.; Evans, W. E.; Mardis, E.; Wilson, R. K.; Downing, J. R.; Zhang, J.; Mullighan, C. G.] St Jude Childrens Res Hosp, Pediat Canc Genome Project, Memphis, TN 38105 USA. [Valentine, M.] St Jude Childrens Res Hosp, Dept Cytogenet Shared Resource, Memphis, TN 38105 USA. [Harvey, R. C.; Chen, I-M.; Willman, C. L.] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. [Harvey, R. C.; Chen, I-M.; Willman, C. L.] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. [Ding, L.; Lu, C.; Fulton, R. S.; Mardis, E.; Wilson, R. K.] Washington Univ, Genome Inst, St Louis, MO 63130 USA. [Ding, L.; Lu, C.; Fulton, R. S.; Mardis, E.; Wilson, R. K.] Washington Univ, Dept Genet, Sch Med, St Louis, MO 63130 USA. [Mardis, E.; Wilson, R. K.] Washington Univ, Siteman Canc Ctr, St Louis, MO 63130 USA. [Devidas, M.] Univ Florida, Coll Med, Gainesville, FL USA. [Reshmi, S.; Smith, A.; Gastier-Foster, J. M.] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. [Heerema, N. A.] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43210 USA. [Marcucci, G.; Bloomfield, C. D.; Mrozek, K.; Kohlschmidt, J.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Winick, N. J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Grayson, G.] Scott & White Hosp & Clin, Temple, TX USA. [Grayson, G.] Texas A&M Hlth Sci Ctr, Temple, TX USA. [Frei-Jones, M.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Kornblau, S. M.; Konopleva, M.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Div Canc Med, Houston, TX 77030 USA. [Kornblau, S. M.; Konopleva, M.] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat, Div Canc Med, Houston, TX 77030 USA. [Larsen, E. C.] Maine Childrens Canc Program, Scarborough, ME USA. [Carroll, W. L.] NYU, Inst Canc, New York, NY USA. [Paietta, E.] Albert Einstein Coll Med, Dept Med Oncol, Bronx, NY 10467 USA. [Carroll, A. J.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Tasian, S. K.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Moore, A. S.] Univ Queensland, Queensland Childrens Med Res Inst, Herston, Qld, Australia. [Moore, A. S.] Royal Childrens Hosp Brisbane, Herston, Qld, Australia. [White, D. L.; Hughes, T. P.] South Australian Hlth & Med Res Inst, Canc Theme, Adelaide, SA, Australia. [Keller, F.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Keller, F.] Emory Univ, Sch Med, Atlanta, GA USA. [Whitlock, J. A.] Hosp Sick Children, Div Haematol Oncol, Toronto, ON M5G 1X8, Canada. [Whitlock, J. A.] Univ Toronto, Toronto, ON, Canada. [Raetz, E. A.] Univ Utah, Hunstman Canc Inst, Salt Lake City, UT USA. [Auvil, J. M. Guidry; Gerhard, D. S.] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Smith, M. A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Devidas, M.; Chen, I-M.; Reshmi, S.; Carroll, W. L.; Auvil, J. M. Guidry; Smith, M. A.; Relling, M. V.; Gerhard, D. S.; Gastier-Foster, J. M.; Loh, M. L.; Downing, J. R.; Hunger, S. P.; Willman, C. L.; Zhang, J.; Mullighan, C. G.] NIH, Childrens Oncol Grp TARGET ALL Project, Bethesda, MD 20892 USA. [Kohlschmidt, J.] Mayo Clin, Alliance Clin Trials Oncol Stat, Rochester, MN USA. [Kohlschmidt, J.] Mayo Clin, Ctr Data, Rochester, MN USA. [Stock, W.] Univ Chicago Med, Chicago, IL USA. [Loh, M. L.] Univ Calif San Francisco, Dept Pediat, Benioff Childrens Hosp, San Francisco, CA USA. [Loh, M. L.] Univ Calif San Francisco, Helen Diller Family Canc Ctr, San Francisco, CA 94143 USA. [Hunger, S. P.] Univ Colorado, Sch Med, Aurora, CO USA. [Hunger, S. P.] Childrens Hosp Colorado, Aurora, CO USA. RP Mullighan, CG (reprint author), St Jude Childrens Res Hosp, 262 Danny Thomas Pl,Mail Stop 342, Memphis, TN 38105 USA. EM charles.mullighan@stjude.org RI LI, YONGJIN/E-1688-2011; Paugh, Steven/A-7739-2008; Mrozek, Krzysztof/A-3142-2008; Moore, Andrew/I-6275-2012; OI Paugh, Steven/0000-0001-5697-9228; Moore, Andrew/0000-0001-8062-1779; Harvey, Richard/0000-0002-4904-9767; Mullighan, Charles/0000-0002-1871-1850; YANG, YUNG-LI/0000-0002-3598-7218; Tasian, Sarah/0000-0003-1327-1662; White, Deborah/0000-0003-4844-333X FU American Lebanese Syrian Associated Charities from National Cancer Institute [CA 21765, U01 CA157937-01, F32 CA141762, R37 CA36401, U24-CA114737, U10 CA21115, CA14958, U10 CA101140, CA145707, U10 CA98543, U10 CA98413, U24 CA114766]; Stand Up to Cancer Innovative Research Grant; St. Baldrick's Foundation Scholar Award; St. Baldrick's Consortium Award from the Leukemia and Lymphoma Society Specialized Center of Research; Leukemia and Lymphoma Society Special Fellow Award; Alex's Lemonade Stand Foundation Young Investigator Awards; Alex's Lemonade Stand Foundation Scholar in Developmental Therapeutics Award; National Institute of General Medical Sciences [92666] FX Supported in part by funding from the American Lebanese Syrian Associated Charities (to St. Jude Children's Research Hospital), grants from the National Cancer Institute (CA 21765, to St. Jude Children's Research Hospital; U01 CA157937-01, to Drs. Willman and Hunger; F32 CA141762, to Dr. Paugh; R37 CA36401, to Dr. Evans; U24-CA114737, U10 CA21115, and CA14958, to Dr. Paietta; U10 CA101140, to Cancer and Leukemia Group B Leukemia Correlative Science; CA145707, to Drs. Willman and Mullighan; and U10 CA98543, U10 CA98413, and U24 CA114766, to the Children's Oncology Group), a Stand Up to Cancer Innovative Research Grant and a St. Baldrick's Foundation Scholar Award (both to Dr. Mullighan), a St. Baldrick's Consortium Award (to Dr. Hunger), a grant from the Leukemia and Lymphoma Society Specialized Center of Research (to Drs. Carroll, Hunger, and Mullighan), a Leukemia and Lymphoma Society Special Fellow Award (to Dr. Roberts), Alex's Lemonade Stand Foundation Young Investigator Awards (to Drs. Roberts and Tasian), an Alex's Lemonade Stand Foundation Scholar in Developmental Therapeutics Award (to Dr. Tasian), and a grant from the National Institute of General Medical Sciences (92666, to Dr. Relling). NR 38 TC 216 Z9 222 U1 5 U2 28 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 SEP 11 PY 2014 VL 371 IS 11 BP 1005 EP 1015 DI 10.1056/NEJMoa1403088 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AO5KD UT WOS:000341382800006 PM 25207766 ER PT J AU Mamounas, EP Cortazar, P Zhang, LJ Von Minckwitz, G Mehta, K Cameron, DA Bonnefoi, HR Gianni, L Valagussa, P Wolmark, N Loibl, S Bogaerts, J Swain, SM Sridhara, R Costantino, JP Rastogi, P Geyer, CE Eidtmann, H Gerber, B Untch, M AF Mamounas, Eleftherios P. Cortazar, Patricia Zhang, Lijun Von Minckwitz, Gunter Mehta, Keyur Cameron, David A. Bonnefoi, Herve R. Gianni, Luca Valagussa, Pinuccia Wolmark, Norman Loibl, Sibylle Bogaerts, Jan Swain, Sandra M. Sridhara, Rajeshwari Costantino, Joseph P. Rastogi, Priya Geyer, Charles E. Eidtmann, Holger Gerber, Bernd Untch, Michael TI Locoregional recurrence (LRR) after neoadjuvant chemotherapy (NAC): Pooled-analysis results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Breast Cancer Symposium CY SEP 04-06, 2014 CL San Francisco, CA SP Amer Soc Clin Oncol C1 Orlando Hlth, Natl Surg Adjuvant Breast & Bowel Project, Orlando, FL USA. Orlando Hlth, UF Hlth Canc Ctr, Orlando, FL USA. US FDA, Silver Spring, MD USA. Goethe Univ Frankfurt, German Breast Grp, Neu Isenburg, Germany. German Breast Grp, Neu Isenburg, Germany. Univ Edinburgh, Edinburgh, Midlothian, Scotland. Inst Bergonie, Ctr Canc, Bordeaux, France. Ist Sci San Raffaele, I-20132 Milan, Italy. Fdn Michelangelo, Milan, Italy. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. Sana Klinikum Offenbach, German Breast Grp, Neu Isenburg, Germany. European Org Res Treatment Canc, Brussels, Belgium. MedStar Washington Hosp Ctr, Washington, DC USA. Univ Pittsburgh, Grad Sch Publ Hlth, Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Richmond, VA USA. NRG Oncol, Richmond, VA USA. Univ Kiel, Kiel, Germany. Univ Rostock, D-18055 Rostock, Germany. Helios Klinikum Berlin Buch, Berlin, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 10 PY 2014 VL 32 IS 26 SU S MA 61 PG 2 WC Oncology SC Oncology GA CN2JK UT WOS:000358246700060 ER PT J AU Pahula, S Beumer, JH Appleman, LJ Tawbi, HAH Stoller, RG Lee, JJ Lin, Y Kiesel, B Yu, J Tan, AR Belani, CP Chew, HK Garcia, AA Morgan, R Chen, AP Giranda, VL Shepherd, SP Chu, E Puhalla, S AF Pahula, Shalu Beumer, Jan Hendrik Appleman, Leonard Joseph Tawbi, Hussein Abdul-Hassan Stoller, Ronald G. Lee, James J. Lin, Yan Kiesel, Brian Yu, Jing Tan, Antoinette R. Belani, Chandra Prakash Chew, Helen K. Garcia, Agustin A. Morgan, Robert Chen, Alice P. Giranda, Vincent L. Shepherd, Stacie Peacock Chu, Edward Puhalla, Shannon TI Outcome of BRCA 1/2-mutated (BRCA plus ) and triple-negative, BRCA, wild type (BRCA-wt) breast cancer patients in a phase I study of single-agent veliparib (V) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Breast Cancer Symposium CY SEP 04-06, 2014 CL San Francisco, CA SP Amer Soc Clin Oncol C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, UPMC, Magee Womens Hosp, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, New Brunswick, NJ USA. Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. Penn State Hershey Canc Inst, Hershey, PA USA. Univ Calif Davis, Sacramento, CA 95817 USA. Univ So Calif, Los Angeles, CA USA. City Hope Natl Med Ctr, Duarte, CA USA. NCI, NIH, Bethesda, MD 20892 USA. Abbott Labs, Abbott Pk, IL 60064 USA. Univ Pittsburgh, Med Ctr, UPMC, Womens Canc Program,Magee Womens Hosp, Pittsburgh, PA USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 10 PY 2014 VL 32 IS 26 SU S MA 135 PG 1 WC Oncology SC Oncology GA CN2JK UT WOS:000358246700133 ER PT J AU Sparano, JA Gray, RJ Zujewski, JA Whelan, TJ Albain, KS Hayes, D Geyer, CE Dees, EC Perez, EA Keane, MM Sologuren, CV Goggins, TF Mayer, IA Brufsky, A Toppmeyer, DL Kaklamani, VG Atkins, JN Berenberg, JL Sledge, GW AF Sparano, Joseph A. Gray, Robert J. Zujewski, Jo Anne Whelan, Timothy Joseph Albain, Kathy S. Hayes, Daniel Geyer, Charles E. Dees, Elizabeth Claire Perez, Edith A. Keane, Maccon M. Sologuren, Carlos Vallejos Goggins, Timothy F. Mayer, Ingrid A. Brufsky, Adam Toppmeyer, Deborah L. Kaklamani, Virginia G. Atkins, James N. Berenberg, Jeffrey L. Sledge, George W. TI Recurrence score and clinicopathologic characteristics of TAILORx participants by race and ethnicity SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Breast Cancer Symposium CY SEP 04-06, 2014 CL San Francisco, CA SP Amer Soc Clin Oncol C1 Montefiore Med Ctr, Bronx, NY 10467 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, NIH, Bethesda, MD 20892 USA. Juravinski Canc Ctr, Hamilton, ON, Canada. Loyola Univ, Med Ctr, Maywood, IL 60153 USA. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Allegheny Canc Ctr, Pittsburgh, PA USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Mayo Clin, Jacksonville, FL 32224 USA. Univ Coll Hosp Galway, Dept Med Oncol, Galway, Ireland. Inst Nacl Enfermedades Neoplas, Lima, Peru. Fox Valley Hematol & Oncol, Appleton, WI USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. Northwestern Univ, Chicago, IL 60611 USA. SE Canc Control Consortium, Goldsboro, NC USA. Univ Hawaii, MBCOPP, Honolulu, HI 96822 USA. Stanford Univ, Palo Alto, CA 94304 USA. RI Whelan, Timothy/D-3185-2017 NR 0 TC 0 Z9 0 U1 0 U2 4 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 SEP 10 PY 2014 VL 32 IS 26 SU S MA 36 PG 1 WC Oncology SC Oncology GA CN2JK UT WOS:000358246700037 ER PT J AU Proctor, LM AF Proctor, Lita M. CA Integrative HMP iHMP Res Network TI The Integrative Human Microbiome Project: Dynamic Analysis of Microbiome-Host Omics Profiles during Periods of Human Health and Disease SO CELL HOST & MICROBE LA English DT Review ID INFLAMMATORY-BOWEL-DISEASE; CROHNS-DISEASE; HUMAN GUT; INTESTINAL MICROBIOTA; ULCERATIVE-COLITIS; FECAL MICROBIOTA; PHENOTYPES; DIVERSITY; OBESITY; PATHOGENESIS AB Much has been learned about the diversity and distribution of human-associated microbial communities, but we still know little about the biology of the microbiome, how it interacts with the host, and how the host responds to its resident microbiota. The Integrative Human Microbiome Project (iHMP, http://hmp2.org), the second phase of the NIH Human Microbiome Project, will study these interactions by analyzing microbiome and host activities in longitudinal studies of disease-specific cohorts and by creating integrated data sets of microbiome and host functional properties. These data sets will serve as experimental test beds to evaluate new models, methods, and analyses on the interactions of host and microbiome. Here we describe the three models of microbiome-associated human conditions, on the dynamics of preterm birth, inflammatory bowel disease, and type 2 diabetes, and their underlying hypotheses, as well as the multi-omic data types to be collected, integrated, and distributed through public repositories as a community resource. RP Proctor, LM (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM lita.proctor@nih.gov RI Tas, Neslihan/D-1172-2015; Fan-Minogue, Hua/B-2189-2016 OI Ryu, Stacy Hyunji/0000-0002-5448-339X; Fan-Minogue, Hua/0000-0002-9139-3668 FU NIH Common Fund Human Microbiome Project (HMP) program [8U54HD080784, 8U54DK102557, 8U54DK102556]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Office of Research on Women's Health (ORWH); National Center for Complementary and Alternative Medicine (NCCAM); Office of Dietary Supplements (ODS) FX This work was funded by the NIH Common Fund Human Microbiome Project (HMP) program through grants 8U54HD080784 to G. Buck, J. Strauss, and K. Jefferson; 8U54DK102557 to R. Xavier and C. Huttenhower; and 8U54DK102556 to M. Snyder and G. Weinstock, with additional cofunding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Office of Research on Women's Health (ORWH), the National Center for Complementary and Alternative Medicine (NCCAM), and the Office of Dietary Supplements (ODS). NR 78 TC 28 Z9 30 U1 4 U2 61 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 SEP 10 PY 2014 VL 16 IS 3 BP 276 EP 289 DI 10.1016/j.chom.2014.08.014 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AP4OL UT WOS:000342057000006 ER PT J AU Kepler, TB Liao, HX Alam, SM Bhaskarabhatla, R Zhang, RJ Yandava, C Stewart, S Anasti, K Kelsoe, G Parks, R Lloyd, KE Stolarchuk, C Pritchett, J Solomon, E Friberg, E Morris, L Karim, SSA Cohen, MS Walter, E Moody, MA Wu, XL Altae-Tran, HR Georgiev, IS Kwong, PD Boyd, SD Fire, AZ Mascola, JR Haynes, BF AF Kepler, Thomas B. Liao, Hua-Xin Alam, S. Munir Bhaskarabhatla, Rekha Zhang, Ruijun Yandava, Chandri Stewart, Shelley Anasti, Kara Kelsoe, Garnett Parks, Robert Lloyd, Krissey E. Stolarchuk, Christina Pritchett, Jamie Solomon, Erika Friberg, Emma Morris, Lynn Karim, Salim S. Abdool Cohen, Myron S. Walter, Emmanuel Moody, M. Anthony Wu, Xueling Altae-Tran, Han R. Georgiev, Ivelin S. Kwong, Peter D. Boyd, Scott D. Fire, Andrew Z. Mascola, John R. Haynes, Barton F. TI Immunoglobulin Gene Insertions and Deletions in the Affinity Maturation of HIV-1 Broadly Reactive Neutralizing Antibodies SO CELL HOST & MICROBE LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; GP41 ANTIBODIES; POTENT; BINDING; INDUCTION; INFECTION; RESPONSES; EPITOPES; DESIGN; VIRUS AB Induction of HIV-1 broad neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development but has remained challenging partially due to unusual traits of bnAbs, including high somatic hypermutation (SHM) frequencies and in-frame insertions and deletions (indels). Here we examined the propensity and functional requirement for indels within HIV-1 bnAbs. High-throughput sequencing of the immunoglobulin (Ig) V(H)DJ(H) genes in HIV-1 infected and uninfected individuals revealed that the indel frequency was elevated among HIV-1-infected subjects, with no unique properties attributable to bnAb-producing individuals. This increased indel occurrence depended only on the frequency of SHM point mutations. Indel-encoded regions were generally proximal to antigen binding sites. Additionally, reconstruction of a HIV-1 CD4-binding site bnAb clonal lineage revealed that a large compound V(H)DJ(H) indel was required for bnAb activity. Thus, vaccine development should focus on designing regimens targeted at sustained activation of bnAb lineages to achieve the required SHM and indel events. C1 [Kepler, Thomas B.; Bhaskarabhatla, Rekha; Yandava, Chandri] Boston Univ, Sch Med, Dept Math & Stat, Dept Microbiol, Boston, MA 02118 USA. [Liao, Hua-Xin; Alam, S. Munir; Zhang, Ruijun; Stewart, Shelley; Anasti, Kara; Kelsoe, Garnett; Parks, Robert; Lloyd, Krissey E.; Stolarchuk, Christina; Pritchett, Jamie; Solomon, Erika; Friberg, Emma; Walter, Emmanuel; Moody, M. Anthony; Haynes, Barton F.] Duke Univ, Human Vaccine Inst, Durham, NC 27710 USA. [Kelsoe, Garnett; Haynes, Barton F.] Dept Immunol, Durham, NC 27710 USA. [Morris, Lynn] Natl Inst Communicable Dis, Ctr HIV & STIs, ZA-2131 Johannesburg, South Africa. [Morris, Lynn; Karim, Salim S. Abdool] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Ctr AIDS Program Res South Africa CAPRISA, ZA-4013 Congella, South Africa. [Cohen, Myron S.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Walter, Emmanuel; Moody, M. Anthony] Dept Pediat, Durham, NC 27710 USA. [Wu, Xueling; Altae-Tran, Han R.; Georgiev, Ivelin S.; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Boyd, Scott D.; Fire, Andrew Z.] Stanford Univ, Ctr Med, Stanford, CA 94305 USA. [Haynes, Barton F.] Duke Univ, Dept Med, Durham, NC 27710 USA. RP Kepler, TB (reprint author), Boston Univ, Sch Med, Dept Math & Stat, Dept Microbiol, Boston, MA 02118 USA. EM tbkepler@bu.edu OI Abdool Karim, Salim/0000-0002-4986-2133 FU National Institutes of Allergy and Infectious Diseases; intramural NIH support for NIAID Vaccine Research Center; NIH, NIAID [AI068501, AI100645, HHSN272201000053C] FX This study was supported by the National Institutes of Allergy and Infectious Diseases and by intramural NIH support for the NIAID Vaccine Research Center, by grants from the NIH, NIAID, AI068501 (the Center for HIV/AIDS Vaccine Immunology), AI100645 (the Center for Vaccine Immunology-Immunogen Discovery), and HHSN272201000053C (Multiscale Systems Immunology). The authors acknowledge the contributions of the Center for HIV/AIDS Vaccine Discovery (CHAVI) Clinical Core Team at Chapel Hill, North Carolina (Joe Eron); Blantyre, Malawi (Johnstone Kumwenda, Taha Taha); Lilongwe, Malawi (Irving Hoffman, Gift Kaminga); Johannesburg, South Africa (Helen Rees); Moshi, Tanzania (Sam Noel, Saidi Kapiga, John Crump); and London, UK (Sarah Fidler). The authors thank Haiyan Chen, Melissa Cooper, Shi-Mao Xia, and Julie Blinn for expert technical assistance. B.F.H., T.B.K., P.D.K., X.W., and J.R.M. have a patent filed on the CH30-CH34 clonal lineage of antibodies. NR 45 TC 28 Z9 28 U1 1 U2 3 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 SEP 10 PY 2014 VL 16 IS 3 BP 304 EP 313 DI 10.1016/j.chom.2014.08.006 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AP4OL UT WOS:000342057000008 PM 25211073 ER PT J AU Del Prete, GQ Ailers, B Moldt, B Keele, BF Estes, JD Rodriguez, A Sampias, M Oswald, K Fast, R Trubey, CM Chertova, E Smedley, J LaBranche, CC Montefiori, DC Burton, DR Shaw, GM Markowitz, M Piatak, M KewalRamani, VN Bieniasz, PD Lifson, JD Hatziioannou, T AF Del Prete, Gregory Q. Ailers, Braiden Moldt, Brian Keele, Brandon F. Estes, Jacob D. Rodriguez, Anthony Sampias, Marissa Oswald, Kelli Fast, Randy Trubey, Charles M. Chertova, Elena Smedley, Jeremy LaBranche, Celia C. Montefiori, David C. Burton, Dennis R. Shaw, George M. Markowitz, Marty Piatak, Michael, Jr. KewalRamani, Vineet N. Bieniasz, Paul D. Lifson, Jeffrey D. Hatziioannou, Theodora TI Selection of Unadapted, Pathogenic SHIVs Encoding Newly Transmitted HIV-1 Envelope Proteins SO CELL HOST & MICROBE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZATION IN-VITRO; PRIMARY INFECTION; ANTIBODIES; MACAQUES; TRANSMISSION; ENV; GLYCOPROTEINS; REPLICATION; CHALLENGE AB Infection of macaques with chimeric viruses based on SIVMAC but expressing the HIV-1 envelope (Env) glycoproteins (SHIVs) remains the most powerful model for evaluating prevention and therapeutic strategies against AIDS. Unfortunately, only a few SHIVs are currently available. Furthermore, their generation has required extensive adaptation of the HIV-1 Env sequences in macaques so they may not accurately represent HIV-1 Env proteins circulating in humans, potentially limiting their translational utility. We developed a strategy for generating large numbers of SHIV constructs expressing Env proteins from newly transmitted HIV-1 strains. By inoculating macaques with cocktails of multiple SHIV variants, we selected SHIVs that can replicate and cause AIDS-like disease in immunologically intact rhesus macaques without requiring animal-to-animal passage. One of these SHIVs could be transmitted mucosally. We demonstrate the utility of the SHIVs generated by this method for evaluating neutralizing antibody administration as a protection against mucosal SHIV challenge. C1 [Del Prete, Gregory Q.; Keele, Brandon F.; Estes, Jacob D.; Oswald, Kelli; Fast, Randy; Trubey, Charles M.; Chertova, Elena; Piatak, Michael, Jr.; Lifson, Jeffrey D.] Leidos Biomedical Res Inc, Frederick Natl Lab, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Ailers, Braiden; Rodriguez, Anthony; Sampias, Marissa; Markowitz, Marty; Bieniasz, Paul D.; Hatziioannou, Theodora] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. [Moldt, Brian; Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, Dept Immunol & Microbiol, La Jolla, CA 92037 USA. [Moldt, Brian; Burton, Dennis R.] Scripps Res Inst, Ctr HIVAIDS Vaccine Immunol & Immunogen Discovery, Dept Immunol & Microbiol, La Jolla, CA 92037 USA. [Smedley, Jeremy] Leidos Biomedical Res Inc, Frederick Natl Lab, Lab Anim Sci Program, Frederick, MD 21702 USA. [LaBranche, Celia C.; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Burton, Dennis R.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Shaw, George M.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [KewalRamani, Vineet N.] Natl Canc Inst, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Bieniasz, Paul D.] Rockefeller Univ, Lab Retrovirol, New York, NY 10016 USA. [Bieniasz, Paul D.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10016 USA. RP Lifson, JD (reprint author), Leidos Biomedical Res Inc, Frederick Natl Lab, AIDS & Canc Virus Program, Frederick, MD 21702 USA. EM lifsonj@mail.nih.gov; thatziio@adarc.org OI Smedley, Jeremy/0000-0003-3369-4662 FU NIH [R21AI093255, R37AI64003, R01AI50111]; Howard Hughes Medical Institute; NIAID-NIH [HHSN27201100016C]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We are grateful to Vicky Coalter, Adam Wiles, Rodney Wiles, and Donald Johnson for assistance with study coordination and processing of nonhuman primate blood and tissues and to Florian Douam and Melinda Ng for assistance in optimizing SHIV cloning procedures. This work was supported by grants from the NIH; R21AI093255 (to T.H.), R37AI64003, and R01AI50111 (to P.D.B.); by the Howard Hughes Medical Institute; by NIAID-NIH Contract No. HHSN27201100016C (to D.C.M.); and in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E (to J.D.L.). Histology support was provided by the Pathology/Histotechnology Laboratory core service located at the Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 25 TC 20 Z9 20 U1 0 U2 1 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 SEP 10 PY 2014 VL 16 IS 3 BP 412 EP 418 DI 10.1016/j.chom.2014.08.003 PG 7 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AP4OL UT WOS:000342057000017 PM 25211081 ER PT J AU Coleman, CN Lawrence, TS Kirsch, DG AF Coleman, C. Norman Lawrence, Theodore S. Kirsch, David G. TI Enhancing the Efficacy of Radiation Therapy: Premises, Promises, and Practicality SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID GENE-EXPRESSION; CANCER-THERAPY; TUMOR; RADIOSENSITIZERS; IMMUNOTHERAPY; HETEROGENEITY; RADIOTHERAPY; PLASTICITY; GUIDELINES; CARCINOMA C1 [Coleman, C. Norman] NCI, Bethesda, MD 20892 USA. [Lawrence, Theodore S.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Kirsch, David G.] Duke Univ, Sch Med, Durham, NC USA. RP Coleman, CN (reprint author), NCI, Bethesda, MD 20892 USA. NR 38 TC 11 Z9 11 U1 0 U2 8 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 SEP 10 PY 2014 VL 32 IS 26 BP 2832 EP + DI 10.1200/JCO.2014.57.3865 PG 6 WC Oncology SC Oncology GA AP4PQ UT WOS:000342060700003 PM 25113766 ER PT J AU Dimitrov, EL Tsuda, MC Cameron, HA Usdin, TB AF Dimitrov, Eugene L. Tsuda, Mumeko C. Cameron, Heather A. Usdin, Ted B. TI Anxiety- and Depression-Like Behavior and Impaired Neurogenesis Evoked by Peripheral Neuropathy Persist following Resolution of Prolonged Tactile Hypersensitivity SO JOURNAL OF NEUROSCIENCE LA English DT Article DE adult neurogenesis; chronic pain; depression; neuropathic pain; reversible neuropathic injury; sciatic nerve ID ADULT HIPPOCAMPAL NEUROGENESIS; SCIATIC-NERVE INJURY; RAT DENTATE GYRUS; CHRONIC PAIN; SIGNAL AMPLIFICATION; CELL-PROLIFERATION; INFLAMMATORY PAIN; MOOD DISORDERS; CHRONIC STRESS; DELTA-FOSB AB Pain and depression are frequently associated with and often persist after resolution of an initial injury. Identifying the extent to which depression remains causally associated with ongoing physical discomfort during chronic pain, or becomes independent of it, is an important problem for basic neuroscience and psychiatry. Difficulty in distinguishing between effects of ongoing aversive sensory input and its long-term consequences is a significant roadblock, especially in animal models. To address this relationship between localized physical discomfort and its more global consequences, we investigated cellular and behavioral changes during and after reversing a mouse model of neuropathic pain. Tactile allodynia produced by placing a plastic cuff around the sciatic nerve resolved within several days when the cuff was removed. In contrast, the changes in elevated O-maze, forced-swim, Y-maze spontaneous alternation and novel-object recognition test performance that developed after nerve cuff placement remained for at least 3 weeks after the nerve cuffs were removed, or 10-15 d following complete normalization of mechanical sensitivity. Hippocampal neurogenesis, measured by doublecortin and proliferating cell nuclear antigen expression, was also suppressed after nerve cuff placement and remained suppressed 3 weeks after cuff removal. FosB expression was elevated in the central nucleus of the amygdala and spinal cord dorsal horn only in mice with ongoing allodynia. In contrast, FosB remained elevated in the basolateral amygdala of mice with resolved nociception and persisting behavioral effects. These observations suggest that different processes control tactile hypersensitivity and the behavioral changes and impaired neurogenesis that are associated with neuropathic allodynia. C1 [Dimitrov, Eugene L.; Tsuda, Mumeko C.; Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. [Cameron, Heather A.] NIMH, Unit Neuroplast, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), NIMH, Sect Fundamental Neurosci, Bldg 35,Room 1B-215,35 Convent Dr, Bethesda, MD 20892 USA. EM usdint@mail.nih.gov RI Cameron, Heather/E-6221-2011 OI Cameron, Heather/0000-0002-3245-5777 FU Intramural Research Program of the National Institutes of Health-National Institute of Mental Health FX This project was supported by the Intramural Research Program of the National Institutes of Health-National Institute of Mental Health. Technical support was provided by Jonathan Kuo. Janice Urban generously provided facilities for some of the work. NR 53 TC 17 Z9 17 U1 1 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 10 PY 2014 VL 34 IS 37 BP 12304 EP 12312 DI 10.1523/JNEUROSCI.0312-14.2014 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AP0QH UT WOS:000341766900007 PM 25209272 ER PT J AU Wang, QS Chu, CH Qian, L Chen, SH Wilson, B Oyarzabal, E Jiang, LL Ali, S Robinson, B Kim, HC Hong, JS AF Wang, Qingshan Chu, Chun-Hsien Qian, Li Chen, Shih-Heng Wilson, Belinda Oyarzabal, Esteban Jiang, Lulu Ali, Syed Robinson, Bonnie Kim, Hyoung-Chun Hong, Jau-Shyong TI Substance P Exacerbates Dopaminergic Neurodegeneration through Neurokinin-1 Receptor-Independent Activation of Microglial NADPH Oxidase SO JOURNAL OF NEUROSCIENCE LA English DT Article DE GPCR independence; NADPH oxidase; neuroinflammation; Parkinson's disease; substance P ID LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; CENTRAL-NERVOUS-SYSTEM; PARKINSONS-DISEASE; OXIDATIVE STRESS; PROGRESSIVE NEURODEGENERATION; CHRONIC NEUROINFLAMMATION; REACTIVE MICROGLIOSIS; BORRELIA-BURGDORFERI; NOX ENZYMES; INHIBITION AB Although dysregulated substance P (SP) has been implicated in the pathophysiology of Parkinson's disease (PD), how SP affects the survival of dopaminergic neurons remains unclear. Here, we found that mice lacking endogenous SP (TAC1(-/-)), but not those deficient in the SP receptor (neurokinin-1 receptor, NK1R), were more resistant to lipopolysaccharide (LPS)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic neurodegeneration than wild-type controls, suggesting a NK1R-independent toxic action of SP. In vitro dose-response studies revealed that exogenous SP enhanced LPS- and 1-methyl-4-phenylpyridinium (MPP+)-induced dopaminergic neurodegeneration in a bimodal manner, peaking at submicromolar and subpicomolar concentrations, but was substantially less effective at intermediate concentrations. Mechanistically, the actions of submicromolar levels of SP were NK1R-dependent, whereas subpicomolar SP-elicited actions required microglial NADPH oxidase (NOX2), the key superoxide-producing enzyme, but not NK1R. Subpicomolar concentrations of SP activated NOX2 by binding to the catalytic subunit gp91(phox) and inducing membrane translocation of the cytosolic subunits p47(phox) and p67(phox). The importance of NOX2 was further corroborated by showing that inhibition or disruption of NOX2 blocked subpicomolar SP-exacerbated neurotoxicity. Together, our findings revealed a critical role of microglial NOX2 in mediating the neuroinflammatory and dopaminergic neurodegenerative effects of SP, which may provide new insights into the pathogenesis of PD. C1 [Wang, Qingshan; Chu, Chun-Hsien; Qian, Li; Chen, Shih-Heng; Wilson, Belinda; Oyarzabal, Esteban; Jiang, Lulu; Hong, Jau-Shyong] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, Neuropharmacol Sect, Res Triangle Pk, NC 27709 USA. [Ali, Syed; Robinson, Bonnie] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Neurochem Lab, Jefferson, AR 72079 USA. [Kim, Hyoung-Chun] Kangwon Natl Univ, Coll Pharm, Neuropsychopharmacol & Toxicol Program, Chunchon 200701, South Korea. RP Wang, QS (reprint author), Natl Inst Environm Hlth Sci, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wangq4@niehs.nih.gov; hong3@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. We thank Anthony Lockhart for assistance with animal colony management and maintenance of the timed pregnant mice. NR 49 TC 12 Z9 12 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 10 PY 2014 VL 34 IS 37 BP 12490 EP 12503 DI 10.1523/JNEUROSCI.2238-14.2014 PG 14 WC Neurosciences SC Neurosciences & Neurology GA AP0QH UT WOS:000341766900022 PM 25209287 ER PT J AU Alia-Klein, N Wang, GJ Preston-Campbell, RN Moeller, SJ Parvaz, MA Zhu, W Jayne, MC Wong, C Tomasi, D Goldstein, RZ Fowler, JS Volkow, ND AF Alia-Klein, Nelly Wang, Gene-Jack Preston-Campbell, Rebecca N. Moeller, Scott J. Parvaz, Muhammad A. Zhu, Wei Jayne, Millard C. Wong, Chris Tomasi, Dardo Goldstein, Rita Z. Fowler, Joanna S. Volkow, Nora D. TI Reactions to Media Violence: It's in the Brain of the Beholder SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; VENTROMEDIAL PREFRONTAL CORTEX; FUNCTIONAL CONNECTIVITY; DECISION-MAKING; DEFAULT MODE; VASCULAR PROCESSES; RESTING STATE; VIDEO GAMES; BLOOD-FLOW; AGGRESSION AB Media portraying violence is part of daily exposures. The extent to which violent media exposure impacts brain and behavior has been debated. Yet there is not enough experimental data to inform this debate. We hypothesize that reaction to violent media is critically dependent on personality/trait differences between viewers, where those with the propensity for physical assault will respond to the media differently than controls. The source of the variability, we further hypothesize, is reflected in autonomic response and brain functioning that differentiate those with aggression tendencies from others. To test this hypothesis we pre-selected a group of aggressive individuals and non-aggressive controls from the normal healthy population; we documented brain, blood-pressure, and behavioral responses during resting baseline and while the groups were watching media violence and emotional media that did not portray violence. Positron Emission Tomography was used with [F-18] fluoro-deoxyglucose (FDG) to image brain metabolic activity, a marker of brain function, during rest and during film viewing while blood-pressure and mood ratings were intermittently collected. Results pointed to robust resting baseline differences between groups. Aggressive individuals had lower relative glucose metabolism in the medial orbitofrontal cortex correlating with poor self-control and greater glucose metabolism in other regions of the default-mode network (DMN) where precuneus correlated with negative emotionality. These brain results were similar while watching the violent media, during which aggressive viewers reported being more Inspired and Determined and less Upset and Nervous, and also showed a progressive decline in systolic blood-pressure compared to controls. Furthermore, the blood-pressure and brain activation in orbitofrontal cortex and precuneus were differentially coupled between the groups. These results demonstrate that individual differences in trait aggression strongly couple with brain, behavioral, and autonomic reactivity to media violence which should factor into debates about the impact of media violence on the public. C1 [Alia-Klein, Nelly; Wang, Gene-Jack; Preston-Campbell, Rebecca N.; Moeller, Scott J.; Parvaz, Muhammad A.; Goldstein, Rita Z.] Icahn Sch Med Mt Sinai, Dept Psychiat, Friedman Brain Inst, New York, NY 10029 USA. [Alia-Klein, Nelly; Moeller, Scott J.; Goldstein, Rita Z.] Icahn Sch Med Mt Sinai, Dept Neurosci, Friedman Brain Inst, New York, NY 10029 USA. [Wang, Gene-Jack; Jayne, Millard C.; Wong, Chris; Tomasi, Dardo; Volkow, Nora D.] NIAAA, Lab Neuroimaging, Bethesda, MD USA. [Zhu, Wei] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. RP Alia-Klein, N (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, Friedman Brain Inst, New York, NY 10029 USA. EM nelly.alia-klein@mssm.edu RI Tomasi, Dardo/J-2127-2015; Moeller, Scott/L-5549-2016; OI Moeller, Scott/0000-0002-4449-0844; Parvaz, Muhammad/0000-0002-2671-2327 FU Brookhaven National Laboratory [DE-AC02-98CH10886]; National Institute of Mental Health [R01MH090134]; National Institute of Mental Health NIDA; NIH [K05DA020001]; National Institute of Alcohol Abuse and Alcoholism FX Funding was provided by (1) Brookhaven National Laboratory under contract DE-AC02-98CH10886, http://www.bnl.gov/world/; (2) National Institute of Mental Health: R01MH090134 (NAK), http://www.nimh.nih.gov/index.shtml; and (3) National Institute of Mental Health NIDA and NIH K05DA020001 (JSF) and the National Institute of Alcohol Abuse and Alcoholism Intramural Program, http://www.drugabuse.gov/ and http://www.niaaa.nih.gov/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 83 TC 3 Z9 3 U1 7 U2 53 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 SEP 10 PY 2014 VL 9 IS 9 AR e107260 DI 10.1371/journal.pone.0107260 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP4EP UT WOS:000342030300069 PM 25208327 ER PT J AU Francischetti, IMB Ma, DY Andersen, JF Ribeiro, JMC AF Francischetti, Ivo M. B. Ma, Dongying Andersen, John F. Ribeiro, Jose M. C. TI Evidence for a Lectin Specific for Sulfated Glycans in the Salivary Gland of the Malaria Vector, Anopheles gambiae SO PLOS ONE LA English DT Article ID BAT DESMODUS-ROTUNDUS; PLATELET-AGGREGATION; INFLAMMATORY RESPONSE; HEMATOPHAGOUS ANIMALS; HEMIPTERA REDUVIIDAE; RHODNIUS-PROLIXUS; IMMUNE-RESPONSE; BRUGIA-MALAYI; HEMAGGLUTININS; PROTEINS AB Salivary gland homogenate (SGH) from the female mosquitoes Anopheles gambiae, An. stephensi, An. freeborni, An. dirus and An. albimanus were found to exhibit hemagglutinating (lectin) activity. Lectin activity was not found for male An. gambiae, or female Ae aegypti, Culex quinquefasciatus, Phlebotomus duboscqi, and Lutzomyia longipalpis. With respect to species-specificity, An. gambiae SGH agglutinates red blood cells (RBC) from humans, horse, sheep, goat, pig, and cow; it is less active for rats RBC, and not detectable for guinea-pigs or chicken RBC. Notably, lectin activity was inhibited by low concentrations of dextran sulfate 50-500 K, fucoidan, heparin, laminin, heparin sulfate proteoglycan, sialyl-containing glycans (e.g. 3'-sialyl Lewis X, and 6'-sialyl lactose), and gangliosides (e.g. GM3, GD1, GD1b, GTB1, GM1, GQ1B), but not by simple sugars. These results imply that molecule(s) in the salivary gland target sulfated glycans. SGH from An. gambiae was also found to promote agglutination of HL-60 cells which are rich in sialyl Lewis X, a glycan that decorates PSGL-1, the neutrophils receptor that interacts with endothelial cell P-selectin. Accordingly, SGH interferes with HL-60 cells adhesion to immobilized P-selectin. Because An. gambiae SGH expresses galectins, one member of this family (herein named Agalectin) was expressed in E. coli. Recombinant Agalectin behaves as a non-covalent homodimer. It does not display lectin activity, and does not interact with 500 candidates tested in a Glycan microarray. Gel-filtration chromatography of the SGH of An. gambiae identified a fraction with hemagglutinating activity, which was analyzed by 1D PAGE followed by in-gel tryptic digestion, and nano-LC MS/MS. This approach identified several genes which emerge as candidates for a lectin targeting sulfated glycans, the first with this selectivity to be reported in the SGH of a blood-sucking arthropod. The role of salivary molecules (sialogenins) with lectin activity is discussed in the context of inflammation, and parasite-vector-host interactions. C1 [Francischetti, Ivo M. B.; Ma, Dongying; Andersen, John F.; Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Francischetti, IMB (reprint author), NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ivofrancischetti@gmail.com OI Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 4 Z9 4 U1 2 U2 22 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 SEP 10 PY 2014 VL 9 IS 9 AR e107295 DI 10.1371/journal.pone.0107295 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP4EP UT WOS:000342030300071 PM 25207644 ER PT J AU Marston, HD Folkers, GK Morens, DM Fauci, AS AF Marston, Hilary D. Folkers, Gregory K. Morens, David M. Fauci, Anthony S. TI Emerging Viral Diseases: Confronting Threats with New Technologies SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID VACCINE; INFECTIONS; ANTIBODIES AB Emerging viral diseases pose ongoing health threats, particularly in an era of globalization; however, new biomedical research technologies such as genome sequencing and structure-based vaccine and drug design have improved our ability to respond to viral threats. C1 [Marston, Hilary D.; Folkers, Gregory K.; Morens, David M.; Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 40 TC 16 Z9 16 U1 4 U2 20 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 SEP 10 PY 2014 VL 6 IS 253 AR 253ps10 DI 10.1126/scitranslmed.3009872 PG 6 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AP0EP UT WOS:000341734400005 PM 25210060 ER PT J AU Matsumoto, S Saito, K Takakusagi, Y Matsuo, M Munasinghe, JP Morris, HD Lizak, MJ Merkle, H Yasukawa, K Devasahayam, N Suburamanian, S Mitchell, JB Krishna, MC AF Matsumoto, Shingo Saito, Keita Takakusagi, Yoichi Matsuo, Masayuki Munasinghe, Jeeva P. Morris, Herman D. Lizak, Martin J. Merkle, Hellmut Yasukawa, Keiji Devasahayam, Nallathamby Suburamanian, Sankaran Mitchell, James B. Krishna, Murali C. TI In Vivo Imaging of Tumor Physiological, Metabolic, and Redox Changes in Response to the Anti-Angiogenic Agent Sunitinib: Longitudinal Assessment to Identify Transient Vascular Renormalization SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID ELECTRON-PARAMAGNETIC-RESONANCE; SENSITIVE CONTRAST AGENTS; ANTIANGIOGENIC THERAPY; GLIOBLASTOMA PATIENTS; KINETIC-PARAMETERS; ANTITUMOR THERAPY; ENHANCED MRI; OXYGENATION; BLOOD; MICROENVIRONMENT AB Aims: The tumor microenvironment is characterized by a highly reducing redox status, a low pH, and hypoxia. Anti-angiogenic therapies for solid tumors frequently function in two steps: the transient normalization of structurally and functionally aberrant tumor blood vessels with increased blood perfusion, followed by the pruning of tumor blood vessels and the resultant cessation of nutrients and oxygen delivery required for tumor growth. Conventional anatomic or vascular imaging is impractical or insufficient to distinguish between the two steps of tumor response to anti-angiogenic therapies. Here, we investigated whether the noninvasive imaging of the tumor redox state and energy metabolism could be used to characterize anti-angiogenic drug-induced transient vascular normalization. Results: Daily treatment of squamous cell carcinoma (SCCVII) tumor-bearing mice with the multi-tyrosine kinase inhibitor sunitinib resulted in a rapid decrease in tumor microvessel density and the suppression of tumor growth. Tumor pO(2) imaging by electron paramagnetic resonance imaging showed a transient increase in tumor oxygenation after 2-4 days of sunitinib treatment, implying improved tumor perfusion. During this window of vascular normalization, magnetic resonance imaging of the redox status using an exogenously administered nitroxide probe and hyperpolarized C-13 MRI of the metabolic flux of pyruvate/lactate couple revealed an oxidative shift in tumor redox status. Innovation: Redox-sensitive metabolic couples can serve as noninvasive surrogate markers to identify the vascular normalization window in tumors with imaging techniques. Conclusion: A multimodal imaging approach to characterize physiological, metabolic, and redox changes in tumors is useful to distinguish between the different stages of anti-angiogenic treatment. C1 [Matsumoto, Shingo; Saito, Keita; Takakusagi, Yoichi; Matsuo, Masayuki; Devasahayam, Nallathamby; Suburamanian, Sankaran; Mitchell, James B.; Krishna, Murali C.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Munasinghe, Jeeva P.; Morris, Herman D.; Lizak, Martin J.] NINDS, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Merkle, Hellmut] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Yasukawa, Keiji] Kyushu Univ, Fac Pharmaceut Sci, Dept Biofunct Sci, Fukuoka 812, Japan. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bldg 10,Room B3B69 10 Ctr Dr, Bethesda, MD 20892 USA. EM murali@helix.nih.gov OI Morris, H. Douglas/0000-0002-7942-3748 FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH); Core-to-Core Program from the Japan Society for the Promotion of Science (JSPS) [19004] FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH). Collaboration with Dr. Yasukawa was also supported by the Core-to-Core Program (Grant No. 19004) from the Japan Society for the Promotion of Science (JSPS). NR 41 TC 8 Z9 8 U1 1 U2 18 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD SEP 10 PY 2014 VL 21 IS 8 BP 1145 EP 1155 DI 10.1089/ars.2013.5725 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AO5CW UT WOS:000341360800001 PM 24597714 ER PT J AU Yawn, BP Buchanan, GR Afenyi-Annan, AN Ballas, SK Hassell, KL James, AH Jordan, L Lanzkron, SM Lottenberg, R Savage, WJ Tanabe, PJ Ware, RE Murad, MH Goldsmith, JC Ortiz, E Fulwood, R Horton, A John-Sowah, J AF Yawn, Barbara P. Buchanan, George R. Afenyi-Annan, Araba N. Ballas, Samir K. Hassell, Kathryn L. James, Andra H. Jordan, Lanetta Lanzkron, Sophie M. Lottenberg, Richard Savage, William J. Tanabe, Paula J. Ware, Russell E. Murad, M. Hassan Goldsmith, Jonathan C. Ortiz, Eduardo Fulwood, Robinson Horton, Ann John-Sowah, Joylene TI Management of Sickle Cell Disease Summary of the 2014 Evidence-Based Report by Expert Panel Members SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID IMMUNIZATION PRACTICES ACIP; ACUTE CHEST SYNDROME; PULMONARY-HYPERTENSION; ADVISORY-COMMITTEE; SYSTEMATIC REVIEWS; CONTROLLED-TRIAL; ANEMIA; HYDROXYUREA; CHILDREN; PREVENTION AB IMPORTANCE Sickle cell disease (SCD) is a life-threatening genetic disorder affecting nearly 100 000 individuals in the United States and is associated with many acute and chronic complications requiring immediate medical attention. Two disease-modifying therapies, hydroxyurea and long-term blood transfusions, are available but underused. OBJECTIVE To support and expand the number of health professionals able and willing to provide care for persons with SCD. EVIDENCE REVIEW Databases of MEDLINE (including in-process and other nonindexed citations), EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, TOXLINE, and Scopus were searched using prespecified search terms and keywords to identify randomized clinical trials, nonrandomized intervention studies, and observational studies. Literature searches of English-language publications from 1980 with updates through April 1, 2014, addressed key questions developed by the expert panel members and methodologists. FINDINGS Strong recommendations for preventive services include daily oral prophylactic penicillin up to the age of 5 years, annual transcranial Doppler examinations from the ages of 2 to 16 years in those with sickle cell anemia, and long-term transfusion therapy to prevent stroke in those children with abnormal transcranial Doppler velocity (>= 200 cm/s). Strong recommendations addressing acute complications include rapid initiation of opioids for treatment of severe pain associated with a vasoocclusive crisis, and use of incentive spirometry in patients hospitalized for a vasoocclusive crisis. Strong recommendations for chronic complications include use of analgesics and physical therapy for treatment of avascular necrosis, and use of angiotensin-converting enzyme inhibitor therapy for microalbuminuria in adults with SCD. Strong recommendations for children and adults with proliferative sickle cell retinopathy include referral to expert specialists for consideration of laser photocoagulation and for echocardiography to evaluate signs of pulmonary hypertension. Hydroxyurea therapy is strongly recommended for adults with 3 or more severe vasoocclusive crises during any 12-month period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome. A recommendation of moderate strength suggests offering treatment with hydroxyurea without regard to the presence of symptoms for infants, children, and adolescents. In persons with sickle cell anemia, preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended with a moderate strength recommendation to maintain sickle hemoglobin levels of less than 30% prior to the next transfusion during long-term transfusion therapy. A strong recommendation to assess iron overload is accompanied by a moderate strength recommendation to begin iron chelation therapy when indicated. CONCLUSIONS AND RELEVANCE Hydroxyurea and transfusion therapy are strongly recommended for many individuals with SCD. Many other recommendations are based on quality of evidence that is less than high due to the paucity of clinical trials regarding screening, management, and monitoring for individuals with SCD. C1 [Yawn, Barbara P.] Olmsted Med Ctr, Rochester, MN 55904 USA. [Buchanan, George R.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Afenyi-Annan, Araba N.] Univ N Carolina, Chapel Hill, NC USA. [Ballas, Samir K.] Thomas Jefferson Univ, Cardeza Fdn, Philadelphia, PA 19107 USA. [Hassell, Kathryn L.] Univ Colorado, Denver, CO 80202 USA. [James, Andra H.] Univ Virginia, Charlottesville, VA USA. [Jordan, Lanetta] Univ Miami, Miller Sch Med, Fdn Sickle Cell Dis Res, Miami, FL 33136 USA. [Lanzkron, Sophie M.] Johns Hopkins Sch Med, Baltimore, MD USA. [Lottenberg, Richard] Univ Florida, Gainesville, FL USA. [Savage, William J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Savage, William J.] Harvard Univ, Sch Med, Boston, MA USA. [Tanabe, Paula J.] Duke Univ, Sch Nursing, Durham, NC USA. [Tanabe, Paula J.] Duke Univ, Sch Med, Durham, NC USA. [Ware, Russell E.] Cincinnati Childrens Hosp Med, Cincinnati, OH USA. [Murad, M. Hassan] Mayo Clin, Coll Med, Rochester, MN USA. [Goldsmith, Jonathan C.; Ortiz, Eduardo; Fulwood, Robinson; John-Sowah, Joylene] NHLBI, Bethesda, MD 20892 USA. [Horton, Ann] Amer Inst Res, Silver Spring, MD USA. RP Yawn, BP (reprint author), Olmsted Med Ctr, Dept Res & Educ, 210 Ninth St SE, Rochester, MN 55904 USA. EM byawn@olmmed.org FU National Heart, Lung, and Blood Institute (NHLBI) FX The National Heart, Lung, and Blood Institute (NHLBI) sponsored the development of this guideline to assist health care professionals in the management of common issues of sickle cell disease. The NHLBI established the expert panel and invited the panel members. All members served as volunteers and received no compensation from the NHLBI or any other entity for their participation. NR 73 TC 175 Z9 175 U1 20 U2 80 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 SEP 10 PY 2014 VL 312 IS 10 BP 1033 EP 1048 DI 10.1001/jama.2014.10517 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA AO5LF UT WOS:000341385600021 PM 25203083 ER PT J AU Ferrucio, B Fannin, R Liu, LW Gerrish, K Maria-Engler, S Paules, R Berlanga, S AF Ferrucio, Bianca Fannin, Richard Liu, Liwen Gerrish, Kevin Maria-Engler, Silvya Paules, Richard Berlanga, Silvia TI Gene expression profiling of cultured human melanocytes exposed to carbaryl and solar radiation SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 50th Congress of the European-Societies-of-Toxicology CY SEP 07-10, 2014 CL Edinburgh, SCOTLAND SP European Soc Toxicol, British Toxicol Soc, Soc Toxicol C1 [Ferrucio, Bianca; Maria-Engler, Silvya; Berlanga, Silvia] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin Chem & Toxicol, Sao Paulo, Brazil. [Fannin, Richard; Liu, Liwen; Gerrish, Kevin; Paules, Richard] NIEHS, Environm Stress & Canc Grp, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. RI Maria-Engler, Silvya/C-4344-2012; Maria-Engler, Silvya/K-5936-2016 OI Maria-Engler, Silvya/0000-0003-4771-6041 NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 EI 1879-3169 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP 10 PY 2014 VL 229 SU S MA P-2.48 BP S108 EP S109 DI 10.1016/j.toxlet.2014.06.394 PG 2 WC Toxicology SC Toxicology GA AO2FY UT WOS:000341134000341 ER PT J AU Smith, A Calley, J Mathur, S Qian, HR Farmen, M Engle, S Wu, H Caiment, F Bushel, P Li, JY Watson, D AF Smith, Aaron Calley, John Mathur, Sachin Qian, Hui-Rong Farmen, Mark Engle, Steve Wu, Han Caiment, Florian Bushel, Pierre Li, Jianying Watson, David TI The rat microRNA body atlas: Towards understanding serum microRNA changes and their utilisation as biomarkers of specific organ toxicity SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 50th Congress of the European-Societies-of-Toxicology CY SEP 07-10, 2014 CL Edinburgh, SCOTLAND SP European Soc Toxicol, British Toxicol Soc, Soc Toxicol C1 [Smith, Aaron; Calley, John; Mathur, Sachin; Qian, Hui-Rong; Farmen, Mark; Engle, Steve; Wu, Han; Watson, David] Eli Lilly, Indianapolis, IN USA. [Caiment, Florian] Maastricht Univ, Universiteitsingel, Netherlands. [Bushel, Pierre; Li, Jianying] NIEHS, Durham, NC USA. RI caiment, florian/N-7623-2015 NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 EI 1879-3169 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP 10 PY 2014 VL 229 SU S MA PS2.3-O1 BP S22 EP S22 DI 10.1016/j.toxlet.2014.06.110 PG 1 WC Toxicology SC Toxicology GA AO2FY UT WOS:000341134000068 ER PT J AU Lekman, M Hossjer, O Andrews, P Kallberg, H Uvehag, D Charney, D Manji, H Rush, JA McMahon, FJ Moore, JH Kockum, I AF Lekman, Magnus Hossjer, Ola Andrews, Peter Kallberg, Henrik Uvehag, Daniel Charney, Dennis Manji, Husseini Rush, John A. McMahon, Francis J. Moore, Jason H. Kockum, Ingrid TI The genetic interacting landscape of 63 candidate genes in Major Depressive Disorder: an explorative study SO BIODATA MINING LA English DT Article DE Additive interaction; Multiplicative interaction; Logistic regression; Data mining and machine learning; Major depressive disorder ID GENOME-WIDE ASSOCIATION; MISSING HERITABILITY; HUMAN-DISEASES; EPISTASIS; BIOINFORMATICS; SUSCEPTIBILITY; SCHIZOPHRENIA; EPIDEMIOLOGY; EVOLUTION; PATHWAYS AB Background: Genetic contributions to major depressive disorder (MDD) are thought to result from multiple genes interacting with each other. Different procedures have been proposed to detect such interactions. Which approach is best for explaining the risk of developing disease is unclear. This study sought to elucidate the genetic interaction landscape in candidate genes for MDD by conducting a SNP-SNP interaction analysis using an exhaustive search through 3,704 SNP-markers in 1,732 cases and 1,783 controls provided from the GAIN MDD study. We used three different methods to detect interactions, two logistic regressions models (multiplicative and additive) and one data mining and machine learning (MDR) approach. Results: Although none of the interaction survived correction for multiple comparisons, the results provide important information for future genetic interaction studies in complex disorders. Among the 0.5% most significant observations, none had been reported previously for risk to MDD. Within this group of interactions, less than 0.03% would have been detectable based on main effect approach or an a priori algorithm. We evaluated correlations among the three different models and conclude that all three algorithms detected the same interactions to a low degree. Although the top interactions had a surprisingly large effect size for MDD (e. g. additive dominant model P-uncorrected = 9.10E-9 with attributable proportion (AP) value = 0.58 and multiplicative recessive model with P-uncorrected = 6.95E-5 with odds ratio (OR estimated from beta 3) value = 4.99) the area under the curve (AUC) estimates were low (< 0.54). Moreover, the population attributable fraction (PAF) estimates were also low (< 0.15). Conclusions: We conclude that the top interactions on their own did not explain much of the genetic variance of MDD. The different statistical interaction methods we used in the present study did not identify the same pairs of interacting markers. Genetic interaction studies may uncover previously unsuspected effects that could provide novel insights into MDD risk, but much larger sample sizes are needed before this strategy can be powerfully applied. C1 [Lekman, Magnus; Uvehag, Daniel; Kockum, Ingrid] Karolinska Inst, Dept Clin Neurosci, Neuroimmunol Unit, Stockholm, Sweden. [Hossjer, Ola] Stockholm Univ, Dept Math, S-10691 Stockholm, Sweden. [Andrews, Peter; Moore, Jason H.] Dartmouth Coll, Geisel Sch Med, Dept Genet & Community & Family Med, Inst Quantitat Biomed Sci, Hanover, NH 03755 USA. [Kallberg, Henrik] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Charney, Dennis] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Manji, Husseini] NIMH, Mol Pathophysiol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rush, John A.] Duke Natl Univ Singapore, Acad Med Res Inst, Singapore, Singapore. [McMahon, Francis J.] NIMH, Genet Basis Mood & Anxiety Disorders Sect, Human Genet Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Lekman, M (reprint author), Karolinska Inst, Dept Clin Neurosci, Neuroimmunol Unit, Stockholm, Sweden. EM magnus.lekman@ki.se OI McMahon, Francis/0000-0002-9469-305X; Rush, Augustus/0000-0003-2004-2382 FU Swedish Research Council [621-2008-4946]; Gustafsson Foundation for Research in Natural Sciences and Medicine, NIH [LM009012, LM010098] FX We would like to acknowledge Dr Henric Zazzi, at PDC Center for High Performance Computing at the Royal Institute of Technology (KTH), Sweden, for help with programming of the JAVA code used for interaction analysis in the additive and multiplicative model. We would also like to thank Dr. Silvia Paddock for all the help in the early phase of this study. This study was supported by grants from, Swedish Research Council, contract nr. 621-2008-4946, the Gustafsson Foundation for Research in Natural Sciences and Medicine, NIH grant LM009012 and LM010098. The authors declare no conflict of interest. NR 54 TC 0 Z9 1 U1 0 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-0381 J9 BIODATA MIN JI BioData Min. PD SEP 9 PY 2014 VL 7 AR 19 DI 10.1186/1756-0381-7-19 PG 18 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AQ3NH UT WOS:000342700200001 PM 25279001 ER PT J AU Qureshi, H Genesca, M Fritts, L McChesney, MB Robert-Guroff, M Miller, CJ AF Qureshi, Huma Genesca, Meritxell Fritts, Linda McChesney, Michael B. Robert-Guroff, Marjorie Miller, Christopher J. TI Infection with Host-Range Mutant Adenovirus 5 Suppresses Innate Immunity and Induces Systemic CD4+T Cell Activation in Rhesus Macaques SO PLOS ONE LA English DT Article ID SIMIAN-IMMUNODEFICIENCY-VIRUS; PLASMACYTOID DENDRITIC CELLS; NEUTRALIZING ANTIBODIES TARGET; ALPHA-INTERFERON RESPONSES; BLOOD MONONUCLEAR-CELLS; T-CELLS; YOUNG-CHILDREN; HIV-1 VACCINE; GAG/POL/NEF VACCINE; ADULT-POPULATIONS AB Ad5 is a common cause of respiratory disease and an occasional cause of gastroenteritis and conjunctivitis, and seroconversion before adolescence is common in humans. To gain some insight into how Ad5 infection affects the immune system of rhesus macaques (RM) 18 RM were infected with a host-range mutant Ad5 (Ad5hr) by 3 mucosal inoculations. There was a delay of 2 to 6 weeks after the first inoculation before plasmacytoid dendritic cell (pDC) frequency and function increased in peripheral blood. Primary Ad5hr infection suppressed IFN-gamma mRNA expression, but the second Ad5hr exposure induced a rapid increase in IFN-gamma mRNA in peripheral blood mononuclear cells (PBMC). Primary Ad5hr infection suppressed CCL20, TNF and IL-1 mRNA expression in PBMC, and subsequent virus exposures further dampened expression of these pro-inflammatory cytokines. Primary, but not secondary, Ad5hr inoculation increased the frequency of CXCR3+ CD4+ T cells in blood, while secondary, but not primary, Ad5hr infection transiently increased the frequencies of Ki67+, HLADR+ and CD95+/CCR5+ CD4+ T cells in blood. Ad5hr infection induced polyfunctional CD4 and CD8+ T cells specific for the Ad5 hexon protein in all of the animals. Thus, infection with Ad5hr induced a complex pattern of innate and adaptive immunity in RM that included transient systemic CD4+ T cell activation and suppressed innate immunity on re-exposure to the virus. The complex effects of adenovirus infection on the immune system may help to explain the unexpected results of testing Ad5 vector expressing HIV antigens in Ad5 seropositive people. C1 [Qureshi, Huma; Genesca, Meritxell; Fritts, Linda; McChesney, Michael B.; Miller, Christopher J.] Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. [Qureshi, Huma; Genesca, Meritxell; Miller, Christopher J.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Robert-Guroff, Marjorie] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. RP Miller, CJ (reprint author), Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. EM cjmiller@ucdavis.edu FU National Institutes of Health, National Institute of Allergy and Infectious Disease [P01 AI82278-01] FX P01 AI82278-01 from the National Institutes of Health, National Institute of Allergy and Infectious Disease to CJM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 3 Z9 5 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 9 PY 2014 VL 9 IS 9 AR e106004 DI 10.1371/journal.pone.0106004 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ3IF UT WOS:000342684500011 PM 25203111 ER PT J AU Shah, SS Macharia, A Makale, J Uyoga, S Kivinen, K Craik, R Hubbart, C Wellems, TE Rockett, KA Kwiatkowski, DP Williams, TN AF Shah, Shivang S. Macharia, Alex Makale, Johnstone Uyoga, Sophie Kivinen, Katja Craik, Rachel Hubbart, Christina Wellems, Thomas E. Rockett, Kirk A. Kwiatkowski, Dominic P. Williams, Thomas N. TI Genetic determinants of glucose-6-phosphate dehydrogenase activity in Kenya SO BMC MEDICAL GENETICS LA English DT Article DE G6PD deficiency; Malaria ID WHOLE-GENOME ASSOCIATION; G6PD DEFICIENCY; SEVERE MALARIA; WEST-AFRICA; POPULATION; RESISTANCE; VARIANT; HETEROGENEITY; SELECTION; SEQUENCE AB Background: The relationship between glucose-6-phosphate dehydrogenase (G6PD) deficiency and clinical phenomena such as primaquine-sensitivity and protection from severe malaria remains poorly defined, with past association studies yielding inconsistent and conflicting results. One possibility is that examination of a single genetic variant might underestimate the presence of true effects in the presence of unrecognized functional allelic diversity. Methods: We systematically examined this possibility in Kenya, conducting a fine-mapping association study of erythrocyte G6PD activity in 1828 Kenyan children across 30 polymorphisms at or around the G6PD locus. Results: We demonstrate a strong functional role for c.202G>A (rs1050828), which accounts for the majority of variance in enzyme activity observed (P = 1.5 x 10(-200), additive model). Additionally, we identify other common variants that exert smaller, intercorrelated effects independent of c.202G>A, and haplotype analyses suggest that each variant tags one of two haplotype motifs that are opposite in sequence identity and effect direction. We posit that these effects are of biological and possible clinical significance, specifically noting that c.376A>G (rs1050829) augments 202AG heterozygote risk for deficiency trait by two-fold (OR = 2.11 [1.12-3.84], P = 0.014). Conclusions: Our results suggest that c.202G>A is responsible for the majority of the observed prevalence of G6PD deficiency trait in Kenya, but also identify a novel role for c.376A>G as a genetic modifier which marks a common haplotype that augments the risk conferred to 202AG heterozygotes, suggesting that variation at both loci merits consideration in genetic association studies probing G6PD deficiency-associated clinical phenotypes. C1 [Shah, Shivang S.; Craik, Rachel; Hubbart, Christina; Rockett, Kirk A.; Kwiatkowski, Dominic P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Macharia, Alex; Makale, Johnstone; Uyoga, Sophie; Williams, Thomas N.] Kilifi Dist Hosp, Ctr Geog Med Res, Kenya Med Res Inst, Wellcome Trust Res Programme, Kilifi, Kenya. [Kivinen, Katja; Kwiatkowski, Dominic P.] Wellcome Trust Sanger Inst, Hinxton, Cambs, England. [Williams, Thomas N.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Med, Oxford OX3 9DU, England. [Shah, Shivang S.; Wellems, Thomas E.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Shah, SS (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. EM ssshah03@gmail.com OI Kivinen, Katja/0000-0002-1135-7625; Kwiatkowski, Dominic/0000-0002-5023-0176 FU Wellcome Trust [WT077383/Z/05/Z]; Bill and Melinda Gates Foundation through the Foundations of the National Institutes of Health, Grand Challenges in Global Health Initiative [566]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH); Wellcome Trust Centre for Human Genetics [075491/Z/04, 090532/Z/09/Z]; Wellcome Trust Sanger Institute [077012/Z/05/Z]; Wellcome Trust (WT Senior Research Fellowship) [091758]; European Union EVIMALAR FP7 Network of Excellence; Medical Scientist Training Program at the NIH; Medical Research Council [G19/9] FX The authors thank all the children and their families who participated in this study. We also thank Metrine Tendwa, Adan Mohammed, and Emily Nyatichi for their efforts in support of this work. This paper is published with the permission of the Director of the Kenya Medical Research Institute. Work was supported in part by the Wellcome Trust (WT077383/Z/05/Z) and the Bill and Melinda Gates Foundation through the Foundations of the National Institutes of Health (566) as part of the Grand Challenges in Global Health Initiative, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH). The Wellcome Trust also provides core awards to Wellcome Trust Centre for Human Genetics (075491/Z/04; 090532/Z/09/Z) and the Wellcome Trust Sanger Institute (077012/Z/05/Z). TNW is funded by the Wellcome Trust (WT Senior Research Fellowship 091758) and the European Union EVIMALAR FP7 Network of Excellence. Travel funds for SS were furnished by Wolfson College and Oxford University Exploration Club. SS is also supported by the Medical Scientist Training Program at the NIH. DPK receives support from the Medical Research Council (G19/9). NR 25 TC 7 Z9 7 U1 2 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD SEP 9 PY 2014 VL 15 AR 93 DI 10.1186/s12881-014-0093-6 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AP5AW UT WOS:000342093100001 PM 25201310 ER PT J AU Zhang, XL Li, B Li, WG Ma, LJ Zheng, DY Li, LP Yang, WJ Chu, M Chen, W Mailman, RB Zhu, J Fan, GP Archer, TK Wang, Y AF Zhang, Xiaoli Li, Bing Li, Wenguo Ma, Lijuan Zheng, Dongyan Li, Leping Yang, Weijing Chu, Min Chen, Wei Mailman, Richard B. Zhu, Jun Fan, Guoping Archer, Trevor K. Wang, Yuan TI Transcriptional Repression by the BRG1-SWI/SNF Complex Affects the Pluripotency of Human Embryonic Stem Cells SO STEM CELL REPORTS LA English DT Article ID CHROMATIN-REMODELING COMPLEX; MAMMALIAN SWI/SNF COMPLEXES; SELF-RENEWAL; BRG1 COMPLEX; MOUSE; ROLES; SUBUNIT; ESBAF; COMPONENTS; EXPRESSION AB The SWI/SNF complex plays an important role in mouse embryonic stem cells (mESCs), but it remains to be determined whether this complex is required for the pluripotency of human ESCs (hESCs). Using RNAi, we demonstrated that depletion of BRG1, the catalytic subunit of the SWI/SNF complex, led to impaired self-renewing ability and dysregulated lineage specification of hESCs. A unique composition of the BRG1-SWI/SNF complex in hESCs was further defined by the presence of BRG1, BAF250A, BAF170, BAF155, BAF53A, and BAF47. Genome-wide expression analyses revealed that BRG1 participated in a broad range of biological processes in hESCs through pathways different from those in mESCs. In addition, chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated that BRG1 played a repressive role in transcriptional regulation by modulating the acetylation levels of H3K27 at the enhancers of lineage-specific genes. Our data thus provide valuable insights into molecular mechanisms by which transcriptional repression affects the self-renewal and differentiation of hESCs. C1 [Zhang, Xiaoli; Li, Bing; Li, Wenguo; Ma, Lijuan; Zheng, Dongyan; Chu, Min; Chen, Wei; Wang, Yuan] E China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China. [Zhang, Xiaoli; Li, Bing; Li, Wenguo; Ma, Lijuan; Zheng, Dongyan; Chu, Min; Chen, Wei; Wang, Yuan] E China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China. [Li, Leping] NIEHS, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Archer, Trevor K.] NIEHS, Chromatin & Gene Express Grp, Mol Carcinogenesis Lab, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Mailman, Richard B.] Penn State Coll Med, Dept Pharmacol, Hershey, PA 17033 USA. [Yang, Weijing; Zhu, Jun] NHLBI, Syst Biol Ctr, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Fan, Guoping] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. RP Wang, Y (reprint author), E China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China. EM ywang@bio.ecnu.edu.cn OI Mailman, Richard/0000-0003-1353-2738 FU Ministry of Science and Technology of China [2010CB945403, 2014CB964800]; National Natural Science Foundation of China [31271589, 30971522]; Science and Technology Commission of Shanghai Municipality [11DZ2260300, 13JC1406402]; NIH [Z01 ES071006-11, ZIC HL006058, ES101765] FX We thank Dr. Jiemin Wong for his critical comments during preparation of this manuscript, Dr. Ting Ni for help with the ChIP-seq analyses, and Dr. Lei Feng for help with the mass spectrometry assays. Microarray analyses were carried out at the Sequencing Core Facility of NIEHS. This work was supported by grants from the Ministry of Science and Technology of China (2010CB945403 and 2014CB964800), the National Natural Science Foundation of China ( 31271589 and 30971522), the Science and Technology Commission of Shanghai Municipality (11DZ2260300 and 13JC1406402), and the Intramural Research Program of the NIH (Z01 ES071006-11 to T.K.A., ZIC HL006058 to J.Z., and ES101765 to L.L.). NR 46 TC 9 Z9 9 U1 0 U2 4 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 SEP 9 PY 2014 VL 3 IS 3 BP 460 EP 474 DI 10.1016/j.stemcr.2014.07.004 PG 15 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AP2TI UT WOS:000341927500009 PM 25241744 ER PT J AU Fernandez, JG Rodriguez, DA Valenzuela, M Calderon, C Urzua, U Munroe, D Rosas, C Lemus, D Diaz, N Wright, MC Leyton, L Tapia, JC Quest, AFG AF Fernandez, Jaime G. Rodriguez, Diego A. Valenzuela, Manuel Calderon, Claudia Urzua, Ulises Munroe, David Rosas, Carlos Lemus, David Diaz, Natalia Wright, Mathew C. Leyton, Lisette Tapia, Julio C. Quest, Andrew F. G. TI Survivin expression promotes VEGF-induced tumor angiogenesis via PI3K/Akt enhanced beta-catenin/Tcf-Lef dependent transcription SO MOLECULAR CANCER LA English DT Article DE Survivin; Angiogenesis; VEGF; beta-catenin; PI3K; Akt ID ENDOTHELIAL GROWTH-FACTOR; APOPTOSIS PROTEIN SURVIVIN; COLON-CARCINOMA CELLS; MELANOMA-CELLS; E-CADHERIN; IN-VIVO; CANCER; SUPPRESSION; CAVEOLIN-1; METASTASIS AB Early in cancer development, tumour cells express vascular endothelial growth factor (VEGF), a secreted molecule that is important in all stages of angiogenesis, an essential process that provides nutrients and oxygen to the nascent tumor and thereby enhances tumor-cell survival and facilitates growth. Survivin, another protein involved in angiogenesis, is strongly expressed in most human cancers, where it promotes tumor survival by reducing apoptosis as well as favoring endothelial cell proliferation and migration. The mechanisms by which cancer cells induce VEGF expression and angiogenesis upon survivin up-regulation remain to be fully established. Since the PI3K/Akt signalling and beta-catenin-Tcf/Lef dependent transcription have been implicated in the expression of many cancer-related genes, including survivin and VEGF, we evaluated whether survivin may favor VEGF expression, release from tumor cells and induction of angiogenesis in a PI3K/Akt-beta-catenin-Tcf/Lef-dependent manner. Here, we provide evidence linking survivin expression in tumor cells to increased beta-catenin protein levels, beta-catenin-Tcf/Lef transcriptional activity and expression of several target genes of this pathway, including survivin and VEGF, which accumulates in the culture medium. Alternatively, survivin downregulation reduced beta-catenin protein levels and beta-catenin-Tcf/Lef transcriptional activity. Also, using inhibitors of PI3K and the expression of dominant negative Akt, we show that survivin acts upstream in an amplification loop to promote VEGF expression. Moreover, survivin knock-down in B16F10 murine melanoma cells diminished the number of blood vessels and reduced VEGF expression in tumors formed in C57BL/6 mice. Finally, in the chick chorioallantoid membrane assay, survivin expression in tumor cells enhanced VEGF liberation and blood vessel formation. Importantly, the presence of neutralizing anti-VEGF antibodies precluded survivin-enhanced angiogenesis in this assay. These findings provide evidence for the existance of a posititve feedback loop connecting survivin expression in tumor cells to PI3K/Akt enhanced beta-catenin-Tcf/Lef-dependent transcription followed by secretion of VEGF and angiogenesis. C1 [Fernandez, Jaime G.; Rodriguez, Diego A.; Valenzuela, Manuel; Calderon, Claudia; Diaz, Natalia; Leyton, Lisette; Quest, Andrew F. G.] Univ Chile, Fac Med, Programa Biol Celular & Mol,ICBM, Lab Comunicac Celulares,Ctr Estudios Mol Celula, Santiago 7, Chile. [Fernandez, Jaime G.] Univ Chile, Hosp Clin, Dept Cirugia, Santiago 7, Chile. [Rodriguez, Diego A.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. [Urzua, Ulises; Tapia, Julio C.] Univ Chile, Fac Med, Programa Biol Celular & Mol, ICBM, Santiago 7, Chile. [Munroe, David] NCI, Lab Mol Technol, FCRF, Frederick, MD 21701 USA. [Rosas, Carlos; Lemus, David] Univ Chile, Fac Med, ICBM, Programa Morfol & Biol Desarrollo, Santiago 7, Chile. [Wright, Mathew C.] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Valenzuela, Manuel; Calderon, Claudia; Quest, Andrew F. G.] Adv Ctr Chron Dis ACCDiS, Santiago, Chile. RP Quest, AFG (reprint author), Univ Chile, Fac Med, Programa Biol Celular & Mol,ICBM, Lab Comunicac Celulares,Ctr Estudios Mol Celula, Santiago 7, Chile. EM aquest@med.uchile.cl RI Urzua, Ulises/A-3982-2013; Tapia, Julio/A-7436-2012; OI Urzua, Ulises/0000-0003-0522-5754 FU CONICYT-FONDAP [15130011]; FONDECYT [1090071, 1130250, 1110149]; Anillo ACT 1111; Iniciative Cientifica Milenio (ICM) [P09-015-F]; CONICYT PhD fellowships FX This study was supported by CONICYT-FONDAP 15130011, FONDECYT 1090071, 1130250 and Anillo ACT 1111 (AFGQ), Fondecyt 1110149 (LL), Iniciative Cientifica Milenio (ICM) P09-015-F (LL), as well as CONICYT PhD fellowships (to JGF, CR, ND, MV, DAR). The authors thank Dr Trevor Jackson for insightful discussions at the onset of the project, Lorena Lobos and Lorena Aguilar for assistance with the mouse experiments and Irma Gonzalez for her assistance in the chick CAM experiments. NR 50 TC 19 Z9 22 U1 0 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD SEP 9 PY 2014 VL 13 AR 209 DI 10.1186/1476-4598-13-209 PG 15 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AP4AP UT WOS:000342019500001 PM 25204429 ER PT J AU Ramayya, AG Zaghloul, KA Weidemann, CT Baltuch, GH Kahana, MJ AF Ramayya, Ashwin G. Zaghloul, Kareem A. Weidemann, Christoph T. Baltuch, Gordon H. Kahana, Michael J. TI Electrophysiological evidence for functionally distinct neuronal populations in the human substantia nigra SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE substantia nigra; human; dopamine; GABA; neuron; reinforcement learning ID VENTRAL TEGMENTAL AREA; MIDBRAIN DOPAMINERGIC-NEURONS; PARS-RETICULATA NEURONS; PARKINSONS-DISEASE; HUMAN BRAIN; SUBTHALAMIC NUCLEUS; REWARD; MONKEY; PREDICTION; RAT AB The human substantia nigra (SN) is thought to consist of two functionally distinct neuronal populations-dopaminergic (DA) neurons in the pars compacta subregion and GABA-ergic neurons in the pars reticulate subregion. However, a functional dissociation between these neuronal populations has not previously been demonstrated in the awake human. Here we obtained microelectrode recordings from the SN of patients undergoing deep brain stimulation (DBS) surgery for Parkinson's disease as they performed a two-alternative reinforcement learning task. Following positive feedback presentation, we found that putative DA and GABA neurons demonstrated distinct temporal dynamics. DA neurons demonstrated phasic increases in activity (250-500 ms post-feedback) whereas putative GABA neurons demonstrated more delayed and sustained increases in activity (500-1000 ms post-feedback). These results provide the first electrophysiological evidence for a functional dissociation between DA and GABA neurons in the human SN. We discuss possible functions for these neuronal responses based on previous findings in human and animal studies. C1 [Ramayya, Ashwin G.] Univ Penn, Dept Neurosci, Neurosc Grad Grp, Philadelphia, PA 19104 USA. [Zaghloul, Kareem A.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Weidemann, Christoph T.] Swansea Univ, Dept Psychol, Swansea, W Glam, Wales. [Baltuch, Gordon H.] Univ Penn, Perelman Sch Med, Dept Neurosurg, Philadelphia, PA 19104 USA. [Kahana, Michael J.] Univ Penn, Dept Psychol, Philadelphia, PA 19104 USA. RP Baltuch, GH (reprint author), Perelman Sch Med, Dept Neurosurg, 235 South 8th St, Philadelphia, PA 19106 USA. EM baltuchg@mail.med.upenn.edu; kahana@psych.upenn.edu RI Weidemann, Christoph/E-8857-2011; OI Weidemann, Christoph T./0000-0002-4280-2744 FU NIH [K99NS067241-01, MH55687]; Dana Foundation FX This work was supported in part by NIH Grants K99NS067241-01 and MH55687 and by the Dana Foundation. We are grateful to the subjects who volunteered in this study. We thank M. Kerr and H. Chaibainou, and the staff of the Pennsylvania Neurological Institute for their help in coordinating patient recruitment for this study. We thank B. C. Lega, M. Donley-Fletcher and M. Kinslow for assistance with intra-operative data collection. We thank N. M. Long, J. F. Burke and M. B. Merkow for insightful comments on this manuscript and general discussion. NR 43 TC 4 Z9 4 U1 0 U2 5 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD SEP 9 PY 2014 VL 8 AR 655 DI 10.3389/fnhum.2014.00655 PG 9 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AO5VF UT WOS:000341412800001 PM 25249957 ER PT J AU Komiya, Y Mandrekar, N Sato, A Dawid, IB Habas, R AF Komiya, Yuko Mandrekar, Noopur Sato, Akira Dawid, Igor B. Habas, Raymond TI Custos controls beta-catenin to regulate head development during vertebrate embryogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SUBCELLULAR-LOCALIZATION; XENOPUS; CELL; TRANSCRIPTION; GASTRULATION; ACTIVATION; NUCLEUS; DAAM1; APC AB Precise control of the canonical Wnt pathway is crucial in embryogenesis and all stages of life, and dysregulation of this pathway is implicated in many human diseases including cancers and birth defect disorders. A key aspect of canonical Wnt signaling is the cytoplasmic to nuclear translocation of beta-catenin, a process that remains incompletely understood. Here we report the identification of a previously undescribed component of the canonical Wnt signaling pathway termed Custos, originally isolated as a Dishevelled-interacting protein. Custos contains casein kinase phosphorylation sites and nuclear localization sequences. In Xenopus, custos mRNA is expressed maternally and then widely throughout embryogenesis. Depletion or overexpression of Custos produced defective anterior head structures by inhibiting the formation of the Spemann-Mangold organizer. In addition, Custos expression blocked secondary axis induction by positive signaling components of the canonical Wnt pathway and inhibited beta-catenin/TCF-dependent transcription. Custos binds to beta-catenin in a Wnt responsive manner without affecting its stability, but rather modulates the cytoplasmic to nuclear translocation of beta-catenin. This effect on nuclear import appears to be the mechanism by which Custos inhibits canonical Wnt signaling. The function of Custos is conserved as loss-of-function and gain-of- function studies in zebrafish also demonstrate a role for Custos in anterior head development. Our studies suggest a role for Custos in fine-tuning canonical Wnt signal transduction during embryogenesis, adding an additional layer of regulatory control in the Wnt-beta-catenin signal transduction cascade. C1 [Komiya, Yuko; Mandrekar, Noopur; Habas, Raymond] Temple Univ, Coll Sci & Technol, Dept Biol, Philadelphia, PA 19122 USA. [Sato, Akira] Osaka Univ, Grad Sch Med, Dept Mol Biol & Biochem, Suita, Osaka 5650871, Japan. [Dawid, Igor B.] NICHHD, Sect Dev Biol, Bethesda, MD 20892 USA. RP Dawid, IB (reprint author), NICHHD, Sect Dev Biol, Bethesda, MD 20892 USA. EM idawid@mail.nih.gov; habas@temple.edu FU New Jersey Commission for Cancer Research; Uehara Memorial Foundation; National Institutes of Health [R01GM086377]; Intramural Research Program of the National Institute of Child Health and Human Development FX We thank Loren Runnels and the R.H. laboratory for discussion and critical comments. We are grateful to Dr. Xi He, in whose laboratory at Harvard Medical School these studies began, and to Dr. Michael Tsang (University of Pittsburgh) for guidance with the zebrafish studies. This work was supported by grants from the New Jersey Commission for Cancer Research (to Y.K. and A.S.), Uehara Memorial Foundation (to A.S.), National Institutes of Health Grant R01GM086377 (to R. H.), and by the Intramural Research Program of the National Institute of Child Health and Human Development. NR 32 TC 0 Z9 0 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 9 PY 2014 VL 111 IS 36 BP 13099 EP 13104 DI 10.1073/pnas.1414437111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO8SV UT WOS:000341625600038 PM 25157132 ER PT J AU Chun, TW Murray, D Justement, JS Blazkova, J Hallahan, CW Fankuchen, O Gittens, K Benko, E Kovacs, C Moir, S Fauci, AS AF Chun, Tae-Wook Murray, Danielle Justement, Jesse S. Blazkova, Jana Hallahan, Claire W. Fankuchen, Olivia Gittens, Kathleen Benko, Erika Kovacs, Colin Moir, Susan Fauci, Anthony S. TI Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE latent HIV; HIV-specific antibodies; HIV envelope protein ID ACTIVE ANTIRETROVIRAL THERAPY; STRUCTURAL BASIS; HUMANIZED MICE; VACCINE; MACAQUES; IDENTIFICATION; TRANSMISSION; PROTECTION; VIREMIA; CURE AB Several highly potent and broadly neutralizing monoclonal antibodies against HIV have recently been isolated from B cells of infected individuals. However, the effects of these antibodies on the persistent viral reservoirs in HIV-infected individuals receiving antiretroviral therapy (ART) are unknown. We show that several HIV-specific monoclonal antibodies-in particular, PGT121, VRC01, and VRC03-potently inhibited entry into CD4(+) T cells of HIV isolated from the latent viral reservoir of infected individuals whose plasma viremia was well controlled by ART. In addition, we demonstrate that HIV replication in autologous CD4(+) T cells derived from infected individuals receiving ART was profoundly suppressed by three aforementioned and other HIV-specific monoclonal antibodies. These findings have implications for passive immunotherapy as an approach toward controlling plasma viral rebound in patients whose ART is withdrawn. C1 [Chun, Tae-Wook; Murray, Danielle; Justement, Jesse S.; Blazkova, Jana; Fankuchen, Olivia; Moir, Susan; Fauci, Anthony S.] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. [Hallahan, Claire W.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Gittens, Kathleen] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Benko, Erika; Kovacs, Colin] Maple Leaf Med Clin, Toronto, ON M5G 1K2, Canada. [Kovacs, Colin] Univ Toronto, Dept Med, Toronto, ON M5G 2C4, Canada. RP Chun, TW (reprint author), NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. EM twchun@nih.gov; afauci@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Dr. Dennis Burton and the National Institutes of Health AIDS Reagent Program for providing HIV-specific mononuclear antibodies. We also thank the study volunteers for participating in this study. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 25 TC 17 Z9 17 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 9 PY 2014 VL 111 IS 36 BP 13151 EP 13156 DI 10.1073/pnas.1414148111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO8SV UT WOS:000341625600047 PM 25157148 ER PT J AU Le Nouen, C Brock, LG Luongo, C McCarty, T Yang, LJ Mehedi, M Wimmer, E Mueller, S Collins, PL Buchholz, UJ DiNapoli, JM AF Le Nouen, Cyril Brock, Linda G. Luongo, Cindy McCarty, Thomas Yang, Lijuan Mehedi, Masfique Wimmer, Eckard Mueller, Steffen Collins, Peter L. Buchholz, Ursula J. DiNapoli, Joshua M. TI Attenuation of human respiratory syncytial virus by genome-scale codon-pair deoptimization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE negative strand RNA virus; pneumovirus; live attenuated vaccine ID OPEN READING FRAMES; VACCINE CANDIDATE; MESSENGER-RNA; REPLICATION; EXPRESSION; GENE; BIAS; TEMPERATURE; REDUCTION; CULTURE AB Human respiratory syncytial virus (RSV) is the most important viral agent of serious pediatric respiratory-tract disease worldwide. A vaccine or generally effective antiviral drug is not yet available. We designed new live attenuated RSV vaccine candidates by codon-pair deoptimization (CPD). Specifically, viral ORFs were recoded by rearranging existing synonymous codons to increase the content of underrepresented codon pairs. Amino acid coding was completely unchanged. Four CPD RSV genomes were designed in which the indicated ORFs were recoded: Min A (NS1, NS2, N, P, M, and SH), Min B (G and F), Min L (L), and Min FLC (all ORFs except M2-1 and M2-2). Surprisingly, the recombinant CPD viruses were temperature-sensitive for replication in vitro (level of sensitivity: Min FLC > Min L > Min B > Min A). All of the CPD mutants grew less efficiently in vitro than recombinant wild-type (WT) RSV, even at the typically permissive temperature of 32 degrees C (growth efficiency: WT > Min L > Min A > Min FLC > Min B). CPD of the ORFs for the G and F surface glycoproteins provided the greatest restrictive effect. The CPD viruses exhibited a range of restriction in mice and African green monkeys comparable with that of two attenuated RSV strains presently in clinical trials. This study provided a new type of attenuated RSV and showed that CPD can rapidly generate vaccine candidates against nonsegmented negative-strand RNA viruses, a large and expanding group that includes numerous pathogens of humans and animals. C1 [Le Nouen, Cyril; Brock, Linda G.; Luongo, Cindy; McCarty, Thomas; Yang, Lijuan; Mehedi, Masfique; Collins, Peter L.; Buchholz, Ursula J.; DiNapoli, Joshua M.] NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Wimmer, Eckard; Mueller, Steffen] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. RP Le Nouen, C (reprint author), NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM lenouenc@niaid.nih.gov; Eckard.Wimmer@stonybrook.edu RI Mehedi, masfique/J-6618-2014 OI Mehedi, masfique/0000-0003-1728-3126 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); NIH [R01 AI07521901 A1] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) (C.L.N., L.G.B., C.L., T.M., L.Y., M.M., P.L.C., U.J.B., and J.M.D.) and in part by NIH Grant R01 AI07521901 A1 (to E. W.). NR 24 TC 21 Z9 21 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 9 PY 2014 VL 111 IS 36 BP 13169 EP 13174 DI 10.1073/pnas.1411290111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO8SV UT WOS:000341625600050 PM 25157129 ER PT J AU Shimada, M Yoshizaki, S Ichino, M Klinman, DM Okuda, K AF Shimada, Masaru Yoshizaki, Shinji Ichino, Motohide Klinman, Dennis M. Okuda, Kenji TI Apoptosis of antigen-specific CTLs contributes to low immune response in gut-associated lymphoid tissue post vaccination SO VACCINE LA English DT Article DE Programmed cell death protein-1 (PD-1); Vaccine; Virus vector; Mouse ID CHRONIC VIRAL-INFECTION; T-CELL EXHAUSTION; IMMUNODEFICIENCY VIRUS CHALLENGE; MUCOSAL IMMUNIZATION; PROTECTIVE IMMUNITY; PROGRAMMED DEATH-1; RHESUS-MONKEYS; SIV INFECTION; ANTIRETROVIRAL THERAPY; GASTROINTESTINAL-TRACT AB The gut-associated lymphoid tissue (GALT) represents a major reservoir of HIV in infected individuals. Vaccines can induce strong systemic immune responses but these have less impact on CD4T cells activity and numbers in GALT. In this study, we vaccinated mice with an adenovirus vector that expressed the envelope gene from HIV and observed immune responses in the peripheral blood, spleen, liver, mesenteric lymph nodes, and Peyer's patches. We found that (1) the number of HIV-specific CD8 T cells was dramatically lower in GALT than in other tissues; (2) the programmed cell death protein-1 (PD-1) was expressed at high levels in HIV-specific CD8 T cells including memory T cells in GALT; and (3) high levels of HIV-specific CD8 T cell apoptosis were occurring in GALT. These results suggest that contributing to GALT becoming an HIV reservoir during infection is a combination of exhaustion and/or dysfunction of HIV-specific CTLs at that site. These results emphasize the importance of developing of an effective mucosal vaccine against HIV. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Shimada, Masaru; Yoshizaki, Shinji; Okuda, Kenji] Yokohama City Univ, Grad Sch Med, Dept Mol Biodef Res, Yokohama, Kanagawa 2360004, Japan. [Ichino, Motohide] Yokohama City Univ, Grad Sch Med, Dept Immunol, Yokohama, Kanagawa 2360004, Japan. [Klinman, Dennis M.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Shimada, M (reprint author), Yokohama City Univ, Grad Sch Med, Dept Mol Biodef Res, Kanazawa Ku, 3-9 Fukuura, Yokohama, Kanagawa 2360004, Japan. EM mshimada@yokohama-cu.ac.jp FU Ministry of Education, Science, Sports and Culture of Japan [26462531] FX We thank Dr. Akio Yamashita for critical reading of the manuscript. This work was partially supported by a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (No. 26462531). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. The authors have declared that no competing interests exist. NR 59 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD SEP 8 PY 2014 VL 32 IS 40 BP 5198 EP 5205 DI 10.1016/j.vaccine.2014.07.046 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AP7PS UT WOS:000342269800009 PM 25066739 ER PT J AU Davis, CF Ricketts, CJ Wang, M Yang, LX Cherniack, AD Shen, H Buhay, C Kang, H Kim, SC Fahey, CC Hacker, KE Bhanot, G Gordenin, DA Chu, A Gunaratne, PH Biehl, M Seth, S Kaipparettu, BA Bristow, CA Donehower, LA Wallen, EM Smith, AB Tickoo, SK Tamboli, P Reuter, V Schmidt, LS Hsieh, JJ Choueiri, TK Hakimi, AA Chin, L Meyerson, M Kucherlapati, R Park, WY Robertson, AG Laird, PW Henske, EP Kwiatkowski, DJ Park, PJ Morgan, M Shuch, B Muzny, D Wheeler, DA Linehan, WM Gibbs, RA Rathmell, WK Creighton, CJ Signoretti, S Seiler, M Chao, H Dahdouli, M Xi, L Kakkar, N Reid, JG Downs, B Drummond, J Morton, D Doddapaneni, H Lewis, L English, A Meng, QC Kovar, C Wang, QY Hale, W Hawes, A Kalra, D Walker, K Murray, BA Sougnez, C Saksena, G Carter, SL Schumacher, SE Tabak, B Zack, TI Getz, G Beroukhim, R Gabriel, SB Ally, A Balasundaram, M Birol, I Brooks, D Butterfield, YS Chuah, E Clarke, A Dhalla, N Guin, R Holt, RA Kasaian, K Lee, D Li, HI Lim, E Ma, Y Mayo, M Moore, RA Mungall, AJ Schein, JE Sipahimalani, P Tam, A Thiessen, N Wong, T Jones, SJ Marra, MA Auman, JT Tan, DH Meng, SW Jones, CD Hoadley, KA Mieczkowski, PA Mose, LE Jefferys, SR Roach, J Veluvolu, U Wilkerson, MD Waring, S Buda, E Wu, JY Bodenheimer, T Hoyle, AP Simons, JV Soloway, MG Balu, S Parker, JS Hayes, DN Perou, CM Weisenberger, DJ Bootwalla, MS Triche, T Lai, PH Van Den Berg, DJ Baylin, SB Chen, FJ Coarfa, C Noble, MS DiCara, D Zhang, HL Cho, J Heiman, DI Gehlenborg, N Voet, D Lin, P Frazer, S Stojanov, P Liu, YC Zou, LH Kim, J Lawrence, MS Protopopov, A Song, XZ Zhang, JH Pantazi, A Hadjipanayis, A Lee, E Luquette, LJ Lee, S Parfenov, M Santoso, N Seidman, J Xu, AW Lee, J Roberts, SA Klimczak, LJ Fargo, D Lang, M Choi, YL Lee, JK Wang, WY Fan, Y Ahn, J Akbani, R Weinstein, JN Haussler, D Stuart, JM Benz, CC Ma, S Radenbaugh, A Zhul, JC Lichtenberg, TM Zmuda, E Black, AD Hanf, B Ramirez, NC Wise, L Bowen, J Leraas, KM Hall, TM Gastier-Foster, JM Kaelin, WG Thorne, L Boice, L Huang, M Vocke, C Peterson, J Worrell, R Merino, M Czerniak, BA Aldape, KD Wood, CG Spellman, PT Atkins, MB Cheville, J Thompson, RH Jensen, MA Pihl, T Wan, YH Ayala, B Baboud, J Velaga, S Walton, J Liu, J Chudamani, S Wu, Y Sheth, M Shaw, KRM Demchok, JA Davidsen, T Yang, LM Wang, ZN Tarnuzzer, RW Zhang, JS Eley, G Felau, I Zenklusen, JC Hutter, CM Guyer, MS Ozenberger, BA Sofia, HJ AF Davis, Caleb F. Ricketts, Christopher J. Wang, Min Yang, Lixing Cherniack, Andrew D. Shen, Hui Buhay, Christian Kang, Hyojin Kim, Sang Cheol Fahey, Catherine C. Hacker, Kathryn E. Bhanot, Gyan Gordenin, Dmitry A. Chu, Andy Gunaratne, Preethi H. Biehl, Michael Seth, Sahil Kaipparettu, Benny A. Bristow, Christopher A. Donehower, Lawrence A. Wallen, Eric M. Smith, Angela B. Tickoo, Satish K. Tamboli, Pheroze Reuter, Victor Schmidt, Laura S. Hsieh, James J. Choueiri, Toni K. Hakimi, A. Ari Chin, Lynda Meyerson, Matthew Kucherlapati, Raju Park, Woong-Yang Robertson, A. Gordon Laird, Peter W. Henske, Elizabeth P. Kwiatkowski, David J. Park, Peter J. Morgan, Margaret Shuch, Brian Muzny, Donna Wheeler, David A. Linehan, W. Marston Gibbs, Richard A. Rathmell, W. Kimryn Creighton, Chad J. Signoretti, Sabina Seiler, Michael Chao, Hsu Dahdouli, Mike Xi, Liu Kakkar, Nipun Reid, Jeffrey G. Downs, Brittany Drummond, Jennifer Morton, Donna Doddapaneni, Harsha Lewis, Lora English, Adam Meng, Qingchang Kovar, Christie Wang, Qiaoyan Hale, Walker Hawes, Alicia Kalra, Divya Walker, Kimberly Murray, Bradley A. Sougnez, Carrie Saksena, Gordon Carter, Scott L. Schumacher, Steven E. Tabak, Barbara Zack, Travis I. Getz, Gad Beroukhim, Rameen Gabriel, Stacey B. Ally, Adrian Balasundaram, Miruna Birol, Inanc Brooks, Denise Butterfield, Yaron S. N. Chuah, Eric Clarke, Amanda Dhalla, Noreen Guin, Ranabir Holt, Robert A. Kasaian, Katayoon Lee, Darlene Li, Haiyan I. Lim, Emilia Ma, Yussanne Mayo, Michael Moore, Richard A. Mungall, Andrew J. Schein, Jacqueline E. Sipahimalani, Payal Tam, Angela Thiessen, Nina Wong, Tina Jones, Steven J. M. Marra, Marco A. Auman, J. Todd Tan, Donghui Meng, Shaowu Jones, Corbin D. Hoadley, Katherine A. Mieczkowski, Piotr A. Mose, Lisle E. Jefferys, Stuart R. Roach, Jeffrey Veluvolu, Umadevi Wilkerson, Matthew D. Waring, Scot Buda, Elizabeth Wu, Junyuan Bodenheimer, Tom Hoyle, Alan P. Simons, Janae V. Soloway, Mathew G. Balu, Saianand Parker, Joel S. Hayes, D. Neil Perou, Charles M. Weisenberger, Daniel J. Bootwalla, Moiz S. Triche, Timothy, Jr. Lai, Phillip H. Van Den Berg, David J. Baylin, Stephen B. Chen, Fengju Coarfa, Cristian Noble, Michael S. DiCara, Daniel Zhang, Hailei Cho, Juok Heiman, David I. Gehlenborg, Nils Voet, Doug Lin, Pei Frazer, Scott Stojanov, Petar Liu, Yingchun Zou, Lihua Kim, Jaegil Lawrence, Michael S. Protopopov, Alexei Song, Xingzhi Zhang, Jianhua Pantazi, Angeliki Hadjipanayis, Angela Lee, Eunjung Luquette, Lovelace J. Lee, Semin Parfenov, Michael Santoso, Netty Seidman, Jonathan Xu, Andrew W. Lee, Junehawk Roberts, Steven A. Klimczak, Leszek J. Fargo, David Lang, Martin Choi, Yoon-La Lee, June-Koo Wang, Wenyi Fan, Yu Ahn, Jaeil Akbani, Rehan Weinstein, John N. Haussler, David Stuart, Josh M. Benz, Christopher C. Ma, Singer Radenbaugh, Amie Zhul, Jingchun Lichtenberg, Tara M. Zmuda, Erik Black, Aaron D. Hanf, Benjamin Ramirez, Nilsa C. Wise, Lisa Bowen, Jay Leraas, Kristen M. Hall, Tracy M. Gastier-Foster, Julie M. Kaelin, William G. Thorne, Leigh Boice, Lori Huang, Mei Vocke, Cathy Peterson, James Worrell, Robert Merino, Maria Czerniak, Bogdan A. Aldape, Kenneth D. Wood, Christopher G. Spellman, Paul T. Atkins, Michael B. Cheville, John Thompson, R. Houston Jensen, Mark A. Pihl, Todd Wan, Yunhu Ayala, Brenda Baboud, Julien Velaga, Sudhakar Walton, Jessica Liu, Jia Chudamani, Sudha Wu, Ye Sheth, Margi Shaw, Kenna R. Mills Demchok, John A. Davidsen, Tanja Yang, Liming Wang, Zhining Tarnuzzer, Roy W. Zhang, Jiashan Eley, Greg Felau, Ina Zenklusen, Jean Claude Hutter, Carolyn M. Guyer, Mark S. Ozenberger, Bradley A. Sofia, Heidi J. CA Canc Genome Atlas Res Network TI The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma SO CANCER CELL LA English DT Article ID HOGG-DUBE-SYNDROME; MITOCHONDRIAL-DNA MUTATIONS; TERT PROMOTER MUTATIONS; HUMAN BREAST-TUMORS; COMPLEX-I; CANCER GENOME; MOLECULAR PORTRAITS; KIDNEY CANCER; ONCOCYTOMA; CHROMOSOME-10 AB We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations. C1 [Davis, Caleb F.; Wang, Min; Buhay, Christian; Gunaratne, Preethi H.; Donehower, Lawrence A.; Morgan, Margaret; Muzny, Donna; Wheeler, David A.; Gibbs, Richard A.; Creighton, Chad J.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Ricketts, Christopher J.; Schmidt, Laura S.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Yang, Lixing; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Cherniack, Andrew D.; Chin, Lynda; Meyerson, Matthew; Henske, Elizabeth P.; Kwiatkowski, David J.] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Shen, Hui; Laird, Peter W.] Univ So Calif, USC Epigenome Ctr, Los Angeles, CA 90033 USA. [Kim, Sang Cheol; Park, Woong-Yang] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Samsung Genome Inst, Seoul, South Korea. [Fahey, Catherine C.; Hacker, Kathryn E.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. [Bhanot, Gyan] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. [Bhanot, Gyan] Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Gordenin, Dmitry A.] NIEHS, Res Triangle Pk, NC 27709 USA. [Chu, Andy; Robertson, A. Gordon] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Gunaratne, Preethi H.] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. [Biehl, Michael] Univ Groningen, Intelligent Syst Grp, Johann Bernoulli Inst Math & Comp Sci, NL-9700 AK Groningen, Netherlands. [Seth, Sahil; Bristow, Christopher A.; Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Dept Genom Med, Houston, TX 77030 USA. [Kaipparettu, Benny A.; Creighton, Chad J.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Kaipparettu, Benny A.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Wallen, Eric M.; Smith, Angela B.; Rathmell, W. Kimryn] Univ N Carolina, Dept Urol, Chapel Hill, NC 27599 USA. [Tickoo, Satish K.; Reuter, Victor] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Tamboli, Pheroze] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Schmidt, Laura S.] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Res, Frederick, MD 21702 USA. [Hsieh, James J.] Weill Cornell Med Coll, Dept Med, New York, NY 10021 USA. [Hsieh, James J.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Choueiri, Toni K.; Meyerson, Matthew; Henske, Elizabeth P.; Kwiatkowski, David J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Choueiri, Toni K.; Hakimi, A. Ari; Henske, Elizabeth P.; Kwiatkowski, David J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Hakimi, A. Ari] Mem Sloan Kettering Canc Ctr, Urol Serv, Dept Surg, New York, NY 10065 USA. [Kucherlapati, Raju; Park, Peter J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Kucherlapati, Raju] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Park, Woong-Yang] Sungkyunkwan Univ, Sch Med, Seoul, South Korea. [Rathmell, W. Kimryn] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Rathmell, W. Kimryn] Univ N Carolina, Dept Med, Div Hematol & Oncol, Chapel Hill, NC 27599 USA. [Creighton, Chad J.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Kang, Hyojin] Korea Inst Sci & Technol Informat, Natl Inst Supercomp & Networking, Taejon, South Korea. [Shuch, Brian] Yale Univ, Sch Med, Dept Urol, New Haven, CT 06520 USA. RP Rathmell, WK (reprint author), Univ N Carolina, Dept Urol, Chapel Hill, NC 27599 USA. EM rathmell@med.unc.edu; creighto@bcm.edu RI Kalra, Divya/N-5453-2014; Laird, Peter/G-8683-2012; Holt, Robert/C-3303-2009; Biehl, Michael/B-5105-2009; Jones, Steven/C-3621-2009; Lee, Semin/S-2629-2016; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011; OI Seth, Sahil/0000-0003-4579-3959; Biehl, Michael/0000-0001-5148-4568; Lee, Semin/0000-0002-9015-6046; Birol, Inanc/0000-0003-0950-7839; Triche, Tim/0000-0001-5665-946X; Lang, Martin/0000-0002-0242-6713; Gordenin, Dmitry/0000-0002-8399-1836; Perou, Charles/0000-0001-9827-2247 FU NIH [5U24CA143843, U54HG003273, 5U24CA143866, KL2TR001109, UL1TR001111, 5P50CA101942, U54 HG003067, K24CA172355]; NIH, National Cancer Institute, Center for Cancer Research; Frederick National Lab, NIH [HHSN261200800001E]; NIH, National Institute of Environmental Health Sciences; Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia [T15 LM007093]; J. Randall AMP; Kathleen L. MacDonald Kidney Cancer Research Fund; Tuttle Family Kidney Cancer Research Fund; Ministry of Health AMP; Welfare, Republic of Korea [HI13C2096]; Korea Institute of Science and Technology Information [K-14-L01-C02-S04, KSC-2013-C3-037] FX We wish to thank all patients and families who contributed to this study. This work was supported by the following grants from the NIH: 5U24CA143843 (D.A.W.), U54HG003273 (R.A.G.), 5U24CA143866 (M.A. Marra), KL2TR001109 and UL1TR001111 (A.B.S.), 5P50CA101942 (S. Signoretti), 5P50CA101942 (T.K.C.), U54 HG003067 (E. Lander); K24CA172355 (W.K.R.), Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (W.M.L., L.S.S., C.J.R., M.J. Merino), with federal funds from the Frederick National Lab, NIH, under contract HHSN261200800001E (L.S.S.), Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (D.A.G., S.A. Roberts, L.J. Klimczak, D. Fargo), and a training fellowship from the Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia (Grant No. T15 LM007093 to C.F.D.). Other grant support includes the J. Randall & Kathleen L. MacDonald Kidney Cancer Research Fund, the Tuttle Family Kidney Cancer Research Fund (J.J.H.), the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI13C2096 to W.-Y.P.), and the Korea Institute of Science and Technology Information (K-14-L01-C02-S04 and KSC-2013-C3-037) (for supercomputing resources including technical support). NR 44 TC 112 Z9 113 U1 8 U2 30 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 SEP 8 PY 2014 VL 26 IS 3 BP 319 EP 330 DI 10.1016/j.ccr.2014.07.014 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AP2AD UT WOS:000341873800006 PM 25155756 ER PT J AU Pitcher, D Duchaine, B Walsh, V AF Pitcher, David Duchaine, Bradley Walsh, Vincent TI Combined TMS and fMRI Reveal Dissociable Cortical Pathways for Dynamic and Static Face Perception SO CURRENT BIOLOGY LA English DT Article ID BIOLOGICAL MOTION; ACQUIRED PROSOPAGNOSIA; FACIAL IDENTITY; VISUAL AREAS; HUMAN BRAIN; RECOGNITION; CORTEX; EXPRESSION; PATIENT; OBJECT AB Faces contain structural information, for identifying individuals, as well as changeable information, which can convey emotion and direct attention. Neuroimaging studies reveal brain regions that exhibit preferential responses to invariant [1, 2] or changeable [3-5] facial aspects but the functional connections between these regions are unknown. We addressed this issue by causally disrupting two face-selective regions with thetaburst transcranial magnetic stimulation (TBS) and measuring the effects of this disruption in local and remote face-selective regions with functional magnetic resonance imaging (fMRI). Participants were scanned, over two sessions, while viewing dynamic or static faces and objects. During these sessions, TBS was delivered over the right occipital face area (rOFA) or right posterior superior temporal sulcus (rpSTS). Disruption of the rOFA reduced the neural response to both static and dynamic faces in the downstream face-selective region in the fusiform gyrus. In contrast, the response to dynamic and static faces was doubly dissociated in the rpSTS. Namely, disruption of the rOFA reduced the response to static but not dynamic faces, while disruption of the rpSTS itself reduced the response to dynamic but not static faces. These results suggest that dynamic and static facial aspects are processed via dissociable cortical pathways that begin in early visual cortex, a conclusion inconsistent with current models of face perception [6-9]. C1 [Pitcher, David] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Duchaine, Bradley] Dartmouth Coll, Dept Psychol & Brain Sci, Hanover, NH 03755 USA. [Walsh, Vincent] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. [Walsh, Vincent] UCL, Dept Psychol, London WC1N 3AR, England. RP Pitcher, D (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM david.pitcher@nih.gov FU Royal Society Industry Research Fellowship FX Thanks to Chris Baker, Joe Devlin, Fred Dick, Nancy Kanwisher, Dwight Kravitz, and Leslie Ungerleider for advice and support. Special thanks to Kelsey Holiday and Geena lanni for help with the control experiment. V.W. is a scientific consultant to the Magstim Co. and is supported by a Royal Society Industry Research Fellowship. NR 33 TC 29 Z9 30 U1 1 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD SEP 8 PY 2014 VL 24 IS 17 BP 2066 EP 2070 DI 10.1016/j.cub.2014.07.060 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AO7OA UT WOS:000341541300034 PM 25131678 ER PT J AU Garcia, GR Gardinassi, LG Ribeiro, JM Anatriello, E Ferreira, BR Moreira, HNS Mafra, C Martins, MM Szabo, MPJ de Miranda-Santos, IKF Maruyama, SR AF Garcia, Gustavo Rocha Gardinassi, Luiz Gustavo Ribeiro, Jose Marcos Anatriello, Elen Ferreira, Beatriz Rossetti Santanna Moreira, Higo Nasser Mafra, Claudio Martins, Maria Marlene Juan Szabo, Matias Pablo Ferreira de Miranda-Santos, Isabel Kinney Maruyama, Sandra Regina TI The sialotranscriptome of Amblyomma triste, Amblyomma parvum and Amblyomma cajennense ticks, uncovered by 454-based RNA-seq SO PARASITES & VECTORS LA English DT Article DE Ticks; Amblyomma cajennense; Amblyomma parvum; Amblyomma triste; Salivary gland; Saliva; Transcriptome; RNA-seq ID DEER BLASTOCERUS-DICHOTOMUS; BLOOD-FEEDING ARTHROPODS; EXPRESSED SEQUENCE TAGS; TROPICAL BONT TICK; 16S RDNA SEQUENCES; RICKETTSIA-PARKERI; SALIVARY-GLANDS; ACARI IXODIDAE; IXODES-RICINUS; HARD TICK AB Background: Tick salivary constituents antagonize inflammatory, immune and hemostatic host responses, favoring tick blood feeding and the establishment of tick-borne pathogens in hosts during hematophagy. Amblyomma triste, A. cajennense and A. parvum ticks are very important in veterinary and human health because they are vectors of the etiological agents for several diseases. Insights into the tick salivary components involved in blood feeding are essential to understanding vector-pathogen-host interactions, and transcriptional profiling of salivary glands is a powerful tool to do so. Here, we functionally annotated the sialotranscriptomes of these three Amblyomma species, which allowed comparisons between these and other hematophagous arthropod species. Methods: mRNA from the salivary glands of A. triste, A. cajennense and A. parvum ticks fed on different host species were pyrosequenced on a 454-Roche platform to generate four A. triste (nymphs fed on guinea pigs and females fed on dogs) libraries, one A. cajennense (females fed on rabbits) library and one was A. parvum (females fed on dogs) library. Bioinformatic analyses used in-house programs with a customized pipeline employing standard assembly and alignment algorithms, protein databases and protein servers. Results: Each library yielded an average of 100,000 reads, which were assembled to obtain contigs of coding sequences (CDSs). The sialotranscriptome analyses of A. triste, A. cajennense and A. parvum ticks produced 11,240, 4,604 and 3,796 CDSs, respectively. These CDSs were classified into over 100 distinct protein families with a wide range of putative functions involved in physiological and blood feeding processes and were catalogued in annotated, hyperlinked spreadsheets. We highlighted the putative transcripts encoding saliva components with critical roles during parasitism, such as anticoagulants, immunosuppressants and anti-inflammatory molecules. The salivary content underwent changes in the abundance and repertoire of many transcripts, which depended on the tick and host species. Conclusions: The annotated sialotranscriptomes described herein richly expand the biological knowledge of these three Amblyomma species. These comprehensive databases will be useful for the characterization of salivary proteins and can be applied to control ticks and tick-borne diseases. C1 [Garcia, Gustavo Rocha; Gardinassi, Luiz Gustavo; Ferreira de Miranda-Santos, Isabel Kinney; Maruyama, Sandra Regina] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Biochem & Immunol, BR-14049 Ribeirao Preto, SP, Brazil. [Ribeiro, Jose Marcos] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Anatriello, Elen; Ferreira, Beatriz Rossetti] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Maternal & Child & Publ Hlth Nursing, BR-14049 Ribeirao Preto, SP, Brazil. [Santanna Moreira, Higo Nasser; Mafra, Claudio] Univ Fed Vicosa, Dept Biochem & Mol Biol, Vicosa, MG, Brazil. [Martins, Maria Marlene; Juan Szabo, Matias Pablo] Univ Fed Uberlandia, Sch Vet Med, BR-38400 Uberlandia, MG, Brazil. RP Maruyama, SR (reprint author), Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Biochem & Immunol, BR-14049 Ribeirao Preto, SP, Brazil. EM srmaruyama@gmail.com RI Anatriello, Elen/N-1429-2015; Garcia, Gustavo/E-5182-2013; de Miranda Santos, Isabel/D-5261-2016; de Miranda Santos, Isabel/B-7597-2012; OI de Miranda Santos, Isabel/0000-0002-0438-4430; Gardinassi, Luiz Gustavo/0000-0002-9027-2688; Maruyama, Sandra/0000-0001-6807-1452; Ribeiro, Jose/0000-0002-9107-0818 FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPq [559603/2009-6]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP [2009/53645-3]; FAPEMIG/CAPES [0979/2013 - 23038.002909/2013-01]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; FAPESP scholarships [2009/51212-2, 2007/50869-2, 2011/23819-0] FX This work was supported by grants from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPq (559603/2009-6), the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP (2009/53645-3), FAPEMIG/CAPES (0979/2013 - 23038.002909/2013-01) and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The authors thank Dr. Joao S. Silva for generous and continuing support of this work, which was partially performed in his laboratory. GRG, EA and LGG were supported by FAPESP scholarships (2009/51212-2, 2007/50869-2 and 2011/23819-0, respectively). NR 103 TC 20 Z9 20 U1 2 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD SEP 8 PY 2014 VL 7 AR 430 DI 10.1186/1756-3305-7-430 PG 18 WC Parasitology SC Parasitology GA AO8RK UT WOS:000341621700001 PM 25201527 ER PT J AU Zhan, L Liu, HX Fang, YP Kong, B He, YQ Zhong, XB Fang, JW Wan, YJY Guo, GL AF Zhan, Le Liu, Hui-Xin Fang, Yaping Kong, Bo He, Yuqi Zhong, Xiao-bo Fang, Jianwen Wan, Yu-Jui Yvonne Guo, Grace L. TI Genome-Wide Binding and Transcriptome Analysis of Human Farnesoid X Receptor in Primary Human Hepatocytes SO PLOS ONE LA English DT Article ID BILE-ACID BIOSYNTHESIS; NUCLEAR RECEPTOR; MOUSE-LIVER; GENE; FXR; IDENTIFICATION; EXPRESSION; MICE; ACTIVATION; REVEALS AB Background & Aims: Farnesoid X receptor (FXR, NR1H4) is a ligand-activated transcription factor, belonging to the nuclear receptor superfamily. FXR is highly expressed in the liver and is essential in regulating bile acid homeostasis. FXR deficiency is implicated in numerous liver diseases and mice with modulation of FXR have been used as animal models to study liver physiology and pathology. We have reported genome-wide binding of FXR in mice by chromatin immunoprecipitation - deep sequencing (ChIP-seq), with results indicating that FXR may be involved in regulating diverse pathways in liver. However, limited information exists for the functions of human FXR and the suitability of using murine models to study human FXR functions. Methods: In the current study, we performed ChIP-seq in primary human hepatocytes (PHHs) treated with a synthetic FXR agonist, GW4064 or DMSO control. In parallel, RNA deep sequencing (RNA-seq) and RNA microarray were performed for GW4064 or control treated PHHs and wild type mouse livers, respectively. Results: ChIP-seq showed similar profiles of genome-wide FXR binding in humans and mice in terms of motif analysis and pathway prediction. However, RNA-seq and microarray showed more different transcriptome profiles between PHHs and mouse livers upon GW4064 treatment. Conclusions: In summary, we have established genome-wide human FXR binding and transcriptome profiles. These results will aid in determining the human FXR functions, as well as judging to what level the mouse models could be used to study human FXR functions. C1 [Zhan, Le; Kong, Bo; Guo, Grace L.] Rutgers State Univ, Dept Pharmacol & Toxicol, Sch Pharm, Piscataway, NJ 08854 USA. [Zhan, Le; Guo, Grace L.] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA. [Liu, Hui-Xin; He, Yuqi; Wan, Yu-Jui Yvonne] Univ Calif, Davis Hlth Syst, Dept Med Pathol & Lab Med, Sacramento, CA USA. [Fang, Yaping] Huazhong Agr Univ, Coll Sci, Inst Comp Applicat, Wuhan, Hubei, Peoples R China. [Zhong, Xiao-bo] Univ Connecticut, Sch Pharm, Dept Pharmaceut Sci, Storrs, CT USA. [Fang, Jianwen] NCI, Biometr Res Branch, Rockville, MD USA. RP Guo, GL (reprint author), Rutgers State Univ, Dept Pharmacol & Toxicol, Sch Pharm, Piscataway, NJ 08854 USA. EM guo@eohsi.rutgers.edu OI Fang, Yaping/0000-0001-6075-0768 FU NIH fund [DK081343, DK090036, GM104037] FX This study was supported by the NIH fund, grants DK081343, DK090036 and GM104037. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 11 Z9 12 U1 3 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 8 PY 2014 VL 9 IS 9 AR e105930 DI 10.1371/journal.pone.0105930 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO4JX UT WOS:000341304700021 PM 25198545 ER PT J AU Pigott, DM Golding, N Mylne, A Huang, Z Henry, AJ Weiss, DJ Brady, OJ Kraemer, MUG Smith, DL Moyes, CL Bhatt, S Gething, PW Horby, PW Bogoch, II Brownstein, JS Mekaru, SR Tatem, AJ Khan, K Hay, SI AF Pigott, David M. Golding, Nick Mylne, Adrian Huang, Zhi Henry, Andrew J. Weiss, Daniel J. Brady, Oliver J. Kraemer, Moritz U. G. Smith, David L. Moyes, Catherine L. Bhatt, Samir Gething, Peter W. Horby, Peter W. Bogoch, Isaac I. Brownstein, John S. Mekaru, Sumiko R. Tatem, Andrew J. Khan, Kamran Hay, Simon I. TI Mapping the zoonotic niche of Ebola virus disease in Africa SO ELIFE LA English DT Article ID SPECIES DISTRIBUTION MODELS; HEMORRHAGIC-FEVER; INFECTIOUS-DISEASES; ZAIRE-EBOLAVIRUS; HUMAN MOBILITY; URBAN-GROWTH; WEST-AFRICA; FRUIT BATS; OUTBREAK; MARBURG AB Ebola virus disease (EVD) is a complex zoonosis that is highly virulent in humans. The largest recorded outbreak of EVD is ongoing in West Africa, outside of its previously reported and predicted niche. We assembled location data on all recorded zoonotic transmission to humans and Ebola virus infection in bats and primates (1976-2014). Using species distribution models these occurrence data were paired with environmental covariates to predict a zoonotic transmission niche covering 22 countries across Central and West Africa. Vegetation, elevation, temperature, evapotranspiration and suspected reservoir bat distributions define this relationship. At-risk areas are inhabited by 22 million people, however the rarity of human outbreaks emphasises the very low probability of transmission to humans. Increasing population sizes and international connectivity by air since the first detection of EVD in 1976 suggest that the dynamics of human-to-human secondary transmission in contemporary outbreaks will be very different to those of the past. [150/150] C1 [Pigott, David M.; Golding, Nick; Mylne, Adrian; Huang, Zhi; Henry, Andrew J.; Weiss, Daniel J.; Brady, Oliver J.; Kraemer, Moritz U. G.; Smith, David L.; Moyes, Catherine L.; Bhatt, Samir; Gething, Peter W.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 2JD, England. [Smith, David L.] Sanaria Inst Global Hlth & Trop Med, London, England. [Horby, Peter W.] Univ Oxford, Epidem Dis Res Grp, Ctr Trop Med & Global Hlth, Oxford OX1 2JD, England. [Bogoch, Isaac I.; 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. [Brownstein, John S.; Mekaru, Sumiko R.] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA USA. [Brownstein, John S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden. [Khan, Kamran] St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. RP Hay, SI (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 2JD, England. EM simon.hay@zoo.ox.ac.uk RI Hay, Simon/F-8967-2015; Smith, David/L-8850-2013; OI Hay, Simon/0000-0002-0611-7272; Smith, David/0000-0003-4367-3849; Pigott, David/0000-0002-6731-4034; Golding, Nick/0000-0001-8916-5570; Gething, Peter/0000-0001-6759-5449; Brady, Oliver/0000-0002-3235-2129; Moyes, Catherine/0000-0002-8028-4079 FU Sir Richard Southwood Graduate Scholarship from the Department of Zoology at the University of Oxford; Bill & Melinda Gates Foundation [OPP1053338, OPP1106023, OPP1068048, K00669X, OPP1093011, OPP1106427, OPP1032350]; BBSRC studentshipGerman Academic Exchange Service (DAAD) through a graduate scholarship; NIH National Library of Medicine [R01LM010812]; NIH/NIAD [U19AI089674]; EU FP7 project PREPARE [602525]; Li Ka Shing Foundation; Canadian Institutes of Health Research; Senior Research Fellowship from the Wellcome Trust [095066]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center; National Institutes of Health FX DMP is funded by a Sir Richard Southwood Graduate Scholarship from the Department of Zoology at the University of Oxford. NG is funded by a grant from the Bill & Melinda Gates Foundation (#OPP1053338). ZH and AH are funded by the Bill & Melinda Gates Foundation (#OPP1106023). OJB is funded by a BBSRC studentship. PWG is a Medical Research Council (UK) Career Development Fellow (#K00669X) and receives support from the Bill & Melinda Gates Foundation (#OPP1068048) which also supports DJW and SB. MUGK is funded by the German Academic Exchange Service (DAAD) through a graduate scholarship. JSB and SRM acknowledge funding from NIH National Library of Medicine (R01LM010812) and from the Bill & Melinda Gates Foundation (#OPP1093011). AJT is supported by funding from NIH/NIAD (U19AI089674) and the Bill & Melinda Gates Foundation (#OPP1106427, #OPP1032350). PWH is funded by the EU FP7 project PREPARE (#602525) and the Li Ka Shing Foundation. KK and IIB acknowledge the support of the Canadian Institutes of Health Research. SIH is funded by a Senior Research Fellowship from the Wellcome Trust (#095066) which also supports AM and a grant from the Bill & Melinda Gates Foundation (#OPP1093011) which also supports CLM. SIH and AJT would also like to acknowledge funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. Funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 151 TC 106 Z9 109 U1 24 U2 45 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD SEP 8 PY 2014 VL 3 AR e04395 DI 10.7554/eLife.04395 PG 47 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AO3UI UT WOS:000341261200002 PM 25201877 ER PT J AU Balsam, J Bruck, HA Rasooly, A AF Balsam, Joshua Bruck, Hugh Alan Rasooly, Avraham TI Webcam-based flow cytometer using wide-field imaging for low cell number detection at high throughput SO ANALYST LA English DT Article ID ARRAY BIOSENSOR; SMART-PHONE; MHEALTH AB Here we describe a novel low-cost flow cytometer based on a webcam capable of tow cell number detection in a large volume which may overcome the limitations of current flow cytometry. Several key elements have been combined to yield both high throughput and high sensitivity. The first element is a commercially available webcam capable of 187 frames per second video capture at a resolution of 320 x 240 pixels. The second element in this design is a 1 W 450 nm laser module for area-excitation, which combined with the webcam allows for rapid interrogation of a flow field. The final element is a 2D flow-cell which overcomes the flow limitation of hydrodynamic focusing and allows for higher sample throughput in a wider flow field. This cell allows for the linear velocity of target cells to be lower than in a conventional "1D" hydrodynamic focusing flow-cells typically used in cytometry at similar volumetric flow rates. It also allows cells to be imaged at the full frame rate of the webcam. Using this webcam-based flow cytometer with wide-field imaging, it was confirmed that the detection of fluorescently tagged 5 gm polystyrene beads in "1D" hydrodynamic focusing flow-cells was not practical for low cell number detection due to streaking from the motion of the beads, which did not occur with the 2D flow-cell design. The sensitivity and throughput of this webcam-based flow cytometer was then investigated using THP-1 human monocytes stained with SYTO-9 florescent dye in the 2D flow-cell The flow cytometer was found to be capable of detecting fluorescently tagged cells at concentrations as low as 1 cell per mL at flow rates of 500 mu L min(-1) in buffer and in blood. The effectiveness of detection was concentration dependent: at 100 cells per mL 84% of the cells were detected compared to microscopy, 10 cells per mL 79% detected and 1 cell per mL 59% of the cells were detected. With the blood samples spiked to 100 cells per mL, the average concentration for all samples was 91.4 cells per mL, with a 95% confidence interval of 86-97 cells per mL. These low cell concentrations and the large volume capabilities of the system may overcome the limitations of current cytometry, and are applicable to rare cell (such as circulating tumor cell) detection The simplicity and low cost of this device suggests that it may have a potential use in developing point-of-care clinical flow cytometry for resource-poor settings associated with global health. C1 [Balsam, Joshua; Rasooly, Avraham] US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Balsam, Joshua; Bruck, Hugh Alan] Univ Maryland, College Pk, MD 20742 USA. [Rasooly, Avraham] Natl Canc Inst, Div Canc Biol, NIH NCI, Rockville, MD 20850 USA. RP Rasooly, A (reprint author), US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. EM rasoolya@mail.nih.gov FU FDA's Center for Devices and Radiological Health; Division of Biology; National Cancer Institute FX This work was supported by the FDA's Center for Devices and Radiological Health, Division of Biology and the National Cancer Institute. The views expressed are those of the authors and do not necessarily reflect the views of the U.S. Government. NR 35 TC 4 Z9 4 U1 3 U2 20 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0003-2654 EI 1364-5528 J9 ANALYST JI Analyst PD SEP 7 PY 2014 VL 139 IS 17 BP 4322 EP 4329 DI 10.1039/c4an00669k PG 8 WC Chemistry, Analytical SC Chemistry GA AN6KJ UT WOS:000340703100026 PM 24995370 ER PT J AU Roberts, LM Ledvina, HE Sempowski, GD Frelinger, JA AF Roberts, Lydia M. Ledvina, Hannah E. Sempowski, Gregory D. Frelinger, Jeffrey A. TI TLR2 signaling is required for the innate, but not adaptive response to LVS clpB SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE Francisella tularensis; TLR2; clpB; T-cells; innate immunity; lung; intranasal ID FRANCISELLA-TULARENSIS LVS; LIVE VACCINE STRAIN; TOLL-LIKE RECEPTORS; IMMUNE-RESPONSE; PROINFLAMMATORY CYTOKINE; INFLAMMATORY RESPONSES; SUBSPECIES TULARENSIS; PROTECTIVE IMMUNITY; DEPENDENT CONTROL; CELL-ACTIVATION AB Toll-like receptor 2 (TLR2) is the best-characterized pattern-recognition receptor for the highly pathogenic intracellular bacterium, Francisella tularensis. We previously identified a mutant in the live vaccine strain (LVS) of Francisella, LVS clpB, which is attenuated, but induces a protective immune response. We sought to determine whether TLR2 signaling was required during the immune response to LVS clpB. TLR2 knock-out (TLR2 KO) mice previously infected with LVS clpB are completely protected during a lethal challenge with LVS. Furthermore, the kinetics and magnitude of the primary T-cell response in B6 and TLR2 KO mice are similar indicating that TLR2 signaling is dispensable for the adaptive immune response to LVS clpB. TLR2 signaling was important, however, for the innate immune response to LVS clpB. We identified three classes of cytokines/chemokines that differ in their dependence on TLR2 signaling for production on day 3 post-inoculation in the bronchoalveolar lavage fluid. IL-1 alpha, IL-1 beta, IL-2, IL-17, MIP-1 alpha, and TNF-alpha production depended on TLR2 signaling, while GM-CSF, IFN-gamma, and VEGF production were completely independent of TLR2 signaling. IL-6, IL-12, IP-10, KC, and MIG production were partially dependent on TLR2 signaling. Together our data indicate that the innate immune response to LVS clpB requires TLR2 signaling for the maximal innate response, whereas TLR2 is not required for the adaptive immune response. C1 [Roberts, Lydia M.; Ledvina, Hannah E.; Frelinger, Jeffrey A.] Univ Arizona, Dept Immunobiol, Tucson, AZ USA. [Sempowski, Gregory D.] Duke Univ, Duke Human Vaccine Inst, Durham, NC USA. RP Roberts, LM (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, Immun Pulm Pathogens Sect,NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM lydia.roberts@nih.gov FU National Institutes of Health [R01 AI078345]; National Institute of Allergy and Infectious Diseases Southeast Regional Center for Excellence for Emerging Infections and Biodefense grant [U54 AI057157]; National Institute of Allergy and Infectious Diseases, National Institutes of Health grant [UC6 AI058607] FX Analysis of 20 cytokines/chemokines in tissue homogenates was performed by Kristina Riebe at the Duke Human Vaccine Institute/Regional Biocontainment Laboratory (RBL) Immunology Unit (Durham, NC, USA). We also thank Paula Campbell of the University of Arizona Flow Cytometry Core Facility. This work was supported by National Institutes of Health grant R01 AI078345 and National Institute of Allergy and Infectious Diseases Southeast Regional Center for Excellence for Emerging Infections and Biodefense grant U54 AI057157. Select studies were performed at Duke RBL, which received partial support for construction from National Institute of Allergy and Infectious Diseases, National Institutes of Health grant UC6 AI058607. The contents of this work are solely responsibility of the authors and do not necessarily represent the official views of NIH. NR 41 TC 3 Z9 3 U1 0 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD SEP 5 PY 2014 VL 5 AR 426 DI 10.3389/fimmu.2014.00426 PG 10 WC Immunology SC Immunology GA CI0QH UT WOS:000354442100001 PM 25250027 ER PT J AU O'Grady, TJ Kitahara, CM DiRienzo, AG Boscoe, FP Gates, MA AF O'Grady, Thomas J. Kitahara, Cari M. DiRienzo, A. Gregory Boscoe, Francis P. Gates, Margaret A. TI Randomization to Screening for Prostate, Lung, Colorectal and Ovarian Cancers and Thyroid Cancer Incidence in Two Large Cancer Screening Trials SO PLOS ONE LA English DT Article ID PAPILLARY MICROCARCINOMA; INCREASING INCIDENCE; CARCINOMA; MANAGEMENT; TRENDS; NODULES AB Background: Thyroid cancer incidence has increased significantly over the past three decades due, in part, to incidental detection. We examined the association between randomization to screening for lung, prostate, colorectal and/or ovarian cancers and thyroid cancer incidence in two large prospective randomized screening trials. Methods: We assessed the association between randomization to low-dose helical CT scan versus chest x-ray for lung cancer screening and risk of thyroid cancer in the National Lung Screening Trial (NLST). In the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO), we assessed the association between randomization to regular screening for said cancers versus usual medical care and thyroid cancer risk. Over a median 6 and 11 years of follow-up in NLST and PLCO, respectively, we identified 60 incident and 234 incident thyroid cancer cases. Cox proportional hazards regression was used to calculate the cause specific hazard ratios (HR) and 95% confidence intervals (CI) for thyroid cancer. Results: In NLST, randomization to lung CT scan was associated with a non-significant increase in thyroid cancer risk (HR = 1.61; 95% CI: 0.96-2.71). This association was stronger during the first 3 years of follow-up, during which participants were actively screened (HR = 2.19; 95% CI: 1.07-4.47), but not subsequently (HR = 1.08; 95% CI: 0.49-2.37). In PLCO, randomization to cancer screening compared with usual care was associated with a significant decrease in thyroid cancer risk for men (HR = 0.61; 95% CI: 0.49-0.95) but not women (HR = 0.91; 95% CI: 0.66-1.26). Similar results were observed when restricting to papillary thyroid cancer in both NLST and PLCO. Conclusion: Our study suggests that certain medical encounters, such as those using low-dose helical CT scan for lung cancer screening, may increase the detection of incidental thyroid cancer. C1 [O'Grady, Thomas J.; DiRienzo, A. Gregory; Boscoe, Francis P.; Gates, Margaret A.] SUNY Albany, Sch Publ Hlth, Rensselaer, NY 12144 USA. [Kitahara, Cari M.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP O'Grady, TJ (reprint author), SUNY Albany, Sch Publ Hlth, Rensselaer, NY 12144 USA. EM togrady@albany.edu RI Kitahara, Cari/R-8267-2016 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. There was no additional funding or support for this work. The funders had no role in the study design, data collection and analysis, decision to publish, or preperation of the manuscript. NR 44 TC 2 Z9 2 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 5 PY 2014 VL 9 IS 9 AR e106880 DI 10.1371/journal.pone.0106880 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AZ1IR UT WOS:000347993600076 PM 25192282 ER PT J AU Slota, C Ulrich, CM Miller-Davis, C Baker, K Wallen, GR AF Slota, Christina Ulrich, Connie M. Miller-Davis, Claiborne Baker, Karen Wallen, Gwenyth R. TI Qualitative inquiry: a method for validating patient perceptions of palliative care while enrolled on a cancer clinical trial SO BMC PALLIATIVE CARE LA English DT Article DE Palliative care; Cancer clinical trial; Palliative care; Pain; Communication ID PARTICIPATION; OUTCOMES; COMMUNICATION; ATTITUDES AB Background: Palliative care is a vital component of patient-centered care. It has increasingly become central to the management and care of seriously ill patients by integrating physical, psychosocial, and spiritual supportive services. Through qualitative inquiry, this paper examines cancer patients' perceptions of the process and outcomes of the pain and palliative care consultative services they received while enrolled in a clinical trial. Methods: A qualitative analysis of open-ended questions was conducted from a sub-sample of patients (n = 34) with advanced cancers enrolled in a randomized controlled trial exploring the efficacy of a palliative care consult service. Two open-ended questions focused on patient perceptions of continued participation on their primary cancer clinical trials and their perceptions of interdisciplinary communication. Results: Three overarching themes emerged when asked whether receiving pain and palliative care services made them more likely to remain enrolled in their primary cancer clinical trial: patients' past experiences with care, self-identified personal characteristics and reasons for participation, and the quality of the partnership. Four themes emerged related to interdisciplinary communication including: the importance of developing relationships, facilitating open communication, having quality communication, and uncertainty about communication between the cancer clinical trial and palliative care teams. Conclusions: Our findings suggest the importance of qualitative inquiry methods to explore patient perceptions regarding the efficacy of palliative care services for cancer patients enrolled in a cancer clinical trial. Validation of patient perceptions through qualitative inquiry regarding their pain and palliative care needs can provide insight into areas for future implementation research. C1 [Slota, Christina; Ulrich, Connie M.] Univ Penn, Sch Nursing, Dept Med Eth & Hlth Policy, New Courtland Ctr Transit & Hlth, Philadelphia, PA 19104 USA. [Miller-Davis, Claiborne; Wallen, Gwenyth R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Baker, Karen] NIH, Pain & Palliat Care Serv, Ctr Clin, Bethesda, MD 20892 USA. RP Wallen, GR (reprint author), NIH, Ctr Clin, 10 Ctr Dr,2B-09, Bethesda, MD 20892 USA. EM gwallen@cc.nih.gov FU National Institutes of Health, Clinical Center FX Funding for the study was obtained from the Intramural Program of the National Institutes of Health, Clinical Center. The authors also wish to acknowledge Dr. Ann Berger, Chief of Pain and Palliative Care Services at the NIH Clinical Center and the entire team for their support. NR 24 TC 0 Z9 0 U1 3 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-684X J9 BMC PALLIAT CARE JI BMC Palliat. Care PD SEP 5 PY 2014 VL 13 AR 43 DI 10.1186/1472-684X-13-43 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AU7OG UT WOS:000345789200001 PM 25276094 ER PT J AU Yang, YM Lee, J Jo, H Park, S Chang, I Muallem, S Shin, DM AF Yang, Yu-Mi Lee, Jiae Jo, Hae Park, Soonhong Chang, Inik Muallem, Shmuel Shin, Dong Min TI Homer2 Protein Regulates Plasma Membrane Ca2+-ATPase-mediated Ca2+ Signaling in Mouse Parotid Gland Acinar Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID METABOTROPIC GLUTAMATE RECEPTORS; POLARIZED EXPRESSION; HIPPOCAMPAL-NEURONS; PURKINJE NEURONS; IP3 RECEPTORS; CALCIUM-PUMP; KINASE-A; INTERACTS; CHANNELS; FAMILY AB Homer proteins are scaffold molecules with a domain structure consisting of an N-terminal Ena/VASP homology 1 protein-binding domain and a C-terminal leucine zipper/coiled-coil domain. The Ena/VASP homology 1 domain recognizes proline-rich motifs and binds multiple Ca2+ -signaling proteins, including G protein-coupled receptors, inositol 1,4,5-triphosphate receptors, ryanodine receptors, and transient receptor potential channels. However, their role in Ca(2+)signaling in nonexcitable cells is not well understood. In this study, we investigated the role of Homer2 on Ca(2+)signaling in parotid gland acinar cells using Homer2-deficient (Homer2(-/-)) mice. Homer2 is localized at the apical pole in acinar cells. Deletion of Homer2 did not affect inositol 1,4,5-triphosphate receptor localization or channel activity and did not affect the expression and activity of sarco/endoplasmic reticulum Ca2+-ATPase pumps. In contrast, Homer2 deletion markedly increased expression of plasma membrane Ca2+-ATPase (PMCA) pumps, in particular PMCA4, at the apical pole. Accordingly, Homer2 deficiency increased Ca(2+)extrusion by acinar cells. These findings were supported by co-immunoprecipitation of Homer2 and PMCA in wild-type parotid cells and transfected human embryonic kidney 293 (HEK293) cells. We identified a Homer-binding PPXXF-like motif in the N terminus of PMCA that is required for interaction with Homer2. Mutation of the PPXXF-like motif did not affect the interaction of PMCA with Homer1 but inhibited its interaction with Homer2 and increased Ca(2+)clearance by PMCA. These findings reveal an important regulation of PMCA by Homer2 that has a central role on PMCA-mediated Ca(2+)signaling in parotid acinar cells. C1 [Yang, Yu-Mi; Lee, Jiae; Park, Soonhong; Chang, Inik; Shin, Dong Min] Yonsei Univ, Coll Dent, PLUS Project BK21, Dept Oral Biol, Seoul 120752, South Korea. [Jo, Hae] Kyung Hee Univ, Coll Life Sci, Gyeonggi 446701, South Korea. [Jo, Hae] Kyung Hee Univ, Grad Sch Biotechnol, Gyeonggi 446701, South Korea. [Muallem, Shmuel] NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Shin, DM (reprint author), Yonsei Univ, Coll Dent, Dept Oral Biol, 50 Yonsei Ro, Seoul 120752, South Korea. EM dmshin@yuhs.ac FU Korea government (MSIP) [NRF-2012R1A2A1A01003487] FX This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported by the grant (NRF-2012R1A2A1A01003487) from the Korea government (MSIP). NR 44 TC 9 Z9 9 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 5 PY 2014 VL 289 IS 36 BP 24971 EP 24979 DI 10.1074/jbc.M114.577221 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP3OH UT WOS:000341985300022 PM 25049230 ER PT J AU Backus, KM Dolan, MA Barry, CS Joe, M McPhie, P Boshoff, HIM Lowary, TL Davis, BG Barry, CE AF Backus, Keriann M. Dolan, Michael A. Barry, Conor S. Joe, Maju McPhie, Peter Boshoff, Helena I. M. Lowary, Todd L. Davis, Benjamin G. Barry, Clifton E., III TI The Three Mycobacterium tuberculosis Antigen 85 Isoforms Have Unique Substrates and Activities Determined by Non-active Site Regions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-WALL; CORYNEBACTERIUM-GLUTAMICUM; MYCOLYL TRANSFERASE; MOLECULAR-DYNAMICS; SMEGMATIS; COMPLEX; ARABINOGALACTAN; FIBRONECTIN; COMPONENTS; INHIBITION AB The three isoforms of antigen 85 (A, B, and C) are the most abundant secreted mycobacterial proteins and catalyze transesterification reactions that synthesize mycolated arabinogalactan, trehalose monomycolate (TMM), and trehalose dimycolate (TDM), important constituents of the outermost layer of the cellular envelope of Mycobacterium tuberculosis. These three enzymes are nearly identical at the active site and have therefore been postulated to exist to evade host immunity. Distal to the active site is a second putative carbohydrate-binding site of lower homology. Mutagenesis of the three isoforms at this second site affected both substrate selectivity and overall catalytic activity in vitro. Using synthetic and natural substrates, we show that these three enzymes exhibit unique selectivity; antigen 85A more efficiently mycolates TMM to form TDM, whereas C (and to a lesser extent B) has a higher rate of activity using free trehalose to form TMM. This difference in substrate selectivity extends to the hexasaccharide fragment of cell wall arabinan. Mutation of secondary site residues from the most active isoform (C) into those present in A or B partially interconverts this substrate selectivity. These experiments in combination with molecular dynamics simulations reveal that differences in the N-terminal helix alpha 9, the adjacent Pro(216)-Phe(228) loop, and helix alpha 5 are the likely cause of changes in activity and substrate selectivity. These differences explain the existence of three isoforms and will allow for future work in developing inhibitors. C1 [Backus, Keriann M.; Boshoff, Helena I. M.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Dolan, Michael A.] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. [Backus, Keriann M.; Barry, Conor S.; Davis, Benjamin G.] Univ Oxford, Chem Res Lab, Dept Chem, Oxford OX1 3TA, England. [Joe, Maju; Lowary, Todd L.] Univ Alberta, Alberta Glyc Ctr, Edmonton, AB T6G 2G2, Canada. [Joe, Maju; Lowary, Todd L.] Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada. [McPhie, Peter] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Davis, BG (reprint author), Univ Oxford, Chem Res Lab, Mansfield Rd, Oxford OX1 3TA, England. EM Ben.Davis@chem.ox.ac.uk; cbarry@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012; Davis, Benjamin/C-5281-2011; OI Davis, Benjamin/0000-0002-5056-407X; Lowary, Todd/0000-0002-8331-8211 FU Colorado State University [HHSN266200400091c]; National Institutes of Health, NIGMS [9P41GM103311] FX Plasmids were obtained from Colorado State University tuberculosis research contract HHSN266200400091c. Molecular graphics and analyses were performed with the UCSF Chimera package. Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by National Institutes of Health, NIGMS, Grant 9P41GM103311). Protein structures were analyzed in PyMOL (38). NR 51 TC 10 Z9 10 U1 0 U2 19 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 SEP 5 PY 2014 VL 289 IS 36 BP 25041 EP 25053 DI 10.1074/jbc.M114.581579 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP3OH UT WOS:000341985300028 PM 25028517 ER PT J AU Dan, HC Ebbs, A Pasparakis, M Van Dyke, T Basseres, DS Baldwin, AS AF Dan, Han C. Ebbs, Aaron Pasparakis, Manolis Van Dyke, Terry Basseres, Daniela S. Baldwin, Albert S. TI Akt-dependent Activation of mTORC1 Complex Involves Phosphorylation of mTOR (Mammalian Target of Rapamycin) by I kappa B Kinase alpha (IKK alpha) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-GROWTH; DOMAIN PHOSPHORYLATION; FEEDBACK INHIBITION; TUMOR SUPPRESSION; GENETIC-ANALYSIS; PROTEIN-KINASE; CANCER; PTEN; PATHWAY; RHEB AB The serine/threonine protein kinase Akt promotes cell survival, growth, and proliferation through phosphorylation of different downstream substrates. A key effector of Akt is the mammalian target of rapamycin (mTOR). Akt is known to stimulate mTORC1 activity through phosphorylation of tuberous sclerosis complex 2 (TSC2) and PRAS40, both negative regulators of mTOR activity. We previously reported that I kappa B kinase alpha (IKK alpha), a component of the kinase complex that leads to NF-kappa B activation, plays an important role in promoting mTORC1 activity downstream of activated Akt. Here, we demonstrate IKK alpha-dependent regulation of mTORC1 using multiple PTEN null cancer cell lines and an animal model with deletion of IKK alpha. Importantly, IKK alpha is shown to phosphorylate mTOR at serine 1415 in a manner dependent on Akt to promote mTORC1 activity. These results demonstrate that IKK alpha is an effector of Akt in promoting mTORC1 activity. C1 [Dan, Han C.; Ebbs, Aaron; Basseres, Daniela S.; Baldwin, Albert S.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA. [Pasparakis, Manolis] Univ Cologne, Inst Genet, Cologne, Germany. [Van Dyke, Terry] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. [Dan, Han C.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Baldwin, AS (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, CB 7295, Chapel Hill, NC 27599 USA. EM abaldwin@med.unc.edu RI Basseres, Daniela/C-6623-2013 OI Basseres, Daniela/0000-0001-7745-3567 FU National Institutes of Health [CA75080, AI35098, CA73756, K99CA149178]; Department of Defense Postdoctoral (DOD) Fellowship [PC060420]; Samuel Waxman Cancer Research Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grants CA75080 (to A. S. B.), AI35098 (to A. S. B.), CA73756 (to A. S. B.), and K99CA149178 (to H. C. D.). Additional support was provided by Department of Defense Postdoctoral (DOD) Fellowship PC060420 (to H. C. D.) and by the Samuel Waxman Cancer Research Foundation (to A. S. B.). NR 58 TC 21 Z9 23 U1 1 U2 11 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 SEP 5 PY 2014 VL 289 IS 36 BP 25227 EP 25240 DI 10.1074/jbc.M114.554881 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP3OH UT WOS:000341985300042 PM 24990947 ER PT J AU Englund, EA Gupta, P Micklitsch, CM Onyshchenko, MI Remeeva, E Neumann, RD Panyutin, IG Appella, DH AF Englund, Ethan A. Gupta, Pankaj Micklitsch, Christopher M. Onyshchenko, Mykola I. Remeeva, Evgenia Neumann, Ronald D. Panyutin, Igor G. Appella, Daniel H. TI PPG Peptide Nucleic Acids that Promote DNA Guanine Quadruplexes SO CHEMBIOCHEM LA English DT Article DE DNA recognition; G-quadruplexes; nucleic acids; nucleobases; peptide nucleic acids ID DUPLEX DNA; STRAND INVASION; HUMAN GENOME; PNA; SEQUENCE; OLIGODEOXYRIBONUCLEOTIDES; STABILIZATION; SPECIFICITY; INHIBITORS; STABILITY AB Recent studies have shown that guanine-rich (G-rich) sequences with the potential to form quadruplexes might play a role in normal transcription as well as overexpression of oncogenes. Chemical tools that allow examination of the specific roles of G-quadruplex formation in vivo, and their association with gene regulation will be essential to understanding the functions of these quadruplexes and might lead to beneficial therapies. Properly designed peptide nucleic acids (PNAs) can invade G-rich DNA duplexes and induce the formation of a G-quadruplex in the free DNA strand. Replacing guanines in the PNA sequence with pyrazolo[3,4-d]pyrimidine guanine (PPG) nucleobases eliminates G-quadruplex formation with PNA and promotes invasion of the target DNA. C1 [Englund, Ethan A.; Gupta, Pankaj; Micklitsch, Christopher M.; Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Onyshchenko, Mykola I.; Remeeva, Evgenia; Neumann, Ronald D.; Panyutin, Igor G.] NIH, Ctr Clin, DHHS, Bethesda, MD 20892 USA. RP Appella, DH (reprint author), NIDDK, Bioorgan Chem Lab, NIH, DHHS, 8 Ctr Dr, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov FU Intramural Research Program at the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK); Clinical Center, National Institutes of Health (NIH) FX This work is supported in part by the Intramural Research Program at the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) and the Clinical Center, National Institutes of Health (NIH). NR 40 TC 1 Z9 1 U1 6 U2 26 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1439-4227 EI 1439-7633 J9 CHEMBIOCHEM JI ChemBioChem PD SEP 5 PY 2014 VL 15 IS 13 BP 1887 EP 1890 DI 10.1002/cbic.201402224 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA AO8EL UT WOS:000341586100006 PM 25044379 ER PT J AU Newmeyer, MN Concheiro, M Huestis, MA AF Newmeyer, Matthew N. Concheiro, Marta Huestis, Marilyn A. TI Rapid quantitative chiral amphetamines liquid chromatography-tandem mass spectrometry: Method in plasma and oral fluid with a cost-effective chiral derivatizing reagent SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Oral fluid; Plasma; Chiral analysis; Marfey's reagent; Amphetamines ID GC-NICI-MS; ENANTIOMERIC DETERMINATION; II METABOLITES; PHASE-I; METHAMPHETAMINE; DRUGS; MDMA; TOXICOLOGY; URINE; SAMPLES AB Methamphetamine is a widely abused psychostimulant containing a chiral center. Consumption of over-the-counter and prescription medications may yield positive amphetamines results, but chiral separation of L- and D-methamphetamine and its metabolite amphetamine can help determine whether the source was licit or illicit. We present the first LC-MS/MS method with precolumn derivatization for methamphetamine and amphetamine chiral resolution in plasma and oral fluid collected with the Oral-Eze (R) and Quantisal (TM) devices. To 0.5 mL plasma, 0.75 mL Oral-Eze, or 1 mL Quantisal specimen racemic d(11)-methamphetamine and amphetamine internal standards were added, followed by protein precipitation. Samples were centrifuged and supernatants loaded onto pre-conditioned Phenomenex (R) Strata (TM)-XC Polymeric Strong Cation solid phase extraction columns. After washing, analytes were eluted with 5% ammonium hydroxide in methanol. The eluate was evaporated to dryness and reconstituted in water. Derivatization was performed with 1-fluoro-2,4-dinitrophenyl-5-L-alanineamide (Marfey's reagent) and heating at 45 degrees C for 1 h. Derivatized enantiomer separations were performed under isocratic conditions (methanol:water, 60:40) with a Phenomenex (R) Kinetex (R) 2.6 mu m C18 column. Analytes were identified and quantified by two MRM transitions and their ratio on a 3200 QTrap (AB Sciex) mass spectrometer in ESI negative mode. In all three matrices, the method was linear for all enantiomers from 1 to 500 mu g/L, with imprecision and accuracy of <= 11.3% and 853-108%, respectively. Extraction efficiencies ranged from 67.4 to 117% and matrix effects from -17.0 to 468%, with variation always <= 19.1%. Authentic plasma and OF specimens were collected from an IRB-approved study that included controlled Vicks (R) VapoInhaler (TM) administration. The present method is sensitive, selective, economic and rapid (separations accomplished in <10 min), and improves methamphetamine result interpretation. Published by Elsevier B.V. C1 [Newmeyer, Matthew N.; Concheiro, Marta; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, IRP, NIH, Baltimore, MD 21224 USA. [Newmeyer, Matthew N.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200 Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov OI Newmeyer, Matthew/0000-0002-0653-1553 FU National Institute on Drug Abuse, National Institutes of Health; Division of Workplace Programs, Substance Abuse and Mental Health Services Administration FX The Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health provided funding for this research. We also thank Ron Flegal and Charles LoDico of the Division of Workplace Programs, Substance Abuse and Mental Health Services Administration for their financial support. NR 22 TC 10 Z9 10 U1 2 U2 47 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD SEP 5 PY 2014 VL 1358 BP 68 EP 74 DI 10.1016/j.chroma.2014.06.096 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AO0DL UT WOS:000340979200009 PM 25065924 ER PT J AU Wilson, WH Pittaluga, S Nicolae, A Camphausen, K Shovlin, M Steinberg, SM Roschewski, M Staudt, LM Jaffe, ES Dunleavy, K AF Wilson, Wyndham H. Pittaluga, Stefania Nicolae, Alina Camphausen, Kevin Shovlin, Margaret Steinberg, Seth M. Roschewski, Mark Staudt, Louis M. Jaffe, Elaine S. Dunleavy, Kieron TI A prospective study of mediastinal gray-zone lymphoma SO BLOOD LA English DT Article ID B-CELL LYMPHOMA; POSITRON-EMISSION-TOMOGRAPHY; CLASSIC HODGKINS LYMPHOMA; DOSE-ADJUSTED EPOCH; INTERNATIONAL WORKSHOP; RADIATION-THERAPY; RITUXIMAB; DISEASE; ABVD AB Mediastinal B-celllymphomas present in the mediastinum and are most frequent in young patients. Nodular sclerosis Hodgkin lymphoma (NSHL) and primary mediastinal B-cell lymphoma (PMBL) are the common types, whereas mediastinal gray-zone lymphoma (MGZL) is extremely rare and has pathological features intermediate between NSHL and PMBL. The indeterminate pathobiology of MGZL has led to uncertainty regarding therapeutic strategy, and its clinical characteristics and treatment have not been characterized. We conducted a prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim in untreated MGZL. We analyzed biomarkers of outcome and compared their clinical and biological characteristics to PMBL. Twenty-four MGZL patients had a median age of 33 years (range, 14 to 59 years), and 46% had mediastinal masses >= 10 cm. At 59 months median follow-up, the event-free survival and overall survival were 62% and 74%, respectively. The serum absolute lymphocyte count, the presence of tumor-infiltrating dendritic cells, CD15 expression on the malignant cells, and tumor morphology were biomarkers of outcome in MGZL. Compared with PMBL, MGZL patients were more likely to be male, express CD15, have lower expression of CD20, and have a worse outcome. DA-EPOCH-R alone is effective in MGZL. The trial was registered at ClinicalTrials.gov (NCT00001337). C1 [Wilson, Wyndham H.; Shovlin, Margaret; Roschewski, Mark; Staudt, Louis M.; Dunleavy, Kieron] NCI, Lymphoid Malignancy Branch, Bethesda, MD 20892 USA. [Pittaluga, Stefania; Nicolae, Alina; Jaffe, Elaine S.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wilson, WH (reprint author), NCI, Lymphoid Malignancy Branch, Ctr Canc Res, Bldg 10,Room 4N-115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wilsonw@mail.nih.gov NR 27 TC 24 Z9 25 U1 0 U2 9 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 SEP 4 PY 2014 VL 124 IS 10 BP 1563 EP 1569 DI 10.1182/blood-2014-03-564906 PG 7 WC Hematology SC Hematology GA AQ4JO UT WOS:000342762300010 PM 25024303 ER PT J AU Kim, W Klarmann, KD Keller, JR AF Kim, Wonil Klarmann, Kimberly D. Keller, Jonathan R. TI Gfi-1 regulates the erythroid transcription factor network through Id2 repression in murine hematopoietic progenitor cells SO BLOOD LA English DT Article ID LOOP-HELIX PROTEINS; STEM-CELLS; STRESS ERYTHROPOIESIS; HUMAN NEUTROPENIA; KNOCKOUT MICE; FACTOR GATA-1; DNA-BINDING; GENE; DIFFERENTIATION; PROLIFERATION AB Growth factor independence 1 (Gfi-1) is a part of the transcriptional network that regulates the development of adult hematopoietic stem and progenitor cells. Gfi-1-null (Gfi-1(-/-)) mice have reduced numbers of hematopoietic stem cells (HSCs), impaired radioprotective function of hematopoietic progenitor cells (HPCs), and myeloid and erythroid hyperplasia. We found that the development of HPCs and erythropoiesis, but not HSC function, was rescued by reducing the expression of inhibitor of DNA-binding protein 2 (Id2) in Gfi-1(-/-) mice. Analysis of Gfi-1(-/-); Id2(+/-) mice revealed that short-term HSCs, common myeloid progenitors (CMPs), erythroid burst-forming units, colony-forming units in spleen, and more differentiated red cells were partially restored by reducing Id2 levels in Gfi-1(-/-) mice. Moreover, short-term reconstituting cells, and, to a greater extent, CMP and megakaryocyte-erythroid progenitor development, and red blood cell production (anemia) were rescued in mice transplanted with Gfi-1(-/-); Id2(+/-) bone marrow cells (BMCs) in comparison with Gfi-1(-/-) BMCs. Reduction of Id2 expression in Gfi-1(-/-) mice increased the expression of Gata1, Eklf, and EpoR, which are required for proper erythropoiesis. Reducing the levels of other Id family members (Id1 and Id3) in Gfi-1(-/-) mice did not rescue impaired HPC function or erythropoiesis. These data provide new evidence that Gfi-1 is linked to the erythroid gene regulatory network by repressing Id2 expression. C1 [Kim, Wonil; Klarmann, Kimberly D.; Keller, Jonathan R.] Leidos Biomed Res Inc, Basic Sci Program, Mouse Canc & Genet Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Keller, JR (reprint author), NCI, Hematopoiesis & Stem Cell Biol Sect, Mouse Canc Genet Program, Ctr Canc Res,NIH,Basic Sci Program,Leidos Biomed, Bldg 560,Room 12-03,1050 Boyles St,POB B, Frederick, MD 21701 USA. EM kellerjo@mail.nih.gov FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the National Institutes of Health, Frederick National Laboratory, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. This research was supported, in part, by the Intramural Research Program of the National Institutes of Health, Frederick National Laboratory, Center for Cancer Research. NR 49 TC 10 Z9 10 U1 0 U2 5 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 SEP 4 PY 2014 VL 124 IS 10 BP 1586 EP 1596 DI 10.1182/blood-2014-02-556522 PG 11 WC Hematology SC Hematology GA AQ4JO UT WOS:000342762300013 PM 25051963 ER PT J AU Oldfield, AJ Yang, PY Conway, AE Cinghu, S Freudenberg, JM Yellaboina, S Jothi, R AF Oldfield, Andrew J. Yang, Pengyi Conway, Amanda E. Cinghu, Senthilkumar Freudenberg, Johannes M. Yellaboina, Sailu Jothi, Raja TI Histone-Fold Domain Protein NF-Y Promotes Chromatin Accessibility for Cell Type-Specific Master Transcription Factors SO MOLECULAR CELL LA English DT Article ID EMBRYONIC STEM-CELLS; DNA BINDING-SITES; CHIP-SEQ DATA; CBF/NF-Y; FACILITATES PLURIPOTENCY; GENES; GENOME; MOUSE; IDENTIFICATION; ACTIVATION AB Cell type-specific master transcription factors (TFs) play vital roles in defining cell identity and function. However, the roles ubiquitous factors play in the specification of cell identity remain underappreciated. Here we show that the ubiquitous CCAAT-binding NF-Y complex is required for the maintenance of embryonic stemcell (ESC) identity and is an essential component of the core pluripotency network. Genome-wide studies in ESCs and neurons reveal that NF-Y regulates not only genes with housekeeping functions through cell type-invariant promoter- proximal binding, but also genes required for cell identity by binding to cell type-specific enhancers with master TFs. Mechanistically, NF-Y's distinct DNA-binding mode promotes master/pioneer TF binding at enhancers by facilitating a permissive chromatin conformation. Our studies unearth a conceptually unique function for histone-fold domain (HFD) protein NF-Y in promoting chromatin accessibility and suggest that other HFD proteins with analogous structural and DNA-binding properties may function in similar ways. C1 [Oldfield, Andrew J.; Yang, Pengyi; Conway, Amanda E.; Cinghu, Senthilkumar; Freudenberg, Johannes M.; Jothi, Raja] NIEHS, Syst Biol Sect, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Yang, Pengyi; Jothi, Raja] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Yellaboina, Sailu] CR Rao Adv Inst Math Stat & Comp Sci, Hyderabad 500046, Andhra Pradesh, India. RP Jothi, R (reprint author), NIEHS, Syst Biol Sect, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM jothi@mail.nih.gov RI Yang, Pengyi/B-1002-2010; Jothi, Raja/G-3780-2015 OI Yang, Pengyi/0000-0003-1098-3138; FU NIEHS Microarray; Next-Generation Sequencing, Confocal Microscopy; Flow Cytometry cores; NIH, National Institute of Environmental Health Sciences [1ZIAES102625] FX We thank K. Adelman, G. Hu, and P. A. Wade for critical comments on the manuscript, and R. S. Williams and T. K. Archer for useful discussion. We thank G. Hu and X. Zheng for guidance on RNAi experiments, S. Peddada for guidance on statistical tests, and J. Hoffman for guidance on DNase experiments. We thank NIEHS Microarray, Next-Generation Sequencing, Confocal Microscopy, and Flow Cytometry cores for their support. This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (R.J., 1ZIAES102625). NR 48 TC 21 Z9 21 U1 0 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD SEP 4 PY 2014 VL 55 IS 5 BP 708 EP 722 DI 10.1016/j.molcel.2014.07.005 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AQ2LW UT WOS:000342618700007 PM 25132174 ER PT J AU Kellman, P Xue, H Chow, K Spottiswoode, BS Arai, AE Thompson, RB AF Kellman, Peter Xue, Hui Chow, Kelvin Spottiswoode, Bruce S. Arai, Andrew E. Thompson, Richard B. TI Optimized saturation recovery protocols for T1-mapping in the heart: influence of sampling strategies on precision SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE T1 mapping; Random error; Precision; SASHA; Saturation recovery; Myocardial fibrosis ID CARDIOVASCULAR MAGNETIC-RESONANCE; ACUTE MYOCARDIAL-INFARCTION; FABRY DISEASE; T1; T2 AB Background: T1-mapping has the potential to detect and quantify diffuse processes such as interstitial fibrosis. Detection of disease at an early stage by measurement of subtle changes requires a high degree of reproducibility. Initial implementation of saturation recovery (SR) T1-mapping employed 3-parameter fitting which was highly accurate but was quite sensitive to noise; 2-parameter fitting greatly reduced the sensitivity to noise at the expense of a small degree of systematic bias. A recently introduced implementation that uses a variable readout flip angle greatly reduces systematic errors in T1-measurement thereby making it feasible to use SR methods with 2-parameter fitting with improved accuracy and precision. SR T1 mapping techniques with multi-heartbeat recovery times have been proposed to better sample the T1 recovery curve, but have not been evaluated for 2-parameter fitting. Methods: An analytic formulation for calculating the standard deviation (SD) for SR T1-mapping with 2-parameter fitting is developed and validated using Monte-Carlo simulation. The coefficient of variation is compared for a brute force optimization of sampling and for several previously described sampling schemes for T1 measurement over several uncertainty ranges. Experimental validation is performed in phantoms over a range of T1, and in-vivo both native and post-contrast. Pixel-wise SD maps are calculated for SR T1-mapping. Results: Sampling schemes that use a non-saturated anchor image and multiple (N) measurements at a single fixed saturation delay are found to be near optimum for the case of known T1 and are close to the brute force optimized solution over wide ranges of native and post-contrast T1 values. The fixed delay sampling scheme is simple to implement and provides an improvement over uniformly distributed schemes. Conclusions: Sampling strategies for saturation recovery methods for myocardial T1-mapping have been optimized and validated experimentally. Reduced SD, or improved precision, may be achieved by using fixed saturation delays when considering native myocardium and post-contrast T1 ranges. Pixel-wise estimates of T1 mapping errors have been formulated and validated for SR fitting methods. C1 [Kellman, Peter; Arai, Andrew E.] NHLBI, NIH, DHHS, Bethesda, MD 20892 USA. [Spottiswoode, Bruce S.] Siemens Med Solut, Chicago, IL USA. [Chow, Kelvin; Thompson, Richard B.] Univ Alberta, Dept Biomed Engn, Edmonton, AB, Canada. RP Kellman, P (reprint author), NHLBI, NIH, DHHS, 10 Ctr Dr MSC-1061, Bethesda, MD 20892 USA. EM kellman@nih.gov FU National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research; NHLBI, NIH, DHHS [HL004607-14CPB] FX Supported by the National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS (HL004607-14CPB). NR 20 TC 13 Z9 13 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD SEP 4 PY 2014 VL 16 AR 55 DI 10.1186/s12968-014-0055-3 PG 15 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AP1QQ UT WOS:000341846400001 PM 25190004 ER PT J AU La Kotan, LD Hutchins, BI Ozkan, Y Demire, F Stoner, H Cheng, PJ Esen, I Gurbuz, F Bicakci, YK Mengen, E Yukse, B Wray, S Topaloglu, AK AF La Kotan, L. Dam Hutchins, B. Ian Ozkan, Yusuf Demire, Fatma Stoner, Hudson Cheng, Paul J. Esen, Ihsan Gurbuz, Fatih Bicakci, Y. Kenan Mengen, Eda Yukse, Bilgin Wray, Susan Topaloglu, A. Kemal TI Mutations in FEZF1 Cause Kallmann Syndrome SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; GONADOTROPIN-RELEASING-HORMONE; OF-FUNCTION MUTATIONS; FINGER GENES FEZF1; OLFACTORY DEVELOPMENT; PROTEIN; NEURONS; RNA; IDENTIFICATION; DEFICIENCY AB Gonadotropin-releasing hormone (GnRH) neurons originate outside the CNS in the olfactory placode and migrate into the CNS, where they become integral components of the hypothalamic-pituitary-gonadal (HPG) axis. Disruption of this migration results in Kallmann syndrome (KS), which is characterized by anosmia and pubertal failure due to hypogonadotropic hypogonadism. Using candidate-gene screening, autozygosity mapping, and whole-exome sequencing in a cohort of 30 individuals with KS, we searched for genes newly associated with KS. We identified homozygous loss-of-function mutations in FEZF1 in two independent consanguineous families each with two affected siblings. The FEZF1 product is known to enable axons of olfactory receptor neurons (ORNs) to penetrate the CNS basal lamina in mice. Because a subset of axons in these tracks is the migratory pathway for GnRH neurons, in FEZF1 deficiency, GnRH neurons also fail to enter the brain. These results indicate that FEZF1 is required for establishment of the central component of the HPG axis in humans. C1 [La Kotan, L. Dam; Topaloglu, A. Kemal] Cukurova Univ, Inst Sci, Dept Biotechnol, TR-01330 Adana, Turkey. [Hutchins, B. Ian; Stoner, Hudson; Cheng, Paul J.; Wray, Susan] NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Ozkan, Yusuf] Firat Univ, Dept Endocrinol, Fac Med, TR-23119 Elazig, Turkey. [Demire, Fatma; Esen, Ihsan] Ankara Pediat Hematol & Oncol Training Hosp, Div Pediat Endocrinol, TR-06200 Ankara, Turkey. [Gurbuz, Fatih; Mengen, Eda; Yukse, Bilgin; Topaloglu, A. Kemal] Cukurova Univ, Div Pediat Endocrinol, Fac Med, TR-01330 Adana, Turkey. [Bicakci, Y. Kenan] Cukurova Univ, Dept Radiol, Fac Med, TR-01330 Adana, Turkey. RP Wray, S (reprint author), NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. EM wrays@ninds.nih.gov; ktopaloglu@cu.edu.tr RI Hutchins, Ian/A-5713-2009; TOPALOGLU, ALI/O-1408-2015; OI Hutchins, Ian/0000-0001-7657-552X; Cheng-Hathaway, Paul/0000-0002-3240-9316; wray, susan/0000-0001-7670-3915 FU Scientific and Technological Research Council of Turkey (TUBITAK) [109S455]; Cukurova University Scientific Research Projects (BAP); International Centre for Genetic Engineering and Biotechnology [CRP/TUR10-01]; Intramural Research Program of the NIH National Institute of Neurological Disorders and Stroke [NS002824-13] FX This work was supported by the Scientific and Technological Research Council of Turkey (TUBITAK, project no. 109S455), by the Cukurova University Scientific Research Projects (BAP), and by International Centre for Genetic Engineering and Biotechnology (CRP/TUR10-01). B.I.H., P.J.C., H.S., and S.W. received support from the Intramural Research Program of the NIH National Institute of Neurological Disorders and Stroke (NS002824-13). NR 33 TC 0 Z9 0 U1 0 U2 6 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 SEP 4 PY 2014 VL 95 IS 3 BP 326 EP 331 DI 10.1016/j.ajhg.2014.08.006 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA AO5RX UT WOS:000341404100009 ER PT J AU Luo, Y Ma, BY Nussinov, R Wei, GH AF Luo, Yin Ma, Buyong Nussinov, Ruth Wei, Guanghong TI Structural Insight into Tau Protein's Paradox of Intrinsically Disordered Behavior, Self-Acetylation Activity, and Aggregation SO JOURNAL OF PHYSICAL CHEMISTRY LETTERS LA English DT Article ID PAIRED HELICAL FILAMENTS; BETA-STRUCTURE; CONFORMATIONAL SELECTION; ALPHA-SYNUCLEIN; ACETYLTRANSFERASE ACTIVITY; ENERGY LANDSCAPE; DYNAMICS; PHOSPHORYLATION; SCATTERING; RESOLUTION AB Tau is an intrinsically disordered protein (IDP) implicated in Alzheimer's disease. Recently, tau proteins were discovered to be able to catalyze self-acetylation, which may promote its pathological aggregation. Understanding the paradox of tau's random-like conformations, aggregation propensity, and enzymatic activity are challenging questions. We characterized the atomic structures of two truncated tau constructs, K18 and K19, consisting of, respectively, only the four- and three-repeats of tau protein, providing structural insights into tau's paradox. Extensive 4.8 mu s replica-exchange molecular dynamics simulations of the tau proteins achieved quantitative correlation with experimental C-alpha chemical shifts. Our results revealed (1) dynamically ordered conformations with dose lysine cysteine distances essential for tau self-acetylation and (2) high beta-sheet content and large hydrophobic surface exposure for the two critical hexapeptides ((275)VQIINK(280) and (306)VQIVYK(311)) crucial for tau aggregation. Together, they illuminate tau's perplexing behavior of how its disordered state can accomplish both roles. C1 [Luo, Yin; Wei, Guanghong] Fudan Univ, State Key Lab Surface Phys, Key Lab Computat Phys Sci MOE, Shanghai 200433, Peoples R China. [Luo, Yin; Wei, Guanghong] Fudan Univ, Dept Phys, Shanghai 200433, Peoples R China. [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 Inst Mol Med, Dept Human Genet & Mol Med, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Wei, GH (reprint author), Fudan Univ, State Key Lab Surface Phys, Key Lab Computat Phys Sci MOE, Shanghai 200433, Peoples R China. EM mabuyong@mail.nih.gov; ghwei@fudan.edu.cn RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NCI, NIH [HHSN261200800001E]; NSF of China [91227102, 11274075] FX B.M and R.N. acknowledge the financial support from NCI, NIH, under Contract Number HHSN261200800001E. G.W. acknowledges the financial support from the NSF of China (Grant No.: 91227102 and 11274075). Simulations were performed using the high-performance computational facilities of the Biowulf PC/Linux cluster at the NIH and National High Performance Computing Center of Fudan University. NR 44 TC 14 Z9 14 U1 1 U2 32 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7185 J9 J PHYS CHEM LETT JI J. Phys. Chem. Lett. PD SEP 4 PY 2014 VL 5 IS 17 BP 3026 EP 3031 DI 10.1021/jz501457f PG 6 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Atomic, Molecular & Chemical SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA AO4UR UT WOS:000341337400019 PM 25206938 ER PT J AU Morens, DM Fauci, AS AF Morens, David M. Fauci, Anthony S. TI Chikungunya at the Door - Deja Vu All Over Again? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID PUBLIC-HEALTH; PROSPECTS; SPREAD; VIRUS C1 [Morens, David M.; Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 40 Z9 42 U1 0 U2 15 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 4 PY 2014 VL 371 IS 10 BP 885 EP 887 DI 10.1056/NEJMp1408509 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AO5NB UT WOS:000341390600003 PM 25029435 ER PT J AU de Vasconcellos, JF Fasano, RM Lee, YT Kaushal, M Byrnes, C Meier, ER Anderson, M Rabel, A Braylan, R Stroncek, DF Miller, JL AF de Vasconcellos, Jaira F. Fasano, Ross M. Lee, Y. Terry Kaushal, Megha Byrnes, Colleen Meier, Emily R. Anderson, Molly Rabel, Antoinette Braylan, Raul Stroncek, David F. Miller, Jeffery L. TI LIN28A Expression Reduces Sickling of Cultured Human Erythrocytes SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; FETAL-HEMOGLOBIN; CELL-DISEASE; GAMMA-GLOBIN; BCL11A; POLYMERIZATION; IDENTIFICATION; THALASSEMIA; REGULATOR; PATIENT AB Induction of fetal hemoglobin (HbF) has therapeutic importance for patients with sickle cell disease (SCD) and the beta-thalassemias. It was recently reported that increased expression of LIN28 proteins or decreased expression of its target let-7 miRNAs enhances HbF levels in cultured primary human erythroblasts from adult healthy donors. Here LIN28A effects were studied further using erythrocytes cultured from peripheral blood progenitor cells of pediatric subjects with SCD. Transgenic expression of LIN28A was accomplished by lentiviral transduction in CD34(+) sickle cells cultivated ex vivo in serum-free medium. LIN28A over-expression (LIN28A-OE) increased HbF, reduced beta (sickle)-globin, and strongly suppressed all members of the let-7 family of miRNAs. LIN28A-OE did not affect erythroblast differentiation or prevent enucleation, but it significantly reduced or ameliorated the sickling morphologies of the enucleated erythrocytes. C1 [de Vasconcellos, Jaira F.; Lee, Y. Terry; Kaushal, Megha; Byrnes, Colleen; Meier, Emily R.; Anderson, Molly; Rabel, Antoinette; Miller, Jeffery L.] NIDDK, Mol Genom & Therapeut Sect, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Fasano, Ross M.; Kaushal, Megha; Meier, Emily R.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Braylan, Raul] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Stroncek, David F.] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDK, Mol Genom & Therapeut Sect, Mol Med Branch, NIH, Bethesda, MD 20892 USA. EM jm7f@nih.gov FU Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases FX The Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases supported this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 5 Z9 5 U1 0 U2 9 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 SEP 4 PY 2014 VL 9 IS 9 AR e106924 DI 10.1371/journal.pone.0106924 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3XV UT WOS:000341271500097 PM 25188417 ER PT J AU Fowler, AK Thompson, J Chen, LX Dagda, M Dertien, J Dossou, KSS Moaddel, R Bergeson, SE Kruman, II AF Fowler, Anna-Kate Thompson, Jeremy Chen, Lixia Dagda, Marisela Dertien, Janet Dossou, Katina Sylvestre S. Moaddel, Ruin Bergeson, Susan E. Kruman, Inna I. TI Differential Sensitivity of Prefrontal Cortex and Hippocampus to Alcohol-Induced Toxicity SO PLOS ONE LA English DT Article ID BASE EXCISION-REPAIR; FUTURE CONSEQUENCES; ETHANOL EXPOSURE; DECISION-MAKING; DRUG-DEPENDENCE; RAT CEREBELLUM; DNA-DAMAGE; CELL-DEATH; BRAIN; STRESS AB The prefrontal cortex (PFC) is a brain region responsible for executive functions including working memory, impulse control and decision making. The loss of these functions may ultimately lead to addiction. Using histological analysis combined with stereological technique, we demonstrated that the PFC is more vulnerable to chronic alcohol-induced oxidative stress and neuronal cell death than the hippocampus. This increased vulnerability is evidenced by elevated oxidative stress-induced DNA damage and enhanced expression of apoptotic markers in PFC neurons. We also found that one-carbon metabolism (OCM) impairment plays a significant role in alcohol toxicity to the PFC seen from the difference in the effects of acute and chronic alcohol exposure on DNA repair and from exaggeration of the damaging effects upon additional OCM impairment in mice deficient in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR). Given that damage to the PFC leads to loss of executive function and addiction, our study may shed light on the mechanism of alcohol addiction. C1 [Fowler, Anna-Kate; Thompson, Jeremy; Chen, Lixia; Dagda, Marisela; Dertien, Janet; Bergeson, Susan E.; Kruman, Inna I.] Texas Tech Univ, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Lubbock, TX 79430 USA. [Dossou, Katina Sylvestre S.; Moaddel, Ruin] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. RP Kruman, II (reprint author), Texas Tech Univ, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Lubbock, TX 79430 USA. EM inna.kruman@ttuhsc.edu FU Foundation for Alcohol Research; South Plains Alcohol and Addiction Research Center; National Institutes of Health Intramural Research Program FX This work was supported by the Foundation for Alcohol Research (to I. I. K.), the South Plains Alcohol and Addiction Research Center and in part, by National Institutes of Health Intramural Research Program (to R. M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 3 Z9 3 U1 4 U2 22 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 SEP 4 PY 2014 VL 9 IS 9 AR e106945 DI 10.1371/journal.pone.0106945 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3XV UT WOS:000341271500101 PM 25188266 ER PT J AU Wilson, IM Vucic, EA Enfield, KSS Thu, KL Zhang, YA Chari, R Lockwood, WW Radulovich, N Starczynowski, DT Banath, JP Zhang, M Pusic, A Fuller, M Lonergan, KM Rowbotham, D Yee, J English, JC Buys, TPH Selamat, SA Laird-Offringa, IA Liu, P Anderson, M You, M Tsao, MS Brown, CJ Bennewith, KL MacAulay, CE Karsan, A Gazdar, AF Lam, S Lam, WL AF Wilson, I. M. Vucic, E. A. Enfield, K. S. S. Thu, K. L. Zhang, Y. A. Chari, R. Lockwood, W. W. Radulovich, N. Starczynowski, D. T. Banath, J. P. Zhang, M. Pusic, A. Fuller, M. Lonergan, K. M. Rowbotham, D. Yee, J. English, J. C. Buys, T. P. H. Selamat, S. A. Laird-Offringa, I. A. Liu, P. Anderson, M. You, M. Tsao, M. S. Brown, C. J. Bennewith, K. L. MacAulay, C. E. Karsan, A. Gazdar, A. F. Lam, S. Lam, W. L. TI EYA4 is inactivated biallelically at a high frequency in sporadic lung cancer and is associated with familial lung cancer risk SO ONCOGENE LA English DT Article DE EYA4; two hit; hypermethylation; tumor suppressor; TSG; non-small-cell lung cancer ID GENE-EXPRESSION SIGNATURE; EYES-ABSENT; SUSCEPTIBILITY LOCUS; DNA METHYLATION; CHROMOSOME 6Q23-25; HISTONE H2AX; ADENOCARCINOMA; GENOME; TUMORIGENESIS; RESOLUTION AB In an effort to identify novel biallelically inactivated tumor suppressor genes (TSGs) in sporadic invasive and preinvasive non-small-cell lung cancer (NSCLC) genomes, we applied a comprehensive integrated multiple 'omics' approach to investigate patient-matched, paired NSCLC tumor and non-malignant parenchymal tissues. By surveying lung tumor genomes for genes concomitantly inactivated within individual tumors by multiple mechanisms, and by the frequency of disruption in tumors across multiple cohorts, we have identified a putative lung cancer TSG, Eyes Absent 4 (EYA4). EYA4 is frequently and concomitantly deleted, hypermethylated and underexpressed in multiple independent lung tumor data sets, in both major NSCLC subtypes and in the earliest stages of lung cancer. We found that decreased EYA4 expression is not only associated with poor survival in sporadic lung cancers but also that EYA4 single-nucleotide polymorphisms are associated with increased familial cancer risk, consistent with EYA4s proximity to the previously reported lung cancer susceptibility locus on 6q. Functionally, we found that EYA4 displays TSG-like properties with a role in modulating apoptosis and DNA repair. Cross-examination of EYA4 expression across multiple tumor types suggests a cell-type-specific tumorigenic role for EYA4, consistent with a tumor suppressor function in cancers of epithelial origin. This work shows a clear role for EYA4 as a putative TSG in NSCLC. C1 [Wilson, I. M.; Vucic, E. A.; Enfield, K. S. S.; Thu, K. L.; Chari, R.; Lockwood, W. W.; Banath, J. P.; Zhang, M.; Pusic, A.; Fuller, M.; Lonergan, K. M.; Rowbotham, D.; Buys, T. P. H.; Bennewith, K. L.; MacAulay, C. E.; Karsan, A.; Lam, S.; Lam, W. L.] British Columbia Canc Res Ctr, Integrat Oncol Genet Unit, Vancouver, BC V5Z 1L3, Canada. [Zhang, Y. A.; Gazdar, A. F.] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. [Chari, R.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Lockwood, W. W.] NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. [Radulovich, N.; Tsao, M. S.] Princess Margaret Hosp, Ontario Canc Inst, Toronto, ON M4X 1K9, Canada. [Starczynowski, D. T.] Cincinnati Childrens Hosp Res Fdn, Div Expt Hematol & Canc Biol, Cincinnati, OH USA. [Yee, J.] Vancouver Gen Hosp, Dept Surg, Vancouver, BC, Canada. [English, J. C.] Vancouver Gen Hosp, Dept Pathol, Vancouver, BC V5Z 1M9, Canada. [Selamat, S. A.; Laird-Offringa, I. A.] Univ So Calif, Dept Biochem & Mol Biol, Los Angeles, CA USA. [Liu, P.; Anderson, M.; You, M.] Med Coll Wisconsin, Ctr Canc, Milwaukee, WI 53226 USA. [Brown, C. J.] Univ British Columbia, Dept Med Genet, Life Sci Ctr, Vancouver, BC, Canada. RP Wilson, IM (reprint author), British Columbia Canc Res Ctr, Integrat Oncol Genet Unit, 675 West 10th Ave, Vancouver, BC V5Z 1L3, Canada. EM iwilson@bccrc.ca RI Brown, Carolyn/A-5159-2014; Karsan, Aly/K-2067-2015; MacAulay, Calum/K-1795-2016; OI Brown, Carolyn/0000-0002-8959-0101; Vucic, Emily/0000-0002-2728-8708; Selamat, Suhaida/0000-0002-7185-6995 FU Canadian Institutes of Health Research (CIHR) [MOP86731, MOP77903, MOP94867]; Canadian Cancer Society [CCS017076, CCS20485]; Terry Fox Foundation [20395]; NCI Early Detection Research Network [5U01 CA84971-10]; Canary Foundation; NIH Genetic Epidemiology of Lung Cancer Consortium [U01CA76293]; CIHR, Canada; Vanier Canada FX We thank Miwa Suzuki, Denise McDougal, Chad Malloff and Bradley Coe for assistance. Grant supports were from Canadian Institutes of Health Research (CIHR MOP86731, MOP77903, MOP94867), Canadian Cancer Society (CCS017076, CCS20485); Terry Fox Foundation (20395); NCI Early Detection Research Network (5U01 CA84971-10), Canary Foundation, NIH Genetic Epidemiology of Lung Cancer Consortium (U01CA76293); and scholarships from CIHR (IMW, EAV, KSSE and WWL) and Vanier Canada (RC, KLT and NR). NR 53 TC 12 Z9 13 U1 1 U2 7 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 SEP 4 PY 2014 VL 33 IS 36 BP 4464 EP 4473 DI 10.1038/onc.2013.396 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AO2MY UT WOS:000341158800002 PM 24096489 ER PT J AU Ajiro, M Zheng, ZM AF Ajiro, Masahiko Zheng, Zhi-Ming TI Oncogenes and RNA splicing of human tumor viruses SO EMERGING MICROBES & INFECTIONS LA English DT Review DE EBV; HBV; HCV; HPV; HTLV-1; KSHV; MCV; RNA splicing ID EPSTEIN-BARR-VIRUS; T-CELL LEUKEMIA; HEPATITIS-B-VIRUS; SARCOMA-ASSOCIATED HERPESVIRUS; HUMAN-PAPILLOMAVIRUS TYPE-16; MEMBRANE-PROTEIN 1; NF-KAPPA-B; GROWTH-FACTOR RECEPTOR; POSTTRANSCRIPTIONAL REGULATORY ELEMENT; ACTIVATED CD40 RECEPTOR AB Approximately 10.8% of human cancers are associated with infection by an oncogenic virus. These viruses include human papillomavirus (HPV), Epstein-Barr virus (EBV), Merkel cell polyomavirus (MCV), human T-cell leukemia virus 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV) and hepatitis B virus (HBV). These oncogenic viruses, with the exception of HCV, require the host RNA splicing machinery in order to exercise their oncogenic activities, a strategy that allows the viruses to efficiently export and stabilize viral RNA and to produce spliced RNA isoforms from a bicistronic or polycistronic RNA transcript for efficient protein translation. Infection with a tumor virus affects the expression of host genes, including host RNA splicing factors, which play a key role in regulating viral RNA splicing of oncogene transcripts. A current prospective focus is to explore how alternative RNA splicing and the expression of viral oncogenes take place in a cell-or tissue-specific manner in virus-induced human carcinogenesis. C1 [Ajiro, Masahiko; Zheng, Zhi-Ming] NCI, Tumor Virus RNA Biol Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Zheng, ZM (reprint author), NCI, Tumor Virus RNA Biol Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM zhengt@exchange.nih.gov FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health; Japan Society for the Promotion of Science (JSPS) FX This research program was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. Masahiko Ajiro was supported by the Japan Society for the Promotion of Science (JSPS) Research Fellowship for Japanese biomedical and behavioral researchers at the National Institutes of Health. NR 248 TC 5 Z9 5 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2222-1751 J9 EMERG MICROBES INFEC JI Emerg. Microbes Infect. PD SEP 3 PY 2014 VL 3 AR e63 DI 10.1038/emi.2014.62 PG 16 WC Immunology; Microbiology SC Immunology; Microbiology GA AU2ED UT WOS:000345428100002 PM 26038756 ER PT J AU Hildesheim, A Wacholder, S Catteau, G Struyf, F Dubin, G Herrero, R Grp, C AF Hildesheim, Allan Wacholder, Sholom Catteau, Gregory Struyf, Frank Dubin, Gary Herrero, Rolando Grp, C. V. T. TI Efficacy of the HPV-16/18 vaccine: Final according to protocol results from the blinded phase of the randomized Costa Rica HPV-16/18 vaccine trial SO VACCINE LA English DT Article DE Human papillomaviruses; Cervical neoplasia; Vaccination; Prevention; Clinical trial ID HUMAN-PAPILLOMAVIRUS TYPE-16; (HPV)-16/18 AS04-ADJUVANTED VACCINE; CROSS-PROTECTIVE EFFICACY; OF-STUDY ANALYSIS; PARTICLE VACCINE; YOUNG-WOMEN; POOLED ANALYSIS; CLINICAL-TRIAL; HPV TYPES; QUADRIVALENT VACCINE AB Background: A community-based randomized trial was conducted in Costa Rica to evaluate the HPV-16/18 AS04-adjuvanted vaccine (NCT00128661). The primary objective was to evaluate efficacy of the vaccine to prevent cervical intraepithelial neoplasia 2 or more severe disease (CIN2+) associated with incident HPV-16/18 cervical infections. Secondary objectives were to evaluate efficacy against CIN2+ associated with incident cervical infection by any oncogenic HPVs and to evaluate duration of protection against incident cervical infection with HPV-16/18. Vaccine safety and immunogenicity over the 4-year follow-up were also evaluated. Methods: We randomized (3727 HPV arm; 3739 control arm), vaccinated (HPV-16/18 or Hepatitis A) and followed (median 53.8 months) 7466 healthy women aged 18-25 years. 5312 women (2635 HPV arm; 2677 control arm) were included in the according to protocol analysis for efficacy. The full cohort was evaluated for safety. Immunogenicity was considered on a subset of 354 (HPV-16) and 379 (HPV-18) women. HPV type was assessed by PCR on cervical specimens. Immunogenicity was assessed using ELISA and inhibition enzyme immunoassays. Disease outcomes were histologically confirmed. Vaccine efficacy and 95% confidence intervals (95%CI) were computed. Results: Vaccine efficacy was 89.8% (95% CI: 39.5-99.5; N = 11 events total) against HPV-16/18 associated CIN2+, 59.9% (95% CI: 20.7-80.8; N = 39 events total) against CIN2+ associated with non-HPV-16/18 oncogenic HPVs and 61.4% (95% CI: 29.5-79.8; N = 51 events total) against CIN2+ irrespective of HPV type. The vaccine had an acceptable safety profile and induced robust and long-lasting antibody responses. Conclusions: Our findings confirm the high efficacy and immunogenicity of the HPV-16/18 vaccine against incident HPV infections and cervical disease associated with HPV-16/18 and other oncogenic HPV types. These results will serve as a benchmark to which we can compare future findings from the ongoing extended follow-up of participants in the Costa Rica trial. Published by Elsevier Ltd. C1 [Hildesheim, Allan; Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Catteau, Gregory; Struyf, Frank] GlaxoSmithKline Vaccines, B-1300 Wavre, Belgium. [Dubin, Gary] GlaxoSmithKline SA, King Of Prussia, PA 19406 USA. [Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, Liberia, Costa Rica. RP Hildesheim, A (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM hildesha@exchange.nih.gov; wacholds@exchange.nih.gov; gregory.x.catteau@gsk.com; frank.struyf@gsk.com; Gary.O.Dubin@gsk.com; HerreroR@iarc.fr RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NCI [N01-CP-11005]; National Institutes of Health Office of Research on Women's Health; Ministry of Health of Costa Rica; US Food and Drug Administration [BB-IND 7920] FX The Costa Rica HPV vaccine trial is a long-standing collaboration between investigators in Costa Rica and the National Cancer Institute (NCI). The trial is sponsored and funded by the NCI (contract N01-CP-11005), with funding support from the National Institutes of Health Office of Research on Women's Health, and done with the support from the Ministry of Health of Costa Rica. Vaccine was provided for our trial by GlaxoSmithKline Biologicals, under a Clinical Trials Agreement with the NCI. GlaxoSmithKline Biologicals also provided support for aspects of the trial associated with regulatory submission needs of the company under US Food and Drug Administration BB-IND 7920. JTS and DRL report that they are named inventors on US Government-owned HPV vaccine patents that are licensed to GlaxoSmithKline and Merck. They are entitled to limited royalties as specified by federal law. Jerome Leemans, publications manager at Keyrus Biopharma (Belgium), coordinated the review/development process for this manuscript on behalf of GlaxoSmithKline Vaccines. NR 39 TC 23 Z9 23 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD SEP 3 PY 2014 VL 32 IS 39 BP 5087 EP 5097 DI 10.1016/j.vaccine.2014.06.038 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AO7UY UT WOS:000341559300030 PM 25018097 ER PT J AU Domthong, U Parikh, CR Kimmel, PL Chinchilli, VM AF Domthong, Uthumporn Parikh, Chirag R. Kimmel, Paul L. Chinchilli, Vernon M. CA Assessment Serial Evaluation TI Assessing the agreement of biomarker data in the presence of left-censoring SO BMC NEPHROLOGY LA English DT Article AB Background: In many clinical biomarker studies, Lin's concordance correlation coefficient (CCC) is commonly used to assess the level of agreement of a biomarker measured under two different conditions. However, measurement of a specific biomarker typically cannot provide accurate numerical values below the lower limit of detection (LLD) of the assay, which results in left-censored data. Most researchers discard the data below the LLD or apply simple data imputation methods in the presence of left-censored data, such as replacing values below the LLD with a fixed number less than or equal to the LLD. This is not statistically optimal, because it often leads to biased estimates and overestimates the precision. Methods: We describe a simple method using a bivariate normal distribution in this situation and apply SAS statistical software to arrive at the maximum likelihood (ML) estimate of the parameters and construct the estimate of the CCC. We conduct a computer simulation study to investigate the statistical properties of the ML method versus the data deletion and simple data imputation method. We also contrast the methods with real data using two urine biomarkers, Interleukin 18 and Cystatin C. Results: The computer simulation studies confirm that the ML procedure is superior to the data deletion and simple data imputation procedures. In all of the simulated scenarios, the ML method yields the smallest relative bias and the highest percentage of the 95% confidence intervals that include the true value of the CCC. In the first simulation scenario (sample size of 100 paired data points, 25% left-censoring for both members of the pair, true CCC of 0.238), the relative bias is -1.43% for the ML method, -40.97% for the data deletion method, and it ranges between -12.94% and -21.72% for the simple data imputation methods. Similarly, when the left-censoring for one of the members of the data pairs increases from 25% to 40%, the relative bias displays the same pattern for all methods. Conclusions: When estimating the CCC from paired biomarker data in the presence of left-censored values, the ML method works better than data deletion and simple data imputation methods. C1 [Domthong, Uthumporn; Chinchilli, Vernon M.] Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA 17033 USA. [Parikh, Chirag R.] Yale Univ, Sch Med, Dept Med, Nephrol Sect, New Haven, CT 06510 USA. [Parikh, Chirag R.] Yale Univ, Sch Med, Program Appl Translat Res, New Haven, CT USA. [Kimmel, Paul L.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Domthong, U (reprint author), Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA 17033 USA. EM uxd101@psu.edu FU National Institute of Digestive, Diabetes and Kidney Diseases of the National Institutes of Health, U.S. Department of Health and Human Services [U01DK082183]; NIH [K24DK090203] FX UD and VMC are supported by research grant U01DK082183 from the National Institute of Digestive, Diabetes and Kidney Diseases of the National Institutes of Health, U. S. Department of Health and Human Services. CRP is supported by the NIH grant K24DK090203. CRP is also member of the NIH-sponsored Assess, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury Consortium (U01DK082185). NR 6 TC 2 Z9 2 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD SEP 3 PY 2014 VL 15 AR 144 DI 10.1186/1471-2369-15-144 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AP0CA UT WOS:000341727300002 PM 25186769 ER PT J AU Su, ZM Zhang, YJ Gendron, TF Bauer, PO Chew, J Yang, WY Fostvedt, E Jansen-West, K Belzil, VV Desaro, P Johnston, A Overstreet, K Oh, SY Todd, PK Berry, JD Cudkowicz, ME Boeve, BF Dickson, D Floeter, MK Traynor, BJ Morelli, C Ratti, A Silani, V Rademakers, R Brown, RH Rothstein, JD Boylan, KB Petrucelli, L Disney, MD AF Su, Zhaoming Zhang, Yongjie Gendron, Tania F. Bauer, Peter O. Chew, Jeannie Yang, Wang-Yong Fostvedt, Erik Jansen-West, Karen Belzil, Veronique V. Desaro, Pamela Johnston, Amelia Overstreet, Karen Oh, Seok-Yoon Todd, Peter K. Berry, James D. Cudkowicz, Merit E. Boeve, Bradley F. Dickson, Dennis Floeter, Mary Kay Traynor, Bryan J. Morelli, Claudia Ratti, Antonia Silani, Vincenzo Rademakers, Rosa Brown, Robert H. Rothstein, Jeffrey D. Boylan, Kevin B. Petrucelli, Leonard Disney, Matthew D. TI Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS SO NEURON LA English DT Article ID C9ORF72 HEXANUCLEOTIDE REPEAT; G-QUADRUPLEX STRUCTURES; FRONTOTEMPORAL DEMENTIA; ANTISENSE TRANSCRIPTS; RNA FOCI; PROTEINS; EXPANSION; DISEASE; FORMS; ALS AB A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ ALS). RNA of the expanded repeat (r(GGGGCC)(exp)) forms nuclear foci or undergoes repeat-associated non-ATG (RAN) translation, producing "c9RAN proteins.'' Since neutralizing r(GGGGCC) exp could inhibit these potentially toxic events, we sought to identify small-molecule binders of r(GGGGCC) exp. Chemical and enzymatic probing of r(GGGGCC) 8 indicate that it adopts a hairpin structure in equilibrium with a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC) exp were designed and found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC) 66 and neurons transdifferentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RANproteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)(exp)-binding small molecules as a possible c9FTD/ALS therapeutic and suggest that c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)(exp). C1 [Su, Zhaoming; Yang, Wang-Yong; Fostvedt, Erik; Disney, Matthew D.] Scripps Florida, Scripps Res Inst, Dept Chem, Jupiter, FL 33458 USA. [Zhang, Yongjie; Gendron, Tania F.; Bauer, Peter O.; Chew, Jeannie; Jansen-West, Karen; Belzil, Veronique V.; Dickson, Dennis; Rademakers, Rosa; Petrucelli, Leonard] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Desaro, Pamela; Johnston, Amelia; Overstreet, Karen; Boylan, Kevin B.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Oh, Seok-Yoon; Todd, Peter K.] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA. [Berry, James D.; Cudkowicz, Merit E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Boeve, Bradley F.] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Floeter, Mary Kay] NINDS, Spast & Spinal Physiol Unit, NIH, Bethesda, MD 20892 USA. [Traynor, Bryan J.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Morelli, Claudia; Ratti, Antonia] IRCCS Ist Auxol Italiano, Dept Neurol & Lab Neurosci, I-20095 Milan, Italy. [Ratti, Antonia; Silani, Vincenzo] Univ Milan, Dino Ferrari Ctr, Dept Pathophysiol & Transplantat, I-20122 Milan, Italy. [Silani, Vincenzo; Brown, Robert H.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. [Rothstein, Jeffrey D.] Johns Hopkins Univ, Brain Sci Inst, Dept Neurol, Baltimore, MD 21205 USA. RP Petrucelli, L (reprint author), Mayo Clin, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM petrucelli.leonard@mayo.edu; disney@scripps.edu RI Su, Zhaoming/E-6146-2015; OI Dickson, Dennis W/0000-0001-7189-7917; Silani, Vincenzo/0000-0002-7698-3854 FU National Institutes of Health (NIH)/National Institute on Aging [R01GM097455, R01AG026251]; NIH/National Institute of Neurological Disorders and Stroke [R21NS074121, R21NS079807, R21NS084528, R01NS088689, R01NS063964, R01NS077402, R01NS050557]; ARRA Award [RC2-NS070-342, P01NS084974]; National Institute of Environmental Health Services [R01 ES20395]; Department of Defense [ALSRP AL130125]; Intramural Program of the NIH, the National Institute on Aging [Z01-AG000949- 02]; National Institute of Neurological Disorders and Stroke [Z01 NS002976-16]; Mayo Clinic Foundation; Mayo Clinic Center for Regenerative Medicine; Mayo Clinic Center for Individualized Medicine; ALS Association; Alzheimer's Association; Robert Packard Center for ALS Research at Johns Hopkins; Target ALS; Canadian Institutes of Health Research; Siragusa Foundation; Robert and Clarice Smith & Abigail Van Buren Alzheimer's Disease Research Foundation; Digiovanni Sundry Fund; ATA; Project ALS; Angel Fund; Italian Ministry of Health [RF-2009-1473856]; European Commission; FRAXA Research Foundation FX We are grateful to patients who donated CSF, skin samples, and postmortem tissue. We acknowledge Lillian Daughrity, Luc Pregent, and Mary Davis for technical support, Dr. Xiangming Kong for help with 1D 1H NMR experiments. This work was supported by the National Institutes of Health (NIH)/National Institute on Aging (R01GM097455 [M. D. D.]; R01AG026251 [L. P.]); NIH/National Institute of Neurological Disorders and Stroke (R21NS074121 [K. B. B., T. F. G.], R21NS079807 [Y. Z.], R21NS084528 [L. P.], R01NS088689 [R. H. B., L. P.], R01NS063964 [L. P.]; R01NS077402 [L. P.]; R01NS050557 [R. H. B.]; ARRA Award RC2-NS070-342 [R. H. B.], P01NS084974 [L. P., D. D., R. R., K. B. B.]); National Institute of Environmental Health Services (R01 ES20395 [L. P.]); Department of Defense (ALSRP AL130125 [L. P., M. D. D.]); the Intramural Program of the NIH, the National Institute on Aging (Z01-AG000949- 02 [B. J. T.]), and the National Institute of Neurological Disorders and Stroke (Z01 NS002976-16 to M. F. K. and B. J. T.); Mayo Clinic Foundation (L. P.); Mayo Clinic Center for Regenerative Medicine (P. O. B.), Mayo Clinic Center for Individualized Medicine (T. F. G., L. P., K. B. B.), ALS Association (K. B. B., P. O. B., L. P., T. F. G., Y. Z., and M. E. D.), Alzheimer's Association (Y. Z.), Robert Packard Center for ALS Research at Johns Hopkins (L. P., J. D. R.), Target ALS (L. P., M. D. D.), Canadian Institutes of Health Research (V. V. B.), Siragusa Foundation (V. V. B.), Robert and Clarice Smith & Abigail Van Buren Alzheimer's Disease Research Foundation (V. V. B.), Digiovanni Sundry Fund (M. E. D.), ATA (M. E. D.), Project ALS (R. H. B.), Angel Fund (R. H. B.), AriSLA cofinanced with support of '5x1000'-Healthcare research of the Italian Ministry of Health (grants EXOMEFALS 2009 [V. S.] and NOVALS 2012 [V. S.]), the Italian Ministry of Health (RF-2009-1473856 [C. M., A. R., V. S.]), and the European Commission (JNPD SOPHIA and STRENGTH [C. M., A. R., V. S.]). Z. S. and V. B. are Milton Safenowitz Postdoctoral Fellows funded by the ALS Association. W-Y. Y is a FRAXA Postdoctoral Fellow funded by FRAXA Research Foundation. Antibodies to c9RAN proteins have been licensed to a commercial entity. R. R. holds a patent on methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene. NR 22 TC 71 Z9 71 U1 3 U2 33 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 SEP 3 PY 2014 VL 83 IS 5 BP 1043 EP 1050 DI 10.1016/j.neuron.2014.07.041 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AO5XB UT WOS:000341419000008 PM 25132468 ER PT J AU Dean, DA Adler, GK Nguyen, DP Klerman, EB AF Dean, Dennis A., II Adler, Gail K. Nguyen, David P. Klerman, Elizabeth B. TI Biological Time Series Analysis Using a Context Free Language: Applicability to Pulsatile Hormone Data SO PLOS ONE LA English DT Article ID SECRETORY ACTIVITY; CIRCADIAN-RHYTHMS; STATISTICAL-MODEL; GROWTH-HORMONE; CORTISOL; SLEEP; AXIS; DECONVOLUTION; DEPRESSION; LIGHT AB We present a novel approach for analyzing biological time-series data using a context-free language (CFL) representation that allows the extraction and quantification of important features from the time-series. This representation results in Hierarchically AdaPtive (HAP) analysis, a suite of multiple complementary techniques that enable rapid analysis of data and does not require the user to set parameters. HAP analysis generates hierarchically organized parameter distributions that allow multi-scale components of the time-series to be quantified and includes a data analysis pipeline that applies recursive analyses to generate hierarchically organized results that extend traditional outcome measures such as pharmacokinetics and inter-pulse interval. Pulsicons, a novel text-based time-series representation also derived from the CFL approach, are introduced as an objective qualitative comparison nomenclature. We apply HAP to the analysis of 24 hours of frequently sampled pulsatile cortisol hormone data, which has known analysis challenges, from 14 healthy women. HAP analysis generated results in seconds and produced dozens of figures for each participant. The results quantify the observed qualitative features of cortisol data as a series of pulse clusters, each consisting of one or more embedded pulses, and identify two ultradian phenotypes in this dataset. HAP analysis is designed to be robust to individual differences and to missing data and may be applied to other pulsatile hormones. Future work can extend HAP analysis to other time-series data types, including oscillatory and other periodic physiological signals. C1 [Dean, Dennis A., II; Klerman, Elizabeth B.] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, Boston, MA 02115 USA. [Dean, Dennis A., II] MIT, Neurosci Stat Res Lab, Cambridge, MA 02139 USA. [Dean, Dennis A., II] Univ Massachusetts, Biomed Engn & Biotechnol Program, Lowell, MA USA. [Dean, Dennis A., II; Adler, Gail K.; Klerman, Elizabeth B.] Harvard Univ, Sch Med, Boston, MA USA. [Adler, Gail K.; Klerman, Elizabeth B.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Nguyen, David P.] NIA, NIH, Baltimore, MD 21224 USA. RP Dean, DA (reprint author), Brigham & Womens Hosp, Div Sleep & Circadian Disorders, 75 Francis St, Boston, MA 02115 USA. EM ddean@research.bwh.harvard.edu FU AFOSR [F49620-95-1-0388, FA9550-06-0080]; NIH [NCRR-GCRC-M01-RR-02635, P01-AG09975, T32 HL07901-10, F31-GM095340-01, K24-HL105664, K02-HD045459, RC2-HL101340, R01-AR43130, K24-HL103845, R01-MH071847, R01 HL098433, R01 HL098433-02S1]; NSBRI through NASA NCC [9-58 HFP01603, HPF00405] FX This work received funding from the following sources: AFOSR F49620-95-1-0388, FA9550-06-0080; NIH NCRR-GCRC-M01-RR-02635, P01-AG09975, T32 HL07901-10 (DAD), F31-GM095340-01 (DAD), K24-HL105664 (EBK), K02-HD045459 (EBK), RC2-HL101340, R01-AR43130 (GKA), K24-HL103845 (GKA), R01-MH071847, R01 HL098433, and R01 HL098433-02S1(DAD), NSBRI through NASA NCC 9-58 HFP01603 and HPF00405. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 0 Z9 0 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 3 PY 2014 VL 9 IS 9 AR e104087 DI 10.1371/journal.pone.0104087 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3TB UT WOS:000341257700008 PM 25184442 ER PT J AU Liu, HN Gao, LD Chowell, G Hu, SX Lin, XL Li, XJ Ma, GH Huang, R Yang, HS Tian, HY Xiao, H AF Liu, Hai-Ning Gao, Li-Dong Chowell, Gerardo Hu, Shi-Xiong Lin, Xiao-Ling Li, Xiu-Jun Ma, Gui-Hua Huang, Ru Yang, Hui-Suo Tian, Huaiyu Xiao, Hong TI Time-Specific Ecologic Niche Models Forecast the Risk of Hemorrhagic Fever with Renal Syndrome in Dongting Lake District, China, 2005-2010 SO PLOS ONE LA English DT Article ID HANTAVIRUS PULMONARY SYNDROME; REPUBLIC-OF-CHINA; NEPHROPATHIA-EPIDEMICA; TEMPORAL DYNAMICS; HANTAAN VIRUS; PREDICTION; INFECTION; AREAS; DISTRIBUTIONS; TRANSMISSION AB Background: Hemorrhagic fever with renal syndrome (HFRS), a rodent-borne infectious disease, is one of the most serious public health threats in China. Increasing our understanding of the spatial and temporal patterns of HFRS infections could guide local prevention and control strategies. Methodology/Principal Findings: We employed statistical models to analyze HFRS case data together with environmental data from the Dongting Lake district during 2005-2010. Specifically, time-specific ecologic niche models (ENMs) were used to quantify and identify risk factors associated with HFRS transmission as well as forecast seasonal variation in risk across geographic areas. Results showed that the Maximum Entropy model provided the best predictive ability (AUC = 0.755). Time-specific Maximum Entropy models showed that the potential risk areas of HFRS significantly varied across seasons. High-risk areas were mainly found in the southeastern and southwestern areas of the Dongting Lake district. Our findings based on models focused on the spring and winter seasons showed particularly good performance. The potential risk areas were smaller in March, May and August compared with those identified for June, July and October to December. Both normalized difference vegetation index (NDVI) and land use types were found to be the dominant risk factors. Conclusions/Significance: Our findings indicate that time-specific ENMs provide a useful tool to forecast the spatial and temporal risk of HFRS. C1 [Liu, Hai-Ning; Lin, Xiao-Ling; Ma, Gui-Hua; Huang, Ru; Tian, Huaiyu; Xiao, Hong] Hunan Normal Univ, Coll Resources & Environm Sci, Changsha, Peoples R China. [Gao, Li-Dong; Hu, Shi-Xiong] Hunan Prov Ctr Dis Control & Prevent, Changsha, Peoples R China. [Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Simon A Levin Math Computat & Modeling Sci Ctr, Tempe, AZ USA. [Li, Xiu-Jun] Shandong Univ, Sch Publ Hlth, Jinan 250100, Peoples R China. [Yang, Hui-Suo] Ctr Dis Control & Prevent Beijing Mil Reg, Beijing, Peoples R China. RP Xiao, H (reprint author), Hunan Normal Univ, Coll Resources & Environm Sci, Changsha, Peoples R China. EM xiaohong.hnnu@gmail.com RI Tian, Huaiyu/G-1934-2016 FU Hunan Provincial Education Department [13A051]; Construct Program of the Key Discipline in Hunan Province, China; National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health [1R01GM100471-01] FX This research was supported by the Scientific Research Fund of Hunan Provincial Education Department (13A051) (http://gov.hnedu.cn/), Construct Program of the Key Discipline in Hunan Province (http://gov.hnedu.cn/), China. G.C. acknowledges support from grant number 1R01GM100471-01 from the National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health (http://www.nigms.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 2 Z9 2 U1 1 U2 18 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 SEP 3 PY 2014 VL 9 IS 9 AR e106839 DI 10.1371/journal.pone.0106839 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3TB UT WOS:000341257700124 PM 25184252 ER PT J AU Yang, XX Morris, SM Gearhart, JM Ruark, CD Paule, MG Slikker, W Mattison, DR Vitiello, B Twaddle, NC Doerge, DR Young, JF Fisher, JW AF Yang, Xiaoxia Morris, Suzanne M. Gearhart, Jeffery M. Ruark, Christopher D. Paule, Merle G. Slikker, William, Jr. Mattison, Donald R. Vitiello, Benedetto Twaddle, Nathan C. Doerge, Daniel R. Young, John F. Fisher, Jeffrey W. TI Development of a Physiologically Based Model to Describe the Pharmacokinetics of Methylphenidate in Juvenile and Adult Humans and Nonhuman Primates SO PLOS ONE LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; SINGLE-DOSE PHARMACOKINETICS; DL-THREO-METHYLPHENIDATE; DEFICIT HYPERACTIVITY DISORDER; MASS-SPECTROMETRIC ANALYSIS; ROUTE DEPENDENT DOSIMETRY; RELEASE METHYLPHENIDATE; HEALTHY-SUBJECTS; RITALINIC ACID; RHESUS-MONKEYS AB The widespread usage of methylphenidate (MPH) in the pediatric population has received considerable attention due to its potential effect on child development. For the first time a physiologically based pharmacokinetic (PBPK) model has been developed in juvenile and adult humans and nonhuman primates to quantitatively evaluate species-and age-dependent enantiomer specific pharmacokinetics of MPH and its primary metabolite ritalinic acid. The PBPK model was first calibrated in adult humans using in vitro enzyme kinetic data of MPH enantiomers, together with plasma and urine pharmacokinetic data with MPH in adult humans. Metabolism of MPH in the small intestine was assumed to account for the low oral bioavailability of MPH. Due to lack of information, model development for children and juvenile and adult nonhuman primates primarily relied on intra-and interspecies extrapolation using allometric scaling. The juvenile monkeys appear to metabolize MPH more rapidly than adult monkeys and humans, both adults and children. Model prediction performance is comparable between juvenile monkeys and children, with average root mean squared error values of 4.1 and 2.1, providing scientific basis for interspecies extrapolation of toxicity findings. Model estimated human equivalent doses in children that achieve similar internal dose metrics to those associated with pubertal delays in juvenile monkeys were found to be close to the therapeutic doses of MPH used in pediatric patients. This computational analysis suggests that continued pharmacovigilance assessment is prudent for the safe use of MPH. C1 [Yang, Xiaoxia; Morris, Suzanne M.; Paule, Merle G.; Slikker, William, Jr.; Twaddle, Nathan C.; Doerge, Daniel R.; Young, John F.; Fisher, Jeffrey W.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Gearhart, Jeffery M.; Ruark, Christopher D.] Henry M Jackson Fdn Adv Mil Med, Wright Patterson AFB, OH USA. [Mattison, Donald R.] Risk Sci Int, Ottawa, ON, Canada. [Mattison, Donald R.] Univ Ottawa, Ottawa, ON, Canada. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. RP Yang, XX (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM xiaoxia.yang@fda.hhs.gov OI Ruark, Christopher/0000-0003-1032-5696; Mattison, Donald/0000-0001-5623-0874 FU NCTR/FDA; FDA Commissioner's Program FX This work was supported by NCTR/FDA and the FDA Commissioner's Program. These sponsors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views presented here do not necessarily reflect the position or opinions of the FDA/NIH nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the views of the FDA/NIH. NR 108 TC 5 Z9 5 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 3 PY 2014 VL 9 IS 9 AR e106101 DI 10.1371/journal.pone.0106101 PG 30 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3TB UT WOS:000341257700031 PM 25184666 ER PT J AU Dix, AV Moss, SM Phan, K Hoppe, T Paoletta, S Kozma, E Gao, ZG Durell, SR Jacobson, KA Appella, DH AF Dix, Andrew V. Moss, Steven M. Phan, Khai Hoppe, Travis Paoletta, Silvia Kozma, Eszter Gao, Zhan-Guo Durell, Stewart R. Jacobson, Kenneth A. Appella, Daniel H. TI Programmable Nanoscaffolds That Control Ligand Display to a G-Protein-Coupled Receptor in Membranes To Allow Dissection of Multivalent Effects SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ADENOSINE A(2A) RECEPTOR; PEPTIDE NUCLEIC-ACID; GPCR DIMERS; CRYSTAL-STRUCTURE; BIVALENT LIGANDS; AMINE CONGENER; BINDING; ANTAGONIST; AGONIST; 1,3-DIPROPYL-8-PHENYLXANTHINE AB A programmable ligand display system can be used to dissect the multivalent effects of ligand binding to a membrane receptor. An antagonist of the A(2A) adenosine receptor, a G-protein-coupled receptor that is a drug target for neurodegenerative conditions, was displayed in 35 different multivalent configurations, and binding to A(2A) was determined. A theoretical model based on statistical mechanics was developed to interpret the binding data, suggesting the importance of receptor dimers. Using this model, extended multivalent arrangements of ligands were constructed with progressive improvements in binding to A. The results highlight the ability to use a highly controllable multivalent approach to determine optimal ligand valency and spacing that can be subsequently optimized for binding to a membrane receptor. Models explaining the multivalent binding data are also presented. C1 [Dix, Andrew V.; Moss, Steven M.; Phan, Khai; Paoletta, Silvia; Kozma, Eszter; Gao, Zhan-Guo; Jacobson, Kenneth A.; Appella, Daniel H.] NIDDK, Lab Bioorgan Chem, Bethesda, MD 20892 USA. [Hoppe, Travis] NIDDK, Lab Biochem & Genet, Bethesda, MD 20892 USA. [Durell, Stewart R.] NCI, Cell Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. RP Appella, DH (reprint author), NIDDK, Lab Bioorgan Chem, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Hoppe, Travis/0000-0002-4694-3050 FU Intramural Research Program of NIDDK, NIH FX This research was supported by the Intramural Research Program of NIDDK, NIH. We gratefully acknowledge Dr. John Lloyd and the mass spectrometry core facility of NIDDK for analysis of all PNA samples. This study utilized the high-performance computational capabilities of the Biowulf Linux duster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). We also thank George Lieman and Lisa Jenkins for review and comments on the manuscript. NR 48 TC 10 Z9 10 U1 0 U2 33 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 3 PY 2014 VL 136 IS 35 BP 12296 EP 12303 DI 10.1021/ja504288s PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA AO3JR UT WOS:000341226000021 PM 25116377 ER PT J AU Resnik, DB Stewart, CN AF Resnik, David B. Stewart, C. Neal, Jr. TI Expanding the Scope of Responsible Conduct of Research Instruction SO ACCOUNTABILITY IN RESEARCH-POLICIES AND QUALITY ASSURANCE LA English DT Article DE trainees; ethics; education; responsible conduct of research; integrity; instruction; faculty; students; staff ID ORGANIZATIONAL JUSTICE; RESEARCH MISCONDUCT; RESEARCH INTEGRITY; NATIONAL-SURVEY AB We argue that responsible conduct research (RCR) instruction should be extended beyond students and trainees funded by the National Institutes of Health (NIH) or National Science Foundation (NSF) to include all students, trainees, faculty, and research staff involved in research. Extending the scope of RCR instruction can help institutions develop and maintain an environment that promotes ethical research conduct. Universities and scientific organizations have objected to expanding the scope of RCR instruction on the grounds that it would be a major undertaking that would require the expenditure of additional institutional resources. We argue, however, that expanding the scope of RCR instruction can be done efficiently without placing undue burdens on institutions. C1 [Resnik, David B.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Stewart, C. Neal, Jr.] Univ Tennessee, Knoxville, KY USA. RP Resnik, DB (reprint author), NIEHS, NIH, 111 Alexander Dr,Box 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov NR 20 TC 0 Z9 0 U1 4 U2 29 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 SEP 3 PY 2014 VL 21 IS 5 BP 321 EP 327 DI 10.1080/08989621.2013.848802 PG 7 WC Medical Ethics SC Medical Ethics GA AE4WB UT WOS:000333985900004 PM 24625184 ER PT J AU Blaszczyk, J Lu, ZW Li, Y Yan, HG Ji, XH AF Blaszczyk, Jaroslaw Lu, Zhenwei Li, Yue Yan, Honggao Ji, Xinhua TI Crystallographic and molecular dynamics simulation analysis of Escherichia coli dihydroneopterin aldolase SO CELL AND BIOSCIENCE LA English DT Article DE Dihydroneopterin aldolase; DHNA; Structure; Dynamics; Catalysis ID ANTIBACTERIAL DRUG DISCOVERY; STAPHYLOCOCCUS-AUREUS; CRYSTAL-STRUCTURE; 7,8-DIHYDRONEOPTERIN ALDOLASE; PLASMODIUM-FALCIPARUM; FOLIC-ACID; BIOSYNTHESIS; MECHANISM; RESISTANCE; INHIBITORS AB Background: Dihydroneopterin aldolase (DHNA) catalyzes the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin and also the epimerization of DHNP to 7,8-dihydromonapterin. Previously, we determined the crystal structure of Staphylococcus aureus DHNA (SaDHNA) in complex with the substrate analogue neopterin (NP). We also showed that Escherichia coli DHNA (EcDHNA) and SaDHNA have significantly different binding and catalytic properties by biochemical analysis. On the basis of these structural and functional data, we proposed a catalytic mechanism involving two proton wires. Results: To understand the structural basis for the biochemical differences and further investigate the catalytic mechanism of DHNA, we have determined the structure of EcDHNA complexed with NP at 1.07-angstrom resolution[PDB:2O90], built an atomic model of EcDHNA complexed with the substrate DHNP, and performed molecular dynamics (MD) simulation analysis of the substrate complex. EcDHNA has the same fold as SaDHNA and also forms an octamer that consists of two tetramers, but the packing of one tetramer with the other is significantly different between the two enzymes. Furthermore, the structures reveal significant differences in the vicinity of the active site, particularly in the loop that connects strands beta 3 and beta 4, mainly due to the substitution of nearby residues. The building of an atomic model of the complex of EcDHNA and the substrate DHNP and the MD simulation of the complex show that some of the hydrogen bonds between the substrate and the enzyme are persistent, whereas others are transient. The substrate binding model and MD simulation provide the molecular basis for the biochemical behaviors of the enzyme, including noncooperative substrate binding, indiscrimination of a pair of epimers as the substrates, proton wire switching during catalysis, and formation of epimerization product. Conclusions: The EcDHNA and SaDHNA structures, each in complex with NP, reveal the basis for the biochemical differences between EcDHNA and SaDHNA. The atomic substrate binding model and MD simulation offer insights into substrate binding and catalysis by DHNA. The EcDHNA structure also affords an opportunity to develop antimicrobials specific for Gram-negative bacteria, as DHNAs from Gram-negative bacteria are highly homologous and E. coli is a representative of this class of bacteria. C1 [Blaszczyk, Jaroslaw; Ji, Xinhua] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Blaszczyk, Jaroslaw; Lu, Zhenwei; Li, Yue; Yan, Honggao] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. RP Yan, HG (reprint author), Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. EM yanh@msu.edu; jix@mail.nih.gov FU NIH [GM51901]; NIH, National Cancer Institute, Center for Cancer Research FX We thank Zbigniew Dauter for assistance during data collection and processing. The X-ray diffraction data were collected at the X9B beamline of National Synchrotron Light Source at Brookhaven National Laboratory. This research was supported by the NIH grant GM51901 (to HY) and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to XJ). NR 43 TC 2 Z9 3 U1 2 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD SEP 2 PY 2014 VL 4 AR 52 DI 10.1186/2045-3701-4-52 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AR8HX UT WOS:000343817300001 PM 25264482 ER PT J AU Huang, B Huang, SG Su, XZ Tong, XX Yan, JP Li, HB Lu, FL AF Huang, Bo Huang, Shiguang Su, Xin-Zhuan Tong, Xinxin Yan, Junping Li, Hongbin Lu, Fangli TI Molecular surveillance of pvdhfr, pvdhps, and pvmdr-1 mutations in Plasmodium vivax isolates from Yunnan and Anhui provinces of China SO MALARIA JOURNAL LA English DT Article DE Plasmodium vivax; Polymorphism; Drug resistance markers; China ID RESISTANCE-ASSOCIATED MUTATIONS; DIHYDROFOLATE-REDUCTASE GENE; AMINO-ACID MUTATIONS; DRUG-RESISTANCE; SULFADOXINE-PYRIMETHAMINE; DIHYDROPTEROATE SYNTHASE; ANOPHELES-SINENSIS; MALARIA; CHLOROQUINE; DHFR AB Background: Plasmodium vivax is the predominant species of human malaria parasites present in China. Although sulphadoxine-pyrimethamine (SP) and chloroquine (CQ) have been widely used for malaria treatment in China, the resistance profiles of these drugs are not available. Analysis of dihydrofolate reductase (dhfr), dihydropteroate synthase (dhps), and multidrug resistance (mdr-1) gene mutations in P. vivax isolates is a valuable molecular approach for mapping resistance to SP and CQ. This study investigates the prevalence of pvdhfr, pvdhps, and pvmdr-1 of P. vivax clinical isolates from China and provides baseline molecular epidemiologic data on SP- and CQ-associated resistance in P. vivax. Methods: Plasmodium vivax clinical isolates were collected from two malaria-endemic regions of China, subtropical (Xishuangbanna, Yunnan province) and temperate (Bozhou, Anhui province), from 2009 to 2012. All isolates were analysed for single nucleotide polymorphism haplotypes in pvdhfr, pvdhps, and pvmdr-1 using direct DNA sequencing. Results: In pvdhfr, 15% of Xishuangbanna isolates carried wild-type (WT) allele, whereas the majority of isolates carried mutant genes with substitutions at five codons. Eight mutant haplotypes of pvdhfr were detected, while limited polymorphism of pvdhfr was found in Bozhou isolates. A size polymorphism was present in pvdhfr, with the three-repeat type being the most predominate in both Xishuangbanna (79%) and Bozhou (97%) isolates. In pvdhps, mutations at four codons were detected in Xishuangbanna isolates leading to six haplotypes, including WT allele, single-mutation, double-mutation, and triple-mutation alleles. All Bozhou isolates carried WT pvhdps. In pvmdr-1, isolates from Xishuangbanna carried mutations at codons Y976F and F1076L, whereas all isolates from Bozhou had only a single mutation at codon F1076L. Conclusions: Plasmodium vivax isolates from subtropical and temperate zones of China are shown to have dramatically different frequencies and patterns of mutations in pvdhfr, pvdhps, and pvmdr-1. Whereas P. vivax populations in subtropical China are highly resistant to SP and CQ, those in the temperate zone may still be susceptible to SP and CQ. This information is useful for establishing treatment policy and provides a baseline for molecular surveillance of drug-resistant P. vivax in these areas. C1 [Huang, Bo; Tong, Xinxin; Yan, Junping; Lu, Fangli] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Parasitol, Guangzhou 510080, Guangdong, Peoples R China. [Huang, Bo; Tong, Xinxin; Yan, Junping; Lu, Fangli] Sun Yat Sen Univ, Key Lab Trop Dis Control, Minist Educ, Guangzhou 510080, Guangdong, Peoples R China. [Huang, Shiguang] Jinan Univ, Sch Med, Guangzhou 510632, Guangdong, Peoples R China. [Su, Xin-Zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Su, Xin-Zhuan] Xiamen Univ, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China. [Li, Hongbin] Xishuangbanna CDC, Jinghong 666100, Yunnan, Peoples R China. RP Lu, FL (reprint author), Sun Yat Sen Univ, Zhongshan Sch Med, Dept Parasitol, Guangzhou 510080, Guangdong, Peoples R China. EM fanglilu@yahoo.com OI Su, Xinzhuan/0000-0003-3246-3248 FU Fogarty International Center of the National Institutes of Health (NIH, USA) [R01TW008151]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX We thank Brenda Rae Marshall, DPSS, NIAID, for editing. This research was supported by the Fogarty International Center of the National Institutes of Health (NIH, USA) under Award Number R01TW008151, and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 51 TC 0 Z9 0 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD SEP 2 PY 2014 VL 13 AR 346 DI 10.1186/1475-2875-13-346 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AP5EW UT WOS:000342103500001 PM 25179752 ER PT J AU Behrens, G Matthews, CE Moore, SC Hollenbeck, AR Leitzmann, MF AF Behrens, Gundula Matthews, Charles E. Moore, Steven C. Hollenbeck, Albert R. Leitzmann, Michael F. TI Body size and physical activity in relation to incidence of chronic obstructive pulmonary disease SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Article ID LUNG-FUNCTION DECLINE; RESPIRATORY-FUNCTION; WAIST CIRCUMFERENCE; ADIPOSE-TISSUE; ELDERLY-MEN; MASS INDEX; COPD; POPULATION; RISK; FAT AB Background: Limited evidence suggests that adiposity and lack of physical activity may increase the risk of chronic obstructive pulmonary disease (COPD). We investigated the relation of body size and physical activity with incidence of COPD. Methods: We obtained data on anthropometric measurements and physical activity from 113 279 participants in the National Institutes of Health-AARP Diet and Health Study who reported no diagnosis of COPD at baseline (1995-1996). We estimated associations between these measurements and subsequent diagnosis of COPD between 1996 and 2006, with extensive adjustment for smoking and other potentially confounding variables. Results: Participants reported 3648 new COPD diagnoses during follow-up. The incidence of COPD was higher in both severely obese (body mass index [BMI]D 35) and underweight (BMID< 18.5) participants, but after adjustment for waist circumference, only underweight remained positively associated with COPD (relative risk [RR]D1.56, 95% confidence interval [CI]D1.15-2.11). Larger waist circumference (highest v. normal categories, adjusted RRD1.72, 95% CID1.37-2.16) and higher waist-hip ratio (highest v. normal categories, adjusted RRD1.46, 95% CID1.23-1.73) were also positively associated with COPD. In contrast, hip circumference (highest v. normal categories, adjusted RR 0.78, 95% CI 0.62-0.98) and physical activity ( 5 v. 0 times/wk, adjusted RRD0.71, 95% CID0.63-0.79) were inversely associated with COPD. Interpretation: Obesity, in particular abdominal adiposity, was associated with an increased risk of COPD, and increased hip circumference and physical activity were associated with a decreased risk of COPD. These findings suggest that following guidelines for a healthy body weight, body shape and physical activity decrease the risk of COPD. C1 [Behrens, Gundula; Leitzmann, Michael F.] Univ Regensburg, Dept Epidemiol & Prevent Med, D-93053 Regensburg, Germany. [Matthews, Charles E.; Moore, Steven C.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Behrens, G (reprint author), Univ Regensburg, Dept Epidemiol & Prevent Med, D-93053 Regensburg, Germany. EM gundula.behrens@klinik.uni-regensburg.de RI matthews, Charles/E-8073-2015; Moore, Steven/D-8760-2016; OI matthews, Charles/0000-0001-8037-3103; Moore, Steven/0000-0002-8169-1661; Behrens, Gundula/0000-0002-9355-6491 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX This research was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 43 TC 4 Z9 4 U1 0 U2 9 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 0820-3946 EI 1488-2329 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD SEP 2 PY 2014 VL 186 IS 12 BP E457 EP E469 DI 10.1503/cmaj.140025 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA AP0MZ UT WOS:000341757500011 PM 25002559 ER PT J AU Cypess, AM Haft, CR Laughlin, MR Hu, HCH AF Cypess, Aaron M. Haft, Carol R. Laughlin, Maren R. Hu, Houchun H. TI Brown Fat in Humans: Consensus Points and Experimental Guidelines SO CELL METABOLISM LA English DT Review ID ADIPOSE-TISSUE THERMOGENESIS; ADULT HUMANS; SUPRACLAVICULAR REGION; ENERGY-EXPENDITURE; BLOOD-FLOW; COLD; ACTIVATION; TEMPERATURE; METABOLISM; ADIPOGENESIS AB As part of a current worldwide effort to understand the physiology of human BAT (hBAT) and whether its thermogenic activity can be manipulated to treat obesity, the workshop "Exploring the Roles of Brown Fat in Humans'' was convened at the National Institutes of Health on February 25-26, 2014. Presentations and discussion indicated that hBAT and its physiological roles are highly complex, and research is needed to understand the health impact of hBAT beyond thermogenesis and body weight regulation, and to define its interactions with core physiological processes like glucose homeostasis, cachexia, physical activity, bone structure, sleep, and circadian rhythms. C1 [Cypess, Aaron M.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Haft, Carol R.; Laughlin, Maren R.] NIDDK, NIH, Bethesda, MD 20892 USA. [Hu, Houchun H.] Childrens Hosp Los Angeles, Dept Radiol, Los Angeles, CA 90027 USA. RP Haft, CR (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM haftc@extra.niddk.nih.gov; maren.laughlin@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; Chugai Pharmaceutical Co., Ltd. through Joslin Diabetes Center; Molecular Metabolism, LLC through Joslin Diabetes Center FX We would like to thank the presenters and attendees of the workshop for their outstanding research and insightful discussion, and the National Institute of Diabetes and Digestive and Kidney Diseases for sponsorship. Special thanks go to Drs. Barbara Cannon, Kong Chen, Rebecca Brown, and Bruce Spiegelman for their insight and helpful comments. A. M. C. is a recipient of sponsored research grants from Chugai Pharmaceutical Co., Ltd., and Molecular Metabolism, LLC, both through Joslin Diabetes Center. NR 55 TC 39 Z9 41 U1 1 U2 30 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 SEP 2 PY 2014 VL 20 IS 3 BP 408 EP 415 DI 10.1016/j.cmet.2014.07.025 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA AO5RL UT WOS:000341402800007 PM 25185947 ER PT J AU Cheng, S Claggett, B Correia, AW Shah, AM Gupta, DK Skali, H Ni, HY Rosamond, WD Heiss, G Folsom, AR Coresh, J Solomon, SD AF Cheng, Susan Claggett, Brian Correia, Andrew W. Shah, Amil M. Gupta, Deepak K. Skali, Hicham Ni, Hanyu Rosamond, Wayne D. Heiss, Gerardo Folsom, Aaron R. Coresh, Josef Solomon, Scott D. TI Temporal Trends in the Population Attributable Risk for Cardiovascular Disease The Atherosclerosis Risk in Communities Study SO CIRCULATION LA English DT Article DE cardiovascular diseases; ethnicity; gender; prevention; race; risk factors ID CORONARY-HEART-DISEASE; ACUTE MYOCARDIAL-INFARCTION; UNITED-STATES ADULTS; BODY-MASS INDEX; BLOOD-PRESSURE; US ADULTS; PROSPECTIVE COHORT; WOMEN; MORTALITY; PREVALENCE AB Background The extent to which the relative contributions of traditional cardiovascular risk factors to incident cardiovascular disease (CVD) may have changed over time remains unclear. Methods and Results We studied 13 541 participants (56% women, 26% black) in the Atherosclerosis Risk in Communities Study, aged 52 to 66 years and free of CVD at exams in 1987 through 1989, 1990 through 1992, 1993 through 1995, or 1996 through 1998. At each examination, we estimated the population attributable risks (PAR) of traditional risk factors (hypertension, diabetes mellitus, obesity, hypercholesterolemia, and smoking) for the 10-year incidence of CVD. Overall, the PAR of all risk factors combined appeared to decrease from the late 1980s to the late 1990s (0.58 to 0.53). The combined PAR was higher in women than men in 1987 through 1989 (0.68 versus 0.51, P<0.001) but not by the late 1990s (0.58 versus 0.48, P=0.08). The combined PAR was higher in blacks than whites in the late 1980s (0.67 versus 0.57, P=0.049), and this difference was more pronounced by the late 1990s (0.67 versus 0.48, P=0.002). By the late 1990s, the PAR of hypertension had become higher in women than men (P=0.02) and also appeared higher in blacks than whites (P=0.08). By the late 1990s, the PAR of diabetes mellitus remained higher in women than men (P<0.0001) and in blacks than whites (P<0.0001). Conclusions The contribution to CVD of all traditional risk factors combined is greater in blacks than whites, and this difference may be increasing. The contributions of hypertension and diabetes mellitus remain especially high, in women as well as blacks. These findings underscore the continued need for individual as well as population approaches to CVD risk factor modification. C1 [Cheng, Susan; Claggett, Brian; Shah, Amil M.; Gupta, Deepak K.; Skali, Hicham; Solomon, Scott D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. [Correia, Andrew W.] NMR Grp Inc, Somerville, MA USA. [Ni, Hanyu] NHLBI, NIH, Bethesda, MD 20892 USA. [Rosamond, Wayne D.; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Coresh, Josef] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Cheng, S (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM scheng@rics.bwh.harvard.edu OI Skali, Hicham/0000-0002-5629-4138 FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100 008C, HHSN268201100009C, HHSN268201100010C, HHSN268 201100011C, HHSN268201100012C]; Ellison Foundation [R00-HL-107642]; [K08-HL-116792] FX The ARIC Study is a collaborative study supported by National Heart, Lung, and Blood Institute contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100 008C, HHSN268201100009C, HHSN268201100010C, HHSN268 201100011C, and HHSN268201100012C. Dr Cheng is supported in part by R00-HL-107642 and a grant from the Ellison Foundation. Dr Shah is supported in part by K08-HL-116792. NR 47 TC 27 Z9 27 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 2 PY 2014 VL 130 IS 10 BP 820 EP 828 DI 10.1161/CIRCULATIONAHA.113.008506 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AO9PW UT WOS:000341689100009 PM 25210095 ER PT J AU Menke, A Rust, KF Fradkin, J Cheng, YLJ Cowie, CC AF Menke, Andy Rust, Keith F. Fradkin, Judith Cheng, Yiling J. Cowie, Catherine C. TI Associations Between Trends in Race/Ethnicity, Aging, and Body Mass Index With Diabetes Prevalence in the United States A Series of Cross-sectional Studies SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID US ADULTS; NATIONAL-HEALTH; PHYSICAL-ACTIVITY; SECULAR CHANGES; AIR-POLLUTION; LIFE-STYLE; OBESITY; MELLITUS; COHORT; ADJUSTMENT AB Background: The increase in the prevalence of diabetes over the past few decades has coincided with an increase in certain risk factors for diabetes, such as a changing race/ethnicity distribution, an aging population, and a rising obesity prevalence. Objective: To determine the extent to which the increase in diabetes prevalence is explained by changing distributions of race/ethnicity, age, and obesity prevalence in U. S. adults. Design: Cross-sectional, using data from 5 NHANES (National Health and Nutrition Examination Surveys): NHANES II (1976-1980), NHANES III (1988-1994), and the continuous NHANES 1999-2002, 2003-2006, and 2007-2010. Setting: Nationally representative samples of the U. S. non-institutionalized civilian population. Patients: 23 932 participants aged 20 to 74 years. Measurements: Diabetes was defined as a self-reported diagnosis or fasting plasma glucose level of 7.0 mmol/L (126 mg/dL) or more. Results: Between 1976 to 1980 and 2007 to 2010, diabetes prevalence increased from 4.7% to 11.2% in men and from 5.7% to 8.7% in women (P for trends for both groups < 0.001). After adjustment for age, race/ethnicity, and body mass index, diabetes prevalence increased in men (6.2% to 9.6%; P for trend < 0.001) but not women (7.6% to 7.5%; P for trend = 0.69). Body mass index was the greatest contributor among the 3 covariates to the change in prevalence estimates after adjustment. Limitation: Some possible risk factors, such as physical activity, waist circumference, and mortality, could not be studied because data on these variables were not collected in all surveys. Conclusion: The increase in the prevalence of diabetes was greater in men than in women in the U. S. population between 1976 to 1980 and 2007 to 2010. After changes in age, race/ethnicity, and body mass index were controlled for, the increase in diabetes prevalence over time was approximately halved in men and diabetes prevalence was no longer increased in women. C1 [Menke, Andy] Social & Sci Syst, Silver Spring, MD 20910 USA. Westat Corp, Rockville, MD 20850 USA. NIDDK, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. RP Menke, A (reprint author), Social & Sci Syst, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. EM amenke@s-3.com FU Centers for Disease Control and Prevention; National Institutes of Diabetes and Digestive and Kidney Diseases; National Institute of Diabetes and Digestive and Kidney Diseases [GS10F0381L] FX Centers for Disease Control and Prevention and National Institutes of Diabetes and Digestive and Kidney Diseases.; By a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (GS10F0381L; Dr. Menke). NR 42 TC 30 Z9 34 U1 0 U2 13 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 2 PY 2014 VL 161 IS 5 BP 328 EP + DI 10.7326/M14-0286 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AO7VT UT WOS:000341561400003 PM 25178569 ER PT J AU Thompson, JR Kamath, N Perry, KL AF Thompson, Jeremy R. Kamath, Nitin Perry, Keith L. TI An Evolutionary Analysis of the Secoviridae Family of Viruses SO PLOS ONE LA English DT Article ID GRAPEVINE-FANLEAF-VIRUS; PICORNA-LIKE VIRUS; INTERSPECIES RECOMBINATION EVENTS; COMPLETE NUCLEOTIDE-SEQUENCE; ARABIS-MOSAIC-VIRUS; RNA VIRUSES; MOTTLE-VIRUS; PLANT-VIRUS; MAXIMUM-LIKELIHOOD; SELECTION PRESSURE AB The plant-infecting Secoviridae family of viruses forms part of the Picornavirales order, an important group of non-enveloped viruses that infect vertebrates, arthropods, plants and algae. The impact of the secovirids on cultivated crops is significant, infecting a wide range of plants from grapevine to rice. The overwhelming majority are transmitted by ecdysozoan vectors such as nematodes, beetles and aphids. In this study, we have applied a variety of computational methods to examine the evolutionary traits of these viruses. Strong purifying selection pressures were calculated for the coat protein (CP) sequences of nine species, although for two species evidence of both codon specific and episodic diversifying selection were found. By using Bayesian phylogenetic reconstruction methods CP nucleotide substitution rates for four species were estimated to range from between 9.29x10(-3) to 2.74x10(-3) (subs/site/year), values which are comparable with the short-term estimates of other related plant-and animal-infecting virus species. From these data, we were able to construct a time-measured phylogeny of the subfamily Comovirinae that estimated divergence of ninety-four extant sequences occurred less than 1,000 years ago with present virus species diversifying between 50 and 250 years ago; a period coinciding with the intensification of agricultural practices in industrial societies. Although recombination (modularity) was limited to closely related taxa, significant and often unique similarities in the protein domains between secovirid and animal infecting picorna-like viruses, especially for the protease and coat protein, suggested a shared ancestry. We discuss our results in a wider context and find tentative evidence to indicate that some members of the Secoviridae might have their origins in insects, possibly colonizing plants in a number of founding events that have led to speciation. Such a scenario; virus infection between species of different taxonomic kingdoms, has significant implications for virus emergence. C1 [Thompson, Jeremy R.; Kamath, Nitin; Perry, Keith L.] Cornell Univ, Dept Plant Pathol & Plant Microbe Biol, Ithaca, NY 14850 USA. [Kamath, Nitin] NIAID, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. RP Thompson, JR (reprint author), Cornell Univ, Dept Plant Pathol & Plant Microbe Biol, Ithaca, NY 14850 USA. EM jrt36@cornell.edu FU Cornell University College of Agriculture and Life Sciences FX This study was supported by Cornell University College of Agriculture and Life Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 5 Z9 5 U1 2 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 2 PY 2014 VL 9 IS 9 AR e106305 DI 10.1371/journal.pone.0106305 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3LR UT WOS:000341231500072 PM 25180860 ER PT J AU Sgourakis, NG Natarajan, K Ying, JF Vogeli, B Boyd, LF Margulies, DH Bax, A AF Sgourakis, Nikolaos G. Natarajan, Kannan Ying, Jinfa Vogeli, Beat Boyd, Lisa F. Margulies, David H. Bax, Ad TI The Structure of Mouse Cytomegalovirus m04 Protein Obtained from Sparse NMR Data Reveals a Conserved Fold of the m02-m06 Viral Immune Modulator Family SO STRUCTURE LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; LIQUID-CRYSTALLINE PHASE; CLASS-I MOLECULES; MURINE CYTOMEGALOVIRUS; CHEMICAL-SHIFTS; T-CELL; IMMUNOGLOBULIN SUPERFAMILY; PERDEUTERATED PROTEINS; STRUCTURE PREDICTION; ANTIGEN PRESENTATION AB Immunoevasins are key proteins used by viruses to subvert host immune responses. Determining their high-resolution structures is key to understanding virus-host interactions toward the design of vaccines and other antiviral therapies. Mouse cytomegalovirus encodes a unique set of immunoevasins, the m02-m06 family, that modulates major histocompatibility complex class I (MHC-I) antigen presentation to CD8+ T cells and natural killer cells. Notwithstanding the large number of genetic and functional studies, the structural biology of immunoevasins remains incompletely understood, largely because of crystallization bottlenecks. Here we implement a technology using sparse nuclear magnetic resonance data and integrative Rosetta modeling to determine the structure of the m04/gp34 immunoevasin extracellular domain. The structure reveals a beta fold that is representative of the m02-m06 family of viral proteins, several of which are known to bind MHC-I molecules and interfere with antigen presentation, suggesting its role as a diversified immune regulation module. C1 [Sgourakis, Nikolaos G.; Ying, Jinfa; Vogeli, Beat; Bax, Ad] Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Natarajan, Kannan; Boyd, Lisa F.; Margulies, David H.] NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Margulies, DH (reprint author), NIAID, Mol Biol Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dhm@nih.gov; bax@nih.gov OI Margulies, David/0000-0001-8530-7375 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Office of the Director, NIH FX We thank Dr. Oliver Lange for providing consultation with setting up the RASREC-Rosetta protocol and Dr. Vitali Tugarinov for assistance with the SIM-HMCM(CGCBCA)CO and HMCM(CG)CBCA triple-resonance experiments. We are grateful to Drs. Nathan May for preparing multiple sequence alignments of the m02 family and to Drs. Yang Shen and Lishan Yao for preliminary work on determining optimal m04 sample conditions, as well as to Dr. Manqing Hong for providing the MULT-1 protein sample. This work is supported by the National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Allergy and Infectious Diseases intramural research programs and the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. NR 62 TC 8 Z9 8 U1 0 U2 7 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 SEP 2 PY 2014 VL 22 IS 9 BP 1263 EP 1273 DI 10.1016/j.str.2014.05.018 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AO5NW UT WOS:000341392800008 PM 25126960 ER PT J AU Lakomek, NA Kaufman, JD Stah, SJ Wingfield, PT AF Lakomek, Nils-Alexander Kaufman, Joshua D. Stah, Stephen J. Wingfield, Paul T. TI HIV-1 Envelope Protein gp41: An NMR Study of Dodecyl Phosphocholine Embedded gp41 Reveals a Dynamic Prefusion Intermediate Conformation SO STRUCTURE LA English DT Article ID MEMBRANE-FUSION; SECONDARY STRUCTURE; CIRCULAR-DICHROISM; CRYOELECTRON MICROSCOPY; GLYCOPROTEIN TRIMER; CHEMICAL-SHIFTS; VIRAL MEMBRANE; DOMAIN; SPECTROSCOPY; ECTODOMAIN AB Human immunodeficiency viral (HIV-1) fusion is mediated by the viral envelope gp120/gp41 complex (ENVelope glycoprotein). After gp120 shedding, gp41 is exposed and elicits membrane fusion via a cascade of conformational changes. In contrast to prefusion and postfusion conformation, little is known about any intermediate conformation. We report on a solution NMR investigation of homotrimeric HIV-1 gp41(27-194), comprising the transmembrane region and reconstituted in dodecyl phosphocholine (DPC) micelles. The protein is mainly a-helical, but experiences internal dynamics on the nanosecond and micro to millisecond time scale and transient a-helical behavior for certain residues in the N-terminal heptad repeat (NHR). Strong lipid interactions are observed, in particular for C-terminal residues of the NHR and imunodominant loop region connecting NHR and C-terminal heptad repeat (CHR). Our data indicate an extended conformation with features anticipated for a prefusion intermediate, presumably in exchange with a lowly populated postfusion six-helical bundle conformation. C1 [Lakomek, Nils-Alexander] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Kaufman, Joshua D.; Stah, Stephen J.; Wingfield, Paul T.] NIAMS, Prot Express Lab, NIH, Bethesda, MD 20892 USA. RP Lakomek, NA (reprint author), Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, D-37077 Gottingen, Germany. EM nall@nmr.mpibpc.mpc.de; wingfiep@mail.nih.gov RI Kaufman, Joel/B-5761-2008; Lakomek, Nils/K-6568-2016 OI Kaufman, Joel/0000-0003-4174-9037; Lakomek, Nils/0000-0002-4285-6339 FU National Institute of Diabetes and Digestive and Kidney Diseases, NIH; Office of the Director, NIH; DFG/NIH [LA 2724/1-1] FX This research was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, and the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH, as well as the DFG/NIH Research Career Transition Award Program (to N.L., LA 2724/1-1). None of the authors have any competing financial interests related to this work. N.L. thanks Dr. Ad Bax and Prof. Dr. Christian Griesinger for allowing him to use their NMR facilities at NIH, Bethesda, MD, USA and the Max-Planck Institute for Biophysical Chemistry, Gottingen, Germany. N.L. is very grateful to Dr. Ad Bax for his continuous support, for receiving an excellent training in NMR spectroscopy, and for allowing him to continue independent research on this research project. NR 49 TC 7 Z9 7 U1 0 U2 20 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 SEP 2 PY 2014 VL 22 IS 9 BP 1311 EP 1321 DI 10.1016/j.str.2014.06.016 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AO5NW UT WOS:000341392800012 PM 25132083 ER PT J AU Zhang, JW Ferre-D'Amare, AR AF Zhang, Jinwei Ferre-D'Amare, Adrian R. TI Dramatic Improvement of Crystals of Large RNAs by Cation Replacement and Dehydration SO STRUCTURE LA English DT Article ID BACTERIAL RIBONUCLEASE-P; PROTEIN CRYSTALS; GLMS RIBOZYME; STRUCTURAL BASIS; GENE-EXPRESSION; CRYSTALLIZATION; DIFFRACTION; RIBOSWITCH; COMPLEX; IONS AB Compared to globular proteins, RNAs with complex 3D folds are characterized by poorly differentiated molecular surfaces dominated by backbone phosphates, sparse tertiary contacts stabilizing global architecture, and conformational flexibility. The resulting generally poor order of crystals of large RNAs and their complexes frequently hampers crystallographic structure determination. We describe and rationalize a postcrystallization treatment strategy that exploits the importance of solvation and counterions for RNA folding. Replacement of Li+ and Mg2+ needed for growth of crystals of a tRNA-riboswitch-protein complex with Sr2+, coupled with dehydration, dramatically improved the resolution limit (8.5-3.2 angstrom) and data quality, enabling structure determination. The soft Sr2+ ion forms numerous stabilizing intermolecular contacts. Comparison of pre- and posttreatment structures reveals how RNA assemblies redistribute as quasi-rigid bodies to yield improved crystal packing. Cation exchange complements previously reported postcrystallization dehydration of protein crystals and represents a potentially general strategy for improving crystals of large RNAs. C1 [Zhang, Jinwei; Ferre-D'Amare, Adrian R.] NHLBI, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, 50 South Dr,MSC 8012, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov FU National Institute of General Medical Sciences [P41GM103403]; U.S. Department of Energy; NHLBI, NIH FX We thank the staff at beamlines 5.0.1 and 5.0.2 of the ALS and ID-24-C and ID-24-E of APS, in particular K. Perry and K. R. Rajashankar of the Northeastern Collaborative Access Team (NE-CAT) of the APS for support in data collection and processing; Y. Liu and Y.-X. Wang of the National Cancer Institute for providing the add riboswitch RNA; G. Piszczek, R. Levine, and D.-Y. Lee of the National Heart, Lung and Blood Institute (NHLBI) for assistance with biophysical and mass spectrometric characterization; and N. Baird, T. Hamma, C. Jones, M. Lau, A. Roll-Mecak, and K. Warner for discussions. This work is partly based on research conducted at the ALS on the Berkeley Center for Structural Biology Beamlines and at the APS on the NE-CAT Beamlines (supported by National Institute of General Medical Sciences grant P41GM103403). Use of ALS and APS was supported by the U.S. Department of Energy. This work was supported in part by the intramural program of the NHLBI, NIH. NR 44 TC 8 Z9 8 U1 0 U2 9 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 SEP 2 PY 2014 VL 22 IS 9 BP 1363 EP 1371 DI 10.1016/j.str.2014.07.011 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AO5NW UT WOS:000341392800018 PM 25185828 ER PT J AU Aldred, KJ Breland, EJ Vickova, V Strub, MP Neuman, KC Kerns, RJ Osheroff, N AF Aldred, Katie J. Breland, Erin J. Vickova, Vladislava Strub, Marie-Paule Neuman, Keir C. Kerns, Robert J. Osheroff, Neil TI Role of the Water-Metal Ion Bridge in Mediating Interactions between Quinolones and Escherichia coli Topoisomerase IV SO BIOCHEMISTRY LA English DT Article ID BACILLUS-ANTHRACIS MUTANTS; DNA GYRASE; STREPTOCOCCUS-PNEUMONIAE; FLUOROQUINOLONE RESISTANCE; STAPHYLOCOCCUS-AUREUS; IIA TOPOISOMERASES; PARC SUBUNIT; IN-VITRO; STRUCTURAL BASIS; PRIMARY TARGET AB Although quinolones have been in clinical use for decades, the mechanism underlying drug activity and resistance has remained elusive. However, recent studies indicate that clinically relevant quinolones interact with Bacillus anthracis (Gram-positive) topoisomerase IV through a critical water-metal ion bridge and that the most common quinolone resistance mutations decrease drug activity by disrupting this bridge. As a first step toward determining whether the water-metal ion bridge is a general mechanism of quinolone-topoisomerase interaction, we characterized drug interactions with wild-type Escherichia coli (Gram-negative) topoisomerase IV and a series of ParC enzymes with mutations (S80L, S80I, S80F, and E84K) in the predicted bridge-anchoring residues. Results strongly suggest that the water metal ion bridge is essential for quinolone activity against E. coli topoisomerase W. Although the bridge represents a common and critical mechanism that underlies broad-spectrum quinolone function, it appears to play different roles in B. anthracis and E. coli topoisomerase W. The water-metal ion bridge is the most important binding contact of clinically relevant quinolones with the Gram-positive enzyme. However, it primarily acts to properly align clinically relevant quinolones with E. coli topoisomerase W. Finally, even though ciprofloxacin is unable to increase levels of DNA cleavage mediated by several of the Ser80 and Glu84 mutant E. coli enzymes, the drug still retains the ability to inhibit the overall catalytic activity of these topoisomerase W proteins. Inhibition parallels drug binding, suggesting that the presence of the drug in the active site is sufficient to diminish DNA relaxation rates. C1 [Aldred, Katie J.; Breland, Erin J.; Vickova, Vladislava; Osheroff, Neil] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. [Osheroff, Neil] Vanderbilt Univ, Sch Med, Dept Med Hematol Oncol, Nashville, TN 37232 USA. [Kerns, Robert J.] VA Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA. [Strub, Marie-Paule; Neuman, Keir C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Osheroff, Neil] Univ Iowa, Div Med & Nat Prod Chem, Coll Pharm, Iowa City, IA 52242 USA. RP Osheroff, N (reprint author), Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. EM neil.osheroff@vanderbilt.edu RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU National Institutes of Health [T32 CA09582, T32 GM07628]; Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health; National Institutes of Health Research [AI87671, GM33944]; United States Veterans Administration Merit Review Award [I01 Bx002198] FX K.J.A. and E.J.B. were trainees under Grants T32 CA09582 and T32 GM07628 from the National Institutes of Health, respectively. V.V. was a trainee in the Vanderbilt International Summer Research Academy. This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health (to K.C.N.), by National Institutes of Health Research Grants AI87671 (to R.J.K.) and GM33944 (to N.O.), and by United States Veterans Administration Merit Review Award I01 Bx002198 (to N.O.). NR 59 TC 8 Z9 8 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 2 PY 2014 VL 53 IS 34 BP 5558 EP 5567 DI 10.1021/bi500682e PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO3LD UT WOS:000341229800011 PM 25115926 ER PT J AU Best, RB AF Best, Robert B. TI Bootstrapping New Protein Folds SO BIOPHYSICAL JOURNAL LA English DT News Item C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Best, RB (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertbe@helix.nih.gov RI Best, Robert/H-7588-2016 OI Best, Robert/0000-0002-7893-3543 NR 10 TC 1 Z9 1 U1 0 U2 4 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 SEP 2 PY 2014 VL 107 IS 5 BP 1040 EP 1041 DI 10.1016/j.bpj.2014.07.021 PG 2 WC Biophysics SC Biophysics GA AO3ZD UT WOS:000341275100004 PM 25185539 ER PT J AU Lauer, MS AF Lauer, Michael S. TI Time to Bring the "Electrocardio-ome" Into Modern Cardiovascular Epidemiology? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE electrocardiography; epidemiology; ischemia; left ventricular hypertrophy; prognosis ID HEALTH C1 [Lauer, Michael S.] NHLBI, Off Director, 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 12 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 2 PY 2014 VL 64 IS 9 BP 907 EP 909 DI 10.1016/j.jacc.2014.05.051 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN8XH UT WOS:000340888600010 PM 25169176 ER PT J AU Viappiani, C Abbruzzetti, S Ronda, L Bettati, S Henry, ER Mozzarelli, A Eaton, WA AF Viappiani, Cristiano Abbruzzetti, Stefania Ronda, Luca Bettati, Stefano Henry, Eric. R. Mozzarelli, Andrea Eaton, William A. TI Experimental basis for a new allosteric model for multisubunit proteins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID T STATE HEMOGLOBIN; OXYGEN-BINDING; SILICA-GELS; QUATERNARY STRUCTURES; HEME REACTIVITY; LIGAND-BINDING; BETA-SUBUNITS; COOPERATIVITY; AFFINITY; MECHANISMS AB Monod, Wyman, and Changeux (MWC) explained allostery in multisubunit proteins with a widely applied theoretical model in which binding of small molecules, so-called allosteric effectors, affects reactivity by altering the equilibrium between more reactive (R) and less reactive (T) quaternary structures. In their model, each quaternary structure has a single reactivity. Here, we use silica gels to trap protein conformations and a new kind of laser photolysis experiment to show that hemoglobin, the paradigm of allostery, exhibits two ligand binding phases with the same fast and slow rates in both R and T quaternary structures. Allosteric effectors change the fraction of each phase but not the rates. These surprising results are readily explained by the simplest possible extension of the MWC model to include a preequilibrium between two tertiary conformations that have the same functional properties within each quaternary structure. They also have important implications for the long-standing question of a structural explanation for the difference in hemoglobin oxygen affinity of the two quaternary structures. C1 [Viappiani, Cristiano; Abbruzzetti, Stefania] Univ Parma, Dept Phys & Earth Sci, I-43124 Parma, Italy. [Ronda, Luca; Bettati, Stefano] Univ Parma, Dept Neurosci, I-43124 Parma, Italy. [Mozzarelli, Andrea] Univ Parma, Dept Pharm, I-43124 Parma, Italy. [Viappiani, Cristiano; Abbruzzetti, Stefania] CNR, Ist Nanosci, NEST, I-56127 Pisa, Italy. [Henry, Eric. R.; Eaton, William A.] NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. RP Viappiani, C (reprint author), Univ Parma, Dept Phys & Earth Sci, I-43124 Parma, Italy. EM cristiano.viappiani@unipr.it; eaton@helix.nih.gov RI Mozzarelli, Andrea/C-3615-2014; abbruzzetti, stefania/M-8640-2015; OI Mozzarelli, Andrea/0000-0003-3762-0062; abbruzzetti, stefania/0000-0001-7685-8554; Ronda, Luca/0000-0002-5389-2669; Viappiani, Cristiano/0000-0001-7470-4770 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; National Institute of Biostructures and Biosystems (Rome, Italy) FX We thank Attila Szabo for many helpful discussions and Nicholas Anthis for preparing the stereo pictures of the hemoglobin structure in SI Text. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (C. V., S. A., W. A. E., and E. R. H.), and by the National Institute of Biostructures and Biosystems (Rome, Italy) (A. M., L. R., and S.B.). NR 55 TC 6 Z9 6 U1 5 U2 37 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 SEP 2 PY 2014 VL 111 IS 35 BP 12758 EP 12763 DI 10.1073/pnas.1413566111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3LN UT WOS:000341230800058 PM 25139985 ER PT J AU Stjepanovic, G Davies, CW Stanley, RE Ragusa, MJ Kim, DJ Hurley, JH AF Stjepanovic, Goran Davies, Christopher W. Stanley, Robin E. Ragusa, Michael J. Kim, Do Jin Hurley, James H. TI Assembly and dynamics of the autophagy-initiating Atg1 complex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE analytical ultracentrifugation; isothermal titration calorimetry; membrane tethering; intrinsically disordered proteins; protein structure ID VELOCITY ANALYTICAL ULTRACENTRIFUGATION; CELLULAR SELF-DIGESTION; HYDROGEN-EXCHANGE; MASS-SPECTROMETRY; PROTEIN INTERACTIONS; EARLY STEPS; GLOBAL ANALYSIS; KINASE COMPLEX; BIOGENESIS; YEAST AB The autophagy-related 1 (Atg1) complex of Saccharomyces cerevisiae has a central role in the initiation of autophagy following starvation and TORC1 inactivation. The complex consists of the protein kinase Atg1, the TORC1 substrate Atg13, and the trimeric Atg17-Atg31-Atg29 scaffolding subcomplex. Autophagy is triggered when Atg1 and Atg13 assemble with the trimeric scaffold. Here we show by hydrogen-deuterium exchange coupled to mass spectrometry that the mutually interacting Atg1 early autophagy targeting/tethering domain and the Atg13 central domain are highly dynamic in isolation but together form a stable complex with similar to 100-nM affinity. The Atg1-Atg13 complex in turn binds as a unit to the Atg17-Atg31-Atg29 scaffold with similar to 10-mu M affinity via Atg13. The resulting complex consists primarily of a dimer of pentamers in solution. These results lead to a model for autophagy initiation in which Atg1 and Atg13 are tightly associated with one another and assemble transiently into the pentameric Atg1 complex during starvation. C1 [Stjepanovic, Goran; Davies, Christopher W.; Ragusa, Michael J.; Kim, Do Jin; Hurley, James H.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Stjepanovic, Goran; Davies, Christopher W.; Ragusa, Michael J.; Kim, Do Jin; Hurley, James H.] Univ Calif Berkeley, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA. [Stanley, Robin E.; Ragusa, Michael J.] NIDDK, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. EM jimhurley@berkeley.edu RI Stjepanovic, Goran/A-7902-2010 OI Stjepanovic, Goran/0000-0002-4841-9949 FU National Institutes of Health [GM111730]; Ruth Kirschstein National Research Service Award [GM112301, GM099319]; Damon Runyon Cancer Research Fellowship; L'Oreal USA Women in Science Fellowship FX We thank J. Doudna for ITC instrument use, J. Kuriyan for SEC-MALS instrument use, and the MacroLab for analytical ultracentrifuge use. This work was supported by National Institutes of Health Grant GM111730 (to J. H. H.), Ruth Kirschstein National Research Service Award Fellowships GM112301 (to C. W. D.) and GM099319 (to M. J. R.), a Damon Runyon Cancer Research Fellowship (to R. E. S.), and a L'Oreal USA Women in Science Fellowship (to R.E.S.). NR 48 TC 17 Z9 17 U1 0 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 SEP 2 PY 2014 VL 111 IS 35 BP 12793 EP 12798 DI 10.1073/pnas.1407214111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3LN UT WOS:000341230800064 PM 25139988 ER PT J AU Luo, N Conwell, MD Chen, XJ Kettenhofen, CI Westlake, CJ Cantor, LB Wells, CD Weinreb, RN Corson, TW Spandau, DF Joos, KM Iomini, C Obukhov, AG Sun, Y AF Luo, Na Conwell, Michael D. Chen, Xingjuan Kettenhofen, Christine Insinna Westlake, Christopher J. Cantor, Louis B. Wells, Clark D. Weinreb, Robert N. Corson, Timothy W. Spandau, Dan F. Joos, Karen M. Iomini, Carlo Obukhov, Alexander G. Sun, Yang TI Primary cilia signaling mediates intraocular pressure sensation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SYNDROME PROTEIN OCRL1; OPEN-ANGLE GLAUCOMA; LOWE-SYNDROME; TRABECULAR MESHWORK; MOUSE MODEL; CELLS; CHANNELS; TRPV4; REGULATOR; DISEASE AB Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-alpha, TGF-beta, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in howthe eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems. C1 [Luo, Na; Conwell, Michael D.; Cantor, Louis B.; Corson, Timothy W.; Sun, Yang] Indiana Univ Sch Med, Dept Ophthalmol, Indianapolis, IN 46202 USA. [Chen, Xingjuan; Obukhov, Alexander G.] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. [Wells, Clark D.; Corson, Timothy W.; Sun, Yang] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Spandau, Dan F.; Sun, Yang] Indiana Univ Sch Med, Dept Dermatol, Indianapolis, IN 46202 USA. [Luo, Na; Conwell, Michael D.; Cantor, Louis B.; Corson, Timothy W.; Sun, Yang] Indiana Univ Sch Med, Glick Eye Inst, Indianapolis, IN 46202 USA. [Kettenhofen, Christine Insinna; Westlake, Christopher J.] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Weinreb, Robert N.] Univ Calif San Diego, Dept Ophthalmol, La Jolla, CA 92037 USA. [Joos, Karen M.] Vanderbilt Eye Inst, Nashville, TN 37212 USA. [Iomini, Carlo] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY 10029 USA. RP Sun, Y (reprint author), Indiana Univ Sch Med, Glick Eye Inst, Indianapolis, IN 46202 USA. EM sunyo@iupui.edu RI Luo, Na/L-4228-2014; Obukhov, Alexander/C-7246-2008; Corson, Timothy/B-6851-2009; OI Luo, Na/0000-0002-8046-9372; Obukhov, Alexander/0000-0002-3862-6004; Corson, Timothy/0000-0002-1402-7875; Conwell, Michael/0000-0003-1562-2729 FU Knights Templar Eye Foundation; Clinician-Scientist award (American Glaucoma Society); Lowe Syndrome Association grant; Research to Prevent Blindness-Glick Eye Institute; Research to Prevent Blindness Dolly Green Special Scholar Award; National Eye Institute Core Grant [5P30EY08126]; Joseph Ellis Family and William Black Research funds; Research to Prevent Blindness Unrestricted Departmental Grant-Vanderbilt; [NIH/NEI022058]; [NIH/NCI151765]; [NIH/NHL115140]; [NIH/NEI22639]; [NIH/KL2TR001106] FX We thank Dr. Wolfgang Liedtke (Duke University) and Dr. David Robertson [Vanderbilt University; National Institutes of Health (NIH)/NHL P01-056693] for the gift of transient receptor potential vanilloid 4 (TRPV4) knockout mice; Charlene Finney and Ratna Prasad for TRPV4-related mouse work; Akhilesh Kumar for assistance with TRPV4 imaging; Vincent Gattone II for assistance with wpk rats; and Drs. Jeffrey Travers and Michael Boulton for thoughtful comments. This work was funded by NIH/NEI022058, Knights Templar Eye Foundation, a Clinician-Scientist award (American Glaucoma Society), a Lowe Syndrome Association grant, and an unrestricted grant from Research to Prevent Blindness-Glick Eye Institute (all to Y.S.); NIH/NCI151765 (to C. D. W.); NIH/NHL115140 (to A.G.O.); NIH/NEI22639 and Research to Prevent Blindness Dolly Green Special Scholar Award (to C.I.); NIH/KL2TR001106 (to T.W.C.); and National Eye Institute Core Grant 5P30EY08126, Joseph Ellis Family and William Black Research funds, and Research to Prevent Blindness Unrestricted Departmental Grant-Vanderbilt (all to K.J.). NR 51 TC 16 Z9 16 U1 1 U2 18 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 SEP 2 PY 2014 VL 111 IS 35 BP 12871 EP 12876 DI 10.1073/pnas.1323292111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3LN UT WOS:000341230800077 PM 25143588 ER PT J AU Li, MH Ablan, SD Miao, CH Zheng, YM Fuller, MS Rennert, PD Maury, W Johnson, MC Freed, EO Liu, SL AF Li, Minghua Ablan, Sherimay D. Miao, Chunhui Zheng, Yi-Min Fuller, Matthew S. Rennert, Paul D. Maury, Wendy Johnson, Marc C. Freed, Eric O. Liu, Shan-Lu TI TIM-family proteins inhibit HIV-1 release SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID T-CELL IMMUNOGLOBULIN; VIRUS TYPE-1 MATRIX; HEPATITIS-A VIRUS; PHOSPHATIDYLSERINE RECEPTORS; PLASMA-MEMBRANE; GENE FAMILY; IMMUNE-RESPONSES; LOW PH; INFECTION; BINDING AB Accumulating evidence indicates that T-cell immunoglobulin (Ig) and mucin domain (TIM) proteins play critical roles in viral infections. Herein, we report that the TIM-family proteins strongly inhibit HIV-1 release, resulting in diminished viral production and replication. Expression of TIM-1 causes HIV-1 Gag and mature viral particles to accumulate on the plasma membrane. Mutation of the phosphatidylserine (PS) binding sites of TIM-1 abolishes its ability to block HIV-1 release. TIM-1, but to a much lesser extent PS-binding deficient mutants, induces PS flipping onto the cell surface; TIM-1 is also found to be incorporated into HIV-1 virions. Importantly, TIM-1 inhibits HIV-1 replication in CD4-positive Jurkat cells, despite its capability of up-regulating CD4 and promoting HIV-1 entry. In addition to TIM-1, TIM-3 and TIM-4 also block the release of HIV-1, as well as that of murine leukemia virus (MLV) and Ebola virus (EBOV); knockdown of TIM-3 in differentiated monocyte-derived macrophages (MDMs) enhances HIV-1 production. The inhibitory effects of TIM-family proteins on virus release are extended to other PS receptors, such as Axl and RAGE. Overall, our study uncovers a novel ability of TIM-family proteins to block the release of HIV-1 and other viruses by interaction with virion- and cell-associated PS. Our work provides new insights into a virus-cell interaction that is mediated by TIMs and PS receptors. C1 [Li, Minghua; Miao, Chunhui; Zheng, Yi-Min; Fuller, Matthew S.; Johnson, Marc C.; Liu, Shan-Lu] Univ Missouri, Bond Life Sci Ctr, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA. [Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Rennert, Paul D.] SugarCone Biotech LLC, Dept Immunotherapy, Holliston, MA 01746 USA. [Maury, Wendy] Univ Iowa, Dept Microbiol, Iowa City, IA 52245 USA. RP Liu, SL (reprint author), Univ Missouri, Bond Life Sci Ctr, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA. EM liushan@missouri.edu RI Liu, Shan-Lu/L-5923-2016; Li, Minghua/M-8776-2016 OI Liu, Shan-Lu/0000-0003-1620-3817; FU National Institutes of Health (NIH) [R01 AI112381, R21 AI109464, R21 AI105584, R56 AI107095, U54 AI057160, R01 GM110776, R01 AI1077519]; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH; Intramural AIDS Targeted Antiviral Program FX We thank Kunio Nagashima and Ferri Soheilian at the Leidos Electron Microscopy Laboratory for their expert assistance with the TEM analysis and Kartik Chandran for providing the VP40-GFP construct. This work was supported by National Institutes of Health (NIH) Grants R01 AI112381, R21 AI109464, R21 AI105584, R56 AI107095, and U54 AI057160 (to S.-L. L.), R01 GM110776 (to M.C.J.), and R01 AI1077519 (to W. M.). Research in the E.O.F. laboratory is supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, and by the Intramural AIDS Targeted Antiviral Program. NR 54 TC 18 Z9 19 U1 1 U2 21 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 SEP 2 PY 2014 VL 111 IS 35 BP E3699 EP E3707 DI 10.1073/pnas.1404851111 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3LN UT WOS:000341230800017 PM 25136083 ER PT J AU Roman-Hernandez, G Peterson, JH Bernstein, HD AF Roman-Hernandez, Giselle Peterson, Janine H. Bernstein, Harris D. TI Reconstitution of bacterial autotransporter assembly using purified components SO ELIFE LA English DT Article ID OUTER-MEMBRANE; ESCHERICHIA-COLI; PROTEIN-TRANSPORT; PASSENGER DOMAIN; VIRULENCE PROTEIN; BETA-DOMAIN; IN-VITRO; SECRETION; TRANSLOCATION; BIOGENESIS AB Autotransporters are a superfamily of bacterial virulence factors consisting of an N-terminal extracellular ("passenger") domain and a C-terminal beta barrel ("beta") domain that resides in the outer membrane (OM). The mechanism by which the passenger domain is secreted is poorly understood. Here we show that a conserved OM protein insertase (the Bam complex) and a molecular chaperone (SurA) are both necessary and sufficient to promote the complete assembly of the Escherichia coli O157:H7 autotransporter EspP in vitro. Our results indicate that the membrane integration of the beta domain is the rate-limiting step in autotransporter assembly and that passenger domain translocation does not require the input of external energy. Furthermore, experiments using nanodiscs strongly suggest that autotransporter assembly is catalyzed by a single copy of the Bam complex. Finally, we describe a method to purify a highly active form of the Bam complex that should facilitate the elucidation of its function. C1 [Roman-Hernandez, Giselle; Peterson, Janine H.; Bernstein, Harris D.] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX We would like to thank Shu-ou Shan for help fitting the data obtained in EspP assembly experiments to kinetic models and Franck Duong for advice on preparing nanodiscs. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 44 TC 20 Z9 20 U1 1 U2 13 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD SEP 2 PY 2014 VL 3 AR e04234 DI 10.7554/eLife.04234 PG 47 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AO3TQ UT WOS:000341259200010 PM 25182416 ER PT J AU Li, RW Dee, D Li, CM Hoffman, HJ Grummer-Strawn, LM AF Li, Ruowei Dee, Deborah Li, Chuan-Ming Hoffman, Howard J. Grummer-Strawn, Laurence M. TI Breastfeeding and Risk of Infections at 6 Years SO PEDIATRICS LA English DT Article DE breastfeeding; infection; Infant Feeding Practice Study II; Year 6 Follow-Up Study ID HELICOBACTER-PYLORI INFECTION; OTITIS-MEDIA; PRESCHOOL-CHILDREN; METAANALYSIS; INFANCY; COHORT; HEALTH; SIZE AB BACKGROUND: Previous studies have shown that breastfeeding is associated with reductions in the risk of common infections among infants; however, whether breastfeeding confers longer term protection is inconclusive. METHODS: We linked data from the 2005-2007 IFPS II (Infant Feeding Practices Study II) and follow-up data collected when the children were 6 years old. Multivariable logistic regression was used, controlling for sociodemographic variables, to examine associations of initiation, duration, exclusivity of breastfeeding, timing of supplementing breastfeeding with formula, and breast milk intensity (proportion of milk feedings that were breast milk from age 0-6 months) with maternal reports of infection (cold/upper respiratory tract, ear, throat, sinus, pneumonia/lung, and urinary) and sick visits in the past year among 6-year-olds (N = 1281). RESULTS: The most common past-year infections were colds/upper respiratory tract (66%), ear (25%), and throat (24%) infections. No associations were found between breastfeeding and colds/upper respiratory tract, lung, or urinary tract infections. Prevalence of ear, throat, and sinus infections and number of sick visits differed according to breastfeeding duration, exclusivity, and timing of supplementing breastfeeding with formula (P<.05). Among children ever breastfed, children breastfed for >= 9 months had lower odds of past-year ear (adjusted odds ratio [aOR]: 0.69 [95% confidence interval (95% CI): 0.48-0.98]), throat (aOR: 0.68 [95% CI: 0.47-0.98]), and sinus (aOR: 0.47 [95% CI: 0.30-0.72]) infections compared with those breastfed >0 to <3 months. High breast milk intensity (>66.6%) during the first 6 months was associated with lower odds of sinus infection compared with low breast milk intensity (<33.3%) (aOR: 0.53 [95% CI: 0.35-0.79]). CONCLUSIONS: This prospective longitudinal study suggests that breastfeeding may protect against ear, throat, and sinus infections well beyond infancy. C1 [Li, Ruowei; Grummer-Strawn, Laurence M.] Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, Atlanta, GA 30341 USA. [Dee, Deborah] Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA 30341 USA. [Li, Chuan-Ming; Hoffman, Howard J.] NIDCD, NIH, Div Sci Programs Epidemiol & Stat Program, Bethesda, MD USA. RP Li, RW (reprint author), Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Nutr Phys Act & Obes, 4770 Buford Highway NE,Mailstop F77, Atlanta, GA 30341 USA. EM ril6@cdc.gov FU US Food and Drug Administration; Centers for Disease Control and Prevention; Office on Women's Health; National Institutes of Health; Maternal and Child Health Bureau in the US Department of Health and Human Services FX This study was funded by the US Food and Drug Administration, Centers for Disease Control and Prevention, Office on Women's Health, National Institutes of Health, and Maternal and Child Health Bureau in the US Department of Health and Human Services. NR 25 TC 8 Z9 11 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD SEP PY 2014 VL 134 SU 1 BP S13 EP S20 DI 10.1542/peds.2014-0646D PG 8 WC Pediatrics SC Pediatrics GA CO2NF UT WOS:000358992600003 PM 25183750 ER PT J AU Perrine, CG Galuska, DA Thompson, FE Scanlon, KS AF Perrine, Cria G. Galuska, Deborah A. Thompson, Frances E. Scanlon, Kelley S. TI Breastfeeding Duration Is Associated With Child Diet at 6 Years SO PEDIATRICS LA English DT Article DE breastfeeding duration; exclusive breastfeeding; diet; fruits; vegetables; sugar-sweetened beverages ID CARDIOVASCULAR RISK; PRESCHOOL-CHILDREN; FOOD NEOPHOBIA; ACCEPTANCE; DETERMINANTS; PATTERNS; INFANT; VEGETABLES; EXPERIENCE; PREDICTORS AB BACKGROUND AND OBJECTIVE: Breastfeeding has been associated with early infant food preferences, but less is known about how breastfeeding is associated with later child diet. The objective of this study was to assess whether any and exclusive breastfeeding duration are associated with child diet at 6 years. METHODS: We linked data from the Infant Feeding Practices Study II and Year 6 Follow-Up. We used approximately monthly questionnaires throughout infancy to calculate any and exclusive breastfeeding duration (n = 1355). We calculated median daily frequency of intake of water, milk, 100% juice, fruits, vegetables, sugar-sweetened beverages, sweets, and savory snacks at 6 years from a dietary screener and examined frequency of consumption of each food or beverage group by any and exclusive breastfeeding duration. We used separate multivariable logistic regression models to calculate odds of consuming more than the median daily frequency of intake of food or beverage items, adjusting for confounders. RESULTS: Intake of milk, sweets, and savory snacks at 6 years was not associated with any or exclusive breastfeeding duration in unadjusted analyses. Frequency of consumption of water, fruits, and vegetables was positively associated, and intake of sugar-sweetened beverages was inversely associated with any and exclusive breastfeeding duration in adjusted models; 100% juice consumption was inversely associated with exclusive breastfeeding duration only. CONCLUSIONS: Among many other health benefits, breastfeeding is associated with a number of healthier dietary behaviors at age 6. The association between breastfeeding and child diet may be an important factor to consider when examining associations between breastfeeding and child obesity and chronic diseases. C1 [Perrine, Cria G.; Galuska, Deborah A.; Scanlon, Kelley S.] Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, Atlanta, GA USA. [Perrine, Cria G.] US Publ Hlth Serv Commissioned Corps, Atlanta, GA USA. [Thompson, Frances E.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Perrine, CG (reprint author), 4770 Buford Hwy NE,Mailstop F-77, Atlanta, GA 30341 USA. EM cperrine@cdc.gov FU US Food and Drug Administration; Centers for Disease Control and Prevention; Office on Women's Health, National Institutes of Health; Maternal and Child Health Bureau in the US Department of Health and Human Services FX This study was funded by the US Food and Drug Administration, Centers for Disease Control and Prevention, Office on Women's Health, National Institutes of Health, and Maternal and Child Health Bureau in the US Department of Health and Human Services. NR 27 TC 13 Z9 13 U1 2 U2 11 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD SEP PY 2014 VL 134 SU 1 BP S50 EP S55 DI 10.1542/peds.2014-0646I PG 6 WC Pediatrics SC Pediatrics GA CO2NF UT WOS:000358992600008 PM 25183756 ER PT J AU Kaplan, RM Riley, WT Mabry, PL AF Kaplan, Robert M. Riley, William T. Mabry, Patricia L. TI News from the NIH: leveraging big data in the behavioral sciences SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT News Item C1 [Kaplan, Robert M.] Agcy Healthcare Res & Qual, Off Director, Rockville, MD 20850 USA. [Riley, William T.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Mabry, Patricia L.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Kaplan, RM (reprint author), Agcy Healthcare Res & Qual, Off Director, 540 Gaither Rd,Suite 2000, Rockville, MD 20850 USA. EM Robert.Kaplan@ahrq.hhs.gov NR 8 TC 4 Z9 4 U1 1 U2 5 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD SEP PY 2014 VL 4 IS 3 BP 229 EP 231 DI 10.1007/s13142-014-0267-y PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CL2PO UT WOS:000356786700001 PM 25264461 ER PT J AU Riley, WT Rivera, DE AF Riley, William T. Rivera, Daniel E. TI Methodologies for optimizing behavioral interventions: introduction to special section SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Editorial Material C1 [Riley, William T.] NIH, Rockville, MD 20850 USA. [Rivera, Daniel E.] Arizona State Univ, Phoenix, AZ USA. RP Riley, WT (reprint author), NIH, 9609 Med Ctr Dr,MSC 9761, Rockville, MD 20850 USA. EM wiriley@mail.nih.gov OI Rivera, Daniel/0000-0002-3141-0577 NR 14 TC 8 Z9 8 U1 1 U2 3 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD SEP PY 2014 VL 4 IS 3 BP 234 EP 237 DI 10.1007/s13142-014-0281-0 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CL2PO UT WOS:000356786700003 PM 25264463 ER PT J AU Lytle, LA Svetkey, LP Patrick, K Belle, SH Fernandez, ID Jakicic, JM Johnson, KC Olson, CM Tate, DF Wing, R Loria, CM AF Lytle, Leslie A. Svetkey, Laura P. Patrick, Kevin Belle, Steven H. Fernandez, I. Diana Jakicic, John M. Johnson, Karen C. Olson, Christine M. Tate, Deborah F. Wing, Rena Loria, Catherine M. TI The EARLY trials: a consortium of studies targeting weight control in young adults SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Young adults; Obesity; Intervention trials; Research consortium ID BODY-MASS INDEX; PHYSICAL-ACTIVITY; US ADULTS; OBESITY; TRENDS; ADOLESCENTS; PREVALENCE; RISK; GAIN; SATISFACTION AB Young adulthood has been identified as a high-risk period for the development of obesity but few interventions have been tested in this population. One way to escalate our learning about effective interventions is to test a number of interventions simultaneously as a consortium of research trials. This paper describes the Early Adult Reduction of weight through LifestYle intervention (EARLY) trials. Seven research sites were funded to conduct intervention trials, agreeing to test similar primary outcomes and cooperating to use a set of common measurement tools. The EARLY consortium was able to work cooperatively using an executive committee, a steering committee, workgroups and subcommittees to help direct the common work and implement a set of common protocol and measurement tools for seven independent but coordinated weight-related intervention trials. Using a consortium of studies to help young adults reach or maintain a healthy weight will result in increased efficiency and speed in understanding the most effective intervention strategies. C1 [Lytle, Leslie A.; Tate, Deborah F.] Univ N Carolina, Dept Hlth Behav, Chapel Hill, NC 27599 USA. [Svetkey, Laura P.] Duke Univ, Durham, NC USA. [Patrick, Kevin] Univ Calif San Diego, San Diego, CA 92103 USA. [Belle, Steven H.] Univ Pittsburgh, Pittsburgh, PA USA. [Fernandez, I. Diana] Univ Rochester, Rochester, NY USA. [Johnson, Karen C.] Univ Tennessee Hlth Sci Ctr, Memphis, TN USA. [Olson, Christine M.] Cornell Univ, Ithaca, NY USA. [Wing, Rena] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Wing, Rena] Brown Univ, Miriam Hosp, Providence, RI USA. [Loria, Catherine M.] NHLBI, Bethesda, MD 20892 USA. [Jakicic, John M.] Univ Pittsburgh, Dept Hlth & Phys Act, Phys Act & Weight Management Res Ctr, Pittsburgh, PA USA. RP Lytle, LA (reprint author), Univ N Carolina, Dept Hlth Behav, Campus Box 7440, Chapel Hill, NC 27599 USA. EM llytle@email.unc.edu FU National Heart, Lung, and Blood Institute [HL096760-02, HL096770-01, HL096628-01, HL096767-01, HL096715-01, HL096720-01, HL090864, HL090875] FX The EARLY trials are funded by National Heart, Lung, and Blood Institute: HL096760-02 (Fernandez and Olson), HL096770-01 (Jakicic), HL096628-01 (Johnson), HL096767-01 (Lytle), HL096715-01 (Patrick), HL096720-01 (Svetkey), HL090864 (Wing), and HL090875 (Espeland). All of the trials are registered as clinical trials: NCT01134783 (CHOICES), NCT01092364 (CITY), NCT01331564 (e-MomsRoc), NCT01121871 (IDEA), NCT01200459 (SMART), NCT01183689 (SNAP), and NCT01199185 (TARGIT). The authors would like to acknowledge all of the investigators involved in the EARLY trials and Megan Treziok and Helena Knego for their help with tables and formatting the manuscript. NR 40 TC 33 Z9 33 U1 3 U2 6 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD SEP PY 2014 VL 4 IS 3 BP 304 EP 313 DI 10.1007/s13142-014-0252-5 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CL2PO UT WOS:000356786700009 PM 25264469 ER PT J AU Chou, WYS Prestin, A Kunath, S AF Chou, Wen-ying Sylvia Prestin, Abby Kunath, Stephen TI Obesity in social media: a mixed methods analysis SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Obesity; Weight stigma; Cyber aggression; Social media; Health communication; Mixed methods; Online social support ID THE-BIGGEST-LOSER; WEIGHT-LOSS; ONLINE DISINHIBITION; STIGMA; TELEVISION; OVERWEIGHT; BIAS; INTERNET; HEALTH; NEWS AB The escalating obesity rate in the USA has made obesity prevention a top public health priority. Recent interventions have tapped into the social media (SM) landscape. To leverage SM in obesity prevention, we must understand user-generated discourse surrounding the topic. This study was conducted to describe SM interactions about weight through a mixed methods analysis. Data were collected across 60 days through SM monitoring services, yielding 2.2 million posts. Data were cleaned and coded through Natural Language Processing (NLP) techniques, yielding popular themes and the most retweeted content. Qualitative analyses of selected posts add insight into the nature of the public dialogue and motivations for participation. Twitter represented the most common channel. Twitter and Facebook were dominated by derogatory and misogynist sentiment, pointing to weight stigmatization, whereas blogs and forums contained more nuanced comments. Other themes included humor, education, and positive sentiment countering weight-based stereotypes. This study documented weight-related attitudes and perceptions. This knowledge will inform public health/obesity prevention practice. C1 [Chou, Wen-ying Sylvia; Prestin, Abby] NCI, Hlth Commun & Informat Res Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, Rockville, MD 20892 USA. [Kunath, Stephen] Georgetown Univ, Dept Linguist, Rockville, MD 20892 USA. RP Chou, WYS (reprint author), NCI, Hlth Commun & Informat Res Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, 9609 Med Ctr Dr 3E614, Rockville, MD 20892 USA. EM chouws@mail.nih.gov NR 51 TC 9 Z9 9 U1 8 U2 31 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD SEP PY 2014 VL 4 IS 3 BP 314 EP 323 DI 10.1007/s13142-014-0256-1 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CL2PO UT WOS:000356786700010 PM 25264470 ER PT J AU Reich, DS AF Reich, D. S. TI Imaging the small parts of the nervous system: spinal cord SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Reich, D. S.] NINDS, NIH, Translat Neuroradiol Unit, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA TC7.3 BP 7 EP 7 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300018 ER PT J AU Vuolo, L Sati, P Absinta, M Cortese, I Reich, DS AF Vuolo, L. Sati, P. Absinta, M. Cortese, I. Reich, D. S. TI In vivo 7T MRI characterization of leptomeningeal enhancement in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Vuolo, L.; Sati, P.; Absinta, M.; Reich, D. S.] NINDS, NIH, Translat Neuroradiol Unit, Bethesda, MD 20892 USA. [Vuolo, L.] Univ Florence, Dept Neurol, Florence, Italy. [Vuolo, L.] Univ Florence, Dept Radiol, Florence, Italy. [Absinta, M.] Univ Vita Salute San Raffaele, Inst Sci, Inst Expt Neurol, Neuroimaging Res Unit, Milan, Italy. [Cortese, I.] NINDS, NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA YI1.4 BP 15 EP 15 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300043 ER PT J AU Absinta, M Vuolo, L Nair, G Sati, P Dragan, M Reyes-Mantilla, MI Filippi, M Calabresi, PA Pardo, CA Reich, DS AF Absinta, M. Vuolo, L. Nair, G. Sati, P. Dragan, M. Reyes-Mantilla, M. I. Filippi, M. Calabresi, P. A. Pardo, C. A. Reich, D. S. TI Is focal leptomeningeal enhancement an in vivo imaging biomarker for meningeal inflammation? SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Absinta, M.; Vuolo, L.; Nair, G.; Sati, P.; Reich, D. S.] NINDS, Translat Neuroradiol Unit, NIH, Bethesda, MD 20892 USA. [Absinta, M.; Filippi, M.] Univ Vita Salute San Raffaele, Inst Expt Neurol, San Raffaele Sci Inst, Neuroimaging Res Unit,Div Neurosci, Milan, Italy. [Dragan, M.] Inst Neurol Disorders & Stroke NINDS, Flow Cytometry Core Facil, NIH, Bethesda, MD USA. [Reyes-Mantilla, M. I.; Calabresi, P. A.; Pardo, C. A.; Reich, D. S.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 1 Z9 1 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA YI2.1 BP 17 EP 17 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300047 ER PT J AU Saidha, S Al-Louzi, OO Ratchford, J Bhargava, P Oh, J Newsome, S Prince, J Pham, D Roy, S Van Zijl, P Balcer, L Frohman, E Reich, D Crainiceanu, C Calabresi, P AF Saidha, S. Al-Louzi, O. Omar Ratchford, J. Bhargava, P. Oh, J. Newsome, S. Prince, J. Pham, D. Roy, S. Van Zijl, P. Balcer, L. Frohman, E. Reich, D. Crainiceanu, C. Calabresi, P. TI Retinal measures reflect global neurodegeneration and inflammation; a 4-year longitudinal study of optical coherence tomography and MRI in MS SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Saidha, S.; Al-Louzi, O. Omar; Ratchford, J.; Bhargava, P.; Oh, J.; Newsome, S.; Calabresi, P.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Prince, J.; Pham, D.; Roy, S.] Johns Hopkins Univ, Dept Elect & Comp Engn, Sch Med, Baltimore, MD 21218 USA. [Prince, J.] Johns Hopkins Univ, Dept Comp Sci, Sch Med, Baltimore, MD 21218 USA. [Pham, D.; Roy, S.; Van Zijl, P.] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD USA. [Balcer, L.] NYU, Dept Neurol, Langone Med Ctr, New York, NY 10016 USA. [Frohman, E.] Univ Texas Southwestern, Dept Neurol & Ophthalmol, Dallas, TX USA. [Reich, D.] Natl Inst Neurol Disorders & Stroke, Translat Neuroradiol Unit, Bethesda, MD USA. [Crainiceanu, C.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA YI2.2 BP 17 EP 18 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300048 ER PT J AU Oh, J Chen, M Vidal-Jordana, A Carass, A Newsome, SD Diener-West, M Saidha, S Zackowski, K Jones, CK van Zijl, PCM Prince, J Calabresi, PA Reich, DS AF Oh, J. Chen, M. Vidal-Jordana, A. Carass, A. Newsome, S. D. Diener-West, M. Saidha, S. Zackowski, K. Jones, C. K. van Zijl, P. C. M. Prince, J. Calabresi, P. A. Reich, D. S. TI Longitudinal change in quantitative spinal cord MRI in multiple sclerosis patients: preliminary results of a 2-year study SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Oh, J.] Univ Toronto, Neurol, Toronto, ON, Canada. [Oh, J.; Vidal-Jordana, A.; Newsome, S. D.; Saidha, S.; Zackowski, K.; Calabresi, P. A.; Reich, D. S.] Johns Hopkins Univ, Neurol, Baltimore, MD USA. [Chen, M.; Carass, A.; Prince, J.] Johns Hopkins Univ, Elect & Comp Engn, Baltimore, MD USA. [Vidal-Jordana, A.] Hosp Univ Vall dHebron, Multiple Sclerosis Ctr Catalonia Cemcat, Neurol, Barcelona, Spain. [Diener-West, M.] Johns Hopkins Univ, Biostat, Baltimore, MD USA. [Zackowski, K.] Johns Hopkins Univ, Phys Med & Rehabil, Baltimore, MD USA. [Zackowski, K.] Kennedy Krieger Inst, Mot Anal Lab, Baltimore, MD USA. [Jones, C. K.; van Zijl, P. C. M.] Kennedy Krieger Inst, FM Kirby Ctr Funct Brain Imaging, Baltimore, MD USA. [Jones, C. K.; van Zijl, P. C. M.; Reich, D. S.] Johns Hopkins Univ, Radiol & Radiol Sci, Baltimore, MD USA. [Prince, J.] Johns Hopkins Univ, Comp Sci, Baltimore, MD USA. [Reich, D. S.] Natl Inst Neurol Disorders & Stroke, Translat Neuroradiol Unit, Bethesda, MD USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA PS3.3 BP 25 EP 26 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300068 ER PT J AU Reich, DS AF Reich, D. S. TI Ultra-high-field MRI SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Reich, D. S.] Natl Inst Neurol Disorders & Stroke, NIH, Translat Neuroradiol Unit, Bethesda, MD USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA PS3.1 BP 25 EP 25 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300066 ER PT J AU Sethi, V Sati, P Nair, G Absinta, M van Geldern, G Dewey, BE Ohayon, J Cortese, I Nath, A Reich, DS AF Sethi, V. Sati, P. Nair, G. Absinta, M. van Geldern, G. Dewey, B. E. Ohayon, J. Cortese, I. Nath, A. Reich, D. S. TI Evolving dark band on T2*weighted high resolution MRI is characteristic of PML SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Sethi, V.; Sati, P.; Nair, G.; Absinta, M.; Dewey, B. E.; Ohayon, J.; Cortese, I.; Reich, D. S.] NINDS, NIH, Translat Neuroradiol Unit, Neuroimmunol Branch, Bethesda, MD 20892 USA. [van Geldern, G.] NINDS, NIH, Bethesda, MD 20892 USA. [Nath, A.] NINDS, NIH, Sect Infect Nervous Syst, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA PS6.6 BP 34 EP 34 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300089 ER PT J AU Sousa, ADA Nicholas, R Johnson, K Darko, S Price, D Douek, DC Jacobson, S Muraro, PA AF Sousa, A. De Paula Alves Nicholas, R. Johnson, K. Darko, S. Price, D. Douek, D. C. Jacobson, S. Muraro, P. A. TI Deep sequencing of T-cell receptor repertoire reveals enrichment of highly expanded clonotypes in cerebrospinal fluid from multiple sclerosis patients SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Sousa, A. De Paula Alves; Johnson, K.; Jacobson, S.] NINDS, Bethesda, MD 20892 USA. [Sousa, A. De Paula Alves; Nicholas, R.; Muraro, P. A.] Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. [Darko, S.; Douek, D. C.] NIAID, Bethesda, MD 20892 USA. [Price, D.] Cardiff Univ, Cardiff CF10 3AX, S Glam, Wales. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA PS10.5 BP 57 EP 57 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300141 ER PT J AU Komori, M Blake, A Lin, YC Ghazali, D Kosa, P Winokur, P Natrajan, M Romm, E Wu, T Bielekova, B AF Komori, M. Blake, A. Lin, Y-C Ghazali, D. Kosa, P. Winokur, P. Natrajan, M. Romm, E. Wu, T. Bielekova, B. TI Increased intrathecal inflammation in progressive multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Komori, M.; Blake, A.; Lin, Y-C; Ghazali, D.; Kosa, P.; Winokur, P.; Natrajan, M.; Romm, E.; Wu, T.; Bielekova, B.] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P200 BP 156 EP 157 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300364 ER PT J AU Lin, YC Winokur, P Blake, A Wu, T Romm, E Bielekova, B AF Lin, Y-C Winokur, P. Blake, A. Wu, T. Romm, E. Bielekova, B. TI Comprehensive Immunophenotyping of CSF cells in relapsing-remitting multiple sclerosis patients with daclizumb therapy SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Lin, Y-C; Winokur, P.; Blake, A.; Wu, T.; Romm, E.; Bielekova, B.] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P198 BP 156 EP 156 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300362 ER PT J AU Herbert, J Ryerson, LZ Tornatore, C Foley, J Weinstock-Guttman, B Kister, I Pandey, K Hojnacki, D Remington, G Frohman, T Major, E Douek, D Qureshi, S Beh, J Okuda, D Utomo, P Hoyt, T Chamot, E Bucello, M Ahsan, I Kolb, C Frohman, E AF Herbert, J. Ryerson, L. Zhovtis Tornatore, C. Foley, J. Weinstock-Guttman, B. Kister, I. Pandey, K. Hojnacki, D. Remington, G. Frohman, T. Major, E. Douek, D. Qureshi, S. Beh, J. Okuda, D. Utomo, P. Hoyt, T. Chamot, E. Bucello, M. Ahsan, I. Kolb, C. Frohman, E. TI Establishment of a global registry for multiple sclerosis patients on extended dose natalizumab schedules SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Herbert, J.; Ryerson, L. Zhovtis; Kister, I.; Utomo, P.] NYU, Langone Med Ctr, Neurol Multiple Sclerosis Comprehens Care Ctr, New York, NY USA. [Tornatore, C.] Georgetown Univ Hosp, Neurol, Washington, DC 20007 USA. [Foley, J.; Hoyt, T.] Rocky Mt MS Clin, Salt Lake City, UT USA. [Weinstock-Guttman, B.; Hojnacki, D.; Bucello, M.; Ahsan, I.; Kolb, C.] SUNY Buffalo, Neurol, Buffalo, NY 14260 USA. [Pandey, K.] Barnabas Hlth MS Ctr, Neurol, Livingston, NJ USA. [Remington, G.; Frohman, T.; Qureshi, S.; Beh, J.; Okuda, D.; Frohman, E.] Univ Texas SW Med Ctr Dallas, Neurol, Dallas, TX 75390 USA. [Major, E.] Natl Inst Neurol Dis & Stroke, Bethesda, MD USA. [Douek, D.] Natl Inst Allergy & Immunol, Bethesda, MD USA. [Chamot, E.] Univ Alabama Birmingham, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P218 BP 164 EP 165 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300382 ER PT J AU Ryerson, LZ Herbert, J Tornatore, C Foley, J Weinstock-Guttman, B Kister, I Pandey, K Hojnacki, D Remington, G Frohman, T Major, E Douek, D Qureshi, S Beh, J Okuda, D Utomo, P Hoyt, T Chamot, E Bucello, M Ahsan, I Kolb, C Frohman, E AF Ryerson, L. Zhovtis Herbert, J. Tornatore, C. Foley, J. Weinstock-Guttman, B. Kister, I. Pandey, K. Hojnacki, D. Remington, G. Frohman, T. Major, E. Douek, D. Qureshi, S. Beh, J. Okuda, D. Utomo, P. Hoyt, T. Chamot, E. Bucello, M. Ahsan, I. Kolb, C. Frohman, E. TI Efficacy of Natalizumab extended dosing in multiple sclerosis: a retrospective multicenter analysis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Ryerson, L. Zhovtis; Herbert, J.; Kister, I.; Utomo, P.] NYU, Langone Med Ctr, New York, NY USA. [Tornatore, C.] Georgetown Univ Hosp, Neurol, Washington, DC 20007 USA. [Foley, J.; Hoyt, T.] Rocky Mt MS Clin, Salt Lake City, UT USA. [Weinstock-Guttman, B.; Hojnacki, D.; Bucello, M.; Ahsan, I.; Kolb, C.] SUNY Buffalo, Neurol, Buffalo, NY 14260 USA. [Pandey, K.] Barnabas Hlth MS Ctr, Neurol, Livingston, NJ USA. [Remington, G.; Frohman, T.; Qureshi, S.; Beh, J.; Okuda, D.; Frohman, E.] Univ Texas SW Med Ctr Dallas, Neurol, Dallas, TX 75390 USA. [Major, E.] NINDS, Bethesda, MD 20892 USA. [Douek, D.] Natl Inst Allergy & Immunol, Bethesda, MD USA. [Chamot, E.] Univ Alabama Birmingham, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P287 BP 194 EP 195 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300451 ER PT J AU Xia, Z Chibnik, L von Korff, A Reich, DS De Jager, PL AF Xia, Z. Chibnik, L. von Korff, A. Reich, D. S. De Jager, P. L. TI Genes and environment in multiple sclerosis (GEMS) study: enabling the prospective study of individuals at risk of multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Xia, Z.; Chibnik, L.; von Korff, A.; De Jager, P. L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Dept Neurol, Boston, MA 02115 USA. [Xia, Z.; De Jager, P. L.] Harvard Univ, Sch Med, Boston, MA USA. [Reich, D. S.] NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P344 BP 220 EP 221 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300507 ER PT J AU Steele, SU Bakshi, AC Xia, Z von Korff, A Owen, EK Cortese, ICM De Jager, PL Reich, DS AF Steele, S. U. Bakshi, A. C. Xia, Z. von Korff, A. Owen, E. K. Cortese, I. C. M. De Jager, P. L. Reich, D. S. TI Magnetic resonance imaging findings in healthy, genetically characterized, asymptomatic first-degree relatives of multiple sclerosis patients SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Steele, S. U.; Bakshi, A. C.; Reich, D. S.] NINDS, Translat Neuroradiol Unit, NIH, Bethesda, MD 20892 USA. [Xia, Z.; von Korff, A.; Owen, E. K.; De Jager, P. L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Dept Neurol, Boston, MA 02115 USA. [Xia, Z.; von Korff, A.; De Jager, P. L.] Harvard Univ, Sch Med, Boston, MA USA. [Cortese, I. C. M.] NINDS, NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P425 BP 255 EP 255 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300586 ER PT J AU Sweeney, E Shinohara, R Gherman, A Reich, D Crainiceanu, C AF Sweeney, E. Shinohara, R. Gherman, A. Reich, D. Crainiceanu, C. TI OASIS and SuBLIME software for MS lesion segmentation SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Sweeney, E.; Crainiceanu, C.] Johns Hopkins, Dept Biostat, Baltimore, MD USA. [Shinohara, R.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Gherman, A.] Johns Hopkins, Inst Med Genet, Baltimore, MD USA. [Reich, D.] NINDS, Translat Neuroradiol Unit, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P442 BP 263 EP 263 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300603 ER PT J AU Sethi, V Nair, G Shea, CD Dewey, BE Reich, DS AF Sethi, V. Nair, G. Shea, C. D. Dewey, B. E. Reich, D. S. TI Slowly expanding lesions in MS: a histopathological mirage? SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Sethi, V.; Nair, G.; Shea, C. D.; Dewey, B. E.; Reich, D. S.] NINDS, NIH, Translat Neuroradiol Unit, Neuroimmunol Branch, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P478 BP 279 EP 279 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300639 ER PT J AU Reich, DS White, R Cortese, ICM Vuolo, L Shea, CD Collins, TL Petkau, AJ AF Reich, D. S. White, R. Cortese, I. C. M. Vuolo, L. Shea, C. D. Collins, T. L. Petkau, A. J. TI Sample-size calculations for short-term proof-of-concept studies of tissue protection and repair in MS lesions via conventional clinical imaging SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Reich, D. S.; Cortese, I. C. M.; Vuolo, L.; Shea, C. D.] NINDS, NIH, Bethesda, MD 20892 USA. [White, R.; Petkau, A. J.] Univ British Columbia, Stat, Vancouver, BC V5Z 1M9, Canada. [Vuolo, L.] Univ Florence, Neurol & Radiol, Florence, Italy. [Collins, T. L.] Myelin Repair Fdn, Saratoga, CA USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P489 BP 284 EP 284 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300650 ER PT J AU Campion, T Smith, P Altmann, DR Turner, BP Evanson, J George, IC Sati, P Reich, DS Miquel, ME Schmierer, K AF Campion, T. Smith, P. Altmann, D. R. Turner, B. P. Evanson, J. George, I. C. Sati, P. Reich, D. S. Miquel, M. E. Schmierer, K. TI FLAIR* for the non-invasive histological diagnosis of MS SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Campion, T.; Smith, P.; Evanson, J.] Royal London Hosp, Barts Hlth NHS Trust, Dept Imaging, London E1 1BB, England. [Altmann, D. R.] London Sch Hygeine & Trop Med, London WC1E 7HT, England. [Turner, B. P.; Schmierer, K.] Royal London Hosp, Dept Neurol, Barts Hlth NHS Trust, London E1 1BB, England. [George, I. C.; Sati, P.; Reich, D. S.] NINDS, NIH, Translat Neuroradiol Unit, Bethesda, MD 20892 USA. [Miquel, M. E.] Barts Hlth NHS Trust, Med Phys, London, England. [Schmierer, K.] Barts & London Queen Marys Sch Med & Dent, Blizard Inst, Expt Med, London, England. RI Reich, Daniel/E-5701-2010; OI Reich, Daniel/0000-0002-2628-4334; Miquel, Marc/0000-0003-2209-2076 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P501 BP 289 EP 290 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300662 ER PT J AU Dewey, BE Vuolo, L Shea, CD Inati, SJ Reich, DS Sati, P AF Dewey, B. E. Vuolo, L. Shea, C. D. Inati, S. J. Reich, D. S. Sati, P. TI Central vein detection in MS lesions using FLAIR* at 7T SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Dewey, B. E.; Vuolo, L.; Shea, C. D.; Reich, D. S.; Sati, P.] NINDS, NIH, Bethesda, MD 20892 USA. [Vuolo, L.] Univ Florence, Dept Neurol, Florence, Italy. [Vuolo, L.] Univ Florence, Dept Radiol, Florence, Italy. [Inati, S. J.] NIMH, NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P523 BP 299 EP 300 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300684 ER PT J AU Mejia, A Sweeney, E Dewey, B Shea, C Sati, P Harezlak, J Reich, D Shinohara, RT AF Mejia, A. Sweeney, E. Dewey, B. Shea, C. Sati, P. Harezlak, J. Reich, D. Shinohara, R. T. TI Statistical estimation of quantitative T1 maps using standard clinical modalities SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Mejia, A.] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. [Sweeney, E.] Johns Hopkins Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Dewey, B.; Shea, C.; Sati, P.; Reich, D.] NINDS, Bethesda, MD 20892 USA. [Harezlak, J.] Indiana Univ, Fairbanks Sch Publ Hlth, Dept Biostat, Indianapolis, IN 46204 USA. [Shinohara, R. T.] Univ Penn, Dept Epidemiol & Biostat, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P526 BP 301 EP 301 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300687 ER PT J AU Gaitan, MI Yanes, P Sati, P Romero, C Reich, DS Correale, J AF Gaitan, M. I. Yanes, P. Sati, P. Romero, C. Reich, D. S. Correale, J. TI Optimal detection of infratentorial lesions with a combined dual-echo sequence: 'P2T' SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Gaitan, M. I.; Yanes, P.; Romero, C.; Correale, J.] FLENI, Neurol Res Inst, Buenos Aires, DF, Argentina. [Sati, P.; Reich, D. S.] NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P535 BP 305 EP 305 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300696 ER PT J AU Absinta, M Govind, N Filippi, M Ray-Chaudhury, A Reyes-Mantilla, MI Pardo, CA Reich, DS AF Absinta, M. Govind, N. Filippi, M. Ray-Chaudhury, A. Reyes-Mantilla, M. I. Pardo, C. A. Reich, D. S. TI Postmortem MRI to guide pathological localization: individualized, 3D-printed cutting boxes for fixed brains SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Absinta, M.; Govind, N.; Reich, D. S.] NINDS, Translat Neuroradiol Unit, NIH, Bethesda, MD 20892 USA. [Absinta, M.; Filippi, M.] Univ Vita Salute San Raffaele, Neuroimaging Res Unit, Inst Expt Neurol, Div Neurosci,San Raffaele Sci Inst, Milan, Italy. [Ray-Chaudhury, A.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Reyes-Mantilla, M. I.; Pardo, C. A.; Reich, D. S.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P687 BP 369 EP 369 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300848 ER PT J AU Steiner, ME Triulzi, DJ Assmann, SF Sloan, SR Delaney, M Blajchman, MA Granger, S D'Andrea, PA Pulkrabek, S Stowell, CP AF Steiner, M. E. Triulzi, D. J. Assmann, S. F. Sloan, S. R. Delaney, M. Blajchman, M. A. Granger, S. D'Andrea, P. A. Pulkrabek, S. Stowell, C. P. CA F Transfusion Med Hemostasis TI Randomized Trial Results: Red Cell Storage Age is Not Associated with a Significant Difference in Multiple-Organ Dysfunction Score or Mortality in Transfused Cardiac Surgery Patients SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Steiner, M. E.; Pulkrabek, S.] Univ Minnesota, Minneapolis, MN USA. [Triulzi, D. J.; D'Andrea, P. A.] Univ Pittsburgh, Pittsburgh, PA USA. [Assmann, S. F.; Granger, S.] NERI, Watertown, MA USA. [Sloan, S. R.] Boston Childrens Hosp, Boston, MA USA. [Delaney, M.] Puget Sound Blood Ctr, Seattle, WA 98104 USA. [Blajchman, M. A.] McMaster Univ, Hamilton, ON, Canada. [Stowell, C. P.] MGH, Boston, MA USA. [F Transfusion Med Hemostasis] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 14 Z9 14 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA P2-030A BP 15A EP 15A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300003 ER PT J AU Srivastava, K Chen, Q Ardinski, SC Lam, K Huvard, MJ Schmid, P Flegel, WA AF Srivastava, K. Chen, Q. Ardinski, S. C. Lam, K. Huvard, M. J. Schmid, P. Flegel, W. A. TI Full-length Nucleotide Sequence of SLC44A2 Alleles Encoding Human Neutrophil Antigen-3 (HNA-3) in African Americans and Caucasians SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Srivastava, K.; Ardinski, S. C.; Lam, K.; Huvard, M. J.; Schmid, P.; Flegel, W. A.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Chen, Q.] Jiangsu Prov Blood Ctr, Nanjing, Jiangsu, Peoples R China. 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA S10-010B BP 21A EP 21A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300017 ER PT J AU Accooe, P Fellowes, VS Byrne, KM Sabatino, M Fowler, D Stroncek, DF AF Accooe, P. Fellowes, V. S. Byrne, K. M. Sabatino, M. Fowler, D. Stroncek, D. F. TI Culture of Rapamycin (Sirolimus)-Generated Allogeneic Th2 Cells with Alternative Protein Sources SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Accooe, P.; Byrne, K. M.; Sabatino, M.; Stroncek, D. F.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Fellowes, V. S.; Fowler, D.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA S18-010C BP 23A EP 24A PG 2 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300026 ER PT J AU Sabino, EC Oliveira, CD Loureiro, P Lopes, M Capuani, LD McClure, C Chowdhury, D Kleinman, S Busch, M Custer, B AF Sabino, E. C. Oliveira, C. D. Loureiro, P. Lopes, M. Capuani, L. D. McClure, C. Chowdhury, D. Kleinman, S. Busch, M. Custer, B. CA NHLBI Recipient Epidemiology Donor TI Symptoms and Outcomes of Dengue Among Transfusion Recipients in Brazil Who Were RNA plus or Who Received an RNA plus unit Compared to RNA- Recipients SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Sabino, E. C.; Capuani, L. D.] Univ Sao Paulo, Sao Paulo, Brazil. [Oliveira, C. D.] Fed Univ Sao Joao de Rei, Divinopolis, Brazil. [Loureiro, P.] Hemope, Recife, PE, Brazil. [Lopes, M.] Hemorio, Rio De Janeiro, Brazil. [McClure, C.; Chowdhury, D.] RTI Int, Rockville, MD USA. [Kleinman, S.; Busch, M.; Custer, B.] Blood Syst Res Inst, San Francisco, CA USA. [NHLBI Recipient Epidemiology Donor] NIH, Bethesda, MD 20892 USA. RI Sabino, Ester/F-7750-2010 OI Sabino, Ester/0000-0003-2623-5126 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA S28-020B BP 28A EP 28A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300036 ER PT J AU Cid, J Ziman, A West, K O'Brien, K Murphy, M Wendel, S Bueno, J Hervig, T Delaney, M Yazer, MH AF Cid, J. Ziman, A. West, K. O'Brien, K. Murphy, M. Wendel, S. Bueno, J. Hervig, T. Delaney, M. Yazer, M. H. TI Low Incidence of Anti-D Alloimmunization Following D plus Platelet Transfusion: Initial Report of the ADAPT Study SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [West, K.] NIH, Bethesda, MD 20892 USA. [Cid, J.] Univ Barcelona, Hosp Clin, Barcelona, Spain. [Yazer, M. H.] Univ Pittsburgh, Pittsburgh, PA USA. [Delaney, M.] Puget Sound Blood Ctr, Seattle, WA 98104 USA. [Hervig, T.] Haukeland Hosp, N-5021 Bergen, Norway. [Wendel, S.] Hosp Sirio Libanes, Sao Paulo, Brazil. [Ziman, A.] Ronald Reagan UCLA Med Ctr, UCLA Hlth Syst, Los Angeles, CA USA. [Murphy, M.] Natl Blood Serv, Oxford, England. [O'Brien, K.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Bueno, J.] Univ Hosp Puerta de Hierro, Madrid, Spain. 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA S40-030G BP 32A EP 33A PG 2 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300048 ER PT J AU Custer, B Sheon, N Siedle-Khan, B Pollack, LM Spencer, BR Bialkowski, W D'Andrea, PA Sullivan, M Glynn, S Williams, A AF Custer, B. Sheon, N. Siedle-Khan, B. Pollack, L. M. Spencer, B. R. Bialkowski, W. D'Andrea, P. A. Sullivan, M. Glynn, S. Williams, A. CA F NHLBI Recipient Epidemiology Don TI Noncompliance with the Men Who Have Sex with Men (MSM) Deferral among Male US Blood Donors SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Custer, B.] Blood Syst Res Inst, San Francisco, CA USA. [Williams, A.] US FDA, Silver Spring, MD USA. [Glynn, S.] NHLBI, Bethesda, MD 20892 USA. [Sullivan, M.] RTI Int, Rockville, MD USA. [D'Andrea, P. A.] Inst Transfus Med, Pittsburgh, PA USA. [Bialkowski, W.] BloodCtr Wisconsin, Milwaukee, WI USA. [Sheon, N.; Siedle-Khan, B.; Pollack, L. M.] USCF, Ctr AIDS Prevent Studies, San Francisco, CA USA. [Spencer, B. R.] ARC, Boston, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA S46-030H BP 35A EP 35A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300054 ER PT J AU Vahidnia, F Stramer, SL Kessler, DA Leparc, GF Krysztof, DE Dodd, RY Glynn, S Custer, B AF Vahidnia, F. Stramer, S. L. Kessler, D. A. Leparc, G. F. Krysztof, D. E. Dodd, R. Y. Glynn, S. Custer, B. TI Motivations for Donating and Attitudes Toward Screening Policies in Donors with Viral Infection SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Vahidnia, F.; Custer, B.] Blood Syst Res Inst, San Francisco, CA USA. [Stramer, S. L.; Krysztof, D. E.; Dodd, R. Y.] Amer Red Cross, Rockville, MD USA. [Kessler, D. A.] New York Blood Ctr, New York, NY 10021 USA. [Leparc, G. F.] OneBlood, Tampa, FL USA. [Glynn, S.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA S49-030H BP 36A EP 37A PG 2 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300057 ER PT J AU Cable, RG Brambilla, D Glynn, S Mast, AE Kiss, JE AF Cable, R. G. Brambilla, D. Glynn, S. Mast, A. E. Kiss, J. E. CA F NHLBI Recipient Epidemiology Don Hemoglobin Iron Recovery Study TI Quantification of Iron Stores, Body Iron, and Iron Absorption in Blood Donors: Effect of Iron Supplementation SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Cable, R. G.] Amer Red Cross, Farmington, CT USA. [Brambilla, D.] RTI Int, Rockville, MD USA. [Glynn, S.] NHLBI, NIH, Bethesda, MD 20892 USA. [Kiss, J. E.] Inst Transfus Med, Pittsburgh, PA USA. [Mast, A. E.] Blood Ctr Wisconsin, Milwaukee, WI USA. [Hemoglobin Iron Recovery Study] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA S50-030H BP 37A EP 37A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300058 ER PT J AU Yuan, Y Adams, SD Dinauer, DM Rosenau, CM Uribe, MR Flegel, WA AF Yuan, Y. Adams, S. D. Dinauer, D. M. Rosenau, C. M. Uribe, M. R. Flegel, W. A. TI KIR mRNA Expression Assays for Natural Killer Cells and Peripheral Blood Mononuclear Cells SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Yuan, Y.; Adams, S. D.; Uribe, M. R.; Flegel, W. A.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Dinauer, D. M.; Rosenau, C. M.] Life Technol, Med Sci Res & Dev, Brown Deer, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP19 BP 61A EP 61A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300113 ER PT J AU Perry, R Shirey, RS Ness, PM King, KE AF Perry, R. Shirey, R. S. Ness, P. M. King, K. E. TI Evaluation of Inconclusive Reactivity Detected in Antibody Screening and Panel Tests by Automated Solid-Phase Red Cell Adherence SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Perry, R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Shirey, R. S.; Ness, P. M.; King, K. E.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP272 BP 165A EP 165A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300364 ER PT J AU West, K Leitman, SF Olivier, K Chang, R Freeman, A Grimes, G Kolf, M Cantilena, C AF West, K. Leitman, S. F. Olivier, K. Chang, R. Freeman, A. Grimes, G. Kolf, M. Cantilena, C. TI Antimicrobial-Infused Cryoprecipitate Gel for the Management of Persistent Pulmonary Mycetoma SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [West, K.; Leitman, S. F.; Cantilena, C.] NIH, Chevy Chase, MD USA. [Chang, R.] NIH, Bethesda, MD 20892 USA. [Olivier, K.; Freeman, A.] NIAID, Bethesda, MD 20892 USA. [Grimes, G.; Kolf, M.] NIH, Pharmaceut Dev Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP363 BP 201A EP 202A PG 2 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300455 ER PT J AU Custer, B Kessler, DA Vahidnia, F Leparc, GF Krysztof, DE Shaz, BH Kamel, H Glynn, S Dodd, RY Stramer, SL AF Custer, B. Kessler, D. A. Vahidnia, F. Leparc, G. F. Krysztof, D. E. Shaz, B. H. Kamel, H. Glynn, S. Dodd, R. Y. Stramer, S. L. CA F NHLBI Retrovirus Epidemiology TI Behavioral Factors Associated with HIV, HBV, HCV, and HTLV Infections in US Blood Donors SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Custer, B.; Vahidnia, F.] Blood Syst Res Inst, San Francisco, CA USA. [Kessler, D. A.; Shaz, B. H.] New York Blood Ctr, Nyc, NY USA. [Leparc, G. F.] OneBlood, Tampa, FL USA. [Kamel, H.] Blood Syst Inc, Scottsdale, AZ USA. [Krysztof, D. E.; Dodd, R. Y.; Stramer, S. L.] Amer Red Cross, Rockville, MD USA. [Glynn, S.; F NHLBI Retrovirus Epidemiology] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP384 BP 209A EP 210A PG 2 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300476 ER PT J AU Zeng, P Wang, J Huang, X Cao, R Zhu, L Lee, T Liu, J Yuan, M Ness, PM Shan, H AF Zeng, P. Wang, J. Huang, X. Cao, R. Zhu, L. Lee, T. Liu, J. Yuan, M. Ness, P. M. Shan, H. CA NHLBI Recipient Epidemiology Donor TI Seroprevalence and Rates of Asymptomatic Viremia of Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) in Chinese Blood Donors SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Zeng, P.; Wang, J.] CAMS, Inst Blood Transfus, Chengdu, Peoples R China. [Huang, X.] Xinyang Blood Ctr, Xinyang, Peoples R China. [Cao, R.] Mianyang Blood Ctr, Mianyang, Peoples R China. [Zhu, L.] Luoyang Blood Ctr, Luoyang, Peoples R China. [Lee, T.] Blood Syst Res Inst, San Francisco, CA USA. [Liu, J.; Ness, P. M.; Shan, H.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Yuan, M.] RTI Int, Rockville, MD USA. [NHLBI Recipient Epidemiology Donor] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP386 BP 210A EP 211A PG 2 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300478 ER PT J AU Williams, JD Robertson, GF Dixon, M Haubert, N Williamson, PC Leparc, GF Caglioti, S Spizman, R Bravo, MD Williams, RC AF Williams, J. Dunn Robertson, G. F. Dixon, M. Haubert, N. Williamson, P. C. Leparc, G. F. Caglioti, S. Spizman, R. Bravo, M. D. Williams, R. C. TI Outcome Assessment with Implementation of Second-Generation Hepatitis B Virus (HBV) NAT in Blood Donation SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Williams, R. C.] NIH, Epidemiol & Clin Res Branch, Phoenix, AZ USA. [Williams, J. Dunn; Robertson, G. F.; Dixon, M.; Haubert, N.; Williamson, P. C.; Leparc, G. F.; Caglioti, S.; Spizman, R.] Creat Testing Solut, Tempe, AZ USA. [Leparc, G. F.] OneBlood, St Petersburg, FL USA. [Bravo, M. D.] Blood Syst Inc, Scottsdale, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP387 BP 211A EP 211A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300479 ER PT J AU Liu, Y He, M Liu, J Liao, H Zhu, L Li, X Wen, X Li, J Chowdhury, D Shan, H AF Liu, Y. He, M. Liu, J. Liao, H. Zhu, L. Li, X. Wen, X. Li, J. Chowdhury, D. Shan, H. CA NHLBI Recipient Epidemiology Donor Evaluation Study-III TI Screening and Confirmatory Test-Ppositive Rates of HBsAg among Blood Donors from Five Chinese Blood Centers SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Liu, Y.; He, M.] Chinese Acad Med Sci, Inst Blood Transfus, Chengdu, Peoples R China. [Liu, J.; Shan, H.] Johns Hopkins Sch Med, Baltimore, MD USA. [Liao, H.] Chongqing Blood Ctr, Chongqing, Peoples R China. [Zhu, L.] Luoyang Blood Ctr, Luoyang, Peoples R China. [Li, X.] Urumqi Blood Ctr, Urumqi, Peoples R China. [Wen, X.] Mianyang Blood Ctr, Miayang, Peoples R China. [Li, J.] Guangxi Blood Ctr, Liuzhou, Peoples R China. [Chowdhury, D.] RTI Int, Rockville, MD USA. [NHLBI Recipient Epidemiology; Donor Evaluation Study-III] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP390 BP 212A EP 212A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300482 ER PT J AU He, M Gao, Z Chowdhury, D Wang, J Mao, W Lv, Y Bi, X Cao, R Xu, J Shan, H AF He, M. Gao, Z. Chowdhury, D. Wang, J. Mao, W. Lv, Y. Bi, X. Cao, R. Xu, J. Shan, H. CA NHLBI Recipient Epidemiology Donor Evaluation Study-III TI High Proportion of Anti-HCV EIA False-positive Results among Chinese Blood Donors: A Multi-Center Study SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [He, M.; Gao, Z.; Wang, J.] Chinese Acad Med Sci, Inst Blood Transfus, Chengdu, Peoples R China. [He, M.; Gao, Z.; Wang, J.] Peking Univ, Chengdu, Peoples R China. [Chowdhury, D.] RTI Int, Rockville, MD USA. [Mao, W.] Chongqing Blood Ctr, Chongqing, Peoples R China. [Lv, Y.] Luoyang Blood Ctr, Luoyang, Peoples R China. [Bi, X.] Urumqi Blood Ctr, Urumqi, Peoples R China. [Cao, R.] Mianyang Blood Ctr, Mianyang, Peoples R China. [Xu, J.] Guangxi Blood Ctr, Liuzhou, Peoples R China. [Shan, H.] Johns Hopkins Sch Med, Baltimore, MD USA. [NHLBI Recipient Epidemiology; Donor Evaluation Study-III] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP392 BP 213A EP 213A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300484 ER PT J AU Chen, Q Liu, Z Xiao, J Flegel, WA AF Chen, Q. Liu, Z. Xiao, J. Flegel, W. A. TI Genotype Frequencies of Human Neutrophil Antigen-3 (HNA-3) Polymorphisms in the Han, Tibetan, and Yi populations of China SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Chen, Q.; Xiao, J.] Jiangsu Prov Blood Ctr, Nanjing, Jiangsu, Peoples R China. [Liu, Z.] Chinese Acad Med Sci, Inst Blood Transfus, Chengdu, Peoples R China. [Liu, Z.] Peking Union Med Coll, Chengdu, Peoples R China. [Flegel, W. A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP403 BP 217A EP 218A PG 2 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300495 ER PT J AU Gharwan, H Neary, NM Link, M Hsieh, MM Fitzhugh, CD Sherins, RJ Tisdale, JF AF Gharwan, Helen Neary, Nicola M. Link, Mary Hsieh, Matthew M. Fitzhugh, Courtney D. Sherins, Richard J. Tisdale, John F. TI SUCCESSFUL FERTILITY RESTORATION AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION SO ENDOCRINE PRACTICE LA English DT Article ID BONE-MARROW-TRANSPLANTATION; IRON OVERLOAD; DISEASE; HYPOGONADISM; PARAMETERS; HYDROXYUREA; RECIPIENTS; RADIATION; THERAPY AB Objective: Myeloablative conditioning regimens given prior to hematopoietic stem cell transplantation (HSCT) frequently cause permanent sterility in men. In patients with sickle cell disease (SCD) we use a nonmyeloablative regimen with sirolimus, alemtuzumab, and low-dose total-body irradiation (300 centigrays) with gonadal shielding preceding allogeneic HSCT. We report here the restoration of azoospermia in a patient with SCD after allogeneic HSCT. We discuss the impact of our patient's underlying chronic medical conditions and the therapies he had received (frequent blood transfusions, iron chelating drugs, ribavirin, hydroxyurea, opioids), as well as the impact of the nonmyeloablative conditioning regimen on male gonadal function, and we review the literature on this topic. Methods: We determined the patient's reproductive hormonal values and his semen parameters before, during, and after HSCT and infertility treatment. In addition, we routinely measured his serum laboratory parameters pertinent to SCD and infertility, such as iron and ferritin levels. A karyotype analysis was performed to assess the potential presence of Klinefelter syndrome. Finally, imaging studies of the patient's brain and testes were done to rule out further underlying pathology. Results: A 42-year-old man with SCD, transfusional iron overload, and hepatitis C underwent a nonmyeloablative allogeneic HSCT. One year later he desired to father a child but was found to be azoospermic in the context of hypogonadotropic hypogonadism. Restoration of fertility was attempted with human chorionic gonadotropin (2,000 IU) plus human menopausal gonadotropin (75 IU follicle-stimulating hormone) injected subcutaneously 3 times weekly. Within 6 months of treatment, the patient's serum calculated free testosterone value normalized, and his sperm count and sperm motility improved. After 10 months, he successfully initiated a pregnancy through intercourse. The pregnancy was uncomplicated, and a healthy daughter was delivered naturally at term. Conclusion: Despite exposure to several gonadotoxins, transfusional iron overload and nonmyeloablative conditioning with radiation causing severe testicular atrophy suggesting extensive damage to seminiferous tubules and possibly Leydig cells, gonadotropins were efficacious in restoring our patient's reproductive capability. C1 [Gharwan, Helen] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Neary, Nicola M.] St George Hosp, Dept Endocrinol, London, England. [Link, Mary; Hsieh, Matthew M.; Fitzhugh, Courtney D.; Tisdale, John F.] NHLBI, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. [Sherins, Richard J.; Tisdale, John F.] Columbia Fertil Associates, Washington, DC USA. RP Gharwan, H (reprint author), NCI, Med Oncol Branch, Bethesda, MD 20892 USA. EM helen.gharwan@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 20 TC 3 Z9 3 U1 0 U2 1 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD SEP PY 2014 VL 20 IS 9 BP E157 EP E161 DI 10.4158/EP13474.CR PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC0LN UT WOS:000350027300002 PM 24936546 ER PT J AU Dettmer, AM Hinde, K Ross, CN Rutherford, JN AF Dettmer, A. M. Hinde, K. Ross, C. N. Rutherford, J. N. TI BEING A SCIENTIST ONLINE: POSSIBILITIES, PRAGMATICS & PITFALLS SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-Society-of-Primatologists CY SEP 12-15, 2014 CL Decatur, GA SP Amer Soc Primatologists C1 [Dettmer, A. M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Poolesville, MD 20837 USA. [Hinde, K.] Harvard Univ, Dept Human Evolutionary Biol, Cambridge, MA 02138 USA. [Ross, C. N.] Texas A&M Univ, Dept Arts & Sci, San Antonio, TX 78224 USA. [Rutherford, J. N.] Univ Illinois, Dept Women Children & Family Hlth Sci, Chicago, IL 60612 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2014 VL 76 SU 1 MA 10 BP 40 EP 40 PG 1 WC Zoology SC Zoology GA CB1GE UT WOS:000349374300011 ER PT J AU Simpson, EA Paukner, A Suomi, SJ Ferrari, PF AF Simpson, E. A. Paukner, A. Suomi, S. J. Ferrari, P. F. TI NEONATAL CAREGIVER-INFANT SOCIAL EXCHANGES AFFECT SOCIAL DEVELOPMENT IN NURSERY-REARED RHESUS MACAQUES (MACACA MULATTA) IN THE FIRST YEAR OF LIFE SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-Society-of-Primatologists CY SEP 12-15, 2014 CL Decatur, GA SP Amer Soc Primatologists C1 [Simpson, E. A.; Ferrari, P. F.] Univ Parma, Dipartimento Neurosci, I-4300 Parma, Italy. [Simpson, E. A.; Paukner, A.; Suomi, S. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2014 VL 76 SU 1 MA 17 BP 42 EP 42 PG 1 WC Zoology SC Zoology GA CB1GE UT WOS:000349374300018 ER PT J AU Gerald, MS AF Gerald, M. S. TI DIFFERENT INSIGHTS ABOUT SOCIAL PROCESSES IN PRIMATES SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-Society-of-Primatologists CY SEP 12-15, 2014 CL Decatur, GA SP Amer Soc Primatologists C1 [Gerald, M. S.] NIA, Div Behav & Social Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2014 VL 76 SU 1 MA 27 BP 45 EP 45 PG 1 WC Zoology SC Zoology GA CB1GE UT WOS:000349374300028 ER PT J AU Jefferson, JP Riddle, A Paukner, A Suomi, SJ AF Jefferson, J. P. Riddle, A. Paukner, A. Suomi, S. J. TI EXPLORING THE AFFECTIVE ASPECTS OF FUR RUBBING IN CAPTIVE BROWN CAPUCHIN (CEBUS APELLA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-Society-of-Primatologists CY SEP 12-15, 2014 CL Decatur, GA SP Amer Soc Primatologists C1 [Jefferson, J. P.] Univ Calif Davis, Anim Behav Grad Grp, Davis, CA 95616 USA. [Riddle, A.; Paukner, A.; Suomi, S. J.] NICHHD, Lab Comparat Ethol, Poolesville, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2014 VL 76 SU 1 MA 43 BP 51 EP 51 PG 1 WC Zoology SC Zoology GA CB1GE UT WOS:000349374300044 ER PT J AU Loveland, DG Dent, BE Skidmore, MA Sorenson, AN Schwandt, ML Lindell, SG Suomi, SJ Barr, CS Higley, JD AF Loveland, D. G. Dent, B. E. Skidmore, M. A. Sorenson, A. N. Schwandt, M. L. Lindell, S. G. Suomi, S. J. Barr, C. S. Higley, J. D. TI MAOA GENOTYPE X ENVIRONMENT INTERACTION AND INFLUENCE ON MONOAMINE NEUROTRANSMITTER FUNCTIONING IN RHESUS MACAQUES (MACACA MULATTA) LIVING IN LARGE OUTDOOR CORRALS SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-Society-of-Primatologists CY SEP 12-15, 2014 CL Decatur, GA SP Amer Soc Primatologists C1 [Loveland, D. G.; Dent, B. E.; Skidmore, M. A.; Sorenson, A. N.; Higley, J. D.] Brigham Young Univ, SWKT 1042, Provo, UT 84602 USA. [Schwandt, M. L.; Lindell, S. G.; Suomi, S. J.; Barr, C. S.] NICHD, NIH, Rockville, MD USA. [Schwandt, M. L.; Lindell, S. G.; Suomi, S. J.; Barr, C. S.] NIAAA, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2014 VL 76 SU 1 MA 64 BP 58 EP 58 PG 1 WC Zoology SC Zoology GA CB1GE UT WOS:000349374300065 ER PT J AU Dettmer, AM Murphy, AM Suomi, SJ AF Dettmer, A. M. Murphy, A. M. Suomi, S. J. TI DEVELOPMENT OF A COGNITIVE TESTING APPARATUS FOR SOCIALLY HOUSED MOTHER-PEER-REARED INFANT RHESUS MONKEYS SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-Society-of-Primatologists CY SEP 12-15, 2014 CL Decatur, GA SP Amer Soc Primatologists C1 [Dettmer, A. M.; Murphy, A. M.; Suomi, S. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2014 VL 76 SU 1 MA 69 BP 59 EP 59 PG 1 WC Zoology SC Zoology GA CB1GE UT WOS:000349374300070 ER PT J AU Dettmer, AM Novak, MA AF Dettmer, A. M. Novak, M. A. TI CHRONIC HORMONES AND DEMOGRAPHIC VARIABLES: CENTER-WIDE STUDIES ON NONHUMAN PRIMATE WELL-BEING SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-Society-of-Primatologists CY SEP 12-15, 2014 CL Decatur, GA SP Amer Soc Primatologists C1 [Dettmer, A. M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Poolesville, MD 20837 USA. [Novak, M. A.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2014 VL 76 SU 1 MA 88 BP 66 EP 66 PG 1 WC Zoology SC Zoology GA CB1GE UT WOS:000349374300089 ER PT J AU Dettmer, AM Rosenberg, K Menard, MT Novak, MA Meyer, JS Suomi, SJ AF Dettmer, A. M. Rosenberg, K. Menard, M. T. Novak, M. A. Meyer, J. S. Suomi, S. J. TI INFLUENCE OF PREGNANCY ON HAIR LOSS AND CHRONIC HORMONE PROFILES IN RHESUS MONKEYS (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-Society-of-Primatologists CY SEP 12-15, 2014 CL Decatur, GA SP Amer Soc Primatologists C1 [Dettmer, A. M.; Suomi, S. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, Poolesville, MD 20837 USA. [Rosenberg, K.; Menard, M. T.; Novak, M. A.; Meyer, J. S.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2014 VL 76 SU 1 MA 92 BP 67 EP 67 PG 1 WC Zoology SC Zoology GA CB1GE UT WOS:000349374300093 ER PT J AU Anderson, SK AF Anderson, Stephen K. TI Probabilistic Bidirectional Promoter Switches: Noncoding RNA Takes Control SO MOLECULAR THERAPY-NUCLEIC ACIDS LA English DT Article DE KIR; Ly49; NK cells; transcription ID ANTISENSE TRANSCRIPTS; RECEPTOR EXPRESSION; GENE-EXPRESSION; NK CELLS; IDENTIFICATION; REPERTOIRE; ASSOCIATION; ELEMENT; CLUSTER; GENOME AB The discovery of probabilistic promoter switches in genes that code for class I major histocompatibility complex receptors in mouse and human provides a useful paradigm to explain programmed cell fate decisions. These switches have preset probabilities of transcribing in either the sense or antisense direction, and the characteristics of individual switches are programmed by the relative affinity of competing transcription factor-binding sites. The noncoding RNAs produced from these switches can either activate or suppress gene transcription, based on their location relative to the promoter responsible for gene expression in mature cells. The switches are active in a developmental phase that precedes gene expression by mature cells, thus temporally separating the stochastic events that determine gene activation from the protein expression phase. This allows the probabilistic generation of variegated gene expression in the absence of selection and ensures that mature cells have stable expression of the genes. Programmed probabilistic switches may control cell fate decisions in many developmental systems, and therefore, it is important to investigate noncoding RNAs expressed by progenitor cells to determine if they are expressed in a stochastic manner at the single cell level. This review provides a summary of current knowledge regarding murine and human switches, followed by speculation on the possible involvement of probabilistic switches in other systems of programmed differentiation. C1 [Anderson, Stephen K.] Leidos Biomed Res Inc, Basic Sci Program, Expt Immunol Lab, Frederick Natl Lab, Frederick, MD USA. [Anderson, Stephen K.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Anderson, SK (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. EM andersonst@mail.nih.gov FU National Cancer Institute (NCI), National Institutes of Health (NIH) [HHSN261200800001E]; NIH, NCI, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under contract HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. NR 29 TC 3 Z9 3 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2162-2531 J9 MOL THER-NUCL ACIDS JI Mol. Ther.-Nucl. Acids PD SEP PY 2014 VL 3 AR e191 DI 10.1038/mtna.2014.42 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CB7WK UT WOS:000349839100002 PM 25181276 ER PT J AU DeCicco-Skinner, KL Henry, GH Cataisson, C Tabib, T Gwilliam, JC Watson, NJ Bullwinkle, EM Falkenburg, L O'Neill, RC Morin, A Wiest, JS AF DeCicco-Skinner, Katie L. Henry, Gervaise H. Cataisson, Christophe Tabib, Tracy Gwilliam, J. Curtis Watson, Nicholas J. Bullwinkle, Erica M. Falkenburg, Lauren O'Neill, Rebecca C. Morin, Adam Wiest, Jonathan S. TI Endothelial Cell Tube Formation Assay for the In Vitro Study of Angiogenesis SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Cancer Biology; Issue 91; Angiogenesis; tube formation; fibroblast; endothelial cell; matrix; 3B-11; basement membrane extract; tubulogenesis ID TUMOR ANGIOGENESIS; BASEMENT-MEMBRANE AB Angiogenesis is a vital process for normal tissue development and wound healing, but is also associated with a variety of pathological conditions. Using this protocol, angiogenesis may be measured in vitro in a fast, quantifiable manner. Primary or immortalized endothelial cells are mixed with conditioned media and plated on basement membrane matrix. The endothelial cells form capillary like structures in response to angiogenic signals found in conditioned media. The tube formation occurs quickly with endothelial cells beginning to align themselves within 1 hr and lumencontaining tubules beginning to appear within 2 hr. Tubes can be visualized using a phase contrast inverted microscope, or the cells can be treated with calcein AM prior to the assay and tubes visualized through fluorescence or confocal microscopy. The number of branch sites/nodes, loops/meshes, or number or length of tubes formed can be easily quantified as a measure of in vitro angiogenesis. In summary, this assay can be used to identify genes and pathways that are involved in the promotion or inhibition of angiogenesis in a rapid, reproducible, and quantitative manner. C1 [DeCicco-Skinner, Katie L.; Henry, Gervaise H.; Tabib, Tracy; Gwilliam, J. Curtis; Watson, Nicholas J.; Bullwinkle, Erica M.; Falkenburg, Lauren; O'Neill, Rebecca C.; Morin, Adam] Amer Univ, Dept Biol, Washington, DC 20016 USA. [Cataisson, Christophe; Wiest, Jonathan S.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP DeCicco-Skinner, KL (reprint author), Amer Univ, Dept Biol, Washington, DC 20016 USA. EM decicco@american.edu FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health; NCI grant [UA5CA152907] FX This research was supported in part by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health, and by NCI grant UA5CA152907. NR 16 TC 6 Z9 7 U1 3 U2 8 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD SEP PY 2014 IS 91 AR e51312 DI 10.3791/51312 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB0FM UT WOS:000349301100010 PM 25225985 ER PT J AU Hoenen, T Watt, A Mora, A Feldmann, H AF Hoenen, Thomas Watt, Ari Mora, Anita Feldmann, Heinz TI Modeling The Lifecycle Of Ebola Virus Under Biosafety Level 2 Conditions With Virus-like Particles Containing Tetracistronic Minigenomes SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Infectious Diseases; Issue 91; hemorrhagic Fevers; Viral; Mononegavirales Infections; Ebola virus; filovirus; lifecycle modeling system; minigenome; reverse genetics; virus-like particles; replication; transcription; budding; morphogenesis; entry ID REVERSE GENETICS; REPLICATION; TRANSCRIPTION; SYSTEMS; GENOME; VP24 AB Ebola viruses cause severe hemorrhagic fevers in humans and non-human primates, with case fatality rates as high as 90%. There are no approved vaccines or specific treatments for the disease caused by these viruses, and work with infectious Ebola viruses is restricted to biosafety level 4 laboratories, significantly limiting the research on these viruses. Lifecycle modeling systems model the virus lifecycle under biosafety level 2 conditions; however, until recently such systems have been limited to either individual aspects of the virus lifecycle, or a single infectious cycle. Tetracistronic minigenomes, which consist of Ebola virus non-coding regions, a reporter gene, and three Ebola virus genes involved in morphogenesis, budding, and entry (VP40, GP(1,2) and VP24), can be used to produce replication and transcription-competent viruslike particles (trVLPs) containing these minigenomes. These trVLPs can continuously infect cells expressing the Ebola virus proteins responsible for genome replication and transcription, allowing us to safely model multiple infectious cycles under biosafety level 2 conditions. Importantly, the viral components of this systems are solely derived from Ebola virus and not from other viruses (as is, for example, the case in systems using pseudotyped viruses), and VP40, GP(1,2) and VP24 are not overexpressed in this system, making it ideally suited for studying morphogenesis, budding and entry, although other aspects of the virus lifecycle such as genome replication and transcription can also be modeled with this system. Therefore, the tetracistronic trVLP assay represents the most comprehensive lifecycle modeling system available for Ebola viruses, and has tremendous potential for use in investigating the biology of Ebola viruses in future. Here, we provide detailed information on the use of this system, as well as on expected results. C1 [Hoenen, Thomas; Watt, Ari; Feldmann, Heinz] NIAID, Lab Virol, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Mora, Anita] NIAID, Res Technol Branch, Div Intramural Res, NIH, Bethesda, MD USA. RP Hoenen, T (reprint author), NIAID, Lab Virol, Div Intramural Res, NIH, Bethesda, MD 20892 USA. EM thomas.hoenen@nih.gov OI Hoenen, Thomas/0000-0002-5829-6305 FU Intramural Research Program of the NIH; NIAID FX The authors are very grateful to Bob Fischer (LV, DIR, NIAID, NIH), who acted as narrator, as well as Austin Athman (RTB, DIR, NIAID, NIH) and Megan Morgan (DOHS, ORS, OD, NIH) for their help with making the movie accompanying this manuscript. Further, we would like to thank Allison Groseth (LV, DIR, NIAID, NIH) for critical reading of the manuscript. This research was supported by the Intramural Research Program of the NIH, NIAID. NR 18 TC 0 Z9 0 U1 1 U2 16 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD SEP PY 2014 IS 91 AR e52381 DI 10.3791/52381 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB0FM UT WOS:000349301100084 ER PT J AU Heitmann, RJ Mumford, SL Hill, MJ Armstrong, AY AF Heitmann, Ryan J. Mumford, Sunni L. Hill, Micah J. Armstrong, Alicia Y. TI Estimated Economic Impact of the Levonorgestrel Intrauterine System on Unintended Pregnancy in Active Duty Women SO MILITARY MEDICINE LA English DT Article ID OPERATION IRAQI FREEDOM; UNITED-STATES; CONTRACEPTIVE USE; HEALTH-CARE; MILITARY; SERVICEWOMEN; FACILITIES; CAMPS; COST AB Unintended pregnancy is reportedly higher in active duty women; therefore, we sought to estimate the potential impact of the levonorgestrel-containing intrauterine system (LNG-IUS) could have on unintended pregnancy in active duty women. A decision tree model with sensitivity analysis was used to estimate the number of unintentional pregnancies in active duty women which could be prevented. A secondary cost analysis was performed to analyze the direct cost savings to the U.S. Government. The total number of Armed Services members is estimated to be over 1.3 million, with an estimated 208,146 being women. Assuming an age-standardized unintended pregnancy rate of 78 per 1,000 women, 16,235 unintended pregnancies occur each year. Using a combined LNG-IUS failure and expulsion rate of 2.2%, a decrease of 794, 1588, and 3970 unintended pregnancies was estimated to occur with 5%, 10% and 25% usage, respectively. Annual cost savings from LNG-IUS use range from $3,387,107 to $47,352,295 with 5% to 25% intrauterine device usage. One-way sensitivity analysis demonstrated LNG-IUS to be cost-effective when the cost associated with pregnancy and delivery exceeded $11,000. Use of LNG-IUS could result in significant reductions in unintended pregnancy among active duty women, resulting in substantial cost savings to the government health care system. C1 [Heitmann, Ryan J.; Hill, Micah J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Heitmann, Ryan J.; Hill, Micah J.] Walter Reed Natl Mil Med Ctr, Bethesda, MD 20814 USA. [Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Armstrong, Alicia Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Contracept Discovery & Dev Branch, NIH, Bethesda, MD 20892 USA. RP Heitmann, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 CRC,Room 1E-3140,10 Ctr Dr, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 47 TC 1 Z9 1 U1 0 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD SEP PY 2014 VL 179 IS 10 BP 1127 EP 1132 DI 10.7205/MILMED-D-14-00055 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA CA7LH UT WOS:000349098300013 PM 25269131 ER PT J AU Korde, N Mailankody, S Landgreni, O AF Korde, Neha Mailankody, Sham Landgreni, Ola TI The Road to Treating Smoldering Multiple Myeloma SO CLINICAL LYMPHOMA MYELOMA & LEUKEMIA LA English DT Article DE High-risk SMM; MGUS; Minimal residual disease; Monoclonal protein; Plasma cells ID UNDETERMINED SIGNIFICANCE MGUS; MULTIPARAMETER FLOW-CYTOMETRY; MONOCLONAL GAMMOPATHY; LONG-TERM; STAGE-I; PROGRESSION; RISK; DISEASE; DEXAMETHASONE; LENALIDOMIDE AB The management of smoldering multiple myeloma (SMM) has been a challenge to clinicians, ever since the condition was first characterized in 1980. While the risk of progression to symptomatic myeloma is greater for SMM (10% per year) compared to MGUS (1% per year), several SMM patients remain asymptomatic for years without evidence of disease progression. Early clinical trials focusing on early treatment of SMM have been equivocal with no clear benefit. However, the last decade has seen a greater understanding of the pathogenesis of plasma cell disorders, including SMM, and development of better therapeutics. A recent randomized trial has provided evidence of clinical benefit with early treatment of high-risk SMM. In this review, we summarize issues related to the early treatment of SMM including risk stratification and possible outcomes with therapy initiation. In the context of reviewing recent clinical trial data supporting early treatment, we define challenges faced by clinicians and provide future directions to the road to treating SMM. C1 [Korde, Neha; Mailankody, Sham; Landgreni, Ola] NCI, Multiple Myeloma Sect, Lymphoid Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Korde, Neha; Landgreni, Ola] Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, New York, NY 10065 USA. RP Korde, N (reprint author), Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. EM neha.korde@gmail.com NR 47 TC 2 Z9 2 U1 0 U2 1 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 2152-2650 EI 2152-2669 J9 CL LYMPH MYELOM LEUK JI Clin. Lymphoma Myeloma Leuk. PD SEP PY 2014 VL 14 SU 3 BP S59 EP S64 DI 10.1016/j.clml.2014.04.012 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA AX5EK UT WOS:000346949500010 PM 25486957 ER PT J AU Gill, AA Enewold, L Zahm, SH Shriver, CD Zheng, L McGlynn, KA Zhu, KM AF Gill, Abegail A. Enewold, Lindsey Zahm, Shelia H. Shriver, Craig D. Zheng, Li McGlynn, Katherine A. Zhu, Kangmin TI Adjuvant Radioactive Iodine Use Among Differentiated Thyroid Cancer Patients in the Military Health System SO MILITARY MEDICINE LA English DT Article ID UNITED-STATES; PAPILLARY; CARCINOMA; GUIDELINES; SURVIVAL; ABLATION; THERAPY; IMPACT AB Objective: Adjuvant radioactive iodine (RAI) for the treatment of differentiated thyroid cancer has been associated with better prognosis, but no consensus has been reached on the best practices for RAI. Limited data on RAI use and factors associated with the receipt of postoperative RAI in the general population are available and, to our knowledge, no data on RAI use among the U.S. Department of Defense (DoD) beneficiaries. Methods: Among 3,002 beneficiaries with differentiated thyroid cancer, who underwent total/near-total thyroidectomy between 1998 and 2007, logistic regression identified factors associated with RAI and examined effect modification by age and tumor size. Results: Fifty-two percent of patients received RAI. Receipt of RAI was more likely among beneficiaries who were diagnosed between 2004 and 2007, active duty members, had indirect care, and more advanced disease, and less likely among those affiliated with the Air Force or had unknown medical coverage. In addition, receipt of RAI significantly varied by tumor size among patients with regional lymph node metastasis. Conclusion: Among DoD beneficiaries, adjuvant RAI use was associated with clinical and nonclinical factors. Although evidence of effect modification between the recipient of RAI by tumor size was apparent, future research with a larger sample size is warranted to confirm results of this study. C1 [Gill, Abegail A.; Enewold, Lindsey; Shriver, Craig D.; Zhu, Kangmin] Walter Reed Natl Mil Med Ctr, John P Murtha Canc Ctr, Rockville, MD 20852 USA. [Zahm, Shelia H.; McGlynn, Katherine A.] NCI, Rockville, MD 20850 USA. [Shriver, Craig D.] Walter Reed Natl Mil Med Ctr, Gen Surg Serv, Bethesda, MD 20889 USA. [Shriver, Craig D.; Zhu, Kangmin] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Zheng, Li] Inova Fairfax Hosp, Inova Educ & Res Ctr, Falls Church, VA 22042 USA. RP Gill, AA (reprint author), Walter Reed Natl Mil Med Ctr, John P Murtha Canc Ctr, 11300 Rockville Pike,Suite 1215, Rockville, MD 20852 USA. RI Zahm, Shelia/B-5025-2015 FU John P. Murtha Cancer Center, Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under the Henry M. Jackson Foundation for the Advancement of Military Medicine; intramural research program of the National Cancer Institute (NCI) FX This project was supported by John P. Murtha Cancer Center, Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine and by the intramural research program of the National Cancer Institute (NCI). The original data linkage was supported by the United States Military Cancer Institute and Division of Cancer Epidemiology and Genetics, NCI. NR 23 TC 0 Z9 1 U1 0 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD SEP PY 2014 VL 179 IS 9 BP 1043 EP 1050 DI 10.7205/MILMED-D-13-00540 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CA7LF UT WOS:000349098100022 PM 25181724 ER PT J AU Kennedy, JL Schroeder, N Palacios, T Rosen, LB Martinez, B Browne, S Borish, L AF Kennedy, Joshua L. Schroeder, Nikhila Palacios, Thamiris Rosen, Lindsey B. Martinez, Bianca Browne, Sarah Borish, Larry TI Fifty-five-year-old man with chronic yeast infections SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; HYPERIMMUNOGLOBULIN-E SYNDROME; ANTI-CYTOKINE AUTOANTIBODIES; TYROSINE-KINASE-2 DEFICIENCY; INTERFERON-ALPHA; STAT1 MUTATIONS; THYMOMA; IMMUNITY; INNATE; INTERLEUKIN-12 AB As immunologists, we are frequently asked to evaluate patients with recurrent infections. These infections can provide us with clues regarding what pathways might be aberrant in a given patient, e.g., specific pyogenic bacteria with Toll-like receptor problems, atypical mycobacteria with interferon gamma receptor autoantibodies, and Candida/staphylococcal infections with cellular immune abnormalities. We present a 55-year-old man who presented to our immunology clinic with onychodystrophy of the toenails and fingernails and recurrent oral-esophageal candidiasis. The differential diagnosis for recurrent yeast infections is complex and includes usual suspects as well as some that are not as straightforward. C1 [Kennedy, Joshua L.] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72202 USA. [Schroeder, Nikhila; Palacios, Thamiris; Borish, Larry] Univ Virginia Hlth Syst, Carter Immunol Ctr, Asthma & Allerg Dis Clin Res Ctr, Charlottesville, VA USA. [Rosen, Lindsey B.; Martinez, Bianca; Browne, Sarah] NIAID, NIH, Bethesda, MD 20892 USA. RP Kennedy, JL (reprint author), Univ Arkansas Med Sci, 13 Childrens Way,Slot 512-13, Little Rock, AR 72202 USA. EM kennedyjoshua@uams.edu FU ARTrust Minigrant; COBRE pilot project grant [1P20GM103625-02]; [KL2TR000063]; [UL1TR000039] FX JL Kennedy received Grants- KL2TR000063; UL1TR000039, ARTrust Minigrant, COBRE pilot project grant 1P20GM103625-02. The remaining authors have no conflicts of interest to declare pertaining to this article NR 29 TC 2 Z9 2 U1 0 U2 1 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 EI 1539-6304 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD SEP-OCT PY 2014 VL 35 IS 5 BP 415 EP 422 DI 10.2500/aap.2014.35.3776 PG 8 WC Allergy SC Allergy GA AZ4GR UT WOS:000348180300013 PM 25295810 ER PT J AU Zand, R Lynch, JK AF Zand, Ramin Lynch, John K. TI Recanalization of Intracranial Carotid Artery Occlusion Associated with Jugular Vein Cannulation SO CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES LA English DT Article C1 [Zand, Ramin; Lynch, John K.] NINDS, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. RP Zand, R (reprint author), NINDS, NIH, Bethesda, MD 20892 USA. EM ramin.zand@gmail.com OI Zand, Ramin/0000-0002-9477-0094 NR 5 TC 0 Z9 0 U1 0 U2 0 PU CANADIAN JOURNAL NEUROLOGICAL SCIENCES INC PI CALGARY PA 709-7015 MACLEOD TRAIL SW, CALGARY, AB T2H 2K6, CANADA SN 0317-1671 J9 CAN J NEUROL SCI JI Can. J. Neurol. Sci. PD SEP PY 2014 VL 41 IS 5 BP 659 EP 660 DI 10.1017/cjn.2014.21 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AY6CB UT WOS:000347654100022 PM 25373820 ER PT J AU Cadmus-Bertram, L Irwin, M Alfano, C Campbell, K Duggan, C Foster-Schubert, K Wang, CY McTiernan, A AF Cadmus-Bertram, Lisa Irwin, Melinda Alfano, Catherine Campbell, Kristin Duggan, Catherine Foster-Schubert, Karen Wang, Ching-Yun McTiernan, Anne TI Predicting Adherence of Adults to a 12-Month Exercise Intervention SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE obesity; physical activity; behavior change; maintenance; BMI ID RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL BREAST-CANCER; OLDER-ADULTS; BODY-FAT; WOMEN; SURVIVORS; OBESITY; WEIGHT; CRYPTS AB Background: The purpose of this study was to (a) examine demographic, psychosocial, and physiological predictors of exercise adherence in a yearlong exercise intervention and (b) describe the trajectory of adherence over time. Methods: Participants were 51 men and 49 women aged 40 to 75 years. The supervised and home-based intervention consisted of 60 minutes/day, 6 days/ week of moderate-to-vigorous intensity exercise. Three adherence measures were used: (1) minutes/week, (2) MET-hours/week, and (3) change in cardiopulmonary fitness (VO(2)max). Predictors of adherence were determined separately by sex using mixed models and multivariable regression. Results: Participants performed 287 98 minutes/week of moderate-to-vigorous activity with 71% adhering to at least 80% (288 minutes/week) of the prescription. Men adhered better than women (P <.001). Among women, adiposity-related variables were significantly related to poorer adherence on all 3 measures (P <.05). A less consistent pattern was observed among men but in follow-up analyses, adiposity was associated with fewer MET-hours/week of exercise. Social support, pain, and perceived benefits were predictive in some models. Men and nonobese women experienced peak adherence at 4 to 6 months, while obese women peaked during months 0 to 3. Conclusions: When provided with supervision and support, previously sedentary men and women can achieve and maintain high levels of aerobic activity. C1 [Cadmus-Bertram, Lisa] Univ Wisconsin Madison, Dept Kinesiol, Madison, WI 53706 USA. [Irwin, Melinda] Yale Univ, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Alfano, Catherine] NCI, Off Canc Survivorship, NIH, DHHS, Bethesda, MD 20892 USA. [Campbell, Kristin] Univ British Columbia, Dept Phys Therapy, Vancouver, BC V5Z 1M9, Canada. [Duggan, Catherine; Foster-Schubert, Karen; Wang, Ching-Yun; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Cadmus-Bertram, L (reprint author), Univ Wisconsin Madison, Dept Kinesiol, Madison, WI 53706 USA. EM cadmusbertra@wisc.edu RI Duggan, Catherine/F-9414-2015 OI Duggan, Catherine/0000-0001-7369-4021 FU National Cancer Institute; National Institutes of Health [R01 CA77572] FX The original study and data collection were supported by the National Cancer Institute, National Institutes of Health (R01 CA77572). NR 25 TC 1 Z9 1 U1 5 U2 17 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 EI 1543-5474 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD SEP PY 2014 VL 11 IS 7 BP 1304 EP 1312 DI 10.1123/jpah.2012-0258 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CA1UA UT WOS:000348695600006 PM 24176780 ER PT J AU Perez, EA Holmes, E De Azambuja, E Dueck, A Baselga, J Viale, G Zujewski, JA Goldhirsch, A Crescenzo, R Pritchard, K Wolff, AC Jackisch, C Lang, I Untch, M Smith, I Boyle, F Xu, B Gomez, HL Gelber, RD Piccart, M AF Perez, E. A. Holmes, E. De Azambuja, E. Dueck, A. Baselga, J. Viale, G. Zujewski, J. A. Goldhirsch, A. Crescenzo, R. Pritchard, K. Wolff, A. C. Jackisch, C. Lang, I. Untch, M. Smith, I. Boyle, F. Xu, B. Gomez, H. L. Gelber, R. D. Piccart, M. TI DISEASE-FREE SURVIVAL (DFS) IN THE LAPATINIB ALONE ARM AND EXPANDED RESULTS OF THE PHASE III ALTTO TRIAL (BIG 2-06; NCCTG (ALLIANCE) N063D) IN THE ADJUVANT TREATMENT OF HER2-POSITIVE EARLY BREAST CANCER (EBC) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Perez, E. A.] Mayo Clin, Jacksonville, FL 32224 USA. [Holmes, E.] Frontier Sci Scotland Ltd, Stat, Kincraig, Scotland. [De Azambuja, E.] Inst Jules Bordet, B-1000 Brussels, Belgium. [Dueck, A.] Mayo Clin, Biostat Sect, Scottsdale, AZ USA. [Baselga, J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Viale, G.] Ist Europeo Oncol, Dept Pathol, Milan, Italy. [Zujewski, J. A.] NCI, Bethesda, MD 20892 USA. [Goldhirsch, A.] European Inst Oncol, Dept Med, Milan, Italy. [Crescenzo, R.] GlaxoSmithKline, Hematol Oncol, Collegeville, PA USA. [Pritchard, K.] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Wolff, A. C.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Jackisch, C.] Klinikum Offenbach GmbH, Oncol, Offenbach, Germany. [Lang, I.] Natl Inst Oncol, Dept Med Oncol, Budapest, Hungary. [Lang, I.] Natl Inst Oncol, Clin Pharmacol B, Budapest, Hungary. [Untch, M.] HELIOS Klinikum Berlin Buch, Frauenklin, Berlin, Germany. [Smith, I.] Royal Marsden Hosp NHS Trust, Sutton, Surrey, England. [Boyle, F.] Univ Sydney, Mater Hosp, Patricia Ritchie Ctr Canc Care & Res, Sydney, NSW, Australia. [Xu, B.] Chinese Acad Med Sci, Canc Hosp, Dept Med, Beijing 100730, Peoples R China. [Gomez, H. L.] Inst Nacl Enfermedades Neoplas, Lima, Peru. [Gelber, R. D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Piccart, M.] Inst Jules Bordet, B-1000 Brussels, Belgium. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA LBA7 DI 10.1093/annonc/mdu438.2 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000010 ER PT J AU Petrini, I Meltzer, PS Kim, I Lucchi, M Park, K Fontanini, G Gao, J Zucali, PA Calabrese, F Favaretto, A Rea, F Wang, Y Giaccone, G AF Petrini, I. Meltzer, P. S. Kim, I. Lucchi, M. Park, K. Fontanini, G. Gao, J. Zucali, P. A. Calabrese, F. Favaretto, A. Rea, F. Wang, Y. Giaccone, G. TI GTF2I MUTATIONS ARE FREQUENT IN THYMIC EPITHELIAL TUMORS SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Petrini, I.] Pisa Univ Hosp, Pisa, Italy. [Meltzer, P. S.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Kim, I.; Park, K.; Wang, Y.; Giaccone, G.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Lucchi, M.] Univ Pisa, Pisa, Italy. [Fontanini, G.] Azienda Osped Univ Pisana, Pisa, Italy. [Gao, J.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Zucali, P. A.] Humanitas Canc Ctr IRCCS, Dept Oncol, Rozzano, Italy. [Calabrese, F.] Univ Padua, Dept Cardiac Thorac & Vasc Sci, Padua, Italy. [Favaretto, A.] Ist Oncol Veneto IOV IRCCS, Padua, Italy. [Rea, F.] Azienda Osped Padova, Padua, Italy. NR 0 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 1557PD DI 10.1093/annonc/mdu357.1 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000440 PM 28171932 ER PT J AU Veronesi, G Lazzeroni, M Szabo, E Brown, P De Censi, A Guerrieri-Gonzaga, A Bellomi, M Radice, D Grimaldi, MC Spaggiari, L Bonanni, B AF Veronesi, G. Lazzeroni, M. Szabo, E. Brown, P. De Censi, A. Guerrieri-Gonzaga, A. Bellomi, M. Radice, D. Grimaldi, M. C. Spaggiari, L. Bonanni, B. TI LONG-TERM EFFECTS OF INHALED BUDESONIDE ON SCREENING-DETECTED LUNG NODULES SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Veronesi, G.; Spaggiari, L.] Ist Europeo Oncol, Milan, Italy. [Lazzeroni, M.; Guerrieri-Gonzaga, A.] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Szabo, E.] NCI, Div Canc Prevent, Washington, DC USA. [Brown, P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [De Censi, A.] Osped Galliera, Genoa, Italy. [Bellomi, M.; Grimaldi, M. C.] Ist Europeo Oncol, Div Radiol, Milan, Italy. [Radice, D.] Ist Europeo Oncol, Div Epidemiol & Biostat, Milan, Italy. [Bonanni, B.] European Inst Oncol, Div Canc Prevent & Genet, Milan, Italy. 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 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 1361P DI 10.1093/annonc/mdu351.2 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000382 PM 28172311 ER PT J AU Werner-Lin, A Hoskins, L Lieber, C Ratner, R AF Werner-Lin, A. Hoskins, L. Lieber, C. Ratner, R. TI A SURVEY OF GENETIC COUNSELLORS ABOUT THE NEEDS OF 18-25 YEAR OLDS FROM FAMILIES WITH HEREDITARY BREAST AND OVARIAN CANCER SYNDROME SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Werner-Lin, A.] Univ Penn, Philadelphia, PA 19104 USA. [Hoskins, L.] NIH, Div Clin Genet & Epidemiol, Bethesda, MD 20892 USA. [Lieber, C.; Ratner, R.] Sarah Lawrence Coll, Bronxville, NY 10708 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 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 493PD PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000214 ER PT J AU Cedillo-Barron, L Garcia-Cordero, J Bustos-Arriaga, J Leon-Juarez, M Gutierrez-Castaneda, B AF Cedillo-Barron, Leticia Garcia-Cordero, Julio Bustos-Arriaga, Jose Leon-Juarez, Moises Gutierrez-Castaneda, Benito TI Antibody response to dengue virus SO MICROBES AND INFECTION LA English DT Review DE Dengue virus; Antibody response; Antibody-enhanced infection ID BORNE ENCEPHALITIS-VIRUS; INNATE IMMUNE-RESPONSE; DEPENDENT ENHANCEMENT; HEMORRHAGIC-FEVER; NONSTRUCTURAL PROTEIN-1; ENVELOPE GLYCOPROTEIN; DISEASE SEVERITY; DOMAIN-III; NEUTRALIZING ANTIBODIES; DENDRITIC CELLS AB In this review, we discuss the current knowledge of the role of the antibody response against dengue virus and highlight novel insights into targets recognized by the human antibody response. We also discuss how the balance of pathological and protective antibody responses in the host critically influences clinical aspects of the disease. (C) 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. C1 [Cedillo-Barron, Leticia; Garcia-Cordero, Julio] CINVESTAV IPN, Dept Biomed Mol, Mexico City 07360, DF, Mexico. [Bustos-Arriaga, Jose] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. [Leon-Juarez, Moises] Inst Nacl Perinatol, Dept Inmunobioquim, Lomas De Virreyes 11000, Mexico. [Gutierrez-Castaneda, Benito] Univ Autonoma Mexico, Fac Estudios Super Iztacala, Lab Inmunol, Tlalnepantla, Estado De Mexic, Mexico. RP Cedillo-Barron, L (reprint author), CINVESTAV IPN, Dept Biomed Mol, Av IPN 2508, Mexico City 07360, DF, Mexico. EM lcedillo@civestav.mx FU National Council for Science and Technology (CONACyT) Grant [CB-2010-01/0154270] FX This work was supported by the National Council for Science and Technology (CONACyT) Grant CB-2010-01/0154270. Additionally, LCB is member of the National System of Researchers, SNI. NR 91 TC 5 Z9 5 U1 5 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD SEP PY 2014 VL 16 IS 9 BP 711 EP 720 DI 10.1016/j.micinf.2014.07.011 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AY9JU UT WOS:000347867100002 PM 25124542 ER PT J AU Kelada, SNP Carpenter, DE Aylor, DL Chines, P Rutledge, H Chesler, EJ Churchill, GA de Villena, FPM Schwartz, DA Collins, FS AF Kelada, Samir N. P. Carpenter, Danielle E. Aylor, David L. Chines, Peter Rutledge, Holly Chesler, Elissa J. Churchill, Gary A. de Villena, Fernando Pardo-Manuel Schwartz, David A. Collins, Francis S. TI Integrative Genetic Analysis of Allergic Inflammation in the Murine Lung SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE allergic airway disease; systems genetics; gene expression quantitative trait loci ID QUANTITATIVE TRAIT LOCI; GENOME-WIDE ASSOCIATION; COLLABORATIVE CROSS; UNITED-STATES; ASTHMA; EXPRESSION; MICE; TIME; SPHINGOLIPIDS; METAANALYSIS AB Airway allergen exposure induces inflammation among individuals with atopy that is characterized by altered airway gene expression, elevated levels of T helper type 2 cytokines, mucus hypersecretion, and airflow obstruction. To identify the genetic determinants of the airway allergen response, we employed a systems genetics approach. We applied a house dust mite model of allergic airway disease to 151 incipient lines of the Collaborative Cross, a new mouse genetic reference population, and measured serum IgE, airway eosinophilia, and gene in the lung. Allergen-induced serum IgE and airway eosinophilia were not correlated. We detected quantitative trait loci (QTL) for airway eosinophilia on chromosome (Chr) 11 (71.802-87.098 megabases [Mb]) and allergen-induced IgE on Chr 4 (13.950-31.660 Mb). More than 4,500 genes expressed in the lung had gene expression QTL (eQTL), the majority of which were located near the gene itself. However, we also detected approximately 1,700 trans-eQTL, and many of these trans-eQTL clustered into two regions on Chr 2. We show that one of these loci (at 147.6 Mb) is associated with the expression of more than 100 genes, and, using bioinformatics resources, fine-map this locus to a 53 kb-long interval. We also use the gene expression and eQTL data to identify a candidate gene, Tlcd2, for the eosinophil QTL. Our results demonstrate that hallmark allergic airway disease phenotypes are associated with distinct genetic loci on Chrs 4 and 11, and that gene expression in the allergically inflamed lung is controlled by both cis and trans regulatory factors. C1 [Kelada, Samir N. P.; Carpenter, Danielle E.; Chines, Peter; Collins, Francis S.] NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. [Kelada, Samir N. P.; Rutledge, Holly; de Villena, Fernando Pardo-Manuel] Univ N Carolina, Dept Genet, Chapel Hill, NC 27510 USA. [Kelada, Samir N. P.] Univ N Carolina, Marsico Lung Inst, Chapel Hill, NC 27510 USA. [de Villena, Fernando Pardo-Manuel] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27510 USA. [Aylor, David L.] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Chesler, Elissa J.; Churchill, Gary A.] Jackson Lab, Bar Harbor, ME 04609 USA. [Schwartz, David A.] Univ Colorado, Dept Med, Denver, CO USA. RP Kelada, SNP (reprint author), Univ N Carolina, Dept Genet, 120 Mason Farm Rd,Room 5072, Chapel Hill, NC 27510 USA. EM samir_kelada@med.unc.edu FU National Human Genome Research Institute (NIH) [ZIA-HG200361]; U.S. Department of Energy, Office of Biological and Environmental Research; NIH [U01CA134240, U01CA105417, F32GM090667, GM070683]; National Institutes of General Medical Sciences Centers of Excellence in Systems Biology program [GM076468] FX This work was supported in part by the intramural program of the National Human Genome Research Institute (NIH) ZIA-HG200361 (F.S.C.), the U.S. Department of Energy, Office of Biological and Environmental Research (E.J.C.), and by NIH grants U01CA134240 and U01CA105417 (for production of Collaborative Cross mice), F32GM090667 (D.L.A.), GM070683 (G.A.C.), and a National Institutes of General Medical Sciences Centers of Excellence in Systems Biology program grant GM076468 (G.A.C.). NR 55 TC 7 Z9 7 U1 1 U2 7 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD SEP PY 2014 VL 51 IS 3 BP 436 EP 445 DI 10.1165/rcmb.2013-0501OC PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA AY2KC UT WOS:000347417800012 PM 24693920 ER PT J AU Yeh, S Suhler, EB Smith, JR Bruce, B Fahle, G Bailey, ST Hwang, TS Stout, JT Lauer, AK Wilson, DJ Rosenbaum, JT Flaxel, CJ AF Yeh, Steven Suhler, Eric B. Smith, Justine R. Bruce, Beau Fahle, Gary Bailey, Steven T. Hwang, Thomas S. Stout, J. Timothy Lauer, Andreas K. Wilson, David J. Rosenbaum, James T. Flaxel, Christina J. TI Combination Systemic and Intravitreal Antiviral Therapy in the Management of Acute Retinal Necrosis Syndrome SO OPHTHALMIC SURGERY LASERS & IMAGING RETINA LA English DT Article ID POLYMERASE-CHAIN-REACTION; SIMPLEX-VIRUS TYPE-2; NECROTIZING HERPETIC RETINOPATHY; VITREOUS PENETRATION; ANTIBODY-PRODUCTION; CASE SERIES; RETINITIS; INJECTIONS; ACYCLOVIR; DIAGNOSIS AB BACKGROUND AND OBJECTIVE: Acute retinal necrosis (ARN) may lead to severe visual loss because of its rapid progression and high likelihood of retinal detachment (RD). This study investigates whether combination systemic and intravitreal antiviral therapy is superior to systemic antiviral therapy alone. PATIENTS AND METHODS: Single-center, interventional, comparative case series of patients with ARN treated with combination systemic antiviral and intravitreal foscarnet injection therapy or systemic antiviral therapy alone. Survival analysis and incidence rates of visual acuity (VA) gain of two lines or greater, severe visual loss of 20/200 or worse, and RD were assessed. RESULTS: Twelve patients received combination therapy and 12 received systemic therapy alone. Patients receiving combination therapy were more likely to gain two or more lines of VA and showed decreased incidences of severe visual loss and RD. CONCLUSION: Combination oral and intravitreal antiviral therapy may improve the likelihood for VA gain and decrease the risk of RD in patients with ARN. Clinicians should consider administering combination systemic and intravitreal antiviral therapy for patients with the ARN syndrome. C1 [Bailey, Steven T.; Hwang, Thomas S.; Stout, J. Timothy; Lauer, Andreas K.; Wilson, David J.; Rosenbaum, James T.; Flaxel, Christina J.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Rosenbaum, James T.] Legacy Good Samaritan Hosp, Devers Eye Inst, Portland, OR USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Smith, Justine R.] Flinders Univ S Australia, Adelaide, SA 5001, Australia. [Fahle, Gary] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Yeh, Steven; Bruce, Beau] Emory Univ, Sch Med, Dept Ophthalmol, Emory Eye Ctr, Atlanta, GA 30322 USA. [Bruce, Beau] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Bruce, Beau] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Bruce, Beau] Emory Univ, Laney Grad Sch, Atlanta, GA 30322 USA. RP Flaxel, CJ (reprint author), Casey Eye Inst, Retina Serv, 3375 SW Terwilliger Blvd, Portland, OR 97239 USA. EM flaxelc@ohsu.edu FU Research to Prevent Blindness; Heed Ophthalmic Foundation; Ronald G. Michels fellowship foundation; William and Mary Bauman Foundation; Stan and Madelle Rosenfeld Family Trust; Fund for Arthritis and Infectious Disease Research; [K23-EY19341] FX Supported in part by unrestricted grants from Research to Prevent Blindness to the Casey Eye Institute and Emory Eye Center. Dr. Yeh has received support from the Heed Ophthalmic Foundation and the Ronald G. Michels fellowship foundation. Dr. Rosenbaum receives support from the William and Mary Bauman Foundation, the Stan and Madelle Rosenfeld Family Trust, and the Fund for Arthritis and Infectious Disease Research. Dr. Bruce has received funding from K23-EY19341. NR 38 TC 4 Z9 5 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 2325-8160 EI 2325-8179 J9 OSLI RETINA JI Ophthalmic Surg. Lasers Imag. Retin. PD SEP-OCT PY 2014 VL 45 IS 5 BP 399 EP 407 DI 10.3928/23258160-20140908-02 PG 9 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA AY0OY UT WOS:000347297300006 PM 25215870 ER PT J AU Grimes, CL Lukacz, ES Gantz, MG Warren, LK Brubaker, L Zyczynski, HM Richter, HE Jelovsek, JE Cundiff, G Fine, P Visco, AG Zhang, M Meikle, S AF Grimes, Cara L. Lukacz, Emily S. Gantz, Marie G. Warren, Lauren Klein Brubaker, Linda Zyczynski, Halina M. Richter, Holly E. Jelovsek, J. Eric Cundiff, Geoffrey Fine, Paul Visco, Anthony G. Zhang, Min Meikle, Susan CA NICHD Pelvic Floor Disorders Netwo TI What Happens to the Posterior Compartment and Bowel Symptoms After Sacrocolpopexy? Evaluation of 5-Year Outcomes From E-CARE SO FEMALE PELVIC MEDICINE AND RECONSTRUCTIVE SURGERY LA English DT Article DE obstructed defecation; posterior prolapse; sacrocolpopexy ID PELVIC ORGAN PROLAPSE; VAGINAL VAULT PROLAPSE; ABDOMINAL SACROCOLPOPEXY; BURCH COLPOSUSPENSION; WOMEN; INCONTINENCE; DYSFUNCTION; DISORDERS; RECTOCELE; DEFECTS AB Objectives: The objective of this study was to describe posterior prolapse (pPOP) and obstructed defecation (OD) symptoms 5 years after open abdominal sacrocolpopexy (ASC). Methods: We grouped the extended colpopexy and urinary reduction efforts trial participants with baseline and 5-year outcomes into 3 groups using baseline posterior Pelvic Organ Prolapse Quantification (POP-Q) points and concomitant posterior repair (PR) (no PR, Ap <0; no PR, Ap >= 0; and +PR). Posterior colporrhaphy, perineorrhaphy, or sacrocolpoperineopexy were included as PR, which was performed at surgeon's discretion. Outcomes were dichotomized into presence/absence of pPOP (Ap >= 0) and OD symptoms (>= 2 on 1 or more questions about digital assistance, excessive straining, or incomplete evacuation). Composite failure was defined by both pPOP and OD symptoms or pPOP reoperation. Results: Ninety participants completed baseline and 5-year outcomes or were retreated with mean follow-up of 7.1 +/- 1.0 years. Of those with no PR (Ap <0), 2 women (2/36; 9%) developed new pPOP with OD symptoms; 1 underwent subsequent PR. Nearly all (23/24; 96%) with no PR (Ap >= 0) demonstrated sustained resolution of pPOP, and none underwent PR. Fourteen percent (4/29) of +PR underwent repeat PR within 5 years, and 12% had recurrent pPOP. Regardless of PR, OD symptoms improved in all groups after ASC, although OD symptoms were still present in 17% to 19% at 5 years. Conclusions: Symptomatic pPOP is common 5 years after ASC regardless of concomitant PR. Obstructed defecation symptoms may improve after ASC regardless of PR. Recurrent pPOP and/or reoperation was highest among those who received concomitant PR at ASC. Further studies identifying criteria for concomitant PR at the time of ASC are warranted. C1 [Grimes, Cara L.] Columbia Univ, Med Ctr, Dept Obstet & Gynecol, New York, NY USA. [Lukacz, Emily S.] UC San Diego Hlth Syst, Dept Reprod Med, San Diego, CA 92037 USA. [Gantz, Marie G.; Warren, Lauren Klein] RTI Int, Res Triangle Pk, NC USA. [Brubaker, Linda] Loyola Univ, Stritch Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Brubaker, Linda] Loyola Univ, Stritch Sch Med, Dept Urol, Chicago, IL 60611 USA. [Zyczynski, Halina M.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Richter, Holly E.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Jelovsek, J. Eric] Cleveland Clin, Obstet Gynecol & Womens Hlth Inst, Cleveland, OH 44106 USA. [Cundiff, Geoffrey] Univ British Columbia, Dept Obstet & Gynaecol, Vancouver, BC V5Z 1M9, Canada. [Fine, Paul] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Visco, Anthony G.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Zhang, Min] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Meikle, Susan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Lukacz, ES (reprint author), UC San Diego Hlth Syst, Dept Reprod Med, 9350 Campus Point Dr 0974, San Diego, CA 92037 USA. EM elukacz@ucsd.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of Research on Women's Health at the National Institutes of Health [U01 HD41249, U10 HD41250, U10 HD41261, U10 HD41267, U10 HD54136, U10 HD54214, U10 HD54215, U10 HD54241, U10 HD054136, U10 HD054215, U10 HD041261, U10 HD041267, U10 HD069006, U10 HD054214, U10 HD041250, U01 HD069031]; Astellas; Warner Chilcott; Pfizer; University of California/Pfizer; Pelvalon; National Institute of Diabetes and Digestion and Kidney Diseases FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Office of Research on Women's Health at the National Institutes of Health (U01 HD41249, U10 HD41250, U10 HD41261, U10 HD41267, U10 HD54136, U10 HD54214, U10 HD54215, U10 HD54241, U10 HD054136, U10 HD054215, U10 HD041261, U10 HD041267, U10 HD069006, U10 HD054214, U10 HD041250, U01 HD069031).; Dr Lukacz is a researcher at Boston Scientific, a consultant at the Renew Medical, consultant at the American Medical Systems, and a consultant and research support at Pfizer. Dr Zyczynski is a consultant at the Johnson & Johnson Inc. Dr Richter is a consultant at IDEO, GlaxoSmithKline, Uromedica, and Xenodyne and was awarded with grants from Astellas, Warner Chilcott, Pfizer, University of California/Pfizer, Pelvalon, and National Institute of Diabetes and Digestion and Kidney Diseases. Other authors have no conflicts of interest to declare. NR 24 TC 5 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2151-8378 J9 FEMALE PELVIC MED RE JI Female Pelvic Med. Reconstr. Surg. PD SEP-OCT PY 2014 VL 20 IS 5 BP 261 EP 266 DI 10.1097/SPV.0000000000000085 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AX7SW UT WOS:000347116000005 PM 25181375 ER PT J AU Zhu, ZY Ramakrishnan, B Li, JY Wang, YP Feng, Y Prabakaran, P Colantonio, S Dyba, MA Qasba, PK Dimitrov, DS AF Zhu, Zhongyu Ramakrishnan, Boopathy Li, Jinyu Wang, Yanping Feng, Yang Prabakaran, Ponraj Colantonio, Simona Dyba, Marzena A. Qasba, Pradman K. Dimitrov, Dimiter S. TI Site-specific antibody-drug conjugation through an engineered glycotransferase and a chemically reactive sugar SO MABS LA English DT Article DE antibody-drug conjugates; ADC; site-specific ADC; glycoengineering; anti-HER2 ID NEONATAL FC-RECEPTOR; MONOCLONAL-ANTIBODIES; HUMAN IGG1; THERAPEUTIC INDEX; BREAST-CANCER; BINDING-SITE; GAMMA-RIII; DESIGN; MODEL; MINIMIZATION AB Conjugation of small molecule drugs to specific sites on the antibody molecule has been increasingly used for the generation of relatively homogenous preparations of antibody-drug conjugates (ADCs) with physicochemical properties similar or identical to those of the naked antibody. Previously a method for conjugation of small molecules to glycoproteins through existing glycans by using an engineered glycotransferase and a chemically reactive sugar as a handle was developed. Here, for the first time, we report the use of this method with some modifications to generate an ADC from a monoclonal antibody, m860, which we identified from a human naive phage display Fab library by panning against the extracellular domain of human HER2. M860 bound to cell surface-associated HER2 with affinity comparable to that of Trastuzumab (Herceptin (R)), but to a different epitope. The m860ADC was generated by enzymatically adding a reactive keto-galactose to m860 using an engineered glycotransferase and conjugating the reactive m860 to aminooxy auristatin F. It exhibited potent and specific cell-killing activity against HER2 positive cancer cells, including trastuzumab-resistant breast cancer cells. This unique ADC may have utility as a potential therapeutic for HER2 positive cancers alone or in combination with other drugs. Our results also validate the keto-galactose/engineered glycotransferase method for generation of functional ADCs, which could potentially also be used for preparation of ADCs targeting other disease markers. C1 [Zhu, Zhongyu; Li, Jinyu; Wang, Yanping; Feng, Yang; Prabakaran, Ponraj; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Lab Expt Immunol, Canc & Inflammat Program,Ctr Canc Res,NIH, Frederick, MD 21701 USA. [Ramakrishnan, Boopathy; Qasba, Pradman K.] NCI, Nanobiol Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Ramakrishnan, Boopathy; Wang, Yanping; Prabakaran, Ponraj; Dyba, Marzena A.] NCI, Basic Sci Program, Frederick Natl Lab Canc Res, Leidos Biomed Res Inc,NIH, Frederick, MD 21701 USA. [Colantonio, Simona] NCI, Antibody Characterizat Lab, Frederick Natl Lab Canc Res, Leidos Biomed Res Inc,NIH, Frederick, MD 21701 USA. [Dyba, Marzena A.] NCI, Struct Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. RP Zhu, ZY (reprint author), NCI, Prot Interact Grp, Lab Expt Immunol, Canc & Inflammat Program,Ctr Canc Res,NIH, Frederick, MD 21701 USA. EM zhongyu.zhu@nih.gov; dimiter.dimitrov@nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [N01-CO-12400, HHSN261200800001E]; SU2C-St. Baldrick's Foundation FX This project was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400, HHSN261200800001E as well as by the SU2C-St. Baldrick's Foundation. NR 39 TC 14 Z9 15 U1 3 U2 18 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1942-0862 EI 1942-0870 J9 MABS-AUSTIN JI mAbs PD SEP-OCT PY 2014 VL 6 IS 5 BP 1190 EP 1200 DI 10.4161/mabs.29889 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AX4BG UT WOS:000346878500008 PM 25517304 ER PT J AU Ying, TL Feng, Y Wang, YP Chen, WZ Dimitrov, DS AF Ying, Tianlei Feng, Yang Wang, Yanping Chen, Weizao Dimitrov, Dimiter S. TI Monomeric IgG1 Fc molecules displaying unique Fc receptor interactions that are exploitable to treat inflammation-mediated diseases SO MABS LA English DT Article DE monomeric Fc; Fc gamma receptors; FcRn; ADCC; chronic inflammation ID ACUTE MYELOID-LEUKEMIA; FAB-ARM EXCHANGE; GAMMA-RI CD64; HIGH-AFFINITY; FUSION PROTEINS; CRYSTAL-STRUCTURE; IN-VIVO; IMMUNOTOXIN; ANTIBODY; VARIANTS AB The IgG1 Fc is a dimeric protein that mediates important antibody effector functions by interacting with Fc gamma receptors (Fc gamma Rs) and the neonatal Fc receptor (FcRn). Here, we report the discovery of a monomeric IgG1 Fc (mFc) that bound to Fc gamma RI with very high affinity, but not to Fc gamma RIIIa, in contrast to wild-type (dimeric) Fc. The binding of mFc to FcRn was the same as that of dimeric Fc. To test whether the high-affinity binding to Fc gamma RI can be used for targeting of toxins, a fusion protein of mFc with a 38 kDa Pseudomonas exotoxin A fragment (PE38), was generated. This fusion protein killed Fc gamma RI-positive macrophage-like U937 cells but not Fc gamma RI-negative cells, and mFc or PE38 alone had no killing activity. The lack of binding to Fc gamma RIIIa resulted in the absence of Fc-mediated cytotoxicity of a scFv-mFc fusion protein targeting mesothelin. The pharmacokinetics of mFc in mice was very similar to that of dimeric Fc. The mFc's unique Fc gamma Rs binding pattern and related functionality, combined with its small size, monovalency and the preservation of FcRn binding which results in relatively long half-life in vivo, suggests that mFc has great potential as a component of therapeutics targeting inflammation mediated by activated macrophages overexpressing Fc gamma RI and related diseases, including cancer. C1 [Ying, Tianlei] Fudan Univ, Shanghai Med Coll, Minist Educ, Key Lab Med Mol Virol, Shanghai 200433, Peoples R China. [Ying, Tianlei] Fudan Univ, Shanghai Med Coll, Minist Hlth, Key Lab Med Mol Virol, Shanghai 200433, Peoples R China. [Ying, Tianlei; Feng, Yang; Wang, Yanping; Chen, Weizao; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21701 USA. [Wang, Yanping] Geneva Fdn, Tacoma, WA USA. RP Ying, TL (reprint author), Fudan Univ, Shanghai Med Coll, Minist Educ, Key Lab Med Mol Virol, Shanghai 200433, Peoples R China. EM tlying@fudan.edu.cn FU NIH, National Cancer Institute, Center for Cancer Research; NIH, National Cancer Institute [N01-CO-12400] FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by Federal funds from the NIH, National Cancer Institute, under Contract No. N01-CO-12400. NR 39 TC 5 Z9 5 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1942-0862 EI 1942-0870 J9 MABS-AUSTIN JI mAbs PD SEP-OCT PY 2014 VL 6 IS 5 BP 1201 EP 1210 DI 10.4161/mabs.29835 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AX4BG UT WOS:000346878500009 PM 25517305 ER PT J AU Elder, JP Ayala, GX McKenzie, TL Litrownik, AJ Gallo, LC Arredondo, EM Talavera, GA Kaplan, RM AF Elder, John P. Ayala, Guadalupe X. McKenzie, Thomas L. Litrownik, Alan J. Gallo, Linda C. Arredondo, Elva M. Talavera, Gregory A. Kaplan, Robert M. TI A Three-Decade Evolution to Transdisciplinary Research: Community Health Research in California-Mexico Border Communities. SO PROGRESS IN COMMUNITY HEALTH PARTNERSHIPS-RESEARCH EDUCATION AND ACTION LA English DT Article DE Transdisciplinary research; team science; Latino/Hispanic health; community health; community-based participatory research ID HISPANIC MIGRANT ADOLESCENTS; SOCIOECONOMIC-STATUS; AMERICAN WOMEN; ALCOHOL-USE; PARTICIPATORY RESEARCH; PREVENTION PROGRAM; LATINO COMMUNITY; UNITED-STATES; TEAM SCIENCE; TOBACCO AB Background: The Institute for Behavioral and Community Health (IBACH) is a transdisciplinary organization with a. team-oriented approach to the translation of research to practice and policy within the context of behavioral medicine. Objectives: This paper tracks the growth of IBACH in the context of evolving, multi-university transdisciplinary research efforts from a behavioral medicine research focus to community approaches to disease prevention and control, ultimately specializing in Latino health research and practice. We describe how this growth was informed by our partnerships with community members and organizations, and training a diverse array of students and young professionals. Methods: Since 1982, IBACH's research has evolved to address a greater breadth of factors associated with health and well-being. This was driven by our strong community focus and emphasis on collaborations, the diversity of our investigative teams, and our emphasis on training. Although behavioral science still forms the core of IBACH's scientific orientation, research efforts extend beyond those traditionally examined. Conclusions: IBACH's "team science" successes have been fueled by a specific population emphasis, making IBACH one of the nation's leaders in Latino health behavior research. C1 [Elder, John P.; Ayala, Guadalupe X.; Gallo, Linda C.; Arredondo, Elva M.; Talavera, Gregory A.] San Diego State Univ, Inst Behav & Community Hlth, San Diego, CA 92182 USA. [Elder, John P.; Ayala, Guadalupe X.; Arredondo, Elva M.; Talavera, Gregory A.] San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92182 USA. [McKenzie, Thomas L.] San Diego State Univ, Sch Exercise & Nutr Sci, San Diego, CA 92182 USA. [Litrownik, Alan J.; Gallo, Linda C.] San Diego State Univ, Dept Psychol, San Diego, CA 92182 USA. [Kaplan, Robert M.] Natl Inst Hlth, Off Behav & Social Sci Res, Bethesda, MD USA. RP Elder, JP (reprint author), San Diego State Univ, Inst Behav & Community Hlth, San Diego, CA 92182 USA. FU NCI NIH HHS [R01 CA140326, R21 CA120929] NR 35 TC 2 Z9 2 U1 2 U2 4 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1557-0541 EI 1557-055X J9 PROG COMM HLTH PARTN JI Prog. Community Health Partnersh. PD FAL PY 2014 VL 8 IS 3 BP 397 EP 404 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AX1DZ UT WOS:000346689600013 PM 25435566 ER PT J AU Kepp, O Senovilla, L Vitale, I Vacchelli, E Adjemian, S Agostinis, P Apetoh, L Aranda, F Barnaba, V Bloy, N Bracci, L Breckpot, K Brough, D Buque, A Castro, MG Cirone, M Colombo, MI Cremer, I Demaria, S Dini, L Eliopoulos, AG Faggioni, A Formenti, SC Fucikova, J Gabriele, L Gaipl, US Galon, J Garg, A Ghiringhelli, F Giese, NA Guo, ZS Hemminki, A Herrmann, M Hodge, JW Holdenrieder, S Honeychurch, J Hu, HM Huang, X Illidge, TM Kono, K Korbelik, M Krysko, DV Loi, S Lowenstein, PR Lugli, E Ma, YT Madeo, F Manfredi, AA Martins, I Mavilio, D Menger, L Merendino, N Michaud, M Mignot, G Mossman, KL Multhoff, G Oehler, R Palombo, F Panaretakis, T Pol, J Proietti, E Ricci, JE Riganti, C Rovere-Querini, P Rubartelli, A Sistigu, A Smyth, MJ Sonnemann, J Spisek, R Stagg, J Sukkurwala, AQ Tartour, E Thorburn, A Thorne, SH Vandenabeele, P Velotti, F Workenhe, ST Yang, HN Zong, WX Zitvogel, L Kroemer, G Galluzzi, L AF Kepp, Oliver Senovilla, Laura Vitale, Ilio Vacchelli, Erika Adjemian, Sandy Agostinis, Patrizia Apetoh, Lionel Aranda, Fernando Barnaba, Vincenzo Bloy, Norma Bracci, Laura Breckpot, Karine Brough, David Buque, Aitziber Castro, Maria G. Cirone, Mara Colombo, Maria I. Cremer, Isabelle Demaria, Sandra Dini, Luciana Eliopoulos, Aristides G. Faggioni, Alberto Formenti, Silvia C. Fucikova, Jitka Gabriele, Lucia Gaipl, Udo S. Galon, Jerome Garg, Abhishek Ghiringhelli, Francois Giese, Nathalia A. Guo, Zong Sheng Hemminki, Akseli Herrmann, Martin Hodge, James W. Holdenrieder, Stefan Honeychurch, Jamie Hu, Hong-Min Huang, Xing Illidge, Tim M. Kono, Koji Korbelik, Mladen Krysko, Dmitri V. Loi, Sherene Lowenstein, Pedro R. Lugli, Enrico Ma, Yuting Madeo, Frank Manfredi, Angelo A. Martins, Isabelle Mavilio, Domenico Menger, Laurie Merendino, Nicolo Michaud, Michael Mignot, Gregoire Mossman, Karen L. Multhoff, Gabriele Oehler, Rudolf Palombo, Fabio Panaretakis, Theocharis Pol, Jonathan Proietti, Enrico Ricci, Jean-Ehrland Riganti, Chiara Rovere-Querini, Patrizia Rubartelli, Anna Sistigu, Antonella Smyth, Mark J. Sonnemann, Juergen Spisek, Radek Stagg, John Sukkurwala, Abdul Qader Tartour, Eric Thorburn, Andrew Thorne, Stephen H. Vandenabeele, Peter Velotti, Francesca Workenhe, Samuel T. Yang, Haining Zong, Wei-Xing Zitvogel, Laurence Kroemer, Guido Galluzzi, Lorenzo TI Consensus guidelines for the detection of immunogenic cell death SO ONCOIMMUNOLOGY LA English DT Review DE ATP release; autophagy; calreticulin; endoplasmic reticulum stress; HMGB1; immunotherapy ID MITOCHONDRIAL-MEMBRANE PERMEABILIZATION; HEAT-SHOCK PROTEINS; GROUP BOX-1 PROTEIN; APOPTOTIC CALRETICULIN EXPOSURE; MOLECULAR-PATTERN MOLECULES; ANTICANCER IMMUNE-RESPONSES; FLOW-CYTOMETRIC DETECTION; HUMAN TUMOR-CELLS; FIND-ME SIGNAL; NECROTIC CELLS AB Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell death" (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine. C1 [Kepp, Oliver; Vacchelli, Erika; Adjemian, Sandy; Aranda, Fernando; Bloy, Norma; Buque, Aitziber; Huang, Xing; Ma, Yuting; Menger, Laurie; Michaud, Michael; Pol, Jonathan; Sukkurwala, Abdul Qader; Kroemer, Guido; Galluzzi, Lorenzo] Ctr Rech Cordeliers, Ligue Natl Canc, Equipe 11, Paris, France. [Kepp, Oliver; Senovilla, Laura; Vacchelli, Erika; Adjemian, Sandy; Aranda, Fernando; Bloy, Norma; Buque, Aitziber; Cremer, Isabelle; Galon, Jerome; Huang, Xing; Ma, Yuting; Menger, Laurie; Michaud, Michael; Pol, Jonathan; Sukkurwala, Abdul Qader; Kroemer, Guido; Galluzzi, Lorenzo] INSERM, U1138, Paris, France. [Kepp, Oliver; Senovilla, Laura; Huang, Xing; Kroemer, Guido] Metabol Platform, Villejuif, France. [Kepp, Oliver; Senovilla, Laura; Huang, Xing; Kroemer, Guido] Cell Biol Platform, Villejuif, France. [Senovilla, Laura; Zitvogel, Laurence] INSERM, U1015, Villejuif, France. [Vitale, Ilio; Sistigu, Antonella] Regina Elena Inst Canc Res, Rome, Italy. [Adjemian, Sandy] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Mol Cell Biol Lab, Sao Paulo, Brazil. [Agostinis, Patrizia; Garg, Abhishek] Univ Leuven, Dept Cellular & Mol Med, Cell Death Res & Therapy, Leuven, Belgium. [Apetoh, Lionel; Ghiringhelli, Francois] INSERM, UMR866, Dijon, France. [Apetoh, Lionel; Ghiringhelli, Francois] Ctr Georges Francois Leclerc, Dijon, France. [Apetoh, Lionel; Ghiringhelli, Francois] Univ Bourgogne, Dijon, France. [Barnaba, Vincenzo; Palombo, Fabio] Univ Roma La Sapienza, Dept Internal Med & Med Sci, I-00185 Rome, Italy. [Barnaba, Vincenzo; Palombo, Fabio] Fdn Cenci Bolognetti, Ist Pasteur, Rome, Italy. [Bracci, Laura; Gabriele, Lucia; Proietti, Enrico] Ist Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, Italy. [Breckpot, Karine] Free Univ Brussels, Dept Biomed Sci Med Sch, Lab Mol & Cellular Therapy, Jette, Belgium. [Brough, David] Univ Manchester, Fac Life Sci, Manchester, Lancs, England. [Castro, Maria G.; Lowenstein, Pedro R.] Univ Michigan, Sch Med, Dept Neurosurg & Cell & Dev Biol, Ann Arbor, MI 48109 USA. [Cirone, Mara; Faggioni, Alberto] Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy. [Colombo, Maria I.] Univ Nacl Cuyo, Inst Histol & Embriol IHEM, Fac Ciencias Med, CONICET,Lab Biol Celular & Mol, RA-5500 Mendoza, Argentina. [Cremer, Isabelle; Galon, Jerome] Univ Paris 06, Paris, France. [Cremer, Isabelle] Ctr Rech Cordeliers, Equipe 13, Paris, France. [Demaria, Sandra] NYU, Sch Med, Dept Pathol, New York, NY USA. [Dini, Luciana] Univ Salento, Dept Biol & Environm Sci & Technol DiSTeBA, Lecce, Italy. [Eliopoulos, Aristides G.] Univ Crete, Sch Med, Div Basic Sci, Mol & Cellular Biol Lab, Iraklion, Greece. [Eliopoulos, Aristides G.] Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, Iraklion, Greece. [Formenti, Silvia C.] NYU, Sch Med, Dept Radiat Oncol, New York, NY USA. [Formenti, Silvia C.] Langone Med Ctr, New York, NY USA. [Fucikova, Jitka; Spisek, Radek] Charles Univ Prague, Fac Med 2, Dept Immunol, Prague, Czech Republic. [Fucikova, Jitka; Spisek, Radek] Charles Univ Prague, Univ Hosp Motol, Prague, Czech Republic. [Fucikova, Jitka; Spisek, Radek] Sotio, Prague, Czech Republic. [Gaipl, Udo S.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Radiat Oncol, D-91054 Erlangen, Germany. [Galon, Jerome; Kroemer, Guido; Galluzzi, Lorenzo] Univ Paris 05, Univ Paris Descartes, Sorbonne Paris Cite, Paris, France. [Galon, Jerome] Ctr Rech Cordeliers, Lab Integrat Canc Immunol, Paris, France. [Giese, Nathalia A.] Univ Heidelberg Hosp, European Pancreas Ctr, Dept Surg, Heidelberg, Germany. [Guo, Zong Sheng; Thorne, Stephen H.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Hemminki, Akseli] Univ Helsinki, Transplantat Lab, Canc Gene Therapy Grp, Haartman Inst, Helsinki, Finland. [Herrmann, Martin] Univ Erlangen Nurnberg, Dept Internal Med 3, D-91054 Erlangen, Germany. [Hodge, James W.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Holdenrieder, Stefan] Univ Hosp Bonn, Inst Clin Chem & Clin Pharmacol, Bonn, Germany. [Honeychurch, Jamie; Illidge, Tim M.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Inst Canc Studies, Fac Med & Human Sci, Manchester, Lancs, England. [Hu, Hong-Min] Southeast Univ, Affiliated Hosp 2, Canc Res & Biotherapy Ctr, Nanjing, Jiangsu, Peoples R China. [Hu, Hong-Min] Providence Portland Med Ctr, Earle A Chiles Res Inst, Lab Canc Immunobiol, Portland, OR USA. [Kono, Koji] Natl Univ Singapore, Dept Surg, Singapore 117548, Singapore. [Kono, Koji] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore. [Korbelik, Mladen] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Krysko, Dmitri V.; Vandenabeele, Peter] VIB Inflammat Res Ctr, Ghent, Belgium. [Krysko, Dmitri V.; Vandenabeele, Peter] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium. [Loi, Sherene] Peter MacCallum Canc Ctr, Div Canc Med, East Melbourne, Vic, Australia. [Loi, Sherene] Peter MacCallum Canc Ctr, Div Res, East Melbourne, Vic, Australia. [Lugli, Enrico; Mavilio, Domenico] Humanitas Clin & Res Ctr, Unit Clin & Expt Immunol, Milan, Italy. [Lugli, Enrico; Mavilio, Domenico] Univ Milan, Dept Med Biotechnol & Translat Med, Rozzano, Italy. [Madeo, Frank] Graz Univ, Inst Mol Biosci, Graz, Austria. [Manfredi, Angelo A.; Rovere-Querini, Patrizia] Univ Vita Salute San Raffaele, Milan, Italy. [Manfredi, Angelo A.; Rovere-Querini, Patrizia] Ist Sci San Raffaele, I-20132 Milan, Italy. [Martins, Isabelle] INSERM, U1030, Villejuif, France. [Martins, Isabelle] Univ Paris 11, Fac Med, Le Kremlin Bicetre, France. [Menger, Laurie] UCL, Dept Res Haematol, Canc Immunol Unit, Inst Canc, London, England. [Merendino, Nicolo; Velotti, Francesca] Univ Tuscia, Dept Ecol & Biol Sci DEB, Viterbo, Italy. [Mossman, Karen L.; Workenhe, Samuel T.] McMaster Immunol Res Ctr, Dept Pathol & Mol Med, Hamilton, ON, Canada. [Mossman, Karen L.; Workenhe, Samuel T.] McMaster Univ, Inst Infect Dis Res, Hamilton, ON, Canada. [Multhoff, Gabriele] Tech Univ Munich, Klinikum Rechts Isar, Dept Radiat Oncol, D-80290 Munich, Germany. [Oehler, Rudolf] Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria. [Panaretakis, Theocharis] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Ricci, Jean-Ehrland] INSERM, U1065, Nice, France. [Ricci, Jean-Ehrland] Ctr Mediterran Med Mol C3M, Equipe Controle Metabol Morts Cellulaires, Nice, France. [Ricci, Jean-Ehrland] Univ Nice Sophia Antipolis, Fac Med, F-06189 Nice, France. [Ricci, Jean-Ehrland] Ctr Hosp Univ Nice, Nice, France. [Riganti, Chiara] Univ Turin, Dept Oncol, Turin, Italy. [Riganti, Chiara] Univ Turin, Subalpine Ctr Res & Expt Med CeRMS, Turin, Italy. [Rubartelli, Anna] Azienda Osped Univ San Martino, Ist Nazl Ric Cancro, Cell Biol Unit, Genoa, Italy. [Smyth, Mark J.] QIMR Berghofer Med Res Inst, Immunol Canc & Infect Lab, Herston, Qld, Australia. [Smyth, Mark J.] Univ Queensland, Sch Med, Herston, Qld, Australia. [Sonnemann, Juergen] Jena Univ Hosp, Childrens Clin, Dept Pediat Haematol & Oncol, Jena, Germany. [Stagg, John] Univ Montreal, Fac Pharm, Ctr Rech, Ctr Hosp, Montreal, PQ H3C 3J7, Canada. [Sukkurwala, Abdul Qader] Dow Univ Hlth Sci, Dow Int Med Coll, Dept Pathol, Karachi, Pakistan. [Tartour, Eric] INSERM, U970, Paris, France. [Tartour, Eric; Kroemer, Guido] Hop Europeen Georges Pompidou, AP HP, Pole Biol, Paris, France. [Thorburn, Andrew] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO USA. [Vandenabeele, Peter] Univ Ghent, Methusalem Program, B-9000 Ghent, Belgium. [Yang, Haining] Univ Hawaii Canc Ctr, Honolulu, HI USA. [Zong, Wei-Xing] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. [Zitvogel, Laurence] Ctr Invest Clin Biotherapie 507 CICBT507, Villejuif, France. RP Galluzzi, L (reprint author), Ctr Rech Cordeliers, Ligue Natl Canc, Equipe 11, Paris, France. EM deadoc@vodafone.it RI Garg, Abhishek/D-5230-2012; Hodge, James/D-5518-2015; Vandenabeele, Peter/C-8597-2009; Breckpot, Karine/A-4298-2008; ILLIDGE, Tim/M-3659-2015; Smyth, Mark/H-8709-2014; Loi, Sherene/H-1979-2016; Krysko, Dmitri/G-9500-2013; Ricci, Jean Ehrland/I-7117-2016; herrmann, martin/A-9597-2013; BRACCI, LAURA/J-8777-2016; Apetoh, Lionel/G-3310-2014; Pol, Jonathan/R-6507-2016; Aranda, Fernando/N-2112-2014 OI Oehler, Rudolf/0000-0003-2891-7155; Brough, David/0000-0002-2250-2381; Gabriele, Lucia/0000-0002-1483-866X; Castro, Maria Graciela/0000-0003-2237-2756; Sistigu, Antonella/0000-0002-2528-1238; Panaretakis, Theocharis/0000-0001-5754-6950; VITALE, ILIO/0000-0002-5918-1841; PROIETTI, ENRICO/0000-0001-9023-2072; Demaria, Sandra/0000-0003-4426-0499; Mavilio, Domenico/0000-0001-6147-0952; Garg, Abhishek/0000-0002-9976-9922; Hodge, James/0000-0001-5282-3154; Breckpot, Karine/0000-0003-4331-3480; ILLIDGE, Tim/0000-0003-3191-7324; Smyth, Mark/0000-0001-7098-7240; Krysko, Dmitri/0000-0002-9692-2047; Ricci, Jean Ehrland/0000-0003-1585-8117; herrmann, martin/0000-0002-0258-2484; BRACCI, LAURA/0000-0002-2535-4353; Apetoh, Lionel/0000-0002-2774-438X; Pol, Jonathan/0000-0002-8355-7562; Aranda, Fernando/0000-0002-9364-474X FU Ligue contre le Cancer (equipe labelisee); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Canceropole Ile-de-France; AXA Chair for Longevity Research; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Medicale (FRM); European Commission (ArtForce); European Research Council (ERC); LabEx Immuno-Oncology; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); SIRIC Cancer Research and Personalized Medicine (CARPEM); Paris Alliance of Cancer Research Institutes (PACRI) FX GL and LG are supported by the Ligue contre le Cancer (equipe labelisee); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Canceropole Ile-de-France; AXA Chair for Longevity Research; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Medicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). NR 288 TC 110 Z9 111 U1 24 U2 87 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 EI 2162-402X J9 ONCOIMMUNOLOGY JI OncoImmunology PD SEP PY 2014 VL 3 IS 9 AR e955691 DI 10.4161/21624011.2014.955691 PG 19 WC Oncology; Immunology SC Oncology; Immunology GA AX4SU UT WOS:000346922400019 PM 25941621 ER PT J AU Alter, BP Clinician, S AF Alter, Blanche P. Clinician, Senior TI Fanconi anemia and the development of leukemia SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE Fanconi anemia; leukemia; myelodysplastic syndrome; bone marrow failure; stem cell transplant ID MARROW FAILURE SYNDROMES; CANCER; FANCD1/BRCA2; ASSOCIATION; MUTATIONS; REGISTRY; HEAD AB Fanconi anemia (FA) is a rare autosomal recessive cancer-prone inherited bone marrow failure syndrome, due to mutations in 16 genes, whose protein products collaborate in a DNA repair pathway. The major complications are aplastic anemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and specific solid tumors. A severe subset, due to mutations in FANCD1/ BRCA2, has a cumulative incidence of cancer of 97% by age 7 years; the cancers are AML, brain tumors, and Wilms tumor; several patients have multiple events. Patients with the other genotypes (FANCA through FANCQ) have cumulative risks of more than 50% of marrow failure, 20% of AML, and 30% of solid tumors (usually head and neck or gynecologic squamous cell carcinoma), by age 40, and they too are at risk of multiple adverse events. Hematopoietic stem cell transplant may cure AML and MDS, and preemptive transplant may be appropriate, but its use is a complicated decision. Published by Elsevier Ltd. C1 [Alter, Blanche P.; Clinician, Senior] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Clinician, S (reprint author), 9609 Med Ctr Dr,Room 6E452, Rockville, MD 20850 USA. EM alterb@mail.nih.gov FU National Institutes of Health; National Cancer Institute; [NO2-CP-11019]; [NO2-CP-65504]; [NO2-CP-65501] FX We are grateful to all the patients who participate in the National Cancer Institute inherited bone marrow failure syndromes (IBMFS) cohort, to the physicians who referred the patients, and to our colleagues in the Clinical Genetics Branch of the NCI and the subspecialty clinics at the National Institutes of Health for their evaluations of the patients. We thank Lisa Leathwood, RN; Ann Carr, MS, CGC; Maureen Risch, RN; and the other members of the IBMFS team at Westat for their extensive efforts. This work was supported in part by the Intramural Program of the National Institutes of Health and the National Cancer Institute and by contracts NO2-CP-11019, NO2-CP-65504, and NO2-CP-65501. NR 16 TC 15 Z9 15 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6926 EI 1532-1924 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD SEP-DEC PY 2014 VL 27 IS 3-4 BP 214 EP 221 DI 10.1016/j.beha.2014.10.002 PG 8 WC Hematology SC Hematology GA AW8YK UT WOS:000346545000002 PM 25455269 ER PT J AU Major, L Musso, C Cochran, E Tonietti, M Mussin, C Brown, R Trifone, L Grabois, F Andres, E Ferraro, M Gorden, P AF Major, L. Musso, C. Cochran, E. Tonietti, M. Mussin, C. Brown, R. Trifone, L. Grabois, F. Andres, E. Ferraro, M. Gorden, P. TI Proteinuric nephropathy in acquired and congenital generalised lipodystrophy: baseline and ater recombinant leptin therapy SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Major, L.] Hosp San Isidro, Buenos Aires, DF, Argentina. [Musso, C.] Hosp Milstein, Buenos Aires, Argentina. [Cochran, E.; Brown, R.; Gorden, P.] NIDDK, NIH, Bethesda, MD USA. [Tonietti, M.; Trifone, L.; Grabois, F.] Hosp Dr R Gutierrez, Rosario, Santa Fe, Argentina. [Mussin, C.] Hosp Cutral Co, Neuquen, Argentina. [Andres, E.; Ferraro, M.] Hosp Dr P Elizalde, Buenos Aires, DF, Argentina. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2014 VL 57 SU 1 MA 864 BP S351 EP S352 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386102127 ER PT J AU Polidori, D Sanghvi, A Seeley, R Hall, K AF Polidori, D. Sanghvi, A. Seeley, R. Hall, K. TI Predicted temporal changes in energy intake and energy expenditure in subjects with type 2 diabetes treated with canagliflozin SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Polidori, D.] Janssen Res & Dev LLC, San Diego, CA USA. [Sanghvi, A.; Hall, K.] NIDDK, NIH, Bethesda, MD 20892 USA. [Seeley, R.] Univ Cincinnati, Cincinnati, OH 45221 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2014 VL 57 SU 1 MA 820 BP S331 EP S332 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386102083 ER PT J AU Raciti, GA Spinelli, R Parrillo, L Zatterale, F Longo, M Campitelli, M Prevenzano, I Falco, R Miele, C Pastan, I Beguinot, F AF Raciti, G. A. Spinelli, R. Parrillo, L. Zatterale, F. Longo, M. Campitelli, M. Prevenzano, I. Falco, R. Miele, C. Pastan, I. Beguinot, F. TI Environmental exposures modulate Ankrd26 gene expression by inducing DNA methylation of its promoter SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Raciti, G. A.; Spinelli, R.; Parrillo, L.; Zatterale, F.; Longo, M.; Campitelli, M.; Prevenzano, I.; Falco, R.; Miele, C.; Beguinot, F.] Natl Council Res CNR, Inst Expt Endocrinol & Oncol IEOS, Naples, Italy. [Raciti, G. A.; Spinelli, R.; Parrillo, L.; Zatterale, F.; Longo, M.; Campitelli, M.; Prevenzano, I.; Miele, C.; Beguinot, F.] Univ Naples Federico II, Dept Translat Med Sci DiSMeT, Naples, Italy. [Pastan, I.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2014 VL 57 SU 1 MA 354 BP S153 EP S153 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386101007 ER PT J AU Ruetten, H Raymond, RH Calle, RA Cao, C Lee, DS Robertson, RP Shankar, SS Staten, M Stefanovski, D Vassileva, MT Vella, A Weir, GC Fryburg, DA AF Ruetten, H. Raymond, R. H. Calle, R. A. Cao, C. Lee, D. S. Robertson, R. P. Shankar, S. S. Staten, M. Stefanovski, D. Vassileva, M. T. Vella, A. Weir, G. C. Fryburg, D. A. CA Beta Cell Team FNIH Biomarkers Con TI Intravenous arginine stimulates GLP-1 release across spectrum of glucose tolerance SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Ruetten, H.] Sanofi Inc, Frankfurt, Germany. [Raymond, R. H.] RSquared Solut, Skillman, NJ USA. [Calle, R. A.; Lee, D. S.] Pfizer Pharmatherapeut R&D, Cambridge, MA 02142 USA. [Cao, C.] Takeda Inc, Chicago, IL USA. [Robertson, R. P.] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Shankar, S. S.] Eli Lilly Inc, Indianapolis, IN USA. [Staten, M.] NIDDK, NIH, Bethesda, MD 20892 USA. [Stefanovski, D.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Vassileva, M. T.] Fdn NIH Biomarkers Consortium, Bethesda, MD USA. [Vella, A.] Mayo Clin, Rochester, MN USA. [Weir, G. C.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Fryburg, D. A.] ROI BioPharma Consulting, East Lyme, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2014 VL 57 SU 1 MA 529 BP S220 EP S221 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386101182 ER PT J AU Schlosser, M Lampasona, V Williams, AJK Mueller, PW Pittman, DL Winter, WE Akolkar, B Achenbach, P AF Schlosser, M. Lampasona, V. Williams, A. J. K. Mueller, P. W. Pittman, D. L. Winter, W. E. Akolkar, B. Achenbach, P. TI Combined appearance of autoantibodies against GAD, IA-2, insulin and ZnT8 in the islet autoantibody standardisation program 2013 proficiency workshop SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Schlosser, M.] Univ Med Ctr Greifswald, Dept Med Biochem & Mol Biol, Karlsburg, Germany. [Lampasona, V.] Ctr Genom Bioinformat & Biostat, Milan, Italy. [Williams, A. J. K.] Univ Bristol, Bristol BS8 1TH, Avon, England. [Mueller, P. W.] Ctr Dis Control & Prevent, Natl Diabet Lab, Atlanta, GA USA. [Pittman, D. L.; Winter, W. E.] Univ Florida, Dept Pathol, Karlsburg, Germany. [Akolkar, B.] Natl Inst Diabet & Digest & Kidney Dis, Div Diabet Endocrinol & Metab Dis, Bethesda, MD USA. [Achenbach, P.] Helmholtz Ctr Munich, Inst Diabet Res, Munich, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2014 VL 57 SU 1 MA 334 BP S145 EP S145 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386100334 ER PT J AU Shankar, SS Raymond, RH Chen, D Cobelli, C Dalla Man, C Lee, DS Robertson, RP Stefanovski, D Vassileva, MT Fryburg, DA AF Shankar, S. S. Raymond, R. H. Chen, D. Cobelli, C. Dalla Man, C. Lee, D. S. Robertson, R. P. Stefanovski, D. Vassileva, M. T. Fryburg, D. A. CA FNIH Biomarkers Consortium TI Across glucose tolerance spectrum, men display greater decreases in insulin secretion than women SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Shankar, S. S.] Eli Lilly & Co, Eli Lilly Res Labs, Indianapolis, IN 46285 USA. [Raymond, R. H.] RSquared Solut, Skillman, NJ USA. [Chen, D.; Lee, D. S.] Pizer Pharmatherapeut R&D, Cambridge, MA USA. [Cobelli, C.; Dalla Man, C.] Univ Padua, I-35100 Padua, Italy. [Robertson, R. P.] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Stefanovski, D.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Vassileva, M. T.] Fdn NIH Biomarkers Consortium, Bethesda, MD USA. [Fryburg, D. A.] ROI BioPharma Consulting, East Lyme, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2014 VL 57 SU 1 MA 500 BP S209 EP S209 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386101153 ER PT J AU van der Berg, JD Bosma, H Caserotti, P Eiriksdottir, G Amardottir, NY Brychta, RJ Chen, KY Sveinsson, T Johannsson, E Launer, LJ Gudnason, V Jonsson, PV Stehouwer, CDA Harris, TB Koster, A AF van der Berg, J. D. Bosma, H. Caserotti, P. Eiriksdottir, G. Amardottir, N. Y. Brychta, R. J. Chen, K. Y. Sveinsson, T. Johannsson, E. Launer, L. J. Gudnason, V. Jonsson, P. V. Stehouwer, C. D. A. Harris, T. B. Koster, A. TI Movement during sedentary time is associated with metabolic outcomes SO DIABETOLOGIA LA English DT Meeting Abstract C1 [van der Berg, J. D.; Bosma, H.; Koster, A.] Maastricht Univ, Social Med CAPHRI Sch Publ Hlth & Primary Care, Maastricht, Netherlands. [Caserotti, P.] Univ Southern Denmark, Inst Sports Sci & Clin Biomech, Odense, Denmark. [Eiriksdottir, G.; Amardottir, N. Y.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Amardottir, N. Y.; Sveinsson, T.] Univ Iceland, Res Ctr Movement Sci, Reykjavik, Iceland. [Brychta, R. J.; Chen, K. Y.] NIDDKD, Diabet Endocrinol & Obes Branch, Bethesda, MD USA. [Johannsson, E.] Iceland Univ Educ, Ctr Sport & Hlth Sci, Laugarvatn, Iceland. [Launer, L. J.; Harris, T. B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. [Gudnason, V.] Univ Iceland, IS-101 Reykjavik, Iceland. [Jonsson, P. V.] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Jonsson, P. V.] Landspitali Natl Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Stehouwer, C. D. A.] Maastricht Univ, Med Ctr, Cardiovasc Res Inst Maastricht CARIM, Dept Internal Med, Maastricht, Netherlands. RI Gudnason, Vilmundur/K-6885-2015; Sveinsson, Thorarinn/F-7554-2010; Bosma, Hans/A-6184-2013 OI Gudnason, Vilmundur/0000-0001-5696-0084; Sveinsson, Thorarinn/0000-0001-8989-5514; NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2014 VL 57 SU 1 MA 63 BP S32 EP S33 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386100063 ER PT J AU Chen, ZS Ozbun, L Chong, NJ Wallecha, A Berzofsky, JA Khleif, SN AF Chen, Zhisong Ozbun, Laurent Chong, Namju Wallecha, Anu Berzofsky, Jay A. Khleif, Samir N. TI Episomal Expression of Truncated Listeriolysin O in LmddA-LLO-E7 Vaccine Enhances Antitumor Efficacy by Preferentially Inducing Expansions of CD4(+)FoxP3(-) and CD8(+) T Cells SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID MONOCYTOGENES-BASED VACCINE; CLASS-I; ESTABLISHED TUMORS; MOUSE MODEL; RESPONSES; DELIVERY; ANTIGEN; GROWTH; E7; DOMINANT AB Studies have shown that Listeria monocytogenes (Lm)-based vaccine expressing a fusion protein comprising truncated listeriolysin O (LLO) and human papilloma virus (HPV) E7 protein (Lm-LLO-E7) induces a decrease in regulatory T cells (Treg) and complete regression of established, transplanted HPV-TC-1 tumors in mice. However, how the Lm-based vaccine causes a decrease in Tregs remains unclear. Using a highly attenuated Lm daldat Delta actA strain (LmddA)-based vaccine, we report here that the vector LmddA was sufficient to induce a decrease in the proportion of Tregs by preferentially expanding CD4(+)FoxP3(-)T cells and CD8(+) T cells by a mechanism dependent on and directly mediated by LLO. Episomal expression of a nonhemolytic truncated LLO in Lm (LmddA-LLO) significantly augmented the expansion, thus further decreasing Treg frequency. Although adoptive transfer of Tregs compromised the antitumor efficacy of the LmddA-LLO-E7 vaccine, a combination of LmddA-LLO and an Lm-based vaccine expressing E7 protein (Lm-E7) induced complete regression against established TC-1 tumors. An engineered LLO-minus Lm expressing perfringolysin O (PFO) that enables the recombinant bacteria to exit from the phagolysosome without LLO confirmed that the adjuvant effect was dependent on LLO. These results suggest that LLO may serve as a promising adjuvant by preferentially inducing the expansions of CD4(+)FoxP3(-) T cells and CD8(+) T cells, thus reducing the ratio of Tregs to CD4(+)FoxP3(-) T cells and to CD8(+) T cells favoring immune responses to eradicate tumor. (C)2014 AACR. C1 [Chen, Zhisong; Ozbun, Laurent; Chong, Namju; Berzofsky, Jay A.] NCI, Ctr Canc Res, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Wallecha, Anu] Advaxis Inc, Princeton, NJ USA. [Khleif, Samir N.] Georgia Regents Univ, Ctr Canc, Augusta, GA 30912 USA. RP Khleif, SN (reprint author), Georgia Regents Univ, Ctr Canc, 1410 Laney Walker Blvd,CN 2133, Augusta, GA 30912 USA. EM berzofsk@helix.nih.gov; skhleif@gru.edu FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH; Advaxis FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. In addition, this work was funded in part by Advaxis through a collaborative research and development agreement. NR 28 TC 4 Z9 4 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD SEP PY 2014 VL 2 IS 9 BP 911 EP 922 DI 10.1158/2326-6066.CIR-13-0197 PG 12 WC Oncology; Immunology SC Oncology; Immunology GA AW2QN UT WOS:000346133700010 PM 24872025 ER PT J AU Christodoulou, AG Kellman, P Liang, ZP AF Christodoulou, Anthony G. Kellman, Peter Liang, Zhi-Pei TI Accelerating Cardiovascular Magnetic Resonance Imaging: Signal Processing Meets Nuclear Spins SO IEEE SIGNAL PROCESSING MAGAZINE LA English DT Editorial Material ID MRI C1 [Christodoulou, Anthony G.] Univ Illinois, Dept Elect & Comp Engn, Urbana, IL 61801 USA. [Kellman, Peter] NHLBI, NIH, Bethesda, MD USA. [Liang, Zhi-Pei] Univ Illinois, Urbana, IL USA. RP Christodoulou, AG (reprint author), Univ Illinois, Dept Elect & Comp Engn, Urbana, IL 61801 USA. EM christo8@illinois.edu; kellmanp@nhlbi.nih.gov; z-liang@illinois.edu RI Magazine, Signal Processing/E-9947-2015 NR 15 TC 0 Z9 0 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1053-5888 EI 1558-0792 J9 IEEE SIGNAL PROC MAG JI IEEE Signal Process. Mag. PD SEP PY 2014 VL 31 IS 5 BP 138 EP 143 DI 10.1109/MSP.2014.2328503 PG 6 WC Engineering, Electrical & Electronic SC Engineering GA AW1IP UT WOS:000346043600015 ER PT J AU Setiawan, VW Schumacher, F Prescott, J Haessler, J Malinowski, J Wentzensen, N Yang, H Chanock, S Brinton, L Hartge, P Lissowska, J Park, SL Cheng, I Bush, WS Crawford, DC Ursin, G Horn-Ross, P Bernstein, L Lu, LG Risch, H Yu, H Sakoda, LC Doherty, J Chen, C Jackson, R Yasmeen, S Cote, M Kocarnik, JM Peters, U Kraft, P De Vivo, I Haiman, CA Kooperberg, C Le Marchand, L AF Setiawan, Veronica Wendy Schumacher, Fredrick Prescott, Jennifer Haessler, Jeffrey Malinowski, Jennifer Wentzensen, Nicolas Yang, Hannah Chanock, Stephen Brinton, Louise Hartge, Patricia Lissowska, Jolanta Park, S. Lani Cheng, Iona Bush, William S. Crawford, Dana C. Ursin, Giske Horn-Ross, Pamela Bernstein, Leslie Lu, Lingeng Risch, Harvey Yu, Herbert Sakoda, Lori C. Doherty, Jennifer Chen, Chu Jackson, Rebecca Yasmeen, Shagufta Cote, Michele Kocarnik, Jonathan M. Peters, Ulrike Kraft, Peter De Vivo, Immaculata Haiman, Christopher A. Kooperberg, Charles Le Marchand, Loic TI Cross-cancer pleiotropic analysis of endometrial cancer: PAGE and E2C2 consortia SO CARCINOGENESIS LA English DT Article ID GENOME-WIDE ASSOCIATION; PROGESTERONE-RECEPTOR GENE; SUSCEPTIBILITY LOCI; BREAST-CANCER; PROSTATE-CANCER; COLORECTAL-CANCER; SCREENING TRIAL; RISK; METAANALYSIS; POPULATION AB Genome-wide association studies (GWAS) have identified a large number of cancer-associated single nucleotide polymorphisms (SNPs), several of which have been associated with multiple cancer sites suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesized that SNPs associated with other cancers may be additionally associated with endometrial cancer. We examined 213 SNPs previously associated with 14 other cancers for their associations with endometrial cancer in 3758 endometrial cancer cases and 5966 controls of European ancestry from two consortia: Population Architecture Using Genomics and Epidemiology and the Epidemiology of Endometrial Cancer Consortium. Study-specific logistic regression estimates adjusted for age, body mass index and the most significant principal components of genetic ancestry w